活化二价锌离子对碱烧伤后角膜融解病理机制中基质金属蛋白酶抑制作用的研宄
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摘要
目的：探讨在碱烧伤后角膜融解损伤病理作用中不同时间内起主要组织损伤作用的基质金属蛋白酶的类型；探讨活化Zn2+离子对碱烧伤后角膜融解损伤不同时期异常高表达的基质金属蛋白酶的抑制作用。
方法：建立中度角膜碱烧伤小鼠实验动物模型,应用明胶酶谱、蛋白质印迹法以及免疫组织化学技术检测碱烧伤后3日、1周以及1个月时角膜组织内基质金属蛋白酶-1,2及9的表达情况。应用不同浓度Zn2+离子溶液(0.1mmol/L及1mmol/L)对碱烧伤后角膜组织进行局部干预。应用明胶酶谱以及蛋白质印迹法检测角膜碱烧伤后3日及1周时不同浓度Zn2+离子溶液实验亚组以及对照组角膜组织内中-1,2及9的表达情况。
结果：应用明胶酶谱方法观察到碱烧伤后3日角膜组织内基质金属蛋白酶-9表达显著的升高,呈现高水平表达,碱烧伤后1周其表达量显著下降,而碱烧伤后1个月时角膜组织内观察不到基质金属蛋白酶-9的表达。基质金属蛋白酶-2与之相反,在碱烧伤后3日角膜组织内仅呈现低水平表达,碱烧伤后1周其角膜组织内表达量显著升高,呈现高水平表达,碱烧伤后1个月时其表达量再次降低,呈现中度水平表达。应用蛋白质印迹法以及免疫组织化学方法观察的碱烧伤后3日、1周及1个月组织内基质金属蛋白酶-9及2的表达变化情况与应用明胶酶谱方法观察的情况相符,即：基质金属蛋白酶-9在碱烧伤后急性期高表达,且其高表达主要位于靠近角膜上皮层区域,而后表达量逐渐降低；基质金属蛋白酶-2在碱烧伤后急性期表达水平较低,而在碱烧伤后1周呈现高水平表达,不同于基质金属蛋白酶-9,其高表达分布于角膜基质内,其后表达量再次降低,呈现中度水平表达。应用蛋白质印迹法以及免疫组织化学方法观察到碱烧伤后组织内不同时期基质金属蛋白酶-1在角膜碱烧伤后组织内的表达变化趋势与基质金属蛋白酶-2相似,在碱烧伤后1周时表达水平最高,其后表达量下降,但其各时期表达量普遍较低。另一方面,研究通过明胶酶谱以及蛋白质印迹法观察到应用活化Zn2+离子干预的实验组较对照组角膜组织在碱烧伤后3日对高水平表达的基质金属蛋白酶-9以及碱烧伤后1周对呈现最高峰表达的基质金属蛋白酶-2及1的表达量均有明显的抑制作用,其抑制作用呈现剂量正相关性。
结论：基质金属蛋白酶-9在碱烧伤后主要通过降解角膜上皮基底膜打通组织屏障使更多免疫损伤介质浸润角膜基质的方式,参与碱烧伤后角膜组织的病理性损伤过程。而基质金属蛋白酶-2则承担了更为重要的实质性组织损伤作用。研究亦从活体体内观察层面证实了活化Zn2+离子的局部应用对角膜碱烧伤后组织内基质金属蛋白酶的表达存在有效的抑制作用,从而为其应用于临床碱烧伤后角膜组织进行保护性治疗提供了理论依据。
Purposes To investigate the main role of different matrix metalloproteinases in corneal melting pathological mechanism and to investigate inhibition of the production of matrix metalloproteinases by the intervention of the activated Zn2+ion in alkali-burned cornea.
Methods Experimental animal model of alkali-burned cornea was established. Research applied gelatin enzyme spectrum, Western Blot technique and immunohistochemistry technique to observe the expression of matrix metalloproteinase-1,2and9in3days,1week and1month after alkali-burn-induced corneal melting. The0.1mmol/L and1mmol/L Zn2+ions solution were applied after alkali burn of corneal tissue. The expression of metalloproteinase-1,2and9were detected by the application of gelatin enzyme spectrum and Western Blot technique in3days and1week in both the treatment group and the control group after corneal alkali burns.
