Centrilobular and perisinusoidal fibrosis in experimental congestive liver in the rat

The pathogenesis of congestive hepatic fibrosis is known to be a reaction of hepatic stromal cells following prolonged congestive heart failure or hepatic outflow obstruction. However, little is known about the fibrotic process itself. This study documents the hepatic morphology and ultrastructure of the fibrotic processes in an experimental model of congestive hepatic fibrosis in rats.

In this model we ligated the abdominal portion of the inferior vena cava in the space between the diaphragm and liver, and observed liver morphology 24 h, 1 week and 6 weeks after the operation. The cytoskeletal components of the hepatic stellate cells and myofibroblasts were identified by immunohistochemistry for glial fibrillary acidic protein (GFAP) and a-smooth muscle actin (a-SM actin). Extracellular matrices of reticulin fibers and fibronectin were localized using silver impregnation and immunohistochemical staining.

Soon after ligation of the vena cava, foci of cells at variable stages of necrosis appeared in the centrilobular areas, the topographical localization of which was highly variable within the liver. The fibrotic processes were subclassified into three stages. In the first stage (24 h after ligation), abundant neutrophils, macrophages and GFAP-positive stellate cells appeared, but a-SM actin-positive cells were not detected in the necrotic areas. In the second stage (1 week after ligation), the GFAP-positive cells disappeared, but a-SM actin-positive myofibroblasts appeared. In the third stage (6 weeks after ligation), a large number of a-SM actin-positive myofibroblasts were observed, and there was heavy deposition of connective tissue proteins, such as reticulin fibers and fibronectin, in centrilobular areas. Two interesting observations were that: (1) the distribution of centrilobular necrosis was highly variable within the liver, and (2) the fibrosis was confined to focal centrilobular areas involving the perivenular sinusoidal area without periportal fibrosis.

These findings suggest that GFAP-positive stellate cells are transformed into a-SM actin-positive myofibroblasts, and these myofibroblasts produce extracellular matrix proteins in centrilobular sinusoidal areas under congestive conditions.