Understanding Mustard Vesicants Distribution and Toxicity in the Eye Using In Vivo and In Silico Models

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Project Summary Mustard vesicating agent sulfur mustard (SM) is the most extensively used warfare agent in history and remains a potential agent of warfare and terrorism. Eye is the most sensitive organ to SM and its analog nitrogen mustard (NM) exposure, resulting in devastating biphasic injury called Mustard Gas Keratopathy. The dose- and time- related severity of symptoms and the mechanism of this biphasic injury involving damage to the most affected cornea and possibly to other ocular tissues is not well understood. In addition, the extent to which mustard vesicants distribute, transport, and persist in various tissues of the eye is largely unknown, which could further identify tissue specific toxicity effects, injury progression and repair process. Such studies could aid in the identification of effective treatment strategies to counter tissue specific acute and long-term ocular complications from mustard vesicants’ exposure, which are elusive. To address this knowledge gap, we will use a synergistic in vivo-in silico approach to determine mustard vesicant ocular distribution and the ensuing corneal injury and repair mechanisms. We will leverage CFD Research’s existing in silico rabbit ocular model that is currently being used to characterize the distribution related toxicity of various chemical threat agents. Using the published data, preliminary in silico modeling studies show that NM penetrates well beyond the cornea. We hypothesize that a synergistic novel in vivo-in silico approach will assist in understanding how mustard vesicants distribute in healthy eyes and the mechanism by which the ocular injury develops, persists, and recovers or reappears as long-term complications. To support this hypothesis, the proposed specific aims will first computationally model NM (SM surrogate used in laboratory settings) related ocular injury and then translate this to simulate SM exposure. Aim 1: Determine Ocular Distribution of Nitrogen Mustard for Various Exposure Scenarios. The computational model will be validated on NM toxicokinetic (TK) profiles from in vivo rabbit studies and then extrapolated within the experimentally tested range to obtain TK profiles for non-tested NM exposure scenarios. Aim 2: Identify Relevant Biomarkers, Mechanisms and Pathways of NM-Induced Corneal Injury Progression and Repair. The combination of time- and dose-dependent transcriptomics and biomarker evaluation, as well as the NM TK analysis proposed under Aim 1, may contribute to determine the pathological mechanisms underlying early and late corneal injury development, progression, and repair related to vesicant bi-phasic keratopathy. Aim 3: Translation of the In Silico NM Rabbit Ocular Model to Simulate SM Exposure. The preliminary evaluations could assess comparisons of in Silico SM corneal injury model with NM, and serve as a vital step for minor alterations or in designing animal studies for additional validation under future studies. A combination of in silico and in vivo studies could serve as a more efficient and potentially more insightful novel approach to evaluate tissue-specific toxicity mechanisms underlying the mustard vesicants’ ocular pathology, and to identify therapeutic strategies that can improve the clinical mustard keratopathy symptoms and enhance wound healing.