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Aurintricarboxylic acid inhibits endothelial activation, complement activation, and von Willebrand factor secretion in vitro and attenuates hyperacute rejection in an ex vivo model of pig-to-human pulmonary xenotransplantation

Cited 13 time in Web of Science Cited 15 time in Scopus
Authors
Kim, Hyun Kyung; Kim, Ji-Eun; Wi, Hyun Cho; Lee, Sang Woo; Kim, Ji Yeon; Kang, Hee Jung; Kim, Young Tae
Issue Date
2008-10-30
Publisher
Wiley-Blackwell
Citation
Xenotransplantation. 2008 Jul;15(4):246-56.
Keywords
AnimalsAurintricarboxylic Acid/administration & dosage/*pharmacologyCells, CulturedComplement Activation/drug effectsEndothelial Cells/drug effectsGraft Rejection/immunology/physiopathology/*prevention & controlHirudins/administration & dosageHumansLung Transplantation/*adverse effects/*immunology/physiologyPerfusionPlatelet Activation/drug effectsRecombinant Proteins/administration & dosageSwineTransplantation, Heterologousvon Willebrand Factor/secretion
Abstract
BACKGROUND: In the xenotransplantation of vascularized organs, such as the lung, a large area of endothelial cell layer is a big hurdle to be overcome. We investigated the potential protective effect of aurintricarboxylic acid (ATA), a known inhibitor of platelet adhesion, on endothelial damage induced by xenogeneic serum. We also assessed its role in hyperacute xenograft rejection using a porcine ex vivo lung perfusion model. METHODS: Porcine endothelial cells were incubated with human serum and other inflammatory stimuli. For the evaluation of von Willebrand factor (vWF) secretion and tissue factor (TF) expression, we used human endothelial cells. E-selectin expression, complement activation, TF expression and platelet activation were investigated by flow cytometry. In an ex vivo porcine lung perfusion model, the porcine lungs were perfused with fresh human whole blood: unmodified blood (n = 5), ATA-treated blood (n = 5), and ATA and lepirudin-treated blood (n = 5). RESULTS: Aurintricarboxylic acid significantly inhibited TNF-alpha- or lipopolysaccharide-induced endothelial E-selectin expression in a dose-dependent manner. ATA also prevented human serum induced-E-selectin expression and human monocytic cell adhesion to porcine endothelial cells. Moreover, ATA abolished thrombin-induced vWF secretion as well as complement activation. However, ATA induced endothelial TF expression and platelet activation in vitro. In ex-vivo experiments, ATA treatment improved pulmonary function and attenuated sequestration of leukocytes. Although ATA did not influence thrombin generation, we were able to minimize its activity by adding lepirudin to the blood with ATA. CONCLUSIONS: Our study demonstrated in vitro protective effect of ATA on the inhibition of endothelial activation and vWF secretion and confirmed detrimental effect of ATA on induction of endothelial TF and platelet activation. The combination of ATA and lepirudin may act beneficially by preventing coagulation perturbation while maintaining improved xenograft survival.
ISSN
1399-3089 (Electronic)
1399-3089 (Linking)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18957047

http://hdl.handle.net/10371/63099
DOI
https://doi.org/10.1111/j.1399-3089.2008.00481.x
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College of Medicine/School of Medicine (의과대학/대학원)Laboratory Medicine (검사의학전공)Journal Papers (저널논문_검사의학전공)
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