Hemin Promotes Corneal Allograft Survival Through the Suppression of Macrophage Recruitment and Activation
Hemin Promotes Corneal Allograft Survival Through the Suppression of Macrophage Recruitment and Activation
复制标题
血红素通过抑制巨噬细胞的招募和激活来促进同种异体角膜移植物的存活
DOI：
10.1167/iovs.17-23327
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发表时间：
2018-08-01
影响因子：
4.4
通讯作者：
Liang, Dan
中科院分区：
文献类型：
--
作者：
Dai, Ye;Cheng, Xiaokang;Liang, Dan
目的。为探讨氯化高铁血红素预防同种异体角膜移植排斥反应(CGR)的作用及其机制，采用大鼠同种异体角膜移植模型，从移植当天起至安乐死前隔天腹腔注射氯化血红素(30 mg/kg)。根据先前发表的系统对同种异体角膜移植的临床体征进行评估和记录。通过组织学、实时荧光定量聚合酶链式反应和免疫印迹检测角膜水肿、巨噬细胞浸润、表型、趋化因子、细胞因子和血红素氧合酶(HO)-1的表达。采用大鼠巨噬细胞系NR8383，探讨氯化高铁血红素在体外的作用机制。结果氯化高铁血红素处理后，角膜移植物存活时间明显延长，角膜水肿减轻，巨噬细胞减少。此外，氯化血红素治疗减轻了角膜移植物中的炎症，其特征是前炎症介质的mRNA水平下调。此外，氯化高铁血红素降低了角膜移植物中促炎症M1巨噬细胞的比例，增加了抗炎M2巨噬细胞的比例。氯化血红素在体内和体外均可诱导HO-1的表达，而联合应用HO-1抑制剂锌原卟啉IX可阻断氯化血红素预防CGR的有益作用。结论我们的结果首次证明美国食品和药物管理局批准的药物氯化血红素能促进角膜移植物的存活。这些发现表明，氯化血红素可能是治疗CGR的一种潜在的替代疗法。
PURPOSE. To explore the roles of hemin in preventing corneal allograft rejection (CGR) and the underlying mechanisms.METHODS. Hemin (30 mg/kg) was intraperitoneally injected into rats with a corneal allograft on alternate days, from the day of transplantation until euthanasia. The clinical signs of the corneal allografts were evaluated and recorded according to a previously published system. Corneal edema, macrophage infiltration, and phenotype, and the expression of chemokines, cytokines, and heme oxygenase (HO)-1 were detected by histology, real-time PCR, and Western blot. The rat macrophage cell line NR8383 was used to explore the mechanisms of action of hemin in vitro.RESULTS. Treatment with hemin significantly prolonged corneal allograft survival, with decreased corneal edema and fewer macrophages. Moreover, hemin treatment alleviated inflammation in the corneal grafts, as characterized by downregulated mRNA levels of proinflammatory mediators. In addition, hemin administration reduced the proportion of proinflammatory M1 macrophages and increased the proportion of anti-inflammatory M2 macrophages in the corneal grafts. Hemin treatment induced HO-1 expression in vivo and in vitro, whereas co-administration of zinc protoporphyrin IX (ZnPP), an HO-1 inhibitor, blocked the beneficial effects of hemin in preventing CGR.CONCLUSIONS. Our results are the first to demonstrate that hemin, a Food and Drug Administration-approved drug, promotes corneal allograft survival. These findings indicate that hemin might be a potential alternative treatment for CGR.