Inflammation in Pulmonary Arterial Hypertension

  • Frédéric Perros
  • Sylvia Cohen-Kaminsky
  • Peter Dorfmüller
  • Alice Huertas
  • Marie-Camille Chaumais
  • David Montani
  • Marc Humbert


The pathophysiology of PAH is not fully elucidated and no curative treatment is yet available. However, the presence of inflammatory cells and the intense release of inflammatory mediators in pulmonary PAH lesions, associated with the high level of pro-inflammatory cytokines and of autoantibodies targeting vascular components in the sera of patients, raise the question of the involvement of inflammation and autoimmunity in the initiation, the perpetuation, and/or the worsening of the ­disease. This review covers PAH immunopathological aspects with a special emphasis on the role of inflammation on the pulmonary vascular remodeling, the potential immunopathological mechanisms of PAH, the relevance of inflammatory mediators as prognostic and predictive markers in PAH, and on the immunomodulatory properties of current PAH therapies.


Pulmonary Arterial Hypertension Pulmonary Arterial Hypertension Patient Pulmonary Vascular Remodel Perivascular Inflammatory Infiltrate IPAH Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Frederic Perros and the team from the INSERM U999 unit are supported by FRM (Fondation pour la Recherche Médicale), team FRM 2010, grant DEQ20100318257.

Peter Dorfmüller and David Montani are supported by the Association HTAPFrance.


  1. 1.
    Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2009;34(6):1219–63.PubMedGoogle Scholar
  2. 2.
    Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351(14):1425–36.PubMedGoogle Scholar
  3. 3.
    Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S43–54.PubMedGoogle Scholar
  4. 4.
    Girerd B, Montani D, Coulet F, et al. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med. 2010;181(8):851–61.PubMedGoogle Scholar
  5. 5.
    Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest. 2005;115(10):2811–21.PubMedGoogle Scholar
  6. 6.
    Klein M, Schermuly RT, Ellinghaus P, et al. Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling. Circulation. 2008;118(20):2081–90.PubMedGoogle Scholar
  7. 7.
    Perros F, Montani D, Dorfmuller P, et al. Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;178(1):81–8.PubMedGoogle Scholar
  8. 8.
    Souza R, Sitbon O, Parent F, Simonneau G, Humbert M. Long term imatinib treatment in pulmonary arterial hypertension. Thorax. 2006;61(8):736.PubMedGoogle Scholar
  9. 9.
    Chen MH, Kerkela R, Force T. Mechanisms of cardiac dysfunction associated with tyrosine kinase inhibitor cancer therapeutics. Circulation. 2008;118(1):84–95.PubMedGoogle Scholar
  10. 10.
    Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006;12(8):908–16.PubMedGoogle Scholar
  11. 11.
    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;151(5):1628–31.PubMedGoogle Scholar
  12. 12.
    Balabanian K, Foussat A, Dorfmuller P, et al. CX(3)C chemokine fractalkine in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2002;165(10):1419–25.PubMedGoogle Scholar
  13. 13.
    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;176(10):1041–7.PubMedGoogle Scholar
  14. 14.
    Dorfmuller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J. 2003;22(2):358–63.PubMedGoogle Scholar
  15. 15.
    Tamby MC, Chanseaud Y, Humbert M, et al. Anti-endothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonary arterial hypertension. Thorax. 2005;60(9):765–72.PubMedGoogle Scholar
  16. 16.
    Terrier B, Tamby MC, Camoin L, et al. Identification of target antigens of antifibroblast antibo­dies in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;177(10):1128–34.PubMedGoogle Scholar
  17. 17.
    Price LC, Montani D, Tcherakian C, et al. Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats. Eur Respir J. 2011;37(4):813–22.PubMedGoogle Scholar
  18. 18.
    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;11(6):664–75.PubMedGoogle Scholar
  19. 19.
    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;283(5):H2021–8.PubMedGoogle Scholar
  20. 20.
    Jouve P, Humbert M, Chauveheid MP, Jais X, Papo T. POEMS syndrome-related pulmonary hypertension is steroid-responsive. Respir Med. 2007;101(2):353–5.PubMedGoogle Scholar
  21. 21.
    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;58(2):521–31.PubMedGoogle Scholar
  22. 22.
    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;18(4 Part 1):533–47.PubMedGoogle Scholar
  23. 23.
    Perros F, Dorfmuller P, Souza R, et al. Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension. Eur Respir J. 2007;29(3):462–8.PubMedGoogle Scholar
  24. 24.
    Wilson DW, Segall HJ, Pan LC, Dunston SK. Progressive inflammatory and structural changes in the pulmonary vasculature of monocrotaline-treated rats. Microvasc Res. 1989;38(1):57–80.PubMedGoogle Scholar
  25. 25.
    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;297(6):L1013–32.PubMedGoogle Scholar
  26. 26.
    Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB. Interleukin-6 overexpression induces pulmonary hypertension. Circ Res. 2009;104(2):236–44, 28p following 44.PubMedGoogle Scholar
  27. 27.
    Hamidi SA, Prabhakar S, Said SI. Enhancement of pulmonary vascular remodelling and inflammatory genes with VIP gene deletion. Eur Respir J. 2008;31(1):135–9.PubMedGoogle Scholar
  28. 28.
    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;295(2):H677–90.PubMedGoogle Scholar
  29. 29.
    Daley E, Emson C, Guignabert C, et al. Pulmonary arterial remodeling induced by a Th2 immune response. J Exp Med. 2008;205(2):361–72.PubMedGoogle Scholar
  30. 30.
    Medoff BD, Okamoto Y, Leyton P, et al. Adiponectin deficiency increases allergic airway inflammation and pulmonary vascular remodeling. Am J Respir Cell Mol Biol. 2009;41(4):397–406.PubMedGoogle Scholar
  31. 31.
    Sehgal PB, Mukhopadhyay S, Patel K, et al. Golgi dysfunction is a common feature in idiopathic human pulmonary hypertension and vascular lesions in SHIV-nef-infected macaques. Am J Physiol Lung Cell Mol Physiol. 2009;297(4):L729–37.PubMedGoogle Scholar
  32. 32.
    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;181(3):279–88.PubMedGoogle Scholar
  33. 33.
    Perros F, Dorfmuller P, Souza R, et al. Fractalkine-induced smooth muscle cell proliferation in pulmonary hypertension. Eur Respir J. 2007;29(5):937–43.PubMedGoogle Scholar
  34. 34.
    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.PubMedGoogle Scholar
  35. 35.
    Swain SD, Han S, Harmsen A, Shampeny K, Harmsen AG. Pulmonary hypertension can be a sequela of prior Pneumocystis pneumonia. Am J Pathol. 2007;171(3):790–9.PubMedGoogle Scholar
  36. 36.
    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;292(6):L1473–9.PubMedGoogle Scholar
  37. 37.
    Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531–62.PubMedGoogle Scholar
  38. 38.
    Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol. 2010;11(1):7–13.PubMedGoogle Scholar
  39. 39.
    Baecher-Allan C, Hafler DA. Suppressor T cells in human diseases. J Exp Med. 2004;200(3):273–6.PubMedGoogle Scholar
  40. 40.
    Crispin JC, Martinez A, Alcocer-Varela J. Quantification of regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun. 2003;21(3):273–6.PubMedGoogle Scholar
  41. 41.
    de Kleer IM, Wedderburn LR, Taams LS, et al. CD4  +  CD25 bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis. J Immunol. 2004;172(10):6435–43.PubMedGoogle Scholar
  42. 42.
    Kriegel MA, Lohmann T, Gabler C, Blank N, Kalden JR, Lorenz HM. Defective suppressor function of human CD4+ CD25+ regulatory T cells in autoimmune polyglandular syndrome type II. J Exp Med. 2004;199(9):1285–91.PubMedGoogle Scholar
  43. 43.
    Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4  +  CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004;199(7):971–9.PubMedGoogle Scholar
  44. 44.
    Matarese G, Carrieri PB, La Cava A, et al. Leptin increase in multiple sclerosis associates with reduced number of CD4(+)CD25+ regulatory T cells. Proc Natl Acad Sci USA. 2005;102(14):5150–5.PubMedGoogle Scholar
  45. 45.
    Nicolls MR, Taraseviciene-Stewart L, Rai PR, Badesch DB, Voelkel NF. Autoimmunity and pulmonary hypertension: a perspective. Eur Respir J. 2005;26(6):1110–8.PubMedGoogle Scholar
  46. 46.
    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;75(3):272–80.PubMedGoogle Scholar
  47. 47.
    Austin ED, Rock MT, Mosse CA, et al. T lymphocyte subset abnormalities in the blood and lung in pulmonary arterial hypertension. Respir Med. 2010;104(3):454–62.PubMedGoogle Scholar
  48. 48.
    Perros F, Cohen-Kaminsky S, Humbert M. Understanding the role of CD4  +  CD25 (high) (so-called regulatory) T cells in idiopathic pulmonary arterial hypertension. Respiration. 2008;75(3):253–6.PubMedGoogle Scholar
  49. 49.
    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;52(12):3792–800.PubMedGoogle Scholar
  50. 50.
    Haroon N, Nisha RS, Chandran V, Bharadwaj A. Pulmonary hypertension not a major feature of early mixed connective tissue disease: a prospective clinicoserological study. J Postgrad Med. 2005;51(2):104–7. discussion 7–8.PubMedGoogle Scholar
  51. 51.
    Fois E, Le Guern V, Dupuy A, Humbert M, Mouthon L, Guillevin L. Noninvasive assessment of systolic pulmonary artery pressure in systemic lupus erythematosus: retrospective analysis of 93 patients. Clin Exp Rheumatol. 2010;28(6):836–41.PubMedGoogle Scholar
  52. 52.
    Launay D, Hachulla E, Hatron PY, Jais X, Simonneau G, Humbert M. Pulmonary arterial hypertension: a rare complication of primary Sjogren syndrome: report of 9 new cases and review of the literature. Medicine (Baltimore). 2007;86(5):299–315.Google Scholar
  53. 53.
    Nunes H, Humbert M, Capron F, et al. Pulmonary hypertension associated with sarcoidosis: mechanisms, haemodynamics and prognosis. Thorax. 2006;61(1):68–74.PubMedGoogle Scholar
  54. 54.
    Minai OA. Pulmonary hypertension in polymyositis-dermatomyositis: clinical and hemodynamic characteristics and response to vasoactive therapy. Lupus. 2009;18(11):1006–10.PubMedGoogle Scholar
  55. 55.
    Chu JW, Kao PN, Faul JL, Doyle RL. High prevalence of autoimmune thyroid disease in pulmonary arterial hypertension. Chest. 2002;122(5):1668–73.PubMedGoogle Scholar
  56. 56.
    Launay D, Souza R, Guillevin L, et al. Pulmonary arterial hypertension in ANCA-associated vasculitis. Sarcoidosis Vasc Diffuse Lung Dis. 2006;23(3):223–8.PubMedGoogle Scholar
  57. 57.
    Garcia-Hernandez FJ, Ocana-Medina C, Gonzalez-Leon R, Garrido-Rasco R, Sanchez-Roman J. Autoimmune polyglandular syndrome and pulmonary arterial hypertension. Eur Respir J. 2006;27(3):657–8.PubMedGoogle Scholar
  58. 58.
    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;177(1):108–13.PubMedGoogle Scholar
  59. 59.
    Lapa M, Dias B, Jardim C, et al. Cardiopulmonary manifestations of hepatosplenic schistosomiasis. Circulation. 2009;119(11):1518–23.PubMedGoogle Scholar
  60. 60.
    Montani D, Achouh L, Marcelin AG, et al. Reversibility of pulmonary arterial hypertension in HIV/HHV8-associated Castleman’s disease. Eur Respir J. 2005;26(5):969–72.PubMedGoogle Scholar
  61. 61.
    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;144(2):275–85.PubMedGoogle Scholar
  62. 62.
    Karmochkine M, Cacoub P, Dorent R, et al. High prevalence of antiphospholipid antibodies in precapillary pulmonary hypertension. J Rheumatol. 1996;23(2):286–90.PubMedGoogle Scholar
  63. 63.
    Riboldi P, Gerosa M, Raschi E, Testoni C, Meroni PL. Endothelium as a target for antiphospholipid antibodies. Immunobiology. 2003;207(1):29–36.PubMedGoogle Scholar
  64. 64.
    Mouthon L, Guillevin L, Humbert M. Pulmonary arterial hypertension: an autoimmune disease? Eur Respir J. 2005;26(6):986–8.PubMedGoogle Scholar
  65. 65.
