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Oxidative Medicine and Cellular Longevity
Volume 2017, Article ID 3940241, 16 pages
https://doi.org/10.1155/2017/3940241
Review Article

Ischemic Retinopathies: Oxidative Stress and Inflammation

1Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, QC, Canada
2Department of Pediatrics, Ophthalmology and Pharmacology, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada

Correspondence should be addressed to José Carlos Rivera; ac.laertnomu@arevir.cj and Sylvain Chemtob; ac.laertnomu@botmehc.niavlys

Received 17 September 2017; Accepted 20 November 2017; Published 19 December 2017

Academic Editor: Alexandra S. Latini

Copyright © 2017 José Carlos Rivera et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Ischemic retinopathies (IRs), such as retinopathy of prematurity (ROP), diabetic retinopathy (DR), and (in many cases) age-related macular degeneration (AMD), are ocular disorders characterized by an initial phase of microvascular changes that results in ischemia, followed by a second phase of abnormal neovascularization that may culminate into retinal detachment and blindness. IRs are complex retinal conditions in which several factors play a key role during the development of the different pathological stages of the disease. Increasing evidence reveals that oxidative stress and inflammatory processes are important contributors to the pathogenesis of IRs. Despite the beneficial effects of the photocoagulation and anti-VEGF therapy during neovascularization phase, the need to identify novel targets to prevent initial phases of these ocular pathologies is still needed. In this review, we provide an update on the involvement of oxidative stress and inflammation in the progression of IRs and address some therapeutic interventions by using antioxidants and anti-inflammatory agents.

1. Introduction

Ischemic retinopathies (IRs), such as retinopathy of prematurity (ROP), diabetic retinopathy (DR), and age-related macular degeneration (AMD), are the main causes of severe visual impairment and sight loss in children, adults (with diabetes), and elderly population, respectively [1, 2]. IRs are biphasic diseases characterized by loss of the preexisting vessel bed and sustained hypoxia that leads to a secondary vasoproliferative phase characterized by anarchic vessel proliferation into the vitreous humor, which can result in retinal detachment and blindness [3]. Importantly, the ensuing ischemic events secondary to initial vessel loss can also have devastating effects on neuronal homeostasis and function [4].

Several factors contribute to the pathogenesis of IRs; however, oxidative stress [5, 6] and inflammatory processes [7, 8] stand as major ones. Oxidative stress is defined as an imbalance favoring generation over the removal of reactive oxygen species (ROS), such as free radicals, nitric oxide (NO), superoxide anion (O2−•), and hydrogen peroxide (H2O2). Free radicals are short-lived reactive molecules that disrupt molecular nature of lipids, amino acids, and nucleic acids. ROS are normal by-products of aerobic metabolism; inefficient removal by antioxidants leads to redox injury and cellular damage [9]. Factors that participate in the pathogenesis of IRs, such as hyperoxia in ROP, hyperglycemia in DR, and lipid accumulation in AMD, are important amplifiers of oxidative stress that cause dysregulation of cell metabolism and participate in limiting antioxidant defenses during the development of the IRs [913].

Inflammation and oxidant stress are tightly intertwined. Inflammation is a cellular response to factors (including those due to oxidant stress) that challenge the homeostasis of the tissues, but this process also acts as a defense mechanism to maintain the equilibrium of the functions. Cytokines and chemokines are signaling proteins that travel throughout the body to exert specific functions in inflammation. However, sustained inflammation can be detrimental to tissue integrity. Increasing evidence shows that a local and/or systemic augmentation of ROS or inflammatory molecules is implicated in the pathogenesis of IRs. Current therapies only target late phases of these ocular pathologies, specifically the vasoproliferative phase. Yet, there is an urgency to tackle the initial ischemic phases. We hereby review prominent concepts that involve oxidative stress and inflammation in the genesis and progression of IRs.

2. Retinopathy of Prematurity (ROP)

ROP is the major cause of visual impairment and blindness in neonates worldwide. A demographic census in 2010 reported ~184,700 preterm babies worldwide with ROP; 20,000 of them were blind or severely visually impaired [14]. This problem is reaching epidemic proportions in middle-income and developing countries; the survival of extremely premature infants is increasing without a significant change in morbidity [15].

2.1. Pathogenesis of ROP

ROP is a disease that affects the immature retinal vascular system and thus occurs in premature infants with an incompletely vascularized retina. Therefore, the incidence and severity of retinopathy are directly proportional to the degree of prematurity. It is widely accepted that the development of ROP progresses through two phases. The first phase begins when retinal vascular growth ceases after premature birth. During this time, the retinal cytoprotective factors, such as insulin-like growth factor-1 (IGF-1), diminish [16] and the vessels become particularly vulnerable to injury caused by any number of stressors, including the amount of oxygen supply. Premature infants are exposed to higher oxygen tension after birth compared to those in utero. This leads to a downregulation of the major hypoxia-driven vascular endothelial growth factor (VEGF), as well as an increase in vasoobliteration of immature retinal capillaries through the actions of oxidant stress and intertwined inflammation [17]. The loss of blood vessels, associated with an increase in maturation-dependent metabolic demand, causes the retina to become gradually hypoxic. In order to ensure an adequate perfusion to the hypoxic retina, an overproduction of hormones and growth factors stimulates an excessive vessel formation at the junction between the vascular and avascular retina. This sets the beginning of the second phase of ROP. Interestingly, these new vessels fail to reperfuse the avascular retina, as instead of growing into areas of need, they grow chaotically into the vitreous, where traction and detachment of the retina as well as bleeding can occur, ultimately resulting in blindness. This critical stage of ROP (defined in humans as stage 4-5) occurs most frequently around 34–36 weeks after conception [18].

2.2. Nitrooxidative Stress, Lipid Oxidation and Nitration, and ROP

The pathogenesis of ROP is related to many causative factors, including low gestational age, low birth weight, genetic components, and relative hyperoxia. Hyperoxia is one of the major environmental predisposing factor to ROP, as it is the molecular basis for generation of reactive oxygen species (Figure 1). Nitric oxide formation also requires oxygen, and based on the redox state of the retina, it can have either beneficial or detrimental effects to the retina. Using the experimental model of oxygen-induced retinopathy (OIR) which shares many features of ROP, it was shown that endothelial nitric oxide synthase expression and activity increase when the redox state is shifted towards an oxidative environment [19]. Under these conditions, nitric oxide reacts with reactive oxygen species resulting in generation of nitrites, nitrates, and most damaging peroxynitrite that cause retinal microvascular degeneration [20] by a process called nitrooxidative stress. Genetic ablation [21] and pharmacologic inhibition of endothelial nitric oxide synthase [22] have been shown to attenuate hyperoxia-induced retinal microvascular degeneration, demonstrating the importance of nitrooxidative stress in ROP.

Figure 1: The effects of oxidant stress on premature retinal vasculature. The premature retina is relatively deficient in antioxidants. Consequently, oxidant stress is more likely to induce peroxidation and nitration that is cytotoxic to retinal microvasculature. Downstream mediators of peroxidation, notably the phospholipids PAF and LPA, the nonenzymatically derived prostanoids, isoprostanes, and nitration products such as trans-arachidonic acids (TAAs), are all cytotoxic to retinovascular endothelium, causing vasoobliteration. PLD: phospholipase D; PLA2: phospholipase A2; PM: plasma membrane; PGS: PG synthase; TXS: thromboxane synthase; TSP-1: thrombospondin-1.

Lipid peroxidation of cell membranes secondary to inadequately high oxygen tension is pivotal to the pathogenesis of ROP (Figure 1). The retina is highly susceptible to lipid peroxidation, being composed of lipids with elevated levels of polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), cis-arachidonic acid, and choline phosphoglyceride. Prostanoids are synthesised from arachidonic acid by the sequential action of phospholipase A2 and cyclooxygenase, which are triggered by oxidant stress and peroxidation. The accumulation of peroxides eventually favours thromboxane A2 production, which is a potent cytotoxic agent in microvessels [23]. Inhibitors of cyclooxygenase and thromboxane A2 synthase selectively curtail oxygen-induced retinal vasoobliteration in mice [23]. Nitrative stress results in cis- to trans-isomerisation of arachidonic acid, and this was shown to contribute to retinal vascular degeneration in a mouse model of ROP [24]. Circulating levels of plasma trans-arachidonic acid are increased in oxygen-induced microvascular degeneration and are known to be secondary to nitrative stress. More specifically, trans-arachidonic acid formation has been shown to be abrogated in mice treated with nitric oxide synthase inhibitors and in mice deficient in endothelial nitric oxide synthase [22]. The endothelial cytotoxicity induced by trans-arachidonic acid results from the formation of the antiangiogenic and proapoptotic thrombospondin-1 [22] via activation of long-chain fatty acid receptor GPR40 [25].

Platelet-activating factor and lysophosphatidic acid are other lipids generated during peroxidation that act as proinflammatory mediators and contribute to microvascular injury in the retina. Platelet-activating factor is abundantly generated during oxidant stress, and its cytotoxic effects are mediated to a large extent by thromboxane A2 [26]. Along the same lines, lysophosphatidic acid is released from lysophosphatidylcholine by the action of lysophospholipase D and can play a role in retinal inflammation leading to microvascular cytotoxicity in OIR [27].

2.2.1. Antioxidant Agents in ROP

Susceptibility of the immature retina to hyperoxia-triggered oxidative stress lies in the incomplete development of its antioxidant system [28, 29]. In order to circumvent this hurdle, supplementation with antioxidants has been attempted. Vitamin E is a naturally occurring free radical scavenger that decreases lipid peroxidation and helps to maintain membrane integrity in retinal cells. Vitamin E normally occurs in its highest concentration in the retina; however, premature infants are born with approximately 10% of adult levels [30]. A few clinical trials have showed a benefit of vitamin E supplementation on the incidence and severity of ROP [31, 32], but these effects have mostly been marginal [33]. In addition, adverse effects from vitamin E supplementation have been reported, resulting in an increased risk of life-threatening infections and bleeding in the brain when injected intravenously [34]. Hence, prophylactic supplementation with vitamin E remains controversial and is currently not regularly utilized.

Vitamin C is another important aqueous phase antioxidant in cells and plasma [35]. Vitamin C has a number of important metabolic functions and is actively transported across the placenta [36]. Vitamin C concentrations in cord plasma are higher than the mother’s and, in term infants, plasma concentrations fall considerably over the first 24 hours of life [37]. Preterm infants generally have higher cord vitamin C concentrations than term infants, and concentrations then decline over a few days [38]. Most preterm infants receive vitamin C as part of a multivitamin supplement, but there are few data on which to base optimum concentrations [39]. In fact, the relation between vitamin C concentration and morbidity in very preterm infants remains controversial. Silvers et al. [40] reported that high plasma vitamin C concentrations were associated with a low antioxidant status and poor outcome in premature infants, as well as, a greater risk of developing bronchopulmonary dysplasia [41]. In contrast, Moison et al. [42] reported lower plasma vitamin C concentrations in preterm infants who developed bronchopulmonary dysplasia compared with those who did not. In a pilot observational study in very low birth weight infants, an increased risk of ROP with higher plasma vitamin C concentrations at day 7 and an increased risk of bronchopulmonary dysplasia with lower concentrations at 28 days were found [43]. Darlow et al. [44] thus hypothesized that maintaining a lower plasma vitamin C concentration in the first week of life and a higher concentration in weeks 3-4 would be accompanied by improved clinical outcome and least morbidity (chronic lung disease and ROP) in very low birth weight infants.

2.3. Inflammation and ROP

The role of inflammation in ROP has been poorly investigated. Recent evidences suggested that prenatal, perinatal, and postnatal inflammation might contribute to a gradual increase in the risk for ROP [7]. Clinical studies found that inflammatory stimuli such as bacteria in the placenta [45] and late bacteremia [46] were risk factors for developing ROP. Moreover, systemic inflammation in animal models in neonates has been shown to perturb retinal vessel development and to induce pathological features of ROP [47, 48]. Furthermore, recent studies by using genetically modified mice with a deficiency in tetrahydrobiopterin (BH4), an essential cofactor implicated in multiple metabolic process, showed that BH4 plays an essential role in maintaining the inflammatory and neurovascular retinal homeostasis [49] and is involved in the development of retinopathy [50].

Cytokines and chemokines are small proteins secreted by immune cells that play a central role in distinct inflammatory processes including the progression of ROP [51]. Cytokines such as IL-1β, TNFα, and IL-6 act as primary initiators of inflammation following infection or tissue damage [52]. Interestingly, IL-1β and TNFα produced by retinal microglia cells following exposure to hypoxia have been associated with deleterious effects in the retina [53]. In OIR model, IL-1β has been associated with retinal microvascular degeneration by inducing semaphorin3A in neurons [54], while in the choroid IL-1β causes direct cytotoxicity to choroidal blood vessels, which results in a hypoxic subretina and consequently loss of retinal pigment epithelium (RPE) and photoreceptor integrity [55].

