Molski Michal, Groth Anne, Allison Anthony C, Hendrickson Mark, Siemionow Maria
Department of General and Vascular Surgery, Nicolaus Copernicus University, Collegium Medicum in Bydgoszcz, Poland.
Ann Plast Surg. 2009 Nov;63(5):564-71. doi: 10.1097/SAP.0b013e3181935a4e.
Ischemia-reperfusion injury (IRI) is a common and serious complication of reperfusion following vascular occlusion. We present a novel interpretation of the pathogenesis of IRI. According to this hypothesis, anoxia resulting from ischemia allows translocation of phosphatidylserine to the surface of endothelial cells (ECs), providing an attachment site for leukocytes and platelets. This attachment impedes blood flow through the microvasculature. During IRI mediators of increased vascular permeability are produced, resulting in edema. We have developed a recombinant homodimer of human Annexin V, Diannexin, to attenuate IRI. Annexin V (36 kDa) rapidly passes from the circulation into the urine. In Diannexin 2 annexin V molecules are joined by a short peptide linker to produce a 73 kDa protein, which exceeds the renal filtration threshold. Diannexin has a half-life of about 2.5 hours in the human circulation. Diannexin also has a higher affinity for phosphatidylserine on cell surfaces than the monomer has. Such binding inhibits leukocyte attachment to ECs, and inflammatory mediator formation, during IRI. The aim of the study now reported was to ascertain the effects of Diannexin on IRI in the rat cremaster muscle flap, as revealed by intravital microscopy. During IRI there was increased attachment of leukocytes to ECs, reduced blood flow and augmented vascular permeability. Administration of Diannexin before or just after ischemia prevented these effects. Diannexin inhibited transmigration of leukocytes during IRI. Edema complicates peripheral vascular surgery, stroke, and other clinical conditions. Diannexin has proven to be safe when administered to patients after major surgical operations, and it may be useful to prevent IRI associated with peripheral vascular surgery.
缺血再灌注损伤（IRI）是血管阻塞后再灌注常见且严重的并发症。我们对IRI的发病机制提出了一种新的解释。根据这一假说，缺血导致的缺氧使磷脂酰丝氨酸易位至内皮细胞（ECs）表面，为白细胞和血小板提供附着位点。这种附着阻碍了微血管中的血流。在IRI期间，会产生增加血管通透性的介质，导致水肿。我们研发了一种重组人膜联蛋白V同二聚体——双安奈新，以减轻IRI。膜联蛋白V（36 kDa）可迅速从循环进入尿液。在双安奈新中，2个膜联蛋白V分子通过一个短肽接头连接，形成一个73 kDa的蛋白质，其超过了肾脏滤过阈值。双安奈新在人体循环中的半衰期约为2.5小时。双安奈新对细胞表面磷脂酰丝氨酸的亲和力也高于单体。这种结合在IRI期间抑制白细胞与ECs的附着以及炎症介质的形成。本研究的目的是通过活体显微镜检查确定双安奈新对大鼠提睾肌皮瓣IRI的影响。在IRI期间，白细胞与ECs的附着增加、血流减少且血管通透性增强。在缺血前或缺血后立即给予双安奈新可预防这些影响。双安奈新在IRI期间抑制白细胞的迁移。水肿会使外周血管手术、中风及其他临床病症变得复杂。已证明在大手术后给患者使用双安奈新是安全的，它可能有助于预防与外周血管手术相关的IRI。
