Inflammation in Pulmonary Arterial Hypertension

CHEST

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Inflammation in Pulmonary Arterial Hypertension Laura C. Price, MBChB; S. John Wort, MBChB, PhD; Frédéric Perros, PhD; Peter Dorfmüller, MD, PhD; Alice Huertas, MD, PhD; David Montani, MD, PhD; Sylvia Cohen-Kaminsky, PhD; and Marc Humbert, MD, PhD

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling of the precapillary pulmonary arteries, with excessive proliferation of vascular cells. Although the exact pathophysiology remains unknown, there is increasing evidence to suggest an important role for inflammation. Firstly, pathologic specimens from patients with PAH reveal an accumulation of perivascular inflammatory cells, including macrophages, dendritic cells, T and B lymphocytes, and mast cells. Secondly, circulating levels of certain cytokines and chemokines are elevated, and these may correlate with a worse clinical outcome. Thirdly, certain inflammatory conditions such as connective tissue diseases are associated with an increased incidence of PAH. Finally, treatment of the underlying inflammatory condition may alleviate the associated PAH. Underlying pathologic mechanisms are likely to be “multihit” and complex. For instance, the inflammatory response may be regulated by bone morphogenetic protein receptor type 2 (BMPR II) status, and, in turn, BMPR II expression can be altered by certain cytokines. Although antiinflammatory therapies have been effective in certain connective-tissue-disease-associated PAH, this approach is untested in idiopathic PAH (iPAH). The potential benefit of antiinflammatory therapies in iPAH is of importance and requires further study. CHEST 2012; 141(1):210–221 Abbreviations: BMPR II 5 bone morphogenetic protein receptor type 2; CCL 5 chemokine (C-C motif) ligand; CD 5 cluster differentiation; CHD 5 congenital heart disease; CRP 5 C-reactive protein; CTD 5 connective tissue disease; CX3CR1 5 chemokine (C-X3-C motif) receptor 1 (fractalkine receptor); DC 5 dendritic cell; EC 5 endothelial cell; ET-1 5 endothelin-1; GC 5 glucocorticoid; iPAH 5 idiopathic pulmonary arterial hypertension; MCP 5 monocyte chemotactic protein; MCT 5 monocrotaline; MCTD 5 mixed connective tissue disease; PAH 5 pulmonary arterial hypertension; PASMC 5 pulmonary artery smooth muscle cells; PDGF 5 platelet-derived growth factor; PH 5 pulmonary hypertension; POEMS 5 polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes; PoPH 5 portopulmonary hypertension; RANTES 5 regulated upon activation, normal T cell expressed and secreted; SLE 5 systemic lupus erythematosus; SSc 5 scleroderma; Tc 5 cytotoxic T; Th 5 T helper; Treg 5 T regulatory; VEGF 5 vascular endothelial growth factor

arterial hypertension (PAH) is a progresPulmonary sive condition defined by mean pulmonary artery

pressure . 25 mm Hg, leading to chronic elevation of pulmonary vascular resistance, right ventricular failure, and early death.1 According to the most recent classification, patients with PAH include those with idiopathic PAH (iPAH), heritable PAH, congenital heart disease (CHD)-associated PAH, connective tissue disease (CTD)-associated PAH, HIV-PAH, portopulmonary hypertension (PoPH), and schistosomiasisassociated PAH.2 Genetic mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR II) (a member of the transforming growth factor superfamily) are seen in 80% of patients with heritable PAH3,4 and in 25% of patients with 210

iPAH.5 The key pathologic change observed in PAH is remodeling of precapillary resistance pulmonary arteries, characterized by thickening of the intima, media, and adventitia. As the disease progresses, intimal fibrosis occurs, along with in situ thrombosis and the development of the characteristic plexiform lesions. Despite the development of “advanced therapies,” based on uncovering abnormalities of endothelial cell (EC) function, survival prospects remain poor.6 A common observation in histopathologic specimens and studies of blood-borne cells and mediators from patients with PAH is the presence of “inflammation.” Inflammation has been defined as a complex series of interactions among soluble factors and cells Translating Basic Research into Clinical Practice

