Original Articles: Mechanisms Of AllergyInhibition of mast cell tryptase by inhaled APC 366 attenuates allergen-induced late-phase airway obstruction in asthma☆,☆☆
Section snippets
Study design
In this randomized, double-blinded, placebo-controlled, 2-period crossover study, subjects were randomized to receive either APC 366 followed by placebo or vice versa. During each of the 2 treatment periods, every subject received the treatment 3 times per day at intervals of 6 hours for 4 consecutive days and 1 time on the fifth day. On day 4, after the 10th dose of medication, every subject underwent allergen challenge followed by repeated spirometry to document an EAR and an LAR. On day 5,
Results
Allergen provocation caused both early- and late-phase falls in FEV1 after both active and placebo treatments (Fig 1).
Discussion
This study has highlighted the contribution of mast cell tryptase to late-phase allergic responses in asthmatics after challenge with inhaled allergen. Short-term administration (by inhalation) of APC 366, a selective tryptase inhibitor, significantly attenuated the LAR by 33% and had a significant effect on the mean maximum fall in FEV1 during the LAR. However, no significant effects were demonstrable on the allergen-induced EAR and BHR. These findings suggest that mast cell tryptase, through
Acknowledgements
We express our thanks to all Clinical Research Fellows in Southampton who provided night medical cover during the study; to the research nurses for their help with patient care, drug administration, and challenges at both centers; to F. Anderson and Dr Dik Ng for help with administration; and to all of the patients without whose participation this study would not have been possible.
References (38)
- et al.
The effect of H1-receptor blockade on the development of early- and late-phase bronchoconstriction and increased bronchial responsiveness in allergen-induced asthma
J Allergy Clin Immunol
(1993) - et al.
Effect of YM264 on the airway responsiveness and late asthmatic response in a guinea pig model of asthma
Chest
(1995) - et al.
Evidence of ongoing mast cell and eosinophil degranulation in symptomatic asthma airway
J Allergy Clin Immunol
(1991) - et al.
Correlation of bronchial eosinophil and mast cell activation with bronchial hyperresponsiveness in children with asthma
J Allergy Clin Immunol
(1992) - et al.
Effect of cyteinyl- leukotriene receptor antagonist ICI 204.219 on allergen-induced bronchoconstriction and airway hyperreactivity in atopic subjects
Lancet
(1991) Antigen and methacholine challenge in children with asthma
J Allergy Clin Immunol
(1979)- et al.
Effects of recombinant human IL-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response
Lancet
(2000) - et al.
Effects of interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response
Lancet
(2000) - et al.
Sputum analysis, bronchial hyperresponsiveness, and airway function in asthma: results of a factor analysis
J Allergy Clin Immunol
(1999) - et al.
Bronchial reactivity increases soon after the immediate response in dual-responding asthmatic subjects
Chest
(1987)
The relationship between airway responsiveness measured before and after allergen-induced late asthmatic responses
Chest
Interactions of mast cell tryptase with thrombin receptors and PAR-2
J Biol Chem
Human late asthmatic reactions
Clin Exp Allergy
Mast cell-leukocyte cytokine cascades in allergic inflammation
Allergy
Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen-induced early and late phase airway obstruction in asthmatics
Am J Respir Crit Care Med
Mast cell protease in asthma
Activation of pulmonary mast cells by bronchoalveolar lavage allergen challenge. In vivo release of histamine and tryptase in atopic and nonatopic subjects with and without asthma
Am Rev Respir Dis
Mast cell tryptase is a mitogen for epithelial cells: stimulation of IL-8 production and intercellular adhesion molecule-1 expression
J Immunol
The role of mast cell tryptase in regulating endothelial cell proliferation, cytokine release and adhesion molecule expression. Tryptase induces expression of mRNA for IL-β and IL-8 and stimulates the selective release of IL-8 from HUVEC
J Immunol
Cited by (134)
Update on Mast Cell Proteases as Drug Targets
2023, Immunology and Allergy Clinics of North AmericaLncRNA-AK007111 affects airway inflammation in asthma via the regulation of mast cell function
2023, International ImmunopharmacologyMast cell tryptases in allergic inflammation and immediate hypersensitivity
2021, Current Opinion in ImmunologyEmerging mechanisms contributing to mast cell-mediated pathophysiology with therapeutic implications
2021, Pharmacology and TherapeuticsAn Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma
2019, CellCitation Excerpt :Tryptase-knockout mice exhibited reduced airway hyperreactivity in an allergen-induced asthma model (Cui et al., 2014). Multiple efforts were devoted to develop oral or inhaled tryptase small molecule inhibitors (SMIs) targeting its active site (Krishna et al., 2001; Sutton et al., 2002; Wright et al., 1999). These SMIs reduced bronchial constriction and improved methacholine-induced airway hyperreactivity in animal models of asthma, and one ameliorated the late asthmatic response in a human phase II allergen challenge study (Krishna et al., 2001; Sutton et al., 2002; Wright et al., 1999).
Mast cell tryptase – Marker and maker of cardiovascular diseases
2019, Pharmacology and Therapeutics
- ☆
This study was sponsored by Axys Pharmaceutical Corporation, San Francisco, Calif.
- ☆☆
Reprint requests: Dr M. T. Krishna, Medical Specialties (RCMB Division), Mail Point 810, Level D, Centre Block, Southampton General Hospital, Tremona Road, Southampton S016 6YD, United Kingdom.