Eicosanoids as Mediators of Inflammation in Diabetic Retinopathy

Abstract

Abstract: : Purpose: Inflammatory–like processes and capillary cell death play important roles in the pathogenesis of diabetic retinopathy. Metabolites of arachidonic acid via the cyclooxygenase and lipoxygenase pathways, collectively known as eicosanoids, are known mediators of inflammation. Investigation of the role of 12–lipoxygenase and its metabolite, 12–HETE, in the pathogenesis of diabetic retinopathy was performed. Methods: Streptozotocin–induced diabetic mice were analyzed for 1) 12–lipoxygenase protein expression by Western blot analysis, 2) 12–HETE generation by HPLC analysis, and 3) leukostasis by in vivo perfusion with concanavalin A. The selective 12–lipoxygenase inhibitor, baicalein, was administered to primary retinal endothelial cell cultures and to streptozotocin–induced diabetic mice. Results: 12–lipoxygenase expression is upregulated 2–fold in retinas from streptozotocin–induced diabetic mice compared to nondiabetic control mice. Similarly, 12–HETE production from diabetic retinas is increased (80pg/mg protein in diabetic retinas and undetectable in nondiabetic retinas). As a measure of the diabetes–induced inflammatory process in vivo, diabetic mice demonstrated an increased attraction of leukocytes to the vascular endothelium. Oral administration of baicalein to diabetic mice for 8 weeks normalized this leukocyte adherence. Primary cultures of retinal endothelial cells exposed to high glucose concentrations (25 mM) experience cell death that is preventable by incubation with baicalein. Conclusions:These experiments suggest that 12–lipoxygenase, through its role in retinal inflammation and retinal cell death, may participate in the pathogenesis of diabetic retinopathy.

Keywords: diabetic retinopathy • eicosanoids • inflammation