结缔组织生长因子在后囊膜混浊中的作用研究
|
摘要
目前白内障的主要治疗方法是手术治疗，通过手术能够获得良好的术后视力。然而后发性白内障(after cataract)(主要表现在后囊膜混浊(posterior capsule opacification，PCO))作为白内障术后最常见的并发症会导致很大一部分患者术后视力的下降，这样需要进一步的激光手术治疗，但有一定风险。
白内障术后，残留的晶状体体上皮细胞(lens epithelial cells，LECs)转分化为肌成纤维细胞(myofibroblast)，增殖、移行到位于光学通路上的晶体后囊膜表面，并引起后囊发生皱缩。转分化的LECs表达myofibroblast的表型标志α-平滑肌肌动蛋白(α-smooth muscle actin，α-SMA)；大量异常的细胞外基质(extracellular materials，ECM)，例如纤维连接蛋白(fibronectin，FN)、(Ⅰ型胶原collagen-Ⅰ，CA-Ⅰ)等聚集于转分化细胞周围，最终导致PCO的发生。
CTGF(connective tissue growth factor，CTGF)是一大小为36～38kDa的富含半胱氨酸多肽生长因子，第一次在人的脐带内皮细胞中发现。作为转化生长因子-β(transforming growth factor-β，TGF-β)的下游调控因子，在细胞增殖、细胞移行、细胞外基质合成、细胞表型转化等方面发挥重要作用。研究表明，CTGF能够上调肺成纤维细胞以及血管平滑肌细胞中CA-Ⅰ以及FN的表达。CTGF的过量表达能够引起肺以及肾的纤维化。同时，有报道证实CTGF在PCO的发生中起着一定作用。因此为了进一步研究CTGF在PCO中的作用，我们进行了本项试验工作，共分为四部分。
第一部分CTGF对体外培养牛眼晶体上皮细胞转分化及迁移的作用研究
目的观察结缔组织生长因子(connective tissue growth factor，CTGF)在体外培养牛眼晶体上皮细胞(bovine lens epithelial cells，BLECs)转分化和迁移中发挥的作用。
方法将体外培养的第2～3代牛眼晶体上皮细胞分为对照组和实验组，实验组分别经0.1×10~6ng·L~(-1)、0.5×10~6ng·L~(-1)、1.0×10~6ng·L~(-1)CTGF处理24h后，采用半定量RT-PCR和Western blotting技术检测α-平滑肌肌动蛋白(α-smooth muscle actin，α-SMA)mRNA以及蛋白表达的变化。迁移实验中，利用transwell小室对晶体细胞的移行能力进行检测。
结果与空白对照组相比，CTGF能够明显促进α-SMA mRNA以及蛋白表达(P＜0.01)，并且呈现剂量依赖性。迁移实验发现，CTGF能够促进晶体上皮细胞的移行，且差异有显著意义(P＜0.01)。
结论CTGF作为TGF-β的下游调节因子，可能在后囊膜混浊(posterior capsuleopacification，PCO)中晶状体上皮细胞移行、转分化以及细胞外基质沉积的过程中发挥重要的作用。
第二部分CTGF SiRNA转染体外培养牛眼晶体上皮细胞的研究
目的观察结缔组织生长因子(connective tissue growth factor，CTGF)干扰RNA(shortinterfering RNA，SiRNA)对牛眼晶体上皮细胞(bovine lens epithelial cells，BLECs)的CTGF、α-平滑肌肌动蛋白(α-smooth muscle actin，α-SMA)及纤维连接蛋白(fibronectin，FN)表达的影响。
方法将体外培养的牛眼晶体上皮细胞分为空白对照组、阴性对照组、刺激组、SiRNA_1组、SiRNA_2组共5组，各实验组先经50nm·L~(-1)浓度的SiRNA处理后再加入转化生长因子-β_1(transforming growth factor-β，TGF-β_1)，然后采用实时荧光定量PCR(Real-Time PCR)检测FN、α-SMA和CTGF mRNA的表达，同时采用Western blotting方法分别检测相应蛋白的表达。
结果Real-Time PCR结果显示，实验组FN、α-SMA和CTGF mRNA的表达与刺激组相比均有不同程度的降低，差异有统计学意义(P＜0.05)。Western blotting结果显示，与刺激组相比，SiRNA对FN、α-SMA和CTGF表达有明显的抑制作用，差异有统计学意义(P＜0.05)。
结论CTGF SiRNA能够明显下调其目标蛋白的表达，并可以抑制α-SMA和细胞外基质的表达。CTGF作为后囊膜混浊(posterior capsule opacification，PCO)中晶体上皮细胞移行、转分化以及细胞外基质沉积的过程中发挥一定作用的细胞因子，可能可以通过干扰CTGF的表达来预防PCO的发生。
第三部分CTGF在牛眼晶体上皮细胞中促进FN表达的机制研究
目的观察JNK和PI3K／Akt信号通路在牛眼晶体上皮细胞(bovine lens epithelial cells，BLECs)中结缔组织生长因子(connective tissue growth factor，CTGF)促进纤维连接蛋白(fibronectin，FN)表达的作用研究。
方法取2～3代细胞分别加入JNK抑制剂SP-600125、Akt抑制剂LY-294002、JNKSiRNA和Akt SiRNA，之后加入CTGF(1μg／ml)孵育24h。采用Western blotting技术检测FN、p-JNK和p-Akt蛋白表达的变化。
结果SP-600125和JNK SiRNA能够抑制CTGF诱导FN的表达(P＜0.05)。然而LY-294002和Akt SiRNA对CTGF诱导FN的表达没有影响(P＞0.05)。
结论CTGF在BLECs中诱导FN的表达是通过JNK信号通路介导的，然而Akt信号通路没有影响。这样对CTGF诱导后囊膜混浊发生机制有了更进一步认识。
第四部分大鼠PCO模型中CTGF和α-SMA表达的研究
目的后囊膜混浊(posterior capsule opacification，PCO)作为后发性白内障(aftercataract)的主要表现形式，是白内障术后最常见的并发症，其严重影响术后视力。本部分主要研究大鼠后发性白内障模型形成过程中结缔组织生长因子(connective tissuegrowth factor，CTGF)和α-平滑肌肌动蛋白(α-smooth muscle actin，α-SMA)的表达变化及其关系。
方法对50只Sprague Dawley(SD)大鼠行晶状体囊外摘除术(extracapsular lensextraction，ECLE)，术后不同时间点进行裂隙灯检测，western blot法检测各时间点后囊膜CTGF和α-SMA表达。
结果通过光镜的检查，在大鼠的PCO模型中可以观察到典型的PCO病理特征。在PCO的发展过程中，CTGF和α-SMA表达发生了变化。α-SMA作为成纤维母细胞的标志，于术后0小时几乎检测不到，3天可检测到表达，7天达到高峰，14天下降，28天明显下降。这一变化说明了晶体上皮细胞(lens epithelial cells，LECs)发生了转分化。CTGF作为转化生长因子-β(transforming growth factor-β，TGF-β)下游的重要调节因子，与α-SMA具有同样的表达趋势。回归分析显示，α-SMA的表达与CTGF的表达密切相关(R~2=0.893，P＜0.05)。
结论结果表明，CTGF可能参与了PCO模型中α-SMA表达的调节，同时α-SMA可以作为PCO的形成过程中晶体上皮细胞转分化的重要标志。
Psterior capsule opacification (PCO) is the the most common complication of catraractsurgery. At present the only means of treating cataract is by surgical intervention, and thisinitially restores high visual quality. Unfortunately, PCO develops in a significantproportion of patients to such an extent that a secondary loss of vision occurs, whichconsequently required further corrective laser surgery which is not without risk.
After cataract surgery, residual LECs transdifferentiate into myofibroblast, and oftenmigrate and proliferate on the posterior capsule, induce capsule wrinkling. Thetransdifferentiated cells expressα-smooth muscle actin (α-SMA) which is the mark ofmyofibroblast; abnormal extracellular materials (ECM), including collagen-Ⅰ(CA-Ⅰ)and fibronectin (FN), accumulate around the transdifferentiated cells, that will induce PCO.
Connective tissue growth factor (CTGF) is a 36 to 38kDa cysteine-rich peptide, and isfirst identified from human umbilical endothelial cells. As the downstream regulatory factorof transforming growth factor-β(TGF-β), CTGF could promote cells proliferation,migration, adhesion, and ECM production. As reported by previous research, CTGFupregulates the expression CA-Ⅰand FN in human lung fibroblasts and vascular smoothmuscle cells. Overproduction of CTGF therefore has been implicated as an importantpathway leading to lung fibrosis and kidney fibrosis. It has been reported that CTGF playsan important role in pathogenesis of PCO. In order to research the effect and possible mechanism of the action about the CTGF on the PCO, we are going to this reseach project,which includes four sections.
PartⅠThe research of migration and transdifferentiation effects ofconnective tissue growth factor in bovine lens epithelial cells
Objective To observe the migration and transdifferentiation effects of connective tissuegrowth factor (CTGF) in bovine lens epithelial cells (BLECs).
Methods Cultured 2～3 passage BLECs were divided into control group and experimentalgroup with 0.1×10~6ng·L~(-1), 0.5×10~6ng·L~(-1), 1.0×10~6ng·L~(-1) CTGF for 24h, the mRNA andprotein ofα-smooth muscle actin (α-SMA) in BLECs were examined respectively bysemiquantitative RT-PCR and Western blotting. In migration experiment, transwell insertswere used to evaluate migration ability of BLECs.
Results In comparison with control group, experimental group could promote theexpression ofα-SMA at mRNA and protein level with dose dependent obviously inBLECs (P＜0.01). In migration experiment, CTGF could significantly promote BLECsmigration (P＜0.01).
Conclusion As the downstream regulatory factor of TGF-β, CTGF play an important rolein lens epithelial cells migration, transdifferentiation and deposition of ECM in posteriorcapsule opacification (PCO).
PartⅡEffect of connective tissue growth factor SiRNA inbovine lens epithelial cells
Objective To observe the effects of connective tissue growth factor (CTGF) SiRNA on the expression of CTGF、α-smooth muscle actin (α-SMA) and fibronectin(FN) in bovine lensepithelial cells (BLECs).
Methods Cultured 2～3 passage BLECs were divided into control group,TGF-β_1+negative SiRNA group, TGF-β_1 group, TGF-β_1+CTGF SiRNA_1 group andTGF-β_1+CTGF SiRNA_2 group. The experimental group was treated by 50nm·L~(-1) SiRNA_1and SiRNA_2, and then incubation with 10.0×10~3ng·L~(-1) TGF-β_1. The mRNA and proteinexpression ofα-SMA, FN and CTGF in BLECs were examined respectively by Real-TimePCR and Western blotting.
Results Real-Time PCR indicated that in comparison with TGF-β_1 group, mRNAexpression of FN,α-SMA and CTGF decreased in tranfection group (P＜0.05). Westernblotting indicated that in comparison with TGF-β_1 group, CTGF SiRNA could inhibitedthe expression of FN,α-SMA and CTGF notablely (P＜0.05).
Conclusion The data suggested that CTGF SiRNA could inhibit the expression of CTGF,α-SMA and ECM. Because CTGF play an essential role in lens epithelial cells migration,transdifferentiation and deposition of ECM in posterior capsule opacification (PCO), thatinterferring of CTGF could prevent PCO.
PartⅢThe research of mechanism at connective tissue growth factorinduced fibronectin expression in bovine lens epithelial cells
Objective To observe the effect of JNK and PI3K/Akt on connective tissue growth factor(CTGF)-induced fibronectin (FN) expression in bovine lens epithelial cells (BLECs).
Methods The Cultured 2～3 passage BLECs were respectively treated by JNK inhibitorSP-600125, Akt inhibitor LY-294002, JNK SiRNA and Akt SiRNA, and then incubationwith 1μg/ml CTGF for 24h. The protein of FN, p-JNK and p-Akt were examined by western blotting.
Results In the presence of JNK inhibitor (SP-600125) or transfected by JNK SiRNA,CTGF-induced protein expression of FN increase was completely inhibited (P＜0.05). Aktinhibitor (LY-294002) and Akt SiRNA had no effect on CTGF-stimulated proteinexpression of FN (P＞0.05).
Conclusion FN expression which induced by CTGF is mediated through the JNK pathway,but not affected by PI3K/Akt pathway. From these, we could know more about theCTGF-induced PCO.
PartⅣThe expression of connective tissue growth factor andα-smoothmuscle actin in rat posterior capsule opacification models
Objective Posterior capsule opacification (PCO), the major complication of cataractsurgery, would induce visual loss. In this study, the expression of connective tissue growthfactor (CTGF) andα-smooth muscle actin (α-SMA) in rat posterior capsule opacificationmodels has been studied.
Methods An extracapsular lens extraction (ECLE), was performed in 50 Sprague-Dawley(SD) adult male rats. The pathological characteristics of PCO were observed in rat modelswith slit lamp at each time point. The posterior capsule was taken out for examining theexpression of CTGF andα-SMA.
Results A classical pathological characteristics of posterior capsule opacification could beobsrved in PCO models with slit lamp. In this process, we detected the expression ofα-SMA and CTGF in the posterior capsules of models,α-SMA, a special hallmark formyofibroblast, increased significantly at 3 day, and reached the peak level at 7 day aftersurgery. However, the expression decreased at 14 day after surgery, and further decreased at28 day. It demonstrated that the lens epithelial cells transdifferentiated into mesenchyme-like cells. CTGF, a major downstream regulatory factor of transforminggrowth factor-β(TGF-β), also showed a significant increase after surgery. The regressionanalysis strongly indicated thatα-SMA expression was associated with CTGF expression(R~2=0.893, P＜0.05).
Conclusions These results suggest that CTGF may be involved in regulatingα-SMAexpression, which is the important marker of transdifferentiation of lens epithelial cells inrat PCO models.
