Reduced oncotic necrosis in fas receptor-deficient C57BL/6J-lpr mice after bile duct ligation
Jaspreet S. Gujral
Liver Research Institute, University of Arizona, Tucson, AZ
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR
Search for more papers by this authorJie Liu
Inorganic Carcinogenesis Section, National Cancer Institute at National Institute of Environmental Health Sciences, Research Triangle Park, NC
Search for more papers by this authorAnwar Farhood
Department of Pathology, University of Texas Health Science Center, Houston. TX
Search for more papers by this authorCorresponding Author
Hartmut Jaeschke Ph.D.
Liver Research Institute, University of Arizona, Tucson, AZ
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR
Liver Research Institute, University of Arizona College of Medicine, 1501 N. Campbell Ave., Room 6309, Tucson, AZ 85724. fax: 520-626-5975===Search for more papers by this authorJaspreet S. Gujral
Liver Research Institute, University of Arizona, Tucson, AZ
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR
Search for more papers by this authorJie Liu
Inorganic Carcinogenesis Section, National Cancer Institute at National Institute of Environmental Health Sciences, Research Triangle Park, NC
Search for more papers by this authorAnwar Farhood
Department of Pathology, University of Texas Health Science Center, Houston. TX
Search for more papers by this authorCorresponding Author
Hartmut Jaeschke Ph.D.
Liver Research Institute, University of Arizona, Tucson, AZ
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR
Liver Research Institute, University of Arizona College of Medicine, 1501 N. Campbell Ave., Room 6309, Tucson, AZ 85724. fax: 520-626-5975===Search for more papers by this authorAbstract
Neutrophils aggravate cholestatic liver injury after bile duct ligation (BDL). Recently, it was suggested that hepatocellular apoptosis might be critical for liver injury in this model. To test the hypothesis that apoptosis could be a signal for neutrophil extravasation and injury, we assessed parameters of apoptosis and inflammation after BDL using 2 different approaches: (1) wild-type and Fas receptor-deficient lpr mice of the C57BL/6J or C3H/HeJ strains, and (2) treatment with the pancaspase inhibitor z-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk)in C3HeB/FeJ mice. After BDL for 3 days, total cell death was estimated to be between 10% and 50% of all cells evaluated. However, less than 0.1% of hepatocytes showed apoptotic morphology in all 3 strains. Processing of procaspase-3, caspase-3 enzyme activities, and immunohistochemical staining for cytokeratin 18 cleavage products indicated no activation of caspases. Real-time reverse-transcriptase polymerase chain reaction analysis revealed increased expression of many inflammatory mediators but no effect on proapoptotic genes. More than 50% of all accumulated neutrophils were extravasated and colocalized with foci of oncotic hepatocytes and chlorotyrosine adducts. z-VAD-fmk treatment had no effect on apoptosis or liver injury after BDL but eliminated apoptosis after galactosamine/endotoxin in C3HeB/FeJ mice. In Fas receptor-deficient lpr mice (C57BL/6J), expression of inflammatory mediators, neutrophil accumulation and extravasation, chlorotyrosine adduct formation, and liver injury were reduced. This protection was not observed in lpr mice of the endotoxin-resistant C3H/HeJ strain. In conclusion, liver injury (oncotic necrosis) after BDL correlated with the severity of the inflammatory response. The minimal amount of apoptosis had no effect on inflammation or on the overall injury. (Hepatology 2004;40:998-1007).
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