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

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.

Inflammasome-Mediated Inflammation in Liver Ischemia-Reperfusion Injury

“…Organs were submitted to 30 min of warm ischemia, 2 h of cold ischemia and preserved in a hypothermic machine perfusion system for 2 h before the implantation of liver grafts in the recipient. Mcc950, a novel NLRP3-inflammasome selective small-molecule inhibitor, was added to the perfusate of the hypothermic machine perfusion and administered to recipients [155]. The study shows that the addition of Mcc950 improved the outcomes of LT from DCD donors via inhibition of the inflammatory response, reduction of hepatocyte apoptosis, and improvement of liver function (Figure 3) [155].…”

“…Mcc950, a novel NLRP3-inflammasome selective small-molecule inhibitor, was added to the perfusate of the hypothermic machine perfusion and administered to recipients [155]. The study shows that the addition of Mcc950 improved the outcomes of LT from DCD donors via inhibition of the inflammatory response, reduction of hepatocyte apoptosis, and improvement of liver function (Figure 3) [155]. In the context of clinical practice, the encouraging results of this experiment in regulating NLRP3 activity in DCD donations with short ischemic periods, urges increased efforts to minimize both warm ischemia and cold ischemia times during DCD organ procurement and transplantation in order to improve the viability of liver grafts and recipients after LT [156,157].…”

The Role of NLRP3 Inflammasome in Cerebrovascular Diseases Pathology and Possible Therapeutic Targets

“…In mice with hypertension, MCC950 reduced blood pressure and limited renal inflammation, fibrosis, and dysfunction (Krishnan et al, 2019). In a porcine liver transplantation model, MCC950 improved the prognosis of organs from donors after circulatory death (Yu, Cheng, et al, 2019). In ischaemia/reperfusion-induced lung injury, reduced the production of IL-1b and IL-18 and inhibited neutrophil infiltration and apoptosis (Xu, Wu, et al, 2018).…”

Structure and Function of Porcine Arteries Are Preserved for up to 6 Days Using the HypoRP Cold-storage Solution

“…The width (A), the length (B) and the angle (C) of collagen fibers within the tunica media were assessed using the CT-FIRE software as described previously. 1 with saponin (open square). AB reduction was determined as AB reduction = FI(Sample)590 -FI(Ctrl)590 / FI(Ctrl+)590-FI(Ctrl-)590.…”