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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG046210-04
Application #
9276576
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Macchiarini, Francesca
Project Start
2014-09-01
Project End
2019-05-31
Budget Start
2017-07-01
Budget End
2018-05-31
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Kurundkar, Ashish; Thannickal, Victor J (2016) Redox mechanisms in age-related lung fibrosis. Redox Biol 9:67-76
Rangarajan, Sunad; Kurundkar, Ashish; Kurundkar, Deepali et al. (2016) Novel Mechanisms for the Antifibrotic Action of Nintedanib. Am J Respir Cell Mol Biol 54:51-9
Rangarajan, Sunad; Locy, Morgan L; Luckhardt, Tracy R et al. (2016) Targeted Therapy for Idiopathic Pulmonary Fibrosis: Where To Now? Drugs 76:291-300
Swamy, Shobha M; Rajasekaran, Namakkal S; Thannickal, Victor J (2016) Nuclear Factor-Erythroid-2-Related Factor 2 in Aging and Lung Fibrosis. Am J Pathol 186:1712-23
Chanda, Diptiman; Kurundkar, Ashish; Rangarajan, Sunad et al. (2016) Developmental Reprogramming in Mesenchymal Stromal Cells of Human Subjects with Idiopathic Pulmonary Fibrosis. Sci Rep 6:37445
Chen, Huaping; Qu, Jing; Huang, Xiangwei et al. (2016) Mechanosensing by the α6-integrin confers an invasive fibroblast phenotype and mediates lung fibrosis. Nat Commun 7:12564
Hecker, Louise; Thannickal, Victor J (2016) Getting to the core of fibrosis: targeting redox imbalance in aging. Ann Transl Med 4:93
Kurundkar, Ashish R; Kurundkar, Deepali; Rangarajan, Sunad et al. (2016) The matricellular protein CCN1 enhances TGF-β1/SMAD3-dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury. FASEB J 30:2135-50
Kulkarni, Tejaswini; O'Reilly, Philip; Antony, Veena B et al. (2016) Matrix Remodeling in Pulmonary Fibrosis and Emphysema. Am J Respir Cell Mol Biol 54:751-60
Pennathur, Subramaniam; Vivekanandan-Giri, Anuradha; Locy, Morgan L et al. (2016) Oxidative Modifications of Protein Tyrosyl Residues Are Increased in Plasma of Human Subjects with Interstitial Lung Disease. Am J Respir Crit Care Med 193:861-8

Showing the most recent 10 out of 19 publications