本文選題：VEGF　切入點：白細胞瘀滯　出處：《天津醫(yī)科大學(xué)》2017年博士論文　論文類型：學(xué)位論文

【摘要】：背景:糖尿病視網(wǎng)膜病變(diabetic retinopathy,DR)中重要血管性改變—視網(wǎng)膜血管閉塞與視網(wǎng)膜靜脈阻塞(retinal vein occlusion,RVO)繼發(fā)的視網(wǎng)膜無灌注發(fā)生及缺血性視網(wǎng)膜病變成為成年人致盲重要原因。多項臨床試驗觀察VEGF中和蛋白治療糖尿病性黃斑水腫(diabetic macular edema,DME)與繼發(fā)于RVO的黃斑水腫發(fā)現(xiàn),抑制視網(wǎng)膜VEGF不僅能顯著改善ME,而且能促進部分已閉塞的血管再通,阻止血管閉塞進展、微血管瘤的發(fā)生,提示VEGF可能在視網(wǎng)膜血管閉塞的發(fā)生中作用顯著。而糖尿病誘發(fā)白細胞瘀滯參與視網(wǎng)膜微血管阻塞發(fā)生,因此本課題就VEGF是否可通過誘發(fā)白細胞瘀滯促進視網(wǎng)膜血管可逆性閉塞及其作用機制尚需進一步探討。目的:(1)探討VEGF對視網(wǎng)膜血管內(nèi)白細胞瘀滯誘導(dǎo)作用;(2)觀察VEGF誘發(fā)白細胞瘀滯是否誘發(fā)可逆性視網(wǎng)膜血管閉塞及視網(wǎng)膜缺氧發(fā)生;(3)探討阻斷VEGF是否能夠逆轉(zhuǎn)視網(wǎng)膜血管閉塞;(4)探討VEGF誘發(fā)白細胞瘀滯的作用機制。方法:(1)C57BL/6鼠玻璃體腔注射不同濃度人VEGF(human VEGF,hVEGF)(0、50、100、200、500、1000ng/μl)后,予rhodamine或者FITC標記刀豆素蛋白(conconavalin,ConA)檢測視網(wǎng)膜血管內(nèi)白細胞黏附,并于熒光顯微鏡下計數(shù)。(2)Tet/opsin/VEGF雙轉(zhuǎn)基因鼠予四環(huán)素誘導(dǎo)視網(wǎng)膜光感受細胞短期內(nèi)過表達較高量hVEGF;Rhodopsin/VEGF轉(zhuǎn)基因鼠于出生后7天光感受細胞慢性持續(xù)性表達低濃度hVEGF,予rhodamine標記ConA標記黏附白細胞并計數(shù)。(3)熒光素鈉血管造影(sodium fluorescein angiography,FA)后眼底照相觀察hVEGF注射、Tet/opsin/VEGF及Rhodopsin/VEGF鼠視網(wǎng)膜血供情況,FITC-ConA灌注后行視網(wǎng)膜hypoxyprobe染色觀察缺氧情況;(4)Tet/opsin/VEGF及Rho/VEGF鼠通過停止四環(huán)素誘導(dǎo)關(guān)閉VEGF表達或應(yīng)用VEGF trap蛋白aflibercept后ConA灌注觀察白細胞黏附,FA觀察視網(wǎng)膜灌注恢復(fù)情況。(5)體外VEGF刺激人視網(wǎng)膜微血管內(nèi)皮細胞(human retinal microvascular endothelial cells,HREC)后實時熒光定量聚合酶鏈反應(yīng)(Quantitative Real Time-Polymerase Chain Reaction,qRT-PCR)檢測黏附分子:細胞間粘附分子1(intercellular cell adhesion molecule-1,ICAM-1)、血管細胞粘附分子1(vascular cell adhesion molecule-1,VCAM-1),選擇素(E-selectin,P-selectin),及NF-κB轉(zhuǎn)錄活性;體內(nèi)qRT-PCR檢測視網(wǎng)膜上述黏附分子及其配體黏附素表達,Western Blot、免疫熒光染色(immunofluorescence assay,IF)檢測視網(wǎng)膜VCAM-1的分布及表達;WB視網(wǎng)膜下轉(zhuǎn)染NF-κB(p65)reportor-luciferase載體檢測視網(wǎng)膜核NF-κB(p65)的表達及其轉(zhuǎn)錄活性。FITC-ConA灌注后視網(wǎng)膜鋪片F(xiàn)4/80、Ly6G免疫熒光檢測黏附白細胞亞型。(6)尾靜脈注射抗VCAM-1抗體及抗VEGFR1抗體后觀察白細胞黏附改變。結(jié)果:(1)玻璃體腔注射50ng以上VEGF 24小時后誘發(fā)視網(wǎng)膜血管大量白細胞瘀滯呈劑量、時間依賴性表現(xiàn)為低劑量VEGF刺激白細胞黏附主要位于分支血管內(nèi);大劑量VEGF刺激白細胞大量瘀滯于擴張靜脈及下游血管內(nèi)。(2)Tet/opsin/VEGF轉(zhuǎn)基因鼠視網(wǎng)膜VEGF表達隨時間增加,血管白細胞瘀滯數(shù)目相應(yīng)增加,且單個白細胞或者呈團塊狀聚集阻塞視網(wǎng)膜血管管腔;四環(huán)素誘導(dǎo)后2天、3天FA觀察到視網(wǎng)膜靜脈明顯擴張、大量視網(wǎng)膜滲漏發(fā)生、及明顯后極部血管閉塞、無灌注發(fā)生;且白細胞黏附處視網(wǎng)膜組織hypoxyprobe染色陽性提示缺氧發(fā)生;Rho/VEGF鼠于出生后20天開始檢測到視網(wǎng)膜白細胞瘀滯發(fā)生于7月達到高峰并維持到15月,且黏附主要發(fā)生在分支血管、血管分叉處,可見單個細胞阻塞血管管腔;FA可見7月、12月鼠視網(wǎng)膜靜脈擴張不明顯,血管排布紊亂,后極部多處小面積無灌注發(fā)生,部分分布于視網(wǎng)膜下新生血管周圍。(3)Tet/opsin/VEGF雙轉(zhuǎn)基因小鼠四環(huán)素誘導(dǎo)后3天FA檢查可見視網(wǎng)膜后極部血管閉塞、小片狀無灌注區(qū)域,而停止誘導(dǎo)14天后繼續(xù)FA造影可見已閉塞血管恢復(fù)灌注,且ConA標記的黏附白細胞數(shù)目較3天時明顯減少;應(yīng)用aflibercept后,部分已閉塞的Rho/VEGF視網(wǎng)膜血管重新開放,血供恢復(fù),同時周圍新生血管也明顯減少;而Tet/opsin/VEGF玻璃體腔注射aflibercept后白細胞黏附較對照組明顯下降,FA可見視網(wǎng)膜血管形態(tài)基本正常、無明顯滲漏及視網(wǎng)膜無灌注發(fā)生。(4)體外VEGF刺激HRECs4小時后,qPCR檢測到VCAM-1、ICAM-1、E-selectin mRNA表達增加,其他黏附分子無明顯改變;NF-κB(p65)活性實驗檢測其轉(zhuǎn)錄活性較PBS刺激組明顯升高。(5)視網(wǎng)膜qPCR結(jié)果發(fā)現(xiàn)VEGF注射后24小時、Tet/opsin/VEGF四環(huán)素誘導(dǎo)后3天VCAM-1 mRNA水平表達升高,其他黏附分子無明顯變化;同時IF發(fā)現(xiàn)到VEGF注射后大量VCAM-1表達于表層及內(nèi)核層視網(wǎng)膜血管;WB檢測到Tet/opsin/VEGF鼠高表達VEGF后3天視網(wǎng)膜胞漿蛋白中VCAM-1表達明顯升高且阻斷VCAM-1后視網(wǎng)膜ConA標記黏附白細胞較IgG組明顯減少,同時WB也檢測核蛋白中NF-κB于VEGF表達1天后開始升高并維持提示NF-κB被激活;NF-κB(p65)reportor-luciferase檢測發(fā)現(xiàn)VEGF注射后luciferase活性較PBS注射組明顯升高,提示VEGF啟動NF-κB轉(zhuǎn)錄活性表達,并啟動下游因子VCAM-1表達參與白細胞瘀滯發(fā)生。