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  • Title: Nitrite-mediated protection against hypochlorous acid-induced chondrocyte toxicity: a novel cytoprotective role of nitric oxide in the inflamed joint?
    Author: Whiteman M, Rose P, Siau JL, Halliwell B.
    Journal: Arthritis Rheum; 2003 Nov; 48(11):3140-50. PubMed ID: 14613276.
    Abstract:
    OBJECTIVE: To examine the potential consequences of overproduction of nitric oxide (NO) and nitrite (NO(2) (-)) in the inflamed rheumatoid joint. METHODS: Human articular chondrocytes in culture were exposed to HOCl (hypochlorous acid, a physiologic oxidant formed in increased amounts at sites of chronic inflammation), and assays of cell viability, intracellular ATP and glutathione (GSH), and lactate dehydrogenase (LDH) were performed. HOCl-induced lipid peroxidation and activation of the MAP kinases ERK-1/2, JNK-1/2, and p38 were also measured. The modulatory effects of NO-derived nitrite (NO(2) (-)) and nitrate (NO(3) (-)) on HOCl-mediated chondrocyte toxicity were investigated. RESULTS: Exposure of human articular chondrocytes to HOCl resulted in a concentration- and time-dependent loss of viability, decrease in ATP and GSH levels, LDH leakage, and cell death. HOCl induced significant lipid peroxidation as well as activation of the MAP kinases ERK-1/2 and p38 but not JNK-1/2. However, the presence of NO(2) (-) but not NO(3) (-) substantially decreased HOCl-dependent cellular toxicity even when NO(2) (-) was added at low (microM) concentrations. In sharp contrast, NO(2) (-) (1 mM) did not inhibit superoxide-, hydroxyl radical-, H(2)O(2)-, or peroxynitrite-mediated cytotoxicity. Furthermore, culture media from cells treated with interleukin-1beta (to generate NO and NO(2) (-)) offered significantly more protection against HOCl-mediated cytotoxicity than culture media from untreated cells. CONCLUSION: These data suggest that NO(2) (-) accumulation at chronically inflamed sites where both HOCl and NO are overproduced may be cytoprotective against damage induced by HOCl. Accumulation of NO(2) (-) could represent a novel cytoprotective role of NO in inflamed joints. A mechanism for this is suggested.
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