Molec. AspectsMed. VoL 11, pp. 425--526,1990 Printed in Great Britain. All rights reserved.

0098-2997/90$0.00 + .50 (~ 1990PergamonPress plc.

LEUCOCYTES A N D P U L M O N A R Y DISORDERS: MOBILIZATION, ACTIVATION A N D ROLE IN PATHOLOGY A. Shock and G. J. Laurent Biochemistry Unit, Department of Thoracic Medicine, National Heart and Lung Institute, University of London, Manresa Road, London, SW3 6LR, U.K.

Contents

OVERVIEW AND STATEMENT OF THE PROBLEM

427

Chapter 1

THE NORMAL ARCHITECTURE OF THE LUNG

428

Chapter 2

THE LEUCOCYTES 2.1 Origins of Cells 2.1.1 Myeloid cells 2.1.2 Lymphoid cells 2.2 Overview of Cells 2.2.1 Neutrophils 2.2.2 Eosinophils 2.2.3 Monocytes and macrophages 2.2.4 Basophils and mast cells 2.2.5 Platelets 2.2.6 Lymphocytes

432 432 432 435 435 435 436 437 438 439 439

Chapter 3

MECHANISMS OF ADHERENCE 3.1 The Integrins 3.1.1 The Leucocyte integrins (a) Nature and distribution of leucocyte integrins (b) The function of leucocyte integrins in relation to inflammation 3.1.2 The cytoadhesins 3.1.3 The VLA integrins 3.1.4 Other integrin members 3.2 Other Adhesion Families 3.2.1 The ELAM-1, GMP-140, LHR, LAM-1 family 3.2.2 The CD2/LFA-3 family 3.2.3 Elastin adhesion proteins

441 441 443 443 444 445 445 445 445 446 446 447

Chapter 4

LEUCOCYTE CHEMOTAXIS AND DIAPEDESIS

448

Chapter 5

IMPORTANT PRODUCTS OF LEUCOCYTES 5.1 Activated Oxygen Species 5.2 Elastases 5.3 Collagenases

452 452 453 454

425

426

Contents 5.4 5.5 5.6 5.7

Chapter 6

Basic Proteins Platelet-Activating Factor Histamine Cytokines and Growth Factors 5.7.1 Tumor necrosis factor 5.7.2 The interleukins 5.7.3 Gamma interferon 5.7.4 Platelet-derived growth factor 5.7,5 Transforming growth factor 13 5.7.6 Insulin-like growth factor-1

THE ROLE OF LEUCOCYTES IN PULMONARY DISEASE 6.1 Emphysema 6.1.1 Neutrophils 6.1.2 Macrophages 6.2 Interstitial Lung Disorders 6.2.1 Cryptogenic fibrosing alveolitis and asbestosis (a) Macrophages (b) Neutrophils (c) Lymphocytes (d) Eosinophils 6.2.2 Sarcoidosis (a) Lymphocytes (b) Macrophages (c) Neutrophils 6.3 Asthma 6.3.1 Eosinophils 6.3.2 Neutrophils 6.3.3 Mast cells and basophils 6.3.4 Lymphocytes 6.3.5 Macrophages 6.3.6 Platelets

454 455 455 456 456 456 457 458 458 458 460 460 462 464 464 465 467 468 470 471 471 471 473 475 475 475 478 478 479 480 480

SUMMARY AND PERSPECTIVES

482

ACKNOWLEDGEMENTS

483

REFERENCES

484

Overview and Statement of the Problem

Inflammatory and i m m u n e e f f e c t o r c e l l s ( l e u c o c y t e s ) are i m p l i c a t e d in a w i d e variety of respiratory diseases including the interstitial lung diseases (such as fibrotic lung disorders), chronic obstructive lung diseases (such as emphysema and bronchitis) and diseases of the airways (such as asthma). All of these disorders are associated with increased numbers of blood cells in lung tissue and t h e r e is abundant evidence that these cells play critical roles in the pathogenesis of disease. They enter tissues as part of a defence mechanism that may be triggered by invading organisms (bacterial or viral), or in response to damage by environmental agents (such as cigarette smoke), or even in response to autoimmune signals. This review describes the origins, structure, and f u n c t i o n s of l e u c o c y t e s , w i t h p a r t i c u l a r e m p h a s i s on their role in inflammatory lung diseases. It thus covers an enormous research area, with each subject itself the possible f o c u s of a spec i a l i z e d review. H o w e v e r , our a i m is to provide an overall perspective and to point the reader in relevant d i r e c t i o n s w h e r e m o r e i n d e p t h i n f o r m a t i o n is required. As such, the present review is particularly directed at non-specialists in biochemical and clinical fields who find themselves bewildered by the vast array of mediators and cell types and how these relate to lung pathology. In Chapter 1 we introduce the cells and macromolecules that comprise the lung barrier and highlight some of the processes leucocytes utilize to gain access to lung tissue. We m a k e no a p o l o g y for the simplicity of this discussion since several important issues are raised and because not all readers will be familiar with the structure of the lung and its connective tissue. Chapter 2 describes the origins and m a j o r f u n c t i o n s of n e u t r o p h i l s , e o s i n o p h i l s , monocytes, macrophages, b a s o p h i l s , m a s t cells, p l a t e l e t s and lymphocytes. Chapters 3 & 4 describe the m e c h a n i s m s i n v o l v e d in the m o v e m e n t of b l o o d c e l l s i n t o t h e l u n g : n a m e l y adherence, chemotaxis and diapedesis. Chapter 5 returns to leucocyte products and describes in some detail the functions of some agents, and will be useful in later sections w h e r e s p e c i f i c c o m p o u n d s are d i s c u s s e d in the c o n t e x t of d i s e a s e processes. This section also provides a glossary of the terms and acronyms which obfuscate this area. Finally, in Chapter 6 we discuss the role of leucocytes in a variety of lung diseases which differ significantly in relation to t h e i r n a t u r e , aetiology and pathogenetic mechanisms.

427

Chapter 1

The Normal Architecture of the Lung

The adult lung is an intricate structure in which a network of conducting airways delivers air to alveoli where gas exchange occurs. To perform this f u n c t i o n , in addition to autocrine and metabolic and host defence roles, the lung has evolved into a highly specialized organ. The gas e x c h a n g e a r e a has b e e n e s t i m a t e d at 20m 2, whilst the alveolar and blood compartments are separated by a very thin barrier. For a detailed description of the n o r m a l a n a t o m y of the lung see B r e w i s (1980), B u r r i (1985) and Weibel (1986). Figure 1 provides a simplified summary of some of the key morphological f e a t u r e s , and will p r o v i d e a u s e f u l p o i n t of cross-reference for later discussions. The trachea, which links the lung to the nasopharyngeal space and the atmosphere, divides into two m a i n b r o n c h i w h i c h f u r t h e r s u b d i v i d e into s m a l l e r s e c o n d a r y bronchi. T h e s e s t r u c t u r e s are comprised of a smooth muscle support, interwoven and attached to cartilaginous discs. They branch into smaller a i r w a y s , not containing cartilage, referred to as bronchioles. The whole of this branching structure is lined with a ciliated epithelium and contains m u c u s - s e c r e t i n g g o b l e t and c l a r a cells. The b e a t i n g of the cilia creates an "elevator", whereby mucus and any entrapped material is constantly moved up to the larynx to be swallowed or expectorated. The m o s t d i s t a l of structures of the bronchopulmonary tree are the alveoli, which do not possess smooth muscle, mucus-secreting cells or a c i l i a t e d epithelium. The whole of the respiratory tract, and in particular the alveolus, is served by a network of capillaries. The a l v e o l i are c o m p l e t e l y l i n e d by a layer of epithelial cells which are of two types (Ward & Nicholas, 1984): type II p n e u m o c y t e s a c t i v e in the s y n t h e s i s and s e c r e t i o n of s u r f a c t a n t , and type I p n e u m o c y t e s w h i c h possess extensive flattened processes covering most of the internal surfaces of the alveoli. To ensure that the alveolar wall does not thicken ( t h r o u g h o e d e m a ) , since the endothelium is a rather "leaky" barrier, sections of epithelial and endothelial basement membranes are physically fused. Between endothelium and epithelium of both alveoli and airway, t h e r e is a n a r r o w interstitial space where the major cell types are the fibroblasts, myofibroblasts and ( e x c e p t in the a l v e o l a r s t r u c t u r e s ) s m o o t h m u s c l e c e l l s . These cells (referred to as mesenchymal cells) produce, and are integrated with, an extracellular matrix consisting of collagen (-60%), elastic fibres containing elastin and s o - c a l l e d microfibrillar components (-30%), proteoglycans (-5%) and several other glycoproteins such as fibronectin, laminin, e n t a c t i n / n i d o g e n and v i t r o n e c t i n (< 5%) (Hance & Crystal, 1975; Rennard et al., 1982). One can also include in this latter category a variety of cell surface adhesion m o l e c u l e s , some of w h i c h are described in detail in this review.

428

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A

429

TERMINAL AIRWAY RI

IoF

F i g . 1. A . T e r m i n a l s t r u c t u r e s of the r e s p i r a t o r y t r e e ; B. S e c t i o n t h r o u g h w a l l of b r o n c h i o l e ; C. Section through a l v e o l a r wall. A b b r e v i a t i o n s : A = alveolus; AD = a l v e o l a r d u c t ; BM = b a s e m e n t m e m b r a n e ; CC = c l a r a c e l l ; CE = c i l i a t e d e p i t h e l i u m ; Co = c o l l a g e n ; E1 = e l a s t i n ; E n = e n d o t h e l i a l c e l l ; E p I = t y p e I e p i t h e l i a l c e l l ; E p I I = t y p e II e p i t h e l i a l c e l l ; F = f i b r o b l a s t ; R B = r e s p i r a t o r y b r o n c h i o l e ; SM = s m o o t h m u s c l e .

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T h e r e are at l e a s t t w e l v e c o l l a g e n types, representing the products of over 20 genes (Burgeson, 1988; Cheah, 1985; Laurent, 1986; Mayne & Burgeson, 1987). The m o s t a b u n d a n t collagens, accounting for around 95% of total, are types I, II and III which form a network within the interstitium linking cells to other structural c o m p o n e n t s and to each other. Types I and III collagens are found in walls of blood vessels, airways and in alveolar septa, whilst type II collagen is confined to b r o n c h i a l c a r t i l a g e in association with other minor collagens. Type IV collagen is a major component of b a s e m e n t m e m b r a n e s a l t h o u g h , in the lung, t h e s e structures also contain type V collagen. Basement membranes function largely as a scaffolding to separate cellular structures from underlying connective tissue. The presence of elastin in the e x t r a c e l l u l a r m a t r i x e n s u r e s that s t r e t c h and u n d e r g o elastic recoil during inspiration/expiration. d e p e n d s u p o n the h i g h l y h y d r o p h o b i c and c r o s s l i n k e d n a t u r e of (Rosenbloom, 1984; Sandberg et al., 1981; Starcher, 1986).

the lung can This property this p r o t e i n

P r o t e o g l y c a n s are c o m p r i s e d of proteins attached to sulphated carbohydrate components (glycosaminoglycans) (reviewed by R a d h a k r i s h n a m u r t h y & B e r e n s o n , 1989; Ruoslahti, 1988a). Structurally they are a very diverse group of proteins because of the glycosaminoglycan content. They are a l s o v e r y l a r g e m o l e c u l e s , some of which have molecular weights in excess of 1 million daltons. These highly charged molecules bind to s e v e r a l m a c r o m o l e c u l e s i n c l u d i n g f i b r o n e c t i n , v i t r o n e c t i n , laminin, c o l l a g e n s , t h r o m b o s p o n d i n and g r o w t h factors. Proteoglycans largely function as cell adhesion molecules but, by v i r t u e of the fact that they b i n d w a t e r and c a t i o n s , also serve as a ground substance to regulate the viscoelastic properties of tissues. They also play roles in matrix assembly and cell differentiation. A r e l a t e d molecule is hyaluronan, not strictly a proteoglycan since it does not possess a protein core. This substance is likely to be i m p o r t a n t s i n c e it aggregates individual proteoglycans to form a strong network. F i b r o n e c t i n (see R u o s l a h t i , 1 9 8 8 b for r e v i e w ) is the prototypic cell adhesion molecule, possessing adhesive properties for collagen, proteoglycans and fibrinogen and for a large range of different cells. Fibronectin is laid down in a h i g h l y s p e c i f i c f a s h i o n to p r o d u c e o r g a n i z e d n e t w o r k s and p l a y s r o l e s in chemotaxis and cell differentiation in addition to cell adhesion (McDonald, 1988). In addition to type IV collagen, basement membranes contain several other distinct proteins including laminin and entactin/nidogen (Furthmayr, 1988). L a m i n i n can a l s o b i n d o t h e r e x t r a c e l l u l a r m a t r i x c o m p o n e n t s such as type IV c o l l a g e n , proteoglycan, entactin/nidogen and to o t h e r l a m i n i n m o l e c u l e s . B e c a u s e of its unique molecular structure, with four arms radiating from a central core, laminin can span the entire basement membrane (for review see Martin & Timpl, 1987). Although the extracellular m a t r i x p r o v i d e s s t a b i l i t y to the lung, it has b e e n proposed to be a dynamic structure in which some components can turn over rapidly (Laurent, 1987; Turino, 1985). Cells are likely to be actively s e c r e t i n g m a t r i x c o m p o n e n t s e v e n in adults, providing the lung with the power to constantly adapt to its environment. The most exciting challenge for those interested in studying lung disorders is to establish how such adaptive pathways go awry. The m a j o r a i m of this r e v i e w is to describe the mechanisms by which leucocytes traverse these barriers, as outlined in a h i g h l y s c h e m a t i c w a y in F i g u r e 2. A d i c u s s i o n of t h e s e mechanisms, and in particular what mediators are released, is highly relevant to undertanding the pathological sequelae of leucocyte a c t i v a t i o n in lung disorders.

Leucocytes and Pulmonary Disorders

431

A.

B.

C.

D.

Circulating leucocytes

Adherence

Chemotaxis/ diapedesis

Function

BLOOD

AIR

Fig. 2. Leucocytes are capable of moving into tissues in response to many signals. The signals are derived from a variety of sources including " r e s i d e n t " cells (eg. endothelial cells, fibroblasts, macrophages), "invading" cells (eg. bacteria, other leucocytes) and soluble factors derived from endogenous pathways (eg. complement, blood clotting pathways). Such activation signals act on circulating leucocytes (A) and induce responses including adherence (B), chemotaxis and diapedesis (C) and are associated with expression of numerous ligands and mediators. Depending on what the initiating signal is, the ultimate function (D)of leucocytes includes phagocytosis, digestion and expression of mediators that modulate surrounding cells and macromolecules. Although the processes described here have been r e duced to discrete stages, they occur progressively and are regulated in a highly complex manner.

Chapter 2

The Leucocytes

One common c l a s s i f i c a t i o n of l e u c o c y t e s (white b l o o d cells) is into polymorp h o n u c l e a r and m o n o n u c l e a r cells. The polymorphonuclear leucocytes, or granulocytes, are so called because they possess a polylobed nucleus and intracellular granules. This group includes neutrophils, eosinophils and b a s o p h i l s . In contrast, monocytes, macrophages and lymphocytes are mononuclear leucocytes. The platelet (a non-nucleated cell) and the mast cell (which is not a blood-borne cell and possesses a more regularly shaped nucleus) do not fit into this classification although both cells contain intracellular granules. A l t h o u g h p l a t e l e t s are not u s u a l l y c o n s i d e r e d to be leucocytes, their common origins with other leucocytes, and their relevance to the present discussion, p e r m i t s their i n c l u s i o n in this review. Neutrophils, eosinophils, monocytes and macrophages are often referred to as phagocytic cells (or phagocytes). It thus follows that m o n o c y t e s and macrop h a g e s are mononuclear phagocytes whilst eosinophils and neutrophils are polymorphonuclear phagocytes, although this latter term is rarely used. In blood, the most abundant leucocytic cells are n e u t r o p h i l s (50-70%) and 1ymp h o c y t e s (20-40%) with monocytes (2-8%), eosinophils (1-4%) and basophils (0.1%) much less prevalent. This analysis does not include platelets which are p r e s e n t in the circulation at around 101~/litre. Nor does it take into account the mast cell and macrophage both of which are tissue-residing cells, the latter d e r i v e d from blood monocytes. The p r e s e n t chapter discusses the origins of leucocytes of the major functions of these cells.

and provides

an overview

2.1 Origins of Cells All leucocytic cells arise from pluripotent stem cells in the bone marrow via two lines of differentiation: i) The lymphoid lineage, producing iymphocytes; and 2) The myeloid lineage, producing the other leucocytes considered in this review, and erythrocytes (red b l o o d cells), not considered here. Figure 3 depicts the cell differentiation pathways in a simplified and schematic form, but for further inf o r m a t i o n readers are d i r e c t e d to more detailed reviews (Golde & Gasson, 1988; Morstyn & Burgess, 1988).

2.1.i

Myeloid cells

A detailed

discussion

of the p r o d u c t i o n

432

of p o l y m o r p h o n u c l e a r

leucocytes

and

Leucocytes and Pulmonary Disorders

433

® HAEMOPOIETIC STEM CELL

®

®

[

I

Eosinophil

I

I

Megakaryocyte

@ Neutrophil

Common lymphoid precursor

Common myeloid precursor

,I.:. ~

® Basophil

Platelet

T-lymphoeytes

Monocyte

Macrophage

B-lymphocytes

Mast cell

Fig. 3. Differentiation pathways for production of leucocytes. The bone marrow haemopoietic stem cell provides precursor cells for two lines of differentiation; myeloid and lymphoid lineages. Within the myeloid series, maturation eventually gives rise to mature leucocytes (neutrophils, eosinophils, basophils, monocytes and platelets) which are released into the circulation. The macrophage and mast cell become fully matured within tissues. L y m phoid precursors also complete their development into mature lymphocytes outside the bone marrow. For further details, refer to text.

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m o n o n u c l e a r p h a g o c y t e s can be found in Cannistra & Griffin (1988) and Morstyn & Burgess (1988). In brief, the b o n e m a r r o w s t e m c e l l s e x i s t in a s p e c i a l i z e d m i c r o e n v i r o n m e n t consisting of fibroblasts, endothelial cells and macrophages set in an extensive extracellular matrix. These structures r e g u l a t e the r e l e a s e of mature haemopoietic progeny although exactly how this process is regulated is unclear. H o w e v e r , a f a m i l y of c i r c u l a t i n g p o l y p e p t i d e m e d i a t o r s (the c o l o n y s t i m u l a t i n g factors, or CSF's) and specific adhesion proteins are intimately involved. The major CSF's involved in this process, and the ones most studied, are i n t e r l e u k i n 3 (IL3), g r a n u l o c y t e - m a c r o p h a g e colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), macrophage colony stimulating factor (M-CSF) and interleukin 5 (IL 5). IL 3 is p r o d u c e d by T lymphocytes and has a wide range of effects on early stem cells and later progenitors and can induce the p r o l i f e r a t i o n of all m o n o n u c l e a r and g r a n u l o c y t i c c e l l s (Yang et al., 1986; Sieff et al., 1987), and is the only factor known that stimulates differentiation of basophils (Valent et al., 1989). GM-CSF is produced by endothelial cells, fibroblasts, epithelial cells and T iymphocytes. As its name implies, this protein possesses the capacity to increase proliferation of both mononuclear and p o l y m o r p h o n u c l e a r cells, a l t h o u g h its activity is not as wide as that of IL 3 (Wong et al., 1985; Sieff et al., 1985). G M - C S F and IL 3 have a broad range of effects on mature neutrophils, eosinophils and monocytes, particularly their ability to "prime" cells for enhanced activation ( p h a g o c y t o s i s , c y t o t o x i c f u n c t i o n s , e n z y m e r e l e a s e and oxidant production) in response to other stimuli (reviewed by Cannistra & Griffin, 1988; M o r s t y n & Burgess, 1988). A d d i t i o n a l l y , t h e s e f a c t o r s can stimulate mediator release from basophils (Hirai et al., 1988; MacDonald et al., 1989). Whilst IL 3 and GM-CSF affect the d i f f e r e n t i a t i o n of s e v e r a l cell types, o t h e r CSF's are more specific. G-CSF, M-CSF and IL 5 are produced by a variety of cells including monocytes, endothelial cells, fibroblasts, and epithelial cells and induce differentiation of neutrophils (Souza et al., 1986), monocytes (Wong et al., 1987) and eosinophils (Lopez et al., 1986; C l u t t e r b u c k et al., 1989), r e s p e c tively. In general, these proteins support terminal stages of differentiation in contrast to IL 3 and GM-CSF which stimulate growth of earlier progenitors. Additionally, whilst IL 3 and GM-CSF have effects on a variety of mature cells, M-CSF, IL 5 and G-CSF retain their lineage specificity with respect to activity on mature cells (Cannistra & Griffin, 1988; Lopez et al., 1988). The m e c h a n i s m s by w h i c h p l a t e l e t s are p r o d u c e d is as yet u n c l e a r , a l t h o u g h megakaryocytes (the immediate precursors of platelets) are d e r i v e d f r o m the same bone marrow stem cells as are other myeloid cells and would appear to develop under the influence of specific colony stimulating factors (for review see Hoffman, 1989). Mast cells are also derived from bone marrow stem cells but become fully differentiated and mature in vascularized tissue, epithelia and serosal c a v i t i e s in m a n y organs of the body. The site of maturation directs their specific phenotype with regard to their morphology and mediator content. Two major p h e n o t y p e s have b e e n distinguished: the "mucosal" mast cell and the "connective tissue" mast cell. The importance of growth factors and of extracellular matrix microenvironments in the d e v e l o p m e n t of the mast cell phenotype has been studied only very recently. The mucosal mast cell develops when mast cell progenitors are cultured in the presence of i n t e r l e u k i n 3 (with interleukin 4 acting as a secondary comitogen) whilst the connective tissue mast cell develops when precursors are cultured on f i b r o b l a s t s in the absence of IL 3 and IL 4, indicating that fibroblasts release distinct differentiation factors ( J a r b o e et al., 1989). On the o t h e r hand, G M - C S F down-

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regulates mast cell precursor growth in the bone marrow (Bressler et al., 1989).

