NEUROPEPTIDERGIC MEDIATION OF THE ACUTE PHASE REACTION

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The response of an organism to infection, known as the acute phase reaction (APR), appears to be mediated primarily by soluble products of mononuclear phagocytes. These soluble mediators or endogenous pyrogens (EPs), such as interleukin-1 (IL-1), may act within the central nervous system (CNS) to mediate many of the changes associated with the APR. The anterior, preoptic area of the hypothalamus (AH/POA) represents one area of the CNS that is known to be sensitive to the EPs and believed to be part of the circuitry involved in the development of the thermal component of the APR. A series of experiments are proposed to elucidate the means by which central mechanisms influence fever and the APR. First, other sites in the CNS (e.g., the ventral septal area or VSA and the organum vasculosum lamina terminalis or OVLT), will be evaluated for their reactivity to the EPs and their involvement in the evocation of the APR. Second, the efficacy of perfusing antipyretics, both exogenous and endogenous (e.g., arginine vasopressin or AVP), directly into these sites in suppressing the thermal and nonthermal components of the APR will be examined. Third, the AVP-induced antagonism of the APR will be characterized using both in vitro and in vivo techniques. Fourth, the effects of electrical stimulation of cell bodies containing AVP on the pathogenesis of fever and the APR will be examined. Fifth, the role of the amines in the evocation and/or suppression of the APR will be determined. Utilizing a microperfusion technique, it will be possible to determine the role of EPs, brain peptides and other putative mediators in the pathogenesis of fever and the APR. The long term goals are to elucidate the mechanism by which pyrogens act to elicit the thermal and nonthermal components of the APR and to identify the means by which the CNS elaborates endogenous antipyretics to prevent the deleterious effects of hyperpyrexias. This information should prove useful in determining the manner in which the CNS directly influences immune, physiologic and hematologic functions during infection. As a result, it may be possible to develop specific therapeutic agents to reduce life-threatening pyrexic responses without precluding the potentially beneficial aspects of fever.