白内障术后，残留的晶状体体上皮细胞(lens epithelial cells，LECs)转分化为肌成纤维细胞(myofibroblast)，增殖、移行到位于光学通路上的晶体后囊膜表面，并引起后囊发生皱缩。转分化的LECs表达myofibroblast的表型标志α-平滑肌肌动蛋白(α-smooth muscle actin，α-SMA)；大量异常的细胞外基质(extracellular materials，ECM)，例如纤维连接蛋白(fibronectin，FN)、(Ⅰ型胶原collagen-Ⅰ，CA-Ⅰ)等聚集于转分化细胞周围，最终导致PCO的发生。
CTGF(connective tissue growth factor，CTGF)是一大小为36～38kDa的富含半胱氨酸多肽生长因子，第一次在人的脐带内皮细胞中发现。作为转化生长因子-β(transforming growth factor-β，TGF-β)的下游调控因子，在细胞增殖、细胞移行、细胞外基质合成、细胞表型转化等方面发挥重要作用。研究表明，CTGF能够上调肺成纤维细胞以及血管平滑肌细胞中CA-Ⅰ以及FN的表达。CTGF的过量表达能够引起肺以及肾的纤维化。同时，有报道证实CTGF在PCO的发生中起着一定作用。因此为了进一步研究CTGF在PCO中的作用，我们进行了本项试验工作，共分为四部分。
第一部分CTGF对体外培养牛眼晶体上皮细胞转分化及迁移的作用研究
目的观察结缔组织生长因子(connective tissue growth factor，CTGF)在体外培养牛眼晶体上皮细胞(bovine lens epithelial cells，BLECs)转分化和迁移中发挥的作用。
方法将体外培养的第2～3代牛眼晶体上皮细胞分为对照组和实验组，实验组分别经0.1×10~6ng·L~(-1)、0.5×10~6ng·L~(-1)、1.0×10~6ng·L~(-1)CTGF处理24h后，采用半定量RT-PCR和Western blotting技术检测α-平滑肌肌动蛋白(α-smooth muscle actin，α-SMA)mRNA以及蛋白表达的变化。迁移实验中，利用transwell小室对晶体细胞的移行能力进行检测。
结果与空白对照组相比，CTGF能够明显促进α-SMA mRNA以及蛋白表达(P＜0.01)，并且呈现剂量依赖性。迁移实验发现，CTGF能够促进晶体上皮细胞的移行，且差异有显著意义(P＜0.01)。
结论CTGF作为TGF-β的下游调节因子，可能在后囊膜混浊(posterior capsuleopacification，PCO)中晶状体上皮细胞移行、转分化以及细胞外基质沉积的过程中发挥重要的作用。
第二部分CTGF SiRNA转染体外培养牛眼晶体上皮细胞的研究
目的观察结缔组织生长因子(connective tissue growth factor，CTGF)干扰RNA(shortinterfering RNA，SiRNA)对牛眼晶体上皮细胞(bovine lens epithelial cells，BLECs)的CTGF、α-平滑肌肌动蛋白(α-smooth muscle actin，α-SMA)及纤维连接蛋白(fibronectin，FN)表达的影响。
方法将体外培养的牛眼晶体上皮细胞分为空白对照组、阴性对照组、刺激组、SiRNA_1组、SiRNA_2组共5组，各实验组先经50nm·L~(-1)浓度的SiRNA处理后再加入转化生长因子-β_1(transforming growth factor-β，TGF-β_1)，然后采用实时荧光定量PCR(Real-Time PCR)检测FN、α-SMA和CTGF mRNA的表达，同时采用Western blotting方法分别检测相应蛋白的表达。
结果Real-Time PCR结果显示，实验组FN、α-SMA和CTGF mRNA的表达与刺激组相比均有不同程度的降低，差异有统计学意义(P＜0.05)。Western blotting结果显示，与刺激组相比，SiRNA对FN、α-SMA和CTGF表达有明显的抑制作用，差异有统计学意义(P＜0.05)。
结论CTGF SiRNA能够明显下调其目标蛋白的表达，并可以抑制α-SMA和细胞外基质的表达。CTGF作为后囊膜混浊(posterior capsule opacification，PCO)中晶体上皮细胞移行、转分化以及细胞外基质沉积的过程中发挥一定作用的细胞因子，可能可以通过干扰CTGF的表达来预防PCO的发生。
第三部分CTGF在牛眼晶体上皮细胞中促进FN表达的机制研究
目的观察JNK和PI3K／Akt信号通路在牛眼晶体上皮细胞(bovine lens epithelial cells，BLECs)中结缔组织生长因子(connective tissue growth factor，CTGF)促进纤维连接蛋白(fibronectin，FN)表达的作用研究。
方法取2～3代细胞分别加入JNK抑制剂SP-600125、Akt抑制剂LY-294002、JNKSiRNA和Akt SiRNA，之后加入CTGF(1μg／ml)孵育24h。采用Western blotting技术检测FN、p-JNK和p-Akt蛋白表达的变化。
结果SP-600125和JNK SiRNA能够抑制CTGF诱导FN的表达(P＜0.05)。然而LY-294002和Akt SiRNA对CTGF诱导FN的表达没有影响(P＞0.05)。
结论CTGF在BLECs中诱导FN的表达是通过JNK信号通路介导的，然而Akt信号通路没有影响。这样对CTGF诱导后囊膜混浊发生机制有了更进一步认识。
第四部分大鼠PCO模型中CTGF和α-SMA表达的研究
目的后囊膜混浊(posterior capsule opacification，PCO)作为后发性白内障(aftercataract)的主要表现形式，是白内障术后最常见的并发症，其严重影响术后视力。本部分主要研究大鼠后发性白内障模型形成过程中结缔组织生长因子(connective tissuegrowth factor，CTGF)和α-平滑肌肌动蛋白(α-smooth muscle actin，α-SMA)的表达变化及其关系。
方法对50只Sprague Dawley(SD)大鼠行晶状体囊外摘除术(extracapsular lensextraction，ECLE)，术后不同时间点进行裂隙灯检测，western blot法检测各时间点后囊膜CTGF和α-SMA表达。
结果通过光镜的检查，在大鼠的PCO模型中可以观察到典型的PCO病理特征。在PCO的发展过程中，CTGF和α-SMA表达发生了变化。α-SMA作为成纤维母细胞的标志，于术后0小时几乎检测不到，3天可检测到表达，7天达到高峰，14天下降，28天明显下降。这一变化说明了晶体上皮细胞(lens epithelial cells，LECs)发生了转分化。CTGF作为转化生长因子-β(transforming growth factor-β，TGF-β)下游的重要调节因子，与α-SMA具有同样的表达趋势。回归分析显示，α-SMA的表达与CTGF的表达密切相关(R~2=0.893，P＜0.05)。
结论结果表明，CTGF可能参与了PCO模型中α-SMA表达的调节，同时α-SMA可以作为PCO的形成过程中晶体上皮细胞转分化的重要标志。
Psterior capsule opacification (PCO) is the the most common complication of catraractsurgery. At present the only means of treating cataract is by surgical intervention, and thisinitially restores high visual quality. Unfortunately, PCO develops in a significantproportion of patients to such an extent that a secondary loss of vision occurs, whichconsequently required further corrective laser surgery which is not without risk.
After cataract surgery, residual LECs transdifferentiate into myofibroblast, and oftenmigrate and proliferate on the posterior capsule, induce capsule wrinkling. Thetransdifferentiated cells expressα-smooth muscle actin (α-SMA) which is the mark ofmyofibroblast; abnormal extracellular materials (ECM), including collagen-Ⅰ(CA-Ⅰ)and fibronectin (FN), accumulate around the transdifferentiated cells, that will induce PCO.
Connective tissue growth factor (CTGF) is a 36 to 38kDa cysteine-rich peptide, and isfirst identified from human umbilical endothelial cells. As the downstream regulatory factorof transforming growth factor-β(TGF-β), CTGF could promote cells proliferation,migration, adhesion, and ECM production. As reported by previous research, CTGFupregulates the expression CA-Ⅰand FN in human lung fibroblasts and vascular smoothmuscle cells. Overproduction of CTGF therefore has been implicated as an importantpathway leading to lung fibrosis and kidney fibrosis. It has been reported that CTGF playsan important role in pathogenesis of PCO. In order to research the effect and possible mechanism of the action about the CTGF on the PCO, we are going to this reseach project,which includes four sections.
PartⅠThe research of migration and transdifferentiation effects ofconnective tissue growth factor in bovine lens epithelial cells
Objective To observe the migration and transdifferentiation effects of connective tissuegrowth factor (CTGF) in bovine lens epithelial cells (BLECs).
Methods Cultured 2～3 passage BLECs were divided into control group and experimentalgroup with 0.1×10~6ng·L~(-1), 0.5×10~6ng·L~(-1), 1.0×10~6ng·L~(-1) CTGF for 24h, the mRNA andprotein ofα-smooth muscle actin (α-SMA) in BLECs were examined respectively bysemiquantitative RT-PCR and Western blotting. In migration experiment, transwell insertswere used to evaluate migration ability of BLECs.
Results In comparison with control group, experimental group could promote theexpression ofα-SMA at mRNA and protein level with dose dependent obviously inBLECs (P＜0.01). In migration experiment, CTGF could significantly promote BLECsmigration (P＜0.01).
Conclusion As the downstream regulatory factor of TGF-β, CTGF play an important rolein lens epithelial cells migration, transdifferentiation and deposition of ECM in posteriorcapsule opacification (PCO).
PartⅡEffect of connective tissue growth factor SiRNA inbovine lens epithelial cells
Objective To observe the effects of connective tissue growth factor (CTGF) SiRNA on the expression of CTGF、α-smooth muscle actin (α-SMA) and fibronectin(FN) in bovine lensepithelial cells (BLECs).
Methods Cultured 2～3 passage BLECs were divided into control group,TGF-β_1+negative SiRNA group, TGF-β_1 group, TGF-β_1+CTGF SiRNA_1 group andTGF-β_1+CTGF SiRNA_2 group. The experimental group was treated by 50nm·L~(-1) SiRNA_1and SiRNA_2, and then incubation with 10.0×10~3ng·L~(-1) TGF-β_1. The mRNA and proteinexpression ofα-SMA, FN and CTGF in BLECs were examined respectively by Real-TimePCR and Western blotting.
Results Real-Time PCR indicated that in comparison with TGF-β_1 group, mRNAexpression of FN,α-SMA and CTGF decreased in tranfection group (P＜0.05). Westernblotting indicated that in comparison with TGF-β_1 group, CTGF SiRNA could inhibitedthe expression of FN,α-SMA and CTGF notablely (P＜0.05).
Conclusion The data suggested that CTGF SiRNA could inhibit the expression of CTGF,α-SMA and ECM. Because CTGF play an essential role in lens epithelial cells migration,transdifferentiation and deposition of ECM in posterior capsule opacification (PCO), thatinterferring of CTGF could prevent PCO.
PartⅢThe research of mechanism at connective tissue growth factorinduced fibronectin expression in bovine lens epithelial cells
Objective To observe the effect of JNK and PI3K/Akt on connective tissue growth factor(CTGF)-induced fibronectin (FN) expression in bovine lens epithelial cells (BLECs).
Methods The Cultured 2～3 passage BLECs were respectively treated by JNK inhibitorSP-600125, Akt inhibitor LY-294002, JNK SiRNA and Akt SiRNA, and then incubationwith 1μg/ml CTGF for 24h. The protein of FN, p-JNK and p-Akt were examined by western blotting.
Results In the presence of JNK inhibitor (SP-600125) or transfected by JNK SiRNA,CTGF-induced protein expression of FN increase was completely inhibited (P＜0.05). Aktinhibitor (LY-294002) and Akt SiRNA had no effect on CTGF-stimulated proteinexpression of FN (P＞0.05).
Conclusion FN expression which induced by CTGF is mediated through the JNK pathway,but not affected by PI3K/Akt pathway. From these, we could know more about theCTGF-induced PCO.
PartⅣThe expression of connective tissue growth factor andα-smoothmuscle actin in rat posterior capsule opacification models
Objective Posterior capsule opacification (PCO), the major complication of cataractsurgery, would induce visual loss. In this study, the expression of connective tissue growthfactor (CTGF) andα-smooth muscle actin (α-SMA) in rat posterior capsule opacificationmodels has been studied.
Methods An extracapsular lens extraction (ECLE), was performed in 50 Sprague-Dawley(SD) adult male rats. The pathological characteristics of PCO were observed in rat modelswith slit lamp at each time point. The posterior capsule was taken out for examining theexpression of CTGF andα-SMA.
Results A classical pathological characteristics of posterior capsule opacification could beobsrved in PCO models with slit lamp. In this process, we detected the expression ofα-SMA and CTGF in the posterior capsules of models,α-SMA, a special hallmark formyofibroblast, increased significantly at 3 day, and reached the peak level at 7 day aftersurgery. However, the expression decreased at 14 day after surgery, and further decreased at28 day. It demonstrated that the lens epithelial cells transdifferentiated into mesenchyme-like cells. CTGF, a major downstream regulatory factor of transforminggrowth factor-β(TGF-β), also showed a significant increase after surgery. The regressionanalysis strongly indicated thatα-SMA expression was associated with CTGF expression(R~2=0.893, P＜0.05).
Conclusions These results suggest that CTGF may be involved in regulatingα-SMAexpression, which is the important marker of transdifferentiation of lens epithelial cells inrat PCO models.
