# Reducing Fibroblast Persistence in Pulmonary Fibrosis as a Mechanism of Resolution

> **NIH NIH R01** · NATIONAL JEWISH HEALTH · 2023 · $547,555

## Abstract

Project Summary
 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
reso...

## Key facts

- **NIH application ID:** 10661572
- **Project number:** 5R01HL147860-05
- **Recipient organization:** NATIONAL JEWISH HEALTH
- **Principal Investigator:** Elizabeth Frances Redente
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $547,555
- **Award type:** 5
- **Project period:** 2019-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10661572

## Citation

> US National Institutes of Health, RePORTER application 10661572, Reducing Fibroblast Persistence in Pulmonary Fibrosis as a Mechanism of Resolution (5R01HL147860-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10661572. Licensed CC0.

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