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
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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。
Neovascular glaucoma (NVG) is a severe form of glaucoma with devastating visual outcome attributed to new blood vessels obstructing aqueous humor outflow, usually secondary to widespread posterior segment ischemia such as proliferative diabetic retinopathy (PDR), central retinal vein occlusion (CRVO) and ocular ischemic syndrome (OIS) et al. Angiogenesis is a physiologic process that involves endothelial cell proliferation, migration, and maturation, and sometimes plays an important role in ocular diseases such as PDR, CRVO, and NVG. Several angiogenic growth factors have been reported to contribute to pathologic angiogenesis. Of these, vascular endothelial growth factor (VEGF) has been shown to be a key molecule in promoting ocular neovascularization.
Bevacizumab (Avastin) is a full-length humanized anti-VEGF monoclonal antibody that is approved for use as an antiangiogenetic agent for metastatic colorectal cancer. It has been increasingly used as an off-label drug in ophthalmology. Recent clinical studies have shown that intravitreal injections of bevacizumab (IVB) have had excellent results in the treatment of angiogenetic pathologies, including neovascular glaucoma.
Although IVB may provide great benefits to halt neovascular activities in a variety of intraocular neovascular pathologies, advancement of neovascular activities may continue even after IVB. A recent study reported that IVB could not prevent re-bleeding in eyes undergoing IVB followed by pars plana vitrectomy to treat diabetic vitreous hemorrhage. We presume that there are other cytokines/chemokines that may have effects to ocular angiogenesis including stromal cell–derived factor–1α(SDF-1α).
SDF-1α, a member of the CXC chemokine family, is a potent chemoattractant for mature mononuclear leukocytes, as well as hematopoietic stem and progenitor cells, and mediates its effects through the chemokine receptor CXCR4. SDF-1 has been reported to enhance adult angiogenesis induced by VEGF, by recruiting haemopoietic stem cells (HSCs). It has been shown to be both necessary and sufficient to promote proliferative retinopathy, and to be present at high concentrations in the vitreous of patients with PDR, retinal vein occlusion (ROV) and retinopathy of prematurity (ROP).
To evaluate the role and mechanism of SDF-1αand VEGF and bevacizumab in NVG secondary to PDR, firstly we studied the role and correlation of SDF-1αand VEGF in NVG secondary to PDR. The role of SDF-1αand VEGF in the migration, proliferation and differentiation of human umbilical vascular endothelial cells (HUVECs) was evaluated by tube-like and capillary-like formation assay and 5′-bromo-2′-deoxyuridine (BrdU) incorporation in vitro. The vitreous samples from patients with NVG secondary to PDR were measured for concentrations of SDF-1αand VEGF by enzyme-linked immunosorbent assay. The correlation of the vitreous levels of SDF-1αand VEGF was analyzed. Secondly, the vitreous levels of bevacizumab and VEGF in patients with NVG secondary to PDR were measured by ELISA, to optimize reinjection intervals to avoid overdosing and underdosing. Bevacizumab enzyme-linked immunosorbent assay standard curve was obtained. Serial dilutions of bevacizumab were measured to calibrate the assay. The vitreous concentrations of VEGF and bevacizumab were assayed by ELISA.The correlation of the vitreous concentrations of VEGF and bevacizumab and the time after IVB and intraocular pharmacokinetics of bevacizumab were analyzed. Thirdly, the effects of different doses of IVB on ischemic retinal diseases were evaluated to optimize intravitreal injection dose. The concentration of VEGF in aqueous humor before IVB was measured by ELISA. The correlation of the concentration of VEGF in aqueous humor and intraocular pressure (IOP) before IVB were analyzed. The concentration of VEGF in aqueous humor and IOP was compared before and after the different dose of IVB. Finally, the role of SDF-1αafter IVB in patients with NVG secondary to PDR was evaluated. The role and correlation of SDF-1α, anti- SDF-1αantibody and bevacizumab in the migration, proliferation and differentiation of HUVECs was evaluated by capillary-like formation assay and BrdU incorporation in vitro. The effects of the vitreous samples on HUVECs proliferation were assayed by BrdU incorporation. Vitreous concentrations of VEGF and SDF-1αwere compared between the patients with NVG and without NVG (control group) and among bevacizumab 1mg group, bevacizumab 0.1mg group and no IVB group.
