Nimesulide as a downregulator of the activity of the neutrophil myeloperoxidase pathway. Focus on the histoprotective potential of the drug during inflammatory processes.
Neutrophils, recruited to tissue sites of inflammation, release a variety of oxidants and enzymes, which are responsible for tissue damage. Among the oxidants released are potent chlorinated compounds, such as hypochlorous acid and chloramines, which induce tissue cell damage and inactivate protease inhibitors, particularly alpha 1-antitrypsin, the specific inhibitor of neutrophil elastase. In studying a rational approach to the pharmacological control of neutrophil-mediated tissue injury, we investigated the activity of the anti-inflammatory drug nimesulide. This agent reduced the function of the myeloperoxidase pathway (which generates hypochlorous acid), by exerting a cell-directed inhibitory activity, as shown by measurement of superoxide anion and hydrogen peroxide production. Nimesulide also inactivated hypochlorous acid directly and protected alpha 1-antitrypsin from the neutrophil-mediated oxidation. Thus, neutrophil elastolytic activity may be attenuated by nimesulide-spared alpha 1-antitrypsin. The prevention of oxidative inactivation of alpha 1-antitrypsin by nimesulide strictly correlates with the drug's ability to suppress the extracellular availability of hypochlorous acid. Taken together, these data suggest that nimesulide may prevent tissue injury at sites of inflammation by maintaining natural host protective systems.
Ottonello
L
L
Department of Internal Medicine, University Medical School, Genova, Italy.
Dapino
P
P
Pastorino
G
G
Montagnani
G
G
Gatti
F
F
Guidi
G
G
Dallegri
F
F
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015536:Down-Regulation; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D013449:Sulfonamides; D009195:Peroxidase; C012655:nimesulide