Pulmonary Pharmacology & Therapeutics xxx (2014) 1e10

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Regulation of pulmonary inflammation by mesenchymal cells Hatem Alkhouri a, Wilfred Jelco Poppinga b, c, d, Navessa Padma Tania b, c, d, Alaina Ammit a, Michael Schuliga e, f, * a

Respiratory Research Group, Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands c Groningen Research Institute of Asthma and COPD (GRIAC), University of Groningen, Groningen, The Netherlands d University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands e Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria, Australia f Lung Health Research Centre, University of Melbourne, Parkville, Victoria, Australia b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 20 December 2013 Received in revised form 1 March 2014 Accepted 10 March 2014

Pulmonary inflammation and tissue remodelling are common elements of chronic respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and pulmonary hypertension (PH). In disease, pulmonary mesenchymal cells not only contribute to tissue remodelling, but also have an important role in pulmonary inflammation. This review will describe the immunomodulatory functions of pulmonary mesenchymal cells, such as airway smooth muscle (ASM) cells and lung fibroblasts, in chronic respiratory disease. An important theme of the review is that pulmonary mesenchymal cells not only respond to inflammatory mediators, but also produce their own mediators, whether pro-inflammatory or pro-resolving, which influence the quantity and quality of the lung immune response. The notion that defective pro-inflammatory or pro-resolving signalling in these cells potentially contributes to disease progression is also discussed. Finally, the concept of specifically targeting pulmonary mesenchymal cell immunomodulatory function to improve therapeutic control of chronic respiratory disease is considered. Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: Cell adhesion molecule (CAM) Chemokine Cytokine Extracellular matrix (ECM) Macrophage Mast cell

1. Introduction Worldwide, more than 250 million people suffer from a debilitating or lethal chronic respiratory disease [1], such as asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) or pulmonary hypertension (PH). Asthma, characterized by airway inflammation, remodelling and hyperreactivity, is one of the most prevalent chronic respiratory diseases, causing w1/4 of a million deaths per year globally [1]. COPD, comprised of irreversible breakdown of lung tissue (emphysema) and airway wall remodelling, contributes to w3 million deaths per year, and is increasing in incidence [1,2]. IPF, albeit less common than asthma or COPD, is a lethal interstitial lung disease

* Corresponding author. Dept. Pharmacology and Therapeutics, Medical Building, University of Melbourne, Grattan St., Parkville, Victoria 3010, Australia. Tel.: þ61 9035 7662; fax: þ61 8344 0241. E-mail address: [email protected] (M. Schuliga).

characterized by a relentlessly progressive and invasive form of lung parenchymal fibrosis [3]. Secondary PH, a comorbidity caused primarily by hypoxia in lung disease, features increased pulmonary vascular resistance [4]. There remains no effective treatment for severe asthma (5e10% of asthmatics), COPD and IPF [5]. The consistent presence of inflammatory cells in the lungs of patients unequivocally establishes pulmonary inflammation as an important component of chronic respiratory disease. The lung inflammatory profiles of patients vary depending on the disease and severity, and change upon exacerbation [6e8]. Airway inflammation in asthma is associated with an increase in mast cells, eosinophils and CD4þ T-helper-2 (Th2) lymphocytes. However, for asthmatics with fixed airway obstruction, the inflammation is more neutrophilic with greater CD8þ T-helper-1 (Th1) cell involvement, akin to COPD, which is also characterized by fixed airway obstruction [7]. Whilst IPF has a predominant Th2 cell profile, the ratio of CD8þ to CD4þ lymphocytes increases with disease severity [8]. Like COPD, neutrophils and macrophages are also present in lung tissue of patients with IPF. In PH, perivascular infiltration of

http://dx.doi.org/10.1016/j.pupt.2014.03.001 1094-5539/Ó 2014 Elsevier Ltd. All rights reserved.

