1. Seferian A, Simonneau G. Therapies for pulmonary arterial hypertension: where are we today, where do we go tomorrow? Eur Respir Rev. 2013;22:217–226. DOI: 10.1183/09059180.00001713.
2. Humbert M, Sitbon O, Chaouat A, Bertocchi Michèle, Habib G, Gressin V, Yaïci A, Weitzenblum E, Cordier J-F, Chabot François, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;122:156–163. DOI: 10.1161/CIRCULATIONAHA.109.911818.
3. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464:104–107. DOI: 10.1038/natur e08780.
4. Garcia-Martinez I, Santoro N, Chen Y, Hoque R, Ouyang X, Caprio S, Shlomchik MJ, Coffman RL, Candia A, Mehal WZ. Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J Clin Invest. 2016;126:859–864. DOI: 10.1172/JCI83885.
5. Han SJ, Li H, Kim M, Shlomchik MJ, Lee HT. Kidney proximal tubular TLR9 exacerbates ischemic acute kidney injury. J Immunol. 2018;201:1073–1085. DOI: 10.4049/jimmunol.1800211.
6. McCarthy CG, Wenceslau CF, Goulopoulou S, Ogbi S, Baban B, Sullivan JC, Matsumoto T, Webb RC. Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats. Cardiovasc Res. 2015;107:119–130. DOI: 10.1093/cvr/cvv137.
7. Oka T, Hikoso S, Yamaguchi O, Taneike M, Takeda T, Tamai T, Oyabu J, Murakawa T, Nakayama H, Nishida K, et al. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature. 2012;485:251–255. DOI: 10.1038/nature10992.
8. Loomis Z, Eigenberger P, Redinius K, Lisk C, Karoor V, Nozik-Grayck E, Ferguson SK, Hassell K, Nuss R, Stenmark K, et al. Hemoglobin induced cell trauma indirectly influences endothelial TLR9 activity resulting in pulmonary vascular smooth muscle cell activation. PLoS One. 2017;12:e0171219. DOI: 10.1371/journal.pone.0171219.
9. Kolettis T, Vlahos AP, Louka M, Hatzistergos KE, Baltogiannis GG, Agelaki MM, Mitsi A, Malamou-Mitsi V. Characterisation of a rat model of pulmonary arterial hypertension. Hellenic J Cardiol. 2007;48:206–210.
10. Franklin BS, Ishizaka ST, Lamphier M, Gusovsky F, Hansen H, Rose J, Zheng W, Ataíde MA, de Oliveira RB, Golenbock DT, et al. Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria. Proc Natl Acad Sci USA. 2011;108:3689–3694. DOI: 10.1073/pnas.1015406108.
11. Lamphier M, Zheng W, Latz E, Spyvee M, Hansen H, Rose J, Genest M, Yang H, Shaffer C, Zhao Y, et al. Novel small molecule inhibitors of TLR7 and TLR9: mechanism of action and efficacy in vivo. Mol Pharmacol. 2014;85:429–440. DOI: 10.1124/mol.113.089821.
12. Long L, Yang X, Southwood M, Lu J, Marciniak SJ, Dunmore BJ, Morrell NW. Chloroquine prevents progression of experimental pulmonary hypertension via inhibition of autophagy and lysosomal bone morphogenetic protein type II receptor degradation. Circ Res. 2013;112:1159–1170. DOI: 10.1161/CIRCRESAHA.111.300483.
13. Lafyatis R, York M, Marshak-Rothstein A. Antimalarial agents: closing the gate on Toll-like receptors? Arthritis Rheum. 2006;54:3068–3070. DOI: 10.1002/art.22157.
14. Willis R, Seif AM, McGwin G Jr, Martinez-Martinez LA, González EB, Dang N, Papalardo E, Liu J, Vilá LM, Reveille JD, et al. Effect of hydroxychloroquine treatment on pro-inflammatory cytokines and disease activity in SLE patients: data from LUMINA (LXXV), a multiethnic US cohort. Lupus. 2012;21:830–835. DOI: 10.1177/0961203312437270.
