Human fibrotic disorders affect many organ systems including heart, blood vessels, kidney, liver and lung. The most common fibrotic lung disease, idiopathic pulmonary fibrosis (IPF) is a disease of aging carries a high morbidity and mortality, with a median survival rate of less than three years. There are currently no U.S. FDA-approved anti-fibrotic drugs. The incidence and prevalence of IPF increase drastically with age;however, despite this strong association, cellular/molecular mechanisms that account for the aging predilection to fibrotic disease have not been elucidated. Recent studies from our laboratory indicate that the biological effects of the ROS-generating enzyme, NADPH oxidase-4 (Nox4) is determined by the capacity of myofibroblasts (MFbs) to maintain redox homeostasis via the induction of the antioxidant response transcription factor, nuclear factor-like 2 (Nrf2), a respons that is deficient with aging. Loss of this cellular homeostatic mechanism results in the emergence of a senescent and apoptosis-resistant phenotype of MFbs, at least in part related to mitochondrial dysfunction. Human subjects with IPF exhibit elevated expression of Nox4 and decreased Nrf2 expression in myofibroblastic foci, supporting this cellular redox imbalance in a human fibrotic disease. In contrast to self-limited, resolving fibrosis in young mice, aged mice manifest an impaired capacity for resolution of fibrosis. This represents, to our knowledge, the first aging model of fibrosis that recapitulates the non-resolving nature of human IPF. The central hypothesis to be tested in this project is that an imbalance of Nox4-Nrf2 induces sustained oxidative stress that induces MFb senescence and apoptosis resistance, leading to persistent fibrosis associated with aging.
Our specific aims are to: (1) Determine mechanisms for the (dys)regulation of Nrf2 expression/induction by oxidative stress with cellular senescence;(2) Determine the role of Nox4-Nrf2 imbalance and mitochondrial bioenergetics in promoting Fb senescence;and (3) Determine whether conditional genetic deletion of Nrf2 in Fbs mediates persistent fibrosis in young mice;and whether Nrf2 induction or Nox4 inhibition (by pharmacologic approaches) promotes fibrosis resolution in aged mice. This grant application is responsive to PA-10-014: Development and Characterization of Animal Models for Aging Research. The completion of the aims in this project will: (a) establish a disease-relevant animal model of non-resolving fibrosis;(b) define mechanisms for the loss of redox homeostatic control in MFbs;(c) establish mechanistic links between mitochondrial dysfunction and senescence;and (d) provide proof-of-concept that correction of cellular redox balance will promote fibrosis resolution and lead to the development of novel therapeutic approaches to non-resolving fibrotic disorders such as IPF.
Idiopathic pulmonary fibrosis is a lethal disease of the lung with no effective therapies. This project evaluates the efficacy of a novel therapeutic approach in an animal model of lung fibrosis that more closely resembles human IPF.
|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|
|Thannickal, Victor J; Zhou, Yong; Gaggar, Amit et al. (2014) Fibrosis: ultimate and proximate causes. J Clin Invest 124:4673-7|