Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease process without any drug therapies proven to be unequivocally effective in modifying disease progression or mortality. Two major impediments to successful drug discovery in IPF are: (1) identification of candidate drugs that target molecular/signaling pathways responsible for promotion/maintenance of pro-fibrotic cellular phenotypes;and (2) identification of reliable animal models to test candidate drugs. Our preliminary data support a critical role for the Rhokinase (ROCK) pathway for regulation of myofibroblast activation and contractility. Pharmacologic agents that inhibit ROCK activity mediate anti-fibrotic effects when the drug is administered during the fibrotic phase of bleomycin-induced lung injury in mice. We also provide in-vivo evidence that this pathway is activated in lungs of human subjects with IPF. Recent evidence supports a role for ROCK in the expression of NADPH oxidase-4 (Nox4) in fibrosis involving other organ systems. Our recent studies indicate an essential role for Nox4 activation in myofibroblast activation and fibrogenic respones to lung injury. We have generated preclinical animal models in aged mice that demonstrates a persistent/progressive fibrotic response to lung injury, a response that is more akin to the clinical phenotype of IPF. In this grant proposal, we focus on further robust validation ofthe ROCK pathway in this aging murine model of pulmonary fibrosis and in human IPF cells/tissues with the eventual goal of successful clinical translation of at least one drug that targets the ROCK pathway.
Our specific aims are to: (1) Validate ROCK activation/regulation in ex-vivo models of IPF-derived myofibroblasts and study crosstalk ofthis pathway with Nox4 activation;and (2) Validation the efficacy of ROCK inhibitors in an aging model of persistent/progressive lung fibrosis. This research project is ideally suited for bringing together multi-disciplinary teams with a common purpose of innovative drug discovery and identification of novel animal models to test efficacy of candidate drugs.
Idiopathic pulmonary fibrosis is a lethal disease ofthe lung with no effective therapies. This project evaluates the efficacy of a novel therapeutic approaches in an animal model of lung fibrosis that more closely resembles human IPF.
|Bai, Guangxing; Hock, Thomas D; Logsdon, Naomi et al. (2014) A far-upstream AP-1/Smad binding box regulates human NOX4 promoter activation by transforming growth factor-Î². Gene 540:62-7|
|Sanders, Yan Y; Hagood, James S; Liu, Hui et al. (2014) Histone deacetylase inhibition promotes fibroblast apoptosis and ameliorates pulmonary fibrosis in mice. Eur Respir J 43:1448-58|
|Hecker, Louise; Logsdon, Naomi J; Kurundkar, Deepali et al. (2014) Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci Transl Med 6:231ra47|
|Bernard, Karen; Hecker, Louise; Luckhardt, Tracy R et al. (2014) NADPH oxidases in lung health and disease. Antioxid Redox Signal 20:2838-53|
|Thannickal, Victor J (2013) Mechanistic links between aging and lung fibrosis. Biogerontology 14:609-15|
|Zhou, Yong; Huang, Xiangwei; Hecker, Louise et al. (2013) Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis. J Clin Invest 123:1096-108|
|Duffield, Jeremy S; Lupher, Mark; Thannickal, Victor J et al. (2013) Host responses in tissue repair and fibrosis. Annu Rev Pathol 8:241-76|
|Huang, Xiangwei; Yang, Naiheng; Fiore, Vincent F et al. (2012) Matrix stiffness-induced myofibroblast differentiation is mediated by intrinsic mechanotransduction. Am J Respir Cell Mol Biol 47:340-8|
|Huang, Xiangwei; Gai, Ying; Yang, Naiheng et al. (2011) Relaxin regulates myofibroblast contractility and protects against lung fibrosis. Am J Pathol 179:2751-65|