Abstract
Pulmonary fibrosis is a fatal respiratory disease that gradually leads to dyspnea, mainly accompanied by excessive collagen production in the fibroblast and myofibroblast through mechanisms such as abnormal alveolar epithelial cells remodeling and stimulation of the extracellular matrix (ECM). Our results show that a small molecule, butylidenephthalide (BP), reduces type I collagen (COL1) expression in Transforming Growth Factor beta (TGF-β)-induced lung fibroblast without altering downstream pathways of TGF-β, such as Smad phosphorylation. Treatment of BP also reduces the expression of transcription factor Sex Determining Region Y-box 2 (SOX2), and the ectopic expression of SOX2 overcomes the inhibitory actions of BP on COL1 expression. We also found that serial deletion of the SOX2 binding site on 3′COL1 promoter results in a marked reduction in luciferase activity. Moreover, chromatin immunoprecipitation, which was found on the SOX2 binding site of the COL1 promoter, decreases in BP-treated cells. In an in vivo study using a bleomycin-induced pulmonary fibrosis C57BL/6 mice model, mice treated with BP displayed reduced lung fibrosis and collagen deposition, recovering in their pulmonary ventilation function. The reduction of SOX2 expression in BP-treated lung tissues is consistent with our findings in the fibroblast. This is the first report that reveals a non-canonical regulation of COL1 promoter via SOX2 binding, and contributes to the amelioration of pulmonary fibrosis by BP treatment.
Highlights
Pulmonary fibrosis is a disease that occurs when scar-like tissue accumulates extracellular matrix (ECM) components in the pulmonary interstitial tissue
We have found in our previous studies that Butylidenephthalide (BP), known as (3E)-3-butylidene-2-benzofuran-1-one in IUPAC, showed anti-fibrotic effects in the liver, with its mechanism enhancing Bone morphogenetic protein 7 (BMP7) expression and reducing TGF-β in hepatic stellate cells (HSC) [16]
Our findings show evidence of BP as a potential therapeutic treatment in pulmonary fibrosis
Summary
Pulmonary fibrosis is a disease that occurs when scar-like tissue accumulates extracellular matrix (ECM) components (such as collagen, elastin, and fibronectin) in the pulmonary interstitial tissue. Such prolonged fibrogenesis makes the pulmonary tissue lose elasticity, resulting in a gradual loss of ability to contract, relax, and exchange gas. The efficacy of current medications is not commensurate with other treatments such as pulmonary transplantation. The biggest disadvantage of pulmonary transplantation is the time it takes to find a suitable transplant. This unmet medical need requires the development of new targets [3]
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