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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 10  |  Issue : 1  |  Page : 3-8

The oxidative and inflammatory nature of age-related macular degeneration


1 State University of Botucatu, UNESP, Campina Grande do Sul, Brazil
2 Department of Ophthalmology, Hospital Angelina Caron, Campina Grande do Sul, Brazil
3 Ophthalmologic Center of Curitiba

Date of Submission11-Dec-2020
Date of Decision10-Mar-2021
Date of Acceptance10-Mar-2021
Date of Web Publication3-Feb-2022

Correspondence Address:
Rogil Jose de Almeida Torres
Rua Emiliano Perneta, 390, Conjunto 1407 - CEP 80420-080, Curitiba, Parana
Brazil
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcor.jcor_268_20

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  Abstract 


The understanding of the effects of oxidation and inflammation on age-related macular degeneration (AMD) genesis has been of utmost importance for the advancement of preventive and therapeutical measures adopted in this disease. Several studies have been conducted on lifestyles, dietary antioxidants, expression of antioxidant enzymes, naturally found in the retina, as well as expression of cytokines, enzymes, and growth factors, with an ultimate goal to prevent or mitigate the visual damage induced by AMD. This article details the disruption of redox homeostasis associated with the increase of cells and inflammatory markers, major factors in triggering and/or aggravating the degenerative macular disease. The data sources used in this review study include Cochrane Database of Systematic Reviews, PubMed, MedlinePlus Health Information, and Elsevier Science.

Keywords: Age-related macular degeneration, chronic inflammation, free radicals, oxidative stress, retinal pigment epithelium


How to cite this article:
de Almeida Torres RJ, de Almeida Torres RJ, Luchini A, Anjos Ferreira AL. The oxidative and inflammatory nature of age-related macular degeneration. J Clin Ophthalmol Res 2022;10:3-8

How to cite this URL:
de Almeida Torres RJ, de Almeida Torres RJ, Luchini A, Anjos Ferreira AL. The oxidative and inflammatory nature of age-related macular degeneration. J Clin Ophthalmol Res [serial online] 2022 [cited 2022 May 16];10:3-8. Available from: https://www.jcor.in/text.asp?2022/10/1/3/337192



Age-related macular degeneration (AMD) is one of the main causes of irreversible vision loss in the elderly.[1] It is a complex, multifactorial disease, associated with aging, and genetic, nutritional, and environmental alterations.[2] A systematic review and meta-analysis has shown that 8.7% of the worldwide population developed AMD, and the projected number of people with the disease in 2020 is around 196 million, reaching 288 million in 2040.[3] On the other hand, another meta-analysis involving 42,080 people over 40 years of age, performed in 14 population-based cohorts from 10 countries in Europe, reported a decrease in AMD prevalence in the last decade.[4] This finding is corroborated by similar findings in a study carried out in North America, with 4819 patients, which revealed that a decrease in AMD prevalence has been observed during the 20th Century.[5] Two studies conducted in different continents reported practically similar results; nevertheless, they presented a more optimistic perspective in relation to most epidemiological studies on AMD. Considering that populational genetic modification takes a significant amount of time to happen, the positive results can ultimately be accounted for by changes in lifestyles.[6] The control of serum cholesterol and tobacco smoking and the adoption of a healthy diet, regular physical exercises, and oral hygiene are related to a decrease in oxidation and inflammation processes that may cause several diseases, AMD included, and represent important factors in the prevention of this disease.[5],[6],[7],[8],[9],[10] The objective of this study is to correlate the unbalance of the redox state with inflammation and AMD.


  Methods of Literature Search Top


A comprehensive review of literature was performed through Cochrane Database, PubMed, MedlinePlus Health Information, and Elsevier Science. We used the following keywords and their synonyms in various combinations: age-related macular degeneration, oxidative stress, chronic inflammation, retinal pigment epithelium (RPE), and free radicals. Articles cited in the reference list of articles obtained through this search were also reviewed whenever relevant.