(6)視網(wǎng)膜鋪片IF檢測到部分ConA標記細胞F4/80陽性提示單核細胞VEGF誘導(dǎo)參與白細胞黏附、少部分表現(xiàn)為Ly6G陽性提示仍有少量中性粒細胞也參與該過程;阻斷VEGFR1后,VEGF誘發(fā)的視網(wǎng)膜血管內(nèi)白細胞瘀滯明顯下降。結(jié)論:1)本研究闡明了視網(wǎng)膜局部VEGF高表達部分能夠通過VEGFR1招募白細胞遷移到視網(wǎng)膜血管網(wǎng),通過激活核轉(zhuǎn)錄因子NF-κB啟動下游因子VCAM-1表達促進白細胞(單核細胞為主)黏附于視網(wǎng)膜血管內(nèi)皮細胞,參與血管阻塞,且部分阻塞為可逆性。2)本研究也充分解釋臨床觀察到的缺血性視網(wǎng)膜病變患者眼內(nèi)注射VEGF中和蛋白治療后出現(xiàn)的已經(jīng)無灌注視網(wǎng)膜血管再灌注及視網(wǎng)膜無灌注進展的減少現(xiàn)象。3)我們研究也表明包括RVO、DR及其他缺血性視網(wǎng)膜病變的病因、病程盡管不同,但是他們均可認為是一類相似疾病即VEGF是加重疾病急劇進展的重要驅(qū)動因子。4)并初步探討一種潛在單獨持續(xù)抑制VEGF或聯(lián)合VEGFR1、VCAM-1可能阻止早期RVO或PDR視網(wǎng)膜血管阻塞及進行性視網(wǎng)膜缺血發(fā)生的方法。
[Abstract]:Background: diabetic retinopathy (diabetic, retinopathy, DR) in the vascular change of retinal vascular occlusion and retinal vein occlusion (retinal vein occlusion, RVO) secondary to retinal non perfusion and ischemic retinopathy as adults to cause blindness. A number of clinical trials on VEGF and protein in the treatment of diabetic macular edema (diabetic macular edema DME), and macular edema secondary to RVO, inhibition of retinal VEGF can not only improve the ME, but also can promote the recanalization of occluded part, prevent blood tube occlusion in micro vascular tumors, suggesting that VEGF may be in retinal vascular occlusion has a significant role. The diabetes induced leukocyte stasis in retinal microvascular obstruction, therefore the issue of whether VEGF can promote blood stasis of white blood cells in retinal blood stagnation reversible closed tube Plug and its mechanism still need to be further explored. Objective: (1) to investigate the induction effect of VEGF on retinal blood white cells in the blood stasis; (2) to observe the VEGF induced leukocyte stasis is induced reversible retinal vascular occlusion and retinal hypoxia; (3) to investigate whether blocking VEGF could reverse (retinal vascular occlusion; 4) to investigate the mechanism of VEGF induced leukocyte stasis. Methods: (1) after intravitreal injection of different concentrations of C57BL/6 (human VEGF, VEGF hVEGF) (0,501002005001000ng/ L), to rhodamine or FITC labeled concanavalin protein (conconavalin, ConA) detection of retinal intravascular leukocyte adhesion, and count in the fluorescence microscope. (2) Tet/opsin/VEGF double transgenic mice with tetracycline induced photoreceptor cells within a short period of over expression of higher levels of hVEGF; Rhodopsin/VEGF transgenic mice at postnatal 7 day feeling expression of chronic persistent Low concentration of hVEGF, with rhodamine labeled ConA labeled leukocyte adhesion and counting. (3) fluorescein angiography (sodium fluorescein angiography, FA) after hVEGF injection for observation of fundus photography, retina blood Tet/opsin/VEGF and Rhodopsin/VEGF rats, FITC-ConA after reperfusion for retinal hypoxia were observed by hypoxyprobe staining; (4) Tet/opsin/VEGF and Rho/VEGF rats by stopping observation of leukocyte adhesion induced by tetracycline ConA perfusion closed VEGF expression or application of VEGF trap protein Aflibercept, FA to