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Original research
Altered purine metabolism at reperfusion affects clinical outcome in lung transplantation
  1. Cristina Baciu1,
  2. Jason Shin1,
  3. Michael Hsin1,
  4. Marcelo Cypel1,2,3,
  5. Shaf Keshavjee1,2,3,
  6. Mingyao Liu1,3
  1. 1Latner Thoracic Surgical Laboratory, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
  2. 2Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
  3. 3Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
  1. Correspondence to Dr. Mingyao Liu, Surgery, University of Toronto, Toronto, Canada; mingyao.liu{at}utoronto.ca

Abstract

Introduction Lung transplantation is an established treatment for patients with end-stage lung disease. However, ischaemia reperfusion injury remains a barrier to achieving better survival outcomes. Here, we aim to investigate the metabolomic and transcriptomic profiles in human lungs before and after reperfusion, to identify mechanisms relevant to clinical outcome.

Methods We analysed 67 paired human lung tissue samples collected from 2008 to 2011, at the end of cold preservation and 2 hours after reperfusion. Gene expression analysis was performed with R. Pathway analysis was conducted with Ingenuity Pathway Analysis. MetaboAnalyst and OmicsNet were used for metabolomics analysis and omics data integration, respectively. Association of identified metabolites with transplant outcome was investigated with Kaplan-Meier estimate and Cox proportional hazard models.

Results Activation of energy metabolism and reduced antioxidative biochemicals were found by metabolomics. Upregulation of genes related to cytokines and inflammatory mediators, together with major signalling pathways were revealed by transcriptomics. Purine metabolism was identified as the most significantly enriched pathway at reperfusion, based on integrative analysis of the two omics data sets. Elevated expression of purine nucleoside phosphorylase (PNP) could be attributed to activation of multiple transcriptional pathways. PNP catabolised reactions were evidenced by changes in related metabolites, especially decreased levels of inosine and increased levels of uric acid. Multivariable analyses showed significant association of inosine and uric acid levels with intensive care unit length of stay and ventilation time.

Conclusion Oxidative stress, especially through purine metabolism pathway, is a major metabolic event during reperfusion and may contribute to the ischaemia reperfusion injury of lung grafts.

  • Lung Transplantation
  • Oxidative Stress

Data availability statement

Data are available upon reasonable request. Raw microarray data and processed files were deposited at NCBI Gene Expression Omnibus (GEO) database, with GEO Series accession number GSE145989.

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Data availability statement

Data are available upon reasonable request. Raw microarray data and processed files were deposited at NCBI Gene Expression Omnibus (GEO) database, with GEO Series accession number GSE145989.

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Footnotes

  • CB and JS contributed equally.

  • Contributors CB participated in the study design, performed metabolomics, transcriptomics and multi-omics analyses and wrote the manuscript. JS contributed to data interpretation and wrote significant part of the manuscript. MH designed the metabolomics and transcriptomic experiments and contributed to sample collection and processing. MC participated in the study design and sample collection, and made critical comments. SK led the research funded by Genome Canada, the biobanking and microarray studies. ML conceived the study design, supervised the project and revised the manuscript. All authors approved the final draft of the manuscript. ML is the guarantor of the study.

  • Funding Canadian Institutes of Health Research (MOP-119514, MOP-31227, PJT-148847) and Genome Canada (#6427).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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