iNOS和MMP-2在豚鼠形觉剥夺性近视中的表达变化
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摘要
背景和目的
近200年来,对近视机制的研究一直是眼科学研究的重要课题。自1977年Wiesel首次用缝合恒河猴眼睑的方法成功诱导出形觉剥夺性近视(formdeprivation myopia,FDM)以来,随着建立近视动物模型方法的日趋完善,对近视的发生发展及转归有了深入研究。目前的研究表明:形觉剥夺主要通过局部视网膜机制来调控邻近巩膜的生长,形觉剥夺可导致视网膜上的多种神经递质与生长因子水平发生改变,它们作为一级信使作用于视网膜色素上皮细胞和脉络膜,使之产生二级信使,再作用于巩膜,进而通过影响巩膜细胞外基质(extracellularmaterial,ECM)的合成或降解,使巩膜重新塑形,眼轴过度延长,形成近视。
形觉剥夺性近视以后极部巩膜的变薄为一个重要的特征,其主要原因是因为巩膜细胞外基质的重塑。基质金属蛋白酶(matrix metalloproteinase,MMPs)是广泛存在于动植物体内的能够降解细胞外基质(ECM)的一组锌离子依赖性蛋白酶系。已有实验表明,小鸡和豚鼠的形觉剥夺眼后极部巩膜活性MMP-2明显增加,恢复期活性MMP-2减少,提示MMP-2与形觉剥夺性近视有关。一氧化氮(NO)是近20年来新发现的视网膜神经递质,与视网膜的发育、视觉兴奋和视觉信息的传导有关。NO由一氧化氮合酶(nitric oxide synthase,NOS)催化左旋精氨酸(L-Arginine,L-Ag)而合成。Fujiis等研究发现,在新生鸡单眼形觉剥夺过程中,视网膜-色素上皮-脉络膜的三种NOS亚型中,只有诱导型一氧化氮合酶(i-NOS)表达水平明显下降,这提示i-NOS可能参与形觉剥夺性近视的形成。
尽管iNOS和MMP-2在形觉剥夺性近视动物模型的变化已分别被证实,但是两者在形觉剥夺性近视的形成过程是否有内在联系尚未被研究。本研究拟建立豚鼠形觉剥夺性近视模型,应用免疫组织化学染色法,研究iNOS和MMP-2在形觉剥夺性近视豚鼠眼后极部的表达变化以及两者的相关性,以进一步揭示形觉剥夺性近视产生的机制,从而为近视的防治提供有价值的参考。
材料与方法
2周龄健康花色豚鼠60只,随机分为4组:Ⅰ组:未遮盖组;Ⅱ组:右眼遮盖3周组;Ⅲ组:右眼遮盖6周组;Ⅳ组:右眼遮盖9周组。Ⅱ、Ⅲ和Ⅳ组均以右眼为实验眼,将直径为15mm的半透明眼罩粘于豚鼠右眼周围皮肤上,并在眼罩下方留有狭长缝隙供透气用;左眼不作任何处理为自身对照组。于不同时间点检测各组豚鼠的双眼屈光度、眼轴长度,HE染色光学显微镜下观察视网膜巩膜病理变化,免疫组织化学染色法检测视网膜iNOS和巩膜MMP-2的蛋白表达。
所有数据均用(?)±s表示,统计学处理采用SPSS13.0统计软件,双眼比较采用配对t检验,组间比较采用单因素方差分析,多个样本均数之间进行LSD两两比较,相关性采用Person积差相关分析,以a=0.05为检验水准。
结果
1.遮盖眼与对照眼屈光度、眼轴比较:遮盖眼由实验前远视眼渐变为近视眼,并随遮盖时间延长,近视度数加深,眼轴延长。遮盖眼与对照眼(正常眼和自身对照眼)相比在统计学上差异具有显著性(P＜0.05),成功建立了实验性近视动物模型。
2.视网膜、巩膜形态学变化:遮盖3、6、9周后,遮盖眼视网膜较自身对照眼和正常对照眼变薄,以内外核层最明显;后极部巩膜变薄、稀疏。
3.免疫组化染色:iNOS在正常和自身对照眼豚鼠的视网膜内呈低水平表达,而在形觉剥夺近视中主要表达于视网膜节细胞层、内核层、感光细胞层和脉络膜间质组织,在神经纤维层和巩膜也有阳性着色。MMP-2主要表达于巩膜,在节细胞层、内核层、感光细胞层也有阳性着色。随着遮盖时间的延长,视网膜iNOS和巩膜MMP-2吸光度值均成增加趋势(P＜0.01)。
4.iNOS和MMP-2的相关性分析:经相关性分析发现,在形觉剥夺的不同阶段,视网膜iNOS和巩膜MMP-2蛋白表达量相关系数为r=0.769,P＜0.05,提示两者蛋白表达具有明显正相关。
结论
1.单眼遮盖可造成豚鼠遮盖眼视网膜中i-NOS和巩膜中MMP-2表达量增加,并随遮盖时间的延长逐渐加强,与近视屈光度增加和眼轴延长趋势相一致,提示iNOS和MMP-2可能参与了形觉剥夺性近视的形成。
2.遮盖眼视网膜iNOS和巩膜MMP-2的表达量在形觉剥夺过程中呈强的正相关。可以推测在形觉剥夺性近视的发展过程中,模糊的物像通过刺激视网膜产生包括NO在内的多种神经递质,直接或间接作用于巩膜,影响MMP-2的表达和活性,最终导致巩膜重塑和近视的形成。
Recent 200 years, the mechanism of myopia has been the focus of scientists' research issues. Since Wiesel built up form deprivation myopia (FDM) on rhesus monkey in 1977 for the first time, people have made a more in-depth research to the occurrence、development and turnover of myopia with this animal model. Current research shows that: form deprivation modulates the development of adjacent sclera mainly through local retinal control mechanism. Form deprivation can lead to changes of various neurotransmitters and growth factors in the retina. As primary messenger, these neurotransmitters and factors act on the retinal pigment epithelium and choroid to produce the secondary messenger, which act on the sclera by influencing the sclera extracellular matrix (ECM) synthesis or degradation, finally make the sclera re-shaped,axial length over-extended and myopia formed.
