Acute respiratory distress syndrome (ARDS) and idiopathic pulmonary fibrosis (IPF) develop in response to alveolar epithelial injury and sloughing, though the outcomes of these conditions are substantially different. ARDS is associated with an early accumulation of pro-fibrotic fibroblasts that deposit collagen and other extracellular matrix components in the injured alveoli and airspaces. Fortunately, the early fibrosis in ARDS patients often resolves and lung structure and function return towards normality in many survivors as homeostasis is restored. In contrast, pro-fibrotic fibroblasts accumulate and persist in the injured alveolar- capillary units in IPF patients, leading to persistent and progressive fibrosis, incremental declines in gas exchange and eventual respiratory failure. What distinguishes these two fundamentally different fibrotic outcomes, i.e. resolution or persistence/progression, is poorly understood and forms the central focus of this application. Our proposal seeks to test the central hypothesis that the development of fibroblast resistance to apoptosis prevents the homeostatic resolution of fibrosis during normal lung repair as seen in ARDS and promotes the persistent and potentially progressive pulmonary fibrosis seen in IPF patients. Furthermore, we propose that impairment of Fas-induced fibroblast apoptosis plays a central role in fibroblast and fibrosis persistence. Based on robust preliminary studies, new genetically-modified mice that have been specifically created for this application and validated animal models of resolving and persistent pulmonary fibrosis, we propose testing this central hypothesis with 3 specific aims.
Aim 1 will test the hypothesis that Fas signaling in lung fibroblasts is required for homeostatic fibrosis resolution. This hypothesis will be tested by deleting Fas in fibroblasts and determining the consequences on fibroblast and fibrosis persistence in the normally resolving model of bleomycin-induced pulmonary fibrosis. By conditionally over-expressing anti-apoptotic genes (Bcl-2 or cFLIPL) in fibroblasts, Aim 2 seeks to test the hypothesis that impaired apoptosis in lung fibroblasts will lead to a failure in homeostatic fibrosis resolution and promote persistent pulmonary fibrosis.
Aim 3 will test the legitimacy of the hypothesis that conditional genetic ablation of pro-fibrotic fibroblasts accelerates the homeostatic resolution of persistent pulmonary fibrosis. Little is known about the mechanisms that control fibroblast apoptosis during injury-induced lung repair or how this process goes awry in persistent pulmonary fibrosis. The proposed studies will provide new understanding about the transition between beneficial, resolving fibrosis as occurs during normal lung repair in the context of ARDS, and detrimental, persistent fibrosis as seen in IPF. Furthermore, the outcome of this work should significantly impact our understanding of the mechanisms that control the resolution of fibrosis and its persistence in other organs and tissues.

Public Health Relevance

Whereas early scar formation (fibrosis) often resolves in patients with acute respiratory distress syndrome, fibrosis is persistent and progressive in the lungs of patients with idiopathic pulmonary fibrosis. The proposed studies seek to investigate the pivotal role of the Fas-death receptor in controlling fibroblast elimination during fibrosis resolution and the consequences of its failure on persistent lung fibrosis. The results of our studies should provide considerable insight into the concept of therapeutically inducing fibroblast apoptosis to promote the resolution of persistent pulmonary fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL140595-02
Application #
9629742
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Craig, Matt
Project Start
2018-02-01
Project End
2021-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206