Sepsis as a result of gram-negative infection is a life threatening complication of trauma, burns, and major surgery. Bacterial products and cytokines that are released by the immune system during sepsis are known to activate the pituitary-adrenal axis through central neural pathways. Adrenal steroid hormones may then cause increased suppression of the immunological response to augment the severity of the sepsis. Nonetheless, the response of the pituitary-adrenal axis to experimentally controlled gram-negative bacteremia and the mechanisms involved in this response have not been studied. Our objective is to determine both the characteristics of this response and the central neural mechanisms that contribute to it. Experiments will be conducted in a chronically cannulated, unanesthetized rat model that is available in this laboratory. This preparation has unstressed baseline values of plasma adrenocorticotropin (ACTH) and corticosterone (B). Gram negative bacteremia is induced by the intravenous injection of live E. coli suspended in sterile saline. The response of ACTH is directly related to the number of organisms injected. The contribution of the free endotoxin included in the injections to this response will be determined as will the effectiveness of dead E. coli in eliciting the response. The response of circulating tumor necrosis factor-alpha(TNF) and interleukin- 1 (IL-1) to the injection of E. coli will be measured since either of these cytokines could activate pathways that elicit ACTH release. Central neural areas that respond to the injection of E. coli will be determined by using immunocytochemistry and in situ hybridization to identify neurones that express the activity-dependent DNA-regulatory protein, Fos, and the hypothalamus will be examined for changes in the mRNA for corticotropin releasing factors. The hormonal response to E. coli will also be tested in the presence of lesions of various circumventricular regions and with the elimination of hemodynamic input by lesions of the nucleus of the solitary tract. To determine whether IL-1 or TNF is involved in the response of ACTH and B to E. coli, rats will be studied after either iv or icv administration of the IL-1 receptor antagonist and after blockade of peripheral TNF. Central neural areas implicated by the experiments above will then be examined immunocytochemically for the presence of several neurotransmitters, and the identified transmitters and their antagonists will be microinjected into these areas to determine the effect of these substances on ACTH release and on the hormonal response to E. coli. the role of both augmented and diminished B feedback and of an earlier episode of transient hypovolemia in the response will also be assessed. Because adrenal steroid hormones may contribute to immunosuppression after trauma and sepsis, the studies should increase our understanding of this complication and possibly suggest new therapies.
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