Role of Zn 2+ in oxidative stress caused by endotoxin challenge

Abstract

The role of Zn 2+ in oxidative stress during endotoxemia was investigated. In rats fed a Zn 2+-deficient diet (Zn 2+ concentration of less than 1.5 mg/kg) for 8 weeks, the Zn 2+ level in the serum was about 62% lower than that in rats fed a Zn 2+-adequate diet (Zn 2+ concentration, 50 mg/kg). The Zn 2+ level in serum 18 h after administration of endotoxin (6 mg/kg, i.p.) to Zn 2+-deficient diet rats was markedly lower than that of the endotoxin/Zn 2+-adequate diet group. Lipid peroxide formation in the liver of Zn 2+-deficient diet rats was markedly increased 18 h after endotoxin injection compared with that in the endotoxin/Zn 2+-adequate diet group. Metallothionein in the liver of endotoxin/Zn 2+-adequate diet rats was increased more than 17-fold by endotoxin administration, while a markedly lower level of metallothionein was observed in the endotoxin/Zn 2+-deficient diet group. On the other hand, treatment with ZnSO 4 (100 μM) significantly increased endotoxin (1 μg/ml)-induced tumor necrosis factor-α (TNF-α) production in J774A.1 cells. Our results clearly demonstrated that treatment with ZnSO 4 significantly inhibited the endotoxin-induced increase in intracellular Ca 2+ level in J774A.1 cells. However, a cell membrane-permeable Zn 2+ chelator, N, N, N′, N′-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN, 1 μM), did not affect the endotoxin-induced TNF-α production or Ca 2+ level in J774A.1 cells. In addition, we investigated whether Zn 2+ can suppress nitric oxide (NO) generation and cytotoxicity in endotoxin-treated cells. Treatment with ZnSO 4 (50 μM) significantly inhibited endotoxin-induced NO production in J774A.1 cells, but did not affect endotoxin-induced cytotoxicity. These findings suggest that zinc may play an important role, at least in part, in the oxidative stress during endotoxemia.