NEUTROPHIL-ASSOCIATED INFLAMMATORY RESPONSES IN RATS ARE INHIBITED BYPHENYLARSINE OXIDE

NADPH oxidase is a phagocyte-specific enzyme which produces O-2(-) and so initiates a cascade of reactive oxygen species formation. Inflamma tory diseases involve overproduction of reactive oxygen species which induce tissue damage. Phenylarsine oxide has been described previously as a complete and direct inhibitor of NADPH oxidase in vitro that act s by covalently binding to vicinal thiol groups of a membrane-associat ed component of the enzyme. In the present work, the potential anti-in flammatory effect of phenylarsine oxide was tested on two experimental models in rats, carrageenan-induced paw oedema and lipopolysaccharide -mediated lung inflammation. Intraperitoneal injection of phenylarsine oxide reduced (i) reactive oxygen species production by rat phagocyte s, (ii) neutrophil infiltration into the lung after inhalation of lipo polysaccharide and (iii) neutrophil-dependent oedema induced by carrag eenan in hindpaws. We conclude that phenylarsine oxide has anti-inflam matory properties which are probably exerted by its ability to inhibit neutrophil NADPH oxidase-dependent reactive oxygen species production . The present work provides the basis for the development of new anti- inflammatory, arsenic-free agents reacting at the phenylarsine oxide s ite, which seems to be the Achilles' heel of NADPH oxidase. (C) 1997 E lsevier Science B.V.