Colistin-induced pulmonary toxicity involves the activation of NOX4/TGF-β/mtROS pathway and the inhibition of Akt/mTOR pathway

Colistin therapy can cause pulmonary toxicity, however, our understanding of the underlying molecular mechanism remains incomplete. This study aimed to investigate the molecular mechanism of colistin-induced pulmonary toxicity in vitro and in vivo. Our results showed that intraperitoneal colistin treatment significantly increased the expression of TGF-β and NOX4 protein and mRNA, then triggers oxidative stress, mitochondrial dysfunction, and apoptosis in the lung tissue of mice and A549 cells. Moreover, colistin treatment significantly increased levels of mitochondrial ROS (mtROS) and autophagy flux in A549 cells. Inhibition of NOX4 protected A549 cells against colistin-induced mtROS and apoptosis. Colistin treatment also down-regulated the expression of p-Akt and p-mTOR proteins (all P