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.
Highlights
Lung transplantation improves the quality of life of terminal lung disease patients [1]
We demonstrated that inhibiting PLK1 alleviates obliterative bronchiolitis (OB) by suppressing the differentiation of myofibroblasts in vivo
The pentose phosphate pathway is enriched in dysfunctional allografts after lung transplantation In a large sample study of consenting adult lung transplant recipients from seven centers, Kieran M Halloran and colleagues identified a set of rejectionassociated transcripts
Summary
Lung transplantation improves the quality of life of terminal lung disease patients [1]. In spite of advances to prevent acute transplant rejection, chronic allograft dysfunction (CAD) is still a major barrier for long-term survival of patients with transplanted organs [2]. Immunosuppression treatment can effectively prevent acute rejection, it has little effect on CAD and long-term survival rates [3]. New treatment methods and drugs targeting CAD are needed to prolong allograft survival. Transplant-associated obliterative bronchiolitis (OB), the main cause of long-term morbidity and mortality after lung transplantation, shares pathogenic features with CAD in other organs, such as the heart, kidney, and liver [4]. Myofibroblasts, a class of mesenchymal cells that are predominantly transdifferentiated from fibroblasts or other mesenchymal cells, are the dominant collagenproducing cells in fibrotic diseases, including CAD [7,8,9,10]. Suppressing the differentiation of myofibroblasts is a potential strategy for inhibiting CAD
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