2.1.2

Lymphoid cells

A f t e r e a r l y d e v e l o p m e n t f r o m b o n e m a r r o w p l u r i p o t e n t s t e m cells, l y m p h o c y t e precursors migrate via the bloodstream to the thymus and thence to secondary lymphoid tissues such as the spleen and lymph nodes where they become T lymphocytes. In contrast, stem cells destined to become B iymphocytes differentiate largely in the bone marrow and migrate directly to secondary lymphoid tissues. The thymus of adults does not receive large n u m b e r s of T cell p r e c u r s o r s since m o s t of the d e v e l o p m e n t a l s t a g e s o c c u r in the foetus. Nevertheless, full differentiation of the different subtypes occurs intra-thymically w h e r e they a d j u s t to self a n t i g e n s and a c q u i r e the m a c h i n e r y necessary for carrying out effector functions such as target cell lysis and l y m p h o k i n e s e c r e t i o n . These functions d e p e n d u p o n the expression of a range of receptors such as those involved in antigen recognition and the major histocompatibility complex, g r o w t h f a c t o r r e c e p tors and h o m i n g r e c e p t o r s . A number of proteins are involved in the growth and differentiation of T lymphocytes including interleukins 2, 4, 6, and 7. The maturation of B lymphocytes is dependent on a number of B cell growth factors (interleukins i, 2, 4, 5, and 7) and differentiation factors (produced by T cells, and modulated by g a m m a - i n t e r f e r o n ) . O t h e r f a c t o r s such as i n t e r l e u k i n 6 can stimulate both growth and differentiation of B lymphocytes. Virgin B lymphocytes mature into memory cells and plasma cells in the secondary lymphoid organs. A detailed discussion of the production and differentiation of 1ymphocytes is not w i t h i n the s c o p e of this r e v i e w and r e a d e r s are directed to several excellent reviews on this topic (Adkins et al., 1987; Hamaoka & Ono, 1986; H o w a r d & Paul, 1983; Kincade et al., 1989; Kishimoto, 1985; von Boehmer, 1988).

2.2 Overview of Cells Leucocytes produce an enormous array of mediators and perform numerous biological functions. The purpose of the present section is to p r o v i d e a b r i e f s u m m a r y of the p r o p e r t i e s of different leucocytes, to provide a framework for later discussions concerning the recruitment and function of these cells in pathological conditions.

2.2.1

Neutrophils

The m o s t a b u n d a n t b l o o d l e u c o c y t e is the neutrophil, lifespan in the circulation of only 1 to 48 hours. The most certainly associated with a single phagocytic neutrophils has been estimated about 126 billion per day

a short-lived cell with a death of this cell is alevent. The "turnover" of in a 70 kg man.

Once they are released from the bone marrow, mature neutrophils are e q u a l l y dist r i b u t e d b e t w e e n circulating and marginated pools. The latter pool represents a population that are sequestered within the capillaries and can be mobilized during exercise and by specific stimuli such as adrenaline. The lung is now known to be a major site for neutrophil margination (Hogg, 1987; Muir et al., 1984). The neutrophil is recognized a s the major line of defence for removal of invading m i c r o o r g a n i s m s (for reviews see Gabig & Babior, 1981; Lehrer, 1988) and has been called the "professional phagocyte" (Wade & Mandell, 1983). P h a g o c y t o s i s , the

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process by which cells extend pseudopods that engulf a particulate substance which is then b r o u g h t into the cell for intracellular digestion, is facilitated if the target is coated with immunoglobulin and c o m p l e m e n t p r o t e i n s since n e u t r o p h i l s possess Fc and C3b receptors. P h a g o c y t o s e d p a r t i c l e s are k i l l e d and d i g e s t e d by a wide range of p r e f o r m e d granule-associated proteins and by newly-formed mediators. These p r o d u c t s have been reviewed on several occasions (Baggiolini & Dewald, 1985; Baggiolini et al., 1978; Henson & Johnston, 1987). Neutrophils possess two major types of intracellular granule which differ in morp h o l o g y and d e v e l o p at different stages during differentiation (Bainton, 1975). Azurophil (primary) granules contain predominantly proteolytic and acid hydrolytic enzymes such as elastase, B-glucuronidase, acid phosphatase and cathepsins B, D and G, but also possess a number of microbicidal cationic proteins (the defensins) and myeloperoxidase. The specific (secondary) granules possess lactoferrin, collagenase, iysozyme and vitamin B12-binding protein, the function of w h i c h is unclear at the present moment. Two further granules have been described: the C particle (or tertiary granule) appears to contain predominantly g e l a t i n a s e whilst a fourth g r a n u l e type p o s s e s s e s latent a l k a l i n e phosphatase (Borregaard et al., 1987). There is compelling evidence for heterogeneity in the morphology and comp o s i t i o n of these d i f f e r e n t granules (Rice et al., 1986), possibly representing release of neutrophils from the bone marrow at different stages of maturation. Apart from an armament of preformed mediators, n e u t r o p h i l s can also s y n t h e s i z e various agents upon activation including oxidants (superoxide, hydrogen peroxide, hypochlorous acid), arachidonic acid metabolites ( p r o s t a g l a n d i n s , leukotrienes, thromboxanes), platelet-activating factor, interleukin i, and nitrous oxide. A l t h o u g h n e u t r o p h i l a c t i v a t i o n p r i m a r i l y involves r e l e a s e of m e d i a t o r s into intracellular compartments, these cells may in some cases extrude their c o n t e n t s into the e x t r a c e l l u l a r milieu, a process commonly referred to as degranulation (Henson, 1980; Klebanoff & Clark, 1978). Degranulation d u r i n g p h a g o c y t o s i s has been named "regurgitation during feeding" or "messy eating", implying accidental release of constituents due to incomplete closure of p h a g o c y t i c vacuoles. Further, a large number of compounds are now known to be capable of inducing direct secretion of granule-associated, and newly-formed, products. These include bacterial products (formyl-Met-Leu-Phe or fMLP), c o m p l e m e n t c o m p o n e n t s (C5a), cytokines (interleukin i, tumor necrosis factor, gamma interferon), growth factors (platelet-derived g r o w t h factor, g r a n u l o c y t e - m a c r o p h a g e colony stimulating factor), and lipid mediators (leukotriene B4, platelet-activating factor). Many of these agents are discussed in further detail in subsequent chapters. Little is known of how neutrophil turnover is regulated. "In vitro" studies have shown that, over time, neutrophils undergo a number of morphological and biochemical changes a s s o c i a t e d with p r o g r a m m e d cell death (or apoptosis) that leads to rapid phagocytosis by macrophages (Savill et al., 1989). This may r e p r e s e n t an important mechanism for the removal of senescent neutrophils "in vivo".

2.2.2

Eosinophils

The eosinophil was first described by Ehrlich over a century ago but its function "in vivo" is still poorly understood. E o s i n o p h i l s have always been thought to serve a defence function and we do know that eosinophils play an important role in the killing of parasites (for reviews see Kay, 1984; Dessein & David, 1982). In recent years, the a s s o c i a t i o n of e o s i n o p h i l s with allergic reactions has been shown and the possibility that these cells can be a s s o c i a t e d with tissue injury

Leucocytes and Pulmonary Disorders

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has been more widely investigated. Like neutrophils, eosinophils contain a diverse array of granule-associated products and have the capacity to generate newly-formed mediators when activated (for review see Dahl et al., 1988; Kay, 1984). Granule-derived products include acid hydrolases such as B-glucuronidase and arylsulphatase, a peroxidase, histaminase, basic proteins (major basic protein, eosinophil cationic protein, eosinophil protein X) and collagenase. Newly-formed m e d i a t o r s include oxidants, arachidonic acid metabolites and platelet-activating factor. Eosinophil granules consist of a crystalloid core, the main component of which is major basic protein, with other components in the matrix surrounding the core. As found with neutrophils, there is considerable m o r p h o l o g i c a l and biochemical heterogeneity of eosinophils isolated from human peripheral blood, which has given rise to the distinction between "normodense" (normal density) and "hypodense" (light density) eosinophils, based on characteristics following separation on density gradients. This distinction may be due to differences in level of maturation and/or degree of prior "in vivo" activation (Fukada & Gleich, 1989). Indeed, "in vitro" activation with inflammatory mediators such as platelet-activating factor causes eosinophils to become hypodense (Yukawa et al., 1989) which is consistent with the "in vivo" association of hypodense eosinophils with a number of diseases associated with eosinophil activation. In c o n t r a s t to the n e u t r o p h i l , the e o s i n o p h i l is weakly phagocytic, and cytotoxicity towards parasites probably occurs following extracellular release of products. However, the extent of tissue injury following eosinophil degranulation is likely to be less marked than that caused by neutrophils since they release smaller quantities of proteolytic enzymes. In comparison to neutrophils, eosinophils also have a slightly longer life-span "in vivo" (several days in the circulation) and tend to reside longer in tissues. This capacity may be due to the fact that endothelial cells (Lamas et al., 1989) and fibroblasts (Vancherri et al., 1988) produce factors that prolong eosinophil survival. Rothenberg et al. (1989) have further shown that the prolonged survival of eosinophils in the presence of fibroblasts is also associated with enhanced eosinophil parasitic cytotoxic activity and in the conversion of normodense to hypodense eosinophils. Similar hypodense, hyperresponsive e o s i n o p h i l s are produced during culture with colony stimulating factors (Owen et al., 1987a; Rothenberg et al., 1988).

2.2.3

Monocytes and macropha~es

Monocytes are circulating leucocytes that, in response to specific signals, move into tissues and develop into highly differentiated cells, known collectively as macrophages (Adams & Hamilton, 1988). The macrophage system throughout the body is o f t e n r e f e r r e d to as the r e t i c u l o e n d o t h e l i a l system or the m o n o n u c l e a r phagocyte system. There are large numbers of macrophages within the airspaces of normal lungs, and these are called alveolar macrophages. Several excellent reviews concerning the monocyte and alveolar macrophage have been p u b l i s h e d (Johnston, 1988; McLennan & DeYoung, 1984; Nathan, 1987; Papadimitriou & Ashman, 1989; Rappolee & Werb, 1988; Takemura & werb, 1984; Ziegler-Heitbrock, 1989). Following maturation within the bone marrow, monocytes enter the bloodstream where they have a half-life in man of around 70 hours whilst the turnover of fully differentiated macrophages is about 1 to 2 weeks. Although there may be limited cell division, most resident macrophages are replenished from new monocyte precursors. The differentiation of monocytes into macrophages is associated with the development of an extensive Golgi/endoplasmic reticulum, necessary for protein synthesis,

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and expression of receptors for a range of molecules including cytokines, connective tissue m a t r i x p r o t e i n s , i m m u n o g l o g u l i n s , complement components and blood coagulation proteins (Adams & Hamilton, 1984). Alveolar macrophages occupy a unique position within the alveolar lumen, in close proximity to m a t e r i a l s brought i n t o the lung by i n s p i r a t i o n or from the bloodstream. They are the most abundant cells found w i t h i n the a l v e o l a r fluid, c o m p r i s i n g 95% or more of total cells in the normal nonsmoking individual. It should be pointed out that a relatively large population of macrophages reside in the lung interstitial compartment where they are in close association with connective tissue structures (Brain, 1988). Whether this population of macrophages differ from their alveolar counterparts in terms of structure and function has yet to be clarified. Macrophages and monocytes are very similar with respect to the m e d i a t o r s they produce, a l t h o u g h the m a c r o p h a g e r e p e r t o i r e is larger (refer to the reviews Ziegler-Heitbrock, 1989; Rappolee & Werb, 1988; P a p a d i m i t r i o u & Ashman, 1989). M a c r o p h a g e s are f u n c t i o n a l l y the most v e r s a t i l e and wide-ranging cells in the myeloid series, producing more than i00 well-described mediators that p l a y roles in host defense, regulation of cell growth and differentiation, wound healing, and regulation of immune functions via the action of s p e c i a l i z e d a n t i g e n - p r e s e n t i n g cells. I n c l u d e d in this set of products are complement proteins, blood clotting factors (eg. coagulation proteins VII, IX, X and V), l y s o s o m a l enzymes, neutral p r o t e a s e s (eg. elastase, collagenase), bactericidal proteins, protease inhibitors (eg. ~-l-proteinase inhibitor, ~-2-macroglobulin), growth factors (eg. t r a n s f o r m ing g r o w t h factor B, c o l o n y s t i m u l a t i n g factors), and c y t o k i n e s (eg. tumor necrosis factor, interleukin I, gamma interferon). The macrophage also produces a range of n e w l y - f o r m e d m e d i a t o r s including oxidants and arachidonic acid metabolites. An unusual feature of macrophage (and monocyte) a c t i v a t i o n is that many stimuli are produced by the cells themselves, indicating that activation is regulated in an autocrine fashion.

2.2.4

Basophils and mast cells

The basophil is the least common of the circulating leucocytes, but, together with the mast cell, plays important and specific roles in inflammatory processes. Our current understanding of the structure and function of these two cell types has been reviewed (Marone, 1988; Marone et al., 1989) with particular reference to the similarities between them. W h i l s t b a s o p h i l s are c i r c u l a t i n g cells, mast cells reside p r e d o m i n a n t l y in tissues. In lung, mast cells are distributed throughout the respiratory tract and are found in large numbers in the alveolar walls and airways. Both cell types are regarded as the important cells in inflammation associated with disorders of IgEdependent hypersensitivity and in the p r o c e s s of I g E - d e p e n d e n t immunity. The b a s o p h i l and the mast cell are the only cells with high-affinity IgE receptors (although macrophages, eosinophils and T lymphocytes possess l o w - a f f i n i t y receptors) and are the major sources of histamine in the body. Both cell types possess large intracellular granules containing a wide range of mediators (for reviews see Caughey, 1989; Kaliner, 1989; Marone, 1988; Marone et al., 1989; Nadel & Caughey, 1989). In addition to histamine, both basophils and mast cells produce lysosomal hydrolases, l e u k o t r i e n e C4 and proteoglycans. Mast cells additionally release heparin, the proteases tryptase and chymase, oxidants, bradykinin, adenosine and a peroxidase. More recently, mast cells have been shown capable of synthesizing cytokines and growth factors such as tumor necrosis factor (Steffen et al., 1989) and interleukins i, 3, 5 and 6, gamma interferon and granulocyte-macrophage colony stimulating factor (Burd et al., 1989). Release of g r a n u l e - a s s o c i a t e d products

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439

occurs primarily in response to allergens and anti-IgE, but several cytokines are also known to cause degranulation (see reviews by Kaliner, 1989; Lett-Brown et al., 1989; Marone et al., 1989). There is considerable evidence for phenotypic and biochemical heterogeneity of mast cells (Irani & Schwartz, 1989; Pearce, 1986; Kitamura, 1989). In human mast cells, the distinction between tryptase positive / chymase negative (T mast cells) and tryptase positive / chymase positive (TC mast cells) has been made. The former are found predominantly in the lung and gastrointestinal mucosa, the latter in skin and bowel submucosa. There is evidence that these biochemical differences give rise to important functional differences. Mast cells often localize to basement membranes and increase in inflammation. This unusual distribution may arise from p r e f e r e n t i a l adherence to laminin-containing surfaces since mast cells possess laminin receptors (Thompson et al., 1989).

2.2.5

Platelets

Human platelets are cytoplasmic fragments of megakaryocytes, which have a short life span in peripheral blood and largely function as mediators of haemostatic reactions. The platelet is an anucleate cell which, in the resting state, has a discoid shape and possesses a smooth rippled surface. A large number of stimuli including collagen, yon Willebrand factor, thrombin, platelet-activating factor, fibrinogen, and several arachidonic acid metabolites induce platelet shape change, adhesion, aggregation and secretion of mediators (see Siess, 1989 for review). This response is typical following exposure of the subendothelial matrix during vascular damage since the platelet adheres strongly to molecules of both the extracellular matrix and blood clotting cascade. The mechanisms involved in platelet adhesion will be discussed in more detail in Chapter 3. The platelet possesses three storage granules (Holmsen & Weiss, 1979; Mackie & Neal, 1988): dense granules, containing serotonin, ADP and ATP; a granules containing platelet-derived growth factor, transforming growth factor B, platelet factor 4, elastase, 8-thromboglobulin, fibrinogen, thrombospondin, a-2-antiplasmin and several other agents involved in the blood clotting system; and finally, lysosomal granules containing acid hydrolase enzymes. Most of these granule products arise during megakaryocyte development although circulating platelets are also capable of "de novo" protein synthesis (Kieffer et al., 1987). Moreover, platelets are capable of producing interleukin 1 and histamine although these do not appear to be localized to granules (Hawrylowicz et al., 1989; Saxena et al., 1989). Other products such as immunoglobulin and albumin are p r o b a b l y taken up from exogenous sources. The platelet also produces a number of newly-formed lipid mediators when stimulated such as p l a t e l e t - a c t i v a t i n g factor and a range of arachidonic acid metabolites. Given that platelets produce such a wide range of products, it is likely that in addition to their role in haemostasis these cells also play critical roles in modulating inflammatory cell traffic and remodelling of the extracellular matrix.

2.2.6

Lymphocytes

The present discussion will make no attempt to summarize the complex immunological functions of T and B Iymphocytes and readers are directed to standard immunology text books for further information (eg. Roitt et al., 1989). It would be useful, however, to comment upon the various subpopulations of T iymphocytes that will be referred to later in this review, and upon the mediators released from these cells which have been noted as particularly relevant to lung disease.

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In the lung around 75% of lymphocytes are T cells, 10% are a n t i b o d y - p r o d u c i n g B cells and the remainder are so-called "null" lymphocytes. There are now known to be a large number of specific B and T lymphocyte s u b p o p u l a t i o n s b a s e d u p o n the m a r k e r s ( d e s i g n a t e d CD m a r k e r s ) that can be i d e n t i f i e d on the cell surface. "Null" (or third generation) lymphocytes typically do not possess the markers expressed by T and B iymphocytes. However, all lymphocytes possess the Fc receptor for immunoglobulins. There are three major subpopulations of T iymphocytes: i). cytotoxic T-cells are r e s p o n s i b l e for lysis of v i t a l l y - i n f e c t e d host cells; 2). suppressor T cells which suppress the response of B iymphocytes and other T cells to antigen; and 3). helper T cells which are important for B lymphocyte antibody production and enable cytotoxic and suppressor T cells to respond to antigen. Based upon the receptors present on the surface of T iymphocytes, helper T cells are classed as CD4+ cells and exhibit antigen response in association w i t h c l a s s II M H C (major h i s t o c o m p a t i b i l i t y c o m p l e x ) m o l e c u l e s , w h i l s t suppressor/cytotoxic T cells are classed CD8+ cells and recognize antigen in association with class I MHC molecules. CD4+ lymphocytes in p a r t i c u l a r a r e c a p a b l e of p r o d u c i n g a n u m b e r of m e d i a t o r s (lymphokines) which affect not only other T cells but also many o t h e r cell types as will be indicated in subsequent chapters. Lymphocyte mediators of relevance to the present discussion include interleukins 2, 3 and 5, g r a n u l o c y t e - m a c r o p h a g e c o l o n y s t i m u l a t i n g factor, gamma interferon and tumor necrosis factor (see Sections 2.1 and 5.7), and a number of proteins with activity against the mononuclear p h a g o c y t e s such as macrophage migration inhibitory factor, macrophage-activating factor and monocyte chemotactic factor (see Bitterman et al., 1981 for review).

Chapter 3

Mechanisms of Adherence

B i o l o g i c a l p r o c e s s e s as d i v e r s e as e m b r y o g e n e s i s , tissue repair, and immune response are regulated by unique families of adhesive cell surface receptors. One family in particular (the integrins) have been well s t u d i e d and are r e l e v a n t to the present discussion. Here, we will describe the structure and function of this fascinating family of proteins, with particular emphasis on their role in directing c e l l u l a r traffic in the lung. Other adhesion families also relevant will be covered later in the chapter.

3.1 The Integrins The term "integrin" refers to a family of g l y c o p r o t e i n s w h i c h are d i v i d e d into three major groups based upon distinct S subunits: 1) the leucocyte integrins, 2) the cytoadhesins, and 3) the VLA integrins. The s i m p l i f i e d s t r u c t u r e of the m o l e c u l e s in these groups and some of their properties are depicted in Table i. They have been reviewed on several occasions (Hemler, 1988; Hogg, 1989; Hynes, 1987; Kuypers & Roos, 1989; Phillips et al., 1988; Wright and Detmers, 1988). The i n t e g r i n s d i s p l a y a strong s t r u c t u r a l h o m o l o g y , both w i t h i n and b e t w e e n groups. There is about 45% homology between the B subunits of each group. All of the B subunits appear to possess a short (about 40 amino acids) cytoplasmic domain and a large (> 680 amino acids) extracellular domain that c o n t a i n s more than 50 cysteine residues, probably in the form of disulphide linkages (reviewed in Phillips et al., 1988). Sequence analysis of the ~ chains GPIIb, FnR=, VnR=, and CDIIc has also revealed at least 20% homology. In 1987, Ruoslahti and Pierschbacher brought together a number of observations and showed that the adherence of cells to several target e x t r a c e l l u l a r m a t r i x and b l o o d p r o t e i n s involved recognition of a unique tripeptide sequence (Arg-Giy-Asp or RGD). For instance, this s e q u e n c e is found in f i b r o n e c t i n , fibrinogen, vitronectin, laminin, type I c o l l a g e n , c o m p l e m e n t component C3bi and von Willebrand factor. In this way, the fibronectin receptor (FnR) r e c o g n i z e s the sequence Giy-Arg-Gly-Asp-Ser in fibronectin, Mac-i recognizes Tyr-Arg-Giy-Asp-Gln in C3bi, and the v i t r o n e c t i n r e c e p t o r (VnR) r e c o g n i z e s T h r - A r g - G i y - A s p - V a l in vitronectin. I n t e g r i n s only r e c o g n i z e their s p e c i f i c ligand (Mac-i will not recognize Tyr-Arg-Gly-Asp-Gln in fibronectin for instance), indicating that amino acids flanking the RGD sequence also play a role in recognition. Further, as will be pointed out later, not all integrins recognize receptors possessing RGD groups.

