Biomedicine & Pharmacotherapy 130 (2020) 110577

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Mechanisms of blue light-induced eye hazard and protective measures: a T

review
Xinli Ouyang, Jing Yang, Zexin Hong, Yide Wu, Yongfang Xie*, Guohui Wang*
Key Laboratory of Biological Medicines in Universities of Shandong Province, Weifang Medical University, Weifang, 261053, China

A R T I C LE I N FO A B S T R A C T

Keywords: The risk of blue light exposure to human health has attracted increased research attention. Blue light, with
Blue light relatively high energy, can cause irreversible photochemical damage to eye tissue. Excessive exposure of the eye
Phototoxicity to blue light tends to cause a series of alterations, such as oxidative stress, mitochondrial apoptosis, in-
Retina flammatory apoptosis, mitochondrial apoptosis and DNA damage, resulting in the development of dry eye
Cornea
disease, glaucoma, and keratitis. Accordingly, physical protection, chemical and pharmaceutical protective
Oxidative stress
measures, gene therapy, and other methods are widely used in the clinical treatment of blue light hazard. We
reviewed the studies on possible blue light-induced signaling pathways and mechanisms in the eye and sum-
marized the therapeutic approaches to addressing blue light hazard.

1. Introduction
Recently, with the emergence of sophisticated lighting technologies,
people have had increased exposure to manufactured light sources (e.g.,
LED lights, mobile phones, computers and other devices) [1]. This light,
with a wavelength between 400 nm and 500 nm, is in the blue range of
the visible spectrum. Blue light has been suggested to affect circadian
entrainment, cause lengthened perceived duration and improve alert-
ness [2,3,4], which is associated with the stimulating of photosensitive
retinal ganglion cells (ipRGCs) [5]. Therefore, it has practical value to
exposure to blue-enriched light for special groups, such as coach dri-
vers, medical workers and soldiers [6]. Additionally, blue light photo-
therapy is an effective method to lower serum bilirubin level of neo-
natal jaundice patients in clinical practice [7,8]. However, the potential
hazard of short-wave light to eye has aroused much concern. Some
studies have indicated that high-energy blue light can penetrate the
cornea and lens and reach the retina directly, causing photochemical
damage to the retina [9]; this is called blue light hazard. Photochemical
damage to the rod cells via blue light hazard has long been recognized
in 1966 [10]. Since then, numerous experiments have confirmed blue
light hazard and found that the degree of damage is related to various
factors such as the intensity of blue light received by the eye, distance of
illumination, direction of the line of sight, and spectrum of the light
source. Javier Vicente-Tejedor et al found that removing the blue
component could protect the function and morphology of the retina
significantly using blue-blocking filters [11].
However, the blue light hazard models in these experiments were
induced after long exposure to blue light. A position statement of the
International Commission on Illumination (CIE) indicated that the blue
light hazard efficiency is intimately related to the maximum blue light
safe radiance or irradiance [12]. No evidence supports that exposure to
blue light increases the risk of photochemical injury during normal use
conditions. An assessment of low-energy light bulbs, computers and
tablets also has shown that the blue light hazard exposure limits are not
exceeded in these devices even under long-term viewing conditions
[13,14]. Additionally, sunlight, as a natural light source, carries high-
energy light that can affect the function of the eye; staring at the sun for
more than 0.5 seconds can cause solar retinitis [15]. This damage will
not occur because of the natural eviction reflex of closing the eye
against bright light. Thus, the potential harmful risks to the eye of
manufactured lights are negligible. Additionally, manufactured light is
safe to use if it is used properly [13]. Importantly, we cannot rule out
the potential blue light-induced hazards for special populations, such as
those who work with high-energy sources, such as welders, searchlight
operators, dentists and projectionists [13–17].
Blue light (441 nm)-induced retinal lesions resulting from photo-
chemical damage and not from thermal injury were first reported in
1978 [18]. Mounting evidence suggests that overexposure to blue light
induces a significant increase in ROS production, which contributes to
the loss of photoreceptors, lipid peroxidation and cell apoptosis [19].
The synergistic effects of blue light and N-retinylidene-N-re-
tinylethanolamine (A2E) and photoreversal of bleaching will further

