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Objective: A central role for eosinophils in the pathogenesis of asthma was recently nullified when it was shown that treatment with anti- IL-5 monoclonal antibody (mAb), mepolizumab, did not affect post-allergen airway hyperresponsiveness (AHR) in mild asthmatics. We hypothesized that the reason was airway remodeling. Design: We evaluated the effects of anti-IL-5 and anti-IL-5 receptor alpha (IL-5Rα) mAbs in murine asthma models with and without remodeling. Materials and Methods: BALB/c mice were immunized with ovalbumin adsorbed to alum at days 0 and 5. The mice without remodeling received inhaled ovalbumin at day 17, while the mice with remodeling received inhaled ovalbumin daily from days 17 to 30. Then, anti-IL-5 mAb or anti-IL-5Rα mAb was given 24 hours before challenge, and AHR were measured 24 hours after challenge. Also, IL-5R„ expression in human airway smooth muscle cells (ASMCs) was measured by immunocytochemistry. The effect of IL-5 on human ASMCs growth and its inhibition by the mAb were determined. Results: Both anti-IL-5 mAb and anti-IL-5Rα mAb inhibited airway eosinophilia and AHR in the mice without remodeling. In the remodeling model, anti-IL-5 mAb suppressed airway eosinophilia but not AHR. However, anti-IL-5Rα mAb inhibited both airway eosinophilia and AHR. Expression of IL-5Rα and growth were stimulated by IL-5 in human ASMCs; and the growth was inhibited by pretreatment with anti-IL-5Rα mAb, but not anti-IL-5 mAb. Conclusion: These results suggest that AHR is caused by IL-5 signaling via expression of 1L-5Rα in human ASMCs, and airway remodeling is more important than inflammation. Monoclonal antibody against IL-5Rα, but not IL-5, can inhibit AHR in asthma with remodeling. [ABSTRACT FROM AUTHOR]