Neutralization of CD95 ligand protects the liver against ischemia-reperfusion injury and prevents acute liver failure

Mohammed Al-Saeedi,Niels Halama,Martina Müller,Hassan Kudsi,Carolin Mogler,Peter H Krammer,Markus W Büchler,Peter Schemmer,Niels Steinebrunner

doi:10.1038/s41419-017-0150-0

Abstract

Ischemia-reperfusion injury is a common pathological process in liver surgery and transplantation, and has considerable impact on the patient outcome and survival. Death receptors are important mediators of ischemia-reperfusion injury, notably the signaling pathways of the death receptor CD95 (Apo-1/Fas) and its corresponding ligand CD95L. This study investigates, for the first time, whether the inhibition of CD95L protects the liver against ischemia-reperfusion injury. Warm ischemia was induced in the median and left liver lobes of C57BL/6 mice for 45 min. CD95Fc, a specific inhibitor of CD95L, was applied prior to ischemia. Hepatic injury was assessed via consecutive measurements of liver serum enzymes, histopathological assessment of apoptosis and necrosis and caspase assays at 3, 6, 12, 18 and 24 h after reperfusion. Serum levels of liver enzymes, as well as characteristic histopathological changes and caspase assays indicated pronounced features of apoptotic and necrotic liver damage 12 and 24 h after ischemia-reperfusion injury. Animals treated with the CD95L-blocker CD95Fc, exhibited a significant reduction in the level of serum liver enzymes and showed both decreased histopathological signs of parenchymal damage and decreased caspase activation. This study demonstrates that inhibition of CD95L with the CD95L-blocker CD95Fc, is effective in protecting mice from liver failure due to ischemia-reperfusion injury of the liver. CD95Fc could therefore emerge as a new pharmacological therapy for liver resection, transplantation surgery and acute liver failure.

Highlights

Ischemia-reperfusion injury is a common pathological process in liver surgery and transplantation, and has considerable impact on the patient outcome and survival
The treatment of mice with CD95Fc significantly reduced the activity of caspase-3 by 4.3-fold (p = 0.0013), of caspase-8 by 2.3-fold (p = 0.0002), and of caspase-9 by Discussion Findings obtained in the present study allow us to propose a new model for the molecular mechanisms of action of the CD95 ligand (CD95L)/receptor signaling pathway in ischemia-reperfusion injury (IRI) of the liver
IRI is a series of events that result in cell death by apoptosis and/or necrosis and serious dysfunction of hepatocytes[10,29]

Summary

Introduction

Ischemia-reperfusion injury is a common pathological process in liver surgery and transplantation, and has considerable impact on the patient outcome and survival. This study demonstrates that inhibition of CD95L with the CD95L-blocker CD95Fc, is effective in protecting mice from liver failure due to ischemia-reperfusion injury of the liver. Upon activation by the CD95 ligand (CD95L), the oligomerization of the CD95 death receptor leads to the recruitment of cytoplasmic adaptor proteins, which activate apical caspases of the apoptotic signaling pathway, mainly caspase-8 and caspase-9. These subsequently mediate the recruitment of downstream effector caspases, such as caspase-3, in the execution phase of apoptosis[15,16,17,18,19,20]. Inhibition of the CD95 signaling pathway may represent a novel and promising approach to protect the liver against IRIrelated diseases

Methods

Findings

Conclusion