Challenges and opportunities in treating inflammation associated with pulmonary hypertension

Expert Review of Cardiovascular Therapy

Volumn 14, Issue 8, 2016, Pages 939-951

  Voelkel, Norbert F ^a   Tamosiuniene, Rasa ^b   Nicolls, Mark R ^b  

^a VIRGINIA COMMONWEALTH UNIVERSITY   (United States)

^b STANFORD UNIVERSITY   (United States)

Author keywords

anti CD20 antibodies; autoimmunity; cytokines; inflammation; leukotrienes; metabolic syndrome; Severe pulmonary hypertension; wound healing

Indexed keywords

CYTOKINE; INTERLEUKIN 1; INTERLEUKIN 6; ANTIINFLAMMATORY AGENT;

ADAPTIVE IMMUNITY; BONE MARROW; CAPILLARY ENDOTHELIAL CELL; EXPERIMENTAL MODEL; HUMAN; IMMUNE RESPONSE; INFLAMMATION; INNATE IMMUNITY; NONHUMAN; NUDE RAT; PHENOTYPE; PULMONARY HYPERTENSION; REVIEW; SCLERODERMA; ANIMAL; FAMILIAL PRIMARY PULMONARY HYPERTENSION; HYPERTENSION, PULMONARY; LUNG; PATHOLOGY; PATHOPHYSIOLOGY;

ANIMALS; ANTI-INFLAMMATORY AGENTS; FAMILIAL PRIMARY PULMONARY HYPERTENSION; HUMANS; HYPERTENSION, PULMONARY; INFLAMMATION; LUNG;

EID: 84965025935     PISSN: 14779072     EISSN: 17448344     Source Type: Journal    
DOI: 10.1080/14779072.2016.1180976     Document Type: Review

References (160)