In the current study, the results showed that HUVEC tube-like and capillary-like formation was significantly enhanced by SDF-1αand VEGF (P﹤0.05) . All of SDF 10ng/ml, SDF 100ng/ml and SDF 1000ng/ml group significantly promoted HUVECs proliferation (P<0.05); SDF 100ng/ml group was strongest and SDF 100ng/ml group was weakest in SDF 10ng/ml, SDF 100ng/ml and SDF 1000ng/ml group. The OD value of VEGF 100ng/ml + SDF 100ng/ml group was significantly higer than VEGF 100ng/ml group (P<0.05). In vitreous sample measurements, both VEGF and SDF-1αlevels in patients with NVG were significantly higher than those in patients without NVG (P<0.01). No significant correlation between VEGF and SDF-1αin vitreous was noted (r=0.41, P>0.05). The concentration of bevacizumab (the range 0-100ng/ml) exhibited a positive correlation with OD value by ELISA. The vitreous concentration of VEGF in patients with PDR showed a negative correlation with the bevacizumab concentration (R=0.96, P<0.001) and a positive correlation with the time after IVB (R=0.96, P<0.001). The vitreous concentration of bevacizumab showed a negative correlation with the time after IVB (R=0.98, P<0.001). The peak concentration (127.1ug/ml) of bevacizumab was observed on the first day after IVB. Estimated half-time (t1/2) of bevacizumab elimination from vitreous was 10.2 days. The average value of VEGF concentration in aqueous humor before IVB (control group 150.1pg/ml; iris neovascularization, INV group 1058.3pg/ml; open-angle neovascular glaucoma, O-NVG group 5856.2pg/ml; closed-angle neovascular glaucoma, C-NVG group 19153.2pg/ml) was obtained. The VEGF concentration of C-NVG group was significantly higher than control, INV and O-NVG group. Intraocular pressure (IOP) showed a positive correlation with the concentration of VEGF in aqueous humor. The average value of VEGF concentration in aqueous humor before and after different doses of IVB (1.0mg group before IVB, 14978.3pg/ml; 0.1mg group before IVB, 5718.2pg/ml; 1.0mg group after IVB, 28.9 pg/ml; 0.1mg group after IVB, 22.2pg/ml) was obtained. There was no difference between 1.0mg and 0.1mg group in the variation of before and after IVB (P=0.140). The VEGF concentration of 1.0mg and 0.1mg groups after IVB in aqueous humor was both lower than control group (150pg/ml). The average value of IOP before and after different doses of IVB (1.0mg group before IVB, 35mmHg; 0.1mg group before IVB, 34mmHg; 1.0mg group after IVB, 23mmHg; 0.1mg group after IVB, 24mmHg) was obtained. There was no difference between IOP of 1.0mg and 0.1mg groups before and after IVB (P=0.892). The enhancement of recombinant human VEGF (10 ng/ml) in HUVECs capillary-like formation was inhibited by treatment with bevacizumab (10 ug/ml). However, the enhancement of recombinant human SDF-1αwas not inhibited by treatment with bevacizumab (10ug/ml). SDF-1αpromoted HUVECs capillary-like formation with bevacizumab (P<0.05). However, the enhancement of recombinant human SDF-1αwas inhibited by treatment with anti- SDF-1αantibody in HUVECs capillary-like formation and proliferation (P<0.05). There was no difference between the treatments with VEGF 100ng/ml and bevacizumab 100ug/ml and the control group in HUVECs proliferation (P>0.05).The treatment with VEGF and bevacizumab and SDF-1αpromoted HUVECs proliferation (P<0.05). The promotion of the treatment with VEGF and bevacizumab and SDF-1αwas inhibited by anti- SDF-1αantibody (P<0.05). Both the vitreous samples before and after IVB in NVG significantly promoted HUVECs proliferation (P<0.01). The promotion of vitreous samples after IVB was weaker than those before IVB (P<0.05). Both VEGF and SDF-1αlevels in patients with NVG were significantly higher than those in patients without NVG (control group) (P<0.05). The vitreous level of VEGF significantly decreased after IVB (P<0.05). The vitreous level of SDF-1αin patients with NVG was higher than control group after IVB (P<0.05), although the vitreous level of SDF-1αdecreased.
In conclusion, the present study demonstrates that both SDF-1αand VEGF may enhance angiogenesis by the promotion of migration and proliferation of HUVECs, and participate in promoting neovascularization in patients with NVG secondary to PDR. We obtain the standard curve of bevacizumab enzyme-linked immunosorbent assay. The vitreous half-life of 1.0 mg intravitreally injected bevacizumab in patients with PDR is 10.2 days. The vitreous concentration of bevacizumab in patients with PDR shows a negative correlation with the time after IVB. The vitreous concentration of VEGF in patients with PDR shows a negative correlation with the bevacizumab concentration and a positive correlation with the time after IVB. The intravitreally injected bevacizumab may be decreased to 0.1mg from 1.0 mg as preoperative adjunctive therapy with invariable therapeutic effect. SDF-1αmay participate in promoting neovascularization in patients with NVG secondary to PDR and sufficiently to facilitate the advancement of neovascular activities even after IVB.
