Abstract

BackgroundChronic fibrosing idiopathic interstitial pneumonia (IIP) is characterized by alveolar epithelial damage, activation of fibroblast proliferation, and loss of normal pulmonary architecture and function. This study aims to investigate the genetic backgrounds of IIP through gene expression profiling and pathway analysis, and to identify potential biomarkers that can aid in diagnosis and serve as novel therapeutic targets.MethodsRNA extracted from lung specimens of 12 patients with chronic fibrosing IIP was profiled using Illumina Human WG-6 v3 BeadChips, and Ingenuity Pathway Analysis was performed to identify altered functional and canonical signaling pathways. For validating the results from gene expression analysis, immunohistochemical staining of 10 patients with chronic fibrosing IIP was performed.ResultsNinety-eight genes were upregulated in IIP patients relative to control subjects. Some of the upregulated genes, namely desmoglein 3 (DSG3), protocadherin gamma-A9 (PCDHGA9) and discoidin domain-containing receptor 1 (DDR1) are implicated in cell-cell interaction and/or adhesion; some, namely collagen type VII, alpha 1 (COL7A1), contactin-associated protein-like 3B (CNTNAP3B) and mucin-1 (MUC1) are encoding the extracellular matrix molecule or the molecules involved in cell-matrix interactions; and the others, namely CDC25C and growth factor independent protein 1B (GFI1B) are known to affect cell proliferation by affecting the progression of cell cycle or regulating transcription. According to pathway analysis, alternated pathways in IIP were related to cell death and survival and cellular growth and proliferation, which are more similar to cancer than to inflammatory response and immunological diseases. Using immunohistochemistry, we further validate that DSG3, the most highly upregulated gene, shows higher expression in chronic fibrosing IIP lung as compared to control lung.ConclusionWe identified several genes upregulated in chronic fibrosing IIP patients as compared to control, and found genes and pathways implicated in cancer, rather than in inflammatory or immunological disease to play important roles in the pathogenesis of IIPs. Moreover, DSG3 is a novel potential biomarker for chronic fibrosing IIP with its significantly high expression in IIP lung.

Highlights

  • Chronic fibrosing idiopathic interstitial pneumonia (IIP) is characterized by alveolar epithelial damage, activation of fibroblast proliferation, and loss of normal pulmonary architecture and function

  • IIP has been further classified into several subtypes, including idiopathic pulmonary fibrosis (IPF), which has the hallmark histopathologic feature described as usual interstitial pneumonia and nonspecific interstitial pneumonia (NSIP) [1,2,3]

  • The present study aims to delineate the molecular mechanisms of pulmonary fibrosis and identify potential disease-specific biomarkers and/or therapeutic targets in the chronic fibrosing IIPs patients by using genomewide microarray analysis followed by canonical pathway analysis

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Summary

Introduction

Chronic fibrosing idiopathic interstitial pneumonia (IIP) is characterized by alveolar epithelial damage, activation of fibroblast proliferation, and loss of normal pulmonary architecture and function. IPF is one of the most common and aggressive types of IIP and is characterized by alveolar epithelial damage that leads to inadequate tissue repair, collagen accumulation, and fibroblast proliferation, the underlying molecular mechanisms remain unclear [5]. Nintedanib, a multiple tyrosine kinase inhibitor, demonstrated clinical efficacy for IPF patients [11]. These drugs only reduce the decline in forced vital capacity, without halting disease progression in all patients. New diagnostic tools and therapeutic strategies, including molecular targeting drugs, are urgently needed

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