{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:52:21Z","timestamp":1790729541828,"version":"4.1.0"},"reference-count":57,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,4,6]],"date-time":"2020-04-06T00:00:00Z","timestamp":1586131200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,4,6]],"date-time":"2020-04-06T00:00:00Z","timestamp":1586131200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001588","name":"Enterprise Ireland","doi-asserted-by":"publisher","award":["CFTD\/2009\/0122"],"award-info":[{"award-number":["CFTD\/2009\/0122"]}],"id":[{"id":"10.13039\/501100001588","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001588","name":"Enterprise Ireland","doi-asserted-by":"publisher","award":["CF\/2012\/2608"],"award-info":[{"award-number":["CF\/2012\/2608"]}],"id":[{"id":"10.13039\/501100001588","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["822258"],"award-info":[{"award-number":["822258"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Pulm Med"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      <jats:italic>NTP42<\/jats:italic>\n                      is a novel antagonist of the thromboxane prostanoid receptor (TP), currently in development for the treatment of pulmonary arterial hypertension (PAH). PAH is a devastating disease with multiple pathophysiological hallmarks including excessive pulmonary vasoconstriction, vascular remodelling, inflammation, fibrosis, in situ thrombosis and right ventricular hypertrophy. Signalling through the TP, thromboxane (TX) A\n                      <jats:sub>2<\/jats:sub>\n                      is a potent vasoconstrictor and mediator of platelet aggregation. It is also a pro-mitogenic, pro-inflammatory and pro-fibrotic agent. Moreover, the TP also mediates the adverse actions of the isoprostane 8-iso-prostaglandin F\n                      <jats:sub>2\u03b1<\/jats:sub>\n                      , a free-radical-derived product of arachidonic acid produced in abundance during oxidative injury. Mechanistically, TP antagonists should treat most of the hallmarks of PAH, including inhibiting the excessive vasoconstriction and pulmonary artery remodelling, in situ thrombosis, inflammation and fibrosis. This study aimed to investigate the efficacy of\n                      <jats:italic>NTP42<\/jats:italic>\n                      in the monocrotaline (MCT)-induced PAH rat model, alongside current standard-of-care drugs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      PAH was induced by subcutaneous injection of 60\u2009mg\/kg MCT in male Wistar\u2013Kyoto rats. Animals were assigned into groups: 1. \u2018No MCT\u2019; 2. \u2018MCT Only\u2019; 3. MCT\u2009+\u2009\n                      <jats:italic>NTP42<\/jats:italic>\n                      (0.25\u2009mg\/kg BID); 4. MCT\u2009+\u2009Sildenafil (50\u2009mg\/kg BID), and 5. MCT\u2009+\u2009Selexipag (1\u2009mg\/kg BID), where 28-day drug treatment was initiated within 24\u2009h post-MCT.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      From haemodynamic assessments\n                      <jats:italic>, NTP42<\/jats:italic>\n                      reduced the MCT-induced PAH, including mean pulmonary arterial pressure (mPAP) and right systolic ventricular pressure (RSVP), being at least comparable to the standard-of-care drugs Sildenafil or Selexipag in bringing about these effects. Moreover,\n                      <jats:italic>NTP42<\/jats:italic>\n                      was superior to Sildenafil and Selexipag in significantly reducing pulmonary vascular remodelling, inflammatory mast cell infiltration and fibrosis in MCT-treated animals.