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Fig. 1. Immunomodulatory functions of pulmonary mesenchymal cells. The solid black arrows designate the pro-inflammatory mediators produced directly or indirectly by pulmonary mesenchymal cells which contribute to pulmonary inflammation in disease. The black hatched arrows represent sources of pro-inflammatory mediators which regulate pulmonary mesenchymal cell function, including the production and expression of pro-inflammatory mediators. The types and phenotype of the pulmonary mesenchymal and inflammatory cells vary for disease and disease severity. Abbreviations are defined in the text.

dendritic cells, macrophages, mast cells, T-lymphocytes (CD4þ and CD8þ) and B-lymphocytes occurs [9]. In chronic respiratory disease, infiltrating inflammatory cells produce an array of inflammatory mediators which act by autocrine and paracrine mechanisms to not only regulate inflammatory cell function, but also pulmonary mesenchymal cells in tissue remodelling. In chronic respiratory disease, there is an important relationship between inflammation and tissue remodelling. The latter describes the structural changes in lung tissue which may contribute to respiratory dysfunction. Pulmonary mesenchymal cells are structural cells with a well-recognized role in tissue remodelling processes in disease. In asthma and COPD, airway smooth muscle (ASM) cell hyperplasia and hypertrophy cause ASM enlargement, whereas airway fibroblasts contribute to sub-epithelial fibrosis in the airway wall [10,11]. In IPF, lung fibroblasts1 have an integral role in the progressive fibrosis which begins in the lung interstitium and invades alveoli spaces [12]. In PH, pulmonary vascular smooth muscle cells have a prominent role in the medial enlargement of blood vessels, which in effect reduces lumen size, increasing vascular resistance [13]. Abnormalities of the extracellular matrix (ECM) are a key feature of tissue remodelling in lung disease [14]. Mesenchymal cells, by the synthesis and deposition of collagens I and III and other ECM components (i.e. fibronectin), expand the volume of the ECM in the sub-epithelial layer of the airway wall, within ASM bundles or in the lung interstitium [15]. Aside from important biomechanical contributions in tissue remodelling, pulmonary mesenchymal cells are also potent producers of an array

1 In the literature, the term lung fibroblast, particularly in cell culture studies, has been used interchangeably to describe fibroblasts obtained from either parenchymal tissue or whole lung (including the airways). For this review, the former definition is used in general discussion to distinguish fibroblasts of parenchymal tissue as compared to the airways. However, it is possible that some of the lung fibroblast studies cited in this review may have used fibroblasts obtained from whole lung tissue instead.

of inflammatory mediators, including cytokines, chemokines and cell adhesion molecules (CAMs) [16e19]. These inflammatory mediators, as well as the ECM produced by pulmonary mesenchymal cells, influence the type and quantity of inflammatory cells that infiltrate airway and lung tissue in chronic respiratory disease. Furthermore, the potential importance of inflammatory responses regulated by pulmonary mesenchymal cells in tissue remodelling is becoming increasingly recognized. In this review, the immunomodulatory functions of pulmonary mesenchymal cells and their potential roles in the progression of chronic respiratory disease will be described. 2. Immunomodulatory function of pulmonary mesenchymal cells This section will provide an overview of the types of immunomodulatory functions of pulmonary mesenchymal cells, as summarized in Fig. 1. 2.1. Pro-inflammatory mediators Pulmonary mesenchymal cells coordinate inflammatory responses by producing pro-inflammatory mediators which lead to inflammatory cell recruitment and activation. The production of pro-inflammatory mediators by ASM cells, particularly in the context of asthma, has been extensively studied and the subject of many reviews, including one recent review [20]. Table 1 provides an overview of the broad range of cytokines, chemokines and CAMs, which have been shown to be expressed by pulmonary mesenchymal cells, primarily in in vitro cell culture studies. The ECM produced by these cells also influences inflammatory cell recruitment. Versican and hyaluronan for instance are ECM components produced by lung fibroblasts which regulate T-cell trafficking and functioning in inflamed lung tissue [21,22]. Proinflammatory mediator expression in pulmonary mesenchymal

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H. Alkhouri et al. / Pulmonary Pharmacology & Therapeutics xxx (2014) 1e10 Table 1 Immunomodulatory proteins expressed by airway smooth muscle (ASM) cells and lung fibroblasts. Type

