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1 Unite de Pharmacologie Cellulaire, Institut Pasteur-INSERM U485, Paris, France, France, Metropolitan
* To whom correspondence should be addressed. E-mail: msinger{at}pasteur.fr.
Antigen induces murine bronchial hyperreactivity (BHR), inflammation, mucus accumulation and airways remodelling. To investigate whether leukotrienes (LT) mediate the effects of antigen (ovalbumin, Ova), we studied 5-lipoxygenase (5-LO) expression in immunized BP2 mice and prevented LT synthesis with the 5-LO inhibitor zileuton or antagonized their effects with receptor antagonists (Cys-LT-ra: MK-571, LY 171883; LTB4-ra: PH-163). Cys-LT content increased in the bronchoalveolar lavage fluid (BALF) already 15 min. after the intratracheal instillation (i.t.) of Ova. Zileuton inhibited LT release in the BALF, eosinophil recruitment in the lungs, and dose-dependently reduced BHR, mucus accumulation, and remodelling, as did the LT-ra. Thus LT, released just after antigen challenge, might constitute the first step accounting for the effects of Ova. Since mucus accumulation is regulated via EGFR, which is also implicated in the effects of LT, we studied this pathway using AG 1478, an EGFR tyrosine kinase inhibitor given at 0.5, 4 and 20 mg/kg. AG 1478 inhibited BHR, inflammation and lung remodelling induced by Ova, or by molecules themselves generated by Ova, such as LT, IL-13, MCP-1, which promote identical effects, suggesting the involvement of the EGFR pathway in the asthma-like syndrome observed.
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