Inhibition of apoptosis induced by ischemia-reperfusion prevents inflammation
Inhibition of apoptosis induced by ischemia-reperfusion prevents inflammation
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DOI：
10.1172/jci6974
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发表时间：
1999-09-01
影响因子：
15.9
通讯作者：
Buurman, WA
中科院分区：
文献类型：
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作者：
Daemen, MARC;van't Veer, C;Buurman, WA
缺血再灌注导致严重的器官损伤和功能障碍。炎症被认为是器官缺血后组织损伤的最重要原因。缺血后引发炎症和器官损伤的机制仍有待阐明，尽管已经假设了不同的原因。我们研究了细胞凋亡在肾缺血后炎症和器官损伤诱导中的作用。通过小鼠模型，我们证明了细胞凋亡与随后的炎症之间的关系。在再灌注时，给予抗凋亡药物IGF-1和zad -fmk（一种caspase灭活剂），不仅可以预防肾细胞凋亡的早期发生，还可以预防炎症和组织损伤。相反，当抗凋亡药物在细胞凋亡发生后给药时，这些保护作用完全消失。凋亡的存在与内皮单核细胞活化多肽II （EMAP-II）的翻译后加工直接相关，这可能解释了再灌注肾脏中凋亡诱导的白细胞内流和隔离。这些结果强烈表明，细胞凋亡是一个关键事件，可以启动再灌注诱导的炎症和随后的组织损伤。新描述的病理生理学见解为有效预防肾脏和其他器官再灌注损伤的临床表现提供了重要机会。
Ischemia followed by reperfusion leads to severe organ injury and dysfunction. Inflammation is considered to be the most important cause of tissue injury in organs subjected to ischemia. The mechanism that triggers inflammation and organ injury after ischemia remains to be elucidated, although different causes have been postulated. We investigated the role of apoptosis in the induction of inflammation and organ damage after renal ischemia. Using a murine model, we demonstrate a relationship between apoptosis and subsequent inflammation. At the time of reperfusion, administration of the antiapoptotic agents IGF-1 and ZVAD-fmk (a caspase inactivator) prevented the early onset of not only renal apoptosis, but also inflammation and tissue injury. Conversely, when the antiapoptotic agents were administered after onset of apoptosis, these protective effects were completely abrogated. The presence of apoptosis was directly correlated with posttranslational processing of the endothelial monocyte-activating polypeptide II (EMAP-II), which may explain apoptosis-induced influx and sequestration of leukocytes in the reperfused kidney. These results strongly suggest that apoptosis is a crucial event that can initiate reperfusion-induced inflammation and subsequent tissue injury. The newly described pathophysiological insights provide important opportunities to effectively prevent clinical manifestations of reperfusion injury in the kidney, and potentially in other organs.