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ME Marin Castano, I Suñer, SW Cousins; Effects of Cigarette Smoke-Derived Toxins on Matrix Metalloproteinases (MMP-s) Production in Human Choroidal Smooth Muscle Cells . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1301.
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Purpose: Epidemiological studies have established a strong correlation between cigarette smoke and age-related macular degeneration, especially choroidal neovascularization. Several components of cigarette smoke, especially hydroquinone (an oxidant) and nicotine (a cholinergic agonist), circulate in the blood of smokers and may injure blood vessels by direct interactions with vascular smooth muscle cells which lie adjacent to vascular endothelium. These two toxins might potentiate neovascularization by dysregulating expression of matrix metalloproteinases of smooth muscle cells, leading to invasion and proliferation of the neighboring endothelium. Our aim was to study the effects of hydroquinone and nicotine on MMP-2 and MMP-9 production in human choroidal smooth muscle cells. Methods: A primary cell line representing a choroid-derived smooth muscle-like cell (h-CSMC) was developed for these experiments. H-CSMC were incubated in phenol red free medium containing 0.1% fetal bovine serum with or without hydroquinone or nicotine at physiologic concentrations relevant to active and passive smokers (1 and 0.01µM respectively) for various times. In a parallel experiment, the cells were incubated for 4 hours with or without hydroquinone at 1 or 0.01µM, washed and then incubated for 20 hours with or without nicotine 1 or 0.01µM. Cell counts and viability assay was performed. The supernatants were collected to assess MMP-2 and MMP-9 activity by zymography. Results: At these physiological concentrations, neither hydroquinone nor nicotine alone killed the h-CSMC. Neither compound alone induced MMP-2 or MMP-9 activity. However, the combination of both components of cigarette smoke killed a significant fraction of h-CSMC (∼ 60 and 29 % of control). Both together also significantly increased MMP-2 (∼ 4.5 - 6.2 fold) and MMP-9 activity (∼3.5 fold) in the surviving population. Conclusions: Hydroquinone and nicotine act synergistically to injure choroidal smooth muscle cells and to upregulate MMP-2 and MMP-9 activity. These data suggest that cigarette smoke-derived toxic chemicals may directly injure choroidal vascular cells, partially explaining the association between smoking and neovascular ARMD. CR: N
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