引文
1. Schaumberg DA,Dana MR, Christen WG,et al.A systematic overview of the incidence of posterior capsule opacification[J]. Ophthalmology, 1998, 105(7):1213-1221
2. Moisseiev J, Bartov E, Schochat A, Blumenthal M. Long-term study of the prevalence of capsular opacification following extracapsular cataract extraction[J]. J Cataract Refract Surg, 1989,15: 531-533
3. Knight-Nanan D, O'Keefe M, Bowell R. Outcome and complications of intraocular lenses in children with cataract[J]. J Catrarct Refract Surg, 1996, 22: 730-736
4. Frezzotti R, Caporossi A. Pathogenesis of posterior capsular opacification. Part Ⅰ.Epidemiological and clinico-statistical data[J]. J Cataract Refract Surg, 1990, 16:347-352
5. Nagata T, Watanabe I. Optic sharp edge or convexity: comparison of effects on posterior capsular opacification[J]. Jpn J Ophthalmol, 1996,40: 397-403
6. Ursell PG,Spalton DJ, Pande MV, Hollick EJ, Barman S, Boyce J, Tilling K.Relationship between intraocular lens biomaterials and posterior capsule opacification[J]. J Cataract Refract Surg, 1998, 24: 352-360
7. Scaramuzza A, Fernando GT, Crayford BB. Posterior capsule opacification and lens epithelial cell layer formation: hydroview hydrogel versus AcrySof acrylic intraocular lenses[J]. J Cataract Refract Surg, 2001, 27:1047-1054
8. Kappelhof J, et al. The pathology of after-cataract[J]. Acta Ophthalmol Suppl, 1992,205: 13
9. Duncan G,Wormstone IM, Liu CS, et al. Thapsigargin-coated intraocular lenses inhibit human lens cell growth[J]. Nat Med, 1997, 3:1026-1028
10. McAvoy JW, Chamberlain CG. Fibroblast growth factor(FGF) induces different responses in lens epithelial cells depending on its concentration[J]. Development, 1989,107: 221-228
11. Brewitt B, Clark JI.Growth and transparency in the lens, an epithelial tissue,stimulated by pulses of PDGF[J]. Science, 1988, 242: 777-779
12. Liu J, Hales AM, Chamberlain CG, McAvoy JW. Induction of cataract-like changes in rat lens epithelial explants by transforming growth factor beta[J]. Invest Ophthalmol Vis Sci, 1994, 35:388-401
13. Lee EH, Joo CK. Role of transforming growth factor-beta in transdifferentiation and fibrosis of lens epithelial cells[J]. Invest Ophthalmol Vis Sci, 1999, 40:2025-2032
14. Wormstone IM, Tamiya S, Anderson I, Duncan G. TGF-beta2-induced matrix modification and cell transdifferentiation in the human lens capsular bag[J]. Invest Ophthalmol Vis Sci, 2002, 43:2301
15．王侃，等．转化生长因子-β与结缔组织生长因子在纤维化中的作用机制[J]．浙江实用医学，2004，9：208
16. Bradham DM, Igarashi A, Potter RL, Grotendorst GR. Connective tissue growth factor: A cysteine-rich mitogen secreted by human vascular endothelial cells is related to the src-induced immediate early gene product cef-10[J]. J Cell Biol, 1991, 114:1285-1294
17. Brigstock DR. The connective tissue growth factor/cysteine-rich61/nephroblastoma overexpressed (CCN) family[J]. Endocr Rev, 1999, 20:189-20
18. Lau LF, Lam SC. The CCN family of angiogenic regulators: the integrin connection[J]. Exp Cell Res, 1999, 248:44-57
19. Perbal B. The CCN family of genes: a brief history[J]. Mol Pathol, 2001, 54:103-104
20. Perbal B. NOV (nephroblastoma overexpressed) and the CCN family of genes: structural and functional issues[J]. Mol Pathol, 2001, 54:57-79
21. Bork P. The modular architecture of a new family of growth regulators related to connective tissue growth factor[J]. FEBS Lett, 1993, 327:125-130
22. Ristimaki A, Honkanen N, Jankala H, Sipponen P, Harkonen M. Expression of cyclooxygenase-2 in human gastric carcinoma[J]. Cancer Res, 1997, 57:1276-1280
23. Thun MJ, Namboodiri MM, Calle EE, et al. Aspirin use and risk of fatal cancer[J]. Cancer Res, 1993, 53:1322-1327
24. Uefuji K, Ichikura T, Mochizuki H. Expression of cyclooxygenase-2 in human gastric adenomas and adenocarcinomas[J]. J Surg Oncol, 2001, 76:26-30
25. Grotendorst GR. Connective growth factor: a mediator of TGF-beta action on fibroblast[J]. Cytokine growth Factor Rev, 1997, 8:171
26. Chen MM, et al. CTGF expression is induced by in cardiac fibroblasts and cardiac myocytes: a potential role in heart fibrosis[J]. J Mol Cell Cardiol, 2000, 32:1805
27. Frazier K, Williams S, Kothapalli D, Klapper H, Grotendorst GR. Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor[J]. J Invest Dermatol, 1996, 107:404-411
28．张憬，等．结缔组织生长因子反义寡核苷酸抑制TGF-betal诱导人肾小管上皮细胞转分化．中国现代医学杂志，2005，15：1316
29．张海燕，等．结缔组织生长因子在转化生长因子β诱导的肾小管上皮细胞转分化中的作用．中国病理生理杂志，2005，21(1)：179-183
30. Evans RA, et al. TGF-betal mediated fibroblast myofibroblast terminal differentiation the role of Smad proteins[J]. Exp Cell Res, 2003, 282:90-100
31. Tahashi Y, et al. Differential regulation of TGF-beta signal in hepatic stellate cells between acute and chronic rat liver injury[J]. Hepatology, 2002, 35:49-61
32. Wunderlich K, et al. Expression of connective tissue growth factor (CTGF) mRNA in plaques of human anterior subcapsular cataracts and membranes of posterior capsule opacification[J]. Curr Eye, 2000, 21:627
33. Wormstone IM, Characterisation of TGF-beta2 signalling and function in a human lens cell line[J]. Exp Eye Res, 2004, 78:705-14
34. Park SK, Kim J, Seomun Y, et al. Hydraogen Peroxide is a novel inducer of connective tissue growth factor[J]. Biochimical and Biophysical Research Communication, 2001, 284 (4): 966- 971
1. Scott JD. Lens changes in retinal detachment[J]. Trans Ophthalmol Soc UK, 1979, 99:241-243
2. Kerstin Wunderlich, Michael Pech, Alex Eberle, Michael Mihatsch, Josef Flammer, Peter Meyer. Expression of connective tissue growth factor (CTGF) mRNA inplaques of human anterior subcapsular cataracts and membranes of posterior capsule opacification[J]. Current Eye Research, 2000, 21(2): 627-636
3. Hay ED. An overview of epithelio-mesenchymal transformation[J]. Acta Anat, 1995, 154:8-20
4. Hay ED, Zuk A. Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced[J]. Am J Kidney Dis, 1995, 26:678-690
5. Pau H, Novotny GE, Arnold G. Ultrastructural investigation of extracellular structures in subcapsular white corrugated cataract(anterior capsular cataract) [J]. Graefes Arch Clin Exp Ophthalmol, 1985, 223:96-100
6. Hatae T, Ishibashi T, Yoshitomi F, Shibata Y. Immunocytochemistry of types Ⅰ-Ⅳ collagen in human anterior subcapsular cataracts[J]. Graefes Arch Clin Exp Ophthalmol, 1993, 231:586-590
7. McAvoy JW, Schulz MW, Maruno KA, Chamberlain CG, Lovicu FJ. TGF-beta induced cataract is characterized by epithelial-mesenchymal transition and apoptosis[J]. Invest Ophthalmol Vis Sci, 1998, 39(4): 30
8. Bradham DM, Igarashi A, Potter RL, Grotendorst GR. Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediately early gene product CEF-10[J]. J Cell Biol, 1991, 114:1285-1294
9．王侃，等．转化生长因子-β与结缔组织生长因子在纤维化中的作用机制[J]．浙江实用医学，2004，9：208
10. Chen CC, Chen N, Lau LF. The angiogenic factors Cyr61 and connective tissue growth factor induce adhesive signaling in primary human skin fibroblasts[J]. J Biol Chem, 2001, 276:10443-10452
11. Ball DK, Rachfal AW, Kemper SA, Brigstock D. The heparinbinging 10kDa fragment of connective tissue growth factor (CTGF) containing module 4 alone stimulates cell adhesion[J]. J Endocrinol, 2003, 176:R1-R7
12. Brigstock DR, Steffen CL, Kim GY, Vegunta RK, Diehl JR, Harding PA. Purification and characterization of novel heparin-binding growth factors in uterine secretory fluids. Identification as heparin-regulated Mr 10,000 forms of connective tissue growth factor[J]. J Biol Chem, 1997, 272:20275-20282
13. Fan WH, Pech M, Karnovsky MJ. Connective tissue growth factor (ctgf) stimulates vascular smooth muscle cell growth and migration in vitro[J]. Eur J Cell Biol, 2000, 79:915-923
14. Grotendorst GR. Connective growth factor: a mediator of TGF-beta action on fibroblast[J]. Cytokine growth Factor Rev, 1997, 8:171
15. Chen MM, et al. CTGF expression is induced by in cardiac fibroblasts and cardiac myocytes: a potential role in heart fibrosis[J]. J Mol Cell Cardiol, 2000, 32:1805
16. Frazier K, Williams S, Kothapalli D, Klapper H, Grotendorst GR. Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor[J]. J Invest Dermatol, 1996, 107:404-411
17．张憬，等．结缔组织生长因子反义寡核苷酸抑制TGF-betal诱导人肾小管上皮细胞转分化[J]．中国现代医学杂志，2005，15：316
18．张海燕，等．结缔组织生长因子在转化生长因子β诱导的肾小管上皮细胞转分化中的作用[J]．中国病理生理杂志，2005，21(1)：179-183
19. Evans RA, et al. TGF-betal mediated fibroblast myofibroblast terminal differentiation the role of Smad proteins[J]. Exp Cell Res, 2003, 282:90-100
20. Tahashi Y, et al. Differential regulation of TGF-beta signal in hepatic stellate cells between acute and chronic rat liver injury[J]. Hepatology, 2002, 35(1): 49-61
21. Wunderlich K, et al. Expression of connective tissue growth factor (CTGF) mRNA in plaques of human anterior subcapsular cataracts and membranes of posterior capsule opacification[J]. Curr Eye, 2000, 21 (2): 627
22. Wormstone IM, Characterisation of TGF-beta2 signalling and function in a human lens cell line[J]. Exp Eye Res, 2004, 78(3): 705-14
23. Chen L, Liu BC, Zhang XL, Zhang JD, Liu H, Li MX. Influence of connective tissue growth factor antisense oligonucleotide on angiotensin ii-induced epithelial mesenchymal transition in hk2 cells[J]. Acta Pharmacol Sin, 2006, 27:1029-1036
24. Burns WC, Twigg SM, Forbes JM, Pete J, Tikellis C, Thallas-Bonke V, Thomas MC, Cooper ME, Kantharidis P. Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition: Implications for diabetic renal disease[J]. J Am Soc Nephrol, 2006,17:2484-2494
1. Kerstin Wundeflich, Michael Pech, Alex Eberle, Michael Mihatsch, Josef Flammer, Peter Meyer. Expression of connective tissue growth factor (CTGF) mRNA inplaques of human anterior subcapsular cataracts and membranes of posterior capsule opacification[J]. Current Eye Research, 2000, 21(2): 627-636
2. Niranjan Awasthi, Wagner BJ. Suppression of Human Lens Epithelial Cell Proliferation by Proteasome Inhibition, a Potential Defense against Posterior Capsular Opacification[J]. Invest Ophthalmol Vis Sci, 2006, 47:4482-4489
3. Bradham DM, Igarashi A, Potter RL, Grotendorst GR. Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediately early gene product CEF-10[J]. J Cell Biol, 1991, 114:1285-1294
4．王侃，等．转化生长因子-β与结缔组织生长因子在纤维化中的作用机制[J]．浙江实用医学，2004，9：208
5. Grotendorst GR. Connective growth factor: a mediator of TGF-beta action on fibroblast[J]. Cytokine growth Factor Rev, 1997, 8:171
6. Chen MM, et al. CTGF expression is induced by in cardiac fibroblasts and cardiac myocytes: a potential role in heart fibrosis[J]. J Mol Cell Cardiol, 2000, 32:1805
7．张憬，等．结缔组织生长因子反义寡核苷酸抑制TGF-betal诱导人肾小管上皮细胞转分化[J]．中国现代医学杂志，2005，15：316
8．张海燕，等．结缔组织生长因子在转化生长因子β诱导的肾小管上皮细胞转分化中的作用[J]．中国病理生理杂志，2005，21(1)：179-183
9. Evans RA, et al. TGF-betal mediated fibroblast myofibroblast terminal differentiation the role of Smad proteins[J]. Exp Cell Res, 2003, 282:90-100
10. Tahashi Y, et al. Differential regulation of TGF-beta signal in hepatic stellate cells between acute and chronic rat liver injury[J]. Hepatology, 2002, 35(1): 49-61
11. Caramori ML, Mayer M. Diabetes and nephrophthy corrupting nephrolhypertents [J]. J Am Soc Nephrol, 2003, 12 (3): 273-282
12. Wunderlich K,et al. Expression of connective tissue growth factor (CTGF) mRNA in plaques of human anterior subcapsular cataracts and membranes of posterior capsule opacification[J]. Curr Eye, 2000, 21(2):627
13. Wormstone IM, Characterisation of TGF-beta2 signalling and function in a human lens cell line[J]. Exp Eye Res, 2004, 78(3): 705-14
14. Gitlin L, Karelsky S, Andino R. Short interference RNA confers intracellular antiviral immunity in human cells[J]. Nature, 2002, 418: 430-434
1. Spalton DJ. Posterior capsular opacification after cataract surgery[J]. Eye, 1999, 13:489-492
2. Bradham DM, Igarashi A, Potter RL, Grotendorst GR. Connective tissue growth factor:A cysteine-rich mitogen secreted by human vascular endothelial cells is related to the src-induced immediate early gene product cef-10[J]. J Cell Biol,1991,114:1285-1294
3. Grotendorst GR. Connective tissue growth factor: A mediator of tgf-beta action on fibroblasts[J]. Cytokine Growth Factor Rev, 1997, 8: 171-179
4. Fan WH, Pech M, Karnovsky MJ. Connective tissue growth factor (ctgf) stimulates vascular smooth muscle cell growth and migration in vitro[J].Eur J Cell Biol, 2000, 79:915-923
5. Frazier K,Williams S, Kothapalli D, Klapper H, Grotendorst GR. Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor[J]. J Invest Dermatol,1996,107: 404-411
6. Chen CM, Wang LF, Chou HC, Lang YD, Lai YP. Up-regulation of connective tissue growth factor in hyperoxia-induced lung fibrosis[J]. Pediatr Res, 2007, 62:128-133
7. Zhang C, Meng X, Zhu Z, Liu J, Deng A. Connective tissue growth factor regulates the key events in tubular epithelial to myofibroblast transition in vitro[J]. Cell Biol Int,2004, 28:863-873
8. Wunderlich K, Pech M, Eberle AN, Mihatsch M, Flammer J, Meyer P. Expression of connective tissue growth factor (ctgf) mrna in plaques of human anterior subcapsular cataracts and membranes of posterior capsule opacification[J].Curr Eye Res, 2000, 21:627-636
9. Kolch W. The regulation of the Ras/Raf/MEK/ERK pathway by protein interactions[J].Biochem,2000, 351: 289-294
10. Turjanski AG,Vaque JP, Gutkind JS. Map kinases and the control of nuclear events[J].Oncogene, 2007, 26: 3240-3253
11. Xie S, Sukkar MB, Issa R, Oltmanns U,Nicholson AG,Chung KF. Regulation of tgf-beta 1-induced connective tissue growth factor expression in airway smooth muscle cells[J]. Am J Physiol Lung Cell Mol Physiol, 2005, 288:L68-76
12. Yang DD, Kuan CY, Whitmarsh AJ, Rinc(?)n M, Zheng TS, Davis RJ, Rakic P, Flavell RA. Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene[J]. Nature, 1997, 389:865-870
13. Kumagae Y, Zhang Y, Kim OJ, Miller CA. Human c-Jun N-terminal kinase expression and activation in the nervous system[J]. Brain Res Mol Brain Res, 1999, 67:10-17
14. Gupta S, Barrett T, Whitmarsh A J, Cavanagh J, Sluss HK, D(?)rijard B, Davis RJ. Selective interaction of JNK protein kinase isoforms with transcription factors[J]. EMBO J, 1996, 15:2760-2770
15. Engelbrecht AM, Niesler C, Page C. p38 and JNK have distinct regulatory functions on the development of apoptosis during simulated ischaemia and reperfusion in neonatal cardiomyocytes[J]. Basic Res Cardiol, 2004, 99:338-350
16．姚毓奇，李晓玫．JNK信号通路研究进展[J]．细胞生物学杂志，2005，27：242-246
17. Widmann C, Gibson S, Jarpe MB, Johnson GL. Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human[J]. Physiol Rev, 1999, 79: 143-180
18. Smith JL, Schaffner AE, Hofmeister JK, et al. ets-2 is a target for an akt (Protein kinase B)/jun N-terminal kinase signaling pathway in macrophages of motheaten-viable mutant mice[J]. Mol Cell Biol, 2000, 20:8026-8034
19. Huang C, Rajfur Z, Botchers C, Schaller MD, Jacobson K. JNK phosphorylates paxillin and regulates cell migration[J]. Nature, 2003, 424:219-223
20. He T, Stepulak A, Holmstr(o｜¨)m TH, Omary MB, Eriksson JE. The intermediate filament protein keratin 8 is a novel cytoplasmic substrate for c-Jun N-terminal kinase. J Biol Chem, 2002, 277:10767-10774
21. Choi J, Park SY, Joo CK. Hepatocyte growth factor induces proliferation of lens epithelial cells through activation of erk1/2 and jnk/sapk[J]. Invest Ophthalmol Vis Sci, 2004, 45:2696-2704
22．李怀富，韩从辉，王玉新，et al．Akt/蛋白激酶B信号传导通路在慢性移植肾肾病早期病变中的作用[J]．中华器官移植杂志，2007，28：290-294
23．夏曙，于世英．PI3K/Akt信号转导通路在恶性肿瘤中的研究进展[J]．肿瘤，2006， 26: 576-578
24. Basile JR, Afkhami T, Gutkind JS. Semaphorin 4D/plexin-Bl induces endothelial cell migration through the activation of PYK2, Src, and the phosphatidylinositol 3-kinase-PKB path-way[J]. Mol Cell Biol,2005,25:6889-6898.
25. Nomura M, Ichimatsu D, Moritani S, et al. Inhibition of epidermal growth factor-induced cell transformation and PKB activation by caffeine[J]. Mol Carcinog,2005, 44: 67-76
26. Belyanskaya LL, Hopkins-Donaldson S, Kurtz S, et al. Cisplatin activates Akt in small cell lung cancer cells and attenuates apoptosis by surviving upregulation[J]. Int J Cancer, 2005,117: 755-763
27. Varma S, Lal BK,Zheng R, et al. Hyperglycemia alters PI3K and Akt signaling and leads to endothelial cell proliferative dysfunction[J].Am J Physiol Heart Cire Physiol,2005,289:1744-1751
28. Katayama K,Fujita N, Tsuruo T. PKB/protein kinase B-independent phosphorylation and inactivation of WEElHu promote cell cycle progression at G2/M transition[J]. Mol Cell Biol, 2005, 25: 5725-5737
29. Grille SJ, Bellacosa A, Upson, et al. The protein kinase akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines[J]. Cancer Res, 2003, 63: 2172-2178
30. Jiang Q, Zhou C, Bi Z, Wan Y. Egf-induced cell migration is mediated by erk and pi3k/akt pathways in cultured human lens epithelial cells[J]. J Ocul Pharmacol Ther,2006, 22: 93-102
31. Yao K, Ye PP, Tan J, Tang XJ, Shen Tu XC. Involvement of pi3k/akt pathway in tgf-beta2-mediated epithelial mesenchymal transition in human lens epithelial cells[J].Ophthalmic Res, 2008, 40: 69-76
1. Spalton DJ. Posterior capsular opacification after cataract surgery[J]. Eye, 1999, 13:489-492
2. Bradham DM, Igarashi A,Potter RL, Grotendorst GR. Connective tissue growth factor:A cysteine-rich mitogen secreted by human vascular endothelial cells is related to the src-induced immediate early gene product cef-10[J]. J Cell Biol,1991,114:1285-1294
3. Grotendorst GR. Connective tissue growth factor: A mediator of tgf-beta action on fibroblasts[J]. Cytokine Growth Factor Rev, 1997, 8: 171-179
4. Fan WH, Pech M, Karnovsky MJ. Connective tissue growth factor (ctgf) stimulates vascular smooth muscle cell growth and migration in vitro[J]. Eur J Cell Biol, 2000,79: 915-923
5. Frazier K,Williams S, Kothapalli D, Klapper H, Grotendorst GR. Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor[J]. J Invest Dermatol,1996,107:404-411
6. Chen CM, Wang LF, Chou HC, Lang YD, Lai YP. Up-regulation of connective tissue growth factor in hyperoxia-induced lung fibrosis[J].Pediatr Res, 2007, 62:128-133
7. Zhang C, Meng X, Zhu Z, Liu J, Deng A. Connective tissue growth factor regulates the key events in tubular epithelial to myofibroblast transition in vitro[J]. Cell Biol Int,2004, 28:863-873
8. Wunderlich K, Pech M, Eberle AN, Mihatsch M, Flammer J, Meyer P. Expression of connective tissue growth factor (ctgf) mrna in plaques of human anterior subcapsular cataracts and membranes of posterior capsule opacification[J]. Curr Eye Res, 2000, 21:627-636
9. Liu J, Hales AM, Chamberlain CG,McAvoy JW. Induction of cataract-like changes in rat lens epithelial explants by transforming growth factor beta[J]. Invest Ophthalmol Vis Sci, 1994, 35: 388-401
10. Frezzotti R, Caporossi A, Mastrangelo D,Hadjistilianou T, Tosi P, Cintorino M,Minacci C. Pathogenesis of posterior capsular opacification. Part ii:Histopathological and in vitro culture findings[J]. J Cataract Refract Surg, 1990,16: 353-360
11. Chen L, Liu BC, Zhang XL, Zhang JD, Liu H, Li MX. Influence of connective tissue growth factor antisense oligonucleotide on angiotensin ii-induced epithelial mesenchymal transition in hk2 cells[J]. Acta Pharmacol Sin, 2006, 27:1029-1036
12. Burns WC, Twigg SM, Forbes JM, Pete J, Tikellis C, Thallas-Bonke V, Thomas MC,Cooper ME, Kantharidis P. Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition:Implications for diabetic renal disease[J]. J Am Soc Nephrol, 2006, 17: 2484-2494
13. Lois N, Dawson R, McKinnon AD, et al.A new model of posterior capsule opacification in rodents[J]. Invest Ophthalmol Vis Sci, 2003, 8(44): 3450-3457
14. Cobo LM, Ohsawa E, Chandler D, et al. Pathogenesis of capsular opacification after extracapsular cataract extraction: an animal model[J]. Ophthalmology, 1984, 91(7):857-863
15. Novotny GE, Pau H. Myofibroblast-like cells in human anterior capsular cataract[J].Virchows Arch APathol Anat Histopathol, 1984, 404: 393-401
16. Pau H, Novotny GE, Arnold G. Ultrastructural investigation of extracellular structures in subcapsular white corrugated cataract (anterior capsular cataract) [J]. Graefes Arch Clin Exp Ophthalmol, 1985, 223: 96-100
17. Hales AM, Schulz MW, Chamberlain CG, McAvoy JW. Tgf-beta 1 induces lens cells to accumulate alpha-smooth muscle actin, a marker for subcapsular cataracts[J]. Curr Eye Res, 1994,13:885-890
18. Kato K, Kurosaka D, Nagamoto T. Apoptotic cell death in rabbit lens after lens extraction[J]. Invest Ophthalmol Vis Sci, 1997, 38: 2322-2330
19. Ihn H. Pathogenesis of fibrosis: role of TGF-b and CTGF[J]. Curr Opin Rheumatol,2002,14:681-695
20. Chen MM, et al. CTGF expression is induced by in cardiac fibroblasts and cardiac myocytes: a potential role in heart fibrosis[J]. J Mol Cell Cardiol, 2000, 32: 1805
21. Duncan MR, Frazier KS, Abramson S, Williams S, Klapper H, Huang X, Grotendorst GR. Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: Down-regulation by camp[J]. FASEB J, 1999, 13:1774-1786
22. Grotendorst GR, Rahmanie H, Duncan MR. Combinatorial signaling pathways determine fibroblast proliferation and myofibroblast differentiation[J]. FASEB J, 2004,18: 469-479
1. Apple DJ, Peng Q, Visessook N, et al. Eradication of posterior capsule opacification:documentation of a marked decrease in Nd:YAG laser posterior capsulotomy rates noted in an analysis of 5416 pseudophakic human eyes obtained postmortem[J].Ophthalmology, 2001,108: 505-518
2. Sundelin K, Sjostrand J. Posterior capsule opacification 5 years after extracapsular cataract extraction [J]. J Cataract Refract Surg, 1999, 25(2): 246-250
3. Schaumberg DA, Dana MR, Christen WG, et al. A systematic overview of the incidence of posterior capsule opacification[J]. Ophthalmology, 1998,105(7):1213-1221
4. Spalton DJ. Posterior capsular opacification after cataract surgery[J]. Eye, 1999, 13:489-492
5. Bradham DM, Igarashi A, Potter RL, Grotendorst GR. Connective tissue growth factor:A cysteine-rich mitogen secreted by human vascular endothelial cells is related to the src-induced immediate early gene product cef-10[J]. J Cell Biol, 1991,114:1285-1294
6. Grotendorst GR. Connective tissue growth factor: A mediator of tgf-beta action on fibroblasts[J]. Cytokine Growth Factor Rev, 1997, 8: 171-179
7. Fan WH, Pech M, Karnovsky MJ. Connective tissue growth factor (ctgf) stimulates vascular smooth muscle cell growth and migration in vitro[J]. Eur J Cell Biol, 2000, 79:915-923
8. Frazier K,Williams S, Kothapalli D, Klapper H, Grotendorst GR. Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor[J]. J Invest Dermatol, 1996,107: 404-411
9. Chen CM, Wang LF, Chou HC, Lang YD, Lai YP. Up-regulation of connective tissue growth factor in hyperoxia-induced lung fibrosis[J]. Pediatr Res, 2007, 62:128-133
10. Zhang C, Meng X, Zhu Z, Liu J, Deng A. Connective tissue growth factor regulates the key events in tubular epithelial to myofibroblast transition in vitro[J]. Cell Biol Int, 2004,28: 863-873
11. Wunderlich K, Pech M, Eberle AN, Mihatsch M, Flammer J, Meyer P. Expression of connective tissue growth factor (ctgf) mrna in plaques of human anterior subcapsular cataracts and membranes of posterior capsule opacification[J]. Curr Eye Res, 2000, 21:627-636
12. Brigstock DR. The connective tissue growth factor/cysteine-rich61/nephroblastoma overexpressed (CCN) family[J]. Endocr Rev, 1999, 20: 189-206
13. Lau LF, Lam SC.The CCN family of angiogenic regulators: the integrin connection[J].Exp Cell Res, 1999, 248: 44-57
14. Perbal B. The CCN family of genes: a brief history[J]. Mol Pathol, 2001, 54: 103-104
15. Perbal B. NOV (nephroblastoma overexpressed) and the CCN family of genes:structural and functional issues[J]. Mol Pathol, 2001, 54: 57-79
16. Bork P. The modular architecture of a new family of growth regulators related to connective tissue growth factor[J]. FEBS Lett, 1993, 327: 125-130
17. Ristimaki A, Honkanen N, Jankala H, Sipponen P, Harkonen M. Expression of cyclooxygenase-2 in human gastric carcinoma[J]. Cancer Res, 1997, 57: 1276-1280
18. Thun MJ, Namboodiri MM, Calle EE, et al. Aspirin use and risk of fatal cancer[J].Cancer Res, 1993, 53:1322-1327
19. Uefuji K, Ichikura T, Mochizuki H. Expression of cyclooxygenase-2 in human gastric adenomas and adenocarcinomas[J]. J Surg Oncol, 2001, 76: 26-30
20.Ihn H. Pathogenesis of fibrosis: role of TGF-b and CTGF[J]. Curr Opin Rheumatol,2002,14: 681-695
21. Chen Y, Segarini P, Raoufi F, Bradham D, Leask A. Connective tissue growth factor is secreted through the Golgi and is degraded in the endosome[J]. Exp Cell Res, 2001, 271:109-117
22. Leask A, Abraham DJ. The role of connective tissue growth factor, a multifunctional matricellular protein, in fibroblast biology[J]. Biochem Cell Biol, 2003, 81: 355-363
23. Chen CC, Chen N, Lau LF. The angiogenic factors Cyr61 and connective tissue growth factor induce adhesive signaling in primary human skin fibroblasts[J]. J Biol Chem,2001, 276:10443-10452
24. Ball DK, Rachfal AW, Kemper SA, Brigstock D. The heparinbinging 10kDa fragment of connective tissue growth factor (CTGF) containing module 4 alone stimulates cell adhesion[J]. J Endocrinol, 2003, 176: R1-R7
25. Brigstock DR, Steffen CL, Kim GY, Vegunta RK, Diehl JR, Harding PA. Purification and characterization of novel heparin-binding growth factors in uterine secretory fluids.Identification as heparin-regulated Mr 10,000 forms of connective tissue growth factor[J]. J Biol Chem, 1997, 272: 20275-20282
26. Kothapalli D, Grotendorst GR. CTGF modulates cell cycle progression in CAMP2 arrested NRK fibroblasts[J]. J Cell Physiol, 2000,182 (1) : 119-123
27. Shimo T, Nakanishi T, Nishida T, Asano M, Kanyama M, Kuboki T, Tamatani T, Tezuka K, Takemura M, Matsumura T, Takigawa M. Connective tissue growth factor induces the proliferation, migration, and tube formation of vascular endothelial cells in vitro and angiogenesis in vivo[J]. J Biochem, 1999,126 :137-145
28. Babic AM, Chen CC, Lau LF. Fispl2/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin alphavbeta3, promotes endothelial cell survival, and induces angiogenesis in vivo[J]. Mol Cell Biol, 1999, 19:2958-2966
29. Wormstone IM, Tamiya S, Eldred JA, et al. Characterisation of TGF-beta signalling and function in a human lens cell line[J]. Exp Eye Res, 2004, 78 (3): 705-714
30. Igarashi A, Okochi H, Bradham DM, Grotendorst GR. Regulation of connective tissue growth factor gene expression in human skin fibroblasts and during wound repair[J].Mol Biol Cell, 1993, 4: 637-645
31. Caramori ML, Mayer M. Diabetes and nephrophthy corrupting nephrolhypertents[J]. J Am Soc Nephrol, 2003,12 (3): 273-282
32. Holmes A, Abraham DJ, Sa S, et al. CTGF and SMADs, maintenance of scleroderma phenotype is independent of SMAD signaling[J]. J Biol Chem, 2001, 276: 10594-10601
33. Leask A, Sa S, Holmes A, et al. The control of ccn2 (ctgf) gene expression in normal and scleroderma fibroblasts [J]. Mol Pathol, 2001, 54: 180-183
34. Leivonen SK, Hakkinen L, Liu D, et al . Smad3 and extracellular signal-regulated kinase 1/2 coordinately mediate transforming growth factor-beta-induced expression of connective tissue growth factor in human fibroblasts[J]. J Invest Dermatol, 2005, 124(6) : 1162-1169
35. Leask A, Holmes A, Abraham DJ, et al . CTGF gene regulation, requirements for its induction by TGF-β in fibroblast[J]. J Bi ol Chem, 2003, 278 (15) : 13008-13015
36. Ishida I, Saika S, Okada Y, et al. Growth factor depositi on in anterior subcapsular cataract[J]. J Cataract Refract Surg 2005,31 (6) : 1219-1225
37. Chambers RC, Leoni P, Blanc-Brude OP, et al. Thrombin is a potent inducer of connective tissue growth factor production via proteolytic activation of protease-activated receptor-1[J]. J Biol Chem, 2000, 275: 35584-35589
38. Dammeier J, Beer HD, Brauchle M, Werner S: Dexamethasone is a novel potent inducer of connective tissue growth factor expression: implications for glucocorticoid therapy [J].J Biol Chem, 1998, 273:18185-18190
39. Duncan MR, Frazier KS, Abramson S, et al. Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: down-regulation by cAMP[J]. FASEB J, 1999,13: 1774-1786
40. Ricupero DA, Rishikof DC, Kuang PP, et al. Regulation of connective tissue growth factor expression by prostaglandin E(2)[J]. Am J Physiol, 1999, 277: L1165-L1171
41. Suzuma K, Naruse K, Suzuma I, et al. Vascular endothelial growth factor induces expression of connective tissue growth factor via KDR, Flt1,and phosphatidylinositol 3-kinase-akt-dependent pathways in retinal vascular cells[J]. J Biol Chem, 2000, 275:40725-40731
42. Pereira RC, Durant D, Canalis E. Transcriptional regulation of connective tissue growth factor by cortisol in osteoblasts[J]. Am J Physiol Endocrinol Metab, 2000, 279:E570-E576
43. Stanhope-Baker P, Williams BR. Identification of connective tissue growth factor as a target of WT1 transcriptional regulation[J]. J Biol Chem, 2000, 275: 38139-38150
44. Abraham DJ, Shiwen X, Black CM, et al. Tumor necrosis factor-alpha suppresses the induction of connective tissue growth factor by transforming growth factor-beta in normal and scleroderma fibroblasts[J]. J Biol Chem, 2000, 275:15220-15225
45. Sudhaakar J, Ravindran RD, Natchiar G Analysis of complications in 1000 cases of posterior chamber intra ocular lens implantation [J]. Indian J Ophtahalmol, 1989, 37:78-79
46. Moisseiev J, Bartov E, Schochat A, Blumenthal M. Long-term study of the prevalence of capsular opacification following extracapsular cataract extraction [J]. J Cataract Refract Surg, 1989,15:531-533
47. Knight-Nanan D, O'Keefe M, Bowell R. Outcome and complications of intraocular lenses in children with cataract[J]. J Catrarct Refract Surg, 1996, 22: 730-736
48. Frezzotti R, Caporossi A. Pathogenesis of posterior capsular opacification. Part ####.Epidemiological and clinico-statistical data[J]. J Cataract Refract Surg, 1990, 16:347-352
49. Nagata T, Watanabe I. Optic sharp edge or convexity: comparison of effects on posterior capsular opacification[J]. Jpn J Ophthalmol, 1996, 40: 397-403
50.Ursell PG,Spalton DJ, Pande MV, Hollick EJ, Barman S, Boyce J, Tilling K.Relationship between intraocular lens biomaterials and posterior capsule opacification[J].J Cataract Refract Surg, 1998, 24: 352-360
51. Scaramuzza A, Fernando GT, Crayford BB. Posterior capsule opacification and lens epithelial cell layer formation: hydroview hydrogel versus AcrySof acrylic intraocular lenses[J]. J Cataract Refract Surg, 2001, 27:1047-1054
52. McDonnell PJ, Krause W, Glaser BM. In vitro inhibition of lens epithelial cell proliferation and migration[J]. Ophthalmic Surg, 1988,19:25-30
53. McAvoy JW, Chamberlain CG.Fibroblast growth factor(FGF) induces different responses in lens epithelial cells depending on its concentration[J]. Development, 1989,107: 221-228
54. Cobo LM,Ohsawa E,Chandler D, Arguello R, George G. Pathogenesis of capsular opacification after extracapsular cataract extraction. An animal model[J].Ophthalmology, 1984, 91: 857-863
55. Behar-Cohen FF, David T, D'Hermies F,Pouliquen YM, Buechler Y, Nova MP, Houston LL,Courtois Y. In vivo inhibition of lens regrowth by fibroblast growth factor 2-saporin[J]. Invest Ophthalmol Vis Sci, 1995, 36: 2434-2448
56. Nagamoto T, Bissen-Miyajima H. A ring to support the capsular bag after continuous curvilinear capsulorhexis[J]. J Cataract Refract Surg, 1994, 20: 417-420
57. Liu CS, Wormstone IM,Duncan G,Marcantonio JM, Webb SF, Davies PD. A study of human lens cell growth in vitro. A model for posterior capsule opacification[J]. Invest Ophthalmol Vis Sic, 1996, 37: 906-914
58. Hollick EJ, Spalton DJ, Ursell PG, et al. The effect of polymethylmethacrylate, silicone,and polyacrylic intraocular lenses on posterior capsular opacification 3 years after cataract surgery[J]. Ophthalmology, 1999,106: 49-54
59. Hynes RO. Integrins: a family of cell surface receptors[J]. Cell, 1987, 48: 549-554
60. Ruosiahti E, Pierschbacher MD. New perspectives in cell adhesion: RGD and integrins[J]. Science, 1987, 238: 491-497
61. Nishi O,Nishi K, Akaishi T, et al. Detection of cell adhesion molecules in lens epithelial cells of human cataracts[J]. Invest Ophthalmol Vis Sci, 1997, 38: 579-585
62. Nishi O,Nishi K, Mano C, et al. Inhibition of migrating lens epithelial cells by blocking the adhesion molecule integrin: a preliminary report[J]. J Cataract Refract Surg,1997,23:860-865
63. Wallentin N,Wickstrom K,Lundberg C. Effect of cataract surgery on aqueous TGF-beta and lens epithelial cell proliferation[J].Invest Ophthalmol Vis Sci, 1998, 39:1410-1418.
64. Pau H, Novotny GE, Arnold G. Ultrastructural investigation of extracellular structures in subcapsular white corrugated cataract(anterior capsular cataract) [J]. Graefes Arch Clin Exp Ophthalmol, 1985, 223: 96-100
65.Hatae T, Ishibashi T, Yoshitomi F, Shibata Y. Immunocytochemistry of types Ⅰ-Ⅳ collagen in human anterior subcapsular cataracts[J]. Graefes Arch Clin Exp Ophthalmol,1993, 231: 586-590
66. McAvoy JW, Schulz MW, Maruno KA, Chamberlain CG, Lovicu FJ. TGF-beta induced cataract is characterized by epithelial-mesenchymal transition and apoptosis[J]. Invest Ophthalmol Vis Sci, 1998, 39(4): 30
67. Bassols A, Massague J. Transforming growth factor beta regulates the expression and structure of extracellular matrix chondroitin/dermatan sulfate proteoglycans[J]. J Biol Chem, 1988, 263: 3039-45
68. Nishi O, Nishi K, Fujiwara T, et al. Effects of the cytokines on the proliferation of and collagen synthesis by human cataract lens epithelial cells[J]. Br J Ophthalmol, 1996, 80:63-68
69. Massague J. The transforming growth factor-beta family[J]. Annu Rev Cell Biol, 1990, 6:597-641
70. Overall CM, Wrana JL, Sodek J. Independent regulation of collagenase, 72-kDa progelatinase, and metalloendoproteinase inhibitor expression in human fibroblasts by transforming growth factor-beta[J]. J Biol Chem, 1989, 264: 1860-1869
71. Duncan G, Wormstone IM, Liu CS, et al. Thapsigargin-coated intraocular lenses inhibit human lens cell growth[J]. Nat Med, 1997, 3:1026-1028
72. Brewitt B, Clark JL Growth and transparency in the lens, an epithelial tissue, stimulated by pulses of PDGF[J]. Science, 1988, 242: 777-779
73. Liu J, Hales AM, Chamberlain CG, McAvoy JW. Induction of cataract-like changes in rat lens epithelial explants by transforming growth factor beta[J]. Invest Ophthalmol Vis Sci, 1994,35: 388-401
74. Lee EH, Joo CK. Role of transforming growth factor-beta in transdifferentiation and fibrosis of lens epithelial cells[J]. Invest Ophthalmol Vis Sci, 1999, 40: 2025-2032
75. Cousins SW, McCabe MM, Danielpour D, Streilein JW. Identification of transforming growth factor-beta as an immunosuppressive factor in aqueous humor [J]. Invest Ophthalmol Vis Sci, 1991, 32: 2201-2211
76. Streilein JW. Ocular immune privilege and the Faustian dilemma. The Proctor lecture[J].Invest Ophthalmol Vis Sci, 1996, 37:1940-1950
77. Kurosaka D, Kato K,Nagamoto T, Negishi K. Growth factors influence contractility and alpha-smooth muscle actin expression in bovine lens epithelial cells [J]. Invest Ophthalmol Vis Sci, 1995, 36: 1701-1708
78. Gordon-Thomson C, de Iongh RU,Hales AM, et al. Differential cataractogenic potency of TGF-beta1,-beta2, and -beta3 and their expression in the postnatal rat eye[J]. Invest Ophthalmol Vis Sci, 1998, 39:1399-1409
79. Kaji Y, Mita T, Obata H, et al. Expression of transforming growth factor beta superfamily and their receptors in the corneal stromal wound healing process after excimer laser keratectomy [letter][J]. Br J Ophthalmol, 1998, 82:462-463
80. Davidson MG, Morgan DK, McGahan MC. Effect of surgical technique on in vitro posterior capsule opacification[J]. J Cataract Refract Surg. 2000, 26: 1550-1554
81.Nishi O, Nishi K, Sakanishi K. Inhibition of migrating lens epithelial cells at the capsular bend created by the rectangular optic edge of a posterior chamber intraocular lens[J]. Ophthalmic Surg Lasers, 1998, 29: 587-594
82. Nishi O,Nishi K, Saitoh I, Sakanishi K. Inhibition of migrating lens epithelial cells by sustained release of ethylenediaminetetraacetic acid[J]. J Cataract Refract Surg, 1996b,22: 863-868
83. Park SK, Kim J, Seomun Y, et al.Hydraogen Peroxide is a novel inducer of connective tissue growth factor[J]. Biochimical and Biophysical Research Communication, 2001,284 (4): 966-971
2. Moisseiev J, Bartov E, Schochat A, Blumenthal M. Long-term study of the prevalence of capsular opacification following extracapsular cataract extraction[J]. J Cataract Refract Surg, 1989,15: 531-533
3. Knight-Nanan D, O'Keefe M, Bowell R. Outcome and complications of intraocular lenses in children with cataract[J]. J Catrarct Refract Surg, 1996, 22: 730-736
4. Frezzotti R, Caporossi A. Pathogenesis of posterior capsular opacification. Part Ⅰ.Epidemiological and clinico-statistical data[J]. J Cataract Refract Surg, 1990, 16:347-352
5. Nagata T, Watanabe I. Optic sharp edge or convexity: comparison of effects on posterior capsular opacification[J]. Jpn J Ophthalmol, 1996,40: 397-403
6. Ursell PG,Spalton DJ, Pande MV, Hollick EJ, Barman S, Boyce J, Tilling K.Relationship between intraocular lens biomaterials and posterior capsule opacification[J]. J Cataract Refract Surg, 1998, 24: 352-360
7. Scaramuzza A, Fernando GT, Crayford BB. Posterior capsule opacification and lens epithelial cell layer formation: hydroview hydrogel versus AcrySof acrylic intraocular lenses[J]. J Cataract Refract Surg, 2001, 27:1047-1054
8. Kappelhof J, et al. The pathology of after-cataract[J]. Acta Ophthalmol Suppl, 1992,205: 13
9. Duncan G,Wormstone IM, Liu CS, et al. Thapsigargin-coated intraocular lenses inhibit human lens cell growth[J]. Nat Med, 1997, 3:1026-1028
10. McAvoy JW, Chamberlain CG. Fibroblast growth factor(FGF) induces different responses in lens epithelial cells depending on its concentration[J]. Development, 1989,107: 221-228
11. Brewitt B, Clark JI.Growth and transparency in the lens, an epithelial tissue,stimulated by pulses of PDGF[J]. Science, 1988, 242: 777-779
12. Liu J, Hales AM, Chamberlain CG, McAvoy JW. Induction of cataract-like changes in rat lens epithelial explants by transforming growth factor beta[J]. Invest Ophthalmol Vis Sci, 1994, 35:388-401
13. Lee EH, Joo CK. Role of transforming growth factor-beta in transdifferentiation and fibrosis of lens epithelial cells[J]. Invest Ophthalmol Vis Sci, 1999, 40:2025-2032
14. Wormstone IM, Tamiya S, Anderson I, Duncan G. TGF-beta2-induced matrix modification and cell transdifferentiation in the human lens capsular bag[J]. Invest Ophthalmol Vis Sci, 2002, 43:2301
15．王侃，等．转化生长因子-β与结缔组织生长因子在纤维化中的作用机制[J]．浙江实用医学，2004，9：208
16. Bradham DM, Igarashi A, Potter RL, Grotendorst GR. Connective tissue growth factor: A cysteine-rich mitogen secreted by human vascular endothelial cells is related to the src-induced immediate early gene product cef-10[J]. J Cell Biol, 1991, 114:1285-1294
17. Brigstock DR. The connective tissue growth factor/cysteine-rich61/nephroblastoma overexpressed (CCN) family[J]. Endocr Rev, 1999, 20:189-20
18. Lau LF, Lam SC. The CCN family of angiogenic regulators: the integrin connection[J]. Exp Cell Res, 1999, 248:44-57
19. Perbal B. The CCN family of genes: a brief history[J]. Mol Pathol, 2001, 54:103-104
20. Perbal B. NOV (nephroblastoma overexpressed) and the CCN family of genes: structural and functional issues[J]. Mol Pathol, 2001, 54:57-79
21. Bork P. The modular architecture of a new family of growth regulators related to connective tissue growth factor[J]. FEBS Lett, 1993, 327:125-130
22. Ristimaki A, Honkanen N, Jankala H, Sipponen P, Harkonen M. Expression of cyclooxygenase-2 in human gastric carcinoma[J]. Cancer Res, 1997, 57:1276-1280
23. Thun MJ, Namboodiri MM, Calle EE, et al. Aspirin use and risk of fatal cancer[J]. Cancer Res, 1993, 53:1322-1327
24. Uefuji K, Ichikura T, Mochizuki H. Expression of cyclooxygenase-2 in human gastric adenomas and adenocarcinomas[J]. J Surg Oncol, 2001, 76:26-30
25. Grotendorst GR. Connective growth factor: a mediator of TGF-beta action on fibroblast[J]. Cytokine growth Factor Rev, 1997, 8:171
26. Chen MM, et al. CTGF expression is induced by in cardiac fibroblasts and cardiac myocytes: a potential role in heart fibrosis[J]. J Mol Cell Cardiol, 2000, 32:1805
27. Frazier K, Williams S, Kothapalli D, Klapper H, Grotendorst GR. Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor[J]. J Invest Dermatol, 1996, 107:404-411
28．张憬，等．结缔组织生长因子反义寡核苷酸抑制TGF-betal诱导人肾小管上皮细胞转分化．中国现代医学杂志，2005，15：1316
29．张海燕，等．结缔组织生长因子在转化生长因子β诱导的肾小管上皮细胞转分化中的作用．中国病理生理杂志，2005，21(1)：179-183
30. Evans RA, et al. TGF-betal mediated fibroblast myofibroblast terminal differentiation the role of Smad proteins[J]. Exp Cell Res, 2003, 282:90-100
31. Tahashi Y, et al. Differential regulation of TGF-beta signal in hepatic stellate cells between acute and chronic rat liver injury[J]. Hepatology, 2002, 35:49-61
32. Wunderlich K, et al. Expression of connective tissue growth factor (CTGF) mRNA in plaques of human anterior subcapsular cataracts and membranes of posterior capsule opacification[J]. Curr Eye, 2000, 21:627
33. Wormstone IM, Characterisation of TGF-beta2 signalling and function in a human lens cell line[J]. Exp Eye Res, 2004, 78:705-14
34. Park SK, Kim J, Seomun Y, et al. Hydraogen Peroxide is a novel inducer of connective tissue growth factor[J]. Biochimical and Biophysical Research Communication, 2001, 284 (4): 966- 971
1. Scott JD. Lens changes in retinal detachment[J]. Trans Ophthalmol Soc UK, 1979, 99:241-243
2. Kerstin Wunderlich, Michael Pech, Alex Eberle, Michael Mihatsch, Josef Flammer, Peter Meyer. Expression of connective tissue growth factor (CTGF) mRNA inplaques of human anterior subcapsular cataracts and membranes of posterior capsule opacification[J]. Current Eye Research, 2000, 21(2): 627-636
3. Hay ED. An overview of epithelio-mesenchymal transformation[J]. Acta Anat, 1995, 154:8-20
4. Hay ED, Zuk A. Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced[J]. Am J Kidney Dis, 1995, 26:678-690
5. Pau H, Novotny GE, Arnold G. Ultrastructural investigation of extracellular structures in subcapsular white corrugated cataract(anterior capsular cataract) [J]. Graefes Arch Clin Exp Ophthalmol, 1985, 223:96-100
6. Hatae T, Ishibashi T, Yoshitomi F, Shibata Y. Immunocytochemistry of types Ⅰ-Ⅳ collagen in human anterior subcapsular cataracts[J]. Graefes Arch Clin Exp Ophthalmol, 1993, 231:586-590
7. McAvoy JW, Schulz MW, Maruno KA, Chamberlain CG, Lovicu FJ. TGF-beta induced cataract is characterized by epithelial-mesenchymal transition and apoptosis[J]. Invest Ophthalmol Vis Sci, 1998, 39(4): 30
8. Bradham DM, Igarashi A, Potter RL, Grotendorst GR. Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediately early gene product CEF-10[J]. J Cell Biol, 1991, 114:1285-1294
9．王侃，等．转化生长因子-β与结缔组织生长因子在纤维化中的作用机制[J]．浙江实用医学，2004，9：208
10. Chen CC, Chen N, Lau LF. The angiogenic factors Cyr61 and connective tissue growth factor induce adhesive signaling in primary human skin fibroblasts[J]. J Biol Chem, 2001, 276:10443-10452
11. Ball DK, Rachfal AW, Kemper SA, Brigstock D. The heparinbinging 10kDa fragment of connective tissue growth factor (CTGF) containing module 4 alone stimulates cell adhesion[J]. J Endocrinol, 2003, 176:R1-R7
12. Brigstock DR, Steffen CL, Kim GY, Vegunta RK, Diehl JR, Harding PA. Purification and characterization of novel heparin-binding growth factors in uterine secretory fluids. Identification as heparin-regulated Mr 10,000 forms of connective tissue growth factor[J]. J Biol Chem, 1997, 272:20275-20282
13. Fan WH, Pech M, Karnovsky MJ. Connective tissue growth factor (ctgf) stimulates vascular smooth muscle cell growth and migration in vitro[J]. Eur J Cell Biol, 2000, 79:915-923
14. Grotendorst GR. Connective growth factor: a mediator of TGF-beta action on fibroblast[J]. Cytokine growth Factor Rev, 1997, 8:171
15. Chen MM, et al. CTGF expression is induced by in cardiac fibroblasts and cardiac myocytes: a potential role in heart fibrosis[J]. J Mol Cell Cardiol, 2000, 32:1805
16. Frazier K, Williams S, Kothapalli D, Klapper H, Grotendorst GR. Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor[J]. J Invest Dermatol, 1996, 107:404-411
17．张憬，等．结缔组织生长因子反义寡核苷酸抑制TGF-betal诱导人肾小管上皮细胞转分化[J]．中国现代医学杂志，2005，15：316
18．张海燕，等．结缔组织生长因子在转化生长因子β诱导的肾小管上皮细胞转分化中的作用[J]．中国病理生理杂志，2005，21(1)：179-183
19. Evans RA, et al. TGF-betal mediated fibroblast myofibroblast terminal differentiation the role of Smad proteins[J]. Exp Cell Res, 2003, 282:90-100
20. Tahashi Y, et al. Differential regulation of TGF-beta signal in hepatic stellate cells between acute and chronic rat liver injury[J]. Hepatology, 2002, 35(1): 49-61
21. Wunderlich K, et al. Expression of connective tissue growth factor (CTGF) mRNA in plaques of human anterior subcapsular cataracts and membranes of posterior capsule opacification[J]. Curr Eye, 2000, 21 (2): 627
22. Wormstone IM, Characterisation of TGF-beta2 signalling and function in a human lens cell line[J]. Exp Eye Res, 2004, 78(3): 705-14
23. Chen L, Liu BC, Zhang XL, Zhang JD, Liu H, Li MX. Influence of connective tissue growth factor antisense oligonucleotide on angiotensin ii-induced epithelial mesenchymal transition in hk2 cells[J]. Acta Pharmacol Sin, 2006, 27:1029-1036
24. Burns WC, Twigg SM, Forbes JM, Pete J, Tikellis C, Thallas-Bonke V, Thomas MC, Cooper ME, Kantharidis P. Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition: Implications for diabetic renal disease[J]. J Am Soc Nephrol, 2006,17:2484-2494
1. Kerstin Wundeflich, Michael Pech, Alex Eberle, Michael Mihatsch, Josef Flammer, Peter Meyer. Expression of connective tissue growth factor (CTGF) mRNA inplaques of human anterior subcapsular cataracts and membranes of posterior capsule opacification[J]. Current Eye Research, 2000, 21(2): 627-636
2. Niranjan Awasthi, Wagner BJ. Suppression of Human Lens Epithelial Cell Proliferation by Proteasome Inhibition, a Potential Defense against Posterior Capsular Opacification[J]. Invest Ophthalmol Vis Sci, 2006, 47:4482-4489
3. Bradham DM, Igarashi A, Potter RL, Grotendorst GR. Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediately early gene product CEF-10[J]. J Cell Biol, 1991, 114:1285-1294
4．王侃，等．转化生长因子-β与结缔组织生长因子在纤维化中的作用机制[J]．浙江实用医学，2004，9：208
5. Grotendorst GR. Connective growth factor: a mediator of TGF-beta action on fibroblast[J]. Cytokine growth Factor Rev, 1997, 8:171
6. Chen MM, et al. CTGF expression is induced by in cardiac fibroblasts and cardiac myocytes: a potential role in heart fibrosis[J]. J Mol Cell Cardiol, 2000, 32:1805
7．张憬，等．结缔组织生长因子反义寡核苷酸抑制TGF-betal诱导人肾小管上皮细胞转分化[J]．中国现代医学杂志，2005，15：316
8．张海燕，等．结缔组织生长因子在转化生长因子β诱导的肾小管上皮细胞转分化中的作用[J]．中国病理生理杂志，2005，21(1)：179-183
9. Evans RA, et al. TGF-betal mediated fibroblast myofibroblast terminal differentiation the role of Smad proteins[J]. Exp Cell Res, 2003, 282:90-100
10. Tahashi Y, et al. Differential regulation of TGF-beta signal in hepatic stellate cells between acute and chronic rat liver injury[J]. Hepatology, 2002, 35(1): 49-61
11. Caramori ML, Mayer M. Diabetes and nephrophthy corrupting nephrolhypertents [J]. J Am Soc Nephrol, 2003, 12 (3): 273-282
12. Wunderlich K,et al. Expression of connective tissue growth factor (CTGF) mRNA in plaques of human anterior subcapsular cataracts and membranes of posterior capsule opacification[J]. Curr Eye, 2000, 21(2):627
13. Wormstone IM, Characterisation of TGF-beta2 signalling and function in a human lens cell line[J]. Exp Eye Res, 2004, 78(3): 705-14
14. Gitlin L, Karelsky S, Andino R. Short interference RNA confers intracellular antiviral immunity in human cells[J]. Nature, 2002, 418: 430-434
1. Spalton DJ. Posterior capsular opacification after cataract surgery[J]. Eye, 1999, 13:489-492
2. Bradham DM, Igarashi A, Potter RL, Grotendorst GR. Connective tissue growth factor:A cysteine-rich mitogen secreted by human vascular endothelial cells is related to the src-induced immediate early gene product cef-10[J]. J Cell Biol,1991,114:1285-1294
3. Grotendorst GR. Connective tissue growth factor: A mediator of tgf-beta action on fibroblasts[J]. Cytokine Growth Factor Rev, 1997, 8: 171-179
4. Fan WH, Pech M, Karnovsky MJ. Connective tissue growth factor (ctgf) stimulates vascular smooth muscle cell growth and migration in vitro[J].Eur J Cell Biol, 2000, 79:915-923
5. Frazier K,Williams S, Kothapalli D, Klapper H, Grotendorst GR. Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor[J]. J Invest Dermatol,1996,107: 404-411
6. Chen CM, Wang LF, Chou HC, Lang YD, Lai YP. Up-regulation of connective tissue growth factor in hyperoxia-induced lung fibrosis[J]. Pediatr Res, 2007, 62:128-133
7. Zhang C, Meng X, Zhu Z, Liu J, Deng A. Connective tissue growth factor regulates the key events in tubular epithelial to myofibroblast transition in vitro[J]. Cell Biol Int,2004, 28:863-873
8. Wunderlich K, Pech M, Eberle AN, Mihatsch M, Flammer J, Meyer P. Expression of connective tissue growth factor (ctgf) mrna in plaques of human anterior subcapsular cataracts and membranes of posterior capsule opacification[J].Curr Eye Res, 2000, 21:627-636
9. Kolch W. The regulation of the Ras/Raf/MEK/ERK pathway by protein interactions[J].Biochem,2000, 351: 289-294
10. Turjanski AG,Vaque JP, Gutkind JS. Map kinases and the control of nuclear events[J].Oncogene, 2007, 26: 3240-3253
11. Xie S, Sukkar MB, Issa R, Oltmanns U,Nicholson AG,Chung KF. Regulation of tgf-beta 1-induced connective tissue growth factor expression in airway smooth muscle cells[J]. Am J Physiol Lung Cell Mol Physiol, 2005, 288:L68-76
12. Yang DD, Kuan CY, Whitmarsh AJ, Rinc(?)n M, Zheng TS, Davis RJ, Rakic P, Flavell RA. Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene[J]. Nature, 1997, 389:865-870
13. Kumagae Y, Zhang Y, Kim OJ, Miller CA. Human c-Jun N-terminal kinase expression and activation in the nervous system[J]. Brain Res Mol Brain Res, 1999, 67:10-17
14. Gupta S, Barrett T, Whitmarsh A J, Cavanagh J, Sluss HK, D(?)rijard B, Davis RJ. Selective interaction of JNK protein kinase isoforms with transcription factors[J]. EMBO J, 1996, 15:2760-2770
15. Engelbrecht AM, Niesler C, Page C. p38 and JNK have distinct regulatory functions on the development of apoptosis during simulated ischaemia and reperfusion in neonatal cardiomyocytes[J]. Basic Res Cardiol, 2004, 99:338-350
16．姚毓奇，李晓玫．JNK信号通路研究进展[J]．细胞生物学杂志，2005，27：242-246
17. Widmann C, Gibson S, Jarpe MB, Johnson GL. Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human[J]. Physiol Rev, 1999, 79: 143-180
18. Smith JL, Schaffner AE, Hofmeister JK, et al. ets-2 is a target for an akt (Protein kinase B)/jun N-terminal kinase signaling pathway in macrophages of motheaten-viable mutant mice[J]. Mol Cell Biol, 2000, 20:8026-8034
19. Huang C, Rajfur Z, Botchers C, Schaller MD, Jacobson K. JNK phosphorylates paxillin and regulates cell migration[J]. Nature, 2003, 424:219-223
20. He T, Stepulak A, Holmstr(o｜¨)m TH, Omary MB, Eriksson JE. The intermediate filament protein keratin 8 is a novel cytoplasmic substrate for c-Jun N-terminal kinase. J Biol Chem, 2002, 277:10767-10774
21. Choi J, Park SY, Joo CK. Hepatocyte growth factor induces proliferation of lens epithelial cells through activation of erk1/2 and jnk/sapk[J]. Invest Ophthalmol Vis Sci, 2004, 45:2696-2704
22．李怀富，韩从辉，王玉新，et al．Akt/蛋白激酶B信号传导通路在慢性移植肾肾病早期病变中的作用[J]．中华器官移植杂志，2007，28：290-294
23．夏曙，于世英．PI3K/Akt信号转导通路在恶性肿瘤中的研究进展[J]．肿瘤，2006， 26: 576-578
24. Basile JR, Afkhami T, Gutkind JS. Semaphorin 4D/plexin-Bl induces endothelial cell migration through the activation of PYK2, Src, and the phosphatidylinositol 3-kinase-PKB path-way[J]. Mol Cell Biol,2005,25:6889-6898.
25. Nomura M, Ichimatsu D, Moritani S, et al. Inhibition of epidermal growth factor-induced cell transformation and PKB activation by caffeine[J]. Mol Carcinog,2005, 44: 67-76
26. Belyanskaya LL, Hopkins-Donaldson S, Kurtz S, et al. Cisplatin activates Akt in small cell lung cancer cells and attenuates apoptosis by surviving upregulation[J]. Int J Cancer, 2005,117: 755-763
27. Varma S, Lal BK,Zheng R, et al. Hyperglycemia alters PI3K and Akt signaling and leads to endothelial cell proliferative dysfunction[J].Am J Physiol Heart Cire Physiol,2005,289:1744-1751
28. Katayama K,Fujita N, Tsuruo T. PKB/protein kinase B-independent phosphorylation and inactivation of WEElHu promote cell cycle progression at G2/M transition[J]. Mol Cell Biol, 2005, 25: 5725-5737
29. Grille SJ, Bellacosa A, Upson, et al. The protein kinase akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines[J]. Cancer Res, 2003, 63: 2172-2178
30. Jiang Q, Zhou C, Bi Z, Wan Y. Egf-induced cell migration is mediated by erk and pi3k/akt pathways in cultured human lens epithelial cells[J]. J Ocul Pharmacol Ther,2006, 22: 93-102
31. Yao K, Ye PP, Tan J, Tang XJ, Shen Tu XC. Involvement of pi3k/akt pathway in tgf-beta2-mediated epithelial mesenchymal transition in human lens epithelial cells[J].Ophthalmic Res, 2008, 40: 69-76
1. Spalton DJ. Posterior capsular opacification after cataract surgery[J]. Eye, 1999, 13:489-492
2. Bradham DM, Igarashi A,Potter RL, Grotendorst GR. Connective tissue growth factor:A cysteine-rich mitogen secreted by human vascular endothelial cells is related to the src-induced immediate early gene product cef-10[J]. J Cell Biol,1991,114:1285-1294
3. Grotendorst GR. Connective tissue growth factor: A mediator of tgf-beta action on fibroblasts[J]. Cytokine Growth Factor Rev, 1997, 8: 171-179
4. Fan WH, Pech M, Karnovsky MJ. Connective tissue growth factor (ctgf) stimulates vascular smooth muscle cell growth and migration in vitro[J]. Eur J Cell Biol, 2000,79: 915-923
5. Frazier K,Williams S, Kothapalli D, Klapper H, Grotendorst GR. Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor[J]. J Invest Dermatol,1996,107:404-411
6. Chen CM, Wang LF, Chou HC, Lang YD, Lai YP. Up-regulation of connective tissue growth factor in hyperoxia-induced lung fibrosis[J].Pediatr Res, 2007, 62:128-133
7. Zhang C, Meng X, Zhu Z, Liu J, Deng A. Connective tissue growth factor regulates the key events in tubular epithelial to myofibroblast transition in vitro[J]. Cell Biol Int,2004, 28:863-873
8. Wunderlich K, Pech M, Eberle AN, Mihatsch M, Flammer J, Meyer P. Expression of connective tissue growth factor (ctgf) mrna in plaques of human anterior subcapsular cataracts and membranes of posterior capsule opacification[J]. Curr Eye Res, 2000, 21:627-636
9. Liu J, Hales AM, Chamberlain CG,McAvoy JW. Induction of cataract-like changes in rat lens epithelial explants by transforming growth factor beta[J]. Invest Ophthalmol Vis Sci, 1994, 35: 388-401
10. Frezzotti R, Caporossi A, Mastrangelo D,Hadjistilianou T, Tosi P, Cintorino M,Minacci C. Pathogenesis of posterior capsular opacification. Part ii:Histopathological and in vitro culture findings[J]. J Cataract Refract Surg, 1990,16: 353-360
11. Chen L, Liu BC, Zhang XL, Zhang JD, Liu H, Li MX. Influence of connective tissue growth factor antisense oligonucleotide on angiotensin ii-induced epithelial mesenchymal transition in hk2 cells[J]. Acta Pharmacol Sin, 2006, 27:1029-1036
12. Burns WC, Twigg SM, Forbes JM, Pete J, Tikellis C, Thallas-Bonke V, Thomas MC,Cooper ME, Kantharidis P. Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition:Implications for diabetic renal disease[J]. J Am Soc Nephrol, 2006, 17: 2484-2494
13. Lois N, Dawson R, McKinnon AD, et al.A new model of posterior capsule opacification in rodents[J]. Invest Ophthalmol Vis Sci, 2003, 8(44): 3450-3457
14. Cobo LM, Ohsawa E, Chandler D, et al. Pathogenesis of capsular opacification after extracapsular cataract extraction: an animal model[J]. Ophthalmology, 1984, 91(7):857-863
15. Novotny GE, Pau H. Myofibroblast-like cells in human anterior capsular cataract[J].Virchows Arch APathol Anat Histopathol, 1984, 404: 393-401
16. Pau H, Novotny GE, Arnold G. Ultrastructural investigation of extracellular structures in subcapsular white corrugated cataract (anterior capsular cataract) [J]. Graefes Arch Clin Exp Ophthalmol, 1985, 223: 96-100
17. Hales AM, Schulz MW, Chamberlain CG, McAvoy JW. Tgf-beta 1 induces lens cells to accumulate alpha-smooth muscle actin, a marker for subcapsular cataracts[J]. Curr Eye Res, 1994,13:885-890
18. Kato K, Kurosaka D, Nagamoto T. Apoptotic cell death in rabbit lens after lens extraction[J]. Invest Ophthalmol Vis Sci, 1997, 38: 2322-2330
19. Ihn H. Pathogenesis of fibrosis: role of TGF-b and CTGF[J]. Curr Opin Rheumatol,2002,14:681-695
20. Chen MM, et al. CTGF expression is induced by in cardiac fibroblasts and cardiac myocytes: a potential role in heart fibrosis[J]. J Mol Cell Cardiol, 2000, 32: 1805
21. Duncan MR, Frazier KS, Abramson S, Williams S, Klapper H, Huang X, Grotendorst GR. Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: Down-regulation by camp[J]. FASEB J, 1999, 13:1774-1786
22. Grotendorst GR, Rahmanie H, Duncan MR. Combinatorial signaling pathways determine fibroblast proliferation and myofibroblast differentiation[J]. FASEB J, 2004,18: 469-479
1. Apple DJ, Peng Q, Visessook N, et al. Eradication of posterior capsule opacification:documentation of a marked decrease in Nd:YAG laser posterior capsulotomy rates noted in an analysis of 5416 pseudophakic human eyes obtained postmortem[J].Ophthalmology, 2001,108: 505-518
2. Sundelin K, Sjostrand J. Posterior capsule opacification 5 years after extracapsular cataract extraction [J]. J Cataract Refract Surg, 1999, 25(2): 246-250
3. Schaumberg DA, Dana MR, Christen WG, et al. A systematic overview of the incidence of posterior capsule opacification[J]. Ophthalmology, 1998,105(7):1213-1221
4. Spalton DJ. Posterior capsular opacification after cataract surgery[J]. Eye, 1999, 13:489-492
5. Bradham DM, Igarashi A, Potter RL, Grotendorst GR. Connective tissue growth factor:A cysteine-rich mitogen secreted by human vascular endothelial cells is related to the src-induced immediate early gene product cef-10[J]. J Cell Biol, 1991,114:1285-1294
6. Grotendorst GR. Connective tissue growth factor: A mediator of tgf-beta action on fibroblasts[J]. Cytokine Growth Factor Rev, 1997, 8: 171-179
7. Fan WH, Pech M, Karnovsky MJ. Connective tissue growth factor (ctgf) stimulates vascular smooth muscle cell growth and migration in vitro[J]. Eur J Cell Biol, 2000, 79:915-923
8. Frazier K,Williams S, Kothapalli D, Klapper H, Grotendorst GR. Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor[J]. J Invest Dermatol, 1996,107: 404-411
9. Chen CM, Wang LF, Chou HC, Lang YD, Lai YP. Up-regulation of connective tissue growth factor in hyperoxia-induced lung fibrosis[J]. Pediatr Res, 2007, 62:128-133
10. Zhang C, Meng X, Zhu Z, Liu J, Deng A. Connective tissue growth factor regulates the key events in tubular epithelial to myofibroblast transition in vitro[J]. Cell Biol Int, 2004,28: 863-873
11. Wunderlich K, Pech M, Eberle AN, Mihatsch M, Flammer J, Meyer P. Expression of connective tissue growth factor (ctgf) mrna in plaques of human anterior subcapsular cataracts and membranes of posterior capsule opacification[J]. Curr Eye Res, 2000, 21:627-636
12. Brigstock DR. The connective tissue growth factor/cysteine-rich61/nephroblastoma overexpressed (CCN) family[J]. Endocr Rev, 1999, 20: 189-206
13. Lau LF, Lam SC.The CCN family of angiogenic regulators: the integrin connection[J].Exp Cell Res, 1999, 248: 44-57
14. Perbal B. The CCN family of genes: a brief history[J]. Mol Pathol, 2001, 54: 103-104
15. Perbal B. NOV (nephroblastoma overexpressed) and the CCN family of genes:structural and functional issues[J]. Mol Pathol, 2001, 54: 57-79
16. Bork P. The modular architecture of a new family of growth regulators related to connective tissue growth factor[J]. FEBS Lett, 1993, 327: 125-130
17. Ristimaki A, Honkanen N, Jankala H, Sipponen P, Harkonen M. Expression of cyclooxygenase-2 in human gastric carcinoma[J]. Cancer Res, 1997, 57: 1276-1280
18. Thun MJ, Namboodiri MM, Calle EE, et al. Aspirin use and risk of fatal cancer[J].Cancer Res, 1993, 53:1322-1327
19. Uefuji K, Ichikura T, Mochizuki H. Expression of cyclooxygenase-2 in human gastric adenomas and adenocarcinomas[J]. J Surg Oncol, 2001, 76: 26-30
20.Ihn H. Pathogenesis of fibrosis: role of TGF-b and CTGF[J]. Curr Opin Rheumatol,2002,14: 681-695
21. Chen Y, Segarini P, Raoufi F, Bradham D, Leask A. Connective tissue growth factor is secreted through the Golgi and is degraded in the endosome[J]. Exp Cell Res, 2001, 271:109-117
22. Leask A, Abraham DJ. The role of connective tissue growth factor, a multifunctional matricellular protein, in fibroblast biology[J]. Biochem Cell Biol, 2003, 81: 355-363
23. Chen CC, Chen N, Lau LF. The angiogenic factors Cyr61 and connective tissue growth factor induce adhesive signaling in primary human skin fibroblasts[J]. J Biol Chem,2001, 276:10443-10452
