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Increased Leukocyte Adhesion causes Vascular Endothelial Cell Death in Diabetic Retinopathy via a Fas-mediated Pathway
1Poulaki V., 1Adamis A., 2Joussen A. M.,
1Harvard Medical School, Massachussets Eye and Ear Infirmary (Boston)
2Universität zu Köln, Zentrum für Augenheilkunde, Abteilung für Netzhaut- und Glaskörperchirurgie (Köln)
Purpose: Increased leukocyte adhesion to the diabetic retinal vasculature is associated with capillary non-perfusion and vascular leakage and correlates with the increased expression of retinal ICAM-1 and CD18 on neutrophils. We now investigate the correlation between leukostasis and endothelial cell death in diabetes. In vivo experiments further eludicate the mechanism of the endothelial damage.
Methods: Long Evans rats were made diabetic with streptozotocin. In vivo static leukocytes were identified in the retinal vasculature by concanavalin A lectin. Cell injury was analysed in vivo using propidium iodide (PI). Surface expression of FasL, TRAIL, and the TRAIL receptors DR4, DR5 were analyzed by flow cytometry. Furthermore, neutrophils were allowed to interact with monolayers of microvascular endothelial cells, in the presence or absence of anti-Fas/ FasL/ DR4 or /DR5 inhibitory antibodies. Cell death was examined via TUNEL assay.
Results: The number of leukocytes in venules and capillaries was significantly increased after one week diabetes (p*0.005). PI positive cells were predominantly found in clusters. In both arterioles and venoles PI positive cells increased significantly after one week diabetes (p*0.005). In vitro, diabetic neutrophils exhibited increased FasL, but not TRAIL or TRAIL receptor, surface expression. Neutrophils from diabetics but not from controls induced endothelial cell apoptosis (p<0.005). Inhibition of Fas/FasL, but not TRAIL/DR4/DR5, interactions with specific blocking antibodies, significantly decreased endothelial cell apoptosis (p< 0.005).
Conclusions: Our data indicate that neutrophils from diabetic rats are capable of inducing Fas-mediated endothelial cell death, resulting in capillary damage and obstruction.
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