Date of Award
8-28-2024
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Pharmacology and Experimental Therapeutics
First Advisor
Simon Kaja
Second Advisor
Gwendolyn Kartje
Abstract
Exposure to particulate matter (PM) constitutes a significant public health concern associated with chronic systemic diseases, including respiratory and airway disease, neurotoxicity, and an increased risk of cardiovascular disease and cancer. Epidemiological evidence shows that populations exposed to high levels of PM have an increase in ocular inflammation, irritation, and conjunctivitis. PM exposure may further exacerbate dry eye disease, particularly in regions characterized by high levels of urban or industrial pollution, wildfire smoke, and heavy traffic. Airborne PM, composed of harmful pollutants and allergens, can be deposited in the cornea and conjunctiva, causing irritation that can develop into chronic ocular surface disease. There is an urgent unmet clinical need for novel targeted therapies that can safely and effectively reduce acute ocular toxicity and prevent long-term deleterious effects of PM exposure on the ocular surface. This dissertation elucidates the cellular mechanisms associated with ocular toxicity of PM using pre-clinical in vitro and in vivo models and determines the feasibility of topically administered targeted therapeutics, such as a synthetic manganese porphyrin-class antioxidant, and a formulation of pooled human immune globulins repurposed FDA-approved for intravenous administration (Flebogamma® 5% DIF), to both prevent and treat ocular surface diseases. The studies herein revealed that PM elicits multifactorial ocular pathology and toxicity through the generation of oxidative stress, secretion of pro-inflammatory cytokines, eliciting mast cell degranulation, and neutrophil activation and neutrophil extracellular trap formation. Topical administration of antioxidants effectively mitigated PM-induced cytotoxicity in vitro and pathology in a novel in vivo rabbit model of PM-associated ocular toxicity. Pooled human immune globulins exerted dose-dependent efficacy against neutrophil extracellular trap formation; safety of topically administered pooled human immune globulins was evaluated in rabbits. Results from this Dissertation provide novel mechanistic insights into the ocular toxicity mediated by particulate matter. Furthermore, efficacy and safety studies on Flebogamma® 5% DIF support the ongoing clinical development and will as critical dose- and dose-regimen justification for an Investigational New Drug (IND) application to the FDA.
Recommended Citation
Iqbal, Sana, "Molecular Mechanisms and Targeted Therapies for Ocular Surface Disease" (2024). Dissertations. 4129.
https://ecommons.luc.edu/luc_diss/4129
Creative Commons License
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