Effects of NecroX compounds on bleomycin-induced pulmonary fibrosis

Abstract

Mitochondrial oxidative damage has been recognized as being involved in many diseases and in the aging process. Fibrotic changes appear as sequelae to insults by a diverse group of infectious, environmental, therapeutic exposures, and senile pulmonary illness. To date, bleomycin-inhaled animal model represents as a relatively well established experimental tool for pulmonary fibrotic changes. In this study, we aimed to investigate the role of mitochondrial ROS in the pathogenesis of bleomycin-induced lung inflammation and fibrosis and the related mechanisms. These results showed that the increased the generation of mitochondrial ROS in inflammatory cells and lung tissues, increased numbers of airway inflammatory cells and increased levels of pro-inflammatory cytokines, TGF-β1, and increased nuclear translocation of NF-κB. In addition, the bleomycin-inhaled mice developed features of pulmonary fibrotic changes, including thickening of the peribronchial smooth muscle layer, and subepithelial collagen deposition, with showing increased the expression of endoplasmic reticulum (ER) stress markers and the protein levels of unfolded-protein response (UPR)-related markers in lung tissues. Administration of NecroX compounds including NecroX-5 and -7 or 4-PBA reduced the pathophysiological features of pulmonary fibrosis, increased NF-κB activation, and TGF-β1 in lungs as well as the increased generation of mitochondrial ROS and increases of ER stress in lung after bleomycin inhalation. These results indicate that reduction of mitochondrial ROS may attenuate pulmonary fibrotic changes through the regulation of NF-κB pathway, providing the therapeutic potential of NecroX compounds as a novel anti-fibrotic agent.