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Review

New therapeutics based on emerging concepts in pulmonary fibrosis

, , &
Pages 69-81 | Received 28 Jul 2018, Accepted 21 Nov 2018, Published online: 28 Nov 2018

References

  • Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012;18:1028–1040.
  • Glasser SW, Hagood JS, Wong S, et al. Mechanisms of Lung Fibrosis Resolution. Am J Pathol. 2016;186:1066–1077.
  • Kaur A, Mathai SK, Schwartz DA. Genetics in idiopathic pulmonary fibrosis pathogenesis, prognosis, and treatment. Front Med (Lausanne). 2017;4:154.
  • Zhang HY, Gharaee-Kermani M, Zhang K, et al. Lung fibroblast alpha-smooth muscle actin expression and contractile phenotype in bleomycin-induced pulmonary fibrosis. Am J Pathol. 1996;148:527–537.
  • Sun KH, Chang Y, Reed NI, et al. alpha-Smooth muscle actin is an inconsistent marker of fibroblasts responsible for force-dependent TGFbeta activation or collagen production across multiple models of organ fibrosis. Am J Physiol Lung Cell Mol Physiol. 2016;310:L824–36.
  • Barron L, Gharib SA, Duffield JS. Lung pericytes and resident fibroblasts: busy multitaskers. Am J Pathol. 2016;186:2519–2531.
  • Kendall RT, Feghali-Bostwick CA. Fibroblasts in fibrosis: novel roles and mediators. Front Pharmacol. 2014;5:123.
  • Hung C, Linn G, Chow YH, et al. Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med. 2013;188:820–830.
  • El Agha E, Moiseenko A, Kheirollahi V, et al. Two-way conversion between lipogenic and myogenic fibroblastic phenotypes marks the progression and resolution of lung fibrosis. Cell Stem Cell. 2017;20:261–273 e3.
  • Maharaj S, Shimbori C, Kolb M. Fibrocytes in pulmonary fibrosis: a brief synopsis. Eur Respir Rev. 2013;22:552–557.
  • Reilkoff RA, Bucala R, Herzog EL. Fibrocytes: emerging effector cells in chronic inflammation. Nat Rev Immunol. 2011;11:427–435.
  • Xu J, Kisseleva T. Bone marrow-derived fibrocytes contribute to liver fibrosis. Exp Biol Med (Maywood). 2015;240:691–700.
  • Sontake V, Shanmukhappa SK, DiPasquale BA, et al. Fibrocytes regulate Wilms tumor 1-positive cell accumulation in severe fibrotic lung disease. J Immunol. 2015;195:3978–3991.
  • Pilling D, Buckley CD, Salmon M, et al. Inhibition of fibrocyte differentiation by serum amyloid P. J Immunol. 2003;171:5537–5546.
  • Murray LA, Chen Q, Kramer MS, et al. TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P. Int J Biochem Cell Biol. 2011;43:154–162.
  • Raghu G, van Den Blink B, Hamblin MJ, et al. Effect of recombinant human pentraxin 2 vs placebo on change in forced vital capacity in patients with idiopathic pulmonary fibrosis: a randomized clinical trial. JAMA. 2018;319:2299–2307.
  • Hashimoto N, Jin H, Liu T, et al. Bone marrow-derived progenitor cells in pulmonary fibrosis. J Clin Invest. 2004;113:243–252.
  • Madala SK, Edukulla R, Schmidt S, et al. Bone marrow-derived stromal cells are invasive and hyperproliferative and alter transforming growth factor-alpha-induced pulmonary fibrosis. Am J Respir Cell Mol Biol. 2014;50:777–786.
  • Moore BB, Murray L, Das A, et al. The role of CCL12 in the recruitment of fibrocytes and lung fibrosis. Am J Respir Cell Mol Biol. 2006;35:175–181.
  • Naik PK, Bozyk PD, Bentley JK, et al. Periostin promotes fibrosis and predicts progression in patients with idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2012;303:L1046–56.
  • Ashley SL, Wilke CA, Kim KK, et al. Periostin regulates fibrocyte function to promote myofibroblast differentiation and lung fibrosis. Mucosal Immunol. 2017;10:341–351.
