Cross-Talk between Transforming Growth Factor-β and Periostin Can Be Targeted for Pulmonary Fibrosis.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized as progressive and irreversible fibrosis in the interstitium of lung tissues. There is still an unmet need to develop a novel therapeutic drug for IPF. We have previously demonstrated that periostin, a matricellular protein, plays an important role in the pathogenesis of pulmonary fibrosis. However, the underlying mechanism of how periostin causes pulmonary fibrosis remains unclear. In this study, we sought to learn whether the cross-talk between TGF-β (transforming growth factor-β), a central mediator in pulmonary fibrosis, and periostin in lung fibroblasts leads to generation of pulmonary fibrosis and whether inhibitors for integrin αVβ3, a periostin receptor, can block pulmonary fibrosis in model mice and the TGF-β signals in fibroblasts from patients with IPF. We found that cross-talk exists between TGF-β and periostin signals via αVβ3/β5 converging into Smad3. This cross-talk is necessary for the expression of TGF-β downstream effector molecules important for pulmonary fibrosis. Moreover, we identified several potent integrin low-molecular-weight inhibitors capable of blocking cross-talk with TGF-β signaling. One of the compounds, CP4715, attenuated bleomycin-induced pulmonary fibrosis in vivo in mice and the TGF-β signals in vitro in fibroblasts from patients with IPF. These results suggest that the cross-talk between TGF-β and periostin can be targeted for pulmonary fibrosis and that CP4715 can be a potential therapeutic agent to block this cross-talk.

• Authors: Yasuhiro Nanri, Satoshi Nunomura, Yasuhiro Terasaki, Tomohito Yoshihara, Yusuke Hirano, Yasuyuki Yokosaki, Yukie Yamaguchi, Carol Feghali-Bostwick, Keiichi Ajito, Shoichi Murakami, Simon J Conway, Kenji Izuhara
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 62 Issue 2 Pg. 204-216 (02 2020) ISSN: 1535-4989 [Electronic] United States
• PMID: 31505128 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CP-4715
• Cell Adhesion Molecules
• POSTN protein, human
• Piperidines
• Pyrimidines
• SMAD3 protein, human
• Smad3 Protein
• Transforming Growth Factor beta
• Bleomycin

Topics

• Animals
• Bleomycin (pharmacology)
• Cell Adhesion Molecules (drug effects, genetics)
• Fibroblasts (drug effects, metabolism)
• Humans
• Idiopathic Pulmonary Fibrosis (drug therapy, metabolism, pathology)
• Lung Diseases (metabolism)
• Mice
• Piperidines (pharmacology)
• Pyrimidines (pharmacology)
• Signal Transduction (drug effects)
• Smad3 Protein (genetics)
• Transforming Growth Factor beta (metabolism)