IL-10 is generally considered an anti-inflammatory cytokine [56], capable of protecting the developing retina against ongoing inflammation. Although a study showed that IL-10 can be implicated in promoting pathological angiogenesis in an OIR mice model [57], in another study, IL-10 was able to inhibit the expression of proinflammatory cytokines on microglial cells [58]. Furthermore, in pregnant rats exposed to systemic inflammation, IL-10 treatment reduced the occurrence of brain damage in their newborn pups [59]. Infants with an IL-10 high-producer allele showed a trend (albeit not significant) towards a lower prevalence of severe ROP [60].

On the other hand, chemokines which induce chemotaxis and regulate movements of immune cells such as microglia to sites of inflammation are of special interest for pathophysiology of ROP. For instance, the chemokine interleukin-8 (IL-8) is implicated in both inflammation and pathological neovascularization in the eye [61]. In humans, higher serum concentration of IL-8 right after birth was associated with later ROP [62]; concordantly in rats, increased levels of an IL-8 homologue were detected during the peak of pathological neovascularization in a model of ROP [63].

An important player in innate immunity called RANTES is suggestive of participating in the development of ROP. Although the role of RANTES in ROP is not known, low concentrations of RANTES have been detected in the vitreous humor of patients with vasoproliferative ROP [64]; low serum levels have also been detected in infants who later developed severe ROP [65, 66]. Further investigations are needed to establish a more convincing role for RANTES in ROP.

MCP-1 is an attracting factor in a variety of immune cells and is expressed in a wide range of tissues including activated microglia in the neuroretina [67]. Preterm infants who later developed ROP tended to have higher cord serum concentrations of MCP-1 than healthy preterm infants [68]. Elevated levels of MCP-1 in the vitreous humor of patients with retinopathy have been documented [69, 70]. In animal models, MCP-1 was associated with retinal neovascularization, possibly by attracting macrophages/microglia during the ischemic phase of retinopathy [71, 72].

2.3.1. Anti-Inflammatory Agents in ROP

Few pharmacological interventions using anti-inflammatory drugs have been tried in ROP. Ketorolac is a nonsteroid anti-inflammatory drug (NSAID) derived from indomethacin that inhibits the synthesis of prostaglandins by competitively blocking the activity of COX 1 and COX 2 [73]. Upon topical application, ketorolac diminishes prostaglandin E2 concentration in aqueous humor [74]. A recent preliminary report suggests that ketorolac in the form of an ophthalmic solution can reduce the risk of developing severe ROP in very preterm newborns, without producing significant adverse side effects [75]. Interestingly, the authors showed that the incidence of severe ROP was significantly lower in very preterm newborns treated with ketorolac, when compared to the controls not receiving such treatment. These results suggest that administration of ketorolac as an ophthalmic solution might be an effective preventive strategy in patient at risk of developing severe ROP.

Dexamethasone, a steroidal anti-inflammatory agent, has also shown to reduce the incidence of ROP [76]. However, its use is associated with significant side effects [77, 78], and its efficacy in preventing ROP is controversial. A prospective randomized, controlled multicenter clinical trial to investigate the benefits of COX inhibitors for prevention of ROP is proposed (NCT02344225).

An anti-IL-1 treatment using a proprietary drug candidate labelled 101.10 (amino acid sequence: rytvela) has shown promising results in animal models. Rivera et al. demonstrated pronounced beneficial effects of 101.10 in a rodent model of ROP [54]. Interestingly, 101.10 markedly reduced retinal inflammation and preserved retinovascular architecture in the animals exposed to the OIR model. However, human clinical trials are still needed to investigate the benefits of 101.10 in preventing ROP progression.

2.3.2. Promising Therapeutic Treatments in ROP

The Caffeine for Apnea of Prematurity (CAP) trial found that caffeine was beneficial in reducing the incidence of severe ROP [79]. Mechanisms implicated in caffeine actions in reducing ROP are still unknown, yet effects on sonic hedgehog [80], matrix metalloproteinases (MMPs) [81], and oxidative stress [82] could be involved. Up to now, a prospective randomized, controlled multicenter clinical trial to investigate the benefits of caffeine on ROP is ongoing (NCT02344225).

Beneficial properties of omega-3 supplementation in ROP have been suggested. Connor et al. [83] showed that dietary omega-3 fatty acids protect against pathologic neovascularization by increasing the formation of cytoprotective and anti-inflammatory metabolites. A meta-analysis showed that long-chain polyunsaturated fatty acid supplementation of infant formulas improves infants’ visual acuity up to 12 months of age [84]. The impact of omega-3-PUFA supplementation specifically on human ROP has started to be addressed; omega-3-containing fish oil emulsion supplementation to premature infants has been shown to be associated with reduced risk for ROP [85]. At present, a trial examining the effects of omega-3 PUFA supplementation to very low birth weight infants on prevention of ROP is ongoing at the University of California (NCT02486042).

3. Diabetic Retinopathy (DR)

DR is a leading cause of vision loss in working adult population and one of the most common complications of diabetes mellitus [1, 86]. It is estimated that the prevalence of diabetes mellitus in adults (aged 20–79 years) will continue to rise in the following years [87]. Therefore, as a result of urbanization and aging population, the number of DR patients is projected to increase from 37.3 million to 56.3 million by 2030 [88].

3.1. Pathogenesis of DR

DR is a progressive disease that develops in stages, from mild nonproliferative DR to moderate severe nonproliferative DR and finally to the ultimate stage of proliferative DR, which is characterized by the growth of abnormal leaky retinal blood vessels and consequently to the detachment of the retina [89]. Throughout the different stages, patients with DR may develop diabetic macular edema (DME) which is due to the breakdown of the blood-retinal barrier (BRB) leading to a vascular leakage of fluid and plasma components at the retina [90]. The inner BRB consists of a single layer of tightly connected endothelial cells which is supported by pericytes. A preserved BRB plays a key role in supporting and maintaining the integrity of the retina and prevents the retinal vessels from leaking [91, 92]. Different factors have been shown to contribute to the BRB breakdown (Figure 2). During diabetes, high glucose levels cause an impairment of the tight junctions which become loosened, and endothelial cells and pericytes undergo apoptosis and thus allow an outward flow of plasma components, including lipid and proteins, into the vitreous. BRB leakage results in the swelling of the macula associated with improper perfusion and development of areas of retinal ischemia [92, 93]. In addition, circulating leukocytes, which become less deformable, adhere with the activated endothelial and participate in capillary occlusion and ischemia [94].

Figure 2: The role of oxidative stress and inflammation in diabetic retinopathy. Hyperglycemia activates PKC, AGEs, polyol, and hexosamine pathways which contribute to oxidative stress and mitochondrial dysfunction leading to pericyte and endothelial cell apoptosis. Upregulation of inflammatory mediators results in cell death and BRB breakdown.

Several studies have shown that vascular endothelial growth factor (VEGF) has a primordial role in the BRB breakdown. VEGF levels are increased in patients with proliferative DR and contribute to retinal vascular permeability [95]. Moreover, VEGF upregulation occurs even before the onset of hypoxia. Indeed, it has been shown that VEGF levels are increased at the early stages of DR, and this could be a consequence of an inflammatory environment characterized by the release of proinflammatory cytokines (i.e., IL-1β and IL-6) and the formation of advanced glycosylation end products (AGEs) [96, 97]. In response to hypoxia and inflammation, VEGF in association with angiopoietin 2 (Ang2) plays a key role in neovascularization and affects the integrity of preexisting vasculature [98]. VEGF antagonists attenuate vascular leakage in DR [99].

Pericyte recruitment to the microvessel wall is primordial for the formation of BRB, and this recruitment is controlled by the platelet-derived growth factor (PDGF) B and PDGF receptor β (PDGFRβ) [100]. Human and animal studies have shown that the loss of pericytes in diabetes is triggered by the activation of nuclear factor kappa B (NF-κB) with an increase in Bax expression causing pericyte apoptosis [101]. Another study has shown that high levels of glucose activated protein kinase Cδ (PKCδ) and p38α mitogen-activated protein kinases (MAPK) which increase the expression of Src homology 2 domain-containing phosphatase (SHP-1), a protein tyrosine phosphatase, resulting in the dephosphorylation of PDGFRβ to induce pericyte apoptosis and acellular capillaries in an NF-κB-independent pathway [102]. Pericyte loss is one of the main characteristics of DR with the formation of microaneurysms and acellular capillaries [103].

A new hypothesis suggests that photoreceptors in the outer retina might also play an important role in the development of diabetic retinopathy [104]. Du and collaborators have proposed that photoreceptors contribute to diabetes-induced degeneration of retinal capillaries [105]. Accordingly, diabetes causes oxidative stress in photoreceptors in part through alteration in ion flux. These abnormalities might affect intermediate cells such as Müller cells and leukocytes which result in characteristic pathologic alteration to the retinal vasculature including increased permeability and nonperfusion [104]. In support to this hypothesis, it was demonstrated that DR was less severe in a group of patients with retinitis pigmentosa [106] and in mice lacking photoreceptors [107].

3.2. Oxidative Stress and DR

The retina is rich in polyunsaturated fatty acids and characterized by a high-energy demand and an exposure to light; together, these conditions favor oxidative stress. Oxidative stress is involved in the pathogenesis of DR, and high levels of ROS have been found in patients with DR [108].

Mitochondria are the major source of ROS or reactive nitrogen species (e.g., superoxide and peroxynitrite). In presence of high glucose, oxidation of carbohydrates leads to an impairment of the electron transport chain and results in the accumulation of electrons at coenzyme Q leading to the generation of superoxide anion from oxygen, which in turn generates other ROS [109]. ROS play a role in the production of cytokines to promote inflammation and facilitate the recruitment of neutrophils to the site of inflammation [110].

ROS production induces major mitochondrial DNA damages which result in defects in transcription of electron transport chain subunits and further exacerbate ROS production [111]. In addition, ROS induce mitochondrial lipid membrane deterioration which leads to the release of cytochrome C and Bax translocation to the mitochondria. These manifestations drive apoptosis in pericytes and endothelial cells in diabetes [112]. Other sources of ROS generation are NAD(P)H oxidase (NOX), cytochrome p450, and nitric oxide synthase [113]. Superoxide anion can also be generated by the uncoupled nitric oxide synthase, and by reacting with NO generates peroxynitrite, which contributes to IR [114].

One of the metabolic manifestations of hyperglycemia that enhance oxidative stress is the polyol pathway, which corresponds to the conversion of glucose to sorbitol by aldose reductase. The aldose pathway has been suggested to contribute in the pericyte loss [115]. The accumulation of AGEs also contributes to retinal damages in DR. AGEs bind with their receptors (RAGEs) in endothelial cells, pericytes, and RPE to induce NADPH-mediated oxidative stress, which in turn induces NF-κB activation and cytokine formation [116].

The hexosamine pathway is another pathway that mediates the high glucose-driven oxidative stress and ensued complications observed in DR. Fructose 6-phosphate is deviated from the glycolytic pathway to be converted to glucosamine 6-phosphate and then to uridine diphosphate N-acetylglucosamine (UDPGlcNAc). UDPGlcNAc attaches to Ser/Thr residues leading to posttranslational modifications of proteins. The hexosamine pathway leads to the activation of plasminogen activator inhibitor-1 (PAI-1) which participates in the pathogenesis of diabetic complications [117, 118].

3.2.1. Antioxidants in DR

Given the role for oxidative stress in the genesis of DR, potential effective interventions can be achieved. Under normal conditions, endogenous antioxidant systems such as superoxide dismutase (SOD), catalase, thioredoxin reductase, glutathione reductase, glutathione peroxidase, GSH, thioredoxin, and tocopherol (vitamin E) ensure the clearance and detoxification of ROS and free radicals and prevent their accumulation. In diabetic rats, these antioxidant molecules have been found to be diminished in the retina [110]. Conversely, overexpression of mitochondrial SOD can be protective against oxidative stress in the retina under diabetes conditions [119].

A number of antioxidant compounds have been shown to be protective in diabetic retinopathy animal models; however, some clinical studies have failed to demonstrate the efficacy of these antioxidants in DR [120122]. Vitamins C and E supplementation may protect against progression of DR [123, 124]. Vitamins C and E enhance the enzymatic activities of glutathione reductase, glutathione peroxidase, and SOD and decrease pericyte dropout in diabetic rats [125]. Lipoic acid, an antioxidant which can scavenge ROS, was found to have beneficial effects in the development of DR by inhibiting capillary cell apoptosis and inhibiting oxidative damage in the retina of diabetic rats [126]. Nicanartine is a lipid-lowering compound which has antioxidant properties and was found to be effective in inhibiting pericyte loss in diabetic rats although it fails to prevent the increase in acellular capillary formation [127].

