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theses

Exposure to mustard gas is a current issue. Recently there has been resurgence in chemical warfare attacks, specifically in the Middle East. In August 2015, artillery shells were fired at Isnibil, a village east of Marea, Syria leaving 23 individuals hospitalized with signs of poisonous mustard gas exposure. Mustard gas attacks in Iraq and Syria resulted in victims presenting with respiratory problems, irritation to the eyes, vomiting, and damage to the skin which included blisters and burns. Skin barrier integrity is essential to human health and wellbeing. The stratum corneum, the outermost layer of the skin, is crucial for the body’s defense against environmental toxins. Disruptions, which occur following chemical exposures, are associated with delayed wound healing and chronic wounds. Nitrogen mustard (NM, bis (2-chloroethyl) methylamine, mechlorethamine), an analog of the chemical warfare agent sulfur mustard (SM, bis (2-chloroethyl) sulfide), is a bifunctional alkylating agent that can induce oxidative stress, DNA damage and inflammation resulting in extensive skin damage. Since sulfur mustard is both lipophilic and volatile, dermal exposure can be localized using vapor cup models. In contrast, NM is hydrophilic; thus, direct application in solvents results in spreading over a relatively large area of skin. This makes quantification of tissue damage difficult to assess. Key to elucidating the mechanism of action of mustards and testing potential countermeasures is the ability to generate reproducible injury in localized areas of the skin in experimental animal models. Despite extensive research, mechanisms underlying the chronological events of NM induced skin injury are not clearly understood, which makes it difficult to develop effective treatments for mitigating vesicant induced damage to the skin. Further understanding the effects of mustards on the skin will help determine potential therapies that can be used to mitigate toxicity. My proposed project focuses on chemical warfare agents and how alterations in oxidative stress and DNA damage proteins can alter skin re-generation following exposure. More specifically, it aims to examine the early chronology of NM damage on skin epithelium. The proposed studies will use a modified semi-occlusive patch test model developed in our laboratory to study skin injury following NM exposure to elucidate the underlying mechanism of action for the development of potential therapeutics.

ETD_10420

Ph.D.

Includes bibliographical references

doi:10.7282/t3-e89j-sh07

ETD doctoral

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