Protein

Pulmonary mesenchymal cell

Cytokines

IL-1 IL-4 IL-6 IL-10 IL-11 IL-13 GM-CSF LIF OX40 ligand CXCL1 (Gro-a) CXCL5 (ENA-78) CXCL6 (GCP-2) CXCL8 (IL-8) CXCL9 (MIG) CXCL10 (IP-10) CXCL11 (ITAC) CXCL12 (SDF-1a) CCL2 (MCP-1) CCL3 (MIP-1a) CCL5 (RANTES) CCL4 (MIP-1b) CCL7 (MCP-3) CCL8 (MCP-2) CCL11 (Eotaxin) CCL16 (MTN-1) CCL17 (TARC) CCL19 (MIP-3) CCL20 (MIP-3a) CX3CL1 (Fractalkine) SCF ICAM-1 VCAM-1 CD40 CD44 CD90 (Thy-1)

ASM [23], lung fibroblasts [19] Lung fibroblasts [24] ASM [25], lung fibroblasts [24] ASM [23] ASM [25] Lung fibroblasts [26] ASM [27], lung fibroblasts [19,28] ASM [29] ASM [30] ASM [31], lung fibroblasts [32] Lung fibroblasts [32] ASM [23] ASM [33], lung fibroblasts [19,26] ASM [34] ASM [35], lung fibroblasts [36] ASM [34] ASM [34], lung fibroblasts [19] ASM [37], lung fibroblasts [19] ASM [38] ASM [39], lung fibroblasts [19,26] ASM [23] ASM [38], lung fibroblasts [40] ASM [37] ASM [41], lung fibroblasts [42] ASM [23] ASM [43] ASM [44] ASM [45] ASM [46] ASM [47] ASM [48], lung fibroblasts [49] ASM [19,48], lung fibroblasts [49] ASM [19,50] ASM [51] Lung fibroblasts [52]

Chemokines

CAMs

Abbreviations: CD, cluster of differentiation; ENA, epithelial-derived neutrophil activating; GM-CSF, granulocyte macrophage-colony stimulating factor; ICAM, intracellular adhesion molecule; IL, interleukin; LIF, leukaemia inhibitory factor; SCF, stem cell factor; VCAM, vascular cell adhesion molecule.

cells is stimulated primarily by cytokines and growth factors produced by inflammatory cells and the epithelium [20]. The regulation of immunomodulatory function of these cells also involves pro-resolving mediators (Section 2.2), the innate immune system (Section 2.3), the plasminogen activation system (Section 2.4) and the coagulation system (Section 2.5). 2.2. Pro-resolving mediators Pulmonary mesenchymal cells may be targets for or produce mediators which have a role in resolving inflammation. Most proresolving mediators with anti-inflammatory activity, including the resolvins, protectins and lipoxins, are derived from dietary omega-3 polyunsaturated fatty acids [53]. Administration of proresolving lipid mediators, including protectin D1, resolvin D1 and resolvin E1, is protective in models of lung injury and disease [54e 57]. Endogenous protectin D1 is increased in the airways in response to allergen challenge, but less so for asthmatics than nonasthmatics [55,58]. Such observations suggest that dys-regulated production of pro-resolving lipid mediators may contribute to chronic respiratory disease [59]. Whilst inflammatory cells are a major source of pro-resolving lipid mediators [55,58,59], pulmonary mesenchymal cells are a target. In cultures of human lung fibroblasts, resolvin D1 inhibits cigarette smoke extract- and IL-1binduced cytokine release [60] and endotoxin-induced COX-2 expression and prostaglandin E2 (PGE2) production [61]. Current

