Advertisement
Heart, Lung and Circulation

Immune Cells in Pulmonary Arterial Hypertension

Published:March 28, 2022DOI:https://doi.org/10.1016/j.hlc.2022.02.007
      Pulmonary arterial hypertension (PAH) is a complex and serious cardiopulmonary disease; it is characterised by increased pulmonary arterial pressure and pulmonary vascular remodelling accompanied by disordered endothelial and smooth muscle cell proliferation within pulmonary arterioles and arteries. Although recent reports have suggested that dysregulated immunity and inflammation are key players in PAH pathogenesis, their roles in PAH progression remain unclear. Intriguingly, altered host immune cell distribution, number, and polarisation within the lung arterial vasculature have been linked to disease development. This review mainly focusses on the roles of different immune cells in PAH and discusses the underlying mechanisms.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Heart, Lung and Circulation
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Hoeper M.M.
        • Bogaard H.J.
        • Condliffe R.
        • Frantz R.
        • Khanna D.
        • Kurzyna M.
        • et al.
        Definitions and diagnosis of pulmonary hypertension.
        J Am Coll Cardiol. 2013; 62: D42-D50
        • Marsh L.M.
        • Jandl K.
        • Grunig G.
        • Foris V.
        • Bashir M.
        • Ghanim B.
        • et al.
        The inflammatory cell landscape in the lungs of patients with idiopathic pulmonary arterial hypertension.
        Eur Respir J. 2018; 51
        • Bhagwani A.R.
        • Farkas D.
        • Harmon B.
        • Authelet K.J.
        • Cool C.D.
        • Kolb M.
        • et al.
        Clonally selected primitive endothelial cells promote occlusive pulmonary arteriopathy and severe pulmonary hypertension in rats exposed to chronic hypoxia.
        Sci Rep. 2020; 10: 1136
        • Hahn S.S.
        • Makaryus M.
        • Talwar A.
        • Narasimhan M.
        • Zaidi G.
        A review of therapeutic agents for the management of pulmonary arterial hypertension.
        Ther Adv Respir Dis. 2017; 11: 46-63
        • Yaghi S.
        • Novikov A.
        • Trandafirescu T.
        Clinical update on pulmonary hypertension.
        J Investig Med. 2020; 68: 821-827
        • Chen Y.
        • Kuang M.
        • Liu S.
        • Hou C.
        • Duan X.
        • Yang K.
        • et al.
        A novel rat model of pulmonary hypertension induced by mono treatment with SU5416.
        Hypertens Res. 2020; 43: 754-764
        • Carman B.L.
        • Predescu D.N.
        • Machado R.
        • Predescu S.A.
        Plexiform arteriopathy in rodent models of pulmonary arterial hypertension.
        Am J Pathol. 2019; 189: 1133-1144
        • Zhu Z.
        • Wang Y.
        • Long A.
        • Feng T.
        • Ocampo M.
        • Chen S.
        • et al.
        Pulmonary vessel casting in a rat model of monocrotaline-mediated pulmonary hypertension.
        Pulm Circ. 2020; 102045894020922129
        • Huertas A.
        • Phan C.
        • Bordenave J.
        • Tu L.
        • Thuillet R.
        • Le Hiress M.
        • et al.
        Regulatory t cell dysfunction in idiopathic, heritable and connective tissue-associated pulmonary arterial hypertension.
        Chest. 2016; 149: 1482-1493
        • Li Y.
        • Yang L.
        • Dong L.
        • Yang Z.W.
        • Zhang J.
        • Zhang S.L.
        • et al.
        Crosstalk between the Akt/mTORC1 and Nf-kappa B signaling pathways promotes hypoxia-induced pulmonary hypertension by increasing DPP4 expression in PASMCS.
        Acta Pharmacol Sin. 2019; 40: 1322-1333
        • Hassoun P.M.
        • Mouthon L.
        • Barbera J.A.
        • Eddahibi S.
        • Flores S.C.
        • Grimminger F.
        • et al.
        Inflammation, growth factors, and pulmonary vascular remodeling.
        J Am Coll Cardiol. 2009; 54: S10-S19
        • Zeng H.W.
        • Liu X.Q.
        • Zhang Y.S.
        Identification of potential biomarkers and immune infiltration characteristics in idiopathic pulmonary arterial hypertension using bioinformatics analysis.
        Front Cardiovasc Med. 2021; 8
        • Li C.
        • Liu P.P.
        • Song R.
        • Zhang Y.Q.
        • Lei S.
        • Wu S.J.
        Immune cells and autoantibodies in pulmonary arterial hypertension.
        Acta Bioch Bioph Sin. 2017; 49: 1047-1057
        • Klouda T.
        • Yuan K.
        Inflammation in pulmonary arterial hypertension.
        Adv Exp Med Biol. 2021; 1303: 351-372
        • Tang C.
        • Luo Y.M.
        • Li S.
        • Huang B.
        • Xu S.F.
        • Li L.S.
        Characteristics of inflammation process in monocrotaline-induced pulmonary arterial hypertension in rats.
        Biomed Pharmacother. 2021; 133
        • Liang S.X.
        • Desai A.A.
        • Black S.M.
        • Tang H.Y.
        Cytokines, chemokines, and inflammation in pulmonary arterial hypertension.
        Adv Exp Med Biol. 2021; 1303: 275-303
        • Barman S.A.
        • Bordan Z.
        • Batori R.
