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

Abstract

Introduction Severe asthma is a lung chronic 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 airway hyperresponsiveness (AHR) and airway remodelling are still largely unknown. Small GTPases of the Rho family (RhoA, Rac1 and Cdc42) play a central role in smooth muscle functions. Recently, we demonstrated that Rac1 play a major role in the control of bronchoconstriction by modulating airway SMC contraction (Andre-Gregoire et al., J Allergy Clin Immunol, 2017). The objective of this study was to assess the role of smooth muscle Rac1 in severe asthma. Methods We developed a new model of severe allergic asthma (house dust mite (HDM) sensitized mice) characterized by AHR and strong airway remodelling, including SMC hyperplasia. Interestingly, as in human severe asthma, this model is associated to an altered sensitivity to inhaled corticoids. To assess the role of Rac1 in aSMCs, SMC-Rac1-KO mice were sensitized to HDM. Results Our results demonstrated that deletion of SMC Rac1 totally prevents AHR and smooth muscle mass increase in this murine model. Furthermore, nebulisation of the Rac1 inhibitor NSC23766 prevents AHR and SMC hyperplasia, but also goblet cell hyperplasia and epithelial cell hypertrophy whereas corticoids treatments has no effect on these parameters. In addition, we observed that nebulisation of NSC23766 decreased eosinophil and neutrophil populations in bronchoalveolar lavages from HDM sensitized asthmatic mice. Discussion In this study, we generated a new model of severe allergic asthma that mimic closely 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 to severe asthma. Compared to classical bronchodilators, Rac1 inhibition presents the additional advantage to decrease pulmonary inflammation. Conclusion Consistant with these datas, inhibition of Rac1 activity may represent a novel therapeutic approach for patients with severe asthma.