Neutrophil-associated inflammatory responses in rats are inhibited by phenylarsine oxide.
NADPH oxidase is a phagocyte-specific enzyme which produces O2- and so initiates a cascade of reactive oxygen species formation. Inflammatory 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 acts by covalently binding to vicinal thiol groups of a membrane-associated component of the enzyme. In the present work, the potential anti-inflammatory 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 phagocytes, (ii) neutrophil infiltration into the lung after inhalation of lipopolysaccharide and (iii) neutrophil-dependent oedema induced by carrageenan in hindpaws. We conclude that phenylarsine oxide has anti-inflammatory 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 site, which seems to be the Achilles' heel of NADPH oxidase.
Roussin
A
A
Institut de Pharmacologie et de Biologie Structurale, CNRS UPR 9062, Toulouse, France.
Le Cabec
V
V
Lonchampt
M
M
De Nadaï
J
J
Canet
E
E
Maridonneau-Parini
I
I
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001152:Arsenicals / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002351:Carrageenan; D004487:Edema / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D008070:Lipopolysaccharides; D008297:Male; D009504:Neutrophils / Q000502:physiology*; D010586:Phagocytes / Q000187:drug effects / Q000378:metabolism; D011654:Pulmonary Edema / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001152:Arsenicals; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; C029341:oxophenylarsine; D002351:Carrageenan