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首页> 外文期刊>Redox Biology >Glutaredoxin deficiency promotes activation of the transforming growth factor beta pathway in airway epithelial cells, in association with fibrotic airway remodeling
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Glutaredoxin deficiency promotes activation of the transforming growth factor beta pathway in airway epithelial cells, in association with fibrotic airway remodeling

机译：戊二醛缺乏症促进了气道上皮细胞中转化生长因子β通道的激活，与纤维化气道重塑相关联

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S-glutathionylation of reactive protein cysteines is a post-translational event that plays a critical role in transducing signals from oxidants into biological responses. S-glutathionylation can be reversed by the deglutathionylating enzyme glutaredoxin (GLRX). We have previously demonstrated that ablation of Glrx sensitizes mice to the development of parenchymal lung fibrosis(1). It remains unclear whether GLRX also controls airway fibrosis, a clinical feature relevant to asthma and chronic obstructive pulmonary disease, and whether GLRX controls the biology of airway epithelial cells, which have been implicated in the pathophysiology of these diseases. In the present study we utilized a house dust mite (HDM) model of allergic airway disease in wild type (WT) and Glrx -/- mice on a C57BL/6 background prone to develop airway fibrosis, and tracheal basal stem cells derived from WT mice, global Glrx -/- mice, or bi-transgenic mice allowing conditional ablation of the Glrx gene. Herein we show that absence of Glrx led to enhanced HDM-induced collagen deposition, elevated levels of transforming growth factor beta 1 (TGFB1) in the bronchoalveolar lavage, and resulted in increases in airway hyperresponsiveness. Airway epithelial cells isolated from Glrx -/- mice or following conditional ablation of Glrx showed spontaneous increases in secretion of TGFB1. Glrx -/- basal cells also showed spontaneous TGFB pathway activation, in association with increased expression of mesenchymal genes, including collagen 1a1 and fibronectin. Overall, these findings suggest that GLRX regulates airway fibrosis via a mechanism(s) that involve the plasticity of basal cells, the stem cells of the airways.
机译：反应性蛋白质半胱氨酸的S-谷胱甘肽是翻译后的事件，在将来自氧化剂的信号转换为生物反应中的发挥着关键作用。 S-谷胱甘肽可以通过玻璃化酶谷氨酸（GLRX）反转。我们之前已经表明，Glrx的消融使小鼠敏化到实质肺纤维化（1）的发展。它仍然尚不清楚GLRX还控制气道纤维化，与哮喘和慢性阻塞性肺病相关的临床特征，以及GLRX是否控制气道上皮细胞的生物学，这涉及这些疾病的病理生理学。在本研究中，我们在野生型（WT）和GLRX - / - 在C57BL / 6背景中的GLRX - / - 小鼠中使用了一个房屋粉尘（HDM）模型，以开发气道纤维化，并来自WT的气管基底干细胞小鼠，全球glrx - / - 小鼠或双转基因小鼠，允许有条件消融Glrx基因。在此，我们表明，没有GLRX导致增强HDM诱导的胶原沉积，在支气管肺泡灌洗中升高了转化生长因子β1（TGFB1）的水平，并导致气道高反应性增加。从GLRX - / - 小鼠分离的气道上皮细胞或在GLRX的条件消融后显示出自发增加TGFB1的分泌。 GLRX - / - 基础细胞还显示出自发TGFB途径激活，与间充质基因的表达相关，包括胶原1A1和纤维凝集素。总体而言，这些研究结果表明，GLRX通过涉及基础细胞的可塑性，气道的干细胞的机制来调节气道纤维化。

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