0
Translating Basic Research Into Clinical Practice |

Inflammation in Pulmonary Arterial HypertensionInflammation in Pulmonary Arterial Hypertension FREE TO VIEW

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; Marc Humbert, MD, PhD
Author and Funding Information

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.

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: marc.humbert@abc.aphp.fr


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.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2012 American College of Chest Physicians


Chest. 2012;141(1):210-221. doi:10.1378/chest.11-0793
Text Size: A A A
Published online

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.

Figures in this Article

Pulmonary arterial hypertension (PAH) is a progressive 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 schistosomiasis-associated 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 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 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.

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 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 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

Figure Jump LinkFigure 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 ×200).Grahic Jump Location
Figure Jump LinkFigure 2. Diagram illustrating a summary of the theoretic involvement of pulmonary vascular inflammation in the pathogenesis of pulmonary arterial hypertension. BMPR II = bone morphogenetic protein receptor type 2; SMC = smooth muscle cell; Tc = cytotoxic T cell; Th = T helper cell; Treg = T regulatory cell.Grahic Jump Location
Circulating and Tissue Factors:

Patients with iPAH have elevated serum levels of cytokines, including IL-1-β, 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 α, 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

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.

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 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 HIV-infected 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

γ Herpes Viruses—Genes coding for human γ herpes virus 8 (or Kaposi sarcoma-associated herpes virus) proteins have been detected in plexiform lesions.68 In support of this observation, human γ herpes virus 8 infection of EC in vitro results in an apoptosis-resistant 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 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 cellular 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-β, IL-6, and tumor necrosis factor α, 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)4+ T helper (Th) cells, CD4+CD25hiFoxP3+CD127low T regulatory (Treg) cells, and CD8+ cytotoxic T (Tc) cells. CD4+ T cells are further subdivided into Th1, Th2, and, recently described, Th17 (IL-17-producing) cells. IL-6 and transforming growth factor β 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 CD8+ 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 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 apoptosis-resistant 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 marrow-derived 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 marrow-derived circulating progenitor cells.32 The increase in mast cell numbers consists mainly of the chymase-secreting 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 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 apoptosis-resistant 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 κ 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 κ 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 β 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

A summary of animal model and clinical data supporting a role for specific cytokines/chemokines in the pathogenesis of PAH is shown in Table 1.106-108 The actions of the more commonly implicated cytokines and chemokines are described.

Table Graphic Jump Location
Table 1 —Source, Target, and Function of Cytokines and Chemokines Implicated in Pulmonary Vascular Inflammation

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

IL-1-β

IL-1-β is a potent proinflammatory cytokine. In human PAH, serum levels are raised33 and these correlate with a worse outcome.34 IL-1-β is produced in large amounts in the MCT model, compared with the chronic hypoxic model.92 Furthermore, repeated treatment with an IL-1 receptor antagonist reduces PH and right ventricular hypertrophy in the MCT-PAH model, although not in the chronic hypoxia counterpart.109

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, 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-13Rα1 and IL-4R, whereas IL-13Rα2 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-13Rα2 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, monocytes, 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 CD4+ and CD8+ 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

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 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

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.

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.

BMPR II

bone morphogenetic protein receptor type 2

CCL

chemokine (C-C motif) ligand

CD

cluster differentiation

CHD

congenital heart disease

CRP

C-reactive protein

CTD

connective tissue disease

CX3CR1

chemokine (C-X3-C motif) receptor 1 (fractalkine receptor)

DC

dendritic cell

EC

endothelial cell

ET-1

endothelin-1

GC

glucocorticoid

iPAH

idiopathic pulmonary arterial hypertension

MCP

monocyte chemotactic protein

MCT

monocrotaline

MCTD

mixed connective tissue disease

PAH

pulmonary arterial hypertension

PASMC

pulmonary artery smooth muscle cells

PDGF

platelet-derived growth factor

PH

pulmonary hypertension

POEMS

polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes

PoPH

portopulmonary hypertension

RANTES

regulated upon activation, normal T cell expressed and secreted

SLE

systemic lupus erythematosus

SSc

scleroderma

Tc

cytotoxic T

Th

T helper

Treg

T regulatory

VEGF

vascular endothelial growth factor

Rubin LJ. Pulmonary arterial hypertension. Proc Am Thorac Soc. 2006;31:111-115 [PubMed] [CrossRef]
 
Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54suppl 1:S43-S54 [PubMed]
 
Lane KB, Machado RD, Pauciulo MW, et al; International PPH Consortium International PPH Consortium Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet. 2000;261:81-84 [PubMed]
 
Machado RD, Aldred MA, James V, et al. Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat. 2006;272:121-132 [PubMed]
 
Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet. 2000;3710:741-745 [PubMed]
 
Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;1222:156-163 [PubMed]
 
Nathan C. Points of control in inflammation. Nature. 2002;4206917:846-852 [PubMed]
 
Zernecke A, Weber C. Inflammatory mediators in atherosclerotic vascular disease. Basic Res Cardiol. 2005;1002:93-101 [PubMed]
 
Raines EW, Ferri N. Thematic review series: the immune system and atherogenesis. Cytokines affecting endothelial and smooth muscle cells in vascular disease. J Lipid Res. 2005;466:1081-1092 [PubMed]
 
Schober A. Chemokines in vascular dysfunction and remodeling. Arterioscler Thromb Vasc Biol. 2008;2811:1950-1959 [PubMed]
 
Stenmark KR, Meyrick B, Galie N, Mooi WJ, McMurtry IF. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol. 2009;2976:L1013-L1032 [PubMed]
 
Sahara M, Sata M, Morita T, Nakamura K, Hirata Y, Nagai R. Diverse contribution of bone marrow-derived cells to vascular remodeling associated with pulmonary arterial hypertension and arterial neointimal formation. Circulation. 2007;1154:509-517 [PubMed]
 
Perros F, Dorfmüller P, Souza R, et al. Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension. Eur Respir J. 2007;293:462-468 [PubMed]
 
Madjdpour C, Jewell UR, Kneller S, et al. Decreased alveolar oxygen induces lung inflammation. Am J Physiol Lung Cell Mol Physiol. 2003;2842:L360-L367 [PubMed]
 
Burke DL, Frid MG, Kunrath CL, et al. Sustained hypoxia promotes the development of a pulmonary artery-specific chronic inflammatory microenvironment. Am J Physiol Lung Cell Mol Physiol. 2009;2972:L238-L250 [PubMed]
 
Frid MG, Brunetti JA, Burke DL, et al. Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol. 2006;1682:659-669 [PubMed]
 
Hong KH, Lee YJ, Lee E, et al. Genetic ablation of the BMPR2 gene in pulmonary endothelium is sufficient to predispose to pulmonary arterial hypertension. Circulation. 2008;1187:722-730 [PubMed]
 
