Modulation of tumor necrosis factor-α and oxidative stress through protein kinase C and P42/44 mitogen-activated protein kinase in lead increases lipopolysaccharide-induced liver damage in rats

Lead (Pb) increases lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α), 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 (MARK) and the causal relationships between TNF-α, 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-α, 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-α expression in peripheral blood cells; however, exposure to Pb + LPS did not induce TNF-α, NO, or LPO production and p42/44 MAPK activation in the liver. Pentoxifylline, a TNF-α 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-α and oxidative stress, but modulation of TNF-α did not affect NO or LPO in rats.