441

NAME

VLA- 6

VLA-6

CD 18

FnR(3

~ GP Ilia

}

/3 Subunit

Lymphocytes, fibroblasts Lymphocytes, platelets Fibroblasts Lymphocytes, monocytes Fibroblasts, monocytes, platelets, endothelial cells Platelets, epithelial cells

Platelets Endothelial, fibroblasts, smooth muscle cells

I Blood leucocytes

CELLS ON WHICH INTEGRINS ARE PRESENT

Laminin, collagen Collagen Laminin, Fn, collagen Fn Fn Laminin

Fn, Fg, Vn, vWF Vn, Fg, vWF, T h r

ICAM-1, ICAM-2 iC3b, Fg, F a c t o r X iC3b

MOLECULES RECOGNIZED BY INTEGRINS

TABLE 1. The integrin family of adhesive glycoproteins. Abbreviations and acronyms: CD, cluster designation; Fg, fibrinogen; Fn, fibronectin: FnR, fibronectin receptor; GP, glycoprotein; iC3b, inactivated complement component C3b; ICAM, intercellular adhesion molecule; LFA-1, leucocyte function-associated antigen-l: M a c - l , Macrophage-1; p150, 95, named after the m o l e c u l a r weights of the a and ~ chains; Thr, thrombospondin: Vn, vitronectin; VnR, vitronectin receptor: VLA, very late antigen: vWF, yon Willebrand Factor. F u r t h e r details can be found in the text.

VLA-I VLA-2 VLA-3 VLA-4 VLA-5(FnR~)

GP lib VnR

CD l l a CD l l b CD l l c

Subunit

SIMPLIFIED CHEMICAL STRUCTURE

VLA-I VLA-2 VLA-3 VLA-4 VLA-5(FnR)

The VLA Integrins

GP IIB-IIIa VnR

The Cytoadhesins

LFA-1 Mac-1 plS0, 95

The Leucocyte Integrins

GROUP

t-

W"

L_

09 ::r O

4~

Leucocytes and Pulmonary Disorders 3.1.i (a)

443

The leucocyte inte~rins Nature and distribution of leucocyte inte~rins

The d i s c o v e r y of the l e u c o c y t e i n t e g r i n s a r o s e f r o m the s t u d y of a c l a s s of p a t i e n t s w i t h a rare, i n h e r i t e d d i s o r d e r of leucocyte function associated with recurrent, and often fatal, bacterial and viral infections (reviewed in Anderson & S p r i n g e r , 1987; T o d d & F r e y e r , 1988). It is now known that leucocyte adhesion deficiency is caused by the failure of leucocytes to e x p r e s s t h r e e d i s t i n c t but related proteins. These proteins have been termed Mac-i (also known as CR3 or MoI), LFA-I and p150,95 (see Table i). The m o l e c u l a r s t r u c t u r e of t h e s e i n t e g r i n s is w e l l - u n d e r s t o o d and has b e e n r e v i e w e d m a n y times (Hogg, 1989; Wright & Detmers, 1988). Each of the molecules consist of two noncovalently linked g l y c o p r o t e i n s to f o r m an u/B dimer. The c h a i n s for LFA-I, Mac-l, and p150,95 are referred to as CDIIa, CDIIb and CDIIc, respectively. The B subunit is common to all three proteins and is c a l l e d CDI8. The ~ and B c h a i n s are synthesized separately, glycosylated and linked prior to membrane insertion. Leukocyte adhesion deficiency is caused by abnormal synthesis of the B chain, the presence of which is critical for normal expression and orientation of these integrins on the cell surface. The distribution of the leucocyte integrins on d i f f e r e n t c e l l s has b e e n e s t a b lished largely by the use of monoclonal antibodies to the ~ subunits. Lymphocytes express large quantities of LFA-I but do not express Mac-I or p150,95. Phagocytic c e l l s such as neutrophils, monocytes and macrophages express all three integrins although in neutrophils Mac-i is predominant. Monocytes express equal proportions of M a c - I and p 1 5 0 , 9 5 but t h e r e is a s h i f t t o w a r d increased p150,95 expression during macrophage differentiation (Hogg et al., 1986). The distribution of this protein family on eosinophils and basophils has not been established. T h e r e is m u c h evidence to suggest that monocyte and neutrophil integrins are not constitutively e x p r e s s e d on the cell s u r f a c e but r a t h e r are u p r e g u l a t e d from intracellular granule stores during cell activation (Lacal et al., 1988; Miller et al., 1987; Springer et al., 1989). Springer et al. (1989) have p r o p o s e d that an alternative name for these granules in neutrophils is "adhesomes". Nevertheless, integrins are expressed on the surface of unstimulated neutrophils, possibly in a latent form, since sulphydryl reducing agents can unmask them (Schwartz & Harlan, 1989). W h e t h e r i n t e g r i n m o l e c u l e s are u p r e g u l a t e d in t h e s e w a y s in o t h e r leucocytes has not been well-studied. T h e r e has b e e n c o n s i d e r a b l e i n t e r e s t in i d e n t i f y i n g the ligands recognized by leucocyte integrins. Mac-i and p150, 95 are known to recognize the c e l l - s u r f a c e bound moiety of complement component C3bi. An RGD sequence in C3bi has been identified and the binding of Mac-i can be inhibited by peptides p o s s e s s i n g this seq u e n c e ( W r i g h t et al., 1987). M a r k s et al. (1989) have shown that complement fixation on endothelial cells c a u s e s r a p i d a d h e r e n c e of n e u t r o p h i l s in a C3bdependent process. As discussed in the next section, adherence of blood cells to endothelial cells is a very important step in the inflammatory response. In addition to C3bi, Mac-I is known to bind several other ligands including fibrinogen (Altieri et al., 1988) and factor X (Altieri & Edgington, 1988). The m a j o r l i g a n d k n o w n to be r e c o g n i z e d by L F A - I is i n t e r c e l l u l a r a d h e s i o n molecule 1 (ICAM-I) or CD54 (Marlin & Springer, 1987; Smith et al., 1988; and s e e review by Wawryk et al., 1989). This molecule has been identified on endothelial cells, f i b r o b l a s t s , e p i t h e l i a l cells, macrophages and B lymphocytes (Dustin et al., 1986), but does not possess an RGD s e q u e n c e . Cell s u r f a c e e x p r e s s i o n of ICAM-I r e q u i r e s the e x p o s u r e of c e l l s to inflammatory mediators such as inter-

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leukin i, e n d o t o x i n , and tumor n e c r o s i s factor and is d e p e n d e n t upon active p r o t e i n s y n t h e s i s i n d i c a t i n g that the m o l e c u l e is not stored in cells. More recently, a protein homologous to ICAM-I has been d e s c r i b e d and called ICAM-2 (Staunton et al., 1989), which may explain observations of LFA-l-dependent, ICAM1-independent binding to endothelial cells. (b)

The function of leucocyte inte@rins

in relation to inflammation

The function of the leucocyte integrins has been most widely studied with regard to a d h e r e n c e of leucocytes to the endothelium since this event is considered the initial event controlling the movement of these cells into tissues. Monoclonal antibodies to CD18 have been shown "in vitro" to prevent the adherence of n e u t r o p h i l s (Harlan et al., 1985; Z i m m e r m a n & McIntyre, 1988), eosinophils (Lamas et al., 1988), basophils (Bochner et al., 1988), monocytes (Wallis et al., 1985) and l y m p h o c y t e s (Haskard et al., 1986) onto endothelial cells. These antibodies also inhibit neutrophil adherence "in vivo" (Arfors et al., 1987; Rosen & Gordon, 1987) and can prevent neutrophil-induced lung injury "ex vivo" (Ismail et al. 1987). Finally, such antibodies inhibit a number of other leucocyte responses such as n e u t r o p h i l (Anderson et al., 1986) and lymphocyte (VanEpps et al., 1989) chemotaxis. Other facts indicating the importance of leucocyte i n t e g r i n s to the a d h e r e n c e p r o c e s s are that n e u t r o p h i l s from p a t i e n t s with leukocyte adhesion deficiency show reduced capacity to adhere to endothelium (Harlan et al., 1985a; Todd & Freyer, 1988) and n e u t r o p h i l s that have been actively attracted to extravascular sites have an increased surface expression of Mac-I (Freyer et al., 1989). A g e n t s c a p a b l e of s t i m u l a t i n g the a d h e s i v e p r o p e r t i e s of neutrophils include platelet-activating factor, leukotriene B4, fMLP and C5a (Tonnesen et al., 1989; Z i m m e r m a n & M c I n t y r e , 1988), tumor necrosis factor (Lo et al., 1989) and interleukin 8 (Carveth et al., 1989). C5a, fMLP, leukotrine B 4 and tumor necrosis factor also s t i m u l a t e monocyte adherence (Miller et al., 1987). Finally, plateletactivating factor and fMLP stimulate the adherence of eosinophils and basophils to endothelial cells (Lamas et al., 1988; Kimani et al., 1988; Bochner et al., 1988). When endothelial cells are challenged with mediators such as interleukin i, tumor necrosis factor and e n d o t o x i n they show an i n c r e a s e d a d h e s i v e c a p a c i t y for neutrophils (Bevilacqua et al., 1985; Pohlman et al., 1986; Pober et al., 1986), eosinophils (Lamas et al., 1988), monocytes ( B e v i l a c q u a et al., 1985) and lymp h o c y t e s ( C a v e n d e r et al., 1986). With regard to neutrophils, maximal adherence occurs when both neutrophil and endothelial cell components are expressed (Pohlman et al., 1986). Stimulation of endothelial cells with thrombin or leukotriene C4 increases adherence of neutrophils by integrin-unrelated m e c h a n i s m s (Dobrina et al., 1989; Z i m m e r m a n & M c I n t y r e , 1988), i n d i c a t i n g that other pathways exist. These mechanisms are likely to include electrical charge, granule-derived p r o d u c t s and arachidonic acid metabolites (see Harlan, 1985 for review). Models of acute i n f l a m m a t i o n o f t e n demonstrate neutrophils in the interstitial compartment of the lung (Damiamo et al., 1980; Snella et al., 1987) where they are likely to come into contact with cell types other than the endothelial cell. We have shown that neutrophils rapidly adhere to fibroblasts in culture by mechanisms that are partly dependent on integrins (Shock & Laurent, 1990). CD 18 is also involved in the adherence of neutrophils to epithelial cells (Simon et al., 1986). There is some evidence that the leucocyte integrins play a role in n o n - a d h e s i v e functions. Mac-i and p150,95 recognize complement components, which are also opsonins, indicating that in addition to adherence to the endothelium, a further important function of these molecules on leucocytes is to facilitate phagocytosis of

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opsonized particles (Graham et al., 1989). The interaction of T lymphocytes with a n t i g e n - c o a t e d t a r g e t s (Dustin & Springer, 1989) and with B l y m p h o c y t e s f o r production of specific antibody (Mazerolles et al., 1988) may also be p a r t l y dependent upon the activity of integrins.

3.1.2

The cytoadhesins

This group of proteins has recently been reviewed by Phillips et al. (1988). The GP (glycoprotein) IIb-IIIa i n t e g r i n is found almost e x c l u s i v e l y on p l a t e l e t s , where it may c o m p r i s e some 1 to 2 % of total platelet protein and appears to be essential for normal platelet aggregation. By this mechanism, GP IIb-IIIa on one platelet recognizes f i b r i n o g e n on the surface of another. In a d d i t i o n to fibrinogen, the GP IIb-IIIa inregrin r e c o g n i z e s f i b r o n e c t i n and yon W i l l e b r a n d factor. The cytoadhesin VnR (vitronectin receptor) is expressed on the surface of several cell types notably on endothelial cells but also on fibroblasts and smooth muscle cells. It is likely that VnR mediates adhesion of endothelial cells to surfaces containing fibrinogen, vitronectin or von Willebrand factor but it may also serve a function similar to G P I I b - I I I a on p l a t e l e t s , that is as a r e c e p t o r f o r fibrinogen to support platelet aggregation (for review see G i l t a y & van Mourik, 1988). It would appear that GPIIb-IIIa and VnR recognize different regions of the fibrinogen molecule (Cheresh et al., 1989).

3.1.3

The VLA integrins

The VLA integrins are so-called because the first two m e m b e r s (VLA-I and VLA-2) were found to be V e r y Late antigens, produced after 2 to 4 weeks in "in vitro" cultures of T lymphocytes. This family is now known to be composed of 6 proteins (Table 1 and see the reviews Hemler, 1988; Yokoyama et al., 1989), and the VLA nomenclature remains despite the fact that the production of VLA-3 to V L A - 6 d o e s not r e q u i r e l o n g - t e r m culture nor is their production limited to T lymphocytes. VLA proteins are expressed by all mammalian cells with the exception of p o l y m o r phonuclear leucocytes and erythrocytes. The majority of the VLA integrins recognize ligands possessing RGD sequences, all recognize components of the extracellular matrix (see Table I), and it w o u l d appear that they are most important as mediators of cell-matrix interactions.

3.1.4

Other integrin members

K a j i j i et al. (1989) have d e s c r i b e d an a d h e s i v e factor on e p i t h e l i a l cells homologous to known integrins and which may represent a new group of integrins. A f u r t h e r factor w h i c h p a r t i c i p a t e s in RGD-stimulated phagocytosis in neutrophils has also been described (Gresham et al., 1989). The activity of this p r o t e i n is d o w n - r e g u l a t e d by n e u t r o p h i l - d e r i v e d oxidants suggesting it may be important in early events of neutrophil activation.

3.2 Other Adhesion Families In addition to the integrins, several other f a m i l i e s of a d h e s i o n p r o t e i n s have been i d e n t i f i e d . Some of these are important with regard to leucocyte function. These i n c l u d e a f a m i l y w i t h four m e m b e r s (ELAM-I, GMP-140, LHR, and LAM-I) r e c e n t l y i d e n t i f i e d , the CD2/LFA-3 family, and a number of proteins involved in

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446 adhesion to elastin.

3.2.1

The ELAM-I, GMP-140 r LHR, LAM-I family

This family consists of four p r o t e i n s w h i c h which share considerable structural homology.

play

diverse

functional

roles

but

Stimulation of endothelial cells with interleukin i, tumor necrosis factor and endotoxin leads to the cell surface expression of a protein w h i c h has b e e n c a l l e d e n d o t h e l i a l l e u c o c y t e a d h e s i o n m o l e c u l e - i (ELAM-I), on the cell surface in a protein synthesis-dependent manner (reviewed by Bevilacqua et al., 1989). This is recognized by receptors on granulocytes such as neutrophils. Three separate adhesion molecules, ELAM-I, ICAM-I and ICAM-2, are t h e r e f o r e p r e s e n t on e n d o t h e l i a l c e l l s and m e d i a t e a d h e s i o n of neutrophils. The functions of ICAM-I and ELAM-I have been compared. Although both proteins are upregulated by the same mediators, cell surface expression of ICAM-I is more prolonged than that of ELAM-I (Pober et al., 1986). Bevilacqua et al. (1989) have suggested that ICAM-I m a y be m o r e imp o r t a n t in c h r o n i c inflammatory processes since it has a wider cell distribution (not only endothelial cells) and because it is e x p r e s s e d for l o n g e r p e r i o d s of time. G M P - 1 4 0 ( g r a n u l e m e m b r a n e protein-140), is present in secretory (alpha) granule membranes of resting platelets that can be r a p i d l y m o b i l i z e d o n t o the p l a t e l e t s u r f a c e upon s t i m u l a t i o n ( J o h n s t o n et al., 1988; Stenberg et al., 1985). This protein regulates the adherence of platelets with n e u t r o p h i l s and m o n o c y t e s (E. L a r s e n et al., 1989) and m a y t h e r e f o r e p l a y an i m p o r t a n t role in haemostasis whereby neutrophils and m o n o c y t e s can d o w n r e g u l a t e t h r o m b o g e n e s i s by r e m o v i n g platelets. Mature lymphocytes have the capacity to continuously recirculate between blood and lymph, necessary for efficient monitoring of antigenic insults. They leave the b l o o d s t r e a m by a d h e r i n g to s o - c a l l e d "high" e n d o t h e l i a l cells, w h i c h have a cuboidal rather than a flat morphology. This process shows remarkable specificity w h i c h is l a r g e l y d e t e r m i n e d by i n t e r a c t i o n s between lymphocyte homing receptor (LHR) molecules on l y m p h o c y t e s w h i c h r e c o g n i z e h i g h - e n d o t h e l i a l c e l l - d e r i v e d ligands (see review by Pals et al. 1989). These latter molecules have been called vascular "addressins" and are likely to mediate tissue-specific transfer into lymp h o i d t i s s u e s (see r e v i e w s by S t r e e t e r et al., 1988; Berg et al., 1989). It should be pointed out h o w e v e r that LHR is a l s o e x p r e s s e d on g r a n u l o c y t e s and m o n o c y t e s ( L e w i n s o h n et al., 1987) and m a y t h e r e f o r e r e p r e s e n t an additional mechanism to the ones described above for localization of these c e l l s to n o n l y m phoid tissues. A c D N A e n c o d i n g a new m e m b e r of this family (lymphocyte-associated molecule-l, LAM-I) has recently been described in lymphocytes (Tedder et al., 1989) a l t h o u g h the precise function of this protein is not known.

3.2.2

The CD2/LFA-3 family

L y m p h o c y t e s p o s s e s s a number of other cell-adhesion receptors in addition to the ones described above (reviewed b y S p r i n g e r et al., 1987; P a t a r r o y o & M a k g o b a , 1989; B i e r e r et al., 1989). CD2 (or LFA-2) is a glycoprotein found on T lymphocytes which recognizes the ligand LFA-3 (also k n o w n as CD58) p r e s e n t on endothelial cells, epithelial cells, fibroblasts and blood cells including red blood cells. In addition to mediating adhesion events, the CD2/LFA-3 system regulates T l y m p h o c y t e - m e d i a t e d f u n c t i o n s such as a n t i g e n - s p e c i f i c c y t o l y s i s and T cell

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proliferation.

3.2.3

Elastin adhesion proteins

Several cell types including monocytes, macrophages, neutrophils and f i b r o b l a s t s p o s s e s s a 67 kD m e m b r a n e - a s s o c i a t e d adhesive protein which can bind laminin and type IV collagen and which recognizes a specific h y d r o p h o b i c s e q u e n c e ( V a l - G l y V a l - A l a - P r o - G l y ) in elastin (Mecham et al., 1989; Senior et al., 1989a). A further protein with a molecular weight of 120 kD has been identified on fibroblasts and s m o o t h m u s c l e c e l l s and c a l l e d elastonectin (for review see Robert et al., 1989) which strongly adheres to insoluble elastin fibres. Elastin p e p t i d e s p o s s e s s i n g the h y d r o p h o b i c sequence referred to above can upregulate expression of elastonectin. These proteins do not appear to be related to other known adhesive proteins, suggesting that there are adhesion families yet to be discovered.

