Gao Yifei, Zhang Haojie, Wang Yujin, Han Ting, Jin Jing, Li Jingxin, Tang Yan, Liu Chuanyong
Department of Physiology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China.
Department of Gastroenterology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China.
Front Pharmacol. 2022 Jun 8;13:899169. doi: 10.3389/fphar.2022.899169. eCollection 2022.
Ischemia/reperfusion injury is a common pathophysiological process in the clinic. It causes various injuries, multiple organ dysfunction, and even death. There are several possible mechanisms about ischemia/reperfusion injury, but the influence on intestinal myenteric neurons and the underlying mechanism are still unclear. C57BL6/J mice were used to establish the ischemia/reperfusion model . Peritoneal macrophages were used for ATP depletion and hypoxia/reoxygenation experiment . L-cysteine, as the substrate of hydrogen sulfide, is involved in many physiological and pathological processes, including inflammation, metabolism, neuroprotection, and vasodilation. In the current study, we confirmed that intestinal ischemia/reperfusion led to the injury of myenteric neurons. From experiments and , we demonstrated that L-cysteine protected myenteric neurons from the injury. AOAA reversed the protective effect of L-cysteine. Also, L-cysteine played a protective role mainly by acting on intestinal macrophages via decreasing the expression of NLRP3, cleaved caspase-1, and mature IL-1β. L-cysteine increased cystathionine beta synthase and HS produced by intestinal macrophages to protect myenteric mature neurons and enteric neural precursor cells from apoptosis. Moreover, the addition of IL-1β-neutralizing antibody alleviated the injury of myenteric neurons and enteric neural precursor cells caused by intestinal ischemia/reperfusion. Our study provided a new target for the protection of myenteric neurons in clinical intestinal ischemia/reperfusion injury.
缺血/再灌注损伤是临床上常见的病理生理过程。它会导致各种损伤、多器官功能障碍甚至死亡。关于缺血/再灌注损伤有几种可能的机制，但对肠肌间神经元的影响及其潜在机制仍不清楚。采用C57BL6/J小鼠建立缺血/再灌注模型。使用腹腔巨噬细胞进行ATP耗竭和缺氧/复氧实验。L-半胱氨酸作为硫化氢的底物，参与许多生理和病理过程，包括炎症、代谢、神经保护和血管舒张。在本研究中，我们证实肠缺血/再灌注导致肌间神经元损伤。从实验 和 中，我们证明L-半胱氨酸可保护肌间神经元免受损伤。氨基氧乙酸（AOAA）逆转了L-半胱氨酸的保护作用。此外，L-半胱氨酸主要通过作用于肠道巨噬细胞，降低NLRP3、裂解的半胱天冬酶-1和成熟白细胞介素-1β的表达发挥保护作用。L-半胱氨酸增加肠道巨噬细胞产生的胱硫醚β合酶和硫化氢，以保护肌间成熟神经元和肠神经前体细胞免于凋亡。此外，添加白细胞介素-1β中和抗体可减轻肠缺血/再灌注引起的肌间神经元和肠神经前体细胞损伤。我们的研究为临床肠缺血/再灌注损伤中保护肌间神经元提供了新的靶点。
