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Review

Challenges and opportunities in treating inflammation associated with pulmonary hypertension

, &
Pages 939-951 | Received 13 Jan 2016, Accepted 18 Apr 2016, Published online: 04 May 2016

References

  • Voelkel NF, Gomez-Arroyo J, Abbate A, et al. Pathobiology of pulmonary arterial hypertension and right ventricular failure. Eur Respir J. 2012;40:1555–1565.
  • Stein PD, Matta F, Hughes PG. Scope of problem of pulmonary arterial hypertension. Am J Med. 2015;128:844–851.
  • Haddad F, Spruijt OA, Denault AY, et al. Right heart score for predicting outcome in idiopathic, familial, or drug- and toxin-associated pulmonary arterial hypertension. JACC Cardiovasc Imaging. 2015;8:627–638.
  • Latus H, Delhaas T, Schranz D, et al. Treatment of pulmonary arterial hypertension in children. Nat Rev Cardiol. 2015;12:244–254.
  • 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;18:533–547.
  • Kay JM, Gillund TD, Heath D. Mast cells in the lungs of rats fed on Crotalaria spectabilis seeds. Am J Pathol. 1967;51:1031–1044.
  • Heath D, Trueman T, Sukonthamarn P. Pulmonary mast cells in mitral stenosis. Cardiovasc Res. 1969;3:467–471.
  • Klob J. Endarteritis pulmonalis obliterans. Wochenblatt der Zeitschrift der K.K Gesellschaft der Aerzte. Vienna, Nov. 1865.
  • Stenmark KR, James SL, Voelkel NF, et al. Leukotriene C4 and D4 in neonates with hypoxemia and pulmonary hypertension. N Engl J Med. 1983;309:77–80.
  • Tuder RM, Groves B, Badesch DB, et al. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol. 1994;144:275–285.
  • 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;151:1628–1631.
  • Wright L, Tuder RM, Wang J, et al. 5-Lipoxygenase and 5-lipoxygenase activating protein (FLAP) immunoreactivity in lungs from patients with primary pulmonary hypertension. Am J Respir Crit Care Med. 1998;157:219–229.
  • 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 Mar;157(3 Pt 1):907–911.
  • Mehta NJ, Khan IA, Mehta RN, et al. HIV-Related pulmonary hypertension: analytic review of 131 cases. Chest. 2000;118:1133–1141.
  • Tuder RM, Chacon M, Alger L, et al. Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis. J Pathol. 2001;195:367–374.
  • Tamby MC, Chanseaud Y, Humbert M, et al. Anti-endothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonary arterial hypertension. Thorax. 2005;60:765–772.
  • Perros F, Dorfmüller P, Souza R, et al. Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension. Eur Respir J. 2007 Mar;29(3):462–468.
  • Hassoun PM, Mouthon L, Barberà JA, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol. 2009;54(1 Suppl):S10–9.
  • Tamosiuniene R, Tian W, Dhillon G, et al. Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension. Circ Res. 2011;109:867–879.
  • Tian W, Jiang X, Tamosiuniene R, et al. Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension. Sci Transl Med. 2013;5(200):200ra117.
  • Le Hiress M, Tu L, Ricard N, et al. Proinflammatory signature of the dysfunctional endothelium in pulmonary hypertension. Role of the macrophage migration inhibitory factor/CD74 complex. Am J Respir Crit Care Med. 2015;192:983–997.
  • Rabinovitch M, Guignabert C, Humbert M, et al. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res. 2014 Jun 20;115(1):165–175.
  • Huertas A, Tu L, Thuillet R, et al. Leptin signalling system as a target for pulmonary arterial hypertension therapy. Eur Respir J. 2015;45:1066–1080.
  • Kawut SM, Bagiella E, Lederer DJ, et al. ASA-STAT study group. Randomized clinical trial of aspirin and simvastatin for pulmonary arterial hypertension: ASA-STAT. Circulation. 2011;123:2985–2993.
