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ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Respiratory Pharmacology
Volume 15 - 2024 |
doi: 10.3389/fphar.2024.1433186
Triiodothyronine Acts on DAO to Regulate Pulmonary Fibrosis Progression by Facilitating Cell Senescence through the p53/p21 Signaling Pathway
Provisionally accepted- 1 Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, Institute of Biomedical Science, College of Life Science, Henan Normal University, Xinxiang, China
- 2 Department of Physiology, Department of Fundamental Medicine, Changzhi Medical College, changzhi, China
- 3 Division of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, United States
Background: Idiopathic pulmonary fibrosis (IPF) is the result of multiple cycles of epithelial cell injury and fibroblast activation; currently, there is no clear etiology. Increasing evidence suggests that protein metabolism and amino acids play a crucial role in IPF, but the role of D-amino acids is not yet clear. The aim of this study was to identify novel mediators in order to test the hypothesis that D-amino acid oxidase (DAO) plays a significant role in the pathogenesis of IPF. Methods: We analyzed DAO gene expression in patients with IPF and mice with bleomycin (BLM)-induced lung fibrosis. We performed in vitro and in vivo assays to determine the effect of DAO on primary type II alveolar epithelial cells from mice and A549 cells. Results: DAO expression was downregulated in the lungs of IPF patients and BLM-induced fibrotic mice. Treatment with D-serine (D-Ser) or drug inhibition of DAO promoted cell senescence through the p53/p21 pathway. Dao-/- mice showed an intensified fibrotic response, and the anti-fibrotic role of T3 was abolished. Conclusions: We concluded that the DAO-p53/p21 axis might be a key anti-fibrotic pathway regulating the progress of fibrosis and facilitating the therapeutic role of T3.
Keywords: Idiopathic Pulmonary Fibrosis, D-amino acid oxidase, Triiodothyronine, anti-fibrotic axis, p53/p21 pathway
Received: 15 May 2024; Accepted: 27 Aug 2024.
Copyright: © 2024 Guo, Xu, Wang, Ding, Li, Zhao, Zhang, Wang, Wang, Zhao, Rosas and Yu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Guoying Yu, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, Institute of Biomedical Science, College of Life Science, Henan Normal University, Xinxiang, China
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