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Royce Mohan, Linda Cauley, Paola Bargagna-Mohan; Type III Intermediate Filament Overexpression in the Genesis of Corneal Fibrosis. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5975.
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The type III intermediate filament (IF) vimentin is highly expressed in the cornea during fibrosis and was recently shown to be therapeutic target for corneal fibrosis (Bargagna-Mohan, JBC 2012). We used bone marrow transplantation (BMT) studies along with withaferin A, a vimentin/desmin-targeting small molecule probe, to investigate the myofibroblast-mediated genesis of corneal fibrosis.
Mice 129Svev wild type (WT) and 129 Svev vimentin-deficient (Vim KO) were subjected to corneal alkali injury with epithelial debridement. BMT from WT donors to Vim KO recipient mice and vice versa was performed and mice subjected to corneal injury. Mice were treated with vehicle or WFA at 2 mg/kg/d by intraperitoneal injection for different periods (1 week to 1 month), and corneas analyzed for opacity till 9 months post-injury using biomicroscopy and computer imaging colorimetric technique. Ocular tissues were analyzed using immunohistochemistry (IHC) and western blotting (WB) for fibrotic markers (vimentin, desmin, Skp2, alpha smooth muscle actin and p27Kip1)
We previously reported that Vim KO mice recover from corneal injury with attenuated fibrosis, which was mimicked by WFA treatment in WT mice. Further improvement in corneal clarity by WFA in Vim KO was attributed to desmin downregulation. Our BMT experiments confirm that vimentin overexpression in corneal myofibroblasts (BM recipients from Vim KO) drive fibrosis, which was comparable with injured WT mice not subjected to BMT. This result was also corroborated in Vim KO mice (BM recipients from WT) that showed improved corneal clarity similar to injured Vim KO mice not subjected to BMT. In our longitudinal study, WFA treatment for 1 month with assessment at 9 months post-injury showed significant improvement in corneal clarity in WT recipients compared to vehicle treated mice (P<0.05). Vim KO mice that initiated with lower levels of corneal opacity at 1 month also maintained greater improvement after WFA treatment at 9 months (P<0.05). WB analysis and IHC results of early time points showed fibrotic corneas elaborating chronic myofibroblast expansion was associated with vimentin, desmin, alpha smooth muscle actin and Skp2 overexpression.
Collectively, our data advances the idea that myofibroblast-overexpression of type III IFs are critical targets for corneal fibrosis and could be pursued for development of new anti-fibrotic drugs.
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