TNF, VAGAL TONE AND GASTRIC MOTILITY

点击翻译按钮获取中文摘要

DESCRIPTION (Adapted from the Abstract): A long-term goal of the Principal Investigator is to explain the physiological mechanisms responsive for the coordination of digestive functions with changes in ingestive behavior. A significant manifestation of the relation between ingestive behavior and digestion involves the suppression of gastric functions and the associated nausea and malaise, lost of appetite, vomiting, and diarrhea that are common symptoms associated with infectious illness and malignancy. The pathophysiological changes are though to be mediated by cytokines liberated by the host in response to antigenic challenge. Yet, the specific site(s) or mechanisms of action of these cytokine-induced responses are not clear. Tumor necrosis factor-alpha (TNF-alpha) is one of the first cytokines to be released and plays a pivotal role in initiating the cascade of cytokine release in the host response of challenge. TNF is thought to be the primary mediator of the gastrointestinal (GI) symptoms evoked during sepsis, malignancy, and other disease processes associated with the suppression of feeding behavior in chronic infectious and malignant disease. Recent studies have demonstrated that the dorsal vagal complex (DVC) is devoid of a blood-brain and that large peptides and proteins (e.g., hormones, immunoglobulin, complement, cytokines) in the circulation readily traverse the extracellular spaces of this area. The DVC contains the circuit through which the brain ultimately controls digestive function. The highest density of saturable, TNF-alpha binding sites has been demonstrated in the brainstem. Thus, the Investigator hypothesizes that TNF-alpha may represent a unique chemical "afferent" signal which directly alters vago-vagal reflex circuit function, resulting in a suppression of gastric functions during infectious and carcinogenic disease. In the proposed experiments, the Investigator focuses on the acute mechanisms of action of the cytokine TNF-alpha within the DVC. From these neurophysiological studies, he and his associates will provide information on how TNF-alpha can control digestive functions by acting on vagal circuits within the brainstem, and a foundation for future studies examining the specific mechanisms of actions of cytokines on the central circuits which may co-regulate digestive functions and ingestive behavior during chronic disease.