Inhibition of TNF-α reduces laser-induced choroidal neovascularization

• Published in: Experimental eye research 2006-12, Vol.83 (6), p.1325-1334
• Main Authors: Shi, Xuan, Semkova, Irina, Müther, Philipp S., Dell, Susanne, Kociok, Norbert, Joussen, Antonia M.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - therapeutic use; Blotting, Western - methods; Choroid - metabolism; choroidal neovascularization; Choroidal Neovascularization - etiology; Choroidal Neovascularization - metabolism; Choroidal Neovascularization - pathology; Choroidal Neovascularization - prevention & control; Etanercept; Immunoglobulin G - therapeutic use; Infliximab; Laser Coagulation - adverse effects; leakage; Mice; Mice, Inbred C57BL; Pigment Epithelium of Eye - metabolism; Receptors, Tumor Necrosis Factor - therapeutic use; TNF-α; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - physiology
• ISSN: 0014-4835; 1096-0007
• DOI: 10.1016/j.exer.2006.07.007

To investigate the role of the TNF-α in the development of laser-induced choroidal neovascularization (CNV) in a mouse model. Four separate laser burns were applied to induce ruptures of Bruch's membrane and subsequent choroidal neovascularization in C57BL/6J mice. TNF-α protein expression was semiquantitatively assessed by Western blot analysis of the choroidal and RPE layer from mice with or without laser treatment. To investigate the effect of TNF-α inhibition on CNV formation, animals were treated for 7 days via intraperitonealy implanted osmotic pumps either 3 days before or after laser injury with recombinant TNF receptor P75 (etanercept), a chimeric monoclonal antibody (infliximab), or a purified rat anti-mouse/rat TNF monoclonal antibody (TNF-mAb), respectively. Fluorescein angiography, flat-mount preparations, and histopathology were performed at day 7, 10, or 14 after laser treatment. Western blotting demonstrated that TNF-α expression was 4.57-fold higher in the choroid and RPE one week after laser injury compared to control mice without laser. When evaluated one and two weeks after laser injury, etanercept and infliximab given from the 3rd day before laser-damage significantly reduced CNV size and pathological fluorescein leakage compared to the control group after laser treatment only. The inhibitory effect of the monoclonal TNF-α antibody on CNV formation was evident two weeks after photocoagulation but not after one week. Only etanercept administered 3 days after laser injury still reduced significantly the development of CNV lesions. Histopathology confirmed that CNV lesions in treated mice were smaller in size compared to the control animals without TNF inhibitor treatment. In conclusion, anti-TNF-α treatment with different inhibitors reduces both the size and the leakage of laser-induced CNV. These results suggest the involvement of TNF-α in the development of laser-induced CNV and its potential use as a therapeutic agent in the age-related macular degeneration.