observe the retinal perfusion recovery. (5) VEGF in vitro stimulation of human retinal microvascular endothelial cells (human retinal microvascular endothelial cells, HREC) by real-time fluorescence quantitative polymerase chain reaction (Quantitative Real Time-Polymerase Chain Reaction, qRT-PCR) detection adhesion molecule: intercellular adhesion molecule 1 (intercellular cell adhesion molecule-1, IC AM-1), vascular cell adhesion molecule 1 (vascular cell adhesion molecule-1, VCAM-1), P-selectin (E-selectin, P-selectin), and NF- kappa B transcription activity; qRT-PCR in the detection of retinal adhesion molecules and their ligands adhesin expression, Western Blot, immunofluorescence staining (immunofluorescence assay IF) to detect the expression and distribution of VCAM-1 in retina WB; subretinal transfection of NF- kappa B (p65) reportor-luciferase carrier detection of retinal nuclear NF- kappa B (p65).FITC-ConA expression and transcription activity of retinal flatmount after reperfusion F4/80, Ly6G immunofluorescence adhesion of leukocyte subpopulations. (6) intravenous injection of anti VCAM-1 antibody and anti VEGFR1 antibody were observed after leukocyte adhesion changes results: (1) intravitreal injection of 50NG VEGF more than 24 hours after a large number of white blood cells induced by retinal vascular stasis in a dose, time-dependent performance for low dose VEGF stimulated leukocyte adhesion and To be located in the branch vessels; high dose VEGF stimulated a large number of white blood cells in venous stasis and expansion of downstream vessels. (2) retinal VEGF transgenic mice Tet/opsin/VEGF expression increased with time, the number of white blood cells and blood stasis increase, single white blood cells or in clumps aggregation of retinal vascular lumen obstruction; 2 days after induction of tetracycline 3 days, FA was observed in the occurrence of a large number of dilated retinal vein, retinal leakage, and obviously the posterior pole of the vascular occlusion, no perfusion occurred; and retinal leukocyte adhesion hypoxyprobe positive staining suggested that hypoxia occurred; Rho/VEGF rats in 20 days after birth to detect retinal leukocyte stasis occurred in July and reached the peak in 15 months, and the adhesion occurs mainly in vascular branches, vascular bifurcation, visible single cells blocking the lumen of blood vessels; FA visible in July, December in retinal vein dilation of blood is not obvious. Tube arrangement disorder, the posterior pole of the multiple small area without perfusion, located on subretinal neovascularization around. (3) Tet/opsin/VEGF double transgenic mice induced by tetracycline in 3 days after the FA examination showed posterior pole retinal vascular occlusion, patchy non perfusion area, stop induced 14 days later to continue FA angiography revealed occlusion vascular perfusion recovery, and the number of leukocyte adhesion to ConA markers compared with 3 days reduced; after the application of Aflibercept, has been part of Rho/VEGF occlusion of the retinal vessels reopened, restore blood supply, but also significantly reduce neovascularization; while Tet/opsin/VEGF