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Alison EM Vickers, Julia E Herrmann, Jianping Gao, Robyn L Fisher, Biochemistry/Molecular Biology; Corneal wound healing is delayed by diclofenac in a human ex vivo front of the eye model with a comparison to rabbit. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):741.
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© ARVO (1962-2015); The Authors (2016-present)
Topical administration of diclofenac (DCF) to relieve pain and inflammation post-surgery can delay corneal wound healing. To characterize human versus rabbit response to DCF following injury, topical DCF (clinical formulation, 0.1%) was administered following an anterior keratectomy (AK) in: 1) a NZW rabbit in vivo study, and 2) ex vivo front of the eye models of rabbit and human. To further characterize DCF effects, gene expression changes were evaluated in the ex vivo models.
A corneal wound was surgically induced (AK) to NZW rabbit eyes in vivo, and on enucleated rabbit and human eyes, as described previously (Stern et al., Cornea 2006). Human eyes were procured with donor consent through Midwest Eye-Banks (Ann Arbor, MI) and The Lions Eye Institute for Transplant and Research (Tampa, FL). This ex vivo front of the eye model, inclusive of the anterior chamber, was established and maintained for several days in culture. Wound closure was quantified with fluorescein, tissue viability was evaluated by ATP levels and gene expression by qRT-PCR.
The AK rabbit in vivo study revealed that DCF delayed wound (8 mm) healing, with a statistically significant delay of wound closure at 48 hr (45%) and 72 hr (64%) than time matched AK controls. In the ex vivo AK eye models, the size of the AK induced injury was selected to parallel the rate of wound closure in AK untreated eyes in vivo. Ex vivo, DCF significantly delayed the rate and area of wound closure in rabbit (2.5 mm) by 80% at 48 hr and human (8 mm) by 53% at 18 hr. DCF treatment reduced the number of genes changed in rabbit (17%) and human (30%) compared to AK only. In rabbit cornea, DCF caused an up-regulation of cytoskeletal, remodeling and immune response genes and an absence of stress response genes. In human cornea, DCF suppressed many cytoskeleton and remodeling gene expression changes (collagen, growth factors and TIMP1).
This human ex vivo front of the eye model reproduced the delay of corneal wound healing by DCF, as seen clinically. Gene expression pathways further defined the DCF effects. This translational research approach, comparing animal and human tissue, can be used to more confidently predict human response to drugs on wound repair.
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