Trichostatin A prevents the accumulation of extracellular matrix in a mouse model of bleomycin‐induced skin fibrosis

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Abstract
Objective: Tissue fibrosis is a hallmark compromising feature of many disorders. In this study, we investigated the antifibrogenic effects of the histone deacetylase inhibitor trichostatin A (TSA) on cytokine‐driven fibrotic responses in vitro and in vivo.Methods: Skin fibroblasts from patients with systemic sclerosis (SSc) and normal healthy control subjects were stimulated with profibrotic cytokines in combination with TSA. Human Colα1(I) and fibronectin were measured using real‐time polymerase chain reaction, and levels of soluble collagen were estimated using the SirCol collagen assay. Electromobilty shift assay and confocal fluorescence microscopy were used to investigate the intracellular distribution of Smad transcription factors. For in vivo analysis, skin fibrosis was quantified by histologic assessment of mouse skin tissue in a model of bleomycin‐induced fibrosis.Results: Reductions in the cytokine‐induced transcription of Colα1(I) and fibronectin were observed in both normal and SSc skin fibroblasts following the addition of TSA. Similarly, the expression of total collagen protein in TSA‐stimulated SSc skin fibroblasts was reduced to basal levels. The mechanism of action of TSA included inhibition of the nuclear translocation and DNA binding of profibrotic Smad transcription factors. Western blot analysis revealed an up‐regulation of the cell cycle inhibitor p21 by TSA, leading to reduced proliferation of fibroblasts. In addition, in bleomycin‐induced fibrosis in mice, TSA prevented dermal accumulation of extracellular matrix in vivo.Conclusion: These findings provide novel insights into the epigenetic regulation of fibrosis. TSA and similar inhibitory compounds appear to represent early therapeutic strategies for achieving reversal of the cytokine‐driven induction of matrix synthesis that leads to fibrosis.

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