The endocrine response to surgical stress requires the coordinated interactions of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. At the cellular level stress results in the preferential expression of a class of genes termed heat shock proteins (HSP). Although originally named on the basis of their expression following heat stimulation, these genes are induced following a variety of environmental and metabolic stressors including hypoxia, toxic agents and trauma. The putative adaptive importance of the these genes is emphasized by their remarkable phylogenetic preservation in every organism tested from bacteria to man. We hypothesize that heat shock proteins play a key role in the response to surgical stress and there is a fundamental interaction between the HPA axis and the expression of these proteins. The universal, parallel, and simultaneous stimulation of these stress response systems appears to be more than a biological coincidence. We suggest that this interaction occurs either at the level of the vascular endothelium or smooth muscle and may represent a final common pathway that links the HPA axis with the cellular stress response. We propose to explore interrelationships between the HPA axis and HSP gene expression in a surgical-stress rat model designed to recapitulate the events that occur in the clinical spectrum of surgical care. (1) We will define the in vivo tissue responsiveness to stress by measuring HSP mRNA expression in organs harvested postoperatively, define the kinetics of HSP expression, and correlate them with circulating levels of adrenocorticotrophic hormone (ACTH) and corticosterone. (2) We will then manipulate the HPA axis in vivo and study the HSP stress response. Specifically, hormone delivery systems will be implanted chronically to diffuse constant levels of corticotropin releasing factor (CRF), dexamethasone (glucocorticoid) or RU 486 (anti-glucocorticoid). Animals will subsequently undergo surgical stress to determine what effects these manipulations have on the HSP response. (3) We will study the mechanism(s) of this response and its functional significance by a) localizing the cellular site of the HSP expression utilizing in situ hybridization, b) characterizing the response at the cellular level utilizing in vitro culture systems, and c) introducing gene constructs which result in either over or under expression of HSP70 in responsive cells using in vivo transfection techniques.
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