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Rose A. Gubitosi-Klug, Reena Bapputty; Beneficial Effects of Leukotriene Receptor Antagonism in the Pathogenesis of Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
Early diabetic retinopathy is characterized by retinal inflammation, vascular permeability, and retinal capillary cell death. Animal models suggest that leukotrienes may be critical pro-inflammotory mediators of this hyperglycemia-induced damage. Our current investigations explore the effects of leukotrienes and leukotriene receptor antagonism in experimental models of early diabetic retinopathy.
We studied the effects of montelukast, a cysteinyl leukotriene receptor antagonist, on leukotriene synthesis, vascular permeability, and endothelial cell death using both mouse and human cells. We recruited patients with diabetes along with age-matched control patients without diabetes from the Case Western University Medical Center. Following isolation, leukocytes were assessed for 1) levels of the leukotriene surface receptor BLT1 (Western blot analysis and flow cytometry), 2) generation of leukotriene B4, and 3) effects on endothelial cell viability when co-cultured with human retinal endothelial cells (hREC; trypan blue exclusion assay). Cultured retinal microvascular endothelial cells were treated with leukotriene C4 (LTC4) and assessed for changes in markers of vascular permeability and inflammation.
When compared to leukocytes from control patients, leukocytes from diabetic patients demonstrated elevations in BLT1 levels (1.4 fold increase; p=0.002) and also show increased LTB4 production (1.3 fold increase; p=0.007) . Diabetes also caused an increase in leukocyte-mediated retinal endothelial cell death. Pretreatment of leukocytes with montelukast suppressed the generation of LTB4. Administration of LTC4 to retinal microvascular endothelial cells in culture resulted in a dose-dependent rise in VEGF release as well as translocation of NF-kappaB to the nucleus; both of which were preventable when cells were treated with montelukast.
Antagonism of the effects of leukotrienes may slow the development of early diabetic retinopathy.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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