Endocrine and molecular responses to surgical stress

Endocrine and molecular responses to surgical stress

ENDOCRINE AND MOLECULAR RESPONSES TO SURGICAL STRESS IN BRIEF Surgical stress results in adaptive responses encompassing a wide variety of homeostat...

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ENDOCRINE AND MOLECULAR RESPONSES TO SURGICAL STRESS

IN BRIEF

Surgical stress results in adaptive responses encompassing a wide variety of homeostatic axes. This monograph focuses on what appear to be the three most universal stress response systems (i.e., the endocrine responses involving the hypothalamic-pituitary-adrenal axis, the sympathetic nervous system, and the acute phase response). The simultaneous activation of these axes results in an array of synergistic responses that act in concert to increase the host’s chance of survival. Surgical stress occurs before, during, and after an operative procedure. It therefore encompasses the sum of stimuli evoked by psychologic stress, tissue injury, intravascular volume redistribution, anesthetic agents, organ system manipulation and dysfunction, and the sequelae of extirpative procedures and perioperative complications. Atferent stimuli from traumatized tissues and baroreceptors stimulate the central nervous system to activate both the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. In addition, tissue damage results in the production of cytokines, which enter the circulation, interact with specific tissue receptors, and elicit the acute-phase response. Corticotrophin-releasing hormone produced after central nervous system activation stimulates the anterior pituitary gland to release adrenocorticotropic hormone, which is transported to the adrenal cortex where it stimulates the synthesis and release of glucocorticoids. Glucocorticoids bind to cytosolic receptors, which act as transcription factors to modulate gene expression. Present in virtually every nucleated cell in the body, these receptors are maintained in a nonactivated state by their interaction with a group of intracellular proteins termed heat shock proteins. After hormone (ligandl binding, the glucocorticoid-receptor-hormone complex is transported to the nucleus and disassociates from the heat shock proteins. This action results in a conformational change (activation) in the hormonereceptor complex that renders it capable of binding to DNA at a specific site, the glucocorticoid response element, which is located in 668

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the promoter region of glucocorticoid responsive genes. Binding of the receptor to the glucocorticoid response element modulates the rate of transcription of specific messenger RNAs, which in turn affect the levels of encoded protein products. These glucocorticoidregulated proteins have a global effect on homeostasis by influencing metabolic pathways, levels of cytokine and hormone receptors, and the synthesis and activity of additional hormones including catecholamines. The acute-phase response is a systemic reaction to local tissue trauma. This response is characterized by fever, leukocytosis, activation of immune function, hypothalamic-pituitary-adrenal axis stimulation, and an alteration in circulating levels of a group of protein kinases known as the acute-phase reactants. Synthesized primarily in the liver, acute-phase reactants are involved in basic host defenses, including coagulation, opsonization, and inhibition of protease activities. Systemic effects of the acute-phase response are mediated by the cytokines interleukin 1, interleukin 6, and tumor necrosis factor-a, which exert their effects primarily by altering gene expression. The acute-phase response is intimately linked to the endocrine responses to stress, particularly the hypothalamic-pituitary-adrenal axis. The autonomic nervous system has evolved in parallel to the hypothalamic-pituitary-adrenal axis. The autonomic nervous system regulates moment-to-moment arousal and has classically been divided into the anatomically, chemically, and functionally distinct sympathetic and parasympathetic components. The sympathetic system is for the most part activated after exposure to stress and results in the secretion of catecholamines that bind to adrenergic receptors. These receptors compromise a subgroup of guanine nucleotide binding protein (G protein)-linked receptors that either stimulate or inhibit adenylate cyclase activity or activate phospholipase C. This activity results in modulation of the levels of the second messengers cyclic adenosine monophosphate, inositol triphosphate, or diacylglycerol. These second messengers, in turn, affect the activity of protein kinases that alter the phosphorylation state of intracellular proteins. These proteins are effecters of the stress response. Catecholamine biosynthesis is remarkably dynamic. In addition to the moment-to-moment control exerted by sympathetic discharge, long-term stimulation results in elevated activity of synthetic enzymes that stimulate additional catecholamine production. Furthermore, an intimate association exists between increased sympathetic activity and hypothalamic-pituitary-adrenal axis activation. These interactions occur at every level tested, including the hypothalamus, pituitary gland, adrenal gland, and adrenergic receptor. Glucocorticoids, catecholamines, and the cytokines associated with the acute-phase response are capable of modulating gene expression. They do so primarily by altering the rate at which a given gene is Cur-r

