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Key inflammatory pathways underlying vascular remodeling in pulmonary hypertension

Bedeutsame inflammatorische Signalwege für vaskuläres Remodeling bei pulmonaler Hypertonie

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Abstract

Independent of the underlying cause, pulmonary hypertension (PH) remains a devastating condition that is characterized by limited survival. Cumulating evidence indicates that in addition to a dysbalance of mediators regulating vascular tone and growth factors promoting vascular remodeling, failure to resolve inflammation and altered immune processes play a pivotal role in the development and progression of PH. Here, we highlight the role of key inflammatory pathways in the pathobiology of vascular remodeling and PH, and discuss potential therapeutic interventions that may halt disease progression or even reverse pulmonary vascular remodeling. Perivascular inflammation is present in all forms of PH, and inflammatory pathways involve numerous mediators and cell types including macrophages, neutrophils, T cells, dendritic cells, and mast cells. Dysfunctional bone morphogenic protein receptor 2 (BMPR2) signaling and dysregulated immunity enable the accumulation of macrophages and other inflammatory cells in obliterative vascular lesions. Regulatory T cells (Tregs) were shown to be of particular relevance in the control of inflammatory responses. Key cytokines/chemokines include interleukin-6, functioning via classic or trans-signaling, macrophage migratory inhibitory factor (MIF), but also other mediators such as neutrophil-derived myeloperoxidase. The expanding knowledge on this topic has resulted in multiple opportunities for sophisticated therapeutic interventions.

Zusammenfassung

Unabhängig von der zugrunde liegenden Ursache bleibt die pulmonale Hypertonie (PH) eine schwerwiegende Erkrankung mit reduzierter Lebenserwartung. Aktuelle Studien zeigen, dass neben einem Ungleichgewicht bei vasoaktiven Mediatoren und Wachstumsfaktoren insbesondere dysregulierte inflammatorische Prozesse sowie eine veränderte Immunität eine entscheidende Rolle für die Entstehung und Progression einer PH spielen. Die Autoren fassen die Rolle bedeutsamer inflammatorischer Signalwege in der Pathobiologie des vaskulären Remodelings und der PH zusammen und präsentieren potenzielle therapeutische Interventionen, welche pulmonal vaskulärem Remodeling entgegenwirken könnten. Perivaskuläre Inflammation findet sich bei allen Formen der PH, und inflammatorische Signalwege umfassen zahlreiche Mediatoren und Zelltypen (Makrophagen, Neutrophile, T‑Zellen, dendritische Zellen und Mastzellen). Dysfunktionelle „bone morphogenic protein receptor 2“ (BMPR2) Signale und fehlregulierte Immunität ermöglichen die Akkumulation von Makrophagen und anderen inflammatorischen Zellen in obliterativen vaskulären Läsionen. Regulatorische T‑Zellen (Tregs) sind für die Kontrolle inflammatorischer Prozesse von besonderer Bedeutung. Zu den wichtigsten Zytokinen/Chemokinen gehören Interleukin-6, welches durch klassisches oder „trans-signaling“ fungiert, der „macrophage migratory inhibitory factor“ (MIF), sowie andere Mediatoren wie aus Neutrophilen freigesetzte Myeloperoxidase. Das zunehmende Verständnis dieser Zusammenhänge bietet multiple Möglichkeiten für neuartige therapeutische Interventionen.

