ABSTRACT

The crystalline lens is highly susceptible to oxidative damage in aging because its cells and their
intracellular proteins are not turned over or replaced, thus providing the basis for cataractogenesis. The
trabecular meshwork, which is the anterior chamber tissue devoted to aqueous humor drainage, has a
particular susceptibility to mitochondrial oxidative injury that affects its endothelium and leads to an
intraocular pressure increase that marks the beginning of glaucoma. Photo-oxidative stress can cause
acute or chronic retinal damage. The pathogenesis of age-related macular degeneration involves
oxidative stress and death of the retinal pigment epithelium followed by death of the overlying
photoreceptors. Accordingly, converging evidence indicates that mutagenic mechanisms of environmental and endogenous sources play a fundamental pathogenic role in degenerative eye diseases(光氧化应激)

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Introduction

These ozone layers prevent almost all short wavelengths of less than 290 nm from reaching the earth’s surface。

They also absorb 70–90% of the UVB.

They also absorb 70–90% of the UVB. Depletion of the ozone layer has led to an increase in solar
UVB radiation reaching the Earth’s surface, with many consequences for human health. The major natural source of ultraviolet
light is the sun, and UV has a strong and deleterious effect on
cellular genetic material by affecting its integrity. UV has been
classified into three bands by wavelength: UVA (320–400 nm),
UVB (290–320 nm) and UVC (<290 nm). UV produces specific
genotoxic effects, inducing mutations and DNA damage. UV lesions
are formed through a photochemical reaction whose efficiency
depends on the wavelength and that follows direct UV energy
absorption by DNA bases [1], lipids and proteins [2]. UV also
induces oxidative stress in irradiated cells through the production
of reactive oxygen species (ROS) by activating riboflavin, tryptophan and porphyrin, which in turn can activate cellular oxygen [3].
Oxidative stress is defined as an imbalance between the
production of ROS and the antioxidant capacity of the cell. The
main consequence of this phenomenon is the damage of cell
macromolecules. Hence, the attack of the ROS, particularly
hydroxyl radicals, on nucleic acids can cause mutations including
helix-distorting nucleotide modifications or fragmentation of the
sugar phosphate backbone. Whereas modified proteins and lipids
can be eliminated through the normal process of cell renewal, DNA
damage must be repaired because it can drive mutagenesis (e.g.,
base substitutions, transitions, transversions, frameshifts, or
chromosomal translocations), disrupt normal gene expression,
and create aberrant protein products that are detrimental to
cellular function or viability by determining cell cycle arrest and
DNA repair or the activation of apoptotic pathways. From a
physiological perspective, DNA damage is detected by sensor
proteins and is then repaired primarily via the base excision repair
pathway. In this pathway, the cells have activated cell cycle
checkpoints, which leads to cell cycle arrest and thus prevents the
replication of damaged and defective DNA [4]. Moreover, cells are
equipped with enzymes that recognize and remove damaged bases
or more complex DNA lesions to prevent mutagenesis and the
cellular dysfunction that underlies cancer, neurodegeneration, and
other disease states [5]. In nuclear and mitochondrial DNA, 8-
OHdG is the most frequently detected and studied DNA lesion and
has therefore been widely used as a biomarker for oxidative stress
[6,7]. In recent years, 8-OHdG has been used widely in many
studies not only as a biomarker for the measurement of
endogenous oxidative DNA damage but also as a risk factor for
many diseases, including cancer [8]. In principle, there are two
major categories of diseases in which oxidative stress plays a
leading role: in the first category, mitochondria are the main site of
elevated ROS production. For instance, in cancer, a pro-oxidative
shift in the systemic thiol/disulfide redox state and impaired
glucose clearance occur in mitochondria. The second category may
be referred to as ‘‘inflammatory oxidative conditions’’ because
these diseases are typically associated with an excessive stimulation of NAD(P)H oxidase activity by cytokines or other agents.
Oxidative stress and inflammation are interlinked and have many
feedback loops; therefore, separating the two processes is difficult.
Many studies are now defining thecritical mitochondrial and
inflammatory pathway changes that underlie this increase in
oxidative stress and inflammation with age [9–11]. Indeed
mitochondrial respiratory function is impaired in the target
tissues of patients with mitochondrial diseases and declines with
age in various human tissues [12]. In aging cells, oxidative stress
also decreases the number of mitochondria and induces the
expression of genes whose products reduce oxidants, and this
process inducing inflammation [13].
The eyes are constantly exposed to solar UV effects (Fig. 1), and
much evidence attributes pathogenesis of the ocular tissues to
such radiation. When UV reaches the eye, the proportion absorbed
by different structures depends on the wavelength [14]. The
shorter wavelengths are mostly absorbed at the cornea, for
example, 92% of 300-nm UV is absorbed at the cornea. A higher
proportion of longer wavelengths passes through the cornea to
reach the lens; thus over 50% of 360-nm UVA is absorbed by the
lens [15]. However, ocular tissues are well equipped with
antioxidant defenses. Corneal epithelial cells, which normally
are exposed to high oxygen levels, have strong antioxidant
defenses that effective for protecting against ROS-related insults.
Conversely, other ocular tissues, such as the trabecular meshwork,
are not directly exposed to light and are located in low-oxygen
compartments; therefore, they are poorly equipped with antioxidant defenses and consequently less able to counteract injurious effects of ROS.

上面的Introduction讲了两个东西:

臭氧层的破坏，加剧了紫外线对眼睛的伤害。

紫外线分为三个部分：

UVA（320–400 nm）

UVB（290-320纳米）

UVC（<290纳米）

角膜吸收92%的300nm的紫外线。

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Antioxidant defenses

154 S.C. Sacca` et al. / Mutation Research 752 (2013) 153–171
substance that delays or inhibits oxidative damage to a target
molecule [19]. Changes in ROS concentration influence the
scavenging capacity. Normally, the amount of ROS in tissues is
relatively low. Increases in superoxide or nitric oxide result in a
temporary imbalance, which constitutes the basis of redox
adjustment. Persistent increases in the production of ROS or
reactive nitrogen species (RNS) can lead to persistent changes in
signal transduction and gene expression that can trigger pathological
conditions. In ocular tissues, these interactions have
peculiar aspects. From the outer to inner sections, the ocular
surface is composed of the tear film, the conjunctiva and the
cornea, which together with the aqueous humor form the first
physical and biochemical barrier of the eye and play a pivotal role
in combating free radicals.

