Sex differences in ASK1-mediated pulmonary fibrosis

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Idiopathic pulmonary fibrosis (IPF) is a devastating illness with a poor prognosis, and both the incidence and prevalence of IPF among U.S. Veterans has increased during the last 10 years. In addition, the occurrence of pulmonary fibrosis developing following acute lung injury has been prominent in survivors of COVID-19. The pathogenic mechanisms underlying the development of fibrosis are not completely understood. The fundamental processes develop due to genetic abnormalities and/or environmental factors that lead to repetitive injury to the alveolar epithelium, dysregulated epithelial repair mechanisms, and an increase in fibroblasts and (apoptosis-resistant) myofibroblasts that produce excessive extracellular matrix. IPF is more prevalent in men than in women, but the reasons for the differences are not well understood. Apoptosis signal regulating kinase 1 (ASK1) is a mitogen activated protein kinase kinase kinase (MAP3K5) that is activated by oxidative stress and causes stimulation of MAPK pathways, but the downstream signaling pathways are highly tissue dependent and have not been investigated in the context of pulmonary fibrosis. The overall objective of this application is to establish that ASK1 is a central mediator of the development of pulmonary fibrosis. The central hypothesis of this proposal is that ASK1 promotes pulmonary fibrosis by p38-mediated inflammation and stimulation of ERK1/2-mediated pathways, and that these pathways are regulated in part by sex hormones. The rationale for the proposed research is that the identification of ASK1 as a central regulator in the development of fibrosis will advance our fundamental understanding and lead to new therapeutic options for the treatment of IPF patients. These mechanisms will be investigated using both ASK1-deficient mice and an ASK1 inhibitor in a bleomycin-induced fibrosis mouse model. In addition, primary cultures of alveolar type II epithelial cell and fibroblasts, as well as cell lines with knockdown of ASK1 and other key mediators, will be used to define specific ASK1-dependent pathways. Aim 1 will test the hypothesis that fibrosis is exacerbated by repetitive oxidative stress that activates p38 signaling via ASK1, and that these pathways are regulated by sex hormones. Aim 2 will test the hypothesis that sex-dependent differences in ASK1 and ERK1/2 activation stimulate pro-fibrotic pathways. These studies will advance our fundamental understanding of fibrosis and sex differences and establish ASK1 as a potential therapeutic target to reduce the progression of IPF.