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References

  1. Galiè N, Humbert M, Vachiery JL et al (2015) ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016(37):67–119

    Google Scholar 

  2. Hoeper MM, Humbert M, Souza R et al (2016) A global view of pulmonary hypertension. Lancet Respir Med 4:306–322

    Article  PubMed  Google Scholar 

  3. Simmoneau G, Montani D, Celermayer DS et al (2019) Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 53(1):1801913

    Article  CAS  Google Scholar 

  4. Humbert M, Guignabert C, Bonnet S et al (2019) Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. Eur Respir J 53(1):1801887

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Olschewski A, Berghausen EM, Eichstaedt CA et al (2018) Pathobiology, pathology and genetics of pulmonary hypertension: update from the Cologne Consensus Conference 2018. Int J Cardiol 272:4–10

    Article  Google Scholar 

  6. Rabinovitch M (2012) Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 122:4306–4313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rosenkranz S (2015) Pulmonary hypertension 2015: current definitions, terminology, and novel treatment options. Clin Res Cardiol 104:197–207

    Article  CAS  PubMed  Google Scholar 

  8. Humbert M, Lau EM, Montani D, Jais X, Sitbon O, Simonneau G (2014) Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation 130:2189–2208

    Article  PubMed  Google Scholar 

  9. Rosenkranz S, Gibbs JSR, Wachter R et al (2016) Left ventricular heart failure and pulmonary hypertension. Eur Heart J 37:942–954

    Article  PubMed  Google Scholar 

  10. Assad TR, Hemnes AR, Larkin EK et al (2016) Clinical and biological insights into combined post- and pre-capillary pulmonary hypertension. J Am Coll Cardiol 68:2525–2536

    Article  PubMed  PubMed Central  Google Scholar 

  11. Grimminger F, Schermuly RT, Ghofrani HA (2010) Targeting non-malignant disorders with tyrosine kinase inhibitors. Nat Rev Drug Discov 9:956–970

    Article  CAS  PubMed  Google Scholar 

  12. Berghausen E, ten Freyhaus H, Rosenkranz S (2013) Targeting of platelet-derived growth factor signaling in pulmonary arterial hypertension. Handb Exp Pharmacol 218:381–408

    Article  CAS  PubMed  Google Scholar 

  13. Ryan JJ (2016) Tyrosine kinase inhibitors in pulmonary vascular disease. Jacc Basic Transl Sci 1:684–686

    Article  PubMed  PubMed Central  Google Scholar 

  14. Crnkovic S, Marsh LM, El Agha E et al (2018) Resident cell lineages are preserved in pulmonary vascular remodeling. J Pathol 244:485–498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Marsh LM, Jandl K, Grünig G et al (2018) The inflammatory cell landscape in the lungs of patients with idiopathic pulmonary arterial hypertension. Eur Respir J 51(1):1701214

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Rabinovitch M, Guignabert C, Humbert M, Nicolls MR (2014) Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res 115:165–175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Price LC, Wort SJ, Perros F et al (2012) Inflammation in pulmonary arterial hypertension. Chest 141:210–221

    Article  CAS  PubMed  Google Scholar 

  18. Savai R, Pullamsetti SS, Kolbe J et al (2012) Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 186:897–908

    Article  CAS  PubMed  Google Scholar 

  19. Sutendra G, Dromparis P, Bonnet S et al (2011) Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNFα contributes to the pathogenesis of pulmonary arterial hypertension. J Mol Med 9:771–783

    Article  CAS  Google Scholar 

  20. Dorfmüller P, Perros F, Balabanian K, Humbert M (2003) Inflammation in pulmonary arterial hypertension. Eur Respir J 22:358–363

    Article  PubMed  Google Scholar 

  21. Thenappan T, Goel A, Marsboom et al (2011) A central role for CD68(+) macrophages in hepatopulmonary syndrome. Reversal by macrophage depletion. Am J Respir Crit Care Med 183:1080–1091

    Article  PubMed  Google Scholar 

  22. Frid MG, Brunetti JA, Burke DL et al (2006) Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol 168:659–669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Vergadi E, Chang MS, Lee C et al (2011) Early macrophage recruitment and alternative activation are critical for the later development of hypoxia-induced pulmonary hypertension. Circulation 123:1986–1995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Porter KM, Walp ER, Elms SC et al (2013) Human immunodeficiency virus-1 transgene expression increases pulmonary vascular resistance and exacerbates hypoxia-induced pulmonary hypertension development. Pulm Circ 3:58–67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yeager ME, Reddy MB, Nguyen CM et al (2012) Activation of the unfolded protein response is associated with pulmonary hypertension. Pulm Circ 2:229–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tamosiuniene R, Tian W, Dhillon G et al (2011) Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension. Circ Res 109:867–879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tian W, Jiang X, Tamosiuniene R et al (2013) Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension. Sci Transl Med 5:200ra117

