POAG is generally associated with elevations in intraocular pressure (IOP) caused by abnormal resistance of aqueous outflow through the trabecular meshwork (TM), a specialized tissue lining the outflow pathway of the eye.
7 8 Elevated IOP can lead to progressive neuropathy and ganglion cell death in the neural retina, conditions that often result in irreversible loss of vision.
9 10 11 12 It has been suggested that age- and disease-related loss of TM cells, followed by substitution with extracellular matrix, contributes to an increased resistance to aqueous outflow and the subsequent increase in IOP found in patients with POAG.
13 14 15 16 17 18 Other possible causes of POAG include mutations of specific genes such as the myocilin (
MYOC)
19 and optineurin (
OPTN)
20 genes, vascular dysregulation,
21 22 and toxicity and mechanical injury induced by IOP.
9 10 11 12 One key suspect in disease progression that has been given much attention recently is local oxidative stress.
23 Oxidative free radicals and reactive oxygen species (ROS) are reported to trigger degeneration in the human TM and its endothelial cell components,
24 subsequently leading to increases in IOP and glaucoma. There is mounting evidence that in the region of the TM, ROS plays a fundamental role in reducing local antioxidant activities,
25 26 reducing outflow, and promoting the activities of superoxide dismutase and glutathione peroxidase
26 in glaucomatous eyes. Indeed, oxidative damage to the DNA of TM cells is significantly higher in affected patients than in age-matched control subjects,
27 as demonstrated by analysis of 8-hydroxy-20-deoxyguanosine (8-OH-dG), the most common oxidative nucleotide modification.
27 Additional studies report a significant correlation among 8-OH-dG levels in the TM, increased IOP, and visual field damage.
23 The importance of oxidative damage in POAG has been further substantiated by the findings that glaucoma-affected patients have a significant depletion of total antioxidant potential in the aqueous humor,
25 an increase in serum antibodies against glutathione-S-transferase,
28 a decrease in plasmatic glutathione levels,
29 and an increase in lipid peroxidation products in the plasma
30 compared with nonaffected persons. These findings provide a basis for the role of oxidative stress in the pathogenesis of glaucoma and provide new insight into the molecular mechanisms involved in this blinding disease.
31 32