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Dexmedetomidine relieves LPS-induced acute lung injury by boosting HIF-1a/ACOD1 driven anti-inflammatory macrophage polarization

Genes & Immunity volume 26, pages 561–576 (2025)Cite this article

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Abstract

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.

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Fig. 1: Dex improved pulmonary function and attenuated pathological lung injury in mice with ALI.
Fig. 2: Dex encouraged alveolar macrophage M2 polarization and autophagy in ALI mice.
Fig. 3: Dex hastened RAW264.7 cell autophagy and M2 polarization by increasing ACOD1.
Fig. 4: Dex intensified macrophage M2 polarization by up-regulating ACOD1 to expedite autophagy.
Fig. 5: Dex advanced M2 polarization and autophagy by raising HIF-1α expression to fortify ACOD1 transcriptional expression.
Fig. 6: Dex redounded macrophage M2 polarization and autophagy via HIF-1α/ACOD1 to ease LPS-induced MPMVEC cell injury.
Fig. 7: Dex alleviated LPS-induced ALI by promoting autophagy and M2 polarization of alveolar macrophages via ACOD1.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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  1. These authors contributed equally: Ning Zhang, Tangbing Chen, Yintao Chang.

Authors and Affiliations

  1. Department of Thoracic Surgery, 905th Hospital of People’s Liberation Army Navy, Naval Medical University, Shanghai, China

    Ning Zhang, Mingzhi Cao, Huan Wang & Hong Jiang

  2. Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Tangbing Chen

  3. Department of Thoracic Surgery, Changzheng Hospital, Naval Medical University, Shanghai, China

    Yintao Chang

  4. Department of Oncology, 905th Hospital of People’s Liberation Army Navy, Naval Medical University, Shanghai, China

    Chengli Wu

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Contributions

Guarantor of integrity of the entire study: Hong Jiang; study concepts: Chengli Wu; study design: Hong Jiang; definition of intellectual content: Chengli Wu; literature research: Mingzhi Cao, and Ning Zhang; experimental studies: Tangbing Chen, and Huan Wang; data acquisition: Tangbing Chen; data analysis: Yintao Chang; statistical analysis: Yintao Chang; manuscript preparation: Ning Zhang; manuscript editing: Ning Zhang; manuscript review: Hong Jiang.

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Correspondence to Chengli Wu or Hong Jiang.

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Zhang, N., Chen, T., Chang, Y. et al. Dexmedetomidine relieves LPS-induced acute lung injury by boosting HIF-1a/ACOD1 driven anti-inflammatory macrophage polarization. Genes Immun 26, 561–576 (2025). https://doi.org/10.1038/s41435-025-00355-1

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