Functional importance of ICAM-1 in the mechanism of neutrophil-induced liver injury in bile duct-ligated mice

• Published in: American journal of physiology: Gastrointestinal and liver physiology Vol. 286; no. 3; p. G499
• Main Authors: Gujral, Jaspreet S, Liu, Jie, Farhood, Anwar, Hinson, Jack A, Jaeschke, Hartmut
• Format: Journal Article
• Language: English
• Published: United States 01-03-2004
• Subjects: Aldehydes; Animals; Bile Ducts - physiology; Bilirubin - blood; Cell Separation; Cholestasis, Intrahepatic - pathology; Humans; Immunohistochemistry; Inflammation - pathology; Intercellular Adhesion Molecule-1 - genetics; Intercellular Adhesion Molecule-1 - physiology; Ligation; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration - genetics; Neutrophil Infiltration - physiology; Oxidative Stress - physiology; Portal System - physiology; RNA, Messenger - biosynthesis; RNA, Messenger - genetics
• ISSN: 0193-1857
• DOI: 10.1152/ajpgi.00318.2003

Cholestasis-induced liver injury during bile duct obstruction causes an acute inflammatory response. 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 days, increased ICAM-1 expression was observed along sinusoids, along portal veins, and on hepatocytes in livers of WT animals. Neutrophils accumulated in sinusoids [358 +/- 44 neutrophils/20 high-power fields (HPF)] and >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 67% reduction in plasma ALT levels and 83% reduction in necrosis after BDL compared with WT animals. The total number of neutrophils in the liver was reduced (126 +/- 25/20 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.