[Frontiers in Bioscience E3, 1524-1533, June 1, 2011]
Oxidative stress in primary open-angle glaucoma
Carl Erb1, Melanie Heinke1
1
TABLE OF CONTENTS
1. ABSTRACT
Glaucoma is the second leading cause of blindness worldwide and is still a mysterium. Despite some risk factors are known, like individually elevated intraocular pressure, myopia, age, genetic factors, as well as vascular risk factors and smoking, the exact mechanism developing a glaucomatous optic neuropathy are still unknown. In the pathogenesis of glaucoma oxidative stress seems to play an important role. The mitochondria have an abnormal DNS and the antioxidative capacity is reduced. In addition, in the anterior segment, e.g. trabecular meshwork as well as in the posterior pole glaucoma patients show an increased oxidative stress. Therefore oxidative stress should be considered in therapeutic approaches to glaucoma patients.
2. INTRODUCTION
Primary open-angle glaucoma (POAG) is described by the European Glaucoma Society as an optic neuropathy with characteristic visual field loss and papillary abnormalities, whose origin is regarded as a multifactorial phenomenon. In addition to individually elevated intra-ocular pressure and excessive diurnal pressure fluctuations, genetic factors, increasing age, myopia, vascular risk factors, and smoking are other risk factors for the development of a glaucomatous optic neuropathy. However, the precise pathogenetic mechanisms which lead to this socio-economically important condition are still largely unknown, although some insight into the complex biochemical processes involved has been gained in the past 20 years. For this reason, the main focus has been on the cellular mechanisms triggered by artificially increasing intra-ocular pressure, to enable the effects of elevated intra-ocular pressure on the structures of the eye to be investigated more precisely in an experimental manner. This has made it possible to show that the structures of both the anterior and posterior chambers of the eye react to elevated intra-ocular pressures, resulting in major biochemical changes. One of the most important intermediate stages occurring between the elevation of intra-ocular pressure and the resulting biochemical changes in the eye is oxidative stress. This is generally understood to mean an imbalance between the formation of free radicals / reactive oxygen species and/or a reduction in the protective systems that buffer the free radicals (1). The cells are thereby flooded with free radicals, and direct and indirect cellular damage occurs, which may lead to organ transformation with a corresponding loss of function. Due to increasing knowledge of the functions of the cell, especially of the mitochondrion, the definition of oxidative stress has recently changed, in that it is understood to be mainly a disturbance of mitochondrial redox signal transmission and redox control (2). Due to these biochemical processes, structural changes also occur on the cell surface, which may lead to immunological reactions, such as auto-immune reactions for example. In addition, oxidative stress causes transformation processes in the retinal ganglion cells and nerve fibres, which result in accelerated apoptosis of the cells.
To summarise, it is useful to have a good knowledge of the processes relating to oxidative stress in glaucoma, because oxidative stress plays an important role as mediator in the subsequent reaction chains, as a general form of biochemical reaction, and this may give rise to new therapeutic options. We will structure our presentation of the current state of knowledge of oxidative stress in POAG by describing the experimental observations and clinical findings for the anterior and posterior chambers of the eye separately.
3. OXIDATIVE STRESS AND THE ANTERIOR CHAMBER
3.1. General
The human eye is exposed to powerful photo-oxidative stress during the day and therefore needs a correctly-functioning buffer system in order to scavenge the free radicals and reactive oxygen species (ROS) constantly being formed. Hydrogen peroxide (H2O2) (3) and superoxide anions, for example, have been found in the aqueous humour. In the anterior chamber of the eye, a particular additional feature is increased stress on the structures due to metabolic end-products which are released into the aqueous humour by the avascular structures of the cornea and lens. The metabolites result from the process of mitochondrial respiration and other metabolic processes and may exhibit the properties of free radicals. This is why an effective protective system consisting of several individual components is necessary. For example:
3.1.1. The aqueous humour acts as a stream of fluid that flushes out free radicals
The aqueous humour, of which approximately 80% is actively secreted and is subject to dynamic neurohumoral secretion control, is formed at the rate of 3.1 �L/minute of aqueous humour in the morning, whilst the output at night is 2.3 �L/minute and drops to 1.6 �L/minute during sleep (4). This ensures that the aqueous humour is replaced approximately every 11/2 - 2 hours at the times when light stress is greatest, and therefore free radicals, cell debris and metabolites are flushed from the eye.
3.1.2. Water-soluble antioxidants
The composition of the aqueous humour can be specifically influenced. This applies in particular to ascorbic acid, which is actively transported into the aqueous humour via a Na+/ascorbate cotransporter (5). Thus very high vitamin C concentrations can be attained in aqueous humour as compared to those in plasma (6). Ascorbic acid (AA) is one of the water-soluble essential nutrients and consequently it must be ingested in food. Its physiological importance lies in collagen biosynthesis, in the breakdown of cholesterol and in the synthesis of neurotransmitters. It is an effective antioxidant, regenerates vitamin E, detoxifies toxic metabolites and stimulates the immune system. In the aqueous humour, AA scavenges 75-85% of free radicals (7) and is therefore the most significant free radical scavenger. In addition, the administration of AA induces a lowering of intra-ocular pressure (8, 9, 10). The action mechanism of AA is still under debate. On the one hand, an osmotic effect has been hypothesised (11), and, on the other, AA has been found to improve trabecular outflow (12), which may be due to stimulation of hyaluronic acid in the trabecular meshwork (TMW) (13). In addition, AA can dose-dependently influence the metabolism of TMW cells (14).
Further water-soluble antioxidative substances in the aqueous humour include L-tyrosine (15) and glutathione (16). Glutathione has been shown to buffer hydrogen peroxide (H2O2) in the anterior chamber of the eye (17).
3.1.3. Fat-soluble antioxidants
Vitamin E (tocopherol) is a fat-soluble essential nutrient and is regarded as the most important lipophilic chain-breaking antioxidant in the human body. Following oral administration, elevated levels of glutathione have been detected in plasma and also in the aqueous humour in man (18), with the consequential hypothesis that vitamin E has an indirect stimulant effect on the antioxidant potential of the aqueous humour.
3.1.4. Specific enzymes
Both catalase (19) and superoxide dismutase (20) have been found in the epithelium and endothelium of the cornea, in the lens, particularly in the epithelium of the lens, in the iris and in the ciliary body, as well as in the TMW (21). There are indications of the presence of glutathione in the iris, ciliary body (22) and TMW (23).
