MACROPHAGE FUNCTION IN SURGICAL SEPSIS

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Sepsis is the major non-neurologic cause of death after major trauma, thermal injury, and major elective surgery, carrying a mortality of 65 percent. Deaths from surgical sepsis are usually related to a breakdown in the patient's immune defenses and/or associated multiple organ failure (MOF), but the reasons for these aberrations in host defense are poorly understood. Since host resistance in early sepsis depends on recognition of antigen (i.e. bacteria) by cells of the monocyte-macrophage lineage, this proposal is designed to examine the early phases of sepsis to ascertain the nature and time course of abnormalities in macrophage function that may lead to subsequent immunosuppression. Since endotoxin has been shown to have profound effects on immune function in various septic models, macrophage antigen presenting cell (APC) function will be studied in endotoxin- resistant (C3H/HeJ) and endotoxin-sensitive (C3H/HeN) mice with intra-abdominal sepsis produced by cecal ligation an puncture (CLP). The successive steps in antigen recognition including macrophage interleukin 1 (I1-1) production, macrophage antigen presentation, and macrophage-T cell interaction will be assayed using the antigen-specific T cell clone D10.G4.1. THE ROLE OF TRAUMA AS AN IMMUNOSUPPRESSIVE FACTOR WILL BE EVALUATED USING A STANDARD HIND LIMB FRACTURE MODEL. SEVERAL STUDIES HAVE PREVIOUSLY EXAMINED POST-TRAUMATIC IMMUNOSUPPRESSION. THIS PROPOSAL WILL EXAMINE THE IMMUNOSUPPRESSIVE EFFECTS OF SEPSIS (CLP) ALONE AS WELL AS THE COMBINED EFFECTS OF SEPSIS AND TRAUMA ON MACROPHAGE FUNCTION. THE CENTRAL HYPOTHESIS OF THIS PROPOSAL IS THAT MACROPHAGE DYSFUNCTION IN THE EARLY PHASES OF SEPSIS IS REVERSIBLE WHILE PROLONGED SEPSIS LEADS TO PROFOUND IRREVERSIBLE IMMUNOSUPPRESSION THAT IS PARTIALLY RESPONSIBLE FOR THE HIGH MORTALITY SEEN IN SURGICAL SEPSIS. If reversible abnormalities in macrophage function can be identified, then therapeutic interventions and pharmacologic manipulations employed early after the onset of sepsis might abrogate the septic insult and its attendant immunosuppression. SUCH THERAPY COULD LEAD TO A MAJOR REDUCTION IN PATIENT MORTALITY FOLLOWING SEPSIS - A PROBLEM THAT AFFECTS AN ESTIMATED 150,000 PATIENTS EACH YEAR IN THE UNITED STATES.