  Oxidative Stress and its Basic Concepts Top


Oxidative stress is the state where there is an imbalance between the antioxidant defense system and the generation of reactive species (of oxygen reactive oxygen species [ROS] or reactive nitrogen species [RNS]). Such imbalance results in oxidation of important biomolecules (lipids, proteins, carbohydrates, and DNA).[11],[12] Reactive species, generated by both enzymatic and nonenzymatic systems, have been associated not only with a large number of physiological processes, but also with nonphysiological ones during the onset and progression of diseases.[13] Also called free radicals, reactive species are highly reactive and include peroxynitrite (ONOO-), hydroxyl (●OH), superoxide (O2¯ •), hydrogen peroxide (H2O2), oxygen singlet (1O2), nitric oxide (●NO), hypochlorous acid, hydroperoxyl radical, alkoxyl radical (LO •), and hydroperoxide (L (R) OOH). The sources that generate reactive species are as follows: mitochondria (incomplete O2 reduction), macrophages and neutrophils, endothelium, epithelium, enzymatic systems (myeloperoxidase; xanthine oxidase, NADPH-oxidase (NOX), NADPH-cytochrome P450 reductase, cyclooxygenase (Cox), and NO synthase [NOS]), reactions with metal (iron and copper) via Fenton and Haber–Weiss reaction, and nonenzymatic reaction between the superoxide and NO radicals resulting in the generation of peroxynitrite. Although reactive species are essential for a variety of cellular defense mechanisms,[14],[15] ROS (as well as RNS) can cause oxidative damage in biomolecules (lipids, proteins, carbohydrates, and DNA) when present in larger quantity than their system-mediated neutralization antioxidant defense.

The NOS enzyme system is an important source of reactive species in several diseases, including AMD. Physiologically, NOS converts L-arginine into NO, providing control of vascular muscle tone. This reaction occurs in the presence of tetrahydrobiopterin (BH4), which is converted into dihydrobiopterin (BH2) by reducing O2 to H2O. In pathological conditions, such as substrate (L-arginine) or cofactor (BH4) deficiency, O2 is not completely reduced to H2O [BH4 and L-arginine deficiency has been demonstrated in non-perfused tissues during shock or ischemia].[16],[17],[18] Such incomplete reduction generates a superoxide radical. The exaggeration of superoxide stimulates the decoupling of the endothelial NOS (eNOS) enzyme, which leads to the contraction of the vessel. It has also been described that the excessive generation of superoxide can increase the activity of NOX which results in the oxidation of BH4, compromising its function as a cofactor. Thus, in the deficiency of cofactors, the decoupling of NOS (eNOS) occurs, inducing vasoconstriction. The eNOS has been demonstrated in atherosclerosis, type 2 diabetes mellitus, hypertension, and hyperhomocysteinemia.[19],[20]

The antioxidant defense system consists of several endogenous and exogenous components. The endogenous ones include reduced glutathione (GSH), GSH-peroxidase (GSH-Px), GSH reductase, superoxide dismutase (SOD), catalase, uric acid, albumin, hemoglobin, transferrin, and bilirubin. On the other hand, the exogenous ones include metal chelators (deferoxamine), Vitamin E (mainly a-tocopherol), carotenoids (a-carotene, b-carotene, lycopene, lutein, zeaxanthin, astaxanthin, and canthaxanthin), Vitamin C, flavonoids, mannitol, and aminoguanidine. Taurine, melatonin, and carnosine are also endogenous compounds, but can be administered as supplements. Healthy diets are important sources of antioxidants, even for those in the endogenous antioxidant category, considering that their function depends on the dietary intake of important components for the proper functioning of these antioxidants. Classic examples are the constituents of red pepper (cysteine), Brazil nut (selenium), and oyster (zinc), important for the function of GSH, GSH-Px, and Zn-SOD, respectively.[20],[21] In addition to the classification that differentiates endogenous from exogenous antioxidants, there is one that emphasizes the hydrophilic and lipophilic compartments. The hydrophilic (aqueous) compartment contains ascorbate, flavonoids, albumin, bilirubin, GSH, GSH-Px, SOD, and catalase, among others. On the other hand, carotenoids and a-tocopherol are present in the lipophilic compartment. It should be noted that the beneficial action of a given antioxidant is the result of a fine balance between antioxidants (present in the hydrophilic and lipophilic compartments) and the magnitude of the generation of ROS and RNS. If this interaction is not respected, an undesirable phenomenon called prooxidant may occur, as, for example, during supplementation with a single antioxidant. Given this fact, it can be inferred that a mixture of antioxidants could prevent the possible undesirable prooxidant action. However, unfortunately, the ideal composition and the appropriate dose of each antioxidant in this mixture is unknown, despite the great efforts in the area.[20]

As mentioned, oxidative stress occurs when the magnitude of production of reactive species exceeds the antioxidant capacity, which results in lipid peroxidation, proteins (carbonylation and/or nitration), carbohydrates (carbonylation), and DNA (oxidation of nitrogenous bases). Injury to these important cellular components induces changes in the cell chemical structure and function, which lead to cell death or apoptosis. Lipid peroxidation corresponds to a self-limited reaction composed of steps of initiation, propagation, and termination.[22] However, the reactive species overload can restart the process and lead an uncontrolled generation of cytotoxic products such as malondialdehyde (MDA). Oxidative DNA damage can occur at the bases (purine and pyrimidine) in the presence of • OH, which, by removing a hydrogen atom from the carbohydrate-hydrogen bonds, generates false bases (called DNA base adducts) that can be produced in the presence or absence of O2. The false bases generated can act as oxidants or as reducers (depending on where the hydrogen atom was removed) and compromise replication and transcription, consequently leading to impaired transmission of genetic information, one of the main functions of DNA.[23] It is also important to highlight the importance of nitration and carbonylation reactions in AMD. Protein nitration is the result of the undesirable action of peroxynitrite, leading to impaired function of the protein.[19] Protein carbonylation occurs as a result of the action of advanced lipid peroxidation products (MDA, glyoxal, acrolein, and 4-hydroxy-nonenal) and advanced glycation (glyoxal and methylglyoxal) on the nucleophilic sites of proteins, peptides (cysteine, lysine, and histidine), aminophospholipids, and DNA. Such aggression generates irreversible carbonylation that leads to the dysfunction of molecules, cells, tissues, and organs. The highlight of this reaction in obesity, a disease associated with AMD, corresponds to impaired insulin function, glucose 6-phosphate dehydrogenase, and endothelial function.[20]


  Oxidative Stress in Age-Related Macular Degeneration Pathogenesis Top


During aging, oxidative damage also keeps increasing gradually because the antioxidant capacity decreases concurrently in mammals. As a result, the inherent repair capacity of RPE cells becomes compromised.[24],[25],[26] A study identified high heme oxygenase-1 (HO-1) and heme HO-2 lysosomal antigen levels in the macular RPE cells of young people, suggesting their protective mechanisms against oxidation. On the other hand, a decrease in catalase immunoreactivity in the cell lysosomes of RPE cells in the elderly, both in normal eyes as well in those affected by AMD, would likely aggravate the AMD progression.[26] In this regard, activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) is of paramount importance in the preservation of vision. Nrf2-pathway is known to be a master regulator of stress response in RPE, and it is also a key component of the transduction machinery to maintain proteostasis, which is altered in AMD.[27] Among the main Nrf2-activated antioxidant and phase-II detoxifying enzymes that neutralize the reactive species in the sensory retina and RPE are the GSH-Px, [28] SOD,[29],[30] HO-1,[26],[31] and catalase.[26],[27],[28],[29],[30],[31],[32]

Studies confirm that the oxidative and nitrosative stress, induced by the imbalance between the oxidant defense and the production of oxygen reactive species, plays a key role in the triggering and progression of AMD.[33] The retina is a tissue prone to oxidative stress due to its high metabolism, large amount of polyunsaturated fatty acid content, exposure to visible light (between 400 and 700 nm), and the presence of photosensitive molecules such as rhodopsin and lipofuscin, an undegradable and autofluorescent metabolite.[33] Throughout life, lipofuscin granules found in RPE cells are exposed to visible light and high oxygen uptake, forming ROS. It is suggested that these reactions to photosensitivity may be involved in AMD genesis, and its ROS, such as O2−, H2O2, and singlet oxygen, would damage RPE cells, inducing their hypofunctioning condition.[34] RPE cell dysfunction causes dysregulated heterophagy or autophagic degradation of photoreceptor outer segments,[35] resulting in lipofuscin accumulation in the lysosomes and consequent disruption of lysosomal enzymes function, which intensifies the oxidative stress and retinal inflammation.[35],[36] In addition, RPE cell dysfunction causes a flawed degradation of the products derived from the phagocytosis of the outer segments of photoreceptor cells, inducing the pathologic accumulation of lipids in the Bruch's membrane (BM),[37] and consequent damage to its permeability. BM is a thin layer of connective and semipermeable tissue that provides nutrients from the choriocapillaris to RPE and outer layers of the sensory retina. This structure also enables the RPE metabolites to move to choriocapillaris. Consequently, a modification in the BM interferes in the nutrition of RPE cells, inducing a gradual atrophic process.[38] Once the RPE atrophic process is established, there is a decrease in blood supply to this layer, inducing a secondary atrophy of the choriocapillaris.[39],[40],[41] As a result, the outer layers of the sensory retina, the RPE, and the choriocapillaris go into hypoxia, causing the death of RPE photoreceptors and atrophy.[40],[42] The chronic retinal ischemia contributes to the increase of the excitatory glutamate, which acts upon the N-methyl-D-aspartate receptors located in the plasma membrane of the retinal glial and neuronal cells.[43] The hyperstimulation of the glutamatergic receptors induces an increase in the intracellular calcium to toxic levels. In turn, the excessive influx of calcium induces the formation of NOS and consequent release of NO. The increase in NO production is cytotoxic and may lead to cell death or apoptosis.[44] Other studies have corroborated these findings, revealing that NO, the most abundant free radical in the body, might be implicated in the pathophysiology of AMD, in association with decreased antioxidant enzymes and increased lipid peroxidation status.[45] Not less important is the fact that hypoxia is the main stimulus for the release of the vascular endothelial growth factor (VEGF).[46] Both hypoxia and VEGF activate NOX,[47] the major source of ROS generation in vascular endothelial cells (EC).[48] Activation of NOX leads to necessary conditions for physiologic and pathologic angiogenesis, including EC migration, proliferation, and tube formation,[49] resulting in the formation of subretinal neovessels.[2]


  Inflammation and Age-Related Macular Degeneration Top


All the layers that form the macular region present cells and important markers involved in the inflammatory reaction and, consequently, in the AMD pathogenesis. In the retina, the response to the inflammatory stimulus is coordinated by the microglial cells.[50] These immune cells are located in the plexiform layer, in the retinal ganglion cell layer, and the nerve fiber layer.[51] The function of the microglial cells is to detect the harmful stimuli to the retina, playing an important role in the retinal homeostasis and its neuroprotection.[52] In response to the inflammatory stimuli, microglia secrete important inflammatory molecules such as proteinases, NO, reactive oxygen intermediates, and proinflammatory cytokines, including interleukin-1 beta (IL-1 β), IL-6, and tumor necrosis factor-α (TNF-α),[50],[53],[54] involved in AMD pathogenesis.[55],[56]

