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1 Liver Research Institute, University of Arizona, Tucson, Arizona, USA; Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
2 Inorganic Carcinogenesis Section, NCI and NIEHS, Research Triangle Park, North Carolina, USA
3 Department of Pathology, UT Health Center, Houston, Texas, USA
4 Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
* To whom correspondence should be addressed. E-mail: Jaeschke{at}email.arizona.edu.
Cholestasis-induced liver injury during bile duct obstruction causes an acute inflammatory response. In order to further characterize the mechanisms underlying the neutrophil-induced cell damage in the bile duct ligation (BDL) model, we performed experiments using wild-type (WT) and ICAM-1-deficient mice. After BDL for 3 d, increased ICAM-1 expression was observed along sinusoids, portal veins, and on hepatocytes in livers of WT animals. Neutrophils accumulated in sinusoids (358±44 neutrophils/20 high power fields, HPF) and more than 50% extravasated into the parenchymal tissue. Plasma alanine transaminase (ALT) levels increased by 23-fold and severe liver cell necrosis (47±11% of total cells) was observed. Chlorotyrosine-protein adducts, a marker for neutrophil-derived hypochlorous acid, and 4-hydroxynonenal adducts, a lipid peroxidation product, were detected in these livers. Neutrophils also accumulated in the portal venules and extravasated into the portal tracts. However, no evidence for chlorotyrosine or 4-hydroxynonenal protein adducts was detected in portal tracts. ICAM-1-deficient mice showed a 67% reduction in plasma ALT levels and 83% reduction in necrosis after BDL compared to WT animals. The total number of neutrophils in the liver was reduced (126±25 per 20 HPF), and 85% of these leukocytes remained in sinusoids. Moreover, these livers showed minimal staining for chlorotyrosine and 4-hydroxynonenal adducts, indicating a substantially reduced oxidant stress, and a diminished cytokine response. Thus, neutrophils relevant for the aggravation of acute cholestatic liver injury in BDL mice accumulate in hepatic sinusoids, extravasate into the tissue dependent on ICAM-1, and cause cell damage involving reactive oxygen formation.
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