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Annie Y. Chan, Robert Chen, Donald S. Stone, Annette Eckerd, Nawajes Mandal; Bioactive Sphingolipids As Mediators Of Ocular Inflammation: Observations In An Animal Model. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1239.
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To characterize and compare the clinical and histological response to intravitreal (IV) ceramide (Cer) injection at varying doses over one month.
Varying doses of C-8 Cer were injected into rat eyes: 2ug (n=14), 10ug (n=16), 20ug (n=14). Controls included IV injection of 100% DMSO (Cer vehicle, n=9), BSS (n=9), needle puncture (n=7) or no intervention (n=3). Dihydroceramide (DHCer, a non-bioactive sphingolipid) was also given IV at 2ug (n=2), 10ug (n=2), and 20ug (n=2). Fundus photos, spectral domain (SD)-OCT, and fluorescein angiography (FA) were performed at 24 hr, 72 hr, 1 week, 2 weeks, and 4 weeks. Additional eyes injected with similar doses were used for histologic comparison. The degree of intravitreal cellular response, retinal edema or hemorrhage, vessel tortuosity, vitreous traction, and corneal changes (neovascularization or ulcers) were documented. Retinal vessel tortuosity was graded on a scale of 0 (least)-3 (most), with a plus to indicate the presence of vessel dilation.
After 72 hours, 71% of the 2ug Cer group exhibited less than grade 2 vessel tortuosity, while 73.3% of the10ug and 64.3% of the 20ug groups showed grade 2 or greater tortuosity respectively. By 1 week, 66.7% of 2ug-injected eyes were less than grade 2, while 78.6% of 10ug-injected eyes and 71.4% of 20ug-injected eyes were grade 2 or greater. At 2 weeks, 100% of 20ug-injected eyes were grade 2 or greater; over half were grade 3 or 3+. Optic nerve traction was present only in 10- or 20ug-injected eyes, was progressive over time, and most severe in 20ug-injected eyes. OCT showed the greatest cellular reaction occurring within 72 hours of injection and at higher doses of Cer. Low-grade inflammation that resolved by 72hrs was observed in DMSO-injected eyes. Each remaining type of control resulted in minimal observable inflammation on OCT or fundus photography. Histologic findings correlated with our imaging.
Sphingolipids such as Cer have recently been recognized as mediators of cellular processes including proliferation, migration, apoptosis, and inflammation. The exact role of these mediators in human ocular diseases remains unexplored. Our data shows that IV injection of C-8 Cer, a bioactive sphingolipid, can generate a localized dose-dependent inflammatory response with an acute phase lasting up to 72 hours after exposure, followed by extensive vitreoretinal fibrosis, especially around the optic nerve. Meanwhile, intravitreal injection of the nonactive form of Cer, DHCer, resulted in virtually no inflammatory response. Finally, we propose that C-8 Cer can be used as a potential model for investigating posterior uveitis, and neovascular retinopathies.
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