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 liver 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 elevated blood HGF and TGF-beta1 levels. We then found that intrasplenic hepatocyte transplantation prolonged survival in FHF rats and triggered hepatocyte proliferation in the native liver. The latter effect was associated with accelerated expression of HGF and c-met mRNA in the liver and lowering of blood HGF and TGF-beta1 levels. In the present study we show that in FHF rats, treatment with a bioartificial liver (BAL) had similar effects.


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 only.


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, maintained higher body core temperature, and showed decreased plasma TGF-beta1 levels. In addition, their liver remnants were HGF positive and showed increased DNA binding of transcription factors engaged in the modulation of hepatocyte proliferation (e.g., STAT3) and liver-specific gene expression (e.g., HNF1, HNF4, C/EBP).


CONCLUSIONS
This study demonstrates that hepatocyte-based extracorporeal support not only can provide metabolic support by increasing the available functional liver mass but also is capable of modifying humoral and molecular mechanisms which are responsible for proliferation and organ-specific functions of residual hepatocytes.
Suh
K S
KS
Department of Surgery, Burns and Allen Research Institute, Los Angeles, California, 90048, USA.
Lilja
H
H
Kamohara
Y
Y
Eguchi
S
S
Arkadopoulos
N
N
Neuman
T
T
Demetriou
A A
AA
Rozga
J
J
D000818:Animals; D004247:DNA / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D005112:Extracorporeal Circulation; D006501:Hepatic Encephalopathy / Q000097:blood* / Q000378:metabolism / Q000401:mortality / Q000628:therapy*; D017228:Hepatocyte Growth Factor / Q000097:blood / Q000378:metabolism; D019164:Liver, Artificial; D008297:Male; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D012260:Ribonucleases / Q000378:metabolism; D015996:Survival Rate; D014157:Transcription Factors / Q000097:blood* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000097:blood
D012333:RNA, Messenger; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D017228:Hepatocyte Growth Factor; D004247:DNA; D019859:Proto-Oncogene Proteins c-met; D012260:Ribonucleases