（超氧化物或一氧化氮会导致ROS的增加）

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2.1

In addition to protection against ultravioletirradiation,tear film
contains many types of components that protect cells on the ocular
surface against physical factors, including humidity [20] and
temperature [21]. Antioxidants play an important role in tear film
(Fig. 2), and various antioxidants are present in human tears.
Ascorbic acid, tyrosine, reduced glutathione, cysteine, and uric acid
(328 mM) are all found in the tear film [22]. It is uncertain whether
tear antioxidants are primarily derived from corneal cells or
lacrimal glands [23]. The total concentration of antioxidants in
tears is approximately 400 mM, with ascorbate and urate
accounting for approximately half of this total [24]. Uric acid is
an important antioxidant in higher primates that participates in a
Fenton-type reaction with peroxide [25]. Vitamin C, or ascorbic
acid, is presentin primary lacrimal gland secretions but has a lower
concentration in basal tears [26]. The tear film also contains
immunoglobulin A, lipocalin (the principal lipid-binding protein in
tears), and other proteins that may protect the cornea from
oxidative damage [27]. Lipocalin is involved in the nonspecific
immune response. Relative to younger patients, old subjects have a
poorer overall defense against photooxidative and oxidative
processes in their tears [28]. Tear lipocalin is decreased in tears
in disorders with reduced lacrimal secretion, such as Sjogren’s
disease [29]. Another protective factor is the K+ concentration.
Indeed, UV radiation involves activation of K+ channels that causes
a loss of intracellular K+
, which in turn leads to activation of
apoptotic pathways [30,31] by activating initiator caspase-8 and
effector caspase-3 and leads to DNA fragmentation in corneal
epithelial cells [32].
Additionally, many antioxidants can act as pro-oxidants by
reducing nonradical forms of oxygen to their radical derivatives,
particularly if redox cycling occurs [18]. The exact mix of pro- and
antioxidant properties of a reducing compound is a complex
interaction involving pH, relative reactivities of radical derivatives,
availability of metal catalysts, oxygen concentration, and so forth
[33]. Amino acids and proteins, especially those rich in sulfhydryl
bonds, are also ROS scavengers. In addition, some compounds have
a relatively low specific antioxidative activity, i.e., on a molar basis,
but when present at high concentrations, they can contribute
significantly to the overall ROS scavenging activity [19]. Therefore,
the antioxidant status of tear fluid may play a role in modulating
wound healing and inflammatory responses in the cornea [34] and
in improving tear stability [35]. Indeed, there is a strong
relationship between the accumulation of oxidative stress and
the etiology of corneal epithelial alterations in blink-suppressed
dry eyes [36]. The main ocular surface pathology related to the
failure of tear antioxidant defenses is dry eye syndrome, in which
oxidative stress is highly involved [28,37]. Ocular dryness is
associated with chronic inflammation, and a vicious cycle of
inflammation and ocular surface injury occurs [37]. Dry eye is a
‘‘multifactorial disease of the tears and ocular surface that results
in symptoms of discomfort, visual disturbance, and tear film
instability with potential damage to the ocular surface (Fig. 3). It is
accompanied by increased osmolarity of the tear film and
inflammation of the ocular surface’’ [38]. In dry eye syndrome,
the expression of antioxidant enzymes such as superoxide
dismutase, catalase, and glutathione peroxidase is much lower
than that in controls, which correlates with the increased severity
of dry eye symptoms [39]（

除了防止紫外线辐射，泪膜

含有多种保护眼部细胞的成分

表面的物理因素，包括湿度[20]和

温度[21]。抗氧化剂在泪膜中起着重要作用

（图2），人类眼泪中存在各种抗氧化剂。

抗坏血酸、酪氨酸、还原型谷胱甘肽、半胱氨酸和尿酸

（328毫米）都在泪膜中找到[22]。目前尚不确定

泪液抗氧化剂主要来自角膜细胞或角膜

泪腺[23]。血液中抗氧化剂的总浓度

含抗坏血酸和尿酸盐的泪液约为400毫米

约占总数的一半[24]。尿酸是

高级灵长类动物中的一种重要抗氧化剂，参与

与过氧化氢的芬顿反应[25]。维生素C或抗坏血酸

酸性物质存在于原发性泪腺分泌物中，但含量较低

集中在基底泪液中[26]。泪膜也含有

免疫球蛋白A，脂质沉积蛋白（主要的脂质结合蛋白）

眼泪），以及其他可能保护角膜免受损伤的蛋白质

氧化损伤[27]。Lipocalin参与非特异性

免疫反应。与年轻患者相比，老年受试者有

对光氧化和氧化损伤的整体防御能力较差

泪水中的过程[28]。泪液脂质沉积蛋白在泪液中减少

泪液分泌减少的疾病，如干燥综合征

疾病[29]。另一个保护因素是K+浓度。

事实上，紫外线辐射涉及K+通道的激活，从而导致

细胞内钾的丢失+

，从而激活

通过激活启动子caspase-8和

效应子caspase-3和导致角膜DNA断裂

上皮细胞[32]。

此外，许多抗氧化剂可以通过以下方式起到促氧化剂的作用：

将非自由基形式的氧还原为自由基衍生物，

尤其是当氧化还原循环发生时[18]。支持和支持的确切组合

还原化合物的抗氧化性能是一个复杂的过程

涉及pH的相互作用，自由基衍生物的相对反应性，

金属催化剂的可用性、氧气浓度等

[33]. 氨基酸和蛋白质，尤其是富含巯基的氨基酸和蛋白质

债券也是活性氧清除剂。此外，一些化合物

相对较低的比抗氧化活性，即以摩尔为基础，

但当高浓度存在时，它们会起作用

对总的活性氧清除活性有显著影响[19]。因此

泪液的抗氧化状态可能在调节

伤口愈合和角膜炎症反应[34]和

提高撕裂稳定性[35]。事实上，这是一个强有力的挑战

氧化应激的积累与衰老的关系

角膜上皮改变的病因

干眼症[36]。主要的眼表病理学与

泪液抗氧化防御系统的失效是干眼症，其中

氧化应激与此密切相关[28,37]。眼睛干燥是一种疾病

与慢性炎症和疾病恶性循环有关

发生炎症和眼表损伤[37]。干眼症是一种疾病

“泪液和眼表的多因素疾病

出现不适、视觉障碍和泪膜症状

眼睛表面可能受损的不稳定性（图3）。它是

伴随着泪膜渗透压的增加和

眼表炎症“[38]。干眼症，

抗氧化酶如超氧化物歧化酶的表达

歧化酶、过氧化氢酶和谷胱甘肽过氧化物酶的含量要低得多

与对照组相比，这与严重程度的增加有关

干眼症的治疗[39]

