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Amelioration of oxidant stress by the defensin lysozyme

Division of Experimental Diabetes and Aging, Department of Geriatrics, and Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York

Submitted 29 July 2005 ; accepted in final form 18 November 2005

Reactive oxidant species (ROS), products of normal metabolism, cause oxidant injury if they accumulate in pathological amounts. Lysozyme (LZ) contains an 18-amino acid domain that binds agents such as advanced glycation end products (AGE) that generate ROS. We examined whether endogenous LZ affected physiological, or baseline, antioxidant balance and provided protection against both acute and chronic oxidant injury, using paraquat and H₂O₂ as agents of acute injury and AGE for chronic injury. Hen egg LZ-Tg mice had threefold higher serum LZ levels and decreased baseline AGE levels in serum and liver. These findings were linked to an enhanced baseline systemic GSH-to-GSSG ratio. Baseline levels of stress response genes p66^Shc and c-Jun were also lower in liver tissue of LZ-Tg mice. Survival from severe oxidant injury induced by paraquat was twofold greater in LZ-Tg mice. In addition, LZ-Tg mice were resistant to chronic exogenous oxidant stress (OS) induced by AGE administration. Preincubation of hepatocytes (Hep G2) with LZ suppressed redox balance at baseline, as well as OS after added paraquat, AGE, or H₂O₂. LZ also ameliorated paraquat-enhanced cell apoptosis in a dose-dependent manner and suppressed AGE-induced p66^Shc expression and c-Jun phosphorylation in Hep G2 cells. Thus LZ provides protection against acute and chronic oxidant injury by mechanisms involving suppression of ROS generation and of OS response genes.

reactive oxygen species; paraquat; glycoxidation; lipoxidation; redox balance; oxidant injury

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