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These findings suggest that\n                      <jats:italic>NTP42<\/jats:italic>\n                      and antagonism of the TP signalling pathway have a relevant role in alleviating the pathophysiology of PAH, representing a novel therapeutic target with marked benefits over existing standard-of-care therapies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12890-020-1113-2","type":"journal-article","created":{"date-parts":[[2020,4,6]],"date-time":"2020-04-06T06:02:48Z","timestamp":1586152968000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension"],"prefix":"10.1186","volume":"20","author":[{"given":"Eamon P.","family":"Mulvaney","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen M.","family":"Reid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Bialesova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"Bouchard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dany","family":"Salvail","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3072-941X","authenticated-orcid":false,"given":"B. Therese","family":"Kinsella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,4,6]]},"reference":[{"key":"1113_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1183\/13993003.01913-2018","volume":"53","author":"G Simonneau","year":"2019","unstructured":"Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53:1.","journal-title":"Eur Respir J"},{"issue":"3","key":"1113_CR2","doi-asserted-by":"publisher","first-page":"e60475","DOI":"10.1371\/journal.pone.0060475","volume":"8","author":"V Capra","year":"2013","unstructured":"Capra V, Busnelli M, Perenna A, Ambrosio M, Accomazzo MR, Gales C, et al. Full and partial agonists of thromboxane prostanoid receptor unveil fine tuning of receptor superactive conformation and g protein activation. PLoS One. 2013;8(3):e60475.","journal-title":"PLoS One"},{"key":"1113_CR3","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1007\/978-3-642-29423-5_11","volume":"210","author":"G Davi","year":"2012","unstructured":"Davi G, Santilli F, Vazzana N. Thromboxane receptors antagonists and\/or synthase inhibitors. Handb Exp Pharmacol. 2012;210:261\u201386.","journal-title":"Handb Exp Pharmacol"},{"issue":"1","key":"1113_CR4","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1111\/j.1472-8206.1997.tb00163.x","volume":"11","author":"P Devillier","year":"1997","unstructured":"Devillier P, Bessard G. Thromboxane A2 and related prostaglandins in airways. Fundam Clin Pharmacol. 1997;11(1):2\u201318.","journal-title":"Fundam Clin Pharmacol"},{"issue":"3\u20134","key":"1113_CR5","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1007\/s10555-011-9297-9","volume":"30","author":"P Ekambaram","year":"2011","unstructured":"Ekambaram P, Lambiv W, Cazzolli R, Ashton AW, Honn KV. The thromboxane synthase and receptor signaling pathway in cancer: an emerging paradigm in cancer progression and metastasis. Cancer Metastasis Rev. 2011;30(3\u20134):397\u2013408.","journal-title":"Cancer Metastasis Rev"},{"issue":"45","key":"1113_CR6","doi-asserted-by":"publisher","first-page":"73171","DOI":"10.18632\/oncotarget.12256","volume":"7","author":"EP Mulvaney","year":"2016","unstructured":"Mulvaney EP, Shilling C, Eivers SB, Perry AS, Bjartell A, Kay EW, et al. Expression of the TPalpha and TPbeta isoforms of the thromboxane prostanoid receptor (TP) in prostate cancer: clinical significance and diagnostic potential. Oncotarget. 2016;7(45):73171\u201387.","journal-title":"Oncotarget"},{"issue":"28","key":"1113_CR7","doi-asserted-by":"crossref","first-page":"26437","DOI":"10.18632\/oncotarget.4664","volume":"6","author":"AG O'Sullivan","year":"2015","unstructured":"O'Sullivan AG, Mulvaney EP, Hyland PB, Kinsella BT. Protein kinase C-related kinase 1 and 2 play an essential role in thromboxane-mediated neoplastic responses in prostate Cancer. Oncotarget. 2015;6(28):26437\u201356.","journal-title":"Oncotarget"},{"issue":"12","key":"1113_CR8","doi-asserted-by":"publisher","first-page":"3153","DOI":"10.1016\/j.bbadis.2017.09.005","volume":"1863","author":"AG O'Sullivan","year":"2017","unstructured":"O'Sullivan AG, Eivers SB, Mulvaney EP, Kinsella BT. Regulated expression of the TPbeta isoform of the human T prostanoid receptor by the tumour suppressors FOXP1 and NKX3.1: implications for the role of thromboxane in prostate cancer. Biochim Biophys Acta. 2017;1863(12):3153\u201369.","journal-title":"Biochim Biophys Acta"},{"issue":"13","key":"1113_CR9","doi-asserted-by":"publisher","first-page":"3115","DOI":"10.1111\/bph.12677","volume":"171","author":"J Bauer","year":"2014","unstructured":"Bauer J, Ripperger A, Frantz S, Ergun S, Schwedhelm E, Benndorf RA. Pathophysiology of isoprostanes in the cardiovascular system: implications of isoprostane-mediated thromboxane A2 receptor activation. Br J Pharmacol. 