A sense phosphorothioate oligodeoxynucleotide containing the transforming growth factor beta regulatory element acts as a novel local nonsteroidal antifibrotic drug.
Fibrosis is a potential response to tissue injury. At present, glucocorticoids with their numerous toxic side effects are the only effective treatment for fibrotic diseases. Granulomas induced by sponge implantation were treated with single-stranded phosphorothioate oligodeoxynucleotides containing the wild type or mutated transforming growth factor-beta response element designed to inhibit the rat proalpha1(I) promoter activity. Single-stranded phosphorothioate oligonucleotides resulted in antifibrotic activity based on their ability to reduce granuloma tissue formation and selectively inhibit collagen synthesis. The mutated single-standed phosphorothioate oligonucleotides or dexamethasone given at an equivalent dose to single-standed phosphorothioate oligonucleotides failed to do so. These data suggest that the phosphorothioate oligodeoxynucleotide containing the transforming growth factor-beta regulatory element has an antifibrotic effect and may be used to inhibit the development of fibrosis.
Cutroneo
K R
KR
Department of Biochemistry, College of Medicine, University of Vermont Burlington, Vermont 05405, USA.
Chiu
J F
JF
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001835:Body Weight; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005355:Fibrosis / Q000473:pathology / Q000517:prevention & control*; D006099:Granuloma / Q000473:pathology / Q000517:prevention & control*; D016014:Linear Models; D009841:Oligonucleotides / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013873:Thionucleotides / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D009841:Oligonucleotides; D013873:Thionucleotides; D016212:Transforming Growth Factor beta; C086722:phosphorothioate-3'-hydroxypropylamine oligonucleotide sT2a; D003907:Dexamethasone