Suppression of inflammatory arthritis by simultaneous inhibition of nitric oxide synthase and NADPH oxidase.
TH1-type proinflammatory cytokines induce the expression of phagocytic nitric oxide synthase (NOS) and prime the membrane-bound NADPH oxidase of neutrophils and monocytes of mice so as to attain an activated state, which upon a second stimulus releases up to 6-fold increased levels of reactive oxygen species (ROS) than do unprimed phagocytes. Enhanced levels of ROS and NO deregulate inflammatory signal transduction pathways, which play a crucial role in the pathogenesis of arthritis. The antiarthritic reactivity of diphenylene iodoniumchloride (DPI), an irreversible inhibitor of NADPH oxidase and NOS, was tested in male DBA/1xB10A(4R) hybrid mice suffering from potassium peroxochromate-induced arthritis. Daily doses of 2.8 mu mol/kg of DPI sufficed to inhibit the arthritis by 50%. A complete inhibition was obtained with 10 mu mol/kg of DPI. The reduction of overt arthritic symptoms correlated well with both the reduced levels of ROS and NO in plasma of DPI-treated mice. Our data support the hypothesis that oxidative stress and nitric oxides play a pivotal role in the pathology of arthritis, which can be therapeutically targetted by NADPH oxidase- and NO synthase-inhibitors.
German Rheumatology Research Center, Department of Biochemistry, Berlin, Germany. RMIESEL@SANGER.OTAGO.AC.NZ
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D000818:Animals; D000893:Anti-Inflammatory Agents; D001168:Arthritis / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D002840:Chromates / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D007249:Inflammation / Q000378:metabolism; D008163:Luminescent Measurements; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009573:Nitrites / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology; D010545:Peroxides / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D002840:Chromates; D004791:Enzyme Inhibitors; D009573:Nitrites; D009861:Onium Compounds; D010545:Peroxides; D017382:Reactive Oxygen Species; D013481:Superoxides; C019537:potassium tetraperoxochromate; D009569:Nitric Oxide; C007517:diphenyleneiodonium; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases; D005980:Glutathione Reductase; D013755:Tetradecanoylphorbol Acetate