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

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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)-α and vascular endothelial growth factor after exposure to LHP. The neovascular response was inhibited by simultaneous administration of TNF-α antibody or pentoxifylline, an inhibitor of TNF-α 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.

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Authors and Affiliations

  1. Department of Clinical Laboratory Science, State University of New York at Buffalo, Buffalo, NY, 14214, USA

    Toshihiko Ueda, Takako Ueda, Shohei Fukuda, Richard Browne, Ahmad Aljada & Donald Armstrong

  2. Department of Pathology, State University of New York at Buffalo, Buffalo, NY, 14214, USA

    Edwin Jenis, Robert Spengler & Richard Chou

  3. Department of Ophthalmology, State University of New York at Buffalo, Buffalo, NY, 14214, USA

    Peter Buch

  4. Department of Medicine, State University of New York at Buffalo, Buffalo, NY, 14214, USA

    Paresh Dandona

  5. Division of Health Sciences and Technology, Harvard University–Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    R. Sasisekharan

  6. Schepens Eye Research Institute, Harvard Medical School, Boston, MA, 02114, USA

    C. Kathleen Dorey

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  1. Toshihiko Ueda
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Ueda, T., Ueda, T., Fukuda, S. et al. Lipid hydroperoxide-induced tumor necrosis factor (TNF)-α, vascular endothelial growth factor and neovascularization in the rabbit cornea: effect of TNF inhibition. Angiogenesis 1, 174–184 (1997). https://doi.org/10.1023/A:1018377621102

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