Pathogenesis of retinopathy of prematurity

Retinopathy of prematurity (ROP) is a blinding disease, initiated by delayed retinal vascular growth after premature birth. There are both oxygen-regulated and non-oxygen-regulated factors, which contribute to both normal vascular development and retinal neovascularization. One important oxygen-regulated factor, critical to both phases of ROP, is vascular endothelial growth factor (VEGF). A critical non oxygen-regulated growth factor is insulin-like growth factor (IGF-1). In knockout mice, lack of IGF-1 prevents normal retinal vascular growth, despite the presence of VEGF, important to vessel development. In vitro, low IGF-1 prevents vascular endothelial growth factor-induced activation of Akt, a kinase critical for vascular endothelial cell survival. Premature infants who develop ROP have lower levels of serum IGF-1 than age-matched infants without disease. CONCLUSION: IGF-1 is critical to normal vascular development. Low IGF-1 predicts ROP and restoration of IGF-1 to normal levels may prevent ROP.     

IGF-1 and retinopathy of prematurity in the preterm infant

BACKGROUND: Retinopathy of prematurity (ROP) continues to be a major cause of blindness in children. Although ablation of the retina reduces the incidence of blindness by suppressing the neovascular phase of ROP, the visual outcomes after treatment are often poor. Preventive therapy is required and will likely come from a better understanding of the pathophysiology of the disease. OBJECTIVES: To study the role of insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) in both the proliferative phase of ROP (phase II) and in the early phase when blood vessels are lost. METHODS: Using both a mouse model of ROP and clinical studies the relationship between IGF-1, VEGF and both vessel loss and vessels proliferation in the retina was studied. RESULTS: IGF-1 is required for maximum VEGF activation of vascular endothelial cell proliferation and survival pathways. IGF-1 levels are deficient after premature birth, setting the stage for retinal vascular loss and ROP. CONCLUSIONS: Restoration of IGF-1 to levels found in utero may help prevent ROP.     

Pathogenesis of retinopathy of prematurity and possible preventive strategies

Retinopathy of Prematurity (ROP) occurs when premature birth interrupts normal retinal vascular development. Postnatal tissue oxygen levels are significantly higher than those present in utero. Oxygen therapy further increases oxygen levels in the developing retina. Hypoxia driven, VEGF mediated, retinal endothelial cell proliferation is reduced. Low IGF-1 levels may also contribute to delayed retinal vascular development. The neural structures of the peripheral avascular retina continue to develop, and become more metabolically active. Complex, as yet poorly understood abnormalities of structural and molecular interactions between immature endothelial cells and immature astrocytes at the anterior "leading edge" of retinal vascular development leads to the development of an ROP ridge. VEGF produced by the hypoxic peripheral retina, along with structural abnormalities of cell relationships within, and at the vitreoretinal interface of the ROP ridge, results in extraretinal angiogenesis - stage 3 ROP. Stage 3 ROP may resolve spontaneously, or may progress to traction retinal detachment and blindness.     

New insights into the development of retinopathy of prematurity – importance of early weight gain

Evidence is accumulating that one of the strongest predictors of retinopathy of prematurity (ROP), in addition to low gestational age, is poor weight gain during the first weeks of life. In infants born preterm, the retina is not fully vascularised. The more premature the child, the larger is the avascular area. In response to hypoxia, vascular endothelial growth factor (VEGF) is secreted. For appropriate VEGF‐induced vessel growth, sufficient levels of insulin‐like growth factor I (IGF‐I) in serum are necessary. IGF‐I is a peptide, related to nutrition supply, which is essential for both pre‐ and post‐natal general growth as well as for growth of the retinal vasculature. In prematurely born infants, serum levels are closely related to gestational age and are lower in more prematurely born infants. At preterm birth the placental supply of nutrients is lost, growth factors are suddenly reduced and general as well as vascular growth slows down or ceases. In addition, the relative hyperoxia of the extra‐uterine milieu, together with supplemental oxygen, causes a regression of already developed retinal vessels. Postnatal growth retardation is a major problem in very preterm infants. Both poor early weight gain and low serum levels of IGF‐I during the first weeks/months of life have been found to be correlated with severity of ROP. Conclusion: This review will focus on the mechanisms leading to ROP by exploring factors responsible for poor early weight gain and abnormal vascularisation of the eye of the preterm infant.     

