297 INHIBITION OF NEUTROPHIL ELASTASE IN CYSTIC FIBROSIS SPUTUM BY NATIVE AND OXIDATION-RESISTANT SECRETORY LEUKOPROTEASE INHIBITOR

Abstract

High neutrophil elastase (NE) activity in the sputum from cystic fibrosis (CF) patients is regarded as an important factor in CF lung pathophysiology. Therefore, a new therapeutic approach is aerosol delivery of antielastases such as secretory leukoprotease inhibitor (SLPI) to CF airways. We investigated the in vitro interactions of CF sputum samples (n=32) with recombinant native SLPI (rSLPI) and its partially oxidation-resistant variant (rSLPI-242; Grunenthal, Germany) in order to estimate their therapeutic potentials. We found that both rSLPI and rSLPI-242 dose-dependently inhibited NE activity in neutrophil-free supernatants from diluted CF sputum; addition of an oxidant resulted in superiority of rSLPI-242 over rSLPI. when fresh, neutrophil-rich CF sputum samples were incubated with rSLPI or rSLPI-242, inhibition of sputum NE activity by rSLPI-242 was significantly higher than inhibition by rSLPI; addition of an antioxidant improved the effect of rSLPI. Secretion induced from porcine tracheal submucosal glands by purified NE or by CF sputum supernatants was inhibited by rSLPI and rSLPI-242, resp., with superiority of rSLPI-242; addition of an antioxidant abrogated this difference, we conclude that either rSLPI or rSLPI-242 may efficiently inhibit NE activity and its effects in CF airways; the oxidation-resistant rSLPI-242 appears to be advantageous.