Bethesda and Baltimore, Md.; and Pittsburgh, Pa. From the Laboratory of Pathology, National Cancer Institute, National Institutes of Health; the Department of Surgery, The Johns Hopkins Medical Institutions; the Howard Hughes Medical Institute-National Institutes of Health Research Scholar Program; and the Division of Pulmonary, Allergy, and Critical Care Medicine and Vascular Medicine Institute, University of Pittsburgh School of Medicine.
Plast Reconstr Surg. 2009 Dec;124(6):1880-1889. doi: 10.1097/PRS.0b013e3181bceec3.
Nitric oxide has prosurvival effects that can limit ischemia-reperfusion injuries. However, the matrix glycoprotein thrombospondin-1 is induced following ischemia-reperfusion injury and limits nitric oxide signaling by engaging its cell surface receptor CD47. In this article, the authors examine whether postinjury blocking of this inhibitory signal can protect from ischemia-reperfusion injury in a rat flap model.
A total of 40 tissue flaps were created in rats based solely on the deep inferior epigastric vessels. Microvascular clamps were used to create 45 minutes of ischemia time to the flaps. The flaps were then treated using a monoclonal antibody to CD47 or an isotype-matched control immunoglobulin G1 5 or 30 minutes after clamp removal. Twenty-four or 72 hours postoperatively, the necrotic area of the flap was determined, and serum, deep inferior epigastric vessels, and flaps were harvested for analysis from five rats in each respective group.
Treatment with a CD47 antibody 5 minutes after reperfusion significantly reduces flap necrosis compared with immunoglobulin G1 control (9 percent versus 43 percent; p < 0.01). The protective effect is even more dramatic when treatment is delayed until 30 minutes after reperfusion (10 percent versus 88 percent for control; p < 0.01). Markers of neutrophil and endothelial cell activation along with total leukocytes are reduced in CD47 antibody-treated flaps, as are tissue malondialdehyde levels. Levels of cyclic guanosine monophosphate are elevated 72 hours postoperatively in the CD47 antibody-treated deep inferior epigastric vessels versus the control flaps.
Therapies targeting the thrombospondin-1 receptor CD47 offer potential for increasing tissue survival in ischemia-reperfusion injuries. The ability to protect when given after ischemia-reperfusion injury enables a broader clinical applicability.
一氧化氮具有生存促进作用，可以限制缺血再灌注损伤。然而，基质糖蛋白血小板反应蛋白-1 在缺血再灌注损伤后被诱导，并通过与细胞表面受体 CD47 结合来限制一氧化氮信号。在本文中，作者研究了在大鼠皮瓣模型中，损伤后阻断这种抑制信号是否可以保护免受缺血再灌注损伤。
在大鼠中仅基于深部腹壁下血管创建了 40 个组织皮瓣。使用微血管夹对皮瓣造成 45 分钟的缺血时间。然后，在夹闭去除后 5 或 30 分钟，用针对 CD47 的单克隆抗体或同种型匹配的对照免疫球蛋白 G1 处理皮瓣。术后 24 或 72 小时，确定皮瓣的坏死面积，并从每组的 5 只大鼠中收获血清、深部腹壁下血管和皮瓣进行分析。
再灌注后 5 分钟用 CD47 抗体治疗可显著减少皮瓣坏死，与免疫球蛋白 G1 对照相比（9%对 43%；p<0.01）。当治疗延迟至再灌注后 30 分钟时，保护作用更加明显（对照为 10%对 88%；p<0.01）。在 CD47 抗体处理的皮瓣中，中性粒细胞和内皮细胞激活的标志物以及总白细胞减少，组织丙二醛水平也降低。与对照皮瓣相比，CD47 抗体处理的深部腹壁下血管中的环鸟苷单磷酸水平在术后 72 小时升高。
针对血小板反应蛋白-1 受体 CD47 的治疗方法为缺血再灌注损伤中增加组织存活提供了潜力。在缺血再灌注损伤后给予保护的能力使临床应用更加广泛。