Chapter 4

Leucocyte Chemotaxis and Diapedesis

In o r d e r to pass into the lung, leucocytes must traverse endothelial, interstitial, b a s e m e n t m e m b r a n e and e p i t h e l i a l b a r r i e r s . The m e c h a n i s m s by w h i c h l e u c o c y t e s are a t t r a c t e d (chemotaxis) and exactly how emigration of leucocytes (diapedesis) is regulated by various receptors and soluble mediators represent important questions which should be addressed. C h e m o t a x i s r e f e r s to the directional migration of cells along chemical gradients and is a property of all leucocytes with the e x c e p t i o n of the p l a t e l e t and the mast cell. Table 2 highlights the important classes of agents capable of initiating chemotactic migration of circulating cells. A d d i t i o n a l l y , many cells have been shown to s e c r e t e c h e m o t a c t i c factors that have been incompletely characterized and their relationship to the mediators shown in Table 2 is unclear. For example, neutrophil chemotactic factors are produced by macrophages (Cohen et al., 1982; Hunninghake et al., 1980a) and lymphocytes (Maestrelli et al., 1988; Spisani et al., 1989). Monocyte chemotactic factors are produced by fibroblasts (C.G. Larsen et al., 1989a; Strieter et al., 1989a), lymphocytes (Yoshimura et al., 1989), e n d o t h e l i a l cells ( S t r i e t e r et al., 1989a) and epithelial cells (Koyama et al., 1989). Mast cells produce chemotactic stimuli for lymphocytes (see Berman et al., 1988) and eosinophils (see Kay, 1984). Most of this information has been gathered from "in vitro" assays and we have very little information regarding the relevance of these findings "in vivo". Indeed, "in vitro" assays c o m m o n l y m e a s u r e m i g r a t i o n using well-defined concentration gradients and it has proved impossible to establish such gradients experimentally "in vivo". This prompts one to ask how directional migration could occur in complex biological systems. Nevertheless, mechanisms do exist by which l e u c o c y t e s can be actively attracted into tissues during inflammation. Several reviews have been concerned with the mechanisms of leucocyte chemotaxis (Devreotes & Zigmond, 1988; Schiffmann, 1982; Snyderman & Goetzl, 1981) but, in e u k a r y o t i c cells, this has only been s t u d i e d in detail with respect to the neutrophil and the present discussion will, therefore, concentrate on this cell. The c h e m o t a c t i c p o t e n t i a l of cells c a p a b l e of m i g r a t i o n arises from the the presence of receptors on the membrane capable of recognizing chemotactic ligands. The receptor for the bacterial-derived N-formyl peptides in p a r t i c u l a r has been studied in detail (Zigmond, 1989). When e x p o s e d to a c h e m o t a c t i c gradient, neutrophils change shape and extend pseudopods, become oriented to the source and "crawl" (rather than "swim") along a surface. The mechanism involves a spatial sensing system whereby the neutrophil compares receptor occupancy over its length

448

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FACTOR

LEUCOCYTES

RESPONSIVE

449 TO FACTOR

B a c t e r i a l products f-Met-Leu-Phe

Neutrophil I , T-lymphocyte 2, monocyte 3 , basophil 4

Blood p r o t e i n s C5a Fibrinopeptides

Neutrophil 1, eosinophil s, basophil 4 , monocyte 3 Neutrophil 6 , eosinophil s , monocyte 3

Extracellular matrix p r o t e i n components Collagen peptides Elastin peptides Fibronectin peptides Laminin peptides

Neutrophil ~ , monocyte ~ Monocyte 3 Monocyte3 Neutrophil 8

Cytokines Interleukin 1 Interleukin 2 Interleukin 8 Tumor necrosis factor

Neutrophil 9, B and T-lymphocyte 0 T-lymphocyte 2 Neutrophil 9 , T-lymphocyte 9 Neutrophil I°, monocyte 10

Growth f a c t o r s Platelet-derived growth f a c t o r T r a n s f o r m i n g growth factor

Neutrophi111, monocyte 11 Monocyte 12

Lipid m e d i a t o r s Leukotriene B 4 Platelet-activating factor

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Neutrophil i, eosinophil 5, basophil 4 monocyte 3 Neutrophi113, eosinophi113

Lehrer et al. (1988). B e r m a n et al. (1988). Riches et al. (1988). Left-Brown et al. (1989); and see references within Czarnetzki & Wullenweber (1988). Kay (1984). Kay et al. (1974); Skogen et al. (1988). Laskin et al. (1986): Senior et al. (1989). Bryant et al. (1987); Terranova et al. (1986). See section 5.7.2. See section 5.7.1. See section 5.7.4. See section 5.7.5. See section 5.5.

TABLE

2. Circulating leucocyte chemotactic factors.

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and coordinates this into a directed response (Haston & Wilkinson, 1987; Devreotes & Zigmond, 1988), which is also extremely sensitive, able to respond to as little as 1% change in the concentration gradient. Marginated (unstimulated) neutrophils within the alveolar capillaries can be o b s e r v e d u n d e r the e l e c t r o n m i c r o s c o p e rolling along the endothelium but rarely sticking. When stimulated with chemoattractants, neutrophils become mechanically "stiffer" and this is sufficient to induce sequestration and retention within the alveolar capillaries (Worthen et al., 1989), ready to move into the alveolus. The reader will note that many of the factors shown in Table 2 are i n i t i a t i n g r e s p o n s e s o t h e r than c h e m o t a x i s such as a d h e s i o n , release of oxidants and enzymes (see Chapters 2 and 3). However, w o u l d s e e m n e c e s s a r y that t h e s e d i s p a r a t e p r o c e s s e s be k e p t separately, an issue which deserves some attention.

also capable of aggregation and i n t u i t i v e l y it and c o n t r o l l e d

It has been shown that adhesion is a transient process (Lo et al., 1989), w h i c h would provide for subsequent chemotaxis and diapedesis of leucocytes into tissues. Thus, stimulation initially causes adhesion to e n d o t h e l i u m f o l l o w e d by loss of adhesive capacity and movement of leucocytes into extravascular locations. Additionally, endothelial cells appear to p o s s e s s d i s t i n c t m e c h a n i s m s that c o n t r o l movement. S t i m u l a t i o n of endothelial cells with cytokines such as interleukin I and tumor necrosis f a c t o r p r o m o t e s b o t h a d h e r e n c e and v e c t o r i a l m i g r a t i o n of neutrophils through intercellular junctions of endothelial cells in the absence of exogenous chemotactic s t i m u l i (Furie & M c H u g h , 1989; M o s e r et al., 1989). A t o p o g r a p h i c a l d i s t r i b u t i o n of endothelial binding sites may also regulate transmigration of monocytes (Pawlowski et al., 1988). Finally, there is also evidence that the integrin adhesion family can regulate transendothelial migration of both neutrophils (Smith et al., 1989) and lymphocytes (VanEpps et al., 1989). The alt e r n a t i v e m e c h a n i s m for p r o m o t i n g directional migration of cells, therefore, is haptotaxis, which involves m i g r a t i o n a l o n g an " a d h e s i o n g r a d i e n t " w h e r e c e l l s respond to signals from the substratum rather than surrounding fluids. Since responses such as release of oxidants and enzymes are also stimulated in the presence of chemotactic factors, one might consider that tissue injury would occur d u r i n g c h e m o t a x i s and diapedesis. For instance, elastase can cause cell detachmant and lysis (Harlan et al., 1985b; S m e d l y et al., 1986) as can b i o l o g i c a l o x i d a n t s ( F a n t o n e & Ward, 1985; Freeman & Crapo, 1982; Weiss & Lobuglio, 1982). It has been suggested that neutrophil migration through basement membrane and int e r s t i t i a l b a r r i e r s m a y i n d e e d be a c c o m p l i s h e d by proteolytic degradation (see review by Senior & Campbell, 1983). Several studies show that e l a s t a s e r e l e a s e may be an essential prerequisite to the movement of neutrophils across endothelial cell and basement membrane b a r r i e r s ( M c L a u g h l i n et al., 1985; H o p k i n s et al., 1985). C o h e n & R o s s i (1983) have f u r t h e r s h o w n that movement of neutrophils across the epithelium occurs at the junction between type I and type II epithelial c e l l s and that the p r o c e s s i n v o l v e s the r e m o v a l of f r a g m e n t s of type I cell membrane into the alveolus. Moreover, several leucocytes including the neutrophil (Schmidt et al., 1989) and macrophage (Stuehr et al., 1989) produce nitric oxide, also known as endothelium-derived relaxing factor (Collier & Vallance, 1989; Palm e r et al., 1987), which would be expected to cause increased blood flow and may cause increased vascular permeability and emigration of leucocytes. Despite the above considerations, it is unlikely that chemotaxis and diapedesis of b l o o d l e u c o c y t e s t h r o u g h i n t e r c e l l u l a r j u n c t i o n s c a u s e s a p p r e c i a b l e damage. Indeed, although movement of neutrophils across both endothelial cell ( S h a s b y et al., 1985) and e p i t h e l i a l cell (Milks et al., 1986) monolayers "in vitro" does result in loss of cellular integrity with subsequent increases in permeability to p r o t e i n s , t h e s e p r o c e s s e s are t e m p o r a r y a n d r e v e r s i b l e since junctions reform rapidly. One w a y in w h i c h i n j u r i o u s p a t h w a y s m a y be l i m i t e d is t h r o u g h the

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process of adaptation (desensitization) whereby there is a decrease in the respons i v e n e s s of c e l l s to stimulus, a concept discussed by Zigmond (1989). Responses such as oxidant production or enzyme release occur transiently, p o s s i b l y b e c a u s e s e c o n d m e s s e n g e r s y s t e m s r e s p o n s i b l e for a c t i v a t i n g t h e s e pathways are downregulated, whilst chemotactic capacity may be m a i n t a i n e d for longer. It w o u l d a l s o a p p e a r that c o n c e n t r a t i o n s of chemoattractant that can induce movement are too low to activate secretory pathways in neutrophils (Guthrie et al., 1984) just as concentrations of stimulus required to induce adherence may be lower than those needed for maximal stimulation of migration. The system would therefore appear to be finely t u n e d such that the r e s p o n s e of these cells in inflammation occurs in a concerted fashion. Damage to host tissues is likely to depend on whether these carefully regulated pathways are i m b a l a n c e d in some way. O n e p a r t i c u l a r p h e n o m e n o n that has r e c e i v e d some attention "in vitro" is that of "priming" (Guthrie et al., 1984; Worthen, 1987) w h i c h s u g g e s t s that c e r t a i n s t i m u l i , such as e n d o t o x i n a n d p l a t e l e t - a c t i v a t i n g factor which stimulate secretion p o o r l y alone, p r i m e l e u c o c y t e s for e n h a n c e d r e s p o n s e s to s e c o n d a r y s t i m u l i , such as C5a or fMLP. The relevance of this phenomenon "in vivo" deserves closer attention. An important question relates to the predominance of neutrophils in early inflamm a t o r y lesions, that are gradually replaced by monocytes. This is important bec a u s e m a n y m e d i a t o r s are c h e m o t a c t i c for b o t h n e u t r o p h i l s and monocytes. Mechanisms that may be in operation include the lower numbers and slower migratory speed of monocytes, whilst Migliorisi et al. (1988) have a d d i t i o n a l l y s h o w n that epithelial junctions are more permeable to neutrophils than monocytes. In an "in vivo" model of lung inflammation, Doherty et al. (1988) showed that retention and m i g r a t i o n of m o n o c y t e s l a g g e d behind that of neutrophils and was dependent upon the p r e s e n c e of n e u t r o p h i l s s i n c e d e p l e t i o n of n e u t r o p h i l s f a i l e d to c a u s e monocyte accumulation. M o r e o v e r , "in v i t r o " s t u d i e s h a v e s h o w n that the mechanisms controlling adherence of these two cell types are different, and favour neutrophil accumulation at inflarmnatory sites (Kamp et al., 1989a).

Chapter 5

Important Products of Leucocytes

In order to appreciate how leucocytes are involved in s p e c i f i c p u l m o n a r y d i s o r ders, it is i m p o r t a n t to understand what agents are released by these cells and what effects they have on neighbouring cells and macromolecules. An indication of the w i d e r a n g e of m e d i a t o r s released from these cells was given in Section 2.2. The p r e s e n t s e c t i o n r e v i e w s b r i e f l y some of the m o s t r e l e v a n t p r o d u c t s of l e u c o c y t e s , p a r t i c u l a r l y those that will be referred to in Chapter 6 concerning their functions in lung pathology.

5.1 Activated Oxygen Species Exposure of phagocytic cells such as neutrophils, eosinophils, monocytes and macrophages to b o t h s o l u b l e and particulate stimuli i n d u c e s the s o - c a l l e d "respiratory burst", a phenomenon associated with i n c r e a s e d o x y g e n c o n s u m p t i o n , activation of the pentose phosphate pathway, and the release of "activated oxygen" s p e c i e s ( o x i d a n t s ) ( r e v i e w e d by B a b i o r , 1984; F a n t o n e & ward, 1982; W e i s s & L o B u g l i o , 1982). Many of the compounds released are free radicals, that is they possess an unpaired electron, which makes t h e m u n s t a b l e and r e a c t i v e m o l e c u l e s (Halliwell & Gutteridge, 1984; Southorn & Powis, 1988a). Most of the o x y g e n consumed during the respiratory burst can be accounted for by the production of the superoxide anion (02-), catalyzed by an e n z y m e (or e n z y m e complex), NAD(P)H oxidase, located in the plasma membrane of activated cells (see reviews by Babior, 1987; Rossi, 1986). The superoxide anion can be protonated under acidic c o n d i t i o n s to f o r m the m o r e r e a c t i v e perhydroxyl radical ( H O e ) . However, under physiological conditions 02dismutates to form hydrogen peroxide (H=02), a reaction c a t a l y z e d by s u p e r o x i d e dismutase. 02- and H202 can interact to form the highly reactive hydroxyl radical (OH'), although the rate constant for this reaction in aqueous solution is v i r t u a l l y zero unless a metal catalyst (such as iron) is present. The mechanism is thought to be a classical Haber-Weiss reaction in which 02- reduces iron which then reacts with H202 in the Fenton reaction to produce O H . Although there is little doubt that metal salts can catalyze the Fenton reaction "in v i t r o " , t h e r e is d e b a t e as to w h e t h e r any free m e t a l is a v a i l a b l e "in vivo" (Cohen et al., 1988; Halliwell & Gutterridge, 1986). Thus, the "in vivo" relevance of OH- radicals has yet to be established.

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One of the most potent oxidant-generating systems is the peroxidase-H202-halide system, which is capable of forming a range of hypohalous acids (eg. HOCI and HOBr). Both neutrophils and eosinophils possess enzymes, referred to as myeloperoxidase and eosinophil peroxidase respectively, capable of catalyzing such reactions. M y e l o p e r o x i d a s e constitutes some 5% by weight of protein in the neutrophil, making it the most abundant protein in the granules of these cells. There would appear to be considerable structural homology between these two enzymes and other peroxidases (Ten et al., 1989), suggesting the presence of a multi-gene family. The halide used by neutrophils is most likely to be chloride, and stimulated neutrophils are known to produce hypochlorous acid (HOCI) (Weiss et al., 1982; Winterbourn, 1985). In contrast, Mayeno et al. (1989) have shown that eosinophil peroxidase p r e f e r e n t i a l l y uses the halide b r o m i d e , r a t h e r t h a n chloride, and generates HOBr. The reaction of HOCI with a variety of amines produces long-lived N-chloramine species (RNHCI), which are powerful oxidising agents and are known to be produced by neutrophils (Grisham et al., 1984; Test et al., 1984). There has been considerable interest in establishing the relative capacity of different cells types to release oxidants. The neutrophil has often been considered the prototypic o x i d a n t - g e n e r a t i n g cell, but it would appear that the oxidative capacity of eosinophils is greater and more prolonged than that of neutrophils (Shult et al., 1985; Yazdanbakhsh et al., 1985). Oxidants are capable of interacting with with all groups of biological compounds (DNA, proteins, carbohydrates and lipids) which explains why these agents possess such efficient m i c r o b i c i d a l properties (reviewed by Baggiolini, 1984; Badwey & Karnovsky, 1980). However, they can also damage host cells and macromolecules by i n d u c i n g changes such as lipid p e r o x i d a t i o n and o x i d a t i o n / f r a g m e n t a t i o n of proteins and DNA (for reviews see Blake et al., 1987; Fantone & Ward, 1982; 1985; Slater, 1984; Southorn & Powis, 1988b; Weiss, 1989; Weiss & LoBuglio, 1982).

5.2 Elastases Neutrophil elastase, present within the azurophil granules of neutrophils, is a serine protease for which large aliphatic residues such as valine and alanine are the p r e f e r r e d cleavage sites. These residues are found in abundance in elastin, the best known substrate, but elastase can attack a wide variety of proteins including types III and IV collagen, proteoglycans, fibronectin, complement proteins and IgG (reviewed by Havemann & Gramse, 1984), IgA (Niederman et al., 1986), ovalbumin (Wright, 1984) and ~-thrombin (Brower et al., 1987). Elastase also possesses the capacity to activate latent collagenases (see Section 5.3) produced by mesenchymal cells (Okada & Nakanishi, 1989). Neutrophils possess two other proteases with the potential to mediate elastin degradation. Cathepsin G possesses minimal elastolytic potential "per se" but can dramatically potentiate the activity of elastase (Boudier et al., 1981; Lucey et al., 1985). A third elastolytic protease, proteinase 3, which is a serine protease, has also been described (Kao et al., 1988) but its role in elastin breakdown under normal and pathological conditions has yet to be established. Murine macrophages synthesize and release a m e t a l l o e l a s t a s e with entirely different properties to the neutrophil enzyme (Banda & Werb, 1981; White et al., 1980). Human alveolar macrophages in direct contact with elastin-coated surfaces also degrade elastin via a metalloprotease-dependent mechanism (Senior et al., 1989b), but it has not been possible thus far to isolate this elastase from these cells.

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Several other cell types i n c l u d i n g p l a t e l e t s (James et al., 1985), m o n o c y t e s (Senior et al. 1982), mast cells and b a s o p h i l s (Meier et al., 1989) contain (serine) elastases, but their exact role in pathology awaits clarification. The activity of elastases is controlled by a number of proteins that inhibit its a c t i v i t y such as ~ - l - p r o t e i n a s e inhibitor and ~-2-macroglobulin, which are circulating inhibitors (reviewed by Travis & Salvesen, 1983), a n t i l e u c o p r o t e a s e , which is produced locally in the lung (reviewed by Morrison, 1987), and by newlydiscovered cellular antielastases (Remold-O'Donnell et al., 1989).

5.3 Collagenases In addition to synthesizing connective tissue components, m e s e n c h y m a l cells also p r o d u c e collagenase, gelatinase and stromelysin, enzymes that can cleave collagen or its breakdown products. The properties of these enzymes were r e c e n t l y summ a r i z e d in this journal ( S a k a m o t o & Sakamoto, 1988). In addition, several leucocytes produce collagenolytic enzymes and these are discussed below. Neutrophil collagenase is a metalloproteinase which can cleave types I, II and III c o l l a g e n but with greater activity against type I (Hasty et al., 1987). The enzyme is found preformed within neutrophil specific granules in a latent form and a c t i v a t e d extracellularly by a mechanism involving hypochlorous acid and cathepsin G (which are also neutrophil products) and oxidised glutathione (Capodici et al., 1989; Tschesche & McCartney, 1981; Weiss & Peppin, 1986). N e u t r o p h i l s also p o s s e s s a g e l a t i n a s e , capable of degrading denatured collagen (Murphy et al., 1980) and native type V collagen (Hibbs et al., 1985). Gelatinase is also p r o d u c e d in a latent form and can be activated by both HOCl-dependent (Peppin & Weiss, 1986) and elastase-dependent (Vissers & Winterbourn, 1988) pathways. M a c r o p h a g e s r e l e a s e both c o l l a g e n o l y t i c and g e l a t i n o l y t i c proteases. A collagenase (Welgus et ai.,1985) and s t r o m e l y s i n ( F r i s c h et al., 1987) w i t h p r o p e r t i e s identical to those of the fibroblast have been identified, whilst the gelatinase is immunologically identical to neutrophil g e l a t i n a s e (Hibbs et al., 1987) and d e g r a d e s the same substrates. In contrast to the neutrophil enzyme, macrophage gelatinase is not stored w i t h i n g r a n u l e s and r e q u i r e s p r o t e i n synthesis. Finally, e o s i n o p h i l s p o s s e s s a g r a n u l e - a s s o c i a t e d collagenase that can cleave types I and III collagen (Hibbs et al., 1982; Davis et al., 1984). The enzyme is a metalloprotease and is released in a latent form. Eosinophil collagenase is one of the few proteolytic enzymes released from eosinophils. The activity of the collagenases is inhibited by c i r c u l a t i n g i n h i b i t o r s such as ~-2-macroglobulin and B-l-anticollagenase and by the tissue inhibitor of metalloproteases (TIMP) which is produced by mesenchymal cells such as fibroblasts (for review see Harris et al., 1984).

5.4 Basic Proteins E o s i n o p h i l s p r o d u c e three highly basic proteins (that is, proteins possessing a high positive charge) referred to as e o s i n o p h i l c a t i o n i c p r o t e i n (ECP), m a j o r basic p r o t e i n (MBP) and eosinophil protein X (EPX) (for reviews see Dahl et al., 1988; G l e i c h & A d o l p h s o n , 1986; V e n g e et al., 1 9 8 8 ) . Another protein, eosinophil-derived n e u r o t o x i n has r e c e n t l y been shown to be identical to EPX

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(Slifman et al., 1989). All three proteins are toxic towards p a r a s i t e s and this is believed to be their major physiological function. Their activity is probably due to target membrane lysis since these h i g h l y basic and h y d r o p h o b i c p r o t e i n s have a high affinity for membranes. More specifically, ECP may cause the formation of membrane pores and EPX can cause c r o s s l i n k i n g of m e m b r a n e s t r u c t u r e s (Venge et al., 1988). The eosinophil basic proteins are also toxic towards mammalian cells, particularly e p i t h e l i a l cells (Dahl et al., 1988; Venge et al., 1988) and interfere with cell-mediated immunity. Finally, MBP and ECP possess the ability to stimulate histamine release from basophils (Dahl et al., 1988; Thomas et al., 1989). A number of low molecular weight cationic proteins, present within the granules of neutrophils, have been described but i n c o m p l e t e l y c h a r a c t e r i z e d and named the "defensins" (Ganz et al., 1985; and see review by Lehrer, 1988). These proteins would appear to be most important in the killing of m i c r o o r g a n i s m s taken up by n e u t r o p h i l s but they may also be toxic to host tissues (Henson & Johnston, 1987; Okrent et al., 1990).