        • Haigh S.
        • Fulton D.J.R.
        Galectin-3 promotes ROS, inflammation, and vascular fibrosis in pulmonary arterial hypertension.
        Adv Exp Med Biol. 2021; 1303: 13-32
        • Farha S.
        • Sharp J.
        • Asosingh K.
        • Park M.
        • Comhair S.A.
        • Tang W.H.
        • et al.
        Mast cell number, phenotype, and function in human pulmonary arterial hypertension.
        Pulm Circ. 2012; 2: 220-228
        • Hu Y.
        • Chi L.
        • Kuebler W.M.
        • Goldenberg N.M.
        Perivascular inflammation in pulmonary arterial hypertension.
        Cells. 2020; 9
        • Humbert M.
        • Monti G.
        • Brenot F.
        • Sitbon O.
        • Portier A.
        • Grangeot-Keros L.
        • 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
        • Siamwala J.H.
        • Zhao A.
        • Barthel H.
        • Pagano F.S.
        • Gilbert R.J.
        • Rounds S.
        Adaptive and innate immune mechanisms in cardiac fibrosis complicating pulmonary arterial hypertension.
        Physiol Rep. 2020; 8e14532
        • Trittmann J.K.
        Keratin 1: A negative regulator of inflammation and potential treatment for pulmonary arterial hypertension.
        Acta Physiol (Oxf). 2021; 231e13594
        • Gomez-Puerto M.C.
        • Sun X.Q.
        • Schalij I.
        • Orriols M.
        • Pan X.
        • Szulcek R.
        • et al.
        MnTBAP reverses pulmonary vascular remodeling and improves cardiac function in experimentally induced pulmonary arterial hypertension.
        Int J Mol Sci. 2020; 21
        • Feng W.
        • Hu Y.
        • An N.
        • Feng Z.
        • Liu J.
        • Mou J.
        • et al.
        Alginate oligosaccharide alleviates monocrotaline-induced pulmonary hypertension via anti-oxidant and anti-inflammation pathways in rats.
        Int Heart J. 2020; 61: 160-168
        • Zhang M.
        • Chang Z.
        • Zhang P.
        • Jing Z.
        • Yan L.
        • Feng J.
        • et al.
        Protective effects of 18beta-glycyrrhetinic acid on pulmonary arterial hypertension via regulation of Rho A/Rho kinsase pathway.
        Chem Biol Interact. 2019; 311: 108749
        • Perros F.
        • Dorfmuller P.
        • Souza R.
        • Durand-Gasselin I.
        • Mussot S.
        • Mazmanian M.
        • et al.
        Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension.
        Eur Respir J. 2007; 29: 462-468
        • Perros F.
        • Dorfmuller P.
        • Montani D.
        • Hammad H.
        • Waelput W.
        • Girerd B.
        • et al.
        Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension.
        Am J Respir Crit Care Med. 2012; 185: 311-321
        • Savai R.
        • Pullamsetti S.S.
        • Kolbe J.
        • Bieniek E.
        • Voswinckel R.
        • Fink L.
        • et al.
        Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension.
        Am J Respir Crit Care Med. 2012; 186: 897-908
        • Sanchez O.
        • Marcos E.
        • Perros F.
        • Fadel E.
        • Tu L.
        • Humbert M.
        • et al.
        Role of endothelium-derived cc chemokine ligand 2 in idiopathic pulmonary arterial hypertension.
        Am J Respir Crit Care Med. 2007; 176: 1041-1047
        • Hautefort A.
        • Girerd B.
        • Montani D.
        • Cohen-Kaminsky S.
        • Price L.
        • Lambrecht B.N.
        • et al.
        T-helper 17 cell polarization in pulmonary arterial hypertension.
        Chest. 2015; 147: 1610-1620
        • Shen Z.
        • Chen L.
        • Hao F.
        • Wang G.
        • Fan P.
        • Liu Y.
        Intron-1 rs3761548 is related to the defective transcription of Foxp3 in psoriasis through abrogating e47/c-myb binding (Retracted Article).
        J Cell Mol Med. 2010; 14: 226-241
        • Savai R.
        • Pullamsetti S.S.
        • Kolbe J.
        • Bieniek E.
        • Voswinkel R.
        • Fink L.
        • et al.
        Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension.
        Eur Resp J. 2013; 42
        • Chen G.
        • Zuo S.
        • Tang J.
        • Zuo C.
        • Jia D.
        • Liu Q.
        • et al.
        Inhibition of CRTH2-mediated th2 activation attenuates pulmonary hypertension in mice.
        J Exp Med. 2018; 215: 2175-2195
        • Harbaum L.
        • Renk E.
        • Yousef S.
        • Glatzel A.
        • Luneburg N.
        • Hennigs J.K.
        • et al.
        Acute effects of exercise on the inflammatory state in patients with idiopathic pulmonary arterial hypertension.
        BMC Pulm Med. 2016; 16: 145
        • Gaowa S.
        • Zhou W.Y.
        • Jiang H.
        Effect of TH17 and Treg axis disorder on outcomes of pulmonary arterial hypertension in connective tissue diseases.
        J Am Coll Cardiol. 2014; 64 (C218-C)
        • Frantz C.
        • Auffray C.
        • Avouac J.
        • Allanore Y.
        Regulatory T cells in systemic sclerosis.
        Front Immunol. 2018; 9
        • Shu T.
        • Xing Y.
        • Wang J.