  • Batra H, Antony VB. The pleural mesothelium in development and disease. Front Physiol. 2014;5:284.
  • Nasreen N, Mohammed KA, Mubarak KK, et al. Pleural mesothelial cell transformation into myofibroblasts and haptotactic migration in response to TGF-beta1 in vitro. Am J Physiol Lung Cell Mol Physiol. 2009;297:L115–24.
  • Chen LJ, Ye H, Zhang Q, et al. Bleomycin induced epithelial-mesenchymal transition (EMT) in pleural mesothelial cells. Toxicol Appl Pharmacol. 2015;283:75–82.
  • Karki S, Surolia R, Hock TD, et al. Wilms’ tumor 1 (Wt1) regulates pleural mesothelial cell plasticity and transition into myofibroblasts in idiopathic pulmonary fibrosis. FASEB J. 2014;28:1122–1131.
  • Mubarak KK, Montes-Worboys A, Regev D, et al. Parenchymal trafficking of pleural mesothelial cells in idiopathic pulmonary fibrosis. Eur Respir J. 2012;39:133–140.
  • Zolak JS, Jagirdar R, Surolia R, et al. Pleural mesothelial cell differentiation and invasion in fibrogenic lung injury. Am J Pathol. 2013;182:1239–1247.
  • von Gise A, Stevens SM, Honor LB, et al. Contribution of fetal, but not adult, pulmonary mesothelium to mesenchymal lineages in lung homeostasis and fibrosis. Am J Respir Cell Mol Biol. 2016;54:222–230.
  • Que J, Wilm B, Hasegawa H, et al. Mesothelium contributes to vascular smooth muscle and mesenchyme during lung development. Proc Natl Acad Sci U S A. 2008;105:16626–16630.
  • Rudat C, Kispert A. Wt1 and epicardial fate mapping. Circ Res. 2012;111:165–169.
  • Sontake V, Kasam RK, Sinner D, et al. Wilms’ tumor 1 drives fibroproliferation and myofibroblast transformation in severe fibrotic lung disease. JCI Insight. 2018;3.e121252
  • Hung CF, Mittelsteadt KL, Brauer R, et al. Lung pericyte-like cells are functional interstitial immune sentinel cells. Am J Physiol Lung Cell Mol Physiol. 2017;312:L556–L567.
  • Maier CL, Shepherd BR, Yi T, et al. Explant outgrowth, propagation and characterization of human pericytes. Microcirculation. 2010;17:367–380.
  • Sava P, Ramanathan A, Dobronyi A, et al. Human pericytes adopt myofibroblast properties in the microenvironment of the IPF lung. JCI Insight. 2017;2.e96352
  • Rock JR, Barkauskas CE, Cronce MJ, et al. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc Natl Acad Sci U S A. 2011;108:E1475–83.
  • Kasai H, Allen JT, Mason RM, et al. TGF-beta1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res. 2005;6:56.
  • Kim KK, Kugler MC, Wolters PJ, et al. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A. 2006;103:13180–13185.
  • Tanjore H, Xu XC, Polosukhin VV, et al. Contribution of epithelial-derived fibroblasts to bleomycin-induced lung fibrosis. Am J Respir Crit Care Med. 2009;180:657–665.
  • Willis BC, Liebler JM, Luby-Phelps K, et al. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. Am J Pathol. 2005;166:1321–1332.
  • Hardie WD, Hagood JS, Dave V, et al. Signaling pathways in the epithelial origins of pulmonary fibrosis. Cell Cycle. 2010;9:2769–2776.
  • Velikoff MCanalis E, et al. Activated alveolar epithelial cells initiate fibrosis through autocrine and paracrine secretion of connective tissue growth factor. Am J Physiol Lung Cell Mol Physiol. 2014;306:L786-L796.
  • Hewlett JC, Kropski JA, Blackwell TS. Idiopathic pulmonary fibrosis: epithelial-mesenchymal interactions and emerging therapeutic targets. Matrix Biol. 2018;71–72:112–127.
  • Aschner Y, Downey GP. Transforming growth factor-beta: master regulator of the respiratory system in health and disease. Am J Respir Cell Mol Biol. 2016;54:647–655.