⁎
Corresponding authors.
E-mail addresses: Xieyongfang@wfmc.edu.cn (Y. Xie), wgh00-wgh00@163.com (G. Wang).

https://doi.org/10.1016/j.biopha.2020.110577
Received 2 June 2020; Received in revised form 23 June 2020; Accepted 26 July 2020
Available online 04 August 2020
0753-3322/ © 2020 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
X. Ouyang, et al.
aggravate photochemical damage and cause the activation of in-
flammatory reactions, DNA damage and inhibition of mitochondria and
lysosome function [20,21,22]. Emerging evidence indicates that blue
light phototoxicity is not only limited to the retina; it also damages the
ocular surface by oxidative stress and the inflammatory response.
Furthermore, some scientific data suggest the transparency of crystal-
line lens becomes reduced with age, causing a progressive increase in
absorbance within the blue light spectrum [23]. Previous epidemiolo-
gical studies have indicated that exposure to blue light may be asso-
ciated with the development of ARM [24]. However, a meta-analysis in
2018 showed no association between sunlight exposure and the risk of
AMD [25], a finding that is consistent with the position statement of
CIE [12]
In recent years, blue light hazard has drawn increasing attention,
and the search for new prophylactic and therapeutic measures to alle-
viate blue light hazard has become an important part of ophthalmology
research. To date, many attempts have been made to reduce blue light
phototoxicity. Currently, many anti-blue light products are available, in
addition to wearing traditional anti-blue light glasses. Some scholars
have also proposed new methods, such as gene therapy, retinal trans-
plantation, and antioxidant base scavengers, among others. This review
summarizes the associated mechanisms and treatment of blue light
hazard for the eye.
2. Effect of Blue Light on the Retina
The retina, as a receptor of light signals, plays a major role in visual
formation. There are two main types of cells involved in the formation
of vision in the retina: photoreceptors (rod cells and cone cells) and
retinal pigment epithelium cells (RPE cells). The main function of
photoreceptors is to detect light photons and convert them into a signal
that can be detected. RPE cells are located between the upper layer of
retinal nerve cells and the choroid and play important roles in eye
development and visual functions, such as growth factor secretion,
antioxidant protection, phagocytosis of cell fragments from the outer
segment of the photoreceptor, blood-retinal barrier maintenance, and
other physiological functions. Thus, maintaining photoreceptor and
RPE cell normality is essential for the development of vision.
Extensive work has shown that excessive exposure to blue light
causes severe photochemical injury of the retina. The possible blue
light-triggered signaling pathways and mechanisms in the retina are
listed in Table 1.
2.1. Lipofuscin and blue light hazard
Phagocytosis of detached photoreceptor outer segments by RPE cells
is important to maintain the normal physiological structure and func-
tion of the retina. Lipofuscin is found in undigested membranous discs
and is located in lysosomal storage bodies. The main ingredient of li-
pofuscin is A2E and its oxidation products [26,27]. As a potential
photosensitizer, A2E has the characteristics of spontaneous fluores-
cence. Sparrow JR et al conducted experiments on RPE cells using ex-
posure to blue light (480 nm) and reported blue light-induced cell death
of A2E-containing RPE cells; the cells that did not contain A2E re-
mained viable [28]. The products generated from the photochemical
changes in A2E can induce the production of reactive oxygen species
(ROS), which may lead to oxidative stress [29]. Moreover, the blue light
hazard exhibited a dependence on A2E concentration.
The blue light hazard mechanisms of the retina with the involve-
ment of lipofuscin mainly include the following:
