Sensitivity of heterozygous α1,6-fucosyltransferase knock-out mice to cigarette smoke-induced emphysema: implication of aberrant transforming growth factor-ß signaling and matrix metalloproteinase gene expression.
J Biol Chem
; 287(20): 16699-708, 2012 May 11.
Article
em En
| MEDLINE
| ID: mdl-22433854
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-ß1 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-ß-Smad signaling is impaired and the MMP-mediated destruction of lung parenchyma is up-regulated.
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Base de dados:
MEDLINE
Assunto principal:
Enfisema Pulmonar
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Poluição por Fumaça de Tabaco
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Transdução de Sinais
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Regulação Enzimológica da Expressão Gênica
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Fator de Crescimento Transformador beta
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Metaloproteinase 9 da Matriz
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Fucosiltransferases
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article