Introduction: Inflammatory markers have been mostly studied by standard statistical analysis focused on single component variations. This study aimed to compare SNMP with CS regarding outlining dynamic networks of inflammation expressed during preservation.

Methods: Porcine liver allografts were preserved with SNMP/HBOC at 21[deg]C (n = 6) and with CSP (n = 6), then transplanted orthotopically after 9 h. Fourteen inflammatory mediators were measured in both tissue and perfusate during liver preservation at multiple time points by Luminex®, and damage markers (AST, ALT) were measured in perfusate. Results were analyzed by 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: SNMP had a significantly higher survival (100%) than the CS group (33%). 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 SNMP, opposed by increased liver damage in the CS group. DyNA also suggested divergent progression of responses over the 9 h preservation time, with CS leading to a stable pattern of IL-18-induced liver damage and SNMP leading to a resolution of the pro-inflammatory response.

Conclusion: Hepatic allograft response to this ischemia-reperfusion insult appears to be influenced by the balance of pro-inflammatory IL-18 and anti-inflammatory IL-1RA. IL-18 is a product of the NLRP3 inflammasome produced in Kupffer cells, while hepatocyte-derived IL-1RA inhibits IL-1β. The balance of these responses affects downstream levels of IFN-γ, and by extension the strength of the IFN-γ-driven positive feedback loop of hepatic damage, via three pathways. One pathway can be downregulated by IL-1RA, one can be upregulated by IL-18, and one can be both downregulated by IL-1RA and upregulated by IL-18. When effective ex-vivo oxygenation is provided, the relative balance of these two mediators may be shifted, altering the level of response to a clinically significant degree. This shift appears to occur early in preservation (during the first 3 h) and upstream in inflammatory response.

CITATION INFORMATION: Sadowsky D, Zamora R, Banan B, Barclay D, Yin J, Vodovotz Y, Fontes P. Subnormothermic Machine Perfusion (SNMP) with a Hemoglobin Based Oxygen Carrier (HBOC) Solution Reprograms Dynamic Inflammation Networks When Compared to Cold Storage (CS) in a Porcine Liver Allograft Model. Am J Transplant. 2016;16 (suppl 3).

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