Form deprivation myopia is characterized by thinning of sclera at posterior pole, which results from scleral extracellular matrix remodeling. Matrix metalloproteinases (MMPs) widely distributed in plants and animals are a group of zinc-dependent protease whose main function is to degrade the extracellular matrix. Experiments have shown that MMP-2 activity in posterior-sclera of form-deprived chicks and guinea pigs eyes increased significantly and decreased in recovery period,which means there is a realationship between MMP-2 and form deprivation myopia. Nitric oxide( NO) is a new class of retinal neurotransmitter discovered in recent years. Nitric oxide plays an important role in the development of the retina and the formation ,regulation, transmission of visual information. Nitric oxide (NO) is synthesized from L-arginine by nitric oxide synthase (NOS) .In 1998, Fujiis found that three isoforms of NOS expressed in neonatal chicken monocular form deprivated retina-pigment epithelium-choroid, but only inducible NOS( iNOS ) level decreased significantly. This indicate i-NOS may be involved in form-deprivation myopia.
Though changes of iNOS and MMP-2 in form-deprivation myopia in animal models have been demonstrated separately, but whether or not there is an intrinsical link between iNOS and MMP-2 in form deprivation myopia has not yet been studied. Our research use immunohistochemistry to study the expression of iNOS and MMP-2 in form-deprivation myopia in guinea pig eyes and the corelation of the two by establishing FDM animal model, which in order to reveal the mechanism of form deprivation myopia and further for the prevention and treatment of myopia.
Materials and Methods
60 twe-week-old healthy multicolor guinea pigs were randomly divided into 4 groups. Group I: Normal control group( not occluded in both eyes ); Group II: the right eye was monocular occluded for 3 weeks; Group III: the right eye was monocular occluded for 6 weeks; Group IV: the right eye was monocular occluded for 9 weeks. All the right eyes in groups II, III, IV underwent form deprivation with translucent goggles(diameter 15mm) and the left eyes were used as control. Before and after occluded for 3 , 6 , 9 weeks, the refractive state and axial length were measured by retinoscope and A-scan ultrasonography respectively, morphological changes in form deprived guinea pigs retina and sclera was observed by routine hematoxylin-eosin (HE) staining, the expression of iNOS protein and MMP-2 protein in retina, choroid and sclera was detected by immunohistochemistry (IHC).
The results are expressed as the mean±the standard error of the mean (SEM).All the datas were analyzed by SPSS 13.0 statistical package. Paired-Samples T test were used to analyze the difference between the experimental and control groups. One-Way ANOVA were used to analyze the difference among the four groups. The relation of two variables was analyzed by the Pearson's correlation analysis. a less than 0.05 was considered statistical significance.
