Imai M, Takigami K, Guckelberger O, Enjyoji K, Smith R N, Lin Y, Csizmadia E, Sévigny J, Rosenberg R D, Bach F H, Robson S C
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Mol Med. 1999 Nov;5(11):743-52.
There is increasing evidence showing that extracellular nucleosides [corrected] may be important mediators of vascular inflammation. Nucleoside [corrected] triphosphate diphosphohydrolase-1 (NTPDase-1, identical to CD39), the major vascular endothelial ectonucleotidase, is responsible for the hydrolysis of both extracellular ATP and ADP in the blood plasma to AMP. Studies were therefore conducted to evaluate the role of vascular NTPDase-1/cd39 in modulating platelet activation and vascular injury in cardiac xenografts.
Cardiac xenografts from both wild-type and cd39 knockout mice (C57BL/6 x 129 Svj) were transplanted into Lewis rats. Alterations in cd39 mRNA transcripts and NTPDase activity expression were evaluated in wild-type grafts in untreated rats and then following complement depletion and immunosuppression. Rejection responses were studied with both mutant and wild-type grafts in the following models: presensitization with or without complement depletion, complement depletion alone, and with chronic immunosuppression to induce long-term graft survival.
NTPDase biochemical activity in wild-type xenografts rapidly decreased after transplantation but soon rebounded with graft survival. Elevated levels of cd39 mRNA with associated increases in NTPDase activity were observed in all long-term surviving wild-type grafts. Hyperacute xenograft rejection times were comparable in wild-type and mutant grafts but cd39-deficient grafts were subject to more rapid rejection and exhibited pronounced vascular injury in complement-depleted, presensitized rats. The cd39-deficient grafts in immunosuppressed recipients were subject to increased intravascular platelet sequestration and fibrin deposition; this resulted in focal myocardial infarction in long-term surviving mutant xenografts.
Augmentation of NTPDase-1 activity may be an important adaptive response for graft survival. Our results suggest that NTPDase-1/cd39 influences pathways of vascular injury in cardiac xenografts.
越来越多的证据表明，细胞外核苷可能是血管炎症的重要介质。核苷三磷酸二磷酸水解酶-1（NTPDase-1，等同于CD39）是主要的血管内皮外核苷酸酶，负责将血浆中的细胞外ATP和ADP水解为AMP。因此，开展了相关研究以评估血管NTPDase-1/CD39在调节心脏异种移植中血小板活化和血管损伤方面的作用。
将野生型和cd39基因敲除小鼠（C57BL/6×129 Svj）的心脏异种移植到Lewis大鼠体内。在未处理的大鼠的野生型移植物中，以及在补体耗竭和免疫抑制后，评估cd39 mRNA转录本和NTPDase活性表达的变化。在以下模型中，对突变型和野生型移植物的排斥反应进行了研究：有或无补体耗竭的预致敏、单独补体耗竭以及慢性免疫抑制以诱导长期移植物存活。
野生型异种移植物中的NTPDase生化活性在移植后迅速下降，但随着移植物存活很快反弹。在所有长期存活的野生型移植物中，均观察到cd39 mRNA水平升高以及NTPDase活性相应增加。野生型和突变型移植物的超急性异种移植排斥时间相当，但在补体耗竭的预致敏大鼠中，cd39缺陷型移植物遭受更快速的排斥，并表现出明显的血管损伤。免疫抑制受体中的cd39缺陷型移植物血管内血小板扣押和纤维蛋白沉积增加；这导致长期存活的突变型异种移植物发生局灶性心肌梗死。
NTPDase-1活性增强可能是移植物存活的重要适应性反应。我们的结果表明，NTPDase-1/CD39影响心脏异种移植中的血管损伤途径。
