• Yuan Li, Hongguang Chen, Ruichen Shu, Xuan Zhang, Guiyue Wang, and Yiqing Yin.
• Department of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
• Shock. 2024 May 1; 61 (5): 766775766-775.

AbstractBackground: Sepsis is a type of life-threatening organ dysfunction that is caused by a dysregulated host response to infection. The lung is the most vulnerable target organ under septic conditions. Pulmonary microvascular endothelial cells (PMVECs) play a critical role in acute lung injury (ALI) caused by severe sepsis. The impairment of PMVECs during sepsis is a complex regulatory process involving multiple mechanisms, in which the imbalance of calcium (Ca 2+ ) homeostasis of endothelial cells is a key factor in its functional impairment. Our preliminary results indicated that hydrogen gas (H 2 ) treatment significantly alleviates lung injury in sepsis, protects PMVECs from hyperpermeability, and decreases the expression of plasma membrane stromal interaction molecule 1 (STIM1), but the underlying mechanism by which H 2 maintains Ca 2+ homeostasis in endothelial cells in septic models remains unclear. Thus, the purpose of the present study was to investigate the molecular mechanism of STIM1 and Ca 2+ release-activated Ca 2+ channel protein1 (Orai1) regulation by H 2 treatment and explore the effect of H 2 treatment on Ca 2+ homeostasis in lipopolysaccharide (LPS)-induced PMVECs and LPS-challenged mice. Methods: We observed the role of H 2 on LPS-induced ALI of mice in vivo . The lung wet/dry weight ratio, total protein in the bronchoalveolar lavage fluid, and Evans blue dye assay were used to evaluate the pulmonary endothelial barrier damage of LPS-challenged mice. The expression of STIM1 and Orai1 was also detected using epifluorescence microscopy. Moreover, we also investigated the role of H 2 -rich medium in regulating PMVECs under LPS treatment, which induced injury similar to sepsis in vitro . The expression of STIM1 and Orai1 as well as the Ca 2+ concentration in PMVECs was examined. Results:In vivo , we found that H 2 alleviated ALI of mice through decreasing lung wet/dry weight ratio, total protein in the bronchoalveolar lavage fluid and permeability of lung. In addition, H 2 also decreased the expression of STIM1 and Orai1 in pulmonary microvascular endothelium. In vitro , LPS treatment increased the expression levels of STIM1 and Orai1 in PMVECs, while H 2 reversed these changes. Furthermore, H 2 ameliorated Ca 2+ influx under sepsis-mimicking conditions. Treatment with the sarco/endoplasmic reticulum Ca 2+ adenosine triphosphatase inhibitor, thapsigargin, resulted in a significant reduction in cell viability as well as a reduction in the expression of junctional proteins, including vascular endothelial-cadherin and occludin. Treatment with the store-operated Ca 2+ entry inhibitor, YM-58483 (BTP2), increased the cell viability and expression of junctional proteins. Conclusions: The present study suggested that H 2 treatment alleviates LPS-induced PMVEC dysfunction by inhibiting store-operated Ca 2+ entry mediated by STIM1 and Orai1 in vitro and in vivo .Copyright © 2023 by the Shock Society.

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