C5 CONVERTASE AND AMPLIFICATION OF LUNG INFLAMMATION

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The purpose of this study is to gain new insights into one of the amplification pathways that is pivotal in induction and perpetuation of acute pulmonary inflammatory reactions resulting in chronic inflammatory lung disease. Using established immunochemical techniques and novel approaches we plan to study the C3 dependent C5 cleaving activity present within the alveoli of normal hamster lungs. This activity will be purified from cell free supernatants of Bronchoalveolar lavage fluid. Its immunobiological, molecular and functional characteristics for interaction with C5 will be studied. Using specific antibodies and immunodetection systems, its constituent complement components will be identified. Collectively, the results obtained will help identify this C5 convertase and to determine if it is analogous to known C5 convertases of the complement system. Using therapeutic agents such as promidine isothiocyanate we will determine if intrapulmonary C5 convertase mediated C5 cleaving could be prevented. Using C14-amino acids and isolated lung cells (alveolar macrophages and alveolar Type II alveolar epithelial cells) we shall investigate whether its constituent complement components could be synthesized within the lung, thus providing an efficient means for the intrapulmonary assembly of the convertase. C5 convertase cleaves C5 specifically by limited proteolysis, thus the process of C5 chemotactic factor generation is very efficient. We shall investigate whether synthesis of C5 by the lung cells can be modulated via immunobiological feedback mechanism by presence of proinflammatory fragments of C3 and C5. Synthesis and release of C5 within the lung in conjunction with normally present C5 convertase is likely to generate chemotactic factors, induce PMN influx and thus initiate acute inflammation. An increase or continued release of C5 is thus likely to result in amplification or perpetuation of acute inflammatory reactions. By rigorous and careful analysis of the investigations we hope to gain new information regarding nature of C5 cleaving activity and C5 synthesis, could thus affecting C5 mediated amplification of inflammation in the lung. Such information will have direct application towards developing new diagnostic and therapeutic modalities for treatment and prevention of chronic and debilitating inflammatory diseases.