Polyphenols contained in green tea have potent antioxidant properties. Green tea supplementation increases retinal GSH levels and the enzymatic activities of catalase and SOD and decreased acellular capillaries in diabetic rats [125, 128]. Benfotiamine, a thiamine derivate (vitamin B1), has been shown to inhibit three ROS production pathways (hexosamines, PKC, and AGEs pathways) implicated in DR pathogenesis, as well as NF-κB activation, and to prevent the increase in acellular capillaries in the retina of diabetic rats [129]. Some lipid-lowering drugs such as fenofibrate have been shown to be beneficial in preventing the progression of DR, given that dyslipidemia and high circulating fatty acids are associated with increased oxidative stress in the retina. Two placebo-controlled randomized trials, the Fenofibrate Intervention and Event Lowering in Diabetes and Early Treatment Diabetic Retinopathy Study (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) eye studies have shown that fenofibrate retards the progression of DR in adult patients with type 2 diabetes [130, 131]. The mechanism by which fenofibrate exerts its protective effect remains to be determined and may involve oxidative stress, apoptosis, inflammation, and BRB preservation [132], possibly by inducing anti-inflammatory effects via sirtuin 1-dependent signaling pathway inhibition of NF-κB in human retinal endothelial cells [133].

3.3. Inflammation and DR

Inflammation has been also suggested to contribute to the development and progression of DR. Activation of Toll-like receptors by pathogen-associated molecular patterns (PAMPs) leads to the release and the nuclear translocation of NF-κB which triggers the transcription of several cytokines and chemokines such as TNFα, IL-1, IL-6, and MCP-1. In diabetes, there is an increase in the activity of TLR2 and TLR4 which participate in microvascular complications [134]. High concentrations of glucose induce the expression of TLR2 and 4 via PKCα and PKCδ, and a knockdown of both TLR2 and TLR4 reduces high glucose-induced NF-κB activation [135]. Some studies have reported that increased plasma levels of free fatty acids (FFAs) can activate TLR2 and TLR4 [136, 137]. Monocytes have been shown to respond to the presence of FFAs by increasing TLR2 and TLR4 expression resulting in increased NF-κB activation [138].

Activated microglial cells are considered to be a major source of proinflammatory cytokines in damaged tissues. In diabetic rats, an increase in the number of activated microglia in the retina was associated with increased production of inflammatory cytokines, ROS and MMPs, and a concomitant loss of neuronal cells in ganglion cell layer and inner nuclear layer [139]. Likewise, several studies have shown that DR is accompanied with an augmentation of inflammatory mediators including ICAM1, VEGF, IL-6, IL-8, and MCP-1 and angiogenic factors such as angiotensin II, angiopoietin-1, angiopoietin-2, and erythropoietin (reviewed in [140]). For instance, high levels of TNFα have been detected in the vitreous humor and serum from DR patients [141143]. It has been shown that TNFα directly contributes to BRB breakdown in DR by activating PKC-ζ/NF-κB pathway which reduces the expression of tight junction proteins claudin-5 and ZO-1 and increases endothelial cell permeability [144]. Blocking TNFα actions by using the specific TNFα inhibitor etanercept [145] disrupts NF-κB activation and inhibits BRB dysfunction.

Other than microglia, Müller cells can also contribute to the inflammatory response in DR, as these cells produce a variety of inflammatory factors [146148]. Besides, several lines of evidence have shown that the adherence of leukocytes contributes directly to the death of endothelial cells via Fas-FasL-mediated mechanism [149]. The adhesion of leukocytes to the diabetic endothelium is mediated by the intracellular adhesion molecule-1 (ICAM-1) and CD18. Neutralization of ICAM-1 and CD18 with specific antibodies attenuates leukocyte adhesion and prevents retinal endothelial cell injury [150].

3.3.1. Anti-Inflammatory Agents in DR

Despite glycemic control, blood pressure control, and lipid-lowering therapy in diabetic patients, the prevalence of DR is increasing and therapeutic approaches are limited. The development of new anti-inflammatory strategies to prevent and treat DR is being proposed. Etanercept is an FDA-approved recombinant fusion protein for the treatment of psoriasis because of its anti-TNFα properties [151]. Acting as a competitive inhibitor of TNFα, etanercept reduces leukocyte adhesion, suppresses BRB breakdown, and decreases their activation [145, 152]. Although other TNFα inhibitors such as pegsunercept have displayed efficacy in animal models, by reducing pericyte dropout and capillary degeneration [153, 154], etanercept failed to demonstrate efficacy in patients with diabetic macular edema refractory to anti-VEGF therapy [155].

Resveratrol (3,5,4-trihydroxystilbene), a naturally occurring polyphenol found in grapes and red wine, is known for its antioxidant and anti-inflammatory properties. Oral resveratrol administration (5 mg/kg) has been shown to improve glucose tolerance, decrease NF-κB activation, and lower TNFα levels in preclinical diabetic models [156]. Resveratrol also exerts its neuroprotective effects on retinal ganglion cells following intravitreal injection, improving their survival by activating sirtuin 1 [157]. Its effects have not been tested in humans with diabetes.

IL-1β [141, 158, 159] and the enzyme caspase-1 generating IL-1β are considered important targets to prevent DR [160]. Accordingly, inhibition of caspase-1 using minocycline or by blocking IL-1R1 receptor prevented diabetes-induced increase in IL-1β and degeneration of retinal capillaries [158]; interestingly, similar effects were seen with exogenous antioxidants [159, 161].

4. Age-Related Macular Degeneration (AMD)

Age-related macular degeneration (AMD) is the most common cause of vision loss in the elderly population and accounts for 8.7% of all blindness worldwide [162]. Its prevalence is increasing as a consequence of an exponential aging in the population. According to a recent systematic review and meta-analysis study [162], the projected number of people with AMD in 2020 is estimated at 196 million and approximately 288 million by 2040.

4.1. Pathogenesis of AMD

Two types of AMD are clinically recognized: dry AMD which is characterized by the formation of extracellular deposits called drusen, followed by RPE and photoreceptor death, and geographic atrophy (GA) and wet AMD which is characterized by choroidal neovascularization [163, 164]. Both forms of AMD result in loss of central vision. To date, laser photocoagulation and anti-VEGF therapy are the most common treatments for wet AMD [165]. However, mechanisms and, therefore, treatments for dry AMD remain largely elusive.

AMD is a multifactorial disorder wherein a complex interplay of genetic and environmental factors contributes to its pathogenesis (Figure 3). Multiple genes involved in lipid metabolism, complement pathway, and extracellular matrix remodeling have been found to be associated with AMD progression [6]. Furthermore, RPE senescence [166], oxidative stress [9], and immune dysfunction [167] are also involved. In the following sections, we will focus our discussion on the role of oxidative stress and inflammation in AMD.

Figure 3: Scheme summarizing the risk factors of AMD, the link between oxidative stress and inflammatory factors involved in the pathogenesis of dry AMD and the current antioxidant/anti-inflammatory therapeutic trials and recommendations. CFH: complement factor H; CFB: complement factor B; C3: complement 3; APOE: apolipoprotein E; NADH: nicotinamide adenine dinucleotide H; SOD2: superoxide dismutase 2; ROS: reactive oxygen species; MCP1: monocyte chemotactic protein 1; CX3CL1: C-X3-C motif chemokine ligand 1; IL-1β: interleukine 1 beta; iNOS: inducible nitric oxide synthase; TNFα: tumor necrosis factor alpha; NRTI: nucleoside reverse transcriptase inhibitor; RPE: retinal pigment epithelium.
4.2. Oxidative Stress and AMD

The outer retina, composed by RPE and photoreceptors, is constantly exposed to an oxidative environment, on one hand arising from the high oxygen delivery from the choroid and, on the other hand, due to constant photic bombardment. Photoreceptors are the main source of ROS in the outer retina due to light exposure and their high metabolic rate-associated oxygen consumption [168]. Outer segments of the photoreceptors which are rich in polyunsaturated fatty acid (PUFA) are sensitive to auto-oxidation and prone to oxidative stress. To maintain the balance in the proportion of oxidant species, photoreceptors have efficient antioxidant defense mechanisms such as SOD1 and SOD2 which transform superoxide (O2) to hydrogen peroxide (H2O2) and superoxide (O2), and glutathione peroxidase (GPx), and/or glutathione reductase (GR) and catalase which convert O2 into H2O and O2 [9]. In addition to its enzymatic defenses, photoreceptors count on its interlink with the multifunctional RPE cells. RPE cells ensure the correct functioning of the outer retina, for instance, by maintaining the structure of the external blood-retinal barrier, secreting growth factors, absorbing excess of light, participating in the photoreceptor outer segment phagocytosis, and cycling of retinoids. RPE daily phagocytes the oxidized membranes of outer segments, contributing in this way, to decrease the oxidative stress in photoreceptors. However, the degradation products of these phagocytized outer segments generate lipofuscin in RPE cells. Due to its molecular composition, lipofuscin is photoreactive and thus increases the susceptibility of RPE to light damage with aging. In addition, phagocytosis process may also generate high level of H2O2 through NADPH oxidase activity and peroxisomal-oxidation, which exposes the RPE to the risk of oxidative stress [169, 170]. Interestingly, photoreceptors and RPE cells can modulate oxidative damage induced by oxidized cellular components with an autophagy process involving activation of p62/Nrf2 pathway [171, 172].

Many factors such as aging, environmental stress, smoke cigarette, and genetic factors are involved in the development of AMD (Figure 3). These elements may also contribute to increase the production of prooxidants and reduce antioxidant defenses. For instance, cigarette smoke contains high level of ROS [173], which has demonstrated to reduce the levels of endogenous antioxidants, such as glutathione, cysteine [174], and SOD [175].

Mutations of genes encoding proteins involved in the mitochondrial respiratory chain (NADH complex, cytochrome complex) have also been shown to lead to pathological oxidative stress increasing the risk for AMD [176]. A similar paradigm also applies to complement factor H defense protein (CFH) [177], and for polymorphisms of NADH dehydrogenase and SOD2 [178].

4.2.1. Antioxidant Agents in AMD

A number of antioxidants have been suggested to confer protection of RPE and photoreceptors. This is the case for carotenoids (lutein, zeaxanthin, and mesozeazanthin) which act as scavengers of ROS [179, 180], alpha-lipoic acid which enhances GPx activity [181], curcumin which augments the expression of the cytoprotective and antioxidant enzyme heme oxygenase-1 in RPE cells, and caffeic acid phenethyl ester (CAPE) which confers photoreceptor protection against H2O2-mediated cell death by increasing the expression of heme oxygenase-1 and supressing NF-κB activation [182, 183]. However, despite the promising effects of these antioxidant molecules in animal models, two large multicenter investigations, the Age-Related Eye Disease Study (AREDS and AREDS2), failed to show convincing efficacy of these types of supplementation for AMD [184, 185].

4.3. Inflammation and AMD

RPE cells exposed to oxidative stress can elicit inflammation [186, 187]. The accumulation of lipids, particularly in the form of drusen, is associated with a chronic inflammation. RPE cell function is crucial for retinal homeostasis, and loss of its integrity and/or function increases the risk of progression of AMD. When oxidative stress exceeds the antioxidant defense capacities, RPE cells release inflammatory chemokines such as MCP-1 and fractalkine (CX3CL1) playing a key role in microglia recruitment in subretinal space [188]. Physiologically, microglial cells are not present in the outer retina; however, their migration increases upon damage to the photoreceptors and/or RPE cells and also when insoluble debris from phagocytosis are accumulated in RPE cells and subretinal space during aging. These oxidized deposits containing advanced glycation end products (AGEs) and lipoxidation end products (ALEs) are recognized and cleared by macrophages [189, 190]. When oxidative stress is sustained, monocytes are recruited from blood circulation. These activated immune cells present in the subretinal space release IL-1β, iNOS, and TNFα, which in turn induce ROS production in RPE through NADPH oxidase activation and increase oxidative damages [191, 192].

Even more, proinflammatory cytokines secreted by infiltrating lymphocytes or macrophages exert senescence and dysfunction to RPE [193, 194]. RPE senescent cells in turn may secrete a range of pleiotropic factors that recruit inflammatory cells and exacerbate inflammation and damage to the outer retina [195]. Accordingly, accumulation of microglia in the outer retina has been associated with RPE and photoreceptor damage in AMD [196, 197]. All these evidences highlight the interwoven relationship between oxidative stress and inflammation in the development of AMD.

4.3.1. Anti-Inflammatory Agents in AMD

Robust evidence suggests that modulation of inflammation could attenuate AMD progression. Rapamycin (sirolimus), an mTOR inhibitor used for its immunosuppressive effect in organ transplantation, has been proposed for AMD therapy. Sirolimus has been shown to preserve RPE and photoreceptors from cell death in a mouse model of retinal degeneration [198]. However, in a phase II clinical trial, the subconjunctival or intravitreal injections of sirolimus every 3 months for 24 months did not reduce geographic atrophy progression in the patients with AMD [199, 200].