Retinopathy of prematurity: the disease process, classifications, screening, treatment, and outcomes

Retinopathy of prematurity (ROP) is the cessation of normal eye development and subsequent abnormal vessel growth that occurs exclusively in premature infants. ROP was first discovered in the 1940s and was for two decades the leading cause of blindness in children. Currently, the disease causes about 500 new cases of blindness per year. The severity of the disease increases with decreasing gestational age. The pathogenesis of ROP involves disruption of normal retinal vascularization. Vessel endothelial growth factor, insulin-like growth factor, and oxygen play important roles in its development. ROP is classified using an international classification system that provides direction for screening and treatment of premature infants. Examinations are performed by ophthalmologists, who identify the scope of vascularization, the degree of abnormal vessel growth, and the amount of the eye that is affected. Treatment modalities include cryosurgery and laser photocoagulation. Long-term outcomes include both structural and functional vision problems.     

Association of genetic polymorphisms of vascular endothelial growth factor and risk for proliferative retinopathy of prematurity

The intention of our retrospective study was to determine whether vascular endothelial growth factor (VEGF) genetic polymorphisms are associated with risk for proliferative retinopathy of prematurity (ROP), a condition that is characterized by abnormal retinal neovascularization and can lead to retinal detachment and result in blindness. We enrolled 86 very low birth weight infants (birth weight < or =1500 g) who had been treated with cryo/laser therapy because of the risk for proliferative ROP (treated group). Their VEGF T-460C and G+405C genotypes were determined from dried blood samples and were compared with VEGF genotypes of 115 VLBW infants who were not treated with cryo/laser therapy (untreated group). We found that the allele frequency of VEGF +405C was higher in the treated group than in the untreated group (0.30 versus 0.41; p <0.05). The likelihood of being treated for ROP was higher in heterozygous and homozygous carriers of VEGF +405C alleles [odds ratios adjusted for risk factors of ROP (95% CI): 2.00 (1.02-3.92; p=0.04) and 3.37 (1.17-9.65; p=0.007), respectively]. VEGF -460TT/+405CC haplotype was more prevalent in the treated patients than in the untreated patients (13 of 86 versus 1 of 115; p <0.001), and the association remained significant (p <0.01) even after the adjustment for risk factors of ROP (gestational age, supplemental oxygen therapy, and gender). These findings suggest that the VEGF genotype may be associated with risk for proliferative ROP in VLBW infants.     

HIF-1α干扰RNA抑制早产儿视网膜病小鼠模型视网膜新生血管形成的研究

目的：探讨特异性抑制缺氧诱导因子-1α（HIF-1α）的表达对早产儿视网膜病变（retinopathy of prematurity,ROP）小鼠模型视网膜新生血管的抑制作用。方法：新生C57BL/6J小鼠48只,随机分为实验组和对照组（每组24只）,采用Smith方法制备ROP模型。生后12 d 时实验组玻璃体腔注射HIF-1α特异性小片段干扰RNA 表达载体pSUPERH1-siHIF-1α,同时对照组玻璃体注射空载体。Western blot检测两组小鼠视网膜HIF-1α和血管内皮生长因子（VEGF）的表达,FITC-Dextran荧光照影视网膜铺片和组织切片观察两组小鼠视网膜新生血管和新生血管内皮细胞核数目的差异。结果：实验组小鼠HIF-1α和VEGF的表达较对照组明显下降（P<0.01）;实验组突破视网膜内界膜血管内皮细胞核数较对照组明显减少（P<0.01）。结论：特异性抑制HIF-1α能有效抑制ROP视网膜新生血管的形成。     

Does insulin-like growth factor 1 contribute in red blood cell transfusions to the pathogenesis of retinopathy of prematurity during retinal neovascularization?

