Effects of the Cytoplasm and Mitochondrial Specific Hydroxyl Radical Scavengers TA293 and mitoTA293 in Bleomycin-Induced Pulmonary Fibrosis Model Mice

Lung fibrosis is the primary pathology in idiopathic pulmonary fibrosis and is considered to result from an increase in reactive oxygen species (ROS) levels in alveolar epithelial cells. However, the exact mechanism underlying lung fibrosis remains unclear and there is no effective therapy. The hydroxyl radical ((OH)-O-center dot) has the strongest oxidizing potential among ROS. Recently, (OH)-O-center dot localized to the cytoplasm (cyto (OH)-O-center dot) was reported to induce cellular senescence, while mitochondria-localized (OH)-O-center dot (mt (OH)-O-center dot) was reported to induce apoptosis. We developed the cyto (OH)-O-center dot- and mt (OH)-O-center dot-scavenging antioxidants TA293 and mitoTA293 to evaluate the effects of cyto (OH)-O-center dot and mt (OH)-O-center dot in a bleomycin (BLM)-induced pulmonary fibrosis model. Treatment of BLM-induced pulmonary fibrosis mice with TA293 suppressed the induction of cellular senescence and fibrosis, as well as inflammation in the lung, but mitoTA293 exacerbated these. Furthermore, in BLM-stimulated primary alveolar epithelial cells, TA293 suppressed the activation of the p-ATM(ser1981)/p-p53(ser15)/p21, p-HRI/p-eIF2(ser51)/ATF4/p16, NLRP3 inflammasome/caspase-1/IL-1 beta/IL1R/p-p38 MAPK/p16, and p21 pathways and the induction of cellular senescence. However, mitoTA293 suppressed the induction of mitophagy, enhanced the activation of the NLRP3 inflammasome/caspase-1/IL1 beta/IL1R/p-p38 MAPK/p16 and p21 pathways, and exacerbated cellular senescence, inflammation, and fibrosis. Our findings may help develop new strategies to treat idiopathic pulmonary fibrosis.

Automated summary

TA293 can suppress cellular senescence, fibrosis, and inflammation in a bleomycin-induced pulmonary fibrosis model, while mitoTA293 can exacerbate these conditions. These findings may help in developing new strategies for treating idiopathic pulmonary fibrosis.