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H.L. Chandler, C.M. H. Colitz, W.W. Miller, D.F. Kusewitt; The Role of Tetracyclines in Healing of Canine Refractory Ulcers . Invest. Ophthalmol. Vis. Sci. 2005;46(13):2597.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Re–epithelialization in refractory corneal ulcers does not occur properly. Normal corneal re–epithelialization resembles the process of epithelial–mesenchymal transition (EMT), the transformation of epithelial cells into more fibroblastic cells. EMT is initiated by growth factors like transforming growth factor–ß (TGF–ß) that stimulate production of Slug. Slug modulates changes in cell adhesion and motility leading to EMT and is required for normal corneal epithelial cell (CEC) migration. Tetracyclines enhance TGF–ß expression. We hypothesize that tetracycline stimulation of TGF–ß activity leads to increased expression of Slug and, ultimately, to the EMT–like changes required for successful corneal wound healing. Methods: Canine refractory corneal ulcers were examined to determine levels of expression of Slug and its putative target genes. Western blotting and real–time RT–PCR were used to examine the expression of Slug protein and mRNA compared to normal corneas. Also, CEC were wounded in vitro and treated with oxytetracycline. Wound closure was monitored and RT–PCR performed to determine Slug expression. Cultured CEC were incubated with oxytetracycline and TGF–ß blocking antibody, and cell migration was monitored. Results: There was decreased expression of Slug protein and mRNA in refractory ulcers compared to normal corneas. Oxytetracycline increased both Slug expression and the rate of wound closure in cultured CEC compared to untreated controls. Blocking the TGF–ß pathway decreased the rate of cell migration in CEC treated with oxytetracycline. Conclusions: Refractory ulcers have even lower Slug expression than normal corneal epithelium, suggesting reduced stimulation of cell migration. In vitro treatment of wounded CEC with oxytetracycline enhanced wound closure and Slug expression. Blocking the TGF–ß pathway decreased the rate of cell migration in tetracycline–treated CEC, suggesting that tetracycline may use this pathway to stimulate wound closure. Treatment of refractory ulcers with tetracycline may increase the expression of Slug and its targets, thus allowing normal re–epithelialization to occur.
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