Multiple organ failure (MOF) is the most common cause of ICU late death following major traumatic injury. Basic and clinical scientists will examine the validity of the hypothesis that post-injury gastrointestinal (gut) dysfunction plays a critical role in the pathogenesis of this lethal and costly entity. Patients at high risk for developing MOF will undergo an evaluation of their intestinal perfusion, motility and mucosal function by small bowel intubation. Strategies to restore normal gut function and institution of enteral feeding will be correlated with clinical outcomes. The mechanism(s) involved in the pathogenesis of post-injury gut stasis (ileus) and mucosal barrier dysfunction will be systematically examined in animal models. The following hypotheses will be pursued: 1) Post- traumatic shock and resuscitation activates cell-specific molecular programs in the gut that promote local injury and dysfunction, and alpha- melanocyte-stimulating hormone can interrupt this program and abrogate gut injury and dysfunction; 2) Nitric oxide production by both constitutive and inducible isoforms of nitric oxide synthase is altered in conditions in which ileus occurs, and the altered levels of nitric oxide produced, in turn, interfere with the fluid-propelling ability of the intestine and with the force generating ability of intestinal smooth muscle, 3) Traumatic stress causes inhibition of gastric acid secretion by the H/K- ATPase via changes in gut peptide expression which are nitric oxide and prostaglandin sensitive; 4) Ileus and its associated bacterial overgrown and luminal accumulation of noxious products provokes or exacerbates a local inflammatory response within the lamina propria of the wall of the intestinal that contributes to the mucosal barrier disruption that characterizes the evolution of MOF. These issues will be studied in naive and modified rats, and wild, mutant, and gene knockout mice utilizing in vivo and in vitro techniques, and in isolated cell systems. Details of activities of the Center can be found on the Internet at
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