Dexamethasone alters the cornea transcriptome to confer protection against ocular sulfur mustard exposure via regulating NFκB and TGFβ signaling in an in vivo rabbit model.

Abstract

Ocular exposure to sulfur mustard (SM), infamously called "King of Battle Gases", may occur during warfare, terrorist activities, or accidentally from improperly discarded munitions/stockpiles. Eyes, particularly corneas, are exceptionally vulnerable to SM toxicity. Notably, SM is a potent genotoxicant that causes damage to proteins, lipids, and nucleic acids. Currently, no approved therapeutics are available for ocular SM injuries. We developed a dexamethasone (DEX; 0.1%) treatment plan (application initiation 2&#xa0;h post-exposure and every 8&#xa0;h thereafter for 28&#xa0;days) that effectively countered mustard vesicant-induced corneal injuries. However, the mechanistic aspects of SM toxicity and DEX efficacy remain elusive. Thus, rRNA-depletion RNA sequencing was performed on day 14 and day 28 post-SM exposure (neat) to assess the progression of SM toxicity and DEX efficacy at the transcriptome level in corneas (in vivo rabbit studies) from control, SM-exposed, and DEX-treated tissues. Transcripts significantly differentially expressed between all three groups (omnibus FDR&#x2009;<&#x2009;0.01) were further analyzed based on pairwise differences between treatment groups. Further, network analyses and functional enrichment studies were performed to decipher SM toxicity and DEX efficacy-associated effects as a function of time. Twenty-day treatment was found to be more effective than 4-day DEX treatment. Main mechanisms associated with DEX efficacy included NF&#x3ba;B and TGF&#x3b2; signaling. The most prominent functional aspects associated with SM toxicity and DEX efficacy were preservation of the corneal structural integrity via regulating collagen networks and angiogenesis. These novel outcomes provide in-depth mechanistic insights into DEX efficacy for treating SM-induced corneal injuries.