REGULATION OF HEPATIC ISCHEMIA/REPERFUSION INJURY

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Ischemia and reperfusion during surgical resection or transplantation of the liver may result in an inflammatory response causing local and remote organ injury. Characteristic features of this pathological process are enhanced production of proinflammatory cytokines and chemokines, and upregulation of vascular adhesion molecules. These mediators promote neutrophil accumulation and tissue injury. However, the events initiating proinflammatory mediators production in vivo are undefined. Likewise, intrinsic mechanisms that serve to prevent inflammatory tissue injury are unknown. The overall objective of this application is to delineate the regulatory mechanisms involved in local and remote organ (lung) injury related to hepatic ischemia and reperfusion. The Specific Aims of this project will: 1) Determine if specific inhibition of NFkB, using in vivo IkB-adenovirus transfection or antisense oligonucleotides, will suppress local and remote organ (lung) injury. The preliminary studies suggest that NFkB is required for in vivo induction of inflammatory responses. Since NFkB is known to regulate the gene expression of cytokines, chemokines, and adhesion molecules, these studies would define the currently unknown role of NFkB during the induction and propagation of inflammatory tissue injury. 2) Determine the regulatory roles of the anti-inflammatory mediators IL-10, IL-13 and SLP1 in hepatic ischemia/ reperfusion injury. The preliminary studies suggest that these mediators may play important roles in the regulation and resolution of inflammatory injury. The investigators will determine whether these mediators are endogenously expressed. Functional roles will be then be evaluated using blocking antibodies. 3) Determine whether exogenous administration of IL-10, IL-13, or SLP1 ameliorates hepatic ischemia/reperfusion injury. Further studies will employ transgenic mice and adenoviral transfection systems for in vivo overexpression of these mediators. This proposal will delineate the regulatory events during liver ischemia/ reperfusion injury and may provide a new understanding of the inflammatory injury common to a variety of pathological states.