Toosendanin alleviates acute lung injury by reducing pulmonary vascular barrier dysfunction mediated by endoplasmic reticulum stress through mTOR

Xiaocheng Mao; Cheng Wang; Hong Tang; Xiaohua Liu; Caihui Wei; Fang Yin; Tianmei Fu; Yangyang Fang; Kuai Yu; Zhanglin Zhang; Chenggao Wu; Hongfei Liu; Aiping Le

doi:10.1016/j.phymed.2024.156277

Toosendanin alleviates acute lung injury by reducing pulmonary vascular barrier dysfunction mediated by endoplasmic reticulum stress through mTOR

Phytomedicine. 2024 Nov 24:136:156277. doi: 10.1016/j.phymed.2024.156277. Online ahead of print.

Authors

Xiaocheng Mao¹, Cheng Wang², Hong Tang¹, Xiaohua Liu¹, Caihui Wei¹, Fang Yin¹, Tianmei Fu¹, Yangyang Fang¹, Kuai Yu¹, Zhanglin Zhang¹, Chenggao Wu³, Hongfei Liu⁴, Aiping Le⁵

Affiliations

¹ Department of Blood Transfusion, Key Laboratory of Jiangxi Province for Transfusion Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, PR China.
² Department of Critical Care Medicine, Medical Center of Anesthesiology and Pain, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, PR China.
³ Department of Blood Transfusion, Key Laboratory of Jiangxi Province for Transfusion Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, PR China. Electronic address: ndyfy3382@ncu.edu.cn.
⁴ Department of Blood Transfusion, Key Laboratory of Jiangxi Province for Transfusion Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, PR China. Electronic address: 352428818018@email.ncu.edu.cn.
⁵ Department of Blood Transfusion, Key Laboratory of Jiangxi Province for Transfusion Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, PR China. Electronic address: ndyfy00973@ncu.edu.cn.

PMID: 39615214
DOI: 10.1016/j.phymed.2024.156277

Abstract

Background: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe clinical conditions with limited treatment options. Toosendanin (TSN), a triterpenoid compound with anti-inflammatory effects, has unclear efficacy in ALI.

Purpose: This study aimed to evaluate TSN's protective effects on ALI and the related mechanisms.

Methods: Lipopolysaccharide (LPS)-induced ALI models were developed in vivo and in vitro. Endothelial permeability was measured using Evans Blue dye; lipid reactive oxygen species (ROS) and apoptosis were assessed using flow cytometry. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were determined, and cell viability was measured. mRNA and protein expression were quantified using qRT-PCR and Western blotting. Network pharmacology and surface plasmon resonance were used to identify and validate TSN's targets.

Results: TSN reduced endothelial permeability and LPS-induced ALI. It lowered ROS levels, lipid peroxidation, endoplasmic reticulum (ER) stress, and apoptosis, both in vitro and in vivo. Network pharmacology identified mTOR as a key target of TSN, and surface plasmon resonance analysis confirmed TSN's direct binding to mTOR, underscoring mTOR's role in TSN's protective effects against ALI. Western blotting showed that TSN inhibits mTOR and its phosphorylation. In vitro, the mTOR activator MHY1485 reversed TSN's protective effects, increasing ER stress, apoptosis, and endothelial permeability. In vivo, TSN and rapamycin synergistically protected against ALI.

Conclusion: This study is the first to demonstrate that TSN protects against ALI by targeting the mTOR pathway, regulating ER stress and apoptosis and mitigating endothelial damage. These findings suggest a novel approach for ALI treatment and underscore TSN's potential clinical value.

Keywords: Acute lung injury; Endoplasmic reticulum stress; Endothelial cells; Toosendanin; mTOR.