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knowledge about the release of pro-resolving mediators by pulmonary mesenchymal cells is limited, aside from the production of annexin A1, an anti-inflammatory protein [24]. Annexin A1, like resolvin D1, is a ligand for the lipoxin A4 receptor, ALX/FPR2. Annexin A1 expression and release are increased in lung fibroblasts following treatment with glucocorticoids [24]. Furthermore, the silencing of annexin A1 augments TNFa-induced IL-6 release from lung fibroblasts [24], suggesting that annexin A1 production may be an important immunomodulatory function of pulmonary mesenchymal cells. 2.3. Toll like receptors (TLRs) Toll-like receptors (TLRs) activate the innate immune system in response to infection and tissue injury. TLR ligands are: (i) derived from pathogens, including bacterial cell-surface lipopolysaccharides (LPS) and the double stranded RNA of viruses; or (ii) formed endogenously, such as fibrinogen [62] and annexin A2 [63]. The binding of TLR ligands to their receptors leads to the activation of nuclear factor NF-kB and/or interferon regulatory transcription factor 3/7, which stimulates the gene expression of inflammatory mediators. The dys-regulation of TLR signalling may contribute to the development of chronic respiratory disease. The activation of TLR4 by fibrinogen cleavage products of coagulation proteases possibly contributes to asthma pathophysiology [62]. Pulmonary mesenchymal cells express TLR2 [64], TLR3 [65], TLR4 [66], and TLR9 [67] and their activation stimulates IL-6, IL-8 and eotaxin production [68,69]. ASM cells release the stress-response protein, annexin A2, which stimulates IL-6 production in both macrophages [70] and ASM cells [63] via TLR4. In lung fibroblasts, TLR3 activation stimulates the production of RANTES, IP-10, IL-8, type 1 IFN, TGF-b, IL-4 and IL-13 [26,71], and TLR4 regulates proliferation [72]. 2.4. The plasminogen activation system In interstitial lung tissue, the conversion of plasminogen to plasmin (“activation”), a pro-inflammatory serine protease [73], contributes to disease [74]. Plasminogen, a plasma protein, is relevant in lung pathology as vascular leak leads to its extravasation into inflamed lung tissue. Both lung fibroblasts and ASM cells activate extracellular plasminogen with subsequent effects on IL-6 and IL-8 production and cell proliferation [63,75e77]. These effects occur at low mg/mL concentrations of plasminogen, substantially lower than that detected in plasma. At higher concentrations of plasminogen, increased PGE2 synthesis and/or apoptosis are observed [63,78]. For ASM cells, plasminogen activation is mediated by the urokinase plasminogen activator (uPA), in a manner accelerated by the annexin A2 hetero-tetramer (AIIt) [63], an extracellular protein complex comprised of annexin A2 and S100A10 (p11). The AIIt also serves as a signal transducer for plasmin in mediating its pro-inflammatory effects on ASM cells [77] and macrophages [79]. Whilst currently little is known about the role of annexin A2 in respiratory disease, it is becoming increasingly recognized for its importance in cancer [80e84]. Both uPA and annexin A2 may be novel drug targets in the treatment of chronic respiratory disease [74] (Section 5.4). 2.5. The coagulation system The coagulation system also contributes to pulmonary inflammation in disease [62,85]. Like plasminogen, the inactive zymogens of coagulation proteases enter inflamed lung tissue as a consequence of vascular leak, in a process accompanied by platelet aggregation and activation of the coagulation cascade [86]. Through the actions of thrombin, the main activator of the coagulation system, TLR4-

