Inhibition of Monocyte Chemoattractant Protein 1 Prevents Conjunctival Fibrosis in an Experimental Model of Glaucoma Filtration Surgery

• Published in: Investigative ophthalmology & visual science Vol. 58; no. 9; pp. 3432 - 3439
• Main Authors: Chong, Rachel Shujuan, Lee, Ying Shi, Chu, Stephanie Wai Ling, Toh, Li Zhen, Wong, Tina Tzee Ling
• Format: Journal Article
• Language: English
• Published: United States 01.07.2017
• Subjects: Animals; Antifibrinolytic Agents - pharmacology; Cell Survival - drug effects; Chemokine CCL2 - antagonists & inhibitors; Chemokine CCL2 - metabolism; Collagen - metabolism; Conjunctiva - drug effects; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Fibroblasts - drug effects; Fibronectins - metabolism; Fibrosis - prevention & control; Filtering Surgery; Glaucoma - drug therapy; Glaucoma - surgery; Glaucoma Drainage Implants; Mice; Mice, Inbred C57BL; Mitomycin - pharmacokinetics; Osteonectin - metabolism; Receptors, CCR2 - antagonists & inhibitors; Transforming Growth Factor beta - metabolism
• ISSN: 1552-5783; 1552-5783
• DOI: 10.1167/iovs.17-21480

To evaluate the effect of treatment with monocyte chemoattractant protein-1 receptor inhibitor (MCP-Ri) to maintain bleb survival and prevent fibrosis in an experimental model of glaucoma filtration surgery (GFS). GFS was performed on one eye of C57/Bl6 mice (n = 36) that was treated with MCP-Ri, mitomycin-C (MMC), or vehicle at the time of surgery. Real-time polymerase chain reaction was used to evaluate conjunctival expression of monocyte chemoattractant protein-1 (MCP-1), TGFB1, TGFB2, collagen 1a1 (Col1a1), sparc (Sparc), and fibronectin at 2 and 7 days following surgery. Anterior segment slit-lamp examination, optical coherence tomography, and confocal microscopy were performed in vivo at day 14. Eyes were processed for immunohistochemical staining of F4/80, a monocyte-macrophage marker, at day 2. In vitro experiments were also performed to compare the effect of MMC, MCP-Ri, and vehicle on the viability of mouse Tenon's fibroblasts. Treatment with MCP-Ri results in a greater reduction in the percentage of F4/80-positive cells in conjunctival blebs and lesser MCP-1 gene expression following experimental GFS than MMC or control. Both MMC and MCP-Ri reduced Col1a1 and Sparc expression, but not fibronectin. TGFB1 decreased with MCP-Ri but not MMC; MMC but not MCP-Ri reduced TGFB2. MMC and MCP-Ri treatment resulted in the preservation of bleb height at day 14, as compared to control. MCP-Ri was less toxic to mouse Tenon's fibroblasts in comparison with MMC. Targeting MCP-1 results in prolonged bleb survival following experimental GFS with less cellular toxicity as compared to MMC. MCP inhibition could provide a safer alternative to conventional antifibrotic adjunctive treatments in GFS.