3.2. Age-related changes
As the secretion of aqueous humour is an active transport process, it too is subject to age-related changes. It is believed that approximately 20% less aqueous humour is formed by the time the 80th year of life is reached, as compared with a 20-year old (24). On the one hand, this means that the time free radicals and metabolic end-products are retained in the aqueous humour is prolonged, and on the other, that the activity of active transport mechanisms declines. This is why the ascorbic acid concentration of the aqueous humour also declines with increasing age (25). The consequence is diminished buffering of free radicals in the aqueous humour, and this is further intensified by the decline in performance of the antioxidative enzyme systems. As far as the TMW is concerned, for example, an age-related decrease in superoxide dismutase has been demonstrated (26). Due to these processes, a preponderance of free radicals occurs and leads, among other things, to accelerated cataract development (27), and also transformation processes in the TMW (28, 29), which result in turn in a slight increase in intra-ocular pressure in advanced age (30).
3.3. In primary open-angle glaucoma
Independently of the age-related changes in the anterior chamber of the eye, protection from free radicals is markedly reduced in primary open-angle glaucoma (POAG), and this leads to pronounced oxidative stress with all its consequences. The aetiology has not yet been completely elucidated. It was shown in a pioneering study that patients with POAG generally have mitochondrial abnormalities (31), which weaken the supply of energy to cells and can lead to morphological and structural cellular changes. Independently of this, the total reactive antioxidant potential in the aqueous humour of glaucoma patients is 64% lower than in cataract patients in the same age group (32). This can be attributed to reduced ascorbic acid (11) and glutathione (33) concentrations. In consequence, superoxide dismutase, on the one hand, is reactively up-regulated (32), and, on the other, lipid peroxidation increases (34, 35). This leads to damage to cell membranes which can significantly influence the physical and chemical properties of the membranes (36). As the TMW has receptors for low-density lipoproteins (LDL) (37), direct impairment of the oxidised LDL on the TMW is to be expected. An additional factor is that oxidised LDL can activate plasminogen activator inhibitor-1 (PAI-1) via autocrine activation of growth factor TGF-β (38), which is produced in the ciliary body (39) and is elevated in the aqueous humour in POAG (40). Interestingly, cultured astrocytes from the optic disk also produce PAI-1 under the effect of TGF-β (41). As a result, the extracellular matrix of the cribriform plate and TMW may be activated and the viscosity of the aqueous humours increased, and this may make it more difficult for the aqueous humour to drain.
As far as oxidative reactions in the aqueous humour are concerned, high concentrations of hydrogen peroxide (H2O2) occur in POAG. H2O2 is stable as an intermediate oxidant. H2O2 has been intensively studied in the eye and, via activation of cytosolic calcium, causes the release of noradrenaline, and activation of nitric oxide synthetase (NOS) and arachidonic acid (overview in 42). It has also been shown in perfusion experiments that H2O2 increases outflow resistance in the glutathione-impoverished TMW (23). On the one hand, this could be caused by contraction of the TMW cells due to the elevated concentrations of cytosolic calcium, and, on the other, by a reorganisation of vimentin and actin, reduced adhesion of TMW cells to fibronectin, laminin and Type I and Type IV collagen, and activation of cell nucleus activation factor NF-κB (43, 95). Another point is that the experimental data have been corroborated by clinical investigations. Elevated levels of adhesion molecules and also of messenger RNA, interleukins and NF-κB have been found in TMW specimens from trabeculectomies (44). Oxidative DNA damage in the TMW was also detected (45), which actually correlates positively with the degree of visual field damage and the level of intra-ocular pressure (46). Finally, there is a pronounced transformation of both the structure and function of the TMW, which provokes accelerated ageing and leads to increased outflow resistance (47, 48, 96). The increase in intra-ocular pressure associated with this then leads to further major biochemical changes, which then result in significant problems, especially in the posterior chamber of the eye.
To what extent an iatrogenic influence on oxidative stress in the TMW exists is still unclear at present. The preservative benzalkonium chloride contained in most eye drops results in any case in the release of superoxide anions on the conjunctiva, and these induce in turn apoptosis of conjunctival cells (49). As increased apoptosis due to benzalkonium chloride was also found in the TMW (50), it is quite conceivable that routine treatment with antiglaucoma drugs containing preservatives sustains oxidative stress and in this respect tends to have a deleterious effect on glaucoma.
4. OXIDATIVE STRESS AND THE POSTERIOR CHAMBER OF THE EYE
4.1. General
Like the anterior chamber of the eye, the retina is intensely exposed to light during the day. Short-wavelength blue light in particular can induce the formation of free radicals (51) and in addition can influence ATP synthesis in the mitochondria of retinal ganglion cells, with the consequence that free radicals may be less well scavenged and thus apoptosis may be set in motion (52). In addition, the retina is very susceptible to oxidative stress due to
- it being responsible for the greatest consumption of oxygen in the eye (53),
- the high proportion of polyunsaturated fatty acids in the outer segments of photoreceptors (54),
- the phagocytosis of the retinal pigment epithelium, which results in free radical formation (55), and
- age-related changes in the retina, which intensify oxidative stress due to the formation of catabolites such as lipofuscin and "advanced glycation end-products" (AGEs).
On account of these stresses due to free radicals, there are also numerous buffer systems in the retina. These include
4.1.1. Pigments
The neuromelanin present in the retinal pigment epithelium and the macular pigments lutein and zeaxanthin have antioxidant properties (56, 57).
4.1.2. Hormones
The production of melatonin (58) and its receptors has been demonstrated in the retina (59). Melatonin has antioxidant properties in that it can itself scavenge free radicals. It stimulates antioxidant enzymes and increases mitochondrial oxidative phosphorylation (60).
4.1.3. Water-soluble antioxidants
Glutathione (61) and ascorbic acid are available as antioxidants in the retina (62, 63), and ascorbic acid has a growth-inhibiting effect on the retinal pigment epithelium (64).
4.1.4. Fat-soluble antioxidants
Vitamin E, a fat-soluble antioxidant, has been found in the retina (65).
4.1.5. Specific enzymes
Catalase, glutathione peroxidase and superoxide dismutase have all been found in the retina (19, 29, 66).
4.2. Age-related changes
The proportion of melanin in the retinal pigment epithelium (67) and of lutein and zeaxanthin in the macula (68) fall with increasing age. At the same time, there is an increase in lipofuscin, a pigment formed from the accumulation of molecular aggregates from photo-oxidative processes (69). Lipofuscin itself acts as a photosensitiser, generates free radicals (69) and inhibits antioxidant processes (70). Due to metabolic stress, "advanced glycation end-products" are formed in addition, which can in turn initiate apoptotic processes, cell proliferation and oxidative stress (71, 72, 73). Finally, considerable age-related changes occur in the posterior chamber of the eye, with a decline in free radical buffering power, as a consequence of which oxidative stress on the retina is actually increased further, for example by the formation of drusen, lipofuscin and "advanced glycation end-products". These changes alone explain why physiological sensory capabilities decline with increasing age, because the complex association of cells that is the "retina" is perceptibly disturbed. If there are pre-existing genetic impairments and/or there is severe toxic (smoking) and vascular damage (diabetes mellitus, hypertension, arteriosclerosis), these age-related transformation processes are intensified, and their final stage is age-related macular degeneration.
