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.

Abstract

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. 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. 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. 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.