Xiaowei Zhou, Liyong Zou, Haoyue Deng, Yuanqun Zhou, Yue Wu, Xingnan Ouyang, Liangming Liu, Li Wang,* Tao Li* 

Department of Shock and Transfusion, Army Medical Center of Army Medical University, Chongqing, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Li Wang; Tao Li, Department of Shock and Transfusion, Army Medical Center of Army Medical University, Chongqing, People’s Republic of China, Email wangli8134@163.com; lt200132@tmmu.edu.cn

Purpose: Cold seawater immersion aggravates hemorrhagic shock-induced homeostasis imbalance and organ dysfunction, leading to increased mortality. Previous studies have shown that treatments targeting oxidative stress and mitochondrial dysfunction have limited efficacy for cold seawater immersion combined with hemorrhagic shock (SIHS). Thus, the mechanisms responsible for SIHS need further investigation.
Methods and Results: Data from the hemorrhagic shock transcriptome and cold seawater immersion targets used for bioinformatics analysis revealed the involvement of endoplasmic reticulum stress (ERS) in SIHS occurrence and progression. Based on these findings, the effects and possible mechanism of inhibiting ERS in SIHS rats were investigated. SIHS causes a lethal triad and impairment of vital organ function, leading to death. Compared to lactated Ringer’s solution, the ERS inhibitor 4-phenylbutyric acid (PBA)significantly ameliorated acidosis and coagulopathy and protected vital organ function while prolonging survival and the golden treatment time. Through target screening and validation, 7 targets were identified for the ERS inhibitor PBA for the treatment of SIHS, among which S1PR1, MMP8 and CFTR may play more important roles.
Conclusion: ERS plays a crucial role in the progression of SIHS. Inhibition of ERS caused by SIHS alleviates the lethal triad, protects organ function, and prolongs survival and the golden treatment time. The ERS inhibitor PBA may be an effective therapeutic measure for treating SIHS.

Keywords: cold seawater immersion, hemorrhagic shock, lethal triad, organ function, ER stress, 4-phenylbutyric acid