Increased expression of OPN contributes to idiopathic pulmonary fibrosis and indicates a poor prognosis

Abstract

Background Idiopathic pulmonary fibrosis (IPF) is fibrotic lung disease with no effective treatment. It is characterized by destruction of alveolar structure and pulmonary interstitial fibrosis, leading to dyspnea and even asphyxia death of patients. Epithelial-mesenchymal transition (EMT) is considered to be a driving factor in the pathogenesis of IPF. Osteopontin (OPN) is a secreted protein widely present in the extracellular matrix and involved in the occurrence and development of a variety of diseases. Methods The original datasets were obtained from NCBI GEO databases analyzed with the online tool GEO2R and EasyGEO. Bleomycin induced mouse pulmonary fibrosis model and OPN/OPN-biotin treated mouse model were established to investigate the role of OPN in mouse pulmonary fibrosis and the target cells of OPN. A549 cells and HBE cells were used to explore the mechanism of OPN-induced epithelial-mesenchymal transition (EMT) in epithelial cells and mass spectrometry was used to detect OPN downstream receptors. Precision-cut lung slices and lentivirus-treated mice with pulmonary fibrosis were used to examine the therapeutic effect of OPN and its downstream pathways on pulmonary fibrosis. Results We demonstrate that the content of OPN in IPF bronchoalveolar lavage fluid (BALF) is high compared to the normal groups, and its expression level is correlated with prognosis. At the animal level, OPN was highly expressed at all stages of pulmonary fibrosis in mice, and the bronchoalveolar lavage fluid (BALF) could accurately reflect its expression in the lung. Next, we reveal that OPN was mainly expressed by macrophages and the main target cells of OPN were epithelial cells. Mice developed pulmonary fibrosis accompanied after treating the mice with OPN. Both in vitro and in vivo experiments confirmed that OPN could induce EMT of alveolar epithelial cells. Mechanistically, OPN binding triggered phosphorylation of FAK by CD44, thus activating snail1-mediated profibrotic protein synthesis. Inhibition of FAK phosphorylation and its downstream pathways can effectively alleviate pulmonary fibrosis in precision sections of lung tissue (PCLS) assay. OPN knockdown in bleomycin-induced lung fibrosis mice led to significantly less fibrosis. Conclusion Our data suggest that OPN mediates lung fibrosis through EMT, implicating its potential therapeutic target and prognostic indicator role for IPF. OPN may be a target for the diagnosis and treatment of IPF.

A preliminary nomogram model for predicting organ damage of patients with diffuse Systemic sclerosis

“…Survival analysis also demonstrated that patients with OPN ≥ 25ng/ml had a higher incidence of organ damage. In idiopathic pulmonary brosis, OPN is involved in in ammatory response, ECM deposition and epithelial-mesenchymal transition [19].OPN is associated with poor prognosis of pulmonary brosis [20].OPN is produced by a variety of cell types, including B cells, T cells, natural killer cells, macrophages, neutrophils, dendritic cells(DCs), bone cells, epithelial cells, and neuronal cells. Binding of OPN to integrin or CD44 is involved in immune response and brosis [21].In terms of immune response, the interaction between OPN and CD44 in Th cells enhances the differentiation of Th1 and Th17 cells.…”

CD44 and its implication in neoplastic diseases

“…OPN, a phosphorylated glycoprotein, which expressed in the mineralized extracellular matrix (ECM) of bone in normal tissues cells such as fibroblasts, osteoblasts, and osteocytes. 150 , 151 As one of the classical and important ligands of CD44, OPN affects the proliferation and invasion of tumor cells as well as inflammation in normal cells, by regulating related signaling pathways. 150 , 152 Activation of the JUN N‐terminal kinase pathway has been shown to contribute to the promotion of clonogenicity and tumor growth in a xenograft model via OPN secreted by tumor‐associated macrophages.…”

Precision cut lung slices: an integrated ex vivo model for studying lung physiology, pharmacology, disease pathogenesis and drug discovery

“…Studies in PCLS have supported a number of different molecules in the pathogenesis of IPF including: a transmembrane protein that can interact with growth factor receptors or extracellular ligands to modulate receptor activation [104]; activation of histone deacetylases [105]; activation of integrins [106]; ion channel activation [107]; a kinase and a signaling microdomain protein [108]; a protein involved in cell fate determination, motility, and organogenesis [109]; and even an miRNA mimic as a potential therapy [110]. Additionally, other pathways have been postulated to be part of specific aspects of the biology of both epithelial cells and fibroblasts that may play a role in the pathology of IPF [111][112][113][114][115][116][117][118][119][120][121]. Studies have utilized PCLS to identify the cell types that drive fibrosis signals and showed the ways in which PCLS can model IPF [122][123][124][125].…”