reduces IOP by the depolymerization of the TM’s hyaluronic acid component (Linner, 1996). In any case, this vitamin is fundamental in ECM homeostasis: vitamin C neutralizes oxygen free radicals and is a reductant of oxidized vitamin E (Varma, 1991). It is also important in protecting cell membranes from lipid peroxidation (Kang et al., 2003).

The amount of vitamin E is low in the anterior chamber of the eye and it is not significantly associated with the risk of POAG. Vitamin E also prevents endogenous mitochondrial production of ROS (Southam et al., 1991).

The ECM degradation may lead to axonal loss in the ONH, and ROS stimulate astrocyte secretions and degrade tropoelastin (Hernandez and Pena, 1997; Hayashi et al., 1998; Tanaka et al., 1999; Hernandez, 2000).

Metalloproteinases

Other molecules that seem to play a very important role on collagen remodeling are the MMPs. MMPs are a family of calciumand zinc-dependent extracellular endoproteinases that degrade ECM proteins (Nagase and Woessner, 1999). MMPs are secreted by cells as proenzymes and are in balance with their tissue inhibitors, which directly downregulate MMPs (Visse and Nagase, 2003). It is interesting to observe that MMPs may also be useful biomarkers of atherosclerotic risk and they serve as predictors of coronary and cerebrovascular disease recurrence (Rodriguez et al., 2007). In any case, in POAG eyes, MMPs levels are high, especially MMP-1 and MMP-3 levels that have a broad range of substrates including collagens, elastin, fibronectin, gelatin, tenascin, and laminin (Ronkko et al., 2007).

Increased MMP activity decreases collagen deposition, and AH outflow facility is increased by stimulating MMP activity. It is possible that elevated MMP levels in the AH of glaucomatous eyes may be produced by inflammatory cells and/or by the trabecular cells (Ronkko et al., 2007). The biologic activity of MMPs is regulated by their activation state, and their conversion to functionally active forms requires a specific multistep activation process involving the proteolytic removal of part of the molecule (Nagase, 1997).

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PAI is a potent, fast-acting, and irreversible inhibitor of active forms of tissue plasminogen representing the real inhibitor of plasmin that is involved in the activation of MMPs (Rondeau et al., 1995).

The elevated levels of TGF-b2 in AH increase the production of ECM components in TM (e.g., fibronectin) and PAI-1 expression in HTM (Fuchshofer et al., 2003). PAI-1 is able to modulate the association between factors such as vitronectin and urokinase-like plasminogen activator with adhesion receptors (Fleenor et al., 2006). Hence, PAI-1 may be involved in TM cell loss, modulating TM cell migration and/or adhesion, including phagocytosis, oxidative stress, MYOC, and the presence of chemoattractants within the AH (Zhou et al., 1999; Hogg et al., 2000; Wentz-Hunter et al., 2004; Fleenor et al., 2006). Thus, it seems possible that an agent that increases one or more MMPs within the TM might have beneficial effects on IOP in patients with glaucoma. Blockage of the endogenous activity of the MMPs reduces outflow facility, probably because ECM turnover, initiated by one or more MMPs, appears to be essential to maintain IOP homeostasis (Bradley et al., 1998). An imbalance in the protease/antiprotease system is also important and may play a role in the pathogenesis of glaucoma (Ronkko et al., 2007).

Other factors of interest

Through the induction of oxidative damage, mechanical and vascular factors lead to the same final pathologic consequence (Prasanna et al., 2005). Among these mechanical factors, neurotrophic factor deprivation deserves to be mentioned. Elevated IOP blocks axonal transport at the level of the lamina cribrosa. One of the molecules delivered to the retina by a retrograde way of axonal transport is brain-derived neurotrophic factor (BDNF). Its importance has been shown by an experimental study on glaucomatous animals in which its intravitreous administration increases the number of surviving RGCs in comparison with untreated eyes (Ko et al., 2001). Another factor that may influence RGCs death in glaucoma is the glial cell activation, which is