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Potential Therapeutic Targets for Lung Repair During Human Ex Vivo Lung Perfusion

Aaron Wong, Ricardo Zamel, Jonathan Yeung, Gary D. Bader, Claudia C. Dos Santos, Xiaohui Bai, Yubo Wang, Shaf Keshavjee, Mingyao Liu
European Respiratory Journal 2020; DOI: 10.1183/13993003.02222-2019
Aaron Wong
1Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Canada
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Ricardo Zamel
2Latner Thoracic Surgical Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
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Jonathan Yeung
2Latner Thoracic Surgical Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
3Toronto Lung Transplant Program, Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Canada
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Gary D. Bader
4Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, Canada
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Claudia C. Dos Santos
1Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Canada
5Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada
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Xiaohui Bai
2Latner Thoracic Surgical Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
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Yubo Wang
2Latner Thoracic Surgical Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
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Shaf Keshavjee
1Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Canada
2Latner Thoracic Surgical Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
3Toronto Lung Transplant Program, Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Canada
6These authors share senior authorship
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Mingyao Liu
1Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Canada
2Latner Thoracic Surgical Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
3Toronto Lung Transplant Program, Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Canada
6These authors share senior authorship
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Abstract

Introduction The ex vivo lung perfusion (EVLP) technique has been developed to assess the function of marginal donor lungs which has significantly increased donor lung utilisation. EVLP has also been explored as a platform for donor lung repair through injury specific treatments such as antibiotics or fibrinolytics. We hypothesised that actively expressed pathways shared between transplantation and EVLP may reveal common mechanisms of injury and potential therapeutic targets for lung repair prior to transplantation.

Materials and Methods A retrospective transcriptomics analyses were performed with peripheral tissue biopsies from “donation after brain death” lungs, with 46 pre/post-transplant pairs and 49 pre/post-EVLP pairs. Pathway analysis was used to identify and compare the responses of donor lungs to transplantation and to EVLP.

Results Twenty-one pathways were enriched predominantly in transplantation, including upregulation of lymphocyte activation and cell death, and downregulation of metabolism and protein synthesis. Seven pathways were enriched predominantly in EVLP, including downregulation of leukocyte functions and upregulation of vascular processes. Twenty-three pathways were commonly enriched, including activation of innate inflammation, cell death, heat stress and downregulation of metabolism. Of the inflammatory clusters, TLR/MYD88 signalling had the greatest number of nodes and was central to inflammation. These mechanisms have been previously speculated as major mechanisms of acute lung injury in animal models.

Conclusion EVLP and transplantation share common molecular features of injury including innate inflammation and cell death. Blocking these pathways during EVLP may allow for lung repair prior to transplantation.

Footnotes

This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.

Conflict of interest: Dr. Wong has nothing to disclose.

Conflict of interest: Dr. Zamel has nothing to disclose.

Conflict of interest: Dr. Yeung has nothing to disclose.

Conflict of interest: Dr. Bader has nothing to disclose.

Conflict of interest: Dr. Dos Santos has nothing to disclose.

Conflict of interest: Dr. Bai has nothing to disclose.

Conflict of interest: Dr. Wang has nothing to disclose.

Conflict of interest: Dr. Keshavjee has nothing to disclose.

Conflict of interest: Dr. Liu has nothing to disclose.

  • Received November 17, 2019.
  • Accepted January 15, 2020.
  • Copyright ©ERS 2020
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Potential Therapeutic Targets for Lung Repair During Human Ex Vivo Lung Perfusion
Aaron Wong, Ricardo Zamel, Jonathan Yeung, Gary D. Bader, Claudia C. Dos Santos, Xiaohui Bai, Yubo Wang, Shaf Keshavjee, Mingyao Liu
European Respiratory Journal Jan 2020, 1902222; DOI: 10.1183/13993003.02222-2019

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Potential Therapeutic Targets for Lung Repair During Human Ex Vivo Lung Perfusion
Aaron Wong, Ricardo Zamel, Jonathan Yeung, Gary D. Bader, Claudia C. Dos Santos, Xiaohui Bai, Yubo Wang, Shaf Keshavjee, Mingyao Liu
European Respiratory Journal Jan 2020, 1902222; DOI: 10.1183/13993003.02222-2019
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