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Abstract
Interstitial pulmonary fibrosis (IPF) is a progressive disease of diverse etiology manifesting with proliferation of lung fibroblasts and accumulation of extracellular matrix deposition in pulmonary interstitium. Recent studies show aberrant expression of mRNAs and microRNAs (miRNAs) in human embryonic pulmonary fibroblasts (HEPFs). In this study, we investigated effects of the YY1/HSF1/miR-214/THY1 axis on the functions of HEPFs and IPF. Loss- and gain-of-function tests were conducted to identify roles of YY1, HSF1, miR-214, and THY1 in IPF. As determined by RT-qPCR or western blot assay, silencing YY1 down-regulated HSF1 expression and attenuated the expression of pro-proliferative and fibrosis markers in HEPFs. Meanwhile, viability of HEPFs was impeded by YY1 knockdown. The binding relationship between miR-214 and THY1 was verified using dual-luciferase reporter assay. In HEPFs, down-regulation of HSF1 reduced miR-214 expression to repress proliferation and fibrogenic transformation of HEPFs, while inhibition of miR-214 expression could restrain the fibrogenic transformation property of HEPFs by up-regulating THY1. Subsequently, IPF model in mice was induced by bleomycin treatment. These animal experiments validated the protective effects of YY1 knockdown against IPF-induced lung pathological manifestations, which could be reversed by THY1 knockdown. Our study demonstrates the important involvement of YY1/HSF1/miR-214/THY1 axis in the development of IPF.
Highlights
Idiopathic pulmonary fibrosis (IPF), characterized by the histopathological pattern of usual interstitial pneumonia, is the most common type of idiopathic interstitial pneumonia [1]
To explore the correlation between Yin-Yang 1 (YY1) and HSF1, siRNAs targeting YY1 were designed to knock down YY1 and HSF1 overexpression plasmid was co-transfected to the human embryonic pulmonary fibroblasts (HEPFs) treated with si-YY1. si-YY1-3 with the best silencing efficiency was firstly determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis (Figure 1A)
Previous studies have demonstrated that YY1 is upregulated in lung fibroblasts induced by transforming growth factor-β (TGF-β) or tumor necrosis factor-α (TNF-α) [4], both of which are central pro-fibrotic mediators of pulmonary fibrosis [14, 15]
Summary
Idiopathic pulmonary fibrosis (IPF), characterized by the histopathological pattern of usual interstitial pneumonia, is the most common type of idiopathic interstitial pneumonia [1]. Micro-injuries that initiate abnormal epithelial-fibroblast communication, and induce matrix-producing myofibroblasts, are considered to contribute to the pathogenesis of IPF [1]. The extracellular matrix components produced by activated myofibroblasts have been reported to further contribute to fibroblast activation, and the altered extracellular matrix itself promotes fibrosis [2]. The precise mechanism by which fibroblasts are activated and contribute to the pathogenesis of IPF remains unclear. Up-regulated YY1 has been reported in multiple types of cancers and has been associated with poor prognosis [3]. Increased YY1 expression has been observed in lung tissues from patients with IPF and murine models of lung fibrosis [4] suggesting its importance in the pathogenesis of IPF
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