Establishing a dexamethasone treatment regimen to alleviate sulfur mustard-induced corneal injuries in a rabbit model.

Sulfur mustard (SM) is an ominous chemical warfare agent. Eyes are extremely susceptible to SM-toxicity; injuries include inflammation, fibrosis, neovascularization (NV), and vision impairment/blindness, depending on the exposure dosage. Effective countermeasures against ocular SM-toxicity remain elusive and are warranted during conflicts/terrorist activities and accidental exposures. We previously determined that dexamethasone (DEX) effectively counters corneal nitrogen mustard toxicity and that the 2 h post-exposure therapeutic window is most beneficial. Here, the efficacy of two DEX dosing frequencies, i.e., every 8 or 12 h (initiated, as previously established, 2 h post-exposure) until 28 days post SM-exposure was assessed. Furthermore, sustained effects of DEX treatments were observed up to day 56 post SM-exposure. Corneal clinical assessments (thickness, opacity, ulceration, and NV) were performed at the day 14, 28, 42, and 56 post SM-exposure timepoints. Histopathological assessments of corneal injuries (corneal thickness, epithelial degradation, epithelial-stromal separation, inflammatory cell, and blood vessel counts) using H&E staining and molecular assessments (COX-2, MMP-9, VEGF, and SPARC expressions) were performed at days 28, 42, and 56 post SM-exposure. Statistical significance was assessed using Two-Way ANOVA, with Holm-Sidak post-hoc pairwise multiple comparisons; significance was established if p<0.05 (data represented as the mean {plus minus} SEM). DEX administration every 8 h was more potent than every 12 h in reversing ocular SM-injury, with most pronounced effects observed at days 28 and 42 post SM-exposure. These comprehensive results are novel and provide a comprehensive DEX-treatment regimen (therapeutic-window and dosing-frequency) for counteracting SM-induced corneal injuries. Significance Statement The study aims to establish a DEX treatment regimen by comparing the efficacy of DEX administration 12 h vs 8 h, initiated at 2 h post-exposure; treatment initiated 2 h post-exposure, and DEX administration every 8 h thereafter was most effective in reversing SM-induced corneal injuries. SM-injury reversal during DEX administration (initial 28 days post-exposure) and sustained (further 28 days after cessation of DEX administration i.e., up to 56 days post-exposure) effects were assessed using clinical, pathophysiological, and molecular biomarkers.