Zhang Ning, Chen Tangbing, Chang Yintao, Cao Mingzhi, Wang Huan, Wu Chengli, Jiang Hong
Department of Thoracic Surgery, 905th Hospital of People's Liberation Army Navy, Naval Medical University, Shanghai, China.
Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Genes Immun. 2025 Sep 24. doi: 10.1038/s41435-025-00355-1.
Acute lung injury (ALI) is a common and life-threatening lung disease. This study investigated the mechanism by which dexmedetomidine (Dex) alleviates lipopolysaccharide (LPS)-induced ALI, focusing on its regulation of macrophage autophagy and polarization. Initially, a mouse model of LPS-induced ALI was pretreated with Dex. Pulmonary function, histopathological changes, apoptosis, macrophage numbers in bronchoalveolar lavage fluid (BALF), M1/M2 macrophage ratios, iNOS/Arg-1/LC3/P62 fluorescence intensity, and autophagy flux were assessed. Subsequently, RAW264.7 macrophages were treated with LPS and Dex, transfected with si-ACOD1 or si-HIF-1α, and co-cultured with mouse pulmonary microvessel endothelial cells (MPMVECs). The results showed that Dex relieved autophagy flux blockage and promoted autophagy in ALI mice. LPS promoted ACOD1 and HIF-1α levels, and Dex further enhanced their levels to boost macrophage autophagy and M2 polarization. ACOD1 was transcriptionally regulated by HIF-1α. Collectively, Dex mitigated LPS-induced MPMVEC injury and ALI by enhancing HIF-1α-mediated ACOD1 transcription, thus promoting macrophage autophagy and M2 polarization.
急性肺损伤（ALI）是一种常见且危及生命的肺部疾病。本研究探讨了右美托咪定（Dex）减轻脂多糖（LPS）诱导的ALI的机制，重点关注其对巨噬细胞自噬和极化的调节作用。首先，用Dex预处理LPS诱导的ALI小鼠模型。评估肺功能、组织病理学变化、细胞凋亡、支气管肺泡灌洗液（BALF）中的巨噬细胞数量、M1/M2巨噬细胞比例、诱导型一氧化氮合酶（iNOS）/精氨酸酶-1（Arg-1）/微管相关蛋白1轻链3（LC3）/p62荧光强度以及自噬通量。随后，用LPS和Dex处理RAW264.7巨噬细胞，用小干扰RNA（si）-ACOD1或si-HIF-1α转染，并与小鼠肺微血管内皮细胞（MPMVECs）共培养。结果表明，Dex减轻了ALI小鼠的自噬通量阻滞并促进了自噬。LPS促进了ACOD1和HIF-1α水平，而Dex进一步提高了它们的水平以促进巨噬细胞自噬和M2极化。ACOD1受HIF-1α转录调控。总之，Dex通过增强HIF-1α介导的ACOD1转录减轻LPS诱导的MPMVEC损伤和ALI，从而促进巨噬细胞自噬和M2极化。
