Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Resuscitation. 2011 Mar;82(3):335-40. doi: 10.1016/j.resuscitation.2010.11.007. Epub 2010 Dec 18.
Ondansetron is a 5-HT3 receptor antagonist with potent antiemetic, analgesic, and antiphlogistic effects. Recent evidence suggests that the co-existence of 5-HT3 receptors in various cell types is involved in inflammation. However, the effects that 5-HT3 antagonists produce in haemorrhagic shock and resuscitation remain unknown. In this study, we hypothesized that ondansetron administration in male rats, after haemorrhagic shock, decreases cytokine production and protects against hepatic injury through a p38 mitogen-activated protein kinase (MAPK) pathway.
Male Sprague-Dawley rats underwent haemorrhagic shock (mean arterial blood pressure 40 mm Hg for 90 min), followed by resuscitation. Various doses of ondansetron (0.1, 0.3, 1, 3 mg kg(-1)) or a single dose of ondansetron (1 mg kg(-1)) with or without a p38 MAPK inhibitor (SB-203580, 2 mg kg(-1)) or vehicle were administered intravenously during resuscitation. Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations and various liver proinflammatory parameters were measured at 24h after resuscitation.
Results show that haemorrhagic shock increases plasma AST and ALT concentrations, hepatic myeloperoxidase activity, cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-3, intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) levels. These parameters were significantly improved in the ondansetron-treated rats subjected to haemorrhagic shock. Ondansetron treatment restored phos-p38 MAPK expression as compared with vehicle-treated haemorrhaged rats. Coadministration of SB-203580 prevented the beneficial effects of ondansetron on postresuscitation proinflammatory responses and hepatic injury.
Ondansetron attenuates hepatic injury following haemorrhagic shock, which is, at least in part, to be due to its anti-inflammatory effect via p38 MAPK signal pathway.
昂丹司琼是一种 5-HT3 受体拮抗剂，具有强大的止吐、镇痛和抗炎作用。最近的证据表明，各种细胞类型中 5-HT3 受体的共存与炎症有关。然而，5-HT3 拮抗剂在失血性休克和复苏中的作用尚不清楚。在这项研究中，我们假设在雄性大鼠失血性休克后给予昂丹司琼，通过 p38 丝裂原活化蛋白激酶（MAPK）途径减少细胞因子的产生并防止肝损伤。
雄性 Sprague-Dawley 大鼠经历失血性休克（平均动脉血压 40mmHg 持续 90min），然后复苏。在复苏期间，给予不同剂量的昂丹司琼（0.1、0.3、1、3mg/kg）或单次剂量的昂丹司琼（1mg/kg），并伴有或不伴有 p38 MAPK 抑制剂（SB-203580，2mg/kg）或载体。在复苏后 24h 测量血浆天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）浓度和各种肝前炎症参数。
结果表明，失血性休克增加了血浆 AST 和 ALT 浓度、肝髓过氧化物酶活性、细胞因子诱导的中性粒细胞趋化因子（CINC）-1、CINC-3、细胞间黏附分子-1（ICAM-1）、白细胞介素-6（IL-6）和肿瘤坏死因子α（TNF-α）水平。这些参数在接受昂丹司琼治疗的失血性休克大鼠中得到了显著改善。与接受载体治疗的失血性大鼠相比，昂丹司琼治疗恢复了磷酸化 p38MAPK 的表达。SB-203580 的共同给药阻止了昂丹司琼对再灌注后前炎症反应和肝损伤的有益作用。
昂丹司琼减轻失血性休克后的肝损伤，至少部分原因是通过 p38 MAPK 信号通路发挥抗炎作用。
