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M. Fujihara, T. Sussan, K. Liby, M. B. Sporn, S. Biswal, J. T. Handa; Cigarette Smoking Induces Ultrastructural Alterations to the RPE in Mice. Invest. Ophthalmol. Vis. Sci. 2008;49(13):211.
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Oxidative and electrophilic injury to the RPE has been proposed to be an important stimulus for age-related macular degeneration (AMD). Cigarette smoking (CS) contains potent oxidants and other damaging electrophiles, and is a major risk factor for AMD. The transcription factor Nrf2 binds to the antioxidant response element (ARE), and activates many cytoprotective enzymes. 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) is a cytoprotective drug that potently protects against cancer in animal models, acting in part by inducing cytoprotective genes through Nrf2-ARE signaling. The purpose of this study was to investigate the effects of CS on the ultrastructure of RPE and Bruch’s membrane (BM) in mice that are susceptible to oxidative and electrophilic stress (i.e. Nrf2-/-), and to determine whether CDDO-Im prevents CS mediated injury.
C57Bl6 wt mice and Nrf2-/- mutant mice were exposed to either filtered air or CS 5h/day for 6 months in a smoking chamber. Mice were fed either a normal diet or a diet containing CDDO-Im (90 mg/kg diet) 3x per week. Eyes were fixed in 2.5% glutaraldehyde/2% paraformaldehyde mix in 0.1M phosphate buffer and examined with a Hitachi H7600 transmission electron microscope.
The RPE of wt mice exposed to air had normal basolateral infoldings and non-thickened BM. The RPE of wt mice exposed to CS had fewer and dilated basolateral infoldings with more empty vacuoles within the RPE. The RPE of Nrf2-/- mice exposed to CS, displayed more significant changes. In addition, BM developed basal deposits in both wt and Nrf2-/- mice exposed to CS. Wt mice exposed to CS and treated with CDDO-Im showed normal ultrastructure.
CS induced ultrastructural degradation to the RPE. Oxidative and electrophilic stresses appear to be involved in at least part of this change, possibly through the Nrf2 pathway. The rescue by CDDO-Im opens up its possibility as a treatment for AMD.
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