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Oxygen-carrying sequential preservation mitigates liver grafts ischemia-reperfusion injury.

ABSTRACT: Oxygen-dependent preservation has been proposed to protect liver grafts from ischemia-reperfusion injury (IRI), but its underlying mechanism remains elusive. Here, we proposed an oxygen-carrying sequential preservation (OCSP) method that combined oxygenated static cold storage (SCS) and normothermic mechanical perfusion. We demonstrated that OCSP, especially with high oxygen partial pressure level (500-650mmHg) during the oxygenated SCS phase, was associated with decreased IRI of liver grafts and improved rat survival after transplantation. A negative correlation between autophagy and endoplasmic reticulum stress response (ERSR) was found under OCSP and functional studies indicated OCSP suppressed ERSR-mediated cell apoptosis through autophagy activation. Further data showed that OCSP-induced autophagy activation and ERSR inhibition were oxygen-dependent. Finally, activated NFE2L2-HMOX1 signaling was found to induce autophagy under OCSP. Together, our findings indicate oxygen-dependent autophagy mitigates liver graft's IRI by ERSR suppression and modulates NFE2L2-HMOX1 signaling under OCSP, providing a theoretical basis for liver preservation using a composite-sequential mode.

SUBMITTER: Li J

PROVIDER: S-EPMC9829800 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Oxygen-carrying sequential preservation mitigates liver grafts ischemia-reperfusion injury.

Li Jianbo J Zha XiangJun X Kang Yan Y Zhang Zhongwei Z Yan Lvnan L Song Lujia L Wang Chengdi C Yang Jiayin J

iScience 20221221 1

Oxygen-dependent preservation has been proposed to protect liver grafts from ischemia-reperfusion injury (IRI), but its underlying mechanism remains elusive. Here, we proposed an oxygen-carrying sequential preservation (OCSP) method that combined oxygenated static cold storage (SCS) and normothermic mechanical perfusion. We demonstrated that OCSP, especially with high oxygen partial pressure level (500-650mmHg) during the oxygenated SCS phase, was associated with decreased IRI of liver grafts an ...[more]

PMID: 36636350

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Project description:BACKGROUND:Liver ischemia reperfusion injury (IRI) remains a challenge in liver transplantation. A number of compounds have previously demonstrated efficacy in mitigating IRI. Herein, we applied three specific additive strategies to a mouse IRI screening model to determine their relative potencies in reducing such injury, with a view to future testing in a large animal and clinical ex situ normothermic perfusion setting: 1) F573, a pan-caspase inhibitor, 2) anti-inflammatory anakinra and etanrecept and 3) BMX-001, a mimetic of superoxide dismutase. METHODS:A non-lethal liver ischemia model in mice was used. Additives in the treatment groups were given at fixed time points before induction of injury, compared to a vehicle group that received no therapeutic treatment. Mice were recovered for 6 hours following the ischemic insult, at which point blood and tissue samples were obtained. Plasma was processed for transaminase levels. Whole liver tissue samples were processed for histology, markers of apoptosis, oxidative stress, and cytokine levels. RESULTS:In an in vivo murine IRI model, the F573 treatment group demonstrated statistically lower alanine aminotransferase (ALT) levels (p = 0.01), less evidence of apoptosis (p = 0.03), and lower cytokine levels compared to vehicle. The etanercept with anakinra treatment group demonstrated significantly lower cytokine levels. The BMX-001 group demonstrated significantly decreased apoptosis (p = 0.01) evident on TUNEL staining. CONCLUSIONS:The administration of pan-caspase inhibitor F573 in a murine in vivo model likely mitigates liver IRI based on decreased markers of cellular injury, decreased evidence of apoptosis, and improved cytokine profiles. Anakinra with etanercept, and BMX-001 did not demonstrate convincing efficacy at reducing IRI in this model, and likely need further optimization. The positive findings set rational groundwork for future translational studies of applying F573 during normothermic ex situ liver perfusion, with the aim of improving the quality of marginal grafts.

Dataset Information

Oxygen-carrying sequential preservation mitigates liver grafts ischemia-reperfusion injury.

Publications

Oxygen-carrying sequential preservation mitigates liver grafts ischemia-reperfusion injury.

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