Extent of liver resection modulates the activation of transcription factors and the production of cytokines involved in liver regeneration.
OBJECTIVE
To investigate the molecular events involved in liver regeneration following subtotal hepatectomy (SH) as previous studies have largely focused on partial hepatectomy (PH).


METHODS
Male Wistar rats were subjected to 70% PH or 90% SH, respectively, and sacrificed at different times after surgery. Untreated and sham-operated animals served as controls. Serum and liver samples were obtained to investigate liver function, apoptosis (TUNEL assay) and transcription factors (NF-kappaB, Stat3; ELISA) or cytokines (HGF, TNF-alpha, IL-6, TGF-alpha, TGF-beta; quantitative RT PCR) involved in liver regeneration.


RESULTS
Serum levels of ALT and AST in animals with 70% PH differed significantly from sham-operated and control animals. We found that the peak concentration 12 h after surgery returned to control levels 7 d after surgery. LDH was increased only at 12 h after 70% PH compared to sham. Bilirubin showed no differences between the sham and 70% resection. After PH, early NF-kappaB activation was detected 12 h after surgery (313.21 +/- 17.22 ng/mL), while there was no activation after SH (125.22 +/- 44.36 ng/mL) compared to controls (111.43 +/- 32.68 ng/mL) at this time point. In SH, however, NF-kappaB activation was delayed until 24 h (475.56 +/- 144.29 ng/mL). Stat3 activation was similar in both groups. These findings correlated with suppressed and delayed induction of regenerative genes after SH (i.e. TNF-alpha 24 h postoperatively: 2375 +/- 1220 in 70% and 88 +/- 31 in 90%; IL-6 12 h postoperatively: 2547 +/- 441 in 70% and 173 +/- 82 in 90%). TUNEL staining revealed elevated apoptosis rates in SH (0.44% at 24 h; 0.63% at 7 d) compared to PH (0.27% at 24 h; 0.15% at 7 d).


CONCLUSIONS
The molecular events involved in liver regeneration are significantly influenced by the extent of resection as SH leads to suppression and delay of liver regeneration compared to PH, which is associated with delayed activation of NF-kappaB and suppression of proregenerative cytokines.
Sowa
Jan-Peter
JP
Department of Gastroenterology and Hepatology, University Hospital of Essen, Hufelandstr. 55, 45122 Essen, Germany.
Best
Jan
J
Benko
Tamas
T
Bockhorn
Maximillian
M
Gu
Yanli
Y
Niehues
Eva-Maria
EM
Bucchi
Agnieska
A
Benedetto-Castro
Eva-Maria
EM
Gerken
Guido
G
Rauen
Ursula
U
Schlaak
Jorg-Friedrich
JF
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D006498:Hepatectomy / Q000379:methods*; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000601:surgery*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D023421:Models, Animal; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D015850:Interleukin-6; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D014157:Transcription Factors; D016211:Transforming Growth Factor alpha; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha