Differential effects of acetylsalicylic acid and mitomycin C on cytokine-induced Tenon’s capsule myofibroblast transdifferentiation and activity: implications for glaucoma surgery.

Paper Presentation | Présentation d'article
5:02 PM, Friday 10 Jun 2022 (8 minutes)

Authors: Anastasiya Vinokurtseva, James J. Armstrong, Erica Li, Hong Liu, Cindy M. L. Hutnik. Schulich School of Medicine.

Author Disclosure Block: A. Vinokurtseva: None. J.J. Armstrong: None. E. Li: None. H. Liu: None. C.M.L. Hutnik: None.

Abstract Body:

Purpose: Inflammation-mediated scarring after bleb-forming glaucoma surgery is associated with high rates of surgical failure. The need to manage this complication has escalated with the rapidly expanding use of minimally invasive glaucoma procedures. Mitomycin C (MMC) is the current gold standard anti- scarring adjuvant in glaucoma surgery. It is an indiscriminate cytotoxic agent with variable and often unpredictable effectiveness. Acetylsalicylic acid (ASA) is unique among non-steroidal anti-inflammatory drugs, exerting its effects through covalent enzyme modifications. It has a repurposed functionality when delivered locally by resolving, rather than suppressing, inflammation that promotes scarring. The aim of this study is to determine whether ASA will decrease inflammatory cytokine-induced myofibroblast scarring activity in human Tenon’s capsule fibroblasts (HTCFs) and to compare the effects of ASA to MMC in in vitro model of subconjunctival scarring.

Study Design: Experimental drug exposure experiments in vitro using glaucoma patient-derived Tenon’s capsule fibroblasts.

Methods: HTCFs in two-dimensional (2D) and 3D models were co-treated with inflammatory and wound healing cytokines with and without ASA, in concentrations ranging from 100-1600 µg/ml, or MMC, in concentrations 0.05-0.2 mg/mL, to assess their effects on HTCF transdifferentiation and activity. To elucidate mechanistic effects of ASA, liquid chromatography tandem mass spectrometry (LC-MS/MS) was used to identify and measure ASA-triggered lipid mediators with predicted pro-resolving properties. Results: ASA treatment resulted in reduction in HTCF-mediated collagen contraction, TGFβ1-induced metabolic activity, and myofibroblast-associated protein expression, in the absence of necrotic cell death. In comparison to MMC, ASA was as effective in reducing markers of inflammation and scarring, while being less cytotoxic. Within cytokine-activated HTCFs, ASA significantly impaired prostaglandin production and significantly increased secretion of the pro-resolving mediators 5- hydroxyeicosatetraenoic acid (HETE), 15-HETE and 18-hydroxyeicosapentaenoic acid (HEPE).

Conclusions: ASA represses cytokine-induced myofibroblastic changes in human Tenon’s capsule fibroblasts, being non-inferior to MMC in vitro. ASA’s unique effects are associated with unique lipid mediator expression profile. Promoting the resolution of inflammation may be a promising strategy to mitigate cellular events associated with cytokine-mediated scarring.

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