Hamidi SA, Prabhakar S, Said SI. Enhancement of pulmonary vascular remodelling and inflammatory genes with VIP gene deletion. Eur Respir J. 2008;311:135-139 [PubMed]
 
Marecki JC, Cool CD, Parr JE, et al. HIV-1 Nef is associated with complex pulmonary vascular lesions in SHIV-nef-infected macaques. Am J Respir Crit Care Med. 2006;1744:437-445 [PubMed]
 
Crosby A, Jones FM, Southwood M, et al. Pulmonary vascular remodeling correlates with lung eggs and cytokines in murine schistosomiasis. Am J Respir Crit Care Med. 2010;1813:279-288 [PubMed]
 
Taraseviciene-Stewart L, Nicolls MR, Kraskauskas D, et al. Absence of T cells confers increased pulmonary arterial hypertension and vascular remodeling. Am J Respir Crit Care Med. 2007;17512:1280-1289 [PubMed]
 
Cool CD, Kennedy D, Voelkel NF, Tuder RM. Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection. Hum Pathol. 1997;284:434-442 [PubMed]
 
Tuder RM, Groves B, Badesch DB, Voelkel NF. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol. 1994;1442:275-285 [PubMed]
 
Hall S, Brogan P, Haworth SG, Klein N. Contribution of inflammation to the pathology of idiopathic pulmonary arterial hypertension in children. Thorax. 2009;649:778-783 [PubMed]
 
Pinto RF, Higuchi Mde L, Aiello VD. Decreased numbers of T-lymphocytes and predominance of recently recruited macrophages in the walls of peripheral pulmonary arteries from 26 patients with pulmonary hypertension secondary to congenital cardiac shunts. Cardiovasc Pathol. 2004;135:268-275 [PubMed]
 
Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease; a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation. 1958;184 Part 1:533-547 [PubMed]
 
Perros F, Dorfmüller P, Montani D, et al. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am J Resp Crit Care Med. In press.
 
Heath D, Yacoub M. Lung mast cells in plexogenic pulmonary arteriopathy. J Clin Pathol. 1991;4412:1003-1006 [PubMed]
 
Mitani Y, Ueda M, Maruyama K, et al. Mast cell chymase in pulmonary hypertension. Thorax. 1999;541:88-90 [PubMed]
 
Hamada H, Terai M, Kimura H, Hirano K, Oana S, Niimi H. Increased expression of mast cell chymase in the lungs of patients with congenital heart disease associated with early pulmonary vascular disease. Am J Respir Crit Care Med. 1999;1604:1303-1308 [PubMed]
 
Le Pavec J, Montani BGD, Perros F, Savale L, Simonneau G, Sitbon O, Humbert . Circulating dendritic cells in idiopathic pulmonary arterial Hypertension and cirrhotic portopulmonary hypertension. Am J Respir Crit Care Med. 2009;1791A4289
 
Montani D, Perros F, Gambaryan N, et al. C-kit-positive cells accumulate in remodeled vessels of idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2011;1841:116-123 [PubMed]
 
Humbert M, Monti G, Brenot F, et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med. 1995;1515:1628-1631 [PubMed]
 
Soon E, Holmes AM, Treacy CM, et al. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation. 2010;1229:920-927 [PubMed]
 
Sanchez O, Marcos E, Perros F, et al. Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2007;17610:1041-1047 [PubMed]
 
Dorfmüller P, Zarka V, Durand-Gasselin I, et al. Chemokine RANTES in severe pulmonary arterial hypertension. Am J Respir Crit Care Med. 2002;1654:534-539 [PubMed]
 
Balabanian K, Foussat A, Dorfmüller P, et al. CX(3)C chemokine fractalkine in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2002;16510:1419-1425 [PubMed]
 
Diller GP, van Eijl S, Okonko DO, et al. Circulating endothelial progenitor cells in patients with Eisenmenger syndrome and idiopathic pulmonary arterial hypertension. Circulation. 2008;11723:3020-3030 [PubMed]
 
Okawa-Takatsuji M, Aotsuka S, Uwatoko S, Kinoshita M, Sumiya M. 1999. Increase of cytokine production by pulmonary artery endothelial cells induced by supernatants from monocytes stimulated with autoantibodies against U1-ribonucleoprotein. Clin Exp Rheumatol. 1999;176:705-712 [PubMed]
 
Humbert M, Monti G, Fartoukh M, et al. Platelet-derived growth factor expression in primary pulmonary hypertension: comparison of HIV seropositive and HIV seronegative patients. Eur Respir J. 1998;113:554-559 [PubMed]
 
Parent F, Bachir D, Inamo J, et al. A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl J Med. 2011;3651:44-53 [PubMed]
 
Niu X, Nouraie M, Campbell A, et al. Angiogenic and inflammatory markers of cardiopulmonary changes in children and adolescents with sickle cell disease. PLoS ONE. 2009;411:e7956 [PubMed]
 
Lesprit P, Godeau B, Authier FJ, et al. Pulmonary hypertension in POEMS syndrome: a new feature mediated by cytokines. Am J Respir Crit Care Med. 1998;1573 pt 1:907-911 [PubMed]
 
Hachulla E, Gressin V, Guillevin L, et al. Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum. 2005;5212:3792-3800 [PubMed]
 
Asherson RA. Pulmonary hypertension in systemic lupus erythematosus. J Rheumatol. 1990;173:414-415 [PubMed]
 
Fagan KA, Badesch DB. Pulmonary hypertension associated with connective tissue disease. Prog Cardiovasc Dis. 2002;453:225-234 [PubMed]
 
Thurnheer R, Jenni R, Russi EW, Greminger P, Speich R. Hyperthyroidism and pulmonary hypertension. J Intern Med. 1997;2422:185-188 [PubMed]
 
Montani D, Achouh L, Marcelin AG, et al. Reversibility of pulmonary arterial hypertension in HIV/HHV8-associated Castleman’s disease. Eur Respir J. 2005;265:969-972 [PubMed]
 
Kawut SM, Krowka MJ, Trotter JF, et al. Pulmonary Vascular Complications of Liver Disease Study Group Clinical risk factors for portopulmonary hypertension. Hepatology. 2008;481:196-203 [PubMed]
 
Karmochkine M, Wechsler B, Godeau P, Brenot F, Jagot JL, Simonneau G. Improvement of severe pulmonary hypertension in a patient with SLE. Ann Rheum Dis. 1996;558:561-562 [PubMed]
 
Tanaka E, Harigai M, Tanaka M, Kawaguchi Y, Hara M, Kamatani N. Pulmonary hypertension in systemic lupus erythematosus: evaluation of clinical characteristics and response to immunosuppressive treatment. J Rheumatol. 2002;292:282-287 [PubMed]
 
Jais X, Launay D, Yaici A, et al. Immunosuppressive therapy in lupus- and mixed connective tissue disease-associated pulmonary arterial hypertension: a retrospective analysis of twenty-three cases. Arthritis Rheum. 2008;582:521-531 [PubMed]
 
