REVISED ABSTRACT: In trauma patients sepsis is a life-threatening complication. Our broad objective is to identify possible mechanisms that underlie the abnormalities in neuroendocrine and adrenocortical function that occur in septic patients at risk for death. We hypothesize that inoculations of E. coli into the peritoneal compartment of chronically prepared rats elicit local actions on the endings of vagal afferent nerves to initiate the neuroendocrine response. In contrast, inoculations of E. coli into the vascular compartment cause an increase in circulating mediators that act on the central nervous system. When simultaneous inoculations are made into both the vascular and peritoneal compartments, the ascending signals synergize to augment the early hormonal response. We will test TNFalpha, cyclooxygenase pathways, and neurokinins as mediators of the responses to peritoneal and intravenous inoculations of E. coli and to simultaneous inoculations of E. coli into both compartments. Selective surgical elimination of the afferent nerves from the subdiaphragmatic vagi to the brain and selective surgical elimination of the efferent nerves from the brain to the subdiaphragmatic vagi will be used to test the role of each of these pathways in the responses to the inoculations of E. coli. Since clinical infections can spread from a local site into the circulation, we will determine the ffect of intravenous inoculations that are done 4 or 24 h after peritoneal inoculations. Immunocytochemistry and in situ hybridization for the immediate-early gene product, Fos, will identify areas in the brain that respond to inoculations of E. coli into either compartment alone and central areas where the ascending signals from both compartments converge after inoculations into both compartments. Mediators implicated by the experiments involving the inoculations of E. coli will be examined with immunocytochemistry or in situ hybridization for possible action in the brain. Such mediators will be blocked pharmacologically or surgically to determine their role in the central neural expression of Fos. The mechanisms revealed are likely to play a significant role in the suppression of host defense and the onset of septic shock.