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activating fibrinogen cleavage products are generated. Interestingly, plasmin is also involved in the formation of fibrinogen cleavage products [87], suggesting that the convergence of both the coagulation and plasminogen activation systems may play an important role in pulmonary inflammation in disease. Thrombin and factor Xa (FXa), another coagulant, also activate PAR receptors, including those on ASM cells and lung fibroblasts [88,89], to elicit proinflammatory and remodelling activities [89e91]. The targeting of thrombin or FXa reduces pulmonary inflammation and tissue remodelling in murine models of lung injury and disease [89,92,93]. 3. Pulmonary mesenchymal cells in chronic respiratory disease 3.1. Asthma In asthma, allergen-induced airway inflammation contributes to airway hyper-responsiveness (AHR), a process that involves spasmodic ASM contraction. Inflammation has direct and indirect roles in AHR, causing vascular leakage, mucus hyper-secretion, epithelial shedding, ASM thickening and sub-epithelial fibrosis [94]. Proinflammatory mediators produced by ASM cells and airway fibroblasts, including IL-8, IP-10, MIP-1a, RANTES and eotaxin, contribute to the recruitment of mast cells, lymphocytes, eosinophils and neutrophils in asthma [34,95e97]. ASM abnormalities in asthmatics may contribute to an increased hyper-secretory phenotype. Cytokine-induced production of IL-8 [98], IP-10 [34], ITAC [34], eotaxin [99] and MIP-3a [100] is greater in cultures of ASM cells obtained from asthmatic donors than non-asthmatics donors. Furthermore, ASM cells of asthmatics produce relatively more collagen, fibronectin and fibulin-1 [101e103], ECM proteins which may facilitate inflammatory cell adhesion and activation. Increased calcium handling, caused by abnormal sarco/endoplasmic reticulum calcium ATPase (SERCA) pump function and expression, increases eotaxin expression in ASM cells of asthmatics [104,105]. Furthermore, JNK signalling and STAT-1 activation are diminished [106,107], whilst p65 NF-kB activation is higher [98,107] in ASM cells of asthmatic than non-asthmatic donors. Additionally, TNF-a induced p38 mitogen-activated protein kinase (MAPK) signalling is greater in ASM cells of donors with severe asthma, than other asthma or control groups [108]. ASM cells of asthmatics lack expression of the full length transcription factor CCAAT/enhancer binding protein (C/ EBPa) [109]. As a consequence, C/EBPb binding to chemokine promoters increases, causing cytokine hyper-secretion [98]. This may be due to lack of an important anti-inflammatory protein, MAPK phosphatase 1 (MKP-1), a critical MAPK deactivator that is explored in greater depth in Section 5.3. Reduced expression of MKP-1 was responsible for over-activation of the p38 MAPK pathway and corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthma [110]. Although airway fibroblast secretory function is an area of active research [28], asthma-associated changes in airway fibroblast inflammatory mediator production is under-explored. Whilst IL-1binduced GM-CSF and IL-8 production is increased more in the airway fibroblasts of asthmatics than non-asthmatics [17], the mechanism behind this differential cytokine production remains unknown. Interestingly, airway fibroblasts of asthmatics in culture express lower levels of IL-13 Ra2 (a decoy receptor for IL-13 signalling) at baseline than airway fibroblasts of controls [111], possibly augmenting IL-13-induced inflammation in asthma [112]. 3.2. COPD COPD, characterized by shortness of breath, cough and mucus hyper-secretion, is caused primarily by tobacco exposure. Genetics/

epigenetics [113,114] and the pulmonary microbiome [115] are also factors that may contribute to COPD. There is an increase in ASM mass in COPD, albeit, primarily in the small airways [116]. Studies investigating the role of ASM cells in COPD are under-represented when compared to asthma, most likely due to ASM-related pathology, such as AHR, being far more pronounced in asthma. In COPD, the number of airway fibroblasts with a more contractile phenotype (myofibroblasts) is greater [21], likely caused by increases in the expression and activity of rho-associated coiled-coil protein kinase 1 (ROCK1) [117]. Such increases will reduce airway elasticity, as will versican, the production of which is increased in airway fibroblasts of COPD patients [118,119]. Airway fibroblasts of COPD patients also express higher levels of IL-6 and IL-8 than controls [119]. Intriguingly, airway fibroblasts from COPD patients, and not from control subjects, produce prostacyclins in response to TGF-b [120]. Prostacyclins have anti-inflammatory effects in pulmonary fibrosis and PH [121]. 3.3. IPF Interstitial lung diseases (ILDs) are characterized by an abnormality in the interstitium, the area in the lung parenchyma between the capillaries and alveolar spaces. In IPF, a lethal form of ILD, the abnormality is a relentlessly progressive form of fibrosis that causes irreversible damage of lung structure and function. Whilst an increased number of inflammatory cells in the lungs of patients with IPF suggest a role of inflammation [122], an abnormal wound-repair response of epithelial/fibroblast origin is thought to be an underlying cause [123]. Lung fibroblasts have a pivotal role in IPF, proliferating and differentiating into collagen producing, contractile myofibroblasts to form fibroblastic foci. The expression of fibroblast growth factor (FGF9) is increased in IPF fibrotic foci in situ and lung fibroblasts of IPF patients in vitro in response to TGF-b1 [124]. By contrast, IFN-inducible expression of STAT1 and IP-10 is repressed in lung fibroblasts of IPF patients [125]. Human lung fibroblasts from IPF patients show constitutive activation of STAT3 [52], which mediates oncostatin M induced fibroblast chemotaxis [126]. Oncostatin M is secreted by inflammatory cells, such as macrophage and dendritic cells upon bacterial infection [127]. Oncostatin M is a potent mediator of pulmonary inflammation [128], and is involved in the induction of pulmonary eosinophilia and goblet cell hyperplasia in mice [129,130], being up-regulated in the lung of IPF patients. Furthermore, in lung fibroblasts, eotaxin expression is induced by oncostatin M, suggesting that lung fibroblasts play an important role in oncostatin M-induced inflammation in IPF [42,131]. 3.4. Pulmonary hypertension PH, whether primary or secondary to an accompanying chronic respiratory disease is characterized by vasoconstriction, in situ thrombosis and pulmonary vascular remodelling. Hypoxia, chronic inflammation and shear stress contribute to PH pathology [132,133]. In proximal pulmonary vessels that were previously muscularized, medial thickening is caused by the hypertrophy, hyperplasia and ECM production of resident pulmonary vascular smooth muscle cells. In previously non-muscular pre-capillary arterioles, the pulmonary vascular smooth muscle cells that contribute to medial thickening are derived from intermediate cells in blood vessels or adventitial fibroblasts, which differentiate into pulmonary vascular smooth muscle cells. In PH, the vascular adventitia has an important role in regulating and contributing to perivascular inflammation [134]. Pulmonary adventitial fibroblasts, through the production and release of pro-inflammatory mediators, induce the infiltration and activation of monocytes and macrophages. Epigenetic alterations in pulmonary adventitial fibroblasts from chronically hypoxic hypertensive calves are linked to a heightened pro-inflammatory