）

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2.2

UVB light comparable in intensity to solar
irradiation readily causes the formation of intracellular ROS in
human corneal epithelial cells [41]. Additionally, intraocular
oxygen is mostly derived from diffusion across the cornea and
from the iris and retinal vasculature [42]. The cornea contains both
low-molecular-weight antioxidants, such as ferritin [43], ascorbic
acid [44], reduced glutathione (GSH) [45] and a-tocopherol [46],
and high-molecular-weight antioxidants, such as catalase, superoxide dismutase, glutathione peroxidase and reductase [47]. Thus,
supplementation of corneal endothelial cells with antioxidative
vitamins (ascorbic acid, tocopherol, and retinoic acid) significantly
inhibits free radical injury, lipid peroxidation, and consequent
apoptosis [48].Ferritin is an iron storage protein that protects DNA
from oxidative damage by UV light and hydrogen peroxide via
Fenton-type reactions [49]. Nuclear localization of ferritin involves
a tissue-specific nuclear transporter, ferritoid [43]. Within corneal
epithelial cell nuclei, ferritin and ferritoid are coassembled into
stable complexes [50] whose functions depend upon one another
[51]. Ferritin may serve two protective roles. The initial protective
role occurs during embryonic development to protect the corneal
epithelium from endogenously produced ROS (e.g., H2O2); the
second role, which occurs after birth, is to protect the corneal
epithelium from environmentally produced oxidative insults (e.g.,
U.V. light) [52].
L-Ascorbate (vitamin C) is present in intra- and extracellular
aqueous compartments and can reduce the tocopheroxyl radical; it
also has a number of metabolically important cofactor functions in
enzyme-catalyzed reactions, especially in hydroxylation reactions.
Vitamin C supports the antioxidant activity of vitamin E and GSH
[53]. According to the hypothesis of Pirie [54], the high ascorbic
acid concentration in the corneal epithelium results from a twostage transfer process: first, transfer from the plasma to the
aqueous humor and second, transfer from the aqueous humor to
the corneal epithelium. Indeed, in the corneal epithelium, the Lascorbate concentration is 1.9 mg/ml, i.e., nearly 14 times higher
than the concentration in the aqueous humor. Ascorbate alone
absorbs 77% of incident radiation [55], and high levels of ascorbic
acid thus prevent UV-induced DNA damage to the lens epithelium
[56]. Furthermore, RNA and ascorbate have a significant UVfiltering effect in the corneal epithelium [57]. It is interesting to
note that endothelial damage arising from the formation of free
radicals generated by high-intensity ultrasound energy during
phacoemulsification is mitigated by approximately 70% through
the addition of ascorbic acid to the irrigation solution [58]. Other
studies have shown a beneficial effect of irrigating solutions
containing GSH in reducing cell loss [59,60].
GSH is ubiquitously synthesized in all cell types [61] and
directly protects cellular functions against ROS through the direct
scavenging of radicals and through its activity as a cofactor for GSH
peroxidases during the metabolism of H2O2 or lipid peroxides [62].
GSH is involved in many cellular functions including: the
scavenging of free radicals and other reactive species, regulation
of DNA and protein synthesis, signal transduction, cell cycle
regulation, proteolysis, immune response and cytokine production, and various metabolic pathways [63]. Furthermore, GSH
regenerates important cellular antioxidants, such as vitamins C
and E, back to their active forms. When the cornea is under
oxidative stress (e.g., in the presence of H2O2), a rapid turnover of
endothelial GSH via glutathione reductase and the hexose
monophosphate shunt is required [64]. At low concentrations of
H2O2 in the aqueous humor, the GSH redox system is more
important than catalase in maintaining the integrity of the corneal
endothelium, whereas catalase assumes greater importance at
higher peroxide concentrations [65,66]. A decline in catalase
activity with age has been observed in the corneal endothelium
and in the iris of rabbits [65], and reduced levels and reduced
cellular uptake of GSH have been observed in the cornea with aging
[67]. GSH plays a fundamental role in cellular metabolism,
including pathways affecting differentiation, proliferation, cellular
senescence and apoptosis [68,69]. In the cornea, GSH is differentially distributed, and the highest levels are found in the
epithelium, where the GSH concentration is 5-fold higher than
that in the stroma [70,71]. The presence of GSH is related to its
pivotal role in maintaining optimum hydration of the cornea [64].
Glutathione reductase is responsible for maintaining GSH in its
reduced state, is involved in the control of corneal hydration [64],
and plays an important role in protecting the cornea against ROS
[65]. GSH corneal depletion resulting from UVB exposure triggers
different intracellular signaling cascades to lead to cytochrome c
release, caspase-9 activation, and induction of apoptosis [72]. The
cornea displays high activation of the pentose phosphate pathway,
which is important in corneal epithelial growth and differentiation
[73] and plays an important role in the corneal antioxidant defense
against UV-induced oxidative stress [74].
Serum albumin is one of the most abundant corneal proteins in
the corneal stroma [75], and its roles include the binding of toxic
metabolites, the maintenance of osmotic balance and the transport
of hormones and fatty acids in the context of the cornea [76].
Furthermore, cornea-specific roles for serum albumin include its
UV-filtering properties [77].
Superoxide dismutase (SOD) is abundant in the human cornea,
and its three isoenzymes exert their actions in their respective
compartments:CuZn-SOD in the cytoplasm, SOD inthe extracellular
space and the third SOD isoenzyme, Mn-SOD, in the mitochondrial
matrix [78]. Cejkova´ et al. [79] found that UVB rays changed the
activity of antioxidant enzymes: repeated irradiation of the cornea
with UVB rays evoked a deficiency in antioxidant enzymes in the
corneal epithelium; however, a shorter irradiation evoked a more
profound decrease of glutathione peroxidase and catalase than of
superoxidedismutase.Interspecies variationshavebeenobservedin
the activity of enzymes participating in the antioxidant/pro-oxidant
balance in the corneal epithelium [80]. The enzyme activity levels
were significantly lower in pterygiumpatients when compared with
controls [81] (Fig. 4). Pterygium is an inflammatory and degenerative ocular surface disease where the bulbar conjunctiva advances
on the cornea and forms a fibro-vascular triangle that progressively
invades the corneal stroma from the nasal limbus. When it extends
to the central optical zone, visual function can be severely impaired.
Genetic components may be involved in pathogenesis but chronic
exposure to UVB was found to be the determining factor in
promoting the development of pterygium [82]. High levels of 8-
OHdG were found in the pterygium; thus, the occurrence of insofar
unidentified gene mutations has been hypothesized [83,84].
Furthermore, in the pterygium, increases in malondialdehyde and
nitric oxide have been observed along with a decrease in antioxidant
enzymes, including SOD, catalase, and glutathione peroxidase（

强度与太阳相当的UVB光

辐射很容易导致细胞内ROS的形成

人类角膜上皮细胞[41]。此外，眼内

氧气主要来自角膜和角膜的扩散

来自虹膜和视网膜血管系统[42]。角膜包含这两种成分

低分子量抗氧化剂，如铁蛋白[43]，抗坏血酸

酸[44]、还原型谷胱甘肽（GSH）[45]和α-生育酚[46]，

以及高分子量抗氧化剂，如过氧化氢酶、超氧化物歧化酶、谷胱甘肽过氧化物酶和还原酶[47]。因此

角膜内皮细胞补充抗氧化剂

维生素（抗坏血酸、生育酚和维甲酸）显著降低

抑制自由基损伤、脂质过氧化和随后的

凋亡[48]。铁蛋白是一种保护DNA的铁存储蛋白

防止紫外线和过氧化氢通过

芬顿型反应[49]。铁蛋白的核定位涉及

一种组织特异性核转运体，铁蛋白样[43]。角膜内

上皮细胞核、铁蛋白和类铁蛋白共组装成

功能相互依赖的稳定配合物[50]