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Li M, Riddle SR, Frid MG et al (2011) Emergence of fibroblasts with a proinflammatory epigenetically altered phenotype in severe hypoxic pulmonary hypertension. J Immunol 187:2711–2722

    Article  CAS  PubMed  Google Scholar 

  29. Sawada H, Saito T, Nickel NP et al (2014) Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension. J Exp Med 211:263–280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Serezani CH, Kane S, Collins L et al (2012) Macrophage dectin-1 expression is controlled by leukotriene B4 via a GM-CSF/PU.1 axis. J Immunol 189:906–915

    Article  CAS  PubMed  Google Scholar 

  31. Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122:787–795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kim YM, Haghighat L, Spiekerkoetter E et al (2011) Neutrophil elastase is produced by pulmonary artery smooth muscle cells and is linked to neointimal lesions. Am J Pathol 179:1560–1572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zaidi SH, You XM, Ciura S et al (2002) Overexpression of the serine elastase inhibitor elafin protects transgenic mice from hypoxic pulmonary hypertension. Circulation 105:516–521

    Article  CAS  PubMed  Google Scholar 

  34. Cowan KN, Heilbut A, Humpl T et al (2000) Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med 6:698–702

    Article  CAS  PubMed  Google Scholar 

  35. Thompson K, Kobayashi J, Childs T et al (1998) Endothelial and serum factors which include apolipoprotein A1 tether elastin to smooth muscle cells inducing serine elastase activity via tyrosine kinase-mediated transcription and translation. J Cell Physiol 174:78–89

    Article  CAS  PubMed  Google Scholar 

  36. Thompson K, Rabinovitch M (1996) Exogenous leukocyte and endogenous elastases can mediate mitogenic activity in pulmonary artery smooth muscle cells by release of extracellular-matrix bound basic fibroblast growth factor. J Cell Physiol 166:495–505

    Article  CAS  PubMed  Google Scholar 

  37. Senior RM, Griffin GL, Mecham RP (1980) Chemotactic activity of elastin-derived peptides. J Clin Invest 66:859–862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Vogt W (2000) Cleavage of the fifth component of complement and generation of a functionally active C5b6-like complex by human leukocyte elastase. Immunobiology 201:470–477

    Article  CAS  PubMed  Google Scholar 

  39. Klinke A, Berghausen EM, Friedrichs K et al (2018) Myeloperoxidase aggravates pulmonary arterial hypertension by activation of vascular Rho-kinase. JCI Insight 3:e97530

    Article  PubMed Central  Google Scholar 

  40. Bordron A, Dueymes M, Levy Y et al (1998) The binding of some human antiendothelial cell antibodies induces endothelial cell apoptosis. J Clin Invest 101:2029–2035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Carvalho D, Savage CO, Black CM, Pearson JD (1996) 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 97:111–119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Arends SJ, Damoiseaux JG, Duijvestijn AM et al (2013) Immunoglobulin G anti-endothelial cell antibodies: inducers of endothelial cell apoptosis in pulmonary arterial hypertension? Clin Exp Immunol 174:433–440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Dib H, Tamby MC, Bussone G et al (2012) Targets of anti-endothelial cell antibodies in pulmonary hypertension and scleroderma. Eur Respir J 39:1405–1414

    Article  CAS  PubMed  Google Scholar 

  44. Tamby MC, Humbert M, Guilpain P et al (2006) Antibodies to fibroblasts in idiopathic and scleroderma-associated pulmonary hypertension. Eur Respir J 28:799–807