As far as the optic nerves are concerned, there is a transformation of the collagen structures, provoked mainly by collagen cross-linking. This results in reduced elasticity, and this is also corroborated by the increase in thickness of the septa within the cribriform plate (74, 75, 76).
4.3. In primary open-angle glaucoma
While age-related changes in themselves place a tremendous stress on the retina and optic disk, additional disturbance is especially harmful. In the context of glaucoma, elevated intra-ocular pressure must be particularly mentioned. Under experimental conditions, elevated intra-ocular pressure results in the following in the retina:
- a reduction in superoxide dismutase (77),
- a reduction in catalase (77),
- a reduction in the concentration of melatonin (77), and
- a reactive increase in lipid peroxidation (77)
and the following in the optic disk:
- activation of nitric oxide synthetase-2 in astrocytes (78).
Due to increased intra-ocular pressure and to the changes mentioned above, astrocytes are activated in the cribriform plate (79) and in turn express COX-2 (80), TNF-α (81) and metalloproteinases (82), for example. The chronic inflammatory reaction triggered thereby leads to a transformation of the collagen structures of the cribriform plate, among other things (83). In addition, biochemical disturbance occur. One example of this is the activation of growth factors, such as TGF-β, which has been found at elevated concentration in the aqueous humour of glaucoma patients (84) and is formed among other things by the activated astrocytes (85). For its part, TGF-β increases the extracellular matrix both in the TMW (86) and in the astrocytes of the cribriform plate (87), and contributes to disturbing outflow as well as to the transformation of the cribriform plate. In the context of increased oxidative stress, TGF-β (88) is secreted in addition, thereby further promoting the biochemical transformation processes in the TMW and cribriform plate.
Due to these serious metabolic changes, accelerated metabolic and structural transformation occurs in the retina and optic disk in glaucoma. The transformation also affects the surface structures of membranes and molecules, which can then lead to immunological abnormalities (97). The influence of systemic vascular diseases, which can lead to endothelial dysfunction and to accelerated arteriosclerosis, results in further damage to the already considerably stressed retina and optic disk in POAG (98). The associated ischaemia promotes oxidative stress in the eye and results in a vicious circle.
5. SYSTEMIC MARKERS FOR OXIDATIVE STRESS IN POAG
POAG appears not to be an exclusively ophthalmological condition. We are still only on the threshold of an understanding of this, but one of the most significant studies was that which provided evidence of mitochondrial abnormalities in POAG patients (31), demonstrating a general metabolic disorder in POAG with restricted capability to cope with oxidative stress. This is the rationale for blood tests in patients with POAG. Reduced glutathione levels and elevated levels of malondialdehyde, a reactive catabolite formed in the course of lipid peroxidation (90), have been found in untreated glaucoma patients (89). There is, in addition, disturbance of the vitamin balance, including reduced vitamin B1 levels (91). This is interesting because vitamin B1 is involved in neuronal glucose metabolism. Under normal conditions, the highest consumption of glucose at any point along the axon of the optic nerve occurs in the disk (92). Accordingly, if too little Vitamin B1 is present in the serum of glaucoma patients, papillary glucose metabolism could be disturbed and neurodegenerative processes promoted. In addition, elevated uric acid and fasting blood glucose concentrations have been found (93).
6. INTENSIFICATION OF OXIDATIVE STRESS IN GLAUCOMA DUE TO SYSTEMIC DISEASE
Patients with POAG frequently have systemic vascular diseases, which can exert a considerable influence on the POAG disease process and promote progression of the glaucomatous optic neuropathy (100, 101). This is mainly because the direct consequences, such as hypoxia, the accumulation of metabolic end-products and free radicals, and the reperfusion syndrome, can exacerbate the biochemical status of the optic nerve. Chronic processes in particular are of significance in this context, because they continuously impact negatively on the oxidative stress and can therefore promote the transformation processes. A classic example of this type of vascular disease is diabetes mellitus, in which endothelial dysfunction occurs and oxidative stress is central to the consequential reactions (102, 103). But endothelial dysfunction and/or increased oxidative stress have been demonstrated in other vascular diseases, such as tinnitus (104) and migraine (105, 106).
7. THE TRIGGERING OF IMMUNOLOGICAL PROCESSES IN GLAUCOMA DUE TO OXIDATIVE STRESS
Many questions remain unanswered when one considers the pathogenesis of glaucomatous optic neuropathy (95,97). Interestingly, however, many of the events come together to form a common final path and are mediated by certain key proteins. If, as in POAG, mitochondrial activity is primarily diminished (31) and it is adversely affected further under elevated intra-ocular pressure (107), free radicals may be less well buffered, and, at the same time, the cells are not supplied with sufficient energy to counteract this stress. Oxidative stress in the eye affected by glaucoma builds up due to increased fluctuations in diurnal pressures, due to the elevated intra-ocular pressure itself, and, indeed, also due to the underlying systemic vascular diseases and/or due to exogenous factors, such as smoking. As a result - in addition - immunological processes are stimulated. Many of the factors described as influencing the pathogenesis of glaucoma, such as:
- elevated free radicals and oxidative stress (108), and also smoking (109),
- short-wavelength light (52),
- ischaemia/reperfusion (110, 111)
- surface antigens of bacteria, such as those of Helicobacter pylori (112,113), and
- inflammation mediators, such as IL-1 (114, 115) and TNF-alpha (81),
activate a nucleoprotein, nuclear factor kappa B (NF-κB). The latter is an important transcription factor, which occurs in almost all cell types and tissues. NF-κB is of major importance in the regulation of the immune response, cell proliferation and apoptosis. After activation (116), the following are stimulated:
- acute-phase response proteins, such as angiotensinogen or complement C3,
- adhesion molecules, such as VCAM-1, ELAM-1, and ICAM-1, and
- cytokines, such as IL-1, IL-2, IL-6, IL-8, G-CSF, GM-CSF, TNF-α, TNF-β, and IFN-β.
Due to this up-regulation of a wide variety of factors, biochemical processes are initiated and advance the process of glaucomatous optic neuropathy and lead to numerous reactions. By way of example, it is to be noted that activation of NF-κB leads, firstly, to activation of endothelin-1 (117), which occurs to a greater degree in POAG in both the serum and aqueous humour and, due an adverse effect on outflow resistance, in the trabecular meshwork, and also, due to disturbed perfusion of the optic nerve, plays a significant role in POAG (118). Secondly, it has been shown that hypoxia-inducible factor 1 (HIF-1) is also up-regulated via NF-κB (119). Elevated HIF-1 has been detected in the retina and optic nerve in cases of POAG (120). It has so far been possible to demonstrate up-regulated NF-κB directly in the trabecular meshwork in glaucoma patients (44,121), and also in the ciliary body in an experimental murine glaucoma model (122).
The role of NF-κB in the immunological context has been confirmed. An almost incalculable number of immune reactions occur due to activation of the widest variety of cytokines. For example, cytokines, and also ischaemia, lead to the induction of HLA-DR expression in the astrocytes of the cribriform plate (123). High concentrations of TGF-β, which have been demonstrated in POAG, cause the activation of microglia with corresponding immunocompetence (124). Finally, in the course of POAG, a powerful immune reaction occurs and leads to auto-immune reactions. The pattern of the reactions is partly known, but the individual reactions have yet to be elucidated (106). One of the antibody reactions consists in the formation of antibodies against heat shock proteins, which normally act to protect cells against powerful stresses, such as those that occur in oxidative stress (125). In addition, studies have shown the formation of antibodies against Helicobacter pylori (112).
8. SUMMARY
While lowering intra-ocular pressures is the dominant therapeutic option in glaucoma treatment strategy today, and its effectiveness has been proven insofar as a high proportion of glaucoma patients benefit from it, one must not overlook the fact that many patients are not sufficiently helped by lowering intra-ocular pressure alone. For example, in the Early Manifest Glaucoma Trial, the glaucoma had progressed after 6 years' follow-up in 45% of the patients treated (93), and this figure actually rose to 59% after 8 years (100), in spite of lowering intra-ocular pressure by 25% to an average of 15.5 mmHg. This is not to question the value of lowering intra-ocular pressure, but the data relating to POAG presented here show emphatically that the therapeutic strategy should be far more comprehensive, in other words, more holistic. In addition to optimally stabilising the metabolism (blood glucose, blood lipids, thyroid) and blood flow (blood pressure, vasospasticity), orthomolecular therapy should be included as well, to bring oxidative stress under control. Lifestyle strategies are, of course, important to this end as well, such as not smoking, adopting regular eating habits and getting sufficient sleep, for example. These measures require close collaboration between patient, ophthalmologist and general practitioner/internal medical specialist and can only work if the patient is aware of the wider significance of the disease glaucoma.
9. REFERENCES
1. H Sies: Oxidative stress: oxidants and antioxidans. London: Academic Press (1991).
2. DP Jones: Disruption of mitochondrial redox circuitry in oxidative stress. Chem Biol Interact, 163:38-53 (2006).
doi:10.1016/j.cbi.2006.07.008
PMid:16970935
3. A Spector, WH Garner: Hydrogen peroxide and human cataract. Exp Eye Res 33: 673-681 (1981).
doi:10.1016/S0014-4835(81)80107-8
4. GR Reiss, DA Lee, JE Topper, RF Brubacker: Aqueous humor flow during sleep. Invest Ophthalmol Vis Sci, 25 :776-778 (1984).
PMid:6724850
5. H Helbig, C Korbmacher, J Wohlfarth, S Berweck, D Kühner, M Wiederholt : Electrogenic Na+-ascorbate cotransport in cultured bovine pigmented ciliary epithelial cells. Cell Physiol 25:C44-C49 (1989).
6. A Ringvold: The significance of ascorbate in the aqueous humour protection against UV-A and UV-B. Exp Eye Res 62:261-264 (1996).
doi:10.1006/exer.1996.0031
PMid:8690035
7. C Erb, K Nau-Staudt, J Flammer, W Nau : Ascorbic acid as a free radical scavenger in porcine and bovine aqueous humour. Ophthalmic Res 36:38-42 (2004).
doi:10.1159/000076108
PMid:15007238
8. SL Fishbein, S Goodstein: The pressure lowering effect of ascorbic acid. Ann Ophthalmol 4: 487-491 (1972).
PMid:5030227
9. E Linner: The pressure lowering effect of ascorbic acid in ocular hypertension. Acta Ophthalmol (Copenh) 47:685-689 (1969).
doi:10.1111/j.1755-3768.1969.tb08156.x
10. TM Shen, MC Yu: Clinical evaluation of glycerine-sodium ascorbate solution in lowering intraocular pressure. Chin Med J (Engl) 1: 64-68 (1975).
11. AT Aleksidze, IN Beradze, OG Golovachev: Effect of the ascorbic acid of the aqueous humor on the lipid peroxidation process in the eye in primary open-angle glaucoma. Oftalmol Zh 2: 114-116 (1989).
PMid:2755654
12. KM Liu, D Swann, P Lee, KW Lam: Inhibition of oxidative degradation of hyaluronic acid by uric acid. Curr Eye Res 3:1049-1053 (1984).
doi:10.3109/02713688409011751
PMid:6488856
13. DO Schachtschabel, E Binninger: Stimulatory effects of ascorbic acid on hyaluronic acid synthesis of in vitro cultured normal and glaucomatous trabecular meshwork cells of the human eye. Z Gerontol 26:243-246 (1993).
PMid:8212793
14. E Higginbotham, BY Yue, E Crean, J Peace:. Effects of ascorbic acid on trabecular meshwork cells in culture. Exp Eye Res 46: 507-516 (1988).
doi:10.1016/S0014-4835(88)80008-3
15. SP Richter, RC Rose: Water soluble antioxidants in mammalian aqueous humor: interaction with UV B and hydrogen peroxide. Vision Res 38:2881-2888 (1998).
doi:10.1016/S0042-6989(98)00069-8
16. MV Riley, RF Meyer, EM Yates: Glutathione in the aqueous humor of human and other species. Invest Ophthalmol Vis Sci 19:94-6 (1980).
PMid:6765938
17. AP Costarides, MV Riley, K Green: Roles of catalase and the glutathione redox cycle in the regulation of anterior-chamber hydrogen peroxide. Ophthalmic Res 23:284-294 (1991).
doi:10.1159/000267124
PMid:1784460
18. C Costagliola, G Iuliano, M Menzione, E Rinaldi, P Vito, G Auricchio: Effect of vitamin E on glutathione content in red blood cells, aqueous humor and lens of humans and other species. Exp Eye Res 43:905-914 (1986).
doi:10.1016/0014-4835(86)90069-2
19. KC Bhuyan, DK Bhuyan: Regulation of hydrogen peroxide in eye humors. Effect of 3-amino-1H-1,2,4-triazole on catalase and glutathione peroxidase of rabbit eye. Biochem Biophys Acta 497:641-651 (1977).
PMid:889879
20. KC Bhuyan, DK Bhuyan: Superoxide dismutase of the eye: relative functions of superoxide dismutase and catalase in protecting the ocular lens from oxidative damage. Biochem Biophys Acta 542:28-38 (1978).
