Echistatin/BYL-719 impedes epithelial-mesenchymal transition in pulmonary fibrosis induced by silica through modulation of the Integrin β1/ILK/PI3K signaling pathway

Int Immunopharmacol. 2024 Jul 30:136:112368. doi: 10.1016/j.intimp.2024.112368. Epub 2024 May 31.

Abstract

Silicosis is a chronic fibroproliferative lung disease caused by long-term inhalation of crystalline silica dust, characterized by the proliferation of fibroblasts and pulmonary interstitial fibrosis. Currently, there are no effective treatments available. Recent research suggests that the Integrin β1/ILK/PI3K signaling pathway may be associated with the pathogenesis of silicosis fibrosis. In this study, we investigated the effects of Echistatin (Integrin β1 inhibitor) and BYL-719 (PI3K inhibitor) on silicosis rats at 28 and 56 days after silica exposure. Histopathological analysis of rat lung tissue was performed using H&E staining and Masson staining. Immunohistochemistry, Western blotting, and qRT-PCR were employed to assess the expression of markers associated with epithelial-mesenchymal transition (EMT), fibrosis, and the Integrin β1/ILK/PI3K pathway in lung tissue. The results showed that Echistatin, BYL 719 or their combination up-regulated the expression of E-cadherin and down-regulated the expression of Vimentin and extracellular matrix (ECM) components, including type I and type III collagen. The increase of Snail, AKT and β-catenin in the downstream Integrin β1/ILK/PI3K pathway was inhibited. These results indicate that Echistatin and BYL 719 can inhibit EMT and pulmonary fibrosis by blocking different stages of Integrinβ1 /ILK/PI3K signaling pathway. This indicates that the Integrin β1/ILK/PI3K signaling pathway is associated with silica-induced EMT and may serve as a potential therapeutic target for silicosis.

Keywords: BYL-719; Echistatin; Epithelial-mesenchymal transformation; ITGB β1/ILK/PI3K signaling pathway; Silicosis.

MeSH terms

  • Animals
  • Epithelial-Mesenchymal Transition* / drug effects
  • Integrin beta1* / genetics
  • Integrin beta1* / metabolism
  • Lung / drug effects
  • Lung / pathology
  • Male
  • Phosphatidylinositol 3-Kinases* / metabolism
  • Protein Serine-Threonine Kinases* / metabolism
  • Pulmonary Fibrosis* / chemically induced
  • Pulmonary Fibrosis* / drug therapy
  • Pulmonary Fibrosis* / metabolism
  • Pulmonary Fibrosis* / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction* / drug effects
  • Silicon Dioxide* / toxicity
  • Silicosis* / drug therapy
  • Silicosis* / metabolism
  • Silicosis* / pathology

Substances

  • Integrin beta1
  • integrin-linked kinase
  • Silicon Dioxide
  • Phosphatidylinositol 3-Kinases
  • Protein Serine-Threonine Kinases