Soluble Epoxide Hydrolase Inhibitors Improve Cornea Alkali Wound Healing

Cornea alkali injuries are difficult to treat and potentially blinding, and there are still no specific treatments. The cytochrome P450 arachidonic acid metabolism pathway generates epoxy fatty acids (EpFAs) which have analgesic, anti-inflammatory, and anti-fibrotic activities. EpFAs have anti-fibrotic effects in several tissues including kidney, heart, liver, and lungs, while the cornea has never been examined. Soluble epoxide hydrolase (sEH) metabolizes EpFAs to biologically less active diols, and its inhibitors (sEHi) can alleviate or prevent fibrosis. The current studies were designed to examine the role of sEHi in NaOH and ammonia wounded corneas and develop new in vitro and in vivo cornea ammonia wound models. Haziness was reduced or eliminated in NaOH wounded mouse corneas treated with sEHi by day 17 post-injury. Ammonia wounded corneas treated with sEHi did not vascularize and most of the haze resolved. αSMA, collagen III, and fibronectin were significantly decreased in NaOH and ammonia wounded corneas treated with sEHi. Fewer CD45⁺ and F4/80⁺ cells were observed in NaOH wounded sEH KO mouse corneas compared to WT by day 31 post-injury. Collagen I and CD45⁺ cells persisted within WT corneas at 31 days post-injury, suggesting more matrix remodeling and inflammation in WT compared to sEH KO corneas. TGFβ1-stimulated αSMA and sEH expression was reduced in human corneal fibroblasts cultured with sEHi. The results demonstrate that sEHi can play a critical role in NaOH and ammonia injury responses and indicate that topical sEHi administration works to effectively treat these wounds.