1. N.F.Voelkel, J.Gomez-Arroyo, A.Abbate, et al. Pathobiology of pulmonary arterial hypertension and right ventricular failure. Eur Respir J. 2012;40:1555–1565.•• This review paper provides a synopsis of pathobiological concepts.
2. P.D.Stein, F.Matta, P.G.Hughes Scope of problem of pulmonary arterial hypertension. Am J Med. 2015;128:844–851.
3. F.Haddad, O.A.Spruijt, A.Y.Denault, 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.
4. H.Latus, T.Delhaas, D.Schranz, et al. Treatment of pulmonary arterial hypertension in children. Nat Rev Cardiol. 2015;12:244–254.• A recent overview of pulmonary hypertension problems in children.
5. D.Heath, J.E.Edwards. 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.•• This is the original description of the grades of severity of pulmonary vascular hypertensive lesions. The data were to a large measure arrived from the analysis of lung vascular lesions observed in patients with congenital heart disease-associated PAH.
6. J.M.Kay, T.D.Gillund, D.Heath. Mast cells in the lungs of rats fed on Crotalaria spectabilis seeds. Am J Pathol. 1967;51:1031–1044.
7. D.Heath, T.Trueman, P.Sukonthamarn. Pulmonary mast cells in mitral stenosis. Cardiovasc Res. 1969;3:467–471.
8. J.Klob. Endarteritis pulmonalis obliterans. Wochenblatt der Zeitschrift der K.K Gesellschaft der Aerzte. Vienna, Nov. 1865.
9. K.R.Stenmark, S.L.James, N.F.Voelkel, et al. Leukotriene C4 and D4 in neonates with hypoxemia and pulmonary hypertension. N Engl J Med. 1983;309:77–80.
10. R.M.Tuder, B.Groves, D.B.Badesch, 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.•• This study addressed the questions: what is the cellular composition of the plexiform lesions? And are the endothelial cells proliferating and phenotypically abnormal?
11. M.Humbert, G.Monti, F.Brenot, 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.•• This study presents one of the corner stones of the ‘inflammation concept’ of severe PAH.
12. L.Wright, R.M.Tuder, J.Wang, 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.•• Using immune histochemistry, the authors demonstrated that genes and proteins representing components of the leukotriene pathway were expressed in the pulmonary vascular lesion endothelial cells, thus providing evidence for inflammatory endothelial cells in PAH.
13. P.Lesprit, B.Godeau, F.J.Authier, 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.
14. N.J.Mehta, I.A.Khan, R.N.Mehta, et al. HIV-Related pulmonary hypertension: analytic review of 131 cases. Chest. 2000;118:1133–1141.• The authors provided the first assessment of AIDS-associated PAH, documenting that PAH in AIDS patients was not anecdotal.
15. R.M.Tuder, M.Chacon, L.Alger, 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.• This study developed the concept of an angiogenic mechanism of lung vessel lumen obliteration.
16. M.C.Tamby, Y.Chanseaud, M.Humbert, et al. Anti-endothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonary arterial hypertension. Thorax. 2005;60:765–772.•• Blood sample analysis has revealed the presence of anti-endothelial cell antibodies in both patients with idiopathic- and scleroderma-associated PAH, providing a mechanistic explanation for pulmonary vascular endothelial cell death.
17. F.Perros, P.Dorfmüller, R.Souza, et al. Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension. Eur Respir J. 2007 Mar;29(3):462–468.
18. P.M.Hassoun, L.Mouthon, J.A.Barberà, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol. 2009;54(1 Suppl):S10–9.
19. R.Tamosiuniene, W.Tian, G.Dhillon, et al. Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension. Circ Res. 2011;109:867–879.•• This investigation established in an animal model of PAH, a potentially fundamental principle of lung vascular homeostasis: regulatory T lymphocytes control vascular injury.
20. W.Tian, X.Jiang, R.Tamosiuniene, et al. Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension. Sci Transl Med. 2013;5(200):200ra117.•• The authors show for the first time that leukotriene B4 causes endothelial cell apoptosis and experimental blockade of LTB4 synthesis prevents the development of severe PAH. Patients with idiopathic or scleroderma-associated PAH can have elevated levels of plasma LTB4.
21. M.Le Hiress, L.Tu, N.Ricard, 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.
22. M.Rabinovitch, C.Guignabert, M.Humbert, et al. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res. 2014 Jun 20;115(1):165–175.
