Hepatocyte proliferation induced in rats by lead nitrate is suppressed by several tumor necrosis factor α inhibitors

Abstract

Lead nitrate induces liver cell proliferation in rats effect on the liver as well as toxic and teratogenic effect without accompanying liver cell necrosis. However, the on various organs. At least two major types of liver mechanism of this proliferation and its effect on hepato-cell proliferation have been shown in rat experimental cytes remain unknown. Therefore, we examined the models: compensatory regeneration caused by necroliver and blood level of hepatocyte growth factor and genic stimulation and hyperplasia induced by mitotumor necrosis factor a (TNF-a) at various intervals to genic agents. 3 The former includes regeneration after determine whether lead nitrate modifies hepatocyte carbon tetrachloride (CCl 4 ) liver injury, D-galactosproliferation by altering the production of these cytoamine liver injury, and choline deficient diet. treatment with these inhibitors suppresses the increase and cyclosporine. 9 Biological and pathological distincof TNF-a messenger RNA (mRNA) in the liver and pre-tions between liver cell regeneration and hyperplasia vents the hepatocyte proliferation induced by lead ni-have been studied to clarify the mechanism of mitotrate. Hepatocyte proliferation occurred by 24 hours and genic stimulation. For example, compensatory cell proreached a peak 48 hours after a single intravenous injec-liferation enhanced the initiation and promotion of cartion of lead nitrate (100 mmol/kg). TNF-a mRNA exprescinogenesis in rat liver, whereas primary hyperplasia sion in the liver was increased 1, 6, and 12 hours after the induced by lead nitrate and ethylene dibromide was injection, whereas no alteration was observed in liver or not carcinogenic.3,10 Transient increases of expression blood level of hepatocyte growth factor. Pretreatment with dexamethasone (4.0 mg/kg), E3330 (100 mg/kg) of some cell cycle-related genes, c-fos and c-myc, were adenosine (0.3 mmol/kg), and pentoxifylline (100 mg/kg), observed in rat models of compensatory regeneration inhibited both TNF-a mRNA expression and hepatocyte such as partial hepatectomized rat and CCl 4 adminisproliferation 48 hours after the injection. These experi-tration. However, this effect was not detected in the mental results strongly support the hypothesis that experimental models using treatment with lead ni- pathways mediating liver cell proliferation induced by Lead nitrate is a mitogen in vivo and has a powerful these mitogens still remains to be investigated. proliferative effect on rat liver without accompanying Recently, it has been shown that several growth fachistopathological liver cell necrosis.1,2 This mitogen is tors, including hepatocyte growth factor (HGF), transan ubiquitous heavy metal salt and has proliferative forming growth factor a (TGF-a), and transforming growth factor b 1 (TGF-b1), regulate liver cell proliferation in the rat models of compensatory regeneration. 13-20 HowAbbreviations: CCl4, carbon tetrachloride; HGF, hepatocyte growth factor; TGF, transforming growth factor; mRNA, messenger RNA; TNF-a, tumor neever, it has b...

Amelioration of lead toxicity on rat liver with Vitamin C and silymarin supplements

“…DNA synthesis was detected in a few scattered hepatocytes and in non-descript periductular cells. Proliferation on non-parenchymal cells reflect a direct mitogenic effect of lead nitrate and that hepatocyte proliferation follows the nonparenchymal cell reaction to lead nitrate (Rijhsinghani et al, 1993;Kubo et al, 1996). Recent studies have shown that lead-induced DNA damage (Fracasso et al, 2002;Valverde et al, 2002;Danadevi et al, 2003;Hengstler et al, 2003;Xu et al, 2003).…”

In vivo hepatocyte proliferation is inducible through a TNF and IL-6-independent pathway

“…Hepatocytes, however can be stimulated to proliferate by treatment with a variety of agents such as triiodothyronine, retinoic acid, peroxisome proliferators, lead nitrate and barbiturates that do not cause tissue loss/injury, but rather an excess of cells . Unlike compensatory regeneration observed after 2/3 PH or chemically-induced cell necrosis, direct hyperplasia induced by primary mitogens is neither accompanied by increased hepatic mRNA levels of growth factor genes such as TGF-a and HGF (Ohmura et al, 1996), nor by increased levels of circulating HGF (Kubo et al, 1996). These ®ndings suggest that the growth factors critical for liver regeneration may not be involved in direct hyperplasia.…”

Gene Expression of Neurotrophins and Their Receptors in Lead Nitrate-Induced Rat Liver Hyperplasia

“…In the LN-untreated (control) liver, the transcripts of NGF, BDNF Ex4, NT3s (E1A and E1B), p75NTR, and all Trk species were clarified to be present, suggesting the possibility that proliferation and/or function of hepatic cells are, at least in part, regulated through a neurotrophin- TNF-␣, but not hepatocyte growth factor (HGF) or transforming growth factor (TGF-␣ or -␤1), hitherto, has been proposed to be a trigger for the LN-induced liver hyperplasia, because its gene expression was enhanced ahead of the initiation of DNA synthesis in the liver after LN-administration (37), and some TNF-␣ inhibitors suppressed the LN-induced hepatocyte growth (38,39). In the present study, the enhanced expression of TNF-␣ gene (a peak at 6 -12 h) by LNadministration was also observed prior to the increase of the liver weight (Figs.…”