Sanchez O, Sitbon O, Jais X, Simonneau G, Humbert M. Immunosuppressive therapy in connective tissue diseases-associated pulmonary arterial hypertension. Chest. 2006;1301:182-189 [PubMed]
 
Jouve P, Humbert M, Chauveheid MP, Jaïs X, Papo T. POEMS syndrome-related pulmonary hypertension is steroid-responsive. Respir Med. 2007;1012:353-355 [PubMed]
 
Zuber JP, Calmy A, Evison JM, et al. Swiss HIV Cohort Study Group Pulmonary arterial hypertension related to HIV infection: improved hemodynamics and survival associated with antiretroviral therapy. Clin Infect Dis. 2004;388:1178-1185 [PubMed]
 
Barnier A, Frachon I, Dewilde J, Gut-Gobert C, Jobic Y, Leroyer C. Improvement of HIV-related pulmonary hypertension after the introduction of an antiretroviral therapy. Eur Respir J. 2009;341:277-278 [PubMed]
 
Degano B, Guillaume M, Savale L, et al. HIV-associated pulmonary arterial hypertension: survival and prognostic factors in the modern therapeutic era. AIDS. 2010;241:67-75 [PubMed]
 
Sitbon O, Lascoux-Combe C, Delfraissy JF, et al. Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med. 2008;1771:108-113 [PubMed]
 
Song Y, Coleman L, Shi J, et al. Inflammation, endothelial injury, and persistent pulmonary hypertension in heterozygous BMPR2-mutant mice. Am J Physiol Heart Circ Physiol. 2008;2952:H677-H690 [PubMed]
 
Nunes H, Humbert M, Sitbon O, et al. Prognostic factors for survival in human immunodeficiency virus-associated pulmonary arterial hypertension. Am J Respir Crit Care Med. 2003;16710:1433-1439 [PubMed]
 
Mehta NJ, Khan IA, Mehta RN, Sepkowitz DA. HIV-related pulmonary hypertension: analytic review of 131 cases. Chest. 2000;1184:1133-1141 [PubMed]
 
Humbert M. Mediators involved in HIV-related pulmonary arterial hypertension. AIDS. 2008;22suppl 3:S41-S47 [PubMed]
 
Ascherl G, Hohenadl C, Schatz O, et al. Infection with human immunodeficiency virus-1 increases expression of vascular endothelial cell growth factor in T cells: implications for acquired immunodeficiency syndrome-associated vasculopathy. Blood. 1999;9312:4232-4241 [PubMed]
 
Caldwell RL, Gadipatti R, Lane KB, Shepherd VL. HIV-1 TAT represses transcription of the bone morphogenic protein receptor-2 in U937 monocytic cells. J Leukoc Biol. 2006;791:192-201 [PubMed]
 
Mette SA, Palevsky HI, Pietra GG, et al. Primary pulmonary hypertension in association with human immunodeficiency virus infection. A possible viral etiology for some forms of hypertensive pulmonary arteriopathy. Am Rev Respir Dis. 1992;1455:1196-1200 [PubMed]
 
Kanmogne GD, Primeaux C, Grammas P. Induction of apoptosis and endothelin-1 secretion in primary human lung endothelial cells by HIV-1 gp120 proteins. Biochem Biophys Res Commun. 2005;3334:1107-1115 [PubMed]
 
Voelkel NF, Cool CD, Flores S. From viral infection to pulmonary arterial hypertension: a role for viral proteins? AIDS. 2008;22suppl 3:S49-S53 [PubMed]
 
Cool CD, Rai PR, Yeager ME, et al. Expression of human herpesvirus 8 in primary pulmonary hypertension. N Engl J Med. 2003;34912:1113-1122 [PubMed]
 
Bull TM, Meadows CA, Coldren CD, et al. Human herpesvirus-8 infection of primary pulmonary microvascular endothelial cells. Am J Respir Cell Mol Biol. 2008;396:706-716 [PubMed]
 
Durrington HJ, Upton PD, Hoer S, et al. Identification of a lysosomal pathway regulating degradation of the bone morphogenetic protein receptor type II. J Biol Chem. 2010;28548:37641-37649 [PubMed]
 
Hashimoto T, Sakata Y, Fukushima K, et al. Pulmonary arterial hypertension associated with chronic active Epstein-Barr virus infection. Intern Med. 2011;502:119-124 [PubMed]
 
Valmary S, Dorfmüller P, Montani D, Humbert M, Brousset P, Degano B. Human γ-herpesviruses Epstein-Barr virus and human herpesvirus-8 are not detected in the lungs of patients with severe pulmonary arterial hypertension. Chest. 2011;1396:1310-1316 [PubMed]
 
Bendayan D, Sarid R, Cohen A, Shitrit D, Shechtman I, Kramer MR. Absence of human herpesvirus 8 DNA sequences in lung biopsies from Israeli patients with pulmonary arterial hypertension. Respiration. 2008;752:155-157 [PubMed]
 
Henke-Gendo C, Mengel M, Hoeper MM, Alkharsah K, Schulz TF. Absence of Kaposi’s sarcoma-associated herpesvirus in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2005;17212:1581-1585 [PubMed]
 
Graham BB, Bandeira AP, Morrell NW, Butrous G, Tuder RM. Schistosomiasis-associated pulmonary hypertension: pulmonary vascular disease: the global perspective. Chest. 2010;137suppl 6:20S-29S [PubMed]
 
Lapa M, Dias B, Jardim C, et al. Cardiopulmonary manifestations of hepatosplenic schistosomiasis. Circulation. 2009;11911:1518-1523 [PubMed]
 
Tuder RM. Pathology of pulmonary arterial hypertension. Semin Respir Crit Care Med. 2009;304:376-385 [PubMed]
 
Graham BB, Mentink-Kane MM, El-Haddad H, et al. Schistosomiasis-induced experimental pulmonary hypertension: role of interleukin-13 signaling. Am J Pathol. 2010;1773:1549-1561 [PubMed]
 
Posada de la Paz M, Philen RM, Borda AI. Toxic oil syndrome: the perspective after 20 years. Epidemiol Rev. 2001;232:231-247 [PubMed]
 
Gómez-Sánchez MA, Mestre de Juan MJ, Gómez-Pajuelo C, López JI, Díaz de Atauri MJ, Martínez-Tello FJ. Pulmonary hypertension due to toxic oil syndrome. A clinicopathologic study. Chest. 1989;952:325-331 [PubMed]
 
Tazelaar HD, Myers JL, Drage CW, King TE Jr, Aguayo S, Colby TV. Pulmonary disease associated with L-tryptophan-induced eosinophilic myalgia syndrome. Clinical and pathologic features. Chest. 1990;975:1032-1036 [PubMed]
 
Perros F, Dorfmüller P, Souza R, et al. Fractalkine-induced smooth muscle cell proliferation in pulmonary hypertension. Eur Respir J. 2007;295:937-943 [PubMed]
 
