Pharmacological Activating Transcription Factor 6 Activation Is Beneficial for Liver Retrieval With ex vivo Normothermic Mechanical Perfusion From Cardiac Dead Donor Rats.

Nuo Cheng,Yuan-Bin Shi,Shui-Jun Zhang,Ji-Hua Shi,Han Yang,Sheng-Li Cao,Yang Jin,Hua-Peng Zhang,Wen-Zhi Guo,Xu-Dong Liu

doi:10.3389/fsurg.2021.665260

Abstract

Background: Normothermic machine perfusion (NMP) could be beneficial for organ retrieval from donors after cardiac death (DCD). Activating transcription factor 6 (ATF6) was recently shown to mitigate liver ischemia/reperfusion injury and confer protection. The aims of this study were to assess the implication of ATF6 in liver retrieval from DCD rat livers with NMP and explore the effect of pharmacologic ATF-6 activation on liver retrieval.Methods: The livers from DCD rats were exposed to 30 min of warm ischemia and 8 h cold preservation followed by 2 h NMP with or without an ATF6 activator in the perfusate. Perfusates and livers were harvested to detect ATF6 expression, liver function, and inflammation.Results: DCD livers with NMP were associated with ATF6 overexpression and activation based on IHC and WB (P < 0.05). The ATF6 activator downregulated perfusate aminotransferases, decreased the Suzuki score, downregulated CD68 and MPO based on IHC, induced the expression of cytochrome c in mitochondria and inhibited the expression of cytochrome c in cytoplasm based on WB, reduced TNFα and IL-6 levels based on ELISA, decreased levels of MDA, GSSG and ATP, and increased SOD activity and GSH levels in the perfused livers (P < 0.05).Conclusion: ATF6 is important for liver retrieval, and an exogenous ATF6 activator accelerates liver retrieval from DCD rats in an ex vivo NMP model.

Highlights

Normothermic machine perfusion (NMP) could be beneficial for organ retrieval from donors after cardiac death (DCD)
To determine whether the Activating transcription factor 6 (ATF6) pathway was activated during liver graft retrieval, we assessed the expression of ATF6 in the liver tissues by IHC analysis
We found that both cytoplasmic and nuclear expression of ATF6 could be detected in the rat liver cells of the NMP group, indicating that NMP induced both the expression and activation of this marker (Figure 2A)

Summary

Introduction

Normothermic machine perfusion (NMP) could be beneficial for organ retrieval from donors after cardiac death (DCD). Methods: The livers from DCD rats were exposed to 30 min of warm ischemia and 8 h cold preservation followed by 2 h NMP with or without an ATF6 activator in the perfusate. Conclusion: ATF6 is important for liver retrieval, and an exogenous ATF6 activator accelerates liver retrieval from DCD rats in an ex vivo NMP model. Compared to that with donors after brain death, DCD grafts suffering warm ischemic injury from donor cardiac arrest might be more susceptible with respect to hypoxic cold preservation and reperfusion injury [1]. ATF6 Benefit Liver in NMP perfusion (NMP), as a major approach to organ retrieval before transplantation, can recreate the physiological environment of cellular metabolism, oxygenation, and nutrition. NMP is a promising tool for graft viability evaluation in DBD and DCD environments [4]

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