        Autoimmunity in pulmonary arterial hypertension: evidence for local immunoglobulin production.
        Front Cardiovasc Med. 2021; 8: 680109
        • Blum L.K.
        • Cao R.R.L.
        • Sweatt A.J.
        • Bill M.
        • Lahey L.J.
        • Hsi A.C.
        • et al.
        Circulating plasmablasts are elevated and produce pathogenic anti-endothelial cell autoantibodies in idiopathic pulmonary arterial hypertension.
        Eur J Immunol. 2018; 48: 874-884
        • Heukels P.
        • Corneth O.B.J.
        • van Uden D.
        • van Hulst J.A.C.
        • van den Toorn L.M.
        • van den Bosch A.E.
        • et al.
        Loss of immune homeostasis in patients with idiopathic pulmonary arterial hypertension.
        Thorax. 2021; 76: 1209-1218
        • Ulrich S.
        • Nicolls M.R.
        • Taraseviciene L.
        • Speich R.
        • Voelkel N.
        Increased regulatory and decreased CD8+ cytotoxic T cells in the blood of patients with idiopathic pulmonary arterial hypertension.
        Respiration. 2008; 75: 272-280
        • Ars C.
        • Thurion P.
        • Delos M.
        • Sibille Y.
        • Pilette C.
        Small airway obstruction in severe pulmonary arterial hypertension correlates with increased airway CD8+ T-cells and fractalkine expression.
        Eur Respir J. 2009; 34: 1494-1496
        • Mao M.
        • Zhang M.
        • Ge A.
        • Ge X.
        • Gu R.
        • Zhang C.
        • et al.
        Granzyme B deficiency promotes osteoblastic differentiation and calcification of vascular smooth muscle cells in hypoxic pulmonary hypertension.
        Cell Death Dis. 2018; 9: 221
        • Dempsey E.C.
        • Badesch D.B.
        • Dobyns E.L.
        • Stenmark K.R.
        Enhanced growth capacity of neonatal pulmonary artery smooth muscle cells in vitro: dependence on cell size, time from birth, insulin-like growth factor i, and auto-activation of protein kinase C.
        J Cell Physiol. 1994; 160: 469-481
        • Pfarr N.
        • Szamalek-Hoegel J.
        • Fischer C.
        • Hinderhofer K.
        • Nagel C.
        • Ehlken N.
        • et al.
        Hemodynamic and clinical onset in patients with hereditary pulmonary arterial hypertension and BMPR2 mutations.
        Respir Res. 2011; 12: 99
        • Pfarr N.
        • Fischer C.
        • Ehlken N.
        • Becker-Grunig T.
        • Lopez-Gonzalez V.
        • Gorenflo M.
        • et al.
        Hemodynamic and genetic analysis in children with idiopathic, heritable, and congenital heart disease associated pulmonary arterial hypertension.
        Respir Res. 2013; 14: 3
        • Loyd J.E.
        • Butler M.G.
        • Foroud T.M.
        • Conneally P.M.
        • Phillips J.A.
        • Newman J.H.
        Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary-hypertension.
        Am J Resp Crit Care. 1995; 152: 93-97
        • Soon E.
        • Crosby A.
        • Southwood M.
        • Yang P.
        • Tajsic T.
        • Toshner M.
        • et al.
        Bone morphogenetic protein receptor type ii deficiency and increased inflammatory cytokine production. A gateway to pulmonary arterial hypertension.
        Am J Respir Crit Care Med. 2015; 192: 859-872
        • Burton V.J.
        • Ciuclan L.I.
        • Holmes A.M.
        • Rodman D.M.
        • Walker C.
        • Budd D.C.
        Bone morphogenetic protein receptor II regulates pulmonary artery endothelial cell barrier function.
        Blood. 2011; 117: 333-341
        • Soon E.
        • Crosby A.
        • Southwood M.
        • Pepke-Zaba J.
        • Upton P.
        • Morrell N.W.
        Mutations in bmpr-ii promote inflammation via altered superoxide signalling: insights into the mechanisms underlying pulmonary arterial hypertension.
        Thorax. 2012; 67: A2-A3
        • Padmanabhan J.
        • Gonzalez A.L.
        The effects of extracellular matrix proteins on neutrophil-endothelial interaction--a roadway to multiple therapeutic opportunities.
        Yale J Biol Med. 2012; 85: 167-185
        • Castanheira F.V.S.
        • Kubes P.
        Neutrophils and NETs in modulating acute and chronic inflammation.
        Blood. 2019; 133: 2178-2185
        • Sweatt A.J.
        • Miyagawa K.
        • Rhodes C.J.
        • Taylor S.
        • Del Rosario P.A.
        • Hsi A.
        • et al.
        Severe pulmonary arterial hypertension is characterized by increased neutrophil elastase and relative elafin deficiency.
        Chest. 2021; 160: 1442-1458
        • Taylor S.
        • Dirir O.
        • Zamanian R.T.
        • Rabinovitch M.
        • Thompson A.A.R.
        The role of neutrophils and neutrophil elastase in pulmonary arterial hypertension.
        Front Med. 2018; 5: 217
        • Aldabbous L.
        • Abdul-Salam V.
        • McKinnon T.
        • Duluc L.
        • Pepke-Zaba J.
        • Southwood M.
        • et al.
        Neutrophil extracellular traps promote angiogenesis: evidence from vascular pathology in pulmonary hypertension.
