POSSIBLE ROLES OF NONPARENCHYMAL CELLS IN HEPATOCYTE PROLIFERATION INDUCED BY LEAD NITRATE AND BY TUMOR-NECROSIS-FACTOR-ALPHA

A single intravenous injection of lead nitrate (LN) to rats induces li ver cell proliferation without causing cell necrosis (direct hyperplas ia), We suggested that liver cell proliferation in this model may be t riggered by the induction of liver tumor necrosis factor alpha (TNF-al pha), Because administration of TNF-alpha in vivo has been shown to in duce proliferation of both parenchymal and nonparenchymal cells of the Liver, we analyzed the temporal sequences of DNA synthesis in both ce ll populations following LN and recombinant TNF-alpha treatment by 5-b romo-2-deoxyuridine (BrdU) immunohistochemistry. The patterns of cell proliferation induced by these agents were further compared with those induced by a single dose of nafenopin (NAF), a direct mitogen which d oes not induce liver TNF-alpha messenger RNA (mRNA), In male Wistar ra ts given a single dose of LN (100 mu mol/kg), BrdU incorporation of he patocytes and nonparenchymal cells (Kupffer cells, endothelial cells a nd periportal nondescript cells) became evident 12 hours after the tre atment; The labeling of all cell types reached a peak. after 38 hours and declined thereafter, Rats given a single intravenous injection of human recombinant TNF-alpha (46 mu g/rat) showed an increase of BrdU l abeling in nonparenchymal cells after 24 hours, whereas the labeling o f hepatocytes became evident at 36 hours, A single intragastric admini stration of NAF resulted in a rapid increase in the number of labeled hepatocytes with no substantial labeling of nonparenchymal cells, Thes e results add further support to the notion that LN-induced liver cell proliferation is mediated by TNF-alpha, and suggest that different ce ll populations are involved in the initial proliferative response of t he liver to mitogens, depending on the capacity of the mitogens to sti mulate TNF-alpha production.