Oxidative stress response signaling pathways in trabecular meshwork cells and their effects on cell viability.

Intraocular pressure is determined by the balance between the inflow and outflow of the aqueous humor. Higher intraocular pressure is a significant risk factor for the progres -sion of glaucoma, and is currently the only target for clinical therapeutic modalities [ 1-3]. The outflow pathway through the trabecular meshwork (TM) and Schlemm’s canal are the main pathways in humans [4-6], and the outflow facility of the pathways is decreased in eyes with glaucoma [7]. An under-lying mechanism of decreased outflow is the overdeposition of extracellular matrix (ECM) in the outflow tissues [ 8]. TM cells are considered to regulate the amount of ECM, because they can simultaneously produce and degrade ECM with matrix metalloproteinases [8]. Thus, TM cell dysfunction might lead to deregulation of the essential turnover of ECM in outflow tissues, resulting in increased outflow resistance. Consistent with this hypothesis, the number of TM cells is decreased in glaucomatous eyes [7].Oxidative stress is an important biologic phenomenon, and is well known to be involved in pathologies of many age-related diseases. Glaucoma is also an age-related disease, and oxidative stress has an important role in glaucoma pathology. For example, oxidative stress marker levels are significantly increased in the aqueous humor of glaucoma patients [9-11], suggesting that outflow tissues, including the TM, in glaucomatous eyes are continuously exposed to oxida -tive stress. In addition, oxidative DNA damage is significantly increased in the TM of glaucoma patients [12,13]. These findings indicate that oxidative damage occurs in the TM of glaucomatous eyes, and may abolish or reduce the function of the TM cells, leading to increased outflow resistance and the risk of glaucoma progression. Though proteolytic cellular systems are reported to have important roles in the oxida-tive stress response in TM cells [14], and chronic oxidative stress induces the activation of NFκB and the upregulation of proinflammatory markers [ 15], the intracellular signaling that is activated directly by oxidative stress has remained unclear. The purpose of this study was to investigate the signaling pathways directly involved in responding to oxidative stress in TM cells, and their effects on cell viability.