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Pathophysiology and inflammatory biomarkers of sulfur mustard-induced corneal injury in rabbits.

ABSTRACT: Sulfur mustard (SM) is a cytotoxic, vesicating, chemical warfare agent, first used in 1917; corneas are particularly vulnerable to SM exposure. They may develop inflammation, ulceration, neovascularization (NV), impaired vision, and partial/complete blindness depending upon the concentration of SM, exposure duration, and bio-physiological conditions of the eyes. Comprehensive in vivo studies have established ocular structural alterations, opacity, NV, and inflammation upon short durations (<4 min) of SM exposure. In this study, detailed analyses of histopathological alterations in corneal structure, keratocytes, inflammatory cells, blood vessels, and expressions of cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-9, vascular endothelial growth factor (VEGF), and cytokines were performed in New Zealand white rabbits, in a time-dependent manner till 28 days, post longer durations (5 and 7 min) of ocular SM exposure to establish quantifiable endpoints of injury and healing. Results indicated that SM exposure led to duration-dependent increases in corneal thickness, opacity, ulceration, epithelial-stromal separation, and epithelial degradation. Significant increases in NV, keratocyte death, blood vessels, and inflammatory markers (COX-2, MMP-9, VEGF, and interleukin-8) were also observed for both exposure durations compared to the controls. Collectively, these findings would benefit in temporal delineation of mechanisms underlying SM-induced corneal toxicity and provide models for testing therapeutic interventions.

SUBMITTER: Goswami DG

PROVIDER: S-EPMC8509852 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Purpose: Exposure to sulfur mustard (SM) may result in severe ocular injuries. While some of the eyes show a clinical resolution of the injury (defined as clinically non-impaired), part of the eyes develop irreversible late ocular pathologies (defined as clinically impaired) that may lead to corneal blindness. Understanding the pathological mechanisms underlying the development of the late pathology may lead to improved treatment options. Therefore, this study aimed to investigate the mRNA expression profiles of corneas from clinically impaired, clinically non-impaired and naïve eyes. Methods: Rabbit eyes were exposed to SM vapor and a clinical follow-up was carried out up to 4 weeks using a slit lamp microscope. At this time point, corneal tissues from clinically impaired, clinically non-impaired and naïve eyes were processed for RNA sequencing (RNA-seq) and differential expression analyses. The differential expression profiles were further subjected to pathway enrichment analysis using Ingenuity Pathway Analysis (IPA). Real-time PCR was used for RNA-seq validation. Results: The late pathology developed in 54%-80% of the eyes following ocular exposure to SM, clinically manifested by inflammation, corneal opacity and neovascularization. RNA-seq results showed significant differences in mRNA levels of hundreds of genes.xls between clinically impaired, clinically non-impaired and naïve corneas. Pathway enrichment analysis showed common pathways that were activated in all of the exposed eyes, such as Th1 and Th2 activation pathway, in addition to pathways that were activated only in the clinically impaired eyes compared to the clinically non-impaired eyes, such as IL-6 and ERK5 signaling. Conclusions: Corneal mRNA expression profiles for the clinically impaired, clinically non-impaired and naïve eyes generated a comprehensive database that revealed new factors and pathways, which for the first time were shown to be involved in SM-induced late pathology. Our data may contribute to the research on both the pathological mechanisms that are involved in the development of the late pathology and the protective pathways that are activated in the clinically non-impaired eyes and may point out towards novel therapeutic strategies for this severe ocular injury.

Project description:Sulfur mustard (SM) is a potent vesicant that targets epithelial cells and tissues. Most vesicant research has been performed using bona fide SM; however, some studies have used simulants, most notably half mustard (2-chloroethyl ethylsulfide; CEES) and nitrogen mustard (mechlorethamine; NM). Although CEES and NM have similarities to SM and can cause vesication, there are distinct differences in the chemical structures and physical properties of these compounds that may impact their toxic effects. Microarray analysis of cultured primary human epidermal keratinocytes (HEK) exposed to each of these vesicants was performed to directly compare the transcriptional responses induced by these vesicants. HEK were exposed in triplicate to concentrations ranging from 0-1000 µM for SM and NM and 0-4000 µM for CEES. Cells were harvested at 1, 2, 4, 8, 16, and 24 h and the RNA isolated for microarray analysis. Transcriptional responses were phenotypically anchored to cell morphology. The dataset was filtered by exposure and timepoint, and an analysis of variance was performed using dose as the factor. The top 500 genes ranked by p-value were analyzed using gene ontology algorithms to identify biological pathways significantly affected by each vesicant. At 2 h post-exposure, p53 signaling, Erk/MAPK signaling, and BMP signaling were significantly affected by all three vesicants. At 4 h post-exposure, p53 signaling , B cell activating factor, and glucocorticoid receptor signaling were significantly affected by all three vesicants. At 8 h post-exposure, there were no significant pathways commonly affected by all three vesicants. These results suggest that, although there are similarities in the transcriptional responses to each of these vesicants, the transcriptional responses appear to differ over time. Thus, extrapolation of results obtained with one vesicant to other vesicants may be complex and may have important implications for the development of vesicant therapeutics.

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Pathophysiology and inflammatory biomarkers of sulfur mustard-induced corneal injury in rabbits.

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