    Article  CAS  PubMed  Google Scholar 

  45. Rich S, Kieras K, Hart K et al (1986) Antinuclear antibodies in primary pulmonary hypertension. J Am Coll Cardiol 8:1307–1311

    Article  CAS  PubMed  Google Scholar 

  46. Tamby MC, Chanseaud Y, Humbert M et al (2005) Anti-endothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonary arterial hypertension. Thorax 60:765–772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Park SH, Chen WC, Durmus N et al (2015) The effects of antigen-specific IgG1 antibody for the pulmonary-hypertension-phenotype and B cells for inflammation in mice exposed to antigen and fine particles from air pollution. PLoS ONE 10:e129910

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Becker MO, Kill A, Kutsche M et al (2014) Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis. Am J Respir Crit Care Med 190:808–817

    Article  CAS  PubMed  Google Scholar 

  49. Huertas A, Phan C, Bordenave J et al (2016) Regulatory T cell dysfunction in idiopathic, heritable and connective tissue-associated pulmonary arterial hypertension. Chest 149:1482–1493

    Article  PubMed  Google Scholar 

  50. Nishizuka Y, Sakakura T (1969) Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science 166:753–755

    Article  CAS  PubMed  Google Scholar 

  51. Kim JM, Rasmussen JP, Rudensky AY (2007) Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 8:191–197

    Article  CAS  PubMed  Google Scholar 

  52. Sakaguchi S (2004) Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531–562

    Article  CAS  PubMed  Google Scholar 

  53. Golembeski SM, West J, Tada Y, Fagan KA (2005) Interleukin-6 causes mild pulmonary hypertension and augments hypoxia-induced pulmonary hypertension in mice. Chest 128:572S–573S

    Article  PubMed  Google Scholar 

  54. Tamosiuniene R, Manouvakhova O, Mesange P et al (2018) Dominant role for regulatory T cells in protecting females against pulmonary hypertension. Circ Res 122:1689–1702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Speich R, Jenni R, Opravil M, Pfab M, Russi EW (1991) Primary pulmonary hypertension in HIV infection. Chest 100:1268–1271

    Article  CAS  PubMed  Google Scholar 

  56. Radstake TR, van Bon L, Broen J et al (2009) Increased frequency and compromised function of T regulatory cells in systemic sclerosis (SSc) is related to a diminished CD69 and TGFbeta expression. PLoS ONE 4:e5981

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Bonelli M, Savitskaya A, Steiner CW et al (2009) Phenotypic and functional analysis of CD4+ CD25− Foxp3+ T cells in patients with systemic lupus erythematosus. J Immunol 182:1689–1695

    Article  CAS  PubMed  Google Scholar 

  58. Covas MI, Esquerda A, García-Rico A, Mahy N (1992) Peripheral blood T‑lymphocyte subsets in autoimmune thyroid disease. J Investig Allergol Clin Immunol 2:131–135

    CAS  PubMed  Google Scholar 

  59. Mandl T, Bredberg A, Jacobsson LT et al (2004) CD4+ T‑lymphocytopenia—a frequent finding in anti-SSA antibody seropositive patients with primary Sjögren’s Syndrome. J Rheumatol 31:726–728

    PubMed  Google Scholar 

  60. Perros F, Dorfmüller P, Souza R et al (2007) Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension. Eur Respir J 29:462–468

    Article  CAS  PubMed  Google Scholar 

  61. Perros F, Dorfmüller P, Montani D et al (2012) Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 185:311–321

    Article  PubMed  Google Scholar 

  62. Carragher DM, Rangel-Moreno J, Randall TD (2008) Ectopic lymphoid tissues and local immunity. Semin Immunol 20:26–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Damsker JM, Hansen AM, Caspi RR (2010) Th1 and Th17 cells: adversaries and collaborators. Ann N Y Acad Sci 1183:211–221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hautefort A, Girerd B, Montani D et al (2015) T‑Helper 17 cell polarization in pulmonary arterial hypertension. Chest 147:1610–1620

