SDF-1α、VEGF和bevacizumab在增殖性糖尿病视网膜病变继发新生血管性青光眼中的作用及机制研究
发布时间：2018-12-05 20:00
【摘要】： 新生血管性青光眼(neovascular glaucoma, NVG)是一种导致视力破坏的严重青光眼,它是由新生血管破坏房水外流通道引起,通常继发于眼后段广泛的缺血性疾病,如增殖性糖尿病性视网膜病变(proliferative diabetic retinopathy, PDR)。血管内皮生长因子(vascular endothelial growth factor,VEGF)已被公认在眼内新生血管形成过程中起着重要作用。 bevacizumab (Avastin)是抗VEGF的单克隆抗体,目前在眼科已越来越广泛地被应用。最新的临床研究表明玻璃体腔内注射bevacizumab(intravitreal injection of bevacizumab, IVB)在治疗眼内新生血管性疾病包括新生血管性青光眼方面取得了显著成果。虽然IVB可以显著抑制眼内新生血管的生成,但是临床观察发现部分患者即使使用了IVB,新生血管仍然在增多,病情仍会继续进展。 基质细胞衍生因子- 1α(stromal cell derived factor -1α, SDF-1α),α组趋化因子家族的一个新成员,最早从骨髓的基质细胞中分离出来,其特异性受体CXCR4广泛地表达在许多组织和器官上,SDF-1/CXCR4在调节免疫和炎症反应、调控造血、恶性肿瘤细胞的浸润转移、血管生成等方面发挥着重要的作用。 为了探讨SDF-1α、VEGF和bevacizumab在增殖性糖尿病视网膜病变继发新生血管性青光眼中的作用及机制,本研究首先在体外实验中,通过在体外血管生成检测和血管内皮细胞增殖检测中加入SDF-1α,观察SDF-1α在其中的作用;体内实验中,检测患者玻璃体中SDF-1α水平和患者玻璃体对血管内皮细胞增殖的作用。结果表明SDF-1α在新生血管形成过程中起到了促进作用,并参与了PDR继发NVG患者病理性新生血管形成过程。接着对PDR患者玻璃体中bevacizumab和VEGF的含量进行了检测和分析,以明确bevacizumab在人眼内的药代动力学情况并为其在临床的应用剂量和使用频率达到最佳化提供了理论依据。然后对不同剂量bevacizumab玻璃体腔注射治疗眼内缺血性疾病继发虹膜新生血管及新生血管性青光眼疗效进行了分析,为bevacizumab的玻璃体腔最佳给药剂量提供依据。进一步,在体外实验中,通过在毛细血管样结构形成和血管内皮细胞增殖检测中分别或同时加入VEGF、bevacizumab和SDF-1α,来观察bevacizumab和SDF-1α之间的关系,同时检测患者IVB前后玻璃体中SDF-1α水平和患者玻璃体对血管内皮细胞增殖的作用。结果显示bevacizumab对SDF-1α促进血管新生作用没有明显抑制,患者IVB后玻璃体中SDF-1α水平高,而且能明显促进血管内皮细胞增殖,表明SDF-1α在患者IVB后新生血管形成过程中起着重要作用。最后在体外实验毛细血管样结构形成和血管内皮细胞增殖检测中同时加入SDF-1α及其抗体,观察抗SDF-1α抗体的作用,结果表明抗SDF-1α抗体对SDF-1α诱导的新生血管形成有抑制作用,这些研究结果提示了抗SDF-1α抗体在治疗缺血性视网膜疾病及IVB治疗后病情进展和复发病例中的可行性。
[Abstract]:Neovascularization glaucoma (neovascular glaucoma, NVG) is a severe visual impairment glaucoma caused by the destruction of the aqueous humor outflow channel by the neovascularization, usually secondary to a wide range of ischemic diseases in the posterior segment of the eye. For example, proliferative diabetic retinopathy (proliferative diabetic retinopathy, PDR).) Vascular endothelial growth factor (vascular endothelial growth factor,VEGF) has been recognized to play an important role in intraocular angiogenesis. Bevacizumab (Avastin) is a monoclonal antibody against VEGF and has been widely used in ophthalmology. Recent clinical studies have shown that intravitreal injection of bevacizumab (intravitreal injection of bevacizumab, IVB) has achieved significant results in the treatment of intraocular neovascular diseases including neovascular glaucoma. Although IVB can significantly inhibit intraocular neovascularization, clinical observation shows that some patients will continue to progress even though the number of IVB, neovascularization is still increasing. Stromal cell derived factor-1 伪 (stromal cell derived factor 1 伪 (SDF-1 伪), a new member of a family of chemokines, was first isolated from bone marrow stromal cells and its specific receptor CXCR4 was widely expressed in many tissues and organs. SDF-1/CXCR4 plays an important role in regulating immune and inflammatory response, regulating hematopoiesis, invasion and metastasis of malignant tumor cells, angiogenesis and so on. To investigate the role and mechanism of SDF-1 伪, VEGF and bevacizumab in secondary angiogenic glaucoma with proliferative diabetic retinopathy, this study was conducted in vitro. The role of SDF-1 伪 was observed by adding SDF-1 伪 into the in vitro angiogenesis test and vascular endothelial cell proliferation test. The level of SDF-1 伪 in vitreous and the effect of vitreous on the proliferation of vascular endothelial cells were measured in vivo. The results showed that SDF-1 伪 played a promoting role in the process of neovascularization and was involved in the pathological angiogenesis in patients with NVG secondary to PDR. Then the contents of bevacizumab and VEGF in the vitreous of PDR patients were detected and analyzed in order to determine the pharmacokinetics of bevacizumab in human eyes and to provide a theoretical basis for optimizing the dosage and frequency of clinical application of bevacizumab. Then the effect of intravitreal injection of different doses of bevacizumab on iris neovascularization and neovascular glaucoma secondary to intraocular ischemic diseases was analyzed, which provided the basis for the best dosage of bevacizumab in vitreous cavity. Furthermore, in vitro, the relationship between bevacizumab and SDF-1 伪 was observed by adding VEGF,bevacizumab and SDF-1 伪 in capillary like structure formation and vascular endothelial cell proliferation, respectively, or at the same time. At the same time, the level of SDF-1 伪 in the vitreous before and after IVB and the effect of vitreous body on the proliferation of vascular endothelial cells were measured. The results showed that bevacizumab had no obvious inhibition on the angiogenesis of SDF-1 伪. The level of SDF-1 伪 in the vitreous of patients with IVB was high, and the proliferation of vascular endothelial cells was obviously promoted. The results suggest that SDF-1 伪 plays an important role in the process of neovascularization after IVB. Finally, SDF-1 伪 and its antibody were added to the experimental capillary like structure formation and vascular endothelial cell proliferation in vitro to observe the effect of anti SDF-1 伪 antibody. The results showed that anti SDF-1 伪 antibody could inhibit angiogenesis induced by SDF-1 伪. These results suggested the feasibility of anti SDF-1 伪 antibody in the treatment of ischemic retinal diseases and the progression and recurrence of IVB.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2010