  • Lam EW, Brosens JJ, Gomes AR, et al. Forkhead box proteins: tuning forks for transcriptional harmony. Nat Rev Cancer. 2013;13:482–495.
  • Balli D, Ustiyan V, Zhang Y, et al. Foxm1 transcription factor is required for lung fibrosis and epithelial-to-mesenchymal transition. Embo J. 2013;32:231–244.
  • Black M, Milewski D, Le T, et al. FOXF1 inhibits pulmonary fibrosis by preventing CDH2-CDH11 cadherin switch in myofibroblasts. Cell Rep. 2018;23:442–458.
  • Im J, Hergert P, Nho RS. Reduced FoxO3a expression causes low autophagy in idiopathic pulmonary fibrosis fibroblasts on collagen matrices. Am J Physiol Lung Cell Mol Physiol. 2015;309:L552–61.
  • Nho RS, Peterson M, Hergert P, et al. FoxO3a (Forkhead Box O3a) deficiency protects Idiopathic Pulmonary Fibrosis (IPF) fibroblasts from type I polymerized collagen matrix-induced apoptosis via caveolin-1 (cav-1) and Fas. PLoS One. 2013;8:e61017.
  • Penke LR, Speth JM, Dommeti VL, et al. FOXM1 is a critical driver of lung fibroblast activation and fibrogenesis. J Clin Invest. 2018;128:2389–2405.
  • Costa RH, Kalinichenko VV, Lim L. Transcription factors in mouse lung development and function. Am J Physiol Lung Cell Mol Physiol. 2001;280:L823–38.
  • Malin D, Kim IM, Boetticher E, et al. Forkhead box F1 is essential for migration of mesenchymal cells and directly induces integrin-beta3 expression. Mol Cell Biol. 2007;27:2486–2498.
  • Chang SK, Noss EH, Chen M, et al. Cadherin-11 regulates fibroblast inflammation. Proc Natl Acad Sci U S A. 2011;108:8402–8407.
  • Agarwal SK, Lee DM, Kiener HP, et al. Coexpression of two mesenchymal cadherins, cadherin 11 and N-cadherin, on murine fibroblast-like synoviocytes. Arthritis Rheum. 2008;58:1044–1054.
  • Melboucy-Belkhir S, Pradere P, Tadbiri S, et al. Forkhead Box F1 represses cell growth and inhibits COL1 and ARPC2 expression in lung fibroblasts in vitro. Am J Physiol Lung Cell Mol Physiol. 2014;307:L838–47.
  • Ho KK, Myatt SS, Lam EW. Many forks in the path: cycling with FoxO. Oncogene. 2008;27:2300–2311.
  • Gomes AR, Zhao F, Lam EW. Role and regulation of the forkhead transcription factors FOXO3a and FOXM1 in carcinogenesis and drug resistance. Chin J Cancer. 2013;32:365–370.
  • Wang IC, Chen YJ, Hughes D, et al. Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase. Mol Cell Biol. 2005;25:10875–10894.
  • Im J, Lawrence J, Seelig D, et al. FoxM1-dependent RAD51 and BRCA2 signaling protects idiopathic pulmonary fibrosis fibroblasts from radiation-induced cell death. Cell Death Dis. 2018;9:584.
  • Wilm B, Munoz-Chapuli R. The role of WT1 in embryonic development and normal organ homeostasis. Methods Mol Biol. 2016;1467:23–39.
  • Chau YY, Hastie ND. The role of Wt1 in regulating mesenchyme in cancer, development, and tissue homeostasis. Trends Genet. 2012;28:515–524.
  • Luzina IG, Salcedo MV, Rojas-Pena ML, et al. Transcriptomic evidence of immune activation in macroscopically normal-appearing and scarred lung tissues in idiopathic pulmonary fibrosis. Cell Immunol. 2018;325:1–13.
  • Martinez-Estrada OM, Lettice LA, Essafi A, et al. Wt1 is required for cardiovascular progenitor cell formation through transcriptional control of Snail and E-cadherin. Nat Genet. 2010;42:89–93.