    Article  PubMed  Google Scholar 

  65. Steiner MK, Syrkina OL, Kolliputi N et al (2009) Interleukin-6 overexpression induces pulmonary hypertension. Circ Res 104:236–244

    Article  CAS  PubMed  Google Scholar 

  66. Fujita M, Shannon JM, Irvin CG et al (2001) Overexpression of tumor necrosis factor-alpha produces an increase in lung volumes and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 280:L39–L49

    Article  CAS  PubMed  Google Scholar 

  67. Huertas A, Perros F, Tu L et al (2014) Immune dysregulation and endothelial dysfunction in pulmonary arterial hypertension: a complex interplay. Circulation 129:1332–1340

    Article  PubMed  Google Scholar 

  68. Ricard N, Tu L, Le Hiress M et al (2014) Increased pericyte coverage mediated by endothelial-derived fibroblast growth factor-2 and interleukin-6 is a source of smooth muscle-like cells in pulmonary hypertension. Circulation 129:1586–1597

    Article  CAS  PubMed  Google Scholar 

  69. Deng Z, Morse JH, Slager SL et al (2000) Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 67:737–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lane KB, Machado RD, Pauciulo MW et al (2000) Heterozygous germline mutations in bmpr2, encoding a tgf-beta receptor, cause familial primary pulmonary hypertension. Nat Genet 26:81–84

    Article  CAS  PubMed  Google Scholar 

  71. Atkinson C, Stewart S, Upton PD et al (2002) Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 105:1672–1678

    Article  CAS  PubMed  Google Scholar 

  72. Song Y, Coleman L, Shi J et al (2008) Inflammation, endothelial injury, and persistent pulmonary hypertension in heterozygous BMPR2-mutant mice. Am J Physiol Heart Circ Physiol 295:H677–H690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Mushaben EM, Hershey GK, Pauciulo MW et al (2012) Chronic allergic inflammation causes vascular remodeling and pulmonary hypertension in BMPR2 hypomorph and wild-type mice. PLoS ONE 7:e32468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Davies RJ, Holmes AM, Deighton J et al (2012) BMP type II receptor deficiency confers resistance to growth inhibition by TGF-β in pulmonary artery smooth muscle cells: role of proinflammatory cytokines. Am J Physiol Lung Cell Mol Physiol 302:L604–L615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Park SH, Chen WC, Hoffman C et al (2013) Modification of hemodynamic and immune responses to exposure with a weak antigen by the expression of a hypomorphic BMPR2 gene. PLoS ONE 8:e55180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Soon E, Crosby A, Southwood M et al (2015) Bone morphogenetic protein receptor type II deficiency and increased inflammatory cytokine production. A gateway to pulmonary arterial hypertension. Am J Respir Crit Care Med 192:859–872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Lee JG, Kay EP (2009) Common and distinct pathways for cellular activities in FGF-2 signaling induced by IL-1beta in corneal endothelial cells. Invest Ophthalmol Vis Sci 50:2067–2076

    Article  PubMed  Google Scholar 

  78. Izikki M, Guignabert C, Fadel E et al (2009) Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents. J Clin Invest 119:512–523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kim J, Kang Y, Kojima Y et al (2013) An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. Nat Med 19:74–82

    Article  CAS  PubMed  Google Scholar 

  80. Savale L, Tu L, Rideau D et al (2009) Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir Res 10:6

    Article  PubMed  PubMed Central  Google Scholar 

  81. Tu L, De Man FS, Girerd B et al (2012) A critical role for p130Cas in the progression of pulmonary hypertension in humans and rodents. Am J Respir Crit Care Med 186:666–676

