The morbidity of hemorrhagic shock/resuscitation is due to a complex inflammatory response set in motion by a decrease in blood volume and the pathophysiologic events which follow. One of the most morbid effects of this and other surgical illnesses is the damage to the gut. The intestine is exquisitely sensitive to shock because of a disproportionate constriction of the splanchnic circulation and because of its role in secreting proinflammatory cytokines into the systemic circulation. Mucosal changes during shock and ischemia reperfusion injury have been demonstrated by others, however, events within the intestinal muscularis remain largely unexplored. We have gained considerable insight into specific molecular mechanisms which initiate the proinflammatory cascade within the muscularis. We propose to investigate the mechanisms involved in three specific pathways which appear to be crucial to the pathophysiological events within the intestinal muscularis. The first pathway investigates functional and molecular mechanisms which are induced solely by the isolated """"""""priming"""""""" events of hemorrhagic shock and ischemia. This pathway is mediated by direct shock/ischemia-induced damage to the intestinal muscularis and/or indirectly by the activation resident muscularis cells (ie. macrophages). The second pathway investigates the mechanisms involved in the resuscitation and reperfusion phases of intestinal injury. Our data demonstrates that during resuscitation or reperfusion, activated macrophages secrete motoractive substances and proinflammatory cytokines which cause the upregulation of adhesion molecules and the massive recruitment of phagocytes into the intestinal muscularis. The extravasated phagocytes then degranulate extruding pernicious amounts of reactive oxygen intermediates and enzymes. The third pathway investigates a novel mechanism by which gastrointestinal smooth muscle and its innervation are directly modulated by endotoxin LPS/CD14 and exotoxin fMLP activation of resident intestinal muscularis macrophages. We hypothesize that stimulation of resident muscularis macrophages initiates the acute and chronic secretion of motoractive substances which have dramatic effects on enteric smooth muscle and its innervation, cytokine production, adhesion molecule expression and recruitment of leukocytes. The objectives of this series final series of experiments are designed to demonstrate this phenomenon and delineate the mechanism(s) involved in this unique pathway.
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