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(American Journal of Pathology. 1998;153:515-525.)
© 1998 American Society for Investigative Pathology

Regular Articles

Evidence of Hepatocyte Apoptosis in Rat Liver after the Administration of Carbon Tetrachloride

Jialan Shi* , Kenichi Aisaki , Yoji Ikawa and Kenjiro Wake*

From the Department of Anatomy,* School of Medicine, and Department of Retroviral Regulation, Medical Research Division, Tokyo Medical and Dental University, Tokyo, Japan

In acute liver injury induced by the injection of CCl₄, cell death has been attributed to the necrosis of hepatocytes in the centrilobular area. In the present study, we re-examined the hepatic injury evoked by CCl₄ in rats and explored the possibility that apoptosis may also contribute to its pathogenesis. Apoptotic hepatocytes were identified and quantified by light and electron microscopy, the in situ immunohistochemical labeling of nuclear DNA fragmentation, flow cytometry, and DNA gel electrophoresis. We found that a substantial number of hepatocytes underwent apoptosis. Apoptotic changes were also observed in ballooned hepatocytes. Apoptotic hepatocytes increased in number at 3 hours and peaked at 6 hours after the CCl₄ injection. Apoptotic bodies were sequestrated in the adjacent hepatocytes and sinusoidal cells. Double staining of the cells with immunostaining for phagocytes and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining for labeling of DNA fragmentation showed that the majority of apoptotic hepatocytes were phagocytosed by Kupffer cells and macrophages. The results indicated that apoptosis occurs in the ballooned and injured hepatocytes of the centrilobular area. What occurs after CCl₄ administration may be important in reducing inflammation, shortening the course of acute hepatic injury, and preventing the development of fibrosis.

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