Date of Award
2022
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Molecular and Cellular Biochemistry Program
Abstract
Dry eye disease represents an urgent unmet clinical need. This dissertation explores the underlying pathophysiological mechanisms of ocular surface disease in small and large animal models and provides feasibility for the development of antioxidants as novel therapeutics for dry eye disease. Dry eye disease affects 50 million Americans every year, and costs about $55 billion annually in the USA. The disease manifests as ocular irritation, burning, foreign body sensation, and blurry/cloudy vision. While it is widely accepted that oxidative stress plays a critical role in the pathophysiology of the disease, little is understood about the underlying molecular mechanisms. The purpose of the dissertation was to investigative oxidative stress-mediated ocular surface pathology and therapeutic efficacy of antioxidants in various preclinical experimental paradigms, including dry eye disease, dietary alcohol administration and particulate matter exposure. The studies revealed that the synthetic antioxidant, Mn-TM-2-PyP, reduces ocular surface damage more than the current standard-of-care approach, Restasis® (cyclosporine). For the first time in the literature, oxidative DNA damage was reported in the corneal tissue of mice induced with dry eye disease by exposure to a desiccating environment. Mn-TM-2-PyP’s efficacy was attributed to its ability to significantly reduce oxidative damage in the cornea. The efficacy of Mn-TM-2-PyP was validated in a novel large animal model, wherein environmental particulate matter was used to induce dry eye disease in rabbits. This is the first report of using particulate matter to induce dry eye disease in rabbits; it produced similar phenotypes to what has been reported in rodents. One way to improve patient compliance with eyedrop dosing regimens is to reduce the number of daily doses necessary. This was addressed by encapsulating a naturally occurring antioxidant, Xanthohumol, into nanoparticles. Nanoparticles have a known burst-release profile, to achieve sustained release of a drug over a longer period of time. Xanthohumol nanoparticles were able to reduce ocular surface damage to a similar extent as Restasis®, and largely reduced oxidative damage in the cornea. Lastly, clinical associations show a link between alcohol use and dry eye disease. Herein, a novel in vivo model of alcohol-induced dry eye disease was established. Chronic moderate alcohol consumption resulted in significant ocular surface damage, reminiscent of dry eye disease in mice. This was associated with dysregulation of the endogenous antioxidant response of the cornea and lacrimal gland, suggesting oxidative stress is present. Together, these data identify oxidative stress as a critical unifying contributor to multiple etiological manifestations of ocular surface pathology and support the future development of topical antioxidants targeting the pathological redox imbalance in ocular surface disease.
Recommended Citation
Ghosh, Anita Kirti, "Molecular Mechanisms of Oxidative Stress-Induced Corneal Damage and the Use of Antioxidants and Therapeutics" (2022). Dissertations. 3923.
https://ecommons.luc.edu/luc_diss/3923
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
Copyright Statement
Copyright © 2022 Anita Kirti Ghosh
