背景近年来研究发现，JAK/信号转导及转录激活蛋白3（STAT3）信号转导通路在近视形成和发展中发挥重要作用，AG490是JAK的一种特异抑制剂，因此可抑制JAK2/STAT信号转导，但AG490是否能抑制或延缓近视的进展尚不清楚。
目的探讨玻璃体腔注射酪氨酸激酶选择性抑制剂AG490后STAT3信号通路的活性及其对豚鼠形觉剥夺性近视（FDM）过程中巩膜重塑的影响。
方法采用随机数字表法将40只豚鼠随机分为正常对照组、模型对照组、PBS对照组和AG490治疗组，其中模型对照组、PBS对照组和AG490治疗组均用半透明眼罩遮盖右眼4周以制备FDM模型，自遮盖当天向PBS对照组和AG490治疗组豚鼠实验眼玻璃体腔分别注射PBS或AG490各5 μl，每2天注射1次，至遮盖结束。分别于实验前及实验后4周检测各组豚鼠双眼的屈光度和眼轴长度，实验4周时摘取实验眼眼球制备巩膜组织切片，采用常规组织病理学检查观察实验眼巩膜的形态学改变，采用免疫组织化学及逆转录PCR（RT-PCR）技术检测各组实验眼巩膜组织中STAT3、p-STAT3、基质金属蛋白酶2（MMP-2）蛋白及其mRNA的表达。
结果与正常对照组比较，模型对照组、PBS对照组和AG490治疗组豚鼠实验眼的近视屈光度增加，眼轴明显增长，AG490治疗组眼轴长度分别短于模型对照组和PBS对照组，4个组间差异均有统计学意义（屈光度： F＝89.063， P＝0.000；眼轴长度： F＝96.145， P＝0.000）。正常对照组豚鼠巩膜组织中STAT3、MMP-2、p-STAT3表达极微弱，AG490治疗组巩膜组织中STAT3、p-STAT3、MMP-2相对表达量（A值）分别为0.064±0.016、0.019±0.002和0.155±0.052，分别低于模型对照组的0.129±0.008、0.071±0.021、0.425±0.004和PBS对照组的0.130±0.004、0.069±0.002、0.421±0.042，差异均有统计学意义（STAT3： t＝4.641，9.364，均 P<0.01; p-STAT3： t＝4.638、4.488，均 P<0.05；MMP-2： t＝9.123、9.029，均 P<0.05），AG490治疗组的表达仍高于正常对照组（ t＝2.674、2.251、2.682，均 P<0.05）。AG490治疗组巩膜组织STAT3 mRNA和MMP-2 mRNA的相对表达量分别为0.295±0.032和0.569±0.019，明显低于模型对照组的0.547±0.015和0.782±0.051以及PBS对照组的0.544±0.015和0.779±0.048，差异均有统计学意义（STAT3 mRNA： t＝10.115、11.703，均 P<0.01；MMP-2 mRNA： t＝9.218、9.494，均 P<0.01），但与正常对照组STAT3 mRNA水平比较仍有明显上调，差异均有统计学意义（ t＝2.576、3.565，均 P<0.05）。
结论AG490可一定程度上阻断FDM眼巩膜组织中STAT3信号转导通路的激活，进而调控其下游靶基因 MMP-2的转录和表达，减缓 FDM眼巩膜的重塑过程，从而一定程度上抑制轴性近视的进展。
BackgroundJAK/ signal transducer and activator of transcription 3 (STAT3) signal pathway plays a critical role during the sclera remodeling of experimental myopia.As a tyrosine kinase inhibitor, AG490 can inhibit the activation of this pathway.But whether AG490 plays a role in delaying the development of myopia is not completely clear.
ObjectiveThis study was to investigate the inhibition of AG490 to activation of STAT3 signaling pathway and the sequential arresting effect on the sclera remodeling in form-deprived myopia (FDM) models.
MethodsForty guinea pigs were randomly divided into the normal control group, model control group, PBS control group and AG490 treatment group.FDM models were established by the occlusion of the right eyes of guinea pigs for consecutive 4 weeks using translucent goggles in the model control group, PBS control group and AG490 treated group, and 25 μl PBS or AG490 were respectively injected into vitreous since the first day of modeling in two-day interval till the fourth week in the PBS control group and AG490 treated group.Refractive state and axial length were examined with retinoscopy and A-scan ultrasonography before and 4 weeks after experiment.The experimental eyes were extracted in the fourth week, and the expressions of scleral STAT3, p-STAT3, metal matrix proteinase-2 (MMP-2) proteins and STAT3 mRNA, MMP-2 mRNA were detected by immunocytochemstry and semi-quantitative reverse transcription PCR (RT-PCR) respectively.The use and care of experimental animals followed ARVO.
ResultsCompared to the normal control group, the negative refraction power and axial length were significantly increased in the model control group, PBS control group and AG490 treated group, and the axial length in the AG490 treated group was smaller than those in the model control group and PBS control group, showing significant differences among the 4 groups (refraction: F=89.063, P=0.000; axial length: F=96.145, P=0.000). The expressions of STAT3, MMP-2 and p-STAT3 in scleral tissue were weaker in the normal control group.The expressional values (A values) of STAT3, p-STAT3 and MMP-2 were 0.064±0.016, 0.019±0.002 and 0.155±0.052 in the AG490 treated group, which were lower than 0.129±0.008, 0.071±0.021, 0.425±0.004 of the model control group and 0.130±0.004, 0.069±0.002, 0.421±0.042 of the PBS control group (STAT3: t=4.641, 9.364, both at P<0.01; p-STAT3: t=4.638, 4.488, both at P<0.05; MMP-2: t=9.123, 9.029, both at P<0.05), however, these expressions were still higher than those of the normal control group ( t=2.674, 2.251, 2.682, all at P <0.05). The expressional levels (A values) of STAT3 mRNA and MMP-2 mRNA in the AG490 treated group were 0.295±0.032 and 0.569±0.019, which were significantly lower than 0.547±0.015 and 0.782±0.051 in the model group as well as 0.544±0.015 and 0.779±0.048 in the PBS control group (STAT3 mRNA: t=10.115, 11.703, both at P<0.01; MMP-2 mRNA: t=9.218, 9.494, both at P<0.01). The expressional levels (A values) of STAT3 mRNA and MMP-2 mRNA in the AG490 treated group were still higher than those in the normal control group ( t=2.576, 3.565, both at P<0.05).
ConclusionsAG490 can ultimately inhibit the development of axial myopia by arresting the activation of STAT3 signaling pathway in the FDM eyes and further regulating the expression of MMP-2 in sclera and delaying the remodeling of sclera.
朱子诚,吴章友,温跃春,等. AG490抑制STAT3信号通路活性对豚鼠形觉剥夺性近视巩膜重塑的调控[J]. 中华实验眼科杂志,2015,33(6)：493-499.
DOI:10.3760/cma.j.issn.2095-0160.2015.06.003版权归中华医学会所有。
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