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Editors Selection IGR 18-4
Basic Science: Wound Healing Modulation
Comment by Ingeborg Stalmans & Alix Somers on:
66257 Inhibition by a retinoic acid receptor γ agonist of extracellular matrix remodeling mediated by human Tenon fibroblasts, Liu Y; Kimura K; Orita T et al., Molecular Vision, 2015; 21: 1368-1377
Filtration surgery remains the gold standard for the treatment of glaucoma in individuals whose intra-ocular pressure (IOP) is uncontrolled by medication or laser treatment. Excessive subconjunctival scar formation, due to excessive synthesis of new extracellular matrix (ECM) and tissue contraction, may interfere with the long term success of this surgery by obstructing the aqueous outflow with subsequent IOP elevation and bleb failure. Nowadays the use of antifibrotic agents such as mitomycin C and 5- fluorouracil are encountered in the daily practice to reduce the risk of excessive postoperative fibrosis, but with the known potential severe side effects.
The wound healing response is mediated by matrix metalloproteinases (MMP's), inflammatory mediators and growth factors including the cytokine transforming growth factor (TGF-β), a key mediator.
Retinoic acids, derivates of vitamin A, have several effects on eye development, immunity and tissue repair. The retinoic acid receptor γ agonist R667 in particular, could be a promising alternative antifibrotic stragey.
Liu et al. have shown that R667 inhibited TGF-β1-induced collagen gel contraction mediated by human Tenon fibroblasts (HTFs) in a concentration -and time-dependent manner. It inhibited the TGF-β1 induced release of MMP-1 and MMP-3 by HTFs as well as the phosphorylation of FAK, a tyrosine kinase protein that plays an important role in focal adhesions and cell contractility. The production of ECM proteins such as fibronectin and type I collagen was attenuated by R667.
The IOP after experimental glaucoma filtration surgery in rat models was also reduced in the R667 group compared with those that received PBS vehicle. The anti-fibrotic effects may contribute to this finding. Unfortunately, the IOP was only measured up to two weeks after surgery.
This is a valuable and interesting study that opens up for new strategies to inhibit scar formation after glaucoma filtration surgery.
Nevertheless, studies for comparison of surgical outcomes for animals treated with mitomycin C and R667 are needed for further evaluation. Future studies are required to assess the pharmacokinetics and toxicity of ocular administration of this drug. Other limitations of this study are the small sample size (five rat models per treatment group) and the short postoperative follow-up period (two weeks).
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