intravitreal injection of Aflibercept after leukocyte adhesion was lower than the control group, visible form the retinal FA is basically normal, no obvious leakage and retinal non perfusion. (4) HRECs4 hours after VEGF stimulation in vitro, qPCR detected VCAM-1, ICAM-1, E-selectin increased the expression of mRNA Plus, other adhesion molecules had no obvious change; NF- kappa B (p65) activity test of its transcriptional activity than PBS stimulation group increased significantly. (5) retinal qPCR results showed that 24 hours after VEGF injection, 3 days VCAM-1 mRNA Tet/opsin/VEGF induced by tetracycline after elevated expression of other adhesion molecules has no obvious change; at the same time to find IF after the injection of VEGF, a high expression of VCAM-1 in the surface and inner retinal vessels; high expression of WB Tet/opsin/VEGF was detected in the retinas of VCAM-1 3 cytoplasmic protein expression was significantly increased and the blocking of VCAM-1 retinal ConA labeled leukocyte adhesion was significantly reduced compared to the IgG VEGF, and WB detection of nuclear protein NF- kappa B expression after 1 days increase and maintain that NF- kappa B was activated in VEGF; NF- kappa B (p65) reportor-luciferase detected VEGF after injection of luciferase activity compared with PBS injection group was significantly increased, suggesting that VEGF promoter NF- kappa B transcription activity table Up, and start the downstream factor of VCAM-1 expression is involved in leukocyte stasis. (6) retinal flatmount IF detected ConA labeled cells of F4/80 positive mononuclear cells induced by VEGF that involved in leukocyte adhesion, few showed positive Ly6G indicates that there are still a few neutrophils are involved in the process; the blocking of VEGFR1, retina the white cells in the VEGF induced vascular stasis decreased significantly. Conclusion: 1) the results of this study demonstrated the high expression of VEGF through VEGFR1 local retinal recruitment of leukocyte migration into retinal vascular network, through the activation of nuclear factor kappa B NF- and downstream factor VCAM-1 expression promote white blood cells (mononuclear cells) in retinal adhesion participate in vascular endothelial cells, vascular obstruction, and partial obstruction of reversible.2) this study also fully explain the ischemic retinopathy in patients with intraocular injection of VEGF and protein was observed after clinical treatment There has been no perfusion of retinal vascular reperfusion and retinal non perfusion progress reduce the phenomenon of.3) our study also showed that including RVO, DR and other causes of ischemic retinopathy, despite the different course, but they can be considered to be a kind of disease that is similar to VEGF with disease progression dramatically important driving factor.4) and preliminary to explore the potential of a single sustained suppression of VEGF or VCAM-1 combined with VEGFR1, RVO or PDR may prevent early retinal vascular occlusion and method of retinal ischemia occurred.

【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R774.1;R587.2

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