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

Bo Lin; Yuying Li; Yi Yao; Binmei Yu; Peng Ke; Tingjie Wang; Weihuang Qiu; Lijun Weng; Menglu Shi; Cailing Guo; Zhongqing Chen; Zhenhua Zeng; Xiang Wang; Xianzhong Lin; Tao Li; Youguang Gao

doi:10.1016/j.freeradbiomed.2024.11.015

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

Free Radic Biol Med. 2024 Nov 12:226:96-108. doi: 10.1016/j.freeradbiomed.2024.11.015. Online ahead of print.

Authors

Bo Lin¹, Yuying Li², Yi Yao³, Binmei Yu¹, Peng Ke⁴, Tingjie Wang¹, Weihuang Qiu¹, Lijun Weng¹, Menglu Shi², Cailing Guo², Zhongqing Chen³, Zhenhua Zeng³, Xiang Wang⁵, Xianzhong Lin⁶, Tao Li⁷, Youguang Gao⁸

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.