title: 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.
abstract: 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.
authors.affiliation: RIKEN Alliance Laboratory, The Institute of Scientific and Industrial Research, Osaka University, Osaka 567-0047, Japan.
authors.forename: Congxiao
authors.initials: C
authors.lastname: Gao
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Maeno
authors.forename: Fumi
authors.initials: F
authors.lastname: Ota
authors.forename: Manabu
authors.initials: M
authors.lastname: Ueno
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Korekane
authors.forename: Shinji
authors.initials: S
authors.lastname: Takamatsu
authors.forename: Ken
authors.initials: K
authors.lastname: Shirato
authors.forename: Akio
authors.initials: A
authors.lastname: Matsumoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Shinobu
authors.initials: S
authors.lastname: Kitazume
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Ohtsubo
authors.forename: Tomoko
authors.initials: T
authors.lastname: Betsuyaku
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Taniguchi
mesh_terms: D000818:Animals; D005647:Fucosyltransferases / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000235:genetics; D006579:Heterozygote; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D014028:Tobacco Smoke Pollution; D016212:Transforming Growth Factor beta; D005647:Fucosyltransferases; C020559:Glycoprotein 6-alpha-L-fucosyltransferase; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse