BLOOD-RETINAL BARRIER (BRB) BREAKDOWN IN EXPERIMENTAL AUTOIMMUNE UVEORETINITIS - COMPARISON WITH VASCULAR ENDOTHELIAL GROWTH-FACTOR, TUMOR-NECROSIS-FACTOR-ALPHA, AND INTERLEUKIN-1-BETA-MEDIATED BREAKDOWN

Experimental autoimmune uveoretinitis (EAU) induced in Lewis rats by i mmunization with S-antigen is a model of human uveitis. By using immun ocytochemical staining for albumin, relatively minor blood-retinal bar rier (BRB) breakdown was initially shown in the peripheral retina 8 da ys after immunization and in the posterior retina by 10 days, Albumin extravasation appeared to occur by opening of the retinal vascular end othelial (RVE) and the retinal pigmented epithelial (RPE) tight juncti ons, by transendothelial vesicular transport, and by permeating damage d RVE cells. Each of three anti-inflammatory agents reduced or delayed autoimmune-mediated cell destruction but did not eliminate any partic ular route of extravasation. Vascular endothelial growth factor (VEGF) , tumor necrosis factor alpha (TNF alpha), and interleukin-1(beta) (IL -1(beta)) are intimately associated with the development of EAU and ar e capable of causing BRB dysfunction, A high percentage of RVE tight j unctions appeared open ultrastructurally after intravitreal injection of VEGF (26.7%), TNF alpha (35.6%), or IL-1(beta) (22.1%) compared wit h saline-injected control (11.4%) or normal, untreated rabbits (4.1%), Heat treatment abolished the effect of IL-1(beta) an the BRB but only partially reduced the effect of VEGF. By 24 hr after injection, the e ffect of TNF alpha had reversed, but: that of IL-1(beta) had not; VEGF -mediated BRB dysfunction was partially reversible, In addition, album in-filled vesicle-like structures were seen in the RVE cytoplasm follo wing treatment with each mediator. This study shows that VEGF, TNF alp ha, and IL-1(beta) each cause BRB breakdown by opening tight junctions between RVE cells and possibly by increasing transendothelial vesicul ar transport. Each of these agents may contribute to BRB breakdown in EAU and in patients with uveitis, (C) 1997 Wiley-Liss, Inc.