JBC && BBRC：低水平肺蛋白Fut8增加吸烟诱导的肺气肿

吸烟是肺气肿(emphysema)的一个主要的风险因素。肺气肿是慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)的主要症状之一。尽管吸烟导致不可逆的细胞损伤，但是大约只有五分之一的长期吸烟者患上这种退化性的肺疾病。这表明一些人拥有让他们容易患上这种疾病的遗传因子，但是其他人含有提供保护的DNA变异体。如今，来自日本RIKEN高级科学研究所的研究人员发现一种基因导致一些人更容易患上吸烟诱导的肺气肿。这一发现可能有助于医生们鉴定出有最高风险患上末期慢性肺疾病的吸烟者。

在Naoyuki Taniguchi的领导下，研究人员之前证实剔除一种被称作α-1,6岩藻糖转移酶(alpha1,6-fucosyltransferase, Fut8)的基因会导致小鼠产生肺阻塞性的特征。Fut8参与一种简单的被称作“核心岩藻糖(core fucose)”的糖结构，而这种核心岩藻糖有助于维持肺部中的肺泡结构。尽管这些动物通常在出生后几天内死亡，但是这项研究提示着破坏这种基因可能导致肺气肿。

为了进一步研究这种可能性，研究人员让只携带一个功能性Fut8基因拷贝的小鼠暴露在香烟烟雾之中。他们发现炎性细胞快速地流入这些动物的肺部，而且只在三个月之后，它们患上肺气肿。研究人员也发现核心岩藻糖控制着参与所谓Smad途径的蛋白，而这种途径接着就调节参与肺泡壁上胞外基质降解的酶活性。

为了在人身上验证这项研究，研究人员测量了已戒烟的人(ex-smoker)血液中的FUT8蛋白水平。他们发现相对于拥有更高FUT8蛋白水平的人们，拥有较低FUT8活性的人们通常拥有更差的肺部功能，而且经历着更加急性加重的COPD。另一个独立的研究小组去年也报道，FUT8基因中的一个特定基因变异体与COPD显著性地相关联。

归纳在一起，这些研究结果证实测量血液中的FUT8水平有助于预测COPD病人的疾病恶化速率，同时还表明FUT8酶活性是COPD病情加重的一个生物标记物，从而有助于为COPD病人提供个人化治疗。

与肺气肿相关的拓展阅读：

• JBC && BBRC：低水平肺蛋白Fut8增加吸烟诱导的肺气肿
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Sensitivity of heterozygous α1,6-fucosyltransferase knock-out mice to cigarette smoke-induced emphysema: implication of aberrant transforming growth factor-β signaling and matrix metalloproteinase gene expression

We previously demonstrated that a deficiency in core fucosylation caused by the genetic disruption of α1,6-fucosyltransferase (Fut8) leads to lethal abnormalities and the development of emphysematous lesions in the lung by attenuation of TGF-β1 receptor signaling. Herein, we investigated the physiological relevance of core fucosylation in the pathogenesis of emphysema using viable heterozygous knock-out mice (Fut8+/−) that were exposed to cigarette smoke (CS). The Fut8+/− mice exhibited a marked decrease in FUT8 activity, and matrix metalloproteinase (MMP)-9 activities were elevated in the lung at an early stage of exposure. Emphysema developed after a 3-month CS exposure, accompanied by the recruitment of large numbers of macrophages to the lung. CS exposure substantially and persistently elevated the expression level of Smad7, resulting in a significant reduction of Smad2 phosphorylation (which controls MMP-9 expression) in Fut8+/− mice and Fut8-deficient embryonic fibroblast cells. These in vivo and in vitro studies show that impaired core fucosylation enhances the susceptibility to CS and constitutes at least part of the disease process of emphysema, in which TGF-β-Smad signaling is impaired and the MMP-mediated destruction of lung parenchyma is up-regulated.

α1,6 Fucosyltransferase (Fut8) is implicated in vulnerability to elastase-induced emphysema in mice and a possible non-invasive predictive marker for disease progression and exacerbations in chronic obstructive pulmonary disease (COPD)

Fut8 (α1,6-Fucosyltransferase) heterozygous knock-out (Fut8+/−) mice had an increased influx of inflammatory cells into the lungs, and this was associated with an up-regulation of matrix metalloproteinases, MMP-2 and MMP-9, after treatment with porcine pancreatic elastase (PPE), exhibiting an emphysema-prone phenotype as compared with wild type mice (Fut8+/+). The present data as well as our previous data on cigarette-smoke-induced emphysema [8] led us to hypothesize that reduced Fut8 levels leads to COPD with increased inflammatory response in humans and is associated with disease progression. To test this hypothesis, symptomatic current or ex-smokers with stable COPD or at risk outpatients were recruited. We investigated the association between serum Fut8 activity and disease severity, including the extent of emphysema (percentage of low-attenuation area; LAA%), airflow limitation, and the annual rate of decline in forced expiratory volume in 1 s (FEV1). Association with the exacerbation of COPD was also evaluated over a 3-year period. Serum Fut8 and MMP-9 activity were measured. Fut8 activity significantly increased with age among the at risk patients. In the case of COPD patients, however, the association was not clearly observed. A faster annual decline of FEV1 was significantly associated with lower Fut8 activity. Patients with lower Fut8 activity experienced exacerbations more frequently. These data suggest that reduced Fut8 activity is associated with the progression of COPD and serum Fut8 activity is a non-invasive predictive biomarker candidate for progression and exacerbation of COPD.