Cell proliferation and oncogene expression after bile duct ligation in the rat: Evidence of a specific growth effect on bile duct cells

Abstract

The proliferative response of the rat liver was measured after temporary or permanent total biliary obstruction (BDO) and in different regions after selective ligation of the lobar ducts draining the right 60% of the hepatic mass. The results were compared with those after 70% partial hepatectomy (PH). Cell proliferation was assessed globally by measuring DNA synthesis and stratified to the separate cell populations with cytostaining techniques that allowed distinction of hepatocytes, duct cells, and nonparenchymal cells (NPCs). In selected experimental groups, gene expression was determined of transforming growth factor-β1 (TGFβ-1), prothrombin, c-erb-B2, transforming growth factor alpha (TGFα), human Cyclophilin (CyP), and 28S ribosomal RNA. The stimulation of a proliferative response to total BDO required obstruction for longer than 24 hours, but after this deligation did not switch off regeneration. In the first week after permanent BDO, there was progressive infiltration of NPCs, fibrous linkage of some portal areas, and a crescendo of DNA synthesis that was obvious at 24 hours, maximal at 48 hours, and back nearly to baseline at 6 days. At the 2-day mark, the bile duct cells had a 17-fold increase in proliferation, accompanied by a threefold to fourfold increase in hepatocyte renewal. Little or no increase in expression of TGFα or the hepatocyte-specific prothrombin gene was detectable in the first 48 hours, whereas levels of the oncogene c-erb-B2 that is associated with cholangiocarcinoma were expressed from 48 to 96 hours. Livers subjected to regional BDO with or without immunosuppressive treatment with FK 506 and cyclosporine had an inflammatory reaction only on the side with ligated ducts. DNA synthesis increased in both the obstructed and freely draining lobes to approximately half the level that occurred after total BDO. The proliferation of the obstructed side was similar to the mixed duct cell/hepatocyte response after total BDO, but this almost exclusively involved duct cells on the freely draining side. In contrast to the findings after BDO, livers after PH regenerated maximally at 24 hours rather than 48 hours, had a predominantly noninflammatory hepatocyte as opposed to duct cell response, and had marked expression of the prothrombin and TGFα genes but only weakly and late of c-erb-B2 messenger RNA. The results show that the liver responds as a whole and in a biologically intelligent way to the nature of the injury inflicted on any part of it. It further implies the presence of humoral communications and control networks that assure organ homeostasis and relate this to total body homeostasis. © 1995