PMid:208649
21. SF Freedman, PJ Anderson, DL Epstein: Superoxide dismutase and catalase of calf trabecular meshwork. Invest Ophthalmol Vis Sci 26:1330-5 (1985).
PMid:4044161
22. RC Rose, SP Richer, AM Bode: Ocular oxidants and antioxidant protection. Proc Soc Exp Biol Med 217:397-407 (1998).
PMid:9521086
23. MG Kahn, FJ Giblin, DL Epstein: Gluthatione in calf trabecular meshwork and its relation to aqueous humor outflow facility. Invest Ophthalmol Vis Sci 24:1283-1287 (1983).
PMid:6885312
24. RF Brubacker: Flow of aqueous humor in humans (The Friedenwald Lecture). Invest Ophthalmol Vis Sci 32:3145-66 (1991).
25. S Altimari, T Mascaro, S Leopardi, L Zompatori, A Missiroli, EM Vingolo: Age-related correlation between ascorbic acid in aqueous humor and serum. Invest Ophthalmol Vis Sci ARVO-Abstract Nr. 3952 (2007).
26. MA De La Paz, DL Epstein: Effect of age on superoxide dismutase activity of human trabecular meshwork. Invest Ophthalmol Vis Sci. 37:1849-53 (1996).
PMid:8759353
27. JA Vinson: Oxidative stress in cataracts. Pathophysiology 13: 151-162 (2006).
doi:10.1016/j.pathophys.2006.05.006
PMid:16765571
28. JW Rohen, E Lütjen: On the age-dependent changes of the trabecular meshwork in the human eye. Graefes Arch Clin Exp Ophthalmol 175:285-307 (1968).
doi:10.1007/BF02440004
29. BT Gabelt, PL Kaufmann: Changes in aqueous humor dynamics with age and glaucoma. Prog Ret Eye Res 24:612-637 (2005).
doi:10.1016/j.preteyeres.2004.10.003
PMid:15919228
30. BEK Klein, R Klein, KLP Lointon: Intraocular pressure in an American community. The Beaver Dam eye study. Invest Ophthalmol Vis Sci 33 :2224-2228 (1992).
PMid:1607232
31. KK Abu-Amero, J Morales, TM Bosley: Mitochondrial abnormalities in patients with primary open-angle glaucoma. Invest Ophthalmol Vis Sci 47:2533-2541 (2006).
doi:10.1167/iovs.05-1639
32. SM Ferreira, SF Lerner, R Brunzini, PA Evelson, SF Llesuy : Oxidative stress markers in aqueous humour of glaucoma patients. Am J Ophthalmol 137:62-69 (2004).
doi:10.1016/S0002-9394(03)00788-8
33. AI Bunin, AA Filina, VP Erichev: A glutathione deficiency in open-angle glaucoma and the approaches to its correction. Vestn Oftalmol 108: 13-15 (1992).
PMid:1295181
34. MA Babizhayev, A Bunin: Lipid peroxidation in open-angle glaucoma. Acta Ophthalmol (Copenh) 67:371-377 (1989).
doi:10.1111/j.1755-3768.1989.tb01617.x
35. NI Kurysheva, MI Vinetskaia, VP Erichev, VP Artamonov, AP Uspenskaia: Contribution of free-radical reactions of chamber humor to the development of primari open-angle glaucoma. Vestn Oftalmol 112:3-5 (1996).
PMid:9019910
36. JI Kourie: Interaction of reactive oxygen species with ion transport mechanisms. Am J Physiol 275:C1-C24 (1998).
37. IL Chang, G. Elner, Y.J. Yue, A. Cornicelli, J.E. Kawa, V.M. Elner : Expression of modified low-density lipoprotein receptors by trabecular meshwork cells. Curr Eye Res 10:1101-1112 (1991).
doi:10.3109/02713689109024127
PMid:1802612
38. CY Song, BC Kim, HK Hong, HS Lee: Oxidized LDL activates PAI-1 transcription through autocrine activation of TGF-beta signalling in mesangial cells. Kidney Int 67:1743-1752 (2005).
doi:10.1111/j.1523-1755.2005.00271.x
PMid:15840021
39. MW Meyer, M von Depka, C Wilhelm, A Schröder, C Erb: Plasminogen activator inhibitor-1 mRNA expression in cultured pigmented ciliary epithelial cells of the porcine eye. Graefes Arch Clin Exp Ophthalmol 240:679-86 (2002).
doi:10.1007/s00417-002-0510-y
PMid:12192463
40. J Dan, D Belyea, G Gertner, I Leshem, M Lusky, R Miskin: Plasminogen activator inhibitor-1 in the aqueous humor of patients with and without glaucoma. Arch Ophthalmol 123:220-4 (2005).
doi:10.1001/archopht.123.2.220
PMid:15710819
41. M Birke, C Neumann, U Welge-Lüßen, A Yu, E Lütjen-Drecoll: Effect of TGF-ß2 on elastin expression and components of the proteolytic system in human optic nerve head astrocytes. Invest Ophthalmol Vis Sci ARVO-abstract 3660 (2007).
42. SE Ohia, CA Opere, AM leDay: Pharmacological consequences of oxidative stress in ocular tissues. Mutation Res 579:22-36 (2005).
doi:10.1016/j.mrfmmm.2005.03.025
PMid:16055157
43. L Zhou, Y Li, BY Yue: Oxidative stress affects cytoskeletal structure and cell-matrix interactions in cells from an ocular tissue: the trabecular meshwork. J Cell Physiol 180:182-189 (1999).
doi:10.1002/(SICI)1097-4652(199908)180:2<182::AID-JCP6>3.0.CO;2-X
44. N Wang, SK Chintala, ME Fini, JS Schuman: Activation of a tissue-specific stress response in the aqueous outflow pathway of the eye defines the glaucoma disease phenotype. Nature Medicine 7:304-309 (2001).
doi:10.1038/85446
PMid:11231628 PMCid:1945815
45. A Izzotti, SC Sacca, C Cartiglia, S De Flora: Oxidative deoxyribonucleic acid damage in the eyes of glaucoma patients. Am J Med 114:638-46 (2003).
doi:10.1016/S0002-9343(03)00114-1
46. SC Sacca, A Pascotto, P Camicione, P Capris, A Izzotti: Oxidative DNA damage in the human trabecular meshwork: clinical correlation in patients with primary open-angle glaucoma. Arch Ophthalmol 123:458-463 (2005).
doi:10.1001/archopht.123.4.458
PMid:15824217
47. A Izzotti, A Bagnis, SC Saccà: The role of oxidative stress in glaucoma. Mutation Research 612:105-114 (2006).
doi:10.1016/j.mrrev.2005.11.001
PMid:16413223
48. J Veach: Functional dichotomy: glutathione and vitamin E in homeostasis relevant to primary open-angle glaucoma. Br J Nutrition 91:809-829 (2004).
doi:10.1079/BJN20041113
PMid:15182385
49. C Debbasch, F Brignole, PJ Pisella, JM Warnet, P Rat, C Baudouin: Quaternary ammoniums and other preservatives' contribution in oxidative stress and apoptosis on Chang conjunctival cells. Invest Ophthalmol Vis Sci 42:642-52 (2001).