Targeting the complement system provides another strategy to tackle inflammation and reduce AMD progression [201]. Encouraging results were observed with the humanized anti-factor D monoclonal antibody complement inhibitor, lampalizumab (Roche Inc.). These results from phase II clinical trial showed a 24% reduction in geographic atrophy after monthly intravitreal injections for 18 months [202]. Along the same lines, the C3 inhibitor APL-2 (Apellis Pharmaceuticals) and the anti-C5 monoclonal antibody LFG316 (Alcon) are currently in phase II clinical trial [203].

In the perspective of targeting inflammation to treat AMD, NLRP3-inflammasome, a key component of the innate immunity, has shown to play an important role in the development of AMD [204]. A number of studies have shown a strong association in the activation of the NLRP3-inflammasome and the development of geographic atrophy in patients with AMD [205, 206]. Interestingly, nucleoside reverse transcriptase inhibitors (NRTIs), administered for human immunodeficiency virus (HIV) patients, have proven to block P2X7-dependent NLRP3 inflammasome activation [207]; currently, clinical trials are under preparation using NRTIs for AMD patients.

5. Conclusion

Oxidative stress and inflammation play an important role in the development of IRs. A better understanding of the mechanisms implicated in early stages should identify new targets that allow the development of new therapeutic approaches. Along these lines, a more profound elucidation of the complex interplay of oxidative stress and inflammatory mediators is required. Although, several epidemiological and animal studies have revealed beneficial effects of antioxidants, results from clinical trials have been at best tepid, possibly because of the complexity in targeting oxidants and more importantly the absence of strategies to deal with biologically active stable product peroxidation such as isoprostanes, neuroprostanes, and isofurans [208]. Specific anti-inflammatory approaches may turn out to be more promising.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this article.

Acknowledgments

Sylvain Chemtob holds a Canada Research Chair (Translational Research in Vision) and the Leopoldine Wolfe Chair in translational research in age-related macular degeneration. Work related to ROP has been supported by Canadian Institutes of Health Research (Sylvain Chemtob).

