Int Ophthalmol Clin. 1975 Winter;15(4):49-66. doi: 10.1097/00004397-197501540-00006.
Tissue collagenases have been implicated in corneal ulceration in human corneal disease and in ulceration of the rabbit cornea that has served as a model system. Such enzymes from the rabbit and human cornea are inhibited by metal-binding agents of the EDTA type, by thiols, and by the human serum antiprotease alpha2-macroglobulin. Determination of the relative efficacies of collagenase inhibitors indicates that EDTA and Ca-EDTA are about one hundred times more effective on a molar basis than L-cysteine and its derivatives, N-acetyl-L-cysteine and D-penicillamine. The alpha2-macroglobulin on a molar basis, is superior as an inhibitor to the metal-binding agents and thiols. Although Ca may be a necessary cofactor of the corneal collagenases, such a requirement has not been established unequivocally. Inhibition and isotope studies do indicate a requirement for Zn. Thiols are thought to inhibit corneal collagenases by binding to or removing an intrinsic metal cofactor (Zn), and/or possibly by reducing one or more disulfide bonds. Inhibition by both EDTA-type agents and thiols is largely reversible by dialysis. The human alpha2-macroglobulin appears to inhibit corneal colleagenases irreversibly by forming tight complexes with them. Ca-EDTA, cysteine, and acetylcysteine, given as eyedrops, are able to prevent or retard ulceration in the alkali-burned rabbit cornea. They appear to have some efficacy in the prevention of corneal ulceration in humans. EDTA-type compounds are quite stable under routine storage, while acetylcysteine is more stable than cysteine. EDTA is quite toxic and should not be used as eye medication. Ca-EDTA has a low toxicity, and cysteine and acetylcysteine have even lower toxicity. It is not yet certain which inhibitor has the most favorable therapeutic index for clinical use, or is the optimal mode of drug delivery known. However, the collagenase inhibitors seem to have therapeutic promise in the prevention of corneal ulceration.
组织胶原酶与人类角膜疾病中的角膜溃疡以及作为模型系统的兔角膜溃疡有关。来自兔和人角膜的此类酶受到EDTA型金属结合剂、硫醇以及人血清抗蛋白酶α2-巨球蛋白的抑制。胶原酶抑制剂相对效力的测定表明，EDTA和Ca-EDTA在摩尔基础上的效力比L-半胱氨酸及其衍生物N-乙酰-L-半胱氨酸和D-青霉胺高约一百倍。α2-巨球蛋白在摩尔基础上作为抑制剂比金属结合剂和硫醇更具优势。尽管钙可能是角膜胶原酶的必要辅因子，但尚未明确确定这种需求。抑制和同位素研究确实表明需要锌。硫醇被认为通过与内在金属辅因子（锌）结合或去除，和/或可能通过还原一个或多个二硫键来抑制角膜胶原酶。EDTA型试剂和硫醇的抑制作用在很大程度上可通过透析逆转。人α2-巨球蛋白似乎通过与角膜胶原酶形成紧密复合物而不可逆地抑制它们。以眼药水形式给予的Ca-EDTA、半胱氨酸和乙酰半胱氨酸能够预防或延缓碱烧伤兔角膜的溃疡。它们在预防人类角膜溃疡方面似乎有一定疗效。EDTA型化合物在常规储存下相当稳定，而乙酰半胱氨酸比半胱氨酸更稳定。EDTA毒性很大，不应用作眼部药物。Ca-EDTA毒性较低，半胱氨酸和乙酰半胱氨酸毒性甚至更低。目前尚不确定哪种抑制剂在临床使用中具有最有利的治疗指数，或者已知的最佳给药方式是什么。然而，胶原酶抑制剂在预防角膜溃疡方面似乎具有治疗前景。
