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  3. Activating Sig-1R inhibits microvascular permeability by reducing LRRK2 expression in lipopolysaccharide-induced acute lung injury

Activating Sig-1R inhibits microvascular permeability by reducing LRRK2 expression in lipopolysaccharide-induced acute lung injury

  • Free Radic Biol Med. 2025 Jan:226:96-108. doi: 10.1016/j.freeradbiomed.2024.11.015.
Bo Lin 1,  Yuying Li 2,  Yi Yao 3,  Binmei Yu 1,  Peng Ke 4,  Tingjie Wang 1,  Weihuang Qiu 1,  Lijun Weng 1,  Menglu Shi 2,  Cailing Guo 2,  Zhongqing Chen 3,  Zhenhua Zeng 3,  Xiang Wang 5,  Xianzhong Lin 6,  Tao Li 7,  Youguang Gao 8
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Anesthesiology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China; Department of Anesthesiology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China.
  • 2 Department of Anesthesiology, Anesthesiology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
  • 3 Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • 4 Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China.
  • 5 Department of Critical Care Medicine, The First People's Hospital of Chenzhou, The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China.
  • 6 Department of Anesthesiology, Anesthesiology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China; Department of Anesthesiology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China. Electronic address: lxzysj@fjmu.edu.cn.
  • 7 Department of Critical Care Medicine, The First People's Hospital of Chenzhou, The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China. Electronic address: litao.7@163.com.
  • 8 Department of Anesthesiology, Anesthesiology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China; Department of Anesthesiology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China. Electronic address: gaoyouguang259@fjmu.edu.cn.
PMID: 39542184 DOI: 10.1016/j.freeradbiomed.2024.11.015
Abstract

Background: Endothelial cells are the first and most damaged target cells during acute lung injury (ALI). Endothelial dysfunction increases pulmonary microvascular permeability, subsequently leading to pulmonary oedema and organ dysfunction; however, clinical treatments against microvascular permeability show poor efficacy. Herein, we aimed to explore the role of the Sigma-1 receptor (Sig-1R) in pulmonary microvascular permeability by constructing ALI animal and cell models, and further investigated the specific mechanisms.

Methods: The effects of Sig-1R on lung injury and endothelial barrier disruption were examined in lipopolysaccharide (LPS)-induced mice and human umbilical vein endothelial cells (HUVECs), respectively. Transcriptome Sequencing was carried out to identify possible targets of Sig-1R, and the specific mechanisms of Sig-1R action were investigated using RNA interference and plasmid transfection.

Results: Analysis of a Gene expression omnibus dataset suggested that Sig-1R plays a protective role against vascular hyperpermeability in ALI. Downregulation of Sig-1R expression and endothelial barrier disruption were both observed in mice and HUVECs upon LPS stimulation. Sig-1R agonists attenuated vascular hyperpermeability in vivo and in vitro, further improving ALI. Sig-1R activation downregulated Leucine-rich repeat kinase 2 (LRRK2) expression in mice and HUVECs. LRRK2 knockdown ameliorated endothelial barrier disruption in mice and HUVECs. Overexpression of LRRK2 reversed the protective effect of Sig-1R activation on LPS-induced endothelial hyperpermeability. Furthermore, Sig1r knockdown exacerbated LPS-induced microvascular hyperpermeability, which was rescued by inhibition of LRRK2.

Conclusions: Sig-1R activation exerts a protective effect against LPS-induced microvascular hyperpermeability by downregulating LRRK2 expression, which could lead to the development of novel therapeutic strategies for treating ALI.

Keywords

Acute lung injury; Apoptosis; Inflammation; LRRK2; Sigma-1 receptor; Vascular permeability.

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