        Arterioscl Throm Vas. 2016; 36: 2078-2087
        • von Nussbaum F.
        • Li V.M.
        • Meibom D.
        • Anlauf S.
        • Bechem M.
        • Delbeck M.
        • et al.
        Potent and selective human neutrophil elastase inhibitors with novel equatorial ring topology: in vivo efficacy of the polar pyrimidopyridazine bay-8040 in a pulmonary arterial hypertension rat model.
        Chemmedchem. 2016; 11: 199-206
        • Vengethasamy L.
        • Hautefort A.
        • Tielemans B.
        • Belge C.
        • Perros F.
        • Verleden S.
        • et al.
        Bmprii influences the response of pulmonary microvascular endothelial cells to inflammatory mediators.
        Pflug Arch Eur J Phy. 2016; 468: 1969-1983
        • Song Y.
        • Coleman L.
        • Shi J.
        • Beppu H.
        • Sato K.
        • Walsh K.
        • et al.
        Inflammation, endothelial injury, and persistent pulmonary hypertension in heterozygous BMPR2-mutant mice (vol 294, pg h677, 2008).
        Am J Physiol-Heart C. 2009; 297 (:H1544-H)
        • George P.M.
        • Badiger R.
        • Shao D.
        • Edwards M.R.
        • Wort S.J.
        • Paul-Clark M.J.
        • 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: 486-491
        • Eichstaedt C.
        • Song J.
        • Viales R.R.
        • Pan Z.
        • Benjamin N.
        • Fischer C.
        • et al.
        First identification of Kruppel-like factor 2 mutation in heritable pulmonary arterial hypertension.
        Am J Resp Crit Care. 2018; 197
        • Hart G.T.
        • Hogquist K.A.
        • Jameson S.C.
        Kruppel-like factors in lymphocyte biology.
        J Immunol. 2012; 188: 521-526
        • Wittner J.
        • Schuh W.
        Kruppel-like factor 2 (KLF2) in immune cell migration.
        Vaccines-Basel. 2021; 9
        • Garg L.
        • Akbar G.
        • Agrawal S.
        • Agarwal M.
        • Khaddour L.
        • Handa R.
        • et al.
        Drug-induced pulmonary arterial hypertension: A review.
        Heart Fail Rev. 2017; 22: 289-297
        • Perez V.D.
        • Kudelko K.
        • Snook S.
        • Zamanian R.T.
        Drugs and toxins-associated pulmonary arterial hypertension: lessons learned and challenges ahead.
        Int J Clin Pract. 2011; 65: 8-10
        • Almodovar S.
        • Swanson J.
        • Giavedoni L.D.
        • Kanthaswamy S.
        • Long C.S.
        • Voelkel N.F.
        • et al.
        Lung vascular remodeling, cardiac hypertrophy, and inflammatory cytokines in SHIVnef-infected macaques.
        Viral Immunol. 2018; 31: 206-222
        • El Chami H.
        • Hassoun P.M.
        Inflammatory mechanisms in the pathogenesis of pulmonary arterial hypertension.
        Compr Physiol. 2011; 1: 1929-1941
        • Tazelaar H.D.
        • Myers J.L.
        • Drage C.W.
        • King Jr., T.E.
        • Aguayo S.
        • Colby T.V.
        Pulmonary disease associated with l-tryptophan-induced eosinophilic myalgia syndrome. Clinical and pathologic features.
        Chest. 1990; 97: 1032-1036
        • MacLean M.R.
        The serotonin hypothesis in pulmonary hypertension revisited: targets for novel therapies (2017 Grover Conference Series).
        Pulmon Circ. 2018; 8
        • Abenhaim L.
        • Humbert M.
        Pulmonary hypertension related to drugs and toxins (vol 14, pg 437, 1999).
        Curr Opin Cardiol. 1999; 14 (:Ar5-Ar)
        • MacLean M.R.
        • Herve P.
        • Eddahibi S.
        • Adnot S.
        5-hydroxytryptamine and the pulmonary circulation: receptors, transporters and relevance to pulmonary arterial hypertension.
        Brit J Pharmacol. 2000; 131: 161-168
        • Fanburg B.L.
        • Lee S.L.
        A new role for an old molecule: Serotonin as a mitogen.
        Am J Physiol-Lung C. 1997; 272: L795-L806
        • MacLean M.R.
        Pulmonary hypertension and the serotonin hypothesis: where are we now?.
        Int J Clin Pract. 2007; 61: 27-31
        • Wan M.J.
        • Ding L.L.
        • Wang D.
        • Han J.W.
        • Gao P.J.
        Serotonin: a potent immune cell modulator in autoimmune diseases.
        Front Immunol. 2020; 11
        • Seiler K.U.
        Aminorex and pulmonary circulation.
        Arzneimittelforschung. 1975; 25: 837
        • Eddahibi S.
        • Adnot S.
        Anorexigen-induced pulmonary hypertension and the serotonin (5-ht) hypothesis: lessons for the future in pathogenesis.
        Respir Res. 2002; 3: 9
        • Walther D.J.
        • Peter J.U.
        • Bashammakh S.
        • Hortnagl H.
        • Voits M.
        • Fink H.
        • et al.
        Synthesis of serotonin by a second tryptophan hydroxylase isoform.
        Science. 2003; 299: 76
        • Dempsie Y.
        • Morecroft I.
        • Welsh D.J.
        • MacRitchie N.A.
