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Vascular repair utilising immobilised heparin conjugate for protection against early activation of inflammation and coagulation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
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2015 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 113, no 6, 1312-1322 p.Article in journal (Refereed) Published
Abstract [en]

Ischaemia-reperfusion injury (IRI) poses a major challenge in many thrombotic conditions and in whole organ transplantation. Activation of the endothelial cells and shedding of the protective vascular glycocalyx during IRI increase the risk of innate immune activation, cell infiltration and severe thrombus formation, promoting damage to the tissue. Here, we present a novel one-step strategy to protect the vas, culature by immobilisation of a unique multi-arm heparin conjugate to the endothelium. Applying a new in vitro blood endothelial cell chamber model, the heparin conjugate was found to bind not only to primary human endothelial cells but also directly to the collagen to which the cells adhered. Incubation of hypoxic endothelial cells with freshly drawn human blood in the blood chambers elicited coagulation activation reflected by thrombin anti-thrombin formation and binding of platelets and neutrophils. Immobilisation of the heparin conjugate to the hypoxic endothelial cells created a protective coating, leading to a Significant reduction of the recruitment of blood cells and coagulation activation compared to untreated hypoxic endothelial cells. This novel approach of immobilising multi-arm heparin conjugates on the endothelial cells and collagen of the basement membrane ensures to protect the endothelium against IRI in thrombotic disorders and in transplantation.

Place, publisher, year, edition, pages
2015. Vol. 113, no 6, 1312-1322 p.
Keyword [en]
Blood coagulation, endothelial cells, heparin, surface modification, collagen
National Category
Cardiac and Cardiovascular Systems Hematology
Identifiers
URN: urn:nbn:se:uu:diva-258043DOI: 10.1160/TH14-09-0724ISI: 000355776400021PubMedID: 25740465OAI: oai:DiVA.org:uu-258043DiVA: diva2:841395
Funder
Swedish Research Council, 90293501, A0290401, A0290402
Available from: 2015-07-13 Created: 2015-07-10 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Vascular Interactions in Innate Immunity and Immunothrombosis:: Models of Endothelial Protection
Open this publication in new window or tab >>Vascular Interactions in Innate Immunity and Immunothrombosis:: Models of Endothelial Protection
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The phenomenon known as immunothrombosis has garnered increased attention over the last few years. Much work has been done to characterize the cross talk between hemostasis and the innate immune system. This thesis outlines the role of the vascular endothelial cells during immunothrombotic events as regulators of coagulation, platelet-, and leukocyte recruitment.

A newly developed method for investigating the interaction between endothelial cells and the blood compartment illustrated the procoagulant and proinflammatory effects elicited by tumor necrosis factor α activated endothelial cells upon exposure to whole blood. The method was utilized in evaluating treatment of endothelial dysfunction and disruption with a heparin conjugate. Damaged or hypoxic endothelial cells, in addition to basement membrane collagen, that were pretreated with the heparin conjugate prior to contact with blood were found to have reduced activation of coagulation, platelet-, and leukocyte recruitment; in contrast to unfractionated heparin, which had no effect on the aforementioned parameters. The treatment was then investigated in the setting of ischemia reperfusion injury during kidney transplantation and the heparin conjugate was found to bind cultured endothelial cells with high avidity under cold storage conditions. Furthermore, it was found to bind to the renal vasculature during static cold storage and was subsequently found to be beneficial with regard to early graft function in an experimental mouse model of syngeneic kidney transplantation. Recipients of kidneys treated with the heparin conjugate had reduced serum creatinine compared to controls 24 hours after transplantation. Lastly, the anticoagulant properties of the heparin conjugate were investigated in comparison to unfractionated heparin. While the conjugate exerted reduced capacity with regard to thrombin inhibition, it rapidly inhibited the binding of platelets to exposed collagen. The conjugate was furthermore found to preferentially locate to sites of endothelial cell activation at early stage during endotoxic shock in mice.

In conclusion, this thesis demonstrates that disrupted functioning of the vascular endothelial cells actively contributes to immunothrombosis, and that it is possible to model endothelial cell function using whole blood assays. Furthermore, this thesis presents a treatment that enhances the hemocompatibility of damaged endothelial cells and subsequently improves the early renal function after kidney transplantation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 52 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1220
Keyword
Endothelial cells, Thrombosis, Innate immunity, Immunothrombosis, Thromboinflammation
National Category
Immunology in the medical area Cell and Molecular Biology
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-283548 (URN)978-91-554-9564-0 (ISBN)
Public defence
2016-06-03, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-05-13 Created: 2016-04-13 Last updated: 2016-06-01

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Nordling, SofiaHong, JaanFromell, KarinEdin, FredrikBrännström, JohanLarsson, RolfNilsson, BoMagnusson, Peetra U.

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