SDF-1α、VEGF和bevacizumab在增殖性糖尿病視網(wǎng)膜病變繼發(fā)新生血管性青光眼中的作用及機制研究
發(fā)布時間：2018-12-05 20:00
【摘要】： 新生血管性青光眼(neovascular glaucoma, NVG)是一種導(dǎo)致視力破壞的嚴重青光眼,它是由新生血管破壞房水外流通道引起,通常繼發(fā)于眼后段廣泛的缺血性疾病,如增殖性糖尿病性視網(wǎng)膜病變(proliferative diabetic retinopathy, PDR)。血管內(nèi)皮生長因子(vascular endothelial growth factor,VEGF)已被公認在眼內(nèi)新生血管形成過程中起著重要作用。 bevacizumab (Avastin)是抗VEGF的單克隆抗體,目前在眼科已越來越廣泛地被應(yīng)用。最新的臨床研究表明玻璃體腔內(nèi)注射bevacizumab(intravitreal injection of bevacizumab, IVB)在治療眼內(nèi)新生血管性疾病包括新生血管性青光眼方面取得了顯著成果。雖然IVB可以顯著抑制眼內(nèi)新生血管的生成,但是臨床觀察發(fā)現(xiàn)部分患者即使使用了IVB,新生血管仍然在增多,病情仍會繼續(xù)進展。 基質(zhì)細胞衍生因子- 1α(stromal cell derived factor -1α, SDF-1α),α組趨化因子家族的一個新成員,最早從骨髓的基質(zhì)細胞中分離出來,其特異性受體CXCR4廣泛地表達在許多組織和器官上,SDF-1/CXCR4在調(diào)節(jié)免疫和炎癥反應(yīng)、調(diào)控造血、惡性腫瘤細胞的浸潤轉(zhuǎn)移、血管生成等方面發(fā)揮著重要的作用。 為了探討SDF-1α、VEGF和bevacizumab在增殖性糖尿病視網(wǎng)膜病變繼發(fā)新生血管性青光眼中的作用及機制,本研究首先在體外實驗中,通過在體外血管生成檢測和血管內(nèi)皮細胞增殖檢測中加入SDF-1α,觀察SDF-1α在其中的作用;體內(nèi)實驗中,檢測患者玻璃體中SDF-1α水平和患者玻璃體對血管內(nèi)皮細胞增殖的作用。結(jié)果表明SDF-1α在新生血管形成過程中起到了促進作用,并參與了PDR繼發(fā)NVG患者病理性新生血管形成過程。接著對PDR患者玻璃體中bevacizumab和VEGF的含量進行了檢測和分析,以明確bevacizumab在人眼內(nèi)的藥代動力學(xué)情況并為其在臨床的應(yīng)用劑量和使用頻率達到最佳化提供了理論依據(jù)。然后對不同劑量bevacizumab玻璃體腔注射治療眼內(nèi)缺血性疾病繼發(fā)虹膜新生血管及新生血管性青光眼療效進行了分析,為bevacizumab的玻璃體腔最佳給藥劑量提供依據(jù)。進一步,在體外實驗中,通過在毛細血管樣結(jié)構(gòu)形成和血管內(nèi)皮細胞增殖檢測中分別或同時加入VEGF、bevacizumab和SDF-1α,來觀察bevacizumab和SDF-1α之間的關(guān)系,同時檢測患者IVB前后玻璃體中SDF-1α水平和患者玻璃體對血管內(nèi)皮細胞增殖的作用。結(jié)果顯示bevacizumab對SDF-1α促進血管新生作用沒有明顯抑制,患者IVB后玻璃體中SDF-1α水平高,而且能明顯促進血管內(nèi)皮細胞增殖,表明SDF-1α在患者IVB后新生血管形成過程中起著重要作用。最后在體外實驗毛細血管樣結(jié)構(gòu)形成和血管內(nèi)皮細胞增殖檢測中同時加入SDF-1α及其抗體,觀察抗SDF-1α抗體的作用,結(jié)果表明抗SDF-1α抗體對SDF-1α誘導(dǎo)的新生血管形成有抑制作用,這些研究結(jié)果提示了抗SDF-1α抗體在治療缺血性視網(wǎng)膜疾病及IVB治療后病情進展和復(fù)發(fā)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 偽 (stromal cell derived factor 1 偽 (SDF-1 偽), 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 偽, VEGF and bevacizumab in secondary angiogenic glaucoma with proliferative diabetic retinopathy, this study was conducted in vitro. The role of SDF-1 偽 was observed by adding SDF-1 偽 into the in vitro angiogenesis test and vascular endothelial cell proliferation test. The level of SDF-1 偽 in vitreous and the effect of vitreous on the proliferation of vascular endothelial cells were measured in vivo. The results showed that SDF-1 偽 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 偽 was observed by adding VEGF,bevacizumab and SDF-1 偽 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 偽 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 偽. The level of SDF-1 偽 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 偽 plays an important role in the process of neovascularization after IVB. Finally, SDF-1 偽 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 偽 antibody. The results showed that anti SDF-1 偽 antibody could inhibit angiogenesis induced by SDF-1 偽. These results suggested the feasibility of anti SDF-1 偽 antibody in the treatment of ischemic retinal diseases and the progression and recurrence of IVB.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2010
【分類號】：R774.1
本文編號：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 偽 (stromal cell derived factor 1 偽 (SDF-1 偽), 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 偽, VEGF and bevacizumab in secondary angiogenic glaucoma with proliferative diabetic retinopathy, this study was conducted in vitro. The role of SDF-1 偽 was observed by adding SDF-1 偽 into the in vitro angiogenesis test and vascular endothelial cell proliferation test. The level of SDF-1 偽 in vitreous and the effect of vitreous on the proliferation of vascular endothelial cells were measured in vivo. The results showed that SDF-1 偽 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 偽 was observed by adding VEGF,bevacizumab and SDF-1 偽 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 偽 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 偽. The level of SDF-1 偽 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 偽 plays an important role in the process of neovascularization after IVB. Finally, SDF-1 偽 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 偽 antibody. The results showed that anti SDF-1 偽 antibody could inhibit angiogenesis induced by SDF-1 偽. These results suggested the feasibility of anti SDF-1 偽 antibody in the treatment of ischemic retinal diseases and the progression and recurrence of IVB.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2010
【分類號】：R774.1
【參考文獻】
相關(guān)期刊論文 前1條
1 王承艷,苗振川,豐美福;基質(zhì)細胞衍生因子SDF及其受體CXCR4在造血干/祖細胞動員及歸巢過程中的作用[J];中國實驗血液學(xué)雜志;2004年01期
，本文編號：2365394
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