One feature of allergic asthma, the EAR (early allergic reaction), is not present in the commonly used mouse models. We therefore investigated the mediators involved in EAR in a guinea-pig in vivo model of allergic airway inflammation. Animals were sensitized using a single OVA (ovalbumin)/alum injection and challenged with aerosolized OVA on day 14. On day 15, airway resistance was assessed after challenge with OVA or MCh (methacholine) using the forced oscillation technique, and lung tissue was prepared for histology. The contribution of mast cell mediators was investigated using inhibitors of the main mast cell mediators [histamine (pyrilamine) and CysLTs (cysteinyl-leukotrienes) (montelukast) and prostanoids (indomethacin)]. OVA-sensitized and challenged animals demonstrated AHR (airway hyper-responsiveness) to MCh, and lung tissue eosinophilic inflammation. Antigen challenge induced a strong EAR in the sensitized animals. Treatment with a single compound, or indomethacin together with pyrilamine or montelukast, did not reduce the antigen-induced airway resistance. In contrast, dual treatment with pyrilamine together with montelukast, or triple inhibitor treatment, attenuated approximately 70% of the EAR. We conclude that, as in humans, the guinea-pig allergic inflammation model exhibits both EAR and AHR, supporting its suitability for in vivo identification of mast cell mediators that contribute to the development of asthma. Moreover, the known mast cell mediators histamine and leukotrienes were major contributors of the EAR. The data also lend further support to the concept that combination therapy with selective inhibitors of key mediators could improve asthma management.
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Research Article|
July 25 2013
Mast cell mediators cause early allergic bronchoconstriction in guinea-pigs in vivo: a model of relevance to asthma
Jason P. Riley;
Jason P. Riley
*Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, U.S.A.
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Barbara Fuchs;
Barbara Fuchs
†Experimental Asthma and Allergy Research, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden
‡Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden
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Lisa Sjöberg;
Lisa Sjöberg
†Experimental Asthma and Allergy Research, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden
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Gunnar P. Nilsson;
Gunnar P. Nilsson
‡Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden
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Lars Karlsson;
Lars Karlsson
*Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, U.S.A.
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Sven-Erik Dahlén;
Sven-Erik Dahlén
†Experimental Asthma and Allergy Research, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden
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Navin L. Rao;
Navin L. Rao
*Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, U.S.A.
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Mikael Adner
†Experimental Asthma and Allergy Research, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden
Correspondence: Associate Professor Mikael Adner (email [email protected]).
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Publisher: Portland Press Ltd
Received:
February 22 2013
Revision Received:
June 13 2013
Accepted:
June 25 2013
Accepted Manuscript online:
June 25 2013
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2013 Biochemical Society
2013
Clin Sci (Lond) (2013) 125 (11): 533–542.
Article history
Received:
February 22 2013
Revision Received:
June 13 2013
Accepted:
June 25 2013
Accepted Manuscript online:
June 25 2013
Citation
Jason P. Riley, Barbara Fuchs, Lisa Sjöberg, Gunnar P. Nilsson, Lars Karlsson, Sven-Erik Dahlén, Navin L. Rao, Mikael Adner; Mast cell mediators cause early allergic bronchoconstriction in guinea-pigs in vivo: a model of relevance to asthma. Clin Sci (Lond) 1 December 2013; 125 (11): 533–542. doi: https://doi.org/10.1042/CS20130092
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