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

## TL;DR

Oxycodone reduces lung damage from endotoxins by influencing a protective pathway involving HO-1 and mitophagy.

## Contribution

The study reveals that oxycodone protects against lung injury by modulating mitophagy through the HO-1 pathway.

## Key findings

- Oxycodone pretreatment reduces lung injury and inflammation in LPS-induced models.
- HO-1 deficiency diminishes oxycodone's protective effects on mitophagy and lung damage.
- Oxycodone increases HO-1 expression while decreasing mitophagy-related proteins like PINK1 and Parkin.

## Abstract

•Oxycodone alleviated the LPS-driven lung pathological injury both in vivo and in vitro.•Oxycodone pretreatment attenuated LPS-induced systemic inflammation and subsequent lung injury.•Oxycodone increases the expression of HO-1 while downregulating the mitophagy-related proteins.•HO-1 deficiency weakens the effect of oxycodone on the expression of mitophagy-related proteins.•Oxycodone attenuates LPS-induced cell injury by regulating mitophagy via the HO-1 pathway.

Oxycodone alleviated the LPS-driven lung pathological injury both in vivo and in vitro.

Oxycodone pretreatment attenuated LPS-induced systemic inflammation and subsequent lung injury.

Oxycodone increases the expression of HO-1 while downregulating the mitophagy-related proteins.

HO-1 deficiency weakens the effect of oxycodone on the expression of mitophagy-related proteins.

Oxycodone attenuates LPS-induced cell 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.