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transcribed into messenger RNA. This result is accomplished through their ability to enhance the expression or activity of so-called transcription factors that interact with specific DNA sequences, termed cis-regulatory elements, present in the promoter regions of responsive genes. A given transcription factor may act either positively or negatively to influence gene expression. In most genes, multiple transcription factors interact at distinct sites to contribute to the overall level of expression. The most important transcription factors associated with the stress response include the glucocorticoid receptor complex, cyclic adenosine monophosphate response element binding protein (CREB), nuclear factor interleukin-6 (NF-ILG), NF-KB, activator protein 1 (AP11, and the heat shock transcription factor (HSF). The importance of these factors in the stress response has been an area of great interest for the last decade. The most ubiquitous response to cellular stress is the induction of a family of proteins termed heat shock proteins. Although originally named on the basis of their increased level of expression after heat stimulation, heat shock proteins are induced in response to a wide variety of environmental and metabolic stresses, including hypoxia, toxic substances, and localized trauma. Elevated levels of heat shock proteins have also been found in certain areas associated with specific chronic disease states in human beings, including the thyroid gland in chronic thyroiditis, the synovial fluid in rheumatoid arthritis, and the plaques removed from atherosclerotic arteries. Their expression has recently been shown to be markedly induced after surgical stress in a rodent model. Increased expression of heat shock proteins occurs selectively in the adrenal cortex and vasculature after moderate surgical stress. This selective heat shock protein induction has been shown to be under endocrine control, such that the is adrenocorticotmpic hormone dependent, adrenal response whereas the vascular response is associated with a,-adrenergic receptor stimulation. In situ hybridization has localized the adrenal response to the adrenal cortex and the vascular induction to the smooth muscle. Interestingly, this heat shock protein stress response has been shown to be markedly attenuated in aged animals. Heat shock proteins are also induced in vivo after severe forms of cardiogenie shock, ischemia, and reperfusion. After severe stress, heat shock proteins that were induced in the liver appeared to be generated at the time of reperfusion and could be inhibited by prior infusion of supemxide dismutase. The heat shock proteins are an important class of stress response proteins and are associated both with the surgical stress response and the classic neuroendocrine response axes. An understanding of their molecular regulation is likely to have important diagnostic, prognostic, and therapeutic ramifications. 660

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Robert Udelsman, MD, is Associate Professor and Director of Endocrine Surgery at The Johns Hopkins Hospital. He received his bachelor’s degree from Lafayette College and his medical degree from The George Washington University School of Medicine. He obtained his surgical residency training in general surgery at The Johns Hopkins Hospital. During his residency, he completed clinical and research fellowships in surgical oncology and endocrinology and metabolism at the National Institutes of Health. He subsequently completed a fellowship in gastrointestinal surgery at The Johns Hopkins Hospital. Dr. Udelsman’s primary research interests are the endocrine and molecular responses to surgical stress.

Nikki J. Holbrook, PhD, is a Senior Investigator and Chief of the Section on Gene E,xpression and Aging at the Gerontology Research Center, National Institute on Aging. She obtained her bachelor’s, master’s, and doctoral degrees in microbiology at the University of South Florida. She completed postdoctoral fellowships in glucocorticoid receptor biochemistry and physiology at the Dartmouth Medical School and molecular biology in the Laboratory of Pathologv at the National Cancer Institute. Her research has focused on the molecular responses to stress, including their regulation, function, and role in disease and the aging process. Curr

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