BACKGROUND: Red blood cell (RBC) transfusions are associated with the development of retinopathy of prematurity (ROP). During the period of retinal neovascularization a rise of insulin-like growth factor 1 (IGF-1) may trigger rapid growth of new blood vessels. OBJECTIVES: To study endocrine factors in RBC transfusions that might be of importance for ROP. METHODS: IGF-1, IGF-2 and their binding proteins 1-3 (IGFBP-1-3) were determined by radioimmunoassays in 7 very-low-birthweight (VLBW) infants with ROP >or= stage 2 receiving a RBC transfusion, in 10 controls (VLBW infants with ROP 相似文献   

血氧浓度波动致新生大鼠增生性视网膜病变的机制研究

目的制备血氧浓度波动所致新生大鼠增生性视网膜病变的模型,进一步探讨早产儿视网膜病（ROP）的发病机制。方法208只新生SD大鼠,随机分为氧气组和对照组,采用免疫组织化学方法以及RT-PCR技术,观察生后14、18、25d视网膜组织中血管内皮生长因子（VEGF）及Flk-1（VEGFR-2）蛋白和mRNA表达水平。并且在氧气暴露后4d,取幼鼠眼球进行视网膜铺片以及组织石蜡切片HE染色,观察视网膜血管的改变情况。结果（1）氧气组18d幼鼠视网膜无血管面积明显大于空气组（P〈0．05）,且突破内界膜的内皮细胞核数目明显多于空气组（P〈0．05）,表明模型建立成功。（2）氧气组视网膜VEGF及Flk-1在14、18d时表达均明显强于对照组（P〈0．05）,在25d时阳性表达明显减弱,与对照组比较,差异无统计学意义（P〉0．05）。且VEGF及Flk-1在18d时表达最强,与14及25d比较,表达强度差异均有统计学意义（P〈0．05）。（3）氧气组视网膜组织VEGF mRNA及Flk-1 mRNA表达水平在14d、18d均明显高于对照组（P〈0．05）。25d时氧气组VEGF mRNA及Flk-1 mRNA表达水平均下降,与对照组比较,差异无统计学意义（P〉0．05）。结论反复血氧浓度的波动可导致新生大鼠视网膜血管增生性病变,血管增生性视网膜组织中VEGF及Flk-1表达明显增强。本研究还提出,ROP视网膜血管增生过程中存在一种正反馈机制即VEGF与Flk-1的上调协同作用,共同促进视网膜新生血管的形成。     

Retinopathy of prematurity: overview of new global problem

Retinopathy of prematurity (ROP) is a disease characterized by abnormal retinal vasculature in preterm infants. It is an important cause of visual disability in premature infants and although the incidence varies among different countries it is increasing as advances in neonatal care result in improved survival. Oxygen, growth factors like vascular endothelial growth factor, and poor postnatal growth play a significant role in the pathogenesis of ROP. Targeting lower oxygen saturation is associated with a reduction in ROP, but with increased mortality. Screening for ROP varies between centres and countries but generally it includes preterm infants (less than 32 weeks’ gestation) and/or those with a birth weight of less than 1500g. ROP has been recently reclassified as type-1-needing treatment and type-2 ROP needing observation, based on the benefits and treatment efficacy. Laser therapy and anti-VEGF are the two main treatments. Recent reports suggest that anti-VEGF therapy may have better visual outcomes (myopia) and a better safety profile. ROP is a global disease of prematurity and understanding the pathogenesis, course of ROP, preventive strategies, treatment options and outcomes are essential for all healthcare professionals caring for preterm babies. This short article describes the evidence for screening, prevention and treatment options and looks ahead to possible advances in the near future.     

Early Aggressive Parenteral Nutrition Induced High Insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP3) Levels Can Prevent Risk of Retinopathy of Prematurity

Objective

To evaluate early aggressive vs. conservative nutrition and its effect on Retinopathy of Prematurity (ROP) in <32 weeks of gestation neonates.

Methods

A prospective, randomized, clinical study was conducted in NICU with a total of 75 preterm infants. In the intervention group, infants received early aggressive nutrition immediately after birth, in the control group infants were started on conventional parenteral nutrition (PN). Blood samples were obtained for Insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP3) levels before commencement of PN on the first postnatal day, and from week 1 to 6 every week. All the infants were examined for ROP.

