Abstract
BackgroundTyrosine 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).MethodsThirteen 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).ResultsGene 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.ConclusionsWe performed a comprehensive kinase expression analysis to explore the potential therapeutic targets for IPF. We found that DCLK1 and STK33 may serve as potential candidate targets for molecular targeted therapy of IPF. In addition, PDK4, ERBB4, PIM2, and SYK might also serve as personalized therapeutic targets of IPF. Additional large-scale studies are warranted to develop personalized therapies for patients with IPF.
Highlights
Tyrosine kinase activation plays an important role in the progression of pulmonary fibrosis
idiopathic pulmonary fibrosis (IPF) lung tissues were harvested from two patients, who underwent lung transplantation, and from three patients, who underwent surgical lung resection for non-small cell lung cancer (NSCLC)
The lung tissues without IPF were harvested from the control patients who underwent surgical lung resection for NSCLC
Summary
Tyrosine kinase activation plays an important role in the progression of pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease that results in fibrotic scarring of the alveolar tissues. Multiple studies have shown that damage to the respiratory epithelium and impairment in its repair mechanism play a central role in the development of IPF [10]. Alveolar type II (AT2) cells play important roles in the pathogenesis of IPF because they act as progenitor cells and help in regeneration of the respiratory epithelium [11, 12]. The incidence of IPF increases with aging, which suggests the existence of a complex relationship between chronic environmental exposure, infection, host defense/ repair pathways, and disease progression
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