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Inhibition of Plexin C1 Protects Against Hepatic Ischemia-Reperfusion Injury*

König, Klemens MD1,2; Granja, Tiago PhD1,2; Eckle, Veit-Simon MD1; Mirakaj, Valbona MD1; Köhler, David PhD1; Schlegel, Martin MD1; Rosenberger, Peter PhD1

doi: 10.1097/CCM.0000000000001609
Online Laboratory Investigations
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Objectives: Hepatic ischemia-reperfusion injury is a disease pattern that is associated with an acute inflammatory reaction. It is well known that neutrophils play an essential role in the early phase of hepatic ischemia-reperfusion injury and determine the extent of tissue damage. Hepatic ischemia-reperfusion injury can result in organ failure, which is linked to high mortality. Recent data indicate that the neuronal guidance receptor Plexin C1 is involved in the control of the acute inflammatory response and, as such, modulates the transmigration of neutrophils. Hence, we investigated the functional role of Plexin C1 in a mouse model of early hepatic ischemia-reperfusion injury.

Design: Animal study.

Setting: University experimental laboratory.

Subjects: Wild-type, PLXNC1−/− and chimeric mice.

Interventions: Hepatic ischemia-reperfusion injury or sham operation.

Measurements and Main Results: We found that the functional inhibition of Plexin C1 in wild-type mice treated with an anti-Plexin C1 antibody and a Semaphorin 7A peptide reduced hepatic ischemia-reperfusion injury, as measured by the levels of lactate dehydrogenase, aspartate, and alanine aminotransferase. This reduction in ischemia-reperfusion injury was accompanied by reduced numbers of neutrophils in ischemic hepatic tissue and reduced serum levels of inflammatory cytokines. Experiments using Plexin C1 receptor–deficient (PLXNC1−/−) mice also demonstrated decreased hepatic ischemia-reperfusion injury. Studies of chimeric mice revealed that the hematopoietic Plexin C1 knockout is crucial for reducing the extent of hepatic ischemia-reperfusion injury.

Conclusions: These results describe a role for Plexin C1 during ischemia-reperfusion injury, highlight the role of hematopoietic Plexin C1 in the development of hepatic ischemia-reperfusion injury, and suggest that Plexin C1 is a potential drug target.

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

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

*See also p. 1623.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by a grant from the Deutsche Forschungsgemeinschaft (DFG) (DFG-RO 3671/6-1 to Dr. Rosenberger).

Dr. König received grant support from European Society of Anesthesiology (ESA research grant 2011). Dr. Eckle’s institution received funding from the German Research Foundation, Ministerium für Ländlichen Raum und Verbraucherschutz Baden-Württemberg, and from Faculty of Medicine, Eberhard Karls Universität Tubingen. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Address requests for reprints to: Peter Rosenberger, MD, PhD, Department of Anaesthesiology and Intensive Care Medicine, Tübingen University Hospital, Eberhard-Karls University Tübingen, Tübingen, Baden-Württemberg, Germany. E-mail: peter.rosenberger@med.uni-tuebingen.de

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