Targeting Galectin-3 Attenuates both Corneal Fibrosis and Retinal Gliosis

Abstract

Purpose: Corneal scarring and retinal gliosis are fibrotic proliferations which commonly lead to significant vision loss. As recent studies have revealed that a carbohydrate-binding protein, galactin-3, plays a critical role in lung and kidney fibrosis, the current study was designed to determine whether a small molecular inhibitor of galectin-3 can prevent fibrosis in the cornea and retina in an experimental mouse model.

Methods: Alkaline burn injury (0.15 N NaOH, 1.5 min) was used to induce corneal fibrosis and retinal gliosis in murine eyes using a procedure described by Mohan et al (Chemistry & Biology, 14; 2007). A galectin-3 inhibitor, TD139 (325 ng in 10µl), or vehicle (10µl PBS containing 0.5 % DMSO) were administered by sub-conjunctival injections every other day. Corneal opacity was scored by slit lamp examination. Corneas and retinal tissues were harvested on day 14 post treatment and subjected to Western blot analysis to detect the expression of αSMA, a marker of corneal fibrosis, and glial fibrillary acidic protein (GFAP), a marker of retinal gliosis.

Results: Eyes receiving TD139 demonstrated significantly reduced corneal opacity scores on day 14 (opacity scores on day 14: Vehicle treatment 2.101±0.21; TD139 treatment 1.14±0.19; N=28; p = 0.002). Control corneal and retinal tissue expressed negligible levels αSMA and GFAP, respectively. As expected, following alkali burn injury, corneal and retinal tissues expressed substantial amounts of αSMA and GFAP, respectively. Western blot analysis revealed that treatment with TD139, sifnificantly reduced αSMA expression in the cornea (TD139 treatment: 0.61±0.25 vs vehicle 1.0 normalized units) and GFAP expression in the retina (TD139 treatment: 0.45 ±0.05 vs vehicle 1.0 normalized units).

Conclusions: Our data provide proof-of-concept that targeting galectin-3 by the novel, small molecule inhibitor, TD139, ameliorates pathological corneal fibrosis as well as retinal gliosis. These findings suggest a potential new therapeutic strategy for prevention of these and perhaps other ocular cicatricial processes.

Keywords: 480 cornea: basic science • 541 glycoconjugates/glycoproteins • 688 retina