    Article  CAS  PubMed  Google Scholar 

  82. Alastalo TP, Li M, Vde PJ et al (2011) Disruption of PPARγ/β-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival. J Clin Invest 121:3735–3746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Hagen M, Fagan K, Steudel W et al (2007) Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle. Am J Physiol Lung Cell Mol Physiol 292:L1473–L1479

    Article  CAS  PubMed  Google Scholar 

  84. Hager-Theodorides AL, Outram SV, Shah DK et al (2002) Bone morphogenetic protein 2/4 signaling regulates early thymocyte differentiation. J Immunol 169:5496–5504

    Article  CAS  PubMed  Google Scholar 

  85. Taraseviciene-Stewart L, Nicolls MR, Kraskauskas D et al (2007) Absence of T cells confers increased pulmonary arterial hypertension and vascular remodeling. Am J Respir Crit Care Med 175:1280–1289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lu L, Ma J, Wang X et al (2010) Synergistic effect of TGF-beta superfamily members on the induction of Foxp3+ Treg. Eur J Immunol 40:142–152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Pullamsetti SS, Seeger W, Savai R (2018) Classical IL-6 signaling: a promising therapeutic target for pulmonary arterial hypertension. J Clin Invest 128:1720–1723

    Article  PubMed  PubMed Central  Google Scholar 

  88. Tamura Y, Phan C, Tu L et al (2018) Ectopic upregulation of membrane-bound IL6R drives vascular remodeling in pulmonary arterial hypertension. J Clin Invest 128:1956–1970

    Article  PubMed  PubMed Central  Google Scholar 

  89. Jasiewicz M, Knapp M, Waszkiewicz E et al (2015) Enhanced IL-6 trans-signaling in pulmonary arterial hypertension and its potential role in disease-related systemic damage. Cytokine 76:187–192

    Article  CAS  PubMed  Google Scholar 

  90. Le Hiress M, Tu L, Ricard N et al (2015) Proinflammatory signature of the dysfunctional endothelium in pulmonary hypertension. Role of the macrophage migration inhibitory factor/CD74 complex. Am J Respir Crit Care Med 192:983–997

    Article  PubMed  CAS  Google Scholar 

  91. El Kasmi KC, Pugliese SC, Riddle SR et al (2014) Adventitial fibroblasts induce a distinct proinflammatory/profibrotic macrophage phenotype in pulmonary hypertension. J Immunol 193:597–609

    Article  PubMed  CAS  Google Scholar 

  92. Hashimoto-Kataoka T, Hosen N, Sonobe T et al (2015) Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension. Proc Natl Acad Sci Usa 112:E2677–E2686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Tu L, Huertas A, Le Hiress M et al (2013) Mif/cd74-dependent interleukin-6 and monocyte chemoattractant protein-1 secretion by pulmonary endothelial cells in idiopathic pulmonary hypertension. Am Thorac Soc 187:A1739

    Google Scholar 

  94. Damico R, Simms T, Kim BS et al (2011) p53 mediates cigarette smoke-induced apoptosis of pulmonary endothelial cells: inhibitory effects of macrophage migration inhibitor factor. Am J Respir Cell Mol Biol 44:323–332

    Article  CAS  PubMed  Google Scholar 

  95. Guignabert C, Montani D (2013) Key roles of Src family tyrosine kinases in the integrity of the pulmonary vascular bed. Eur Respir J 41:3–4

    Article  CAS  PubMed  Google Scholar 

  96. Leng L, Metz CN, Fang Y et al (2003) MIF signal transduction initiated by binding to CD74. J Exp Med 197:1467–1476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Nagaraj C, Tang B, Bálint Z et al (2013) Src tyrosine kinase is crucial for potassium channel function in human pulmonary arteries. Eur Respir J 41:85–95

    Article  CAS  PubMed  Google Scholar 

  98. Stein R, Mattes MJ, Cardillo TM et al (2007) CD74: a new candidate target for the immunotherapy of B‑cell neoplasms. Clin Cancer Res 13:5556s–5563s