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phenotype with the expression of IL-1b, IL-6, MCP-1, CXCL12, RANTES, CCR7, CXCR4, GM-CSF and VCAM-1 being increased [19]. In severe PH, the epigenetic reprogramming of human pulmonary adventitial fibroblasts to a pro-inflammatory phenotype is associated with the decreased expression of miR-124, which regulates Notch1/ PTEN/FOXO3/p21Cip1 and p27Kip1 signalling [135]. Interestingly, aberrant PTEN phosphatase activity may also contribute to the proinflammatory phenotype of pulmonary vascular smooth muscle cells in PH. PTEN, which inhibits Akt/PI3kinase signalling, regulates a number of cell processes including inflammation [136]. Selective deletion of the PTEN gene in pulmonary vascular smooth muscle cells increases macrophage infiltration and vascular remodelling in a murine model of PH [137]. 4. Interactions between pulmonary mesenchymal cells and inflammatory cells 4.1. Mast celleairway smooth muscle cell interactions Mast celleASM cell interactions have an important role in asthma pathophysiology [138]. The number of mast cells within the ASM layer of asthmatics is higher than non-asthmatics, correlating with disease severity [138e141]. In asthma, the mast cells residing in the ASM layer are predominantly mast cellTC [35], being smaller and less granular [30] compared to the mast cells found elsewhere in the airway wall, or within the ASM layer of non-asthmatics. Mast cell recruitment to the ASM layer requires mast cell expression of chemokine receptors and ASM cell production of chemokines. Lung mast cells express a wide range of chemokine receptors, including CCR3, CXCR1, 2, 3 and 4, with CXCR3 being the most highly expressed on mast cells within the ASM layer in asthma [23,34]. Important chemokines produced by ASM cells involved in mast cell recruitment include: IL-8 (binds CXCR1) [142]; IP-10 (binds CXCR3) [23,34]; SDF-1a (binds CXCR4) [143]; RANTES (binds CCR1, 3 and 5) [144]; and eotaxin (binds CCR3) [142]. These chemokines, in conjunction with SCF and TGF-b, are involved in the movement of mast cells to the ASM layer [145]. ASM cells of asthmatics produce higher levels of IP-10 than ASM cells of non-asthmatics following treatment with Th1 cytokines [34]. Under Th2 inflammatory conditions, mast cell chemotaxis involves IL-8 and eotaxin [142]. Interestingly, the ASM cells of non-asthmatics release factor(s) that inhibit mast cell chemotaxis under either Th1 or Th2 inflammatory conditions [142]. CXCL1 is an inhibitory factor of mast cell migration, and is produced less in ASM cells of asthmatics than nonasthmatics [146]. Upon ASMemast cell contact, ASM cells induce mast cell proliferation and maintain mast cell survival [147]. This interaction is mediated by membrane-bound SCF expressed on ASM cells and soluble IL-6 and CADM1 produced by mast cells [147]. In addition, numerous mast cell produced mediators directly affect ASM cell function, a topic that has been extensively reviewed [148e150]. These mediators cause exaggerated bronchoconstriction and also modulate ASM cell secretory function [146]. 4.2. Monocyte/macrophageefibroblast interactions In chronic respiratory disease, blood circulating monocytes infiltrate lung tissue to differentiate into macrophages or dendritic cells. The phagocytic and antigen presenting functions of these cells are important in innate and adaptive immunity respectively. Fibroblasts are ideally suited to regulate monocyte trafficking, differentiation and functioning because of their synthetic capacity and sentinel-like positioning in interstitial spaces. Monocytes stimulate GM-CSF production by lung fibroblasts in a manner involving physical contact between the two cell types [28]. Lung fibroblast production of GM-CSF, which regulates monocyte/macrophage

