Contribution of the separate complement pathways for outcome and negative effects on innate immune functions during sepsis

根据美国和德国的估计，败血症每年造成的死亡人数可能超过急性心肌梗死。然而，导致临床定义的脓毒症症状的潜在病理生理机制尚不清楚。最近的出版物揭示了补体分裂产物C5a在败血症期间负责有害影响的重要作用。补体激活可以通过不同的机制发生，激活三种已知的独立途径。补体激活的终点总是包括强效炎性C5a和终端膜攻击复合物（MAC）的形成。C5a会引发免疫能态细胞胞内信号的显著变化，导致急性炎症反应（Ü2自由基产生等）。然而，在脓毒症期间，C5a的不受控制的激活将导致这种免疫功能的关闭。到目前为止，导致脓毒症期间C5a形成的不同补体途径的触发因素和贡献尚不清楚。该项目的目标是确定3个单独的补体途径对败血症期间补体激活的有害影响的贡献。用抗体或拮抗剂特异性阻断主要补体通路的可能性代表了一种潜在的预防策略，可以用于脓毒症高风险患者，并将在稍后的人类研究中基于概述的拟议研究结果进行研究。

According to estimates in the USA and Germany, sepsis may account for more deaths per year than acute myocardial infarction. Yet, the underlying pathophysiological mechanisms leading to the clinically defined symptoms of sepsis are poorly understood. Recent publications have revealed an important role of the complement split product C5a being responsible for harmful effects during sepsis. Complement activation can occur through different mechanisms activating three known separate pathways. The end point of complement activation always involves formation of the potent inflammatory C5a and the terminal membrane attack complex (MAC). C5a will trigger significant changes in intracellular signaling of immune competent cells leading to acute inflammatory responses (Ü2 radical production etc.). However, activation of C5a in an uncontrolled manner during sepsis will lead to a shut down of such immune functions. Until now the triggers and the contribution of the separate complement pathways leading to formation of C5a during sepsis are not known in detail. The goal of this project is to define the contribution of the 3 separate complement pathways for harmful effects of complement activation during sepsis. The possibility to specifically block the main contributing complement pathway with antibodies or antagonists represents a potential preventive strategy for patients at high risk of developing sepsis and will be investigated later in humans based on the results of the outlined proposed studies.