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贝伐单抗再探讨:其在不同眼部疾病小鼠模型中的应用。

Bevacizumab revisited: its use in different mouse models of ocular pathologies.

作者信息

Hollanders Karolien, Van Bergen Tine, Van de Velde Sarah, Sijnave Davine, Vandewalle Evelien, Moons Lieve, Stalmans Ingeborg

机构信息

Laboratory of Ophthalmology, KU Leuven , Leuven , Belgium .

出版信息

Curr Eye Res. 2015 May;40(6):611-21. doi: 10.3109/02713683.2014.943910. Epub 2014 Aug 12.

Abstract

PURPOSE

Previous reports have yielded conflicting data on the activity of bevacizumab (Avastin), a recombinant humanized monoclonal antibody against VEGF-A, in the mouse. The current study was designed to further explore the use of this VEGF inhibitor in various murine models of ocular diseases and compare it to the widely used murine anti-VEGF-R2 neutralizing antibody (DC101).

METHODS

Murine models of laser-induced choroidal neovascularization (CNV), oxygen-induced retinopathy (OIR) and glaucoma filtration surgery (GFS) were used to investigate the effect of bevacizumab. Mice either received an intravitreal (CNV-OIR) or subconjunctival (GFS) injection. In all models, they were divided in two groups (n = 10 per group). In the first group, one eye was injected with bevacizumab (1 µl; 25 µg) and the other eye was used as a negative control and received an injection of NaCl (1 µl; 0.9%). In the second group, one eye was injected with DC101 (1 µl; 6.2 µg), whereas an isotype-matched control antibody (1C8; 4.8 µg) was administered in the contralateral eye. Treatment outcome was studied by clinical investigation (GFS) and immunohistological analysis of angiogenesis (CD31/FITC-dextran/H&E) and fibrosis (Sirius Red).

RESULTS

Analysis of blood vessel density (CNV) and blood vessel growth (OIR) showed a comparable decrease after intravitreal administration of bevacizumab or DC101. Furthermore, in the mouse model of GFS, clinical investigation of the bleb and a CD31 staining on sections demonstrated that subconjunctival injection of both antibodies similarly improved the surgical outcome (bleb area and survival) by reducing angiogenesis. Moreover, morphometric analysis after Sirius Red staining showed a comparable reduction in collagen deposition after administration of the inhibitors.

CONCLUSION

Our findings consistently demonstrate that bevacizumab is as effective as the murine anti-VEGF-R2 antibody (DC101) in mouse models of CNV, OIR and GFS, thus confirming its suitability for translational ophthalmological research.

摘要

目的

既往报道关于贝伐单抗(阿瓦斯汀)(一种抗VEGF - A的重组人源化单克隆抗体)在小鼠体内的活性得出了相互矛盾的数据。当前研究旨在进一步探索这种VEGF抑制剂在各种眼部疾病小鼠模型中的应用,并将其与广泛使用的小鼠抗VEGF - R2中和抗体(DC101)进行比较。

方法

使用激光诱导脉络膜新生血管(CNV)、氧诱导视网膜病变(OIR)和青光眼滤过手术(GFS)的小鼠模型来研究贝伐单抗的作用。小鼠接受玻璃体内注射(用于CNV - OIR)或结膜下注射(用于GFS)。在所有模型中,将它们分为两组(每组n = 10)。在第一组中,一只眼睛注射贝伐单抗(1μl;25μg),另一只眼睛作为阴性对照,注射NaCl(1μl;0.9%)。在第二组中,一只眼睛注射DC101(1μl;6.2μg),而对侧眼睛注射同型对照抗体(1C8;4.8μg)。通过临床研究(GFS)以及对血管生成(CD31/FITC - 葡聚糖/H&E)和纤维化(天狼星红)的免疫组织学分析来研究治疗结果。

结果

玻璃体内注射贝伐单抗或DC10后,对血管密度(CNV)和血管生长(OIR)的分析显示出相似的降低。此外,在GFS小鼠模型中,对滤过泡的临床研究以及切片上的CD31染色表明,结膜下注射两种抗体通过减少血管生成同样改善了手术结果(滤过泡面积和存活情况)。而且,天狼星红染色后的形态计量分析显示,给予抑制剂后胶原沉积的减少程度相当。

结论

我们的研究结果一致表明,在CNV、OIR和GFS小鼠模型中,贝伐单抗与小鼠抗VEGF - R2抗体(DC101)一样有效,从而证实了其适用于转化性眼科研究。

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