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D. Hos, F. Bock, T. Dietrich, J. Onderka, F. E. Kruse, K. H. Thierauch, C. Cursiefen; Tyrosine Kinase Inhibitors Block Inflammatory Corneal Hem- and Lymphangiogenesis and Improve Graft Survival After Corneal Transplantation. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1696.
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© ARVO (1962-2015); The Authors (2016-present)
Neovascularisation of the normally avascular cornea is the main risk factor for immune rejections after corneal transplantation and the main sight-threatening complication of a variety of diseases. Purpose of this study was to analyze whether tyrosine kinase inhibitors (TKIs) can inhibit not only hem-, but also lymphangiogenesis, and whether treatment with TKIs after normal-risk corneal transplantation can improve graft survival.
Three 11-0 nylon sutures were placed in the corneal stroma of 6 week old Balb/C mice and left in place for 14 days. Meanwhile, one treatment group received the TKI PTK787/ZK 222584 (PTK/ZK; 75 mg/kg, orally, twice a day), the other treatment group received another TKI (ZK 261991: ZK991; 50 mg/kg, orally, twice a day), control mice received equal amounts of the substances' vehicle (both compounds: Schering AG, Berlin). Afterwards, whole mount preparations of the corneas were performed. For immunohistochemistry, LYVE-1 antibody as a specific lymphatic vascular marker and CD-31 as a panendothelial marker were used. The fluorescence microscopic pictures were analyzed morphometrically on digitized whole mounts using analySIS^B® software.Normal-risk allogeneic (C57BL/6 to Balb/C) corneal transplantations were performed. The treatment group received the TKI ZK991 (50 mg/kg, orally, twice a day, for 2 weeks), the control group received an equal amount of the substances' vehicle. Corneal sutures were removed after 7 days, grafts were then examined once a week for 8 weeks microscopically and were scored clinically (as previously described).
Treatment with TKIs resulted in a significant reduction of neovascularisation. In comparison to controls, hemangiogenesis was inhibited by 26% (PTK/ZK; p=0.0006) and 50% (ZK991; p<0.0001), lymphangiogenesis was inhibited by 61% (PTK/ZK; p<0.0001) and 76% (ZK991; p<0.0001). Comparing the survival proportions after corneal transplantation, treatment with ZK991 significantly improved the graft survival rate (survival rates: ZK991: 68%; control: 33%; p=0.0167).
Receptor tyrosine kinases seem to play a functional and pivotal role in mediating inflammatory neovascularisation. Therefore, TKIs are potent inhibitors of hem- and lymphangiogenesis in the cornea, and TKIs may be used to promote corneal graft survival after corneal transplantation.
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