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that can arise in response to traumatic, infectious, postischemic, toxic, or autoimmune injury.7 Indeed, it is well recognized that inflammatory processes such as these promote the development and progression of systemic vascular disease.8-10 This article reviews the evidence supporting a role for inflammation in the pathogenesis of PAH. Evidence for Inflammation in PAH Animal Models Several animal models have been used to investigate the pathogenesis of pulmonary hypertension (PH); monocrotaline (MCT), chronic hypoxia, and increased pulmonary blood flow have been studied. These models have been reviewed recently by Stenmark et al.11 Although convenient, none completely reflects human disease. Monocrotaline: MCT is a plant-derived alkaloid, injection of which leads to endothelial injury followed by intense perivascular inflammation and the development of severe PH in rats. Inflammatory cells involved consist mainly of bone-marrow-derived macrophages,12 immature dendritic cells (DCs),13 and a minority of lymphocytes. Pulmonary artery medial hypertrophy and vascular remodeling (without plexiform lesions) follow this initial inflammatory phase, with severe PH observed after 3 weeks.11 Elevated serum and pulmonary cytokine and chemokine Manuscript received March 29, 2011; revision accepted July 14, 2011. Affiliations: From Faculté de Médecine (Drs Price, Perros, Dorfmüller, Huertas, Montani, Cohen-Kaminsky, and Humbert), Université Paris-Sud, Kremlin Bicêtre, France; Service de Pneumologie et Réanimation Respiratoire (Drs Price, Perros, Dorfmüller, Huertas, Montani, Cohen-Kaminsky, and Humbert), Centre National de Référence de l’Hypertension Artérielle Pulmonaire, Hôpital Antoine-Béclère, Assistance Publique, Hôpitaux de Paris, Clamart, France; INSERM U999 (Drs Price, Perros, Dorfmüller, Huertas, Montani, Cohen-Kaminsky, and Humbert), Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France; and the Department of Pulmonary Hypertension (Drs Price and Wort), National Heart and Lung Institute, Imperial College London, Royal Brompton Hospital, London, England. Drs Price and Wort contributed equally to this article. Funding/Support: Dr Price receives funding from the British Heart Foundation. Dr Perros is supported by the FRM [Grant DEQ20100318257]. Drs Montani and Dorfmüller are supported by a grant from Association HTAPFrance. Correspondence to: Marc Humbert, MD, PhD, Service de Pneumologie et Réanimation Respiratoire, Centre National de Référence de l’Hypertension Pulmonaire Sévère, Hôpital Antoine Béclère, Assistance Publique Hôpitaux de Paris, Université Paris-Sud 11, 157, Rue de la Porte de Trivaux, 92140 Clamart, France; e-mail: [email protected] © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/ site/misc/reprints.xhtml). DOI: 10.1378/chest.11-0793 www.chestpubs.org

levels precede the development of pulmonary vascular remodeling. Chronic Hypoxia and Other Models: Rodents exposed to chronic hypoxia develop mild to moderate PH characterized by muscularization of small, previously nonmuscularized pulmonary arteries. Within hours of a hypoxic insult, there is an increase in lung permeability, followed by recruitment of alveolar macrophages and upregulation of inflammatory mediators, including chemokines and chemokine receptors.14,15 Hypertrophy and proliferation of pulmonary artery smooth muscle follows, associated with accumulation of perivascular inflammatory cells, shown to be derived from mesenchymal precursors of a monocyte/macrophage lineage (including fibrocytes).16 Perivascular inflammatory cell infiltrates are also seen around remodeled vessels in other animal models, such as in the mouse model of BMPR II gene deletion,17 the vasoactive intestinal polypeptide deletion model,18 the simian immunodeficiency virus macaque model (a model of HIV-PAH),19 the mouse model of schistosomiasis-induced PAH,20 and the vascular endothelial growth factor (VEGF) receptor-2 blockade model using SU5416. In this last model, EC proliferation is associated with infiltration of mast cells, B cells, and macrophages, as well as endothelial antibody deposition. VEGF receptor-2 blockade leads to much more severe PAH in athymic nude mice, suggesting that a deficient T-cell system contributes to PAH development in this model.21 Evidence for Inflammation in Human PAH One may argue that inflammation is to be expected in artificial animal models consisting of a direct inflammatory insult (MCT) and hypoxia. However, several lines of evidence support the hypothesis that inflammation may also be important in human PAH. Histologic Evidence: As observed in animal models, a mononuclear cell inflammatory infiltrate is often observed around remodeled vessels, including plexiform lesions in human PAH. The cells involved have been shown to be mostly T cells, macrophages, and, to a lesser extent, B cells (Fig 1).22-26 It has been recently shown that in patients with iPAH, although not in those with Eisenmenger PAH, formation of a tertiary lymphoid follicle composed of B lymphocytes, T lymphocytes, and DCs occurs near remodeled pulmonary arteries. These organized structures appear to have connections to diseased vessels via a stromal network and are supplied by lymphatic channels.27 Perivascular mast cells are also seen in many types of PAH, including iPAH and CHD-PAH.28-30 More recently, DC have been found in the adventitia and media of muscular pulmonary arteries in human iPAH. 13 CHEST / 141 / 1 / JANUARY, 2012

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Figure 1. Elastic staining of paraffin-embedded lung tissue. A pulmonary arterial lesion from a patient with idiopathic pulmonary arterial hypertension, illustrating the perivascular lymphocytic infiltrate (center), a small pulmonary artery (left), and a bronchiole (right) (hematoxylin and eosin elastic stain; original magnification 3 200).

