Pharmacological Approaches to Modulate the Scarring Process after Glaucoma Surgery

Abstract

Glaucoma is an acquired optic neuropathy that results in a characteristic optic nerve head appearance and visual field loss. Reducing the IOP is the only factor that can be modified, and the progression of the disease can be managed through medication, laser treatment, or surgery. Filtering procedures are used when target pressure cannot be obtained with less invasive methods. Nevertheless, these procedures require accurate control of the fibrotic process, which can hamper filtration, thus, negatively affecting the surgical success. This review explores the available and potential pharmacological treatments that modulate the scarring process after glaucoma surgery, analyzing the most critical evidence available in the literature. The modulation of scarring is based on non-steroidal anti-inflammatory drugs (NSAIDs), mitomycin, and 5-fluorouracil. In the long term, the failure rate of filtering surgery is mainly due to the limitations of the current strategies caused by the complexity of the fibrotic process and the pharmacological and toxicological aspects of the drugs that are currently in use. Considering these limitations, new potential treatments were investigated. This review suggests that a better approach to tackle the fibrotic process may be to hit multiple targets, thus increasing the inhibitory potential against excessive scarring following surgery.

Keywords: fibrosis; glaucoma; glaucoma surgery; intraocular pressure.

Figure 1

Schematic overview of the wound healing process following glaucoma surgery. The process is divided into the following four stages: hemostasis, inflammatory phase, proliferative phase, and tissue remodeling. In hemostasis, there is a platelet plug formation and the coagulation cascade activation in the first 24 h, thanks to red blood cells and platelets. In the inflammatory phase, neutrophils, macrophages, and lymphocytes are involved in the next 1–5 days. Fibroblasts and endothelial cells act in the proliferation phase one to two weeks after surgery. A scar is formed at the end of the tissue remodeling phase, thanks to myofibroblasts [6].

Figure 2

Scheme of drugs currently used and under investigation for controlling the scarring process. On the receptor, TGF beta-2 (TGFβrII), decorin, S58 aptamer, and lerdelimumab act by blocking proliferation, fibroblast migration, and cell contraction. Monoclonal antibodies such as bevacizumab and ranibizumab act on the matrix Vascular Endothelial Growth Factor (VEGF) receptor by blocking proliferation, invasion, angiogenesis, and anti-apoptosis. Infliximab works peculiarly against human Tumor necrosis factor alpha (TNF-α), avoiding the translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) into the nucleus and its consequent gene expression, which is also inhibited by glucocorticoids. NSAIDs alleviate inflammation via inhibition of the cyclooxygenase (COX) isozymes. Finally, 5-Fluorouracile (5-FU) and Mitomycin C (MMC) are the most used antimetabolite adjuncts to trabeculectomy surgery and are used to limit conjunctival scarring. TNFR1 (Tumor necrosis factor receptor 1); PLA2 (phospholipase); AA (Arachidonic acid); NSAIDs (Non-steroidal anti-inflammatory drugs); IKB (inhibitor of nuclear factor kappa B); TS (tymidylate synthase); TRAF (TNF-Receptor Associated Factor); TNF (Receptor Associated Factors); TRADD (Tumor necrosis factor receptor type 1-associated DEATH domain protein), MEKK (stress-activated protein kinase/c-Jun N-terminal kinase); NIK (Mitogen-activated protein kinase 14 also known as NF-kappa-B-inducing kinase); GRα (glucocorticoid receptor alpha).