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。
Neovascular glaucoma (NVG) is a severe form of glaucoma with devastating visual outcome attributed to new blood vessels obstructing aqueous humor outflow, usually secondary to widespread posterior segment ischemia such as proliferative diabetic retinopathy (PDR), central retinal vein occlusion (CRVO) and ocular ischemic syndrome (OIS) et al. Angiogenesis is a physiologic process that involves endothelial cell proliferation, migration, and maturation, and sometimes plays an important role in ocular diseases such as PDR, CRVO, and NVG. Several angiogenic growth factors have been reported to contribute to pathologic angiogenesis. Of these, vascular endothelial growth factor (VEGF) has been shown to be a key molecule in promoting ocular neovascularization.
Bevacizumab (Avastin) is a full-length humanized anti-VEGF monoclonal antibody that is approved for use as an antiangiogenetic agent for metastatic colorectal cancer. It has been increasingly used as an off-label drug in ophthalmology. Recent clinical studies have shown that intravitreal injections of bevacizumab (IVB) have had excellent results in the treatment of angiogenetic pathologies, including neovascular glaucoma.
Although IVB may provide great benefits to halt neovascular activities in a variety of intraocular neovascular pathologies, advancement of neovascular activities may continue even after IVB. A recent study reported that IVB could not prevent re-bleeding in eyes undergoing IVB followed by pars plana vitrectomy to treat diabetic vitreous hemorrhage. We presume that there are other cytokines/chemokines that may have effects to ocular angiogenesis including stromal cell–derived factor–1α(SDF-1α).
SDF-1α, a member of the CXC chemokine family, is a potent chemoattractant for mature mononuclear leukocytes, as well as hematopoietic stem and progenitor cells, and mediates its effects through the chemokine receptor CXCR4. SDF-1 has been reported to enhance adult angiogenesis induced by VEGF, by recruiting haemopoietic stem cells (HSCs). It has been shown to be both necessary and sufficient to promote proliferative retinopathy, and to be present at high concentrations in the vitreous of patients with PDR, retinal vein occlusion (ROV) and retinopathy of prematurity (ROP).
To evaluate the role and mechanism of SDF-1αand VEGF and bevacizumab in NVG secondary to PDR, firstly we studied the role and correlation of SDF-1αand VEGF in NVG secondary to PDR. The role of SDF-1αand VEGF in the migration, proliferation and differentiation of human umbilical vascular endothelial cells (HUVECs) was evaluated by tube-like and capillary-like formation assay and 5′-bromo-2′-deoxyuridine (BrdU) incorporation in vitro. The vitreous samples from patients with NVG secondary to PDR were measured for concentrations of SDF-1αand VEGF by enzyme-linked immunosorbent assay. The correlation of the vitreous levels of SDF-1αand VEGF was analyzed. Secondly, the vitreous levels of bevacizumab and VEGF in patients with NVG secondary to PDR were measured by ELISA, to optimize reinjection intervals to avoid overdosing and underdosing. Bevacizumab enzyme-linked immunosorbent assay standard curve was obtained. Serial dilutions of bevacizumab were measured to calibrate the assay. The vitreous concentrations of VEGF and bevacizumab were assayed by ELISA.The correlation of the vitreous concentrations of VEGF and bevacizumab and the time after IVB and intraocular pharmacokinetics of bevacizumab were analyzed. Thirdly, the effects of different doses of IVB on ischemic retinal diseases were evaluated to optimize intravitreal injection dose. The concentration of VEGF in aqueous humor before IVB was measured by ELISA. The correlation of the concentration of VEGF in aqueous humor and intraocular pressure (IOP) before IVB were analyzed. The concentration of VEGF in aqueous humor and IOP was compared before and after the different dose of IVB. Finally, the role of SDF-1αafter IVB in patients with NVG secondary to PDR was evaluated. The role and correlation of SDF-1α, anti- SDF-1αantibody and bevacizumab in the migration, proliferation and differentiation of HUVECs was evaluated by capillary-like formation assay and BrdU incorporation in vitro. The effects of the vitreous samples on HUVECs proliferation were assayed by BrdU incorporation. Vitreous concentrations of VEGF and SDF-1αwere compared between the patients with NVG and without NVG (control group) and among bevacizumab 1mg group, bevacizumab 0.1mg group and no IVB group.
