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.
Highlights
Organ availability for liver transplantation continues to fall well short of demand
We have recently reported on the first application of an machine perfusion (MP) protocol in which liver allografts were fully oxygenated, under dual pressures and subnormothermic conditions, with a new hemoglobin-based oxygen carrier (HBOC) solution developed for ex vivo utilization
Dynamic Network Analysis (DyNA) suggested divergent progression of responses over the 9 h preservation time, with cold static preservation (CSP) leading to a stable pattern of IL-18-induced liver damage and MP leading to a resolution of the pro-inflammatory response
Summary
Organ availability for liver transplantation continues to fall well short of demand. During 2012 in the United States, 6,256 transplants were performed compared with 10,143 candidates added to the waiting list. MP devices were initially developed for kidney preservation, with research focused primarily on flow and pulsatile pressures under hypothermic (4◦C) conditions These devices used standard, non-oxygenated preservation solutions, such as UW, for perfusate (Daemen et al, 1997). 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 developed for ex vivo utilization. In those studies, MP improved organ function postoperatively and reduced inflammation in porcine livers. We sought to refine our knowledge regarding the impact of MP by defining dynamic networks of inflammation in both tissue and perfusate
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