2014;171(13):3115\u201331.","journal-title":"Br J Pharmacol"},{"issue":"2","key":"1113_CR10","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1016\/j.ijcard.2014.05.014","volume":"175","author":"R Zhang","year":"2014","unstructured":"Zhang R, Sun ML, Fan YF, Jiang X, Zhao QH, He J, et al. Plasma 15-F2t-isoprostane in idiopathic pulmonary arterial hypertension. Int J Cardiol. 2014;175(2):268\u201373.","journal-title":"Int J Cardiol"},{"issue":"Supplement C","key":"1113_CR11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.freeradbiomed.2017.11.007","volume":"115","author":"B Arezzini","year":"2018","unstructured":"Arezzini B, Vecchio D, Signorini C, Stringa B, Gardi C. F2-isoprostanes can mediate bleomycin-induced lung fibrosis. Free Radic Biol Med. 2018;115(Supplement C):1\u20139.","journal-title":"Free Radic Biol Med"},{"issue":"3","key":"1113_CR12","first-page":"280","volume":"59","author":"AB Roehl","year":"2009","unstructured":"Roehl AB, Steendijk P, Baumert JH, Schnoor J, Rossaint R, Hein M. Comparison of 3 methods to induce acute pulmonary hypertension in pigs. Comp Med. 2009;59(3):280\u20136.","journal-title":"Comp Med"},{"issue":"11","key":"1113_CR13","doi-asserted-by":"publisher","first-page":"e002569","DOI":"10.1161\/CIRCINTERVENTIONS.115.002569","volume":"8","author":"AM Rothman","year":"2015","unstructured":"Rothman AM, Arnold ND, Chang W, Watson O, Swift AJ, Condliffe R, et al. Pulmonary artery denervation reduces pulmonary artery pressure and induces histological changes in an acute porcine model of pulmonary hypertension. Circ Cardiovasc Interv. 2015;8(11):e002569.","journal-title":"Circ Cardiovasc Interv"},{"issue":"1","key":"1113_CR14","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1016\/S0003-4975(03)01489-9","volume":"77","author":"MR Bonnell","year":"2004","unstructured":"Bonnell MR, Urdaneta F, Kirby DS, Valdez NR, Beaver TM, Lobato EB. Effects of sildenafil analogue UK 343-664 on a porcine model of acute pulmonary hypertension. Ann Thorac Surg. 2004;77(1):238\u201342.","journal-title":"Ann Thorac Surg"},{"issue":"4","key":"1113_CR15","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1111\/j.1748-1716.2012.02437.x","volume":"205","author":"D Kylhammar","year":"2012","unstructured":"Kylhammar D, Radegran G. Cyclooxygenase-2 inhibition and thromboxane a (2) receptor antagonism attenuate hypoxic pulmonary vasoconstriction in a porcine model. Acta Physiol (Oxford). 2012;205(4):507\u201319.","journal-title":"Acta Physiol (Oxford)"},{"key":"1113_CR16","volume-title":"(inventors) Thromboxane receptor antagonists patent U.S. Patent No. 10,357,504. June 13","author":"BT Kinsella","year":"2016","unstructured":"Kinsella BT, Reid HM. (inventors) Thromboxane receptor antagonists patent U.S. Patent No. 10,357,504. June 13; 2016."},{"key":"1113_CR17","volume-title":"(inventors) Thromboxane receptor antagonists patent U.S. Patent No. 9,932,304. June 16","author":"BT Kinsella","year":"2015","unstructured":"Kinsella BT, Reid HM. (inventors) Thromboxane receptor antagonists patent U.S. Patent No. 9,932,304. June 16; 2015."},{"issue":"1","key":"1113_CR18","doi-asserted-by":"publisher","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","volume":"7","author":"P Bankhead","year":"2017","unstructured":"Bankhead P, Loughrey MB, Fernandez JA, Dombrowski Y, McArt DG, Dunne PD, et al. QuPath: open source software for digital pathology image analysis. Sci Rep. 2017;7(1):16878.","journal-title":"Sci Rep"},{"issue":"10","key":"1113_CR19","doi-asserted-by":"publisher","first-page":"2811","DOI":"10.1172\/JCI24838","volume":"115","author":"RT Schermuly","year":"2005","unstructured":"Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest. 2005;115(10):2811\u201321.","journal-title":"J Clin Invest"},{"issue":"7\u20138","key":"1113_CR20","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1002\/mrd.22489","volume":"82","author":"J Schindelin","year":"2015","unstructured":"Schindelin J, Rueden CT, Hiner MC, Eliceiri KW. The ImageJ ecosystem: an open platform for biomedical image analysis. Mol Reprod Dev. 2015;82(7\u20138):518\u201329.","journal-title":"Mol Reprod Dev"},{"issue":"4","key":"1113_CR21","first-page":"291","volume":"23","author":"AC Ruifrok","year":"2001","unstructured":"Ruifrok AC, Johnston DA. Quantification of histochemical staining by color deconvolution. Anal Quant Cytol Histol. 