Redundant effects of Pirfenidone against fibroblast activation and severe fibrotic lung disease

Idiopathic Pulmonary Fibrosis (IPF) is a progressive chronic lung disease characterized by excess deposition of extracellular matrix (ECM) proteins in the lung. TGFa is a is a ligand for the epidermal growth factor receptor, and found elevated in several fibrotic lung diseases including IPF. Notably, lung-specific overexpression of TGFa alone in adult mice can cause progressive and extensive adventitial and subpleural fibrosis similar to IPF. Pirfenidone, an FDA approved drug has been shown to improve the decline in lung function in IPF patients. However, the mechanism of action of pirfenidone largely unknown. In the current study, we investigated the effects of pirfenidone using a mouse model of TGFa-induced pulmonary fibrosis and fibroblasts isolated from IPF lungs. Total lung transcriptome analysis suggest a significant overlap in dysregulated gene transcripts between TGFa model and IPF. In vivo studies demonstrate a significant improvement in lung function with pirfenidone therapy compared to vehicle-treated TGFa mice on Dox for six wks. However, pirfenidone treatment did not affect fibroproliferation, myofibroblast transformation, and ECM deposition during TGFa-induced pulmonary fibrosis. In summary, pirfenidone treatment improved lung function but had a limited or no effect on the expression of collagen, ECM genes, fibroproliferation and migration of lung-resident fibroblasts. Overall design: mRNA profiles of control and TGFalpha mice on Dox for 6weeks and treated with eaither vehicle or pirfenidone for the last 3 weeks and measured changes in total lung transcripts