  • Erzurum S, Rounds SI, Stevens T, et al. Strategic plan for lung vascular research: an NHLBI-ORDR workshop report. Am J Respir Crit Care Med. 2010;182:1554–1562.
  • Quarck R, Wynants M, Verbeken E, et al. Contribution of inflammation and impaired angiogenesis to the pathobiology of chronic thromboembolic pulmonary hypertension. Eur Respir J. 2015;46:431–443.
  • Humbert M, Ghofrani HA. The molecular targets of approved treatments for pulmonary arterial hypertension. Thorax. 2016 Jan;71(1):73–83.
  • Pal J, Sen K, Sarkar G, et al. Effect of antiretroviral therapy on pulmonary hypertension in HIV patients. J Indian Med Assoc. 2013;111(845–6):849.
  • Kumar R, Mickael C, Chabon J, et al. The causal role of IL-4 and IL-13 in schistosoma mansoni pulmonary hypertension. Am J Respir Crit Care Med. 2015;192:998–1008.
  • Daley E, Emson C, Guignabert C, et al. Pulmonary arterial remodeling induced by a Th2 immune response. J Exp Med. 2008;205:361–372.
  • Ono S, Westcott JY, Voelkel NF. PAF antagonists inhibit pulmonary vascular remodeling induced by hypobaric hypoxia in rats. J Appl Physiol (1985). 1992 Sep;73(3):1084–1092.
  • Stenmark KR, Morganroth ML, Remigio LK, et al. Alveolar inflammation and arachidonate metabolism in monocrotaline-induced pulmonary hypertension. Am J Physiol. 1985;248(6 Pt 2):H859–866.
  • Whyte MK, Walmsley SR. The regulation of pulmonary inflammation by the hypoxia-inducible factor-hydroxylase oxygen-sensing pathway. Ann Am Thorac Soc. 2014;11(Suppl 5):S271–276.
  • Palazon A, Goldrath AW, Nizet V, et al. HIF transcription factors, inflammation, and immunity. Immunity. 2014;41(4):518–528.
  • Murugesan P, Hildebrandt T, Bernlöhr C, et al. Inhibition of kinin B1 receptors attenuates pulmonary hypertension and vascular remodeling. Hypertension. 2015;66(4):906–912.
  • Dewachter C, Belhaj A, Rondelet B, et al. Myocardial inflammation in experimental acute right ventricular failure: effects of prostacyclin therapy. J Heart Lung Transplant. 2015;34(10):1334–1345.
  • Al-Husseini A, Wijesinghe DS, Farkas L, et al. Increased eicosanoid levels in the Sugen/chronic hypoxia model of severe pulmonary hypertension. PLoS One. 2015;10(3):e0120157. doi:10.1371/journal.pone.0120157.
  • Bull TM, Cool CD, Serls AE, et al. Primary pulmonary hypertension, Castleman’s disease and human herpesvirus-8. Eur Respir J. 2003;22(3):403–407.
  • Bogaard HJ, Al Husseini A, Farkas L, et al. Severe pulmonary hypertension: The role of metabolic and endocrine disorders. Pulm Circ. 2012;2(2):148–154.
  • 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):920–927.
  • Hata AN, Breyer RM. Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharm & Therap. 2004;103:147–166.
  • Zhou W, Blackwell TS, Goleniewska K, et al. Prostaglandin I2 analogs inhibit Th1 and Th2 effector cytokine production by CD4 T cells. J Leukoc Biol. 2007;81:809–817.
  • Sun JC, Ugolini S, Vivier E. Immunological memory within the innate immune system. EMBO J. 2014;33(12):1295–1303.
  • Man SM, Kanneganti TD. Converging roles of caspases in inflammasome activation, cell death and innate immunity. Nat Rev Immunol. 2016 Jan;16(1): 7–21. doi:10.1038/nri.2015.7. 2015 Dec 14 Epub.