Furthermore, circulating DC are increased in number in patients with iPAH and PoPH.31 In addition, there is evidence of expansion of the vasa vasorum in human iPAH, which may act as a recruitment pathway for further inflammatory cells, including fibrocytes (Fig 2).32 Circulating and Tissue Factors: Patients with iPAH have elevated serum levels of cytokines, including

IL-1-b, IL-6, and IL-8,33,34 and chemokines such as chemokine (C-C motif) ligand (CCL)2/monocyte chemotactic protein (MCP)-1,35 CCL5/regulated upon activation, normal T cell expressed and secreted (RANTES),36 and CXC3CL1/fractalkine.37 Tumor necrosis factor a, IL-6, MCP-1, and C-reactive protein (CRP) are also increased in CHD-PAH.38 Elevated levels of inflammatory cytokines are also characteristic of CTD39 and HIV-associated PAH.40 Furthermore, in patients with sickle cell disease who develop precapillary PH (3%),41 serum cytokines are significantly elevated and are independently associated with hemodynamic markers.42 These data suggest that the increased levels of such mediators are common to the pathology of PAH per se and are not restricted to one particular subtype. Inflammatory Conditions Are Associated With PAH: PAH is a recognized complication of a number of “inflammatory” conditions, including the syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS syndrome),43 CTD (including scleroderma [SSc-PAH], mixed CTD [MCTD], and systemic lupus erythematosus [SLE]),44-46 Hashimoto thyroiditis,47 and Castleman disease.48 Additionally, the risk of developing PoPH is significantly increased in patients with advanced liver disease due to autoimmune hepatitis, compared with less “inflammatory” causes.49

Figure 2. Diagram illustrating a summary of the theoretic involvement of pulmonary vascular inflammation in the pathogenesis of pulmonary arterial hypertension. BMPR II 5 bone morphogenetic protein receptor type 2; SMC 5 smooth muscle cell; Tc 5 cytotoxic T cell; Th 5 T helper cell; Treg 5 T regulatory cell. 212

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Treatment of Inflammatory Conditions May Improve Associated PAH: Antiinflammatory therapies targeting an underlying inflammatory condition may improve the associated PAH. This has been reported in PAH associated with SLE,50-53 MCTD,52,53 POEMS syndrome,54 and Castleman disease,48 although not with SSc-PAH. The evidence that treating chronic infections associated with PAH to improve PAH is less clear. Hemodynamic improvement is reported in some cases of HIV-associated PAH following antiretroviral therapy.55,56 However, more recent studies suggest that, compared with advanced PAH therapies, antiretroviral therapy treatment is not associated with hemodynamic improvements,57 and the prevalence of HIV-related PAH, in fact, remains similar to that prior to the era of antiretroviral therapy58: Further well-designed studies are needed. Similarly, treatment of schistosomiasis-associated PAH with the antiparasitic agent praziquantel is not believed to have a significant effect on the pulmonary circulation. How Inflammation Might Contribute to the Pathophysiology of PAH Background Currently, it is unclear how inflammation may contribute to the pathogenesis of PAH. Indeed, it is possible that inflammation may initiate vascular remodeling (ie, be an “initial hit”), be integral in its propagation (a “secondary hit”), or just be a reactive response to ongoing remodeling (“bystander” phenomenon). Initial hits may include infections, drugs, or toxins. There may be a relationship between such an inflammatory hit and other factors such as BMPR II status,59 which may alter the subsequent inflammatory response. Whatever the exact relationship, there is evidence for activation of both the innate immune system (eg, through activation of macrophages/monocytes) and adaptive immunity (eg, through specific T-cell and B-cell receptors). The cytokines and chemokines subsequently produced may propagate further inflammatory processes and, either on their own or through production of growth factors, drive vascular remodeling processes. B-cell production of autoantibodies may favor an antiapoptotic phenotype of EC. A summary of possible inflammatory pathways is shown in Figure 2. A more detailed description of cells and processes that may be involved follows. Possible Inflammatory Triggers Infections and Toxins: The most obvious link between inflammation and vascular remodeling is the possibility of an initial infectious or toxic “hit.” We summarize the evidence for infections and toxic www.chestpubs.org

