The Role of Complement in the Pathogenesis of Emphysema

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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.