2012年10月20日 訊 /生物谷BIOON/ --吸菸是肺氣腫(emphysema)的一個主要的風險因素。肺氣腫是慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)的主要症狀之一。儘管吸菸導致不可逆的細胞損傷，但是大約只有五分之一的長期吸菸者患上這種退化性的肺疾病。這表明一些人擁有讓他們容易患上這種疾病的遺傳因子，但是其他人含有提供保護的DNA變異體。如今，來自日本RIKEN高級科學研究所的研究人員發現一種基因導致一些人更容易患上吸菸誘導的肺氣腫。這一發現可能有助於醫生們鑑定出有最高風險患上末期慢性肺疾病的吸菸者。
在Naoyuki Taniguchi的領導下，研究人員之前證實剔除一種被稱作α-1,6巖藻糖轉移酶(alpha1,6-fucosyltransferase, Fut8)的基因會導致小鼠產生肺阻塞性的特徵。Fut8參與一種簡單的被稱作「核心巖藻糖(core fucose)」的糖結構，而這種核心巖藻糖有助於維持肺部中的肺泡結構。儘管這些動物通常在出生後幾天內死亡，但是這項研究提示著破壞這種基因可能導致肺氣腫。
為了進一步研究這種可能性，研究人員讓只攜帶一個功能性Fut8基因拷貝的小鼠暴露在香菸煙霧之中。他們發現炎性細胞快速地流入這些動物的肺部，而且只在三個月之後，它們患上肺氣腫。研究人員也發現核心巖藻糖控制著參與所謂Smad途徑的蛋白，而這種途徑接著就調節參與肺泡壁上胞外基質降解的酶活性。
為了在人身上驗證這項研究，研究人員測量了已戒菸的人(ex-smoker)血液中的FUT8蛋白水平。他們發現相對於擁有更高FUT8蛋白水平的人們，擁有較低FUT8活性的人們通常擁有更差的肺部功能，而且經歷著更加急性加重的COPD。另一個獨立的研究小組去年也報導，FUT8基因中的一個特定基因變異體與COPD顯著性地相關聯。
歸納在一起，這些研究結果證實測量血液中的FUT8水平有助於預測COPD病人的疾病惡化速率，同時還表明FUT8酶活性是COPD病情加重的一個生物標記物，從而有助於為COPD病人提供個人化治療。(生物谷Bioon.com)
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
Congxiao Gao‡§,1,2, Toshitaka Maeno¶,1, Fumi Ota‡§, Manabu Ueno¶, Hiroaki Korekane‡§, Shinji Takamatsu‡§, Ken Shirato‡‖, Akio Matsumoto‡,**, Satoshi Kobayashi§, Keiichi Yoshida§, Shinobu Kitazume§, Kazuaki Ohtsubo‡§, Tomoko Betsuyaku‡‡ and Naoyuki Taniguchi
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)
Koichiro Kamioa, 1, Takayuki Yoshidab, 1, Congxiao Gaoc, 1, Takeo Ishiia, Fumi Otac, Takashi Motegia, Satoshi Kobayashic, Reiko Fujinawac, Kazuaki Ohtsuboc, Shinobu Kitazumec, Takashi Angatac, Arata Azumaa, Akihiko Gemmaa, Masaharu Nishimurab, Tomoko Betsuyakud, Kozui Kidaa, , Naoyuki Taniguchi
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.