Mechanisms of Inflammatory Liver Injury: Adhesion Molecules and Cytotoxicity of Neutrophils

During recent years, increasing experimental evidence has suggested that hepatic nonparenchymal cells, in particular Kupffer cells and neutrophils, can contribute significantly to the pathogenesis of liver injury in various chemical toxicities. Neutrophils are central to the mechanism of injury after hepatic ischemia reperfusion and endotoxemia. In this symposium summary, an overview of critical aspects of neutrophil-dependent liver injury is presented. A general introduction to the involvement of adhesion molecules in neutrophil rolling and transendothelial migration is provided. Mediators and mechanisms of neutrophil sequestration in the liver vasculature, extravasation, and adherence-dependent cytotoxicity are discussed using the examples of endotoxin-induced hepatic failure and ischemia-reperfusion injury. These processes involve a complex network of inflammatory mediators including cytokines, chemokines, and lipid-derived compounds. The role of neutrophil-derived cytotoxic mediators, e.g., reactive oxygen and proteases, in the molecular mechanisms of parenchymal cell injury is discussed. Furthermore, interactions between neutrophils and contractile, perisinusoidal, stellate cells that influence microvascular blood flow in the liver are discussed. Results of these and other investigations are leading to increased understanding of the complex interactions between neutrophils and tissues that result in injury.