Reactive oxygen and activated complement factors play critical roles in inflammatory liver injury (e.g., endotoxemia and ischemia/reperfusion). During the early phase, extracellular oxidant stress by Kupffer cells, detoxification of reactive oxygen by extracellular glutathione and massive neutrophil localization in the liver have all been demonstrated. Their previous studies of rats and mice supported by ES06091 have revealed an important contribution of Kupffer cells in the early phases of inflammation, but their data indicated that the influx of neutrophils is the critical feature without which parenchymal cell injury is minimal or absent. Thus, the focus of the current application is on the mechanisms by which neutrophils invade the liver and effect hepatotoxicity. It is now generally accepted that adhesion is necessary for leukocyte emigration, and experiments both in vitro and in vivo show that adhesion is a multistep process potentially involving members of several gene families. They will investigate adhesion molecules that potentially support neutrophil localization in tissue, and adhesion molecules that potentially modulate the adhesive process by interfering with adhesion, or by signaling enhanced adhesive and secretory functions of the neutrophil. They will perform these studies in mouse models of liver injury because they have extensive experience with these models and will perform experiments in mice with targeted deletions of the relevant adhesion molecules. In addition, they will perform studies in vitro using murine cells from normal and adhesion molecule-deficient mice, and using human cells to obtain cross-species comparisons.
Specific Aim 1 will determine in mouse models of inflammatory liver injury the contributions of the selectin family of adhesion molecules to the localization and activation of neutrophils in the liver.
Specific Aim 2 will determine in mouse models of inflammatory liver injury the contributions of beta2-integrins and ICAM-1 to localization of neutrophils in liver and to parenchymal cell damage.
Specific Aim 3 will determine if neutrophil adhesion promotes cytotoxicity in hepatocytes in vitro and will define the specific adhesion molecules involved and the stimuli that modulate their contribution to neutrophil-hepatocyte adhesion.
Specific Aim 4 will define the potential sources and function of soluble ICAM-1 in inflammatory liver injury.
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