The Role of Complement in the Pathogenesis of Emphysema

描述（由申请人提供）：肺气肿发生的最重要因素是吸入香烟烟雾。肺气肿的发病机制是复杂的，但目前持有的假说描述了炎症细胞衍生的蛋白酶和肺的抗蛋白水解防御之间的不平衡。炎性细胞的流入归因于许多信号传导途径，包括但不限于IL-8、IL-6和TNF-α。肺中最有效的过敏毒素可能是C3 a和C5 a，补体激活后产生的补体裂解片段。补体系统在宿主免疫中起关键作用，但该系统的过度或不适当激活可导致直接组织损伤，并通过产生C3 a和C5 a导致过度炎症。体外和体内研究表明，香烟烟雾和弹性蛋白酶，肺气肿的关键介质，可以诱导补体成分的激活和裂解。我们的工作假设是补体效应机制在肺气肿的发展中起作用。具体来说，我们假设弹性蛋白酶和香烟烟雾激活补体旁路途径，导致肺部炎症和肺气肿的发展。我们进一步假设，补体效应蛋白的产生，在激活后，如C3调理素，补体过敏毒素，和膜攻击复合物的形成直接促进肺部炎症，并在这样做促进肺损伤和肺气肿。我们建议利用两种模型的肺气肿，弹性蛋白酶和香烟暴露模型。我们提出，补体缺乏/抑制策略应用于这些模型将提供保护，免受炎症和损伤，并防止肺气肿。具体目标是：1）确定参与肺气肿发病机制的补体激活和效应机制。补体激活产物会影响炎症过程，导致组织损伤并促进炎症。将在利用补体蛋白缺陷小鼠的研究中研究特异性补体效应分子在引起炎症、组织损伤和肺气肿中的作用。2)确定补体抑制蛋白治疗肺气肿的疗效。对于临床治疗相关性，将通过利用与肺气肿的弹性蛋白酶模型一致的新型补体抑制剂来研究补体抑制对肺气肿发病机制的影响。3)确定补体抑制在慢性香烟烟雾暴露肺气肿模型中的作用。在这个目标中，我们将研究补体抑制对肺部炎症、损伤和慢性烟雾吸入导致的肺气肿发展的影响，这是一种临床相关的模型，并绘制了与肺气肿相关的慢性炎症。

DESCRIPTION (provided by applicant): The single most important factor in the development of emphysema is cigarette smoke inhalation. The pathogenesis of emphysema is complex, but the currently held hypothesis describes an imbalance between inflammatory cell derived proteases and the antiproteolytic defenses of the lung. The influx of inflammatory cells has been attributed to a number of signaling pathways including, but not limited to, IL-8, IL-6 and TNF-alpha. Perhaps the most potent anaphylatoxins present in the lung are C3a and C5a, complement cleavage fragments produced following complement activation. The complement system plays a key role in host immunity, but excessive or inappropriate activation of the system can lead to direct tissue injury and, via the production of C3a and C5a, excessive inflammation. In vitro and in vivo studies have shown that cigarette smoke and elastases, key mediators of emphysema, can induce activation and cleavage of complement components. Our working hypothesis is that complement effector mechanisms play a role in the development of emphysema. Specifically, we hypothesize that activation of the alternative pathway of complement, by elastases and cigarette smoke, leads to lung inflammation and development of emphysema. We further hypothesize that the production of complement effector proteins, upon activation, such as C3 opsonins, complement anaphylatoxins, and formation of the membrane attack complex directly promote lung inflammation and in doing so promote lung injury and emphysema. We propose to utilize two models of emphysema, the elastase and cigarette exposure models. We propose that complement deficiency/inhibitory strategies applied to these models will provide protection from inflammation and injury, and prevent emphysema. Specific aims are: 1) Determine complement activation and effector mechanism(s) involved in pathogenesis of emphysema. Complement activation products can affect inflammatory processes, causing tissue damage and promoting inflammation. The role of specific complement effector molecules in causing inflammation, tissue damage and emphysema will be investigated in studies utilizing mice deficient in complement proteins. 2) Determine the efficacy of complement inhibitory proteins for therapy of emphysema. For clinical therapeutic relevance, the effect of complement inhibition on the pathogenesis of emphysema will be investigated by utilizing novel complement inhibitors in concert with elastase model of emphysema. 3) Determine the effect of complement inhibition in a chronic cigarette smoke exposure model of emphysema. In this aim, we will investigate the effect of complement inhibition on lung inflammation, injury and the development of emphysema resulting from chronic smoke inhalation, a model that is clinically relevant and maps the chronic inflammation associated with emphysema.