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Walid Abdallah, Stan G Louie, Kathy E Rodgers, Gere S diZerega, Mark S Humayun; The Effect of RAS Activation on Corneal Wound Healing in an Animal Model. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2046.
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© ARVO (1962-2015); The Authors (2016-present)
Activation of the renin-angiotensin system (RAS) has been recently shown to promote wound healing and facilitate tissue regeneration. In this study, a novel investigational drug (USB004); known to activate the Mas receptor; is evaluated in a full thickness corneal wound-healing model using rabbits.
Fifteen rabbits were randomly assigned into one of three treatment groups to receive either 0.03% or 0.3% USB004 or vehicle control groups once daily for 28 days. The right eyes of the animals were used for the study, where a full-thickness corneal tunnel was created using a 3.2mm corneal blade followed by applying the test article topically. Confocal microscopy determined clinical parameters (edema, haze) and cellular changes (stromal hypercellularity, re-epithelialization), Seidel’s test and in vivo leakage pressure were used to determine the stability of corneal wound, whereas histology and immunohistochemistry were used to quantify stromal edema, inflammation, and re-epithelialization at the end of the study.
Anterior chamber (AC) formation was noted on Day 4 in the 0.3% group, with all 5 animals receiving this dosage were able to fully formed AC by Day 6. The 0.03% UBS004-treated animals had full AC on Day 6, with the remaining animal having fully formed AC on Day 8. The first record of 100% AC formation in the vehicle group was on Day 12, with all AC complete on Day 14 (Week 2). Wound healing, as determined by absence of aqueous leakage in the Seidel’s test, occurred by Day 10 in all USB004-treated animals, while healing was not observed in any vehicle control-treated animals in the Seidel’s test. As demonstrated in the in vivo leakage pressure test, strength of healing was increased following treatment with 0.3% USB004 and 0.03% USB004, compared to vehicle. The mean leakage pressure for rabbits receiving 0.3% or 0.03% USB004 was 79.3±6 and 77.3±3.2 mmHg respectively. The mean pressure for vehicle-treated animals was 38.7±3.2 mmHg. Finally, regular distribution of keratocytes and lamellae in USB004-treated animals, which was not seen in the vehicle control group, indicated corneal healing. Effects of 0.03% and 0.3% USB004 on corneal healing were confirmed using SEM and immunostaining.
Topical ophthalmic application of USB004 to a full-thickness corneal wound reduces stromal edema and inflammation, promoting faster wound closure and a more uniform repair of the epithelial basal lamina.
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