Endothelial cell activation mediated by cold ischemia-released mitochondria is partially inhibited by defibrotide and impacts on early allograft function following liver transplantation.

DAMPs (danger-associated molecular patterns) are self-molecules of the organism that appear after damage. The endothelium plays several roles in organ rejection, such as presenting alloantigens to T cells and contributing to the development of inflammation and thrombosis. This study aimed to assess whether DAMPs present in the organ preservation solution (OPS) after cold ischemic storage (CIS) contribute to exacerbating the endothelial response to an inflammatory challenge and whether defibrotide treatment could counteract this effect. The activation of cultured human umbilical vein endothelial cells (HUVECs) was analyzed after challenging with end-ischemic OPS (eiOPS) obtained after CIS. Additionally, transwell assays were performed to study the ability of eiOPS to attract lymphocytes across the endothelium. The study revealed that eiOPS upregulated the expression of MCP-1 and IL-6 in HUVECs. Moreover, eiOPS increased the membrane expression of ICAM-1and HLA-DR, which facilitated leukocyte migration toward a chemokine gradient. Furthermore, eiOPS demonstrated its chemoattractant ability. This activation was mediated by free mitochondria. Defibrotide was found to partially inhibit the eiOPS-mediated activation. Moreover, the eiOPS-mediated activation of endothelial cells (ECs) correlated with early allograft dysfunction in liver transplant patients. Our finding provide support for the hypothesis that mitochondria released during cold ischemia could trigger EC activation, leading to complications in graft outcomes. Therefore, the analysis and quantification of free mitochondria in the eiOPS samples obtained after CIS could provide a predictive value for monitoring the progression of transplantation. Moreover, defibrotide emerges as a promising therapeutic agent to mitigate the damage induced by ischemia in donated organs.

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Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: P.P. is scientific consultant of Glenmak Ltd. P.P. is co-inventor on patent application to use NLRP3 inflammasome as biomarker of disease, which have been licensed to Viva in vitro diagnostics S.L, a company co-funded by P.P., A.B.-M. and L.M-A. A.B-M. is co-inventor on provisional patent application of an in vitro method for predicting organ transplant rejection, but declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The rest of authors of this manuscript have no conflicts to disclose.