[51]. 铁蛋白可能有两种保护作用。最初的保护措施

在胚胎发育过程中起到保护角膜的作用

来自内源性产生的ROS（例如H2O2）的上皮；这个

第二个作用发生在出生后，是保护角膜

环境产生的氧化损伤（例如。，

紫外线灯[52]。

L-抗坏血酸（维生素C）存在于细胞内和细胞外

水相隔室，能减少生育酚自由基；信息技术

还具有许多代谢上重要的辅助因子功能

酶催化反应，尤指羟基化反应。

维生素C支持维生素E和GSH的抗氧化活性

[53]. 根据Pirie[54]的假设，高抗坏血酸

角膜上皮中的酸浓度来自两个阶段的转移过程：首先，从血浆转移到角膜

房水，第二，从房水转移到

角膜上皮。事实上，在角膜上皮中，Lascorbate浓度为1.9 mg/ml，即高出近14倍

而不是房水中的浓度。单用抗坏血酸

吸收77%的入射辐射[55]，以及高水平的抗坏血酸

因此，酸可以防止紫外线诱导的晶状体上皮DNA损伤

[56]. 此外，RNA和抗坏血酸在角膜上皮中具有显著的紫外线过滤作用[57]。这很有趣

注意内皮损伤是由自由基的形成引起的

由高强度超声能量产生的自由基

超声乳化术可通过以下方法减轻约70%

向灌溉溶液中添加抗坏血酸[58]。另外

研究表明，灌溉溶液具有有益的效果

含有GSH以减少细胞损失[59,60]。

GSH在所有类型的细胞中普遍合成[61]和

直接保护细胞功能，防止活性氧通过直接

清除自由基并通过其作为GSH辅助因子的活性

过氧化氢或脂质过氧化物代谢过程中的过氧化物酶[62]。

GSH参与许多细胞功能，包括：

清除自由基和其他活性物质，调节

DNA和蛋白质合成，信号转导，细胞周期

调节、蛋白质水解、免疫反应和细胞因子产生，以及各种代谢途径[63]。此外，GSH

再生重要的细胞抗氧化剂，如维生素C

E，回到它们的活动形式。当角膜处于

氧化应激（例如，在存在H2O2的情况下），即

通过谷胱甘肽还原酶和己糖的内皮GSH

需要单磷酸盐分流[64]。在低浓度

H2O2在房水中，GSH氧化还原系统的活性更强

在维持角膜完整性方面比过氧化氢酶更重要

内皮细胞，而过氧化氢酶在

过氧化氢浓度较高[65,66]。过氧化氢酶的下降

在角膜内皮中观察到随年龄增长的活性

在兔子的虹膜[65]中，降低了水平，降低了

随着年龄的增长，在角膜中观察到细胞摄取GSH

[67]. GSH在细胞代谢中起着重要作用，

包括影响分化、增殖和细胞凋亡的途径

衰老和凋亡[68,69]。在角膜中，GSH的分布存在差异，最高水平出现在角膜中

GSH浓度是上皮细胞的5倍

在基质中[70,71]。GSH的存在与其功能有关

在维持角膜最佳水合作用方面发挥关键作用[64]。

谷胱甘肽还原酶负责维持GSH在其体内的活性

还原状态，参与控制角膜水合作用[64]，

在保护角膜免受活性氧侵害方面起着重要作用

[65]. UVB暴露引发GSH角膜耗竭

不同的细胞内信号级联导致细胞色素

）

It is well established that in humans, the corneal
epithelium acts as a UV filter to protect internal eye structures
through three different mechanisms [85]: (1) absorption of UVB
with wavelengths roughly below 310 nm; (2) fluorescence-mediated ray transformation to longer wavelengths; (3) fluorescence
reduction. The extremely high ascorbate concentration in the
corneal epithelium plays a key role in these processes [85]. The total
activity of superoxide dismutase is much higher in the normal
corneal epithelium than the activity of catalase, which is higher than
the activity of glutathione peroxidase [86].
Even if catalase is a major enzyme involved in the detoxification of H2O2 in cells, its expression under oxidative stress is not
predictable and its activity may be decreased, increased or
unchanged [87]. Regardless, H2O2 induces a significant amount of
catalase expression and smaller increases in GPx and Mn-SOD
expression [88]. The regulation of SOD isoenzymes in mammalian
tissues primarily occurs in a manner that is coordinated by
inflammatory cytokines, rather than as a response of individual
cells to oxidants [89]. Indeed, UVB modulates expression of
antioxidants and proinflammatory mediators by corneal epithelial cells by distinct mechanisms [90]. It has been shown that
suppression of proinflammatory cytokines contributes strongly to
reduced matrix metalloproteinase and xanthine oxidase expression in the UVB-irradiated corneal epithelium and to decreased
development of an antioxidant/pro-oxidant imbalance [91].
Alterations in the expression of these mediators are important
in regulating inflammation and protecting the cornea from UVBinduced oxidative stress. Failure of these homeostatic mechanisms results in ocular diseases.
In Fuch’s endothelial dystrophy (Fig. 5), oxidative damage
occurring in the corneal endothelium results in alteration of gene
expression with downregulation of the antioxidant response
element (ARE), reduced transcription of a major factor that
regulates ARE-dependent antioxidants, and elevated oxidative
mitochondrial DNA damage [92,93]. Additionally, the dystrophic
cells produce abnormal extracellular matrix that forms excrescences called guttata in the central cornea that progressively
spread, enlarge, and coalesce to form a membrane that covers the
whole endothelial surface. This process is accompanied by
progressive endothelial cell loss. In advanced stages, the excrescences become clinically evident and endothelial function is
compromised. Thus, the clinical phase is characterized by
progressive corneal edema and loss of transparency [94].
Glutathione peroxidase (GPX) catalyzes the reduction of lipid
hydroperoxides to water or alcohol and H2O2 to water and
molecular oxygen with concomitant oxidation of GSH [95]. GPX is
localized predominantly to the epithelium and endothelium of the
cornea [77]. The catalyzed reactions minimize the destructive
effects of ROS in these corneal tissue layers, thus preventing the
propagation of peroxide-dependent chain reactions that result in
cell membrane degeneration [95]. Oxidative stress, including GPX
failure, starts a cascade of events that ultimately leads to
keratoconus (Fig. 6). Keratoconus is a condition in which the
cornea assumes a conical shape because of thinning and
protrusion. Keratoconus progression leads to severe visual
impairment because of irregular myopic astigmatism with high
order aberrations and, in advanced forms, leads to corneal scarring.
Keratoconic corneal fibroblasts increase their ROS/RNS production
in response to oxidative stress, which induces increased catalase
activity. Activation of degradative enzymes leads to the degradation of tissue inhibitors of metalloproteinases with matrix
degradation, increased activity of proteinases and decreased
activity of proteinase inhibitors that clinically manifests as stromal
thinning [96,97]. Damage to mitochondrial DNA plays a role in this
disease. Mitochondrial DNA (mtDNA) is more prone to damage, as
it has a less efficient repair system than nuclear DNA [98].
Mitochondrial damage induces a decrease in OXPHOS and an
increase in ROS products and thus may alter gene expression and
induce apoptosis and loss of cell viability. Keratoconic corneas
exhibit higher levels of mtDNA damage and increased numbers of
mtDNA rearrangements, deletions and mutations [98,99]. Keratocytes from keratoconus corneas were found to have 4-fold more
interleukin 1 binding sites when compared with non-keratoconus
corneas [100], which may result in increased sensitivity of the
keratocytes in keratoconus corneas to interleukin 1, which has
been shown to induce apoptosis of stromal keratocytes. Thus,
apoptosis has been found in the stromal keratocytes of keratoconus corneas but not in normal controls [101].（

