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Targeting of Rac1 prevents bronchoconstriction and airway hyperresponsiveness

Abstract : BACKGROUND: The molecular mechanisms responsible for airway smooth muscle cells (aSMC) contraction and proliferation in airway hyperresponsiveness (AHR) associated with asthma are still largely unknown. The small GTPases of the Rho family (RhoA, Rac1 and Cdc42) play a central role in SMC functions including migration, proliferation and contraction. OBJECTIVE: The objective of this study is to identify the role of Rac1 in aSMC contraction and to investigate its involvement in AHR associated with allergic asthma. METHODS: To define the role of Rac1 in aSMC, ex- and in vitro analyses of bronchial reactivity were performed on bronchi from smooth muscle (SM)-specific Rac1 knockout mice (SM-Rac1-KO) and human individuals. In addition, this murine model was exposed to allergens (ovalbumin or house dust mite extract) to decipher in vivo the implication of Rac1 in AHR. RESULTS: The specific SMC deletion or pharmacological inhibition of Rac1 in mice prevented the bronchoconstrictor response to methacholine. In human bronchi a similar role of Rac1 was observed during bronchoconstriction. We further demonstrated that Rac1 activation is responsible for bronchoconstrictor-induced increase in intracellular Ca(2+) concentration and contraction both in murine and human bronchial aSMC, through its association with phospholipase C β2 and the stimulation of inositol 1,4,5-trisphosphate production. In vivo, Rac1 deletion in SMC or pharmacological Rac1 inhibition by nebulization of NSC23766 prevented AHR in murine models of allergic asthma. Moreover, nebulization of NSC23766 decreased eosinophil and neutrophil populations in bronchoalveolar lavages from asthmatic mice. CONCLUSION: Our data reveal an unexpected and essential role of Rac1 in the regulation of intracellular Ca(2+) and contraction of aSMC, and the development of AHR. Rac1 thus appears as an attractive therapeutic target in asthma, with a combined beneficial action on both bronchoconstriction and pulmonary inflammation.
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https://hal.archives-ouvertes.fr/hal-01828862
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Soumis le : mercredi 11 juillet 2018 - 08:48:44
Dernière modification le : mardi 16 avril 2019 - 16:48:02
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Gwennan André-Grégoire, Florian Dilasser, Julie Chesné, Faouzi Braza, Antoine Magnan, et al.. Targeting of Rac1 prevents bronchoconstriction and airway hyperresponsiveness. Journal of Allergy and Clinical Immunology, Elsevier, 2017, Equipe III, ⟨10.1016/j.jaci.2017.09.049⟩. ⟨hal-01828862⟩

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