Role of oxidative stress in Ophthalmology
Disease entity: Oxidative stress in ocular diseases
What is oxidative stress:
It is an imbalance between the generation of free radicals and the ability of antioxidants to neutralize them. Normally, cells produce metabolic-derived end products and generate energy by reducing molecular oxygen to water. During this process, small amounts of partially reduced reactive oxygen species are produced as byproducts of mitochondrial respiration. Reactive oxygen species (ROS) can damage the component of the cell (lipid, proteins, and nucleic acid). Cells have an antioxidant system to counter the effect of ROS.
In ocular tissue, metabolism occurs in the cornea, natural crystalline lens, retinal pigment epithelium. Glucose is metabolized through series of cellular cycles (glycolysis, Krebs cycle, hexose monophosphate shunt, sorbitol pathway). ATP and NADPH are byproducts of cellular metabolic activities and maintain cellular homeostasis.
Oxidants and antioxidants mechanism in eye:
Free radicals like superoxide anion, hydroxyl ion, hydroperoxyl, lipid peroxyl, singlet oxygen, hydrogen peroxide are generated from different sources. The endogenous sources of ROS include cellular metabolic activities, inflammation, respiratory burst (NADPH oxidase). The exogenous sources of ROS include ultraviolet, ionizing, gamma radiation, and x rays. These radiations are capable to interact with ocular tissue and generate reactive oxygen species. Nitrogen dioxide and nitrates are generated by macrophage.
1) Vitamin A, C, E, beta-carotene
2) Enzyme system: a) Mitochondria: Superoxide dismutase, glutathione peroxidase b) Peroxisome: Catalase c) Cytosol: Superoxide dismutase, glutathione peroxidase, ferritin, ceruloplasmin
3) Minerals: Selenium, copper, zinc
Effects of ROS at cellular level
•Lipid peroxidation within the plasma membrane
•Protein cross-linking and fragmentation
•Apoptosis of cell, necrosis, and autophagy response
Importance of the role of oxidative stress in ocular diseases:
1) Anterior segment disease: Dry eye disease, Meibomian gland disease, cataract
3) Posterior segment disease: Age-related macular degeneration, diabetic retinopathy
4) Role in fungal keratitis, retinitis pigmentosa at the experimental level
A) Dry eye disease and Meibomian gland disease:
Aging, cigarette smoke, low humidity, sunlight, pollutants are risk factors to produce ROS. Loss of homeostasis, hyperosmolarity, ocular surface inflammation in dry eye disease releases pro-inflammatory cytokines (IL1, 6). Excess production of ROS can cause ocular surface damage .Normal tear film contain antioxidants like lactoferrin, ascorbate which protect the ocular surface against ROS. The accumulation of ROS in ocular surface due superoxide dismutase deficiency lead to dry eye disease and meibomian gland disease. Studies show the role of oxidative damage in the dry eye disease spectrum (Sjogren's and non-Sjogren's syndrome):
|Cejkova. J et al||2008||Decrease the expression of superoxide dismutase, catalase, and glutathione peroxidise in conjunctival epithelium occurs in Sjogrens syndrome associated dry eye disease.|
|Wakamatsu et al||2013||Oxidative stress marker (lipid peroxidation) has role in pathogenesis of Sjogrens syndrome associated dry eye disease.|
|Choi et al||2016||Increase in level of malondialdehyde in tear film occurs in non Sjogrens syndrome associated dry eye disease.
B) Glaucoma: Raised intraocular pressure inhibits axoplasmic flow across the optic nerve. An excess amount of ROS production can cause retinal ganglion cell apoptosis and trabecular meshwork damage. Oxidative damage of trabecular meshwork can alter aqueous outflow. Antioxidative agents are the future mode of treatment in the prevention of glaucoma progression.
C) Cataract: A natural crystalline lens is a transparent avascular structure. Different metabolic activities, antioxidative mechanism, and Na+ K+ pump helps in keeping the lens clear. Radiation, aging, diabetes causes reduction of antioxidant enzymes leads to cataract.
Role of free radical formation and its neutralization in the lens:
Lens receives O2 from the aqueous humor. Glucose metabolized in the lens through different pathways like anaerobic glycolysis, Krebs cycle, hexose monophosphate shunt, sorbitol pathway. These cellular activities produce reactive oxygen species. Sunlight absorbed by photosensitizer undergoes photoexcitation (photoexcited singlet state converted into intermediate excited triplet state). This triplet state allow for interaction with another molecule to produce ROS. Antioxidants such as glutathione peroxidase, catalase, superoxide dismutase, and ascorbate present in lens epithelium and fibers. Glutathione peroxidase neutralizes hydrogen peroxide and lipid peroxide. Ascorbate present in outer layers of lens reacts with superoxide, peroxide, hydroxyl ion and produces dehydroascorbate product. Ascorbate also scavenges singlet oxygen and thiol radical. Aromatic amino acid (Tryptophan), fluorophores and 3-hydroxykinurenine provide protection against UV rays in the lens. (Fig.1)
Action of reactive oxygen species in lens:
• Polymerization and cross-linkage of crystallin proteins. Finally, lead to inactivation of catalase and glutathione enzyme.
• Membrane lipid peroxidation leads to the formation of malondialdehyde.
• DNA base modification (8 hydroxy guanosine) and distortion of DNA helical structure at 8,5 cyclopurine deoxyribonucleosides.
D) Role in retinal disorders: RPE-Bruchs complex act as a barrier and plays a key role in the management of metabolic waste and oxidative stress. Studies show dysregulation of the antioxidant enzyme system leads to retinal conditions like age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, retina of prematurity.
Diabetic retinopathy is a microvascular complication of diabetes. Abnormal glucose metabolism produces advanced glycation end products which further get accumulate in the retinal vascular cell. Increase signaling to caspase 3 causes retinal capillary cell apoptosis. Decrease of the level of the antioxidant enzyme in retinal tissue produces ROS which further release pro-inflammatory cytokines lead to dysfunction of the vascular endothelial cell. Vascular permeability and increase in expression of VEGF cause retinal neovascularization. Excess glucose convert into sorbitol by aldose reductase which needs NADPH. Further sorbitol transforms into fructose by sorbitol dehydrogenase. Increase the metabolism through the polyol pathway cause consumption of NADPH( Nicotinamide adenine dinucleotide) and decrease of its availability for regeneration of glutathione enzyme system.
Role in Age-related macular degeneration: Age-related macular degeneration (ARMD) is a progressive, degenerative disorder principally affects retinal pigment epithelium, Bruch's membrane and choriocapillaris. Its pathogenesis involves oxidative damage to the RPE-Bruchs complex. Constant exposure to ultraviolet rays leads to the production of ROS and oxidative damage to RPE-Bruch's complex. The thickening of the collagenous layer within Bruch's membrane and calcification (elastin, collagen degeneration) occurs after the damage of RPE-Bruch’s complex. An increase in advanced glycation end products and a decrease in antioxidant mechanism make the RPE-Bruchs barrier more hydrophobic which further, impedes nutrients and fluid passage through the outer retina and choroid.
Role in retinitis pigmentosa: It is a hereditary disease that is characterized by degeneration of photoreceptors (rod-cone dystrophy). Studies have been carried out to find out the role of oxidative stress in retinal pigment epithelium degeneration. The metabolic support of photoreceptors hampered, due to a defective antioxidant mechanism. Recent studies explained the role of autophagy and oxidative stress in retinitis pigmentosa. Shen et al carried out a study in transgenic pigs and explained the cause of cone degeneration in RP. They found cone degeneration is because of oxidative damage produced by hyperoxia in the outer retina due to decreased oxygen consumption in rod receptors death.
Role in retinopathy of prematurity (ROP): Niesman et al explained the role of antioxidants in ROP in an animal model. In humans role of it in ROP is still in the investigation phase.
E) Role of oxidative damage in the pathogenesis of fungal keratitis is at experimental stage.
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