5.5 Platelet-Activating Factor Platelet-activating factor (PAF) is produced by a wide variety of cells including platelets, mast cells, basophils, eosinophils, neutrophils, monocytes, m a c r o p h a g e s and endothelial cells (Bratton & Henson, 1989). A wide variety of biological effects have now been a t t r i b u t e d to PAF including bronchoconstriction, increased vascular permeability and bronchial hyperresponsiveness. These p r o p e r t i e s have been covered in several reviews (Barnes et al., 1988; Braquet et al., 1987). A discussion of the effects of PAF on inflarm~atory cells is highly relevant in the present context (for r e v i e w see V a r g a f t i g & B o u r g a i n , 1989). PAF can induce platelet activation (aggregation, mediator release) but has a number of effects on other leucocytes. On neutrophils, PAF is capable of s t i m u l a t i n g c h e m o t a x i s and aggregation (O'Flaherty et al., 1981) and modulating oxidant production (Dewald & Baggiolini, 1985). The chemotactic potential of PAF for eosinophils is very much greater than for neutrophils (Wardlaw et al., 1986). Other effects on eosinophils include stimulation of leukotriene C4 production (Owen et al., 1987b), i n c r e a s e d c y t o t o x i c i t y t o w a r d parasites (MacDonald et al., 1986) and stimulation of enzyme secretion and oxidant production (Kroegel et al., 1989). Finally, PAF increases a number of r e s p o n s e s in m a c r o p h a g e s i n c l u d i n g p r o d u c t i o n of o x i d a n t s and the mediators interleukin 1 and tumor necrosis factor (DuBois et al., 1989a). Thus, in addition to direct effects on pulmonary structures, PAF also s t i m u l a t e s l e u c o c y t e s to r e l e a s e a host of mediators which, in turn, can modulate the surrounding environment.

5.6 Histamine Histamine is produced by the decarboxylation of histidine and is stored within the g r a n u l e s of b a s o p h i l s and mast ceils in association with glycosaminoglycans such as heparin and chondroitin-4-sulphate (for review see B a r n e s et al., 1988). Once released, h i s t a m i n e exerts effects through highly specific receptors and its effects on airways include bronchoconstriction, inducement of a i r w a y s e c r e t i o n and microvascular leakage. The e f f e c t s of h i s t a m i n e on l e u c o c y t e s include s t i m u l a t i o n of c h e m o t a x i s in eosinophils (Clark et al., 1975) and neutrophils (Seligmann et al., 1983). It can also inhibit neutrophil adherence and release of oxidants and enzymes (Seligman et

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1983).

5.7 Cytokines and G r o w t h Factors term cytokine is used to describe compounds released by cells which exert effects on s u r r o u n d i n g cells (a paracrine function) or on themselves (an autocrine function). When cytokines are produced by specific cell types, this is often indicated by an a l t e r n a t i v e prefix. For example, m o n o k i n e s are p r o d u c e d by mononuclear cells and lymphokines are produced by lymphocytes. Growth factors in g e n e r a l exert growth-stimulatory activities on surrounding cells, but since many cytokines also possess such a c t i v i t y , the p r e s e n t d i s c u s s i o n d e s c r i b e s these agents in one section. The

5.7.1

Tumor necrosis

factor

Tumor n e c r o s i s factor (TNF, also known as c a c h e c t i n ) is a p r o t e i n p r o d u c e d primarily by monocytes and macrophages (but also by T lymphocytes) in response to such agents as endotoxin, interleukin i and gamma interferon (reviewed by Beutler & Cerami, 1988; 1989). The name TNF arose from its ability to be toxic towards tumor cells but it has a number of other b i o l o g i c a l p r o p e r t i e s . Notably, it can act as a mitogen for fibroblasts (Sugarman et al., 1985; Vilcek et al., 1987) and stimulate production of c o l l a g e n in some fibroblast culture systems (Duncan & Berman, 1989), although the overall effect of TNF is likely to be c a t a b o l i c b e c a u s e it also s t i m u l a t e s collagenase and prostaglandin E2 expression by fibroblasts (Duncan & Berman, 1989; Dayer et al., 1985). Additionally, this protein stimulates interleukin i production by m a c r o p h a g e s , m o n o c y t e s and endothelial cells indicating another way in which TNF can influence connective tissue metabolism. TNF is also likely to play an important role in inflammatory processes since it c a n a t t r a c t and a c t i v a t e several inflammatory cells (for reviews see Beutler & Cerami, 1988; 1989; O p p e n h e i m et al., 1989). TNF e n h a n c e s n e u t r o p h i l and e o s i n o p h i l a d h e r e n c e to e n d o t h e l i u m (see S e c t i o n 3.1) and augments neutrophil phagocytosis, enzyme release and oxidant production. It is also chemotactic for n e u t r o p h i l s and m o n o c y t e s and e n h a n c e s the cytotoxic functions of eosinophils toward parasitic organisms. Finally, TNF stimulates lymphokine release and interleukin 2 r e c e p t o r expression in T lymphocytes and promotes proliferation and antibody production in B lymphocytes.

5.7.2

The interleukins

The interleukins are now known to be a family of 8 proteins, the majority of which a c t as r e g u l a t o r s of the growth and differentiation of lymphocytes. Several of these proteins (IL i, IL 2, and IL 8) will be discussed in relation to pulmonary d i s e a s e in Chapter 6 and deserve closer attention. The role interleukins play in the growth and differentiation of leucocytes was discussed in Section 2.1, but for

f u r t h e r information regarding the biological roles of IL 3 to IL 7 the reader is directed to several reviews (Schrader, 1986; Paul & O'Hara, 1987; Kishimoto, 1989; Mizel, 1989). IL 1 (for r e v i e w s see D i N a r e l l o , 1988; M a r t i n & Resch, 1988) is p r o d u c e d by monocytes and macrophages p r e d o m i n a n t l y , but also by f i b r o b l a s t s , e n d o t h e l i a l cells, B iymphocytes, platelets (Hawrylowicz et al., 1989) and neutrophils (Tiku et al., 1986a). I L i was originally identified as endogenous pyrogen, a compound

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produced as part of the acute phase response, involved in the production of fever. We now know that IL 1 has a w i d e r range of b i o l o g i c a l e f f e c t s which include stimulation of B lymphocyte growth, stimulation of IL 2 production, and promotion of IL 2 receptor expression in T lymphocytes. The effects of IL 1 on mesenchymal cells are equivocal and depend on culture conditions. It can stimulate fibroblast proliferation (Schmidt et a i . , 1 9 8 2 ) but this action a p p e a r s to d e p e n d on the presence of a d d i t i o n a l growth factors (Singh et al., 1988) or c y t o k i n e s (particularly TNF) (Elias et al., 1988). Likewise, in smooth m u s c l e cells IL 1 potentiates cell growth in the presence of other growth factors but has no effect alone (Bonin et al., 1989). IL 1 has a number of important effects on i n f l a m m a t o r y cells (Martin & Resch, 1988; Oppenheim et al., 1989). It is a neutrophil chemoattractant and can enhance release of oxidants and e n z y m e s from n e u t r o p h i l s ( F e r r a n t e et al., 1988) and eosinophils (Pincus et al., 1986). Ii 1 also potentiates histamine release from IgE-stimulated basophils (Massey et al., 1989). Finally, it is a chemoattractant for T l y m p h o c y t e s and s t i m u l a t e s IL 2, gamma-interferon and colony stimulating factor expression by these cells. IL 2 (reviewed by Smith, 1984) is produced by T lymphocytes and f i b r o b l a s t s and functions largely as a T lymphocyte mitogen. Resting T lymphocytes are unresponsive to IL 2 but, in the presence of an antigen-presenting cell and antigen, they b e c o m e r e s p o n s i v e in a process that is associated with upregulation of the IL 2 receptor. IL 2 also activates several macrophage and monocyte functions including o x i d a n t p r o d u c t i o n , m i c r o b i c i d a l a c t i v i t y and tumor necrosis factor production (Economou et al., 1989; Wahl et al., 1987a). Since macrophages and neutrophils release inhibitors of IL 1 and IL 2 ( K a s h i w a d o et al., 1989; Tiku et al., 1986b), it is apparent that mechanisms exist for suppression of the activity of these proteins, which may be of most i m p o r t a n c e with regard to suppression of T cell activation. IL 8, also known as neutrophil-activating peptide-i (NAP-l), was originally recognized as a monocyte-derived neutrophil chemotactic factor (Yoshimura et al., 1987; Walz et al., 1987). It is a small peptide released primarily by monocytes but also by endothelial cells and fibroblasts (Strieter et al., 1989b; van D a m m m e et al., 1989) in response to stimuli such as IL 1 and tumor necrosis factor. In addition to chemotaxis, IL 8 also stimulates enzyme release and o x i d a n t p r o d u c t i o n in neutrophils (Baggiolini et al., 1989; Willems et al. 1989). Furthermore, Colditz et al. (1989) have shown that i n t r a d e r m a l i n j e c t i o n of IL 8 can induce dramatic neutrophil emigration "in vivo". IL 8 was classed as an interleukin when it was found to be a chemoattractant for lymphocytes (C.G. Larsen et al., 1989b), and it w o u l d now a p p e a r that IL 8 is a chemoattractant only for neutrophils and lymphocytes. However, it can stimulate secretion of h i s t a m i n e and l e u k o t r i e n e s from basophils (Dahinden et al., 1989; White et al., 1989).

5.7.3

Gamma interferon

In c o n t r a s t to the interleukins which generally up-regulate the immune response, the i n t e r f e r o n s are p r o t e i n s w i t h a n t i v i r a l , a n t i p r o l i f e r a t i v e and immunor e g u l a t o r y a c t i v i t i e s and in this respect, g a m m a interferon, produced by lymphocytes and macrophages, has a wider range of a c t i v i t i e s than ~ - i n t e r f e r o n or S-interferon (see review by Pestka et al., 1987). Gamma interferon regulates both humoral and cell-mediated irmnunological functions such as a c t i v a t i o n of n a t u r a l k i l l e r cells, u p r e g u l a t i o n of Fc and interleukin 2 receptors on monocytes, and enhancement of major histocompatibility complex (MHC) expression.

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Gamma interferon also inhibits fibroblast collagen p r o d u c t i o n (Duncan & Berman, 1985; Jimenez et al., 1984). With reference to macrophages, gamma interferon can augment antigen presentation, enhance phagocytosis and cytotoxicity, and stimulate arachidonic acid metabolism (Rankin et al., 1989). It also primes neutrophils for enhanced release of both oxidants and granule enzymes ( C a s s a t e l l a et al., 1988) and stimulates oxidant production and microbicidal activity of monocytes although this is inhibited by interleukin 4 (Lehn et al., 1989). Gamma interferon and interleukin 4 generally possess opposing effects and production of the interferon by mononuclear cells is inhibited by interleukin 4 (Peleman et al., 1989). Finally, gamma interferon is capable of stimulating adherence of both neutrophils and l y m p h o c y t e s to endothelium "in vitro" and "in vivo" by mechanisms related to upregulation of ICAM-I (see Section 3.1) and by other m e e h a n s i s m s (Hendriks et al., 1989; Pober et al., 1986).

5.7.4

Platelet-derived

growth factor

P l a t e l e t - d e r i v e d g r o w t h factor (PDGF) is a p r o t e i n produced by platelets, endothelial cells, smooth muscle cells, m o n o c y t e s and m a c r o p h a g e s and f u n c t i o n s p r i m a r i l y as a g r o w t h s t i m u l a t o r for mesenchymal cells (fibroblasts and smooth muscle cells) although they are also chemotactic for these cells (for reviews see Deuel, 1987; Heldin et al., 1985; Huang et al., 1988). Paradoxically, PDGF possesses chemotactic potential for neutrophils and m o n o c y t e s (Deuel et al., 1982) and activates a number of neutrophil responses associated with increased receptor expression (Lanser et al., 1988).

5.7.5

Transforming

growth factor B

Transforming growth factor S (TGF 5) is a polypeptide produced by monocytes, macr o p h a g e s and p l a t e l e t s which appears to function largely to stimulate extracellular matrix deposition (Assoian, 1988; Rizzino, 1988; Sporn et al., 1987). TGF B s t i m u l a t e s the synthesis of collagen, fibronectin and proteoglycans in fibroblast cultures whilst decreasing collagenase expression and increasing c o l l a g e n a s e inhibitor production. It also p o s s e s s e s chemotactic properties for fibroblasts. With regard to growth, TGF B has been shown to be s t i m u l a t o r y only in c e r t a i n fibroblast lines (Moses et al., 1987) and this may be mediated through autocrine stimulation of growth factor production by the fibroblasts themselves. In other cells, TGF ~ has inhibitory effects on growth. In general, TGF B does not exert effects on leucocytes although it has been shown to be a chemotactic factor for monocytes and stimulates interleukin 1 p r o d u c t i o n by t h e s e c e l l s (Wahl et al., 1987b). However, it can i n d i r e c t l y r e g u l a t e leucocyte functions since it has been shown to inhibit neutrophil a d h e r e n c e when c u l t u r e d with e n d o t h e l i a l cells (Gamble & Vadas, 1988) although it upregulates fibroblast synthesis and cell surface expression of VLA integrins (Heino et al., 1989).

5.7.6

Insulin-like growth factor-i

I n s u l i n - l i k e g r o w t h f a c t o r - i (IGF-I), because of its structural homologies to produced primarily in the liver but it muscle cells and stimulates cell growth F r o e s c h et al., 1985; Van Wyck, 1984). by fibroblasts (Goldstein et al., 1989).

also known as somatomedin C, was so named proinsulin. It is a c i r c u l a t i n g factor is also produced by fibroblasts and smooth in an autocrine fashion (for reviews see IGF-I also stimulates collagen synthesis A polypeptide released from macrophages

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with mitogenic activity for fibroblasts, originally named alveolar macrophagederived growth factor (Bitterman et al., 1982), is now known to be an IGF-l-like molecule (Rom et al., 1988).

Chapter 6

The Role of Leucocytes in Pulmonary Disease

L e u c o c y t e s have been i m p l i c a t e d in v a r i o u s p u l m o n a r y disorders, the nature of w h i c h v a r y in terms of a e t i o l o g y , p a t h o l o g i c a l features, a n d p a t h o g e n e t i c mechanisms. An understanding of how leucocytes are mobilized and attracted into the lung, and which mediators they release, should provide important clues to the pathogenetic pathways involved. There are numerous approaches to this problem including the study of leucocytes in model "in vitro" systems that aim to mimic beh a v i o u r "in vivo", or the analysis of cells and mediators removed from the lungs of patients with pulmonary diseases. Only by pursuing such studies can we hope to u n d e r s t a n d the c o m p l e x ways in which leucocyte behaviour is regulated "in vivo" under both normal and pathological conditions. With this i n f o r m a t i o n , more rational and effective treatments can be designed to control the disease process. In this chapter, we discuss five pulmonary disorders, chosen because they vary in their nature and pathogenesis. These are e m p h y s e m a , c r y p t o g e n i c f i b r o s i n g alveolitis, asbestosis, sarcoidosis, and asthma.

6.1 Emphysema Pulmonary emphysema is defined as permanent dilation of the respiratory airspaces distal to the terminal bronchiole, accompanied by destruction of the interalveolar septa and other respiratory tissues, and without obvious fibrosis (Snider et al., 1986). The impetus for research in emphysema came from two early observations. Gross and colleagues (Gross et al., 1965) reported that animals developed emphysema-like lesions f o l l o w i n g the i n t r a t r a c h e a l i n s t i l l a t i o n of papain, and in s u b s e q u e n t studies e m p h y s e m a has been p r o d u c e d in experimental animals using a variety of proteases, sharipg the property that they degrade elastin (Snider et al., 1986). The second observation was that familial ~-l-proteinase i n h i b i t o r d e f i c i e n c y is a s s o c i a t e d with the p r e m a t u r e o c c u r r e n c e of e m p h y s e m a in humans (Laurell & Eriksson, 1963). a-l-proteinase inhibitor (also known as ~ - l - a n t i t r y p s i n ) is an acute phase glycoprotein produced by the liver and by alveolar macrophages that is a ubiquitous component in blood and tissues. It has a molecular weight of 51 kD and serves as an i n h i b i t o r of serine p r o t e a s e s , n o t a b l y n e u t r o p h i l e l a s t a s e (Carrell et al., 1982; Kalsheker, 1989; Perlmutter & Pierce, 1989). The so-called ZZ p h e n o t y p e results from a single amino acid substitution, resulting in blood concentrations of ~-l-proteinase inhibitor less than o n e - s i x t h of normal. Individuals with this phenotype are also prone to develop chronic liver disease due

460

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Cigarette smoke

461

I

I Neutrophil

Maerophage

I

I

JoZ1~st~se

[

*Other proteases [

l*Oxid~ts]

EMPHYSEMA I

J

/ Fig. 4. Outline for the role of leucocytes in emphysema. Cigarette smoke causes attraction of neutrophils into the lung and activation of both neutrophils and macrophages to produce elastases and oxidants. The capacity of the neutrophil in these respects is greater "than that of the macrophage. These events are believed to give rise to e m p h y s e m a via a triad of events: degradation of elastin, inactivation of antiproteases (notably of ot-l-proteinase inhibitor) and interference with elastin synthesis. Inset at base of figure depicts enlarged airspaces within alveolar structures.

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to the intrahepatic accumulation in the secretory pathway.

of the Z protein,

probably

arising

from a defect

These two o b s e r v a t i o n s i n d i c a t e d that an a l t e r a t i o n in the normal homeostatic balance between enzymes and their inhibitors in the lung can cause emphysema, and led to the so-called protease/antiprotease imbalance hypothesis. Most individuals with emphysema (98%) have normal circulating (and lung) levels of the inhibitor. The common characteristic of this group of patients is that they smoke cigarettes (Hutchison, 1982). This fact, together with the k n o w l e d g e that ~ - l - p r o t e i n a s e inhibitor-deficient i n d i v i d u a l s who also smoke are in double jeopardy (Janus et al., 1985; Tobin et al., 1983), has led to exhaustive research efforts to investigate the role of s m o k i n g in e s t a b l i s h i n g derangements between elastases and their inhibitors in the a-l-proteinase inhibitor-sufficient lung. The current view concerning the pathogenesis of smoking-related emphysema, as summ a r i z e d in n u m e r o u s reviews (Cohen, 1983; Flenley et al., 1986; Janoff, 1985; Niewoehner, 1988; Snider, 1984; Stone, 1983) m a i n t a i n s that inflammatory leucocytes, in p a r t i c u l a r the n e u t r o p h i l , p l a y a central role as indicated in Figure 4.

6.1.1

Neutrophils

Neutrophils are most often implicated in the p a t h o g e n e s i s of e m p h y s e m a b e c a u s e these cells possess a powerful elastase (Section 5.2) which is capable of inducing emphysema in experimental animals (Snider et al., 1986). The i m p o r t a n c e of the n e u t r o p h i l has also been e s t a b l i s h e d by studies e m p l o y i n g the beige mouse, a strain deficient in neutrophil elastase. In a study where neutrophils were continuously attracted into the lung with endotoxin, beige mice failed to develop emphysema whilst animals without the mutation did so (Starcher & Williams, 1989). It is w e l l - e s t a b l i s h e d that the p e r i p h e r a l n e u t r o p h i l count is i n c r e a s e d in smokers (see B r i d g e s et al., 1985 for instance). Furthermore, the numbers of neutrophils are increased in the lungs of smokers ( H u n n i n g h a k e & Crystal, 1983; R e y n o l d s & Newball, 1974), an effect that can be m i m i c k e d e x p e r i m e n t a l l y in animals (Kilburn & McKenzie, 1975; Ludwig et al., 1985) and in humans (MacNee et al., 1989). A n u m b e r of mechanisms by which smoking can induce recruitment of neutrophils to the lung have been established. Cigarette smoke components can a c t i v a t e the alternative pathway of complement (Kew et al., 1986) causing the production of C5a, the most potent neutrophil chemotaxin known. Nicotine also possesses the capacity to i n c r e a s e the c h e m o t a c t i c responsiveness of neutrophils at physiological concentrations and is chemotactic "per se" at h i g h e r levels (Totti et al., 1984). A l v e o l a r macrophages also release neutrophil chemotactic factors, including LTB4, complement-derived peptides, and specific peptides distinct from complement (Cohen et al., 1982; Hunninghake et al., 1980a; Reynolds, 1983), such as interleukin 8. Finally, p e p t i d e s d e r i v e d from c o n n e c t i v e tissue p r o t e i n s have c h e m o t a c t i c p r o p e r t i e s for n e u t r o p h i l s (see Table 2), as does denatured ~-l-proteinase inhibitor (Banda et al., 1988), r a i s i n g the p o s s i b i l i t y that c o n n e c t i v e tissue b r e a k d o w n i n i t i a t e d by n e u t r o p h i l s may e s t a b l i s h a v i c i o u s c i r c l e that continuously amplifies the inflammatory response. There is some evidence that the elastase c o n t e n t of n e u t r o p h i l s , or the amount r e l e a s e d when s t i m u l a t e d , is increased in both smokers and in patients with emphysema, but this is not unequivocal (reviewed by Janoff, 1985). There has been much interest