  • Csermely P, Schnaider T, Soti C, et al. The 90-kDa molecular chaperone family: structure, function, and clinical applications. A comprehensive review. Pharmacol Ther. 1998;79:129–168.
  • Chen B, Piel WH, Gui L, et al. The HSP90 family of genes in the human genome: insights into their divergence and evolution. Genomics. 2005;86:627–637.
  • Haase M, Fitze G. HSP90AB1: helping the good and the bad. Gene. 2016;575:171–186.
  • Zuehlke AD, Beebe K, Neckers L, et al. Regulation and function of the human HSP90AA1 gene. Gene. 2015;570:8–16.
  • Biaoxue R, Xiling J, Shuanying Y, et al. Upregulation of Hsp90-beta and annexin A1 correlates with poor survival and lymphatic metastasis in lung cancer patients. J Exp Clin Cancer Res. 2012;31:70.
  • Rong B, Zhao C, Liu H, et al. Identification and verification of Hsp90-beta as a potential serum biomarker for lung cancer. Am J Cancer Res. 2014;4:874–885.
  • Korfei M, Schmitt S, Ruppert C, et al. Comparative proteomic analysis of lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and lung transplant donor lungs. J Proteome Res. 2011;10:2185–2205.
  • Bellaye PS, Burgy O, Causse S, et al. Heat shock proteins in fibrosis and wound healing: good or evil? Pharmacol Ther. 2014;143:119–132.
  • Bellaye PS, Shimbori C, Yanagihara T, et al. Synergistic role of HSP90alpha and HSP90beta to promote myofibroblast persistence in lung fibrosis. Eur Respir J. 2018;51:1700386.
  • Dong H, Luo L, Zou M, et al. Blockade of extracellular heat shock protein 90alpha by 1G6-D7 attenuates pulmonary fibrosis through inhibiting ERK signaling. Am J Physiol Lung Cell Mol Physiol. 2017;313:L1006–L1015.
  • Sibinska Z, Tian X, Korfei M, et al. Amplified canonical transforming growth factor-beta signalling via heat shock protein 90 in pulmonary fibrosis. Eur Respir J. 2017;49:1501941.
  • Sontake V, Wang Y, Kasam RK, et al. Hsp90 regulation of fibroblast activation in pulmonary fibrosis. JCI Insight. 2017;2:e91454.
  • Tomcik M, Zerr P, Pitkowski J, et al. Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-beta signalling to prevent fibrosis. Ann Rheum Dis. 2014;73:1215–1222.
  • Biernacka A, Dobaczewski M, Frangogiannis NG. TGF-beta signaling in fibrosis. Growth Factors. 2011;29:196–202.
  • Pohlers D, Brenmoehl J, Loffler I, et al. TGF-beta and fibrosis in different organs - molecular pathway imprints. Biochim Biophys Acta. 2009;1792:746–756.
  • Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-beta: the master regulator of fibrosis. Nat Rev Nephrol. 2016;12:325–338.
  • Munger JS, Huang X, Kawakatsu H, et al. The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell. 1999;96:319–328.
  • Madala SK, Korfhagen TR, Schmidt S, et al. Inhibition of the alphavbeta6 integrin leads to limited alteration of TGF-alpha-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2014;306:L726–35.
  • Raghu G, Mouded DA, Culver MJ, et al. Randomized, double-blind, placebo-controlled, multiple dose, dose-escalation study of BG00011 (Formerly STX-100) in patients with idiopathic pulmonary fibrosis (IPF). Am J Respir Crit Care Med. 2018;197:A7785.
  • Gieseck RL 3rd, Wilson MS, Wynn TA. Type 2 immunity in tissue repair and fibrosis. Nat Rev Immunol. 2018;18:62–76.
  • Heaney LG, Djukanovic R, Woodcock A, et al. Research in progress: medical research council United Kingdom Refractory Asthma Stratification Programme (RASP-UK). Thorax. 2016;71:187–189.
  • Wilson MS, Madala SK, Ramalingam TR, et al. Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent. J Exp Med. 2010;207:535–552.
  • Wynn TA. Type 2 cytokines: mechanisms and therapeutic strategies. Nat Rev Immunol. 2015;15:271–282.
