REGULATION OF MACROPHAGE INTERLEUKIN-1 BETA PRODUCTION

最近的研究表明，脓毒症相关组织 伤害可能在很大程度上是由于以下因素造成的 内毒素对循环吞噬细胞和血管内皮的影响。 目前的概念表明，内毒素的影响可能是由 由单因子、白介素1和肿瘤坏死因子 (肿瘤坏死因子)。此应用程序建议从 多角度的。首先，脓毒症和脓毒症患者- 成人诱发呼吸窘迫综合征(ARDS)及其对照 将被评估是否有IL-1/肿瘤坏死因子激活的证据 使用最新技术的生物液和单核巨噬细胞 抗原性酶联免疫分析和信使核糖核酸分析。第二, 控制单核细胞产生和释放的因素将是 已评估。这些研究将包括对 人类内毒素反应性的异质性 内毒素受体密度与单核细胞反应性的关系 制作。他们还将研究IL-1的自然调节 单核细胞调节的发生模式，即固有的 外周血单核细胞与肺泡巨噬细胞的差异 单核细胞释放。此外，抑制单核细胞因子 将对行动进行详细评估。这项评估将包括 天然产生的单核细胞因子抑制剂的特征 可能代表单核因子作用的蛋白质调节剂，因此 脓毒症诱导组织发育的强效调节剂 受伤。最后，敏感的mrna探针将用于分析 人和动物组织中活体激活的证据 IL-1/肿瘤坏死因子基因。特别是，败血症的动物模型将是 原位杂交法定位单核细胞来源的研究 制作。总而言之，这些研究不仅应该澄清 脓毒症诱发的细胞机制 伤害，例如ARDS，但也描述了修改和/或 预防内毒素血症造成的破坏性后果。

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.