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Role of Neutrophils in the Pathogenesis of Acute Inflammatory Liver Injury

¹ Department of Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX 77843-4467, USA
² Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160

Correspondence: Address correspondence to: Shashi K. Ramaiah, Department of Pathobiology, College of Veterinary Medicine, Texas A&M University, MS-4467, College Station, TX 77843-4467; e-mail:sramaiah{at}cvm.tamu.edu

Polymorphonuclear leukocytes (neutrophils) are essential in the defense against invading microorganisms, tissue trauma or any inciting inflammatory signals. Hepatic infiltration of neutrophils is an acute response to recent or ongoing liver injury, hepatic stress or unknown systemic inflammatory signals. Once neutrophils reach the liver, they can cause mild-to-severe tissue damage and consequent liver failure. For neutrophils to appear in the liver, neutrophils have to undergo systemic activation (priming) by inflammatory mediators such as cytokines, chemokines, complement factors, immune complexes, opsonized particles and other biologically active molecules, e.g., platelet activating factor. Neutrophils accumulated in the hepatic microvasculature (sinusoids and postsinusoidal venules) can extravasate (transmigrate) into the hepatic parenchyma if they receive a signal from distressed cells. Transmigration can be mediated by a chemokine gradient established towards the hepatic parenchyma and generally involves orchestration by adhesion molecules on neutrophils (β₂ integrins) and on endothelial cells (intracellular adhesion molecules, ICAM-1). After transmigration, neutrophils adhere to distressed hepatocytes through their β₂ integrins and ICAM-1 expressed on hepatocytes. Neutrophil contact with hepatocytes mediate oxidative killing of hepatocytes by initiation of respiratory burst and neutrophil degranulation leading to hepatocellular oncotic necrosis. Neutrophil-mediated liver injury has been demonstrated in a variety of diseases and chemical/drug toxicities. Relevant examples are discussed in this review.

Key Words: Inflammation • injury • liver • neutrophils • toxicity

Toxicologic Pathology, Vol. 35, No. 6, 757-766 (2007)
DOI: 10.1080/01926230701584163


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