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Targeting of Rac1 prevents bronchoconstriction and airway hyperresponsiveness
Journal of Allergy and Clinical Immunology ( IF 11.4 ) Pub Date : 2017-11-16 , DOI: 10.1016/j.jaci.2017.09.049
Gwennan André-Grégoire , Florian Dilasser , Julie Chesné , Faouzi Braza , Antoine Magnan , Gervaise Loirand , Vincent Sauzeau

Background

The molecular mechanisms responsible for airway smooth muscle cells' (aSMCs) 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 was 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 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 Ca2+ concentration and contraction both in murine and in human bronchial aSMCs, through its association with phospholipase C β2 and the stimulation of inositol 1,4,5-trisphosphate production. In vivo, Rac1 deletion in SMCs 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 mice with asthma.

Conclusions

Our data reveal an unexpected and essential role of Rac1 in the regulation of intracellular Ca2+ and contraction of aSMCs, 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.



中文翻译:

靶向Rac1可防止支气管收缩和气道高反应性

背景

与哮喘相关的气道平滑肌细胞(aSMCs)收缩和增殖的气道高反应性(AHR)的分子机制仍然是未知的。Rho家族的小GTP酶(RhoA,Rac1和Cdc42)在SMC功能(包括迁移,增殖和收缩)中起着核心作用。

客观的

这项研究的目的是确定Rac1在SMC收缩中的作用,并调查其在与过敏性哮喘相关的AHR中的作用。

方法

要定义在ASMC,Rac1的作用,并在体外对平滑肌(SM)特异性Rac1的基因敲除小鼠和人类个体支气管进行支气管反应性的分析。另外,该鼠模型暴露于变应原(卵清蛋白或屋尘螨提取物)以体内解读Rac1在AHR中的意义。

结果

小鼠中特定的SMC缺失或Rac1的药理抑制作用阻止了支气管收缩剂对乙酰甲胆碱的反应。在人支气管中,在支气管收缩过程中观察到了Rac1的类似作用。我们进一步证明,Rac1激活通过与磷脂酶Cβ2的缔合和刺激肌醇1,4,5-三磷酸酯的产生,导致支气管收缩剂诱导的鼠类和人支气管aSMC中细胞内Ca 2+浓度和收缩的增加。。体内,SMC中Rac1的缺失或NSC23766雾化的药理性Rac1抑制作用在变应性哮喘小鼠模型中预防了AHR。此外,NSC23766的雾化减少了哮喘小鼠支气管肺泡灌洗液中嗜酸性粒细胞和嗜中性粒细胞的数量。

结论

我们的数据揭示了Rac1在调节细胞内Ca 2+和aSMC的收缩以及AHR的发展中具有出乎意料且必不可少的作用。因此,Rac1在哮喘中似乎是有吸引力的治疗靶标,并且对支气管收缩和肺部炎症都有共同的有益作用。

更新日期:2017-11-16
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