Sensitivity of Heterozygous α1,6-Fucosyltransferase Knock-out Mice to Cigarette Smoke-induced Emphysema
Sensitivity of Heterozygous α1,6-Fucosyltransferase Knock-out Mice to Cigarette Smoke-induced Emphysema
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杂合子 α1,6-岩藻糖基转移酶敲除小鼠对香烟烟雾引起的肺气肿的敏感性
DOI：
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发表时间：
2012
影响因子：
4.8
通讯作者：
N. Taniguchi
中科院分区：
文献类型：
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作者：
Cong‐xiao Gao;T. Maeno;F. Ota;Manabu Ueno;H. Korekane;S. Takamatsu;K. Shirato;Akio Matsumoto;Satoshi Kobayashi;Keiichi Yoshida;S. Kitazume;K. Ohtsubo;T. Betsuyaku;N. Taniguchi
背景：Fut 8 −/−小鼠表现出肺气肿病变，其主要风险因素是暴露于香烟烟雾（CS）。结果如下：Fut 8 +/−小鼠出现CS诱导的肺气肿病变，这与异常的Smad 7-Smad 2-基质金属蛋白酶信号通路有关。结论：Fut 8基因切除增加了对CS诱导的肺气肿的敏感性。意义：核心岩藻糖基化似乎参与了慢性阻塞性肺疾病的发展。我们先前证明，α 1，6-岩藻糖基转移酶（Fut 8）的遗传破坏引起的核心岩藻糖基化缺陷通过减弱TGF-β1受体信号传导导致致命异常和肺气肿病变的发展。在此，我们使用暴露于香烟烟雾（CS）的活的杂合敲除小鼠（Fut 8 +/−）研究了核心岩藻糖基化在肺气肿发病机制中的生理相关性。Fut 8 +/−小鼠在暴露的早期阶段表现出FUT 8活性的显著降低，并且肺中的基质金属蛋白酶（MMP）-9活性升高。肺气肿发展后，3个月的CS暴露，伴随着大量的巨噬细胞的招募到肺。CS暴露显著且持续地提高了Smad 7的表达水平，导致Fut 8 +/−小鼠和Fut 8缺陷型胚胎成纤维细胞中Smad 2磷酸化（控制MMP-9表达）显著降低。这些体内和体外研究表明，受损的核心岩藻糖基化增强了对CS的易感性，并构成了肺气肿疾病过程的至少一部分，其中TGF-β-Smad信号传导受损，MMP介导的肺实质破坏上调。
Background: Fut8−/− mice show emphysematous lesions, the major risk factor for which is exposure to cigarette smoke (CS). Results: Fut8+/− mice developed CS-induced emphysematous lesions, which are associated with an aberrant Smad7-Smad2-matrix metalloproteinase signaling pathway. Conclusion: Genetic ablation of Fut8 increases sensitivity to CS-induced emphysema. Significance: Core fucosylation appears to be involved in the development of chronic obstructive pulmonary disease. 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.