INFLAMMATORY RESPONSE OF THE LOCAL SHWARTZMAN REACTION

局部炎症构成了对感染的重要防御。 在一些 然而，在某些情况下，炎症反应本身可引起严重的局部和 全身性损伤，由宿主衍生的因素如免疫 复合物，或由微生物衍生的因子，如内毒素。 这种炎症的引发剂可能不会对患者产生影响。 它们不直接影响宿主的新陈代谢，也不对宿主组织有很高的毒性。 细菌内毒素在局部Shwartzman病发病中的作用 反应说明了这一原则。 内毒素似乎会引起 产生宿主因子，继而导致炎症。 炎症通路和特异性介质的鉴定将 有助于制定具体战略， 炎症的有害后遗症，如内毒素血症和休克。 此外，赋予内毒素敏感性的试剂可能是 一般炎症和重要的发病机制，许多人类 疾病 局部Shwartzman反应将被用于一种策略中，以描绘 一个潜在的调解人。 Hageman因子，一种丝氨酸蛋白酶， 可以启动导致趋化活性的蛋白水解途径， 补体激活和激肽形成。 内毒素可以激活哈格曼 因子 然而，Hageman因子在体内的作用尚不清楚。 本研究的目的是：1）完善方案， 在正常模型中诱导局部Shwartzman反应的时机; 2） 表征施用后随时间的炎性变化 正常和Hageman因子缺陷模型中的内毒素; 3） 测量Hageman因子和其他炎症成分的滴度， 4）纯化Hageman因子， 缺陷模型，有和没有针对hageman的抗体 因子; 5）在所述细胞中给予酵母聚糖活化的血清或免疫沉淀物， 正态和亏损模型; 6）在一个非完全的 或白细胞减少正常和Hageman因子缺陷模型。 最近 开发了特异性针对30 KD的单克隆抗体 片段和Hageman因子的50 KD片段将用于测量 Hageman因子可能在血浆中被激活， 受伤的组织部位

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.