Participation of different cell types in the restitutive response of the rat liver to periportal injury induced by allyl alcohol

Background/Aim: Restitution of periportal liver necrosis induced by allyl a lcohol involves proliferation and differentiation of putative liver stent c ells. The participation of different non-epithelial cell types required to restore the liver cord structure in this process has not been well document ed. The aim of the study was to determine the anatomic relationships among cells of liver lineage, extracellular matrix, and non-parenchymal cells dur ing repair of periportal liver injury. Methods: Periportal liver injury in rats was induced by intraperitoneal inj ection of allyl alcohol. Cells of the liver lineage, as well as Kupffer cel ls, hepatic stellate cells, macrophages, and the extracellular matrix compo nents fibronectin and laminin were localized using immunohistologic methods for 7 days after injury. Results: During the first day there was loss of periportal hepatocytes, as well as sinusoidal nonparenchymal cells, including macrophages, Kupffer cel ls and hepatic stellate cells. After day 1 macrophages appeared within the necrotic zone, increased until days 3-4, and then decreased to a few cells within reappearing sinusoids. At days 25 there was first proliferation of s mall "null" intraportal cells, which later acquired markers of ductular (OV -6, CKan) and liver cell differentiation (alphafetoprotein, carbamoylphosph ate synthetase-I), eventually assuming mature hepatocyte morphology. There was also moderate bile duct hyperplasia with extension of small newly-forme d ducts from the intraportal zone into the immediate periportal zone. Kupff er cells and hepatic stellate cells became enlarged at the borders of the n ecrotic and non-necrotic central zone and then appeared to migrate into the oval cell population expanding across the periportal zone. During the rest itution phase, hepatic stellate cells were closely associated with the prol iferating oval cells, surrounding small aggregates of oval cells which appe ared to be forming liver cords. Kupffer cells also stained for fibronectin, and fibronectin was seen at the intersection of the injured portal and uni njured central zones and around the expanding oval cells. In some intraport al zones, the laminin surrounding the bile ducts was lost. It was speculate d that this may permit proliferating ductular cells to migrate out of the b ile ducts into the periportal zone. By days 6 and 7 most of the injured liv er was restored to normal, with a few foci of chronic inflammation remainin g. Conclusions: There is a close anatomic relationship between immature liver lineage cells (oval/duct cells) and non-parenchymal cells during the restit utive repair of periportal injury. The nature of this relationship to the p ossible production of growth factors and expression of growth factor recept ors by the cells involved during the restitution process is discussed.