REGULATION OF MACROPHAGE INTERLEUKIN-1 BETA PRODUCTION

最近的研究表明，脓毒症相关组织 伤害的发生可能在很大程度上是由于 内毒素对循环吞噬细胞和血管内皮细胞的作用。 目前的概念表明，内毒素的影响可能是介导的， 白细胞介素1（IL-1）和肿瘤坏死因子 （TNF）。 本申请建议从以下方面研究这一概念： 多视角。 首先，脓毒症和败血症患者- 诱导成人呼吸窘迫综合征（ARDS）和对照组 将评价其体内IL-1/TNF活化的证据。 生物流体和单核吞噬细胞 抗原酶联免疫测定和mRNA分析。 第二、 控制单核因子产生和释放的因素将是 评估。 这些研究将包括对 人体内毒素反应性的异质性， 内毒素受体密度和单核因子反应性 生产 他们还将研究IL-1的调节， 单核因子调节的发生模型，即，固有的 血单核细胞和肺泡巨噬细胞之间的差异， 单核因子释放 此外，抑制单核因子 将对行动进行详细评估。 评估将包括 天然存在的单核因子抑制剂的表征， 可能代表单核因子作用的蛋白质调节剂， 脓毒症诱导组织发育的有效调节剂 损伤 最后，敏感的mRNA探针将用于分析 人和动物组织的体内激活的证据， IL-1/TNF基因。 特别地，将制备脓毒症的动物模型。 用原位杂交技术定位单核因子的来源 生产 这些研究不仅可以澄清 可能导致脓毒症诱导的细胞机制 损伤，如ARDS，但也描绘了新的方式来修改和/或 预防内毒素血症造成的毁灭性后果。

Recent investigations have suggested that sepsis associated tissue injury may occur in large part as a result of the effects of endotoxin upon circulating phagocytes and vascular endothelium. Current concepts suggest that the endotoxin effects may be mediated by the monokines, interleukin 1 (IL-1) and tumor necrosis factor (TNF). This application proposes to study this concept from multiple perspectives. First, patients with sepsis and sepsis- induced adult respiratory distress syndrome (ARDS) and controls will be evaluated for evidence of IL-1/TNF activation in their biological fluids and mononuclear phagocytes using state of the art antigenic enzyme linked immunoassays and mRNA analysis. Second, factors that control monokine production and release will be evaluated. These studies will include a characterization of the heterogeneity in endotoxin responsiveness in humans as measured by endotoxin receptor density and by responsiveness for monokine production. They will also study IL-1 regulation in a naturally occurring model of monokine regulation, i.e., the inherent differences between blood monocytes and alveolar macrophages in monokine release. In addition, factors that inhibit monokine action will be evaluated in detail. This evaluation will include the characterization of natural occurring monokine inhibitors that may represent protein modulators of monokine action and hence potent modulators of the development of sepsis-induced tissue injury. Finally, sensitive mRNA probes will be used to analyze human and animal tissue for the evidence of in vivo activation of IL-1/TNF genes. In particular, an animal model of sepsis will be studied with in situ hybridization localize the origin of monokine production. Taken together these studies should not only clarify the cellular mechanisms that may predispose to sepsis-induced injury such as ARDS, but also delineate new ways to modify and/or prevent the devastating consequences that result from endotoxemia.