ROLES OF GROWTH-FACTORS AND OF TUMOR-NECROSIS-FACTOR-ALPHA ON LIVER-CELL PROLIFERATION INDUCED IN RATS BY LEAD NITRATE

BACKGROUND: A single intravenous injection of lead nitrate to rats ind uces a synchronized wave of hepatocyte proliferation without accompany ing liver cell necrosis. However, the mechanism of the mitogenic effec t of lead nitrate is not known, and whether hepatocyte growth factor ( HGF), transforming growth factor-alpha (TGF-alpha), and transforming g rowth factor-beta 1 (TGF-beta 1) play any role in it have not been inv estigated, These growth factors have indeed been shown to provide eith er positive or negative stimuli for liver cell regeneration after part ial hepatectomy or liver cell necrosis. Moreover, there are reports sh owing that administration of non-necrogenic doses of tumor necrosis fa ctor-alpha (TNF-alpha) to rats lead to an enhanced proliferation of he patocytes and liver nonparenchymal cells, Lead is known to sensitize a nimals to lethal effects of bacterial lipopolysaccharides (LPS), sugge sting that lead nitrate may modify the production of TNF-alpha in resp onse to endogenous LPS of intestinal origin. An enhanced production of TNF-alpha could therefore be involved in the mitogenic action of lead nitrate. EXPERIMENTAL DESIGN: We investigated first whether a single intravenous dose of lead nitrate (100 mu mole/kg) to rats modifies the production of HGF, TGF-alpha, and TGF-beta 1, by examining the steady -state level of their mRNA in the liver by Northern blot analyses. The response of rats given lead nitrate to various doses of LPS was next evaluated to determine whether lead-treated rats have an enhanced sens itivity to LPS. Finally, the level of TNF-alpha mRNA was examined in t he liver of rats at various time periods after a single injection of l ead nitrate, RESULTS: No changes were observed in the liver levels of mRNAs for HGF, TGF-alpha, and TGF-beta 1 at various time intervals aft er a single injection of lead nitrate. All rats given only single inje ctions of LPS up to 100 mu g survived. However, lead nitrate-treated r ats tolerated LPS at dosages of only 6 mu g. The liver of control rats showed a single 1.6 kb TNF-alpha transcript, whereas 1.8-kb transcrip ts were seen at 1 hour after lead nitrate injection, and persisted for 12 hours. The 1.8 kb TNF-alpha transcript was also present in the spl een of control rats, and its expression was enhanced in lead nitrate-t reated rats. CONCLUSIONS: Stimulation of hepatocyte proliferation indu ced by lead nitrate was not accompanied by changes in liver levels of HGF, TGF-alpha, or TGF-beta 1 mRNA, Lead nitrate, however, enhanced ex pression of TNF-alpha at a time preceding the onset of hepatocyte DNA synthesis, indicating that TNF-alpha may trigger the lead nitrate-indu ced proliferation of hepatocytes.