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Hydrogen Preconditioning During Ex Vivo Lung Perfusion Improves the Quality of Lung Grafts in Rats

Noda, Kentaro1,2; Shigemura, Norihisa1,3; Tanaka, Yugo1; Bhama, Jay1; D’Cunha, Jonathan1; Kobayashi, Hirosuke2; Luketich, James D.1; Bermudez, Christian A.1

Transplantation:
doi: 10.1097/TP.0000000000000254
Basic and Experimental Research
Abstract

Background: Although the benefits of ex vivo lung perfusion (EVLP) have been globally advocated, the potentially deleterious effects of applying EVLP, in particular activation of proinflammatory cascades and alteration of metabolic profiles, are rarely discussed. This study examined proinflammatory events and metabolic profiles in lung grafts on EVLP and tested whether preconditioning lung grafts with inhaled hydrogen, a potent, cytoprotective gaseous signaling molecule, would alter the lungs’ response to EVLP.

Methods: Rat heart-lung blocks were mounted on an acellular normothermic EVLP system for 4 hr and ventilated with air or air supplemented with 2% hydrogen. Arterial and airway pressures were monitored continuously; perfusate was sampled hourly to examine oxygenation. After EVLP, the lung grafts were transplanted orthotopically into syngeneic rats, and lung function was examined.

Results: Placing lung grafts on EVLP resulted in significant upregulation of the messenger RNAs for several proinflammatory cytokines, higher glucose consumption, and increased lactate production. Hydrogen administration attenuated proinflammatory changes during EVLP through upregulation of the heme oxygenase-1. Hydrogen administration also promoted mitochondrial biogenesis and significantly decreased lactate production. Additionally, in the hydrogen-treated lungs, the expression of hypoxia-inducible factor-1 was significantly attenuated during EVLP. These effects were maintained throughout EVLP and led to better posttransplant lung graft function in the recipients of hydrogen-treated lungs.

Conclusions: Lung grafts on EVLP exhibited prominent proinflammatory changes and compromised metabolic profiles. Preconditioning lung grafts using inhaled hydrogen attenuated these proinflammatory changes, promoted mitochondrial biogenesis in the lungs throughout the procedure, and resulted in better posttransplant graft function.

Author Information

1 Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA.

2 Department of Medical Engineering, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan.

3 Address correspondence to: Norihisa Shigemura, M.D., Ph.D., 200 Lothrop Street Suite C-900, Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213.

This study was supported by grants from the research funds of the Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center.

The authors declare no conflicts of interest.

E-mail: shigemuran@upmc.edu

All authors reviewed and approved the final article. K.N., N.S., Y.T., and C.A.B. participated in research design. K.N., N.S., and Y.T. participated in the performance of the research. K.N., N.S., and Y.T. participated in the data analysis. K.N., N.S., J.B., J.D., H.K., and J.D.L. participated in the writing of the article.

Received 14 February 2014. Revision requested 4 March 2014.

Accepted 15 April 2014.

© 2014 by Lippincott Williams & Wilkins