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dc.contributor.authorAppa, Rupa Shree
dc.contributor.authorØie, Cristina Ionica
dc.contributor.authorBrodin, Ellen
dc.contributor.authorHansen, John-Bjarne
dc.contributor.authorSmedsrød, Bård
dc.date.accessioned2011-01-05T13:59:57Z
dc.date.available2011-01-05T13:59:57Z
dc.date.issued2010
dc.description.abstractWe here report on a study carried out to determine the early clearance kinetics, and organ, cell(s) and receptor(s) responsible for the clearance of full length TFPI purified from BHK cells (TFPI<sup>BHK</sup>). Following intravenous administration, <sup>125</sup>I-TFPI<sup>BHK</sup> was cleared with a biphasic elimination curve, and with a significantly slower t<sub>1/2</sub>α compared to recombinant human TFPI from <i>E.Coli</i> (TFPI<sup>E.Coli</sup>) (1.95±0.10 versus 1.42±0.07 min, respectively, p<0.001). Studies on organ and cell distribution revealed that liver parenchymal cells (PCs) were responsible for 96% of the uptake of TFPI<sup>BHK</sup> and 81% of TFPI<sup>E.Coli</sup>, whereas the nonparenchymal cells (NPCs) were responsible for 4% and 19%, respectively. Pre-administration of excessive amounts of unlabeled TFPI<sup>BHK</sup> prolonged blood clearance of <sup>125</sup>I-TFPI<sup>BHK</sup>. Unlabelled TFPI<sup>BHK</sup> inhibited endocytosis of <sup>125</sup>I-TFPI<sup>BHK</sup> in PCs <i>in vitro</i>, whereas blocking of LDL-receptor related protein-1 (LRP-1) by receptor-associated protein (RAP) affected neither blood clearance nor endocytosis of <sup>125</sup>I-TFPI<sup>BHK</sup> in PCs. In addition, TFPI<sup>BHK</sup> was also found in the kidneys and this could be reduced in the presence of RAP. Asialoorosomucoid (ASOR), a potent inhibitor of the asialoglycoprotein receptor (ASGP-R), prolonged the circulatory survival of <sup>125</sup>I-m-TFPI by 1.5-fold (p<0.001). <i>In vitro</i>, ASOR and other ASGP-R antagonists significantly inhibited endocytosis of <sup>125</sup>I-TFPI<sup>BHK</sup> in PCs. Moreover, unlabelled TFPI<sup>BHK</sup> markedly decreased endocytosis of <sup>125</sup>I-asialofetuin. In conclusion, our findings suggest that ASGP-R mediated endocytosis in the liver is involved in the clearance of TFPI<sup>BHK</sup>.en
dc.descriptionThis article is part of Cristina Ionica Øie's doctoral thesis, which is available in Munin at <a href=http://hdl.handle.net/10037/2910>http://hdl.handle.net/10037/2910</a>en
dc.format.extent655009 bytes
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/10037/2912
dc.identifier.urnURN:NBN:no-uit_munin_2645
dc.language.isoengen
dc.rights.accessRightsopenAccess
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710en
dc.titleAsialoglycoprotein Receptor (ASGP-R) is Liver Parenchymal Cells is Involved in Elimination of Recombinant Human TFPIen
dc.typeJournal articleen
dc.typeTidsskriftartikkelen


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