EFFECT OF SIALOADENECTOMY AND EPIDERMAL GROWTH-FACTOR ADMINISTRATION ON LIVER-REGENERATION AFTER PARTIAL-HEPATECTOMY

Epidermal growth factor (EGF), a mitogen in vitro for hepatocytes, pro duces in various cell lines changes similar to those observed very rap idly in hepatocytes after partial hepatectomy (PH). These changes incl ude ion movements, membrane hyperpolarization and proto oncogene expre ssion. A stimulatory effect of EGF on liver regeneration can therefore tentatively be associated with the events occurring within the first 3 hours after a PH, sometimes referred to as the ''priming phase.'' To assess this hypothesis, we examined in Wistar rats the effect of EGF deprivation produced by sialoadenectomy (SX) performed before or after a PH of 70%. SX at the time of PH significantly decreased the H-3-thy midine uptake in the DNA 24 hours later (147 +/- 14 DPM per microgram of DNA, mean +/- SE) compared with a simple PH (322 +/- 16; P < .01), but also compared with results obtained when PH is combined with a sha m sialoadenectomy (SSX) or in rats pair-fed with the sialoadenectomize d rats. This incomplete inhibition was confirmed by a decreased rise i n thymidine kinase (TK) activity and by reduced proliferating cell nuc lear antigen (PCNA) labeling and mitotic indices 30 hours after PH. By contrast, SX did not inhibit the early expression of c-jun and c-fos, or of c-myc, 30 or 120 minutes after PH, respectively. A reduction of DNA synthesis was also obtained when SX was performed 3 hours after P H (127 +/- 15 DPM per microgram of DNA vs. 350 +/- 21 in SSX; P < .001 ) but not when SX was delayed until the 6th or the 17th hour after PH. It was sufficient to administer EGF (40 mu g) hom the third to the ni nth hour to correct the reduction of [H-3]thymidine uptake in rats sia loadenectomized before PH. These results indicate that the diminished EGF availability following SX decreases or at least delays liver regen eration, and that the effect of EGF on liver regeneration does not see m related to the early changes of proto-oncogene expression, but rathe r to events occuring later, at the time of reported internalization an d binding of EGF to its nuclear receptors.