Role of NADPH oxidase-derived superoxide in reduced size liver ischemia and reperfusion injury
Role of NADPH oxidase-derived superoxide in reduced size liver ischemia and reperfusion injury
复制标题
DOI：
10.1016/j.abb.2003.08.035
复制
发表时间：
2004-03-01
影响因子：
3.9
通讯作者：
Grisham, MB
中科院分区：
文献类型：
--
作者：
Harada, H;Hines, IN;Grisham, MB
肝切除伴随缺血和再灌注（I/R）期是进行减体积肝移植（如劈离肝或肝供体移植）所必需的。虽然使用这些类型的手术已经取得了很大的进展，但供体和受体仍然存在很大的风险，大量患者发生肝损伤和肝衰竭。本研究的目的是评估超氧化物（O-2（-））和肿瘤坏死因子-α（TNF-α）在缩小肝脏合并缺血和再灌注（RSL + I/R）小鼠模型的病理生理学中的作用。我们发现，所有接受RSL + I/R的雄性小鼠在手术后3-5天内死亡。死亡率总是在肝损伤和TNF-α（在没有中性粒细胞浸润的情况下表达）急剧增加之前。使用长寿命的聚阳离子形式的人锰超氧化物歧化酶（pcMnSOD）、NADPH氧化酶缺陷小鼠（gp 91（-/-））或针对小鼠TNF-α的单克隆抗体，我们证明肝细胞损伤（和死亡率）显著减弱。此外，我们发现pcMnSOD管理或NADPH缺乏减少TNF-α的表达。总之，我们的数据表明，NADPH氧化酶衍生的O-2（-）通过其增强TNF-α表达的能力在RSL + I/R诱导的肝损伤的病理生理学中起重要作用。我们认为，针对清除O-2（-）抑制NADPH氧化酶和/或免疫中和TNF-α的治疗可能有助于限制需要切除和I/R的外科手术（如劈肝或活体肝移植）引起的肝损伤。(C)2003年由Elsevier Inc.出版
Hepatic resection with concomitant periods of ischemia and reperfusion (I/R) is required to perform reduced size liver transplantation such as split liver or liver donor transplantation. Although great progress has been made using these types of surgeries, there remains substantial risk to both donors and recipients, with a significant number of patients developing liver injury and failure. The objective of this study was to assess the roles of superoxide (O-2(-)) and tumor necrosis factor-alpha (TNF-alpha) in the pathophysiology of a mouse model of reduced size liver combined with ischemia and reperfusion (RSL + I/R). We found that all male mice subjected to RSL + I/R died within 3-5 days following surgery. Mortality was always preceded by dramatic increases in liver injury and TNF-alpha( expression in the absence of neutrophil infiltration. Using a long-lived, polycationic form of human manganese superoxide dismutase (pcMnSOD), NADPH oxidase-deficient mice (gp91(-/-)) or a monoclonal antibody directed against mouse TNF-alpha, we demonstrated that hepatocellular injury (and mortality) were significantly attenuated. In addition, we found that pcMnSOD administration or NADPH deficiency reduced expression of TNF-alpha. Taken together, our data suggest that NADPH oxidase-derived O-2(-) plays an important role in the pathophysiology of RSL + I/R-induced liver injury via its ability to enhance expression of TNF-alpha. We propose that therapies directed toward scavenging of O-2(-) inhibiting NADPH oxidase, and/or immuno-neutralizing TNF-alpha may prove useful in limiting the liver injury induced by surgical procedures that require resection and I/R such as split liver or living donor liver transplantation. (C) 2003 Published by Elsevier Inc.