Dexmedetomidine protects against acute lung injury in mice via the DUSP1/MAPK/NF-κB axis by inhibiting miR-152-3p.

Abstract

Acute lung injury (ALI) is a debilitating condition in clinics. Dexmedetomidine (Dex) is known for its anti-apoptotic and anti-inflammatory properties. This study attempted to investigate the protective mechanism of Dex in ALI mice. Mice were pretreated with Dex before model establishment by tracheal injection of lipopolysaccharide (LPS). Pulmonary function indexes and wet-to-dry (W/D) ratio were measured. Pulmonary pathological changes were observed through HE staining, CD31+-positive mouse pulmonary microvascular endothelial cells (MPMVECs) were counted through immunofluorescence staining, and apoptosis was detected through TUNEL staining. miR-152-3p mimic, sh-DUSP1, or p38 MAPK inhibitor was delivered into MPMVECs, followed by combined treatment of Dex and LPS. miR-152-3p expression, apoptosis, levels of apoptosis- and MAPK/NF-κB pathway-associated proteins, and inflammatory factors were measured through RT-qPCR, flow cytometry, Western blot, and ELISA. The binding relationship of miR-152-3p and DUSP1 was verified through bioinformatics software and dual-luciferase assay. ALI mouse model was established after injection of miR-152-3p antagomir. Dex improved ALI mouse pulmonary function and mitigated injury in mice and MPMVECs. miR-125-3p overexpression or sh-DUSP1 partially abolished the protection of Dex on MPMVECs. miR-152-3p targeted DUSP1. sh-DUSP1 partially averted the protection of Dex on MPMVECs. Dex inhibited the activation of the MAPK/NF-κB pathway in MPMVECs mediated by LPS, which was partially reversed by sh-DUSP1. The p38 MAPK inhibitor SB203580 antagonized the protective effect of Dex on MPMVECs mediated by sh-DUSP1. Similarly, downregulation of miR-152-3p mitigated ALI via the DUSP1/MAPK/NF-κB axis in vivo. Dex relieved ALI in mice via the DUSP1/MAPK/NF-κB axis by down-regulating miR-152-3p.