MOLECULAR PATHOGENESIS OF GUT INJURY IN MULTIPLE ORGAN FAILURE

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Gut hypoperfusion is a common early event in trauma patients likely to progress to multiple organ failure (MOF). This ischemia/reperfusion injury precipitates a local hyperinflammatory response that likely promotes the evolution of both early and late MOF. While much is known about the pathophysiologic responses of the gut to shock and ischemia/reperfusion injury, little is known about the molecular programs induced in the gut and remote organs by these insults, or the mechanisms by which these responses may be regulated to therapeutic benefit. This project seeks to characterize these signaling events by examining the stress responses of the gut, lung, and liver in animal model of endotoxemia and mesenteric ischemia/reperfusion injury, and in cultured epithelial cells and muscularis macrophages from the small intestine. These animal and in vitro data characterize the molecular stress response of the gut, lungs, and liver in rats following lipopolysaccharide (LPS) administration and mesenteric ischemia/reperfusion. The activation and cellular distribution of stress-kinase cascades, inducible transcription factors, and their target pro-inflammatory genes will be analyzed. The molecular signaling events identified at the tissue level will be mechanistically dissected in Aim 2, using cultures of small intestinal epithelial cells and gut macrophages exposed to LPS or oxidant stress. Aim 3 will examine the effects of alpha-melanocyte stimulating hormone (alpha-MSH), an endogenous anti-inflammatory peptide known to abrogate ischemia/reperfusion injury. The salutary effects of alpha-MSH in diverse forms of inflammation, combined with its ability to influence multiple pro-inflammatory genes, suggest that it acts at common, early step in the inflammatory cascade, presumably at the level of gene transcription. Accordingly, Aim 4 seeks to characterize mechanism by which alpha-MSH inhibits activation of the molecular stress response controlling the expression of pro-inflammatory genes in cultured macrophage cell lines and intestinal macrophages. These studies involve collaborations with all projects of the Center, and they should provide important insights into the mechanisms by which inflammatory signals alter gene expression in the gut and, more broadly, the pathobiology of MOF. It is anticipated that these studies will facilitate the rational development of novel therapies that selectively and beneficially regulate the expression of genes promoting this syndrome.