title: Anti-inflammatory and anticoagulant effects of transgenic expression of human thrombomodulin in mice.
abstract: Thrombomodulin (TBM) is an important vascular anticoagulant that has species specific effects. When expressed as a transgene in pigs, human (h)TBM might abrogate thrombotic manifestations of acute vascular rejection (AVR) that occur when GalT-KO and/or complement regulator transgenic pig organs are transplanted to primates. hTBM transgenic mice were generated and characterized to determine whether this approach might show benefit without the development of deleterious hemorrhagic phenotypes. hTBM mice are viable and are not subject to spontaneous hemorrhage, although they have a prolonged bleeding time. They are resistant to intravenous collagen-induced pulmonary thromboembolism, stasis-induced venous thrombosis and pulmonary embolism. Cardiac grafts from hTBM mice to rats treated with cyclosporine in a model of AVR have prolonged survival compared to controls. hTBM reduced the inflammatory reaction in the vein wall in the stasis-induced thrombosis and mouse-to-rat xenograft models and reduced HMGB1 levels in LPS-treated mice. These results indicate that transgenic expression of hTBM has anticoagulant and antiinflammatory effects that are graft-protective in murine models.
authors.affiliation: Immunology Research Centre, The University of Melbourne, St. Vincent's Hospital, Fitzroy, VIC 3065, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Crikis
authors.forename: X M
authors.initials: XM
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Dezfouli
authors.forename: K M
authors.initials: KM
authors.lastname: Dwyer
authors.forename: L M
authors.initials: LM
authors.lastname: Murray-Segal
authors.forename: E
authors.initials: E
authors.lastname: Salvaris
authors.forename: C
authors.initials: C
authors.lastname: Selan
authors.forename: S C
authors.initials: SC
authors.lastname: Robson
authors.forename: H H
authors.initials: HH
authors.lastname: Nandurkar
authors.forename: P J
authors.initials: PJ
authors.lastname: Cowan
authors.forename: A J F
authors.initials: AJ
authors.lastname: d'Apice
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats; D013552:Swine; D018180:Thrombomodulin; D019076:Transgenes / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D018180:Thrombomodulin; D016572:Cyclosporine