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function, is in turn increased by TNF-a and/or IL-1b, cytokines produced by activated macrophages. In mouse models of PH, pulmonary adventitial fibroblasts produce soluble mediators, including GM-CSF, which influence monocyte/macrophage cell adhesion, infiltration and cytokine production [135]. Airway fibroblasts from patients with COPD express higher levels of the integrin avb8, which activates TGF-b, in turn stimulating CCL2 and CCL20 production in airway fibroblasts by an autocrine manner [151]. In a murine model of COPD, avb8-regulated CCL2 and CCL20 production stimulates dendritic cell migration to boost an adaptive immune response [151]. Alternatively activated (M2) macrophages, induced by Th2 cytokines (i.e. IL-4 and IL-13), are increasingly being recognized for their role in chronic respiratory disease. M2 activated macrophages are the pre-dominant macrophage phenotype present in the lungs of IPF patients [152] and are detected in higher numbers in the lung of COPD patients who continue smoking than those who stop [153]. The M2 macrophages have an impaired role in innate immunity, but produce a myriad of pro-inflammatory and pro-fibrogenic mediators such as TGF-b, IL-13, CCL2, CCL17, CCL18 and CCL22 [152]. Alveolar macrophages from non-IPF donors produce more CCL18 when either treated with Th2 cytokines, co-cultured with lung fibroblasts or exposed to native collagen [154]. The latter effect of collagen occurs in a manner mediated by the b2-integrin [154]. As CCL18 stimulates collagen production in lung fibroblasts, an axis between M2 macrophages and lung fibroblasts, involving a CCL18driven positive feedback loop, may perpetuate fibrosis in IPF [154]. 5. Novel strategies to target pulmonary mesenchymal cell immunomodulatory function 5.1. cAMP elevating agents There is still a need to find new therapies for chronic respiratory diseases for which, anti-inflammatory glucocorticoids alone are ineffective [155]. Roflumilast, an oral phosphodiesterase (PDE4) inhibitor, is an anti-inflammatory drug for COPD, but has side effects including nausea. Interestingly, both PDE4 inhibitors and b2adrenergic receptor agonists cause a rise in intracellular second messenger cyclic AMP (cAMP), but are used pharmacologically for different targets, one inflammation, the other bronchoconstriction (in asthma and COPD). In cultures of normal human lung fibroblasts, roflumilast, and the b2-agonist, indacaterol, act synergistically to attenuate inflammatory cytokine secretion and differentiation into a pro-fibrotic phenotype [156]. The levels of PGE2, an endogenous lipid mediator that increases cAMP production, are higher in lung [157] and lung fibroblasts from COPD patients [158,159]. However, in COPD, PGE2 effects on the cAMP pathway are reduced due to an increase in PDE4 activity [157]. As increased PDE4 activity also reduces b2-agonist effectiveness, these findings imply the potential benefit of combining PDE4 inhibitors with cyclic AMP elevating agonists. Interestingly, the addition of plasmin(ogen) to lung fibroblasts from IPF patients overcomes a similar PGE2 resistance, by rearranging the intracellular compartmentalization of the cAMP pathway [160]. This rearrangement is mediated by an increased expression of the A-kinase anchoring protein AKAP9, a scaffolding protein for protein kinase A (PKA), which amplifies the downstream pathway of PGE2ecAMPePKA [160]. Thus the anti-inflammatory and anti-fibrotic properties of PGE2 on pulmonary mesenchymal cells may potentially be restored in chronic respiratory diseases by approaches that rearrange cAMP compartmentalization [160]. 5.2. TGF-b1 pathways Aberrant TGF-b1 signalling, important in regulating pulmonary mesenchymal cell function, contributes to pulmonary inflammation

