Integrated long non-coding RNA analyses identify novel regulators of epithelial-mesenchymal transition in the mouse model of pulmonary fibrosis.

Hao Sun,Junjie Chen,Jiang Kang,Lei Jiang,Jinsong Zhang,Jun Wang,Wei Chen,Wenyi Qian,Li Qiao

doi:10.1111/jcmm.12783

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease characterized by aberrant accumulation of fibroblast population and deposition of extra cellular matrix. Increasing evidence support that epithelial‐mesenchymal transition (EMT) of alveolar epithelial cells is a critical process in the pathogenesis of IPF. Although delivery of bleomycin to induce acute lung injury is the most well‐studied animal model of pulmonary fibrosis, there is considerable interest to pursue other models to understand the common and/or specific pathological mechanisms. In this study, we established a mouse model of pulmonary injury and progressive interstitial fibrosis via intraperitoneal injection of paraquat, a widely used herbicide known to cause pulmonary fibrosis in human. Using transcriptome sequencing and microarray analysis, we profiled expression of long non‐coding RNAs (lncRNAs) and identified 513 up‐regulated and 204 down‐regulated lncRNAs in paraquat‐induced fibrotic lung tissues. Gene ontology analysis revealed that the differentially expressed lncRNAs are implicated in cell differentiation, epithelium morphogenesis and wound healing, pathways closely associated with EMT. Furthermore, we identified the evolutionally conserved target genes of two up‐regulated lncRNAs, uc.77 and 2700086A05Rik, as Zeb2 and Hoxa3, respectively, both of which are important modulators of EMT. Consistently, overexpression of uc.77 or 2700086A05Rik in human lung epithelial cells induced EMT as demonstrated by changes in gene and protein expression of various EMT markers and cell morphology. Collectively, our results uncovered a crucial role of lncRNA in the regulation of EMT during lung fibrosis and provide potential avenues for the discovery of novel molecular markers and therapeutic targets for IPF.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease of the lung interstitium with poor prognosis [1]
With a cut-off fold change of ≥5.0, we identified 513 up-regulated and 204 down-regulated long non-coding RNAs (lncRNAs) in the paraquat-induced fibrotic lung tissues compared to normal tissues (Table S2), suggesting that there was an extensive remodelling of the cellular lncRNA transcriptome during the fibrosis development upon paraquat treatment
We provide evidence that misregulation of lncRNAs is a prominent feature associated with the development of pulmonary fibrosis induced by paraquat in mouse

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease of the lung interstitium with poor prognosis [1]. The exact cause of IPF remains unknown, it is believed that IPF originates from repetitive micro-injuries to the alveolar epithelium which may result from cigarette smoking, inhalation of dust, or occupation-related exposure to hazardous chemicals [1, 2]. Considerable efforts have been made to develop animal models of pulmonary fibrosis to understand the pathological mechanisms of IPF. An anti-cancer chemotherapeutic agent, is commonly used to induce acute lung damage and fibrosis in rodents [3]. While studies using these models have generated important molecular insights, it remains unclear whether signalling pathways mediating bleomycin-induced lung fibro-.

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Conclusion