Suppression of inflammatory arthritis by simultaneous inhibition of nitric oxide synthase and NADPH oxidase.

Abstract

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.

• Authors: R Miesel, M Kurpisz, H Kroger
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 20 Issue 1 Pg. 75-81 ( 1996) ISSN: 0891-5849 [Print] United States
• PMID: 8903681 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Chromates
• Enzyme Inhibitors
• Nitrites
• Onium Compounds
• Peroxides
• Reactive Oxygen Species
• Superoxides
• potassium tetraperoxochromate
• Nitric Oxide
• diphenyleneiodonium
• Nitric Oxide Synthase
• NADPH Oxidases
• Glutathione Reductase
• Tetradecanoylphorbol Acetate

Topics

• Animals
• Anti-Inflammatory Agents
• Arthritis (drug therapy, metabolism, physiopathology)
• Chromates (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Glutathione Reductase (antagonists & inhibitors)
• Inflammation (metabolism)
• Luminescent Measurements
• Male
• Mice
• Mice, Inbred Strains
• NADPH Oxidases (antagonists & inhibitors)
• Nitric Oxide (metabolism, pharmacology)
• Nitric Oxide Synthase (antagonists & inhibitors)
• Nitrites (metabolism)
• Onium Compounds (pharmacology)
• Peroxides (pharmacology)
• Reactive Oxygen Species (metabolism)
• Superoxides (metabolism)
• Tetradecanoylphorbol Acetate (pharmacology)