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Inhibition of Neogenin Dampens Hepatic Ischemia-Reperfusion Injury

Schlegel, Martin MD; Granja, Tiago PhD; Kaiser, Sebastian BSc; Körner, Andreas MD; Henes, Janek MD; König, Klemens MD; Straub, Andreas MD; Rosenberger, Peter MD, PhD; Mirakaj, Valbona MD

doi: 10.1097/CCM.0000000000000485
Online Laboratory Investigations
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Objective: Liver ischemia and reperfusion injury is a common source of significant morbidity and mortality following liver transplantation, hemorrhagic shock, or major hepatic surgery. Based on studies showing a critical role for the neuronal guidance receptor neogenin (Neo1) outside the nervous system in mediating tissue adaption during acute inflammation, we hypothesized that Neo1 enhances hepatic ischemia and reperfusion injury.

Design: Animal study.

Setting: University-based experimental laboratory.

Subjects: Wid-type, neogenin deficient and chimeric mice.

Interventions: Neogenin expression was evaluated during inflammatory stimulation in vitro and during ischemia and reperfusion injury in vivo, intravital microscopy performed to study intravascular flow characteristics. The extent of liver injury was evaluated using histology, serum levels of lactate dehydrogenase, aspartate, and alanine aminotransferase. The functional role of Neo1 during liver IR was evaluated in mice with gene targeted repression of neogenin (Neo1-/-), bone marrow chimeric animals and controls. In addition, functional inhibition of neogenin was performed using antibody injection.

Measurements and Main Results: We observed an induction of Neo1 during inflammation in vitro and ischemia and reperfusion in vivo. Intravital microscopy demonstrated a decreased ability of Neo1−/− leukocytes to attach to endothelial vascular wall during inflammation. Subsequent studies in Neo1−/− mice showed attenuated serum levels of lactate dehydrogenase, aspartate, alanine, and proinflammatory cytokines during hepatic ischemia and reperfusion injury. This was associated with improved hepatic histology scores. Studies in chimeric animals demonstrated that the hematopoietic Neo1 expression to be crucial for the observed results. Treatment with an anti-Neo1 antibody resulted in a significant reduction of experimental hepatic ischemia and reperfusion injury, involving attenuated variable of lactate dehydrogenase, alanine, aspartate, and cytokine levels.

Conclusions: These data provide a unique role for Neo1 in the development of hepatic ischemia and reperfusion injury and identified Neo1 as a potential target to prevent liver dysfunction in the future.

1Department of Anaesthesiology and Intensive Care Medicine, Tübingen University Hospital, Eberhard-Karls University, Tübingen, Germany.

2Clinic of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt am Main, Frankfurt, Germany.

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Dr. Mirakaj was supported by a grant from the Interdisziplinäres Zentrum für Klinische Forschung Nachwuchsgruppe (2110-0-0). Dr. Straub was supported, in part, by a grant from the Deutsche Forschungsgemeinschaft (DFG) (DFG STR 687/4-1). The remaining authors have disclosed that they do not have any potential conflicts of interest.

Address requests for reprints to: Valbona Mirakaj, MD, Department of Anaesthesiology and Intensive Care Medicine, Tübingen University Hospital, Eberhard-Karls University Tübingen, Tübingen, Germany. E-mail: valbona.mirakaj@uni-tuebingen.de

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