Portacaval shunt causes apoptosis and liver atrophy in rats despite increases in endogenous levels of major hepatic growth factors

Abstract

Background/Aims-The response to the liver damage caused by portacaval shunt (PCS) is characterized by low-grade hyperplasia and atrophy. To clarify mechanisms of this dissociation, we correlated the expression of 'hepatotrophic factors' and the antihepatotrophic and proapoptotic peptide, transforming growth factor (TGF)-β, with the pathologic changes caused by PCS in rats.Methods-PCS was created by side-to-side anastomosis between the portal vein and inferior vena cava, with ligation of the hilar portal vein. Hepatic growth mediators were measured to 2 months.Results-The decrease in the liver/body weight ratio during the first 7 days which stabilized by day 15, corresponded to parenchymal cell apoptosis and increases in hepatic TGF-β concentration that peaked at 1.4 × baseline at 15 days before returning to control levels by day 30. Variable increases in the concentrations of growth promoters (hepatocyte growth factor, TGF-α and augmenter of liver regeneration) also occurred during the period of hepatocellular apoptosis.Conclusions-The development of hepatic atrophy was associated with changes in TGF-β concentration, and occurred despite increased expression of multiple putative growth promoters. The findings suggest that apoptosis set in motion by TGF-β constrains the amount of hepatocyte proliferation independently from control of liver volume.

Expression of Transforming Growth Factor-α and -β in Hepatic Lobes After Hemihepatic Portal Vein Embolization

“…Furthermore, the expression of TGF-β was also elevated in the nonembolized hypertrophying lobe, although to a lesser degree compared with that in the embolized lobe. The upregulation of growth stimulatory factors, including TGF-α, has also been reported in a rat model of portacaval shunt, in which the apoptotic effect of TGF-β was postulated to overwhelm the significant increase in growth promoters [9]. A similar increase in TGF-β during hepatocyte replication has been reported in regenerating livers after partial hepatectomy in rats [6,7]; this increase was hypothesized to prevent uncontrolled growth during liver regeneration.…”

“…Portacaval shunt is accompanied by hepatocyte apoptosis, resulting in liver atrophy. A recent study showed that hepatic atrophy after portacaval shunt occurred despite the upregulation of (hepatotrophic) peptides, including HGF and TGF-α [9]. This study also revealed that the expression of TGF-β was increased during the same phase of hepatotrophic factor upregulation.…”

Regional and transient ischemia/reperfusion injury in the liver improves therapeutic efficacy of allogeneic intraportal hepatocyte transplantation in low-density lipoprotein receptor deficient Watanabe rabbits

“…Removal or permanent blood vessel ligation of one or more liver lobes induces cell proliferation and restoration of the original cell mass from the remaining liver [13,14]. Transplanted hepatocytes proliferate in response to reduction of the liver mass at the same rate as host cells.…”

ALR, the multifunctional protein

“…Emellett patkányokon végzett részleges hepatectomiát, illetve porta-cava sönt kialakítását követően szintén ALR-felszabadulást fi gyeltek meg a keringésben [24,52,53]. Az eredmények alapján megállapították, hogy a szérum ALR-szintje a májkárosodások jó indikátora lehet.…”

“…Igaz, hogy az ALR a többi emelkedett szintű növekedési faktorral (HGF, TGF-α, TGF-β) együtt sem képes megakadályozni patkányban a portacava sönt okozta májatrófi át [52], egy korábbi kísérlet-ben exogén ALR, HGF és TGF-α adagolásával sikerült megelőzni azt [13]. Az ALR génterápiás alkalmazásá-nak lehetőségét is tesztelték már patkánymodellen [54], és biztató eredményeket értek el.…”