title: Role of neutrophils in acute inflammatory liver injury.
abstract: Hepatic infiltration of polymorphonuclear leukocytes (neutrophils) is an early response to tissue injury, cellular stress or systemic inflammation. Neutrophil activation is vital for host-defense and the removal of cell debris but can also cause additional tissue damage or even liver failure. In order to prevent the detrimental effects of neutrophils without compromising host-defense reactions, it is important to understand the mechanisms of neutrophil hepatotoxicity. The first step in the pathophysiology is the priming and recruitment of neutrophils into the liver vasculature by inflammatory mediators, e.g. cytokines, chemokines, or complement factors. Most critical for parenchymal cell damage is the accumulation in sinusoids, which does not depend on cellular adhesion molecules. The next step is the extravasation into the parenchyma. This process requires a chemotactic signal from hepatocytes or already extravasated neutrophils and depends on cellular adhesion molecules on neutrophils (beta(2) or beta(1) integrins) and on endothelial cells (intercellular or vascular cell adhesion molecules). The third step is the direct contact with target cells (hepatocytes), which involves beta(2) integrins and triggers the full activation of the neutrophil with a long-lasting adherence-dependent oxidant stress and degranulation. The oxidants diffuse into hepatocytes and trigger an intracellular oxidant stress, mitochondrial dysfunction and eventually cause oncotic necrotic cell death. Neutrophil-derived proteases facilitate extravasation and are involved in the regulation of inflammatory mediator production. Based on these mechanisms, it appears that strengthening of the intracellular defense mechanisms in hepatocytes may be the most promising therapeutic approach to selectively prevent neutrophil-mediated tissue damage without compromising their host-defense function.
authors.affiliation: Liver Research Institute, University of Arizona, College of Medicine, Tucson, AZ 85737, USA. jaeschke@email.arizona.edu
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D000818:Animals; D006505:Hepatitis / Q000276:immunology*; D006801:Humans; D009504:Neutrophils / Q000276:immunology*