(1) The inflammatory response
Blue light exposure can further increase ROS production. ROS ac-
cumulation can upregulate the activity of C-C chemokine receptor
(CCR2 and CCR3) and promote the release of inflammatory factors,
2
Biomedicine & Pharmacotherapy 130 (2020) 110577
such as interleukin 1 (IL-1), tumor necrosis factor-α (TNF-α), caspase-1,
and monocyte adhesion factor (MCP-1), leading to the destruction of
the blood-retinal barrier and inflammatory reactions (Fig. 1) [30–32].
Additionally, blue light-mediated death involves the activation of the
NLRP3 inflammasome in RPE cells. The microglia are mainly activated
in retinal pigment epithelium (RPE) cells, and caspase-1 and IL-1 ac-
cumulation in the microglial cells is mediated by the NLRP3, causing
macrophage recruitment to the RPE choroid, damage to blood vessels
and death of photoreceptors [30].
(2) DNA damage
The direct action of blue light on DNA has been described. Pei Chen
et al demonstrated blue light-induced DNA double-strand breaks and
pronounced accumulation of DNA breaks in RPE cells in vitro and in
vivo [33,34]. Additionally, singlet oxygen may not only mediate nDNA
damage directly but may also cause mtDNA damage. Furthermore,
mtDNA is not protected by histones, and the damage repair system is
not efficient compared with that of nDNA, increasing the susceptibility
of mtDNA to light hazard [35,36]. Furthermore, the damaged mtDNA
further disrupts the integrity of the mitochondrial respiratory chain,
causing a cycle of ROS-mediated mtDNA damage (Fig. 2).
(3) Damage of mitochondria
Mitochondria have long been considered the vital energy organ of a
cell and the main switch that triggers apoptosis. Emerging evidence
indicates that mitochondria are a target of blue light hazard [20]. TEM
results showed that mitochondria exhibit swollen states with disrupted
membranes, and the inner cristae disappear after blue light exposure.
Mitochondria are the target organelles of ROS. The short-wave blue
light increases the intracellular ROS level and induces oxidative stress.
Excessive ROS stimulate mitochondrial fission through alterations in
the expression of mitochondrial dynamics-related protein, accompanied
by the upregulated expression of the mitochondrial mitotic protein
Drp1 and downregulated expression of the fusion protein Mfn2 [37].
Furthermore, blue light can destroy mitochondrial calcium home-
ostasis, which may destroy the transmembrane potential (MMP) and
increase mitochondrial membrane permeability. Cytochrome C and
apoptosis-inducing factor 1 (Apaf-1) in the mitochondria are released
into the cytoplasm, activating the downstream precursors of caspase-3,
caspase-6, and caspase-7 by the caspase cascade (Fig. 2) [38]. The ac-
tivated caspase protein plays an important role in programmed cell
apoptosis. Furthermore, many mitochondria are located in retinal
ganglion cells. Studies have shown that high-energy blue LED light
negatively affects mitochondrial function by decreasing ATP levels and
activating AIF and heme oxygenase-1 (ho-1), which may lead to the
development of glaucoma diabetes [39–41].
(4) Damage of lysosomes
As mentioned in previous studies, lipofuscin accumulates in lyso-
somes via phagocytosis with age. Blue light-activated A2E inhibits ly-
sosomal autophagy function by oxidative stress damage. This process
has been reported to be associated with the inhibition of mTOR or ac-
tivation of transcription factors, increased lysosomal-related gene ex-
pression and lysosomal membrane permeabilization, and cytosolic
leakage of lysosomal enzymes [42–44].
In summary, lipofuscin, as the main chromophobe in the retina,
produces monomeric oxygen, hydrogen peroxide, and hydroxyl free
radicals under blue light stimulation. Thus, it causes inflammatory
damage and DNA damage, inhibits mitochondria and lysosome func-
tion, and induces cell apoptosis by the caspase cascade.
 Table 1
Mechanisms for blue light-induced retina damage
X. Ouyang, et al.

