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Pharmacological targeting of anaphylatoxin receptors during the effector phase of allergic asthma suppresses airway hyperresponsiveness and airway inflammation

 
: Bälder, R.; Fuchs, B.; Bautsch, W.; Zwirner, J.; Kohl, J.; Hoymann, H.G.; Glaab, T.; Erpenbeck, V.; Krug, N.; Braun, A.

The Journal of immunology 174 (2005), No.2, pp.783-789
ISSN: 0022-1767
ISSN: 1048-3233
ISSN: 1047-7381
ISSN: 1550-6606
English
Journal Article
Fraunhofer ITEM ()
Aspergillus fumigatus; bronchial hyperreactivity; inflammation mediator; membrane protein; Animals; Asthma; Bronchoalveolar lavage; Cytokines; Immunoglobulin E - Receptors; Lungs; Mice; Receptors; Signal transduction

Abstract
Airway hyperresponsiveness and airway inflammation are hallmarks of allergic asthma, the etiology of which is crucially linked to the presence of Th2 cytokines. A role for the complement anaphylatoxins C3a and C5a in allergic asthma was suggested, as deficiencies of the C3a receptor (C3aR) and of complement factor C5 modulate airway hyperresponsiveness, airway inflammation, and Th2 cytokine levels. However, such models do not allow differentiation of effects on the sensitization phase and the effector phase of the allergic response, respectively. In this study, we determined the role of the anaphylatoxins on the effector phase of asthma by pharmacological targeting of the anaphylatoxin receptors. C3aR and C5a receptor (C5aR) signaling was blocked using the nonpeptidic C3aR antagonist SB290157 and the neutralizing C5aR mAb 20/70 in a murine model of Aspergillus fumigatus extract induced pulmonary allergy. Airway hyperresponsiveness was substantially improved after C5aR blockade but not after C3aR blockade. Airway inflammation was significantly reduced in mice treated with the C3aR antagonist or the anti-C5aR mAb, as demonstrated by reduced numbers of neutrophils and eosinophils in bronchoalveolar lavage fluid. Of note, C5aR but not C3aR inhibition reduced lymphocyte numbers in bronchoalveolar lavage fluid. Cytokine levels of IL-5 and IL-13 in bronchoalveolar lavage fluid were not altered by C3aR or C5aR blockade. However, blockade of both anaphylatoxin receptors markedly reduced IL-4 levels. These data suggest an important and exclusive role for C5aR signaling on the development of airway hyperresponsiveness during pulmonary allergen challenge, whereas both anaphylatoxins contribute to airway inflammation and IL-4 production.

: http://publica.fraunhofer.de/documents/N-34418.html