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A. Kitano, O. Yamanaka, Y. Okada, K. Shirai, S. Saika; A Histone Deacetylase Inhibitor, Trichostatin A, Suppresses TGFb/Smad Signal and Has a Therapeutic Effects on Experimental Alkali Burn in Mice. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3065.
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To examine the effects of a histone deacetylase inhibitor, Trichostatin A, on TGF-b/Smad signal in vitro and on the healing process (inflammation and scarring) in an alkali-burned, cornea in mice.
(1) Cultured human subconjunctival fibroblasts with or without concentrations of TSA were cultured in the presence or absence of TGFbeta1 for specific culture intervals. Activation of Smad2 signal was examined by western blotting. Effects of TSA on exprewssion of TGFbeta1 and collagen 1 mRNA was also examined by real-time RT-PCR. (2) Three micro l of 1 N NaOH was applied to the right eye of WT (n=28) mice to produce an ocular surface alkali burn under general anesthesia. The mice were received intraperitoneal injection of TSA (600 micro g/Kg daily) or its vehicle. Eyes were histologically and examined at 5 to10 days after alkali burn. Immunohisochemistry was conducted by using an antibody against alpha-SMA or F4/80 macrophage antigen.
(1) TSA at 500 nM suppressed Smad2 phosphorylation in the cultured cells at 2hr. TSA also reduced expression of TGFbeta1 and collagen Ia2. (2) Stroma of treated with TSA healing cornea seemed more transparent as compared with that of the control mice at day 5 and 10 post-alkali burn. HE histology indicated more marked inflammation in the thickened stroma in the cornea of the TSA injected mice. Immunohistochemical examinations show less alpha-SMA and F4/80 in the cornea of the TSA treated mice after alkali burn. Systemic TSA suppressed inflammation and scarring in mice.
TSA has anti-Smad effects in cultured fibroblasts and reduced fibrogenic reaction in an alkali-burend cornea in mice. TSA might have a therapeutic potential in ocular fibrotis disease of corneal scarring.
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