Experimental animal Blue light irradiation device/mode Subject tissue/cell Action Target/pathway Reference

N/A white fluorescent light, 403, 435, 546 Murine photoreceptor-derived cell AMD; Retinal pigmentosa CCR3 [30]
and 577 nm, 12 h line (661 W)
C57BL/6 J mice, ♂, 8 LED, 480 nm, 3 M Retina Reduces ONL thickness; photoreceptor apoptosis; activates microglia; NLRP3; IL-1β [31]
w retinal degeneration
BALB/c mice, ♂, 7–8 White fluorescence lamp, 3000 lux, 20 Retina Oxidative stress; increases the ROS level; upregulates inflammatory MCP-1; IL-6 [32]
w min cytokines; AMD
N/A Tungsten halogen source, 430 nm, 5 Human adult retinal pigment Induces DNA damage N/A [33]
min epithelium cells (ARPE-19)
SD rats, 1 d Blue light, 900 and 1500 lux, 2 h; light- Retinal cells Induces cell apoptosis in retinal neurocytes; Induces DNA double-strand Ku80 [34]
blocking stainless steel boxes, 1500 breaks
lux, 1 M
N/A Sol 500 light source, 390–550 nm, 0–9 Human retinal pigment epithelium Increases superoxide radical levels; induces mtDNA damage N/A [36]
h cells
N/A LED, 450 nm, 12 h Retinal neuronal cells (R28) Induces alterations in mitochondrial fission and fusion proteins; shifts Drp1; Mfn2; PINK1; Mitochondrial pathway [37]
mitochondrial dynamics to fission; increases the intracellular ROS
level; disrupts mitochondrial MMP
N/A Mercury lamp, 480 nm, 5 h Human adult retinal pigment Induces apoptosis Caspase cascade; Caspase-3; Bcl-2 [38]
epithelium cells (ARPE-19)
N/A LED, 465–475 nm, 8–48 h A lineage of mouse neuronal Inhibits the electron transport system AIF; RIP1; RIP3; HO-1 [39]
precursor cells (RGC-5)
N/A LED, 410–530 nm, 24 h Retinal neuronal cells (R28) Oxidative stress; decreases cell survival; decreases ATP levels Brn3a; Ho-1; GFAP immunoreactivity [40]
N/A LED, 430 nm, 30 min Human adult retinal pigment Increases the intracellular ROS level; Inhibits autophagy; lysosomal LC3-II; mTOR [42]
epithelium cells (ARPE-19) damage

