Sevoflurane alleviates intestinal ischemia–reperfusion injury in aged mice

Cai, Yujing¹; Wu, Yanan¹; Guo, Zhimin¹; Ye, Yingxian¹; Zhu, Yi¹; Wen, Lanqi¹; Li, Haifeng¹; Han, Xue²;Chen, Daili^3,*;Duan, Xuefei^1,*1,*

¹Department of Anesthesiology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong Province, China

²Department of Anesthesiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China

³Department of Anesthesiology, Shenzhen Maternity & Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, Guangdong Province, China

Abstract

Sevoflurane is a widely used inhalation anesthetic during the perioperative period. Recent studies have suggested that sevoflurane has an enteroprotective effect, but its mechanism is unclear. To explore the mechanism of sevoflurane in intestinal ischemia‒reperfusion injury, an intestinal ischemia‒reperfusion injury mouse model was established. First, intestinal ischemia‒reperfusion injury was compared between aged and young mice. The results showed that intestinal ischemia‒reperfusion injury caused pathological intestinal injury and disrupted the intestinal mucosal barrier. The aged mice had more severe intestinal ischemia‒reperfusion injury than the young mice and therefore had a lower survival rate. The aged mice subsequently received sevoflurane via inhalation. Sevoflurane alleviated the pathological injury to the intestinal mucosa and repaired the function of the intestinal mucosal barrier in aged mice, thus increasing the level of intestinal mucosal hypoxia-inducible factor-1α and improving the survival rate of aged mice. However, preoperative administration of the hypoxia-inducible factor-1α inhibitor BAY87-2243 could counteract the enteroprotective effect of sevoflurane and lower the expression level of heme oxygenase-1, a downstream antioxidant enzyme of hypoxia-inducible factor-1α. Our findings suggest that sevoflurane alleviates intestinal ischemia‒reperfusion injury in aged mice by repairing the intestinal mucosal barrier through the activation of hypoxia-inducible factor-1α/heme oxygenase-1, providing a new target for the treatment of intestinal ischemia‒reperfusion injury in aged mice.

七氟醚是围手术期广泛使用的吸入麻醉剂。最新研究表明其具有肠道保护作用，但具体机制尚不明确。为探究七氟醚对肠缺血再灌注损伤的作用机制，本研究建立肠缺血再灌注损伤小鼠模型。

研究首先对比了老年鼠与年轻鼠的肠缺血再灌注损伤差异，结果显示：
1）肠缺血再灌注损伤可导致肠道病理性损伤和肠黏膜屏障破坏；
2）老年鼠损伤程度较年轻鼠更严重，生存率更低。

后续对老年鼠实施七氟醚吸入干预发现：
1）七氟醚能减轻老年鼠肠黏膜病理损伤，修复肠黏膜屏障功能；
2）其作用机制与提升肠黏膜缺氧诱导因子-1α（HIF-1α）水平相关，并显著提高老年鼠生存率；
3）术前给予HIF-1α抑制剂BAY87-2243可抵消七氟醚的肠道保护作用，并降低其下游抗氧化酶血红素加氧酶-1（HO-1）的表达水平。

本研究揭示：七氟醚通过激活HIF-1α/HO-1通路修复肠黏膜屏障，从而缓解老年鼠肠缺血再灌注损伤，为老年群体肠缺血再灌注损伤治疗提供了新靶点。