  • Mackey D, McFall AJ. MAMPs and MIMPs: proposed classifications for inducers of innate immunity. Mol Microbiol. 2006;61(6):1365–1371.
  • Hauge A, Staub NC. Prevention of hypoxic vasoconstriction in cat lung by histamine-releasing agent 48/80. J Appl Physiol. 1969;26:693–699.
  • Rai PR, Cool CD, King JA, et al. The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;178:558–564.
  • Wasiuk A, De Vries VC, Hartmann K, et al. Mast cells as regulators of adaptive immunity to tumours. Clin Exp Immunol. 2009;155:140–146.
  • Piconese S, Gri G, Tripodo C, et al. Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation. Blood. 2009;114:2639–2648.
  • Perros F, Dorfmüller P, Montani D, et al. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;185:311–321.
  • Meng X, Yang J, Dong M, et al. Regulatory T cells in cardiovascular diseases. Nat Rev Cardiol. 2015;13:167–179. doi:10.1038/nrcardio.2015.169. [Epub ahead of print].
  • Nicolls MR, Mizuno S, Taraseviciene-Stewart L, et al. New models of pulmonary hypertension based on VEGF receptor blockade-induced endothelial cell apoptosis. Pulm Circ. 2012;2(4):434–42.2.
  • 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;175(12):1280–1289.
  • Miyata M, Sakuma F, Ito M, et al. Athymic nude rats develop severe pulmonary hypertension. Int Arch Allergy Immunol. 2000;121(3):246–252.
  • Nicolls MR, Taraseviciene-Stewart L, Rai PR, et al. Autoimmunity and pulmonary hypertension: a perspective. Eur Respir J. 2005;26(6):1110–1118.
  • Tamosiuniene R, Nicolls MR. Regulatory T cells and pulmonary hypertension. Trends Cardiovasc Med. 2011;21(6):166–171.
  • Tian W, Jiang X, Sung YK, et al. Leukotrienes in pulmonary arterial hypertension. Immunol Res. 2014;58:387–393.
  • Qian J, Tian W, Jiang X, et al. LTB4 activates pulmonary artery adventitial fibroblasts in pulmonary hypertension. Hypertension. in press;2015.
  • Awad KS, Elinoff JM, Wang S, et al. Raf/ERK drives the proliferative and invasive phenotype of BMPR2-silenced pulmonary artery endothelial cells. Am J Physiol Lung Cell Mol Physiol. 2015 Nov 20. doi:10.1152/ajplung.00303.2015. ajplung.00303.
  • Li B, Lalani AS, Harding TC, et al. Vascular endothelial growth factor blockade reduces intratumoral regulatory T cells and enhances the efficacy of a GM-CSF-secreting cancer immunotherapy. Clin Cancer Res. 2006;12:6808–6816. administration
  • Kaur S, Chang T, Singh SP, et al. .CD47 signaling regulates the immunosuppressive activity of VEGF in T cells. J Immunol. 2014;193:3914–3924.
  • Davies RJ, Holmes AM, Deighton J, et al. 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. 2012;302:L604–615.
  • Kearns MT, Dalal S, Horstmann SA, et al. Vascular endothelial growth factor enhances macrophage clearance of apoptotic cells. Am J Physiol Lung Cell Mol Physiol. 2012;302:L711–718.
  • Vandivier RW, Henson PM, Douglas IS. Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease. Chest. 2006;129:1673–1682.
  • Voelkel NF, Tuder RM, Bridges J, et al. Interleukin-1 receptor antagonist treatment reduces pulmonary hypertension generated in rats by monocrotaline. Am J Respir Cell Mol Biol. 1994;11:664–675.
  • Hashimoto-Kataoka T, Hosen N, Sonobe T, et al. Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension. Proc Natl Acad Sci U S A. 2015;112(20):E2677–2686.