Findings

Infants in the early aggressive group had a reduction in the risk of ROP of 5% (2 from 40); the number of infants needed treatment averaged 3.7 (2.7 to 5.2). A total of 11 neonates in the conventional group were detected having ROP (P<0.05). Overall, IGF-I levels were higher in the aggressive PN (APN) vs the conventional PN (CPN). ROP development was higher in the CPN compared to the APN. IGF-1levels were lower in ROP developers compared with non-ROP in the APN group. There was no difference in IGF-I levels in ROP developers versus non-ROP in the CPN group. IGF-1 levels were lower in the CPN group compared with the APN group in the third week in ROP developers. There was a correlation between ROP and IGF-1 levels. Through ROC analysis, IGF-1 was demonstrated as being a sensitive marker for ROP.

Conclusion

IGF-1 levels were higher in the APN group versus the CPN group. This may indicate that IGF-1 levels simply being higher is not enough; rather, that being higher above a cutoff value may prevent ROP.     

Retinopathy of prematurity: New developments bring concern and hope

Blindness from retinopathy of prematurity (ROP) in Australian and New Zealand is an uncommon event although 3% of <31 weeks gestation infants receive treatment for the disease. New world‐wide estimates of the incidence of blindness from ROP are much higher than previously at 20 000 children annually. The impact of severe ROP can be reduced through good evidence‐based care of very preterm infants and careful organisation of eye examinations and follow‐up services. Recent oxygen saturation targeting trial results might mean the adoption of higher targets than formerly in very preterm infants and will require vigilance to ensure all eligible infants are examined appropriately. A true screening examination for acute ROP might involve non‐opthalmologists obtaining photographic retinal images and remote reading of these. Although treatment with laser gives good outcomes, there is interest in intravitreal anti‐vascular endothelial factor agents, but issues concerning the systemic safety and retinal results of such treatment are unresolved.     

血管内皮生长因子及其受体在早产儿视网膜病大鼠模型中的表达和作用

目的　探讨血管内皮生长因子 (VEGF)及受体 (flt 1和flk 1)的表达规律与早产儿视网膜病 (ROP)视网膜血管变化的关系。方法　 86例新生未成熟SD大鼠随机分为高氧组和对照组 ,各组再随机分为 1、3、7及 14天 4个组。高氧组吸入 75 %的氧 ( 7天后置入空气中饲养 )建立ROP大鼠模型 ,对照组则在空气中饲养。取视网膜组织制作标本 ,HE染色及CD34标记血管内皮细胞观察视网膜血管改变 ,采用免疫组织化学方法测定VEGF、flt 1及flk 1在视网膜的表达。结果　①随着天数增加对照组毛细血管密度指数 (RCDI)呈逐渐上升趋势 (F =2 1 5 89,P <0 0 1) ,7天时高氧组RCDI最低 ,停氧 7天 (即 14天 )时增加 ,(F =6 7 885 ,P <0 0 1) ;② 7天时VEGF及flk 1在对照组视网膜中表达最强 ,与第 1天和第 14天比较 ,表达强度差异均有显著意义 (P <0 0 5 ) ;③高氧组 7天时与对照组比较 ,VEGF及flk 1的表达明显减弱 ,统计学处理差异有显著意义 (P <0 0 5 ) ;而高氧组 14天VEGF及flk 1的表达增强 ,与对照组比较 ,差异有显著意义 (P <0 0 5 ) ;④flt 1随着血管的改变 ,其表达部位有所变化 ,但高氧组和对照组总体表达强度变化不明显 ,P >0 0 5。结论　当未成熟的视网膜处于高氧状态时 ,VEGF及flk 1表达减弱 ,视网膜血管减少 ;当视网     

Late postnatal systemic steroids predispose to retinopathy of prematurity in very-low-birth-weight infants: a comparative study

