Activation of autophagy during normothermic machine perfusion of discarded livers is associated with improved hepatocellular function

Anders Ohman, Siavash Raigani, John C. Santiago, Megan G. Heaney, Joan M. Boylan, Nicola Parry, Cailah Carroll, Sofia G. Baptista, Korkut Uygun, Philip A. Gruppuso, Jennifer A. Sanders, Heidi Yeh

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Liver transplantation is hampered by a severe shortage of donor organs. Normothermic machine perfusion (NMP) of donor livers allows dynamic preservation in addition to viability assessment before transplantation. Little is known about the injury and repair mechanisms induced during NMP. To investigate these mechanisms, we examined gene and protein expression changes in a cohort of discarded human livers, stratified by hepatocellular function, during NMP. Six human livers acquired through donation after circulatory death (DCD) underwent 12 h of NMP. Of the six livers, three met predefined criteria for adequate hepatocellular function. We applied transcriptomic profiling and protein analysis to evaluate temporal changes in gene expression during NMP between functional and nonfunctional livers. Principal component analysis segregated the two groups and distinguished the various perfusion time points. Transcriptomic analysis of biopsies from functional livers indicated robust activation of innate immunity after 3 h of NMP followed by enrichment of prorepair and prosurvival mechanisms. Nonfunctional livers demonstrated delayed and persistent enrichment of markers of innate immunity. Functional livers demonstrated effective induction of autophagy, a cellular repair and homeostasis pathway, in contrast to nonfunctional livers. In conclusion, NMP of discarded DCD human livers results in innate immune-mediated injury, while also activating autophagy, a presumed mechanism for support of cellular repair. More pronounced activation of autophagy was seen in livers that demonstrated adequate hepatocellular function.

Original languageEnglish (US)
Pages (from-to)G21-G33
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume322
Issue number1
DOIs
StatePublished - Jan 2022

Bibliographical note

Funding Information:
A.O. and J.C.S. are supported by National Institute of Environmental Health Sciences (T32ES007272). S.R. and H.Y. are supported by the Massachusetts General Hospital Executive Committee on Research. This research was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases (R01DK096075, R01DK107875, and R01DK114506), the National Science Foundation (EEC 1941543, ATP-Bio), and the Rhode Island Hospital/Brown University Department of Pediatrics. We thank the University of Arkansas Proteomics Core, which is supported by National Institutes of Health Grant Nos. R24GM137786, P20GM121293, and S10OD026736, for their valuable input and for processing our samples.

Publisher Copyright:
Copyright © 2022 the American Physiological Society.

Keywords

  • Autophagy
  • Ischemia reperfusion injury
  • Liver transplantation
  • Machine perfusion
  • Normothermic

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

Fingerprint

Dive into the research topics of 'Activation of autophagy during normothermic machine perfusion of discarded livers is associated with improved hepatocellular function'. Together they form a unique fingerprint.

Cite this