  • Barzilai S, Blecher-Gonen R, Barnett-Itzhaki Z, et al. M-sec regulates polarized secretion of inflammatory endothelial chemokines and facilitates CCL2-mediated lymphocyte transendothelial migration. J Leukoc Biol. 2015;98. pii: jlb.3VMA0915-427R. [Epub ahead of print].
  • Salmeron K, Aihara T, Redondo-Castro E, et al. Bix GIL-1alpha induces angiogenesis in brain endothelial cells in vitro: implications for brain angiogenesis after acute injury. J Neurochem. 2015 Nov 6. doi:10.1111/jnc.13422. [Epub ahead of print].
  • Sager HB, Heidt T, Hulsmans M, et al. Targeting interleukin-1β reduces leukocyte production after acute myocardial infarction. Circulation. 2015;132:1880–1890.
  • Berda-Haddad Y, Robert S, Salers P, et al. Sterile inflammation of endothelial cell-derived apoptotic bodies is mediated by interleukin-1α. Proc Natl Acad Sci U S A. 2011;108:20684–20689.
  • Idan C, Peleg R, Elena V, et al. IL-1α is a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity. Sci Rep. 2015;5:14756.
  • McCarthy DA, Clark RR, Bartling TR, et al. Redox control of the senescence regulator interleukin-1α and the secretory phenotype. J Biol Chem. 2013;288:32149–32159.
  • Moore KW, de Waal Malefyt R, Coffman RL, et al. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683–765.
  • Cavelti-Weder C, Timper K, Seelig E, et al. Development of an interleukin-1β vaccine in patients with type 2 diabetes. Mol Ther. 2015;doi:10.1038/mt.2015.227 [Epub ahead of print].
  • Genovese MC, Braun DK, Erickson JS, et al. Safety and efficacy of open-label subcutaneous ixekizumab treatment for 48 weeks in a phase II study in biologic-naive and TNF-IR patients with rheumatoid arthritis. J Rheumatol. 2016;43:289–297.
  • Carbone C, Tamburrino A, Piro G, et al. Combined inhibition of IL1, CXCR1/2, and TGFβ signaling pathways modulates in-vivo resistance to anti-VEGF treatment. Anticancer Drugs. 2016;27(1):29–40.
  • Groh M, Rogowska K, Monsarrat O, et al. Interleukin-1 receptor antagonist for refractory anti-MDA5 clinically amyopathic dermatomyopathy. Clin Exp Rheumatol. 2015 Nov–Dec;33(6):904–905.
  • Young KC, Hussein SM, Dadiz R, et al. Toll-like receptor 4-deficient mice are resistant to chronic hypoxia-induced pulmonary hypertension. Exp Lung Res. 2010;36(2):111–119.
  • Schuettpelz LG, Borgerding JN, Christopher MJ, et al. G-CSF regulates hematopoietic stem cell activity, in part, through activation of Toll-like receptor signaling. Leukemia. 2014;28(9):1851–1860.
  • George PM, Badiger R, Shao D, et al. Viral Toll Like Receptor activation of pulmonary vascular smooth muscle cells results in endothelin-1 generation; relevance to pathogenesis of pulmonary arterial hypertension. Biochem Biophys Res Commun. 2012;426(4):486–491.
  • Taraseviciute A, Voelkel NF. Severe pulmonary hypertension in postmenopausal obese women. Eur J Med Res. 2006;11(5):198–202.
  • Sweeney L, Voelkel NF. Estrogen exposure, obesity and thyroid disease in women with severe pulmonary hypertension. Eur J Med Res. 2009;14(10):433–442.
  • Gopal DM, Santhanakrishnan R, Wang YC, et al. Impaired right ventricular hemodynamics indicate preclinical pulmonary hypertension in patients with metabolic syndrome. J Am Heart Assoc. 2015;4(3):e001597.