BACKGROUND AND OBJECTIVE: Retinopathy of prematurity (ROP) develops mostly in very-low-birth-weight (VLBW) premature infants. Besides prematurity and hyperoxia, other variables have been brought up as risk factors for ROP. We aimed to search risk factors for ROP by comparing two groups of preemies, one with and the other without ROP. PATIENTS AND METHODS: During 2004-2006, 27 VLBW premature infants developed ROP (ROP group). For each neonate in the ROP group, we chose a neonate born at similar gestational age (GA) (+/-1 week) but without ROP (control group). For each neonate of both groups, we recorded demographic, maternal, gestational, intrapartum, neonatal, interventional, growth and ophthalmologic data from patients' medical records. RESULTS: Eleven of the tested variables were significantly different between the ROP and control groups in univariate analysis. However, only seven of these variables remained significantly different between groups when controlling each variable for GA: bronchopulmonary dysplasia (BPD, p=0.04), duration of hospitalization (p=0.017), high-frequency oscillatory ventilation (HFOV, p=0.033), duration of oxygen therapy (p=0.023), surfactant therapy (p=0.045), inhaled steroids (p=0.015) and systemic steroids for BPD (p=0.007). These seven significant variables were related to respiratory morbidity and interventions. Multiple stepwise logistic regression including all significant variables in the univariate analysis showed that only systemic steroids remained significantly different between groups (p=0.007, OR 5.42, 95% CI 1.60-18.34). CONCLUSION: Significantly more neonates in the ROP group received late postnatal systemic steroids as compared to controls. We speculate that steroids, by altering insulin growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) expression, might contribute to the pathogenesis of ROP.     

An Update on Retinopathy of Prematurity (ROP)

Retinopathy of prematurity (ROP) is a proliferative retinal vascular disease affecting the retina of premature infants. The clinical spectrum of ROP varies from spontaneous regression to bilateral retinal detachment and total blindness. Between these two extremes lies the form of ROP, which is amenable to treatment with laser photocoagulation, anti-vascular endothelial growth factor drugs or surgery. Increasing rates of preterm births coupled with better survival rates but lack of uniform quality of neonatal care and delays in diagnosis have led to increasing ROP blindness. Atypical forms of Aggressive Posterior ROP are seen in heavier birth weight babies in developing countries. Prevention of ROP by following stringent protocols for supplemental oxygen, prevention of sepsis, timely screening and laser treatment by a concerted and collaborative effort of neonatologists and ophthalmologists are required to fight the blindness from ROP.     

Effects of brief, clustered versus dispersed hypoxic episodes on systemic and ocular growth factors in a rat model of oxygen-induced retinopathy

Oxygen fluctuation patterns in preterm infants who develop retinopathy of prematurity (ROP) are varied and poorly represented in animal models. We examined the hypothesis that clustered (CL) episodes of hypoxia during hyperoxia results in a more severe form of oxygen-induced retinopathy (OIR) than dispersed episodes. Rat pups were exposed to alternating cycles of 1) 50% O2 with three CL episodes of 12% O2 every 6 h; or 2) 50% O2 with one episode of 12% O2 every 2 h, for 7 (P7) or 14 (P14) days postnatal age. Pups were killed after hyperoxia, or placed in room air (RA) until P21. RA littermates were killed at P7, P14, and P21. Systemic and ocular vascular endothelial growth factor (VEGF), soluble VEGFR-1 (sVEGFR-1), insulin-like growth factor I (IGF-I), and growth hormone were examined. All hyperoxia-exposed retinas had evidence of neovascularization. Animals in the CL group had a more severe form of OIR at P21 evidenced by vascular tufts, leaky vessels, retinal hemorrhage, and vascular overgrowth. These characteristics were associated with low body weight; high systemic and ocular VEGF; and low systemic and high ocular sVEGFR-1 and IGF-I. These data suggest that preterm infants who experience CL fluctuations in Pao2 during supplemental O2 therapy are at a higher risk for severe ROP.     

