Bioartificial liver treatment in rats with fulminant hepatic failure: Effect on DNA-binding activity of liver-enriched and growth-associated transcription factors

Background. We earlier described a model of fulminant hepatic failure (FHF) in the rat where partial hepatectomy is combined with induction of right l iver lobe necrosis. In FHF rats, lack of regeneration of the residual liver was associated with delayed expression of HGF and HGF receptor c-met and e levated blood HGF and TGF-beta 1 levels. We then found that intrasplenic he patocyte transplantation prolonged survival in FHF rats and triggered hepat ocyte proliferation in the native liver. The latter effect was associated w ith accelerated expression of HGF and c-met mRNA in the liver and lowering of blood HGF and TGF-beta 1 levels. In the present study we show that in FH F rats, treatment with a bioartificial liver (BAL) had similar effects. Materials and methods. FHF was induced in inbred Lewis rats and after 4 h, Group 1 rats were subjected to a 4-h whole blood perfusion through the BAL loaded with 3 x 10(8) microcarrier-attached syngeneic hepatocytes, whereas Group 2 control rats were treated with the BAL containing microcarriers onl y. Results. Compared to sham-BAL-treated rats, the test rats lived longer (28 +/- 5 vs 17 +/- 2 h; P = 0.0005), had better coagulation parameters, mainta ined higher body core temperature, and showed decreased plasma TGF-beta 1 l evels. In addition, their liver remnants were HGF positive and showed incre ased DNA binding of transcription factors engaged in the modulation of hepa tocyte proliferation (e.g., STAT3) and liver-specific gene expression (e.g. , HNF1, HNF4, C/EBP). Conclusions. This study demonstrates that hepatocyte-based extracorporeal s upport not only can provide metabolic support by increasing the available f unctional liver mass but also is capable of modifying humoral and molecular mechanisms which are responsible for proliferation and organ-specific func tions of residual hepatocytes. (C) 1999 Academic Press.