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A Sense Oligodeoxynucleotide as a Novel Nonsteroidal Antifibrotic Drug*: Comparison to Glucocorticoids

Kenneth Cutroneo, PhD
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*From the Department of Biochemistry, College of Medicine, University of Vermont, Burlington, VT.

Correspondence to: Kenneth Cutroneo, PhD, The University of Vermont College of Medicine, Health Science Complex, Given Building, Burlington, VT 05405-0068



Chest. 2001;120(1_suppl):S62. doi:10.1378/chest.120.1_suppl.S62
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Mutation of the transforming growth factor (TGF)-β element in the ColCAT plasmid decreased chloramphenicol acetyltransferase expression.1 Dexamethasone treatment of fibroblasts caused a decrease binding of the TGF-β activator protein to the TGF-β element, whereas TGF-β treatment resulted in increased binding of this transacting factor.2 Sense phosphorothioate oligodeoxynucleotides (ssPT) containing the TGF-β element were used as “decoys” to compete with the TGF-β element in the pro-α1 (I) collagen gene for the TGF-β activator protein. Fibroblasts were pretreated with ssPT and challenged with exogenous TGF-β. Pretreatment with ssPT resulted in inhibition of TGF-β–induced increase in collagen synthesis and decreased binding of the TGF-β activator protein to DNA as determined by gel mobility shift analysis. To assess the effect of ssPT on collagen synthesis increased by endogenous TGF-β, the sponge-induced granuloma model of wound healing was used. ssPT resulted in a significant decrease in granuloma growth. Granuloma growth was linearly correlated to collagen synthesis. The wild-type TGF-β element had the base sequence 5′-TGCCCACGGCCAG-3′, and the messenger TGF-β element had the base sequence 5′-TGTGCGCGGCCCT-3′. In the messenger ssPT-treated group, there was no decrease in granuloma growth or collagen synthesis. Acute ssPT treatment did not effect collagen synthesis. ssPT act as novel nonsteroidal antifibrotic drugs that mimic the effects of glucocorticoids on collagen synthesis, not only in cell culture where collagen synthesis is increased by the addition of exogenous TGF-β, but also in sponge-induced granulomas in which collagen synthesis is increased by endogenous TGF-β.

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