23. A.Huertas, L.Tu, R.Thuillet, et al. Leptin signalling system as a target for pulmonary arterial hypertension therapy. Eur Respir J. 2015;45:1066–1080.• A very good overview of the data regarding an involvement of leptin in inflammation and PAH.
24. S.M.Kawut, E.Bagiella, D.J.Lederer, et al. ASA-STAT study group. Randomized clinical trial of aspirin and simvastatin for pulmonary arterial hypertension: ASA-STAT. Circulation. 2011;123:2985–2993.
25. S.Erzurum, S.I.Rounds, T.Stevens, et al. Strategic plan for lung vascular research: an NHLBI-ORDR workshop report. Am J Respir Crit Care Med. 2010;182:1554–1562.
26. R.Quarck, M.Wynants, E.Verbeken, et al. Contribution of inflammation and impaired angiogenesis to the pathobiology of chronic thromboembolic pulmonary hypertension. Eur Respir J. 2015;46:431–443.
27. M.Humbert, H.A.Ghofrani. The molecular targets of approved treatments for pulmonary arterial hypertension. Thorax. 2016 Jan;71(1):73–83.
28. J.Pal, K.Sen, G.Sarkar, et al. Effect of antiretroviral therapy on pulmonary hypertension in HIV patients. J Indian Med Assoc. 2013;111(845–6):849.
29. R.Kumar, C.Mickael, J.Chabon, 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.
30. E.Daley, C.Emson, C.Guignabert, et al. Pulmonary arterial remodeling induced by a Th2 immune response. J Exp Med. 2008;205:361–372.
31. S.Ono, J.Y.Westcott, N.F.Voelkel. PAF antagonists inhibit pulmonary vascular remodeling induced by hypobaric hypoxia in rats. J Appl Physiol (1985). 1992 Sep;73(3):1084–1092.• One of the early studies that established an experimental link between chronic hypoxia-induced PAH and inflammation.
32. K.R.Stenmark, M.L.Morganroth, L.K.Remigio, et al. Alveolar inflammation and arachidonate metabolism in monocrotaline-induced pulmonary hypertension. Am J Physiol. 1985;248(6 Pt 2):H859–866.
33. M.K.Whyte, S.R.Walmsley. The regulation of pulmonary inflammation by the hypoxia-inducible factor-hydroxylase oxygen-sensing pathway. Ann Am Thorac Soc. 2014;11(Suppl 5):S271–276.• This paper summarizes studies and data that explain the role of the transcription factor HIF-1 alpha in inflammatory pulmonary vascular remodeling.
34. A.Palazon, A.W.Goldrath, V.Nizet, et al. HIF transcription factors, inflammation, and immunity. Immunity. 2014;41(4):518–528.
35. P.Murugesan, T.Hildebrandt, C.Bernlöhr, et al. Inhibition of kinin B1 receptors attenuates pulmonary hypertension and vascular remodeling. Hypertension. 2015;66(4):906–912.
36. C.Dewachter, A.Belhaj, B.Rondelet, et al. Myocardial inflammation in experimental acute right ventricular failure: effects of prostacyclin therapy. J Heart Lung Transplant. 2015;34(10):1334–1345.• Potential anti-inflammatory action profile of prostacyclin and evidence for inflammation in right heart failure.
37. A.Al-Husseini, D.S.Wijesinghe, L.Farkas, 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.• Increased levels of leukotrienes, measured by mass spectroscopy in the right ventricle tissue from animals with severe PAH.
38. T.M.Bull, C.D.Cool, A.E.Serls, et al. Primary pulmonary hypertension, Castleman’s disease and human herpesvirus-8. Eur Respir J. 2003;22(3):403–407.• A case report describing the intersection between a malignancy, viral infection and PAH.
39. H.J.Bogaard, A.Al Husseini, L.Farkas, et al. Severe pulmonary hypertension: The role of metabolic and endocrine disorders. Pulm Circ. 2012;2(2):148–154.• This paper provides an overview of the relationship between thyroid disease and PAH.
40. E.Soon, A.M.Holmes, C.M.Treacy, et al. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation. 2010;122(9):920–927.• A retrospective analysis suggests that high levels of interleukins are associated with a bad prognosis in PAH.
41. A.N.Hata, R.M.Breyer. Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharm & Therap. 2004;103:147–166.
42. W.Zhou, T.S.Blackwell, K.Goleniewska, et al. Prostaglandin I2 analogs inhibit Th1 and Th2 effector cytokine production by CD4 T cells. J Leukoc Biol. 2007;81:809–817.
43. J.C.Sun, S.Ugolini, E.Vivier. Immunological memory within the innate immune system. EMBO J. 2014;33(12):1295–1303.
44. S.M.Man, T.D.Kanneganti. 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.
45. D.Mackey, A.J.McFall. MAMPs and MIMPs: proposed classifications for inducers of innate immunity. Mol Microbiol. 2006;61(6):1365–1371.
