空白对照组：无任何干预措施。伪造模组：给予灭菌注射用水兔眼球结膜下注射，每侧兔眼0.3 mL，2侧/次，每周1次，共8周。MMP-1组：给予MMP-1灭菌注射用水溶液兔眼球结膜下注射，每侧兔眼0.3 ml L，2侧/次，每周1次，共8周。MMP-3组：给予MMP-3灭菌注射用水溶液兔眼球结膜下注射，每侧兔眼0.3 L，2侧/次，每周1次，共8周。
(A) The nasal point, the intersection of the nasal vertical line of the limbal cornea and the lower eyelid margin ；(B) the central point, the intersection of the central vertical line of the cornea and the lower eyelid margin； (C) the temporal point, the intersection of the temporal vertical line of the limbal cornea and the lower eyelid margin.
(A) Control group; (B) Pseudo Model group; (C) MMP-1 group; (D) MMP-3 group. No conjunctival folds were observed in Figures A, B, and D, while the black arrow in Figure C indicates bulbar conjunctival folds.
(A) Control group, the red dot was the lower eyelid; (B) Pseudo Model group: the red triangle representing the cornea and the red pentagon representing the iris; (C) MMP-1 group; (D) MMP-3 group. In FIG. A, B and D, conjunctival folds were not observed. In FIG. C, the red thin arrow pointed to conjunctival folds, while the red thick arrow pointed to bulbar conjunctiva and its lower sclera.
(A) Control group, the fine arrow indicated complete lacrimal ferns; (B) Pseudo Model group, complete lacrimal ferns; (C) MMP-1 group, the black triangle showed that the lacrimal fernion crystalline structure was completely destroyed; (D) MMP-3 group, the black pentagon showed partial destruction of lacrimal ferns crystalline structure.
(A) Control group; (B) Pseudo Model group; (C) MMP-1 group; (D) MMP-3 group. In the figure, it can be seen that after HE staining, the nucleus of the conjunctival tissue is blue, while the cytoplasm, muscle fibers, collagen fibers, etc. are red in varying shades. The conjunctival epithelium consists of two to four layers of epithelial cells.
(A) Control group; (B) Pseudo Model group; (C) MMP-1 group; (D) MMP-3 group. The red arrows in Figures A and B indicate dense and parallel arrangement of collagen fibers; The red pentagram in Figures C shows that the collagen fibers are loosely combined and lose their parallel arrangement structure; The collagen fibers in the left area of the red triangle star in Figure D are loosely bound, while a parallel arrangement structure can still be seen in the right area.
(A) Control group; (B) Pseudo Model group; (C) MMP-1 group; (D) MMP-3 group. In Figure A and B, the black arrows show that the elastic fibers are dyed purple, slim, complete and walk naturally. In Figure C, the black five-pointed star shows that the elastic fibers are broken into small segments and distributed in clusters. In Figure D, the elastic fiber fragments can be seen in the left area of the black triangle star, and the intact elastic fiber can be seen in the right area.
3 讨论
到目前为止，构建CCH疾病动物模型的问题尚没有明确答案。该病发病相关的因素包括：老龄化[3]、基因突变[4]、下睑缘张力增高[5]、细胞凋亡[6]、紫外线辐射[7]、氧化应激[8]、屈光不正和眼轴长度[9]、眼泪的渗透压、热休克蛋白[10]、佩戴角膜接触镜(干燥和摩擦引起结膜炎症)[11]、自身免疫性甲状腺疾病(机体过度表达炎症因子)[12]等。上述病因诱使炎症因子增多，导致MMP与基质金属蛋白酶组织抑制因子(tissue inhibitor of metalloproteinase,TIMP)的平衡失调，或者直接影响MMP活性(譬如老龄化[13])，引起弹力纤维的降解变性。结膜固有层中弹力纤维明显减少可引起球结膜弹性下降、张力降低。进而球结膜与眼球的附着力下降，在下睑缘的反复挤压下形成皱褶[14]。结膜皱褶突出于眼球表面曲面，影响眼泪的流动和泪河的形成[15]。引起结膜松弛症患者的泪液排泄延缓[16]。泪液清除延迟导致泪液中炎症因子大量堆积，形成恶性循环，致结膜松弛不断进展。
1. 上海市普陀区卫生系统自主创新项目(PTKWWS201812)；上海市卫生健康委员会科研课题(202040418)。This work was supported by the Health System Independent Innovation Project of Shanghai Putuo District (PTKWWS201812) and Research Project of Shanghai Municipal Health Commission(202040418).
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