Idiopathic pulmonary fibrosis: Epithelial-mesenchymal interactions and emerging therapeutic targets

Abstract Background: Tyrosine kinase activation plays an important role in the progression of pulmonary fibrosis. In this study, we analyzed the expression of 612 kinase-coding and cancer-related genes using next-generation sequencing to identify potential therapeutic targets for idiopathic pulmonary fibrosis (IPF).Methods: Thirteen samples from five patients with IPF (Cases 1-5) and eight samples from four patients without IPF (control) were included in this study. Six of the thirteen samples were obtained from different lung segments of a single patient who underwent bilateral pneumonectomy. Gene expression analysis of IPF lung tissue samples (n=13) and control samples (n=8) was performed using SureSelect RNA Human Kinome Kit. The expression of the selected genes was further confirmed at the protein level by immunohistochemistry (IHC).Results: Gene expression analysis revealed a correlation between the gene expression signatures and the degree of fibrosis, as assessed by Ashcroft score. In addition, the expression analysis indicated a stronger heterogeneity among the IPF lung samples than among the control lung samples. In the integrated analysis of the 21 samples, DCLK1 and STK33 were found to be upregulated in IPF lung samples compared to control lung samples. However, the top most upregulated genes were distinct in individual cases. DCLK1, PDK4, and ERBB4 were upregulated in IPF case 1, whereas STK33, PIM2, and SYK were upregulated in IPF case 2. IHC revealed that these proteins were expressed in the epithelial layer of the fibrotic lesions.Conclusions: We performed a comprehensive kinase expression analysis to explore the potential therapeutic targets for IPF. DCLK1 and STK33 can serve as potential candidate targets for molecular targeted therapy of IPF. In addition, PDK4, ERBB4, PIM2, and SYK may serve as personalized therapeutic targets of IPF.

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Myriad Functions of Stanniocalcin-1 (STC1) Cover Multiple Therapeutic Targets in the Complicated Pathogenesis of Idiopathic Pulmonary Fibrosis (IPF)

Clinical Medicine Insights Circulatory Respiratory and Pulmonary Medicine ◽

10.4137/ccrpm.s23285 ◽

2015 ◽

Vol 9s1 ◽

pp. CCRPM.S23285 ◽

Cited By ~ 5

Author(s):

Shinya Ohkouchi ◽

Manabu Ono ◽

Makoto Kobayashi ◽

Taizou Hirano ◽

Yutaka Tojo ◽

...

Keyword(s):

Wound Healing ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Aerobic Glycolysis ◽

Therapeutic Targets ◽

Vascular Leakage ◽

Single Drug ◽

The Status ◽

Endothelial Homeostasis ◽

Temporal And Spatial Heterogeneity

Idiopathic pulmonary fibrosis (IPF) is an intractable disease for which the pathological findings are characterized by temporal and spatial heterogeneity. The pathogenesis is composed of myriad factors, including repetitive injuries to epithelial cells, alterations in immunity, the formation of vascular leakage and coagulation, abnormal wound healing, fibrogenesis, and collagen accumulation. Therefore, the molecular target drugs that are used or attempted for treatment or clinical trials may not cover the myriad therapeutic targets of IPF. In addition, the complicated pathogenesis results in a lack of informative biomarkers to diagnose accurately the status of IPF. These facts point out the necessity of using a combination of drugs, that is, each single drug with molecular targets or a single drug with multiple therapeutic targets. In this review, we introduce a humoral factor, stanniocalcin-1 (STC1), which has myriad functions, including the maintenance of calcium homeostasis, the promotion of early wound healing, uncoupling respiration (aerobic glycolysis), reepithelialization in damaged tissues, the inhibition of vascular leakage, and the regulation of macrophage functions to keep epithelial and endothelial homeostasis, which may adequately cover the myriad therapeutic targets of IPF.

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Integrative analysis of lung molecular signatures reveals key drivers of idiopathic pulmonary fibrosis

BMC Pulmonary Medicine ◽

10.1186/s12890-021-01749-3 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Sung Kyoung Kim ◽

Seung Min Jung ◽

Kyung-Su Park ◽

Ki-Jo Kim

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Signaling Pathway ◽

Cellular Senescence ◽

Therapeutic Targets ◽

Molecular Signatures ◽

Molecular Subgroups ◽

P53 Signaling ◽

Key Driver ◽

P53 Signaling Pathway

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a devastating disease with a high clinical burden. The molecular signatures of IPF were analyzed to distinguish molecular subgroups and identify key driver genes and therapeutic targets. Methods Thirteen datasets of lung tissue transcriptomics including 585 IPF patients and 362 normal controls were obtained from the databases and subjected to filtration of differentially expressed genes (DEGs). A functional enrichment analysis, agglomerative hierarchical clustering, network-based key driver analysis, and diffusion scoring were performed, and the association of enriched pathways and clinical parameters was evaluated. Results A total of 2,967 upregulated DEGs was filtered during the comparison of gene expression profiles of lung tissues between IPF patients and healthy controls. The core molecular network of IPF featured p53 signaling pathway and cellular senescence. IPF patients were classified into two molecular subgroups (C1, C2) via unsupervised clustering. C1 was more enriched in the p53 signaling pathway and ciliated cells and presented a worse prognostic score, while C2 was more enriched for cellular senescence, profibrosing pathways, and alveolar epithelial cells. The p53 signaling pathway was closely correlated with a decline in forced vital capacity and carbon monoxide diffusion capacity and with the activation of cellular senescence. CDK1/2, CKDNA1A, CSNK1A1, HDAC1/2, FN1, VCAM1, and ITGA4 were the key regulators as evidence by high diffusion scores in the disease module. Currently available and investigational drugs showed differential diffusion scores in terms of their target molecules. Conclusions An integrative molecular analysis of IPF lungs identified two molecular subgroups with distinct pathobiological characteristics and clinical prognostic scores. Inhibition against CDKs or HDACs showed great promise for controlling lung fibrosis. This approach provided molecular insights to support the prediction of clinical outcomes and the selection of therapeutic targets in IPF patients.

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