Bull TM, Coldren CD, Moore M, et al. Gene microarray analysis of peripheral blood cells in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004;1708:911-919 [PubMed]
 
Quarck R, Nawrot T, Meyns B, Delcroix M. C-reactive protein: a new predictor of adverse outcome in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;5314:1211-1218 [PubMed]
 
Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007;84:345-350 [PubMed]
 
Daley E, Emson C, Guignabert C, et al. Pulmonary arterial remodeling induced by a Th2 immune response. J Exp Med. 2008;2052:361-372 [PubMed]
 
Ulrich S, Nicolls MR, Taraseviciene L, Speich R, Voelkel N. Increased regulatory and decreased CD8+ cytotoxic T cells in the blood of patients with idiopathic pulmonary arterial hypertension. Respiration. 2008;753:272-280 [PubMed]
 
Rich S, Kieras K, Hart K, Groves BM, Stobo JD, Brundage BH. Antinuclear antibodies in primary pulmonary hypertension. J Am Coll Cardiol. 1986;86:1307-1311 [PubMed]
 
Tamby MC, Chanseaud Y, Humbert M, et al. Anti-endothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonary arterial hypertension. Thorax. 2005;609:765-772 [PubMed]
 
Tamby MC, Humbert M, Guilpain P, et al. Antibodies to fibroblasts in idiopathic and scleroderma-associated pulmonary hypertension. Eur Respir J. 2006;284:799-807 [PubMed]
 
Carvalho D, Savage CO, Black CM, Pearson JD. IgG antiendothelial cell autoantibodies from scleroderma patients induce leukocyte adhesion to human vascular endothelial cells in vitro. Induction of adhesion molecule expression and involvement of endothelium-derived cytokines. J Clin Invest. 1996;971:111-119 [PubMed]
 
Bordron A, Dueymes M, Levy Y, et al. The binding of some human antiendothelial cell antibodies induces endothelial cell apoptosis. J Clin Invest. 1998;10110:2029-2035 [PubMed]
 
Gladman DD, Kung TN, Siannis F, Pellett F, Farewell VT, Lee P. HLA markers for susceptibility and expression in scleroderma. J Rheumatol. 2005;328:1481-1487 [PubMed]
 
Vajner L, Vytásek R, Lachmanová V, et al. Acute and chronic hypoxia as well as 7-day recovery from chronic hypoxia affects the distribution of pulmonary mast cells and their MMP-13 expression in rats. Int J Exp Pathol. 2006;875:383-391 [PubMed]
 
Kalesnikoff J, Galli SJ. New developments in mast cell biology. Nat Immunol. 2008;911:1215-1223 [PubMed]
 
Davie NJ, Crossno JT Jr, Frid MG, et al. Hypoxia-induced pulmonary artery adventitial remodeling and neovascularization: contribution of progenitor cells. Am J Physiol Lung Cell Mol Physiol. 2004;2864:L668-L678 [PubMed]
 
Perros F, Montani D, Dorfmüller P, et al. Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;1781:81-88 [PubMed]
 
Hassoun PM, Mouthon L, Barberà JA, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol. 2009;54suppl 1:S10-S19 [PubMed]
 
Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB. Interleukin-6 overexpression induces pulmonary hypertension. Circ Res. 2009;1042:236-244 [PubMed]
 
Li XQ, Wang HM, Yang CG, Zhang XH, Han DD, Wang HL. Fluoxetine inhibited extracellular matrix of pulmonary artery and inflammation of lungs in monocrotaline-treated rats. Acta Pharmacol Sin. 2011;322:217-222 [PubMed]
 
Barnes PJ. Nuclear factor-kappa B. Int J Biochem Cell Biol. 1997;296:867-870 [PubMed]
 
Raychaudhuri B, Dweik R, Connors MJ, et al. Nitric oxide blocks nuclear factor-kappaB activation in alveolar macrophages. Am J Respir Cell Mol Biol. 1999;213:311-316 [PubMed]
 
Hagen M, Fagan K, Steudel W, et al. Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2007;2926:L1473-L1479 [PubMed]
 
Brock M, Trenkmann M, Gay RE, et al. Interleukin-6 modulates the expression of the bone morphogenic protein receptor type II through a novel STAT3-microRNA cluster 17/92 pathway. Circ Res. 2009;10410:1184-1191 [PubMed]
 
Price LC, Montani D, Tcherakian C, et al. Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats. Eur Respir J. 2011;374:813-822 [PubMed]
 
Hecker M, Zaslona Z, Kwapiszewska G, et al. Dysregulation of the IL-13 receptor system: a novel pathomechanism in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2010;1826:805-818 [PubMed]
 
Molet S, Furukawa K, Maghazechi A, Hamid Q, Giaid A. Chemokine- and cytokine-induced expression of endothelin 1 and endothelin-converting enzyme 1 in endothelial cells. J Allergy Clin Immunol. 2000;1052 pt 1:333-338 [PubMed]
 
Heresi GA, Aytekin M, Newman J, Dweik RA. CXC-chemokine ligand 10 in idiopathic pulmonary arterial hypertension: marker of improved survival. Lung. 2010;1883:191-197 [PubMed]
 
Voelkel NF, Tuder RM, Bridges J, Arend WP. Interleukin-1 receptor antagonist treatment reduces pulmonary hypertension generated in rats by monocrotaline. Am J Respir Cell Mol Biol. 1994;116:664-675 [PubMed]
 
Gourh P, Arnett FC, Assassi S, et al. Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations. Arthritis Res Ther. 2009;115:R147 [PubMed]
 
Eddahibi S, Chaouat A, Tu L, et al. Interleukin-6 gene polymorphism confers susceptibility to pulmonary hypertension in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2006;36:475-476 [PubMed]
 
Miyata M, Sakuma F, Yoshimura A, Ishikawa H, Nishimaki T, Kasukawa R. Pulmonary hypertension in rats. 2. Role of interleukin-6. Int Arch Allergy Immunol. 1995;1083:287-291 [PubMed]
 
Savale L, Tu L, Rideau D, et al. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir Res. 2009;10:6 [PubMed]
 
Imaizumi T, Yoshida H, Satoh K. Regulation of CX3CL1/fractalkine expression in endothelial cells. J Atheroscler Thromb. 2004;111:15-21 [PubMed]
 
Bhargava A, Kumar A, Yuan N, Gewitz MH, Mathew R. Monocrotaline induces interleukin-6 mRNA expression in rat lungs. Heart Dis. 1999;13:126-132 [PubMed]
 
Langleben D, Reid LM. Effect of methylprednisolone on monocrotaline-induced pulmonary vascular disease and right ventricular hypertrophy. Lab Invest. 1985;523:298-303 [PubMed]
 
Bonnet S, Rochefort G, Sutendra G, et al. The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proc Natl Acad Sci U S A. 2007;10427:11418-11423 [PubMed]
 
