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Michael K Fink, Suneel Gupta, Steven Ebers, Ethan Crider, Michael Possin, Elizabeth A Giuliano, Prashant Rajiv Sinha, Frank G. Rieger, Rajiv R Mohan; ROCK Inhibitor HA1077: Potently Inhibits Corneal Fibrosis and Neovascularization. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
Rho associated Kinase (ROCK) pathways regulate cellular proliferation, migration, adhesion, wound healing, fibrosis, and angiogenesis in vivo. We tested the postulate that topical ROCK inhibitor HA1077 application to the eye will attenuate corneal fibrosis and neovascularization in vivo in a rabbit disease model by preventing exuberant wound healing.
Twelve New Zealand White rabbits were used under IACUC protocol. Corneal fibrosis and neovascularization (CNV) were produced by a single topical alkali (1N NaOH) application for 1min to the central cornea. Following corneal wounding, animals were divided into two groups: Group-1 served as controls and received 50uL Balanced Salt Solution (BSS) topically twice daily for 3 days. Group-2 served as treatment cohort and received 50uL HA1077 (3nM) topically twice daily for 3 days. Contralateral untreated eyes served as negative controls. Serial slit- and stereomicroscopy evaluated for the presence and degree of ocular inflammation, corneal edema, and corneal opacity. Intraocular pressures were recorded with an applanation tonometer. Corneas were harvested on day-14 with H&E and immunofluorescence staining employed to characterize levels of fibrosis, CNV, inflammation, and apoptosis.
Biomicroscopy detected a significant decrease (~2.8 fold; p<0.01) in corneal fibrosis and CNV in eyes treated with HA1077 compared to BSS-treated controls. Further, HA1077-treated corneas showed significant decreases in fibrosis markers (smooth muscle actin, fibronectin, and F-actin; 55-60%; p<0.0001), and did not exhibit significantly increased numbers of CD11b+ (2-11%) or TUNEL+ (0-5%) cells compared to BSS-treated controls during immunofluorescence analyses. A substantial decrease in CNV was also noted in HA1077-treated eyes as compared to BSS-treated controls (quantification pending). Clinical eye examinations and histological evaluation did not reveal evidence of acute toxicity from HA1077 topical application.
ROCK inhibitor HA1077 is a viable option for treating corneal fibrosis and neovascularization resulting from chemical injuries. Additional in vivo analysis is warranted.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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