Results The high-level expression of matrix metalloproteinase-9was detected by the application of gelatinases spectrum in3days after corneal alkali burns, but it significantly decreased in1week and become almost indetectable in1month. By contrast, matrix metalloproteinases-2was low-leveled expressed in the3days after corneal alkali burns, but significantly increased in1week and was medium-leveled expressed in1month. The same results were proved by the application of Western Blot technique and immunohistochemistry technique that matrix metalloproteinases-9was high-leveled expressed in3days after corneal alkali burns and matrix metalloproteinases-2was high-leveled expressed in1week after corneal alkali burns. It was also observed that matrix metalloproteinase-1was persistently low-leveled expressed in3days,1week and1month after corneal alkali burns. On the other hand, it was observed that the high-leveled expression of matrix metalloproteinase-9was significantly inhibited in3days after corneal alkali burns by the intervention of Zn2+ ions solution by means of gelatinases spectrum and Western Blot technique. It was also observed that the expression of matrix metalloproteinase-2and matrix metalloproteinase-1were significantly inhibited in1week by the same means. The inhibition of the expression of matrix metalloproteinase-1,2and9by the intervention of Zn2+ions solution was proved to be all dose-related.
Conclusions In the pathological damage process of corneal tissue, matrix metalloproteinases-9degradated the corneal epithelial basement membrane barriers to bring more infiltration of inflammatory substances in the corneal stroma after alkali burn.Howerver, matrix metalloproteinase-2played the more important role of corneal tissue damage.The activated Zn2+ions can effectively inhibit the expression of different kinds of matrix metalloproteinases which were observed with the ability to damage corneal tissue in different specific phases after corneal alkali burns. Therefore, the activated Zn2+ions can protect corneal tissue from the damage of alkali burn.
方法：建立中度角膜碱烧伤小鼠实验动物模型,应用明胶酶谱、蛋白质印迹法以及免疫组织化学技术检测碱烧伤后3日、1周以及1个月时角膜组织内基质金属蛋白酶-1,2及9的表达情况。应用不同浓度Zn2+离子溶液(0.1mmol/L及1mmol/L)对碱烧伤后角膜组织进行局部干预。应用明胶酶谱以及蛋白质印迹法检测角膜碱烧伤后3日及1周时不同浓度Zn2+离子溶液实验亚组以及对照组角膜组织内中-1,2及9的表达情况。
结果：应用明胶酶谱方法观察到碱烧伤后3日角膜组织内基质金属蛋白酶-9表达显著的升高,呈现高水平表达,碱烧伤后1周其表达量显著下降,而碱烧伤后1个月时角膜组织内观察不到基质金属蛋白酶-9的表达。基质金属蛋白酶-2与之相反,在碱烧伤后3日角膜组织内仅呈现低水平表达,碱烧伤后1周其角膜组织内表达量显著升高,呈现高水平表达,碱烧伤后1个月时其表达量再次降低,呈现中度水平表达。应用蛋白质印迹法以及免疫组织化学方法观察的碱烧伤后3日、1周及1个月组织内基质金属蛋白酶-9及2的表达变化情况与应用明胶酶谱方法观察的情况相符,即：基质金属蛋白酶-9在碱烧伤后急性期高表达,且其高表达主要位于靠近角膜上皮层区域,而后表达量逐渐降低；基质金属蛋白酶-2在碱烧伤后急性期表达水平较低,而在碱烧伤后1周呈现高水平表达,不同于基质金属蛋白酶-9,其高表达分布于角膜基质内,其后表达量再次降低,呈现中度水平表达。应用蛋白质印迹法以及免疫组织化学方法观察到碱烧伤后组织内不同时期基质金属蛋白酶-1在角膜碱烧伤后组织内的表达变化趋势与基质金属蛋白酶-2相似,在碱烧伤后1周时表达水平最高,其后表达量下降,但其各时期表达量普遍较低。另一方面,研究通过明胶酶谱以及蛋白质印迹法观察到应用活化Zn2+离子干预的实验组较对照组角膜组织在碱烧伤后3日对高水平表达的基质金属蛋白酶-9以及碱烧伤后1周对呈现最高峰表达的基质金属蛋白酶-2及1的表达量均有明显的抑制作用,其抑制作用呈现剂量正相关性。
结论：基质金属蛋白酶-9在碱烧伤后主要通过降解角膜上皮基底膜打通组织屏障使更多免疫损伤介质浸润角膜基质的方式,参与碱烧伤后角膜组织的病理性损伤过程。而基质金属蛋白酶-2则承担了更为重要的实质性组织损伤作用。研究亦从活体体内观察层面证实了活化Zn2+离子的局部应用对角膜碱烧伤后组织内基质金属蛋白酶的表达存在有效的抑制作用,从而为其应用于临床碱烧伤后角膜组织进行保护性治疗提供了理论依据。
Purposes To investigate the main role of different matrix metalloproteinases in corneal melting pathological mechanism and to investigate inhibition of the production of matrix metalloproteinases by the intervention of the activated Zn2+ion in alkali-burned cornea.
