MOLECULAR BIOLOGY OF SHOCK-INDUCED ILEUS

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

Hemorrhagic shock is the most common cause of death among individuals between the ages of 20 and 35. There is little doubt that the gut plays a seminal role in the pathophysiology of the body's response to hemorrhagic shock. During hemorrhagic shock (HS) the survival response maintains central blood pressure at the expense of the mesenteric circulation leaving the gut particularly vulnerable to hypoxia. Hemorrhagic shock and resuscitation (HS/R)-induced intestinal stasis followed by mucosal barrier breakdown and the generation of locally produced cytokines have been proposed as the cause of systemic infection, the systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF) following hemorrhagic shock. However, the molecular mechanisms which are initiated within the gut muscularis and the subsequent functional sequelae, are poorly understood. We hypothesize the hemorrhagic shock initiates a definable molecular inflammatory response within the intestinal wall that is characterized by the activation of transcription factors (HIF-1 and NF-kappaB), the up- regulation of kinetically active substances (iNOS, COX-2 and IL- 6/vasoactive intestinal peptide) and an increase in adhesion molecule expression with leukocyte recruitment. We further hypothesize that these events within the gut wall lead locally to ileus and systematically to the activation of circulating leukocytes and the recruitment of leukocytes into organs, including the intestine. We have chosen to focus on a particular redox sensitive cascade of events, which we believe to be seminal to the development of the severe complications of hemorrhagic shock. The existing literature and our preliminary data establishes a logical threat through the importance of establishing a connection between the specific events being studied in this grant. It is the primary objective of this component of the center grant proposal to elucidate the sequence of molecular and functional events initiated by HS/R, which leads to ileus.