**5. Exposure of trabecular meshwork to mechanical stress**

In order to survive, TM cells must be able to constantly adapt to their continuously changing environment. Similar to any other cell in the body, TM cells are exposed to a variety of environmental stresses. Due to the location of cells of the TM, one of the major types of stress these cells are exposed to is mechanical stress. IOP continuously fluctuates throughout the day with a higher IOP occurring during the nocturnal period. The fluctuation in IOP is part of a normal physiological process and is unavoidable. Fluctuations in IOP occur with blinking, eye

normally present in the aqueous humor and is suggested to be the key source of oxidative stress for the TM [67]. Initially, the concentration of H2O2, a reactive oxygen species (ROS), was reported to be between 25-60 µM in the aqueous humor using the dichloropheno-indopheno (DCPIP) assay [5,68-70]. However, technical issues with the DCPIP method, including the interference of ascorbic acid with the assay [70] and the spontaneous auto-oxidization of DCPIP in the presence of oxygen [71], has resulted in the re-examination of H2O2 in the aqueous humor. Different methods have indicated that H2O2 is present in the aqueous humor, but at much lower concentrations than previously thought [70,71]. An accurate concentration of H2O2 is still difficult to obtain and may vary greatly between individuals. Since cells of the TM are in direct contact with aqueous humor, these cells are exposed both intracellularly and

Genetics and Environmental Stress Factor Contributions to Anterior Segment Malformations and Glaucoma

Free radicals at lower concentrations are beneficial to the cell (reviewed in [72,73]). Low concentrations of ROS act as second messengers for signal transduction and gene regula‐ tion. For example, low concentrations of ROS activate the Nuclear factor kappa-B (NF-κB) transcription factor, which plays a key role in many cellular processes including inflamma‐ tion, cell proliferation, and apoptosis (reviewed in [74]) However, higher concentrations of free radicals can have negative effects on the cell (Figure 5). Free radicals can damage proteins and DNA, promote lipid peroxidation, disrupt mitochondrial function, and trigger cell death (reviewed in [73]). Cells have an antioxidant defense mechanism to counter the deleterious effects of ROS. For example, superoxide dismutase (SOD) is an antioxidant enzyme that

must then be converted into H2O by two other antioxidant enzymes: peroxisomal catalases and the family of glutathione peroxidases (GPx). In the event that H2O2 is not converted, then it may split into the hydroxyl radical (OH•), which can be dangerous because it can react with almost any macromolecule within a short diffusion distance. Cells, through the activity of nitric oxide synthase, are able to produce the free radical nitric oxide (NO ). NO itself is hardly toxic and is in fact important in regulating various cellular functions. In fact NO has been suggested to increase aqueous humor outflow by relaxing the ciliary smooth muscles [76,77]. However, NO becomes dangerous when it spontaneously reacts with

highly reactive and can damage biological molecules resulting in cell death (reviewed in [79]). In this way, the antioxidant defense mechanism also functions in minimizing the

Chronic oxidative stress is recognized to be a major contributor to the aging process and various diseases including neurodegenerative diseases such as Parkinson's [80,81] and Alzheimer [82-84], cancer [72,85], and cardiovascular diseases [86]. Since POAG is an agerelated disease, chronic oxidative stress is also suggested to have a role in the pathophysiology of this disease (reviewed in [87]). In POAG, both the RGCs and the anterior segment structures such as the TM are exposed to chronic oxidative stress conditions. TM cells are exposed to acute oxidative stress under normal physiological conditions [67]. The presence of cellular defense mechanisms in TM cells enables TM cells to quickly and effectively respond and adapt to their environment (Figure 2). Two cellular defense mechanisms present in TM cells are the

, forming the powerful oxidant peroxynitrite (ONOO-) [78]. Peroxynitrite is


http://dx.doi.org/10.5772/54653

35

extracellularly to oxidative stress.

converts superoxide free radical anion (O2

deleterious effects of reactive nitrogen species (RNS).

superoxide O2


**Figure 4. Trabecular meshwork of glaucoma phenotype**. Similar to normal non-aging and aging conditions, tra‐ becular meshwork (TM) cells are exposed to a variety of stresses. However, other unknown factors are present to ini‐ tiate the cascade of events that lead to the development of glaucoma. Also, genetic mutations could compromise normal TM cell function. All of these factors are predicted to result in TM cell death (dotted circles) to the extent that the TM tissue is no longer able to function properly. Consequently, there will be dysregulation of aqueous humor drainage resulting in increased intraocular pressure (IOP), which would ultimately lead to retinal ganglion cell (RGC) death and glaucoma.

movements, and even with a change in body position. A supine body position has been shown to result in higher IOP compared with an upright body position [64,65]. The temporary fluctuation in IOP can vary up to 10mmHg [66]. This change in IOP results in distortions (including stretching and compression) of the cells and is sensed by the cells of the TM as mechanical stress.