    Arends SJ, Damoiseaux J, Duijvestijn A, et al. Prevalence of anti-endothelial cell antibodies in idiopathic pulmonary arterial hypertension. Eur Respir J. 2010;35(4):923–5.PubMedGoogle Scholar
  66. 66.
    Taraseviciene-Stewart L, Kasahara Y, Alger L, et al. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J. 2001;15(2):427–38.PubMedGoogle Scholar
  67. 67.
    Renaudineau Y, Dugue C, Dueymes M, Youinou P. Antiendothelial cell antibodies in systemic lupus erythematosus. Autoimmun Rev. 2002;1(6):365–72.PubMedGoogle Scholar
  68. 68.
    Negi VS, Tripathy NK, Misra R, Nityanand S. Antiendothelial cell antibodies in scleroderma correlate with severe digital ischemia and pulmonary arterial hypertension. J Rheumatol. 1998;25(3):462–6.PubMedGoogle Scholar
  69. 69.
    Li MT, Ai J, Tian Z, et al. Prevalence of anti-endothelial cell antibodies in patients with pulmonary arterial hypertension associated with connective tissue diseases. Chin Med Sci J. 2010;25(1):27–31.PubMedGoogle Scholar
  70. 70.
    Quismorio Jr FP, Sharma O, Koss M, et al. Immunopathologic and clinical studies in pulmonary hypertension associated with systemic lupus erythematosus. Semin Arthritis Rheum. 1984;13(4):349–59.PubMedGoogle Scholar
  71. 71.
    Nakagawa N, Osanai S, Ide H, et al. Severe pulmonary hypertension associated with primary Sjogren’s syndrome. Intern Med. 2003;42(12):1248–52.PubMedGoogle Scholar
  72. 72.
    Heath D, Yacoub M. Lung mast cells in plexogenic pulmonary arteriopathy. J Clin Pathol. 1991;44(12):1003–6.PubMedGoogle Scholar
  73. 73.
    Tucker A, McMurtry IF, Alexander AF, Reeves JT, Grover RF. Lung mast cell density and distribution in chronically hypoxic animals. J Appl Physiol. 1977;42(2):174–8.PubMedGoogle Scholar
  74. 74.
    Benoist C, Mathis D. Mast cells in autoimmune disease. Nature. 2002;420(6917):875–8.PubMedGoogle Scholar
  75. 75.
    Satoh T, Kimura K, Okano Y, Hirakata M, Kawakami Y, Kuwana M. Lack of circulating autoantibodies to bone morphogenetic protein receptor-II or activin receptor-like kinase 1 in mixed connective tissue disease patients with pulmonary arterial hypertension. Rheumatology (Oxford). 2005;44(2):192–6.Google Scholar
  76. 76.
    Tamby MC, Humbert M, Guilpain P, et al. Antibodies to fibroblasts in idiopathic and ­scleroderma-associated pulmonary hypertension. Eur Respir J. 2006;28(4):799–807.PubMedGoogle Scholar
  77. 77.
    Terrier B, Tamby MC, Camoin L, et al. Antifibroblast antibodies from systemic sclerosis patients bind to {alpha}-enolase and are associated with interstitial lung disease. Ann Rheum Dis. 2010;69(2):428–33.PubMedGoogle Scholar
  78. 78.
    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;53(14):1211–8.PubMedGoogle Scholar
  79. 79.
    Soon E, Holmes AM, Treacy CM, et al. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation. 2010;122(9):920–7.PubMedGoogle Scholar
  80. 80.
    Otterdal K, Smith C, Oie E, et al. Platelet-derived LIGHT induces inflammatory responses in endothelial cells and monocytes. Blood. 2006;108(3):928–35.PubMedGoogle Scholar
  81. 81.
    Otterdal K, Andreassen AK, Yndestad A, et al. Raised LIGHT levels in pulmonary arterial hypertension: potential role in thrombus formation. Am J Respir Crit Care Med. 2008;177(2):202–7.PubMedGoogle Scholar
  82. 82.
    Heresi GA, Aytekin M, Newman J, Dweik RA. CXC-chemokine ligand 10 in idiopathic pulmonary arterial hypertension: marker of improved survival. Lung. 2010;188(3):191–7.PubMedGoogle Scholar
  83. 83.
