Hepatic ischemia/reperfusion (I/R) injury is a major complication of trauma surgery, liver transplantation and resectional surgery, and hemorrhagic shock. The long-term goal of this proposal is to determine the molecular and cellular mechanisms by which hepatic I/R leads to induction and propagation of inflammatory liver injury.
Aim 1 will address the hypothesis that NF-kB activation occurs in Kupffer cells during the ischemic period and that this is the initial event leading to the inflammatory cascade. This, along with the converse notion that NF-kappaB activation in hepatocytes after reperfusion may be a protective mechanism that promotes liver recovery and repair, will be studied with primary liver cell isolates as well as our whole animal model using novel fusion protein constructs containing mutant forms of the NF-kappaB inhibitory protein, IkappaBalpha.
Aim 2 will address the hypothesis that the nuclear receptors and transcription factors, PPARalpha and PPARgamma, are central regulatory factors for the initiation of inflammation and regulation of oxidant-induced hepatocyte injury, respectively. We provide evidence that PPARgamma is deactivated during the ischemic period and that this may facilitate transactivation of NF-kappaB. We will determine the mechanisms by which PPARgamma is down-regulated by ischemia and whether agonistic modulation of PPARgamma can suppress I/R injury. Our data suggest that PPARa modulates hepatocyte expression of inducible nitric oxide synthase (iNOS). We will determine the mechanisms by which PPARalpha is activated after reperfusion and the manner in which it controls iNOS gene expression.
Aim 3 will delineate the mechanism of action of IL-12 in the liver after I/R. Our laboratory discovered that IL-12 is Produced in the liver during hepatic ischemia and that IL-12 is required for the production of TNF alpha and the promotion of neutrophil-dependent liver injury. We will determine the cellular source(s) and target(s) of IL-12 as well as the signaling mechanism by which IL-12 functions in liver cells.
Aim 4 will address the hypothesis that liver recruitment of CD4 T cells during early reperfusion is prerequisite for the subsequent recruitment of neutrophils and hepatocellular injury. We will determine the mechanisms by which CD4 T cells are recruited into the liver after reperfusion and how these cells promote the recruitment of neutrophils. These studies will greatly advance our knowledge of the pathophysiology of hepatic I/R injury and may identify several potential therapeutic targets.
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