Abstract
Long non-coding RNAs (lncRNAs) have emerged as critical factors for regulating multiple biological processes during organ fibrosis. However, the mechanism of lncRNAs in idiopathic pulmonary fibrosis (IPF) remains incompletely understood. In the present study, two sets of lncRNAs were defined: IPF pathogenic lncRNAs and IPF progression lncRNAs. IPF pathogenic and progression lncRNAs-mRNAs co-expression networks were constructed to identify essential lncRNAs. Network analysis revealed a key lncRNA CTD-2528L19.6, which was up-regulated in early-stage IPF compared to normal lung tissue, and subsequently down-regulated during advanced-stage IPF. CTD-2528L19.6 was indicated to regulate fibroblast activation in IPF progression by mediating the expression of fibrosis related genes LRRC8C, DDIT4, THBS1, S100A8 and TLR7 et al. Further studies showed that silencing of CTD-2528L19.6 increases the expression of Fn1 and Collagen I both at mRNA and protein levels, promoted the transition of fibroblasts into myofibroblasts and accelerated the migration and proliferation of MRC-5 cells. In contrast, CTD-2528L19.6 overexpression alleviated fibroblast activation in MRC-5 cells induced by TGF-β1. LncRNA CTD-2528L19.6 inhibited fibroblast activation through regulating the expression of LRRC8C in vitro assays. Our results suggest that CTD-2528L19.6 may prevent the progression of IPF from early-stage and alleviate fibroblast activation during the advanced-stage of IPF. Thus, exploring the regulatory effect of lncRNA CTD-2528L19.6 may provide new sights for the prevention and treatment of IPF.
Highlights
Introduction Idiopathic PulmonaryFibrosis (IPF) is a progressive and chronic disorder that has been characterized by excessive wound repair and fibrosing interstitial pneumonia of unknown etiology[1,2]
Two Long non-coding RNAs (lncRNAs) and 48 mRNAs were significantly differentially expressed in all three comparisons (P < 0.01, Student’s t-test, Fig. 1A; Supplementary Fig. S2A)
LncRNA CTD-2528L19.6, NR2F1-AS1 were significantly up-regulated in early-stage of idiopathic pulmonary fibrosis (IPF) compared with normal lung and downregulated in advanced-stage of IPF (P < 0.01, Student’s ttest, Fig. 1B, C)
Summary
Fibrosis (IPF) is a progressive and chronic disorder that has been characterized by excessive wound repair and fibrosing interstitial pneumonia of unknown etiology[1,2]. IPF is likely driven by abnormal epithelium and propagated by dysregulated overabundant, heterogeneous fibroblast population in various states of activation[3,4,5]. It has been reported that transforming growth factor-β1 (TGF-β1) plays a key role in the development of IPF and TGF-β1 gene polymorphisms may affect disease progression in patients with IPF6. Survival rate of the advanced-stage IPF patients at 5 years is much lower than that of early-stage IPF7. Emerging evidence indicates that genetic studies may hold promise in the connections between early-stage and advancedstage disease[8], no special study focuses on analyzing the difference of gene expression during different stages of IPF. A comprehensive understanding of the pathogenesis and progression mechanisms involved in IPF remains elusive
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