INACTIVATION OF ALPHA-1-PROTEINASE INHIBITOR BY NEUTROPHIL METALLOPROTEINASES - CRUCIAL ROLE OF THE MYELOPEROXIDASE SYSTEM AND EFFECTS OF THE ANTIINFLAMMATORY DRUG NIMESULIDE

Supernatants, obtained from normal neutrophil polymorphonuclear leukoc ytes (PMN), challenged with opsonized zymosan (OPZ), were found to ina ctivate the PMN elastase inhibitor, alpha1-proteinase inhibitor (A1PI) . As the supernatants were treated with methionine to quench residual oxidants, primarily chloramines, the observed inactivation of A1PI app ears to be due to enzymes. The activity of the supernatants was in fac t inhibited by metalchelators and by the tissue inhibitor of metallopr oteinases (TIMP), which is consistent with the intervention of metallo proteinases. Supernatants from normal PMN triggered by OPZ in the pres ence of inhibitors of the myeloperoxidase (MPO) system as well as supe rnatants from MPO-deficient PMN were inactive but displayed the capaci ty of inactivating A1PI after treatment with the metalloproteinases ac tivator 4-aminophenylmercuric acetate. These data suggest that the A1P I inactivation is due to metalloenzymes released by PMN as latent mole cules, in turn activated by the MPO system. The MPO-dependent autoacti vation of latent metalloenzymes by PMN, with consequent A1PI inactivat ion, was inhibited by the nonsteroidal anti-inflammatory drug nimesuli de (NMS). As PMN-derived HOCl is well known to inactivate A1PI directl y, through a process previously shown to be inhibitable by NMS, the pr esent results suggest: (1) both the oxidative and proteolytic inactiva tion of A1PI depend on the HOCl-generating MPO system; (2) the tissue- destructive activity of PMN elastase could be controlled by interferin g pharmacologically with the PMN-MPO system, directly and indirectly r esponsible for the breakdown of the tissue antielastase screen.