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Victoria E. Tovell, Peng T. Khaw, Maryse Bailly; Rac1 Inhibition Prevents Conjunctival Tissue Contraction and Remodeling in a New Model of Conjunctival Contraction. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1934. doi: https://doi.org/.
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In the eye, many types of surgery fail due to contraction and scarring at the surgical site. Glaucoma filtration surgery is one of the most effective methods of lowering intraocular pressure. However, scarring and contraction at the surgical site caused by activated Tenon’s fibroblasts, can lead to failure of the surgery. Small Rho-family GTPases have recently been unveiled as promising targets for anti-scarring therapies. The aim of this study was to investigate the effects of Rac1 inhibition on human Tenon’s fibroblast (HTF)-mediated matrix contraction and a new model of ex vivo intact conjunctiva contraction and remodeling.
The effect of the rac1 inhibitor (NSC23766) was tested on serum stimulated HTFs using a fibroblast populated collagen lattice model of contraction. Porcine conjunctiva was used to investigate the effects of NSC 23766 on serum stimulated tissue contraction using our ex vivo model. Toxicology was carried out using the Lactate Dehydrogenase assay and the LIVEDEAD viability assay. Tissue remodeling and matrix fiber integrity was monitored using confocal reflection microscopy.
Both continued and transient exposure to NSC23766 (50uM, 24 hr exposure) significantly inhibited HTF-mediated 3D collagen matrix contraction following serum stimulation. Similarly contraction of ex vivo segments of conjunctiva was inhibited by a single 24hr-long weekly treatment with NSC23766 (50uM). NSC23766 treatment prevented the extracellular matrix fibre degradation and tissue remodeling associated with serum-stimulated contraction, both in vitro and ex vivo. Exposures shorter than 24 hours at higher concentrations were also found to inhibit contraction in vitro (200uM, 30min exposure). Effective doses and exposures of NSC23766 were found to be non-toxic.
Rac1 is important for fibroblast contraction and it may be a useful target for preventing conjunctival scarring since only relatively short exposures are required to inhibit contraction.
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