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首页> 外文期刊>Journal of ocular pharmacology and therapeutics: The official journal of the Association for Ocular Pharmacology and Therapeutics >New Insights on Complement Inhibitor CD59 in Mouse Laser-Induced Choroidal Neovascularization: Mislocalization After Injury and Targeted Delivery for Protein Replacement
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New Insights on Complement Inhibitor CD59 in Mouse Laser-Induced Choroidal Neovascularization: Mislocalization After Injury and Targeted Delivery for Protein Replacement

机译：对小鼠激光诱导的脉络膜新血管形成补体抑制剂CD59的新见解：损伤后的错误定位，靶向递送蛋白质替代品

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Purpose: The membrane attack complex (MAC) in choriocapillaris (CC) and retinal pigment epithelium (RPE) increase with age and disease (age-related macular degeneration). MAC assembly can be inhibited by CD59, a membrane-bound regulator. Here we further investigated the role of CD59 in murine choroidal neovascularization (CNV), a model involving both CC and RPE, and tested whether CR2-CD59, a soluble targeted form of CD59, provides protection. Methods: Laser-induced CNV was generated in wild type and CD59a-deficient mice (CD59(-/-)). CNV size was measured by optical coherence tomography, and CR2-CD59 was injected intraperitoneally. Endogenous CD59 localization and MAC deposition were identified by immunohistochemistry and quantified by confocal microscopy. Cell-type-specific responses to MAC were examined in retinal pigment epithelial cells (ARPE-19) and microvascular endothelial cells (HMEC-1). Results: CD59 levels were severely reduced and protein was mislocalized in the RPE surrounding the lesion. CNV lesion size and subretinal fluid accumulation were exacerbated in CD59(-/-) when compared with those in WT mice, and an increase in MAC deposition was noted. In contrast, CR2-CD59 significantly reduced both structural features of CNV severity. In vitro, MAC inhibition in ARPE-19 cells prevented barrier function loss and accelerated wound healing and cell adhesion, whereas in HMEC-1 cells, CR2-CD59 decelerated wound healing and cell adhesion. Conclusion: These data further support the importance of CD59 in controlling ocular injury responses and indicate that pharmacological inhibition of the MAC with CR2-CD59 may be a viable therapeutic approach for reducing complement-mediated ocular pathology.
机译：目的：膜攻击复合体（MAC）在芝麻皮菌（CC）和视网膜颜料上皮（RPE）随年龄和疾病增加（年龄相关的黄斑变性）。可以通过CD59，膜结合的调节器抑制MAC组件。在这里，我们进一步研究了CD59在鼠脉络膜新生血管（CNV）中的作用，涉及CC和RPE的模型，并测试CR2-CD59是否可溶性靶向形式的CD59，提供保护。方法：激光诱导的CNV在野生型和CD59a缺陷小鼠中产生（CD59（ - / - ））。通过光学相干断层扫描测量CNV尺寸，CR2-CD59注射腹膜内。通过免疫组织化学鉴定内源性CD59定位和MAC沉积，并通过共聚焦显微镜量化。在视网膜色素上皮细胞（ARPE-19）和微血管内皮细胞（HMEC-1）中检查对MAC的细胞型特异性响应。结果：CD59水平严重降低，蛋白质在病变周围的RPE中误差。与WT小鼠的那些相比，CD59（ - / - ）在CD59（ - / - ）中加剧了CNV病变尺寸和分子液累积，并注意到MAC沉积的增加。相比之下，CR2-CD59显着降低了CNV严重程度的结构特征。在体外，ARPE-19细胞中的MAC抑制阻碍了屏障功能损失和加速伤口愈合和细胞粘附，而在HMEC-1细胞中，CR2-CD59减速伤口愈合和细胞粘附。结论：这些数据进一步支持CD59控制眼部损伤反应的重要性，并表明MAC与CR2-CD59的药理学抑制可能是降低补体介导的眼病理学的可行治疗方法。

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