in establishing

how elastase

gains

access

to elastin

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in emphysema. In a d d i t i o n to toxic r e l e a s e of e l a s t a s e from n e u t r o p h i l s in response to cigarette smoke, macrophages are known to produce a factor that causes non-cytotoxic degranulation of neutrophils (Cohen et al., 1982; MacArthur et al., 1987). Whether this peptide is upregulated in cigarette smokers is not k n o w n as yet. However, there is e v i d e n c e that e l a s t a s e levels in the lavage fluid of cigarette smokers is increased relative to nonsmokers (see N i e w o e h n e r , 1988 for discussion). Indeed, there would appear to be a rapid increase in serum levels of this enzyme immediately following inhalation of cigarette smoke (Abboud et al., 1986). One study detected (immunologically) neutrophil elastase in the interstitial compartment of emphysematous lungs in man (Damiano et al., 1986), a l t h o u g h this work has been c r i t i c i z e d on m e t h o d o l o g i c a l g r o u n d s (Fox et al., 1988). Nevertheless, if elastase is deposited on interstitial elastin as cells t r a v e r s e the a l v e o l a r wall, w i d e s p r e a d d e s t r u c t i o n of lung s t r u c t u r e s w o u l d p r o b a b l y result. Neutrophils certainly degrade e l a s t i n as they m i g r a t e across e l a s t i n coated filters (Sandhaus, 1983) and several "in vitro" studies have suggested that elastase secretion is an e s s e n t i a l feature of n e u t r o p h i l m o v e m e n t across endothelium (Hopkins et al., 1985) and basement membranes (McLaughlin et al., 1985). It should also be pointed out that neutrophils release two o t h e r p r o t e a s e s with elastolytic potential, those being cathepsin G and proteinase-3 (see Section 5.2). N e u t r o p h i l s are also known to i n a c t i v a t e antiproteases. Since it possesses a methionine group at its active centre, ~-l-proteinase inhibitor is extremely sensitive to o x i d a t i v e i n a c t i v a t i o n , c a u s i n g loss of inhibitory capacity towards elastase (Beatty et al., 1980; Johnson & Travis, 1979). Oxidative inactivation of ~-l-proteinase i n h i b i t o r has been produced by the action of cigarette smoke, an e x t r e m e l y rich source of free r a d i c a l s (see r e v i e w by Cross, 1 9 8 7 ) a n d by neutrophil-derived oxidants, where the myeloperoxidase system plays a major role (Carp & Janoff, 1980; C l a r k et al., 1981; Shock & Baum, 1988; Zaslow et al., 1983). It should also be noted that oxidised ~-l-proteinase inhibitor not only loses its ability to inhibit elastase but also becomes a target for this protease (Ossanna et al. 1986). Several other neutrophil-derived proteases including collagenase and gelatinase (see S e c t i o n 5.3) can c l e a v e ~ - l - p r o t e i n a s e inhibitor directly (Vissers et al., 1988). Several groups have investigated the "in vivo" relevance of neutrophil-dependent inactivation of ~-l-proteinase inhibitor, but evidence is equivocal as to whether inactive inhibitor can be detected in lavage fluid or serum of either cigarette smokers or patients with emphysema (see Niewoehner, 1988 for review). A number of acid-stable, low molecular weight elastase i n h i b i t o r s , p r o d u c e d locally at the lung surface, have been described and their role in elastase inhibition may have been u n d e r e s t i m a t e d (Morrison, 1987). One of these, c a l l e d ant i l e u c o p r o t e a s e or b r o n c h i a l mucous proteinase inhibitor, is sensitive to inactivation by biological oxidants (Kramps et al., 1988). There is compelling evidence that elastase that has adsorbed onto e l a s t i n fibres is p r o t e c t e d from i n h i b i t i o n by ~-l-proteinase inhibitor (Bruch & Bieth, 1986; Hornebeck & Schnebli, 1982; Reilly & Travis, 1980) but not by low molecular weight i n h i b i t o r s (Bruch & Bieth, 1986; Laurent et al., 1987). Moreover, other studies have shown that neutrophils, in close apposition to connective tissue substrates, can r e l e a s e e l a s t a s e into an e x c l u d e d microenvironment which is then protected from antiprotease inhibition ( C a m p b e l l & C a m p b e l l , 1988; Weiss et al., 1986). Therefore, oxidative inactivation of e-l-proteinase inhibitor may not be a necessary prerequisite of elastin degradation, a l t h o u g h the d e g r e e of d a m a g e may be greater if oxidation occurs (Weiss et al., 1986; McGowan & Murray, 1987). Oxidants, connective

from n e u t r o p h i l s or cigarette smoke, also have the capacity to damage tissue components. Research has demonstrated the oxidative f r a g m e n t a -

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tion of many proteins including collagen (Curran et al., 1984; Riley & Kerr, 1985) and elastin (Rao et al., 1987). Furthermore, oxidised proteins can be m o r e susc e p t i b l e to p r o t e o l y t i c b r e a k d o w n (Wolff & Dean, 1986), although there is some debate as to whether this is the case with elastin (Beatty et al., 1984; McGowan & Murray, 1987). A further way oxidants have been linked to emphysema is their possible effects on elastin synthesis. For instance, cigarette smoke can s u p p r e s s the a c t i v i t y of lysyl oxidase both "in vitro" (Laurent et al., 1983) and "in vivo" (Osman et al., 1985), whilst neutrophils can also oxidise lysine r e s i d u e s in e l a s t i n (Clark et al., 1986). The e n z y m e i y s y l o x i d a s e is r e s p o n s i b l e for crosslinking lysine residues on adjacent elastin molecules, essential for the normal formation of mature e l a s t i n . The concept that emphysema could result from effects on synthetic rather than degradative pathways was proposed by one of us p r e v i o u s l y (Laurent, 1986), but has yet to be tested.

6.1.2

Macrophages

A l t h o u g h the n u m b e r s of neutrophils in lavage fluid from smokers are moderately increased, the macrophage remains the predominant cell type and m a y be i n c r e a s e d 20 t i m e s in s m o k e r s r e l a t i v e to n o n s m o k e r s (Plowman, 1982; Niewoehner et al., 1974). Cigarette smoke activates alveolar macrophage metabolism, l e a d i n g to inc r e a s e d e x t r a c e l l u l a r r e l e a s e of enzymes (Rodriguez et al., 1977; White et al., 1979) and hydrogen peroxide production (Drath et al., 1979; Hoidal et al., 1981). It has b e e n k n o w n for some time that macrophages from smokers contain intracellular deposits of smoke-derived material (Brody & Craighead, 1975; P r a t t et al., 1971), s u g g e s t i n g that these cells attempt to remove smoke-related particulates. The c a p a c i t y of a l v e o l a r m a c r o p h a g e s to s y n t h e s i z e and r e l e a s e neutrophil chemotactic factors was discussed above. The p o s s i b i l i t y that macrophages produce their own metalloelastase was discussed in Section 5.2. In addition, these c e l l s c o n t a i n c a t h e p s i n s B and D, b o t h of w h i c h are i n c r e a s e d in a l v e o l a r m a c r o p h a g e s and l a v a g e f l u i d from c i g a r e t t e smokers (Chang et al., 1986; 1989). Much of the elastase in macrophages appears to be of neutrophil origin, internalized v i a r e c e p t o r s on the macrophage membrane (Campbell et al., 1979; McGowan et al., 1983). This indicates that this cell may play a protective role by scavenging neutrophil elastase. However, sequestered elastase can be subsequently released (Campbell & Wald, 1983; McGowan et al., 1984), s u g g e s t i n g that t h e s e cells can o p e r a t e as a "sink" for elastase, releasing the enzyme slowly onto the lung surface.

6.2 Interstitial Lung Disorders The interstitial lung disorders are a h e t e r o g e n e o u s g r o u p of d i s e a s e s c h a r a c terized by inflammation in alveolar walls and airspaces leading to excess deposition of connective tissue proteins. The initiating agent m a y be known, as w i t h asbestosis and bleomycin-induced lung injury, but in other cases there are unknown causes such as in cryptogenic fibrosing alveolitis (CFA, also known as idiopathic pulmonary fibrosis). Another disorder of unknown cause is sarcoidosis, a systemic disorder in which there is often lung involvement characterized by granuloma formation in the interstitium. The concept t h a t b l o o d - b o r n e i n f l m m a t o r y c e l l s p l a y a c e n t r a l role in the pathogenesis of interstitial lung disorders is widely accepted. It is now c l e a r

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that these disorders are frequently characterized by an "alveolitis", that is, by the accumulation of inflammatory and immune effector cells (Crystal et al., 1984a; 1984b; K e o g h & Crystal, 1982; Snider, 1983; 1986). These changes are assumed to cause the pathological derangements. A corollary to this concept is that the more p r o n o u n c e d the " i n i t i a l " alveolitis, the worse the disease should be. Using an animal model, Shen et al. (1988) have shown that there is i n d e e d a r e l a t i o n s h i p between t h e s e v e r i t y of the initial acute lung injury (various amounts of bleomycin and degree of hyperoxia) and the severity of subsequent chronic inflammation and fibrosis. It should also be pointed out that a role for blood-derived proteins in the p a t h o g e n e s i s of the i n t e r s t i t i a l lung d i s e a s e s has also been proposed (Gray et al., 1990; Harrison & Laurent, 1990; Laurent et al., 1990). The p a t h o l o g i c a l features of CFA and asbestosis are virtually identical, despite the fact that there is a known cause in one case and n o t the o t h e r . The a e t i o l o g i c a l agent in sarcoidosis is likewise unknown and the pathological features (specifically a granulomatous rather than n o n - g r a n u l o m a t o u s inflammation) are different to those of CFA and asbestosis. The pathogenetic mechanisms of sarcoidosis also appear to be different. For this reason, the p r e s e n t section is divided into two sections: i) Cryptogenic fibrosing alveolitis and asbestosis; 2) Sarcoidosis.

6.2.1

Cryptogenic

fibrosin~ alveolitis and asbestosis

Patients with CFA commonly present with cough and dyspnea on exertion, often after a v i r a l - l i k e illness. The chest r a d i o g r a p h f r e q u e n t l y shows reticulonodular shadowing that is most evident at the bases, although a normal chest X-ray may be present. In these cases, early changes can be detected by CT scan (Harrison et al., 1989). The disease is insidious in onset and is often fatal after about 5 years. The radiological, physiological and pathological features are almost identical in CFA and asbestosis, and diagnosis of the latter disorder requires a history of asbestos exposure. In patients with asbestosis, the presence of asbestos fibres (ferruginous bodies) in the lung can often be demonstrated. The initiating stimulus in CFA is not known, although there is some evidence that immune c o m p l e x e s are involved. For instance, d e p o s i t s of in~nunoglobulin and c o m p l e m e n t have been i d e n t i f i e d in the a l v e o l a r walls by i m m u n o f l u o r e s c e n c e (Crystal et al., 1976; Dreisin et al., 1978), although electron microscopy studies have not confirmed this (Corrin et al., 1985). Circulating immune complexes have also been identified in blood and lavage fluid (Dreisin et al., 1978; Hunninghake et al., 1981). Hunninghake et al. (1981) also p r o v i d e d e v i d e n c e that a l v e o l a r m a c r o p h a g e s from p a t i e n t s with CFA had been exposed to immune complexes in that their IgG and Fc receptors demonstrated an increased o c c u p a n c y and there was an i n c r e a s e in i n t r a c y t o p l a s m i c f l u o r e s c e n c e for IgG, s u g g e s t i n g that they had phagocytosed IgG complexes. In contrast with CFA, the fibrogenic compound in a s b e s t o s i s is well u n d e r s t o o d . A s b e s t o s d e s c r i b e s six chemically and physically distinct types of material: the serpentine chrysotile, and the amphiboles c r o c i d o l i t e , amosite, a n t h o p h y l i t e , t r e m o l i t e and actinolite. These crystalline silicate compounds possess different pathogenetic potential that is dependent upon their physical c h a r a c t e r i s t i c s and solubility which determine deposition and clearance in the airways (see Mossman & Gee, 1989 for review). Asbestos fibres can activate the a l t e r n a t i v e p a t h w a y of complement (Brody, 1986) which can then activate leucocytes. B l e o m y c i n is an a n t i b i o t i c u s e f u l in the treatment of several lung tumours and carcinomas. This drug does, however, possess toxic side-effects in the lung which ultimately give rise to fibrosis. For this reason, bleomycin-induced lung injury

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A. Shock and G. J. Laurent

Neutrophil

Macrophage

l

1

• Proteases eg. e o l l a g e n a s e eOxidants

eGrowth factor products and eytokines eg. PDGF, T G F ¢ , I G F - 1

IFIBROSISI

Fig. 5. Outline f o r the r o l e of l e u c o c y t e s in f i b r o t i c lung d i s e a s e . A s t i m u l u s , which can be known (eg. a s b e s t o s , b l e o m y c i n ) o r unknown a c t s p r i m a r i l y on the m a c r o p h a g e to p r o d u c e g r o w t h f a c t o r s and o t h e r c y t o k i n e s which s t i m u l a t e growth, m a t r i x p r o t e i n s y n t h e s i s and c h e m o t a x i s of f i b r o b l a s t s . Activation of n e u t r o p h i l s l e a d s to r e l e a s e of p r o t e a s e s and oxidants which can d a m a g e both c e l l s and m a c r o m o l e c u l e s and p o t e n t i a t e m a c r o p h a g e act ivation. T h e s e e v e n t s lead to e x c e s s i v e deposition of c o n n e c t i v e t i s s u e and lung f i b r o s i s , as indicated in bottom inset.

Leucocytes and Pulmonary Disorders has become a useful model of fibrotic lung disease in experimental fore, the lesion will also be discussed in the following section.

467 animals;

there-

In CFA and asbestosis the alveolar leucocyte infiltrate consists primarily of macrophages but there are also increased numbers of neutrophils and, less commonly, of e o s i n o p h i l s and lymphocytes in the airspaces and/or interstitium. There have been several reviews concerning the pathogenesis of CFA (Crystal et al., 1984a; H a r r i s o n & Laurent, 1990) and a s b e s t o s i s (deShazo, 1982; Mossman & Gee, 1989). The current perceptions concerning the role of leucocytes in these d i s o r d e r s is shown in Figure 5. F i b r o t i c lung d i s e a s e s are associated with considerable damage to cellular components of the lung parenchyma, including endothelial and epithelial cell destruction (Corrin et al., 1985). These disorders are also associated with diffuse int e r s t i t i a l f i b r o s i s and e x c e s s i v e d e p o s i t i o n of c o n n e c t i v e tissue p r o t e i n s , n o t a b l y collagen. In the a d v a n c e d stages there is loss of normal alveolar architecture and replacement with dense bundles of collagen. These issues have been r e v i e w e d p r e v i o u s l y (Laurent, 1985; L a u r e n t et al., 1988; Harrison & Laurent, 1990) and will not be considered in the present discussion. (a)

Macrophages

The a l v e o l a r m a c r o p h a g e is b e l i e v e d to be t h e k e y e f f e c t o r c e l l in the p a t h o g e n e s i s of CFA and a s b e s t o s i s and invariably remains the predominant cell type in the alveolar structures of p a t i e n t s with these d i s o r d e r s , d e s p i t e increases of other leucocytes. A l v e o l a r m a c r o p h a g e s have been known for some time to be capable of synthesizing and r e l e a s i n g f i b r o b l a s t g r o w t h factors and m e d i a t o r s that s t i m u l a t e m a t r i x p r o t e i n synthesis. These include platelet-derived growth factor, transforming growth factor B, fibronectin, fibroblast growth factor, interleukin i, a and 5 interferon, tumor necrosis factor and a protein with properties similar to insulinlike growth factor-l. Some of these proteins were d e s c r i b e d in some detail in Chapter 5 and are discussed with particular reference to fibrosis by Agelli & Wahl (1986) and Goldstein & Fine (1986). Increased quantities of growth-promoting mediators are released from the a l v e o l a r macrophages of patients with CFA (Bitterman et al., 1983; Martinet et al., 1987), and the lavage fluid from such patients possess more fibroblast g r o w t h - p r o m o t i n g activity relative to healthy controls or patients with interstitial lung diseases other than CFA (Cantin et al., 1988). The a l v e o l a r m a c r o p h a g e in the lungs of p a t i e n t s e x p o s e d to asbestos is also hyperactivated and releases increased quantities of fibroblast growth factors (Rom et al., 1987). Other studies have shown that m a c r o p h a g e s from p a t i e n t s with a s b e s t o s i s show e n h a n c e d p r o d u c t i o n of oxidants (Rom et al., 1987), leukotriene B4 (Garcia et al., 1989) and n e u t r o p h i l chemotactic factors (Hayes et al., 1988). Animal models employing bleomycin (Jordana et al., 1988a; Suwabe et al., 1988) and asbestos (Bissonette & Rola-Pleszczynski, 1989) have demonstrated an "in vivo" activation of alveolar macrophages, assessed by the spontaneous release of cytokines such as interleukin i, tumor necrosis factor and B interferon. M a c r o p h a g e s from the lungs of a n i m a l s e x p o s e d to b l e o m y c i n (Kovacs & Kelly, 1985) and asbestos (Lemaire et al., 1986) also secrete growth-promoting mediators. These cells are also i m p l i c a t e d by a study by K h a l i l et al. (1989), who demonstrated increased collagen deposition following bleomycin instillation, a s s o c i a t e d with large increases in lung levels of transforming growth factor B, which was shown to be of macrophage origin.

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Stimulation of macrophages "in vitro" with bleomycin also stimulates production of growth factors ( D e n h o l m & Phan, 1989) w h i l s t t r e a t m e n t with a s b e s t o s causes release of factors that stimulate fibroblast collagen synthesis (Aalto & Heppleston, 1984) and of cytokines such as tumor necrosis factor (DuBois et al., 1989b) and interleukin 1 (Sestini et al., 1986). Asbestos can also d i r e c t l y s t i m u l a t e c o l l a g e n s y n t h e s i s in f i b r o b l a s t cultures (Richards & Jacoby, 1976; Mossman et al., 1986). The release of growth factors and cytokines under these c o n d i t i o n s would a p p e a r to be d e p e n d e n t upon the s t i m u l a t i o n of l e u k o t r i e n e s y n t h e s i s (notably of leukotriene B4) since inhibitors of this pathway p r e v e n t the effects "in vitro" ( D e n h o l m & Phan, 1989; DuBois et al., 1989b) and can partially suppress bleomycin-induced fibrosis "in vivo" (Phan & Kunkel, 1986). Paradoxically, m a c r o p h a g e s from bleomycin-treated animals release more prostaglandin E2 (Clark et al., 1983), which can down-regulate collagen production by fibroblasts. In CFA, there is an increase in collagenase levels in bronchoalveolar lavage fluid (Gadek et al., 1979), although this could be of macrophage, neutrophil, eosinophil or fibroblast origin. Whatever the source, increased levels of collagenase might i n t e r f e r e with n o r m a l collagen homeostasis. There is evidence, however, that a decrease in lung collagenolytic activity o c c u r s in the d e v e l o p m e n t of fibrosis (Selman et al., 1986), possibly due to the increased collagenase inhibitor content in lavage fluid of patients (Montano et al., 1989). Therefore, the increased collagen deposition in CFA may arise partly from suppressed collagen breakdown. Such a mechanism, operating both intracellularly and extracellularly, has been observed by us in bleomycin-induced fibrosis (Laurent & McAnulty, 1983). C h e m o t a c t i c factors for both n e u t r o p h i l s (see C h a p t e r 4) and fibroblasts are p r o d u c e d by m a c r o p h a g e s . I n c l u d e d in the latter c a t e g o r y are f i b r o n e c t i n , complement-derived peptides, platelet-derived growth factor (see review by Grotendorst et al., 1985), and collagen-derived fragments (Postlethwaite et al., 1978). Cantin et al. (1989) have shown that lavage levels of another macrophage product, plasminogen activator, are increased in asbestos-exposed i n d i v i d u a l s with early lung disease, r e l a t i v e to subjects with a d v a n c e d or no lung disease. These authors suggest that activation of plasmin, which can d e g r a d e p r o t e i n s such as fibrin and elastin (Chapman et al., 1984) and fibronectin and laminin, may be be a part of the initial asbestos-induced lesion. Patients with CFA possess a unique profile of macrophage subsets (Noble et al., 1989). The idea that macrophages exhibit heterogeneity in their morphology is now w i d e l y accepted, but only when the d i s t i n c t f u n c t i o n s of t h e s e d i f f e r e n t p h e n o t y p e s are known will we understand what implications they have for diseases such as CFA and asbestosis. (b)

Neutrophils

Analysis of cells recovered from the lungs of CFA p a t i e n t s by b r o n c h o a l v e o l a r lavage or by b i o p s y demonstrate that, on average, 10% to 20% of this population are neutrophils (Hunninghake et al., 1978; Reynolds et al., 1977). There is also c o n c l u s i v e e v i d e n c e that increased numbers of neutrophils are present in lavage fluid of patients with asbestosis, where numbers correlate with d u r a t i o n of exposure, and in asbestos-exposed individuals without clinical disease (Delclos et al., 1989; Garcia et al., 1989; R o b i n s o n et al., 1986; X a u b e r t et al., 1986). N e u t r o p h i l s are probably attracted into the lung by the action of a specific alveolar macrophage-derived chemotactic factor (see Chapter 4), possibly released in response to immune complexes (Hunninghake et al. 1981) or asbestos particles. As discussed in Section 2.2.1, neutrophils possess the capacity to produce an array of toxic proteases and oxidants, and these may be of relevance to the destructive effects on endothelial and epithelial cells observed in the lung parenchyma

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of patients with CFA and asbestosis. The proteolytic enzymes of n e u t r o p h i l s include collagenolytic and elastolytic proteases that can degrade most components of the extracellular matrix, but their precise role in lung f i b r o t i c d i s o r d e r s has yet to be clarified. Several groups have investigated the role of neutrophils in the animal model of bleomycin-induced lung fibrosis. Firstly, a series of e x p e r i m e n t s d e m o n s t r a t e d that the a d m i n i s t r a t i o n of an anti-neutrophil serum with bleomycin resulted in a higher rate of collagen synthesis and an increase in lung collagen c o n t e n t relative to a n i m a l s e x p o s e d to b l e o m y c i n alone (Clark & Kuhn, 1982; Thrall et al., 1981). A second series of e x p e r i m e n t s e m p l o y e d b e i g e m i c e , animals with n e u t r o p h i l s p o s s e s s i n g a d e f e c t in enzyme release and which cannot degranulate their contents. Bleomycin exposure in these mice resulted in higher rates of collagen s y n t h e s i s and i n c r e a s e d lung c o l l a g e n contents relative to control mice (Phan et al., 1983). These studies indicate that, in normal animals, neutrophils may "protect" against the d e v e l o p m e n t of lung fibrosis, either by increasing collagen breakdown or by down-regulating the activity of fibrogenic factors. F u r t h e r m o r e , O s a n a i et al. (1988) have shown that cigarette smoke, which caused a sustained increase in numbers of neutrophils in the lung, can partially prevent bleomycin-induced fibrotic changes a s s e s s e d morphologically. These authors conclude that by keeping levels of n e u t r o p h i l s high, c i g a r e t t e smoke can a m e l i o r a t e the f i b r o t i c effect of bleomycin. This data should be interpreted with care and the changes cannot be considered advantageous since cigarette smoke can m o d i f y b l e o m y c i n - i n d u c e d lung injury to p r o d u c e e m p h y s e m a (Takada et al., 1987). These studies may have very important implications for the regulation of connective tissue metabolism in many d i s e a s e s and are analogous to the situation with cadmium chloride, which induces lung fibrosis when instilled alone, but emphysema if S aminoproprionitrile (which inhibits c r o s s l i n k i n g r e a c t i o n s in c o l l a g e n and elastin) is also i n t r o d u c e d (Niewoehner & Hoidal, 1982). Despite these considerations, human studies suggest that a high neutrophil alveolitis is linked to increased severity of fibrotic disease (Haslam et al., 1980; Keogh et al., 1981). There is some evidence for the involvement of o x i d a n t s in lung fibrosis, since these species can damage a wide range of cells and proteins (see Section 5.1). It has been shown that neutrophils isolated from the lavage fluid of CFA p a t i e n t s spontaneously release increased quantities of oxidants and are cytotoxic toward an epithelial cell line (Cantin et al., 1987). This study also showed that levels of the n e u t r o p h i l product myeloperoxidase at the lung surface are also increased in CFA, and this may therefore represent the most important system for cytotoxic effects in this disease. There is c o n s i d e r a b l e e v i d e n c e that free r a d i c a l species are involved in "in vitro" and animal models of fibrosis. B l e o m y c i n is c o n v e r t e d into an active species after complexing with iron and oxygen (see Hay et al., 1987 for review). The conversion can be mediated by activated neutrophils "in vitro" (Trush, 1984). It is a p p a r e n t that the availability of iron may be a rate-limiting step in this mechanism. Indeed, animals that are rendered iron-deficient do not show any increase in c o l l a g e n c o n t e n t in contrast to that observed in iron-replete animals (Chandler et al., 1988). Further, we have shown that administration of iron can e n h a n c e bleomycin-induced lung damage, assessed as lung permeability changes (Hay et al., 1987). Moreover, several attempts have been m a d e to p r e v e n t b l e o m y c i n induced c h a n g e s in collagen metabolism by using potential antioxidants or agents that increase the antioxidant defence at the lung surface. Our g r o u p ( S h a h z e i d i et al., 1990) have shown that one such c o m p o u n d , N-acetylcysteine, can reduce bleomycin-induced increases in lung collagen levels. However, this has not been the u n i v e r s a l finding since Giri et al. (1988) have not been able to show such a

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protective

effect with this agent.

