Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling; however, the molecular mechanisms underlying its occurrence and development are not yet fully understood. Despite it having a variety of beneficial pharmacological activities, the effects of catalpol (CAT), which is extracted from Rehmannia glutinosa, in IPF are not known. In this study, the differentially expressed genes, proteins, and pathways of IPF in the Gene Expression Omnibus database were analyzed, and CAT was molecularly docked with the corresponding key proteins to screen its pharmacological targets, which were then verified using an animal model. The results show that collagen metabolism imbalance, inflammatory response, and epithelial-mesenchymal transition (EMT) are the core processes in IPF, and the TGF-β1/Smad3 and Wnt/β-catenin pathways are the key signaling pathways for the development of pulmonary fibrosis. Our results also suggest that CAT binds to TGF-βR1, Smad3, Wnt3a, and GSK-3β through hydrogen bonds, van der Waals bonds, and other interactions to downregulate the expression and phosphorylation of Smad3, Wnt3a, GSK-3β, and β-catenin, inhibit the expression of cytokines, and reduce the degree of oxidative stress in lung tissue. Furthermore, CAT can inhibit the EMT process and collagen remodeling by downregulating fibrotic biomarkers and promoting the expression of epithelial cadherin. This study elucidates several key processes and signaling pathways involved in the development of IPF, and suggests the potential value of CAT in the treatment of IPF.
Highlights
Pulmonary fibrosis (PF), which usually manifests at the end stages of various interstitial lung diseases, is characterized by alveolar epithelial cell damage and abnormal deposition of extracellular matrix (ECM) (Herrera et al, 2018)
We used the GEO2R online software to analyze the microarray data provided by the original submitter and identify differentially expressed genes (DEGs) with recognition thresholds set to false discovery rate (FDR) < 0.05 and |log2 fold change (FC)| > 1
GO analysis of the DEGs revealed that they were mainly involved in humoral immunity, collagen metabolism, epithelial cell proliferation, mesenchymal development, and cell matrix adhesion, which is consistent with the strong inflammatory response and the imbalance of collagen metabolism observed in idiopathic pulmonary fibrosis (IPF) (Xin et al, 2019)
Summary
Pulmonary fibrosis (PF), which usually manifests at the end stages of various interstitial lung diseases, is characterized by alveolar epithelial cell damage and abnormal deposition of extracellular matrix (ECM) (Herrera et al, 2018). There are a variety of causes of PF—idiopathic pulmonary fibrosis (IPF) is a form of an unexplained and severe PF with a 5-years survival rate of less than 30% (Nalysnyk et al, 2012). The only drugs recommended for the treatment of mild-tomoderate IPF are pirfenidone (PFD) and nintedanib, both of which, fail to prolong the survival of patients (Ogura et al, 2015; Jo et al, 2016). With the development of high-throughput microarray and sequencing technologies in recent years, it has become possible to investigate the gene expression profiles of IPF and the corresponding changes in PF tissue and key genes. The differentially expressed gene (DEG) data obtained in this manner has in many cases enabled the successful screening of potential drugs by the docking of small molecular compounds with the corresponding proteins
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