Polyethylene Glycol Preconditioning: An Effective Strategy to Prevent Liver Ischemia Reperfusion Injury

Abstract

Hepatic ischemia reperfusion injury (IRI) is an inevitable clinical problem for liver surgery. Polyethylene glycols (PEGs) are water soluble nontoxic polymers that have proven their effectiveness in various in vivo and in vitro models of tissue injury. The present study aims to investigate whether the intravenous administration of a high molecular weight PEG of 35 kDa (PEG 35) could be an effective strategy for rat liver preconditioning against IRI. PEG 35 was intravenously administered at 2 and 10 mg/kg to male Sprague Dawley rats. Then, rats were subjected to one hour of partial ischemia (70%) followed by two hours of reperfusion. The results demonstrated that PEG 35 injected intravenously at 10 mg/kg protected efficiently rat liver against the deleterious effects of IRI. This was evidenced by the significant decrease in transaminases levels and the better preservation of mitochondrial membrane polarization. Also, PEG 35 preserved hepatocyte morphology as reflected by an increased F-actin/G-actin ratio and confocal microscopy findings. In addition, PEG 35 protective mechanisms were correlated with the activation of the prosurvival kinase Akt and the cytoprotective factor AMPK and the inhibition of apoptosis. Thus, PEG may become a suitable agent to attempt pharmacological preconditioning against hepatic IRI.

Protective Role of Hepatocyte Cyclooxygenase‐2 Expression Against Liver Ischemia–Reperfusion Injury in Mice

“…(40) It has been described that the activation of both AKT and AMPK is part of a protective mechanism to prevent IRI. (41) Our results agree with this notion, showing increases not only in the pAKT/AKT ratio but also in the pAMPK to AMPK ratio in hCOX-2-Tg mice after IRI.…”

“…The increase in the pAKT/AKT ratio in hCOX‐2‐Tg mice after IRI may be due to a direct AKT activation through COX‐2‐dependent PGE 2 acting through EP2/EP4 Gβγ dimers, as reported by Rizzo . It has been described that the activation of both AKT and AMPK is part of a protective mechanism to prevent IRI . Our results agree with this notion, showing increases not only in the pAKT/AKT ratio but also in the pAMPK to AMPK ratio in hCOX‐2‐Tg mice after IRI.…”

Polyethylene Glycol 35 as a Perfusate Additive for Mitochondrial and Glycocalyx Protection in HOPE Liver Preservation

“…More recently, it has been demonstrated that intravenous (i.v.) PEG35 administration is also protective against liver warm ischemia reperfusion injury [ 25 ]. This protection has been reviewed in other organs, such as pancreas in an inflammation model [ 26 ].…”

Preconditioning-Like Properties of Short-Term Hypothermia in Isolated Perfused Rat Liver (IPRL) System

“…Due to the wide diversity of mechanisms involved in IRI, many therapeutic mechanisms have been suggested to prevent hepatic damage [ 7 ]. Pharmacological interventions [ 2 , 8 , 9 , 10 ] and the different preconditioning mechanisms are the most common strategies [ 11 , 12 , 13 ].…”