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. 2017 May 13;486(4):1021-1026.
doi: 10.1016/j.bbrc.2017.03.155. Epub 2017 Mar 29.

Activation and overexpression of Sirt1 attenuates lung fibrosis via P300

Zhilin Zeng  1 , Sheng Cheng  2 , Huilong Chen  3 , Qinghai Li  1 , Yinan Hu  1 , Qi Wang  1 , Xianying Zhu  1 , Jun Wang  1
Affiliations

Activation and overexpression of Sirt1 attenuates lung fibrosis via P300

Zhilin Zeng et al. Biochem Biophys Res Commun. .

Abstract

Persistent fibroblast activation is a predominant feature of idiopathic pulmonary fibrosis (IPF), but the transcriptional and epigenetic mechanisms controlling this process are not well understood. Silent information regulator type-1 (Sirt1) is a member of class Ⅲ histone deacetylase with important regulatory roles in a variety of pathophysiologic processes, but its role in fibrotic lung diseases is not clearly elucidated. Sirt1 expression in lung tissues of IPF patients and in a mouse model of bleomycin (BLM)-induced lung fibrosis were evaluated by immunofluorescence. The function of Sirt1 in BLM-induced lung fibrosis in the mouse model or transforming growth factor β1 (TGF-β1)-mediated lung fibroblast cellular model was investigated by Sirt1 activation, overexpression and knockdown of Sirt1. Finally, the involvement of p300 signaling pathways was assessed. In this study, we found up-regulation of Sirt1 in BLM-induced lung fibrosis, as well as in the lungs of IPF patients, including in the aggregated pulmonary fibroblasts of fibrotic foci. Activation or overexpression of Sirt1 attenuated TGF-β1-mediated lung fibroblast differentiation and activation and diminished the severity of experimental lung fibrosis in mice. Whereas knockdown of Sirt1 promoted the pro-fibrogenic activity of TGF-β1 in lung fibroblasts. A potential mechanism for the role of Sirt1 in lung fibrosis was through regulating the expression of p300. Thus, we characterized Sirt1 as an important regulator of lung fibrosis and provides a proof of principle for activation or overexpression of Sirt1 as a potential novel therapeutic strategy for IPF.

Keywords: Bleomycin; Lung fibrosis; Resveratrol; SRT1720; Silent information regulator type-1.

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