  • Park SW, Ahn MH, Jang HK, et al. Interleukin-13 and its receptors in idiopathic interstitial pneumonia: clinical implications for lung function. J Korean Med Sci. 2009;24:614–620.
  • Murray LA, Zhang H, Oak SR, et al. Targeting interleukin-13 with tralokinumab attenuates lung fibrosis and epithelial damage in a humanized SCID idiopathic pulmonary fibrosis model. Am J Respir Cell Mol Biol. 2014;50:985–994.
  • Ramalingam TR, Pesce JT, Sheikh F, et al. Unique functions of the type II interleukin 4 receptor identified in mice lacking the interleukin 13 receptor alpha1 chain. Nat Immunol. 2008;9:25–33.
  • Kolodsick JE, Toews GB, Jakubzick C, et al. Protection from fluorescein isothiocyanate-induced fibrosis in IL-13-deficient, but not IL-4-deficient, mice results from impaired collagen synthesis by fibroblasts. J Immunol. 2004;172:4068–4076.
  • Fichtner-Feigl S, Strober W, Kawakami K, et al. IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis. Nat Med. 2006;12:99–106.
  • Singh B, Kasam RK, Sontake V, et al. Repetitive intradermal bleomycin injections evoke T-helper cell 2 cytokine-driven pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2017;313:L796–L806.
  • Gause WC, Wynn TA, Allen JE. Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths. Nat Rev Immunol. 2013;13:607–614.
  • Hams E, Armstrong ME, Barlow JL, et al. IL-25 and type 2 innate lymphoid cells induce pulmonary fibrosis. Proc Natl Acad Sci U S A. 2014;111:367–372.
  • Parker JM, Glaspole IN, Lancaster LH, et al. A phase 2 randomized controlled study of tralokinumab in subjects with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2018;197:94–103.
  • Swigris JJ, Ogura T, Scholand M, et al. The RIFF study (Cohort A): a phase II, randomized, double-blind, placebo-controlled trial of lebrikizumab as monotherapy in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2018;197:A6167.
  • Raghu G, Richeldi L, Crestani B, et al. Safety and efficacy of SAR156597 in Idiopathic Pulmonary Fibrosis (IPF): a phase 2, randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med. 2018;197:A2441.
  • Tager AM, LaCamera P, Shea BS, et al. The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat Med. 2008;14:45–54.
  • Funke M, Zhao Z, Xu Y, et al. The lysophosphatidic acid receptor LPA1 promotes epithelial cell apoptosis after lung injury. Am J Respir Cell Mol Biol. 2012;46:355–364.
  • Xu MY, Porte J, Knox AJ, et al. Lysophosphatidic acid induces alphavbeta6 integrin-mediated TGF-beta activation via the LPA2 receptor and the small G protein G alpha(q). Am J Pathol. 2009;174:1264–1279.
  • Oikonomou N, Mouratis MA, Tzouvelekis A, et al. Pulmonary autotaxin expression contributes to the pathogenesis of pulmonary fibrosis. Am J Respir Cell Mol Biol. 2012;47:566–574.
  • Coornaert B, Duys I, Van Der Schueren J, et al. Autotaxin inhibitor GLPG1690 affects TGFβ-induced production of the pro-fibrotic mediators CTGF, IL-6 and ET-1 in fibroblasts. Am J Respir Crit Care Med. 2017;195:A2404.
  • Maher TM, van der Aar EM, Van de Steen O, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1690, a novel autotaxin inhibitor, to treat idiopathic pulmonary fibrosis (FLORA): a phase 2a randomised placebo-controlled trial. Lancet Respir Med. 2018;6:627-635.
  • Zank DC, Bueno M, Mora AL, et al. Idiopathic pulmonary fibrosis: aging, mitochondrial dysfunction, and cellular bioenergetics. Front Med (Lausanne). 2018;5:10.
  • Schafer MJ, White TA, Iijima K, et al. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun. 2017;8:14532.
  • Lehmann M, Korfei M, Mutze K, et al. Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo. Eur Respir J. 2017;50:1602367.
  • Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015;14:644–658.
