USP18 mitigates lipopolysaccharide-induced oxidative stress and inflammation in human pulmonary microvascular endothelial cells through the TLR4/NF-κB/ROS signaling

As a type I interferon response gene, ubiquitin-specific protease 18 (USP18) has been shown to be widely involved in oxidative stress and immune regulation processes. However, the relationship between USP18 and acute lung injury (ALI) is unclear. This study aimed to analyze the role of USP18 in the pathogenesis of ALI. Lipopolysaccharide (LPS) treatment up-regulated the expression of USP18 mRNA and protein in human pulmonary microvascular endothelial cells (hPMVECs). USP18 overexpression increased the viability of LPS-induced hPMVECs, and reduced LPS-induced cell damage. Additionally, USP overexpression increased the activity of SOD and CAT, and reduced the production of NO and MDA in LPS-induced hPMVECs. Moreover, overexpression of USP18 inhibited the secretion of IL-1 beta, IL-6, TNF-alpha, and IL-18 in LPS-induced hPMVECs. USP18 overexpression restrained LPS-induced upregulation of TLR4 and the excessive phosphorylation of p65 and I kappa B alpha, as well as the production of reactive oxygen species (ROS). TLR4 agonist MPLA attenuated the inhibitory effect of USP18 overexpression on LPS-induced oxidative stress and inflammation in hPMVECs. In addition, USP18 ameliorated LPS induced ALI in vivo. In conclusion, USP18 may resist LPS-induced oxidative stress and inflammatory response in hPMVECs by inhibiting the TLR4/NF-kappa B/ROS signaling pathway, which may provide new and complementary strategies for ALI treatment.