众所周知，人类的角膜

上皮细胞起到紫外线过滤器的作用，保护眼睛内部结构

通过三种不同的机制[85]：（1）吸收UVB

波长大约低于310纳米；（2） 荧光介导的射线转换到更长波长；（3） 荧光

减少维生素C的浓度极高

角膜上皮在这些过程中起着关键作用[85]。总数

正常人的超氧化物歧化酶活性要高得多

角膜上皮细胞的过氧化氢酶活性比正常人高

谷胱甘肽过氧化物酶的活性[86]。

即使过氧化氢酶是细胞内参与H2O2解毒的主要酶，其在氧化应激下的表达也不受影响

可预测，其活动可能减少、增加或减少

未变[87]。不管怎样，H2O2诱导了大量的

过氧化氢酶的表达和GPx和Mn-SOD的小幅度增加

表达式[88]。哺乳动物SOD同工酶的调节

组织主要以一种由

炎性细胞因子，而不是作为个体的反应

细胞对氧化剂的反应[89]。事实上，UVB可以调节基因的表达

抗氧化剂和促炎介质通过不同的机制被角膜上皮细胞吸收[90]。事实证明

抑制促炎细胞因子有助于促进炎症反应

UVB照射后角膜上皮中基质金属蛋白酶和黄嘌呤氧化酶的表达降低，并且

抗氧化剂/促氧化剂失衡的发展[91]。

这些介质表达的改变很重要

调节炎症，保护角膜免受紫外线诱导的氧化应激。这些稳态机制的失效会导致眼部疾病。

在Fuch的内皮营养不良（图5）中，氧化损伤

发生在角膜内皮细胞导致基因改变

表达下调抗氧化反应

元素（ARE），一个主要因子的转录减少

调节因子依赖于抗氧化剂，并提高氧化应激水平

线粒体DNA损伤[92,93]。此外，营养不良

细胞产生异常的细胞外基质，在角膜中央形成一种名为guttata的排泄物，这种排泄物会逐渐扩散

扩散、扩大并结合形成一层膜，覆盖

整个内皮表面。这个过程伴随着

进行性内皮细胞丢失。在晚期，排泄物在临床上变得明显，内皮功能受损

妥协的。因此，临床阶段的特点是

进行性角膜水肿和透明性丧失[94]。

谷胱甘肽过氧化物酶（GPX）催化脂质的减少

过氧化氢转化为水或酒精，过氧化氢转化为水和水

伴随GSH氧化的分子氧[95]。GPX是

主要局限于子宫的上皮和内皮

角膜[77]。催化反应将破坏性降低到最低程度

活性氧在这些角膜组织层中的作用，从而防止

过氧化物依赖链式反应的传播，导致

细胞膜退化[95]。氧化应激，包括GPX

失败会引发一连串事件，最终导致

圆锥角膜（图6）。圆锥角膜是指

由于角膜变薄和变薄，角膜呈圆锥形

突出。圆锥角膜的进展会导致严重的视力损害

由于高度近视的不规则散光造成的损害

顺序畸变，在高级形式下，会导致角膜瘢痕。

圆锥角膜成纤维细胞增加ROS/RNS的产生

作为对氧化应激的反应，氧化应激诱导过氧化氢酶增加

活动降解酶的激活导致基质金属蛋白酶组织抑制剂的降解

降解，蛋白酶活性增加，酶活性降低

临床表现为基质蛋白的蛋白酶抑制剂的活性

变薄[96,97]。线粒体DNA的损伤在这一过程中发挥了作用

病线粒体DNA（mtDNA）更容易受损，就像

它的修复系统不如核DNA[98]。

线粒体损伤导致OXPHOS和an的减少

活性氧产物增加，从而可能改变基因表达和功能

诱导细胞凋亡和丧失细胞活力。圆锥角膜

表现出更高水平的线粒体DNA损伤和数量增加

线粒体DNA重排、缺失和突变[98,99]。圆锥角膜的角膜细胞被发现有4倍以上的细胞

与非圆锥角膜相比，白细胞介素1结合位点

角膜[100]，这可能导致角膜的敏感性增加

圆锥角膜中的角膜细胞对白细胞介素1的反应

已经证明诱导基质角膜细胞凋亡。因此

在圆锥角膜的基质角膜细胞中发现了凋亡，但在正常对照组中没有发现[101]

）

Antioxidant enzyme activity decreases in aged corneas [102].
These enzymes are able to handle basal or low levels of ROS, but
they can be overwhelmed during acute stress [77]. Aldehyde
dehydrogenase 3A1 (ALDH3A1) is a water-soluble protein with
many similarities to the lens crystallins and is primarily expressed
in corneal epithelial cells and stromal keratocytes but is absent
from endothelial cells. ALDH3A1 plays a critical, multifunctional
role in defending the cornea from UV-induced oxidative stress
[103]. Indeed, 20–40% of the soluble protein content of the cornea
is an ALDH3 isoenzyme, which directly absorbs UV radiation and
removes cytotoxic aldehydes produced by UV-induced lipid
peroxidation [104]. ALDH3 corneal isoenzyme has various
biological functions such as the metabolism of toxic aldehydes
produced during the peroxidation of cellular lipids, the generation
of the antioxidant NADPH, the direct absorption of UV light, the
scavenging of ROS, and chaperone-like activity [105]. Another
corneal crystallin is ALDH1A1, which constitutes approximately 3%
of the total soluble protein in the human cornea [106]. Both
ALDH3A1 and ALDH1A1 catabolize toxic aldehydes produced by
ROS-induced lipid peroxidation. ALDH1A1 may compensate for the
lack of ALDH3A1 to satisfy the structural demands and protective
requirements of the cornea against UV-induced oxidative damage
[77], thus performing one or more of the functions ascribed to
ALDH3A1 [107]. The absence of these enzymes significantly
increases the risk for cataract formation [108].