2001;23(4):291\u20139.","journal-title":"Anal Quant Cytol Histol"},{"issue":"5","key":"1113_CR22","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1164\/rccm.201510-1959ED","volume":"193","author":"CM St Croix","year":"2016","unstructured":"St Croix CM, Steinhorn RH. New thoughts about the origin of Plexiform lesions. Am J Respir Crit Care Med. 2016;193(5):484\u20135.","journal-title":"Am J Respir Crit Care Med"},{"issue":"1","key":"1113_CR23","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1161\/CIRCRESAHA.113.301141","volume":"115","author":"M Rabinovitch","year":"2014","unstructured":"Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res. 2014;115(1):165\u201375.","journal-title":"Circ Res"},{"issue":"5","key":"1113_CR24","doi-asserted-by":"publisher","first-page":"3016","DOI":"10.21037\/jtd.2018.05.59","volume":"10","author":"J Xu","year":"2018","unstructured":"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(5):3016\u201326.","journal-title":"J Thorac Dis"},{"key":"1113_CR25","doi-asserted-by":"publisher","first-page":"j5492","DOI":"10.1136\/bmj.j5492","volume":"360","author":"T Thenappan","year":"2018","unstructured":"Thenappan T, Ormiston ML, Ryan JJ, Archer SL. Pulmonary arterial hypertension: pathogenesis and clinical management. BMJ. 2018;360:j5492.","journal-title":"BMJ"},{"issue":"5","key":"1113_CR26","first-page":"L811","volume":"311","author":"JC Huetsch","year":"2016","unstructured":"Huetsch JC, Suresh K, Bernier M, Shimoda LA. Update on novel targets and potential treatment avenues in pulmonary hypertension. Am J Phys Lung Cell Mol Phys. 2016;311(5):L811\u2013L31.","journal-title":"Am J Phys Lung Cell Mol Phys"},{"issue":"6","key":"1113_CR27","doi-asserted-by":"publisher","first-page":"2952","DOI":"10.1161\/01.CIR.90.6.2952","volume":"90","author":"S Fuse","year":"1994","unstructured":"Fuse S, Kamiya T. Plasma thromboxane B2 concentration in pulmonary hypertension associated with congenital heart disease. Circulation. 1994;90(6):2952\u20135.","journal-title":"Circulation"},{"issue":"4","key":"1113_CR28","doi-asserted-by":"publisher","first-page":"612","DOI":"10.1016\/S0022-5223(19)36690-5","volume":"101","author":"KC Bui","year":"1991","unstructured":"Bui KC, Hammerman C, Hirschl R, Snedecor SM, Cheng KJ, Chan L, et al. Plasma prostanoids in neonatal extracorporeal membrane oxygenation. Influence of meconium aspiration. J Thorac Cardiovasc Surg. 1991;101(4):612\u20137.","journal-title":"J Thorac Cardiovasc Surg"},{"issue":"2","key":"1113_CR29","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1056\/NEJM199207093270202","volume":"327","author":"BW Christman","year":"1992","unstructured":"Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med. 1992;327(2):70\u20135.","journal-title":"N Engl J Med"},{"issue":"1","key":"1113_CR30","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1513\/AnnalsATS.201508-543OC","volume":"13","author":"N Al-Naamani","year":"2016","unstructured":"Al-Naamani N, Palevsky HI, Lederer DJ, Horn EM, Mathai SC, Roberts KE, et al. Prognostic significance of biomarkers in pulmonary arterial hypertension. Ann Am Thorac Soc. 2016;13(1):25\u201330.","journal-title":"Ann Am Thorac Soc"},{"issue":"7","key":"1113_CR31","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.1038\/sj.bjp.0704416","volume":"134","author":"SD Katugampola","year":"2001","unstructured":"Katugampola SD, Davenport AP. Thromboxane receptor density is increased in human cardiovascular disease with evidence for inhibition at therapeutic concentrations by the AT (1) receptor antagonist losartan. Br J Pharmacol. 