Lipid Mediators of Inflammation and Resolution: Investigating the Association with Abnormal Wound Healing and Surgical Outcome
Quality Improvement & Outcomes
The clinical success rates of traditional glaucoma surgery, as well as the rapidly evolving area of minimally invasive glaucoma surgery, stand to benefit greatly from novel, yet feasible and practical strategies to modulate inflammation-driven fibrotic wound healing. As this concept is foundational and translatable, it has the potential to revolutionize care in other ophthalmic diseases including uveitis, corneal neovascularization, macular scarring, and proliferative vitreoretinopathy as well as to any inflammation-mediated fibrotic process. This will directly translate into improved surgical success rates for patients with the potential for reduced morbidity and long-term cost savings by limiting the need for secondary interventions due to inflammation-driven scarring. This Innovation Fund project has resulted in a patented adjunctive surgical therapy which, if commercialized, would be accessible to the global market for utilization.
Inflammation-driven scarring is a major contributor to surgical failure. The current gold standard anti-scarring adjuvant mitomycin C (MMC) has variable effectiveness and is associated with significant risks. Acetylsalicylic acid (ASA) and more potent novel derivatives, when delivered locally, modify the pro-inflammatory cyclooxygenase (COX-2) enzyme through specific acetylation, forcing it to produce endogenous resolving mediators. This strongly signals for the resolution of inflammation and to mitigate inflammation-mediated fibrosis. The aim of this study was to compare the effects of ASA and its novel derivatives with MMC in an in vitro model of subconjunctival scarring.
METHODS & RESULTS
Glaucoma patient-derived Tenon’s capsule fibroblasts (HTCFs) cultured within subconjunctival tissue mimetics were treated with TGFβ1 plus or minus ASA, novel ASA-derivatives, or MMC. ASA and novel derivatives were at least as effective as MMC (with significantly less cytotoxicity) at minimizing in vitro scaring activity as measured through collagen contraction, collagen remodeling, MTT, LDH, immunofluorescence, and Western blot assays. To elucidate the mechanistic effects of ASA and its novel derivatives, liquid chromatography tandem mass spectrometry (LC-MS/MS) was used to quantify pro-inflammatory and pro-resolving lipid mediator secretion. ASA and novel derivatives significantly impaired secretion of all analyzed pro-inflammatory lipid mediators and significantly increased secretion of multiple pro-resolving lipid mediators.
ASA and its novel derivatives reduce in vitro wound healing within a subconjunctival tissue mimetic, with an effect that is non-inferior to MMC. These effects are associated with a unique lipid mediator expression profile, suggesting that inducing the resolution of inflammation through ASA and its novel derivatives represent a promising strategy to mitigate inflammation-driven scarring.
Paper Publications: 6
1. DOI: https://doi.org/10.2147/OPTH.S245915
2. DOI: https://doi.org/10.1016/j.exer.2019.03.015
3. DOI: https://doi.org/10.1016/j.jcjo.2018.04.004
4. DOI: https://doi.org/10.1097/IJG.0000000000000820
6. DOI:https://doi.org/10.1016/j.exer.2022.109284.Epub2022 Oct 21.
Conference Proceedings – Podium
1. Podium: 26
2. Poster: 27
1. Patents: 1
2. Material Transfer Agreements: 1
National Research Awards: 5