Hashimoto Kohei, Kim Hyunhee, Oishi Hisashi, Chen Manyin, Iskender Ilker, Sakamoto Jin, Ohsumi Akihiro, Guan Zehong, Hwang David, Waddell Thomas K, Cypel Marcelo, Liu Mingyao, Keshavjee Shaf
Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
J Thorac Cardiovasc Surg. 2016 Mar;151(3):861-869. doi: 10.1016/j.jtcvs.2015.10.112. Epub 2015 Nov 11.
We hypothesized that administration of a homodimer of recombinant annexin V, diannexin, could shield phosphatidylserine on the endothelium, and inhibit leukocyte and platelet adhesion, thereby potentially reducing ischemia reperfusion injury (IRI) in lung transplantation. This hypothesis was tested using a rat syngeneic single left-lung transplant model.
Rats were randomly assigned to receive diannexin (DN group; n = 10) or normal saline (control group; n = 10). Diannexin (1000 μg/kg) was administered to the donor lung in the pulmonary flush solution, and to the recipient intravenously, 5 minutes after initiation of reperfusion. Grafts were reperfused for 2 hours.
The transplanted grafts in the DN group performed significantly better in gas exchange with higher partial pressure of oxygen (control group: 179 ± 121 vs DN group: 330 ± 54 mm Hg; P = .007) and lower partial pressure of carbon dioxide (control: 55.1 ± 26 vs DN: 34.2 ± 11 mm Hg; P = .04), as well as lower peak airway pressure (control: 20.5 ± 8.5 vs DN: 12.0 ± 7.9 cm H2O; P = .035) after 2 hours of reperfusion. Wet-to-dry lung weight ratio (P = .054), and alveolar fibrin deposition score (P = .04), were reduced in the DN group. Caspase-cleaved cytokeratin 18 in plasma (a marker of epithelial apoptosis) was significantly reduced in the DN group (P = .013). Furthermore, gene-expression levels of proinflammatory cytokines in the transplanted graft, including interleukin-6 (P = .04) and macrophage inflammatory protein 2 (P = .03) were significantly decreased in the DN group.
A homodimer of recombinant annexin V reduced ischemia reperfusion injury in a lung transplant animal model, by reducing cell death and tissue inflammation.
我们推测给予重组膜联蛋白V的同型二聚体——双安奈新，可保护内皮细胞上的磷脂酰丝氨酸，并抑制白细胞和血小板黏附，从而有可能减轻肺移植中的缺血再灌注损伤（IRI）。我们使用大鼠同基因单左肺移植模型对这一假设进行了验证。
将大鼠随机分为两组，分别给予双安奈新（DN组；n = 10）或生理盐水（对照组；n = 10）。在肺灌洗溶液中向供体肺给予双安奈新（1000 μg/kg），并在再灌注开始5分钟后经静脉给予受体。移植物再灌注2小时。
DN组移植的移植物在气体交换方面表现明显更好，氧分压更高（对照组：179±121 vs DN组：330±54 mmHg；P = 0.007），二氧化碳分压更低（对照组：55.1±26 vs DN组：34.2±11 mmHg；P = 0.04），再灌注2小时后气道峰压也更低（对照组：20.5±8.5 vs DN组：12.0±7.9 cmH₂O；P = 0.035）。DN组的肺湿重与干重比（P = 0.054）和肺泡纤维蛋白沉积评分（P = 0.04）降低。DN组血浆中半胱天冬酶切割的细胞角蛋白18（上皮细胞凋亡标志物）显著降低（P = 0.013）。此外，DN组移植移植物中促炎细胞因子的基因表达水平，包括白细胞介素-6（P = 0.04）和巨噬细胞炎性蛋白2（P = 0.03）显著降低。
重组膜联蛋白V的同型二聚体通过减少细胞死亡和组织炎症，减轻了肺移植动物模型中的缺血再灌注损伤。
