Doctor of Philosophy
Pathology and Laboratory Medicine
Hutnik, Cindy M.L.
Dysregulated wound healing contributes to most currently unanswered ophthalmological morbidity. Opacification and structure altering contractures compromise the delicate ocular anatomy upon which ocular function and healthy vision are reliant. Glaucoma filtration surgery, corneal stromal injury, proliferative vitreoretinopathy and age-related macular degeneration are major contributors to ocular morbidity – all with myofibroblast transdifferentiation and pathognomonic scarring activity at their core.
This thesis aims to revaluate the means by which dysregulated ocular wound healing is combated with evidence describing a novel strategy to mitigate its effects. A translational approach was used. An initial retrospective analysis of over ten thousand glaucoma surgeries found that perioperative NSAID exposure was significantly associated with surgical success. The current standard of care, corticosteroids, showed no such association. This was surprising and provided impetus to evaluate these clinical findings within the basic science lab.
The subsequent project examined the relative effects of NSAIDs to that of corticosteroids on the in vitro wound healing activity of ocular fibroblasts. Relative to steroids, NSAID exposure resulted in more ordered extracellular matrix remodelling, less cell-mediated collagen contraction and greater impairment of myofibroblast associated protein expression.
We hypothesized that these differences were due to NSAIDs more specific targeting of COX enzyme activity. By sparing lipoxygenase activity, competitive NSAIDs leave intact the biosynthetic machinery responsible for signaling the endogenous resolution of inflammation. This system involves the collective effects of the pro-resolving superfamily of lipid mediators and promotes the active resolution of inflammatory processes.
To assess the anti-fibrotic potential of inducing resolution within inflammation-induced ocular fibroblasts, two COX2 Ser516 acetylating molecules were utilized to modify the COX2 enzyme such that it: 1) ceases prostaglandin production, and 2) gains the capacity to produce pro-resolving lipid mediators. When applied to inflammation-induced ocular fibroblasts, a reduction in in vitro wound healing phenomena was observed with a corresponding shift in pro-/anti-fibrogenic transcription factor expression and downregulation of myofibroblast associated proteins.
Together these findings suggest that the resolution of inflammation and the resolution of fibroproliferation may be controlled by a common signaling system, and that interventions promoting the production of resolving lipid mediators could have significant anti-cicatrizing properties.
Summary for Lay Audience
Glaucoma surgery aims to reduce the pressure within a patient's eye. To accomplish this, a surgical drainage pathway is created for excess fluid within the eye to drain out of the eye. After surgery, inflammation occurs, which is the body's natural mechanism for healing damaged tissues. If left unchecked, inflammation will result in an overactive wound healing response - leading to scarring at the surgical site. This scarring, in turn, leads to a reduction in outflow through the new drainage pathway, and a failure to control the pressure in the eye. All current methods of inflammation control function by blocking it from taking place. This works against the body's natural system and is the root of the side effects associated with immune-suppressing drugs. This thesis details the search for and early development of an alternative method to modulate inflammation, a method that works more harmoniously with the body's endogenous processes to promote the natural conclusion of inflammation, in a timely manner prone to fewer unwanted side effects.
Armstrong, James J., "Modulation of Inflammation Driven Wound Healing after Glaucoma Surgery" (2019). Electronic Thesis and Dissertation Repository. 6534.
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