Research Paper Volume 12, Issue 12 pp 11636—11652
PLK1 Inhibition alleviates transplant-associated obliterative bronchiolitis by suppressing myofibroblast differentiation
- 1 Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
- 2 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
Received: January 6, 2020 Accepted: April 17, 2020 Published: June 15, 2020
https://doi.org/10.18632/aging.103330How to Cite
Copyright © 2020 Yu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Chronic allograft dysfunction (CAD) resulting from fibrosis is the major limiting factor for long-term survival of lung transplant patients. Myofibroblasts promote fibrosis in multiple organs, including the lungs. In this study, we identified PLK1 as a promoter of myofibroblast differentiation and investigated the mechanism by which its inhibition alleviates transplant-associated obliterative bronchiolitis (OB) during CAD. High-throughput bioinformatic analyses and experiments using the murine heterotopic tracheal transplantation model revealed that PLK1 is upregulated in grafts undergoing CAD as compared with controls, and that inhibiting PLK1 alleviates OB in vivo. Inhibition of PLK1 in vitro reduced expression of the specific myofibroblast differentiation marker α-smooth muscle actin (α-SMA) and decreased phosphorylation of both MEK and ERK. Importantly, we observed a similar phenomenon in human primary fibroblasts. Our results thus highlight PLK1 as a promising therapeutic target for alleviating transplant-associated OB through suppression of TGF-β1-mediated myofibroblast differentiation.
Abbreviations
α-SMA: α-smooth muscle actin; CAD: chronic allograft dysfunction; GAPDH: glyceraldehyde-phosphate dehydrogenase; G6PD: glucose-6-phosphate dehydrogenase; H&E: haematoxylin and eosin; OB: obliterative bronchiolitis; PPP: pentose phosphate pathway; qRT-PCR: quantitative real-time PCR.