2001;134(7):1385\u201392.","journal-title":"Br J Pharmacol"},{"issue":"2","key":"1113_CR32","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1086\/686140","volume":"6","author":"JD West","year":"2016","unstructured":"West JD, Voss BM, Pavliv L, de Caestecker M, Hemnes AR, Carrier EJ. Antagonism of the thromboxane-prostanoid receptor is cardioprotective against right ventricular pressure overload. Pulm Circ. 2016;6(2):211\u201323.","journal-title":"Pulm Circ"},{"issue":"2","key":"1113_CR33","doi-asserted-by":"publisher","first-page":"220","DOI":"10.4103\/2045-8932.97609","volume":"2","author":"S Farha","year":"2012","unstructured":"Farha S, Sharp J, Asosingh K, Park M, Comhair SA, Tang WH, et al. Mast cell number, phenotype, and function in human pulmonary arterial hypertension. Pulm Circ. 2012;2(2):220\u20138.","journal-title":"Pulm Circ"},{"issue":"3","key":"1113_CR34","first-page":"289","volume":"55","author":"RM Marks","year":"1986","unstructured":"Marks RM, Roche WR, Czerniecki M, Penny R, Nelson DS. Mast cell granules cause proliferation of human microvascular endothelial cells. Lab Investig. 1986;55(3):289\u201394.","journal-title":"Lab Investig"},{"issue":"8","key":"1113_CR35","doi-asserted-by":"publisher","first-page":"4045","DOI":"10.4049\/jimmunol.170.8.4045","volume":"170","author":"SH Cho","year":"2003","unstructured":"Cho SH, Yao Z, Wang SW, Alban RF, Barbers RG, French SW, et al. Regulation of activin a expression in mast cells and asthma: its effect on the proliferation of human airway smooth muscle cells. J Immunol. 2003;170(8):4045\u201352.","journal-title":"J Immunol"},{"issue":"1","key":"1113_CR36","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1111\/imr.12626","volume":"282","author":"P Bradding","year":"2018","unstructured":"Bradding P, Pejler G. The controversial role of mast cells in fibrosis. Immunol Rev. 2018;282(1):198\u2013231.","journal-title":"Immunol Rev"},{"issue":"1","key":"1113_CR37","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1046\/j.1523-1747.1999.00624.x","volume":"113","author":"JD Morrow","year":"1999","unstructured":"Morrow JD, Oates JA, Roberts LJ 2nd, Zackert WE, Mitchell TA, Lazarus G, et al. Increased formation of thromboxane in vivo in humans with mastocytosis. J Invest Dermatol. 1999;113(1):93\u20137.","journal-title":"J Invest Dermatol"},{"key":"1113_CR38","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1186\/1465-9921-12-60","volume":"12","author":"BK Dahal","year":"2011","unstructured":"Dahal BK, Kosanovic D, Kaulen C, Cornitescu T, Savai R, Hoffmann J, et al. Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats. Respir Res. 2011;12:60.","journal-title":"Respir Res"},{"issue":"6","key":"1113_CR39","doi-asserted-by":"publisher","first-page":"1400","DOI":"10.1183\/09031936.00043310","volume":"37","author":"J Hoffmann","year":"2011","unstructured":"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(6):1400\u201310.","journal-title":"Eur Respir J"},{"key":"1113_CR40","first-page":"6","volume":"5","author":"H Luitel","year":"2017","unstructured":"Luitel H, Sydykov A, Schymura Y, Mamazhakypov A, Janssen W, Pradhan K, et al. Pressure overload leads to an increased accumulation and activity of mast cells in the right ventricle. Phys Rep. 2017;5:6.","journal-title":"Phys Rep"},{"issue":"3","key":"1113_CR41","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1378\/chest.91.3.356","volume":"91","author":"S Rich","year":"1987","unstructured":"Rich S, Hart K, Kieras K, Brundage BH. Thromboxane synthetase inhibition in primary pulmonary hypertension. Chest. 1987;91(3):356\u201360.","journal-title":"Chest"},{"issue":"2","key":"1113_CR42","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1152\/japplphysiol.01337.2004","volume":"99","author":"CD Fike","year":"2005","unstructured":"Fike CD, Zhang Y, Kaplowitz MR. Thromboxane inhibition reduces an early stage of chronic hypoxia-induced pulmonary hypertension in piglets. J Appl Physiol (1985). 