The role of free radicals and oxidants in asbestosis has recently been summarized (Mossman & Marsh, 1989). Asbestos fibres are cytotoxic towards epithelial cells, fibroblasts and endothelial cells via free radicals mechanisms, possibly i n v o l v i n g lipid p e r o x i d a t i o n ( W e i t z m a n & W e i t b u r g , 1985). A s b e s t o s can also stimulate chemiluminescence (Doll et al., 1982) and enzyme release (Elferink et al., 1989) by n e u t r o p h i l s . In a n o t h e r "in vitro" system, Kamp et al. (1989b) showed that e p i t h e l i a l cell d a m a g e i n d u c e d by a s b e s t o s r e q u i r e d close association of neutrophils w i t h both target cells and a s b e s t o s and o c c u r e d by a h y d r o g e n peroxide-dependent mechanism. Finally, it is well known that asbestosis is more p r e v a l e n t in a s b e s t o s workers who also smoke c i g a r e t t e s , and explant studies have shown that smoke can potentiate asbestos p a r t i c l e uptake, an effect m e d i a t e d by free r a d i c a l s p r o b a b l y present in cigarette smoke (Churg et al., 1989). (c)

Lymphocytes

H y p o t h e s e s regarding the involvement of iymphocytes in CFA are based on the supposition that immunoglobulin-containing immune complexes represent the trigger in the d i s e a s e process. Although the proportion of both T and B lymphocytes in the lung, relative to other leucocytes, are the same as those in control subjects, the total n u m b e r s may be higher, suggesting that local production of immunoglobulins may be higher. Additionally, the i n t e r s t i t i u m is f r e q u e n t l y p a c k e d with lymphocytes. If there is an i n i t i a t i n g antigen, its identity has not been established, although a component of the extracellular matrix has been p r o p o s e d (for review see Crystal et al., 1984a). A number of studies using the bleomycin model suggest an important role for lymphocytes in this disease. Karpel et al. (1989) showed that lymphocytes from the lavage fluid of b l e o m y c i n - e x p o s e d animals had a four-fold greater proliferative response to interleukin 2 and demonstrated enhanced c y t o t o x i c functions, whilst S c h r i e r et al. (1983) showed that nude mice, that are deplete of T lymphocytes, demonstrate a reduced fibrotic response to bleomycin, a s s e s s e d by c o l l a g e n synthesis rates and deposition. Furthermore, Piguet et al. (1989) have shown that the bleomycin lesion is associated with large increases in tumor n e c r o s i s factor (a growth stimulator) levels in the lung; this increase, and the fibrotic lesion, could be prevented by lymphocyte depletion. Lymphocytes are known to release factors that s t i m u l a t e g r o w t h and collagen production by fibroblasts (Wahl et al., 1978; and see Section 2.2.6) and fibroblast chemotactic factors (Postlethwaite et al., 1976). Several i m m u n o l o g i c a l a b n o r m a l i t i e s a p p e a r to exist in the lungs of asbestosexposed individuals, including decreased cell-mediated i m m u n i t y and h y p e r a c t i v e h u m o r a l r e s p o n s e s (Hartman, 1985; d e S h a z o et al., 1986). An increase in the CD4+:CD8+ ratio of lymphocyte subsets has also been observed in patients with asb e s t o s i s (Costabel et al., 1987) or in asbestos-exposed subjects without disease (Delclos et al., 1989; Wallace et al., 1989), although Gellert et al. (1985) have demonstrated a decrease in this ratio. Thus, i y m p h o c y t e s a p p e a r to m o d u l a t e the fibrotic response in experimentallyinduced fibrosis and have the potential to release fibrogenic factors. Nevertheless, i n c r e a s e d numbers of lavage fluid lymphocytes may predict whether patients will respond successfully to steroid treatment (Haslam et al., 1980).

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Eosino~hils

There is evidence for increased numbers of eosinophils i n t h e l u n g s o f some p a t i e n t s with CFA (Davis et al., 1984; Pantin et al., 1988) and a s b e s t o s i s (Robinson et al., 1986; Garcia et al., 1989). There is also evidence for the inv o l v e m e n t of e o s i n o p h i l s in the p a t h o g e n e s i s of lung fibrosis. These cells produce a collagenase (Section 5.3) and s e v e r a l other p r o t e i n s that can d a m a g e e p i t h e l i a l i n t e g r i t y (Section 5.4). Hallgren et al. (1989) have recently highlighted elevations of both eosinophils and eosinophil cationic p r o t e i n in lavage fluid of CFA patients, relative to control subjects, and found a relationship between measures of eosinophil activation and impaired lung function. Several reports, from our laboratory and others, have shown that e o s i n o p h i l s can promote fibroblast growth (Pincus et al., 1987; Shock et al., 1990). Our own work demonstrated that the growth factor is r e l e a s e d in a c o n s t i t u t i v e m a n n e r after relatively short-term culture of eosinophils "in vitro".

6.2.2

Sarcoidosis

Sarcoidosis is a multisystem disease of unknown aetiology associated with the formation of noncaseating granulomas in several organs. The present discussion concentrates on the lung where the lesion has been most studied and because morbidity in sarcoidosis is most often linked to pulmonary manifestations. The aetiology of pulmonary sarcoidosis is not known although a v a r i e t y of p o t e n tial stimuli includings drugs, chemicals, and infectious organisms have been implicated (reviewed by T h o m a s & H u n n i n g h a k e , 1987). Of some i n t e r e s t in this respect is the disease berylliosis which shares several features with sarcoidosis. In this disorder, beryllium binds to cells and cell p r o t e i n s , alters their imm u n o g e n i c p r o p e r t i e s , and p r o v o k e s an immune response. The causative agent in sarcoidosis may behave in a similar fashion. Although the aetiologic agent responsible for sarcoidosis is unknown, it is accepted that some stimulus or antigen induces a granulomatous reaction. In active sarcoid granulomas the characteristic histological picture is of a tightly packed c e n t r a l follicle of macrophages, epitheloid cells, and multinucleated giant cells bounded by lymphocytes, monocytes and fibroblasts. The presence of a mononuclear cell infiltration (lymphocytes and macrophages) is recognized as an initial event in this disease (reviewed by Thomas & Hunninghake, 1987; Crystal et al., 1984b). For instance, "early" lesions tend to be a s s o c i a t e d with large influxes of mononuclear cells but little evidence of granuloma formation, w h i l s t "late" lesions involve a lower intensity alveolitis and more granulomas. The current view concerning the involvement of leucocytes in sarcoidosis is shown in Figure 6. (a)

Lymphocytes

There is a l a r g e i n c r e a s e in the n u m b e r and proportion of l y m p h o c y t e s ( p a r t i c u l a r l y of T iymphocytes) in bronchoavleolar lavage fluid of patients with sarcoidosis (Crystal et al., 1981; Keogh et al., 1983), and it would a p p e a r that the most important mediators responsible for maintaining the T cell alveolitis are interleukins i and 2. Interleukin 1 is produced p r i m a r i l y by m a c r o p h a g e s w h i c h increases interleukin 2 production and interleukin 2 receptor expression in T iymphocytes. In addition to their growth-promoting a c t i v i t i e s (see S e c t i o n 5.7.2), both interleukin 1 and interleukin 2 are chemotactic for T cells (see Table 2) and increase the adherence of lymphocytes to endothelial cells (see Chapter 3). Once stimulated, therefore, T iymphocytes have the capacity to further stimulate their own proliferation and activation.

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Unknown stimulus [

I Macrophage (monocyte)

eCytokines eg. ILl eGrowth factors

T-lymphocyte

eCytokines eg. IL2 eMacrophage activators

Fig. 6. Outline f o r the r o l e of l e u c o c y t e s in s a r c o i d o s i s . A s t i m u l u s a c t i v a t e s T l y m p h o c y t e s and m a c r o p h a g e s to r e l e a s e c y t o k i n e s which g e n e r a t e a s e l f - p e r p e t u a t i n g influx of both cell t y p e s . M a c r o p h a g e s a l s o s e c r e t e g r o w t h - p r o m o t i n g s u b s t a n c e s f o r m e s e n c h y m a l c e l l s . The p a r t i c u l a r f e a t u r e of this d i s e a s e is a g r a n u l o m a c o m p o s e d of d e n s e l y p a c k e d epitheloid and a c t i v a t e d m o n o n u c l e a r l e u c o c y t e s , as indicated in bottom i n s e t .

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An increased CD4+: CD8+ T lymphocyte ratio has been o b s e r v e d (Ainslie et al., 1989; Hunninghake & Crystal, 1981; Ginns et al., 1982; Ward et al., 1989), a ratio which has been used as a marker for pulmonary sarcoidosis relative to o t h e r diseases. Moreover, inactive or stable disease is accompanied by a decrease in this ratio (Hunninghake & Crystal, 1981), indicating that depressed immune activity is a s s o c i a t e d with less severe lesions. Bronchoalveolar lavage studies have also shown that T lymphocytes from patients with sarcoidosis are f u n c t i o n a l l y active. For instance, they p r o l i f e r a t e at a faster rate and spontaneously release lymp h o k i n e s such as m a c r o p h a g e migration inhibitory factor, interleukin 2 ( H u n n i n g h a k e et al., 1983; P i n k s t o n et al., 1983), monocyte chemotactic factor (Hunninghake & Crystal, 1981; Rossi et al., 1986) and gamma-interferon (Moseley et al., 1986; Robinson et al., 1985). Amongst other effects, these products help to attract, immobilize and activate alveolar macrophages. A central role for activated, interleukin-2-producing ceils has, t h e r e f o r e , been implicated in sarcoidosis. Since production of this lymphokine is also associated with increased expression of interleukin 2 receptors, one might expect an increase in lavage cells p o s s e s s i n g such r e c e p t o r s , although positive (Ainslie et al., 1989; Hancock et al., 1987; Semenzato et al., 1984) and negative (Muller-Quernheim et al., 1986; S a l t i n i et al., 1986) results have been obtained with respect to this issue. T lymphocyte activation w o u l d a p p e a r to be c o m p a r t m e n t a l i z e d at specific d i s e a s e sites w h i c h cannot be e f f e c t i v e l y sampled by bronchoalveolar lavage (Muller-Quernheim et al., 1989). Nevertheless, T cells in the bloodstream of s a r c o i d p a t i e n t s possess increased interleukin 2 receptor levels and have the potential to proliferate at an e x a g g e r a t e d rate r e l a t i v e to n o r m a l T cells in r e s p o n s e to i n t e r l e u k i n 2 (Konishi et al., 1988). They may, therefore, have a "proliferative advantage" when localized at the disease site. Abnormal regulation of T lymphocytes may also e x p l a i n the i n c r e a s e d B cell activity o b s e r v e d in s a r c o i d o s i s p a t i e n t s . In fact, Gerli et al. (1989) have recently shown that the majority of T lymphocytes present in the lavage fluid from s a r c o i d o s i s p a t i e n t s are CD4+ cells of the type that induce maximal B cell immunoglobulin secretion. This would explain why there are relatively high numbers of B lymphocytes and plasma cells at sarcoid granuloma sites. Gerli et al. (1989) certainly found evidence for increased levels of i m m u n o g l o b u l i n in lavage fluid from sarcoidosis patients. The usefulness of lymphocyte counts in the diagnosis and prediction of outcome of sarcoidosis has not always been viewed favourably (Turner-Warwick et al., 1986). Nevertheless, high levels of lymphocytes in bronchalveolar lavage have been associated with poor prognosis in sarcoidosis (Buchalter et al., 1985; I s r a e l - B i e t et al., 1985; Keogh et al., 1983), and a decrease in lymphocytes can be correlated with clinical improvement (Carreiro et al., 1984). Additionally, part of the beneficial action of corticosteroids (the usual treatment for sarcoidosis) may be due to the capacity of these compounds to suppress T lymphocyte proliferation and production of interleukin 2 (Pinkston et al., 1987), and therefore to reduce the T cell alveolitis (Ceuppens et al., 1984; Rossi et al., 1985). (b)

Macrophages

The increased numbers of macrophages at the lung surface of s a r c o i d o s i s p a t i e n t s is b e l i e v e d to be due to the expression of T lymphocyte-derived chemotactic factors ( H u n n i n g h a k e et al., 1980b) w h i c h a t t r a c t m o n o c y t e s into the lung, and several recent papers (Agostini et al., 1989; Barth et al., 1988) have shown that the increased numbers of macrophages in the lungs of s a r c o i d o s i s p a t i e n t s is d e r i v e d p r i m a r i l y from an increased influx of blood monocytes. However, there is evidence that the alveolar macrophage population in this d i s o r d e r has a g r e a t e r self-proliferative c a p a c i t y compared with normal macrophages (Bitterman et al.,

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1984). Several studies suggest that alveolar macrophages from the l a v a g e f l u i d of sarc o i d o s i s p a t i e n t s are a l s o " a c t i v a t e d " . For example, such cells release more oxidants, a capacity that increases with the intensity of a l v e o l i t i s ( C a s s a t e l l a et al., 1989), a n d show e n h a n c e d m i c r o b i c i d a l a c t i v i t y . Therefore, there is evidence that alveolar macrophages from sarcoid patients are "primed" for enhanced production of inflammatory mediators. Cassatella et al. (1989) suggest that gamma interferon, a product of activated T lymphocytes, may be the priming agent. Alveolar macrophages have also been shown to spontaneously r e l e a s e i n t e r l e u k i n 1 ( H u n n i n g h a k e , 1984), and to show increased interleukin i production, relative to macrophages from control subjects, when stimulated (Yamaguchi et al., 1988). In this latter study, production of interleukin 1 was correlated to the intensity of lymphocyte alveolitis. S i m i l a r l y , s t i m u l a t e d m a c r o p h a g e s f r o m the l a v a g e of patients with "active" disease release more tumor necrosis factor than normal subjects or patients with "inactive" disease (Spatafora et al., 1989). Further, there is evidence for an altered pattern of macrophage phenotypes in the lungs of s a r c o i d o s i s patients (Ainslie et al., 1989; Hance et al., 1985; Spiteri et al., 1988), possibly of macrophages with particular capacity to activate T lymphocytes. S p e c i f i c a l l y , Spurzem et al. (1989) have suggested that the dominant CD4+ T cell a l v e o l i t i s m a y be a f e a t u r e of the i n c r e a s e d a n t i g e n - p r e s e n t i n g c a p a c i t y of s a r c o i d a l v e o l a r macrophages since these cells demonstrate enhanced expression of HLA class II molecules. Overall, these o b s e r v a t i o n s s u g g e s t that the activity of the alveolar macrophage might determine the nature and outcome of the immunological aberrations in sarcoidosis. In addition to their role in immunological dysfunction, m a c r o p h a g e s m a y also be involved in the vascular changes that sometimes occur in this disease. Recently, macrophages from the lungs of sarcoidosis patients were shown to be capable of inducing angiogenesis when introduced intradermally in mice (Meyer et al., 1989a). B e c a u s e m a c r o p h a g e products of the coagulation and fibrinolytic pathways can influence inflammation and tissue repair, it is of considerable interest that, relative to c o n t r o l groups, there is an increased coagulant activity and a decreased fibrinolytic activity in the lavage fluid of sarcoidosis patients (Hasday et al., 1988), indicating that conditions at the lung surface of these patients may favour fibrin deposition. Such an event may induce neutrophil sequestration in the lung (Cooper et al., 1988). A common end-stage event in sarcoidosis is pulmonary fibrosis, which is consistent with the presence of increased numbers of fibroblasts, p r i m a r i l y at the site of granuloma formation. T h e r e is c i r c u m s t a n t i a l evidence that the same cells associated with the alveolitis of sarcoidosis m a y m e d i a t e the f i b r o t i c response. C e l l s r e c o v e r e d by b r o n c h o a l v e o l a r lavage from the lungs of patients with sarcoidosis spontaneously release factors that stimulate fibroblast growth and t h e r e is some e v i d e n c e that this activity is gamma interferon (Moseley et al., 1986). Nevertheless, macrophages release other factors capable of stimulating f i b r o b l a s t growth and collagen synthesis such as interleukin i, platelet-derived growth factor, transforming growth factor B, a peptide with properties s i m i l a r to i n s u l i n like g r o w t h f a c t o r I, and fibronectin (see Section 5.7 and 6.2.1(a)). Furthermore, interleukin 2 stimulates tumor necrosis factor production by alveolar macrop h a g e s w h i c h is a l s o c a p a b l e of a f f e c t i n g f i b r o b l a s t g r o w t h ( S e c t i o n 5.7). Finally, the lavage fluid from patients with sarcoidosis contains factors capable of s t i m u l a t i n g m i g r a t i o n of f i b r o b l a s t s and e n d o t h e l i a l cells (Meyer et al., 1989b).

Leucocytes and Pulmonary Disorders Stimulated macrophages release prostaglandin E2 r e l a t i o n to the p r e s e n t discussion: firstly, and, secondly, prevent granuloma formation, at al., 1983). It is of some importance therefore veolar macrophages from sarcoidosis patients is (Wolter et al., 1983). (c)

475

which has two important effects in it can inhibit collagen production least in animal models (Chensue et that the production of PGE2 by aldecreased relative to normal cells

Neutrophils

A l t h o u g h there are no c o n s i s t e n t increases in neutrophil numbers in the lavage fluid of sarcoidosis patients, there is evidence that the functional a c t i v i t y of these cells is altered. Kelly et al. (1988a) discovered that chemiluminescence (a measure of oxidant-generating capacity) by both n e u t r o p h i l s and a l v e o l a r macrop h a g e s was g r e a t e r in sarcoidosis patients than in control groups, although the effect was only significant in later aspirates of a s e q u e n t i a l lavage p r o t o c o l . This s u g g e s t s that the oxidative capacity of these cells at the periphery of the lung is greater. There is also evidence for increased elastin-degrading activity in cells from the lavage fluid of sarcoidosis patients, particularly in patients with a d v a n c e d disease, and this may t h e r e f o r e reflect the e x t e n t of tissue destruction (Mordelet-Dambrine et al., 1988). Although the source of the elastase is not known, the i n h i b i t o r p r o f i l e was c o n s i s t e n t with an e n z y m e with the properties of neutrophil elastase.