Ikeda Y, Yonemitsu Y, Kataoka C, et al. Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary hypertension in rats. Am J Physiol Heart Circ Physiol. 2002;2835:H2021-H2028 [PubMed]
 
Suzuki C, Takahashi M, Morimoto H, et al. Mycophenolate mofetil attenuates pulmonary arterial hypertension in rats. Biochem Biophys Res Commun. 2006;3492:781-788 [PubMed]
 
Kato T, Kitamura H, Kanisawa M. Comparative effects of isosorbide dinitrate, prednisolone, indomethacin, and elastase on the development of monocrotaline-induced pulmonary hypertension. Exp Mol Pathol. 1989;503:303-315 [PubMed]
 
Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest. 2005;11510:2811-2821 [PubMed]
 
Morelli S, Giordano M, De Marzio P, Priori R, Sgreccia A, Valesini G. Pulmonary arterial hypertension responsive to immunosuppressive therapy in systemic lupus erythematosus. Lupus. 1993;26:367-369 [PubMed]
 
Le Pavec J, Humbert M, Mouthon L, Hassoun PM. Systemic sclerosis-associated pulmonary arterial hypertension. Am J Respir Crit Care Med. 2010;18112:1285-1293 [PubMed]
 
Katsushi H, Kazufumi N, Hideki F, et al. Epoprostenol therapy decreases elevated circulating levels of monocyte chemoattractant protein-1 in patients with primary pulmonary hypertension. Circ J. 2004;683:227-231 [PubMed]
 
Strassheim D, Riddle SR, Burke DL, Geraci MW, Stenmark KR. Prostacyclin inhibits IFN-gamma-stimulated cytokine expression by reduced recruitment of CBP/p300 to STAT1 in a SOCS-1-independent manner. J Immunol. 2009;18311:6981-6988 [PubMed]
 

Figures

Figure Jump LinkFigure 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 ×200).Grahic Jump Location
Figure Jump LinkFigure 2. Diagram illustrating a summary of the theoretic involvement of pulmonary vascular inflammation in the pathogenesis of pulmonary arterial hypertension. BMPR II = bone morphogenetic protein receptor type 2; SMC = smooth muscle cell; Tc = cytotoxic T cell; Th = T helper cell; Treg = T regulatory cell.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Source, Target, and Function of Cytokines and Chemokines Implicated in Pulmonary Vascular Inflammation

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

References

Rubin LJ. Pulmonary arterial hypertension. Proc Am Thorac Soc. 2006;31:111-115 [PubMed] [CrossRef]
 
Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54suppl 1:S43-S54 [PubMed]
 
Lane KB, Machado RD, Pauciulo MW, et al; International PPH Consortium International PPH Consortium Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet. 2000;261:81-84 [PubMed]
 
Machado RD, Aldred MA, James V, et al. Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat. 2006;272:121-132 [PubMed]
 
Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet. 2000;3710:741-745 [PubMed]
 
Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;1222:156-163 [PubMed]
 
Nathan C. Points of control in inflammation. Nature. 2002;4206917:846-852 [PubMed]
 
Zernecke A, Weber C. Inflammatory mediators in atherosclerotic vascular disease. Basic Res Cardiol. 2005;1002:93-101 [PubMed]
 
Raines EW, Ferri N. Thematic review series: the immune system and atherogenesis. Cytokines affecting endothelial and smooth muscle cells in vascular disease. J Lipid Res. 2005;466:1081-1092 [PubMed]
 
Schober A. Chemokines in vascular dysfunction and remodeling. Arterioscler Thromb Vasc Biol. 2008;2811:1950-1959 [PubMed]
 
Stenmark KR, Meyrick B, Galie N, Mooi WJ, McMurtry IF. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol. 2009;2976:L1013-L1032 [PubMed]
 
Sahara M, Sata M, Morita T, Nakamura K, Hirata Y, Nagai R. Diverse contribution of bone marrow-derived cells to vascular remodeling associated with pulmonary arterial hypertension and arterial neointimal formation. Circulation. 2007;1154:509-517 [PubMed]
 
Perros F, Dorfmüller P, Souza R, et al. Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension. Eur Respir J. 2007;293:462-468 [PubMed]
 
Madjdpour C, Jewell UR, Kneller S, et al. Decreased alveolar oxygen induces lung inflammation. Am J Physiol Lung Cell Mol Physiol. 2003;2842:L360-L367 [PubMed]
 
Burke DL, Frid MG, Kunrath CL, et al. Sustained hypoxia promotes the development of a pulmonary artery-specific chronic inflammatory microenvironment. Am J Physiol Lung Cell Mol Physiol. 2009;2972:L238-L250 [PubMed]
 
Frid MG, Brunetti JA, Burke DL, et al. Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol. 2006;1682:659-669 [PubMed]
 
Hong KH, Lee YJ, Lee E, et al. Genetic ablation of the BMPR2 gene in pulmonary endothelium is sufficient to predispose to pulmonary arterial hypertension. Circulation. 2008;1187:722-730 [PubMed]
 
Hamidi SA, Prabhakar S, Said SI. Enhancement of pulmonary vascular remodelling and inflammatory genes with VIP gene deletion. Eur Respir J. 2008;311:135-139 [PubMed]
 
Marecki JC, Cool CD, Parr JE, et al. HIV-1 Nef is associated with complex pulmonary vascular lesions in SHIV-nef-infected macaques. Am J Respir Crit Care Med. 2006;1744:437-445 [PubMed]
 
Crosby A, Jones FM, Southwood M, et al. Pulmonary vascular remodeling correlates with lung eggs and cytokines in murine schistosomiasis. Am J Respir Crit Care Med. 2010;1813:279-288 [PubMed]
 
Taraseviciene-Stewart L, Nicolls MR, Kraskauskas D, et al. Absence of T cells confers increased pulmonary arterial hypertension and vascular remodeling. Am J Respir Crit Care Med. 2007;17512:1280-1289 [PubMed]
 
Cool CD, Kennedy D, Voelkel NF, Tuder RM. Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection. Hum Pathol. 1997;284:434-442 [PubMed]
 
Tuder RM, Groves B, Badesch DB, Voelkel NF. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol. 1994;1442:275-285 [PubMed]
 
Hall S, Brogan P, Haworth SG, Klein N. Contribution of inflammation to the pathology of idiopathic pulmonary arterial hypertension in children. Thorax. 2009;649:778-783 [PubMed]
 
Pinto RF, Higuchi Mde L, Aiello VD. Decreased numbers of T-lymphocytes and predominance of recently recruited macrophages in the walls of peripheral pulmonary arteries from 26 patients with pulmonary hypertension secondary to congenital cardiac shunts. Cardiovasc Pathol. 2004;135:268-275 [PubMed]
 
Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease; a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation. 1958;184 Part 1:533-547 [PubMed]
 
Perros F, Dorfmüller P, Montani D, et al. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am J Resp Crit Care Med. In press.
 
