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S. Nakao, Y. Hata, M. Miura, K. Noda, T. Hisatomi, T. Nakazawa, Y. Jin, M. R. Dana, T. Ishibashi, A. Hafezi-Moghadam; Role of Stromal Fibroblast Activation in Inflammatory Angiogenesis in the Cornea. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4815.
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Inflammation can cause corneal angiogenesis and significant loss of visual acuity. Corneal stromal fibroblasts are normally quiescent but readily respond to injury and transit into activated phenotypes under pathological conditions. However, the role of corneal stromal fibroblasts in inflammatory angiogenesis remains to be investigated.
To induce inflammatory angiogenesis, IL-1β pellets (30ng) were implanted in the corneas of male BALB/c mice (6-10 wks old) using the established micro-pocket assay. To characterize the cells that are involved in corneal inflammation, immunohistochemistry was performed in IL-1β-implanted corneas on day 2 and 4, using Abs against pIΚB-α, IΚB-α or CD11b. The expression of angiogenesis-related cytokines (i.e. VEGF-A) in IL-1β-implanted corneas and in IL-1β-treated corneal fibroblasts (MK/T1 cells) were examined using ELISA. To examine the role of NF-ΚB activation, a selective NF-ΚB inhibitor (SN50) was applied topically twice a day in IL-1β-implanted eyes.
IL-1β caused IΚB-α phosphorylation mainly in corneal stromal cells but not in infiltrated CD11b+ cells 2 days after implantation (CD11b+, 13 ± 4.6 cells/field; CD11b-, 94 ± 29.3 cells/field). In contrast, both cell types were positive for phosphorylated IΚB-α, 4 days after IL-1β implantation (CD11b+, 38.8 ± 14.0 cells/field; CD11b-, 49.5 ± 10.9 cells/field). IL-1β induced expression of VEGF-A and NF-ΚB signaling in corneal fibroblasts in vitro. A selective NF-ΚB inhibitor significantly attenuated IL-1β-induced corneal angiogenesis by 65.7% (P = 0.002).
These findings suggest that NF-ΚB activation in the corneal stromal fibroblasts is an important early event during IL-1β -induced corneal angiogenesis. Inhibition of NF-ΚB may become an attractive therapeutic strategy in prevention and treatment of inflammatory corneal angiogenesis.
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