24. Ball DK, Rachfal AW, Kemper SA, Brigstock D. The heparinbinging 10kDa fragment of connective tissue growth factor (CTGF) containing module 4 alone stimulates cell adhesion[J]. J Endocrinol, 2003, 176: R1-R7
25. Brigstock DR, Steffen CL, Kim GY, Vegunta RK, Diehl JR, Harding PA. Purification and characterization of novel heparin-binding growth factors in uterine secretory fluids.Identification as heparin-regulated Mr 10,000 forms of connective tissue growth factor[J]. J Biol Chem, 1997, 272: 20275-20282
26. Kothapalli D, Grotendorst GR. CTGF modulates cell cycle progression in CAMP2 arrested NRK fibroblasts[J]. J Cell Physiol, 2000,182 (1) : 119-123
27. Shimo T, Nakanishi T, Nishida T, Asano M, Kanyama M, Kuboki T, Tamatani T, Tezuka K, Takemura M, Matsumura T, Takigawa M. Connective tissue growth factor induces the proliferation, migration, and tube formation of vascular endothelial cells in vitro and angiogenesis in vivo[J]. J Biochem, 1999,126 :137-145
28. Babic AM, Chen CC, Lau LF. Fispl2/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin alphavbeta3, promotes endothelial cell survival, and induces angiogenesis in vivo[J]. Mol Cell Biol, 1999, 19:2958-2966
29. Wormstone IM, Tamiya S, Eldred JA, et al. Characterisation of TGF-beta signalling and function in a human lens cell line[J]. Exp Eye Res, 2004, 78 (3): 705-714
30. Igarashi A, Okochi H, Bradham DM, Grotendorst GR. Regulation of connective tissue growth factor gene expression in human skin fibroblasts and during wound repair[J].Mol Biol Cell, 1993, 4: 637-645
31. Caramori ML, Mayer M. Diabetes and nephrophthy corrupting nephrolhypertents[J]. J Am Soc Nephrol, 2003,12 (3): 273-282
32. Holmes A, Abraham DJ, Sa S, et al. CTGF and SMADs, maintenance of scleroderma phenotype is independent of SMAD signaling[J]. J Biol Chem, 2001, 276: 10594-10601
33. Leask A, Sa S, Holmes A, et al. The control of ccn2 (ctgf) gene expression in normal and scleroderma fibroblasts [J]. Mol Pathol, 2001, 54: 180-183
34. Leivonen SK, Hakkinen L, Liu D, et al . Smad3 and extracellular signal-regulated kinase 1/2 coordinately mediate transforming growth factor-beta-induced expression of connective tissue growth factor in human fibroblasts[J]. J Invest Dermatol, 2005, 124(6) : 1162-1169
35. Leask A, Holmes A, Abraham DJ, et al . CTGF gene regulation, requirements for its induction by TGF-β in fibroblast[J]. J Bi ol Chem, 2003, 278 (15) : 13008-13015
36. Ishida I, Saika S, Okada Y, et al. Growth factor depositi on in anterior subcapsular cataract[J]. J Cataract Refract Surg 2005,31 (6) : 1219-1225
37. Chambers RC, Leoni P, Blanc-Brude OP, et al. Thrombin is a potent inducer of connective tissue growth factor production via proteolytic activation of protease-activated receptor-1[J]. J Biol Chem, 2000, 275: 35584-35589
38. Dammeier J, Beer HD, Brauchle M, Werner S: Dexamethasone is a novel potent inducer of connective tissue growth factor expression: implications for glucocorticoid therapy [J].J Biol Chem, 1998, 273:18185-18190
39. Duncan MR, Frazier KS, Abramson S, et al. Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: down-regulation by cAMP[J]. FASEB J, 1999,13: 1774-1786
40. Ricupero DA, Rishikof DC, Kuang PP, et al. Regulation of connective tissue growth factor expression by prostaglandin E(2)[J]. Am J Physiol, 1999, 277: L1165-L1171
41. Suzuma K, Naruse K, Suzuma I, et al. Vascular endothelial growth factor induces expression of connective tissue growth factor via KDR, Flt1,and phosphatidylinositol 3-kinase-akt-dependent pathways in retinal vascular cells[J]. J Biol Chem, 2000, 275:40725-40731
42. Pereira RC, Durant D, Canalis E. Transcriptional regulation of connective tissue growth factor by cortisol in osteoblasts[J]. Am J Physiol Endocrinol Metab, 2000, 279:E570-E576
43. Stanhope-Baker P, Williams BR. Identification of connective tissue growth factor as a target of WT1 transcriptional regulation[J]. J Biol Chem, 2000, 275: 38139-38150
44. Abraham DJ, Shiwen X, Black CM, et al. Tumor necrosis factor-alpha suppresses the induction of connective tissue growth factor by transforming growth factor-beta in normal and scleroderma fibroblasts[J]. J Biol Chem, 2000, 275:15220-15225
45. Sudhaakar J, Ravindran RD, Natchiar G Analysis of complications in 1000 cases of posterior chamber intra ocular lens implantation [J]. Indian J Ophtahalmol, 1989, 37:78-79
46. Moisseiev J, Bartov E, Schochat A, Blumenthal M. Long-term study of the prevalence of capsular opacification following extracapsular cataract extraction [J]. J Cataract Refract Surg, 1989,15:531-533
47. Knight-Nanan D, O'Keefe M, Bowell R. Outcome and complications of intraocular lenses in children with cataract[J]. J Catrarct Refract Surg, 1996, 22: 730-736
48. Frezzotti R, Caporossi A. Pathogenesis of posterior capsular opacification. Part ####.Epidemiological and clinico-statistical data[J]. J Cataract Refract Surg, 1990, 16:347-352
49. Nagata T, Watanabe I. Optic sharp edge or convexity: comparison of effects on posterior capsular opacification[J]. Jpn J Ophthalmol, 1996, 40: 397-403
50.Ursell PG,Spalton DJ, Pande MV, Hollick EJ, Barman S, Boyce J, Tilling K.Relationship between intraocular lens biomaterials and posterior capsule opacification[J].J Cataract Refract Surg, 1998, 24: 352-360
51. Scaramuzza A, Fernando GT, Crayford BB. Posterior capsule opacification and lens epithelial cell layer formation: hydroview hydrogel versus AcrySof acrylic intraocular lenses[J]. J Cataract Refract Surg, 2001, 27:1047-1054
52. McDonnell PJ, Krause W, Glaser BM. In vitro inhibition of lens epithelial cell proliferation and migration[J]. Ophthalmic Surg, 1988,19:25-30
53. McAvoy JW, Chamberlain CG.Fibroblast growth factor(FGF) induces different responses in lens epithelial cells depending on its concentration[J]. Development, 1989,107: 221-228
54. Cobo LM,Ohsawa E,Chandler D, Arguello R, George G. Pathogenesis of capsular opacification after extracapsular cataract extraction. An animal model[J].Ophthalmology, 1984, 91: 857-863
55. Behar-Cohen FF, David T, D'Hermies F,Pouliquen YM, Buechler Y, Nova MP, Houston LL,Courtois Y. In vivo inhibition of lens regrowth by fibroblast growth factor 2-saporin[J]. Invest Ophthalmol Vis Sci, 1995, 36: 2434-2448
56. Nagamoto T, Bissen-Miyajima H. A ring to support the capsular bag after continuous curvilinear capsulorhexis[J]. J Cataract Refract Surg, 1994, 20: 417-420
57. Liu CS, Wormstone IM,Duncan G,Marcantonio JM, Webb SF, Davies PD. A study of human lens cell growth in vitro. A model for posterior capsule opacification[J]. Invest Ophthalmol Vis Sic, 1996, 37: 906-914
58. Hollick EJ, Spalton DJ, Ursell PG, et al. The effect of polymethylmethacrylate, silicone,and polyacrylic intraocular lenses on posterior capsular opacification 3 years after cataract surgery[J]. Ophthalmology, 1999,106: 49-54
59. Hynes RO. Integrins: a family of cell surface receptors[J]. Cell, 1987, 48: 549-554
60. Ruosiahti E, Pierschbacher MD. New perspectives in cell adhesion: RGD and integrins[J]. Science, 1987, 238: 491-497
61. Nishi O,Nishi K, Akaishi T, et al. Detection of cell adhesion molecules in lens epithelial cells of human cataracts[J]. Invest Ophthalmol Vis Sci, 1997, 38: 579-585
62. Nishi O,Nishi K, Mano C, et al. Inhibition of migrating lens epithelial cells by blocking the adhesion molecule integrin: a preliminary report[J]. J Cataract Refract Surg,1997,23:860-865
63. Wallentin N,Wickstrom K,Lundberg C. Effect of cataract surgery on aqueous TGF-beta and lens epithelial cell proliferation[J].Invest Ophthalmol Vis Sci, 1998, 39:1410-1418.
64. Pau H, Novotny GE, Arnold G. Ultrastructural investigation of extracellular structures in subcapsular white corrugated cataract(anterior capsular cataract) [J]. Graefes Arch Clin Exp Ophthalmol, 1985, 223: 96-100
65.Hatae T, Ishibashi T, Yoshitomi F, Shibata Y. Immunocytochemistry of types Ⅰ-Ⅳ collagen in human anterior subcapsular cataracts[J]. Graefes Arch Clin Exp Ophthalmol,1993, 231: 586-590
66. McAvoy JW, Schulz MW, Maruno KA, Chamberlain CG, Lovicu FJ. TGF-beta induced cataract is characterized by epithelial-mesenchymal transition and apoptosis[J]. Invest Ophthalmol Vis Sci, 1998, 39(4): 30
67. Bassols A, Massague J. Transforming growth factor beta regulates the expression and structure of extracellular matrix chondroitin/dermatan sulfate proteoglycans[J]. J Biol Chem, 1988, 263: 3039-45
68. Nishi O, Nishi K, Fujiwara T, et al. Effects of the cytokines on the proliferation of and collagen synthesis by human cataract lens epithelial cells[J]. Br J Ophthalmol, 1996, 80:63-68
69. Massague J. The transforming growth factor-beta family[J]. Annu Rev Cell Biol, 1990, 6:597-641
70. Overall CM, Wrana JL, Sodek J. Independent regulation of collagenase, 72-kDa progelatinase, and metalloendoproteinase inhibitor expression in human fibroblasts by transforming growth factor-beta[J]. J Biol Chem, 1989, 264: 1860-1869
71. Duncan G, Wormstone IM, Liu CS, et al. Thapsigargin-coated intraocular lenses inhibit human lens cell growth[J]. Nat Med, 1997, 3:1026-1028
72. Brewitt B, Clark JL Growth and transparency in the lens, an epithelial tissue, stimulated by pulses of PDGF[J]. Science, 1988, 242: 777-779
73. Liu J, Hales AM, Chamberlain CG, McAvoy JW. Induction of cataract-like changes in rat lens epithelial explants by transforming growth factor beta[J]. Invest Ophthalmol Vis Sci, 1994,35: 388-401
74. Lee EH, Joo CK. Role of transforming growth factor-beta in transdifferentiation and fibrosis of lens epithelial cells[J]. Invest Ophthalmol Vis Sci, 1999, 40: 2025-2032
75. Cousins SW, McCabe MM, Danielpour D, Streilein JW. Identification of transforming growth factor-beta as an immunosuppressive factor in aqueous humor [J]. Invest Ophthalmol Vis Sci, 1991, 32: 2201-2211
76. Streilein JW. Ocular immune privilege and the Faustian dilemma. The Proctor lecture[J].Invest Ophthalmol Vis Sci, 1996, 37:1940-1950
77. Kurosaka D, Kato K,Nagamoto T, Negishi K. Growth factors influence contractility and alpha-smooth muscle actin expression in bovine lens epithelial cells [J]. Invest Ophthalmol Vis Sci, 1995, 36: 1701-1708
78. Gordon-Thomson C, de Iongh RU,Hales AM, et al. Differential cataractogenic potency of TGF-beta1,-beta2, and -beta3 and their expression in the postnatal rat eye[J]. Invest Ophthalmol Vis Sci, 1998, 39:1399-1409
79. Kaji Y, Mita T, Obata H, et al. Expression of transforming growth factor beta superfamily and their receptors in the corneal stromal wound healing process after excimer laser keratectomy [letter][J]. Br J Ophthalmol, 1998, 82:462-463
80. Davidson MG, Morgan DK, McGahan MC. Effect of surgical technique on in vitro posterior capsule opacification[J]. J Cataract Refract Surg. 2000, 26: 1550-1554
81.Nishi O, Nishi K, Sakanishi K. Inhibition of migrating lens epithelial cells at the capsular bend created by the rectangular optic edge of a posterior chamber intraocular lens[J]. Ophthalmic Surg Lasers, 1998, 29: 587-594
82. Nishi O,Nishi K, Saitoh I, Sakanishi K. Inhibition of migrating lens epithelial cells by sustained release of ethylenediaminetetraacetic acid[J]. J Cataract Refract Surg, 1996b,22: 863-868
83. Park SK, Kim J, Seomun Y, et al.Hydraogen Peroxide is a novel inducer of connective tissue growth factor[J]. Biochimical and Biophysical Research Communication, 2001,284 (4): 966-971