  • Sato N, Takasaka N, Yoshida M, et al. Metformin attenuates lung fibrosis development via NOX4 suppression. Respir Res. 2016;17:107.
  • Rangarajan S, Bone NB, Zmijewska AA, et al. Metformin reverses established lung fibrosis in a bleomycin model. Nat Med. 2018;24:1121–1127.
  • Wang Q, Usinger W, Nichols B, et al. Cooperative interaction of CTGF and TGF-beta in animal models of fibrotic disease. Fibrogenesis Tissue Repair. 2011;4:4.
  • Lipson KE, Wong C, Teng Y, et al. CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis. Fibrogenesis Tissue Repair. 2012;5:S24.
  • Huber PE, Sebastian B, Peschke P, et al. Reversal of established fibrosis by treatment with the Anti-CTGF monoclonal antibody FG-3019 in a murine model of radiation-induced pulmonary fibrosis. Am J Respir Crit Care Med. 2010;181:A1054.
  • Raghu G, Scholand MB, de Andrade J, et al. FG-3019 anti-connective tissue growth factor monoclonal antibody: results of an open-label clinical trial in idiopathic pulmonary fibrosis. Eur Respir J. 2016;47:1481–1491.
  • Conte E, Gili E, Fruciano M, et al. PI3K p110gamma overexpression in idiopathic pulmonary fibrosis lung tissue and fibroblast cells: in vitro effects of its inhibition. Lab Invest. 2013;93:566–576.
  • Lawrence J, Nho R. The Role of the Mammalian Target of Rapamycin (mTOR) in pulmonary fibrosis. Int J Mol Sci. 2018;19:778.
  • Hsu HS, Liu CC, Lin JH, et al. Involvement of ER stress, PI3K/AKT activation, and lung fibroblast proliferation in bleomycin-induced pulmonary fibrosis. Sci Rep. 2017;7:14272.
  • White ES, Atrasz RG, Hu B, et al. Negative regulation of myofibroblast differentiation by PTEN (Phosphatase and Tensin Homolog Deleted on chromosome 10). Am J Respir Crit Care Med. 2006;173:112–121.
  • Xia H, Khalil W, Kahm J, et al. Pathologic caveolin-1 regulation of PTEN in idiopathic pulmonary fibrosis. Am J Pathol. 2010;176:2626–2637.
  • Madala SK, Thomas G, Edukulla R, et al. p70 ribosomal S6 kinase regulates subpleural fibrosis following transforming growth factor-alpha expression in the lung. Am J Physiol Lung Cell Mol Physiol. 2016;310:L175–86.
  • Gokey JJ, Sridharan A, Xu Y, et al. Active epithelial Hippo signaling in idiopathic pulmonary fibrosis. JCI Insight. 2018;3:e98738.
  • Lu Y, Azad N, Wang L, et al. Phosphatidylinositol-3-kinase/akt regulates bleomycin-induced fibroblast proliferation and collagen production. Am J Respir Cell Mol Biol. 2010;42:432–441.
  • Tulek B, Kiyan E, Toy H, et al. Anti-inflammatory and anti-fibrotic effects of sirolimus on bleomycin-induced pulmonary fibrosis in rats. Clin Invest Med. 2011;34:E341.
  • Axell-House DB, Yu V, Zhang Z, et al. Fibrocytes in pulmonary fibrosis: double-blind placebo-controlled crossover pilot study of sirolimus in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2018;197:A4353.
  • Mercer PF, Woodcock HV, Eley JD, et al. Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti-fibrotic agent in IPF. Thorax. 2016;71:701–711.
  • Maher TM, Bareille P, Costa MJ, et al. Marshall a randomised, placebo-controlled, double-blind, repeat dose escalation study with Omipalisib (gsk2126458) in patients with Idiopathic Pulmonary Fibrosis (ipf). Am J Respir Crit Care Med. 2017;195:A7010.
  • Madala SK, Edukulla R, Phatak M, et al. Dual targeting of MEK and PI3K pathways attenuates established and progressive pulmonary fibrosis. PloS one. 2014;9:e86536.
