12 - Oxidation state of peroxiredoxin 4 in lungs from patients with pulmonary fibrosis and mouse models of fibrosis

Abstract

Rationale Every year 34,000 people in the United States are diagnosed with Idiopathic Pulmonary Fibrosis (IPF). The average survival time for these patients is only 3-5 years after diagnosis. Recently we have shown that the overexpression of the ER localized peroxidase, Peroxiredoxin 4 (Prdx4) attenuates murine type II alveolar cells cell death and decreases collagen deposition in mouse models of pulmonary fibrosis. The goal of this study is to understand the redox status of Prdx4 in IPF and experimental models of lung fibrosis. Methods C57B6 mice were oropharyngeal instilled with bleomycin. After the establishment of pulmonary fibrosis Prdx4 was overexpressed by instillation of Adeno-Peroxiredoxin 4 (AdPrdx4). Mouse lung tissue as well as samples from IPF patients were analyzed for Prdx4 content and redox status. Results The overexpression of Prdx4 in mice with bleomycin-induced fibrosis resulted in a significant decrease in collagen content in mouse lungs overexpressing Prdx4 compared to mice receiving AdCtrl. Lung tissue from mice with bleomycin-induced fibrosis and patients with IPF showed altered Prdx4 oxidation states, with a shift towards high molecular weight complexes. A dramatic increase in only high molecular weight Prdx4 protein was observed in the bronchoaveolar lavage fluid from mice with bleomycin-induced fibrosis, along with increases in overoxidized Prdx (Prdx-SO3), suggesting that overoxidized high molecular weight Prdx4 complexes are selectively released from cells in models of pulmonary fibrosis. Conclusion This data reveals that an altered redox status of Prdx4 occurs in IPF and mouse models of pulmonary fibrosis and that augmentation of Prdx4 has a potential positive therapeutic relevance in pulmonary fibrosis.