Tryptase inhibitors block allergen-induced airway and inflammatory responses in allergic sheep.
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)
Clark
J M
JM
Department of Molecular Pharmacology, Arris Pharmaecutical Corporation, South San Francisco, California 94080, USA.
Abraham
W M
WM
Fishman
C E
CE
Forteza
R
R
Ahmed
A
A
Cortes
A
A
Warne
R L
RL
Moore
W R
WR
Tanaka
R D
RD
D000403:Airway Resistance / Q000187:drug effects; D000485:Allergens / Q000008:administration & dosage; D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology; D017165:Ascaris suum; D001249:Asthma / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001980:Bronchi / Q000098:blood supply / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002199:Capillary Permeability; D002217:Carbachol / Q000494:pharmacology; D053818:Chymases; D004151:Dipeptides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008407:Mast Cells / Q000378:metabolism; D012697:Serine Endopeptidases / Q000502:physiology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D012756:Sheep; D053802:Tryptases
D000485:Allergens; D000947:Antigens, Helminth; D001562:Benzimidazoles; D004151:Dipeptides; C094700:N-(1-hydroxy-2-naphthoyl)arginyl-prolinamide; D015842:Serine Proteinase Inhibitors; C025426:bis(5-amidino-2-benzimidazolyl)methane; D002217:Carbachol; D012697:Serine Endopeptidases; C083294:chymase 2; D053818:Chymases; D053802:Tryptases