HORMONE AND CYTOKINE REGULATION OF ENDOTOXIN INJURY

虽然进行性多系统器官衰竭（MOF）是一个重要的疾病， 严重受伤或感染的病人比例， 这种病态的潜在机制在很大程度上仍不明确。 巨噬细胞/单核细胞和多形核细胞调节异常 (PMN)功能，包括持续降低细胞表面TNF受体 活动是MOF和死亡率的常见预警。 TNF的连接 受体和/或相关的Fas受体（Fas）可沉淀 程序性细胞死亡（凋亡），但内毒素和几个前 炎性细胞因子蛋白可延迟巨噬细胞/单核细胞和PMN 凋亡 这表明，正常的神经系统功能失调， 巨噬细胞/单核细胞和中性粒细胞凋亡可能是一个统一的机制 对于未能解决正在进行的炎症后遗症在多器官功能衰竭患者。 与改变的T淋巴细胞活性，以及 应激诱导激素改变TNF和Fas配体（FasL） 表达，我们认为，损伤和感染的激素环境 还影响人类巨噬细胞/单核细胞和PMN的凋亡。 的 上述问题将在人内毒素血症中通过评估 巨噬细胞/单核细胞和PMN细胞因子受体（包括Fas）表达， 通过特异性炎症配体的调节和受体的调节 和抗凋亡蛋白（bcl-2）表达（特异性目的I）。 两者 这些过程在体内的正常时间顺序和调制 这些事件的反调节激素（具体目标2）将是 测定 生物修饰这些细胞反应的努力将 用粒细胞/单核细胞集落刺激因子（GM- CSF），其在免疫受损患者中恢复细胞因子受体 （具体目标3）。 这些反应将与三个反应进行对比。 前瞻性评估的高风险患者人群，包括重度 感染、多发性创伤和烧伤（具体目标4）， 恢复期患者或进展性实体瘤患者之间的差异 也将寻求器官和免疫系统功能障碍。

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.