Methods Experimental animal model of alkali-burned cornea was established. Research applied gelatin enzyme spectrum, Western Blot technique and immunohistochemistry technique to observe the expression of matrix metalloproteinase-1,2and9in3days,1week and1month after alkali-burn-induced corneal melting. The0.1mmol/L and1mmol/L Zn2+ions solution were applied after alkali burn of corneal tissue. The expression of metalloproteinase-1,2and9were detected by the application of gelatin enzyme spectrum and Western Blot technique in3days and1week in both the treatment group and the control group after corneal alkali burns.
Results The high-level expression of matrix metalloproteinase-9was detected by the application of gelatinases spectrum in3days after corneal alkali burns, but it significantly decreased in1week and become almost indetectable in1month. By contrast, matrix metalloproteinases-2was low-leveled expressed in the3days after corneal alkali burns, but significantly increased in1week and was medium-leveled expressed in1month. The same results were proved by the application of Western Blot technique and immunohistochemistry technique that matrix metalloproteinases-9was high-leveled expressed in3days after corneal alkali burns and matrix metalloproteinases-2was high-leveled expressed in1week after corneal alkali burns. It was also observed that matrix metalloproteinase-1was persistently low-leveled expressed in3days,1week and1month after corneal alkali burns. On the other hand, it was observed that the high-leveled expression of matrix metalloproteinase-9was significantly inhibited in3days after corneal alkali burns by the intervention of Zn2+ ions solution by means of gelatinases spectrum and Western Blot technique. It was also observed that the expression of matrix metalloproteinase-2and matrix metalloproteinase-1were significantly inhibited in1week by the same means. The inhibition of the expression of matrix metalloproteinase-1,2and9by the intervention of Zn2+ions solution was proved to be all dose-related.
Conclusions In the pathological damage process of corneal tissue, matrix metalloproteinases-9degradated the corneal epithelial basement membrane barriers to bring more infiltration of inflammatory substances in the corneal stroma after alkali burn.Howerver, matrix metalloproteinase-2played the more important role of corneal tissue damage.The activated Zn2+ions can effectively inhibit the expression of different kinds of matrix metalloproteinases which were observed with the ability to damage corneal tissue in different specific phases after corneal alkali burns. Therefore, the activated Zn2+ions can protect corneal tissue from the damage of alkali burn.
引文
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[1]韩春茂,姚玉峰,余朝恒.眼烧伤的激素治疗.中华烧伤杂志,2001,17(6)：330-332.
[2]Davis AR, Ali QK, Aclimandos WA, Hunter PA.Topical steroid use in the treatment of ocular alkali burns. Br J Ophthalmol.1997 Sep;81(9):732-734.
[3]Sekundo W, Augustin AJ, Strempel Ⅰ.Topical allopurinol or corticosteroids and acetylcysteine in the early treatment of experimental corneal alkali burns:a pilot study. Eur J Ophthalmol.2002 Sep-Oct; 12(5)366-372.
[4]Donshik PC, Berman MB, Dohlman CH, Gage J, Rose J.Effect of topical corticosteroids on ulceration in alkali-burned corneas.Arch Ophthalmol.1978 Nov;96(11):2117-2120.
[5]李雪,徐锦堂,崔浩,胡琦.TGF-β2局部应用对大鼠角膜碱烧伤后CD44和E-selectin表达的影响.眼科新进展,2006,26(7)：491-496.
[6]Yang H, Li X, Ma J, Lv X, Zhao S, Lang W, Zhang Y. Blockade of the intermediate conductance Ca(2+)-activated K(+) channel inhibits the angiogenesis induced by epidermal growth factor in the treatment of corneal alkali burn. Exp Eye Res.2013,7:76-87.
[7]Kao WW, Zhu G, Kao CW.Effects of polymorphonuclear neutrophils on protein synthesis by alkali-injured rabbit corneas.Cornea.1993 Nov;12(6):522-531.
[8]Piso DY, Ribeiro AP, Silva ML, Guimaraes PJ, Morales A, Martins BC, Padua IM,Renzo R, Andrade AL, Uscategui RR, Laus JL.Effects of antiproteolytic agents on corneal epithelial viability and matrix metalloproteinase-2 and metalloproteinase-9 activity in alkali-burned corneas of rats. Vet Ophthalmol.2013,25:120-132.
[9]Kim EC, Kim TK, Park SH, Kim MS.The wound healing effects of vitamin A eye drops after a corneal alkali burn in rats. Acta Ophthalmol.2012,90(7):540-546.
[10]Takahashi H, Igarashi T, Fujimoto C, Ozaki N, Ishizaki M.Immunohistochemical observation of amniotic membrane patching on a corneal alkali burn in vivo. Jpn J Ophthalmol.2007,51(1):3-9.
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