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and remodelling in disease [151,161,162]. Inhibiting specific aspects of TGF-b1 signalling may be an effective strategy to treat chronic respiratory disease [120]. The TGF-b1 superfamily member, activin A, is linked with the progression of PH, stimulating pulmonary vascular smooth muscle cell proliferation [163]. Administration of follistatin, an endogenous inhibitor of activin A attenuates inflammation and remodelling in a murine model of pulmonary fibrosis [164] and asthma [160]. TGF-b1-inducible connective tissue growth factor (CTGF) is implicated in the pathogenesis of IPF. Inhibition of CTGF reduces collagen promoter activity and its expression in bleomycininduced mice lung fibroblasts, suggesting CTGF neutralization may be an option for the treatment of IPF [165]. HS 6-O-sulfotransferases 1 (HS6ST1) is up-regulated in lung fibroblasts of IPF patients [166], and its silencing reduces TGF-b1 activation and subsequent collagen I and a-smooth muscle actin expression. Such data suggests that HS6ST1 inhibition could potentially reduce TGF-b1-mediated lung fibrosis. Interestingly, the IL-6 antagonist Sant7 attenuates TGF-b1-induced proliferation of lung fibroblasts obtained from ILD patients [167], suggesting that targeting IL-6 may selectively block an important TGFb1-mediated fibrotic response. Finally, inhibition of GSK-3, a mediator of TGF-b1-induced pulmonary mesenchymal cell differentiation, may also be a potential molecular target for chronic lung diseases [168,169]. 5.3. MKP-1 In recent years, the important anti-inflammatory role played by the MAPK deactivator MKP-1 in regulating inflammation in asthma has emerged. Upregulation of MKP-1 is one of the ways in which common anti-asthma medicines, such as b2-agonists and glucocorticoids, mediate their anti-inflammatory effects [31,170,171]. MKP-1 is a critical negative feedback controller, limiting the extent and duration of pro-inflammatory MAPK-driven cellular signalling pathways in pulmonary mesenchymal cells such as ASM [172,173]. Without MKP-1, MAPK-mediated inflammation can continue unchecked with the clinical consequence in chronic respiratory disease underscored by recent demonstration of relative corticosteroid insensitivity in cells from people with severe asthma [108]. The concept of enhancing MKP-1 expression and/or activity to control inflammation is currently under investigation [174], as is the potential use of p38 MAPK inhibitors to improve corticosteroid-mediated therapeutic control of chronic respiratory disease, especially in severe asthma [108]. Further studies are warranted. 5.4. Urokinase & annexin A2 Urokinase and annexin A2 production by pulmonary mesenchymal cells is potentially important in chronic respiratory disease (Section 2.4). Both uPA and annexin A2 are becoming increasingly recognized as important pathological mediators, particularly in cancer, and their targeting by either pharmacological or antibodybased therapies reduces tumour growth and/or metastasis in a number of pre-clinical cancer models [80e84]. Furthermore, uPA inhibitors are well tolerated in humans and have provided promising results in recent phase I and II trials for cancer [81]. Both uPA and annexin A2 gene-deletion reduce pulmonary inflammation in various murine models [77,175,176], and uPA antibodies reduce inflammation and oedema in a mouse model of acute lung injury [177]. However, further pre-clinical characterization of these inhibitors as therapy for chronic respiratory disease is required. 6. Conclusion In disease, pulmonary mesenchymal cells not only respond to inflammatory mediators, but also contribute to inflammation by producing chemokines, cytokines, CAMs and ECM matrix which recruit

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Regulation of pulmonary inflammation by mesenchymal cells.

Pulmonary inflammation and tissue remodelling are common elements of chronic respiratory diseases such as asthma, chronic obstructive pulmonary diseas...
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