Establishing a Dexamethasone Treatment Regimen To Alleviate Sulfur Mustard–Induced Corneal Injuries in a Rabbit Model

Abstract

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 SMexposure. 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 ± 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 SMexposure. These comprehensive results are novel and provide a comprehensive DEX-treatment regimen (therapeutic-window and dosing-frequency) for counteracting SM-induced corneal injuries.

Progress and Challenges in Developing Medical Countermeasures for Chemical, Biological, Radiological, and Nuclear Threat Agents

“…Focusing on corneal injury, Agarwal and team assessed the efficacy of dexamethasone in countering ocular SM toxicity, evaluating two dosing frequencies ( Mishra et al, 2024b ). Administering dexamethasone every 8 hours proved more potent than every 12 hours in reversing corneal SM injuries, suggesting a novel and comprehensive treatment regimen for immediate and sustained effects up to 56 days post-exposure.…”