6.3 Asthma There is no universally accepted definition for asthma, but it is agreed it is a disease involving airway n a r r o w i n g ( b r o n c h o c o n s t r i c t i o n ) and b r o n c h i a l hyperresponsiveness in response to stimuli that have little or no effect in normal subjects (Woolcock, 1988). The term h y p e r r e s p o n s i v e n e s s refers to an i n c r e a s e d p r o p e n s i t y of the a i r w a y s to constrict in response to stimuli such as exercise, cold air, methacholine, leukotrienes and histamine (Boushey et al., 1980). Allergic bronchial asthma (also known as atopic asthma), associated with the production of IgE, is also often linked with hyperresponsiveness to specific i n h a l e d allergens in addition to nonspecific stimuli. A n u m b e r of histopathological/structural features are commonly observed in asthma, including epithelial damage and desquamation, the presence of lumenal mucous plugs d u e to m u c o u s hypersecretion, mucosal oedema, smooth muscle cell hypertrophy/hyperplasia, leucocyte infiltration, and s u b e p i t h e l i a l f i b r o s i s associated with excessive deposition of collagen. The role of inflammation in asthma has been widely studied and reviewed (Barnes & Costello, 1987; Chung, 1986; Hargreave et al., 1986; Holgate, 1988; Nadel, 1984; Kay, 1988) and the concept that leucocytes play a central role in the pathogenesis of this disease will be explored in this chapter. Given that airway hyperresponsiveness is such an important characteristic of asthma, the relationship between this feature and airway inflammation will be particularly addressed. The current view concerning the involvement of leucocytes in asthma is shown in Figure 7.

6.3.1

Eosinophils

The a s s o c i a t i o n of e o s i n o p h i l s w i t h asthma, such eosinophilia with disease severity (Honsinger et al., has long been recognized. Increased

numbers

of eosinophils

have been detected

as a c o r r e l a t i o n of b l o o d 1972; Burrows et al., 1980)

in lavage fluid from patients

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Antigen Other stimulus I

~ Eosinophil +

~ Mast cell

Macrophage @

Neutrophil

,'Hist~ine,[: [Auo~tF]riene~s ~ •

IBronchialhyperreaetivityI

SEF

Fig. 7. Outline for the role of l e u c o c y t e s in a s t h m a . In r e s p o n s e to antigen o r o t h e r stimulus, the i m m e d i a t e a s t h m a t i c r e s p o n s e is b r o n c h o c o n s t r i c tion in r e s p o n s e to m a s t cell h i s t a m i n e . P l a t e l e t - a c t i v a t i n g f a c t o r (PAF) and the leukotrienes, r e l e a s e d f r o m s e v e r a l l e u c o c y t e s , also induce b r o n c h o c o n s t r i c t i o n . The late a s t h m a t i c r e s p o n s e is a s s o c i a t e d with a c t ivation of l e u c o c y t e s and r e l e a s e of m e d i a t o r s that induce m i c r o v a s c u l a r leakage, m u c u s h y p e r s e c r e t i o n leading to the p r e s e n c e of m u c u s plugs, epithelial damage, s m o o t h m u s c l e h y p e r p l a s i a and subepithelial collagen deposition, as depicted in the bottom inset. T h e s e changes c a u s e bronchial h y p e r r e s p o n s i v e n e s s and u l t i m a t e l y lead to a s t h m a . DE = d a m a g e d epithelium; MP = m u c u s plug; S E F = subepithelial f i b r o s i s .

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with allergic asthma (Seltzer et al., 1986; Metzger et al., 1985; 1986) and during a l l e r g e n - i n d u c e d late asthmatic reactions (Bruijnzeel et al., 1986; deMonchy et al., 1985; Diaz et al., 1989; Lam et al., 1987). Moreover, these increases can be correlated with airway hyperresponsiveness (Ferguson & Wong, 1989; Kelly et al., 1988b; Wardlaw et al., 1988). Elevations in b r o n c h o a l v e o l a r lavage levels of eosinophil products (major basic protein and eosinophil protein X) have also been detected during allergen-induced reactions (Diaz et al., 1989) and once again these can be correlated with airway responsiveness (Wardlaw et al., 1988). The cationic proteins of eosinophils have all been shown to have cytotoxic effects on lung epithelial cells (see Section 5.4), and may, therefore, contribute to the epithelial shedding and damage observed in asthma. In support of this view, there is evidence for eosinophil basic protein deposition in areas of epithelial damage in the airways of asthmatics (Filley et al., 1982). Moreover, ultrastructural analysis of lavage eosinophils of late asthmatics indicate that these cells have undergone partial degranulation, notably of major basic protein (Metzger et al., 1986; 1987). This protein potentiates smooth muscle reactivity to agents such as histamine (Flavahan et al., 1988). This may be a feature of the capacity of major basic protein to stimulate basophil secretion of histamine (Thomas et al., 1989). There is also evidence for increased serum levels of eosinophil cationic protein and eosinophil protein X in allergen-induced asthma which may be related to the chronicity of the late-phase reaction. A further eosinophil product that may be involved in asthma is platelet-activating factor which has the capacity to induce a prolonged increase in bronchial hyperreactivity in humans (Barnes et al., 1989; Cuss et al., 1986). This factor also has bronchoconstrictor activities, both in asthmatic patients and in normal subjects (Chung & Barnes, 1989; Rubin et al., 1987). Additionally, PAF antagonists can suppress allergen-induced bronchoconstriction in guinea pigs (Darius et al., 1986). Platelet activating factor is a relatively selective chemoattractant for eosinophils "in vitro" (Wardlaw et al., 1986), and can induce eosinophil recruitment into the lungs of animals "in vivo" (Lellouch-Tubiana et al., 1988), which would serve to perpetuate the inflammation. As pointed out in Section 5.5, p l a t e l e t - a c t i v a t i n g factor activates oxidant and basic protein release from eosinophils and the eosinophils from asthmatic subjects would appear to be more responsive in these respects (Chanez et al., 1988). Other effects of plateletactivating factor on airways that may be of relevance to asthma are induction of m i c r o v a s c u l a r leakage, increased airway secretion, and depressed mucociliary transport (see Barnes et al., 1989). In spite of these suggestions no study has yet correlated platelet-activating factor in asthmatic airways with the severity of asthma, largely because it is rapidly metabolized in the lung. Finally, eosinophils produce a number of arachidonic acid metabolites possessing a broad range of activities potentially relevant to the pathogenesis of asthma such as mucus hypersecretion and bronchconstriction. LTC4 and LTD4 are p a r t i c u l a r l y important since they produce a slow, sustained bronchoconstriction. Pichurko et al. (1989) have compared the bronchoconstrictor activity of histamine and LTC4 and found that whilst histamine was effective in the peripheral airways only, LTC4 was capable of inducing constriction in both peripheral and central airways, indicating more extensive airway narrowing in response to this leukotriene. This supports other work that leukotrienes induce a widespread b r o n c h o c o n s t r i c t i o n response (Barnes et al., 1984). More recently, it has been confirmed that there is increased airway deposition of collagen beneath epithelial basement membranes in patients with asthma (Roche et al., 1989), which accompanies changes in airway inflammation (Beasley et al., 1989). This work indicated that interstitial cells were overproducing connective tissue components. Work from our laboratory (Shock et al., 1990) and from others

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(Pincus et al., 1987) has shown that e o s i n o p h i l s p r o d u c e factors capable of s t i m u l a t i n g f i b r o b l a s t proliferation. Another mediator relevant to asthma, histamine, can also enhance fibroblast growth (Jordana et al., 1988b).

6.3.2

Neutrophils

I n c r e a s e d n u m b e r s of n e u t r o p h i l s have been d e t e c t e d in the lavage fluid of a s t h m a t i c s both b e f o r e ( d e M o n c h y et al., 1985) and after (Diaz et al., 1989; Metzger et al., 1986; de Monchy et al., 1985; Fick et al., 1987) a l l e r g e n challenge, and f o l l o w i n g exposure to methacholine (Kelly et al., 1988b). Moreover, neutrophils increase in lavage fluid of h e a l t h y s u b j e c t s f o l l o w i n g e x p o s u r e to ozone (Seltzer et al., 1986) or toluene diisocyanates (Fabbri et al., 1987), two procedures known to induce airway hyperresponsiveness. A neutrophil-rich inflammation has also been associated with hyperresponsiveness in several animal models, including those occuring with ozone (Holtzman et al., 1983), a n t i g e n (Chung et al., 1985), platelet activating factor (Chung et al., 1986), LTB4 (O'Byrne et al., 1985) and endotoxin (Pauwels, 1989). In ozone-induced h y p e r r e s p o n s i v e n e s s , the influx of n e u t r o p h i l s and the hyperresponsiveness were directly related since it could be abrogated by prior neutrophil depletion. However, other e v i d e n c e suggests that n e u t r o p h i l s enter airways after hyperresponsiveness to ozone develops (Murlas & Roum, 1985). There are increased levels of a neutrophil chemotactic factor in the c i r c u l a t i o n of p a t i e n t s with a l l e r g e n - or exercise-induced asthmatic reactions (Lee et al., 1983; Nagy et al., 1982) and b l o o d n e u t r o p h i l s from a s t h m a t i c p a t i e n t s are s l i g h t l y more responsive to the chemotactic properties of platelet-activating factor than control neutrophils (Rabier et al., 1989). There is evidence that other functional properties of n e u t r o p h i l s ( r e c e p t o r expression, cytotoxicity) are i n c r e a s e d during the late-phase asthmatic response (Moqbel et al., 1986; Carroll et al., 1985; Durham et al., 1984; P a p a g e o r g i o u et al., 1983). Further, the c a p a c i t y of lavage n e u t r o p h i l s from a s t h m a t i c s to produce oxidants (assessed by c h e m i l u m i n e s c e n c e ) is g r e a t e r after n o n s p e c i f i c b r o n c h i a l c h a l l e n g e (Kelly et al., 1988b). Although there is no direct evidence that oxygen free radicals are involved in asthma (see Barnes et al., 1988), such species can profoundly influence vascular permeability and other airway functions. Ascorbate acts as a potent antioxidant, although this is not the only property of this compound, and can d e c r e a s e n o n s p e c i f i c bronchoconstriction in asthmatics (Mohsenin et al., 1983). Although neutrophil-derived supernatants can induce hyperreactivity in rabbit airways (Irvin et al., 1985), the association of neutrophils with hyperresponsiveness in such models may be temporal and not related in a causal way with the asthmatic condition. To date, no specific neutrophil-derived factor has been directly implicated in asthma although this cell (like the eosinophil) can produce plateleta c t i v a t i n g factor and a r a c h i d o n i c acid m e t a b o l i t e s which might explain their potential to induce bronchial hyperresponsiveness.

6.3.3

Mast cells and basophils

Mast cells are u b i q u i t o u s t h r o u g h o u t the r e s p i r a t o r y tract, u s u a l l y in the e p i t h e l i u m and p a r e n c h y m a but also in the lumen of the airway where thay are recoverable by bronchoalveolar lavage. The number of mast cells is i n c r e a s e d in the lavage fluid of asthmatics (Pearce et al. 1987; Flint et al., 1985a; Kirby et al., 1987), and this correlates with bronchial hyperresponsiveness. The role of the mast cell in asthma has been extensively reviewed (Kaliner, 1989; Friedman &

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1987).

Mast cells and basophils possess high affinity IgE receptors on their surfaces and are therefore likely to play an important role in atopic allergic asthma. Allergen binding via IgE receptors leads to release of granule-associated products and synthesis of new mediators (see Section 2.2.4). Mast cells have been i m p l i c a t e d in the p a t h o l o g y of asthma largely because of their ability to store and release the bronchoconstrictor h i s t a m i n e . Histamine can also cause microvascular leakage and stimulate airway secretion. Infused histamine induces bronchoconstriction in asthmatic subjects, and b r o n c h i a l responsiveness to inhaled histamine is greater in asthmatic subjects than in normal subjects (see Barnes et al., 1988). Allergic asthmatics have a higher lavage fluid c o n c e n t r a t i o n of h i s t a m i n e than controls (Casolaro et al., 1989; Godard et al., 1982; Zehr et al. 1989), levels which correlate with numbers of lavage mast cells and with bronchial hyperreactivity. The mast cell and b a s o p h i l a p p e a r to be more "activated" in asthma compared to that of control cells since they release more h i s t a m i n e u n d e r b a s a l c o n d i t i o n s (Pearce et al., 1987) and when stimulated (Casolaro et al., 1989; Findlay & Lichtenstein, 1980; Lebel et al., 1988). The e n h a n c e d s p o n t a n e o u s r e l e a s e of histamine from mast cells c o r r e l a t e s with bronchial hyperresponsiveness (Flint et al., 1985a; Neijens et al., 1982). The h i s t a m i n e c o n t e n t of lavage mast cells from a l l e r g i c asthmatics is lower than that of controls, suggesting previous "in vivo" activation and degranulation. Mast cells release a host of other mediators when stimulated including a tryptase, w h i c h m a y p r o m o t e b r o n c h o s p a s m by v i r t u e of the fact that it d e g r a d e s the bronchodilator vasointestinal peptide but does not p o s s e s s s i l m i l a r a c t i v i t y on the b r o n c h o c o n s t r i c t o r , s u b s t a n c e P (discussed by Caughey, 1989). Further, in canine airways at l e a s t , mast cell tryptase dramatically potentiates bronchoconstriction towards histamine (Sekizawa et al., 1989). A d e n o s i n e is a f u r t h e r p r o d u c t of mast cells which possesses bronchoconstrictor activity, and this is observed in asthmatic but not in normal subjects (Cushley et al., 1983). The m e c h a n i s m is not u n d e r s t o o d a l t h o u g h it m a y be an i n d i r e c t mechanism since adenosine can stimulate histamine release from mast cells. In summary, the prominent position of mast cells throughout the respiratory tract, t o g e t h e r with its p o s s e s s i o n of high affinity IgE receptors and its ability to release bronchoconstrictors when challenged indicate a primary role for the mast cell in asthma. C u r r e n t e v i d e n c e insists that the major role of mast cells in asthma is in the initial bronchoconstrictor response rather than during late-phase reactions. Indeed, drugs such as sodium cromoglycate, nedocromil sodium and salbutamol, common treatments for acute bouts of asthma, are c a p a b l e of i n h i b i t i n g both mediator release from mast cells and allergen-induced responses in the airway and circulation (Flint et al., 1985b; Howarth et al., 1985; Leung et al., 1988)

6.3.4

Lymphocytes

Lymphocytes are thought to p l a y a c e n t r a l role in the p a t h o g e n e s i s of atopic asthma. The enhanced production of IgE by lymphocytes will not be discussed here (see Ford-Hutchison, 1988); rather, we will describe some of the o t h e r m e d i a t o r s produced by lymphocytes. Although only small elevations in lymphocyte numbers occur in the lavage fluid of asthmatics, Kelly et al. (1989) have demonstrated an increase in T lymphocytes in

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a g r o u p of stable asthmatics. There is also evidence for a decreased CD4+:CDS+ lymphocyte ratio in lavage following allergen challenge (Gonzales et al., 1987). T lymphocytes are known to release a factor that stimulates histamine release from mast cells (Sedgwick et al., 1981). Such responses have been correlated with hyperresponsiveness in asthmatics (Alan et al., 1987). Lymphocyte products such as interleukin I, interleukin 2, chemotactic factors and colony stimulating factors can regulate the f u n c t i o n s of o t h e r l e u c o c y t e s (see Ford-Hutchison, 1988). Parish & Luckhurst (1982) have shown that iymphocytes from asthmatic patients are more "activated" and release such products s p o n t a n e o u s l y . Furthermore, circulating T iymphocytes from patients with acute, severe asthma exhibit signs of activation, such as i n c r e a s e d e x p r e s s i o n of several r e c e p t o r s (VLA-I and interleukin 2 receptor), indices that tended to decrease when patients improved (Corrigan et al., 1988).

6.3.5

Macrophages

The alveolar macrophage remains the dominant cell type in the lungs of a s t h m a t i c patients and this, together with the fact that the macrophage is such an important effector cell, suggests that it may play important roles in asthma. Certainly, i n c r e a s e d n u m b e r s of lavage macrophages can be correlated with bronchial hyperresponsiveness in asthmatic children (Ferguson & Wong, 1989). Macrophages possess IgE receptors with a lower affinity than the receptors on mast cells but s h a r i n g p r o p e r t i e s with those found on eosinophils and T lymphocytes (Capron et al., 1986). Similar receptors have been found on m o n o c y t e s , and the i n c i d e n c e of such r e c e p t o r s on both of these cells is increased in atopic and non-atopic asthmatics (Joseph et al., 1983). S t i m u l a t i o n of m a c r o p h a g e s from a s t h m a t i c p a t i e n t s with anti-IgE or allergen induces the release of granule enzymes (Joseph et al., 1983) and c h e m o t a c t i c factors for eosinophils and n e u t r o p h i l s (Gosset et al., 1984). Furthermore, antigen stimulation of alveolar macrophages from untreated a s t h m a t i c s causes r e l e a s e of g r e a t e r q u a n t i t i e s of p l a t e l e t a c t i v a t i n g factor than m a c r o p h a g e s from theophylline-treated subjects (see Braquet et al., 1987). Finally, Tonnel et al. (1983) d e m o n s t r a t e d i n c r e a s e d quantities of B-glucuronidase in lavage fluid from asthmatic patients after local allergen provocation; such changes could not be detected in lavage fluid from normal subjects following this insult. Macrophages isolated from the lavage fluid of asthmatics following allergen challenge or methacholine exposure show evidence of being activated, such as increased p e r o x i d a t i v e a c t i v i t y (Metzger et al., 1987), increased chemiluminescence (Kelly et al., 1988b), and increased numbers of complement rosettes (Diaz et al., 1989). There is also evidence for "hyperactivated" monocytes in the circulation following allergen or exercise challenge, as evidenced by increased expression of receptors and increased cytotoxicity (Durham et al. 1984; Gin et al., 1985). Lastly, although the idea has yet to be tested, future work may bring to light a role for macrophage-derived fibrogenic factors in the fibrotic changes observed in the airways of asthmatics.

6.3.6

Platelets

A l t h o u g h there has not been a large effort to assess the role of platelets and their products in asthma, platelet depletion in experimental animals is known to p r e v e n t platelet-activating factor-induced bronchoconstriction (Vargaftig et al., 1980) and suppress e o s i n o p h i l i n f i l t r a t i o n i n d u c e d with a n t i g e n or p l a t e l e t activating factor (Lellouch-Tubiana et al., 1988). Since these cells also release

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growth-promoting agents (Section 2.2.5), they may be relevant to the hypertrophic changes observed in bronchial smooth muscle, and to the fibrotic lesion observed in the subepithelial space. Further work is needed to establish what role this cell plays in asthma.

Summary and Perspectives

This review has summarized the structure and function of leucocytes with particular emphasis on the mechanisms by which they enter tissues, the mediators they release when activated, and how they have been implicated in lung pathology. Several processes have evolved to control movement of leucocytes into tissues (adhesion, diapedesis and chemotaxis). Our current understanding of the adherence process is now extensive, and is known to be mediated by several families of glycoproteins, notably the integrins. This family includes the leucocyte int e g r i n s , w h i c h m e d i a t e adhesion of inflammatory cells to endothelium, the cytoadhesins which largely mediate platelet-matrix interactions, and the VLA integrins which mediate adhesion of (largely non-inflammatory) cells to the extracellular matrix. We now know that complementary ligands on "opposing" cells such as endothelial cells (ICAM's/ELAM's) are further capable of modulating the adherence process. Our understanding of the mechanisms controlling chemotaxis and diapedesis is less advanced, although numerous agents capable of initiating these responses are known. Once they enter tissues, the leucocytes produce a wide range of mediators including p r o t e o l y t i c enzymes (eg. elastases, collagenases), growth factors and cytokines (eg. interleukins, platelet-derived growth factor, transforming growth factor S), and activated lipids (eg. leukotrienes, platelet-activating factor). These same mediators can often control activation of leucocytes, thereby producing a complex regulatory feedback system. The involvement of leucocytes in pulmonary disease has largely been studied with respect to the mediators they produce. In this way, neutrophils are thought to play a central role in the pathogenesis of emphysema since they produce potent elastin-degrading proteases and oxidants which can disrupt the protease/antiprotease balance in the lung in favour of degradative pathways. Macrophages also produces such species, but this cell is believed to be more important in maintaining neutrophil influx in this disorder. In contrast, the macrophage is generally believed to play a more central role in interstitial lung disorders such as CFA, asbestosis and sarcoidosis because it produces factors that stimulate the growth of, and connective tissue protein synthesis by, mesenchymal cells. The role of lymphocyte products in initiating and maintaining granuloma formation in sarcoidosis has also been highlighted. Finally, the importance of eosinophil and m a s t cell mediators has been p a r t i c u l a r l y emphasized in the pathogenesis of asthma. These include platelet-activating factor, histamine and proteins which are capable of inducing the cardinal signs of this disease such as bronchoconstriction and epithelial damage that ultimately give rise to bronchial

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It is a p p a r e n t that the d i s e a s e p r o c e s s w i l l d e p e n d not o n l y on the type of l e u c o c y t e w h i c h enters the tissue and the mediators it releases, but also on the mechanisms controlling adherence, chemotaxis and d i a p e d e s i s . N e v e r t h e l e s s , alt h o u g h the p a t h o g e n e s i s of a p a r t i c u l a r disorder is almost certainly dependent upon multiple, interrelated pathways, it must be reasonably well-defined since the e n d - r e s u l t is a s e p a r a t e disease entity. A challenge for the future will be to better understand the mechanisms of leucocyte trafficking, how different e f f e c t o r f u n c t i o n s of l e u c o c y t e s are provoked in different disease states, and how these can be modulated for therapeutic intervention.

Acknowledgements We are indebted to the following people for their help in the preparation of this manuscript: Mr. J.S. Campa, Dr. K.F. Chung, Dr. N.K. Harrison, Dr. R.J. McAnulty, and Dr. D. Rogers. We would also like to thank Miss Valerie Wheeler for excellent secretarial assistance. T h a n k s are f u r t h e r e x t e n d e d to the A r t h r i t i s and Rheumatism Council of Great Britain, the Clinical R e s e a r c h C o m m i t t e e of the National Heart and Chest Hospital and the Medical Research Council of Great Britain who have funded our research over the years.

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