Different susceptibility of elastase inhibitors to inactivation by proteinases from Staphylococcus aureus and Pseudomonas aeruginosa
Research article published in Biological chemistry Hoppe-Seyler (1991)
Abstract
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 STAP. rAAT and alpha 1-AT were 13-fold and 17,000-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.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Summary
Different susceptibility of elastase inhibitors to inactivation by proteinases from Staphylococcus aureus and Pseudomonas aeruginosa.
Why This Matters for Hirudotherapy
This in vitro study examined how bacterial proteinases from Staphylococcus aureus (STAP) and Pseudomonas aeruginosa (PsE) inactivate elastase inhibitors, including alpha 1-antitrypsin, recombinant AAT, recombinant SLPI, and the leech-derived inhibitor eglin C. Eglin C was markedly more resistant to STAP inactivation than alpha 1-AT (approximately 50,000-fold), and was also more resistant to PsE (approximately 17,000-fold), though PsE inactivated all inhibitors faster than STAP. The authors concluded rSLPI may be most appropriate for anti-elastase therapy in cystic fibrosis. Eglin C is a proteinase inhibitor derived from leeches, providing a direct ASH connection. This work demonstrates the robustness of a leech-derived inhibitor against bacterial proteolysis compared to human endogenous inhibitors. However, this is purely in vitro work focused on therapeutic candidate evaluation for CF, not hirudotherapy, and the authors did not select eglin C as the preferred candidate.
Citation
Different susceptibility of elastase inhibitors to inactivation by proteinases from Staphylococcus aureus and Pseudomonas aeruginosa
Sponer M et al. · Biological chemistry Hoppe-Seyler, 1991
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