46. A.Hauge, N.C.Staub. Prevention of hypoxic vasoconstriction in cat lung by histamine-releasing agent 48/80. J Appl Physiol. 1969;26:693–699.
47. P.R.Rai, C.D.Cool, J.A.King, et al. The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;178:558–564.•• In this publication the authors propose a paradigm shift in order to explain the development of complex pulmonary vascular lesions in PAH. They propose-based on the seminal paper by Hanahan and Weinberg: “The Hallmarks of Cancer”, that a quasi-malignant process may be the underlying pathomechanism for the emergence of apoptosis-resistant endothelial cell proliferation in PAH.
48. A.Wasiuk, V.C.De Vries, K.Hartmann, et al. Mast cells as regulators of adaptive immunity to tumours. Clin Exp Immunol. 2009;155:140–146.
49. S.Piconese, G.Gri, C.Tripodo, 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.
50. F.Perros, P.Dorfmüller, D.Montani, et al. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;185:311–321.
51. X.Meng, J.Yang, M.Dong, 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].
52. M.R.Nicolls, S.Mizuno, L.Taraseviciene-Stewart, et al. New models of pulmonary hypertension based on VEGF receptor blockade-induced endothelial cell apoptosis. Pulm Circ. 2012;2(4):434–42.2.
53. L.Taraseviciene-Stewart, M.R.Nicolls, D.Kraskauskas, 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.•• In the athymic rat model lack of T lymphocytes facilitates angio-obliterative PAH, illustrating for the first time the importance of T cells in the control of pulmonary vascular remodeling.
54. M.Miyata, F.Sakuma, M.Ito, et al. Athymic nude rats develop severe pulmonary hypertension. Int Arch Allergy Immunol. 2000;121(3):246–252.
55. M.R.Nicolls, L.Taraseviciene-Stewart, P.R.Rai, et al. Autoimmunity and pulmonary hypertension: a perspective. Eur Respir J. 2005;26(6):1110–1118.
56. R.Tamosiuniene, M.R.Nicolls. Regulatory T cells and pulmonary hypertension. Trends Cardiovasc Med. 2011;21(6):166–171.
57. W.Tian, X.Jiang, Y.K.Sung, et al. Leukotrienes in pulmonary arterial hypertension. Immunol Res. 2014;58:387–393.
58. J.Qian, W.Tian, X.Jiang, et al. LTB4 activates pulmonary artery adventitial fibroblasts in pulmonary hypertension. Hypertension. in press;2015.
59. K.S.Awad, J.M.Elinoff, S.Wang, 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.•• Pulmonary vascular endothelial cell proliferation is controlled by BMPR2 signaling; these in vitro studies can provide a link to inflammation and PAH.
60. B.Li, A.S.Lalani, T.C.Harding, 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
61. S.Kaur, T.Chang, S.P.Singh, et al.CD47 signaling regulates the immunosuppressive activity of VEGF in T cells. J Immunol. 2014;193:3914–3924.
62. R.J.Davies, A.M.Holmes, J.Deighton, 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.
63. M.T.Kearns, S.Dalal, S.A.Horstmann, et al. Vascular endothelial growth factor enhances macrophage clearance of apoptotic cells. Am J Physiol Lung Cell Mol Physiol. 2012;302:L711–718.
64. R.W.Vandivier, P.M.Henson, I.S.Douglas. Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease. Chest. 2006;129:1673–1682.
65. N.F.Voelkel, R.M.Tuder, J.Bridges, 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.
66. T.Hashimoto-Kataoka, N.Hosen, T.Sonobe, 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.•• The studies presented in this paper emphasize the importance of IL-6 in PAH development.
67. S.Barzilai, R.Blecher-Gonen, Z.Barnett-Itzhaki, 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].
68. K.Salmeron, T.Aihara, E.Redondo-Castro, 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].
69. H.B.Sager, T.Heidt, M.Hulsmans, et al. Targeting interleukin-1β reduces leukocyte production after acute myocardial infarction. Circulation. 2015;132:1880–1890.
70. Y.Berda-Haddad, S.Robert, P.Salers, 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.
71. C.Idan, R.Peleg, V.Elena, et al. IL-1α is a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity. Sci Rep. 2015;5:14756.
72. D.A.McCarthy, R.R.Clark, T.R.Bartling, et al. Redox control of the senescence regulator interleukin-1α and the secretory phenotype. J Biol Chem. 2013;288:32149–32159.
73. K.W.Moore, R.de Waal Malefyt, R.L.Coffman, et al. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683–765.
74. C.Cavelti-Weder, K.Timper, E.Seelig, 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].
