The pathophysiology of Idiopathic pulmonary fibrosis (IPF), a rapidly progressive and deadly fibrotic lung disease remains poorly understood. Aging is a well-recognized risk factor for IPF, and IPF disproportionately affects the aging veteran population. Given this shift in demographic, it is critical to understand the contribution of aging to the cellular/molecular mechanism(s) leading to the pathogenesis of age-related diseases, such as IPF. In resolving fibrosis, lung myofibroblasts (the key `scar tissue generating' cell) undergo apoptosis to promote healing. In contrast, myofibroblasts from aged mice with non-resolving fibrosis acquire a senescent and apoptosis-resistant phenotype, mediated in part by persistent expression of NADPH- oxidase-4 (Nox4). Similarly, lung myofibroblasts from IPF patients exhibit senescence and apoptosis- resistance, associated with elevated Nox4 expression. However, the mechanisms that drive persistence of Nox4 and apoptosis-resistance of myofibroblasts in the context of aging/IPF remain unknown. We have identified a critical role for Nampt, a known regulator of innate immune responses and apoptosis, in driving the senescent and apoptosis-resistant myofibroblast phenotype in age-associated pathological lung fibrosis. We demonstrate that Nampt is upregulated in vivo in 2 injury models of age-dependent fibrosis, and in fibrotic regions of the IPF lung. Intracellular Nampt (iNampt) is persistently expressed in senescent and IPF fibroblasts, which fail to undergo apoptosis, and these cells secrete significantly elevated levels of extracellular Nampt (eNampt). We found that eNampt mediates profibrotic effects via TLR4, including myofibroblast differentiation, oxidative signaling, senescence, and apoptosis-resistance. Our data suggest that defective TGF-mediated downregulation of iNampt in senescent/IPF fibroblasts contributes to persistent iNampt expression, subsequent elevated eNampt levels, which promotes profibrotic effects. Reductions in Nampt expression facilitated myofibroblast apoptosis and led to protection from fibrosis in vivo. The mechanisms that drive continued propagation of fibrogenic responses, beyond initial injury, are not well understood. We propose a novel auto-regulatory mechanism (eNampt/iNampt), which temporally reinforces profibrotic responses in age-dependent pathological fibrosis. These studies will prvide insight into novel age-relevant mechanisms/cellular phenotypes in IPF pathogenesis. Further, we will evaluate the pre-clinical efficacy of FK-866 (iNampt inhibitor currently in phase II clinical trials as an anti-cancer agent) in rigorous aging animal models of fibrosis, enhancing the potential fo rapid clinical translation of novel therapeutics for IPF.

Public Health Relevance

Idiopathic pulmonary fibrosis (IPF) is a rapidly progressive and deadly fibrotic lung disease, with a median survival rate of less than 3 years. IPF disproportionately affects the aging veteran population. No drug treatment has been shown to definitively improve quality of life for IPF patients; clearly, improved therapies for IPF are needed. Although aging is a well-recognized risk factor for IPF, the contribution of aging to the cellular/molecular mechanism(s) leading to this disease remains poorly understood. These studies will provide novel insight into why the healing process `goes awry' in aging, resulting in susceptibility to disease. Further, we will evaluate the preclinical efficacy of a drug candidate (currently in phase II clinical trials for cancer indications) for IPF.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Veterans Health Administration
United States
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