15. Yoshida K, Abe K, Ishikawa M, Saku K, Shinoda-Sakamoto M, Ishikawa T, Watanabe T, Oka M, Sunagawa K, Tsutsui H. Inhibition of TLR9-NF-kappaB-mediated sterile inflammation improves pressure overload-induced right ventricular dysfunction in rats. Cardiovasc Res. 2019;115:658–668. DOI: 10.1093/cvr/cvy209.
16. Abe K, Toba M, Alzoubi A, Ito M, Fagan KA, Cool CD, Voelkel NF, McMurtry IF, Oka M. Formation of plexiform lesions in experimental severe pulmonary arterial hypertension. Circulation. 2010;121:2747–2754. DOI: 10.1161/CIRCULATIONAHA.109.927681.
17. Toba M, Alzoubi A, O’Neill KD, Gairhe S, Matsumoto Y, Oshima K, Abe K, Oka M, McMurtry IF. Temporal hemodynamic and histological progression in Sugen5416/hypoxia/normoxia-exposed pulmonary arterial hypertensive rats. Am J Physiol Heart Circ Physiol. 2014;306:H243–H250. DOI: 10.1152/ajpheart.00728.2013.
18. Schwenke DO, Pearson JT, Sonobe T, Ishibashi-Ueda H, Shimouchi A, Kangawa K, Umetani K, Shirai M. Role of Rho-kinase signaling and endothelial dysfunction in modulating blood flow distribution in pulmonary hypertension. J Appl Physiol (1985). 2011;110:901–908. DOI: 10.1152/ japplphysiol.01318.2010.
19. Pacher P, Nagayama T, Mukhopadhyay P, Batkai S, Kass DA. Measurement of cardiac function using pressure-volume conductance catheter technique in mice and rats. Nat Protoc. 2008;3:1422–1434. DOI: 10.1038/nprot.2008.138.
20. Kuck JL, Obiako BO, Gorodnya OM, Pastukh VM, Kua J, Simmons JD, Gillespie MN. Mitochondrial DNA damage-associated molecular patterns mediate a feed-forward cycle of bacteria-induced vascular injury in perfused rat lungs. Am J Physiol Lung Cell Mol Physiol. 2015;308:L1078–L1085. DOI: 10.1152/ajplung.00015.2015.
21. Guignabert C, Phan C, Seferian A, Huertas A, Tu LY, Thuillet R, Sattler C, Le Hiress M, Tamura Y, Jutant E-M, et al. Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension. J Clin Invest. 2016;126:3207–3218. DOI: 10.1172/JCI86249.
22. Tamura Y, Phan C, Tu L, Le Hiress M, Thuillet R, Jutant EM, Fadel E, Savale L, Huertas A, Humbert M, et al. Ectopic upregulation of membrane-bound IL6R drives vascular remodeling in pulmonary arterial hypertension. J Clin Invest. 2018;128:1956–1970. DOI: 10.1172/JCI96462.
23. Kuwabara Y, Tanaka-Ishikawa M, Abe K, Hirano M, Hirooka Y, Tsutsui H, Sunagawa K, Hirano K. Proteinase-activated receptor 1 antagonism ameliorates experimental pulmonary hypertension. Cardiovasc Res. 2019;115:1357–1368. DOI: 10.1093/cvr/cvy284.
24. Abe K, Shinoda M, Tanaka M, Kuwabara Y, Yoshida K, Hirooka Y, McMurtry IF, Oka M, Sunagawa K. Haemodynamic unloading reverses occlusive vascular lesions in severe pulmonary hypertension. Cardiovasc Res. 2016;111:16–25. DOI: 10.1093/cvr/cvw070.
25. Bliksoen M, Mariero LH, Torp MK, Baysa A, Ytrehus K, Haugen F, Seljeflot I, Vaage J, Valen G, Stenslokken KO. Extracellular mtDNA activates NF-kappaB via toll-like receptor 9 and induces cell death in cardiomyocytes. Basic Res Cardiol. 2016;111:42. DOI: 10.1007/s0039 5-016-0553-6.
