Abstract
Background: Ischaemia-reperfusion injury (IRI) is the main cause of complications following liver transplantation. Reactive oxygen species (ROS) were thought to be the main regulators of IRI. However recent studies demonstrate that ROS activates the cytoprotective mechanism of autophagy promoting cell survival. Liver IRI initially damages the liver endothelial cells (LEC) but whether ROS-autophagy promotes cell survival in LEC during IRI is not known.
Methods: Primary human LEC were isolated from human liver tissue and exposed to an in vitro model of IRI to assess the role of autophagy in LEC. The role of autophagy during liver IRI in vivo was assessed using a murine model of partial liver IRI.
Results: During IRI ROS specifically activate ATG7 promoting autophagic flux and the formation of LC3B positive puncta around mitochondria in primary human LEC.Inhibition of ROS reduces autophagic flux in LEC during IRI inducing necrosis. In addition siRNA knockdown of ATG7 sensitized LEC to necrosis during IRI. In vivo murine livers in uninjured liver lobes demonstrate autophagy within LEC that is reduced following IRI with concomitant reduction in autophagic flux and increased cell death.
Conclusion: These findings demonstrate that during liver IRI ROS-dependent
autophagy promotes LEC survival and therapeutic targeting of this signaling pathway may reduce liver IRI following transplantation.
Methods: Primary human LEC were isolated from human liver tissue and exposed to an in vitro model of IRI to assess the role of autophagy in LEC. The role of autophagy during liver IRI in vivo was assessed using a murine model of partial liver IRI.
Results: During IRI ROS specifically activate ATG7 promoting autophagic flux and the formation of LC3B positive puncta around mitochondria in primary human LEC.Inhibition of ROS reduces autophagic flux in LEC during IRI inducing necrosis. In addition siRNA knockdown of ATG7 sensitized LEC to necrosis during IRI. In vivo murine livers in uninjured liver lobes demonstrate autophagy within LEC that is reduced following IRI with concomitant reduction in autophagic flux and increased cell death.
Conclusion: These findings demonstrate that during liver IRI ROS-dependent
autophagy promotes LEC survival and therapeutic targeting of this signaling pathway may reduce liver IRI following transplantation.
Original language | English |
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Journal | Liver Transplantation |
Early online date | 24 Jul 2018 |
DOIs | |
Publication status | E-pub ahead of print - 24 Jul 2018 |
Bibliographical note
From: Otto Schuck <[email protected]>Date: 5 June 2018 at 00:17:46 BST
To: [email protected]
Subject: Early Accept - Manuscript ID LT-17-755.R2
Reply-To: [email protected]
04-Jun-2018
Dr. Ricky Bhogal
Dr. Bhogal, Ricky
Wolfson Drive
Birmingham
B15 2TT
Birmingham
West Midlands
United Kingdom of Great Britain and Northern Ireland
B15 2TT
LT-17-755.R2
The ROS-Mitophagy Signalling Pathway Regulates Liver Endothelial Cell Survival during Ischaemia-Reperfusion Injury
Keywords
- Autophagy
- Free radicals
- Ischaemic liver injury
- Necrosis