Circulating Neutrophils and Liver Injury in Rat Models of Experimental Alcoholic Liver Disease |
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Authors: | Aron D Ross Victor Saldivia Betzavel Oporto Frederick J Carmichael Ross Cameron Yedy Israel |
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Institution: | Departments of Pharmacology and Pathology (A.D.R., V.S., B.O., F.J.C., R.C.,), Faculty of Medicine, University of Toronto, and the Addiction Research Foundation (A.D.R., V.S., B.O., F.J.C., R.C.), Toronto, Ontario, Canada;the Department of Pathology (A.D.R., Y.I.), Thomas Jefferson University, Philadelphia, Pennsylvania, and the Center for Gene Pharmacotherapy University of Chile (Y.I). |
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Abstract: | The present study examined the relationship between circulating neutrophils and liver injury in two widely used rat models of chronic ethanol administration. Hematological alterations, liver histopathology, and biochemical indices of liver injury were assessed in rats receiving chronic ethanol by oral liquid diet feeding (Lieber-DeCarli method) or by continuous intragastric infusion (Tsukamoto-French method). Oral administration of ethanol did not affect circulating neutrophil counts, but resulted in minimal liver injury characterized by elevated serum alanine aminotransferase (79%), increased liver mass (15%), and moderate steatosis. In contrast, rats receiving ethanol by continuous intragastric infusion showed an ~ 2-fold increase in circulating neutrophils, and a moderate degree of liver injury, indicated by a 169% elevation of serum alanine aminotransferase and a 2-fold increase in liver mass. Liver biopsies from these rats showed severe steatosis and scattered necrotic hepatocytes, and some neutrophil infiltrates. To determine whether an increase in the number of circulating neutrophils could potentiate liver injury induced by oral ethanol feeding, rats were treated with human recombinant granulocyte colony-stimulating factor at a dose of 100 μg/kg/day (sc) for 4 days. Treatment with granulocyte colony-stimulating factor resulted in a 6- to 9-fold increase in circulating neutrophil counts. Nevertheless, this change did not enhance the minor degree of ethanol-induced liver injury in this model. Our results indicate that, whereas neutrophil leukocytosis accompanies more severe manifestations of ethanol hepatotoxicity in rats, this condition per se does not directly induce or exacerbate ethanol-induced liver injury. |
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Keywords: | Alcoholic Liver Disease Ethanol G-CSF Neutrophil |
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