factors implicated as potential inflammatory triggers in PAH. Viruses HIV—PAH is a rare but life-threatening complication of HIV infection, with a prevalence in HIVinfected patients of 0.5%.56 The onset of PAH in these patients confers a worse prognosis,60 and it should be excluded in those presenting with unexplained breathlessness. Pulmonary vascular remodeling in HIV-PAH appears similar to that in other subtypes of PAH. Plexiform lesions are seen in 80% of cases,61 and there is a pronounced inflammatory component.22,62 The precise mechanism by which HIV leads to pulmonary vascular remodeling is unknown, but it is likely to be a multifactorial process, and at least in part related to the induction of proinflammatory cytokines and growth factors, such as platelet-derived growth factor (PDGF)40 and VEGF,63 from the induced chronic state of immune activation. As in other causes of PAH, dysregulated BMPR II signaling is likely to be involved,64 although germline BMPR II mutations are not usual in these cases.60 Interestingly, the virus is not seen within the EC of vascular lesions themselves65; therefore, indirect action by HIV proteins is implicated. For example, the envelope protein glycoprotein-120 (responsible for HIV binding and entry into macrophages) has been shown to induce apoptosis and increase endothelin-1 secretion from EC in vitro.66 Furthermore, HIV-1 negative factor (nef) antigen, crucial for maintenance of the HIV viral load, has been localized to cells within complex vascular lesions in patients with HIV-PAH,19 with a proposed mechanism being an increase in EC apoptosis followed by the emergence of apoptosis-resistant EC with a hyperproliferative phenotype.67 g Herpes Viruses—Genes coding for human g herpes virus 8 (or Kaposi sarcoma-associated herpes virus) proteins have been detected in plexiform lesions.68 In support of this observation, human g herpes virus 8 infection of EC in vitro results in an apoptosisresistant cell phenotype,69 as well as a reduction in BMPR II expression.70 In addition, chronic active Epstein-Barr virus infection has been associated with high circulating IL-6 levels in humans, and with the development of PAH.71 However, it is important to note that neither of these viral associations has been replicated in subsequent studies.72-74 Of course, it remains possible that there are geographic differences in possible infectious insults. Parasites Schistosomiasis is likely to be the most common cause of PAH worldwide: 200 million people are CHEST / 141 / 1 / JANUARY, 2012

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infected, and the associated prevalence of PAH is 2% to 5%.75 The development of PAH is thought to follow hepatosplenic infection with Schistosoma mansoni and the subsequent development of portal hypertension: after entering the skin, the fresh-water parasite migrates to the lungs and then to the portal venous system, where it matures.76 The deposition of eggs in liver veins leads to presinusoidal granulomatous inflammation, peri-portal fibrosis, and portal hypertension. The resultant opening of portocaval shunts both increases pulmonary blood flow and creates a pathway for eggs to lodge in the pulmonary capillaries.75,76 Histologically, pulmonary vascular lesions are similar to those seen in iPAH, including the presence of plexiform lesions.77 The development of schistosomiasis-associated PAH is thought to be due to the deposition of eggs in lung tissue causing mechanical vessel impaction and focal arteritis, inflammation relating to the formation of granulomas around the eggs, and increased pulmonary blood flow. The contribution of inflammation to vascular remodeling in this setting is not well understood, However, using murine models, it appears that a switch from a Th1 to a Th2 immune response is important.20,78 Although these models are important in enhancing our understanding of this globally important cause of PAH, the phenotype does not accurately reflect human disease in that there is less PoPH. Toxic Factors: PAH is associated with a variety of drugs and toxins. The most common class of drugs implicated is appetite suppressants, which include drugs such as dexfenfluramine. The most well documented toxic insult (“toxic inflammatory PH”) occurred after ingestion of adulterated food oil. This led to acute lung injury associated with eosinophilia and myalgia.79 PAH occurred in 20% of hospitalized patients 2 to 4 months from onset and in 8% of longer-term survivors. Pathologic changes included classic plexiform lesions associated with perivascular inflammatory cell infiltrates.80 PAH has also been described in some patients taking l-tryptophan who subsequently developed “eosinophilia myalgia syndrome.” Lung histology demonstrated vascular remodeling associated with lymphocytic and eosinophilic infiltrates.81 Role of Cytokines and Chemokines Cytokines and chemokines (soluble cytokines that act as chemoattractants) are important mediators of inflammation. Chemokines play a role in leukocyte recruitment and trafficking. Both these groups of mediators (which have overlaps) are produced predominantly by inflammatory cells of the innate immune system but can also be produced by any of the cel214

