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

Francisco Villalba-López; David García-Bernal; Sandra V Mateo; Daniel Vidal-Correoso; Marta Jover-Aguilar; Felipe Alconchel; Laura Martínez-Alarcón; Víctor López-López; Antonio Ríos-Zambudio; Pedro Cascales; José A Pons; Pablo Ramírez; Pablo Pelegrín; Alberto Baroja-Mazo

doi:10.1016/j.biopha.2023.115529

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

Biomed Pharmacother. 2023 Nov:167:115529. doi: 10.1016/j.biopha.2023.115529. Epub 2023 Sep 18.

Authors

Affiliations

¹ Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain.
² Department of Biochemistry and Molecular Biology B and Immunology, Faculty of Medicine, University of Murcia, 30120 Murcia, Spain; Hematopoietic Transplant and Cell Therapy Group, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain. Electronic address: david.garcia23@um.es.
³ Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain; General Surgery and Abdominal Solid Organ Transplantation Unit, University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain.
⁴ Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain; Hepatology and Liver Transplant Unit, University Clinical Hospital Virgen de la Arrixaca, 30120 Murcia, Spain.
⁵ Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain; Department of Biochemistry and Molecular Biology B and Immunology, Faculty of Medicine, University of Murcia, 30120 Murcia, Spain.
⁶ Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain. Electronic address: alberto.baroja@ffis.es.

PMID: 37729732
DOI: 10.1016/j.biopha.2023.115529

Abstract

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.

Keywords: Cold ischemia; Defibrotide; Endothelial cells; Liver transplant; Mitochondria.