A final line of defense against oxidative damage in cornea is
provided by the melanocytes of the limbal area of the cornea,
which play a role as scavengers of free radicals [109].
Overall, the cornea is well equipped with antioxidant defenses
because of the remarkable exposure of this tissue to environmental
mutagens. Indeed, a recent study showed that the cornea contains
a high amount of a mitochondrial DNA deletion that is commonly
related to eye photo-aging and occurs especially in sun-exposed
ocular tissues such as the cornea and iris. This deletion is related to
photo-aging rather than chronological aging of the human eye
[110]. High levels of this mitochondrial DNA deletion have been
detected in the corneal stroma but not in the corneal epithelium
and endothelium because ofthe high concentration of antioxidants
present in these corneal layers（衰老角膜的抗氧化酶活性降低[102]。

这些酶能够处理基本或低水平的活性氧，但

在急性压力下，他们可能会不知所措[77]。醛

脱氢酶3A1（ALDH3A1）是一种水溶性蛋白质，具有

与晶状体晶体蛋白有许多相似之处，主要表现为

在角膜上皮细胞和基质角膜细胞中，但不存在

来自内皮细胞。ALDH3A1起着关键、多功能的作用

保护角膜免受紫外线诱导的氧化应激的作用

[103]. 事实上，角膜中20-40%的可溶性蛋白质含量

是ALDH3同功酶，可直接吸收紫外线辐射和

去除紫外线诱导脂质产生的细胞毒性醛类

过氧化作用[104]。ALDH3角膜同工酶具有多种多样性

生物功能，如有毒醛的代谢

在细胞脂质过氧化过程中产生的

抗氧化剂NADPH对紫外线的直接吸收

清除活性氧和伴侣样活性[105]。另一个

角膜晶体蛋白是ALDH1A1，约占3%

人类角膜中的总可溶性蛋白质[106]。二者都

醛类H3A1和醛类H1A1分解代谢由细菌产生的有毒醛类

活性氧诱导脂质过氧化。ALDH1A1可以补偿

缺乏ALDH3A1，以满足结构要求和保护要求

角膜对紫外线诱导氧化损伤的要求

[77]，从而执行一个或多个

ALDH3A1[107]。这些酶的缺失显著增加

增加白内障形成的风险[108]。

防止角膜氧化损伤的最后一道防线是

由角膜缘的黑素细胞提供，

作为自由基清除剂发挥作用[109]。

总的来说，角膜具有良好的抗氧化防御能力

因为这种组织明显暴露在环境中

诱变剂。事实上，最近的一项研究表明，角膜含有

线粒体DNA大量缺失，通常

与眼睛的光老化有关，尤其是在阳光照射下

眼睛组织，如角膜和虹膜。此删除与

人眼的光老化而非按时间顺序老化

[110]. 这种线粒体DNA缺失的高水平已经被证实

在角膜基质中检测到，但在角膜上皮中未检测到

由于抗氧化剂的高浓度

存在于这些角膜层中）

###########################################################################

2.3. The anterior chamber

The anterior chamber is a space that is surrounded by
endothelium and filled with a liquid called the aqueous humor
(AH), which constantly wets the inner walls of the anterior
chamber, which comprises the endothelia of the iris, cornea, and
trabecular meshwork. AH has the task of protecting and supplying
nutrition to the cornea, lens and trabecular meshwork [111]. AH is
protected against free radical and oxidant stress by a system that
includes antioxidant enzymes, chelating proteins, and antioxidants, both lipid and water-soluble. Oxygen levels are substantially lower in AH near the anterior chamber angle than beneath
the central cornea. Hypoxia leads to a decrease in the oxygen levels
in the AH of the anterior chamber angle but not in the AH adjacent
to the central cornea [42]. The protein concentration in the
aqueous fluid is 0.1–0.2% of the concentration in plasma, and the
concentration of amino acids is higher than that in plasma.
Ascorbate [112], lactate, and bicarbonate concentrations are also
high in AH [113]. The aqueous production shows an age-related
decline that approximately amounts to 15–35% over the age range
of 20–80 years [114–116]. Additionally, human outflow facility
decreases with age. The age-related decrease is approximately 30%
from young (40 years) to old (60 years) individuals [116]. Anterior
chamber endothelial cells are constantly in contact with free
radicals and engage in antioxidant activity that counteracts the
toxic effects of oxidative stress. AH antioxidant defenses are
numerous [117] and include vitamins, enzymes, and proteins such
as albumins that protect the trabecular meshwork (TM) [118]. TM
is the anterior chamber tissue that is devoted to AH drainage, and
its progressive alteration leads to the occurrence of primary openangle glaucoma (POAG), which is the main cause of irreversible
blindness worldwide. Oxidative stress targeting TM is a main
pathogenic mechanism for the development of glaucoma [119] and
related intraocular pressure increase [120]. Numerous studies
have demonstrated a strong correlation between oxidative stress
and apoptosis in different cell types [121,122]. Thus, oxidative
stress leads to apoptosis when antioxidant capacity is insufficient
[121]. As in the cornea, where the number of corneal fibroblasts
declines in normal corneas with age in response to oxidative stress
[123], in TM, an endothelial cell loss of 0.58% per year has been
observed [124]. This loss has been attributed to the free radicals
that are formed in AH [125]. During the course of glaucoma, many
of the alterations observed in the TM structure are caused by the
loss of endothelial cells [117] (Fig. 7). The most well-known free
radical chain reaction is lipid peroxidation. In this process, a free
radical removes a hydrogen atom from a lateral chain of a
polyunsaturated fatty acid. Ifthe free radicals ofthe chains are not
deactivated, their chemical reactivity can damage cellular
macromolecules. The main targets of peroxidation reactions are
proteins, cell membranes, and nucleic acids (DNA and RNA),
including mitochondrial DNA (mtDNA). Indeed, mtDNA is less
protected than nuclear DNA and is therefore more sensitive to free
radical attack [126,127]. Nitric oxide (NO) is the mediator of the

endothelium-derived relaxing factor produced by the ciliary
body, trabecular meshwork [128], and endothelium [129]. NO is a
potent antioxidative agent that suppresses iron-induced generation of hydroxyl radicals via the Fenton reaction, which interrupts
the chain reaction of lipid peroxidation, augments the antioxidative potency of reduced GSH and inhibits cysteine proteases
[130]. Thus, NO is involved in the control of basal blood flow in the
choroid, optic nerve, and retina. Abnormalities in the L-arginine/
nitric oxide system have been observed in a variety of ocular
diseases, including diabetic retinopathy, retinopathy of prematurity, and glaucoma [131]. The TM is present in the 3608 angle
formed by the cornea and the iris and, in contrast with the cornea
and iris, is not directly exposed to environmental light, which is a
major determinant for inducing antioxidant defenses in directly
exposed tissues. Regardless, TM is the most ROS-sensitive tissue
of the ocular anterior chamber [132]. （

