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.
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