lular components of the vascular wall or adventitia.7 Indeed, in PAH, there is an increase in levels of both serum and tissue cytokines and chemokines, including IL-1, IL-6,33,34 CCL2/MCP-1, CCL5/RANTES, and CX3CL 1 chemokine (C-X3-C motif) ligand 1 (CX3CL1)/fractalkine.36,37,82 Circulating mononuclear cells of patients with PAH express increased levels of chemokines and chemokine receptors compared with those of normal individuals. Furthermore, profiling their expression differs between patients with PAH and control subjects.83 Importantly, levels of certain cytokines, such as IL1-b, IL-6, and tumor necrosis factor a, are predictive of outcome in patients with PAH.34 Finally, CRP, a circulating marker of inflammation and tissue damage, has been shown to be increased in patients with PAH, correlates with severity of disease, and is predictive of response to therapy.84 Further details supporting important roles for cytokines and chemokines are described in the section, “Role of Individual Cytokines/Chemokines in PAH.” Role of Specific Inflammatory Cells in PAH Role of T Cells: T cells are essential components of the adaptive immune response, and, broadly, three subsets are described: cluster differentiation (CD)41 T helper (Th) cells, CD41CD25hiFoxP31CD127low T regulatory (Treg) cells, and CD81 cytotoxic T (Tc) cells. CD41 T cells are further subdivided into Th1, Th2, and, recently described, Th17 (IL-17-producing) cells. IL-6 and transforming growth factor b induce differentiation of these highly proinflammatory and autoimmunity-inducing Th17 cells from naive precursors.85 Overall, Th cells stimulate B-cell differentiation and macrophage activation, and Tc cells bind to major histocompatibility complex class 1 molecules and kill infected cells. Treg cells are important in balancing Th1 and Th2 responses, maintaining self-tolerance, and controlling autoimmunity. Several lines of evidence support a role for T cells in the development of PAH. In animal models, the athymic nude rat (without T cells) develops PAH more readily than do those with intact T-cell production.22 In the MCT model, depletion of Th cells, as well as those of Th2, ameliorates the extent of PAH, again suggesting the importance of a Th2 antigen-driven immune response.86 Whereas T-cell infiltrates are increased in patients with iPAH,23,27 it appears that there is a decrease in CD81 Tc cells and an increase in Treg cells.87 The precise role of Treg cells in PAH is currently being investigated. Role of B Cells and Autoantibodies: B cells generate antibodies to specific antigenic epitopes. Levels of antinuclear antibodies are increased in patients Translating Basic Research into Clinical Practice

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with PAH,88 and autoantibodies directed against EC89 and fibroblasts90 have been described. These autoantibodies may play a role by inducing adhesion molecule expression91 or inducing EC apoptosis,92 which may, in turn, contribute to the an apoptosisresistant phenotype. Finally, the development of PAH in patients with SSc is seen in association with specific subsets of human leukocyte antigen alleles,93 although the significance of this is uncertain. Role of Mast Cells: Mast cells are bone marrowderived cells resident in many tissues, containing characteristic large granules rich in histamine and heparin. Although well described in hypersensitivity reactions, they are also important in wound healing and as a defense against pathogens. Accumulation of mast cells has been described in several types of PAH.28,30 A recent study has identified an increase in c-kit-positive cells (including mast cells) in remodeled vessels, as well as mobilization of bone marrowderived circulating progenitor cells.32 The increase in mast cell numbers consists mainly of the chymasesecreting subset, numbers of which correlate with the hemodynamic severity of the disease.30 How mast cells may contribute to PAH pathophysiology is not clear, but proposed mechanisms include direct vasoactive effects28 and stimulation of remodeling by increased production of matrix metalloproteinases.94 Mast cells have also been shown, in vivo, to have important antiinflammatory and immunosuppressive functions (eg, through actions of IL-10)95; it may be, as is the case with T cells, that mast cells develop subsets that both potentiate and control inflammatory processes in PAH. Role of Monocytes/Macrophages and DC: Macrophages are the versatile phagocytes that differentiate from tissue monocytes. Along with DC, they are professional antigen-presenting cells, displaying antigen bound to major histocompatibility complex class 2, ready for recognition by T cells. Increased numbers of these cell types are present around remodeled vessels in PAH,13 and increased levels of circulating DC are seen.31 DC additionally “orchestrate” the inflammatory response and can differentiate into other cell phenotypes, including EC.13 Recruitment of Bone Marrow-Derived Cells in PAH Circulating cells derived from the bone marrow may be involved in vascular remodeling. For instance, c-kit-positive hematopoietic cells (fibrocytes) have been shown to be an important source of vascular cells, both in the chronic hypoxic animal model96 and in human iPAH.32 Furthermore, expansion of the vasa vasorum with increased expression of the chemotactic signal chemokine (C-X-C motif) ligand 12/stromal www.chestpubs.org

