Endothelial dysfunction in steatotic human donor livers: A pilot study of the underlying mechanism during subnormothermic machine perfusion

Irene Beijert, Safak Mert, Viola Huang, Negin Karimian, Sharon Geerts, Ehab O.A. Hafiz, James F. Markmann, Heidi Yeh, Robert J. Porte, Korkut Uygun*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Scopus)
8 Downloads (Pure)

Abstract

Background.
Steatosis is a major risk factor for primary nonfunction in liver transplantations. Steatotic livers recover poorly from ischemia reperfusion injury, in part due to alterations in the microcirculation, although the exact mechanism is unclear. In this study, we tested if there were any alterations in the shear stress sensing Kruppel-like factor 2 (KLF2) and its likely downstream consequences in the ex vivo perfused human liver endothelium, which would imply perturbations in microcirculatory flow in macrosteatotic livers disrupts laminar flow to evaluate if this is a potential therapeutic target for steatotic livers.

Methods.
Using a subnormothermic machine perfusion system, 5 macrosteatotic and 4 nonsteatotic human livers were perfused for 3 hours. Flow, resistance, and biochemical profile were monitored. Gene expression levels of nitric oxide synthase 3 (eNOS), KLF2, and thrombomodulin were determined. Nitric oxide (NO) was measured in the perfusion fluid and activation of eNOS was measured with Western blotting.

Results.
Flow dynamics, injury markers, and bile production were similar in both groups. Kruppel-like factor 2 expression was significantly higher in nonsteatotic livers. Western blotting analyses showed significantly higher levels of activated eNOS in nonsteatotic livers, consistent with an increase in NO production over time. Macrosteatotic livers showed decreased KLF2 upregulation, eNOS activity, and NO production during machine perfusion.

Conclusions.
These results indicate a perturbed KLF2 sensing in steatotic livers, which aligns with perturbed microcirculatory state. This may indicate endothelial dysfunction and contribute to poor posttransplantation outcomes in fatty livers, and further studies to confirm by evaluation of flow and testing treatments are warranted.

Original languageEnglish
Article numbere345
Pages (from-to)528-538
Number of pages11
JournalTransplantation Direct
Volume4
Issue number5
DOIs
Publication statusPublished - May 2018
Externally publishedYes

Bibliographical note

Funding Information:
US National Institutes of Health (grants R01DK096075, R01DK107875 and R21EB020819) and the Shriners Hospitals for Children is gratefully acknowledged. The authors would like to gratefully acknowledge the New England Donor Services (NEDS), National Institute of Health (NIH) and Shriners Hospitals for Children-Boston for supporting this work.

Publisher Copyright:
Copyright © 2018 The Author(s).

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