References

  1. J. H. Kempen, B. J. O’Colmain, C. Leske et al., “The prevalence of diabetic retinopathy among adults in the United States,” Archives of Ophthalmology, vol. 122, pp. 552–563, 2004. View at Publisher · View at Google Scholar · View at Scopus
  2. C. Gilbert, J. Rahi, M. Eckstein, J. O'Sullivan, and A. Foster, “Retinopathy of prematurity in middle-income countries,” Lancet, vol. 350, no. 9070, pp. 12–14, 1997. View at Publisher · View at Google Scholar · View at Scopus
  3. P. Sapieha, D. Hamel, Z. Shao et al., “Proliferative retinopathies: angiogenesis that blinds,” The International Journal of Biochemistry & Cell Biology, vol. 42, no. 1, pp. 5–12, 2010. View at Publisher · View at Google Scholar · View at Scopus
  4. A. B. Fulton, R. M. Hansen, A. Moskowitz, and J. D. Akula, “The neurovascular retina in retinopathy of prematurity,” Progress in Retinal and Eye Research, vol. 28, no. 6, pp. 452–482, 2009. View at Publisher · View at Google Scholar · View at Scopus
  5. Y. Wu, L. Tang, and B. Chen, “Oxidative stress: implications for the development of diabetic retinopathy and antioxidant therapeutic perspectives,” Oxidative Medicine and Cellular Longevity, vol. 2014, Article ID 752387, 12 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus
  6. P. X. Shaw, T. Stiles, C. Douglas et al., “Oxidative stress, innate immunity, and age-related macular degeneration,” AIMS Molecular Science, vol. 3, no. 2, pp. 196–221, 2016. View at Publisher · View at Google Scholar
  7. J. Lee and O. Dammann, “Perinatal infection, inflammation, and retinopathy of prematurity,” Seminars in Fetal & Neonatal Medicine, vol. 17, no. 1, pp. 26–29, 2012. View at Publisher · View at Google Scholar · View at Scopus
  8. F. Semeraro, A. Cancarini, R. dell'Omo, S. Rezzola, M. R. Romano, and C. Costagliola, “Diabetic retinopathy: vascular and inflammatory disease,” Journal of Diabetes Research, vol. 2015, Article ID 582060, 16 pages, 2015. View at Publisher · View at Google Scholar · View at Scopus
  9. S. G. Jarrett and M. E. Boulton, “Consequences of oxidative stress in age-related macular degeneration,” Molecular Aspects of Medicine, vol. 33, no. 4, pp. 399–417, 2012. View at Publisher · View at Google Scholar · View at Scopus
  10. K. Haskins, B. Bradley, K. Powers et al., “Oxidative stress in type 1 diabetes,” Annals of the New York Academy of Sciences, vol. 1005, no. 1, pp. 43–54, 2003. View at Publisher · View at Google Scholar · View at Scopus
  11. H. Wang, S. X. Zhang, and M. E. Hartnett, “Signaling pathways triggered by oxidative stress that mediate features of severe retinopathy of prematurity,” JAMA Ophthalmology, vol. 131, no. 1, pp. 80–85, 2013. View at Publisher · View at Google Scholar · View at Scopus
  12. R. A. Kowluru, J. Tang, and T. S. Kern, “Abnormalities of retinal metabolism in diabetes and experimental galactosemia: VII. Effect of long-term administration of antioxidants on the development of retinopathy,” Diabetes, vol. 50, no. 8, pp. 1938–1942, 2001. View at Publisher · View at Google Scholar
  13. M. Brownlee, “The pathobiology of diabetic complications: a unifying mechanism,” Diabetes, vol. 54, no. 6, pp. 1615–1625, 2005. View at Publisher · View at Google Scholar · View at Scopus
  14. H. Blencowe, J. E. Lawn, T. Vazquez, A. Fielder, and C. Gilbert, “Preterm-associated visual impairment and estimates of retinopathy of prematurity at regional and global levels for 2010,” Pediatric Research, vol. 74, Supplement 1, pp. 35–49, 2013. View at Publisher · View at Google Scholar · View at Scopus
  15. K. Gergely and A. Gerinec, “Retinopathy of prematurity--epidemics, incidence, prevalence, blindness,” Bratislavske Lekarske Listy, vol. 111, no. 9, pp. 514–517, 2010. View at Google Scholar
  16. A. Hellström, E. Engström, A.-L. Hård et al., “Postnatal serum insulin-like growth factor I deficiency is associated with retinopathy of prematurity and other complications of premature birth,” Pediatrics, vol. 112, no. 5, pp. 1016–1020, 2003. View at Publisher · View at Google Scholar · View at Scopus
  17. J. C. Rivera, P. Sapieha, J. S. Joyal et al., “Understanding retinopathy of prematurity: update on pathogenesis,” Neonatology, vol. 100, no. 4, pp. 343–353, 2011. View at Publisher · View at Google Scholar · View at Scopus
  18. G. Holmstrom, A. Hellstrom, P. Jakobsson, P. Lundgren, K. Tornqvist, and A. Wallin, “Evaluation of new guidelines for ROP screening in Sweden using SWEDROP - a national quality register,” Acta Ophthalmologica, vol. 93, no. 3, pp. 265–268, 2015. View at Publisher · View at Google Scholar · View at Scopus
  19. M. H. Beauchamp, F. Sennlaub, G. Speranza et al., “Redox-dependent effects of nitric oxide on microvascular integrity in oxygen-induced retinopathy,” Free Radical Biology & Medicine, vol. 37, no. 11, pp. 1885–1894, 2004. View at Publisher · View at Google Scholar · View at Scopus
  20. X. Gu, A. B. El-Remessy, S. E. Brooks, M. Al-Shabrawey, N. T. Tsai, and R. B. Caldwell, “Hyperoxia induces retinal vascular endothelial cell apoptosis through formation of peroxynitrite,” American Journal of Physiology Cell Physiology, vol. 285, no. 3, pp. C546–C554, 2003. View at Publisher · View at Google Scholar
  21. S. E. Brooks, X. Gu, S. Samuel et al., “Reduced severity of oxygen-induced retinopathy in eNOS-deficient mice,” Investigative Ophthalmology & Visual Science, vol. 42, no. 1, pp. 222–228, 2001. View at Google Scholar
  22. E. Kermorvant-Duchemin, F. Sennlaub, M. Sirinyan et al., “Trans-arachidonic acids generated during nitrative stress induce a thrombospondin-1-dependent microvascular degeneration,” Nature Medicine, vol. 11, no. 12, pp. 1339–1345, 2005. View at Publisher · View at Google Scholar · View at Scopus
  23. M. H. Beauchamp, A. K. Martinez-Bermudez, F. Gobeil Jr et al., “Role of thromboxane in retinal microvascular degeneration in oxygen-induced retinopathy,” Journal of Applied Physiology, vol. 90, no. 6, pp. 2279–2288, 2001. View at Google Scholar
  24. M. Balazy and S. Chemtob, “Trans-arachidonic acids: new mediators of nitro-oxidative stress,” Pharmacology & Therapeutics, vol. 119, no. 3, pp. 275–290, 2008. View at Publisher · View at Google Scholar · View at Scopus
  25. J. C. Honore, A. Kooli, D. Hamel et al., “Fatty acid receptor Gpr40 mediates neuromicrovascular degeneration induced by transarachidonic acids in rodents,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 33, no. 5, pp. 954–961, 2013. View at Publisher · View at Google Scholar · View at Scopus
  26. M. H. Beauchamp, A. M. Marrache, X. Hou et al., “Platelet-activating factor in vasoobliteration of oxygen-induced retinopathy,” Investigative Ophthalmology & Visual Science, vol. 43, no. 10, pp. 3327–3337, 2002. View at Google Scholar
  27. S. Brault, F. Gobeil Jr., A. Fortier et al., “Lysophosphatidic acid induces endothelial cell death by modulating the redox environment,” AJP: Regulatory, Integrative and Comparative Physiology, vol. 292, pp. R1174–R1183, 2007. View at Publisher · View at Google Scholar · View at Scopus
  28. S. Perrone, S. Negro, M. L. Tataranno, and G. Buonocore, “Oxidative stress and antioxidant strategies in newborns,” The Journal of Maternal-Fetal & Neonatal Medicine, vol. 23, Supplement 3, pp. 63–65, 2010. View at Publisher · View at Google Scholar · View at Scopus
  29. S. Y. Shim and H. S. Kim, “Oxidative stress and the antioxidant enzyme system in the developing brain,” Korean Journal of Pediatrics, vol. 56, pp. 107–111, 2013. View at Publisher · View at Google Scholar · View at Scopus
  30. J. C. Nielsen, M. I. Naash, and R. E. Anderson, “The regional distribution of vitamins E and C in mature and premature human retinas,” Investigative Ophthalmology & Visual Science, vol. 29, no. 1, pp. 22–26, 1988. View at Google Scholar
  31. H. M. Hittner, A. J. Rudolph, and F. L. Kretzer, “Suppression of severe retinopathy of prematurity with vitamin E supplementation. Ultrastructural mechanism of clinical efficacy,” Ophthalmology, vol. 91, no. 12, pp. 1512–1523, 1984. View at Publisher · View at Google Scholar
  32. T. N. Raju, P. Langenberg, V. Bhutani, and G. E. Quinn, “Vitamin E prophylaxis to reduce retinopathy of prematurity: a reappraisal of published trials,” The Journal of Pediatrics, vol. 131, no. 6, pp. 844–850, 1997. View at Publisher · View at Google Scholar · View at Scopus
  33. D. P. Muller, “Vitamin E therapy in retinopathy of prematurity,” Eye, vol. 6, no. 2, pp. 221–225, 1992. View at Publisher · View at Google Scholar · View at Scopus
  34. L. P. Brion, E. F. Bell, and T. S. Raghuveer, “Vitamin E supplementation for prevention of morbidity and mortality in preterm infants,” Cochrane Database of Systematic Reviews, no. 4, article CD003665, 2003. View at Publisher · View at Google Scholar
  35. B. Halliwell, “Vitamin C: antioxidant or pro-oxidant in vivo?” Free Radical Research, vol. 25, no. 5, pp. 439–454, 1996. View at Publisher · View at Google Scholar
  36. M. L. Streeter and P. Rosso, “Transport mechanisms for ascorbic acid in the human placenta,” The American Journal of Clinical Nutrition, vol. 34, no. 9, pp. 1706–1711, 1981. View at Google Scholar
  37. B. M. Hamil, B. Munks, E. Z. Moyer, M. Kaucher, and H. H. Williams, “Vitamin C in the blood and urine of the newborn and in the cord and maternal blood,” American Journal of Diseases of Children, vol. 74, no. 4, pp. 417–433, 1947. View at Publisher · View at Google Scholar
  38. T. M. R. N. Berger, M. E. Avery, and B. Frei, “Vitamin C in premature and full-term human neonates,” Redox Report, vol. 2, no. 4, pp. 257–262, 1996. View at Publisher · View at Google Scholar
  39. “Nutrient needs and feeding of premature infants. Nutrition Committee, Canadian Paediatric Society,” CMAJ: Canadian Medical Association Journal, vol. 152, no. 11, pp. 1765–1785, 1995.
  40. K. M. Silvers, A. T. Gibson, and H. J. Powers, “High plasma vitamin C concentrations at birth associated with low antioxidant status and poor outcome in premature infants,” Archives of Disease in Childhood Fetal and Neonatal Edition, vol. 71, no. 1, pp. F40–F44, 1994. View at Publisher · View at Google Scholar
  41. K. M. Silvers, A. T. Gibson, J. M. Russell, and H. J. Powers, “Antioxidant activity, packed cell transfusions, and outcome in premature infants,” Archives of Disease in Childhood Fetal and Neonatal Edition, vol. 78, no. 3, pp. F214–F219, 1998. View at Publisher · View at Google Scholar
  42. R. M. Moison, D. Vanzoerengrobben, A. A. Haasnoot, and H. Berger, “Early biochemical detection of bronchopulmonary dysplasia (BPD) in preterm babies,” Pediatric Research, vol. 37, no. 4, pp. A343–A343, 1995. View at Google Scholar
  43. K. B. Sluis, T. Inder, and A. Wilkinson, “Plasma and endotracheal vitamin C concentrations in premature infants: relationship to outcome measures,” in Proceedings of the 14th Annual Congress of the Australian Perinatal Society, 1996.
  44. B. A. Darlow, H. Buss, F. McGill, L. Fletcher, P. Graham, and C. C. Winterbourn, “Vitamin C supplementation in very preterm infants: a randomised controlled trial,” Archives of Disease in Childhood - Fetal and Neonatal Edition, vol. 90, pp. F117–F122, 2005. View at Publisher · View at Google Scholar · View at Scopus
  45. M. L. Chen, E. N. Allred, J. L. Hecht et al., “Placenta microbiology and histology, and the risk for severe retinopathy of prematurity,” Investigative Opthalmology & Visual Science, vol. 52, pp. 7052–7058, 2011. View at Publisher · View at Google Scholar · View at Scopus
  46. K. W. Tolsma, E. N. Allred, M. L. Chen, J. Duker, A. Leviton, and O. Dammann, “Neonatal bacteremia and retinopathy of prematurity: the ELGAN study,” Archives of Ophthalmology, vol. 129, pp. 1555–1563, 2011. View at Publisher · View at Google Scholar · View at Scopus
  47. S. Tremblay, K. Miloudi, S. Chaychi et al., “Systemic inflammation perturbs developmental retinal angiogenesis and neuroretinal function,” Investigative Opthalmology & Visual Science, vol. 54, pp. 8125–8139, 2013. View at Publisher · View at Google Scholar
  48. H. K. Hong, H. J. Lee, J. H. Ko et al., “Neonatal systemic inflammation in rats alters retinal vessel development and simulates pathologic features of retinopathy of prematurity,” Journal of Neuroinflammation, vol. 11, p. 87, 2014. View at Publisher · View at Google Scholar · View at Scopus
  49. J. C. Rivera, B. Noueihed, A. Madaan et al., “Tetrahydrobiopterin (BH4) deficiency is associated with augmented inflammation and microvascular degeneration in the retina,” Journal of Neuroinflammation, vol. 14, no. 1, p. 181, 2017. View at Publisher · View at Google Scholar
  50. K. S. Edgar, N. Matesanz, T. A. Gardiner, Z. S. Katusic, and D. M. McDonald, “Hyperoxia depletes (6R)-5,6,7,8-tetrahydrobiopterin levels in the neonatal retina: implications for nitric oxide synthase function in retinopathy,” The American Journal of Pathology, vol. 185, no. 6, pp. 1769–1782, 2015. View at Publisher · View at Google Scholar · View at Scopus
  51. J. C. Rivera, M. Holm, D. Austeng et al., “Retinopathy of prematurity: inflammation, choroidal degeneration, and novel promising therapeutic strategies,” Journal of Neuroinflammation, vol. 14, no. 1, p. 165, 2017. View at Publisher · View at Google Scholar
  52. C. Gabay and I. Kushner, “Acute-phase proteins and other systemic responses to inflammation,” New England Journal of Medicine, vol. 340, no. 6, pp. 448–454, 1999. View at Publisher · View at Google Scholar · View at Scopus
  53. V. Sivakumar, W. S. Foulds, C. D. Luu, E. A. Ling, and C. Kaur, “Retinal ganglion cell death is induced by microglia derived pro-inflammatory cytokines in the hypoxic neonatal retina,” The Journal of Pathology, vol. 224, no. 2, pp. 245–260, 2011. View at Publisher · View at Google Scholar · View at Scopus
