The Role of Complement in the Pathogenesis of Emphysema

补体在肺气肿发病机制中的作用

基本信息

批准号：
7783443
负责人：
Carl Atkinson
金额：
$ 36.88万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7783443
关键词：
Acute Address Affect Alternative Complement Pathway Alveolar Alveolar wall Anaphylatoxins Animals Anti-Inflammatory Agents Anti-inflammatory Breathing C5a anaphylatoxin receptor Cause of Death Cell Adhesion Molecules Cells Cessation of life Chronic Cigarette Clinical Clinical Research Complement Complement 3a Complement 3d Receptors Complement 5a Complement Activation Complement Inactivators Complement Membrane Attack Complex Complement Receptor Complex Data Deposition Development Disease Disease Progression Effector Cell Elastases Epithelial Cells Family suidae Foundations Generations Health Care Costs IL8 gene Immune Immune system Immunity Immunosuppression In Vitro Individual Inflammation Inflammatory Inflammatory Infiltrate Injury Interleukin-6 Investigation Irrigation Knockout Mice Lead Lectin Leukotriene B4 Ligands Link Liquid substance Lung Lung Inflammation Maps Mediator of activation protein Modeling Mus Nature Opsonin Pancreatic Elastase Pathogenesis Pathway interactions Patients Peptide Hydrolases Peptides Play Process Production Protease Inhibitor Proteins Pulmonary Emphysema Relative (related person)Respiratory Failure Role Serum Signal Pathway Site Smoking Structure System Therapeutic Tissues Treatment Efficacy Tumor Necrosis Factor-alpha Up-Regulation Work activation product alpha 1-Antitrypsin alveolar type II cell base cell motility chemokine cigarette smoking clinically relevant complement deficiency complement pathway complement system cytokine disability early onset human TNF protein immune function in vivo inhibitor/antagonist lung injury macrophage neutrophil novel premature prevent public health relevance receptor reconstitution research study response smoke inhalation smoking cessation stem

项目摘要

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.

描述（由申请人提供）：肺气肿发展的最重要因素是吸入香烟烟雾。肺气肿的发病机理很复杂，但是当前持有的假设描述了炎性细胞衍生的蛋白酶与肺的抗蛋白水解防御之间的不平衡。炎症细胞的涌入归因于许多信号通路，包括但不限于IL-8，IL-6和TNF-alpha。肺中存在的最有效的过敏毒素也许是C3A和C5A，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，但是系统过多或不适当的激活会导致直接组织损伤，并且通过产生C3A和C5A，过度炎症。体外和体内研究表明，香烟烟雾和弹性酶，肺气肿的主要介体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。具体而言，我们假设通过弹性和香烟烟雾激活补体途径，导致肺气肿的肺部炎症和发育。我们进一步假设补体效应蛋白的产生在激活后，例如C3 opsonins，补体过敏毒素，以及膜攻击复合物的形成直接促进肺部炎症，并促进肺损伤和肺气肿。我们建议利用两种模型的肺气肿，弹性酶和香烟暴露模型。我们建议对这些模型应用的补体缺乏/抑制策略将提供免受炎症和伤害的保护，并防止肺气肿。具体目的是：1）确定与肺气肿发病机理有关的补体激活和效应机制。补体激活产物会影响炎症过程，从而导致组织损伤并促进炎症。在利用缺乏补体蛋白质的小鼠的研究中，将研究特定补体效应分子在引起炎症，组织损伤和肺气肿引起炎症，组织损伤和肺气肿的作用。 2）确定补体抑制蛋白对肺气肿的治疗的疗效。对于临床治疗相关性，补体抑制对肺气肿发病的影响将通过与肺气肿的弹性酶模型一起使用新型补体抑制剂进行研究。 3）确定在肺气肿的慢性香烟烟雾暴露模型中补体抑制作用的影响。在此目标中，我们将研究补体抑制对肺部炎症，损伤和肺气肿的发展的影响，该模型在临床上是相关的，并将与肺气肿相关的慢性炎症绘制。公共卫生相关性：肺气肿是一种炎症性疾病，预计将成为第三常见的死亡原因，并在医疗保健费用方面造成了巨大负担。当前的抗炎疗法几乎没有疗效，并且该疾病的发展尚未减弱。这里提出的研究将研究先天免疫系统的新型靶向抑制剂的治疗功效，以抑制炎症并防止破坏性的肺损伤，这是肺气肿的标志。