Results
1. Comparison of refraction state and axial length between the occluded eyes and control eyes: The longer the eye was occluded, the axial length was longer, and more severe the myopia was. There was significant differences between the occluded eyes and the control ( normal and self ) eyes (P <0.05), FDM of guinea pig has been successed established.
2. Morphology change in retina and sclera: After occluded for 3, 6, 9 weeks, the posterior retina of the occluded eyes was thinner than that of the control eyes, most obvious in inner and outer nuclear layer,the posterior sclera of the occluded eyes was thin, too.
3. Immunohistochemistry: iNOS was low expressed in the retina in normal and self-controlled eyes, but in FDM eyes,it was mainly expressed in the retinal ganglion cell, inner nuclear, photoreceptor cell and choroid mesenchymal organization. The nerve fiber layer and sclera also had positive staining. MMP-2 was mainly expressed in the sclera, but the ganglion cell layer, inner nuclear layer and photoreceptor cell layer also had positive staining. As form deprivation time prolonged, retinal iNOS and scleral MMP-2 absorbance showed an increasing tendency (P <0.05).
4. Correlation analysis between retinal iNOS and scleral MMP-2 absorbance: Correlation analysis showed that expression of retinal iNOS and scleral MMP-2 protein at different form deprivation stages has obvious positive correlation( r = 0.769, P<0.05)
Conclusions
1. The expression of iNOS in the FDM retina and MMP-2 in the FDM sclera increase according to the monocular deprivation time. This result suggest that retinal iNOS and sclera MMP-2 may be involved in the occurrence of FDM.
2. Expression of retinal iNOS and scleral MMP-2 protein at different form deprivation stages has obvious positive correlation. We can speculate that during form deprivation myopia development process, the fuzzy object-image stimulate the retina to generate a variety of neurotransmitters including NO, which have an directly or indirectly impact of the MMP-2 expression and activity in the sclera, finally result in scleral remodeling and myopia formation.
近200年来,对近视机制的研究一直是眼科学研究的重要课题。自1977年Wiesel首次用缝合恒河猴眼睑的方法成功诱导出形觉剥夺性近视(formdeprivation myopia,FDM)以来,随着建立近视动物模型方法的日趋完善,对近视的发生发展及转归有了深入研究。目前的研究表明:形觉剥夺主要通过局部视网膜机制来调控邻近巩膜的生长,形觉剥夺可导致视网膜上的多种神经递质与生长因子水平发生改变,它们作为一级信使作用于视网膜色素上皮细胞和脉络膜,使之产生二级信使,再作用于巩膜,进而通过影响巩膜细胞外基质(extracellularmaterial,ECM)的合成或降解,使巩膜重新塑形,眼轴过度延长,形成近视。
形觉剥夺性近视以后极部巩膜的变薄为一个重要的特征,其主要原因是因为巩膜细胞外基质的重塑。基质金属蛋白酶(matrix metalloproteinase,MMPs)是广泛存在于动植物体内的能够降解细胞外基质(ECM)的一组锌离子依赖性蛋白酶系。已有实验表明,小鸡和豚鼠的形觉剥夺眼后极部巩膜活性MMP-2明显增加,恢复期活性MMP-2减少,提示MMP-2与形觉剥夺性近视有关。一氧化氮(NO)是近20年来新发现的视网膜神经递质,与视网膜的发育、视觉兴奋和视觉信息的传导有关。NO由一氧化氮合酶(nitric oxide synthase,NOS)催化左旋精氨酸(L-Arginine,L-Ag)而合成。Fujiis等研究发现,在新生鸡单眼形觉剥夺过程中,视网膜-色素上皮-脉络膜的三种NOS亚型中,只有诱导型一氧化氮合酶(i-NOS)表达水平明显下降,这提示i-NOS可能参与形觉剥夺性近视的形成。
尽管iNOS和MMP-2在形觉剥夺性近视动物模型的变化已分别被证实,但是两者在形觉剥夺性近视的形成过程是否有内在联系尚未被研究。本研究拟建立豚鼠形觉剥夺性近视模型,应用免疫组织化学染色法,研究iNOS和MMP-2在形觉剥夺性近视豚鼠眼后极部的表达变化以及两者的相关性,以进一步揭示形觉剥夺性近视产生的机制,从而为近视的防治提供有价值的参考。
