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.
Background. N-acetylcysteine (NAC) is a potentially effective drug for treating ischemia–reperfusion injury in transplanted livers, but its effect remains controversial. Methods. A systematic review and meta-analysis of relevant clinical trials published and registered in the Cochrane Library, MEDLINE, EMBASE, ClinicalTrial.gov, WHO ICTRP, etc, before March 20, 2022 were conducted and registered with PROSPERO (CRD42022315996). Data were pooled using a random effects model or a fixed effects model based on the amount of heterogeneity. Results. Thirteen studies with 1121 participants, 550 of whom received NAC, were included. Compared with the control, NAC significantly reduced the incidence of primary graft nonfunction (relative risk [RR], 0.27; 95% confidence interval [CI], 0.08-0.96), the incidence of postoperative complications (RR, 0.52; 95% CI, 0.41-0.67), the peak postoperative aspartate transferase level (mean difference [MD], −267.52; 95% CI, −345.35 to −189.68), and the peak alanine transferase level (MD, −293.29; 95% CI, −370.39 to −216.20). NAC also improved 2-y (RR, 1.18; 95% CI, 1.01-1.38) graft survival rate. However, NAC increased the intraoperative cryoprecipitate (MD, 0.94; 95% CI, 0.42-1.46) and red blood cell (MD, 0.67; 95% CI, 0.15-1.19) requirements. Moreover, NAC was administered in various modes in these studies, including to the donor, recipient, or both. Subgroup analysis and network meta-analysis showed that NAC administration to recipients could play a more significant role than the other 2 administration modes. Conclusions. Our study supports the protective effect of NAC against LT-induced ischemia–reperfusion injury and shows better clinical outcomes of NAC administration to recipients.
Background:Donor-specific tolerance is the ultimate goal in organ transplantation. Diverse approaches, including the use of mesenchymal stem cells (MSCs), have been investigated to induce graft tolerance. Non-stimulated MSCs showed limited regulatory functions through interaction with multiple immune-regulatory cells, such as regulatory T cells (Tregs). To augment their functions, MSCs have been preconditioned with toll-like receptor (TLR3/4) agonist in autoimmune disease models, but results were conflicting. Material/Methods:We evaluated the immunomodulatory effects of mouse adipose-derived mesenchymal stem cells (ADSCs) preconditioned with various combinations of TLR3/4 agonist and antagonists, including polyinosinic-polycytidylic acid poly(I:C)-TLR3 agonist, lipopolysaccharide (LPS) -TLR4 agonist, and TAK242-TLR4 antagonist. In vitro and in vivo experiments including mixed lymphocyte reaction, cytokines measurement, Tregs analysis, and a fully mismatched MHC heterotopic heart transplantation in mice (BALB/c to C57BL/6) were conducted. Results:ADSCs preconditioned with poly(I:C) showed the highest efficiency in inhibiting lymphocyte proliferation, which was correlated with the upregulation of fibrinogen-like protein 2 (FGL2), an effector molecule of Tregs. The mean survival of cardiac allografts was extended from 8 to 12 days by intravenous injection of a single dose of ADSCs preconditioned with TLR3 agonist. The proportion of Tregs in the recipient's spleen was significantly increased by injecting the poly(I:C)-stimulated ADSCs. Conclusions:These results show that short-term TLR3 agonist preconditioning enhances the immunomodulatory efficacy of ADSCs, which can induce the generation of Tregs and upregulate the expression of FGL2, thereby improving the outcome of patients receiving organ transplantation.
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