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Christian Vorwerk, Vladislavs Sokalskis, Alexander Zabelyshenskiy, Hagen Thieme, Lars Choritz; Targeting specific TGF-β signaling pathways to prevent bleb fibrosis after glaucoma drainage device surgery. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4476.
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© ARVO (1962-2015); The Authors (2016-present)
Bleb fibrosis is one of the major reasons for failed filtering surgery in glaucoma patients. Antifibrotic substances like Mitomycin C and 5-fluorouracil are successfully used to prevent bleb failure, however because of their modes of action they can have potentially vision-threatening side effects. The aim of this study was to investigate in vitro the potential of two drugs targeting specific signaling pathways downstream of the TGF-β receptor to prevent Tenon fibroblast proliferation, migration and myofibroblast transdifferentiation.
Primary cultures of human Tenon’s Fibroblasts (HTF), stimulated with TGF-β2 (1ng/ml), were treated with different concentrations of either Imatinib, Rapamycin or vehicle (control). Proliferation was determined indirectly via repeated measurement of cell viability using resazurin dye. Migration was measured with a scratch wound healing assay, whereas myofibroblast transdifferentiation was assessed by alpha-smooth muscle expression (αSMA) using qPCR.
Both Imatinib and Rapamycin significantly inhibited TGF-β-induced HTF proliferation. While Rapamycin showed a dose dependent effect at a concentration as low as 10-11 mol/l (p<0.05); (maximal effect at 10-8 mol/l (p<0.001), IC50=3.8*10-11 mol/l) and no toxicity up to 10-6 mol/l), Imatinib was only effective at 10-8 mol/l and caused a loss of cells above 10-6 mol/l. Migration was not affected by Rapamycin, while Imatinib dose dependently inhibited HTF migration above 10-7 mol/l. Neither drug inhibited αSMA in TGF-β-stimulated HTF.
Imatinib and Rapamycin both inhibit TGF-β-induced HTF proliferation, but have differential effects on HTF Migration while leaving myofibroblast transdifferentiation unaffected. Both drugs may have some benefit in prevention of bleb fibrosis after filtering surgery. More importantly, pharmacological targeting of specific pathways of TGF-β pleiotrophic effects in vivo may lead to a better understanding of the underlying pathomechanisms of bleb fibrosis after glaucoma drainage devices surgery.
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