Tissue remodeling following submassive hemorrhagic necrosis in rat livers induced by an intraperitoneal injection of dimethylnitrosamine

We examined regeneration and fibrosis in the necrotic areas of hepatic stellate cells (HSCs). Acute hepatic injury was induced in rats by administration of an intraperitoneal injection of high-dose dimethylnitrosamine (50 mg/kg body weight). Liver samples were obtained from rats 6, 12, 24, 36 h and 2, 3, 5, 7, 10, and 14 days after the injection. They were examined by light and electron microscopy and by immunohistochemical methods. Hemorrhagic necrosis became most prominent 36 h after treatment and extended into zones 3 and 2. In the submassive necrotic areas the sinusoidal structure was destroyed. No HSCs positive for a-smooth muscle actin or desmin were present. On day 5, when necrotic tissues were almost removed by infiltrating macrophages, HSCs strongly positive for a-smooth muscle actin and desmin appeared along the surface of the preserved parenchyma and migrated into the necrotic areas along the residual reticulin fibers. By day 14 most of the necrotic areas were almost completely replaced by the regeneration of hepatocytes and central to central (C-C) bridging fibrosis. Our results indicate that following submassive complete necrosis, HSCs in the preserved liver parenchyma have roles in the formation of sinusoidal wall for remodeling in necrotic areas via their activation, proliferation, and migration into the necrotic areas.