  54. J. C. Rivera, N. Sitaras, B. Noueihed et al., “Microglia and interleukin-1beta in ischemic retinopathy elicit microvascular degeneration through neuronal semaphorin-3A,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 33, no. 8, pp. 1881–1891, 2013. View at Publisher · View at Google Scholar · View at Scopus
  55. T. E. Zhou, J. C. Rivera, V. K. Bhosle et al., “Choroidal involution is associated with a progressive degeneration of the outer retinal function in a model of retinopathy of prematurity,” The American Journal of Pathology, vol. 186, no. 12, pp. 3100–3116, 2016. View at Publisher · View at Google Scholar · View at Scopus
  56. S. M. Opal and V. A. DePalo, “Anti-inflammatory cytokines,” Chest, vol. 117, no. 4, pp. 1162–1172, 2000. View at Publisher · View at Google Scholar
  57. D. S. Dace, A. A. Khan, J. Kelly, and R. S. Apte, “Interleukin-10 promotes pathological angiogenesis by regulating macrophage response to hypoxia during development,” PLoS One, vol. 3, no. 10, article e3381, 2008. View at Publisher · View at Google Scholar · View at Scopus
  58. S. G. Kremlev and C. Palmer, “Interleukin-10 inhibits endotoxin-induced pro-inflammatory cytokines in microglial cell cultures,” Journal of Neuroimmunology, vol. 162, no. 1-2, pp. 71–80, 2005. View at Publisher · View at Google Scholar · View at Scopus
  59. S. Rodts-Palenik, J. Wyatt-Ashmead, Y. Pang et al., “Maternal infection-induced white matter injury is reduced by treatment with interleukin-10,” American Journal of Obstetrics and Gynecology, vol. 191, no. 4, pp. 1387–1392, 2004. View at Publisher · View at Google Scholar · View at Scopus
  60. M. Dordelmann, J. Kerk, F. Dressler et al., “Interleukin-10 high producer allele and ultrasound-defined periventricular white matter abnormalities in preterm infants: a preliminary study,” Neuropediatrics, vol. 37, no. 03, pp. 130–136, 2006. View at Publisher · View at Google Scholar · View at Scopus
  61. H. Ghasemi, T. Ghazanfari, R. Yaraee, S. Faghihzadeh, and Z. M. Hassan, “Roles of IL-8 in ocular inflammations: a review,” Ocular Immunology and Inflammation, vol. 19, no. 6, pp. 401–412, 2011. View at Publisher · View at Google Scholar · View at Scopus
  62. R. C. Silveira, J. B. Fortes Filho, and R. S. Procianoy, “Assessment of the contribution of cytokine plasma levels to detect retinopathy of prematurity in very low birth weight infants,” Investigative Ophthalmology & Visual Science, vol. 52, no. 3, pp. 1297–1301, 2011. View at Publisher · View at Google Scholar · View at Scopus
  63. M. R. Powers, M. H. Davies, and J. P. Eubanks, “Increased expression of chemokine KC, an interleukin-8 homologue, in a model of oxygen-induced retinopathy,” Current Eye Research, vol. 30, no. 4, pp. 299–307, 2005. View at Publisher · View at Google Scholar · View at Scopus
  64. T. Sato, S. Kusaka, H. Shimojo, and T. Fujikado, “Simultaneous analyses of vitreous levels of 27 cytokines in eyes with retinopathy of prematurity,” Ophthalmology, vol. 116, no. 11, pp. 2165–2169, 2009. View at Publisher · View at Google Scholar · View at Scopus
  65. G. Hellgren, K. Willett, E. Engstrom et al., “Proliferative retinopathy is associated with impaired increase in BDNF and RANTES expression levels after preterm birth,” Neonatology, vol. 98, no. 4, pp. 409–418, 2010. View at Publisher · View at Google Scholar · View at Scopus
  66. B. G. Sood, A. Madan, S. Saha et al., “Perinatal systemic inflammatory response syndrome and retinopathy of prematurity,” Pediatric Research, vol. 67, no. 4, pp. 394–400, 2010. View at Publisher · View at Google Scholar · View at Scopus
  67. Y. Yao and S. E. Tsirka, “Monocyte chemoattractant protein-1 and the blood-brain barrier,” Cellular and Molecular Life Sciences, vol. 71, no. 4, pp. 683–697, 2014. View at Publisher · View at Google Scholar · View at Scopus
  68. H. Yu, L. Yuan, Y. Zou et al., “Serum concentrations of cytokines in infants with retinopathy of prematurity,” APMIS, vol. 122, no. 9, pp. 818–823, 2014. View at Publisher · View at Google Scholar · View at Scopus
  69. T. Yoshimura, K. H. Sonoda, M. Sugahara et al., “Comprehensive analysis of inflammatory immune mediators in vitreoretinal diseases,” PLoS One, vol. 4, no. 12, article e8158, 2009. View at Publisher · View at Google Scholar · View at Scopus
  70. S. Rusnak, J. Vrzalova, M. Sobotova, L. Hecova, R. Ricarova, and O. Topolcan, “The measurement of intraocular biomarkers in various stages of proliferative diabetic retinopathy using multiplex xMAP technology,” Journal of Ophthalmology, vol. 2015, Article ID 424783, 6 pages, 2015. View at Publisher · View at Google Scholar · View at Scopus
  71. S. Yoshida, A. Yoshida, T. Ishibashi, S. G. Elner, and V. M. Elner, “Role of MCP-1 and MIP-1alpha in retinal neovascularization during postischemic inflammation in a mouse model of retinal neovascularization,” Journal of Leukocyte Biology, vol. 73, no. 1, pp. 137–144, 2003. View at Publisher · View at Google Scholar · View at Scopus
  72. S. Yoshida, A. Yoshida, and T. Ishibashi, “Induction of IL-8, MCP-1, and bFGF by TNF-alpha in retinal glial cells: implications for retinal neovascularization during post-ischemic inflammation,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 242, no. 5, pp. 409–413, 2004. View at Publisher · View at Google Scholar · View at Scopus
  73. L. D. Waterbury, D. Silliman, and T. Jolas, “Comparison of cyclooxygenase inhibitory activity and ocular anti-inflammatory effects of ketorolac tromethamine and bromfenac sodium,” Current Medical Research and Opinion, vol. 22, no. 6, pp. 1133–1140, 2006. View at Publisher · View at Google Scholar · View at Scopus
  74. U. Acar, D. E. Acar, C. Tanriverdi et al., “Prostaglandin E2 levels of aqueous and vitreous humor in ketorolac 0.4% and nepafenac 0.1% administered healthy rabbits,” Ocular Immunology and Inflammation, vol. 25, no. 3, pp. 323–327, 2017. View at Publisher · View at Google Scholar · View at Scopus
  75. M. Avila-Vazquez, R. Maffrand, M. Sosa et al., “Treatment of retinopathy of prematurity with topical ketorolac tromethamine: a preliminary study,” BMC Pediatrics, vol. 4, no. 1, p. 15, 2004. View at Publisher · View at Google Scholar · View at Scopus
  76. R. D. Higgins, A. L. Mendelsohn, M. J. DeFeo, R. Ucsel, and K. D. Hendricks-Munoz, “Antenatal dexamethasone and decreased severity of retinopathy of prematurity,” Archives of Ophthalmology, vol. 116, no. 5, pp. 601–605, 1998. View at Publisher · View at Google Scholar
  77. L. W. Doyle, R. A. Ehrenkranz, and H. L. Halliday, “Dexamethasone treatment in the first week of life for preventing bronchopulmonary dysplasia in preterm infants: a systematic review,” Neonatology, vol. 98, no. 3, pp. 217–224, 2010. View at Publisher · View at Google Scholar · View at Scopus
  78. A. R. Stark, W. A. Carlo, J. E. Tyson et al., “Adverse effects of early dexamethasone treatment in extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network,” New England Journal of Medicine, vol. 344, no. 2, pp. 95–101, 2001. View at Publisher · View at Google Scholar · View at Scopus
  79. B. Schmidt, R. S. Roberts, P. Davis et al., “Long-term effects of caffeine therapy for apnea of prematurity,” New England Journal of Medicine, vol. 357, no. 19, pp. 1893–1902, 2007. View at Publisher · View at Google Scholar · View at Scopus
  80. N. Sahir, P. Evrard, and P. Gressens, “Caffeine induces sonic hedgehog gene expression in cultured astrocytes and neurons,” Journal of Molecular Neuroscience, vol. 24, no. 2, pp. 201–206, 2004. View at Publisher · View at Google Scholar · View at Scopus
  81. W. H. Liu and L. S. Chang, “Caffeine induces matrix metalloproteinase-2 (MMP-2) and MMP-9 down-regulation in human leukemia U937 cells via Ca2+/ROS-mediated suppression of ERK/c-fos pathway and activation of p38 MAPK/c-jun pathway,” Journal of Cellular Physiology, vol. 224, no. 3, pp. 775–785, 2010. View at Publisher · View at Google Scholar · View at Scopus
  82. S. D. Varma, K. R. Hegde, and S. Kovtun, “Oxidative stress in lens in vivo: inhibitory effect of caffeine. A preliminary report,” Molecular Vision, vol. 16, pp. 501–505, 2010. View at Google Scholar
  83. K. M. Connor, J. P. SanGiovanni, C. Lofqvist et al., “Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis,” Nature Medicine, vol. 13, no. 7, pp. 868–873, 2007. View at Publisher · View at Google Scholar · View at Scopus
  84. A. Qawasmi, A. Landeros-Weisenberger, and M. H. Bloch, “Meta-analysis of LCPUFA supplementation of infant formula and visual acuity,” Pediatrics, vol. 131, no. 1, pp. e262–e272, 2013. View at Publisher · View at Google Scholar · View at Scopus
  85. D. Pawlik, R. Lauterbach, M. Walczak, J. Hurkala, and M. P. Sherman, “Fish-oil fat emulsion supplementation reduces the risk of retinopathy in very low birth weight infants: a prospective, randomized study,” JPEN Journal of Parenteral and Enteral Nutrition, vol. 38, no. 6, pp. 711–716, 2014. View at Publisher · View at Google Scholar · View at Scopus
  86. N. Cheung, P. Mitchell, and T. Y. Wong, “Diabetic retinopathy,” Lancet, vol. 376, no. 9735, pp. 124–136, 2010. View at Publisher · View at Google Scholar · View at Scopus
  87. K. Ogurtsova, J. D. da Rocha Fernandes, Y. Huang et al., “Global estimates for the prevalence of diabetes for 2015 and 2040,” Diabetes Research and Clinical Practice, vol. 128, pp. 40–50, 2017. View at Publisher · View at Google Scholar
  88. Y. Zheng, M. He, and N. Congdon, “The worldwide epidemic of diabetic retinopathy,” Indian Journal of Ophthalmology, vol. 60, no. 5, pp. 428–431, 2012. View at Publisher · View at Google Scholar · View at Scopus
  89. A. W. Stitt, T. M. Curtis, M. Chen et al., “The progress in understanding and treatment of diabetic retinopathy,” Progress in Retinal and Eye Research, vol. 51, pp. 156–186, 2016. View at Publisher · View at Google Scholar · View at Scopus
  90. X. Zhang, H. Zeng, S. Bao, N. Wang, and M. C. Gillies, “Diabetic macular edema: new concepts in patho-physiology and treatment,” Cell & Bioscience, vol. 4, no. 1, p. 27, 2014. View at Publisher · View at Google Scholar · View at Scopus
  91. G. Bergers and S. Song, “The role of pericytes in blood-vessel formation and maintenance,” Neuro-Oncology, vol. 7, no. 4, pp. 452–464, 2005. View at Publisher · View at Google Scholar · View at Scopus
  92. N. S. Harhaj and D. A. Antonetti, “Regulation of tight junctions and loss of barrier function in pathophysiology,” The International Journal of Biochemistry & Cell Biology, vol. 36, no. 7, pp. 1206–1237, 2004. View at Publisher · View at Google Scholar · View at Scopus
  93. J. Cunha-Vaz, R. Bernardes, and C. Lobo, “Blood-retinal barrier,” European Journal of Ophthalmology, vol. 21, Supplement 6, pp. S3–S9, 2011. View at Publisher · View at Google Scholar · View at Scopus
  94. A. M. Joussen, V. Poulaki, M. L. Le et al., “A central role for inflammation in the pathogenesis of diabetic retinopathy,” The FASEB Journal, vol. 18, no. 12, pp. 1450–1452, 2004. View at Publisher · View at Google Scholar · View at Scopus
  95. L. P. Aiello, R. L. Avery, P. G. Arrigg et al., “Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders,” New England Journal of Medicine, vol. 331, no. 22, pp. 1480–1487, 1994. View at Publisher · View at Google Scholar · View at Scopus
  96. N. Ferrara, “Vascular endothelial growth factor: basic science and clinical progress,” Endocrine Reviews, vol. 25, no. 4, pp. 581–611, 2004. View at Publisher · View at Google Scholar · View at Scopus
  97. T. Y. Wong, C. M. Cheung, M. Larsen, S. Sharma, and R. Simo, “Diabetic retinopathy,” Nature Reviews Disease Primers, vol. 2, article 16012, 2016. View at Publisher · View at Google Scholar · View at Scopus
  98. H. Oh, H. Takagi, K. Suzuma, A. Otani, M. Matsumura, and Y. Honda, “Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells,” Journal of Biological Chemistry, vol. 274, no. 22, pp. 15732–15739, 1999. View at Publisher · View at Google Scholar · View at Scopus
  99. N. Ferrara, H. P. Gerber, and J. LeCouter, “The biology of VEGF and its receptors,” Nature Medicine, vol. 9, no. 6, pp. 669–676, 2003. View at Publisher · View at Google Scholar · View at Scopus
  100. P. Lindblom, H. Gerhardt, S. Liebner et al., “Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall,” Genes & Development, vol. 17, no. 15, pp. 1835–1840, 2003. View at Publisher · View at Google Scholar · View at Scopus
  101. G. Romeo, W. H. Liu, V. Asnaghi, T. S. Kern, and M. Lorenzi, “Activation of nuclear factor-kappaB induced by diabetes and high glucose regulates a proapoptotic program in retinal pericytes,” Diabetes, vol. 51, no. 7, pp. 2241–2248, 2002. View at Publisher · View at Google Scholar
  102. P. Geraldes, J. Hiraoka-Yamamoto, M. Matsumoto et al., “Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy,” Nature Medicine, vol. 15, no. 11, pp. 1298–1306, 2009. View at Publisher · View at Google Scholar · View at Scopus
  103. T. S. Devi, K. Hosoya, T. Terasaki, and L. P. Singh, “Critical role of TXNIP in oxidative stress, DNA damage and retinal pericyte apoptosis under high glucose: implications for diabetic retinopathy,” Experimental Cell Research, vol. 319, no. 7, pp. 1001–1012, 2013. View at Publisher · View at Google Scholar · View at Scopus
  104. T. S. Kern and B. A. Berkowitz, “Photoreceptors in diabetic retinopathy,” Journal of Diabetes Investigation, vol. 6, no. 4, pp. 371–380, 2015. View at Publisher · View at Google Scholar · View at Scopus
  105. Y. Du, A. Veenstra, K. Palczewski, and T. S. Kern, “Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina,” Proceedings of the National Academy of Sciences, vol. 110, no. 41, pp. 16586–16591, 2013. View at Publisher · View at Google Scholar · View at Scopus
  106. G. B. Arden, “The absence of diabetic retinopathy in patients with retinitis pigmentosa: implications for pathophysiology and possible treatment,” British Journal of Ophthalmology, vol. 85, no. 3, pp. 366–370, 2001. View at Publisher · View at Google Scholar · View at Scopus