早产儿视网膜病1082例筛查报告及诊治分析

目的 探讨早产儿视网膜病(ROP)的早期诊治方法,分析其筛查结果.方法 由眼底病专科医生应用双目间接眼底镜对本院新生儿科2004年7月至2009年6月收治的胎龄＜34周或出生体质量＜2000 g的住院早产儿进行ROP筛查.首次筛查时间为纠正胎龄32～34周或生后4～6周,对检出的阈值期或阈值前期1型ROP(重症)患儿全部给予眼底激光光凝术,对视网膜血管未发育成熟、1～2期或阈值前期2型(轻度)ROP患儿进行密切随访,直至视网膜血管发育至锯齿缘或发展成为重症.对所有的临床资料进行回顾性分析.结果 5年共收治早产儿2 295例,符合筛查标准的早产儿1 082例,占47.14%;检出ROP总阳性病例154例,占筛查对象的14.23%(154/1082);其轻度ROP86例,占7.94%(86/1 082);重症ROP 68例,占6.28%(68/1 082).68例重症ROP患儿中,有6例出院后随访期间发现进展为重症ROP而再入院,有2例放弃治疗1年后证实全部失明.66例(132只眼)接受各种治疗,其中63例单用光凝术治疗;3例急进性后极ROP中2例采用玻璃体腔内注入血管内皮生长因子拮抗剂(Avastin)联合光凝术治疗,1例单用光凝术治疗者治疗后仍出现部分视网膜脱离,经玻璃体视网膜手术后仍失明;随访结果65例成功的保存了视力,成功率98.48%(65/66).在观察期间未达到光凝治疗条件,因原发病恶化死亡10例,经光凝治疗后的患儿未出现死亡.结论 ROP筛查是防止ROP病情发展的有效措施,对重症ROP及时给予光凝术治疗是安全有效的方法,对急进性后极ROP可用玻璃体腔内注入血管内皮生长因子拮抗剂联合光凝术治疗抢救视力.     

On safety, pharmacokinetics and dosage of bevacizumab in ROP treatment - a review

Off-label intravitreal use of the vascular endothelial growth factor (VEGF) antibody bevacizumab for retinopathy of prematurity (ROP) increases despite lack of studies on safety, pharmacokinetics and dosage in developing individuals. Systemic absorption has been considered negligible. A literature search was performed with emphasis on potential adverse systemic effects in developing individuals. CONCLUSION: Intravitreal bevacizumab enters the general circulation, suppresses plasma VEGF levels and remains in the blood for more than 8 weeks in primates. Possible adverse effects on VEGF-dependent development must be considered.     

1~24月婴幼儿胰岛素样生长因子-1水平及与生长发育的关系

目的：分析1~24月龄婴幼儿血清胰岛素样生长因子-1（IGF-1）水平及其与生长发育的关系。方法：525名健康婴幼儿入选本研究（早产儿125名,足月儿400名）,测量体重/身长,酶联免疫吸附法检测血清IGF-1水平。结果：早产组婴儿期血清IGF-1水平在生后1.5月为最低（86±60 ng/mL）,此后一直维持较高水平,生后4~12月显著高于足月组。足月组婴儿期血清IGF-1水平在生后1.5月为最高(116±52 ng/mL),此后缓慢下降,生后8月时降至最低（69±58 ng/mL）。不论是早产儿还是足月儿体重/身长SDS与血清IGF-I水平均存在着正相关关系。结论：血清IGF-1水平均与婴幼儿期生长发育速度密切相关。［中国当代儿科杂志,2010,12（6）：459-461］     

缺氧诱导因子-1α在婴幼儿血管瘤及血管畸形中的表达与意义

目的 本研究拟通过检测缺氧诱导因子-1α(hypoxia inducible factor-1α,HIF-1α)、血管内皮生长因子(vascular endothelial growth factor,VEGF)、细胞增殖核抗原Ki-67、血管内皮标志抗原CD34在婴幼儿血管瘤不同时期、血管畸形和儿童正常皮肤中的表达,探讨缺氧在血管瘤血管生成、细胞增殖中的作用.方法 采用免疫组织化学S-P染色法,检测CD34、HIF-1α、VEGF和Ki-67在小儿血管瘤、血管畸形及正常皮肤组织中的表达,并计算微血管密度(MVD).结果 不同时期血管瘤之间,血管瘤与血管畸形、正常皮肤之间HIF-1α、VEGF、Ki-67、MVD均有显著性差异(P<0.05).血管瘤中HIF-1α表达分别与VEGF、Ki-67、MVD表达呈正相关;而血管畸形HIF-1α与VEGF表达不存在相关关系.结论 缺氧是不同时期血管瘤的普遍现象.HIF-1α能促进血管瘤血管生成.而在血管畸形中可能不存在缺氧的微环境,是"血管内皮细胞生长正常的血管形态异常",因此在血管畸形中不会发生内皮细胞的增殖,也不存在类似血管瘤那样出现增生期和消退期.