State University of New York, Department of Ophthalmology, Health Science Center, Level 2, Room 152, Stony Brook, NY 11794, USA.
Pharmacol Res. 2011 Dec;64(6):614-23. doi: 10.1016/j.phrs.2011.06.013. Epub 2011 Jun 21.
Beyond their decades of long use as broad-spectrum antibiotics, tetracyclines and their derivatives have been shown to exhibit non-antimicrobial properties including their ability to interact with matrix metalloproteinases (MMP), tissue inhibitors of MMPs, growth factors and cytokines. As such, they are capable of affecting inflammation, immunomodulation, cell proliferation, and angiogenesis. Although they have been used to treat a variety of conditions including acne, cutaneous sarcoid, and rheumatoid arthritis, amongst others, their use in treating ophthalmologic disease is in its infancy.
A literature review on the role of non-antimicrobial properties of tetracyclines, semisynthetic tetracyclines, and chemically modified non-antibacterial tetracyclines (CMTs) and their clinical properties was performed. The effects of these compounds in relation to ophthalmic disease are presented.
Due to their non-antimicrobial properties, tetracyclines and their derivatives are capable of influencing a wide variety of ocular diseases in animal models. By affecting expression of MMP-9 and tumor necrosis factor (TNF)-α, these compounds decrease corneal permeability, improve corneal smoothness, and reduce meibomian gland dysfunction; this improves the tear film which in turn restores the optical quality of the tear film and cornea. Sterile corneal ulceration may be inhibited via anticollagenase activity; this has been demonstrated in both animal models and case reports. CMTs suppress cataractogenesis in a diabetic rat model, possibly by affecting MMPs. With respect to retinal disease, tetracyclines can inhibit both microglial-mediated cell death and retinal cell apoptosis as well as prevent retinal capillary damage via caspase inhibition thus preventing retinal neovascularization. Experimental choroidal neovascularization is reduced by inhibition of MMP-2 and MMP-9, elevation of pigment epithelial derived growth factor (PEDF), and reduction of vascular endothelial growth factor (VEGF) expression via Fas ligand.
Due to their non-antimicrobial properties, tetracyclines and their derivatives are capable of influencing a wide variety of ocular disease in animal models. Research suggests that they are able to reduce inflammation in the eyelid meibomian glands, improve optical clarity of the cornea, retard cataract formation, and limit ocular angiogenesis. They may have a role in treating the leading causes of vision loss: cataract, age-related macular degeneration, and diabetic retinopathy, all of which are anticipated to increase in incidence due to the aging population.
Tetracyclines, semisynthetic tetracyclines, and CMTs may have a role in the treatment of several important ophthalmologic diseases; however, further research is required, including prospective multicenter clinical trials.
除了作为广谱抗生素使用几十年外，四环素及其衍生物还具有非抗菌特性，包括与基质金属蛋白酶 (MMP)、MMP 组织抑制剂、生长因子和细胞因子相互作用的能力。因此，它们能够影响炎症、免疫调节、细胞增殖和血管生成。尽管它们已被用于治疗多种疾病，包括痤疮、皮肤结节病和类风湿性关节炎等，但它们在眼科疾病治疗中的应用仍处于起步阶段。
对四环素、半合成四环素和化学修饰非抗菌四环素 (CMTs) 的非抗菌特性及其临床特性进行了文献综述。介绍了这些化合物与眼科疾病的关系。
由于其非抗菌特性，四环素及其衍生物能够影响动物模型中的多种眼部疾病。通过影响 MMP-9 和肿瘤坏死因子 (TNF)-α 的表达，这些化合物降低了角膜通透性，改善了角膜平整度，并减少了睑板腺功能障碍；这改善了泪膜，从而恢复了泪膜和角膜的光学质量。通过抗胶原酶活性可以抑制无菌性角膜溃疡；这在动物模型和病例报告中均得到了证实。CMTs 通过影响 MMP 抑制糖尿病大鼠模型中的白内障形成。关于视网膜疾病，四环素可以抑制小胶质细胞介导的细胞死亡和视网膜细胞凋亡，并通过抑制半胱天冬酶来防止视网膜毛细血管损伤，从而防止视网膜新生血管形成。通过抑制 MMP-2 和 MMP-9、升高色素上皮衍生生长因子 (PEDF) 和降低血管内皮生长因子 (VEGF) 表达，实验性脉络膜新生血管减少。
由于其非抗菌特性，四环素及其衍生物能够影响动物模型中的多种眼部疾病。研究表明，它们能够减少眼睑睑板腺的炎症，提高角膜的光学清晰度，延缓白内障形成，并限制眼部血管生成。它们可能在治疗白内障、年龄相关性黄斑变性和糖尿病性视网膜病变等导致视力丧失的主要原因方面发挥作用，由于人口老龄化，这些疾病的发病率预计会增加。
四环素、半合成四环素和 CMTs 可能在几种重要的眼科疾病治疗中发挥作用；然而，需要进一步的研究，包括前瞻性多中心临床试验。