2005;99(2):670\u20136.","journal-title":"J Appl Physiol (1985)"},{"issue":"5","key":"1113_CR43","doi-asserted-by":"publisher","DOI":"10.1067\/mhj.2002.121806","volume":"143","author":"D Langleben","year":"2002","unstructured":"Langleben D, Christman BW, Barst RJ, Dias VC, Galie N, Higenbottam TW, et al. Effects of the thromboxane synthetase inhibitor and receptor antagonist terbogrel in patients with primary pulmonary hypertension. Am Heart J. 2002;143(5):E4.","journal-title":"Am Heart J"},{"issue":"2","key":"1113_CR44","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1513\/AnnalsATS.201609-674OC","volume":"14","author":"GL Pagani-Estevez","year":"2017","unstructured":"Pagani-Estevez GL, Swetz KM, McGoon MD, Frantz RP, Tointon SK, Karnyski AM, et al. Characterization of prostacyclin-associated leg pain in patients with pulmonary arterial hypertension. Ann Am Thorac Soc. 2017;14(2):206\u201312.","journal-title":"Ann Am Thorac Soc"},{"issue":"1","key":"1113_CR45","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1111\/j.1365-2125.2004.02083.x","volume":"58","author":"BD Guth","year":"2004","unstructured":"Guth BD, Narjes H, Schubert HD, Tanswell P, Riedel A, Nehmiz G. Pharmacokinetics and pharmacodynamics of terbogrel, a combined thromboxane A2 receptor and synthase inhibitor, in healthy subjects. Br J Clin Pharmacol. 2004;58(1):40\u201351.","journal-title":"Br J Clin Pharmacol"},{"issue":"4","key":"1113_CR46","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1165\/rcmb.2008-0109TR","volume":"39","author":"LJ Janssen","year":"2008","unstructured":"Janssen LJ. Isoprostanes and lung vascular pathology. Am J Respir Cell Mol Biol. 2008;39(4):383\u20139.","journal-title":"Am J Respir Cell Mol Biol"},{"issue":"4","key":"1113_CR47","first-page":"L363","volume":"302","author":"JG Gomez-Arroyo","year":"2012","unstructured":"Gomez-Arroyo JG, Farkas L, Alhussaini AA, Farkas D, Kraskauskas D, Voelkel NF, et al. The monocrotaline model of pulmonary hypertension in perspective. Am J Phys Lung Cell Mol Phys. 2012;302(4):L363\u20139.","journal-title":"Am J Phys Lung Cell Mol Phys"},{"issue":"7","key":"1113_CR48","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1161\/CIRCRESAHA.117.312579","volume":"122","author":"S Provencher","year":"2018","unstructured":"Provencher S, Archer SL, Ramirez FD, Hibbert B, Paulin R, Boucherat O, et al. Standards and methodological rigor in pulmonary arterial hypertension preclinical and translational research. Circ Res. 2018;122(7):1021\u201332.","journal-title":"Circ Res"},{"issue":"3","key":"1113_CR49","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.ddmod.2011.02.005","volume":"7","author":"L Zhao","year":"2010","unstructured":"Zhao L. Chronic hypoxia-induced pulmonary hypertension in rat: the best animal model for studying pulmonary vasoconstriction and vascular medial hypertrophy. Drug Discov Today Dis Model. 2010;7(3):83\u20138.","journal-title":"Drug Discov Today Dis Model"},{"issue":"6","key":"1113_CR50","first-page":"L1013","volume":"297","author":"KR Stenmark","year":"2009","unstructured":"Stenmark KR, Meyrick B, Galie N, Mooi WJ, McMurtry IF. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am J Phys Lung Cell Mol Phys. 2009;297(6):L1013\u201332.","journal-title":"Am J Phys Lung Cell Mol Phys"},{"key":"1113_CR51","first-page":"4","volume":"4","author":"KL Colvin","year":"2014","unstructured":"Colvin KL, Yeager ME. Animal Models of Pulmonary Hypertension: Matching Disease Mechanisms to Etiology of the Human Disease. J Pulm Respir Med. 2014;4:4.","journal-title":"J Pulm Respir Med"},{"key":"1113_CR52","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.ejphar.2017.05.048","volume":"810","author":"L Bhat","year":"2017","unstructured":"Bhat L, Hawkinson J, Cantillon M, Reddy DG, Bhat SR, Laurent CE, et al. RP5063, a novel, multimodal, serotonin receptor modulator, prevents monocrotaline-induced pulmonary arterial hypertension in rats. Eur J Pharmacol. 2017;810:92\u20139.","journal-title":"Eur J Pharmacol"},{"issue":"3","key":"1113_CR53","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1124\/jpet.108.138305","volume":"326","author":"K Kuwano","year":"2008","unstructured":"Kuwano K, Hashino A, Noda K, Kosugi K, Kuwabara K. A long-acting and highly selective prostacyclin receptor agonist prodrug, 2-{4-[(5,6-diphenylpyrazin-2-yl) (isopropyl) amino]butoxy}-N-(methylsulfonyl) acetam ide (NS-304), ameliorates rat pulmonary hypertension with unique relaxant responses of its active form, {4-[(5,6-diphenylpyrazin-2-yl) (isopropyl) amino] butoxy} acetic acid (MRE-269), on rat pulmonary artery. J Pharmacol Exp Ther. 2008;326(3):691\u20139.","journal-title":"J Pharmacol Exp Ther"},{"issue":"6","key":"1113_CR54","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1016\/j.chest.2017.10.007","volume":"152","author":"NS Hill","year":"2017","unstructured":"Hill NS, Gillespie MN, McMurtry IF. Fifty years of Monocrotaline-induced pulmonary hypertension: what has it meant to the field? Chest. 