Hepatic Artery Reconstruction Prevents Ischemic Graft Injury, Inhibits Graft Rejection, and Mediates Long-term Graft Acceptance in Rat Liver Transplantation

Ishii, Eiichi; Shimizu, Akira; Kuwahara, Naomi; Kanzaki, Go; Higo, Seiichiro; Terasaki, Yasuhiro; Arai, Takashi; Nagasaka, Shinya; Masuda, Yuki; Fukuda, Yuh

doi:10.1016/j.transproceed.2013.01.086

Cited by 10 publications

(7 citation statements)

References 12 publications

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“…First, previous studies in rats have shown consistently that a nonarterialized rat OLT model was highly suitable for rejection studies within 4 weeks after OLT. 9,11,31,32 Second, additional hepatic artery reconstruction prolonged survival but finally failed to prevent chronic rejection and graft dysfunction. 31,32 Translation of our results to the human situation may require longer follow-up and experiments in large animals.…”

Section: Discussionmentioning

confidence: 99%

“…9,11,31,32 Second, additional hepatic artery reconstruction prolonged survival but finally failed to prevent chronic rejection and graft dysfunction. 31,32 Translation of our results to the human situation may require longer follow-up and experiments in large animals. Further investigations should also include nonstandard liver grafts, that is, extended criteria grafts or liver grafts donated after cardiac death, as we choose in this study an experimental model without previous exposure to warm or cold ischemia.…”

Section: Discussionmentioning

confidence: 99%

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Hypothermic Oxygenated Perfusion (HOPE) Downregulates the Immune Response in a Rat Model of Liver Transplantation

et al. 2014

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OBJECTIVE: To evaluate the impact of a novel oxygenated perfusion approach on rejection after orthotopic liver transplantation (OLT). BACKGROUND: Hypothermic oxygenated perfusion (HOPE) was designed to prevent graft failure after OLT. One of the mechanisms is downregulation of Kupffer cells (in situ macrophages). We, therefore, designed experiments to test the effects of HOPE on the immune response in an allogeneic rodent model of nonarterialized OLT. METHODS: Livers from Lewis rats were transplanted into Brown Norway rats to induce liver rejection in untreated recipients within 4 weeks. Next, Brown Norway recipients were treated with tacrolimus (1 mg/kg), whereas in a third group, liver grafts from Lewis rats underwent HOPE or deoxygenated machine perfusion for 1 hour before implantation, but recipients received no immunosuppression. In a last step, low-dose tacrolimus treatment (0.3 mg/kg) was assessed with and without HOPE. RESULTS: Allogeneic OLT without immunosuppression led to death within 3 weeks after nonarterialized OLT due to severe acute rejection. Full-dose tacrolimus prevented rejection, whereas low-dose tacrolimus led to graft fibrosis within 4 weeks. HOPE treatment without immunosuppression also protected from lethal rejection. The combination of low-dose tacrolimus and 1-hour HOPE resulted in 100% survival within 4 weeks without any signs of rejection. CONCLUSIONS: We demonstrate that allograft treatment by HOPE not only protects against preservation injury but also impressively downregulates the immune system, blunting the alloimmune response. Therefore, HOPE may offer many beneficial effects, not only to rescue marginal grafts but also by preventing rejection and the need for immunosuppression.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hypothermic Oxygenated Perfusion (HOPE) Downregulates the Immune Response in a Rat Model of Liver Transplantation

et al. 2014

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“…It has been amply demonstrated that - in contrast to the human situation - OLT and P-OLT in rats can be successfully performed without the technically complicated rearterialization of the graft [3,9,15,94]; nonetheless, the arterial flow has essential functions, and omitting rearterialization can substantially influence bile duct circulation (and thereby the rate of biliary complications) [18,95,96], graft microcirculation [97], and immunological functions [98]. This was also confirmed during our own investigations: we observed considerable differences in hepatocellular injury (AST and ALT levels) and graft microcirculation with and without arterial reconstruction [unpubl.…”

Section: Technical Issues Concerning P-olt In Ratsmentioning

confidence: 99%

Improving Research Practice in Rat Orthotopic and Partial Orthotopic Liver Transplantation: A Review, Recommendation, and Publication Guide

