The Role of Complement in the Pathogenesis of Emphysema

描述(由申请人提供)：在肺气肿的发展中，最重要的一个因素是吸入香烟烟雾。肺气肿的发病机制很复杂，但目前持有的假说描述了炎症细胞衍生的蛋白水解酶和肺的抗蛋白分解防御之间的失衡。炎症细胞的大量涌入被归因于许多信号通路，包括但不限于IL-8、IL-6和肿瘤坏死因子-α。也许肺中存在的最强的过敏毒素是C3a和C5a，这是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着关键作用，但该系统过度或不适当的激活可导致直接的组织损伤，并通过产生C3a和C5a而导致过度炎症。体外和体内研究表明，香烟烟雾和弹力酶是肺气肿的关键介质，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生发展中起作用。具体地说，我们假设弹性蛋白酶和香烟烟雾激活补体的替代途径，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，在激活时，如C3调色素，补体过敏毒素，以及膜攻击复合体的形成，直接促进肺部炎症，从而促进肺损伤和肺气肿。我们建议使用两种肺气肿模型，弹性酶模型和香烟暴露模型。我们认为，补体缺乏/抑制策略应用于这些模型将提供炎症和损伤的保护，并防止肺气肿。具体目标为：1)明确补体活化及其效应机制(S)参与肺气肿的发病机制。补体激活产物可以影响炎症过程，导致组织损伤和促进炎症。特定补体效应分子在引起炎症、组织损伤和肺气肿中的作用将在利用补体蛋白缺陷小鼠的研究中进行调查。2)测定补体抑制蛋白治疗肺气肿的疗效。在临床治疗方面，将利用新型补体抑制剂与肺气肿弹性酶模型相结合，研究补体抑制在肺气肿发病机制中的作用。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。为此，我们将研究补体抑制对慢性烟雾吸入所致肺部炎症、损伤和肺气肿发展的影响，这是一种具有临床相关性并映射与肺气肿相关的慢性炎症的模型。 公共卫生相关性：肺气肿是一种炎症性疾病，预计将成为第三大最常见的死亡原因，并在医疗保健成本方面造成巨大负担。目前的抗炎疗法收效甚微，而且病情发展有增无减。这里提出的研究将调查新型靶向先天免疫系统抑制剂的治疗效果，目的是抑制炎症和防止破坏性肺损伤，这是肺气肿的标志。

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. PUBLIC HEALTH RELEVANCE: Emphysema is an inflammatory disease, which is predicted to become the third commonest cause of death, and presents a huge burden in terms of health care costs. Current anti-inflammatory therapies have little efficacy, and the disease progresses unabated. The studies proposed here will investigate the therapeutic efficacy of novel targeted inhibitors of the innate immune system, with the aim to inhibit inflammation and prevent the destructive lung damage, which is the hallmark of emphysema.