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Ramaprasad Talahalli, Simona Zarini, Nader Sheibani, Robert C. Murphy, Rose A. Gubitosi-Klug; Increased Synthesis of Leukotrienes in the Mouse Model of Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2010;51(3):1699-1708. doi: 10.1167/iovs.09-3557.
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Evidence suggests that capillary degeneration in early diabetic retinopathy results from chronic inflammation, and leukotrienes have been implicated in this process. The authors investigated the cellular sources of leukotriene biosynthesis in diabetic retinas and the effects of hyperglycemia on leukotriene production.
Retinas and bone marrow cells were collected from diabetic and nondiabetic mice. Mouse retinal glial cells and retinal endothelial cells (mRECs) were cultured under nondiabetic and diabetic conditions. Production of leukotriene metabolites was assessed by mass spectrometry, and Western blot analysis was used to quantitate the expression of enzymes and receptors involved in leukotriene synthesis and signaling.
Bone marrow cells from nondiabetic mice expressed 5-lipoxygenase, the enzyme required for the initiation of leukotriene synthesis, and produced leukotriene B4 (LTB4) when stimulated with the calcium ionophore A23187. Notably, LTB4 synthesis was increased threefold over normal (P < 0.03) in bone marrow cells from diabetic mice. In contrast, retinas from nondiabetic or diabetic mice produced neither leukotrienes nor 5-lipoxygenase mRNA. Despite an inability to initiate leukotriene biosynthesis, the addition of exogenous leukotriene A4 (LTA4; the precursor of LTB4) to retinas resulted in robust production of LTB4. Similarly, retinal glial cells synthesized LTB4 from LTA4, whereas mRECs produced both LTB4 and the cysteinyl leukotrienes. Culturing the retinal cells in high-glucose concentrations enhanced leukotriene synthesis and selectively increased expression of the LTB4 receptor BLT1. Antagonism of the BLT1 receptor inhibited LTB4-induced mREC cell death.
Transcellular delivery of LTA4 from marrow-derived cells to retinal cells results in the generation of LTB4 and the death of endothelial cells and, thus, might contribute to chronic inflammation and retinopathy in diabetes.
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