In the BM, the pathologic accumulation of lipids generates the drusen and other extracellular deposits, important risk factors for the development of AMD.[42],[43] The drusen contain immunological and inflammatory markers such as serum amyloid P component, apolipoprotein E, immunoglobulin light chains, factor X, prothrombin and complement proteins (C3a, C5a, and C5b-9 complex), C-reactive protein (CRP), vitronectin, ubiquitin, and integrins.[57],[58],[59],[60] Beside the drusen, the choriocapillaris, the RPE cells, and photoreceptors also present inflammatory and immunological markers such as Factor X, fibrinogen, immunoglobulin, HLA-DR, amyloid A component, apolipoprotein B/E, CRP, complement C3, C5, MCP-1, prothrombin, ubiquitin, and VEGF.[61],[62],[63],[64],[65],[66] Studies show that ECs and RPE-activated cells, as well as the macrophages, attracted to the macular region, due to the accumulation of oxidized lipids, secrete inflammatory cytokines, enzymes, and growth factors that promote the progression and consequent aggravation of AMD.[55],[56] It is important to highlight that besides the oxidized LDL, the native LDL also induces the increase in the adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) contributing to the accumulation of macrophages.[67] These findings support the current understanding that inflammation plays a critical regulatory role in AMD. It often exacerbates the oxidative stress, creating a self-perpetuating, vicious cycle of oxidation and inflammation,[68],[69] therefore aggravating AMD. One of the means to perpetuate this cycle is the activation of the nuclear factor kappa β, involved in the regulation of gene expression associated with the immune and inflammatory responses.[70] This nuclear transcription factor mediates the synthesis of cytokines, such as TNF-α, IL-1 β, IL-2, IL-6, and IL-8, as well as the expression of Cox-2, inducible NOS, acute phase proteins, such as CRP, and adhesion molecules such as E-selectin, Vascular cell adhesion molecule 1 (VCAM-1), and ICAM-1,[70],[71] all directly involved in AMD pathogenesis.[72],[73],[74],[75],[76],[77],[78],[79],[80]

The intracellular multiprotein complex, denominated inflammasome, also plays a relevant role in the activation of the enzymes of the cysteine–aspartic proteases family (CASPASES). Its activation is key component of the innate immunity, which, when overactive, has been associated with many human immune diseases.[81],[82] The role of the NLRP3 inflammasome in AMD pathogenesis has been extensively investigated. The drusen, a hallmark of AMD progression, present a rich proteinaceous composition, including complement regulators, amyloid-beta, and oxidation by-products,[59],[83] closely related to the activation of NLRP3 inflammasome.[84],[85],[86] The assembly of the active inflammasome results in the autoactivation of caspase-1, which subsequently cleaves the proinflammatory cytokines IL-1 β and IL-18 into their mature and secreted forms.[87] Studies have shown that the proinflammatory cytokine IL-1 β is responsible for the damage of the outer segments and the death of rods as well as for the increased expression in the patients' vitreous affected by polypoidal choroidal vasculopathy.[73],[88],[89] Conversely, IL-18 has been reported to play a destructive role in AMD with the choroid geographic atrophy (GA)[90] and protective one in wet AMD.[84]


  Conclusion Top


Considering the redox state and inflammatory imbalance role (activation of RPE, ECs and macrophage cells, and the concomitant increase of inflammatory cytokine expression, enzymes, and growth factors) on AMD pathogenesis, the use of antioxidant and anti-inflammatory compounds should be considered in preventive and therapeutic strategies. Although an effective treatment for dry AMD, with choroid GA, has not been found yet, and limited results for wet-AMD treatment with anti-VEGF therapy have been obtained, important advances have been achieved and several research studies have been carried out in the molecular field related to inflammatory cytokines and enzymes, adding to the overly studies on growth factors. In addition, the identification of modifiable factors of the degenerative macular disease, strongly associated with the oxidative stress and inflammation, such as smoking, diet, exposure to visible light (400–700 nm), and physical activities, among others, has encouraged the populations in several countries to change their lifestyle, thus preventing the onset or the progression of this disease. Further studies are needed to explore AMD pathogenesis and therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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