Diepenhorst Gwendolyn M P, van Gulik Thomas M, Hack C Erik
Department of Surgery, Surgical Laboratory, Academic Medical Center, Amsterdam, the Netherlands.
Ann Surg. 2009 Jun;249(6):889-99. doi: 10.1097/SLA.0b013e3181a38f45.
Ischemia-reperfusion (I/R) injury provides a substantial limitation to further improvements in the development of therapeutic strategies for ischemia-related diseases. Studies in animal I/R models, including intestinal, hindlimb, kidney, and myocardial I/R models, have established a key role of the complement system in mediation of I/R injury using complement inhibitors and knock-out animal models. As complement activation has been shown to be an early event in I/R injury, inhibiting its activation or its components may offer tissue protection after reperfusion. However, clinical study results using complement inhibitors have largely been disappointing. Therefore, identification of a more specific pathogenic target for therapeutic intervention seems to be warranted. For this purpose more detailed knowledge of the responsible pathway of complement activation in I/R injury is required. Recent evidence from in vitro and in vivo models suggests involvement of both the classic and the lectin pathways in I/R injury via exposition of neo-epitopes in ischemic membranes. However, most of these findings have been obtained in knock-out murine models and have for a large part remained unconfirmed in the human setting. The observation that the relative role of each pathway seems to differ among organs complicates matters further. Whether a defective complement system protects from I/R injury in humans remains largely unknown. Most importantly, involvement of mannose-binding lectin as the main initiator of the lectin pathway has not been demonstrated at tissue level in human I/R injury to date. Thus, conclusions drawn from animal I/R studies should be extrapolated to the human setting with caution.
缺血再灌注（I/R）损伤严重限制了缺血相关疾病治疗策略的进一步发展。在动物I/R模型（包括肠道、后肢、肾脏和心肌I/R模型）中的研究，通过使用补体抑制剂和基因敲除动物模型，证实了补体系统在介导I/R损伤中起关键作用。由于补体激活已被证明是I/R损伤中的早期事件，抑制其激活或其成分可能在再灌注后提供组织保护。然而，使用补体抑制剂的临床研究结果大多令人失望。因此，确定一个更具特异性的治疗干预致病靶点似乎很有必要。为此，需要更详细地了解I/R损伤中补体激活的相关途径。来自体外和体内模型的最新证据表明，经典途径和凝集素途径均通过缺血细胞膜上新表位的暴露参与I/R损伤。然而，这些发现大多是在基因敲除小鼠模型中获得的，在很大程度上尚未在人体中得到证实。各途径的相对作用在不同器官中似乎有所不同，这一观察结果使情况更加复杂。补体系统缺陷是否能保护人类免受I/R损伤在很大程度上仍然未知。最重要的是，迄今为止，在人类I/R损伤的组织水平上，尚未证实甘露糖结合凝集素作为凝集素途径的主要启动子的参与情况。因此，从动物I/R研究得出的结论应谨慎地外推至人体情况。
