Inhibition of Neogenin Dampens Hepatic Ischemia-Reperfusion Injury
Inhibition of Neogenin Dampens Hepatic Ischemia-Reperfusion Injury
复制标题
DOI：
10.1097/ccm.0000000000000485
复制
发表时间：
2014-09
影响因子：
8.8
通讯作者：
Martin Schlegel;T. Granja;S. Kaiser;Andreas Körner;J. Henes;K. König;A. Straub;P. Rosenberger;V. Mirakaj
中科院分区：
文献类型：
--
作者：
Martin Schlegel;T. Granja;S. Kaiser;Andreas Körner;J. Henes;K. König;A. Straub;P. Rosenberger;V. Mirakaj
目的：肝缺血再灌注损伤是肝移植、失血性休克或肝脏大手术后发病率和死亡率的常见原因。基于显示神经系统外的神经元引导受体再生蛋白（Neo 1）在急性炎症期间介导组织适应中的关键作用的研究，我们假设Neo 1增强肝脏缺血和再灌注损伤。设计：动物实验。单位：高校实验室。受试者：野生型、再生蛋白缺陷和嵌合小鼠。干预：再生蛋白表达进行了评估，在体外炎症刺激过程中，在体内缺血和再灌注损伤，活体显微镜进行研究血管内流动特性。肝损伤程度采用组织学、血清乳酸脱氢酶、天冬氨酸和丙氨酸转氨酶水平进行评价。在具有再生蛋白基因靶向抑制（Neo 1-/-）的小鼠、骨髓嵌合动物和对照中评价Neo 1在肝脏IR期间的功能作用。此外，使用抗体注射进行再生蛋白的功能抑制。测量和主要结果：我们观察到体外炎症和体内缺血和再灌注期间Neo 1的诱导。活体显微镜检查表明，炎症期间Neo 1 −/−白细胞附着于内皮血管壁的能力降低。随后在Neo 1 −/−小鼠中的研究显示，在肝缺血和再灌注损伤期间，乳酸脱氢酶、天冬氨酸、丙氨酸和促炎细胞因子的血清水平降低。这与肝脏组织学评分改善相关。在嵌合体动物中的研究表明，造血Neo 1表达对于观察到的结果至关重要。用抗Neo 1抗体治疗导致实验性肝缺血和再灌注损伤显著减少，涉及乳酸脱氢酶、丙氨酸、天冬氨酸和细胞因子水平的衰减变量。结论：这些数据提供了一个独特的作用，Neo 1在肝脏缺血和再灌注损伤的发展，并确定Neo 1作为一个潜在的目标，以防止肝功能障碍的未来。
Objective:Liver ischemia and reperfusion injury is a common source of significant morbidity and mortality following liver transplantation, hemorrhagic shock, or major hepatic surgery. Based on studies showing a critical role for the neuronal guidance receptor neogenin (Neo1) outside the nervous system in mediating tissue adaption during acute inflammation, we hypothesized that Neo1 enhances hepatic ischemia and reperfusion injury. Design:Animal study. Setting:University-based experimental laboratory. Subjects:Wid-type, neogenin deficient and chimeric mice. Interventions:Neogenin expression was evaluated during inflammatory stimulation in vitro and during ischemia and reperfusion injury in vivo, intravital microscopy performed to study intravascular flow characteristics. The extent of liver injury was evaluated using histology, serum levels of lactate dehydrogenase, aspartate, and alanine aminotransferase. The functional role of Neo1 during liver IR was evaluated in mice with gene targeted repression of neogenin (Neo1-/-), bone marrow chimeric animals and controls. In addition, functional inhibition of neogenin was performed using antibody injection. Measurements and Main Results:We observed an induction of Neo1 during inflammation in vitro and ischemia and reperfusion in vivo. Intravital microscopy demonstrated a decreased ability of Neo1−/− leukocytes to attach to endothelial vascular wall during inflammation. Subsequent studies in Neo1−/− mice showed attenuated serum levels of lactate dehydrogenase, aspartate, alanine, and proinflammatory cytokines during hepatic ischemia and reperfusion injury. This was associated with improved hepatic histology scores. Studies in chimeric animals demonstrated that the hematopoietic Neo1 expression to be crucial for the observed results. Treatment with an anti-Neo1 antibody resulted in a significant reduction of experimental hepatic ischemia and reperfusion injury, involving attenuated variable of lactate dehydrogenase, alanine, aspartate, and cytokine levels. Conclusions:These data provide a unique role for Neo1 in the development of hepatic ischemia and reperfusion injury and identified Neo1 as a potential target to prevent liver dysfunction in the future.