Functional importance of ICAM-1 in the mechanism of neutrophil-induced liver injury in bile duct-ligated mice
| Autor: | Hartmut Jaeschke, Jack A. Hinson, Jie Liu, Jaspreet S. Gujral, Anwar Farhood |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Pathology
medicine.medical_specialty Physiology Neutrophile Cell Separation Cholestasis Intrahepatic Biology Lesion Mice Cholestasis Physiology (medical) medicine Animals Humans RNA Messenger Ligation Cell damage Inflammation Mice Knockout Liver injury Aldehydes ICAM-1 Hepatology Bile duct Gastroenterology Bilirubin Intercellular Adhesion Molecule-1 medicine.disease Immunohistochemistry Mice Inbred C57BL Oxidative Stress Portal System medicine.anatomical_structure Neutrophil Infiltration Bile Ducts medicine.symptom |
| Zdroj: | American Journal of Physiology-Gastrointestinal and Liver Physiology. 286:G499-G507 |
| ISSN: | 1522-1547 0193-1857 |
| DOI: | 10.1152/ajpgi.00318.2003 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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