Treatment of liver ischemia-reperfusion injury by limiting thrombospondin-1/CD47 signaling.
Treatment of liver ischemia-reperfusion injury by limiting thrombospondin-1/CD47 signaling.
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DOI：
10.1016/j.surg.2008.07.009
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发表时间：
2008-11
期刊：
影响因子：
3.8
通讯作者：
Roberts, David D.
中科院分区：
文献类型：
--
作者：
Isenberg, Jeff S.;Maxhimer, Justin B.;Powers, Perlita;Tsokos, Maria;Frazier, William A.;Roberts, David D.
缺血再灌注 (I/R) 损伤仍然是移植手术的主要并发症，约占肝移植失败的 80%，也是其他病理状况发病的主要来源。内皮细胞的激活和炎症细胞的募集对于 I/R 损伤的引发和扩散至关重要，而这种损伤可能受到生物活性气体一氧化氮 (NO) 的限制。凝血反应蛋白-1 (TSP1) 通过 CD47 限制血管细胞中的 NO 信号传导和体内缺血性损伤，这一发现表明 I/R 损伤可能是该信号传导途径的另一个重要靶点。野生型、TSP1 缺失和 CD47 缺失小鼠经历了肝 I/R 损伤。野生型动物在肝 I/R 损伤前用 CD47 或对照抗体进行预处理。通过激光多普勒成像、血清酶、组织学和免疫组织学评估组织灌注。与野生型小鼠相比，遭受次全肝 I/R 损伤的 TSP1 缺失和 CD47 缺失小鼠显示出灌注改善。接受肝脏 I/R 治疗的无效小鼠肝酶释放减少，损伤的组织学证据也较少。 I/R 损伤后肝组织中 TSP1 表达升高表明，防止其与 CD47 相互作用可能具有保护作用。因此，使用阻断性 CD47 抗体对野生型小鼠进行预处理可改善 I/R 损伤后组织灌注的恢复并保持肝脏完整性。肝 I/R 损伤后的组织存活和灌注受到 TSP1 和 CD47 的限制。在 I/R 损伤之前靶向 CD47 可增强肝 I/R 损伤模型中的组织存活和灌注，并提出了在移植手术中增强器官存活的治疗方法。
Ischemia-reperfusion (I/R) injury remains a primary complication of transplant surgery, accounting for ∼80% of liver transplant failures, and a major source of morbidity in other pathologic conditions. Activation of endothelium and inflammatory cell recruitment are central to the initiation and promulgation of I/R injury, which can be limited by the bioactive gas nitric oxide (NO). The discovery that thrombsospondin-1 (TSP1), via CD47, limits NO signaling in vascular cells and ischemic injuries in vivo suggested that I/R injury could be another important target of this signaling pathway. Wild type, TSP1 null and CD47 null mice underwent liver I/R injury. Wild type animals were pretreated with CD47 or control antibodies prior to liver I/R injury. Tissue perfusion via laser Doppler imaging, serum enzymes, histology and immunohistology were assessed. TSP1 null and CD47 null mice subjected to subtotal liver I/R injury showed improved perfusion relative to wild type mice. Null mice subjected to liver I/R had decreased liver enzyme release and less histologic evidence of injury. Elevated TSP1 expression in liver tissue following I/R injury suggested that preventing its interaction with CD47 could be protective. Thus, pretreatment of wild type mice using a blocking CD47 antibody improved recovery of tissue perfusion and preserved liver integrity following I/R injury. Tissue survival and perfusion after liver I/R injury are limited by TSP1 and CD47. Targeting CD47 prior to I/R injury enhances tissue survival and perfusion in a model of liver I/R injury and suggests therapeutics for enhancing organ survival in transplantation surgery.
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DOI：
10.1073/pnas.92.9.3978
发表时间：
1995-04-25
影响因子：
11.1
作者：
COOPER, D;LINDBERG, FP;VADAS, MA
通讯作者：
VADAS, MA
影响因子：
20.1
作者：
Isenberg, Jeff S.;Romeo, Martin J.;Roberts, David D.
通讯作者：
Roberts, David D.
影响因子：
9
作者：
Isenberg, Jeff S.;Pappan, Loretta K.;Roberts, David D.
通讯作者：
Roberts, David D.
影响因子：
7.4
作者：
Iwase, Hirotaro;Robin, Emmanuel;Schumacker, Paul T.
通讯作者：
Schumacker, Paul T.
影响因子：
0.9
作者：
Kupiec-Weglinski, JW;Busuttil, RW
通讯作者：
Busuttil, RW