Blockade of thrombospondin-1-CD47 interactions prevents necrosis of full thickness skin grafts
Blockade of thrombospondin-1-CD47 interactions prevents necrosis of full thickness skin grafts
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DOI：
10.1097/sla.0b013e31815685dc
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发表时间：
2008-01-01
影响因子：
9
通讯作者：
Roberts, David D.
中科院分区：
文献类型：
--
作者：
Isenberg, Jeff S.;Pappan, Loretta K.;Roberts, David D.
背景：皮肤移植物的存活和愈合需要快速恢复无血管移植物的血流。移植物血管化过程中的失败或延迟是发病率和死亡率的重要来源。血液流动和血管生长的主要调节剂之一是一氧化氮（NO）。分泌的蛋白质血小板反应蛋白-1（TSPI）限制NO刺激的血流和生长以及缺血的复合组织存活。我们在此证明了TSP 1在调节全层皮肤移植物（FTSG）survival.Methods和Results的作用：FTSG一贯失败的野生型C57 BL/6小鼠，但缺乏TSP 1或其受体CD 47的小鼠存活。然而，TSPI受体CD 36的消融并没有改善FTSG存活率。值得注意的是，野生型FTSG在TSP 1缺失或CD 47缺失小鼠中存活，表明创伤床中的TSP 1表达是移植物存活的主要决定因素。增加NO流量可适度提高野生型小鼠FTSG存活率，但通过抗体阻断TSPI与CD 47的结合或反义morpholino寡核苷酸抑制CD 47可显著提高移植物存活率。阻断TSP 1结合或抑制CD 47表达显著增加移植物存活。这种方法的治疗应用可能包括烧伤患者和需要移植物或组织瓣用于闭合和重建各种病因的复杂伤口的更广泛人群。
Background: Skin graft survival and healing requires rapid restoration of blood flow to the avascular graft. Failure or delay in the process of graft vascularization is a significant source of morbidity and mortality. One of the primary regulators of blood flow and vessel growth is nitric oxide (NO). The secreted protein thrombospondin-1 (TSPI) limits NO-stimulated blood flow and growth and composite tissue survival to ischemia. We herein demonstrate a role for TSP 1 in regulating full thickness skin graft (FTSG) survival.Methods and Results: FTSG consistently fail in wild type C57BL/6 mice but survive in mice lacking TSP1 or its receptor CD47. Ablation of the TSPI receptor CD36, however, did not improve FTSG survival. Remarkably, wild type FTSG survived on TSP I null or CD47 null mice, indicating that TSP1 expression in the wound bed is the primary determinant of graft survival. FTSG survival in wild type mice could be moderately improved by increasing NO flux, but graft survival was increased significantly through antibody blocking of TSPI binding to CD47 or antisense morpholino oligonucleotide suppression of CD47.Conclusions: TSP1 through CD47 limits skin graft survival. Blocking TSP1 binding or suppressing CD47 expression drastically increases graft survival. The therapeutic applications of this approach could include burn patients and the broader group of people requiring grafts or tissue flaps for closure and reconstruction of complex wounds of diverse etiologies.