Heath D, Yacoub M. Lung mast cells in plexogenic pulmonary arteriopathy. J Clin Pathol. 1991;4412:1003-1006 [PubMed]
 
Mitani Y, Ueda M, Maruyama K, et al. Mast cell chymase in pulmonary hypertension. Thorax. 1999;541:88-90 [PubMed]
 
Hamada H, Terai M, Kimura H, Hirano K, Oana S, Niimi H. Increased expression of mast cell chymase in the lungs of patients with congenital heart disease associated with early pulmonary vascular disease. Am J Respir Crit Care Med. 1999;1604:1303-1308 [PubMed]
 
Le Pavec J, Montani BGD, Perros F, Savale L, Simonneau G, Sitbon O, Humbert . Circulating dendritic cells in idiopathic pulmonary arterial Hypertension and cirrhotic portopulmonary hypertension. Am J Respir Crit Care Med. 2009;1791A4289
 
Montani D, Perros F, Gambaryan N, et al. C-kit-positive cells accumulate in remodeled vessels of idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2011;1841:116-123 [PubMed]
 
Humbert M, Monti G, Brenot F, et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med. 1995;1515:1628-1631 [PubMed]
 
Soon E, Holmes AM, Treacy CM, et al. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation. 2010;1229:920-927 [PubMed]
 
Sanchez O, Marcos E, Perros F, et al. Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2007;17610:1041-1047 [PubMed]
 
Dorfmüller P, Zarka V, Durand-Gasselin I, et al. Chemokine RANTES in severe pulmonary arterial hypertension. Am J Respir Crit Care Med. 2002;1654:534-539 [PubMed]
 
Balabanian K, Foussat A, Dorfmüller P, et al. CX(3)C chemokine fractalkine in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2002;16510:1419-1425 [PubMed]
 
Diller GP, van Eijl S, Okonko DO, et al. Circulating endothelial progenitor cells in patients with Eisenmenger syndrome and idiopathic pulmonary arterial hypertension. Circulation. 2008;11723:3020-3030 [PubMed]
 
Okawa-Takatsuji M, Aotsuka S, Uwatoko S, Kinoshita M, Sumiya M. 1999. Increase of cytokine production by pulmonary artery endothelial cells induced by supernatants from monocytes stimulated with autoantibodies against U1-ribonucleoprotein. Clin Exp Rheumatol. 1999;176:705-712 [PubMed]
 
Humbert M, Monti G, Fartoukh M, et al. Platelet-derived growth factor expression in primary pulmonary hypertension: comparison of HIV seropositive and HIV seronegative patients. Eur Respir J. 1998;113:554-559 [PubMed]
 
Parent F, Bachir D, Inamo J, et al. A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl J Med. 2011;3651:44-53 [PubMed]
 
Niu X, Nouraie M, Campbell A, et al. Angiogenic and inflammatory markers of cardiopulmonary changes in children and adolescents with sickle cell disease. PLoS ONE. 2009;411:e7956 [PubMed]
 
Lesprit P, Godeau B, Authier FJ, et al. Pulmonary hypertension in POEMS syndrome: a new feature mediated by cytokines. Am J Respir Crit Care Med. 1998;1573 pt 1:907-911 [PubMed]
 
Hachulla E, Gressin V, Guillevin L, et al. Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum. 2005;5212:3792-3800 [PubMed]
 
Asherson RA. Pulmonary hypertension in systemic lupus erythematosus. J Rheumatol. 1990;173:414-415 [PubMed]
 
Fagan KA, Badesch DB. Pulmonary hypertension associated with connective tissue disease. Prog Cardiovasc Dis. 2002;453:225-234 [PubMed]
 
Thurnheer R, Jenni R, Russi EW, Greminger P, Speich R. Hyperthyroidism and pulmonary hypertension. J Intern Med. 1997;2422:185-188 [PubMed]
 
Montani D, Achouh L, Marcelin AG, et al. Reversibility of pulmonary arterial hypertension in HIV/HHV8-associated Castleman’s disease. Eur Respir J. 2005;265:969-972 [PubMed]
 
Kawut SM, Krowka MJ, Trotter JF, et al. Pulmonary Vascular Complications of Liver Disease Study Group Clinical risk factors for portopulmonary hypertension. Hepatology. 2008;481:196-203 [PubMed]
 
Karmochkine M, Wechsler B, Godeau P, Brenot F, Jagot JL, Simonneau G. Improvement of severe pulmonary hypertension in a patient with SLE. Ann Rheum Dis. 1996;558:561-562 [PubMed]
 
Tanaka E, Harigai M, Tanaka M, Kawaguchi Y, Hara M, Kamatani N. Pulmonary hypertension in systemic lupus erythematosus: evaluation of clinical characteristics and response to immunosuppressive treatment. J Rheumatol. 2002;292:282-287 [PubMed]
 
Jais X, Launay D, Yaici A, et al. Immunosuppressive therapy in lupus- and mixed connective tissue disease-associated pulmonary arterial hypertension: a retrospective analysis of twenty-three cases. Arthritis Rheum. 2008;582:521-531 [PubMed]
 
Sanchez O, Sitbon O, Jais X, Simonneau G, Humbert M. Immunosuppressive therapy in connective tissue diseases-associated pulmonary arterial hypertension. Chest. 2006;1301:182-189 [PubMed]
 
Jouve P, Humbert M, Chauveheid MP, Jaïs X, Papo T. POEMS syndrome-related pulmonary hypertension is steroid-responsive. Respir Med. 2007;1012:353-355 [PubMed]
 
Zuber JP, Calmy A, Evison JM, et al. Swiss HIV Cohort Study Group Pulmonary arterial hypertension related to HIV infection: improved hemodynamics and survival associated with antiretroviral therapy. Clin Infect Dis. 2004;388:1178-1185 [PubMed]
 
Barnier A, Frachon I, Dewilde J, Gut-Gobert C, Jobic Y, Leroyer C. Improvement of HIV-related pulmonary hypertension after the introduction of an antiretroviral therapy. Eur Respir J. 2009;341:277-278 [PubMed]
 
Degano B, Guillaume M, Savale L, et al. HIV-associated pulmonary arterial hypertension: survival and prognostic factors in the modern therapeutic era. AIDS. 2010;241:67-75 [PubMed]
 
Sitbon O, Lascoux-Combe C, Delfraissy JF, et al. Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med. 2008;1771:108-113 [PubMed]
 
Song Y, Coleman L, Shi J, et al. Inflammation, endothelial injury, and persistent pulmonary hypertension in heterozygous BMPR2-mutant mice. Am J Physiol Heart Circ Physiol. 2008;2952:H677-H690 [PubMed]
 
Nunes H, Humbert M, Sitbon O, et al. Prognostic factors for survival in human immunodeficiency virus-associated pulmonary arterial hypertension. Am J Respir Crit Care Med. 2003;16710:1433-1439 [PubMed]
 
