DIFFERENT SUSCEPTIBILITY OF ELASTASE INHIBITORS TO INACTIVATION BY PROTEINASES FROM STAPHYLOCOCCUS-AUREUS AND PSEUDOMONAS-AERUGINOSA

被引:36
作者
SPONER, M [1 ]
NICK, HP [1 ]
SCHNEBLI, HP [1 ]
机构
[1] CIBA GEIGY AG,DIV PHARMACEUT,CH-4002 BASEL,SWITZERLAND
来源
BIOLOGICAL CHEMISTRY HOPPE-SEYLER | 1991年 / 372卷 / 11期
关键词
PROTEINASE INHIBITORS; STAPHYLOCOCCUS-AUREUS PROTEINASE; PSEUDOMONAS-AERUGINOSA ELASTASE; PROTEOLYTIC CLEAVAGE;
D O I
10.1515/bchm3.1991.372.2.963
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Neutrophil elastase is thought to contribute to the lung pathology in patients with cystic fibrosis (CF). Therefore, intrapulmonary application of elastase inhibitors might be beneficial for these patients. Inactivation of such inhibitors by bacterial proteinases, however, is an important consideration in this therapy. We studied the effects of Staphylococcus aureus proteinase (STAP) and Pseudomonas aeruginosa elastase (PsE) on native (alpha-1-AT) and recombinant (rAAT) alpha-1-antitrypsin, recombinant secretory leukocyte proteinase inhibitor (rSLPI) and the leech inhibitor eglin C. All inhibitors were inactivated by these bacterial proteinases showing pronounced differences in their susceptibilities to proteolytic cleavage. Comparing the turnover rate (mol of inhibitor inactivated by one mol bacterial proteinase/min), rAAT and alpha-1-AT were approximately 20 000-fold more susceptible to STAP than rSLPI and 50 000-fold more susceptible than eglin C. Pseudomonas aeruginosa elastase inactivated all inhibitors more rapidly than STAR rAAT and alpha-1-AT were 13-fold and 17000-fold more susceptible than rSLPI and eglin C, respectively. Incubation of the rAAT-elastase complex with equimolar amounts of STAP did not result in release of elastase activity. Upon simultaneous addition of STAP and leukocyte elastase to rAAT, there was undisturbed elastase inhibition indicating that complex formation with elastase proceeded at a faster rate than inactivation of rAAT by the bacterial proteinase. From these results of inactivation in vitro and considering the immunogenic potential of the inhibitors studied here, we conclude that rSLPI may be the appropriate choice for anti-elastase therapy in CF.
引用
收藏
页码:963 / 970
页数:8
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