Severe trauma induces aberrant inflammatory monokine, depressed immunostimulatory monokine production and diminished monocyte (Mphi) antigen-presenting cell(APC) capacity. This contradictory appearance of over activated and depressed MO functions is linked to development of post-injury Multiple Organ Dysfunction Syndrome (MODS) and could result if the post-injury microenvironment preferentially favored Mphi to inflammatory macrophage differentiation over differentiation to DC, the most potent APC. We found that trauma patients who develop post-injury MODS and Mphi APC defects have a MO to DC differentiation defect corresponding to their increased pathology. We will now test the hypothesis that severe injury induced PGE2 production, heat shock protein release, and activation of innate immunity receptors combines to alter MO receptor expression, signal transduction, and monokine production, unbalancing MO differentiation toward inflammatory macrophage and away from DC generation and tissue DC replacement by: I. Determining if the post-injury differential EP expression correlates to patient Mphi differentiation dysfunctions, altered TLR expression, and/or altered HSP-27 induced responses. II. Linking alteration in EP and/or TLR receptors to altered signal transduction during Mphi to DC vs. Mphi to Mac differentiation in patients and normals. Ill. Determining how activation of tissue DC alters after trauma and whether tissue DC or tissue Mac EP and TLR changes parallel the peripheral MO alterations. These experiments should provide insight into how aberrant macrophage function and depressed monocyte APC function develop after severe injury. The interaction of HSP-27 in the development or amelioration of these Mphi dysfunctions will also be dissected with possible prophylactic implications. Most importantly these experiments may suggest how currently available EP and/or TLR agonist or antagonist might be utilized therapeutically in the modulation of MODS development in trauma patients.
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