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Effect of the Selective NLRP3 Inflammasome Inhibitor mcc950 on Transplantation Outcome in a Pig Liver Transplantation Model With Organs From Donors After Circulatory Death Preserved by Hypothermic Machine Perfusion

Yu, Yang, PhD1; Cheng, Ying, MD1; Pan, Qi, PhD1; Zhang, Yi-Jie, PhD1; Jia, De-Gong, MM1; Liu, Yong-Feng, MD1

doi: 10.1097/TP.0000000000002461
Original Basic Science—Liver

Background We investigated whether the outcome of organs from donors after circulatory death (DCD) can be improved by the addition of mcc950 to the perfusate of the hypothermic machine perfusion (HMP) system and intravenous mcc950 injection after transplantation in a pig liver transplantation model.

Methods Thirty-six healthy Bama mini pigs randomized into 3 groups. All the DCD livers were preserved in an HMP system after 2 hours of simple cold storage. In HMP-Postop group, mcc950 was added to the perfusate; in the control group and Postop group, the perfusate was normal LPS. After transplantation, the pigs in the Postop group and HMP-Postop group were intravenously administered 3 mg/kg mcc950, at the time of reperfusion and on day 2 and day 3 after transplantation. During the 3-day follow-up period, general operative characteristics, and serological markers and histological features related to ischemia reperfusion injury were examined.

Results The HMP-Postop group suffer the lightest ischemia reperfusion injury (IRI), and functioned best after transplantation. Model for the Early Allograft Function Score (predictor of long-term survival), degree of injury in the hepatocytes and rate of apoptosis was lowest in the HMP-Postop group. Further, in the HMP-Postop group, the nucleotide-binding domain leucine-rich repeat containing family pyrin domain containing 3 inflammasome pathway activation was lowest, and the level of IL-1β was lowest. Postop group functioned better than control group, but not comparable with HMP-Postop group.

Conclusions The outcome of DCD organs can be improved by the addition of mcc950 to the perfusate of the HMP system and intravenous injection of mcc950 after transplantation.

The authors investigate the protective role of NLRP3 inflammasome inhibitor mcc950 on graft function in a pig donation after cardiac death liver transplantation model with hypothermia machine perfusion. It is demonstrated that the treatment improves the graft function by attenuating inflammatory response and hepatic apoptosis.

1 Department of Hepatobiliary and transplantation Surgery, the First Affliated Hospital of China Medical University, Shenyang, The People's Republic of China.

Received 17 May 2018. Revision received 4 September 2018.

Accepted 10 September 2018.

The authors declare no conflicts of interest.

This study is funded by National natural science foundation of China (grant 02046) and Basic Research on Key Laboratory of Liaoning Provincial Department of Education (grant LS201603).

Y.Y., Y.C., and Y.-F.L. designed the study, analyzed the data, interpreted the data and wrote the article. Y.Y., Q.P., Y.-J.Z., and D.-G.J, performed the experiments, analyzed the data and participated in drafting the article. Y.Y. and Q.P. interpreted the data. Y.C. and Y.-F.L. contributed to the conception of the study, interpreted the data, and revised the article critically.

Correspondence: Yong-Feng Liu, MD, First Affiliated Hospital, China Medical University, 155 Nanjing Street, Shenyang, Liaoning Province 110000, The People's Republic of China. (gdwkkyxx@sina.com).

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