3
N/A Blue light, 448 nm, 6 h Human adult retinal pigment Lysosomal membrane permeabilization; Secretory inflammatory caspase-1; NLRP3; IL-1β; IL-18 [43]
epithelium cells (ARPE-19) cytokines; cytosolic leakage of lysosomal enzymes
N/A LED, 464 nm, 24 h Murine photoreceptor-derived cell Promotes the nuclear transport of transcription factor EB; increases TFEB pathway [44]
line (661 W) lysosomal-related gene expression; morphological changes in lysosomal
structure; lysosomal membrane permeabilization
SD rats, ♂, 10–12 w Xenon arc reflector lamp, 403 nm, 9 d Retina Causes retinal degeneration; Causes photoreceptor apoptosis AP-1 [45]
SD rats, ♂, 10–12 w Blue light, 403, 30 min Retina Induces photoreversal of rhodopsin bleaching; N/A [46]
ddY mice, ♂, 8 w LED, 456 nm, 5 d Retina Decreases visual function; alters rhodopsin localization S-opsin [47]
N/A LED, 400 nm, 15 h Human retinal pigment epithelium AMD VEGFa; VEGFR1 [50]
cells
N/A Halogen lamp, 460 nm, 48 h Human retinal pigment epithelium Inhibits the growth of RPE cells Photooxidative mechanism; HGF [52]
cells
N/A LED, 464 nm, 24 h Mouse retinal ganglion cell line Causes morphological changes; decreases cell viability; induces cell Bcl-2; Bax; caspase-3; Nrf2; HO-1; JNK/p38 [53]
(RGC-5) death MAPK; Mitochondria-dependent apoptosis
pathway
N/A LED, 10000 lux, 9 h Human adult retinal pigment Induces cell apoptosis GADD45α; p53; PI3K/AKT pathway [54]
epithelium cells (ARPE-19)
N/A LED, 460 nm, 0–12 h Human adult retinal pigment Causes fundus damage; decreases total retinal thickness; causes neuron Caspase-3; Zo-1; VEGF; CCL-2, GLUT-1, IL-1β, [55]
epithelium cells (ARPE-19) transduction injury MMP-9; EPO
N/A LED, 465 nm, 6–24 h Murine photoreceptor-derived cell Reactive oxygen species; increases in nuclear translocation of Nrf2 Nrf2 [56]
line (661 W)
N/A LED, 464 nm, 3–24 h Murine photoreceptor-derived cell Induces the aggregation of S-opsin; causes ER stress UPR factor; bip; ATF4; grp94 [57]
line (661 W)
N/A LED, 470 nm, 4 h Human adult retinal pigment Decreases RPE barrier function; oxidative stress PKC-ζ [60]
epithelium cells (hTERT-RPE1,
ARPE-19)
C57BL/6 mice, ♂ LED, 410, 440 and 480 nm, 3h Trigeminal ganglia Decreases neural cell viability; modifies neuronal morphology; Kinase pathway; Inflammation; pERK1/2 [61]
oxidative stress signaling
Biomedicine & Pharmacotherapy 130 (2020) 110577
X. Ouyang, et al.
Fig. 1. Inflammatory pathway caused by blue light hazard.
2.2. Rhodopsin and blue light hazard
Rhodopsin, as a chromophore in rod cells, comprises 11-cis-retinal
and opsin. Rhodopsin plays a vital role in the process of light reception
and dark vision formation in the retina. It is now clear that rhodopsin is
the chromophore for light damage. Christian Grimm found that mice
without rhodopsin are protected against blue light damage, and those
with rhodopsin showed strong light hazard after blue light irradiation
[45]. Blue light can restore activatable rhodopsin by a process called
photoreversal of bleaching and can increase its photon absorption ca-
pacity. Furthermore, blue light-altered rhodopsin localization from the
inner and outer segments to ONL activated the activity of the tran-
scriptional activator AP-1 in photoreceptor cells, causing apoptosis
[46,47]. In summary, rhodopsin is an initiator of blue light-induced
damage; the main mechanism is via photoreversal of bleaching.
2.3. Growth factors and blue light hazard
The balance between VEGF and PEDF in the retina plays an im-
portant role in maintaining the formation of new blood vessels and the
permeability of retinal blood vessels. Vascular endothelial growth
factor (VEGF) plays a central role in stimulating vascular endothelial
cell proliferation, and PEDF is effective in inhibiting this process
[48,49]. Melanie Marie [50] found that the photosensitizer A2E can
upregulate VEGF mRNA levels and downregulate PEDF by activating L-
type calcium channels in A2E-loaded RPE cells. As a result, the dynamic
balance between VEGF and PEDF is destroyed [51]. VEGF activation
further enhances blue light toxicity for RPE cells. These results suggest
that blue light irradiation induces vascular dysplasia and increases
Fig. 2. Endoplasmic reticulum and mitochondrial pathway caused by blue light hazard.
4
Biomedicine & Pharmacotherapy 130 (2020) 110577
vascular permeability. Hepatocyte growth factor (HGF) is a pleiotropic
growth factor that can stimulate the growth and migration of various
ocular cells. Thus, it has a protective effect on the RPE and retinal
neurons. HGF mRNA levels are decreased by blue light exposure in RPE
and retinal neurons, possibly enhancing blue light toxicity [52]. Thus,
blue light irradiation could damage the balance of VEGF and PEDF and
inhibit HGF secretion, findings related to the occurrence of eye diseases
such as diabetic retinopathy (PDR) and glaucoma.
2.4. Related genes of blue light hazard
Extensive work has shown that many genes are differentially regu-
lated after blue light illumination. The caspase-dependent apoptotic
pathway is the main avenue of blue light injury. Exposure to LED light
activates caspase-3 and caspase-9. These events may be associated with
lysosomal membrane permeabilization [38]. Bcl-2 and Bax play central
roles in the regulation of the mitochondrial apoptosis pathway. The
anti-apoptotic protein Bcl-2 is located in the outer membrane of mi-
tochondria and inhibits cytochrome C release. Pro-apoptotic Bax is lo-
cated in the cytoplasm and is transferred to mitochondria after re-
ceiving the apoptotic signal to promote cytochrome C [53]. Long-term
blue light exposure significantly enhances Bax expression and inhibits
Bcl-2 expression, events associated with GADD45α upregulation.
GADD45α upregulation may be mediated by the PI3K/AKT and p53
pathways, and apoptosis is induced by initiating the MKK/JNK pathway
and mitochondrial apoptosis pathway [54,55]. Furthermore, previous
work has demonstrated that the continuous activation of JNK and p38
pathways could phosphorylate c-jun and c-fos after blue light irradia-
tion, inducing apoptosis [53].
X. Ouyang, et al. Biomedicine & Pharmacotherapy 130 (2020) 110577