derived factor-1 creates a potential path for the recruited vascular progenitors (as well as inflammatory cells) to pulmonary vascular lesions.32 Role of Growth Factors in Inflammation Growth factors, including PDGF,97 epidermal growth factor, VEGF, serotonin, and fibroblast growth factor 2, are important contributors to the apoptosisresistant phenotype and to remodeling in PAH. 98 There is overlap whereby some inflammatory cytokines, notably IL-6, also act as growth factors to vascular cells. For example, IL-6 triggers vascular smooth muscle cell proliferation through upregulated expression of VEGF and its receptor VEGFR2.99 Inflammatory end points can also be modulated by growth factors: For example, serotonin reuptake inhibition attenuates matrix remodeling through reduced metalloproteinases as well as through reduced inflammatory cytokine expression in the MCT model.100 Signaling Pathways and Interactions With BMPR II Several common transcription factor pathways are likely to be involved in the onset and propagation of pulmonary vascular inflammation. For instance, nuclear factor k B signaling is activated by many cytokines and extracellular inflammatory triggers and is key to the action of many of these mediators.101 Indeed, activation of nuclear factor k B signaling is suggested in human iPAH.102 Other putative transcription factors important in systemic vascular inflammation include c-Jun-N-terminal kinase (JNK), just another kinase (JAK), and signal transducer and activator of transcription (STAT), although these have not yet been studied in the context of pulmonary vascular inflammation. The most important member of the transforming growth factor b signaling pathway in PAH is BMPR II, in which growth-inhibitory signaling is mediated through Smad proteins. A reduction in BMPR II expression is characteristic of PAH and contributes to the proliferative vascular cell phenotype. It has been shown that an important feedback loop exists between BMPR II and IL-6, so that disordered BMPR II signaling may cause cytokine dysregulation.103 Furthermore, cytokines such as IL-6 may directly affect BMPR II expression.104 In the MCT model, pulmonary BMPR II expression is decreased, whereas treatment with dexamethasone restores this reduction.105 Role of Individual Cytokines/Chemokines in PAH A summary of animal model and clinical data supporting a role for specific cytokines/chemokines in CHEST / 141 / 1 / JANUARY, 2012

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Table 1—Source, Target, and Function of Cytokines and Chemokines Implicated in Pulmonary Vascular Inflammation Cytokine/Chemokine IL-1-b

Cellular Source Macrophages, lymphocytes, EC, PASMC Th2 cells, mast cells

33,34

IL-434,86

Cellular Target

Biologic Function

Many cell types

Proinflammatory, stimulates endothelial and PASMC activation Proliferation and differentiation of B cells and Th2 cells

T cells, B cells, mast cells, macrophages, hematopoietic progenitors T cells, B cells, EC, PASMC

IL-633,34

Macrophages, EC, PASMC, T cells

IL-834

Monocytes, EC, T cells

Neutrophils, T cells, monocytes

IL-1034

Macrophages, Th2 cells, Treg cells, B cells, mast cells

Macrophages, T cells, B cells

IL-1234

Th1 cells

T cells, macrophages

IL-1386,106

Many cells, especially Th2 cells

Similar to IL-4

TNF-a34

Macrophages, T cells, B cells, NK cells, PASMC

Many cell types

TGF-b34

Platelet, macrophages, Th2 cells, Treg cells, B cells, PASMC

Many cell types

CCL2/MCP-135

Many cells including EC, PASMC

Monocytes, memory T cells, DC, basophils

CCL5/RANTES36

T cells, EC

CXCL10108

Monocytes, EC, and fibroblasts in response to IFN-g

T cells, monocytes, eosinophils, basophils (any cell expressing CCR5 receptor) Binds to cell surface receptor CXCR3 on monocytes/macrophages, T cells, NK cells, DC

