INFLAMMATORY RESPONSE OF THE LOCAL SHWARTZMAN REACTION

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Local inflammation constitutes an important defense to infection. In some cases, however, the inflammatory reaction itself can cause severe local and systemic injury, either initiated by host-derived factors such as immune complexes, or by factors derived from microorganisms, such as endotoxin. The initiators of such inflammation may not exert their effects on the host's metabolism directly, nor may they be highly toxic to host tissues. The role of bacterial endotoxin in the pathogenesis of the local Shwartzman reaction illustrates this principle. Endotoxin appears to elicit the production of host factors which in turn result in inflammation. Identification of inflammatory pathways and specific mediators would contribute to the design of specific strategies to arrest the development of harmful sequelae to inflammation, such as endotoxemia and shock. Moreover, the agents conferring endotoxin sensitivity may be mediators of general inflammation and important in the pathogenesis of many human diseases. The local Shwartzman reaction will be used in a strategy to delineate the role of one such potential mediator. Hageman factor, a serine protease, can initiate proteolytic pathways which result in chemotactic activity, complement activation, and kinin formation. Endotoxin can activate Hageman factor. However, the in vivo contribution of Hageman factor is unclear. The objectives of this investigation are: 1) To refine the protocol and timing to induce a local Shwartzman reaction in a normal model; 2) To characterize the inflammatory changes over time after administration of endotoxin in the normal and in a Hageman factor-deficient model; 3) To measure titers of Hageman factor and other inflammatory components in tissue and in plasma; 4) To give purified Hageman factor in the normal and deficient model, with and without antibodies directed against hageman factor; 5) To give zymosan-activated serum or immune precipitates in the normal and deficient model; and 6) To test the system in a decomplemented or leukopenic normal and Hageman factor-deficient model. Recently developed monoclonal antibodies specifically directed against the 30 KD fragment and the 50 KD fragments of Hageman factor will be used to measure directly for Hageman factor that may have been activated in plasma and at the injured tissue site.