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(American Journal of Pathology. 2005;166:1405-1418.)
© 2005 American Society for Investigative Pathology

Expression of Smad7 in Mouse Eyes Accelerates Healing of Corneal Tissue after Exposure to Alkali

Shizuya Saika^*, Kazuo Ikeda, Osamu Yamanaka^*, Takeshi Miyamoto^*, Yoshitaka Ohnishi^*, Misako Sato, Yasuteru Muragaki, Akira Ooshima, Yuji Nakajima, Winston W.-Y. Kao, Kathleen C. Flanders^¶ and Anita B. Roberts^¶

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

Damage to the cornea from chemical burns is a serious clinical problem that often leads to permanent visual impairment. Because transforming growth factor (TGF)-ß has been implicated in the response to corneal injury, we evaluated the effects of altered TGF-ß signaling in a corneal alkali burn model using mice treated topically with an adenovirus (Ad) expressing inhibitory Smad7 and mice with a targeted deletion of the TGF-ß/activin signaling mediator Smad3. Expression of exogenous Smad7 in burned corneal tissue resulted in reduced activation of Smad signaling and nuclear factor-B signaling via RelA/p65. Resurfacing of the burned cornea by conjunctival epithelium and its differentiation to cornea-like epithelium were both accelerated in Smad7-Ad-treated corneas with suppressed stromal ulceration, opacification, and neovascularization 20 days after injury. Introduction of the Smad7 gene suppressed invasion of monocytes/macrophages and expression of monocyte/macrophage chemotactic protein-1, TGF-ß1, TGF-ß2, vascular endothelial growth factor, matrix metalloproteinase-9, and tissue inhibitors of metalloproteinase-2 and abolished the generation of myofibroblasts. Although acceleration of healing of the burned cornea was also observed in mice lacking Smad3, the effects on epithelial and stromal healing were less pronounced than those in corneas treated with Smad7. Together these data suggest that overexpression of Smad7 may have effects beyond those of simply blocking Smad3/TGF-ß signaling and may represent an effective new strategy for treatment of ocular burns.

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