Iguratimod decreases bleomycin-induced pulmonary fibrosis in association with inhibition of TNF-α in mice.

Abstract

Severe interstitial lung disease secondary to connective tissue diseases, characterized by pulmonary inflammation and fibrosis, often have very poor prognosis due to lack of effective treatments. Iguratimod (IGU) shows encouraging efficacy in treating connective tissue diseases, however, the underlying mechanism is still to be elucidated. In this study, we investigated the impact of IGU on bleomycin-induced interstitial lung disease and the related tumor necrosis factor-α (TNF-α) signaling pathway in mice and in the alveolar epithelial cell A549. We found IGU decreased pulmonary inflammation and fibrosis and expression of fibrosis-related genes such as Collagen I, α-smooth muscle actin (α-SMA) and matrix metalloproteinase-2 (MMP-2) induced by bleomycin. IGU inhibited epithelial-mesenchymal transition as evidenced by decreased E-cadherin expression but increased vimentin expression. IGU reduced TNF-α production in the pulmonary fibrosis murine model and in the in vitro cultured A549 cells. Furthermore, IGU ameliorated TNF-α-induced severe pulmonary fibrosis and inhibited TNF-α-induced activation of NF-κB. In addition, IGU decreased IL-6 production and phosphorylation of STAT3. In conclusion, the IGU-mediated anti-fibrogenesis effect was associated with the inhibition of TNF-α and NF-κB.

• Authors: Siqi Shao, Ziye Qu, Yiwen Liang, Yan Xu, Dongmei Zhou, Danhua Li, Ying Zhang, Songlou Yin
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 99 Pg. 107936 (Oct 2021) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 34284287 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Actins
• Cadherins
• Chromones
• NF-kappa B
• Sulfonamides
• Transcription Factor RelA
• Tumor Necrosis Factor-alpha
• Vimentin
• Bleomycin
• iguratimod
• Collagen
• Matrix Metalloproteinase 2

Topics

• A549 Cells
• Actins (metabolism)
• Animals
• Bleomycin (metabolism)
• Cadherins (genetics, metabolism)
• Chromones (metabolism)
• Collagen (metabolism)
• Disease Models, Animal
• Epithelial-Mesenchymal Transition
• Humans
• Matrix Metalloproteinase 2
• Mice
• NF-kappa B (metabolism)
• Pneumonia (metabolism)
• Pulmonary Fibrosis (metabolism)
• Signal Transduction
• Sulfonamides (metabolism)
• Transcription Factor RelA (metabolism)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors)
• Vimentin (genetics, metabolism)