  107. T. E. de Gooyer, K. A. Stevenson, P. Humphries, D. A. Simpson, T. A. Gardiner, and A. W. Stitt, “Retinopathy is reduced during experimental diabetes in a mouse model of outer retinal degeneration,” Investigative Opthalmology & Visual Science, vol. 47, no. 12, pp. 5561–5568, 2006. View at Publisher · View at Google Scholar · View at Scopus
  108. S. Roy, T. S. Kern, B. Song, and C. Stuebe, “Mechanistic insights into pathological changes in the diabetic retina: implications for targeting diabetic retinopathy,” The American Journal of Pathology, vol. 187, no. 1, pp. 9–19, 2017. View at Publisher · View at Google Scholar
  109. C. M. Bergamini, S. Gambetti, A. Dondi, and C. Cervellati, “Oxygen, reactive oxygen species and tissue damage,” Current Pharmaceutical Design, vol. 10, no. 14, pp. 1611–1626, 2004. View at Publisher · View at Google Scholar · View at Scopus
  110. R. A. Kowluru and P. S. Chan, “Oxidative stress and diabetic retinopathy,” Experimental Diabetes Research, vol. 2007, Article ID 43603, 12 pages, 2007. View at Publisher · View at Google Scholar · View at Scopus
  111. R. C. Scarpulla, “Nucleus-encoded regulators of mitochondrial function: integration of respiratory chain expression, nutrient sensing and metabolic stress,” Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, vol. 2012, pp. 1088–1097, 1819. View at Publisher · View at Google Scholar · View at Scopus
  112. R. A. Kowluru and S. N. Abbas, “Diabetes-induced mitochondrial dysfunction in the retina,” Investigative Opthalmology & Visual Science, vol. 44, no. 12, pp. 5327–5334, 2003. View at Publisher · View at Google Scholar · View at Scopus
  113. W. Droge, “Free radicals in the physiological control of cell function,” Physiological Reviews, vol. 82, no. 1, pp. 47–95, 2002. View at Publisher · View at Google Scholar
  114. S. P. Narayanan, M. Rojas, J. Suwanpradid, H. A. Toque, R. W. Caldwell, and R. B. Caldwell, “Arginase in retinopathy,” Progress in Retinal and Eye Research, vol. 36, pp. 260–280, 2013. View at Publisher · View at Google Scholar · View at Scopus
  115. K. Miwa, J. Nakamura, Y. Hamada et al., “The role of polyol pathway in glucose-induced apoptosis of cultured retinal pericytes,” Diabetes Research and Clinical Practice, vol. 60, no. 1, pp. 1–9, 2003. View at Publisher · View at Google Scholar · View at Scopus
  116. S. Yamagishi, S. Maeda, T. Matsui, S. Ueda, K. Fukami, and S. Okuda, “Role of advanced glycation end products (AGEs) and oxidative stress in vascular complications in diabetes,” Biochimica et Biophysica Acta (BBA) - General Subjects, vol. 2012, pp. 663–671, 1820. View at Publisher · View at Google Scholar · View at Scopus
  117. D. XL, D. Edelstein, L. Rossetti et al., “Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation,” Proceedings of the National Academy of Sciences, vol. 97, pp. 12222–12226, 2000. View at Publisher · View at Google Scholar · View at Scopus
  118. Y. Q. Chen, M. Su, R. R. Walia, Q. Hao, J. W. Covington, and D. E. Vaughan, “Sp1 sites mediate activation of the plasminogen activator inhibitor-1 promoter by glucose in vascular smooth muscle cells,” Journal of Biological Chemistry, vol. 273, no. 14, pp. 8225–8231, 1998. View at Publisher · View at Google Scholar · View at Scopus
  119. R. A. Kowluru, V. Kowluru, Y. Xiong, and Y. S. Ho, “Overexpression of mitochondrial superoxide dismutase in mice protects the retina from diabetes-induced oxidative stress,” Free Radical Biology and Medicine, vol. 41, no. 8, pp. 1191–1196, 2006. View at Publisher · View at Google Scholar · View at Scopus
  120. E. J. Mayer-Davis, R. A. Bell, B. A. Reboussin, J. Rushing, J. A. Marshall, and R. F. Hamman, “Antioxidant nutrient intake and diabetic retinopathy: the San Luis Valley diabetes study,” Ophthalmology, vol. 105, no. 12, pp. 2264–2270, 1998. View at Publisher · View at Google Scholar
  121. A. E. Millen, M. Gruber, R. Klein, B. E. Klein, M. Palta, and J. A. Mares, “Relations of serum ascorbic acid and alpha-tocopherol to diabetic retinopathy in the third National Health and Nutrition Examination Survey,” American Journal of Epidemiology, vol. 158, no. 3, pp. 225–233, 2003. View at Publisher · View at Google Scholar · View at Scopus
  122. J. J. Garcia-Medina, M. D. Pinazo-Duran, M. Garcia-Medina, V. Zanon-Moreno, and S. Pons-Vazquez, “A 5-year follow-up of antioxidant supplementation in type 2 diabetic retinopathy,” European Journal of Ophthalmology, vol. 21, no. 5, pp. 637–643, 2011. View at Publisher · View at Google Scholar · View at Scopus
  123. R. Pazdro and J. R. Burgess, “The role of vitamin E and oxidative stress in diabetes complications,” Mechanisms of Ageing and Development, vol. 131, no. 4, pp. 276–286, 2010. View at Publisher · View at Google Scholar · View at Scopus
  124. A. Jariyapongskul, T. Rungjaroen, N. Kasetsuwan, S. Patumraj, J. Seki, and H. Niimi, “Long-term effects of oral vitamin C supplementation on the endothelial dysfunction in the iris microvessels of diabetic rats,” Microvascular Research, vol. 74, no. 1, pp. 32–38, 2007. View at Publisher · View at Google Scholar · View at Scopus
  125. G. T. Mustata, M. Rosca, K. M. Biemel et al., “Paradoxical effects of green tea (Camellia sinensis) and antioxidant vitamins in diabetic rats: improved retinopathy and renal mitochondrial defects but deterioration of collagen matrix glycoxidation and cross-linking,” Diabetes, vol. 54, no. 2, pp. 517–526, 2005. View at Publisher · View at Google Scholar · View at Scopus
  126. R. A. Kowluru and S. Odenbach, “Effect of long-term administration of alpha-lipoic acid on retinal capillary cell death and the development of retinopathy in diabetic rats,” Diabetes, vol. 53, no. 12, pp. 3233–3238, 2004. View at Publisher · View at Google Scholar · View at Scopus
  127. H. P. Hammes, A. Bartmann, L. Engel, and P. Wulfroth, “Antioxidant treatment of experimental diabetic retinopathy in rats with nicanartine,” Diabetologia, vol. 40, no. 6, pp. 629–634, 1997. View at Publisher · View at Google Scholar · View at Scopus
  128. B. Kumar, S. K. Gupta, T. C. Nag, S. Srivastava, and R. Saxena, “Green tea prevents hyperglycemia-induced retinal oxidative stress and inflammation in streptozotocin-induced diabetic rats,” Ophthalmic Research, vol. 47, no. 2, pp. 103–107, 2012. View at Publisher · View at Google Scholar · View at Scopus
  129. H. P. Hammes, X. Du, D. Edelstein et al., “Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy,” Nature Medicine, vol. 9, no. 3, pp. 294–299, 2003. View at Publisher · View at Google Scholar · View at Scopus
  130. A. C. Keech, P. Mitchell, P. A. Summanen et al., “Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial,” The Lancet, vol. 370, no. 9600, pp. 1687–1697, 2007. View at Publisher · View at Google Scholar · View at Scopus
  131. Group AS, Group AES, E. Y. Chew, W. T. Ambrosius et al., “Effects of medical therapies on retinopathy progression in type 2 diabetes,” New England Journal of Medicine, vol. 363, no. 3, pp. 233–244, 2010. View at Publisher · View at Google Scholar · View at Scopus
  132. T. Y. Wong, R. Simo, and P. Mitchell, “Fenofibrate - a potential systemic treatment for diabetic retinopathy?” American Journal of Ophthalmology, vol. 154, pp. 6–12, 2012. View at Publisher · View at Google Scholar · View at Scopus
  133. S. Zhao, J. Li, N. Wang et al., “Fenofibrate suppresses cellular metabolic memory of high glucose in diabetic retinopathy via a sirtuin 1-dependent signalling pathway,” Molecular Medicine Reports, vol. 12, no. 4, pp. 6112–6118, 2015. View at Publisher · View at Google Scholar · View at Scopus
  134. I. Jialal and H. Kaur, “The role of Toll-like receptors in diabetes-induced inflammation: implications for vascular complications,” Current Diabetes Reports, vol. 12, no. 2, pp. 172–179, 2012. View at Publisher · View at Google Scholar · View at Scopus
  135. M. R. Dasu, S. Devaraj, L. Zhao, D. H. Hwang, and I. Jialal, “High glucose induces toll-like receptor expression in human monocytes: mechanism of activation,” Diabetes, vol. 57, no. 11, pp. 3090–3098, 2008. View at Publisher · View at Google Scholar · View at Scopus
  136. T. Coll, X. Palomer, F. Blanco-Vaca et al., “Cyclooxygenase 2 inhibition exacerbates palmitate-induced inflammation and insulin resistance in skeletal muscle cells,” Endocrinology, vol. 151, no. 2, pp. 537–548, 2010. View at Publisher · View at Google Scholar · View at Scopus
  137. H. Shi, M. V. Kokoeva, K. Inouye, I. Tzameli, H. Yin, and J. S. Flier, “TLR4 links innate immunity and fatty acid-induced insulin resistance,” Journal of Clinical Investigation, vol. 116, no. 11, pp. 3015–3025, 2006. View at Publisher · View at Google Scholar · View at Scopus
  138. M. R. Dasu and I. Jialal, “Free fatty acids in the presence of high glucose amplify monocyte inflammation via Toll-like receptors,” AJP: Endocrinology and Metabolism, vol. 300, no. 1, pp. E145–E154, 2011. View at Publisher · View at Google Scholar · View at Scopus
  139. X. X. Zeng, Y. K. Ng, and E. A. Ling, “Neuronal and microglial response in the retina of streptozotocin-induced diabetic rats,” Visual Neuroscience, vol. 17, no. 3, pp. 463–471, 2000. View at Publisher · View at Google Scholar · View at Scopus
  140. A. P. Adamis and A. J. Berman, “Immunological mechanisms in the pathogenesis of diabetic retinopathy,” Seminars in Immunopathology, vol. 30, no. 2, pp. 65–84, 2008. View at Publisher · View at Google Scholar · View at Scopus
  141. N. Demircan, B. G. Safran, M. Soylu, A. A. Ozcan, and S. Sizmaz, “Determination of vitreous interleukin-1 (IL-1) and tumour necrosis factor (TNF) levels in proliferative diabetic retinopathy,” Eye, vol. 20, no. 12, pp. 1366–1369, 2006. View at Publisher · View at Google Scholar · View at Scopus
  142. G. A. Limb, A. H. Chignell, W. Green, F. LeRoy, and D. C. Dumonde, “Distribution of TNF alpha and its reactive vascular adhesion molecules in fibrovascular membranes of proliferative diabetic retinopathy,” British Journal of Ophthalmology, vol. 80, no. 2, pp. 168–173, 1996. View at Publisher · View at Google Scholar
  143. A. M. Abu el Asrar, D. Maimone, P. H. Morse, S. Gregory, and A. T. Reder, “Cytokines in the vitreous of patients with proliferative diabetic retinopathy,” American Journal of Ophthalmology, vol. 114, no. 6, pp. 731–736, 1992. View at Publisher · View at Google Scholar
  144. C. A. Aveleira, C. M. Lin, S. F. Abcouwer, A. F. Ambrosio, and D. A. Antonetti, “TNF-α signals through pkcζ/NF-κB to alter the tight junction complex and increase retinal endothelial cell permeability,” Diabetes, vol. 59, no. 11, pp. 2872–2882, 2010. View at Publisher · View at Google Scholar · View at Scopus
  145. A. M. Joussen, V. Poulaki, N. Mitsiades et al., “Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-α suppression,” The FASEB Journal, vol. 17, no. 1, pp. 76–78, 2002. View at Publisher · View at Google Scholar
  146. X. Liu, F. Ye, H. Xiong et al., “IL-1β upregulates IL-8 production in human Müller cells through activation of the p38 MAPK and ERK1/2 signaling pathways,” Inflammation, vol. 37, no. 5, pp. 1486–1495, 2014. View at Publisher · View at Google Scholar · View at Scopus
  147. Y. Du, V. P. Sarthy, and T. S. Kern, “Interaction between NO and COX pathways in retinal cells exposed to elevated glucose and retina of diabetic rats,” AJP: Regulatory, Integrative and Comparative Physiology, vol. 287, no. 4, pp. R735–R741, 2004. View at Publisher · View at Google Scholar · View at Scopus
  148. J. Wang, X. Xu, M. H. Elliott, M. Zhu, and Y. Z. Le, “Muller cell-derived VEGF is essential for diabetes-induced retinal inflammation and vascular leakage,” Diabetes, vol. 59, no. 9, pp. 2297–2305, 2010. View at Publisher · View at Google Scholar · View at Scopus
  149. A. M. Joussen, V. Poulaki, N. Mitsiades et al., “Suppression of Fas-FasL-induced endothelial cell apoptosis prevents diabetic blood-retinal barrier breakdown in a model of streptozotocin-induced diabetes,” FASEB Journal, vol. 17, no. 1, pp. 76–78, 2003. View at Publisher · View at Google Scholar
  150. A. M. Joussen, T. Murata, A. Tsujikawa, B. Kirchhof, S. E. Bursell, and A. P. Adamis, “Leukocyte-mediated endothelial cell injury and death in the diabetic retina,” The American Journal of Pathology, vol. 158, no. 1, pp. 147–152, 2001. View at Publisher · View at Google Scholar
  151. E. Ducharme and J. M. Weinberg, “Etanercept,” Expert Opinion on Biological Therapy, vol. 8, no. 4, pp. 491–502, 2008. View at Publisher · View at Google Scholar · View at Scopus
  152. A. M. Joussen, S. Doehmen, M. L. Le et al., “TNF-alpha mediated apoptosis plays an important role in the development of early diabetic retinopathy and long-term histopathological alterations,” Molecular Vision, vol. 15, pp. 1418–1428, 2009. View at Google Scholar
  153. Y. Behl, P. Krothapalli, T. Desta, A. DiPiazza, S. Roy, and D. T. Graves, “Diabetes-enhanced tumor necrosis factor-α production promotes apoptosis and the loss of retinal microvascular cells in type 1 and type 2 models of diabetic retinopathy,” The American Journal of Pathology, vol. 172, no. 5, pp. 1411–1418, 2008. View at Publisher · View at Google Scholar · View at Scopus
  154. Y. Behl, P. Krothapalli, T. Desta, S. Roy, and D. T. Graves, “FOXO1 plays an important role in enhanced microvascular cell apoptosis and microvascular cell loss in type 1 and type 2 diabetic rats,” Diabetes, vol. 58, no. 4, pp. 917–925, 2009. View at Publisher · View at Google Scholar · View at Scopus
  155. M. K. Tsilimbaris, T. D. Panagiotoglou, S. K. Charisis, A. Anastasakis, T. S. Krikonis, and E. Christodoulakis, “The use of intravitreal etanercept in diabetic macular oedema,” Seminars in Ophthalmology, vol. 22, no. 2, pp. 75–79, 2007. View at Publisher · View at Google Scholar · View at Scopus