Strikingly, NF-E2-related factor 2 (Nrf2) has been reported to par-

Reference
ticipate in the protection from endogenous and exogenous stresses in

[62]
[63]

[64]

[67]
retinal tissues as a stress-response transcription factor. Excessive ROS
activates Nrf2 through the mitogen-activated protein kinase (MAPK)

HO-1; Prx-1; CAT;

pathway after blue light irradiation, protecting retinal pigment epi-

IL-6; IL-β; MDA;

Target/pathway

MAPK pathway
thelial cells from oxidant-induced cell death [56]. Under the condition

IL-6; CXCL8
of oxidative stress, ROS activates Nrf2 through the MAPK pathway,
maintains intracellular REDOX homeostasis, and protects against oxi-

SOD-2
N/A
dative stress, apoptosis and inflammation in the retina [56].
Additionally, endoplasmic reticulum stress is partially involved in

Lipid oxidative stress; increases inflammatory T cells; leads to corneal opacity and
blue LED light-induced retinal damage (Fig. 2). Previous studies suggest

Decreases cellular viability; affects cellular morphology; provokes reactive ROS

neovascularization; induces inflammation and tissue damage; dry eye disease

that exposure to excessive light induced the aggregation of S-opsin and

Decreases corneal epithelial viability; produces ROS; causes ocular surface

upregulated the expression of GRP78 and CHOP, inducing the ER stress

overproduction; increases inflammation; alters mitochondrial membrane

(ERS) and unfolded protein response (UPR) signaling pathways [57,
58]. Excessive light increases the phosphorylation of PERK, which
could further inhibit elF2 expression and upregulate ATF4 expression.

Oxidative stress; decreases corneal epithelium cell viability

ATF4 can activate two important target genes—CHOP and
CADD34—controlling the expression of apoptosis-related genes.

2.5. Other mechanisms

Docosahexaenoic acid (DHA) is an unsaturated fatty acid in RPE

cells. Singlet oxygen and hydrogen peroxide could mediate the lipid
peroxidation of DHA and produce HOHA. HOHA generally causes cell
apoptosis by destroying mitochondria and lysosomes. Additionally,

potential; oxidative stress

HOHA is a precursor to CEP. The CEP immune response leads to the
production of interferon-γ (IFN-γ) and interleukin-17 (Il-17) by CEP-
specific T cells, causing cellular inflammation [59].
RPE cell tight junctions form a blood-retinal barrier between the
choroid and retinal cells. The blood-retinal barrier plays a key role in

damage;
the transport of nutrients, water, and electrolytes. Blue light decreases
Action

the barrier function by downregulating the scaffold protein Zonulae

occludentes-1 (zo-1) expression through the PKC-ζ pathway [60]. Fur-
thermore, oxidative stress, produced by LED exposure, upregulated the
Human corneal epithelium cell line (HCE)
Human corneal epithelial cell line (HCE);

unfolded protein response genes. It decreases trigeminal neural cell

Human conjunctival epithelium cell line

Human corneal epithelial cells (HCE-2)

viability, impacts the primary culture of neural cells, and increases cell
death [61].