PMid:11222522
50. P Hamard, C Blondin, C Debbasch, JM Warnet, C Baudouin, F Brignole : In vitro effects of preserved and unpreserved antiglaucoma drugs on apoptotic marker expression by human trabecular cells. Graefes Arch Clin Exp Ophthalmol 241:1037-43 (2003).
doi:10.1007/s00417-003-0777-7
PMid:14605906
51. M Rozanowska, J Jarvis-Evans, W Korytowski, M Boulton, JM Burke, T Sarna: Blue light-induced reactivity of retinal age pigment. In vitro generation of oxygen-reactive species. J Biol Chem 270:18825-30 (1995).
PMid:7642534
52. NN Osborne, G Lascaratos, AJ Bron, G Chidlow, JPM Wood: A hypothesis to suggest that light is a risk factor in glaucoma and the mitochondrial optic neuropathies. Br J Ophthalmol 90:237-241 (2006).
doi:10.1136/bjo.2005.082230
PMid:16424541 PMCid:1860161
53. W Sickel: Retinal metabolism in dark and light. In: Handbook of sensory physiology. Ed: MHF Fuortes. Berlin. Springer-Verlag: 667-727 (1972).
54. N.G. Bazan: The metabolism of omega-3 polyunsaturated fatty acids in the eye: the possible role of docosahexaenoic acid and docosanoids in retinal physiology and ocular pathology. Prog Clin Biol Res 312:95-112 (1989).
PMid:2529559
55. DJjr Tate, MV Miceli, DA Newsome: Phagocytosis and H2O2 induce catalase and metallothionein gene expression in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 36:1271-9 (1995).
PMid:7775104
56. X Zhang, C Erb, J Flammer, WM Nau: Absolute rate constants for the quenching of reactive excited states by melanin and related 5,6-dihydroxyindole metabolites: implications for their antioxidant activity. Photochem Photobiol 71:524-33 (2000).
doi:10.1562/0031-8655(2000)071<0524:ARCFTQ>2.0.CO;2
57. W Schalch: Carotenoids in the retina-a review of their possible role in preventing or limiting damage caused by light and oxygen. EXS 62:280-98 (1992).
PMid:17266777
58. PO Lundmark, SR Pandi-Perumal, V Srinivasan, DP Cardinali: Role of melatonin in the eye and ocular dysfunctions. Vis Neurosci 23:853-862 (2006).
doi:10.1017/S0952523806230189
59. P Alarma-Estrany, J Pintor: Melatonin receptors in the eye: location, second messengers and role in ocular physiology. Pharmacol Ther 113:507-522 (2007)
doi:10.1016/j.pharmthera.2006.11.003
PMid:1450592
60. RJ Reiter, DX Tan, JC Mayo, RM Sainz, J Leon, Z Czarnocki: Melatonin as an antioxidant : biochemical mechanisms and pathophysiological implications in humans. Acta Biochem Pol 50:1129-1146 (2003).
PMid:14740000
61. E Ganea, JJ Harding: Glutathione-related enzymes and the eye. Curr Eye Res 31:1-11 (2006).
doi:10.1080/02713680500477347
PMid:16421014
62. PA Friedman, ML Zeidel: Victory at C. Nat Med 5:620-1 (1999).
doi:10.1038/9463
PMid:10371497
63. BJ Woodfort, MO Tso, KW Lam: Reduced and oxidized ascorbates in guinea pig retina under normal and light-exposed conditions. Invest Ophthalmol Vis Sci 24:862-7 (1983).
64. A Heckelen, M Hermel, B Kondring, NF Schrage: Ascorbic acid reversibly inhibits proliferation of retinal pigment epithelial cells. Acta Ophthalmol Scand 82:564-568 (2004).
doi:10.1111/j.1600-0420.2004.00317.x
PMid:15453854
65. DM Snodderly: Evidence for protection against age-related macular degeneration by carotenoids and antioxidant vitamins. Am J Clin Nutr 62 (Suppl):1448S-1461S (1995).
PMid:7495246
66. NA Rao, G Thael, JM Delmage, A Sevanian: Superoxide dismutase in ocular structures. Invest Ophthalmol Vis Sci 26:1778-1781 (1985).
PMid:4066214
67. SY Schmidt, RD Peisch : Melanin concentration in normal retinal pigment epithelium. Regional variation and age-related reduction. Invest Ophthalmol Vis Sci 27:1063-1067 (1986).
PMid:3721785
68. AJ Whitehead, JA Mares, RP Danis: Macular Pigment. A review of current knowledge. Arch Ophthalmol 124:1038-1045 (2006).
doi:10.1001/archopht.124.7.1038
PMid:16832030
69. M Boulton, M Rózanowska, B Rózanowski, T Wess: The photoreactivity of ocular lipofuscin. Photochem Photobiol Sci 3:759-764 (2004).
doi:10.1039/b400108g
70. FA Shamsi, M Boulton: Inhibition of RPE lysosomal and antioxidant activity by the age pigment lipofuscin. Invest Ophthalmol Vis Sci 42:3041-6 (2001).
PMid:11687553
71. PJ Thornalley: Cell activation by glycated proteins. AGE receptors, receptor recognition factors and functional classification of AGEs. Cell Mol Biol 44:1013-1023 (1998).
PMid:9846883
72. Y Yamada, K Ishibashi, IA Bhutto, J Tian, GA Lutty, JT Handa: The expression of advanced glycation endproduct receptors in RPE cells associated with basal deposits in human maculas. Exp Eye Res 82:840-848 (2006).
doi:10.1016/j.exer.2005.10.005
PMid:16364296
73. F Reber, M Kasper, A Siegner, E Kniep, G Seigel, RH Funk: Alteration of the intracellular pH and apoptosis induction in a retinal cell line by the AGE-inducing agent glyoxal. Graefes Arch Clin Exp Ophthalmol 240:1022-1032 (2002).
doi:10.1007/s00417-002-0588-2
PMid:12483325
74. J Albon, WS Karwatowski, DL Easty, TJ Sims, VC Duance: Age related changes in the non-collagenous components of the extracellular matrix of the human lamina cribrosa. Br J Ophthalmol 84:311-7 (2000).
doi:10.1136/bjo.84.3.311
PMid:10684844 PMCid:1723409
75. J Albon, PP Purslow, WS Karwatowski, DL Easty: Age related compliance of the lamina cribrosa in human eyes. Br J Ophthalmol 84:318-23 (2000).
doi:10.1136/bjo.84.3.318
PMid:10684845 PMCid:1723411
76. J Albon, WS Karwatowski, N Avery, DL Easty, VC Duance: Changes in the collagenous matrix of the aging human lamina cribrosa. Br J Ophthalmol 79:368-75 (1995).
doi:10.1136/bjo.79.4.368
PMid:7742286 PMCid:505104
77. MC Moreno, J Campanelli, P Sande, DA Sanez, MI Keller Sarmiento, RE Rosenstein: Retinal oxidative stress induced by high intraocular pressure. Free Radical Biol Med 37:803-12 (2004).
doi:10.1016/j.freeradbiomed.2004.06.001
PMid:15384194
78. B Liu, B Neufeld: Nitric oxide synthase-2 in human optic nerve head astrocytes induced by elevated pressure in vitro. Arch Ophthalmol 119:240-5 (2001).
