Lipid hydroperoxide-induced tumor necrosis factor (TNF)- , vascular endothelial growth factor and neovascularization in the rabbit cornea: effect of TNF inhibition

Abstract

Lipid hydroperoxides (LHP) at high concentrations are cytotoxic, but at sublethal concentration, they induce synthesis of cytokine vascular growth factors. Intracorneal injections of 30 μg LHP placed 5 mm from the superior limbus stimulated early vasodilation of limbal vasculature and a rapidly developing, sustained neovascularization. Under these conditions, vessels grew at the rate of 0.3 mm/day to a total length of 7.5 mm, 25 days after injection. Cholesterol peroxides were less effective. Developing vessels were oriented towards the stimulus. Around the developing vessel there was dissolution of the stromal extracellular matrix. The most distal endothelial cells displayed prominent endoplasmic reticulum, a lack of basement membrane or tight junction complexes and leakage of fluorescein dye. Both the injection site and superior quadrant showed increased levels of tumor necrosis factor (TNF)-alpha and vascular endothelial growth factor after exposure to LHP. The neovascular response was inhibited by simultaneous administration of TNF-alpha antibody or pentoxifylline, an inhibitor of TNF-alpha synthesis. This corneal model of peroxide-induced neovascularization should prove useful for temporal studies of events in the initiation and propagation of signals leading to neovascularization, and for evaluating effects of treatment on neovascular growth.

Angiogenic Effect of Lipid Hydroperoxide on Bovine Aortic Endothelial Cells.

“…Similarly, our data show that above 10-5 M, 18:2-OOH, a product of oxidative reactions, is cytotoxic but at sub-lethal levels can induce neovascularization. A similar result was obtained in the retina and cornea of albino rabbits [6]. Lipid peroxy radicals are formed by the decomposition of LHP in the presence of ferric iron or cupric iron [25].…”

“…In contrast, the bFGF concentration in the presence of 10-' M 18:2-OOH was increased to 3.8± 1.7 pg/mg protein after 1 h and to 5. of LHP stimulated neovascularization, and LHP appeared to mediate the vascular process in a dose-dependent manner by increasing the concentrations of both VEGF and TNF-a at picomole threshold levels [6]. We could not detect VEGF or TNF-a in the present culture medium.…”

“…Angiogenesis is a major process in diabetic retinopathy, and plasma LHP levels are particularly increased in patients with retinopathy [5] . Exogenous LHP at sub-lethal concentrations induces neovascularization in the rabbit retina [6].…”

Potent anti-tumor and prolonged survival effects of E. coli-derived non-glycosylated kringle domain of tissue-type plasminogen activator

“…Decreased expression of vWF and ·-SMA is consistent with reduced expression of the important angiogenic factors, angiogenin and VEGF. TNF-· is known to be pro-angiogenic in vivo, despite its reported anti-angiogenic properties in vitro (27,28). Down-regulation of VEGF has also been observed following administration of several angiogenesis inhibitors, including recombinant PK1-3 (26), plasminogen kringle 5 (PK5) (29) and apolipoprotein kringles (14), and also following adenoviral vector delivery of angiostatin and endostatin (30).…”

Effect of a Dihydrobenzofuran Derivative on Lipid Hydroperoxide-Induced Rabbit Corneal Neovascularization

“…We previously reported that LHP induces neovascularizaion (NV) in a New Zealand albino rabbit corneal model (21,22) through upregulation of particular cytokines, especially tumor necrosis factor-alpha (TNF-α) and VEGF. The NV response was enhanced by hyperglycemic conditions (23), and it was suppressed by vitamin E treatment (24).…”