        • Herold N.
        • Loughlin L.
        • et al.
        Converging evidence in support of the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension with novel transgenic mice.
        Circulation. 2008; 117: 2928-2937
        • Liu Y.L.
        • Li M.
        • Warburton R.R.
        • Hill N.S.
        • Fanburg B.L.
        The 5-HT transporter transactivates the PDGF beta receptor in pulmonary artery smooth muscle cells.
        Faseb J. 2007; 21: 2725-2734
        • Liu Y.
        • Tian H.Y.
        • Yan X.L.
        • Fan F.L.
        • Wang W.P.
        • Han J.L.
        • et al.
        Serotonin inhibits apoptosis of pulmonary artery smooth muscle cell by pERK1/2 and PDK through 5-HT1B receptors and 5-ht transporters.
        Cardiovasc Pathol. 2013; 22: 451-457
        • Marcos E.
        • Fadel E.
        • Sanchez O.
        • Humbert M.
        • Dartevelle P.
        • Simonneau G.
        • et al.
        Serotonin transporter and receptors in various forms of human pulmonary hypertension.
        Chest. 2005; 128 (552s-3s)
        • Slauson D.O.
        • Walker C.
        • Kristensen F.
        • Wang Y.
        • de Weck A.L.
        Mechanisms of serotonin-induced lymphocyte proliferation inhibition.
        Cell Immunol. 1984; 84: 240-252
        • O'Connell P.J.
        • Wang X.
        • Leon-Ponte M.
        • Griffiths C.
        • Pingle S.C.
        • Ahern G.P.
        A novel form of immune signaling revealed by transmission of the inflammatory mediator serotonin between dendritic cells and t cells.
        Blood. 2006; 107: 1010-1017
        • Gordon J.
        • Barnes N.M.
        Lymphocytes transport serotonin and dopamine: agony or ecstasy?.
        Trends Immunol. 2003; 24: 438-443
        • Matsuda H.
        • Ushio H.
        • Geba G.P.
        • Askenase P.W.
        Human platelets can initiate t cell-dependent contact sensitivity through local serotonin release mediated by IgE antibodies.
        J Immunol. 1997; 158: 2891-2897
        • Meredith E.J.
        • Chamba A.
        • Holder M.J.
        • Barnes N.M.
        • Gordon J.
        Close encounters of the monoamine kind: Immune cells betray their nervous disposition.
        Immunology. 2005; 115: 289-295
        • Mikulski Z.
        • Zaslona Z.
        • Cakarova L.
        • Hartmann P.
        • Wilhelm J.
        • Tecott L.H.
        • et al.
        Serotonin activates murine alveolar macrophages through 5-HT2C receptors.
        Am J Physiol Lung Cell Mol Physiol. 2010; 299: L272-L280
        • Shajib M.S.
        • Baranov A.
        • Khan W.I.
        Diverse effects of gut-derived serotonin in intestinal inflammation.
        Acs Chem Neurosci. 2017; 8: 920-931
        • Leon-Ponte M.
        • Ahern G.P.
        • O'Connell P.J.
        Serotonin provides an accessory signal to enhance t-cell activation by signaling through the 5-HT7 receptor.
        Blood. 2007; 109: 3139-3146
        • Price L.C.
        • Wort S.J.
        • Perros F.
        • Dorfmuller P.
        • Huertas A.
        • Montani D.
        • et al.
        Inflammation in pulmonary arterial hypertension.
        Chest. 2012; 141: 210-221
        • Dhillon N.K.
        • Li F.
        • Xue B.
        • Tawfik O.
        • Morgello S.
        • Buch S.
        • et al.
        Effect of cocaine on human immunodeficiency virus-mediated pulmonary endothelial and smooth muscle dysfunction.
        Am J Resp Cell Mol. 2011; 45: 40-52
        • Sharma H.
        • Chinnappan M.
        • Agarwal S.
        • Dalvi P.
        • Gunewardena S.
        • O’Brien-Ladner A.
        • et al.
        Macrophage--derived extracellular vesicles mediate smooth muscle hyperplasia: role of altered miRNA cargo in response to HIV infection and substance abuse (vol 32, pg 5174, 2018).
        Faseb J. 2021; 35
        • Shimoda L.A.
        • Wang J.
        • Sylvester J.T.
        Ca2+ channels and chronic hypoxia.
        Microcirculation. 2006; 13: 657-670
        • Wang J.
        • Weigand L.
        • Lu W.
        • Sylvester J.T.
        • Semenza G.L.
        • Shimoda L.A.
        Hypoxia inducible factor 1 mediates hypoxia-induced TRPC expression and elevated intracellular ca2+ in pulmonary arterial smooth muscle cells.
        Circ Res. 2006; 98: 1528-1537
        • Tcherakian C.
        • Rivaud E.
        • Catherinot E.
        • Zucman D.
        • Metivier A.C.
        • Couderc L.J.
        [pulmonary arterial hypertension related to HIV: Is inflammation related to il-6 the cornerstone?].
        Rev Pneumol Clin. 2011; 67: 250-257
        • Morris A.
        • Gingo M.R.
        • George M.P.
        • Lucht L.
        • Kessinger C.
        • Singh V.
        • et al.
        Cardiopulmonary function in individuals with HIV infection in the antiretroviral therapy era.
        AIDS. 2012; 26: 731-740
        • Honeycutt J.B.
        • Thayer W.O.
        • Baker C.E.
