Targeted Death of Collagen1a1-Expressing Fibroblasts Reduces Silica-Induced Pulmonary Fibrosis

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PROJECT SUMMARY A key feature of progressive fibrotic diseases of the lungs, including in patients with silicosis, is the excessive deposition of scar tissue and extracellular matrix (ECM), particularly collagen1a1 (Col1a1). Fibroblasts are known to be resistant to apoptosis and persist in fibrotic lungs, continuing to lay down matrix, contributing to a progressive and persistent phenotype in patients. Fibroblasts that participate in this pathogenic process have most commonly been identified by αSMA staining and termed myofibroblasts. However, recent work by our group and others has shown that αSMA does not identify all pathogenic fibroblasts in pulmonary fibrosis. This proposal seeks to address the central hypothesis that elimination of persistent collagen-producing fibroblasts is critical in halting disease progression. Based on our robust preliminary studies, we propose three specific aims to test this central hypothesis. Specific Aim 1 will determine the accumulation and localization of Col1a1+ fibroblasts to the fibrosis associated after silica exposure using a lineage tracing strategy. We hypothesize that Col1a1+ fibroblasts accumulate and persist in mouse lungs during silica-induced pulmonary fibrosis. In Aims 2 and 3 we ask if the loss of Col1a1+ fibroblasts prevents fibrosis progression. Specific Aim 2 will test the hypothesis that the progression of silica-induced pulmonary fibrosis in mice is arrested after the selective and targeted ablation of Col1a1+ fibroblasts. Specific Aim 3 will test the hypothesis that genetic loss of the anti-apoptotic protein Bcl-2 in Col1a1+ fibroblasts promotes their susceptibility to undergo intrinsic apoptosis during silica-induced pulmonary fibrosis resulting in the arrest of disease progression. There are currently no FDA approved therapies for silicosis and no therapies that stop or reverse fibrosis for pulmonary fibrosis in general. Thus, there is a critical need to identify molecular pathways or cell populations that are targetable for therapeutic intervention. Additionally, the proposed studies will provide a novel and mechanistic understanding about pathogenic fibroblast accumulation and persistence in driving the progression of silica-induced pulmonary fibrosis.