Table 3.
Key Studies of the Effects of Prostaglandin-Related Compounds on Matrix Metalloproteinase Expression and the Morphology of Aqueous Humor Outflow Pathways
| Study | PG or PGA | Experimental model | Duration of exposure | Effects |
|---|---|---|---|---|
| Uveoscleral tissues | ||||
| Lütjen-Drecoll et al.61 | PGF2α tromethamine salt, PGF2α isopropyl ester | Cynomolgus monkeys | Once or twice daily topical treatment for 4–8 days | Ciliary muscle showed empty spaces between muscle fiber bundles, and loss of reticular fibers and ground substance in the enlarged spaces could be responsible for the increase in uveoscleral outflow |
| Lindsey et al.62 | PGF2α, 17-phenyltrinor-PGF2α, 11-deoxy-PGE1 | Human ciliary smooth muscle cells | Exposure for 1–3 days | Increased proMMP-1 and -3 concentrations in the culture medium |
| Weinreb et al.63 | PGF2α, 17-phenyltrinor-PGF2α, 11-deoxy-PGE1, latanoprost acid | Human ciliary smooth muscle cells | Exposure for 1–3 days | Increased concentration of MMP-1, -2, -3, and -9 in the culture medium |
| Sagara et al.127 | PGF2α-isopropyl ester | Cynomolgus monkeys | Twice daily topical treatment for 5 days | Significant reductions in scleral collagen (most notably type I and III) immunoreactivity in the ciliary muscle and adjacent sclera |
| Kim et al.64 | Latanoprost acid, PGF2α, 17-phenyltrinor-PGF2α | Human scleral organ cultures | Exposure for 24, 48, or 72 h | Increased transscleral permeability accompanied by increased MMP expression (MMP-2 > MMP-3 > MMP-1) |
| Gaton et al.65 | PGF2α-isopropyl ester | Cynomolgus monkeys | Twice daily topical treatment for 5 days | Significant increase in MMP (-1, -2, and -3) expression in tissues of uveoscleral outflow pathway |
| Weinreb and Lindsey66 | Latanoprost acid | Human ciliary smooth muscle cells | Exposure to concentrations of 8–1,000 nM for 24 h | Concentration-dependent increases in MMP-1, -3, and -9 mRNA levels |
| Anthony et al.67 | Latanoprost acid | Human ciliary smooth muscle cells | Exposure to concentrations of 1–1,000 nM for 6, 18, or 24 h | Concentration- and time-dependent increase in TIMP-1 protein and TIMP-1 mRNA levels, brief and minor increase in TIMP-2 protein |
| Richter et al.76 | Bimatoprost 0.03%, latanoprost 0.005%, sulprostone 0.03%, AH13205 0.1% | Cynomolgus monkeys | Topical treatment for 1 year | Enlarged and more organized spaces between muscle bundles of ciliary muscle for outflow; doubling in number of nerve fiber bundles in ciliary muscle |
| Hinz et al.128 | Latanoprost acid | Human nonpigmented ciliary epithelial cells | Exposure for 24 h | Increase in COX-2 mRNA expression leading to increased levels of PGE2 in culture medium and increased expression of MMP-1 mRNA |
| Oh et al.68 | Latanoprost acid | Human ciliary body tissue and smooth muscle cells | Exposure for 24 h | Upregulation of MMP-3, -9 (low expression), -17, TIMP-3 mRNA expression; downregulation of MMP-1, -2, -12, -14, -15, -16, TIMP-4 mRNA expression |
| Ooi et al.86 | Bimatoprost acid, latanoprost acid, unoprostone acid | Human ciliary body smooth muscle cells isolated from donor corneoscleral rims | Exposure for 24 h | The different PGAs produced different ratios of MMP/TIMP, potentially related to their differences in intraocular pressure-lowering efficacy; for example, all PGAs increased MMP-1, -3, and -9; MMP-2 levels were decreased by unoprostone and unaffected by bimatoprost and latanoprost; and all PGAs increased TIMP-3, but only unoprostone increased TIMP-1 and -4 |
| Trabecular meshwork and aqueous humor | ||||
| Richter et al.76 | Bimatoprost 0.03%, latanoprost 0.005%, sulprostone 0.03%, AH13205 0.1% | Cynomolgus monkeys | Topical treatment for 1 year | Disconnection of some endothelial cells of the inner wall of Schlemm's canal from the subendothelial layer, with loss of ECM underneath the endothelium and through the juxtacanalicular region |
| Oh et al.69 | Latanoprost acid | Human TM tissue and endothelial cells | Exposure for 24 h | Increase in mRNA expression of MMP-1, -3, -17, -24 and decrease in mRNA expression of MMP-11 and -15; upregulation of TIMP-2, -3, -4 |
| Wan et al.58 | Bimatoprost | Human anterior segments and TM cells | Increase in outflow facility by 40% on average; increase in hydraulic conductivity of trabecular meshwork cell monolayers by 78% | |
| Bahler et al.70 | Latanoprost acid, PGE1 | Cultured human anterior segments, including TM and Schlemm's canal | Continuous infusion up to 72 h | Focal detachment and loss of Schlemm's canal cells; no consistent change in MMP-2, -3, or -9 activity in the anterior segments |
| Yamada et al.87 | Bimatoprost acid, latanoprost acid, tafluprost acid | Human nonpigmented ciliary epithelial cell cultures | Exposure for 24 h | Each PGA induced a concentration-dependent increase in mRNA levels for MMP-1, -2, -3, -9, and -17 and decrease in mRNA levels for TIMP-1 and -2 |
Adapted from Toris et al.60 Update on the Mechanism of Action of Topical Prostaglandins for Intraocular Pressure Reduction, S107–120, Copyright © 2008, with permission from Elsevier.
COX-2, cyclooxygenase-2; ECM, extracellular matrix; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase; TM, trabecular meshwork; PG, prostaglandin; PGA, prostaglandin analog/prostamide.