title: Modulation of tumor necrosis factor-alpha and oxidative stress through protein kinase C and P42/44 mitogen-activated protein kinase in lead increases lipopolysaccharide-induced liver damage in rats.
abstract: Lead (Pb) increases lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO), lipid peroxidation (LPO), and liver damage. In this study, we investigated the role of protein kinase C (PKC) and p42/44 mitogen-activated protein kinase (MAPK) and the causal relationships between TNF-alpha, NO, and LPO in Pb-increased LPS-induced liver damage in rats. Treatment with PKC and p42/44 MAPK inhibitors significantly reduced Pb + LPS-induced NO, TNF-alpha, LPO, and liver damage, which was revealed by elevated serum levels of aspartate aminotransferase and alanine aminotransferase. Pb + LPS coexposure significantly increased phosphorylation of p42/44 MAPK and TNF-alpha expression in peripheral blood cells; however, exposure to Pb + LPS did not induce TNF-alpha, NO, or LPO production and p42/44 MAPK activation in the liver. Pentoxifylline, a TNF-alpha inhibitor, also reduced liver damage but did not alter NO or LPO in Pb + LPS-treated rats. Thus, Pb increased LPS-induced liver damage through PKC and p42/44 MAPK modulation of TNF-alpha and oxidative stress, but modulation of TNF-alpha did not affect NO or LPO in rats.
authors.affiliation: Department of Environmental and Occupational Health, and Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan 70428.
authors.forename: Yu-Jung
authors.initials: YJ
authors.lastname: Cheng
authors.forename: Ming-Yie
authors.initials: MY
authors.lastname: Liu
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000470:Alkaloids; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D053119:Benzophenanthridines; D002070:Butadienes / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D007854:Lead / Q000494:pharmacology*; D015227:Lipid Peroxidation; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000293:injuries* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D018384:Oxidative Stress; D010617:Phenanthridines / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000470:Alkaloids; D053119:Benzophenanthridines; D002070:Butadienes; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009570:Nitriles; D010617:Phenanthridines; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; D007854:Lead; D009569:Nitric Oxide; C016299:chelerythrine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3