¡¡¡¡In this study, we found that, although the expression of TIMPª²3 mRNA increased after laser photocoagulation, CNV still developed. This may be due to the imbalance between MMPs and TIMPs: a few expressions for both MMPª²9 and TIMPª²3 mRNA could be detected at 1 day after laser photocoagulation. The expressions increased significantly, especially for the TIMPª²3 at 3 days after laser. Along the time, although expression of TIMPª²3 mRNA stabilized in a higher level, the expression of MMPª²9 mRNA was not inhibited completely, and moreover it still increased. The imbalance between MMPª²9 and TIMPª²3 breakdown the acceleration inhibition balance of degradation of ECM, and the predominant former may activate the "angiogenic switch" [10]. As a result, the CNV was induced at 1 week after laser photocoagulation. Studies have indicated that an imbalance of MMPs and their inhibitors may be involves in the pathogenesis of ocular diseases such as glaucoma [11, 12], corneal diseases [13, 14] and proliferative retinopathy [15ª²17]. Then the new balance rebuilt between MMPª²9 and TIMPª²3 made the CNV exist for a longer period. In our previous studies [18], we have confirmed that CNV may be induced at 1 week after laser photocoagulation, and the incidence of CNV at 1 week, 2 weeks and 4 weeks were similar.

¡¡¡¡The mechanisms that trigger release of MMPs and TIMPs during CNV induced by laser photocoagulation are unclear. It is suggested by observations that cytokines such as tumor necrosis factor ¦Á (TNF¦Á) and interleukinª²1 (ILª²1) may induce production of MMPs and TIMPs by vascular endothelial cells, fibroblasts, and retinal pigment epithelial cells [19]. Majka et al[20] also found that TNF¦Á and VEGF had a role in the regulation of extracelluar proteinase expression during retinal neovascularization. The stimulation of TNF¦Á could enhance the production of MMPs in retinal microvascular endothelial cell. VEGF also played a role in this process through its regulation of TNF¦Áª²converting enzyme (TACE).

¡¡¡¡In summary, both MMPª²9 and TIMPª²3 play a role during the development of CNV in the murine model. It is the imbalance between the changes of MMPª²9 and TIMPª²3 that accelerates the degradation of ECM, and then is involved in the pathogenesis of CNV.

¡¡¡¡¡¾²Î¿¼ÎÄÏס¿

¡¡¡¡1 Guo L, Hussain AA, Limb GA, Marshall J. Ageª²dependent variation in metalloproteinase activity of isolated human Bruch¬ðs membrane and choroid. Invest Ophthalmol Vis Sci 1999;409(11):2676ª²2682

¡¡¡¡2 Plantner JJ, Smine A, Quinn TA. Matrix metalloproteinases and metalloproteinase inhibitors in human interphotoreceptor matrix and vitreous. Curr Eye Res 1998;17(2):132ª²140

¡¡¡¡3 De La Paz MA, Itoh Y, Toth CA, Nagase H. Matrix metalloproteinases and their inhibitors in human vitreous. Invest Ophthalmol Vis Sci 1998;39(7):1256ª²1260

¡¡¡¡4 Steen B,Sejersen S, Berglin L,Seregard S,Kvanta A.Matrix metalloproteinases and metalloproteinase inhibitors in choroidal neovascular membranes. Invest Ophthalmol Vis Sci 1998;39(11):2194ª²2200

¡¡¡¡5 Das A,McLamore A,Song W,McGuire PG.Retinal neovascularization is suppressed with a matrix metalloproteinase inhibitor. Arch Ophthalmol 1999;117(4):498ª²503

¡¡¡¡6 Leco KJ, Khokha R, Pavloff N, Hawkes SP, Edwards DR. Tissue inhibitor of metalloproteinasesª²3 (TIMPª²3) is an extracellular matrixª²associated protein with a distinctive pattern of expression in mouse cells and tissues. J Biol Chem 1994;269(12):9352ª²9360

¡¡¡¡7 Fariss RN, Apte SS, Olsen BR, Iwata K, Milam AH. Tissue inhibitor of metalloproteinasesª²3 is a component of Bruch¬ðs membrane of the eye. Am J Pathol 1997;150(1):323ª²328

¡¡¡¡8 Takahashi T, Nakamura T, Hayashi A, Kamei M, Nakabayashi M, Okada AA, Tomita N, Kaneda Y, Tano Y. Inhibition of experimental choroidal neovascularization by overexpression of tissuse inhibitor of metalloproteinasesª²3 in retinal pigment epithelium cells. Am J Ophthalmol 2000;130(6):774ª²781

¡¡¡¡9 Murata T, Cui J, Taba KE, Oh JY, Spee C, Hinton DR, Ryan SJ. The possibility of gene therapy for the treatment of choroidal neovascularization. Am J Ophthalmol 2000;107(7):1364ª²1373

¡¡¡¡10 Arbiser JL, Moses MA, Fernandez CA, Ghiso N, Cao Y, Klauber N, Frank D, Brownlee M, Flynn E, Parangi S, Byers HR, Folkman J. Oncogenic Hª²ras stimulates tumor angiogenesis by two distinct pathways. Proc Natl Acad Sci USA 1997;94(3): 861ª²866

¡¡¡¡11 M¢|¢|tt¢| M, Tervahartiala T, Harju M, Airaksinen J, Autioª²Harmainen H, Sorsa T. Matrix metalloproteinases and their tissue inhibitors in aqueous humor of patients with primary openª²angle glaucoma, exfoliation syndrome, and exfoliation glaucoma. J Glaucoma 2005;14(1):64ª²69

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