Abstract

Objective: Heat stroke (HS) elicits the systemic inflammatory responses that result in multiple organ dysfunction (MOD). Heat shock response and autophagy are activated during heat stress for removal of damaged organelles and proteins, emerging as a major regulator of cellular homeostasis. Ethyl pyruvate (EP) is a derivative of pyruvic acid and possesses antioxidant and anti-inflammatory effects. This study aims to investigate the effects of EP on MOD in HS rats and explore the possible mechanisms.

Method: Anesthetized rats were placed in a heating chamber (42 °C) to elevate the core body temperature attaining to 42.9 °C. Rats were then moved to room temperature and monitored for 6 h. EP (60 mg/kg, i.v.) was administered 30 min prior to heat exposure.

Results: Results showed that EP significantly reduced HS-induced increases in plasma levels of LDH, CPK, GPT and CK-MB, reversed the decrease of platelet counts, and alleviated intestinal mucosal and pulmonary damage. Moreover, EP reduced pro-inflammatory protein, including TNF-α, IL-6, IL-1β, HMGB1 and iNOS, and induced stress proteins, heme oxygenase-1 (HO-1), heat shock protein (HSP) 70 and HSP90 in the liver of HS rats. The levels of HS-activated autophagy-regulatory proteins were affected by EP, in which the phosphorylated mTOR and AKT were reduced, and the phosphorylated AMPK increased, accompanied with upregulation in ULK1, Atg7, Atg12 and LC3II, and downregulation of p62.

Conclusion: In conclusion, EP ameliorated HS-induced inflammatory responses and MOD, and the underlying mechanism is associated with the induction of the stress proteins HO-1 and HSP70 as well as restorage of autophagy.

摘要

目的：中暑（HS）引发全身炎症反应，导致多器官功能障碍（MOD）。热激反应和自噬在热应激期间被激活，以去除受损的细胞器和蛋白质，成为细胞稳态的主要调节剂。丙酮酸乙酯 (EP) 是丙酮酸的衍生物，具有抗氧化和抗炎作用。本研究旨在探讨EP对HS大鼠MOD的影响并探讨其可能的机制。

方法：将麻醉大鼠置于加热室（42℃）中，使核心体温升高至42.9℃。然后将大鼠移至室温并监测 6 小时。EP (60 mg/kg, iv) 在热暴露前 30 分钟给药。

结果：结果表明，EP 显着降低了 HS 诱导的血浆 LDH、CPK、GPT 和 CK-MB 水平的升高，逆转了血小板计数的下降，并减轻了肠粘膜和肺损伤。此外，EP 减少促炎蛋白，包括 TNF-α、IL-6、IL-1β、HMGB1 和 iNOS，以及诱导应激蛋白、血红素加氧酶-1 (HO-1)、热休克蛋白 (HSP) 70 和 HSP90在 HS 大鼠的肝脏中。HS 激活的自噬调节蛋白水平受 EP 影响，其中磷酸化 mTOR 和 AKT 降低，磷酸化 AMPK 增加，伴随 ULK1、Atg7、Atg12 和 LC3II 的上调和 p62 的下调。

结论：总之，EP可改善HS诱导的炎症反应和MOD，其潜在机制与应激蛋白HO-1和HSP70的诱导以及自噬的恢复有关。