TRYPTASE INHIBITORS BLOCK ALLERGEN-INDUCED AIRWAY AND INFLAMMATORY RESPONSES IN ALLERGIC SHEEP

Tryptase, a mast cell serine protease, has been implicated in the path ophysiology of allergic asthma, but formal evidence to support this hy pothesis has been limited by the lack of specific inhibitors for use i n vivo. Therefore, in this study we examined the effects of two inhibi tors of tryptase, APC 366 [N-(1-hydroxy-2-naphthoyl)-L-arginyl-L-proli namide hydrochloride] and BABIM [bis(5-amidino-2-abenzimidazolyl)metha ne] on antigen-induced early and late responses, airway responsiveness as measured by carbachol provocation, microvascular permeability as m easured by bronchoalveolar lavage (BAL) albumin concentrations, and ti ssue eosinophilia from biopsies in allergic sheep. APC 366 and BABIM w ere administered by aerosol in all experiments. In vehicle control tri als, antigen challenge resulted in peak early and late increases in sp ecific lung resistance (SR(L)) of (mean +/- SE, n = 6) 259 +/- 30% and 183 +/- 27% over baseline, respectively. Treatment with APC 366 (9 mg /3 ml H2O given 0.5 h before, 4 h after, and 24 h after antigen challe nge) slightly reduced the peak early response (194 +/- 41%), but signi ficantly inhibited the late response (38 +/- 6%, p < 0.05 versus contr ol trials). Twenty-four hours after challenge, APC 366 also completely blocked the antigen-induced airway hyperresponsiveness to inhaled car bachol observed in the control trial. In the APC 366 trial, PC400 (the cumulative number of carbachol breath units [BU] that increased SR(L) by 400%) was 22.3 +/- 3.3 before and 22.6 +/- 3.6 BU after challenge as compared with the control trial where PC400 was 20.4 +/- 3.2 before and fell to 7.0 +/- 1.5 BU after challenge (p < 0.05 versus baseline and drug treated). Similar results were obtained with BABIM (9 mg/3 ml ) using the same treatment regimen. APC 366 also showed antiinflammato ry activity by significantly inhibiting post antigen-induced BAL album in and tissue eosinophilia when compared with control trials. Prophyla ctic administration of APC 366 (18 mg twice a day for 3 d plus 18 mg 0 .5 h before antigen challenge) provided a significantly greater reduct ion in the early response (SR(L) 310 +/- 62 control trials and 100 +/- 10 drug treated, p < 0.05) as compared with the acute treatment. This multiple treatment regimen also blocked the late airway response and the postchallenge airway hyperresponsiveness as well. These results su ggest that mast cell tryptase plays an important role in airway respon ses, including airway inflammation, to inhaled antigen. Inhibition of this enzyme may represent a new target for therapeutic intervention in the treatment of asthma.