    Idzko M, Hammad H, van Nimwegen M, et al. Inhaled iloprost suppresses the cardinal features of asthma via inhibition of airway dendritic cell function. J Clin Invest. 2007;117(2):464–72.PubMedGoogle Scholar
  84. 84.
    Jaffar Z, Ferrini ME, Buford MC, Fitzgerald GA, Roberts K. Prostaglandin I2-IP signaling blocks allergic pulmonary inflammation by preventing recruitment of CD4+ Th2 cells into the airways in a mouse model of asthma. J Immunol. 2007;179(9):6193–203.PubMedGoogle Scholar
  85. 85.
    Zhou W, Hashimoto K, Goleniewska K, et al. Prostaglandin I2 analogs inhibit proinflammatory cytokine production and T cell stimulatory function of dendritic cells. J Immunol. 2007;178(2):702–10.PubMedGoogle Scholar
  86. 86.
    Raychaudhuri B, Malur A, Bonfield TL, et al. The prostacyclin analogue treprostinil blocks NFkappaB nuclear translocation in human alveolar macrophages. J Biol Chem. 2002;277(36):33344–8.PubMedGoogle Scholar
  87. 87.
    Zardi EM, Zardi DM, Cacciapaglia F, et al. Endothelial dysfunction and activation as an expression of disease: role of prostacyclin analogs. Int Immunopharmacol. 2005;5(3):437–59.PubMedGoogle Scholar
  88. 88.
    Goya K, Otsuki M, Xu X, Kasayama S. Effects of the prostaglandin I2 analogue, beraprost sodium, on vascular cell adhesion molecule-1 expression in human vascular endothelial cells and circulating vascular cell adhesion molecule-1 level in patients with type 2 diabetes mellitus. Metabolism. 2003;52(2):192–8.PubMedGoogle Scholar
  89. 89.
    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;68(3):227–31.PubMedGoogle Scholar
  90. 90.
    Rose F, Hattar K, Gakisch S, et al. Increased neutrophil mediator release in patients with pulmonary hypertension–suppression by inhaled iloprost. Thromb Haemost. 2003;90(6):1141–9.PubMedGoogle Scholar
  91. 91.
    Oudiz RJ, Farber HW. Dosing considerations in the use of intravenous prostanoids in pulmonary arterial hypertension: an experience-based review. Am Heart J. 2009;157(4):625–35.PubMedGoogle Scholar
  92. 92.
    Aronoff DM, Peres CM, Serezani CH, et al. Synthetic prostacyclin analogs differentially regulate macrophage function via distinct analog-receptor binding specificities. J Immunol. 2007;178(3):1628–34.PubMedGoogle Scholar
  93. 93.
    Browatzki M, Schmidt J, Kubler W, Kranzhofer R. Endothelin-1 induces interleukin-6 release via activation of the transcription factor NF-kappaB in human vascular smooth muscle cells. Basic Res Cardiol. 2000;95(2):98–105.PubMedGoogle Scholar
  94. 94.
    Helset E, Lindal S, Olsen R, Myklebust R, Jorgensen L. Endothelin-1 causes sequential trapping of platelets and neutrophils in pulmonary microcirculation in rats. Am J Physiol. 1996;271(4 Pt 1):L538–46.PubMedGoogle Scholar
  95. 95.
    Finsnes F, Skjonsberg OH, Tonnessen T, Naess O, Lyberg T, Christensen G. Endothelin production and effects of endothelin antagonism during experimental airway inflammation. Am J Respir Crit Care Med. 1997;155(4):1404–12.PubMedGoogle Scholar
  96. 96.
    Finsnes F, Lyberg T, Christensen G, Skjonsberg OH. Effect of endothelin antagonism on the production of cytokines in eosinophilic airway inflammation. Am J Physiol Lung Cell Mol Physiol. 2001;280(4):L659–65.PubMedGoogle Scholar
  97. 97.
    Verma S, Li SH, Badiwala MV, et al. Endothelin antagonism and interleukin-6 inhibition attenuate the proatherogenic effects of C-reactive protein. Circulation. 2002;105(16):1890–6.PubMedGoogle Scholar
  98. 98.
    Uhlmann D, Gabel G, Ludwig S, et al. Effects of ET(A) receptor antagonism on proinflammatory gene expression and microcirculation following hepatic ischemia/reperfusion. Micro­circulation. 2005;12(5):405–19.PubMedGoogle Scholar
  99. 99.
