Tryptase, a mast cell
serine protease, has been implicated in the pathophysiology of allergic
asthma, but formal evidence to support this hypothesis has been limited by the lack of specific inhibitors for use in vivo. Therefore, in this study we examined the effects of two inhibitors of
tryptase,
APC 366 [N-(1-hydroxy-2-naphthoyl)-L-arginyl-L-
prolinamide hydrochloride] and
BABIM [bis(5-amidino-2-benzimidazolyl)methane] on
antigen-induced early and late responses, airway responsiveness as measured by
carbachol provocation, microvascular permeability as measured by bronchoalveolar lavage (BAL)
albumin concentrations, and tissue
eosinophilia from biopsies in allergic sheep.
APC 366 and
BABIM were administered by
aerosol in all experiments. In vehicle control trials,
antigen challenge resulted in peak early and late increases in specific lung resistance (SRL) 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 challenge) slightly reduced the peak early response (194 +/- 41%), but significantly inhibited the late response (38 +/- 6%, p < 0.05 versus control trials). Twenty-four hours after challenge,
APC 366 also completely blocked the
antigen-induced
airway hyperresponsiveness to inhaled
carbachol observed in the control trial.(ABSTRACT TRUNCATED AT 250 WORDS)