Characterization of complement activation in cutaneous ischemia-reperfusion (CI/R) injury, the role of MBL and C1q in Cl/R, and the mechanism of CI/R related injury

短暂性缺血后血流恢复后的组织损伤被称为缺血再灌注（I/R）损伤。皮肤缺血再灌注（Cl/R）损伤是多种情况下常见的临床问题：慢性伤口，例如糖尿病足溃疡、动脉粥样硬化性溃疡、压疮和静脉淤积伤口，以及烧伤伤口和重建手术中的游离组织转移。补体激活在I/R相关的局部和远处组织损伤中起重要作用。目前已知三种不同的补体途径，即经典途径、凝集素途径和替代途径。虽然不同的补体通路在不同器官系统（心脏、肾脏、肝脏、肠道、肌肉）的I/R损伤中的作用已被彻底研究，但补体通路在人体最大器官皮肤的I/R损伤中的作用尚不清楚。在小鼠Cl/R模型中，使用缺乏C1q（经典途径抑制）或甘露糖结合凝集素（MBL；凝集素途径抑制）或两种途径下游效应蛋白的小鼠，我建议确定实验性Cl/R后导致组织破坏的事件。在本提案中，我将研究Cl/R后补体系统的作用，特别是MBL与C1q（即凝集素与经典途径）的作用以及Cl/R后MBL和/或C1q依赖性损伤的机制。我还打算确定小鼠补体成分C5和C3a以及天然抗体在Cl/R损伤中的作用。在确定了Cl/R的主要启动途径后，我计划研究这一途径在糖尿病Cl/R损伤中的作用。

Tissue injury following restoration of blood flow after transient ischemia is known as ischemia-reperfusion (I/R) injury. Cutaneous ischemia-reperfusion (Cl/R) injury is a common clinical problem in multiple settings: chronic wounds, for example diabetic foot ulcers, atherosclerotic ulcers, pressure ulcers and venous stasis wounds, in addition to burn wounds and free tissue transfer in reconstructive surgery. Complement activation plays an important role in local and remote tissue injury associated with I/R. Three different complement pathways, the classical, lectin and alternative pathway, have been recognized. While the involvement of the different complement pathways in I/R injury of various organ systems (heart, kidneys, liver, gut, muscle) has been thoroughly investigated, the role of the complement pathways in I/R injury of the skin, the largest organ of the body, is not known. In a mouse model of Cl/R and using mice deficient in either C1q (inhibition of the classical pathway) or mannose binding lectin (MBL; inhibition of the lectin pathway), or effector proteins downstream of both pathways, I propose to identify the events leading to tissue destruction following experimental Cl/R. In this proposal, I will investigate the role of the complement system following Cl/R, specifically the role of MBL vs. C1q (i.e. lectin vs. classical pathway) and the mechanisms of MBL- and/or C1q dependent injury following Cl/R. I also intend to determine the role of the mouse complement components C5 and C3a and the role of natural antibodies in Cl/R injury. After identifying the major initiating pathway(s) in Cl/R, I plan to investigate the role of this (these) pathway(s) in diabetic Cl/R injury.