In the current study, the results showed that HUVEC tube-like and capillary-like formation was significantly enhanced by SDF-1αand VEGF (P﹤0.05) . All of SDF 10ng/ml, SDF 100ng/ml and SDF 1000ng/ml group significantly promoted HUVECs proliferation (P<0.05); SDF 100ng/ml group was strongest and SDF 100ng/ml group was weakest in SDF 10ng/ml, SDF 100ng/ml and SDF 1000ng/ml group. The OD value of VEGF 100ng/ml + SDF 100ng/ml group was significantly higer than VEGF 100ng/ml group (P<0.05). In vitreous sample measurements, both VEGF and SDF-1αlevels in patients with NVG were significantly higher than those in patients without NVG (P<0.01). No significant correlation between VEGF and SDF-1αin vitreous was noted (r=0.41, P>0.05). The concentration of bevacizumab (the range 0-100ng/ml) exhibited a positive correlation with OD value by ELISA. The vitreous concentration of VEGF in patients with PDR showed a negative correlation with the bevacizumab concentration (R=0.96, P<0.001) and a positive correlation with the time after IVB (R=0.96, P<0.001). The vitreous concentration of bevacizumab showed a negative correlation with the time after IVB (R=0.98, P<0.001). The peak concentration (127.1ug/ml) of bevacizumab was observed on the first day after IVB. Estimated half-time (t1/2) of bevacizumab elimination from vitreous was 10.2 days. The average value of VEGF concentration in aqueous humor before IVB (control group 150.1pg/ml; iris neovascularization, INV group 1058.3pg/ml; open-angle neovascular glaucoma, O-NVG group 5856.2pg/ml; closed-angle neovascular glaucoma, C-NVG group 19153.2pg/ml) was obtained. The VEGF concentration of C-NVG group was significantly higher than control, INV and O-NVG group. Intraocular pressure (IOP) showed a positive correlation with the concentration of VEGF in aqueous humor. The average value of VEGF concentration in aqueous humor before and after different doses of IVB (1.0mg group before IVB, 14978.3pg/ml; 0.1mg group before IVB, 5718.2pg/ml; 1.0mg group after IVB, 28.9 pg/ml; 0.1mg group after IVB, 22.2pg/ml) was obtained. There was no difference between 1.0mg and 0.1mg group in the variation of before and after IVB (P=0.140). The VEGF concentration of 1.0mg and 0.1mg groups after IVB in aqueous humor was both lower than control group (150pg/ml). The average value of IOP before and after different doses of IVB (1.0mg group before IVB, 35mmHg; 0.1mg group before IVB, 34mmHg; 1.0mg group after IVB, 23mmHg; 0.1mg group after IVB, 24mmHg) was obtained. There was no difference between IOP of 1.0mg and 0.1mg groups before and after IVB (P=0.892). The enhancement of recombinant human VEGF (10 ng/ml) in HUVECs capillary-like formation was inhibited by treatment with bevacizumab (10 ug/ml). However, the enhancement of recombinant human SDF-1αwas not inhibited by treatment with bevacizumab (10ug/ml). SDF-1αpromoted HUVECs capillary-like formation with bevacizumab (P<0.05). However, the enhancement of recombinant human SDF-1αwas inhibited by treatment with anti- SDF-1αantibody in HUVECs capillary-like formation and proliferation (P<0.05). There was no difference between the treatments with VEGF 100ng/ml and bevacizumab 100ug/ml and the control group in HUVECs proliferation (P>0.05).The treatment with VEGF and bevacizumab and SDF-1αpromoted HUVECs proliferation (P<0.05). The promotion of the treatment with VEGF and bevacizumab and SDF-1αwas inhibited by anti- SDF-1αantibody (P<0.05). Both the vitreous samples before and after IVB in NVG significantly promoted HUVECs proliferation (P<0.01). The promotion of vitreous samples after IVB was weaker than those before IVB (P<0.05). Both VEGF and SDF-1αlevels in patients with NVG were significantly higher than those in patients without NVG (control group) (P<0.05). The vitreous level of VEGF significantly decreased after IVB (P<0.05). The vitreous level of SDF-1αin patients with NVG was higher than control group after IVB (P<0.05), although the vitreous level of SDF-1αdecreased.
In conclusion, the present study demonstrates that both SDF-1αand VEGF may enhance angiogenesis by the promotion of migration and proliferation of HUVECs, and participate in promoting neovascularization in patients with NVG secondary to PDR. We obtain the standard curve of bevacizumab enzyme-linked immunosorbent assay. The vitreous half-life of 1.0 mg intravitreally injected bevacizumab in patients with PDR is 10.2 days. The vitreous concentration of bevacizumab in patients with PDR shows a negative correlation with the time after IVB. The vitreous concentration of VEGF in patients with PDR shows a negative correlation with the bevacizumab concentration and a positive correlation with the time after IVB. The intravitreally injected bevacizumab may be decreased to 0.1mg from 1.0 mg as preoperative adjunctive therapy with invariable therapeutic effect. SDF-1αmay participate in promoting neovascularization in patients with NVG secondary to PDR and sufficiently to facilitate the advancement of neovascular activities even after IVB.
引文
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