  • Mathew R. Pulmonary hypertension and metabolic syndrome: Possible connection, PPARγ and Caveolin-1. World J Cardiol. 2014;6(8):692–697.
  • Dam V, Sikder T, Santosa S. From neutrophils to macrophages: differences in regional adipose tissue depots. Obes Rev. 2015 Dec 14. doi:10.1111/obr.12335. [Epub ahead of print].
  • Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011;29:415–445.
  • Ussavarungsi K, Thomas CS, Burger CD. Prevalence of metabolic syndrome in patients with pulmonary hypertension. Clin Respir J. 2015 Oct 23. doi:10.1111/crj.12406. [Epub ahead of print].
  • Huertas A, Tu L, Gambaryan N, et al. Leptin and regulatory T-lymphocytes in idiopathic pulmonary arterial hypertension. Eur Respir J. 2012;40(4):895–904.
  • Velarde GP, Sherazi S, Kraemer DF, et al. Clinical and biochemical markers of cardiovascular structure and function in women with the metabolic syndrome. Am J Cardiol. 2015 Dec 1;116(11):1705–1710.
  • Seleit I, Bakry OA, Samaka RM, et al. Immunohistochemical evaluation of leptin expression in wound healing: a clue to exuberant scar formation. Appl Immunohistochem Mol Morphol. 2016;24:296–306.
  • Bain GH, Collie-Duguid E, Murray GI, et al. Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas. Br J Cancer. 2015;113(11):1641.
  • Tao JH, Barbi J, Pan F. Hypoxia-inducible factors in T lymphocyte differentiation and function. A review in the theme: cellular responses to hypoxia. Am J Physiol Cell Physiol. 2015;309:C580–589.
  • D’Ignazio L, Bandarra D, Rocha S. NF-κB and HIF crosstalk in immune responses. FEBS J. 2015 Oct 29. doi:10.1111/febs.13578. [Epub ahead of print].
  • Mascanfroni ID, Takenaka MC, Yeste A, et al. Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α. Nat Med. 2015;21:638–646.
  • Cero FT, Hillestad V, Sjaastad I, et al. Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice. Am J Physiol Lung Cell Mol Physiol. 2015;309(4):L378–387.
  • Montani D, Seferian A, Savale L, et al. Drug-induced pulmonary arterial hypertension: a recent outbreak. Eur Respir Rev. 2013 Sep 1;22(129):244–250.
  • Carlsen J, Hasseriis Andersen K, Boesgaard S, et al. Pulmonary arterial lesions in explanted lungs after transplantation correlate with severity of pulmonary hypertension in chronic obstructive pulmonary disease. J Heart Lung Transplant. 2013;32(3):347–354.
  • Trip P, Nossent EJ, de Man FS, et al. Severely reduced diffusion capacity in idiopathic pulmonary arterial hypertension: patient characteristics and treatment responses. Eur Respir J. 2013;42(6):1575–1585.
  • Kearley J, Silver JS, Sanden C, et al. Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection. Immunity. 2015;42(3):566–579.
  • Yuan F, Fu X, Shi H, et al. Induction of murine macrophage M2 polarization by cigarette smoke extract via the JAK2/STAT3 pathway. PLoS One. 2014;9(9):e107063.
  • Heijink IH, Pouwels SD, Leijendekker C, et al. Cigarette smoke-induced damage-associated molecular pattern release from necrotic neutrophils triggers proinflammatory mediator release. Am J Respir Cell Mol Biol. 2015;52(5):554–562.
  • Shinomiya S, Naraba H, Ueno A, et al. Regulation of TNFalpha and interleukin-10 production by prostaglandins I(2) and E(2): studies with prostaglandin receptor-deficient mice and prostaglandin E-receptor subtype-selective synthetic agonists. Biochem Pharmacol. 2001;61(9):1153–1160.
  • Lindemann S, Gierer C, Darius H. Prostacyclin inhibits adhesion of polymorphonuclear leukocytes to human vascular endothelial cells due to adhesion molecule independent regulatory mechanisms. Basic Res Cardiol. 2003;98(1):8–15.
