Antiinflammatory effects of NADPH oxidase inhibitors.
Proinflammatory cytokines prime the membrane-bound NADPH oxidase of neutrophils and monocytes of mice suffering from experimental arthritis so as to attain an activated state, which, upon a second stimulus, releases 6-fold increased levels of reactive oxygen species (ROS) than do unprimed phagocytes. Enhanced NADPH oxidase activity deregulates ROS-dependent signal transduction pathways of inflammation, which play a crucial role in the pathogenesis of arthritis. The antiarthritic reactivity of two inhibitors of NADPH oxidase, diphenylene iodoniumchloride (DPI) and staurosporine, was tested in male DBA/1 x B10A(4R) hybrid mice suffering from potassium peroxochromate arthritis. Daily doses of 2.8 mumol/kg of DPI or 30 nmol/kg of staurosporine sufficed to inhibit the arthritis by 50%. A complete inhibition was obtained with 10 mumol/kg of DPI, and 100 nmol/kg of staurosporine suppressed the arthritis by 85%. The onset, progression, and remission of arthritis correlated to both the activity of phagocytic NADPH oxidase (r = 0.750) and to overt disease symptoms as judged by the arthritis index. Our data support the hypothesis that oxidative stress plays a pivotal role in the pathology of arthritis, which can be therapeutically targeted by NADPH oxidase inhibitors.
Miesel
R
R
Department of Biochemistry, Deutsches Rheuma-ForschungsZentrum, Berlin, Germany.
Sanocka
D
D
Kurpisz
M
M
Kröger
H
H
D000470:Alkaloids / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D001168:Arthritis / Q000139:chemically induced / Q000517:prevention & control*; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D002840:Chromates / Q000633:toxicity; D008163:Luminescent Measurements; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D019255:NADPH Oxidases; D009861:Onium Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects*; D010545:Peroxides / Q000633:toxicity; D010586:Phagocytes / Q000187:drug effects* / Q000201:enzymology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016897:Respiratory Burst / Q000187:drug effects*; D013047:Specific Pathogen-Free Organisms; D019311:Staurosporine
D000470:Alkaloids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001713:Biphenyl Compounds; D002840:Chromates; D009861:Onium Compounds; D010545:Peroxides; D017382:Reactive Oxygen Species; C031291:diphenyliodonium; C019537:potassium tetraperoxochromate; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; D019311:Staurosporine