Rationale: Asthma is a very frequent airway disease and asthma control determinants have been associated to indoor allergens sensitization. The most frequent allergens are the house dust mites (HDM), which act in vivo on bronchial epithelial layer. Severe asthma has also been associated to bronchial remodeling and more specifically to the increased mass of bronchial smooth muscle (BSM). However, the relationship between HDM stimulation of the bronchial epithelial layer and BSM remodeling is unknown.

Objectives: To evaluate whether epithelial stimulation with HDM induces BSM cell proliferation in severe asthmatics.

Methods: 22 severe asthmatics and 27 non asthmatic subjects were recruited. We have developed an in vitro culture model combining an epithelium layer in air liquid interface (ALI) interacting with BSM. We assessed BSM proliferation using BrdU incorporation. We explored the role of epithelium-derived mediators using RT-PCR and ELISA both in vitro and in vivo. Finally leukotrienes receptor expression was assessed both in vitro by flow cytometry and RT-PCR and ex vivo by laser micro dissection and RT-PCR.

Measurements and Main Results: We found that epithelial stimulation by HDM selectively increased the proliferation of asthmatic BSM cells and not that of non asthmatics. The mechanism involved an epithelial PAR-2 dependent production of leukotrienes C4 associated to an over-expression of leukotrienes receptor CysLTR1 by asthmatic BSM cells both in vitro and ex vivo.

Conclusions: This work demonstrates the selective role of HDM on BSM remodeling in severe asthmatic patients and points out different therapeutic targets at both epithelial and smooth muscle levels.