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

Abstract

Organ transplantation is a multifactorial process in which proper graft preservation is a mandatory step for the success of the transplantation. Hypothermic preservation of abdominal organs is mostly based on the use of several commercial solutions, including UW, Celsior, HTK and IGL-1. The presence of the oncotic agents HES (in UW) and PEG35 (in IGL-1) characterize both solution compositions, while HTK and Celsior do not contain any type of oncotic agent. Polyethylene glycols (PEGs) are non-immunogenic, non-toxic and water-soluble polymers, which present a combination of properties of particular interest in the clinical context of ischemia-reperfusion injury (IRI): they limit edema and nitric oxide induction and modulate immunogenicity. Besides static cold storage (SCS), there are other strategies to preserve the organ, such as the use of machine perfusion (MP) in dynamic preservation strategies, which increase graft function and survival as compared to the conventional static hypothermic preservation. Here we report some considerations about using PEG35 as a component of perfusates for MP strategies (such as hypothermic oxygenated perfusion, HOPE) and its benefits for liver graft preservation. Improved liver preservation is closely related to mitochondria integrity, making this organelle a good target to increase graft viability, especially in marginal organs (e.g., steatotic livers). The final goal is to increase the pool of suitable organs, and thereby shorten patient waiting lists, a crucial problem in liver transplantation.

HOPE (hypothermic oxygenated perfusion) strategies in the era of dynamic liver graft preservation

“…The fact that benefits of HOPE come through mitochondrial regulation leads us to think that any additional strategies that improve the mitochondrial integrity would enhance these positive effects. Indeed, in our previous investigations on PEG35 in hypothermic static preservation using IGL-1 solution [4] , and on using PEG35 rinse solution for washing-out UW preserved livers [5] , we have demonstrated the protective role of PEG35 in preserving mitochondria. In a recent contribution [4] , we discuss and extend some of these results of the use of PEG35 in a new perfusate (IGL-2) for HOPE.…”

“…Indeed, in our previous investigations on PEG35 in hypothermic static preservation using IGL-1 solution [4] , and on using PEG35 rinse solution for washing-out UW preserved livers [5] , we have demonstrated the protective role of PEG35 in preserving mitochondria. In a recent contribution [4] , we discuss and extend some of these results of the use of PEG35 in a new perfusate (IGL-2) for HOPE. Taking this into consideration, we think that PEG35 in a HOPE perfusate could lead to an additive better protection of the integrity of mitochondrial machinery and its basal activity function.…”

“…Given the proved mitochondrial protection mediated by HOPE [ 2 , 3 ] and PEG35 protection in static preservation [ 4 , 5 ], we hypothesized that they could have additive effects on the mitochondria, and PEG would enhance HOPE protection. Previously, we reported some preliminary data on the effectiveness of PEG35 in a perfusate solution (IGL-2) during HOPE [4] .…”

“…Given the proved mitochondrial protection mediated by HOPE [ 2 , 3 ] and PEG35 protection in static preservation [ 4 , 5 ], we hypothesized that they could have additive effects on the mitochondria, and PEG would enhance HOPE protection. Previously, we reported some preliminary data on the effectiveness of PEG35 in a perfusate solution (IGL-2) during HOPE [4] . In this sense, IGL-2 could be a suitable tool in HOPE strategies, being especially promising for rescuing vulnerable liver grafts (DCD and steatotic grafts) for transplantation [7] , for the following reasons: PEG35 promotes the activation of cytoprotective and preconditioning agents, such as e-NOS and AMPK activation [5] .…”

New Insights in Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury 2.0: An Updated Overview

“…However, the establishment of new markers to evaluate the quality of the liver grafts is a pending challenge for the immediate future in IRI investigations [31][32][33]. Recently, a new perfusate named IGL2 containing PEG35 as oncotic agent [34] has been proposed for HOPE. IGL2 benefits are associated with a better preservation of the mitochondria integrity, thus assuring the most suitable restoration of the mitochondrial function and avoiding the inherent redox stress, as suggested by Hofmann et al [35].…”