PMid:11176986
79. L Yuan, AH Neufeld: Activated microglia in the human glaucomatous optic nerve head. J Neurosci Res 64:523-32 (2001).
doi:10.1002/jnr.1104
PMid:11391707
80. C Maihöfner, U Schlötzer-Schrehardt, H Gühring, HU Zeilhofer, GOH. Naumann, A Pahl, C Mardin, ER Tamm, K Brune: Expression of cyclooxygenase-1 and -2 in normal and glaucomatous human eyes. Invest Ophthalmol Vis Sci 42:2616-2624 (2001).
81. G Tezel, LY Li, RV Patil, MB Wax : TNF-alpha and TNF-alpha receptor-1 in the retina of normal and glaucomatous eyes. Invest Ophthalmol Vis Sci 42:1787-1794 (2001).
PMid:11431443
82. OA. Agapova, CS Ricard, M Salvador-Silva, MR Hernandez: Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human optic nerve head astrocytes. Glia 33:205-216 (2001).
83. AG Böhm, E Spörl : Neue biomechanische Aspekte zur Bedeutung der Lamina cribrosa und der peripapillären Sklera beim Glaukom. In: Search on Glaukom: Chronobiologie und Chronopharmakologie beim Glaukom. Ed : C Erb. Amsterdam, Excerpta Medica : 52-60 (2006).
PMid:7698265
84. RC Tripathi, J Li, WF Chan, BJ Tripathi: Aqueous humor in glaucomatous eyes contains an increased level of TGF-beta 2. Exp Eye Res 59:723-727 (1994).
doi:10.1006/exer.1994.1158
85. R Fuchshofer, M Birke, U Welge-Lüssen, D Kook, E Lütjen-Drecoll: Transforming growth factor-beta 2 modulated extracellular matrix component expression in cultured human optic nerve head astrocytes. Invest Ophthalmol Vis Sci 46:568-78 (2005).
doi:10.1167/iovs.04-0649
86. J Gottanka, D Chan, M Eichhorn, E Lütjen-Drecoll, CR Ethier : Effects of TGF-ß2 in perfused human eyes. Invest Ophthalmol Vis Sci 45:153-158 (2004).
doi:10.1167/iovs.03-0796
PMid:17217916
87. R Fuchshofer : The pathogenic role of transforming growth factor-ß2 in glaucomatous damage to the optic nerve head. Exp Eye Res (Epub ahead in print) (2010).
88. K Yao, J Tan, WZ Gu, PP Ye, KJ Wang : Reactive oxygen species mediates the apoptosis induced by transforming growth factor beta(2) in human lens epithelial cells. Biochem Biophys Res Commun 354:278-83 (2007).
doi:10.1016/j.bbrc.2006.12.198
89. D Gherghel, HR Griffiths, EJ Hilton, IA Cunliffe, SL Hosking: Systemic reduction in glutathione levels occurs in patients with primary open-angle glaucoma. Invest Ophthalmol Vis Sci 46:877-83 (2005).
doi:10.1167/iovs.04-0777
PMid:15332106
90. O Yildirim, NA Ates, B Ercan, N Muslu, A Unlu, L Tamer, U Atik : Role of oxidative stress enzymes in open-angle glaucoma. Eye 19:580-583 (2005).
doi:10.1038/sj.eye.6701565
PMid:485004
91. ER Asregadoo: Blood levels of thiamine and ascorbic acid in chronic open angle glaucoma. Ann Ophthalmol 11:1095-1100 (1979).
92. GO Sperber, A Bill: Blood flow and glucose consumption in the optic nerve, retina and brain: effects of high intraocular pressure. Exp Eye Res 41:639-53 (1985).
doi:10.1016/0014-4835(85)90036-3
PMid:11284749
93. M Elisaf, G Kitsos, E Bairaktari, R Kalaitzidis, C Kalogeropoulos, K Psilas : Metabolic abnormalities in patients with primary open-angle glaucoma. Acta Ophthalmol Scand 79:129-132 (2001).
doi:10.1034/j.1600-0420.2001.079002129.x
PMid:12365904
94. A Heijl, MC Leske, B Bengtsson, L Hyman, B Bengtsson, M Hussein, Early Manifest Glaucoma Trial Group: Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol 120: 1268-1279 (2002).
PMid:20155656
95. C Erb: Importance of the nuclear factor kappaB for the primary open angle glaucoma-a hypothesis. Klin Monatsbl Augenheilkd 227:120-127 (2010).
doi:10.1055/s-0029-1245132
PMid:20155653
96. U Welge-Lüßen, K Birke: Oxidative stress in the trabecular meshwork of POAG. Klin Monatsbl Augenheilkd 227:99-107 (2010).
doi:10.1055/s-0029-1245171
PMid:20155655
97. FH Grus: Relationship between oxidative stress and autoimmunity in glaucoma. Klin Monatsbl Augenheilkd 227:114-119 (2010).
doi:10.1055/s-0029-1245150
PMid:19668439 PMCid:2699797
98. J Flammer, IO Haefliger, S Orgül: Vascular dysregulation: a principal risk factor for glaucomatous damage ? J Glaucoma 8:212.219 (1999).
99. D Moore, A Harris, D WuDunn, N Kheradiya, B Siesky: Dysfunctional regulation of ocular blood flow: A risk factor for glaucoma? Clin Ophthalmol 2:849-861 (2008).
