Macrophage populations and apoptotic cells in the liver before spontaneoushepatitis in Long-Evans Cinnamon (LEC) rats

The inbred mutant strains of Long-Evans Cinnamon (LEC) rats spontaneously d evelops acute hepatitis as a result of abnormal copper accumulation, follow ed by chronic hepatitis, cholangiofibrosis and hepatocellular carcinoma. To shed some light on the role of macrophages in the liver failure, immunohis tochemical methods were used to investigate the kinetics of macrophage popu lations in the liver of male LEC rats, in relation to the appearance of myo fibroblastic cells and hepatocyte apoptosis. Rats examined at 24 weeks of a ge and moribund rats killed at 22-25 weeks of age had increased serum conce ntrations of aspartate aminotransferase and alanine aminotransferase, with jaundice and histological changes indicative of hepatic failure, whereas ra ts examined at 8, 12, 16 or 20 weeks old showed no such abnormal findings. Immunolabelling with ED1 (a monoclonal antibody recognizing rat macrophages ) and ED2 (a monoclonal antibody specific for rat resident macrophages) rev ealed that numbers of blood monocyte-derived macrophages and Kupffer cells began to increase markedly at 16 weeks of age (before the onset of hepatiti s). However, alpha-smooth muscle actin (SMA)-positive myofibroblastic cells (modulated perisinusoidal cells) and hepatocyte apoptosis, demonstrable by the TUNEL method, were rarely seen at 8, 12; 16, 20 or 24 weeks. There was no close relationship between macrophage expansion and the appearance of m yofibroblastic cells or hepatocyte apoptosis. In moribund rats, only a felv Sn IA-positive cells were seen in the periportal zones; hepatocytes underg oing apoptosis increased in number, and macrophages engulfing apoptotic bod ies were observed occasionally, suggesting that apoptosis was related to he patic failure as an early event. In addition, immunohistochemical examinati on demonstrated abnormal deposits of laminin along the sinusoids from 20 we eks, as an initial extracellular matrix protein in LEC rat livers. (C) 1999 W.B. Saunders Company Limited.