The tryptase inhibitor APC-366 reduces the acute airway response to allergen in pigs sensitized to Ascaris suum.
BACKGROUND
Tryptase is a mast cell serine protease that is released during mast cell degranulation. It has been implicated as an important enzyme in the pathophysiology of asthma, but its role in this disease is not fully elucidated.


OBJECTIVE
In this study, we investigated the effects of a tryptase inhibitor, APC-366, on the acute allergic airway reaction in specific pathogen-free pigs sensitized to the antigen Ascaris suum.


METHODS
APC-366 (5 mg in 1 mL of water, each dose) was given as an aerosol to seven pigs two times (t); at t = - 60 min and t = - 15 min Control pigs received water. Ascaris antigen (in 2 mL saline) was nebulized to the airways over approximately 5 min at t = 0. All aerosols were generated with an ultrasonic nebulizer.


RESULTS
The allergen challenge caused an acute reaction with a significant increase in airway resistance (R(aw)) in the control pigs from 3.3 +/- 0.6 cmH20/l/s to 10.2 +/- 2.3 cmH20/l/s, while in the APC-366-treated pigs, the R(aw) increased from 2.6 +/- 0.4 cmH20/l/s to 4.5 +/- 0.7 cmH20/l/s (P < 0.05 compared to controls). The dynamic lung compliance (C(dyn)) decreased significantly in the control pigs, but not in the APC-366-treated animals. The histamine concentration in urine in the control pigs was elevated immediately after allergen challenge, while this release was markedly reduced in the APC-366-treated pigs.


CONCLUSIONS
The tryptase inhibitor APC-366 reduces the acute airway response to allergen significantly. There is also a reduced elevation in urine histamine concentration after challenge in the treated pigs, compared to controls. These results indicate that inhibition of mast cell tryptase might be a useful anti-allergic treatment in asthma.
Sylvin
H
H
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. Helena.Sylvin@labmed.ki.se
Dahlbäck
M
M
Van Der Ploeg
I
I
Alving
K
K
D000403:Airway Resistance / Q000187:drug effects* / Q000502:physiology*; D000485:Allergens / Q000187:drug effects* / Q000276:immunology*; D000818:Animals; D017165:Ascaris suum / Q000187:drug effects* / Q000276:immunology*; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001985:Bronchial Provocation Tests; D004151:Dipeptides / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006632:Histamine / Q000652:urine; D007114:Immunization; D008170:Lung Compliance / Q000187:drug effects / Q000502:physiology; D008297:Male; D023421:Models, Animal; D010100:Oxygen / Q000502:physiology; D012697:Serine Endopeptidases / Q000494:pharmacology*; D013552:Swine / Q000276:immunology*; D013997:Time Factors; D053802:Tryptases
D000485:Allergens; D004151:Dipeptides; D004791:Enzyme Inhibitors; C094700:N-(1-hydroxy-2-naphthoyl)arginyl-prolinamide; D006632:Histamine; D012697:Serine Endopeptidases; D053802:Tryptases; D010100:Oxygen