2017;152(6):1106\u20138.","journal-title":"Chest"},{"issue":"1","key":"1113_CR55","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1093\/eurheartj\/ehv317","volume":"37","author":"N Galie","year":"2016","unstructured":"Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC\/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67\u2013119.","journal-title":"Eur Heart J"},{"issue":"3","key":"1113_CR56","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1016\/j.chest.2018.11.030","volume":"155","author":"JR Klinger","year":"2019","unstructured":"Klinger JR, Elliott CG, Levine DJ, Bossone E, Duvall L, Fagan K, et al. Therapy for pulmonary arterial hypertension in adults: update of the CHEST guideline and expert panel report. Chest. 2019;155(3):565\u201386.","journal-title":"Chest"},{"issue":"11","key":"1113_CR57","doi-asserted-by":"publisher","first-page":"804","DOI":"10.1503\/cmaj.151075","volume":"188","author":"N Hambly","year":"2016","unstructured":"Hambly N, Alawfi F, Mehta S. Pulmonary hypertension: diagnostic approach and optimal management. CMAJ. 2016;188(11):804\u201312.","journal-title":"CMAJ"}],"container-title":["BMC Pulmonary Medicine"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12890-020-1113-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12890-020-1113-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12890-020-1113-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T14:10:44Z","timestamp":1666275044000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcpulmmed.biomedcentral.com\/articles\/10.1186\/s12890-020-1113-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,6]]},"references-count":57,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["1113"],"URL":"https:\/\/doi.org\/10.1186\/s12890-020-1113-2","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.2.18445\/v1","asserted-by":"object"},{"id-type":"doi","id":"10.21203\/rs.2.18445\/v2","asserted-by":"object"},{"id-type":"doi","id":"10.21203\/rs.2.18445\/v3","asserted-by":"object"},{"id-type":"doi","id":"10.21203\/rs.2.18445\/v4","asserted-by":"object"}]},"ISSN":["1471-2466"],"issn-type":[{"value":"1471-2466","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,6]]},"assertion":[{"value":"28 November 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 March 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 April 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All animal studies were performed at the facilities of IPS Therapeutique (IPST; Sherbrooke, Quebec, Canada). The institutional animal ethics committee of IPST approved the studies in strict accordance with the guidelines of the Canadian Council on Animal Care and the US NIH Guide for the Care and Use of Laboratory Animals. Human lung tissue was obtained from the Royal Papworth Hospital NHS Foundation Trust Tissue Bank (Cambridge, UK). Written consent was obtained for all tissue samples using Royal Papworth Hospital NHS Foundation Trust Tissue Bank\u2019s ethical approval (East of England - Cambridge East Research Ethics Committee 08\/H0304\/56\u2009+\u20095).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"EPM, HMR, LB and BTK are employees of ATXA Therapeutics Ltd. BTK is also a member of the board of directors of ATXA Therapeutics Ltd. The authors EPM, HMR, LB and BTK declare that they have no competing interests. AB and DS were employees of IPS Therapeutique Inc. at the time of conducting the work reported in this manuscript. This work was sponsored by ATXA Therapeutics Ltd. The authors AB and DS certify that they have no affiliations with, or involvement in, any organisation or entity with any financial or non-financial interest in the subject matter or materials discussed in this manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"85"}}