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RECEPTORS AND SIGNAL TRANSDUCTION

Effect of overexpression of ppar on the healing process of corneal alkali burn in mice

Department of ¹Ophthalmology, Wakayama Medical University, Wakayama, Japan; ²Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; ³Department of Anatomy, Graduate School of Medicine, Osaka City University, Abeno, Osaka, Japan; and ⁴Department of Ophthalmology, University of Cincinnati Medical Center, Cincinnati, Ohio

Submitted 18 June 2006 ; accepted in final form 30 October 2006

Wound healing involves both local cells and inflammatory cells. Alkali burn of ocular surface tissue is a serious clinical problem often leading to permanent visual impairment resulting from ulceration, scarring and neovascularization during healing. Behaviors of corneal cells and inflammatory cells are orchestrated by growth factor signaling networks that have not been fully uncovered. Here we showed that adenoviral gene introduction of peroxisome proliferator-activated receptor- (PPAR) inhibits activation of ocular fibroblasts and macrophages in vitro and also induced anti-inflammatory and anti-fibrogenic responses in an alkali-burned mouse cornea. PPAR overexpression suppressed upregulation of inflammation/scarring-related growth factors and matrix metalloproteinases (MMPs) in macrophages. It also suppressed expression of such growth factors and collagen I2 and myofibroblast generation upon exposure to TGF1. Exogenous PPAR did not alter phosphorylation of Smad2, but inhibited its nuclear translocation. PPAR overexpression enhanced proliferation of corneal epithelial cells, but not of fibroblasts in vitro. Epithelial cell expression of MMP-2/-9 and TGF1 and its migration were suppressed by PPAR overexpression. In vivo experiments showed that PPAR gene introduction suppressed monocytes/macrophages invasion and suppressed the generation of myofibroblasts, as well as upregulation of cytokines/growth factors and MMPs in a healing cornea. In vivo re-epitheliazation with basement membrane reconstruction in the healing, burned, cornea was accelerated by PPAR-Ad expression, although PPAR overexpression was considered to be unfavorable for cell migration. Together, these data suggest that overexpression of PPAR may represent an effective new strategy for treatment of ocular surface burns.

peroxisome proliferator-activated receptor-; gene therapy; macrophage; fibroblast; Smad

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