Machine Perfusion of Porcine Livers with Oxygen-Carrying Solution Results in Reprogramming of Dynamic Inflammation Networks

Abstract

Background: Ex vivo machine perfusion (MP) can better preserve organs for transplantation. We have recently reported on the first application of an MP protocol in which liver allografts were fully oxygenated, under dual pressures and subnormothermic conditions, with a new hemoglobin-based oxygen carrier (HBOC) solution specifically developed for ex vivo utilization. In those studies, MP improved organ function post-operatively and reduced inflammation in porcine livers. Herein, we sought to refine our knowledge regarding the impact of MP by defining dynamic networks of inflammation in both tissue and perfusate.Methods: Porcine liver allografts were preserved either with MP (n = 6) or with cold static preservation (CSP; n = 6), then transplanted orthotopically after 9 h of preservation. Fourteen inflammatory mediators were measured in both tissue and perfusate during liver preservation at multiple time points, and analyzed using Dynamic Bayesian Network (DyBN) inference to define feedback interactions, as well as Dynamic Network Analysis (DyNA) to define the time-dependent development of inflammation networks.Results: Network analyses of tissue and perfusate suggested an NLRP3 inflammasome-regulated response in both treatment groups, driven by the pro-inflammatory cytokine interleukin (IL)-18 and the anti-inflammatory mediator IL-1 receptor antagonist (IL-1RA). Both DyBN and DyNA suggested a reduced role of IL-18 and increased role of IL-1RA with MP, along with increased liver damage with CSP. DyNA also suggested divergent progression of responses over the 9 h preservation time, with CSP leading to a stable pattern of IL-18-induced liver damage and MP leading to a resolution of the pro-inflammatory response. These results were consistent with prior clinical, biochemical, and histological findings after liver transplantation.Conclusion: Our results suggest that analysis of dynamic inflammation networks in the setting of liver preservation may identify novel diagnostic and therapeutic modalities.

Inflammasome-Mediated Inflammation in Liver Ischemia-Reperfusion Injury

“…Not only would survival rates and post-operative recovery improve, but the donor pool could be significantly broadened by upgrading the health status of the donor organ prior to removal. In large animal models, inflammasome activation has been studied in allografts preserved in machine perfusion and submitted to LT [154]. Results indicated that NLRP3 inflammasome regulates inflammatory response (reducing IL-18 and increasing IL-1RA levels) [154].…”

Optimizing Livers for Transplantation Using Machine Perfusion versus Cold Storage in Large Animal Studies and Human Studies: A Systematic Review and Meta-Analysis

“…A total of 26 potential studies were read in full text. Seven of these studies were excluded after reading the full text; among these, 4 studies[ 8 – 10 , 18 ] used simulated reperfusion in vitro instead of liver transplantation and 3 studies [ 19 – 21 ] had insufficient data. Finally, 19 studies (8 human studies and 11 animal studies) were included in this meta-analysis, as shown in the study selection flow diagram ( Figure 1 ).…”

Normothermic Ex-vivo Liver Perfusion and the Clinical Implications for Liver Transplantation

“…It is worth noting, however, that other studies have shown decreased inflammation with NMP, even in the absence of added anti-inflammatory compounds. 36 The concept of the addition of therapeutic compounds to the NMP perfusion circuit to improve outcomes following transplantation remains one of the areas of greatest potential growth in NMP technology and is, therefore, worth pursuing.…”