Oxycodone attenuates endotoxin-induced acute lung injury by regulating mitophagy via the HO-1 pathway

Endotoxin-induced Acute Lung Injury (ALI) is a severe clinical syndrome with limited treatment. Oxycodone can alleviate the endotoxin-induced ALI, but the exact mechanism remains unclear. The previous study showed that Heme Oxygenase-1 (HO-1) plays a protective role against endotoxin-induced ALI by regulating mitophagy. Thus, the authors aimed to elucidate whether oxycodone attenuates lung injury by regulating mitophagy via the HO-1 pathway. Lipopolysaccharide (LPS) ‒ stimulated mice and Mouse Lung Epithelial (MLE12) cells were used to create the model of ALI. After pre-treatment with Oxycodone for the LPS-induced model in vivo and in vitro, markers of cell and tissue damage, oxidative stress, inflammation, and mitophagy were detected. HO-1 knockout mice and HO-1 siRNA in vitro were used to further clarify the role of Oxycodone. Pre-treatment with oxycodone could alleviate lung pathological damage, reduce oxidative stress and inflammatory cytokines, increase the expression of HO-1 while down-regulate the mitophagy-related proteins (PINK1, Parkin, LC3 II/I). Furthermore, treatment with oxycodone in HO-1-knockout mice or HO-1 siRNA-transfected MLE12 cells revealed the protective role of the HO-1 pathway on oxycodone-mediated mitophagy in LPS-induced ALI. HO-1 deficiency partially counteracts the beneficial effects of oxycodone on pulmonary protection and inhibition of mitophagy both in vivo and in vitro. Oxycodone pretreatment attenuated LPS-induced systemic inflammation and subsequent lung injury by regulating mitophagy via the HO-1 pathway.