Inactivation of alpha-1-proteinase inhibitor by neutrophil metalloproteinases. Crucial role of the myeloperoxidase system and effects of the anti-inflammatory drug nimesulide.
Supernatants, obtained from normal neutrophil polymorphonuclear leukocytes (PMN), challenged with opsonized zymosan (OPZ), were found to inactivate the PMN elastase inhibitor, alpha 1-proteinase inhibitor (A1PI). As the supernatants were treated with methionine to quench residual oxidants, primarily chloramines, the observed inactivation of A1PI appears to be due to enzymes. The activity of the supernatants was in fact inhibited by metal-chelators and by the tissue inhibitor of metalloproteinases (TIMP), which is consistent with the intervention of metalloproteinases. Supernatants from normal PMN triggered by OPZ in the presence of inhibitors of the myeloperoxidase (MPO) system as well as supernatants from MPO-deficient PMN were inactive but displayed the capacity of inactivating A1PI after treatment with the metalloproteinases activator 4-aminophenylmercuric acetate. These data suggest that the A1PI inactivation is due to metalloenzymes released by PMN as latent molecules, in turn activated by the MPO system. The MPO-dependent autoactivation of latent metalloenzymes by PMN, with consequent A1PI inactivation, was inhibited by the nonsteroidal anti-inflammatory drug nimesulide (NMS). As PMN-derived HOCl is well known to inactivate A1PI directly, through a process previously shown to be inhibitable by NMS, the present results suggest: (1) both the oxidative and proteolytic inactivation of A1PI depend on the HOCl-generating MPO system; (2) the tissue-destructive activity of PMN elastase could be controlled by interfering pharmacologically with the PMN-MPO system, directly and indirectly responsible for the breakdown of the tissue antielastase screen.
Department of Internal Medicine, University of Genova Medical School, Italy.
L
L
Ottonello
P
P
Dapino
F
F
Dallegri
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D019272:Leukocyte Elastase; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology*; D010196:Pancreatic Elastase / Q000378:metabolism*; D009195:Peroxidase / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology*; D000515:alpha 1-Antitrypsin / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D013449:Sulfonamides; D000515:alpha 1-Antitrypsin; D009195:Peroxidase; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; D008666:Metalloendopeptidases; C012655:nimesulide