  • Elisa T, Antonio P, Giuseppe P, et al. Endothelin receptors expressed by immune cells are involved in modulation of inflammation and in fibrosis: relevance to the pathogenesis of systemic sclerosis. J Immunol Res. 2015;2015:147616. doi:10.1155/2015/147616. Epub 2015 May 18.
  • Knobloch J, Feldmann M, Wahl C, et al. Endothelin receptor antagonists attenuate the inflammatory response of human pulmonary vascular smooth muscle cells to bacterial endotoxin. J Pharmacol Exp Ther. 2013;346(2):290–299.
  • Brun H, Holmstrøm H, Thaulow E, et al. Patients with pulmonary hypertension related to congenital systemic-to-pulmonary shunts are characterized by inflammation involving endothelial cell activation and platelet-mediated inflammation. Congenit Heart Dis. 2009;4(3):153–159.
  • Tsai BM, Turrentine MW, Sheridan BC, et al. Differential effects of phosphodiesterase-5 inhibitors on hypoxic pulmonary vasoconstriction and pulmonary artery cytokine expression. Ann Thorac Surg. 2006;81(1):272–278.
  • Pifarré P, Gutierrez-Mecinas M, Prado J, et al. Phosphodiesterase 5 inhibition at disease onset prevents experimental autoimmune encephalomyelitis progression through immunoregulatory and neuroprotective actions. Exp Neurol. 2014;251:58–71.
  • Califano JA, Khan Z, Noonan KA, et al. Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma. Clin Cancer Res. 2015;21(1):30–38.
  • Westermann D, Becher PM, Lindner D, et al. Selective PDE5A inhibition with sildenafil rescues left ventricular dysfunction, inflammatory immune response and cardiac remodeling in angiotensin II-induced heart failure in vivo. Basic Res Cardiol. 2012;107(6):308.
  • Denton CP, Black CM. Pulmonary hypertension in systemic sclerosis. Rheum Dis Clin North Am. 2003;29(2):335–349, vii.
  • Kuhn KP, Byrne DW, Arbogast PG, et al. Outcome in 91 consecutive patients with pulmonary arterial hypertension receiving epoprostenol. Am J Respir Crit Care Med. 2003;167(4):580–586.
  • Chung L, Liu J, Parsons L, et al. Characterization of connective tissue disease-associated pulmonary arterial hypertension from REVEAL: identifying systemic sclerosis as a unique phenotype. Chest. 2010;138(6):1383–1394.
  • Chung L, Farber HW, Benza R, et al. Unique predictors of mortality in patients with pulmonary arterial hypertension associated with systemic sclerosis in the REVEAL registry. Chest. 2014;146(6):1494–1504.
  • Cool CD, Kennedy D, Voelkel NF, et al. Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection. Hum Pathol. 1997;28(4):434–442.
  • Sgonc R, Gruschwitz MS, Dietrich H, et al. Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. J Clin Invest. 1996;98(3):785–792.
  • Wusirika R, Ferri C, Marin M, et al. The assessment of anti-endothelial cell antibodies in scleroderma-associated pulmonary fibrosis. A study of indirect immunofluorescent and western blot analysis in 49 patients with scleroderma. Am J Clin Pathol. 2003;120(4):596–606.
  • Vercellotti GM. Effects of viral activation of the vessel wall on inflammation and thrombosis. Blood Coagul Fibrinolysis. 1998;9(Suppl 2):S3–6.
  • Longo F, Saletta S, Lepore L, et al. Localized scleroderma after infection with Epstein-Barr virus. Clin Exp Rheumatol. 1993;11(6):681–683.
  • Magro CM, Nuovo G, Ferri C, et al. Parvoviral infection of endothelial cells and stromal fibroblasts: a possible pathogenetic role in scleroderma. J Cutan Pathol. 2004;31(1):43–50.
