The anti-inflammatory drug nimesulide rescues alpha-1-proteinase inhibitor from oxidative inactivation by phagocytosing neutrophils.
When neutrophils are recruited to tissue sites and exposed to phagocytosable targets, they release oxidants which may be responsible for the local inactivation of alpha-1-proteinase inhibitor (A1PI). Consequently, A1PI becomes incapable of inhibiting the proteolytic activity of elastase, released at the same time by neutrophils as a result of leakage from phagocytic vacuoles. In the present paper we show that phagocytosing neutrophils inactivate A1PI via a process inhibitable by chemical agents known to interfere with the hypochlorous acid (HOCl)-generating myeloperoxidase pathway. The anti-inflammatory drug nimesulide (NMS), which is able to efficiently limit the extracellular availability of HOCl in the neutrophil surroundings, was found to prevent the inactivation of A1PI by neutrophils. The results provide evidence for a possible way to control neutrophil elastase activity by rescuing its natural inhibitor (A1PI) at inflamed tissue sites during infectious and noninfectious processes.
Dallegri
F
F
Department of Internal Medicine, University of Genova, Italy.
Ottonello
L
L
Dapino
P
P
Bevilacqua
M
M
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D005609:Free Radicals; D006801:Humans; D066298:In Vitro Techniques; D019272:Leukocyte Elastase; D008297:Male; D009504:Neutrophils / Q000276:immunology*; D010196:Pancreatic Elastase / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology*; D013449:Sulfonamides / Q000494:pharmacology*; D000515:alpha 1-Antitrypsin / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005609:Free Radicals; D013449:Sulfonamides; D000515:alpha 1-Antitrypsin; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; C012655:nimesulide