        • Ribeiro R.M.
        • Lada S.M.
        • Cao Y.F.
        • et al.
        Hiv persistence in tissue macrophages of humanized myeloid-only mice during antiretroviral therapy.
        Nat Med. 2017; 23: 638
        • Schweitzer F.
        • Tarantelli R.
        • Rayens E.
        • Kling H.M.
        • Mattila J.T.
        • Norris K.A.
        Monocyte and alveolar macrophage skewing is associated with the development of pulmonary arterial hypertension in a primate model of HIV infection.
        Aids Res Hum Retrov. 2019; 35: 63-74
        • Rabacal W.
        • Schweitzer F.
        • Rayens E.
        • Tarantelli R.
        • Whang P.
        • Jimenez V.C.
        • et al.
        Statin treatment prevents the development of pulmonary arterial hypertension in a nonhuman primate model of HIV-associated PAH.
        Sci Rep-Uk. 2019; 9
        • Chalifoux L.V.
        • Simon M.A.
        • Pauley D.R.
        • Mackey J.J.
        • Wyand M.S.
        • Ringler D.J.
        Arteriopathy in macaques infected with simian immunodeficiency virus.
        Lab Invest. 1992; 67: 338-349
        • Fan Y.
        • Hao Y.J.
        • Gao D.
        • Li G.T.
        • Zhang Z.L.
        • Gao L.
        Phenotype and function of macrophage polarization in monocrotaline-induced pulmonary arterial hypertension rat model.
        Physiol Res. 2021; 70: 213-226
        • Mosser D.M.
        • Edwards J.P.
        Exploring the full spectrum of macrophage activation.
        Nat Rev Immunol. 2008; 8: 958-969
        • Gheryani N.
        • Coffelt S.B.
        • Gartland A.
        • Rumney R.M.H.
        • Kiss-Toth E.
        • Lewis C.E.
        • et al.
        Generation of a novel mouse model for the inducible depletion of macrophages in vivo.
        Genesis. 2013; 51: 41-49
        • Zawia A.
        • Arnold N.D.
        • West L.
        • Pickworth J.A.
        • Turton H.
        • Iremonger J.
        • et al.
        Altered macrophage polarization induces experimental pulmonary hypertension and is observed in patients with pulmonary arterial hypertension.
        Arterioscl Throm Vas. 2021; 41: 430-445
        • Tian W.
        • Jiang X.G.
        • Tamosiuniene R.
        • Sung Y.K.
        • Qian J.
        • Dhillon G.
        • et al.
        Blocking macrophage leukotriene b-4 prevents endothelial injury and reverses pulmonary hypertension.
        Sci Transl Med. 2013; 5
        • Mouthon L.
        • Guillevin L.
        • Humbert M.
        Pulmonary arterial hypertension: an autoimmune disease?.
        Eur Respir J. 2005; 26: 986-988
        • van Uden D.
        • Boomars K.
        • Kool M.
        Dendritic cell subsets and effector function in idiopathic and connective tissue disease-associated pulmonary arterial hypertension.
        Front Immunol. 2019; 10: 11
        • Yu Y.R.
        • Mao L.
        • Piantadosi C.A.
        • Gunn M.D.
        Ccr2 deficiency, dysregulation of notch signaling, and spontaneous pulmonary arterial hypertension.
        Am J Respir Cell Mol Biol. 2013; 48: 647-654
        • Gaowa S.
        • Zhou W.
        • Yu L.
        • Zhou X.
        • Liao K.
        • Yang K.
        • et al.
        Effect of th17 and treg axis disorder on outcomes of pulmonary arterial hypertension in connective tissue diseases.
        Mediators Inflamm. 2014; 2014: 247372
        • Edwards A.L.
        • Gunningham S.P.
        • Clare G.C.
        • Hayman M.W.
        • Smith M.
        • Frampton C.M.A.
        • et al.
        Professional killer cell deficiencies and decreased survival in pulmonary arterial hypertension.
        Respirology. 2013; 18: 1271-1277
        • Pullamsetti S.S.
        • Savai R.
        • Janssen W.
        • Dahal B.K.
        • Seeger W.
        • Grimminger F.
        • et al.
        Inflammation, immunological reaction and role of infection in pulmonary hypertension.
        Clin Microbiol Infec. 2011; 17: 7-14
        • Kherbeck N.
        • Tamby M.C.
        • Bussone G.
        • Dib H.
        • Perros F.
        • Humbert M.
        • et al.
        The role of inflammation and autoimmunity in the pathophysiology of pulmonary arterial hypertension.
        Clin Rev Allerg Immu. 2013; 44: 31-38
        • Gashouta M.A.
        • Humbert M.
        • Hassoun P.M.
        Update in systemic sclerosis-associated pulmonary arterial hypertension.
        Presse Med. 2014; 43: E293-E304
        • Negi V.S.
        • Tripathy N.K.
        • Misra R.
        • Nityanand S.
        Antiendothelial cell antibodies in scleroderma correlate with severe digital ischemia and pulmonary arterial hypertension.
        J Rheumatol. 1998; 25: 462-466
        • Graham B.B.
        • Chabon J.
        • Bandeira A.
        • Espinheira L.
        • Butrous G.
        • Tuder R.M.
        Significant intrapulmonary schistosoma egg antigens are not present in schistosomiasis-associated pulmonary hypertension.
        Pulm Circ. 2011; 1: 456-461
        • Kolosionek E.