  • Ferri C, Longombardo G, Mugnaini P. Hepatitis E virus and systemic sclerosis. Qjm. 1998;91(5):375.
  • Ferri C, Zakrzewska K, Longombardo G, et al. Parvovirus B19 infection of bone marrow in systemic sclerosis patients. Clin Exp Rheumatol. 1999;17(6):718–720.
  • Harel L, Straussberg R, Rudich H, et al. Raynaud’s phenomenon as a manifestation of parvovirus B19 infection: case reports and review of parvovirus B19 rheumatic and vasculitic syndromes. Clin Infect Dis. 2000;30(3):500–503.
  • Abu-Shakra M, Sukenik S, Buskila D. Systemic sclerosis: another rheumatic disease associated with hepatitis C virus infection. Clin Rheumatol. 2000;19(5):378–380.
  • Hamamdzic D, Kasman LM, LeRoy EC. The role of infectious agents in the pathogenesis of systemic sclerosis. Curr Opin Rheumatol. 2002;14(6):694–698.
  • Neidhart M, Kuchen S, Distler O, et al. Increased serum levels of antibodies against human cytomegalovirus and prevalence of autoantibodies in systemic sclerosis. Arthritis Rheum. 1999;42(2):389–392.
  • Vaughan JH, Shaw PX, Nguyen MD, et al. Evidence of activation of 2 herpesviruses, Epstein-Barr virus and cytomegalovirus, in systemic sclerosis and normal skins. J Rheumatol. 2000;27(3):821–823.
  • Carapeto FJ, Winkelmann RK. Peripheral blood lymphocyte distribution in scleroderma. Dermatologica. 1975;151(4):228–235.
  • Barnett AJ, Tait BD, Barnett MA, et al. T lymphocyte subset abnormalities and HLA antigens in scleroderma (systemic sclerosis). Clin Exp Immunol. 1989;76(1):24–29.
  • Ingegnoli F, Trabattoni D, Saresella M, et al. Distinct immune profiles characterize patients with diffuse or limited systemic sclerosis. Clin Immunol. 2003;108(1):21–28.
  • Sato S, Fujimoto M, Hasegawa M, et al. Altered blood B lymphocyte homeostasis in systemic sclerosis: expanded naive B cells and diminished but activated memory B cells. Arthritis Rheum. 2004;50(6):1918–1927.
  • Sato S, Hasegawa M, Fujimoto M, et al. Quantitative genetic variation in CD19 expression correlates with autoimmunity. J Immunol. 2000;165(11):6635–6643.
  • Cepeda EJ, Reveille JD. Autoantibodies in systemic sclerosis and fibrosing syndromes: clinical indications and relevance. Curr Opin Rheumatol. 2004;16(6):723–732.
  • Hayakawa I, Hasegawa M, Takehara K, et al. Anti-DNA topoisomerase IIalpha autoantibodies in localized scleroderma. Arthritis Rheum. 2004;50(1):227–232.
  • Nagai M, Hasegawa M, Takehara K, et al. Novel autoantibody to Cu/Zn superoxide dismutase in patients with localized scleroderma. J Invest Dermatol. 2004;122(3):594–601.
  • Morse J, Barst R, Horn E, et al. Pulmonary hypertension in scleroderma spectrum of disease: lack of bone morphogenetic protein receptor 2 mutations. J Rheumatol. 2002;29(11):2379–2381.
  • Crilly A, Hamilton J, Clark CJ, et al. Analysis of transforming growth factor beta1 gene polymorphisms in patients with systemic sclerosis. Ann Rheum Dis. 2002;61(8):678–681.
  • Tan FK, Wang N, Kuwana M, et al. Association of fibrillin 1 single-nucleotide polymorphism haplotypes with systemic sclerosis in Choctaw and Japanese populations. Arthritis Rheum. 2001;44(4):893–901.