Fractalkine/CX3CL137,82

Macrophages, T cells, PASMC, EC

Soluble form CD41 and CD81 T cells, monocytes, cell-bound form targets activated EC

Differentiation of myeloid cells, induction of acute phase proteins, PASMC proliferation Proinflammatory, promotes leukocyte arrest Antiinflammatory, inhibits Th1 response, promotes proliferation and differentiation of Treg cells; promotes differentiation and maturation of B cells, plasma cells (and antibody production) Proinflammatory, promotes NK cell and cytotoxic lymphocyte activity, induces IFN-g Important in allergic and parasitic disorders Proinflammatory, fever, neutrophil activation, bone resorption, anticoagulant, tumor necrosis Antiinflammatory, profibrotic, promotes wound healing, angiogenesis, suppresses Th1 and Th2 responses Monocyte migration into tissue to become tissue macrophages (especially with PAH EC), may increase ET-1 and ECE-1107 Chemoattractant for monocytes and T cells, may also induce ET-1 and ECE-1107 Chemoattractant for monocytes/macrophages, T cells, NK cells, DC; promotes T-cell adhesion to EC; inhibits angiogenesis Soluble form chemoattracts T cells and monocytes; cell-bound form interacts with CX3CR1, promotes leukocyte adhesion to activated EC; growth factor for PASMC

CCL 5 chemokine (C-C motif) ligand; CCR 5 chemokine (C-C motif) receptor; CD 5 cluster differentiation; CX3CL1 5 chemokine (C-X3-C motif) ligand 1 (frackalkine); CX3CR1 5 chemokine (C-X3-C motif) receptor 1 (fractalkine receptor); CXCL 5 chemokine (C-X-C motif) ligand; CXCR 5 chemokine (C-X-C motif) receptor; DC 5 dendritic cell; EC 5 endothelial cell; ECE-1 5 endothelin converting enzyme; ET-1 5 endothelin-1; IFN-g 5 g interferon; MCP-1 5 monocyte chemotactic protein; NK 5 natural killer; PAH 5 pulmonary arterial hypertension; PASMC 5 pulmonary artery smooth muscle cell; RANTES 5 regulated by T cells, activation upon secretion; TGF-b 5 transforming growth factor b; Th 5 T helper; TNF-a 5 tumor necrosis factor a; Treg 5 T regulatory.

the pathogenesis of PAH is shown in Table 1.106-108 The actions of the more commonly implicated cytokines and chemokines are described.

treatment with an IL-1 receptor antagonist reduces PH and right ventricular hypertrophy in the MCTPAH model, although not in the chronic hypoxia counterpart.109

IL-1-b IL-1-b is a potent proinflammatory cytokine. In human PAH, serum levels are raised33 and these correlate with a worse outcome.34 IL-1-b is produced in large amounts in the MCT model, compared with the chronic hypoxic model.92 Furthermore, repeated 216

IL-6 IL-6 is a proinflammatory cytokine synthesized by many cell types. Plasma levels of IL-6 are elevated in iPAH,33 and they correlate with severity of disease and with increased mortality.34 In patients with SSc, Translating Basic Research into Clinical Practice

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elevated circulating IL-6 levels predict the presence of associated PAH.110 Elevated serum IL-6 levels also correlate with hemodynamic severity in PH in patients with COPD111 and in other forms of PAH, including sickle cell disease-associated PAH.42 Pulmonary IL-6 production is increased in experimental PH112 and is thought to reflect increased production by both inflammatory cells and vascular cells.113 In turn, IL-6 has many effects on inflammatory and vascular cells that may promote vascular remodeling. These include accumulation of perivascular T lymphocytes,99 stimulation of EC to produce chemokines,114 promotion of pulmonary artery smooth muscle cells (PASMC), and proliferation of EC.99,113 IL-13 IL-13 is a cytokine secreted by many cells, especially Th2 cells and mast cells. It is important in forming granulomata in response to parasites (including schistosomiasis) and its effects on immune cells are similar to those of IL-4 (see Table 1). The active IL-13 receptors are IL-13Ra 1 and IL-4R, whereas IL-13Ra 2 functions as a negative-regulating decoy receptor. Loss of IL-13 signaling reduces pulmonary vascular remodeling in models of PH78,86 and its effects on T cells suggest an indirect role in regulating Th2 responsiveness.86 A relative increase in IL-13Ra 2 compared with the active receptors is observed in PASMC from patients with iPAH, as well as in MCT-PAH and hypoxic PH models.106 Perhaps surprisingly, IL-13 is antiproliferative to PASMC in vitro, with an associated reduction in endothelin-1 release.106 Overall, these data suggest that dysregulated signaling of this Th2 cytokine is likely to contribute to vascular remodeling in PAH. CCL2/MCP-1 MCP-1 (CCL2) is a chemokine produced by vascular cells that stimulates monocytes/macrophage activation and migration, with actions mediated via the chemokine (C-C motif) receptor. Elevated levels of MCP-1 are found in the plasma and lung of patients with iPAH,35 although they do not correlate with disease severity. Furthermore, PASMC and EC from patients with iPAH overexpress MCP-1. In addition, PASMC from patients with iPAH express increased levels of the chemokine (C-C motif) receptor, exhibit exaggerated migratory and proliferative responses to MCP-1, and are blocked by MCP-1-blocking antibodies.35 CCL5/RANTES RANTES (or CCL5) is a chemokine that mediates the trafficking and homing of T lymphocytes, monowww.chestpubs.org

cytes, basophils, eosinophils, and natural killer cells through different chemokine receptors. Pulmonary RANTES messenger RNA is elevated in patients with PAH shown to be from EC origin.36 As yet, there have been no further studies of RANTES in PAH to elucidate further mechanisms. CX3CL1/Fractalkine Fractalkine (CX3CL1) is a chemokine expressed as a soluble or in a membrane-bound form, whose effects are mediated through chemokine (C-X3-C motif) receptor 1 (fractalkine receptor) (CX3CR1), a receptor expressed by many cell types. Elevated levels of soluble fractalkine are seen in patients with PAH,37 although there are no studies associating these with outcome. Fractalkine is upregulated on both CD41 and CD81 T lymphocytes in PAH,37 and it is likely that the increased expression of CX3CR1 on diseased PASMC contributes to the perivascular inflammatory cell influx.82 Fractalkine has also been shown to induce PASMC proliferation in MCT-induced PH (although not migration).82 Antiinflammatory Therapies Therapies specifically targeting inflammation are of interest and appear to work in experimental PH. However, they have not yet been formally tested in human PAH. Animal Models Several antiinflammatory treatments, including the use of an IL-1-receptor antagonist106 and glucocorticoids (GC),109,115-120 have been shown to prevent PH development when used early in MCT-exposed rats. GC have also been shown to reverse established PH and improve survival later in this model.105 Of several potential GC-mediated mechanisms, a reduction in IL-6-expressing adventitial inflammatory cells, as well as a direct antiproliferative effect on PASMC, has been observed.105 Other possible treatments include the targeting of growth factors, such as the use of tyrosine kinase inhibitors to block the PDGF receptor.97,121 Human Disease There is logic in the use of antiinflammatory therapies, because circulating cytokines and CRP levels correlate with severity and outcome in human PAH.34,84 PAH end points are also improved in some patients when the primary inflammatory condition is treated (eg, POEMS syndrome,54 SLE,50,51,122 and MCTD).52 However, this is not the case in SSc-associated PAH CHEST / 141 / 1 / JANUARY, 2012

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for several proposed reasons, including a more pronounced fibrotic vascular disease and the presence of major comorbidities.123 In CTD-PAH, PAH improvements are seen notably in the earlier stages of disease,52,53 possibly reflecting the earlier inflammatory/proliferative stage of the disease. Finally, it is notable that conventional PAH therapies may also act on inflammatory end points: For example, prostacyclins reduce high circulating MCP-1 levels124 and inhibit cytokine-driven monocyte function.125

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Conclusions Perivascular inflammation is common in remodeling vessels, both in animal models and in human PAH. However, it is unclear whether such inflammatory processes are integral to the initiation and propagation of vascular remodeling, or are just bystander phenomena. Certainly, there is evidence that treating inflammation in animal models and in human PAH associated with a strong inflammatory profile (eg, MCTD, POEMS syndrome) ameliorates pulmonary vascular remodeling (and improves clinical outcome). The ongoing challenge is to fully characterize the inflammatory processes in other human conditions associated with PAH and to determine whether antiinflammatory strategies will be useful in their treatment in the future.

10. 11.

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Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Wort has relationships with Actelion, Bayer Schering, GSK, Novartis, and Pfizer. Drs Montani and Humbert have relationships with drug companies including Actelion, Bayer Schering, GSK, Lilly, Novartis, Pfizer, and United Therapeutics. In addition to being investigators in trials involving these companies, relationships include consultancy services and memberships of scientific advisory boards. Drs Price, Perros, Dorfmüller, Huertas, and Cohen-Kaminsky have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript.

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