Mehta NJ, Khan IA, Mehta RN, Sepkowitz DA. HIV-related pulmonary hypertension: analytic review of 131 cases. Chest. 2000;1184:1133-1141 [PubMed]
 
Humbert M. Mediators involved in HIV-related pulmonary arterial hypertension. AIDS. 2008;22suppl 3:S41-S47 [PubMed]
 
Ascherl G, Hohenadl C, Schatz O, et al. Infection with human immunodeficiency virus-1 increases expression of vascular endothelial cell growth factor in T cells: implications for acquired immunodeficiency syndrome-associated vasculopathy. Blood. 1999;9312:4232-4241 [PubMed]
 
Caldwell RL, Gadipatti R, Lane KB, Shepherd VL. HIV-1 TAT represses transcription of the bone morphogenic protein receptor-2 in U937 monocytic cells. J Leukoc Biol. 2006;791:192-201 [PubMed]
 
Mette SA, Palevsky HI, Pietra GG, et al. Primary pulmonary hypertension in association with human immunodeficiency virus infection. A possible viral etiology for some forms of hypertensive pulmonary arteriopathy. Am Rev Respir Dis. 1992;1455:1196-1200 [PubMed]
 
Kanmogne GD, Primeaux C, Grammas P. Induction of apoptosis and endothelin-1 secretion in primary human lung endothelial cells by HIV-1 gp120 proteins. Biochem Biophys Res Commun. 2005;3334:1107-1115 [PubMed]
 
Voelkel NF, Cool CD, Flores S. From viral infection to pulmonary arterial hypertension: a role for viral proteins? AIDS. 2008;22suppl 3:S49-S53 [PubMed]
 
Cool CD, Rai PR, Yeager ME, et al. Expression of human herpesvirus 8 in primary pulmonary hypertension. N Engl J Med. 2003;34912:1113-1122 [PubMed]
 
Bull TM, Meadows CA, Coldren CD, et al. Human herpesvirus-8 infection of primary pulmonary microvascular endothelial cells. Am J Respir Cell Mol Biol. 2008;396:706-716 [PubMed]
 
Durrington HJ, Upton PD, Hoer S, et al. Identification of a lysosomal pathway regulating degradation of the bone morphogenetic protein receptor type II. J Biol Chem. 2010;28548:37641-37649 [PubMed]
 
Hashimoto T, Sakata Y, Fukushima K, et al. Pulmonary arterial hypertension associated with chronic active Epstein-Barr virus infection. Intern Med. 2011;502:119-124 [PubMed]
 
Valmary S, Dorfmüller P, Montani D, Humbert M, Brousset P, Degano B. Human γ-herpesviruses Epstein-Barr virus and human herpesvirus-8 are not detected in the lungs of patients with severe pulmonary arterial hypertension. Chest. 2011;1396:1310-1316 [PubMed]
 
Bendayan D, Sarid R, Cohen A, Shitrit D, Shechtman I, Kramer MR. Absence of human herpesvirus 8 DNA sequences in lung biopsies from Israeli patients with pulmonary arterial hypertension. Respiration. 2008;752:155-157 [PubMed]
 
Henke-Gendo C, Mengel M, Hoeper MM, Alkharsah K, Schulz TF. Absence of Kaposi’s sarcoma-associated herpesvirus in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2005;17212:1581-1585 [PubMed]
 
Graham BB, Bandeira AP, Morrell NW, Butrous G, Tuder RM. Schistosomiasis-associated pulmonary hypertension: pulmonary vascular disease: the global perspective. Chest. 2010;137suppl 6:20S-29S [PubMed]
 
Lapa M, Dias B, Jardim C, et al. Cardiopulmonary manifestations of hepatosplenic schistosomiasis. Circulation. 2009;11911:1518-1523 [PubMed]
 
Tuder RM. Pathology of pulmonary arterial hypertension. Semin Respir Crit Care Med. 2009;304:376-385 [PubMed]
 
Graham BB, Mentink-Kane MM, El-Haddad H, et al. Schistosomiasis-induced experimental pulmonary hypertension: role of interleukin-13 signaling. Am J Pathol. 2010;1773:1549-1561 [PubMed]
 
Posada de la Paz M, Philen RM, Borda AI. Toxic oil syndrome: the perspective after 20 years. Epidemiol Rev. 2001;232:231-247 [PubMed]
 
Gómez-Sánchez MA, Mestre de Juan MJ, Gómez-Pajuelo C, López JI, Díaz de Atauri MJ, Martínez-Tello FJ. Pulmonary hypertension due to toxic oil syndrome. A clinicopathologic study. Chest. 1989;952:325-331 [PubMed]
 
Tazelaar HD, Myers JL, Drage CW, King TE Jr, Aguayo S, Colby TV. Pulmonary disease associated with L-tryptophan-induced eosinophilic myalgia syndrome. Clinical and pathologic features. Chest. 1990;975:1032-1036 [PubMed]
 
Perros F, Dorfmüller P, Souza R, et al. Fractalkine-induced smooth muscle cell proliferation in pulmonary hypertension. Eur Respir J. 2007;295:937-943 [PubMed]
 
Bull TM, Coldren CD, Moore M, et al. Gene microarray analysis of peripheral blood cells in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004;1708:911-919 [PubMed]
 
Quarck R, Nawrot T, Meyns B, Delcroix M. C-reactive protein: a new predictor of adverse outcome in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;5314:1211-1218 [PubMed]
 
Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007;84:345-350 [PubMed]
 
Daley E, Emson C, Guignabert C, et al. Pulmonary arterial remodeling induced by a Th2 immune response. J Exp Med. 2008;2052:361-372 [PubMed]
 
Ulrich S, Nicolls MR, Taraseviciene L, Speich R, Voelkel N. Increased regulatory and decreased CD8+ cytotoxic T cells in the blood of patients with idiopathic pulmonary arterial hypertension. Respiration. 2008;753:272-280 [PubMed]
 
Rich S, Kieras K, Hart K, Groves BM, Stobo JD, Brundage BH. Antinuclear antibodies in primary pulmonary hypertension. J Am Coll Cardiol. 1986;86:1307-1311 [PubMed]
 
Tamby MC, Chanseaud Y, Humbert M, et al. Anti-endothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonary arterial hypertension. Thorax. 2005;609:765-772 [PubMed]
 
Tamby MC, Humbert M, Guilpain P, et al. Antibodies to fibroblasts in idiopathic and scleroderma-associated pulmonary hypertension. Eur Respir J. 2006;284:799-807 [PubMed]
 
Carvalho D, Savage CO, Black CM, Pearson JD. IgG antiendothelial cell autoantibodies from scleroderma patients induce leukocyte adhesion to human vascular endothelial cells in vitro. Induction of adhesion molecule expression and involvement of endothelium-derived cytokines. J Clin Invest. 1996;971:111-119 [PubMed]
 
