Abstract
Tissue remodeling/fibrosis is a main feature of idiopathic pulmonary fibrosis (IPF), which results in the replacement of normal lung parenchyma with a collagen-rich extracellular matrix produced by fibroblasts and myofibroblasts. Epithelial-mesenchymal transition (EMT) in type 2 lung epithelial cells is a key process in IPF, which leads to fibroblasts and myofibroblasts accumulation and excessive collagen deposition. DEC1, a structurally distinct class of basic helix-loop-helix proteins, is associated with EMT in cancer. However, the functional role of DEC1 in pulmonary fibrosis (PF) remains elusive. Herein, we aimed to explore DEC1 expression in IPF and bleomycin (BLM)-induced PF in mice and the mechanisms underlying the fibrogenic effect of DEC1 in PF in vivo and in vitro by Dec1-knockout (Dec1 −/−) mice, knockdown and overexpression of DEC1 in alveolar epithelial cells (A549 cells). We found that the expression of DEC1 was increased in IPF and BLM-injured mice. More importantly, Dec1 −/− mice had reduced PF after BLM challenge. Additionally, DEC1 deficiency relieved EMT development and repressed the PI3K/AKT/GSK-3β/β-catenin integrated signaling pathway in mice and in A549 cells, whereas DEC1 overexpression in vitro had converse effects. Moreover, the PI3K/AKT and Wnt/β-catenin signaling inhibitors, LY294002 and XAV-939, ameliorated BLM-meditated PF in vivo and relieved EMT in vivo and in vitro. These pathways are interconnected by the GSK-3β phosphorylation status. Our findings indicated that during PF progression, DEC1 played a key role in EMT via the PI3K/AKT/GSK-3β/β-catenin integrated signaling pathway. Consequently, targeting DEC1 may be a potential novel therapeutic approach for IPF.
Highlights
Idiopathic pulmonary fibrosis (IPF), the most common type of idiopathic interstitial pneumonia (IIP), is a chronic, irreversible and typically fatal fibrotic lung disease, which is characterized by overproduction and disorganized deposition of extracellular matrix (ECM) proteins, together with abnormal proliferation of mesenchymal cells, leading to distortion of pulmonary architecture and impairment of pulmonary functions (Okamoto et al, 2011; Wolters et al., Dec1 Deficiency Ameliorates Pulmonary Fibrosis2018)
Before we study the functional role of differentiated embryonic chondrocyte expressed gene 1 (DEC1) in PF, we first measured the expression of DEC1 in lung tissues from idiopathic pulmonary fibrosis (IPF) patients
We found that DEC1 was highly expressed in IPF and IIP patients by analyzing data from Gene Expression Omnibus (GEO) database (GSE53845 and GSE5774) (Figure 1C)
Summary
Idiopathic pulmonary fibrosis (IPF), the most common type of idiopathic interstitial pneumonia (IIP), is a chronic, irreversible and typically fatal fibrotic lung disease, which is characterized by overproduction and disorganized deposition of extracellular matrix (ECM) proteins, together with abnormal proliferation of mesenchymal cells, leading to distortion of pulmonary architecture and impairment of pulmonary functions (Okamoto et al, 2011; Wolters et al., Dec Deficiency Ameliorates Pulmonary Fibrosis2018). Idiopathic pulmonary fibrosis (IPF), the most common type of idiopathic interstitial pneumonia (IIP), is a chronic, irreversible and typically fatal fibrotic lung disease, which is characterized by overproduction and disorganized deposition of extracellular matrix (ECM) proteins, together with abnormal proliferation of mesenchymal cells, leading to distortion of pulmonary architecture and impairment of pulmonary functions The incidence and prevalence of IPF reportedly range from 2 to 30 cases per 100,000 person-years and 10–60 cases per 100,000 people, respectively. Only two drugs, nintedanib and pirfenidone, are FDA-approved for the treatment of IPF, but they only reduce the rate of lung function decline, and they may have several serious side effects (Kasam et al, 2020). It is necessary to investigate the precise mechanisms underlying IPF and identify new antifibrotic therapeutic approaches
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