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

• 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
• ISSN: 0282-0080; 1573-4986
• DOI: 10.1023/A:1006926217748

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.