Essential role of smooth muscle Rac1 in severe asthma associated-airway hyperresponsiveness and remodelling

Abstract

Introductionn: Severe asthma is a chronic lung disease characterized by inflammation, airway hyperresponsiveness (AHR), airway remodelling and corticoid resistance. The molecular mechanisms underlying airway smooth muscle cells (aSMC) contraction and proliferation involved in AHR and remodelling are still largely unknown. Small GTPases of the Rho family (RhoA, Rac1 and Cdc42) are key regulators of SM functions. Recently, we demonstrated that Rac1 controls bronchoconstriction by modulating aSMC contraction (Andre et al., JACI, 2017). The objective of this study was to assess the role of SM Rac1 in severe asthma-associated airway remodelling. Methods and Results: We developed a new model of severe allergic asthma (house dust mite (HDM)-sensitized mice) characterized by AHR, strong airway remodelling with SMC hyperplasia and a reduced sensitivity to inhaled corticoids. In mice harbouring SMC specific Rac1 deletion, AHR and aSMC hyperplasia were not observed. A similar inhibition of AHR and aSMC hyperplasia was obtained by the pharmacological inhibition of Rac1 by nebulisation of NSC23766. Moreover, the Rac1 inhibitor prevented goblet cell hyperplasia and epithelial cell hypertrophy whereas corticoids treatments had no effect. Nebulisation of NSC23766 also decreased eosinophil and neutrophil populations in bronchoalveolar lavages from HDM sensitized asthmatic mice. Conclusion: In this study, we generated a new mouse model of severe allergic asthma that closely mimics the human pathology. We demonstrated that Rac1 plays an essential role in aSMC contraction and hyperplasia, and that its inhibition prevents AHR and airway remodelling associated with severe asthma.