title: TNF-alpha is critical for ischemia-induced leukostasis, but not retinal neovascularization nor VEGF-induced leakage.
abstract: Vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-alpha) show significant overlap with regard to their effects in the eye. It has been postulated that VEGF-induced leukostasis, breakdown of the blood-retinal barrier, and ischemia-induced retinal neovascularization may be mediated, at least in part, through TNF-alpha. In this study, we used mice deficient in TNF-alpha to test our hypothesis. Compared to wild type mice, TNF-alpha-deficient mice showed an 80% reduction in leukocyte accumulation in retinal vessels after intravitreous injection of VEGF, and 100% reductions after intravitreous injections of interleukin-1beta (IL-1beta) or platelet-activating factor (PAF). The increase in retinal vascular permeability induced by injection of PAF was significantly reduced in mice lacking TNF-alpha, but VEGF- and IL-1beta-induced leakage was unaffected. Compared to wild type mice with oxygen-induced ischemic retinopathy, TNF-alpha-deficient mice with ischemic retinopathy showed significantly reduced leukostasis and mild reduction in vascular leakage, but no significant difference in retinal neovascularization. These data suggest that TNF-alpha mediates VEGF-, IL-1beta-, and PAF-induced leukostasis and vascular leakage mediated by PAF, but not leakage caused by VEGF or IL-1beta. Ischemia-induced retinal neovascularization, which has previously been shown to require VEGF, does not require TNF-alpha and is unaffected by attenuation of leukostasis.
authors.affiliation: The Department of Ophthalmology, The Johns Hopkins University School of Medicine, Maumenee 825, 600 N. Wolfe Street Baltimore, Maryland 21287-9289, United States. svinores@jhmi.edu
authors.forename: Stanley A
authors.initials: SA
authors.lastname: Vinores
authors.forename: Wei-Hong
authors.initials: WH
authors.lastname: Xiao
authors.forename: Jikui
authors.initials: J
authors.lastname: Shen
authors.forename: Peter A
authors.initials: PA
authors.lastname: Campochiaro
mesh_terms: D000818:Animals; D001813:Blood-Retinal Barrier / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D053583:Interleukin-1beta / Q000494:pharmacology; D007511:Ischemia / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism*; D018921:Leukostasis / Q000139:chemically induced / Q000209:etiology*; D051379:Mice; D018345:Mice, Knockout; D010100:Oxygen; D010972:Platelet Activating Factor / Q000494:pharmacology; D015861:Retinal Neovascularization / Q000378:metabolism*; D012171:Retinal Vessels; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D053583:Interleukin-1beta; D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D010100:Oxygen