Role of Peroxiredoxin 4 in Collagen Deposition in Mouse Models of Fibrosis

Abstract

Rationale: Every year 34,000 people in the USA are diagnosed with Idiopathic Pulmonary Fibrosis (IPF). The average survival time for these patients is only 3-5 years after diagnosis. Lung epithelial cell injury via the Fas cell death pathway has been shown to be important in the progression of IPF. Fas s-glutathionylation enhances the apoptotic signal in murine type II alveolar cells. Recently we have shown that the overexpression of the ER localized peroxidase, Peroxiredoxin 4 (Prdx4) attenuates Fas s-glutathionylation and cell death in murine type II alveolar cells. The goal of this study is to understand the role of Prdx4 in experimental models of lung fibrosis. C57B6 mice were oropharyngeal instilled with Bleomycin or AdTGFb1. After the establishment of pulmonary fibrosis Prdx4 was overexpressed by instillation of Adeno-Peroxiredoxin 4 (AdPrdx4). One week after the administration of AdPrdx4 mice lungs were harvested to determine extent of fibrosis and oxidation state of Fas. The overexpression of Prdx4 was confirmed in mouse lung homogenates by qRT-PCR, western blot and immunohistochemistry. Hydroxyproline analysis of mouse lungs showed a significant decrease in collagen content in mouse lungs overexpressing Prdx4 compared to mice receiving AdCtrl. Similarly, expression of alpha smooth muscle actin, a marker for fibroblast activation, was attenuated following administration of AdPrdx4. This data reveals that augmentation of Prdx4 has a potential positive therapeutic relevance in pulmonary fibrosis.