Functional importance of ICAM-1 in the mechanism of neutrophil-induced liver injury in bile duct-ligated mice.
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.
Gujral
Jaspreet S
JS
Liver Research Institute, University of Arizona, Tucson, AZ 85724, USA.
Liu
Jie
J
Farhood
Anwar
A
Hinson
Jack A
JA
Jaeschke
Hartmut
H
D000447:Aldehydes; D000818:Animals; D001652:Bile Ducts / Q000502:physiology*; D001663:Bilirubin / Q000097:blood; D002469:Cell Separation; D002780:Cholestasis, Intrahepatic / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology*; D008026:Ligation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics* / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D011168:Portal System / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
D000447:Aldehydes; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1; C027576:4-hydroxy-2-nonenal; D001663:Bilirubin