75. M.C.Genovese, D.K.Braun, J.S.Erickson, 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.
76. C.Carbone, A.Tamburrino, G.Piro, 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.
77. M.Groh, K.Rogowska, O.Monsarrat, et al. Interleukin-1 receptor antagonist for refractory anti-MDA5 clinically amyopathic dermatomyopathy. Clin Exp Rheumatol. 2015 Nov–Dec;33(6):904–905.
78. K.C.Young, S.M.Hussein, R.Dadiz, et al. Toll-like receptor 4-deficient mice are resistant to chronic hypoxia-induced pulmonary hypertension. Exp Lung Res. 2010;36(2):111–119.
79. L.G.Schuettpelz, J.N.Borgerding, M.J.Christopher, et al. G-CSF regulates hematopoietic stem cell activity, in part, through activation of Toll-like receptor signaling. Leukemia. 2014;28(9):1851–1860.
80. P.M.George, R.Badiger, D.Shao, 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.
81. A.Taraseviciute, N.F.Voelkel. Severe pulmonary hypertension in postmenopausal obese women. Eur J Med Res. 2006;11(5):198–202.• This paper focuses the attention on a hitherto not recognized association between severe PH and obesity. Typically PAH had been understood as a disease of young women.
82. L.Sweeney, N.F.Voelkel. Estrogen exposure, obesity and thyroid disease in women with severe pulmonary hypertension. Eur J Med Res. 2009;14(10):433–442.
83. D.M.Gopal, R.Santhanakrishnan, Y.C.Wang, et al. Impaired right ventricular hemodynamics indicate preclinical pulmonary hypertension in patients with metabolic syndrome. J Am Heart Assoc. 2015;4(3):e001597.
84. R.Mathew. Pulmonary hypertension and metabolic syndrome: Possible connection, PPARγ and Caveolin-1. World J Cardiol. 2014;6(8):692–697.
85. V.Dam, T.Sikder, S.Santosa. From neutrophils to macrophages: differences in regional adipose tissue depots. Obes Rev. 2015 Dec 14. doi:10.1111/obr.12335. [Epub ahead of print].
86. M.F.Gregor, G.S.Hotamisligil. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011;29:415–445.•• An expert review discussing obesity as a cause of inflammation.
87. K.Ussavarungsi, C.S.Thomas, C.D.Burger. Prevalence of metabolic syndrome in patients with pulmonary hypertension. Clin Respir J. 2015 Oct 23. doi:10.1111/crj.12406. [Epub ahead of print].
88. A.Huertas, L.Tu, N.Gambaryan, et al. Leptin and regulatory T-lymphocytes in idiopathic pulmonary arterial hypertension. Eur Respir J. 2012;40(4):895–904.
89. G.P.Velarde, S.Sherazi, D.F.Kraemer, 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.
90. I.Seleit, O.A.Bakry, R.M.Samaka, et al. Immunohistochemical evaluation of leptin expression in wound healing: a clue to exuberant scar formation. Appl Immunohistochem Mol Morphol. 2016;24:296–306.
91. G.H.Bain, E.Collie-Duguid, G.I.Murray, 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.
92. J.H.Tao, J.Barbi, F.Pan. 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.
93. L.D’Ignazio, D.Bandarra, S.Rocha. NF-κB and HIF crosstalk in immune responses. FEBS J. 2015 Oct 29. doi:10.1111/febs.13578. [Epub ahead of print].
94. I.D.Mascanfroni, M.C.Takenaka, A.Yeste, et al. Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α. Nat Med. 2015;21:638–646.•• This study links immune regulation with the aryl hydrocarbon receptor /ARNT/cytochrome p450 pathway; it may be highly relevant in the context of drug-induced PAH.
95. F.T.Cero, V.Hillestad, I.Sjaastad, 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.
96. D.Montani, A.Seferian, L.Savale, et al. Drug-induced pulmonary arterial hypertension: a recent outbreak. Eur Respir Rev. 2013 Sep 1;22(129):244–250.
97. J.Carlsen, K.Hasseriis Andersen, S.Boesgaard, 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.•• This is the only study that has examined the lung vascular pathology in patients with COPD-associated severe PAH and describes the occurrence of complex pulmonary vascular lesions.
98. P.Trip, E.J.Nossent, F.S.de Man, et al. Severely reduced diffusion capacity in idiopathic pulmonary arterial hypertension: patient characteristics and treatment responses. Eur Respir J. 2013;42(6):1575–1585.•• This report describes remarkable and severe impairment of the lung diffusion capacity in Dutch patients with idiopathic PAH who are smokers.
99. J.Kearley, J.S.Silver, C.Sanden, 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.
100. F.Yuan, X.Fu, H.Shi, et al. Induction of murine macrophage M2 polarization by cigarette smoke extract via the JAK2/STAT3 pathway. PLoS One. 2014;9(9):e107063.