前房是一个周围有

内皮细胞，充满一种叫做房水的液体

（啊），它不断地浸湿前壁的内壁

由虹膜、角膜和角膜的内皮细胞组成

小梁网。啊有保护和供应的任务

角膜、晶状体和小梁网的营养[111]。啊是

保护免受自由基和氧化应激的系统

包括抗氧化酶、螯合蛋白和抗氧化剂，包括脂溶性和水溶性。前房角附近AH的氧气水平明显低于下方

中央角膜。缺氧导致氧气水平下降

在前房角的AH中，但不在相邻的AH中

到中央角膜[42]。细胞内的蛋白质浓度

水溶液浓度为血浆浓度的0.1–0.2%，且

氨基酸的浓度高于血浆中的浓度。

抗坏血酸[112]、乳酸和碳酸氢盐的浓度也很低

AH含量高[113]。产水量与年龄有关

在年龄范围内，下降约为15–35%

20-80年[114-116]。此外，还提供了人员外流设施

随着年龄的增长而减少。与年龄相关的下降约为30%

从年轻人（40岁）到老年人（60岁）[116]。先前的

腔室内皮细胞不断与自由基接触

自由基和参与抗氧化活性，以抵消

氧化应激的毒性作用。啊，抗氧化防御是

包括维生素、酶和蛋白质等

作为保护小梁网（TM）的蛋白[118]。商标

是用于AH引流的前房组织，以及

其进行性改变导致原发性开角型青光眼（POAG）的发生，这是不可逆性青光眼的主要原因

全世界失明。氧化应激靶向TM是一个主要的

青光眼的发病机制[119]和

相关眼压升高[120]。大量研究

已经证明氧化应激和

以及不同类型细胞的凋亡[121122]。因此，氧化

当抗氧化能力不足时，应激会导致细胞凋亡

[121]. 在角膜中，角膜成纤维细胞的数量

正常角膜对氧化应激的反应随年龄增长而下降

[123]在TM中，内皮细胞每年损失0.58%

观察[124]。这种损失可归因于自由基

它们形成于AH[125]中。在青光眼的病程中，许多

在TM结构中观察到的大部分变化是由

内皮细胞的丢失[117]（图7）。最著名的免费

自由基链式反应是脂质过氧化。在这个过程中，一个自由的

自由基从分子的侧链中除去一个氢原子

多不饱和脂肪酸。如果链上的自由基不是

如果失去活性，它们的化学反应会损害细胞

大分子。过氧化反应的主要目标是

蛋白质、细胞膜和核酸（DNA和RNA），

包括线粒体DNA（mtDNA）。事实上，线粒体DNA的数量更少

比核DNA受到保护，因此对游离DNA更敏感

激进攻击[126127]。一氧化氮（NO）是脑缺血的介质

睫状体产生的内皮源性舒张因子

身体、小梁网[128]和内皮[129]。不，这是一个

强效抗氧化剂，通过Fenton反应抑制铁诱导的羟基自由基生成，该反应可中断

脂质过氧化的连锁反应，增强还原GSH的抗氧化能力，抑制半胱氨酸蛋白酶

[130]. 因此，NO参与了大脑基底血流量的控制

脉络膜、视神经和视网膜。L-精氨酸异常/

一氧化氮系统已在多种眼部疾病中被观察到

疾病，包括糖尿病视网膜病变、早产儿视网膜病变和青光眼[131]。TM以3608角存在

由角膜和虹膜形成，与角膜形成对比

虹膜不会直接暴露在环境光下，这是一种

直接诱导小鼠抗氧化防御的主要决定因素

暴露的组织。无论如何，TM是ROS最敏感的组织

关于眼前房的研究[132]。）

We do not yet know exactly
why glaucoma develops, but it is certain that oxidative stress in
TM exerts a pathogenic role the generation of glaucoma-inducing
mitochondrial damage and the triggering of apoptosis and cell
loss [133]. Indeed, the antioxidant enzymes superoxide dismutases 1/2 and glutathione S transferase 1 are significantly downregulated in POAG patients when compared with controls,
whereas the pro-oxidant enzyme nitric oxide synthetase 2 and
glutamate ammonia ligase are significantly up-regulated in POAG
patients when compared with controls [134]. Genetic factors are
most likely very important and contribute to development of
oxidative stress. For instance, deletion of the GSH transferase
isoenzyme GSTM1 has been associated with an increased risk of
developing cancer [135] and with increased levels of promutagenic DNA adducts in subjects exposed to environmental risk
factors for cancer [136] and atherosclerosis [137]. Several lines of
evidence suggest that GSH may also be relevant in the
pathogenesis of glaucoma. Indeed, this enzyme may protect
against oxidative stress in the retina, which is the target tissue of
advanced POAG [138]. The GSTM1 null polymorphism is
associated with POAG in the Arab population [139], the Brazilian
population [140], the Turkish population [141], and female
Pakistani patients afflicted by pseudoexfoliative glaucoma
[142], but not in the Chinese population [143]. In Caucasians,
clinical studies have not always obtained homogeneous results
[144]. Regardless, GSTM1 homozygous deletion carriers have
been shown to have higher levels of oxidative damage in the TM
than their wild type counterparts [119]. In glaucoma, antioxidant
defenses, particularly glutathione, are decreased at a systemic
level [145]. In POAG, increased levels of lipid peroxidation
products occur in the AH, the TM, and Schlemm’s canal [146].
TM DNA damage results in transcription injury and consequent
damages to protein expression. Indeed, in POAG patients, AH
proteome changes reflect molecular and cellular damages that
occur in primary POAG target tissues, i.e., the TM and optic nerve
head [147]. Apoptosis occurring in ocular tissues during POAG is
induced by a variety of mechanisms, which primarily include
mitochondrial damage through the intrinsic activation pathway
[148] but also inflammation [149], vascular dysregulation [150],
and hypoxia [151].
Additionally, the iris tissue contributes to the antioxidant
defenses of the ocular anterior chamber. Indeed, the protective
antioxidant system of the iris includes low-molecular-weight
antioxidants that are present in this pigmented tissue at high
concentrations [152]. The iris is enriched with melanocytes
containing the pigment melanin, whose function is to prevent
light scattering. Melanin is a potent antioxidantthatis likely to be a
major contributor to the low sensitivity of the iris to hydrogen
peroxide [132]. Several mechanisms have been put forward to
explain the putative protective effect of heavy iris pigmentation,
including its positive correlation with choroidal melanin [153] and
macular pigment [154], its association with ethnic origin, and its
effect of reducing the amount of light entering the eye [155].
Furthermore, melanin absorbs UV radiation and blue light more
efficiently than visible light of longer wavelengths [156].
Together with melanin, the spectral properties of the extracellular matrix also contribute to the antioxidant activity defending
the iris [157]. Macular pigment depletion may occur as a result of
oxidative stress in eyes with light-colored irises because of
increased light transmission [158]. The opening in the iris, the
pupil, expands and contracts to control the amount of incoming
light. Therefore, the iris modulates the amount of the damage that
light may cause to the ocular posterior segment.（我们还不确切知道