  • Susol E, Rands AL, Herrick A, et al. Association of markers for TGFbeta3, TGFbeta2 and TIMP1 with systemic sclerosis. Rheumatology (Oxford). 2000;39(12):1332–1336.
  • Morelli S, Ferri C, Di Francesco L, et al. Plasma endothelin-1 levels in patients with systemic sclerosis: influence of pulmonary or systemic arterial hypertension. Ann Rheum Dis. 1995;54(9):730–734.
  • Carreira PE. Pulmonary hypertension in autoimmune rheumatic diseases. Autoimmun Rev. 2004;3(4):313–320.
  • Voelkel NF, Tuder RM. Cellular and molecular mechanisms in the pathogenesis of severe pulmonary hypertension. Eur Respir J. 1995;8(12):2129–2138.
  • Harrison NK, Myers AR, Corrin B, et al. Structural features of interstitial lung disease in systemic sclerosis. Am Rev Respir Dis. 1991;144(3 Pt 1):706–713.
  • Jimenez SA, Derk CT. Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis. Ann Intern Med. 2004;140(1):37–50.
  • Inaoki M, Sato S, Weintraub BC, et al. CD19-regulated signaling thresholds control peripheral tolerance and autoantibody production in B lymphocytes. J Exp Med. 1997;186(11):1923–1931.
  • Asano N, Fujimoto M, Yazawa N, et al. B Lymphocyte signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse. Am J Pathol. 2004;165(2):641–650.
  • Saito E, Fujimoto M, Hasegawa M, et al. CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse. J Clin Invest. 2002;109(11):1453–1462.
  • Hasegawa M, Hamaguchi Y, Yanaba K, et al. B-lymphocyte depletion reduces skin fibrosis and autoimmunity in the tight-skin mouse model for systemic sclerosis. Am J Pathol. 2006;169(3):954–966.
  • Sato S, Fujimoto M, Hasegawa M, et al. Altered B lymphocyte function induces systemic autoimmunity in systemic sclerosis. Mol Immunol. 2004;41(12):1123–1133.
  • Fujimoto M, Sato S. B lymphocytes and systemic sclerosis. Curr Opin Rheumatol. 2005;17(6):746–751.
  • Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531–562.
  • Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol. 2007;8:191–197.
  • Shih FF, Mandik-Nayak L, Wipke BT, et al. Massive thymic deletion results in systemic autoimmunity through elimination of CD4+ CD25+ T regulatory cells. J Exp Med. 2004;199(3):323–335.
  • McGonagle D, Tan AL, Madden J, et al. Successful treatment of resistant scleroderma-associated interstitial lung disease with rituximab. Rheumatology (Oxford). 2008;47(4):552–553.
  • Bogaard HJ, Abe K, Vonk Noordegraaf A, et al. The right ventricle under pressure: cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest. 2009;135(3):794–804.
  • Voelkel NF, Bogaard HJ, Gomez-Arroyo J. The need to recognize the pulmonary circulation and the right ventricle as an integrated functional unit: facts and hypotheses (2013 Grover Conference series). Pulm Circ. 2015;5(1):81–89.
  • Lindner D, Zietsch C, Tank J, et al. Cardiac fibroblasts support cardiac inflammation in heart failure. Basic Res Cardiol. 2014;109(5):428.
  • Spiekerkoetter E, Tian X, Cai J, et al. FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J Clin Invest. 2013;123(8):3600–3613.
  • Spiekerkoetter E, Sung YK, Sudheendra D, et al. Low-dose FK506 (Tacrolimus) in end-stage pulmonary arterial hypertension. Am J Respir Crit Care Med. 2015;192(2):254–257.
  • Nickel NP, Spiekerkoetter E, Gu M, et al. Elafin reverses pulmonary hypertension via Caveolin-1-dependent bone morphogenetic protein signaling. Am J Respir Crit Care Med. 2015;191(11):1273–1286.

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