PMid:17628686
100. MC Leske, A Heijl, L Hyman, B Bengtsson, L Dong, Z Yang, EMGT Group: Predictors of long-term progression in the early manifest glaucoma trial. Ophthalmology 114: 1965-1972 (2007).
doi:10.1016/j.ophtha.2007.03.016
PMid:18695095
101. BC Chauhan, FS Mikelberg, AG Balaszi, RP LeBlanc, MR Lesk, GE Trope, Canadian Glaucoma Study Group: Canadian Glaucoma Study: 2. risk factors for the progression of open angle glaucoma. Arch Ophthalmol 126:1030-1036 (2008).
doi:10.1001/archopht.126.8.1030
PMid:18200806 PMCid:2350146
102. HA Hadi, JA Suwaidi: Endothelial dysfunction in diabetes mellitus. Vasc Health Risk Manag 3:853-876 (2007).
103. P Rösen, Ch Bellin: Diabetes und oxidativer Stress. Blickpunkt Der Mann 2:23-30 (2004).
PMid:16753839
104. S Neri, S Signorelli, D Pulvirentil: Oxidative stress, nitric oxide, endothelial dysfunction and tinnitus. Free Radic Res 40:615-618 (2006).
doi:10.1080/10715760600623825
PMid:17202769
105. G Yilmaz, H Sürer, LE Inan, Ö Coskun, D Yücel: Increased nitrosative and oxidative stress in platelets of migraine patients. Tohoku J Exp Med 211:23-30 (2007).
doi:10.1620/tjem.211.23
PMid:19689607
106. GE Tietjen: Migraine as a systemic vasculopathy. Cephalalgia 29:987-996 (2009).
doi:10.1111/j.1468-2982.2009.01937.x
107. WK Ju, KY Kim, JD Lindsey, M Angert, KX Duong-Polk, RT Scott, JJ Kim, I Kukhmazov, MH Ellisman, GA Perkins, RN Weinreb: Intraocular Pressure Elevation Induces Mitochondrial Fission and Triggers OPA1 Release in Glaucomatous Optic Nerve. Invest Ophthalmol Vis Sci 49:4903-11 (2008).
doi:10.1167/iovs.07-1661
PMid:16413223
108. A Izzotti, A Bagnis, SC Saccà: The role of oxidative stress in glaucoma. Mutation Research 612:105-114 (2006).
doi:10.1016/j.mrrev.2005.11.001
PMid:18204137
109. E Hasnis, M Bar-Shai, Z Burbea, AZ Reznick: Mechanisms underlyind cigarette smoke-induced NF-kappaB activation in human lymphocytes: the role of reactive nitrogen species. J Physiol Pharmacol 58 (Suppl 5):275-287 (2007).
110. J Flammer: Die Rolle der Reperfusion in der Induktion der Apoptose. In: Neuronale Konzepte beim Glaukom. Eds: Erb C, Arend O. Uni-Med, Bremen: 68-70 (2005).
PMid:15859924
111. LH Toledo-Pereyra, AH Toledo, J Walsh, F Lopez-Neblina: Molecular signaling pathways in ischemia/reperfusion. Exp Clin Transplant 2:174-177 (2004).
112. J Kountouras, C Zavos, N Grigoriadis, G Deretzi, P Katsinelos, D Tzilves: Helicobacter pylori infection as an environmental familial clustering risk factor for primary open-angle glaucoma. Clin Experiment Ophthalmol 36:296-7 (2008).
doi:10.1111/j.1442-9071.2008.01729.x
PMid:18202112
113. A Saha, CE Hammond, M Trojanowska, AJ Smolka: Helicobacter pylori-induced H,K-ATPase alpha-subunit gene repression is mediated by NF-kappaB p50 homodimer promoter binding. Am J Physiol Gastrointest Liver Physiol 294:G795-807 (2008).
doi:10.1152/ajpgi.00431.2007
PMid:17149369
114. CY Wang, YC Shen, FY Lo, CH Su, SH Lee, KH Lin, HY Tsai, NW Kuo, SS Fan: Polymorphism in the IL-1alpha (889) locus associated with elevated risk of primary open angle glaucoma. Mol Vis 12: 1380-1385 (2006).
PMid:11747366
115. S Yoneda, H Tanihara, N Kido, Y Honda, W Goto, H Hara, N Miyawaki: Interleukin-1beta mediates ischemic injury in the rat retina. Exp Eye Res 73:661-667 (2001).
doi:10.1006/exer.2001.1072
PMid:12166787
116. Z Sun, R Anderson: NF-kB activation and inhibition: a review. Shock 18:99-106 (2002).
doi:10.1097/00024382-200208000-00001
PMid:17827914
117. M Ohkita, M Takaoka, Y Matsumura:Endothelin-1 production and its involvement in cardiovascular diseases. Yakugaku Zasshi 127:1319-1329 (2007).
doi:10.1248/yakushi.127.1319
PMid:18493277
118. BC Chauhan: Endothelin and its potential role in glaucoma. Can J Ophthalmol 43:356-360 (2008).
PMid:17272744
119. S Bonello, C Zähringer, RS BelAiba, T Djordjevic, J Hess, C Michiels, T Kietzmann, A Görlach: Reactive oxygen species activate the HIV-1alpha promoter via a functional NF-kB site. Arterioscler Thromb Vasc Biol 27:755-761 (2007).
doi:10.1161/01.ATV.0000258979.92828.bc
PMid:15364715
120. G Tezel, MB Wax: Hypoxia-inducible factor 1alpha in the glaucomatous retina and optic nerve head. Arch Ophthalmol 122:1348-1356 (2004).
doi:10.1001/archopht.122.9.1348
121. L Zhou, Y Li, BY Yue: Oxidative stress affects cytoskeletal structure and cell-matrix interactions in cells from an ocular tissue: the trabecular meshwork. J Cell Physiol 180:182-189 (1999).
doi:10.1002/(SICI)1097-4652(199908)180:2<182::AID-JCP6>3.0.CO;2-X
PMid:15985430
122. X Zhou, F Li, L Kong, H Tomita, C Li, W Cao: Involvement of inflammation, degradation, and apoptosis in a mouse model of glaucoma. J Biol Chemistry 280:31240-31248 (2005).
doi:10.1074/jbc.M502641200
PMid:11157868
123. J Yang, P Yang, G Tezel, RV Patil, MR Hernandez, MB Wax: Induction of HLA-DR expression in human lamina cribrosa astrozytes by cytokines and simulated ischemia. Invest Ophthalmol Vis Sci 42:365-371 (2001).
124. Y Zhong, CK Leung, CP Pang: Glial cells and glaucomatous neuropathy. Chin Med J 120 :326-335 (2007).
125. MB Wax, G Tezel, I Saito: Anti-Ro/SS-A positivity and heat shock protein antibodies in patients with normal pressure glaucoma. Am J Ophthalmol 125:145-157 (1998
doi:10.1016/S0002-9394(99)80084-1
PMid:11241738
Key Words: Oxidative Stress, Glaucoma, NF-κB, trabecular meshwork, Review
Send correspondence to: Carl Erb, Schlosspark-Klinik, Department of Ophthalmology, Heubnerweg 2, 14059 Berlin, Germany, Tel: 49-30-3264-1258, Fax: 49-30-3264-1257, E-mail:Carl.erb@schlosspark-klinik.de