        • Graham B.B.
        • Tuder R.M.
        • Butrous G.
        Pulmonary vascular disease associated with parasitic infection--the role of schistosomiasis.
        Clin Microbiol Infect. 2011; 17: 15-24
        • Ferreira Rde C.
        • Montenegro S.M.
        • Domingues A.L.
        • Bandeira A.P.
        • Silveira C.A.
        • Leite L.A.
        • et al.
        Tgf beta and il13 in schistosomiasis mansoni associated pulmonary arterial hypertension; a descriptive study with comparative groups.
        BMC Infect Dis. 2014; 14: 282
        • Burke M.L.
        • Jones M.K.
        • Gobert G.N.
        • Li Y.S.
        • Ellis M.K.
        • Mcmanus D.P.
        Immunopathogenesis of human schistosomiasis.
        Parasite Immunol. 2009; 31: 163-176
        • Van Dyken S.J.
        • Locksley R.M.
        Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease.
        Annu Rev Immunol. 2013; 31: 317-343
        • Martinez F.O.
        • Gordon S.
        The m1 and m2 paradigm of macrophage activation: time for reassessment.
        F1000Prime Rep. 2014; 6: 13
        • Sica A.
        • Mantovani A.
        Macrophage plasticity and polarization: in vivo veritas.
        J Clin Invest. 2012; 122: 787-795
        • Gordon S.
        • Martinez F.O.
        Alternative activation of macrophages: mechanism and functions.
        Immunity. 2010; 32: 593-604
        • Stacher E.
        • Graham B.B.
        • Hunt J.M.
        • Gandjeva A.
        • Groshong S.D.
        • McLaughlin V.V.
        • et al.
        Modern age pathology of pulmonary arterial hypertension.
        Am J Respir Crit Care Med. 2012; 186: 261-272
        • Pinto R.F.
        • Higuchi Mde L.
        • Aiello V.D.
        Decreased numbers of t-lymphocytes and predominance of recently recruited macrophages in the walls of peripheral pulmonary arteries from 26 patients with pulmonary hypertension secondary to congenital cardiac shunts.
        Cardiovasc Pathol. 2004; 13: 268-275
        • Yin X.
        • Xin M.
        • Ding S.
        • Gao F.
        • Wu F.
        • Wang J.
        • et al.
        Predictive role of perioperative neutrophil to lymphocyte ratio in pediatric congenital heart disease associated with pulmonary arterial hypertension.
        BMC Surg. 2021; 21: 3
        • Gursoy M.
        • Salihoglu E.
        • Hatemi A.C.
        • Hokenek A.F.
        • Ozkan S.
        • Ceyran H.
        Inflammation and congenital heart disease associated pulmonary hypertension.
        Heart Surg Forum. 2015; 18: E38-E41
        • Hamada H.
        • Terai M.
        • Kimura H.
        • Hirano K.
        • Oana S.
        • Niimi H.
        Increased expression of mast cell chymase in the lungs of patients with congenital heart disease associated with early pulmonary vascular disease.
        Am J Respir Crit Care Med. 1999; 160: 1303-1308
        • Xu J.
        • Wang J.
        • Shao C.
        • Zeng X.
        • Sun L.
        • Kong H.
        • et al.
        New dynamic viewing of mast cells in pulmonary arterial hypertension (pah): Contributors or outsiders to cardiovascular remodeling.
        J Thorac Dis. 2018; 10: 3016-3026
        • Kosanovic D.
        • Dahal B.K.
        • Peters D.M.
        • Seimetz M.
        • Wygrecka M.
        • Hoffmann K.
        • et al.
        Histological characterization of mast cell chymase in patients with pulmonary hypertension and chronic obstructive pulmonary disease.
        Pulm Circ. 2014; 4: 128-136
        • Berk B.C.
        Angiotensin ii signal transduction in vascular smooth muscle: Pathways activated by specific tyrosine kinases.
        J Am Soc Nephrol. 1999; 10: S62-S68
        • Bartelds B.
        • van Loon R.L.E.
        • Mohaupt S.
        • Wijnberg H.
        • Dickinson M.G.
        • Boersma B.
        • et al.
        Mast cell inhibition improves pulmonary vascular remodeling in pulmonary hypertension.
        Chest. 2012; 141: 651-660
        • Maeda N.Y.
        • Aiello V.D.
        • Santos P.C.
        • Thomaz A.M.
        • Kajita L.J.
        • Bydlowski S.P.
        • et al.
        Relation of macrophage migration inhibitory factor to pulmonary hemodynamics and vascular structure and carbamyl-phosphate synthetase i genetic variations in pediatric patients with congenital cardiac shunts.
        Mediators Inflamm. 2019; 2019: 7305028
        • Calandra T.
        • Bernhagen J.
        • Mitchell R.A.
        • Bucala R.
        The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor.
        J Exp Med. 1994; 179: 1895-1902
        • Zamanian R.T.
        • Badesch D.
        • Chung L.
        • Domsic R.T.
        • Medsger T.
        • Pinckney A.
        • et al.
        Safety and efficacy of b-cell depletion with rituximab for the treatment of systemic sclerosis-associated pulmonary arterial hypertension: a multicenter, double-blind, randomized, placebo-controlled trial.
        Am J Respir Crit Care Med. 2021; 204: 209-221
        • Lescoat A.
        • Lecureur V.
        • Varga J.
