Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN 37232-2650, USA.
Am J Respir Crit Care Med. 2013 Jan 1;187(1):34-41. doi: 10.1164/rccm.201204-0786OC. Epub 2012 Nov 29.
Asthma is a heterogeneous lung disorder characterized by airway inflammation and airway dysfunction, manifesting as hyperresponsiveness and obstruction. Glutathione S-transferase M1 (GSTM1) is a multifunctional phase II enzyme and regulator of stress-activated cellular signaling relevant to asthma pathobiology. A common homozygous deletion polymorphism of the GSTM1 gene eliminates enzyme activity.
To determine the effect of GSTM1 on airway inflammation and reactivity in adults with established atopic asthma in vivo.
Nineteen GSTM1 wild-type and eighteen GSTM1-null individuals with mild atopic asthma underwent methacholine and inhaled allergen challenges, and endobronchial allergen provocations through a bronchoscope.
The influx of inflammatory cells, panels of cytokines and chemokines linked to asthmatic inflammation, F(2)-isoprostanes (markers of oxidative stress), and IgE were measured in bronchoalveolar lavage fluid at baseline and 24 hours after allergen instillation. Individuals with asthma with the GSTM1 wild-type genotype had greater baseline and allergen-provoked airway neutrophilia and concentrations of myeloperoxidase than GSTM1-null patients. In contrast, the eosinophilic inflammation was unaffected by GSTM1. The allergen-stimulated generation of acute-stress and proneutrophilic mediators, tumor necrosis factor-α, CXCL-8, IL-1β, and IL-6, was also greater in the GSTM1 wild-type patients. Moreover, post-allergen airway concentrations of IgE and neutrophil-generated mediators, matrix metalloproteinase-9, B-cell activating factor, transforming growth factor-β1, and elastase were higher in GSTM1 wild-type individuals with asthma. Total airway IgE correlated with B-cell activating factor concentrations. In contrast, levels of F(2)-isoprostane were comparable in both groups. Finally, GSTM1 wild-type individuals with asthma required lower threshold concentrations of allergen to produce bronchoconstriction.
The functional GSTM1 genotype promotes neutrophilic airway inflammation in humans with atopic asthma in vivo.
哮喘是一种异质性肺部疾病，其特征为气道炎症和气道功能障碍，表现为气道高反应性和气道阻塞。谷胱甘肽 S-转移酶 M1（GSTM1）是一种多功能的 II 相酶和应激激活细胞信号的调节剂，与哮喘发病机制相关。GSTM1 基因的常见纯合缺失多态性消除了酶的活性。
确定 GSTM1 对已确诊的特应性哮喘成人患者体内气道炎症和反应性的影响。
19 名 GSTM1 野生型和 18 名 GSTM1 缺失型轻度特应性哮喘患者接受了乙酰甲胆碱和吸入变应原挑战，并通过支气管镜进行了支气管内变应原激发。
在基线和变应原滴注后 24 小时，测量支气管肺泡灌洗液中的炎症细胞流入、与哮喘炎症相关的细胞因子和趋化因子谱、F(2)-异前列烷（氧化应激标志物）和 IgE。具有 GSTM1 野生型基因型的哮喘患者在基线和变应原激发后具有更大的气道中性粒细胞增多和髓过氧化物酶浓度，而非 GSTM1 缺失型患者。相比之下，GSTM1 对嗜酸性粒细胞炎症没有影响。GSTM1 野生型患者的急性应激和嗜中性粒细胞生成介质、肿瘤坏死因子-α、CXCL-8、IL-1β和 IL-6 的生成也更大。此外，GSTM1 野生型哮喘患者在变应原后气道中 IgE 和中性粒细胞生成的介质、基质金属蛋白酶-9、B 细胞激活因子、转化生长因子-β1 和弹性蛋白酶的浓度也更高。总气道 IgE 与 B 细胞激活因子浓度相关。相比之下，两组的 F(2)-异前列烷水平相当。最后，GSTM1 野生型哮喘患者需要更低的变应原阈值浓度才能引起支气管收缩。
功能性 GSTM1 基因型促进特应性哮喘患者体内的中性粒细胞气道炎症。
