1. Morphology Morphology of the Airway Wall in Asthma and in Chronic Obstructive Pulmonary Disease 1 , 2 PETER K. JEFFERY
Introduction
T he terms asthma and chronic obstructive pulmonary disease (COPD) are imprecise and have defied satisfactory definition by experienced clinicians and researchers. For the purpose of the present symposium the definitions of asthma and COPD have been agreed upon (1). It is widely recognized that both asthma and COPD are not disease entities but rather each is a complex of conditions that have in common airflow limitation (obstruction) (figure 1). In the former, the airflow limitation is usually variable over short periods of time and reversible, albeit an underlying irreversible component may persist. In the latter, the limitation (particularly to expiratory airflow) is usually, but not always, persistent and typically shows a more rapid progressive deterioration with age than normal. Asthma comprises at least extrinsic (atopic or allergic) and intrinsic (nonatopic) divisions, each of which present clinically in a variety of ways: the pathologist distinguishes, however, only one group. COPD encompasses the conditions of (1) chronic bronchitis (i.e.,mucous hypersecretion), (2) adult chronic bronchiolitis (i.e.,small or peripheral airways disease), and (3) emphysema. The first is clinically defined on the basis of long-standing productive cough (at least 3 months of each of 2 consecutive yrs), the second is difficult to define (albeit many tests of small airways function have been developed) and the last is defined in morbid anatomic terms as permanent, destructive enlargement of part or all of the acinus (i.e., air spaces beyond the terminal bronchiolus). Therefore, a comparison of the airway wall in asthma and COPD is by definition made difficult because of the clinical heterogeneity that exists. The following necessarily requires, therefore, a degree of oversimplification.
Sputum Early clues as to the mucosal changes in these conditions have come from studies of sputa and more recently by examination of airway fluids obtained at bronchial or bronchoalveolar lavage (HAL). Corkscrew-shaped twists of condensed mucus (Curshmann's spirals), clumps of surface airway epithelial cells (Creola bodies) (2), and the presence of Charcot-Leyden crystals (composed of eosinophil cell membrane and granular lysophospholipase) together with eosinophils and metachromatic cells are characteristic features of asthmatic sputa that are not usually found in sputa from bronchitic patients (3). Sputa 1152
SUMMARY Asthma and chronic obstructive pulmonary disease (COPO) are complex conditions with imprecise definitions, which make definitive morphologic comparisons difficult. Broadly, the airways in asthma are occluded by tenacious plugs of exudate and mucus, and there is fragility of airway surface epithelium, thickening of the reticular layer beneath the epithelial basal lamina, and bronchial vessel congestion and edema. There is increased inflammatory infiltrate comprising "activated" lymphocytes and eosinophils with release of granular content in the latter, and there is enlargement of bronchial smooth muscle, particularly in medium-sized bronchi. Three conditions contribute to COPO.In ctuonic bronchitis there is mucous hypersecretion with enlargement of tracheobronchial submucosal glands and a disproportionate increase of mucous acini. In small or peripheral airways disease, there is inflammation of bronchioli and mucous metaplasia and hyperplasia, with increased intraluminal mucus, increased wall muscle, fibrosis, and airway stenoses. Respiratory bronchiolitis is a critically important early lesion that may predispose to the development of centrilobular emphysema. The severity of emphysema, rather than type, appears to be the most important determinant of chronic deterioration of airflow, and in this there may be significant loss of elastic recoil prior to the observed morphologic destruction of the acinus. AM REV RESPIR DIS 1991; 143:1152-1158
from the latter may be mucoid or, during infective exacerbations, purulent when neutrophils are present. Compared with healthy subjects, HAL in mild (atopic) asthma demonstrates the presence of sloughed epithelial cells and eosinophils (and their secreted products (e.g., eosinophil cationic protein and major basic protein (4, 5), whereas in smokers (i.e., early bronchitis), macrophages predominate and there is also neutrophil recruitment (6, 7).
Postmortem Changes Postmortem studies of fatal asthma have shown widespread plugging of small bronchi and consequent failure of the lungs to retract on opening the pleural cavities (8-10). The tenacity and widespread nature of the plugging has been emphasized by Dunnill (9) who observed that even a l.5-m head of intrabronchial fixation pressure could not shift the occluding plugs, and fixation of the lungs had to be accomplished by the vascular route. Reid (11) has reported interesting exceptions when, rarely, a patient with asthma may suddenly die and the airways are found to be empty of mucus. Histochemically the airway plugs in asthma are a mixture of inflammatory exudate and mucus in which lie desquamated surface epithelial cells, lymphocytes, and eosinophils often arranged in concentric or spiral patterns in cross section. The arrangement of these elements deep within the plug suggests that the changes have not been the response to a single (fatal) event but rather reflect the chronic nature of the inflammatory process. In chronic bronchitis there also is an excess of mucus in the airways, but this typically lacks the marked eosinophilia and ob-
vious epithelial content seen in asthma. There is little evidence of destructive emphysema in fatal asthma, and right ventricular hypertrophy is uncommon; in contrast, both are common findings in COPD.
