NecroX Improves PHMG-induced Lung Injury by Regulating Mitochondrial Oxidative Stress and ER Stress.

Various environmental compounds are inducers of lung injury. Mitochondria are crucial organelles that can be impacted by many lung diseases. NecroX is an indole-derived antioxidant that specifically targets mitochondria. We aimed to evaluate therapeutic potential and related molecular mechanisms of NecroX in preclinical models of fatal lung injury. We investigated the therapeutic effects of NecroX on two different experimental models of lung injury induced by polyhexamethylene guanidine (PHMG) and bleomycin, respectively. We also performed transcriptome analysis of lung tissues from PHMG-exposed mice and compared the expression profiles with those from dozens of bleomycin-induced fibrosis public datasets. Respiratory exposure to PHMG and bleomycin led to fatal lung injury manifesting extensive inflammation followed by fibrosis. These specifically impacted mitochondria in regard to biogenesis, mitochondrial DNA integrity, and generation of mitochondrial reactive oxygen species in various cell types. NecroX significantly improved the pathobiologic features of the PHMG- and bleomycin-induced lung injuries through regulation of mitochondrial oxidative stress. Endoplasmic reticulum (ER) stress was also implicated in PHMG-associated lung injuries of mice and human, and NecroX improved PHMG-induced lung injury and the subsequent fibrosis, in part, via regulation of ER stress in mice. Gene expression profiles of PHMG-exposed mice were highly consistent with public datasets of bleomycin-induced lung injury models. Pathways related to mitochondrial activities, including oxidative stress, oxidative phosphorylation and mitochondrial translation were up-regulated and these patterns were significantly reversed by NecroX. These findings demonstrate that NecroX possesses therapeutic potential in fatal lung injury of humans.