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(American Journal of Pathology. 2005;166:1393-1403.)
© 2005 American Society for Investigative Pathology

Therapeutic Effect of Topical Administration of SN50, an Inhibitor of Nuclear Factor-{kappa}B, in Treatment of Corneal Alkali Burns in Mice

Shizuya Saika*, Takeshi Miyamoto*, Osamu Yamanaka*, Tadashi Kato*, Yoshitaka Ohnishi*, Kathleen C. Flanders{dagger}, Kazuo Ikeda{ddagger}, Yuji Nakajima{ddagger}, Winston W.-Y. Kao§, Misako Sato, Yasuteru Muragaki and Akira Ooshima

From the Departments of Ophthalmology* and Pathology, Wakayama Medical University, Wakayama, Japan; the Department of Anatomy,{ddagger} Graduate School of Medicine, Osaka City University, Osaka, Japan; the Laboratory of Cell Regulation and Carcinogenesis,{dagger} National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and the Department of Ophthalmology,§ University of Cincinnati Medical Center, Cincinnati, Ohio

We evaluated the therapeutic efficacy of topical administration of SN50, an inhibitor of nuclear factor-{kappa}B, in a corneal alkali burn model in mice. An alkali burn was produced with 1 N NaOH in the cornea of C57BL/6 mice under general anesthesia. SN50 (10 µg/µl) or vehicle was topically administered daily for up to 12 days. The eyes were processed for histological or immunohistochemical examination after bromodeoxyuridine labeling or for semiquantification of cytokine mRNA. Topical SN50 suppressed nuclear factor-{kappa}B activation in local cells and reduced the incidence of epithelial defects/ulceration in healing corneas. Myofibroblast generation, macrophage invasion, activity of matrix metalloproteinases, basement membrane destruction, and expression of cytokines were all decreased in treated corneas compared with controls. To elucidate the role of tumor necrosis factor (TNF)-{alpha} in epithelial cell proliferation, we performed organ culture of mouse eyes with TNF-{alpha}, SN50, or an inhibitor of c-Jun N-terminal kinase (JNK) and examined cell proliferation in healing corneal epithelium in TNF-{alpha}–/– mice treated with SN50. An acceleration of epithelial cell proliferation by SN50 treatment was found to depend on TNF-{alpha}/JNK signaling. In conclusion, topical application of SN50 is effective in treating corneal alkali burns in mice.




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