CFTR antisense phosphorothioate oligodeoxynucleotides (S-ODns) induce tracheo-bronchial mucin (TBM) mRNA expression in human airway mucosa

Mucus hypersecretion is a critical component of cystic fibrosis (CF) pathogenesis. The effects of dysfunction of the cystic fibrosis transmembrane regulator (CFTR) on mucin expression were examined using the tracheo-bronchial mucin (TBM) gene as an indicator. TBM mRNA expression was assessed in a hu...

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Bibliographic Details
Published in:Glycoconjugate journal 1999-01, Vol.16 (1), p.7-11
Main Authors: Verma, M, Baraniuk, J, Blass, C, Ali, M, Yuta, A, Biedlningmaier, J, Davidson, E A
Format: Article
Language:English
Subjects:
Cells, Cultured
Cystic fibrosis
Cystic Fibrosis - genetics
Cystic Fibrosis - metabolism
Cystic Fibrosis Transmembrane Conductance Regulator - genetics
Enzymes
Gene expression
Gene Expression Regulation - drug effects
Humans
Nasal Mucosa - metabolism
Oligonucleotides, Antisense - genetics
Oligonucleotides, Antisense - pharmacology
Proteins
Ribonucleic acid
RNA
RNA, Messenger - biosynthesis
RNA, Messenger - genetics
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Summary:Mucus hypersecretion is a critical component of cystic fibrosis (CF) pathogenesis. The effects of dysfunction of the cystic fibrosis transmembrane regulator (CFTR) on mucin expression were examined using the tracheo-bronchial mucin (TBM) gene as an indicator. TBM mRNA expression was assessed in a human bronchial epithelial cell line (HBE1) and human nasal mucosal explants in vitro. Antisense phosphorothioate oligodeoxynucleotides (S-ODN) to TBM suppressed baseline expression of TBM mRNA in both systems, but had no effect on glyceraldehyde phosphate dehydrogenase mRNA (GAPDH) expression. Sense and missense (multiple scrambled control oligonucleotides) S-ODNs had no effect. 8Br-cAMP and PGE1 significantly elevated TBM mRNA expression. These increases were also specifically inhibited by the antisense S-ODNs. In order to induce a CF-like state, S-ODN to CFTR were added to explants. Antisense CFTR S-ODNs were anticipated to reduce the expression of cellular CFTR protein, and the level of CFTR function. Antisense, but not sense or missense, CFTR S-ODN significantly increased TBM mRNA expression. These data suggest that mucin hypersecretion in CF may be a direct consequence of CFTR dysfunction; the specific mechanism through which this effect is mediated is not known.
ISSN:0282-0080
1573-4986
DOI:10.1023/A:1006926217748