为什么会发生青光眼，但可以肯定的是

TM在诱导青光眼的发生中发挥致病作用

线粒体损伤与细胞凋亡和凋亡的触发

损失[133]。事实上，与对照组相比，POAG患者的抗氧化酶超氧化物歧化酶1/2和谷胱甘肽S转移酶1显著下调，

而促氧化酶一氧化氮合成酶2和

谷氨酸氨连接酶在POAG中显著上调

与对照组相比，患者[134]。遗传因素是

很可能非常重要，并有助于

氧化应激。例如，GSH转移酶的缺失

同功酶GSTM1与癌症风险增加有关

正在发生癌症[135]，并且暴露于环境风险的受试者中促突变DNA加合物水平增加

癌症[136]和动脉粥样硬化[137]的因素。几行

有证据表明，GSH可能也与疾病有关

青光眼的发病机制。事实上，这种酶可以保护

对抗视网膜中的氧化应激，视网膜是糖尿病的靶组织

高级POAG[138]。GSTM1空多态性是

与阿拉伯人口中的POAG有关[139]，巴西人

人口[140]、土耳其人口[141]和女性

巴基斯坦假剥脱性青光眼患者

[142]，但不在中国人口中[143]。在白种人中，

临床研究并不总是获得一致的结果

[144]. 无论如何，GSTM1纯合缺失携带者

已经证明TM中有更高水平的氧化损伤

与野生型的同类相比[119]。在青光眼中，抗氧化剂

防御系统，尤其是谷胱甘肽，在全身水平降低

级别[145]。在POAG中，脂质过氧化水平增加

产品出现在AH、TM和施勒姆运河[146]。

TM DNA损伤会导致转录损伤，并导致

蛋白质表达受损。的确，在POAG患者中，啊

蛋白质组的变化反映了

发生在原发性POAG靶组织，即TM和视神经

头[147]。POAG期间发生在眼组织中的细胞凋亡

由多种机制诱导，主要包括

线粒体通过内在激活途径受损

[148]还有炎症[149]，血管失调[150]，

和缺氧[151]。

此外，虹膜组织有助于抗氧化

眼前房的防御。事实上，保护主义

鸢尾的抗氧化系统包括低分子量

这种色素组织中存在的抗氧化剂

浓度[152]。虹膜富含黑素细胞

含有黑色素，其功能是防止

光散射。黑色素是一种强有力的抗氧化剂，很可能是

虹膜对氢的敏感性低的主要原因

过氧化物[132]。已经提出了几种机制来解决这个问题

解释重度虹膜色素沉着的假定保护作用，

包括其与脉络膜黑色素的正相关[153]和

黄斑色素[154]，它与种族起源的关系，以及

减少进入眼睛的光量的效果[155]。

此外，黑色素更能吸收紫外线和蓝光

比波长更长的可见光更有效[156]。

与黑色素一起，细胞外基质的光谱特性也有助于抗氧化活性

虹膜[157]。黄斑色素耗竭可能是由于

浅颜色虹膜眼睛的氧化应激

透光率增加[158]。虹膜上的开口

管理、扩展和收缩，以控制传入数据的数量

光因此，虹膜会调节受损的程度

光线可能导致眼球后段受损。

）

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2.4

Among the general population, exposure to sunlight has been
frequently associated with cataract development. However, this
relationship has not been observed in all studies. Thus, it is likely
that cataracts result from a complex gene–environment interaction. Regardless, high amounts of cataracts have been detected in
populations that have a high annual exposure to sunlight and UVR
[159]. A cataract is the opacification of the lens that occurs when
the refractive index of the lens varies significantly over distances
approximating the wavelength of the transmitted light [160].
The lens is positioned behind the iris, and its function is to focus
light onto the retina. The lens has three main parts: the lens
capsule, the lens epithelium, and the lens fibers. The lens capsule is
a smooth, transparent basement membrane that completely
surrounds the lens. The capsule is elastic and is composed of
collagen. The lens epithelium is located in the anterior portion of
the lens between the lens capsule and the lens fibers and is a
simple cuboidal epithelium. The cells of the lens epithelium also
serve as the progenitors for new lens fibers [161]. During aging, old
lens epithelial cells are not lost. Rather, they lose their organelles
and are compressed into the center, or nucleus, of the lens. There is
a coincident dehydration of the proteins and the lens itself. The
solid mass of the lens is composed of 98% protein, including three
main types, i.e., a-, b- and g-crystallins, which account for nearly
90% of the total lens proteins. Among these three classes of
crystallins, a-crystallin is the predominant type [162]. A primary
function of crystallins is to focus light on the retina by maintaining
the necessary refractive characteristics and clarity of the lens. Lens
proteins undergo very little turnover, but they do undergo various
changes during aging and cataractogenesis, including increased
crystallin proteolysis, fragmentation and aggregation [163]. In
addition to the structural role of a-crystallin in the lens, it also
functions as a chaperone [162]. Chaperone activity is susceptible to
modulation by low-molecular-weight compounds such as adenosine triphosphate and glutathione whose concentrations change
with aging [164,165]. In aged human lens, glycation and ultraviolet
irradiation result in a loss of a-crystallin chaperone activity
[166,167] that induces increased crystallin aggregation, light
scattering and loss of lens transparency [168]. Because these
proteins undergo minimal turnover as the lens ages, they are
subject to the chronic stresses of exposure to light and oxygen
[169]. The molecular basis of UVB damage has been linked to the
generation of ROS [170]. In addition to environmental stress,
oxidant radicals derived from H2O2 or mitochondrial respiration
are involved [171]. Because crystallins and other proteins in lens
fiber do not regenerate and must serve the lens for the lifetime of
the individual, a highly active antioxidant defense against UVinduced DNA damage to the lens is present. Lens cells have
abundant antioxidant enzymes [172], even if the lens appears to be
exposed to relatively low levels of oxygen and its cells have no
mitochondria, which are the main endogenous source of ROS. The
antioxidant systems of the lens include SOD [173] and glutathione
160 S.C. Sacca` et al. / Mutation Research 752 (2013) 153–171
peroxidase [174], and endogenous free radical scavengers such as
ascorbic acid and GSH [175]. Catalase, which catalyzes the
decomposition of hydrogen peroxide into water and oxygen and
prevents cell damage from high levels of ROS, seems to have little
importance in cataract pathogenesis [176]. ROS cause strand
breaks in DNA and base modifications such as 8-hydroxy 2-
deoxyguanosine (8-OHdG). DNA damage by H2O2 induces lens
repair within 30 min of exposure, whereas DNA strand breaks by
UV in lens epithelium occur later during the repair phase [177].
UVB predominantly induces apoptosis in human lens epithelial
cells, whereas H2O2 induces necrosis; indeed, in lenses, rapid
necro