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Y. Zhou, W. C. Gordon, J. Elison, S. Hong, H. Thompson, N. G. Bazan; Lipoxin A4 or Lipoxin A4-Epimer 15 Are Suppressors of Experimental Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3432.
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Arachidonic acid-derived lipoxins are potent mediators of the resolution phase of inflammation response and dysfunctional immunity.
Eyes of anesthetized mice were dilated and a model for laser-induced choroidal neovascularization was set up, in which 4 lesions were administered to each retina at positions of 3, 6, 9, and 12 o’clock, centered around the optic nerve. Each pulse, delivered by a green diode Lumenis Novus-Spectra ophthalmic laser mounted on a Topcon slit lamp (SL-D7), was 50 µm diameter, 200 mW of energy, and 100 mS duration, and produced a retinal bubble as Bruch’s membrane was breached. Lipoxin A4, lipoxin A4-epimer 15 (both Calbiochem), and vehicle (saline/ethanol) were delivered (30 µg/kg bw, ip) once daily for 14 days. At days 7, 10, and 14, images of FITC leakage were obtained immediately following ip delivery of FITC and 5 min later, from each lesion. These images were captured and viewed with the Topcon IMAGEnet 2000 LITE digital imaging system, and then ranked as strong, moderate, slight, and none by an Ophthalmologist, where only strong is considered clinically relevant in human. Eyes were then collected 1 day later and fixed, and retinas removed, leaving a flat-mounted choroid which was labeled with FITC-conjugated isolectin B4 (specific for endothelial cells). Diameters of choroidal lesions (laser + 15 days) were then plotted to determine degree of neovascularization associated with each drug treatment.
In control retinas (vehicle alone), 80% of laser-induced lesions showed strong leakage after 7 days, 73% after 10 days, and 67% after 14 days, while lipoxin A4 treatments demonstrated 33%, 35%, and 30% strong leakage, respectively, and the lipoxin A4-epimer 15 exhibited 46%, 52%, and 25% strong leakage for these time points. Also, the number of none leakage burn sites was 48% for lipoxin A4 and 40% for lipoxin A4-epimer 15, as compared to 16% in control retina sites at day 14. Endothelial cell labeling indicated that lesion sites on the choroid were about 125 µm in diameter (50 µm initial lesion) in control retinas, while the lipoxin A4 and lipoxin A4-epimer 15 treatments were about 75 µm in diameter.
Both lipoxin A4 and the epimer 15 form moderated the effects of laser-induced choroidal neovascularization approximately equally. Lipoxin A4 and Lipoxin A4-epimer 15 treatments produced 54 % and 60% reduction in leakage, respectively, and 39% and 43% reduction in damage site diameter. These effects had been established by day 7, indicating that these compounds protected by acting on early events induced by the laser damage.
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