    Article  CAS  PubMed  Google Scholar 

  99. Tu L, Dewachter L, Gore B et al (2011) Autocrine fibroblast growth factor-2 signaling contributes to altered endothelial phenotype in pulmonary hypertension. Am J Respir Cell Mol Biol 45:311–322

    Article  CAS  PubMed  Google Scholar 

  100. Bernhagen J, Krohn R, Lue H et al (2007) MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med 13:587–596

    Article  CAS  PubMed  Google Scholar 

  101. Zhang B, Luo Y, Liu ML et al (2012) Macrophage migration inhibitory factor contributes to hypoxic pulmonary vasoconstriction in rats. Microvasc Res 83:205–212

    Article  CAS  PubMed  Google Scholar 

  102. Zhang Y, Talwar A, Tsang D et al (2012) Macrophage migration inhibitory factor mediates hypoxia-induced pulmonary hypertension. Mol Med 18:215–223

    Article  CAS  PubMed  Google Scholar 

  103. Zhang B, Shen M, Xu M et al (2012) Role of macrophage migration inhibitory factor in the proliferation of smooth muscle cell in pulmonary hypertension. Mediators Inflamm 2012:840737

    PubMed  PubMed Central  Google Scholar 

  104. Le Hiress M, Akagah B, Bernadat G et al (2018) Design, synthesis, and biological activity of new N‑(Phenylmethyl)-benzoxazol-2-thiones as macrophage Migration Inhibitory Factor (MIF) antagonists: efficacies in experimental pulmonary hypertension. J Med Chem 61:2725–2736

    Article  PubMed  CAS  Google Scholar 

  105. Michelakis ED, Gurtu V, Webster L et al (2017) Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients. Sci Transl Med 9:eaao4583

    Article  PubMed  CAS  Google Scholar 

  106. Calvier L, Chouvarine P, Legchenko E et al (2017) PPARγ links BMP2 and TGFβ1 pathways in vascular smooth muscle cells, regulating cell proliferation and glucose metabolism. Cell Metab 25:1118–1134

    Article  CAS  PubMed  Google Scholar 

  107. Legchenko E, Chouvarine P, Borchert P et al (2018) PPARγ agonist pioglitazone reverses pulmonary hypertension and prevents right heart failure via fatty acid oxidation. Sci Transl Med 10:eaao303

    Article  PubMed  CAS  Google Scholar 

  108. Klinke A, Möller A, Pekarova M et al (2014) Protective effects of 10-nitro-oleic acid in a hypoxia-induced murine model of pulmonary hypertension. Am J Respir Cell Mol Biol 51:155–162

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Authors and Affiliations

  1. Klinik III für Innere Medizin, Herzzentrum, Universität zu Köln, Kerpener Str. 62, 50937, Cologne, Germany

    E. M. Berghausen, L. Feik, M. Zierden, M. Vantler & S. Rosenkranz MD

  2. Center for Molecular Medicine Cologne (CMMC), Universität zu Köln, Cologne, Germany

    E. M. Berghausen, M. Zierden, M. Vantler & S. Rosenkranz MD

  3. Cologne Cardiovascular Research Center (CCRC), Universität zu Köln, Cologne, Germany

    L. Feik & S. Rosenkranz MD

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  3. M. Zierden
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  4. M. Vantler
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  5. S. Rosenkranz MD
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Correspondence to S. Rosenkranz MD.

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E.M. Berghausen, L. Feik, M. Zierden, M. Vantler, and S. Rosenkranz declare that they have no competing interests.

This article does not contain any studies with human participants or animals performed by any of the authors.

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Berghausen, E.M., Feik, L., Zierden, M. et al. Key inflammatory pathways underlying vascular remodeling in pulmonary hypertension. Herz 44, 130–137 (2019). https://doi.org/10.1007/s00059-019-4795-6

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