26. Tanaka M, Abe K, Oka M, Saku K, Yoshida K, Ishikawa T, McMurtry IF, Sunagawa K, Hoka S, Tsutsui H. Inhibition of nitric oxide synthase unmasks vigorous vasoconstriction in established pulmonary arterial hypertension. Physiol Rep. 2017;5:e13537. DOI: 10.14814/phy2.13537.
27. Courboulin A, Tremblay VL, Barrier M, Meloche J, Jacob MH, Chapolard M, Bisserier M, Paulin R, Lambert C, Provencher S, et al. Kruppel-like factor 5 contributes to pulmonary artery smooth muscle proliferation and resistance to apoptosis in human pulmonary arterial hypertension. Respir Res. 2011;12:128. DOI: 10.1186/1465-9921-12-128.
28. Paulin R, Courboulin A, Meloche J, Mainguy V, Dumas de la Roque E, Saksouk N, Cote J, Provencher S, Sussman MA, Bonnet S. Signal transducers and activators of transcription-3/pim1 axis plays a critical role in the pathogenesis of human pulmonary arterial hypertension. Circulation. 2011;123:1205–1215. DOI: 10.1161/CIRCULATIO NAHA.110.963314.
29. Guignabert C, Raffestin B, Benferhat R, Raoul W, Zadigue P, Rideau D, Hamon M, Adnot S, Eddahibi S. Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats. Circulation. 2005;111:2812–2819. DOI: 10.1161/CIRCULATIO NAHA.104.524926.
30. Miyauchi T, Yorikane R, Sakai S, Sakurai T, Okada M, Nishikibe M, Yano M, Yamaguchi I, Sugishita Y, Goto K. Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension. Circ Res. 1993;73:887–897. DOI: 10.1161/01.RES.73.5.887.
31. Latz E, Schoenemeyer A, Visintin A, Fitzgerald KA, Monks BG, Knetter CF, Lien E, Nilsen NJ, Espevik T, Golenbock DT. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol. 2004;5:190–198. DOI: 10.1038/ni1028.
32. Park B, Brinkmann MM, Spooner E, Lee CC, Kim YM, Ploegh HL. Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9. Nat Immunol. 2008;9:1407–1414. DOI: 10.1038/ni.1669.
33. Otsuki S, Sawada H, Yodoya N, Shinohara T, Kato T, Ohashi H, Zhang E, Imanaka-Yoshida K, Shimpo H, Maruyama K, et al. Potential contribution of phenotypically modulated smooth muscle cells and related inflammation in the development of experimental obstructive pulmonary vasculopathy in rats. PLoS One. 2015;10:e0118655. DOI: 10.1371/journ al.pone.0118655.
34. Soon E, Holmes AM, Treacy CM, Doughty NJ, Southgate L, Machado RD, Trembath RC, Jennings S, Barker L, Nicklin P, et al. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation. 2010;122:920–927. DOI: 10.1161/CIRCULATIONAHA.109.933762.
35. Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB. Interleukin-6 overexpression induces pulmonary hypertension. Circ Res. 2009;104:236–244, 228p following 244. DOI: 10.1161/CIRCR ESAHA.108.182014.
36. Savale L, Tu L, Rideau D, Izziki M, Maitre B, Adnot S, Eddahibi S. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir Res. 2009;10:6. DOI: 10.1186/1465-9921-10-6.
37. Li J, Ma Z, Tang Z-L, Stevens T, Pitt B, Li S. Song Li. CpG DNA-mediated immune response in pulmonary endothelial cells. Am J Physiol Lung Cell Mol Physiol. 2004;287:L552–L558. DOI: 10.1152/ajplung.00436.2003.
38. Pietra GG, Capron F, Stewart S, Leone O, Humbert M, Robbins IM, Reid LM, Tuder RM. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol. 2004;43:25s–32s. DOI: 10.1016/j. jacc.2004.02.033.
39. Meyrick B. The pathology of pulmonary artery hypertension. Clin Chest Med. 2001;22:393–404, vii. DOI: 10.1016/S0272-5231(05)70279-3.