EPIDERMAL GROWTH-FACTOR SECRETED FROM THE SALIVARY-GLAND IS NECESSARYFOR LIVER-REGENERATION

Partial hepatectomy (PH) in rats induces a synchronized burst of DNA r eplication in the remnant liver that peaks at 24 h post-PH. We report here that removal of the major salivary glands before one-third and tw o-thirds PH prevents the proliferative response in the remaining liver . Twelve days after one-third PH, the remnant liver is 89% of the norm al liver weight in nonsalivectomized rats but only 55% in salivectomiz ed animals. This indicates that salivectomy does not merely delay the first round of cell division but that it prevents actual regeneration. Salivectomy alters the early protooncogene response to partial hepate ctomy. In salivectomized rats, the characteristic peak of c-myc mRNA s ynthesis at 2-4 h after PH is significantly decreased compared with no nsalivectomized rats. The peak of DNA synthesis at 24 h after PH in sa livectomized rats is also dramatically decreased. DNA synthesis as mea sured by [H-3]thymidine incorporation into DNA of hepatic cells is dec reased similar to 90% in salivectomized rats vs. nonsalivectomized rat s 22-26 h after PH. Ligation of the venous drainage of the salivary gl and results in the same inhibitory effect on DNA synthesis, indicating 1) that the salivary gland must release circulating factor(s), and 2) that the early increase in c-myc expression and the subsequent DNA sy nthesis, both of which reflect the stimulation of cellular proliferati on in the regenerating liver, are induced by humoral factor(s) release d from the salivary glands. Injection of exogenous epidermal growth fa ctor (EGF) in salivectomized rats results in restoration of both the D NA synthetic and c-myc responses at levels characteristic of those of liver regeneration. Thus our results suggest that salivary gland relea se of EGF may trigger the early events of liver regeneration.