101. I.H.Heijink, S.D.Pouwels, C.Leijendekker, 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.
102. S.Shinomiya, H.Naraba, A.Ueno, 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.
103. S.Lindemann, C.Gierer, H.Darius. 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.
104. T.Elisa, P.Antonio, P.Giuseppe, 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.
105. J.Knobloch, M.Feldmann, C.Wahl, 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.
106. H.Brun, H.Holmstrøm, E.Thaulow, 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.
107. B.M.Tsai, M.W.Turrentine, B.C.Sheridan, 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.
108. P.Pifarré, M.Gutierrez-Mecinas, J.Prado, et al. Phosphodiesterase 5 inhibition at disease onset prevents experimental autoimmune encephalomyelitis progression through immunoregulatory and neuroprotective actions. Exp Neurol. 2014;251:58–71.
109. J.A.Califano, Z.Khan, K.A.Noonan, et al. Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma. Clin Cancer Res. 2015;21(1):30–38.
110. D.Westermann, P.M.Becher, D.Lindner, 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.• Sildenafil affects inflammation in the left ventricle in heart failure – corresponding data for the right ventricle and PAH are lacking.
111. C.P.Denton, C.M.Black. Pulmonary hypertension in systemic sclerosis. Rheum Dis Clin North Am. 2003;29(2):335–349, vii.
112. K.P.Kuhn, D.W.Byrne, P.G.Arbogast, et al. Outcome in 91 consecutive patients with pulmonary arterial hypertension receiving epoprostenol. Am J Respir Crit Care Med. 2003;167(4):580–586.• A useful analysis of the efficacy of prostacyclin treatment for PAH.
113. L.Chung, J.Liu, L.Parsons, 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.
114. L.Chung, H.W.Farber, R.Benza, 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.• Prognosis of patients with scleroderma-associated PAH based on analysis of a PAH registry.
115. C.D.Cool, D.Kennedy, N.F.Voelkel, 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.
116. R.Sgonc, M.S.Gruschwitz, H.Dietrich, 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.•• A seminal paper investigating the role of endothelial cell apoptosis in the pathogenesis of scleroderma.
117. R.Wusirika, C.Ferri, M.Marin, 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.
118. G.M.Vercellotti. Effects of viral activation of the vessel wall on inflammation and thrombosis. Blood Coagul Fibrinolysis. 1998;9(Suppl 2):S3–6.
119. F.Longo, S.Saletta, L.Lepore, et al. Localized scleroderma after infection with Epstein-Barr virus. Clin Exp Rheumatol. 1993;11(6):681–683.
120. C.M.Magro, G.Nuovo, C.Ferri, et al. Parvoviral infection of endothelial cells and stromal fibroblasts: a possible pathogenetic role in scleroderma. J Cutan Pathol. 2004;31(1):43–50.
121. C.Ferri, G.Longombardo, P.Mugnaini. Hepatitis E virus and systemic sclerosis. Qjm. 1998;91(5):375.
122. C.Ferri, K.Zakrzewska, G.Longombardo, et al. Parvovirus B19 infection of bone marrow in systemic sclerosis patients. Clin Exp Rheumatol. 1999;17(6):718–720.
123. L.Harel, R.Straussberg, H.Rudich, 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.
124. M.Abu-Shakra, S.Sukenik, D.Buskila. Systemic sclerosis: another rheumatic disease associated with hepatitis C virus infection. Clin Rheumatol. 2000;19(5):378–380.
125. D.Hamamdzic, L.M.Kasman, E.C.LeRoy. The role of infectious agents in the pathogenesis of systemic sclerosis. Curr Opin Rheumatol. 2002;14(6):694–698.
126. M.Neidhart, S.Kuchen, O.Distler, et al. Increased serum levels of antibodies against human cytomegalovirus and prevalence of autoantibodies in systemic sclerosis. Arthritis Rheum. 1999;42(2):389–392.
127. J.H.Vaughan, P.X.Shaw, M.D.Nguyen, 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.
128. F.J.Carapeto, R.K.Winkelmann. Peripheral blood lymphocyte distribution in scleroderma. Dermatologica. 1975;151(4):228–235.
129. A.J.Barnett, B.D.Tait, M.A.Barnett, et al. T lymphocyte subset abnormalities and HLA antigens in scleroderma (systemic sclerosis). Clin Exp Immunol. 1989;76(1):24–29.
130. F.Ingegnoli, D.Trabattoni, M.Saresella, et al. Distinct immune profiles characterize patients with diffuse or limited systemic sclerosis. Clin Immunol. 2003;108(1):21–28.
131. S.Sato, M.Fujimoto, M.Hasegawa, 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.
132. S.Sato, M.Hasegawa, M.Fujimoto, et al. Quantitative genetic variation in CD19 expression correlates with autoimmunity. J Immunol. 2000;165(11):6635–6643.
133. E.J.Cepeda, J.D.Reveille. Autoantibodies in systemic sclerosis and fibrosing syndromes: clinical indications and relevance. Curr Opin Rheumatol. 2004;16(6):723–732.
134. I.Hayakawa, M.Hasegawa, K.Takehara, et al. Anti-DNA topoisomerase IIalpha autoantibodies in localized scleroderma. Arthritis Rheum. 2004;50(1):227–232.
135. M.Nagai, M.Hasegawa, K.Takehara, et al. Novel autoantibody to Cu/Zn superoxide dismutase in patients with localized scleroderma. J Invest Dermatol. 2004;122(3):594–601.
136. J.Morse, R.Barst, E.Horn, et al. Pulmonary hypertension in scleroderma spectrum of disease: lack of bone morphogenetic protein receptor 2 mutations. J Rheumatol. 2002;29(11):2379–2381.
137. A.Crilly, J.Hamilton, C.J.Clark, et al. Analysis of transforming growth factor beta1 gene polymorphisms in patients with systemic sclerosis. Ann Rheum Dis. 2002;61(8):678–681.
138. F.K.Tan, N.Wang, M.Kuwana, 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.
139. E.Susol, A.L.Rands, A.Herrick, et al. Association of markers for TGFbeta3, TGFbeta2 and TIMP1 with systemic sclerosis. Rheumatology (Oxford). 2000;39(12):1332–1336.
140. S.Morelli, C.Ferri, L.Di Francesco, 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.
141. P.E.Carreira. Pulmonary hypertension in autoimmune rheumatic diseases. Autoimmun Rev. 2004;3(4):313–320.
142. N.F.Voelkel, R.M.Tuder. Cellular and molecular mechanisms in the pathogenesis of severe pulmonary hypertension. Eur Respir J. 1995;8(12):2129–2138.
143. N.K.Harrison, A.R.Myers, B.Corrin, et al. Structural features of interstitial lung disease in systemic sclerosis. Am Rev Respir Dis. 1991;144(3 Pt 1):706–713.
144. S.A.Jimenez, C.T.Derk. Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis. Ann Intern Med. 2004;140(1):37–50.
145. M.Inaoki, S.Sato, B.C.Weintraub, et al. CD19-regulated signaling thresholds control peripheral tolerance and autoantibody production in B lymphocytes. J Exp Med. 1997;186(11):1923–1931.
146. N.Asano, M.Fujimoto, N.Yazawa, 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.
147. E.Saito, M.Fujimoto, M.Hasegawa, 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.
148. M.Hasegawa, Y.Hamaguchi, K.Yanaba, 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.
149. S.Sato, M.Fujimoto, M.Hasegawa, et al. Altered B lymphocyte function induces systemic autoimmunity in systemic sclerosis. Mol Immunol. 2004;41(12):1123–1133.
150. M.Fujimoto, S.Sato. B lymphocytes and systemic sclerosis. Curr Opin Rheumatol. 2005;17(6):746–751.
151. S.Sakaguchi. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531–562.•• A comprehensive review of Treg functions.
152. J.M.Kim, J.P.Rasmussen, A.Y.Rudensky. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol. 2007;8:191–197.
153. F.F.Shih, L.Mandik-Nayak, B.T.Wipke, 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.
154. D.McGonagle, A.L.Tan, J.Madden, et al. Successful treatment of resistant scleroderma-associated interstitial lung disease with rituximab. Rheumatology (Oxford). 2008;47(4):552–553.
155. H.J.Bogaard, K.Abe, A.Vonk Noordegraaf, et al. The right ventricle under pressure: cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest. 2009;135(3):794–804.•• The authors provide a comprehensive overview of mechanisms of right heart failure in severe PAH; this paper also addresses the need to focus treatment of the dysfunctional right ventricle.
156. N.F.Voelkel, H.J.Bogaard, J.Gomez-Arroyo. 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.
157. D.Lindner, C.Zietsch, J.Tank, et al. Cardiac fibroblasts support cardiac inflammation in heart failure. Basic Res Cardiol. 2014;109(5):428.
158. E.Spiekerkoetter, X.Tian, J.Cai, et al. FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J Clin Invest. 2013;123(8):3600–3613.•• This paper provides a novel and innovative treatment approach for severe PAH; it describes a high-throughput screening method to identify existing compounds that increase the expression of BMPR2 and how treatment with tacrolimus can reverse severe experimental PAH.
159. E.Spiekerkoetter, Y.K.Sung, D.Sudheendra, et al. Low-dose FK506 (Tacrolimus) in end-stage pulmonary arterial hypertension. Am J Respir Crit Care Med. 2015;192(2):254–257.
160. N.P.Nickel, E.Spiekerkoetter, M.Gu, 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.