  156. F. Ghadiri Soufi, E. Arbabi-Aval, M. Rezaei Kanavi, and H. Ahmadieh, “Anti-inflammatory properties of resveratrol in the retinas of type 2 diabetic rats,” Clinical and Experimental Pharmacology and Physiology, vol. 42, no. 1, pp. 63–68, 2015. View at Publisher · View at Google Scholar · View at Scopus
  157. S. H. Kim, J. H. Park, Y. J. Kim, and K. H. Park, “The neuroprotective effect of resveratrol on retinal ganglion cells after optic nerve transection,” Molecular Vision, vol. 19, pp. 1667–1676, 2013. View at Google Scholar
  158. J. A. Vincent and S. Mohr, “Inhibition of caspase-1/interleukin-1β signaling prevents degeneration of retinal capillaries in diabetes and galactosemia,” Diabetes, vol. 56, pp. 224–230, 2007. View at Publisher · View at Google Scholar · View at Scopus
  159. R. A. Kowluru and S. Odenbach, “Role of interleukin-1β in the development of retinopathy in rats: effect of antioxidants,” Investigative Opthalmology & Visual Science, vol. 45, no. 11, pp. 4161–4166, 2004. View at Publisher · View at Google Scholar · View at Scopus
  160. S. Mohr, X. Xi, J. Tang, and T. S. Kern, “Caspase activation in retinas of diabetic and galactosemic mice and diabetic patients,” Diabetes, vol. 51, no. 4, pp. 1172–1179, 2002. View at Publisher · View at Google Scholar
  161. F. Yulek, M. Or, C. Ozogul et al., “Effects of stobadine and vitamin E in diabetes-induced retinal abnormalities: involvement of oxidative stress,” Archives of Medical Research, vol. 38, pp. 503–511, 2007. View at Publisher · View at Google Scholar · View at Scopus
  162. W. L. Wong, X. Su, X. Li et al., “Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis,” Lancet Globalization and Health, vol. 2, pp. e106–e116, 2014. View at Publisher · View at Google Scholar · View at Scopus
  163. J. Z. Nowak, “Age-related macular degeneration (AMD): pathogenesis and therapy,” Pharmacological Reports, vol. 58, no. 3, pp. 353–363, 2006. View at Google Scholar
  164. K. M. Gehrs, D. H. Anderson, L. V. Johnson, and G. S. Hageman, “Age-related macular degeneration—emerging pathogenetic and therapeutic concepts,” Annals of Medicine, vol. 38, no. 7, pp. 450–471, 2006. View at Publisher · View at Google Scholar · View at Scopus
  165. H. R. Coleman, C. C. Chan, F. L. Ferris 3rd, and E. Y. Chew, “Age-related macular degeneration,” Lancet, vol. 372, no. 9652, pp. 1835–1845, 2008. View at Publisher · View at Google Scholar · View at Scopus
  166. M. R. Kozlowski, “RPE cell senescence: a key contributor to age-related macular degeneration,” Medical Hypotheses, vol. 78, no. 4, pp. 505–510, 2012. View at Publisher · View at Google Scholar · View at Scopus
  167. J. Ambati, J. P. Atkinson, and B. D. Gelfand, “Immunology of age-related macular degeneration,” Nature Reviews Immunology, vol. 13, no. 6, pp. 438–451, 2013. View at Publisher · View at Google Scholar · View at Scopus
  168. Y. DY and S. J. Cringle, “Retinal degeneration and local oxygen metabolism,” Experimental Eye Research, vol. 80, pp. 745–751, 2005. View at Publisher · View at Google Scholar · View at Scopus
  169. B. S. Winkler, M. E. Boulton, J. D. Gottsch, and P. Sternberg, “Oxidative damage and age-related macular degeneration,” Molecular Vision, vol. 5, p. 32, 1999. View at Google Scholar
  170. M. V. Miceli, M. R. Liles, and D. A. Newsome, “Evaluation of oxidative processes in human pigment epithelial cells associated with retinal outer segment phagocytosis,” Experimental Cell Research, vol. 214, no. 1, pp. 242–249, 1994. View at Publisher · View at Google Scholar · View at Scopus
  171. I. Johansson, V. T. Monsen, K. Pettersen et al., “The marine n-3 PUFA DHA evokes cytoprotection against oxidative stress and protein misfolding by inducing autophagy and NFE2L2 in human retinal pigment epithelial cells,” Autophagy, vol. 11, no. 9, pp. 1636–1651, 2015. View at Publisher · View at Google Scholar · View at Scopus
  172. L. Wang, M. Cano, S. Datta et al., “Pentraxin 3 recruits complement factor H to protect against oxidative stress-induced complement and inflammasome overactivation,” The Journal of Pathology, vol. 240, no. 4, pp. 495–506, 2016. View at Publisher · View at Google Scholar · View at Scopus
  173. D. F. Church and W. A. Pryor, “Free-radical chemistry of cigarette smoke and its toxicological implications,” Environmental Health Perspectives, vol. 64, pp. 111–126, 1985. View at Publisher · View at Google Scholar
  174. S. E. Moriarty, J. H. Shah, M. Lynn et al., “Oxidation of glutathione and cysteine in human plasma associated with smoking,” Free Radical Biology and Medicine, vol. 35, no. 12, pp. 1582–1588, 2003. View at Publisher · View at Google Scholar · View at Scopus
  175. M. Fujihara, N. Nagai, T. E. Sussan, S. Biswal, and J. T. Handa, “Chronic cigarette smoke causes oxidative damage and apoptosis to retinal pigmented epithelial cells in mice,” PLoS One, vol. 3, no. 9, article e3119, 2008. View at Publisher · View at Google Scholar · View at Scopus
  176. C. L. Nordgaard, P. P. Karunadharma, X. Feng, T. W. Olsen, and D. A. Ferrington, “Mitochondrial proteomics of the retinal pigment epithelium at progressive stages of age-related macular degeneration,” Investigative Opthalmology & Visual Science, vol. 49, no. 7, pp. 2848–2855, 2008. View at Publisher · View at Google Scholar · View at Scopus
  177. G. S. Hageman, D. H. Anderson, L. V. Johnson et al., “A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration,” Proceedings of the National Academy of Sciences, vol. 102, no. 20, pp. 7227–7232, 2005. View at Publisher · View at Google Scholar · View at Scopus
  178. S. O'Neill, J. Brault, M. J. Stasia, and U. G. Knaus, “Genetic disorders coupled to ROS deficiency,” Redox Biology, vol. 6, pp. 135–156, 2015. View at Publisher · View at Google Scholar · View at Scopus
  179. M. Boulton, M. Rozanowska, and B. Rozanowski, “Retinal photodamage,” Journal of Photochemistry and Photobiology B: Biology, vol. 64, no. 2-3, pp. 144–161, 2001. View at Publisher · View at Google Scholar · View at Scopus
  180. A. Kijlstra, Y. Tian, E. R. Kelly, and T. T. Berendschot, “Lutein: more than just a filter for blue light,” Progress in Retinal and Eye Research, vol. 31, no. 4, pp. 303–315, 2012. View at Publisher · View at Google Scholar · View at Scopus
  181. S. Johnsen-Soriano, M. Garcia-Pous, E. Arnal et al., “Early lipoic acid intake protects retina of diabetic mice,” Free Radical Research, vol. 42, no. 7, pp. 613–617, 2008. View at Publisher · View at Google Scholar · View at Scopus
  182. J. M. Woo, D. Y. Shin, S. J. Lee et al., “Curcumin protects retinal pigment epithelial cells against oxidative stress via induction of heme oxygenase-1 expression and reduction of reactive oxygen,” Molecular Vision, vol. 18, pp. 901–908, 2012. View at Google Scholar
  183. H. Chen, J. T. Tran, R. E. Anderson, and M. N. Mandal, “Caffeic acid phenethyl ester protects 661W cells from H2O2-mediated cell death and enhances electroretinography response in dim-reared albino rats,” Molecular Vision, vol. 18, pp. 1325–1338, 2012. View at Google Scholar
  184. Age-Related Eye Disease Study Research G, “A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss,” Archives of Ophthalmology, vol. 119, no. 10, pp. 1417–1436, 2001. View at Publisher · View at Google Scholar
  185. Group AR, E. Y. Chew, T. Clemons et al., “The age-related eye disease study 2 (AREDS2): study design and baseline characteristics (AREDS2 report number 1),” Ophthalmology, vol. 119, no. 11, pp. 2282–2289, 2012. View at Publisher · View at Google Scholar · View at Scopus
  186. J. G. Hollyfield, V. L. Bonilha, M. E. Rayborn et al., “Oxidative damage-induced inflammation initiates age-related macular degeneration,” Nature Medicine, vol. 14, no. 2, pp. 194–198, 2008. View at Publisher · View at Google Scholar · View at Scopus
  187. J. Zhou, Y. P. Jang, S. R. Kim, and J. R. Sparrow, “Complement activation by photooxidation products of A2E, a lipofuscin constituent of the retinal pigment epithelium,” Proceedings of the National Academy of Sciences, vol. 103, no. 44, pp. 16182–16187, 2006. View at Publisher · View at Google Scholar · View at Scopus
  188. M. Zhang, G. Xu, W. Liu, Y. Ni, and W. Zhou, “Role of fractalkine/CX3CR1 interaction in light-induced photoreceptor degeneration through regulating retinal microglial activation and migration,” PLoS One, vol. 7, no. 12, article e35446, 2012. View at Publisher · View at Google Scholar · View at Scopus
  189. J. V. Glenn and A. W. Stitt, “The role of advanced glycation end products in retinal ageing and disease,” Biochimica et Biophysica Acta (BBA) - General Subjects, vol. 1790, no. 10, pp. 1109–1116, 2009. View at Publisher · View at Google Scholar · View at Scopus
  190. W. Ma, S. Coon, L. Zhao, R. N. Fariss, and W. T. Wong, “A2E accumulation influences retinal microglial activation and complement regulation,” Neurobiology of Aging, vol. 34, no. 3, pp. 943–960, 2013. View at Publisher · View at Google Scholar · View at Scopus
  191. D. Yang, S. G. Elner, X. Chen, M. G. Field, H. R. Petty, and V. M. Elner, “MCP-1-activated monocytes induce apoptosis in human retinal pigment epithelium,” Investigative Opthalmology & Visual Science, vol. 52, no. 8, pp. 6026–6034, 2011. View at Publisher · View at Google Scholar · View at Scopus
  192. M. Suzuki, M. Tsujikawa, H. Itabe et al., “Chronic photo-oxidative stress and subsequent MCP-1 activation as causative factors for age-related macular degeneration,” Journal of Cell Science, vol. 125, no. 10, pp. 2407–2415, 2012. View at Publisher · View at Google Scholar · View at Scopus
  193. J. L. Ren, J. S. Pan, L. YP, P. Sun, and J. Han, “Inflammatory signaling and cellular senescence,” Cellular Signalling, vol. 21, no. 3, pp. 378–383, 2009. View at Publisher · View at Google Scholar · View at Scopus
  194. R. K. Kutty, W. Samuel, K. Boyce et al., “Proinflammatory cytokines decrease the expression of genes critical for RPE function,” Molecular Vision, vol. 22, pp. 1156–1168, 2016. View at Google Scholar
  195. M. C. Marazita, A. Dugour, M. D. Marquioni-Ramella, J. M. Figueroa, and A. M. Suburo, “Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: implications for age-related macular degeneration,” Redox Biology, vol. 7, pp. 78–87, 2016. View at Publisher · View at Google Scholar · View at Scopus
  196. M. R. Damani, L. Zhao, A. M. Fontainhas, J. Amaral, R. N. Fariss, and W. T. Wong, “Age-related alterations in the dynamic behavior of microglia,” Aging Cell, vol. 10, no. 2, pp. 263–276, 2011. View at Publisher · View at Google Scholar · View at Scopus
  197. F. Cruz-Guilloty, A. M. Saeed, J. J. Echegaray et al., “Infiltration of proinflammatory m1 macrophages into the outer retina precedes damage in a mouse model of age-related macular degeneration,” International Journal of Inflammation, vol. 2013, Article ID 503725, 12 pages, 2013. View at Publisher · View at Google Scholar · View at Scopus
  198. C. Zhao, D. Yasumura, X. Li et al., “mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice,” Journal of Clinical Investigation, vol. 121, no. 1, pp. 369–383, 2011. View at Publisher · View at Google Scholar · View at Scopus
  199. W. T. Wong, S. Dresner, F. Forooghian et al., “Treatment of geographic atrophy with subconjunctival sirolimus: results of a phase I/II clinical trial,” Investigative Opthalmology & Visual Science, vol. 54, no. 4, pp. 2941–2950, 2013. View at Publisher · View at Google Scholar · View at Scopus
  200. P. A. Petrou, D. Cunningham, K. Shimel et al., “Intravitreal sirolimus for the treatment of geographic atrophy: results of a phase I/II clinical trial,” Investigative Opthalmology & Visual Science, vol. 56, no. 1, pp. 330–338, 2014. View at Publisher · View at Google Scholar · View at Scopus
  201. M. J. Geerlings, E. K. de Jong, and A. I. den Hollander, “The complement system in age-related macular degeneration: a review of rare genetic variants and implications for personalized treatment,” Molecular Immunology, vol. 84, pp. 65–76, 2017. View at Publisher · View at Google Scholar · View at Scopus
  202. W. Rhoades, D. Dickson, and D. V. Do, “Potential role of lampalizumab for treatment of geographic atrophy,” Clinical Ophthalmology, vol. 9, pp. 1049–1056, 2015. View at Publisher · View at Google Scholar · View at Scopus
  203. S. Datta, M. Cano, K. Ebrahimi, L. Wang, and J. T. Handa, “The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD,” Progress in Retinal and Eye Research, vol. 60, pp. 201–218, 2017. View at Publisher · View at Google Scholar
  204. J. Gao, R. T. Liu, S. Cao et al., “NLRP3 inflammasome: activation and regulation in age-related macular degeneration,” Mediators of Inflammation, vol. 2015, Article ID 690243, 11 pages, 2015. View at Publisher · View at Google Scholar · View at Scopus
  205. V. Tarallo, Y. Hirano, B. D. Gelfand et al., “DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88,” Cell, vol. 149, no. 4, pp. 847–859, 2012. View at Publisher · View at Google Scholar · View at Scopus
  206. N. Kerur, Y. Hirano, V. Tarallo et al., “TLR-independent and P2X7-dependent signaling mediate Alu RNA-induced NLRP3 inflammasome activation in geographic atrophy,” Investigative Opthalmology & Visual Science, vol. 54, no. 12, pp. 7395–7401, 2013. View at Publisher · View at Google Scholar · View at Scopus
  207. B. J. Fowler, B. D. Gelfand, Y. Kim et al., “Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity,” Science, vol. 346, no. 6212, pp. 1000–1003, 2014. View at Publisher · View at Google Scholar · View at Scopus
  208. L. J. Roberts 2nd, J. P. Fessel, and S. S. Davies, “The biochemistry of the isoprostane, neuroprostane, and isofuran pathways of lipid peroxidation,” Brain Pathology, vol. 15, no. 2, pp. 143–148, 2006. View at Publisher · View at Google Scholar