HORMONE AND CYTOKINE REGULATION OF ENDOTOXIN INJURY

虽然进行性多系统器官衰竭(MOF)对 遭受严重伤害或感染的患者比例， 这种病态疾病背后的机制(S)在很大程度上仍不清楚。 巨噬细胞/单核细胞和多形核细胞的调节失调 中性粒细胞(PMN)功能，包括细胞表面肿瘤坏死因子受体持续减少 活动是MOF和死亡率的常见前兆。肿瘤坏死因子结扎术 受体和/或相关的Fas受体(Fas)可能沉淀 细胞程序性死亡(细胞凋亡)，但内毒素和几个亲 炎性细胞因子蛋白可延缓巨噬细胞/单核细胞和中性粒细胞 细胞凋亡。这表明，正常的调节失调 巨噬细胞/单核细胞和中性粒细胞凋亡可能是一种统一的机制 未能解决多器官功能衰竭患者持续的炎性后遗症。 与T淋巴细胞活性改变有关，并与 应激诱导的激素改变肿瘤坏死因子和Fas配体(FasL) 表达，我们认为损伤和感染的激素环境 也影响人类巨噬细胞/单核细胞和中性粒细胞的凋亡。这个 上述问题将通过评估人类内毒素血症来解决 巨噬细胞/单核细胞和PMN细胞因子受体(包括Fas)的表达， 特异性炎性配体的调节和受体的调节 和抗凋亡蛋白(Bcl2)的表达(特异靶I)。这两个 体内这些过程的正常时间序列及其调控 这类事件的反调节激素(特定目标2)将是 下定决心。对这些细胞反应进行生物修饰的努力将 用粒细胞/单核细胞集落刺激因子(GM- 恢复免疫功能低下患者的细胞因子受体 (具体目标3)。这些回答将与三分之一的回答形成对比 前瞻性评估高危患者人群，包括严重 感染、多发创伤和烧伤(具体目标4) 恢复期患者与进展期患者的区别 器官和免疫系统功能障碍也将被寻求。

While progressive multi-system organ failure (MOF) afflicts a significant proportion of patients sustaining severe injury or infection, the mechanism(s) underlying this morbid condition remains largely undefined. Dysregulation of both macrophage/monocyte and polymorphonuclear cell (PMN) function, including persistently reduced cell surface TNF receptor activity are frequent premonitors of MOF and mortality. Ligation of TNF receptors and/or the related Fas receptor (Fas) may precipitate programmed cell death (apoptosis), yet endotoxin and several pro- inflammatory cytokine proteins may delay both macrophage/monocyte and PMN apoptosis. This suggests that dysregulation of normal macrophage/monocyte and PMN apoptosis may represent a unifying mechanism for the failure to resolve ongoing inflammatory sequalae in MOF patients. In association with altered T lymphocyte activity, and the capacity of stress-induced hormones to alter both TNF and Fas ligand (FasL) expression, we propose that the hormonal milieu of injury and infection also influences apoptosis of macrophage/monocyte and PMNs in humans. The above issues will be addressed in human endotoxinemia by assessment of macrophage/monocyte and PMN cytokine receptor (including Fas) expression, modulation by specific inflammatory ligands, and regulation of receptor and anti-apoptotic protein (bcl-2) expression (Specific Aim I). Both the normal temporal sequence of these processes in vivo and the modulation of such events by counter-regulatory hormones (Specific Aim 2) will be determined. Efforts to biologically modify these cellular responses will be undertaken with granulocyte/monocyte colony stimulating factor (GM- CSF) which restores cell cytokine receptors in immunocompromised patients (Specific Aim 3). These responses will be contrasted to those in three prospectively assessed high-risk patient populations, including severe infection, poly-trauma, and burn injury (Specific Aim 4) where differences between recovering patients or those with progressive solid organ and immune system dysfunction will also be sought.