Secretory leukocyte protease inhibitor, but not alpha-1 protease inhibitor, blocks tryptase-induced bronchoconstriction

Alpha-1-protease inhibitor (α₁-PI) and secretory leukocyte protease inhibitor (SLPI) are two natural airway serine protease inhibitors. While inhibition of neutrophil elastase is a function common to both α₁PI and SLPI, we showed previously that they exhibit different patterns of protection against antigen-induced changes in airway function in allergic sheep. Specifically, the protective effect seen with SLPI was similar to the profile of action of synthetic tryptase inhibitors in the model. Based on these data, and the fact that tryptase is a serine protease, we hypothesized that SLPI, but not α₁-PI, would block tryptase-induced bronchoconstriction. To test this, we compared the responses to inhaled tryptase in five sheep without treatment or after treatment with either aerosol α₁-PI (10 mg) or aerosol SLPI (50 mg). The doses of α₁-PI and SLPI selected had been shown to be effective in previous antigen-provocation studies. Treatments were given 30 rain before aerosol challenge with tryptase (500 ng). Tryptase alone increased (mean ± SEM) pulmonary resistance (R_L) 142 ± 24% over baseline. Pretreatment with α₁-PI had no effect on the tryptase response (R_L increased 122 ± 20%). Pretreatment with SLPI, however, blocked the tryptase-induced response (R_L increased only 40 ± 4%; P<0.05 vs. tryptase). These are the first studies comparing the inhibitory activity of SLPI and α₁-PI on inhaled tryptase-induced bronchoconstriction. We conclude that, in vivo, SLPI, but not α₁-PI, can block tryptase-induced bronchoconstriction and that this activity may explain the differential effects of these two serine protease inhibitors on antigen-induced airway responses in allergic sheep,