Expression of presumed specific early and late factors associated with liver regeneration in different rat surgical models

Experiments performed on the portal branch ligation (PBL) model indicate th at early changes observed after surgery are not related to the regenerative process because they also occur in atrophying lobes. To further confirm th e lack of specificity of the early events and to exclude the influence of c irculatory factors released by proliferating lobes on their occurrence, we investigated this response after sham operation (SO) and portacaval shunt ( PCS), a model characterized by liver atrophy. We also attempted to determin e expression of later events associated specifically with regeneration, ie, expression of p53 or c-Ha-ras, or inhibition of proliferation, ie, interle ukin-1 beta (IL-1 beta) and transforming growth factor-1 beta (TGF-beta1) a fter partial (PH) and temporary partial (TPH) hepatectomy, SO and PCS. Nucl ear factor-kappaB (NF-kappaB) and signal transducer and activator of transc ription 3 (STAT3) DNA binding were assessed by electrophoretic mobility shi ft assay (EMSA), interleukin-6 (IL-6) mRNA by reverse transcription-polymer ase chain reaction (RT-PCR), c-myc and c-jun mRNAs by Northern blot analysi s at 0.5 and 2 hours, p53 and c-Ha-ras mRNAs by Northern blot analysis at 8 and 24 hours, and IL-1 beta and TGF-beta1 by RT-PCR at 24 hours. The early response including an increase of NF-kappaB, STAT3, IL-6, and immediate-ea rly genes expression was present after PH, PCS, and SO. In SO, slight diffe rences were observed in comparison with PH: no NF-kappaB p65/p50 DNA bindin g was observed, only three of six SO rats were positive for IL-6, and immed iate-early genes induction showed differences in the intensity of the respo nse. At later times, p53 mRNA increased at 8 hours after PH and TPH, c-Ha-r as mRNA at 24 hours after PH, and IL-1 beta mRNA at 24 hours after PCS. Ear ly events are not specifically associated with the reduction of liver mass or with the regenerative process, are not predictive of future cell fate, a nd are most likely related to surgical stress. p53 and c-Ha-ras induction i s closely associated with cell cycle progression whereas IL-1 beta, but not TGF-beta1, appears to be one of the negative growth regulators that might play an important role in atrophy.