材料与方法
2周龄健康花色豚鼠60只,随机分为4组:Ⅰ组:未遮盖组;Ⅱ组:右眼遮盖3周组;Ⅲ组:右眼遮盖6周组;Ⅳ组:右眼遮盖9周组。Ⅱ、Ⅲ和Ⅳ组均以右眼为实验眼,将直径为15mm的半透明眼罩粘于豚鼠右眼周围皮肤上,并在眼罩下方留有狭长缝隙供透气用;左眼不作任何处理为自身对照组。于不同时间点检测各组豚鼠的双眼屈光度、眼轴长度,HE染色光学显微镜下观察视网膜巩膜病理变化,免疫组织化学染色法检测视网膜iNOS和巩膜MMP-2的蛋白表达。
所有数据均用(?)±s表示,统计学处理采用SPSS13.0统计软件,双眼比较采用配对t检验,组间比较采用单因素方差分析,多个样本均数之间进行LSD两两比较,相关性采用Person积差相关分析,以a=0.05为检验水准。
结果
1.遮盖眼与对照眼屈光度、眼轴比较:遮盖眼由实验前远视眼渐变为近视眼,并随遮盖时间延长,近视度数加深,眼轴延长。遮盖眼与对照眼(正常眼和自身对照眼)相比在统计学上差异具有显著性(P＜0.05),成功建立了实验性近视动物模型。
2.视网膜、巩膜形态学变化:遮盖3、6、9周后,遮盖眼视网膜较自身对照眼和正常对照眼变薄,以内外核层最明显;后极部巩膜变薄、稀疏。
3.免疫组化染色:iNOS在正常和自身对照眼豚鼠的视网膜内呈低水平表达,而在形觉剥夺近视中主要表达于视网膜节细胞层、内核层、感光细胞层和脉络膜间质组织,在神经纤维层和巩膜也有阳性着色。MMP-2主要表达于巩膜,在节细胞层、内核层、感光细胞层也有阳性着色。随着遮盖时间的延长,视网膜iNOS和巩膜MMP-2吸光度值均成增加趋势(P＜0.01)。
4.iNOS和MMP-2的相关性分析:经相关性分析发现,在形觉剥夺的不同阶段,视网膜iNOS和巩膜MMP-2蛋白表达量相关系数为r=0.769,P＜0.05,提示两者蛋白表达具有明显正相关。
结论
1.单眼遮盖可造成豚鼠遮盖眼视网膜中i-NOS和巩膜中MMP-2表达量增加,并随遮盖时间的延长逐渐加强,与近视屈光度增加和眼轴延长趋势相一致,提示iNOS和MMP-2可能参与了形觉剥夺性近视的形成。
2.遮盖眼视网膜iNOS和巩膜MMP-2的表达量在形觉剥夺过程中呈强的正相关。可以推测在形觉剥夺性近视的发展过程中,模糊的物像通过刺激视网膜产生包括NO在内的多种神经递质,直接或间接作用于巩膜,影响MMP-2的表达和活性,最终导致巩膜重塑和近视的形成。
Recent 200 years, the mechanism of myopia has been the focus of scientists' research issues. Since Wiesel built up form deprivation myopia (FDM) on rhesus monkey in 1977 for the first time, people have made a more in-depth research to the occurrence、development and turnover of myopia with this animal model. Current research shows that: form deprivation modulates the development of adjacent sclera mainly through local retinal control mechanism. Form deprivation can lead to changes of various neurotransmitters and growth factors in the retina. As primary messenger, these neurotransmitters and factors act on the retinal pigment epithelium and choroid to produce the secondary messenger, which act on the sclera by influencing the sclera extracellular matrix (ECM) synthesis or degradation, finally make the sclera re-shaped,axial length over-extended and myopia formed.
Form deprivation myopia is characterized by thinning of sclera at posterior pole, which results from scleral extracellular matrix remodeling. Matrix metalloproteinases (MMPs) widely distributed in plants and animals are a group of zinc-dependent protease whose main function is to degrade the extracellular matrix. Experiments have shown that MMP-2 activity in posterior-sclera of form-deprived chicks and guinea pigs eyes increased significantly and decreased in recovery period,which means there is a realationship between MMP-2 and form deprivation myopia. Nitric oxide( NO) is a new class of retinal neurotransmitter discovered in recent years. Nitric oxide plays an important role in the development of the retina and the formation ,regulation, transmission of visual information. Nitric oxide (NO) is synthesized from L-arginine by nitric oxide synthase (NOS) .In 1998, Fujiis found that three isoforms of NOS expressed in neonatal chicken monocular form deprivated retina-pigment epithelium-choroid, but only inducible NOS( iNOS ) level decreased significantly. This indicate i-NOS may be involved in form-deprivation myopia.