Surface Epithelium Histologic shedding and damage of airway surface epithelium is prominent in asthma and is seen both in fatal asthma and in biopsy specimens of patients with mild disease (figure 2). The greater the loss of surface epithelium in biopsy specimens the greater appears to be the degree of airway responsiveness (12), and this reflects the extreme fragility of the lining (8, 12-14). A recent biopsy study comparing the epithelial tight junctions of asthmatic, normal, and bronchitic subjects indicates that epithelial tight junctions may be deranged or damaged in asthma and thereby contribute to its fragility (15). Squamous metaplasia may be seen occasionally in both asthma and COPD, but its character differs (9, 16). The stratified squamous epithelium seen in COLD is likely to be a multifocal response to repeated irritation by tobacco smoke and a forerunner of malignancy, whereas in asthma it is usually simple in type and most probably the expression of a normal process of healing and repair because of epithelial fragility, loss, and continuous replacement as a result of increased mitotic activity. By elec1 From the Department of Lung Pathology, Brompton Hospital, London, United Kingdom. 2 Correspondence and requests for reprints should be addressed to Dr. P. K. Jeffery, Department of Lung Pathology, NHLI, Brompton Hospital, London SW3 6HP, UK.
1153
AIRWAY WALL IN ASTHMA AND COPO
airflow limitation (obstruction)
I I
Limitation:
Condition:
Variable
I
Astbms
«
-
-
(hyperreactivltyl
Airway:
I
Bronchi
-
-
-
-
I
-
I I
Persis,pnl
I
I
Chronic broricbius - - - - - - - - - Chronic bronchiolitis --- - - - EmphysemJ
(mucous hvpersecreuonr
Bronchi
(small airways disease)
(destructive}
Bronchioli (2-3 mm dial
ACinus
less than 2 mm in diameter (see 22). In contrast there may be striking increases in bronchiolar smooth muscle in smokers (see 31and 32) and in some patients with emphysema. As the proportion of the airway wall occupied by muscle normally increases markedly in the small airways (as much as five times comparing airways of 1 and 0.1 em in diameter), the functional consequences of smooth muscle hypertrophy are likely to be greatest in small bronchi and bronchioles.
Potpnti
Introduction
T he terms asthma and chronic obstructive pulmonary disease (COPD) are imprecise and have defied satisfactory definition by experienced clinicians and researchers. For the purpose of the present symposium the definitions of asthma and COPD have been agreed upon (1). It is widely recognized that both asthma and COPD are not disease entities but rather each is a complex of conditions that have in common airflow limitation (obstruction) (figure 1). In the former, the airflow limitation is usually variable over short periods of time and reversible, albeit an underlying irreversible component may persist. In the latter, the limitation (particularly to expiratory airflow) is usually, but not always, persistent and typically shows a more rapid progressive deterioration with age than normal. Asthma comprises at least extrinsic (atopic or allergic) and intrinsic (nonatopic) divisions, each of which present clinically in a variety of ways: the pathologist distinguishes, however, only one group. COPD encompasses the conditions of (1) chronic bronchitis (i.e.,mucous hypersecretion), (2) adult chronic bronchiolitis (i.e.,small or peripheral airways disease), and (3) emphysema. The first is clinically defined on the basis of long-standing productive cough (at least 3 months of each of 2 consecutive yrs), the second is difficult to define (albeit many tests of small airways function have been developed) and the last is defined in morbid anatomic terms as permanent, destructive enlargement of part or all of the acinus (i.e., air spaces beyond the terminal bronchiolus). Therefore, a comparison of the airway wall in asthma and COPD is by definition made difficult because of the clinical heterogeneity that exists. The following necessarily requires, therefore, a degree of oversimplification.
