Inhalation of crystalline silica in the mining and quarrying industries leads to serious lung inflammation and fibrosis for which there are no therapies. The pathogenic mechanisms of silicosis, as well as other types of lung fibrosis, are poorly understood, but the cytokine TGFB appears key. This is the result of TGFB's effects on pulmonary fibroblasts, particularly its ability to induce extracellular matrix (ECM) production and to drive myofibroblast differentiation. Inhibiting TGFB-mediated pro-fibrotic activities on fibroblasts is thus an attractive therapeutic target. Recently, a receptor/ transcription factor called peroxisome proliferator activated receptor gamma (PPAR() and its natural (15d-PGJ2) and synthetic ligands have emerged as important inhibitors of inflammation. PPARy also has important roles in lipid metabolism. The role of the PPAR( pathway in modulating pulmonary fibrosis is unknown. The overall hypothesis to be tested is that activation of the peroxisome proliferator activated receptor gamma (PPARy) pathway ameliorates pulmonary fibrosis, and that the PPARy pathway can be targeted as a novel therapy for human pulmonary fibrosis. Both natural (15d-PGJ2) and synthetic PPARy agonists (e.g. rosiglitazone, ciglitazone) will be tested for their ability to inhibit key TGFB-mediated fibroblast activation events in vitro (including myofibroblast differentiation and ECM production), and for their ability to inhibit lung fibrosis in vivo. The following 3 specific aims will test the overall hypothesis:
Aim 1. To determine the efficacy of selected PPARy agonists in inhibiting key TGFB-stimulated pro-fibrotic activities in pulmonary fibroblasts.
Aim 2. To determine if PPARy agonists mediate inhibition of key TGFB-induced pro-fibrotic activities in fibroblasts through both PPARy-dependent and independent pathways.
Aim 3. To determine the role of the PPAR( pathway as a modulator of pulmonary fibrosis in vivo, and to determine the efficacy of 15d-PGJ2 and selected PPARy agonists as anti-fibrotics in a silica model of lung fibrosis.
These aims will identify the mechanism of action of PPARy agonists as anti-fibrotics and will generate exciting evidence supporting their utility as novel and efficacious therapies for scarring of the lungs, as well as other organs.
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