【分类号】：R774.1
本文编号：2365394
[Abstract]:Neovascularization glaucoma (neovascular glaucoma, NVG) is a severe visual impairment glaucoma caused by the destruction of the aqueous humor outflow channel by the neovascularization, usually secondary to a wide range of ischemic diseases in the posterior segment of the eye. For example, proliferative diabetic retinopathy (proliferative diabetic retinopathy, PDR).) Vascular endothelial growth factor (vascular endothelial growth factor,VEGF) has been recognized to play an important role in intraocular angiogenesis. Bevacizumab (Avastin) is a monoclonal antibody against VEGF and has been widely used in ophthalmology. Recent clinical studies have shown that intravitreal injection of bevacizumab (intravitreal injection of bevacizumab, IVB) has achieved significant results in the treatment of intraocular neovascular diseases including neovascular glaucoma. Although IVB can significantly inhibit intraocular neovascularization, clinical observation shows that some patients will continue to progress even though the number of IVB, neovascularization is still increasing. Stromal cell derived factor-1 伪 (stromal cell derived factor 1 伪 (SDF-1 伪), a new member of a family of chemokines, was first isolated from bone marrow stromal cells and its specific receptor CXCR4 was widely expressed in many tissues and organs. SDF-1/CXCR4 plays an important role in regulating immune and inflammatory response, regulating hematopoiesis, invasion and metastasis of malignant tumor cells, angiogenesis and so on. To investigate the role and mechanism of SDF-1 伪, VEGF and bevacizumab in secondary angiogenic glaucoma with proliferative diabetic retinopathy, this study was conducted in vitro. The role of SDF-1 伪 was observed by adding SDF-1 伪 into the in vitro angiogenesis test and vascular endothelial cell proliferation test. The level of SDF-1 伪 in vitreous and the effect of vitreous on the proliferation of vascular endothelial cells were measured in vivo. The results showed that SDF-1 伪 played a promoting role in the process of neovascularization and was involved in the pathological angiogenesis in patients with NVG secondary to PDR. Then the contents of bevacizumab and VEGF in the vitreous of PDR patients were detected and analyzed in order to determine the pharmacokinetics of bevacizumab in human eyes and to provide a theoretical basis for optimizing the dosage and frequency of clinical application of bevacizumab. Then the effect of intravitreal injection of different doses of bevacizumab on iris neovascularization and neovascular glaucoma secondary to intraocular ischemic diseases was analyzed, which provided the basis for the best dosage of bevacizumab in vitreous cavity. Furthermore, in vitro, the relationship between bevacizumab and SDF-1 伪 was observed by adding VEGF,bevacizumab and SDF-1 伪 in capillary like structure formation and vascular endothelial cell proliferation, respectively, or at the same time. At the same time, the level of SDF-1 伪 in the vitreous before and after IVB and the effect of vitreous body on the proliferation of vascular endothelial cells were measured. The results showed that bevacizumab had no obvious inhibition on the angiogenesis of SDF-1 伪. The level of SDF-1 伪 in the vitreous of patients with IVB was high, and the proliferation of vascular endothelial cells was obviously promoted. The results suggest that SDF-1 伪 plays an important role in the process of neovascularization after IVB. Finally, SDF-1 伪 and its antibody were added to the experimental capillary like structure formation and vascular endothelial cell proliferation in vitro to observe the effect of anti SDF-1 伪 antibody. The results showed that anti SDF-1 伪 antibody could inhibit angiogenesis induced by SDF-1 伪. These results suggested the feasibility of anti SDF-1 伪 antibody in the treatment of ischemic retinal diseases and the progression and recurrence of IVB.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2010
【分类号】：R774.1
【参考文献】
相关期刊论文 前1条
1 王承艳,苗振川,丰美福;基质细胞衍生因子SDF及其受体CXCR4在造血干/祖细胞动员及归巢过程中的作用[J];中国实验血液学杂志;2004年01期
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