Involvement of small airways, those of less than 2 mm in internal diameter, is present in all stages of asthma and contributes substantially to the pathophysiologic expression of asthma. Therefore, small airways are increasingly viewed as a potential target in optimal asthma control. Airway tone, which is increased in asthma, is mainly controlled by the vagus nerve that releases acetylcholine (ACh) and activates muscarinic ACh receptors (mAChRs) post-synaptically on airway smooth muscle (ASM). In small airways, M3 mAChRs are expressed, but there is no vagal innervation. Non-neuronal ACh released from the epithelial cells that may express choline acetyltransferase (ChAT) in response to inflammatory stimuli, as well as from other structural cells in the airways, including fibroblasts and mast cells, can activate these receptors. By antagonizing M3 mAChR, the contraction of the ASM is prevented and, potentially, local inflammation can be reduced and the progression of remodeling may be affected. In fact, ACh also contributes to inflammation and remodeling of the airways and regulates the growth of ASM. Several experimental studies have demonstrated the potential benefit derived from the use of mAChR antagonists, mainly long-acting mAChR antagonists (LAMAs), on small airways in asthma. However, there are several confounding factors that may cause a wrong estimation of the relationship between LAMAs and small airways in asthma.

Background and Purpose Airway hyperresponsiveness (AHR) is a central abnormality in asthma. Interleukin-5 (IL-5) may modulate AHR in animal models of asthma, but inconsistent data are available on the impact of targeting IL-5 pathway against AHR. The difference between targeting IL-5 or IL-5Rα in modulating AHR remains to be understood in human airways. The aim of this study was to compare the role of the anti-IL-5Rα benralizumab and the anti-IL-5 mepolizumab against AHR, and to assess whether these agents influence the levels of cyclic adenosine monophosphate (cAMP). Experimental Approach Passively sensitized human airways were treated with benralizumab and mepolizumab. The primary endpoint was the inhibition of AHR to histamine; the secondary endpoints were the protective effect against AHR to parasympathetic activation and mechanical stress, and the tissue modulation of cAMP. Key Results Benralizumab and mepolizumab significantly (P<0.001 vs. positive control) prevented the AHR to histamine (maximal effect -134.14±14.93% and -108.29±32.16%, respectively), with benralizumab being 0.73±0.10 logarithm significantly (P<0.05) more potent than mepolizumab. Benralizumab and mepolizumab significantly (P<0.001 vs. positive control) inhibited the AHR to transmural stimulation and mechanical stress. Benralizumab was 0.45±0.16 logarithm significantly (P<0.05) more potent than mepolizumab against AHR to parasympathetic activation. The effect of these agents was significantly correlated (P<0.001) with increased levels of cAMP. Conclusion Targeting the IL-5/IL-5Rα axis is an effective strategy to prevent the AHR. Benralizumab resulted more potent than the mepolizumab and the concentration dependent beneficial effects of both these agents were related with improved levels of cAMP in hyperresponsive airways.