    Hauck EF, Hoffmann JF, Heimann A, Kempski O. EndothelinA receptor antagonist BSF-208075 causes immune modulation and neuroprotection after stroke in gerbils. Brain Res. 2007;1157:138–45.PubMedGoogle Scholar
  100. 100.
    Guruli G, Pflug BR, Pecher S, Makarenkova V, Shurin MR, Nelson JB. Function and survival of dendritic cells depend on endothelin-1 and endothelin receptor autocrine loops. Blood. 2004;104(7):2107–15.PubMedGoogle Scholar
  101. 101.
    Karavolias GK, Georgiadou P, Gkouziouta A, et al. Short and long term anti-inflammatory effects of bosentan therapy in patients with pulmonary arterial hypertension: relation to clinical and hemodynamic responses. Expert Opin Ther Targets. 2010;14(12):1283–9.PubMedGoogle Scholar
  102. 102.
    Wang T, Liu Y, Chen L, et al. Effect of sildenafil on acrolein-induced airway inflammation and mucus production in rats. Eur Respir J. 2009;33(5):1122–32.PubMedGoogle Scholar
  103. 103.
    Toward TJ, Smith N, Broadley KJ. Effect of phosphodiesterase-5 inhibitor, sildenafil (Viagra), in animal models of airways disease. Am J Respir Crit Care Med. 2004;169(2):227–34.PubMedGoogle Scholar
  104. 104.
    Serafini P, Meckel K, Kelso M, et al. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med. 2006;203(12):2691–702.PubMedGoogle Scholar
  105. 105.
    Shenoy P, Agarwal V. Phosphodiesterase inhibitors in the management of autoimmune disease. Autoimmun Rev. 2010;9(7):511–5.PubMedGoogle Scholar
  106. 106.
    Dewar AL, Domaschenz RM, Doherty KV, Hughes TP, Lyons AB. Imatinib inhibits the in vitro development of the monocyte/macrophage lineage from normal human bone marrow progenitors. Leukemia. 2003;17(9):1713–21.PubMedGoogle Scholar
  107. 107.
    Seggewiss R, Price DA, Purbhoo MA. Immunomodulatory effects of imatinib and second-generation tyrosine kinase inhibitors on T cells and dendritic cells: an update. Cytotherapy. 2008;10(6):633–41.PubMedGoogle Scholar
  108. 108.
    Appel S, Boehmler AM, Grunebach F, et al. Imatinib mesylate affects the development and function of dendritic cells generated from CD34+ peripheral blood progenitor cells. Blood. 2004;103(2):538–44.PubMedGoogle Scholar
  109. 109.
    Taieb J, Chaput N, Menard C, et al. A novel dendritic cell subset involved in tumor immunosurveillance. Nat Med. 2006;12(2):214–9.PubMedGoogle Scholar

Copyright information

© Springer-Verlag London Limited 2012

Authors and Affiliations

  • Frédéric Perros
    • 1
    • 2
    • 3
    • 4
    • 5
  • Sylvia Cohen-Kaminsky
    • 1
    • 2
    • 3
    • 4
  • Peter Dorfmüller
    • 1
    • 2
    • 3
    • 4
  • Alice Huertas
    • 1
    • 2
    • 3
    • 4
  • Marie-Camille Chaumais
    • 1
    • 3
    • 4
    • 6
  • David Montani
    • 1
    • 2
    • 3
    • 4
  • Marc Humbert
    • 1
    • 2
    • 3
    • 4
  1. 1.Faculté de médecineUniv. Paris-SudParisFrance
  2. 2.Service de Pneumologie et Réanimation Respiratoire, AP-HP, Centre National de Référence de l’Hypertension Pulmonaire SévèreHôpital Antoine BéclèreClamartFrance
  3. 3.INSERM U999, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation ThérapeutiqueLe Plessis-RobinsonFrance
  4. 4.Centre Chirurgical Marie LannelongueLe Plessis-RobinsonFrance
  5. 5.INSERM U999, Centre Chirurgical Marie LannelongueLe Plessis-RobinsonFrance
  6. 6.Service de pharmacieHôpital Antoine Béclère, Assistance Publique des Hôpitaux de ParisClamartFrance

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