Bordron A, Dueymes M, Levy Y, et al. The binding of some human antiendothelial cell antibodies induces endothelial cell apoptosis. J Clin Invest. 1998;10110:2029-2035 [PubMed]
 
Gladman DD, Kung TN, Siannis F, Pellett F, Farewell VT, Lee P. HLA markers for susceptibility and expression in scleroderma. J Rheumatol. 2005;328:1481-1487 [PubMed]
 
Vajner L, Vytásek R, Lachmanová V, et al. Acute and chronic hypoxia as well as 7-day recovery from chronic hypoxia affects the distribution of pulmonary mast cells and their MMP-13 expression in rats. Int J Exp Pathol. 2006;875:383-391 [PubMed]
 
Kalesnikoff J, Galli SJ. New developments in mast cell biology. Nat Immunol. 2008;911:1215-1223 [PubMed]
 
Davie NJ, Crossno JT Jr, Frid MG, et al. Hypoxia-induced pulmonary artery adventitial remodeling and neovascularization: contribution of progenitor cells. Am J Physiol Lung Cell Mol Physiol. 2004;2864:L668-L678 [PubMed]
 
Perros F, Montani D, Dorfmüller P, et al. Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;1781:81-88 [PubMed]
 
Hassoun PM, Mouthon L, Barberà JA, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol. 2009;54suppl 1:S10-S19 [PubMed]
 
Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB. Interleukin-6 overexpression induces pulmonary hypertension. Circ Res. 2009;1042:236-244 [PubMed]
 
Li XQ, Wang HM, Yang CG, Zhang XH, Han DD, Wang HL. Fluoxetine inhibited extracellular matrix of pulmonary artery and inflammation of lungs in monocrotaline-treated rats. Acta Pharmacol Sin. 2011;322:217-222 [PubMed]
 
Barnes PJ. Nuclear factor-kappa B. Int J Biochem Cell Biol. 1997;296:867-870 [PubMed]
 
Raychaudhuri B, Dweik R, Connors MJ, et al. Nitric oxide blocks nuclear factor-kappaB activation in alveolar macrophages. Am J Respir Cell Mol Biol. 1999;213:311-316 [PubMed]
 
Hagen M, Fagan K, Steudel W, et al. Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2007;2926:L1473-L1479 [PubMed]
 
Brock M, Trenkmann M, Gay RE, et al. Interleukin-6 modulates the expression of the bone morphogenic protein receptor type II through a novel STAT3-microRNA cluster 17/92 pathway. Circ Res. 2009;10410:1184-1191 [PubMed]
 
Price LC, Montani D, Tcherakian C, et al. Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats. Eur Respir J. 2011;374:813-822 [PubMed]
 
Hecker M, Zaslona Z, Kwapiszewska G, et al. Dysregulation of the IL-13 receptor system: a novel pathomechanism in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2010;1826:805-818 [PubMed]
 
Molet S, Furukawa K, Maghazechi A, Hamid Q, Giaid A. Chemokine- and cytokine-induced expression of endothelin 1 and endothelin-converting enzyme 1 in endothelial cells. J Allergy Clin Immunol. 2000;1052 pt 1:333-338 [PubMed]
 
Heresi GA, Aytekin M, Newman J, Dweik RA. CXC-chemokine ligand 10 in idiopathic pulmonary arterial hypertension: marker of improved survival. Lung. 2010;1883:191-197 [PubMed]
 
Voelkel NF, Tuder RM, Bridges J, Arend WP. Interleukin-1 receptor antagonist treatment reduces pulmonary hypertension generated in rats by monocrotaline. Am J Respir Cell Mol Biol. 1994;116:664-675 [PubMed]
 
Gourh P, Arnett FC, Assassi S, et al. Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations. Arthritis Res Ther. 2009;115:R147 [PubMed]
 
Eddahibi S, Chaouat A, Tu L, et al. Interleukin-6 gene polymorphism confers susceptibility to pulmonary hypertension in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2006;36:475-476 [PubMed]
 
Miyata M, Sakuma F, Yoshimura A, Ishikawa H, Nishimaki T, Kasukawa R. Pulmonary hypertension in rats. 2. Role of interleukin-6. Int Arch Allergy Immunol. 1995;1083:287-291 [PubMed]
 
Savale L, Tu L, Rideau D, et al. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir Res. 2009;10:6 [PubMed]
 
Imaizumi T, Yoshida H, Satoh K. Regulation of CX3CL1/fractalkine expression in endothelial cells. J Atheroscler Thromb. 2004;111:15-21 [PubMed]
 
Bhargava A, Kumar A, Yuan N, Gewitz MH, Mathew R. Monocrotaline induces interleukin-6 mRNA expression in rat lungs. Heart Dis. 1999;13:126-132 [PubMed]
 
Langleben D, Reid LM. Effect of methylprednisolone on monocrotaline-induced pulmonary vascular disease and right ventricular hypertrophy. Lab Invest. 1985;523:298-303 [PubMed]
 
Bonnet S, Rochefort G, Sutendra G, et al. The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proc Natl Acad Sci U S A. 2007;10427:11418-11423 [PubMed]
 
Ikeda Y, Yonemitsu Y, Kataoka C, et al. Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary hypertension in rats. Am J Physiol Heart Circ Physiol. 2002;2835:H2021-H2028 [PubMed]
 
Suzuki C, Takahashi M, Morimoto H, et al. Mycophenolate mofetil attenuates pulmonary arterial hypertension in rats. Biochem Biophys Res Commun. 2006;3492:781-788 [PubMed]
 
Kato T, Kitamura H, Kanisawa M. Comparative effects of isosorbide dinitrate, prednisolone, indomethacin, and elastase on the development of monocrotaline-induced pulmonary hypertension. Exp Mol Pathol. 1989;503:303-315 [PubMed]
 
Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest. 2005;11510:2811-2821 [PubMed]
 
Morelli S, Giordano M, De Marzio P, Priori R, Sgreccia A, Valesini G. Pulmonary arterial hypertension responsive to immunosuppressive therapy in systemic lupus erythematosus. Lupus. 1993;26:367-369 [PubMed]
 
Le Pavec J, Humbert M, Mouthon L, Hassoun PM. Systemic sclerosis-associated pulmonary arterial hypertension. Am J Respir Crit Care Med. 2010;18112:1285-1293 [PubMed]
 
Katsushi H, Kazufumi N, Hideki F, et al. Epoprostenol therapy decreases elevated circulating levels of monocyte chemoattractant protein-1 in patients with primary pulmonary hypertension. Circ J. 2004;683:227-231 [PubMed]
 
Strassheim D, Riddle SR, Burke DL, Geraci MW, Stenmark KR. Prostacyclin inhibits IFN-gamma-stimulated cytokine expression by reduced recruitment of CBP/p300 to STAT1 in a SOCS-1-independent manner. J Immunol. 2009;18311:6981-6988 [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543