Sputum Early clues as to the mucosal changes in these conditions have come from studies of sputa and more recently by examination of airway fluids obtained at bronchial or bronchoalveolar lavage (HAL). Corkscrew-shaped twists of condensed mucus (Curshmann's spirals), clumps of surface airway epithelial cells (Creola bodies) (2), and the presence of Charcot-Leyden crystals (composed of eosinophil cell membrane and granular lysophospholipase) together with eosinophils and metachromatic cells are characteristic features of asthmatic sputa that are not usually found in sputa from bronchitic patients (3). Sputa 1152
SUMMARY Asthma and chronic obstructive pulmonary disease (COPO) are complex conditions with imprecise definitions, which make definitive morphologic comparisons difficult. Broadly, the airways in asthma are occluded by tenacious plugs of exudate and mucus, and there is fragility of airway surface epithelium, thickening of the reticular layer beneath the epithelial basal lamina, and bronchial vessel congestion and edema. There is increased inflammatory infiltrate comprising "activated" lymphocytes and eosinophils with release of granular content in the latter, and there is enlargement of bronchial smooth muscle, particularly in medium-sized bronchi. Three conditions contribute to COPO.In ctuonic bronchitis there is mucous hypersecretion with enlargement of tracheobronchial submucosal glands and a disproportionate increase of mucous acini. In small or peripheral airways disease, there is inflammation of bronchioli and mucous metaplasia and hyperplasia, with increased intraluminal mucus, increased wall muscle, fibrosis, and airway stenoses. Respiratory bronchiolitis is a critically important early lesion that may predispose to the development of centrilobular emphysema. The severity of emphysema, rather than type, appears to be the most important determinant of chronic deterioration of airflow, and in this there may be significant loss of elastic recoil prior to the observed morphologic destruction of the acinus. AM REV RESPIR DIS 1991; 143:1152-1158
from the latter may be mucoid or, during infective exacerbations, purulent when neutrophils are present. Compared with healthy subjects, HAL in mild (atopic) asthma demonstrates the presence of sloughed epithelial cells and eosinophils (and their secreted products (e.g., eosinophil cationic protein and major basic protein (4, 5), whereas in smokers (i.e., early bronchitis), macrophages predominate and there is also neutrophil recruitment (6, 7).
Postmortem Changes Postmortem studies of fatal asthma have shown widespread plugging of small bronchi and consequent failure of the lungs to retract on opening the pleural cavities (8-10). The tenacity and widespread nature of the plugging has been emphasized by Dunnill (9) who observed that even a l.5-m head of intrabronchial fixation pressure could not shift the occluding plugs, and fixation of the lungs had to be accomplished by the vascular route. Reid (11) has reported interesting exceptions when, rarely, a patient with asthma may suddenly die and the airways are found to be empty of mucus. Histochemically the airway plugs in asthma are a mixture of inflammatory exudate and mucus in which lie desquamated surface epithelial cells, lymphocytes, and eosinophils often arranged in concentric or spiral patterns in cross section. The arrangement of these elements deep within the plug suggests that the changes have not been the response to a single (fatal) event but rather reflect the chronic nature of the inflammatory process. In chronic bronchitis there also is an excess of mucus in the airways, but this typically lacks the marked eosinophilia and ob-
vious epithelial content seen in asthma. There is little evidence of destructive emphysema in fatal asthma, and right ventricular hypertrophy is uncommon; in contrast, both are common findings in COPD.
Surface Epithelium Histologic shedding and damage of airway surface epithelium is prominent in asthma and is seen both in fatal asthma and in biopsy specimens of patients with mild disease (figure 2). The greater the loss of surface epithelium in biopsy specimens the greater appears to be the degree of airway responsiveness (12), and this reflects the extreme fragility of the lining (8, 12-14). A recent biopsy study comparing the epithelial tight junctions of asthmatic, normal, and bronchitic subjects indicates that epithelial tight junctions may be deranged or damaged in asthma and thereby contribute to its fragility (15). Squamous metaplasia may be seen occasionally in both asthma and COPD, but its character differs (9, 16). The stratified squamous epithelium seen in COLD is likely to be a multifocal response to repeated irritation by tobacco smoke and a forerunner of malignancy, whereas in asthma it is usually simple in type and most probably the expression of a normal process of healing and repair because of epithelial fragility, loss, and continuous replacement as a result of increased mitotic activity. By elec1 From the Department of Lung Pathology, Brompton Hospital, London, United Kingdom. 2 Correspondence and requests for reprints should be addressed to Dr. P. K. Jeffery, Department of Lung Pathology, NHLI, Brompton Hospital, London SW3 6HP, UK.
1153
AIRWAY WALL IN ASTHMA AND COPO
airflow limitation (obstruction)
I I
Limitation:
Condition:
Variable
I
Astbms
«
-
-
(hyperreactivltyl
Airway:
I
Bronchi
-
-
-
-
I
-
I I
Persis,pnl
I
I
Chronic broricbius - - - - - - - - - Chronic bronchiolitis --- - - - EmphysemJ
(mucous hvpersecreuonr
Bronchi
(small airways disease)
(destructive}
Bronchioli (2-3 mm dial
ACinus
less than 2 mm in diameter (see 22). In contrast there may be striking increases in bronchiolar smooth muscle in smokers (see 31and 32) and in some patients with emphysema. As the proportion of the airway wall occupied by muscle normally increases markedly in the small airways (as much as five times comparing airways of 1 and 0.1 em in diameter), the functional consequences of smooth muscle hypertrophy are likely to be greatest in small bronchi and bronchioles.
Potpnti
