Effects of an eosinophil chemotaxis inhibitor, TAK-661, on antigen-induced asthmatic responses in allergic sheep.
Eosinophils have been shown to play a role in allergen-induced airway responses. The aim in this study was to examine the effects of TAK-661, a newly developed product as a specific inhibitory agent of eosinophil chemotaxis, on antigen-induced asthmatic responses in allergic sheep model. Seven Ascaris-sensitive, "dual-respondent" allergic sheep were provocated by an Ascaris suum antigen or phosphate-buffered saline 2 hrs after intra-stomach administration of TAK-661 or a placebo. Pulmonary resistances were measured throughout the experiment, and airway responsiveness to methacholine, bronchoalveolar lavage (BAL), and histological examination were performed 8 hrs after the antigen challenge. Antigen provocation induced dual-phase bronchoconstriction, eosinophilia in BAL and eosinophil infiltration into the airway wall, and an increase in airway responsiveness in placebo-treated sheep. The administration of TAK-661 significantly reduced the bronchoconstriction during the late phase, along with the inhibition of eosinophilia in BAL and the eosinophil infiltration into the airway wall. TAK-661 had a tendency to reduce early-phase bronchoconstriction and airway hyperresponsiveness, but there were no significant differences. These findings suggest that the eosinophil accumulation into the airway induced by antigen provocation may contribute to the development of late-phase bronchoconstriction, however, the development of airway hyperresponsiveness during late asthmatic response may not always be due to only eosinophilic inflammation in the airway.
The First Department of Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390 Japan. Keisaku@hsp.md.shinshu-u.ac.jp
K
K
Fujimoto
T
T
Tsunoda
T
T
Koizumi
K
K
Kubo
D000818:Animals; D000941:Antigens / Q000009:adverse effects*; D001249:Asthma / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology*; D016084:Bronchoconstriction / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002631:Chemotactic Factors, Eosinophil / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000097:blood; D004195:Disease Models, Animal; D004341:Drug Evaluation; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000188:drug therapy / Q000276:immunology; D012756:Sheep; D013997:Time Factors; D016896:Treatment Outcome
D000941:Antigens; D002631:Chemotactic Factors, Eosinophil