Article Text
Abstract
Background Severe asthma is a chronic lung disease characterised by inflammation, airway hyperresponsiveness (AHR) and airway remodelling. The molecular mechanisms underlying uncontrolled airway smooth muscle cell (aSMC) proliferation involved in pulmonary remodelling are still largely unknown. Small G proteins of the Rho family (RhoA, Rac1 and Cdc42) are key regulators of smooth muscle functions and we recently demonstrated that Rac1 is activated in aSMC from allergic mice. The objective of this study was to assess the role of Rac1 in severe asthma-associated airway remodelling.
Methods and results Immunofluorescence analysis in human bronchial biopsies revealed an increased Rac1 activity in aSMC from patients with severe asthma compared with control subjects. Inhibition of Rac1 by EHT1864 showed that Rac1 signalling controlled human aSMC proliferation induced by mitogenic stimuli through the signal transducer and activator of transcription 3 (STAT3) signalling pathway. In vivo, specific deletion of Rac1 in SMC or pharmacological inhibition of Rac1 by nebulisation of NSC23766 prevented AHR and aSMC hyperplasia in a mouse model of severe asthma. Moreover, the Rac1 inhibitor prevented goblet cell hyperplasia and epithelial cell hypertrophy whereas treatment with corticosteroids had less effect. Nebulisation of NSC23766 also decreased eosinophil accumulation in the bronchoalveolar lavage of asthmatic mice.
Conclusion This study demonstrates that Rac1 is overactive in the airways of patients with severe asthma and is essential for aSMC proliferation. It also provides evidence that Rac1 is causally involved in AHR and airway remodelling. Rac1 may represent as an interesting target for treating both AHR and airway remodelling of patients with severe asthma.
- asthma
- asthma pharmacology
- respiratory muscles
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Footnotes
FD and LR contributed equally.
Contributors Conception and design : MP, AM, GL and VS. Experimentation: FD, LR, DH, MK, MR, CB, CT, MCD, LDC., NH, GB and VS. Analysis and interpretation: FD, MP, GL and VS. Drafting the manuscript: FD, GL and VS. Authors FD and LR contributed equally to this work.
Funding This work was supported by grants from the Institut de Recherche en Santé Respiratoire des Pays de la Loire (G-Rar and NARACAS projects), the Société d’Accélération du Transfert de Technologie (project number STRAS-2117) and the Institut National de la Santé et de la Recherche Médicale (INSERM). LR was supported by a grant from MRES. FD and DH were supported by a grant from Fondation Recherche Médicale.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval All experimental procedures and animal care were performed in accordance with the Regional Ethical Committee for Animal Experiments of the Pays de la Loire and conform to the ARRIVE guidelines.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Vincent SAUZEAU, PhDvincent.sauzeau@inserm.fr.