Blocking TG2 attenuates bleomycin-induced pulmonary fibrosis in mice through inhibiting EMT

Respir Physiol Neurobiol. 2020 May:276:103402. doi: 10.1016/j.resp.2020.103402. Epub 2020 Jan 29.

Abstract

Background: Epithelial-mesenchymal transformation (EMT) is a central mechanism for the occurrence and development of pulmonary fibrosis. Therefore, to identify the key target molecules regulating the EMT process is considered as an important direction for the prevention and treatment of pulmonary fibrosis. Transglutaminase 2 (TG2) has been recently found to play an important role in the regulation of inflammation and the generation of extracellular matrix. Here, our study focuses on the roles of TG2 in pulmonary fibrosis and EMT.

Methods: at first, the expression of TG2 and the EMT-related markers like E-cadherin, Vimentin, and α-SMA were detected with Western Blotting, immunohistochemistry and other methods in the mice with pulmonary fibrosis induced by bleomycin. Further, MLE 12 cells were used to study the effects on EMT of the inhibition of TG2 in vitro. Finally, GK921, an inhibitor against TG2, was used to show its function in both prevention and treatment of pulmonary fibrosis induced by bleomycin in mice.

Results: bleomycin succeeded to induce pulmonary fibrosis in mice, with increased TG2 expression, EMT and Akt activation. Knock-down of TG2 by siRNA technique in MLE 12 cell (a mouse alveolar epithelial cell line) and GK921 (an inhibitor of TG2) all inhibited the EMT process, however SC79, an activator of Akt rescued above inhibition. Finally, GK921 alleviated pulmonary fibrosis in mice induced by bleomycin.

Conclusion: Blocking TG2 reduces bleomycin-induced pulmonary fibrosis in mice via inhibiting EMT.

Keywords: Bleomycin; Epithelial mesenchymal transformation (EMT); GK921; Pulmonary fibrosis; Transglutaminase 2 (TG2).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / pharmacology
  • Actins / drug effects
  • Actins / metabolism
  • Animals
  • Antibiotics, Antineoplastic / toxicity
  • Benzopyrans / pharmacology
  • Bleomycin / toxicity
  • Cadherins / drug effects
  • Cadherins / metabolism
  • Cell Line
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial-Mesenchymal Transition / drug effects
  • Epithelial-Mesenchymal Transition / physiology*
  • GTP-Binding Proteins / antagonists & inhibitors
  • GTP-Binding Proteins / genetics*
  • GTP-Binding Proteins / metabolism
  • Gene Knockdown Techniques
  • In Vitro Techniques
  • Mice
  • Protein Glutamine gamma Glutamyltransferase 2
  • Pulmonary Fibrosis / genetics*
  • Pulmonary Fibrosis / metabolism
  • Pyrazines / pharmacology
  • Respiratory Mucosa / cytology
  • Transglutaminases / antagonists & inhibitors
  • Transglutaminases / genetics*
  • Transglutaminases / metabolism
  • Vimentin / drug effects
  • Vimentin / metabolism

Substances

  • 2-amino-6-chloro-alpha-cyano-3-(ethoxycarbonyl)-4H-1-benzopyran-4-acetic acid ethyl ester
  • 3-(phenylethynyl)-2-(2-(pyridin-2-yl)ethoxy)pyrido(3,2-b)pyrazine
  • Acetates
  • Actins
  • Antibiotics, Antineoplastic
  • Benzopyrans
  • Cadherins
  • Cdh1 protein, mouse
  • Pyrazines
  • Vim protein, mouse
  • Vimentin
  • alpha-smooth muscle actin, mouse
  • Bleomycin
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases
  • GTP-Binding Proteins