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Oxidative Medicine and Cellular Longevity
Volume 2017 (2017), Article ID 8325754, 12 pages
https://doi.org/10.1155/2017/8325754
Research Article

Modulation of Glutathione Hemostasis by Inhibition of 12/15-Lipoxygenase Prevents ROS-Mediated Cell Death after Hepatic Ischemia and Reperfusion

1Department of General, Visceral, Vascular and Transplant Surgery, University Hospital Munich, Ludwig-Maximilians University of Munich, Campus Großhadern, Munich, Germany
2Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany
3Department of Internal Medicine II, University Hospital Munich, Ludwig-Maximilians University of Munich, Campus Großhadern, Munich, Germany
4Institute of Laboratory Medicine, University Hospital Munich, Ludwig-Maximilians University of Munich, Campus Großhadern, Munich, Germany

Correspondence should be addressed to Moritz Drefs

Received 29 March 2017; Accepted 18 June 2017; Published 24 July 2017

Academic Editor: Andrey A. Zamyatnin Jr.

Copyright © 2017 Moritz Drefs et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background. Reactive oxygen species- (ROS-) mediated ischemia-reperfusion injury (IRI) detrimentally impacts liver transplantation and resection. 12/15-Lipoxygenase (12/15-LOX), an antagonistic protein of the glutathione peroxidase 4 (GPX4) signaling cascade, was proven to mediate cell death in postischemic cerebral and myocardial tissue. The aim of this study was to investigate the impact of 12/15-LOX inhibition on hepatic IRI. Methods. Livers of C57BL/6 mice were exposed to 60 minutes of partial warm ischemia and 90 minutes of reperfusion after previous Baicalein administration, an inhibitor of 12/15-LOX. Tissue samples were analyzed by TUNEL assay, Western blot, and spectral photometry. Results. TUNEL labeling showed a significant reduction of hepatic cell death following baicalein pretreatment. Western Blot analysis revealed a significant downregulation of Jun-amino-terminal-kinase (JNK), caspase-3, and poly-ADP-ribose-polymerase (PARP), besides considerably lowered p44/42-MAP-kinase (ERK1/2) expression after Baicalein administration. A significant elevation of glutathione oxidation was measured in Baicalein pretreated livers. Conclusion. Our data show that inhibition of 12/15-lipoxygenase causes significant cell death reduction after hepatic ischemia and reperfusion by enhancing glutathione metabolism. We conclude that GPX4-dependent cell death signaling cascade might play a major role in development of hepatic IRI, in which the investigated proteins JNK, caspase-3, ERK1/2, and PARP might contribute to tissue damage.