Reactivity of an active center analog of Cu2Zn2superoxide dismutase in murine model of acute and chronic inflammation

Abstract

The antiinflammatory efficacy of CuPu(Py)2 ([[N,N'-bis(2-pyridylmethylene)-1,4-butanediamine] (N,N',N'',N''')]-Cu2+), a serum stable active center analog of Cu2Zn2superoxide dismutase (SOD), was tested in vitro and in vivo in male Wistar rats suffering from potassium peroxochromate-induced inflammation. Parameters including 99mTc gamma-scintigraphic imaging, the arthritis score, the plasma superoxide dismutase activity, the inhibition of plasma sulfhydryl depletion as well as mitogenic and phagocytic responses were used to quantify the disease activity. All parameters improved impressively during the treatment with CuPu(Py)2 and resembled those of healthy animals after 21 days. The arthritis score was inhibited by 80% (P > 0.001) and the plasma SOD activity enhanced by 380% (P > 0.001). The depletion of plasma sulfhydryls and the leukocytic responses to concanavalin A, tetradecanoylphorbolacetate, and lipopolysaccharide were significantly reduced (P > 0.001) and correlated well with the arthritis score. The collapse of antioxidant defenses in human plasma as well as the depolymerization of hyaluronic acid was mimicked in vitro and successfully inhibited by CuPu(Py)2. Oxidant-induced injury of plasma components during the aqueous decay of potassium peroxochromate were demonstrated to activate the oxidative burst of phagocytes in human blood. The role of impaired pro- and antioxidant balances in the etiology of inflammatory and autoimmune rheumatic diseases is discussed.

Priming of NADPH oxidase by tumor necrosis factor alpha in patients with inflammatory and autoimmune rheumatic diseases

“…Whether the oxidizing activity of phagocytes in rheumatic patients described here is a consequence of the inflammation associated with arthritis or is also capable of itself modulating the development of the disease by interaction with T and B cells is unclear at present. Nevertheless, inhibition of oxidative stress by selective inhibitors of NADPH oxidase [41] or a serum stable active center analogue of Cu2Zn2 superoxide dismutase have been shown to be exceptionally effective in suppressing the development of arthritis in both inflammatory and autoimmune animal models of arthritis [42,43], Our data support the hypothesis that reactive oxygen species are major signal transducers in inflammatory and rheumatic diseases. ROS may be responsible for the molecular coordination of unspecific and specific defenses by transfeting extracellular signals into specific patterns of gene expression in the nucleus.…”

Toll-Like Receptor 4–Mediated Nuclear Factor Kappa B Activation Is Essential for Sensing Exogenous Oxidants to Propagate and Maintain Oxidative/Nitrosative Cellular Stress

“…Furthermore, PPC has been used as an oxidant-induced injury model to study arthritis [36]. The products of aqueous decay of PPC have been shown to activate the oxidative burst of phagocytes in human blood [37]. The choice of a Cr salt with (+VI) valency state was therefore based on its ability to generate a robust amount of prooxidants in biological systems, and not based on its clinical utility as a trace metal element per se.…”

“…To this end, we examined responses of mice to an orofacial inflammatory pain with IMM injection of PPC to mimic a model of “sterile” inflammation [74], [75]. PPC decays slowly in vivo to generate the same reactants that are produced physiologically by activated phagocytes [27], [37]. These reactants can maintain the inflammatory process for a long time by reducing cellular antioxidant defenses.…”

Male Genital Tract Inflammation: The Role of Selected Interleukins in Regulation of Pro‐Oxidant and Antioxidant Enzymatic Substances in Seminal Plasma

“…Superoxide dismutase (SOD) activity was quantified by chemiluminescence (Miesel and Weser; 1991; Miesel and Haas, 1993) using the xanthine/xanthine oxidase lucigenin assay. A final volume of 1 mL of the sample contained the following components: 100 μL of seminal plasma, 100 mM diethylenetriaminepentaacetic acid (DTPA), 100 mM lucigenin, 180 nM xanthine oxidase, and 50 mM xanthine in 50 nM HEPES (pH 7.4).…”