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

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.

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The essential role of p21 in radiation-induced cell cycle arrest of vascular smooth muscle cell

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2004.06.017 ◽

2004 ◽

Vol 37 (4) ◽

pp. 871-880 ◽

Cited By ~ 20

Author(s):

Hyo-Soo Kim ◽

Hyun-Jai Cho ◽

Hyun-Ju Cho ◽

Sun-Jung Park ◽

Kyung-Woo Park ◽

...

Keyword(s):

Cell Cycle ◽

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cell ◽

Cell Cycle Arrest ◽

Muscle Cell ◽

Essential Role ◽

Cycle Arrest ◽

Radiation Induced

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Mast cells are associated with exacerbations and eosinophilia in children with severe asthma

European Respiratory Journal ◽

10.1183/13993003.00947-2016 ◽

2016 ◽

Vol 48 (5) ◽

pp. 1320-1328 ◽

Cited By ~ 17

Author(s):

Guillaume Lezmi ◽

Louise Galmiche-Rolland ◽

Sabine Rioux ◽

Francis Jaubert ◽

Isabelle Tillie-Leblond ◽

...

Keyword(s):

Smooth Muscle ◽

Mast Cells ◽

Severe Asthma ◽

Airway Smooth Muscle ◽

Eosinophilic Inflammation ◽

Symptomatic Group ◽

Mucosal Mast Cells ◽

Bronchial Biopsies ◽

Positive Correlations

The role of mast cells in the pathogenesis of childhood asthma is poorly understood. We aimed to estimate the implication of airway mucosal mast cells in severe asthma and their relationship with clinical, functional, inflammatory and remodelling parameters.Bronchial biopsies were performed in 36 children (5–18 years) with severe asthma: 24 had frequent severe exacerbations and/or daily symptoms in the previous year (symptomatic group), and 12 had few symptoms and a persistent obstructive pattern (paucisymptomatic group). Nine children without asthma were included as control subjects. We assessed mast cells in the submucosa and airway smooth muscle using c-kit antibodies and in the entire biopsy area using Giemsa.The number of submucosal mast cells was higher in the symptomatic group than in the paucisymptomatic group (p=0.02). The number of submucosal mast cells correlated with the number of severe exacerbations (p=0.02, r=0.37). There were positive correlations between the number of submucosal mast cells (p<0.01, r=0.44), airway smooth muscle mast cells (p=0.02, r= 0.40), mast cells stained by Giemsa (p<0.01, r=0.44) and submucosal eosinophils.Mast cells are associated with severe exacerbations and submucosal eosinophilic inflammation in children with severe asthma.

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MicroRNA-143/-145 in Cardiovascular Diseases

BioMed Research International ◽

10.1155/2015/531740 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 40

Author(s):

Wang Zhao ◽

Shui-Ping Zhao ◽

Yu-Hong Zhao

Keyword(s):

Smooth Muscle ◽

Cardiovascular Diseases ◽

Vascular Smooth Muscle Cells ◽

Essential Role ◽

Recent Progress ◽

Potential Role ◽

Phenotypic Switching ◽

Diagnostic Biomarkers ◽

Potential Strategy

MicroRNAs (miRNAs) play an essential role in the onset and development of many cardiovascular diseases. Increasing evidence shows that miRNAs can be used as potential diagnostic biomarkers for cardiovascular diseases, and miRNA-based therapy may be a promising therapy for the treatment of cardiovascular diseases. The microRNA-143/-145 (miR-143/-145) cluster is essential for differentiation of vascular smooth muscle cells (VSMCs) and determines VSMC phenotypic switching. In this review, we summarize the recent progress in knowledge concerning the function of miR-143/-145 in the cardiovascular system and their role in cardiovascular diseases. We discuss the potential role of miR-143/-145 as valuable biomarkers for cardiovascular diseases and explore the potential strategy of targeting miR-143 and miR-145.

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Effect of sodium deficiency of the action potential of the smooth muscle of ureter

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1964.206.1.205 ◽

1964 ◽

Vol 206 (1) ◽

pp. 205-210 ◽

Cited By ~ 14

Author(s):

Makoto Kobayashi ◽

Hiroshi Irisawa

Keyword(s):

Smooth Muscle ◽

Action Potential ◽

Action Potentials ◽

Essential Role ◽

Choline Chloride ◽

Resting Potential ◽

Sodium Deficiency ◽

Repolarization Phase ◽

Extracellular Sodium

Action potentials of the smooth muscle of cat ureter were studied by using ultramicroelectrodes. Among 193 penetrations, the resting potential averaged 45 mv and the amplitude of action potential 32 mv. In four instances a slight overshoot was recorded. Action potential consisted of a relatively rapid rising phase followed by a slow repolarization phase, and its duration was about 0.3 sec. Effects of sodium deficiency on action potential were studied by using three different sodium substitutes. Both the height and the rising rate of action potential decreased as the concentration of extracellular sodium was reduced, indicating that the action potential of ureter muscle can be explained on the basis of sodium theory. The duration of the action potential was prolonged when sucrose or choline chloride was used as a sodium substitute; on the other hand, it shortened when tris chloride was employed. The essential role of sodium ions in the development of the action potential in ureter muscle is discussed.

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Interleukin-17 cytokine signalling in patients with asthma

European Respiratory Journal ◽

10.1183/09031936.00002314 ◽

2014 ◽

Vol 44 (5) ◽

pp. 1319-1331 ◽

Cited By ~ 38

Author(s):

Anders Lindén ◽

Barbro Dahlén

Keyword(s):

Smooth Muscle ◽

Severe Asthma ◽

Interleukin 17 ◽

Causative Role ◽

Neutrophil Accumulation ◽

T Helper 17 ◽

Clinical Investigations ◽

T Helper 17 Cell ◽

Global Health Problem

Asthma remains a global health problem and, therefore, more effective pharmacotherapy is needed. This is particularly true for chronic and severe asthma. In these clinical phenotypes, chronic inflammation involving neutrophils is likely to play a pathogenic role, making it interesting to target cytokine signalling involved in the accumulation of neutrophils. Therefore, it is of interest that the archetype T-helper 17 cell cytokine interleukin (IL)-17A, perhaps also IL-17F, controls neutrophil accumulation, mucus secretion, macrophage mobilisation and smooth muscle reactivity in various experimental airway models. However, much less is known about the involvement of signalling via IL-17 cytokines in humans with asthma. Existing evidence suggests that these cytokines are released from several types of immune cells in asthma and, for IL-17A, there is a local increase associated with disease severity, with the mobilisation of neutrophils and smooth muscle cells locally in the airways. Even though the causative role of IL-17 cytokines remains unclear, there is potential for clinical utility in targeting IL-17A specifically in patients with moderate-to-severe asthma and high reversibility. There is a need for new and well-powered clinical investigations of signalling via IL-17 cytokines in this clinical phenotype.

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