Post-trauma development of aberrantly increased monocyte/macrophage production of proinflammatory cytokines parallels depressed macrophage (MP) antigen presenting function and decreased immunostimulatory monokines. This paradoxical development of dual and conflicting MP dysfunction has been linked to development of post-injury sepsis and MODS. However, a connection between the mechanisms of development for these two seemingly disparate MP dysfunctions and their direct contribution to post-injury MODS have been controversial. This controversy centers on which monokines/mediators are pivotal in MODS, how trauma triggers dysfunctional monokine production, what role inflammatory MP dysfunctions play in T cell immunosuppression, and whether organ localized or systemic MP are the chief perpetrators of monokine induced pathology. To unify the seemingly paradoxical roles of depressed human MP activity resulting in post-trauma immunosuppression, while increased MP activity effects MODS, the investigators propose this hypothesis: the circulating MP population represents a continuum of partially differentiated MP which mature to inflammatory MP or potent antigen presenting dendritic cells (DC) depending on host defense needs. Trauma induced mediators tip this equilibrium toward inflammatory MP by activating signal transduction cascades in an unbalanced fashion with consequent altered MP receptor ligand expression, dysfunction of endogenous monokine regulatory pathways, as well as disruption of MP to DC conversion. These cumulative dysfunctions produce MODS. The hypothesis is tested by 1) determining if post-trauma loss of endogenous monokine regulating functions parallel particular alterations in MP receptor/ligand expression, aberrant production of mTNFa, selective activation of signal transduction cascades and increased MODS score; 2) elucidating if depressed antigen presenting cell capacity results from failure to differentiate MP to mature dendritic cells (DC) with a resultant loss of IL-12 production, decreased expression of costimulation molecules (B7.1/B7.2), as well as depressed CD40 expression, with consequent MP/DC apoptosis and/or induction of T cell anergy; and 3) delineating if peripheral MP dysfunctions are accurate markers for MP changes at a target organ (lung) characterizing both the temporal relationship between peripheral blood MP and bronchoalveolar lavage (BAL) MP dysfunctions and any unique BAL MP dysfunction correlated to increasing MODS score/Murray score.
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