Interstitial lung diseases (ILD) include a devastating group of fibrotic parenchymal diseases with high morbidity and mortality, for which there are limited effective therapies. Pulmonary fibrosis (PF) develops in ILD patients in response to alveolar epithelial injury and the subsequent activation and accumulation of pro-fibrotic fibroblasts, which deposit collagen and other extracellular matrix (ECM) components. The accumulation and persistence of pro-fibrotic fibroblasts and the deposition of ECM leads to progressive fibrosis resulting in declining gas exchange in the alveolar-capillary units. The inhalation of silicate dust, cigarette smoke and toxic chemicals are known risk factors for developing fibrotic lung disease and these exposures have disproportionally affected US veteran's, coal miners and construction workers. PF is generally believed to be irreversible. Consequently, it becomes increasingly important to identify molecular pathways that are targetable for therapeutic intervention. This proposal seeks to address this unmet need by investigating the central hypothesis that the development of pro-fibrotic fibroblast resistance to apoptosis contributes to progressive fibrotic disease. Furthermore, we propose that expression of the anti-apoptotic gene Bcl-2 plays a central role in mediating the persistence of pro-fibrotic fibroblasts. Based on robust preliminary studies in a silica-induced model of pulmonary fibrosis, we propose testing this central hypothesis with 3 specific aims:
Specific Aim 1 will test the hypothesis that in vivo ablation of pro-fibrotic lung fibroblasts will induce the resolution of persistent pulmonary fibrosis initiated by the intratracheal instillation of silica particles.
Specific Aim 2 will test the hypothesis that reducing the resistance to apoptosis in pro-fibrotic fibroblasts promotes the resolution of progressive pulmonary fibrosis. This hypothesis will be tested using a genetic approach to determine if conditional deletion of the anti-apoptotic gene Bcl-2 in pro-fibrotic fibroblasts leads to the apoptosis of fibrotic lung fibroblasts and the resolution of persistent fibrosis in a model of silica-induced pulmonary fibrosis.
Specific Aim 3 will test the hypothesis that clinically relevant Bcl-2 inhibitors will therapeutically target pro- fibrotic fibroblasts and promote the resolution of established pulmonary fibrosis. This hypothesis will be tested by treating mice with a small molecule inhibitor to reduce Bcl-2 activity, prevent fibroblast survival and promote the resolution of persistent fibrosis in vivo. Mice will be followed using micro-CT imaging to monitor disease development, progression and resolution. The proposed studies will provide new understanding about the targeting of pro-fibrotic fibroblasts for death and how this may aid in the resolution of fibrosis. 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

Interstitial lung diseases are often a fatal condition that leads to progressive scarring of the lungs, but little is known about if or how to induce resolution of this persistent disease in humans. The proposed studies seek to investigate the pivotal role of Bcl-2 as a driver of pro-fibrotic fibroblast survival in silica induced lung fibrosis and the consequences of its loss on fibrosis resolution. The results of our studies should provide insight into the development of novel therapeutic strategies to induce fibrosis resolution that will improve the outcomes for patients with fibrotic lung disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Craig, Matt
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National Jewish Health
United States
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