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

Abstract

BackgroundSevere 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 resultsImmunofluorescence 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.ConclusionThis 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.

Rac1 as a Target to Treat Dysfunctions and Cancer of the Bladder

“…For these reasons, it is not surprising that this Rho GTPase is now viewed as a potential target to treat various oncologic and non-oncologic diseases [ 30 ]. The list of pathologies addressable with Rac1 inhibitors has expanded significantly in recent years to include diabetes, neurodevelopmental disorders, pulmonary hypertension, asthma and other pathologies [ 25 , 128 , 129 , 130 , 131 ]. In cancer, Rac1 is receiving more and more attention given the large implications of the protein in metastasis, drug resistance and immune modulation [ 43 , 46 , 132 ].…”

“…Rac1 contributes to the regulation of blood pressure and the pathogenesis of pulmonary hypertension [ 25 ]. The protein is implicated in asthma-associated airway remodeling [ 130 ] and other pathophysiological processes. The focus on bladder presented here shall not underestimate the potential benefit of targeting Rac1 in other pathologies.…”

Research progress of icariin, an extract of traditional Chinese medicine, in the treatment of asthma

“…The excessive proliferation of ASMC not only promotes the occurrence of airway hyperresponsiveness but also can modify the extracellular matrix and promote the production of inflammatory factors to further aggravate airway inflammation, which seriously affects the prognosis of asthma patients. 54 In vitro experiments have shown that icariin can not only induce S phase acceleration and G2/M phase arrest of airway smooth muscle cells to inhibit cell proliferation but also promote the expression of apoptosis-related genes to promote cell apoptosis. 55 In addition, a study using ovalbumin (OVA)-induced asthmatic mice conducted by Lingli Hu et al demonstrated that icariin intervention can significantly downregulate the expression of TGF-β1, vascular endothelial growth factor (VEGF), IL-13 (interleukin-13), endothelin-1 (ET-1), and other important cytokines in airway remodeling, inhibiting the activity of the MAPK/Erk signaling pathway and thereby inhibiting the proliferation of AMSCs and improving the airway remodeling process by affecting multiple targets.…”

Rac1, A Potential Target for Tumor Therapy

“…Studies have shown that Rac1 plays an important role in the contraction of various smooth muscles, such as bronchial smooth muscle, bladder smooth muscle, and prostate smooth muscle (180)(181)(182)(183). Although both EHT1864 and NSC23766 are Rac1 inhibitors, they have different pharmacological mechanisms in the inhibition of different smooth muscles (182,184,185), and EHT1864 tends to perform better (186,187). In recent years, new Rac1 inhibitors have been continuously developed.…”