Though changes of iNOS and MMP-2 in form-deprivation myopia in animal models have been demonstrated separately, but whether or not there is an intrinsical link between iNOS and MMP-2 in form deprivation myopia has not yet been studied. Our research use immunohistochemistry to study the expression of iNOS and MMP-2 in form-deprivation myopia in guinea pig eyes and the corelation of the two by establishing FDM animal model, which in order to reveal the mechanism of form deprivation myopia and further for the prevention and treatment of myopia.
Materials and Methods
60 twe-week-old healthy multicolor guinea pigs were randomly divided into 4 groups. Group I: Normal control group( not occluded in both eyes ); Group II: the right eye was monocular occluded for 3 weeks; Group III: the right eye was monocular occluded for 6 weeks; Group IV: the right eye was monocular occluded for 9 weeks. All the right eyes in groups II, III, IV underwent form deprivation with translucent goggles(diameter 15mm) and the left eyes were used as control. Before and after occluded for 3 , 6 , 9 weeks, the refractive state and axial length were measured by retinoscope and A-scan ultrasonography respectively, morphological changes in form deprived guinea pigs retina and sclera was observed by routine hematoxylin-eosin (HE) staining, the expression of iNOS protein and MMP-2 protein in retina, choroid and sclera was detected by immunohistochemistry (IHC).
The results are expressed as the mean±the standard error of the mean (SEM).All the datas were analyzed by SPSS 13.0 statistical package. Paired-Samples T test were used to analyze the difference between the experimental and control groups. One-Way ANOVA were used to analyze the difference among the four groups. The relation of two variables was analyzed by the Pearson's correlation analysis. a less than 0.05 was considered statistical significance.
Results
1. Comparison of refraction state and axial length between the occluded eyes and control eyes: The longer the eye was occluded, the axial length was longer, and more severe the myopia was. There was significant differences between the occluded eyes and the control ( normal and self ) eyes (P <0.05), FDM of guinea pig has been successed established.
2. Morphology change in retina and sclera: After occluded for 3, 6, 9 weeks, the posterior retina of the occluded eyes was thinner than that of the control eyes, most obvious in inner and outer nuclear layer,the posterior sclera of the occluded eyes was thin, too.
3. Immunohistochemistry: iNOS was low expressed in the retina in normal and self-controlled eyes, but in FDM eyes,it was mainly expressed in the retinal ganglion cell, inner nuclear, photoreceptor cell and choroid mesenchymal organization. The nerve fiber layer and sclera also had positive staining. MMP-2 was mainly expressed in the sclera, but the ganglion cell layer, inner nuclear layer and photoreceptor cell layer also had positive staining. As form deprivation time prolonged, retinal iNOS and scleral MMP-2 absorbance showed an increasing tendency (P <0.05).
4. Correlation analysis between retinal iNOS and scleral MMP-2 absorbance: Correlation analysis showed that expression of retinal iNOS and scleral MMP-2 protein at different form deprivation stages has obvious positive correlation( r = 0.769, P<0.05)
Conclusions
1. The expression of iNOS in the FDM retina and MMP-2 in the FDM sclera increase according to the monocular deprivation time. This result suggest that retinal iNOS and sclera MMP-2 may be involved in the occurrence of FDM.
2. Expression of retinal iNOS and scleral MMP-2 protein at different form deprivation stages has obvious positive correlation. We can speculate that during form deprivation myopia development process, the fuzzy object-image stimulate the retina to generate a variety of neurotransmitters including NO, which have an directly or indirectly impact of the MMP-2 expression and activity in the sclera, finally result in scleral remodeling and myopia formation.
引文
1.McBrien NA,Adams DW.A longitudinal investigation of adult-onset and adult-progression of myopia in an occupational group[J].Invest Ophthalmol Vis Sci,1997,38(2):321-333.
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3.Wiesel TN,Raviola E.Myopia and eye enlargement after neonatal lid fusion in monkeys[J].Nature,1977,266(5597):66-68.
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