  • Chien JW, Richards TJ, Gibson KF, et al. Serum lysyl oxidase-like 2 levels and idiopathic pulmonary fibrosis disease progression. Eur Respir J. 2014;43:1430–1438.
  • Barry-Hamilton V, Spangler R, Marshall D, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med. 2010;16:1009–1017.
  • Knipe RS, Tager AM, Liao JK. The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis. Pharmacol Rev. 2015;67:103–117.
  • Knipe RS, Probst CK, Lagares D, et al. The Rho Kinase Isoforms ROCK1 and ROCK2 each contribute to the development of experimental pulmonary fibrosis. Am J Respir Cell Mol Biol. 2018;58:471–481.
  • Shimizu Y, Dobashi K, Sano T, et al. ROCK activation in lung of idiopathic pulmonary fibrosis with oxidative stress. Int J Immunopathol Pharmacol. 2014;27:37–44.
  • Zhou Y, Huang X, Hecker L, et al. Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis. J Clin Invest. 2013;123:1096–1108.
  • Jiang C, Huang H, Liu J, et al. Fasudil, a Rho-kinase inhibitor, attenuates bleomycin-induced pulmonary fibrosis in mice. Int J Mol Sci. 2012;13:8293–8307.
  • Bei Y, Hua-Huy T, Duong-Quy S, et al. Long-term treatment with fasudil improves bleomycin-induced pulmonary fibrosis and pulmonary hypertension via inhibition of Smad2/3 phosphorylation. Pulm Pharmacol Ther. 2013;26:635–643.
  • Alagha K, Secq V, Pahus L, et al. We should prohibit warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2015;191:958–960.
  • Noth I, Anstrom KJ, Calvert SB, et al. A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2012;186:88–95.
  • Raghu G, Behr J, Brown KK, et al. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann Intern Med. 2013;158:641–649.
  • King TE Jr, Behr J, Brown KK, et al. BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2008;177:75–81.
  • Raghu G, Million-Rousseau R, Morganti A, et al. Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial. Eur Respir J. 2013;42:1622–1632.
  • Daniels CE, Lasky JA, Limper AH, et al. Imatinib treatment for idiopathic pulmonary fibrosis: randomized placebo-controlled trial results. Am J Respir Crit Care Med. 2010;181:604–610.
  • Martinez FJ, de Andrade JA, Anstrom KJ et al. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2093–2101.
  • Raghu G, Anstrom KJ, King TE Jr, et al.; Idiopathic Pulmonary Fibrosis Clinical Research N. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366:1968–1977.
  • Raghu G, Martinez FJ, Brown KK, et al. CC-chemokine ligand 2 inhibition in idiopathic pulmonary fibrosis: a phase 2 trial of carlumab. Eur Respir J. 2015;46:1740–1750.
  • Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008;68:4774–4782.
  • Wollin L, Maillet I, Quesniaux V, et al. Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J Pharmacol Exp Ther. 2014;349:209–220.
  • Bahudhanapati H, Kass DJ. Unwinding the Collagen Fibrils: elucidating the mechanism of pirfenidone and nintedanib in pulmonary fibrosis. Am J Respir Cell Mol Biol. 2017;57:10–11.
  • Didiasova M, Singh R, Wilhelm J, et al. Pirfenidone exerts antifibrotic effects through inhibition of GLI transcription factors. FASEB J. 2017;31:1916–1928.
  • Liu Y, Lu F, Kang L, et al. Pirfenidone attenuates bleomycin-induced pulmonary fibrosis in mice by regulating Nrf2/Bach1 equilibrium. BMC Pulm Med. 2017;17:63.
  • Costabel U, Albera C, Lancaster LH, et al. An open-label study of the long-term safety of pirfenidone in patients with idiopathic pulmonary fibrosis (RECAP). Respiration. 2017;94:408–415.
  • Vancheri C, Kreuter M, Richeldi L, et al. Nintedanib with add-on pirfenidone in idiopathic pulmonary fibrosis. Results of the INJOURNEY trial. Am J Respir Crit Care Med. 2018;197:356–363.
  • Noble PW, Barkauskas CE, Jiang D. Pulmonary fibrosis: patterns and perpetrators. J Clin Invest. 2012;122:2756–2762.

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