Vascular repair utilising immobilised heparin conjugate for protection against early activation of inflammation and coagulation.
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 vasculature 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.
Sofia
S
Nordling
Jaan
J
Hong
Karin
K
Fromell
Fredrik
F
Edin
Johan
J
Brännström
Rolf
R
Larsson
Bo
B
Nilsson
Peetra Magnusson, Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Dag Hammarskjolds vag 20, SE-751 85 Uppsala, Sweden, Tel.: +46 723888418, Fax: +46 186110222, E-mail: peetra.magnusson@igp.uu.se.
Peetra U
PU
Magnusson
D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology*; D000925:Anticoagulants / Q000378:metabolism / Q000494:pharmacology*; D000990:Antithrombin III / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D015687:Cell Hypoxia; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D006493:Heparin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D010973:Platelet Adhesiveness / Q000187:drug effects; D011485:Protein Binding; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013927:Thrombosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; C046193:antithrombin III-protease complex; D000990:Antithrombin III; D006493:Heparin; D003094:Collagen; D010447:Peptide Hydrolases
Blood coagulation; collagen; endothelial cells; heparin; surface modification