        Contribution of monocytes and macrophages to the pathogenesis of systemic sclerosis: Recent insights and therapeutic implications.
        Curr Opin Rheumatol. 2021; 33: 463-470
        • Houssaini A.
        • Abid S.
        • Mouraret N.
        • Wan F.
        • Rideau D.
        • Saker M.
        • et al.
        Rapamycin reverses pulmonary artery smooth muscle cell proliferation in pulmonary hypertension.
        Am J Respir Cell Mol Biol. 2013; 48: 568-577
        • Nishimura T.
        • Faul J.L.
        • Berry G.J.
        • Veve I.
        • Pearl R.G.
        • Kao P.N.
        40-o-(2-hydroxyethyl)-rapamycin attenuates pulmonary arterial hypertension and neointimal formation in rats.
        Am J Respir Crit Care Med. 2001; 163: 498-502
        • McMurtry M.S.
        • Bonnet S.
        • Michelakis E.D.
        • Bonnet S.
        • Haromy A.
        • Archer S.L.
        Statin therapy, alone or with rapamycin, does not reverse monocrotaline pulmonary arterial hypertension: the rapamcyin-atorvastatin-simvastatin study.
        Am J Physiol Lung Cell Mol Physiol. 2007; 293: L933-L940
        • Seyfarth H.J.
        • Hammerschmidt S.
        • Halank M.
        • Neuhaus P.
        • Wirtz H.R.
        Everolimus in patients with severe pulmonary hypertension: a safety and efficacy pilot trial.
        Pulm Circ. 2013; 3: 632-638
        • Hillyard D.Z.
        • Cameron A.J.
        • McDonald K.J.
        • Thomson J.
        • MacIntyre A.
        • Shiels P.G.
        • et al.
        Simvastatin inhibits lymphocyte function in normal subjects and patients with cardiovascular disease.
        Atherosclerosis. 2004; 175: 305-313
        • Kao P.N.
        Simvastatin treatment of pulmonary hypertension: an observational case series.
        Chest. 2005; 127: 1446-1452
        • Maxova H.
        • Herget J.
        • Vizek M.
        Lung mast cells and hypoxic pulmonary hypertension.
        Physiol Res. 2012; 61: 1-11
        • Hoffmann J.
        • Yin J.
        • Kukucka M.
        • Yin N.
        • Saarikko I.
        • Sterner-Kock A.
        • et al.
        Mast cells promote lung vascular remodelling in pulmonary hypertension.
        Eur Respir J. 2011; 37: 1400-1410
        • Zhu R.
        • Chen L.
        • Xiong Y.Q.
        • Wang N.N.
        • Xie X.C.
        • Hong Y.Q.
        • et al.
        An upregulation of CD8(+)CD25(+)Foxp3(+) T cells with suppressive function through interleukin 2 pathway in pulmonary arterial hypertension.
        Exp Cell Res. 2017; 358: 182-187
        • Tuder R.M.
        • Groves B.
        • Badesch D.B.
        • Voelkel N.F.
        Exuberant endothelial-cell growth and elements of inflammation are present in plexiform lesions of pulmonary-hypertension.
        Am J Pathol. 1994; 144: 275-285
        • Tamosiuniene R.
        • Manouvakhova O.
        • Mesange P.
        • Saito T.
        • Qian J.
        • Sanyal M.
        • et al.
        Dominant role for regulatory T cells in protecting females against pulmonary hypertension.
        Circ Res. 2018; 122: 1689-1702
        • Wilkins M.R.
        • Ali O.
        • Bradlow W.
        • Wharton J.
        • Taegtmeyer A.
        • Rhodes C.J.
        • et al.
        Simvastatin as a treatment for pulmonary hypertension trial.
        Am J Respir Crit Care Med. 2010; 181: 1106-1113
        • Cowan K.N.
        • Heilbut A.
        • Humpl T.
        • Lam C.
        • Ito S.
        • Rabinovitch M.
        Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor.
        Nat Med. 2000; 6: 698-702
        • Kim Y.M.
        • Haghighat L.
        • Spiekerkoetter E.
        • Sawada H.
        • Alvira C.M.
        • Wang L.
        • et al.
        Neutrophil elastase is produced by pulmonary artery smooth muscle cells and is linked to neointimal lesions.
        Am J Pathol. 2011; 179: 1560-1572
        • Nickel N.P.
        • Spiekerkoetter E.
        • Gu M.
        • Li C.G.
        • Li H.
        • Kaschwich M.
        • et al.
        Elafin reverses pulmonary hypertension via caveolin-1-dependent bone morphogenetic protein signaling.
        Am J Respir Crit Care Med. 2015; 191: 1273-1286
        • Chun H.J.
        • Yu P.B.
        Elafin in pulmonary arterial hypertension. Beyond targeting elastases.
        Am J Respir Crit Care Med. 2015; 191: 1217-1219
        • Zaidi S.H.
        • You X.M.
        • Ciura S.
        • Husain M.
        • Rabinovitch M.
        Overexpression of the serine elastase inhibitor elafin protects transgenic mice from hypoxic pulmonary hypertension.
        Circulation. 2002; 105: 516-521
        • Tamosiuniene R.
        • Tian W.
        • Dhillon G.
        • Wang L.
        • Sung Y.K.
        • Gera L.
        • et al.
        Regulatory t cells limit vascular endothelial injury and prevent pulmonary hypertension.
        Circ Res. 2011; 109: 867-879