Czigány

Iwasaki²,

Yagi³

et al. 2015

Eur Surg Res

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Background: Due to a worldwide shortage of donor organs for liver transplantation, alternative approaches, such as split and living donor liver transplantations, were introduced to increase the donor pool and reduce mortality on liver transplant waiting lists. Numerous details concerning the mechanisms and pathophysiology of liver regeneration, small-for-size syndrome, rejection, and tolerance in partial liver transplantation facilitated the development of various animal models. The high number of preclinical animal studies contributed enormously to our understanding of many clinical aspects of living donor and partial liver transplantations. Summary: Microsurgical rat models of partial orthotopic liver transplantation are well established and widely used. Nevertheless, several issues regarding this procedure are controversial, not clarified, or not yet properly standardized (graft rearterialization, size reduction techniques, etc.). The major aim of this literature review is to give the reader a current overview of rat orthotopic liver transplantation models with a special focus on partial liver transplantation. The aspects of model evolution, microsurgical training, and different technical problems are analyzed and discussed in detail. Our further aim in this paper is to elaborate a detailed publication guide in order to improve the quality of reporting in the field of rat liver transplantation according to the ARRIVE guidelines and the 3R principle. Key Messages: Partial orthotopic liver transplantation in rats is an indispensable, reliable, and cost-efficient model for transplantation research. A certain consensus on different technical issues and a significant improvement in scientific reporting are essential to improve transparency and comparability in this field as well as to foster refinement.

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“…First, we used arterialized grafts. Although it does not affect survival in rodents transplanted with uninjured livers [35, 36], it has been proven to help function recovery in ischemic grafts[37]. Second, spleno-systemic shunts protected the recipients from any portal clamping-related shock, avoiding the synergy bad organ/surgical stress, causing deaths non necessarily related to the status of the grafts only.…”

Section: Discussionmentioning

confidence: 99%

The impact of short-term machine perfusion on the risk of cancer recurrence after rat liver transplantation with donors after circulatory death

et al. 2019

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Hypothermic and normothermic ex vivo liver perfusions promote organ recovery after donation after circulatory death (DCD). We tested whether these perfusions can reduce the risk of hepatocellular carcinoma (HCC) recurrence in a 1h-DCD syngeneic transplantation model, using Fischer F344 rats. DCD grafts were machine perfused for 2h with hypothermic perfusion (HOPE) or normothermic perfusion (NORMO), and transplanted. After reperfusion, we injected HCC cells into the vena porta. On day 28 after transplantation, we assessed tumour volumes by MRI. Control rats included transplantations with Fresh and non-perfused DCD livers. We observed apoptotic-necrotic hepatocyte foci in all DCD grafts, which were more visible than in the Fresh liver grafts. Normothermic perfusion allowed a faster post-transplant recovery, with lower day 1 levels of transaminases compared with the other DCD. Overall, survival was similar in all four groups and all animals developed HCCs. Total tumor volume was lower in the Fresh liver recipients compared to the DCD and DCD+HOPE recipients. Volumes in DCD+NORMO recipients were not significantly different from those in the Fresh group. This experiment confirms that ischemia/reperfusion injury promotes HCC cell engraftment/growth after DCD liver transplantation. Using the present extreme 1h ischemia model, both hypothermic and normothermic perfusions were not effective in reducing this risk.

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Hepatic Artery Reconstruction Prevents Ischemic Graft Injury, Inhibits Graft Rejection, and Mediates Long-term Graft Acceptance in Rat Liver Transplantation

Cited by 10 publications

References 12 publications

Hypothermic Oxygenated Perfusion (HOPE) Downregulates the Immune Response in a Rat Model of Liver Transplantation

Hypothermic Oxygenated Perfusion (HOPE) Downregulates the Immune Response in a Rat Model of Liver Transplantation

Improving Research Practice in Rat Orthotopic and Partial Orthotopic Liver Transplantation: A Review, Recommendation, and Publication Guide

The impact of short-term machine perfusion on the risk of cancer recurrence after rat liver transplantation with donors after circulatory death

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