3. Effect of Blue Light on the Ocular Surface

Histologically, the ocular surface includes tear film, corneal epi-

Subject tissue/cell

thelial tissue, and conjunctival tissue. The ocular surface is susceptible

Ocular surface
(IOBA-NHC)

to light hazard and abnormalities as the first barrier against irradiant

energy. Extensive work has shown that the mechanism of blue light
hazard on the ocular surface involves oxidative stress damage, ocular
surface inflammation, and cell apoptosis (Table 2).
LED, 410, 480, 525, 580, 595, 630 and 850

Long-term blue light exposure significantly causes oxidative damage

based fiber device, 390, 420, 430, 480 and

and apoptosis to the cornea. Excessive ROS in the cornea not only in-
Xenon-based device, 380–525 nm; LED-

crease the production rate of O2•− in mitochondria and damage mi-

Mechanisms for blue light-induced ocular surface damage
Blue light irradiation device/mode

tochondrial function [62] but also induce inflammatory cytokines and

macrophage recruitment. The oxidation product mediates the activa-
tion of the NLRP3 inflammasome. The active NLRP3 inflammasome
hydrolyzes the precursor of IL-1 and releases active IL-1, further pro-
LED, 405 nm, 3 min

LED, 410 nm, 10 d

moting the secretion of IL-6 through the P38 and JNK signaling path-
ways [63,64]. The inflammatory response in the cornea is associated
630 nm; 17 h

with the development of dry eye disease. The release of inflammatory

nm, 24 h

factors reduces the secretion of tears and mucin, increases the in-
stability of tear film, promotes the evaporation of tears, and finally
causes the hyperosmotic environment of the eye surface [65,66,67].
C57BL/6 mice, ♀, 6–8

Additionally, conjunctival cells seem to be more vulnerable than

Experimental animal

corneal cells. The cornea has a powerful antioxidative defense me-

chanism: blue light induces the upregulation of superoxide dismutase
(SOD1) in corneal epithelial cells, exerting a protective effect on the
cornea. However, the expression of SOD1 has not changed abruptly,
Table 2

w
N/A
N/A

N/A

and the expression of glutathione peroxidase (GPx1) is downregulated

in conjunctival epithelial cells, increasing blue light hazard [64].

5
X. Ouyang, et al.
Furthermore, the conjunctiva actively participates in the immune de-
fense of the ocular surface and contains various immune cells, making
the conjunctiva the first site of eye inflammation. Moreover, most of the
conjunctiva is exposed to the outside world and is more vulnerable to
damage and conjunctivitis. The conjunctiva contains various immune
cells that can participate in the immune defense of the ocular surface.
Therefore, the conjunctiva is sensitive to inflammation.
Taken together, the above findings indicate that overexposure to
blue light with short wavelengths can increase oxidative stress, increase
the expression of inflammatory factors in the cornea and tear film,
decrease cell viability, and cause dry eye.
4. Preventive Measures against Blue Light Hazard
Based on the pathogenesis of blue light hazard, various methods
have been developed to reduce the damage caused by blue light to the
eye. The traditional blue light protection measures are physical pro-
tection, such as blue light glasses, eyewear shields, and blue light
emission control software. They can filter high-energy short-wave blue
light to improve vision and protect against damage. Additionally,
chemical and drug protective measures, retinal transplantation, gene
therapy, and other methods are widely used in the clinical treatment of
light hazard.
4.1. Antioxidants
Oxidative stress plays an important role in blue light hazard. Studies
have confirmed that antioxidants, such as lutein, curcumin, vitamin E,
and Prunella vulgaris, can suppress the accumulation of oxidative
stressors. A2E is produced by free-radical scavenging, MAPK pathways,
and inflammatory cytokine signaling. Lutein is a carotenoid widely
found in nature and the main constituent pigment in the macular area
of the retina. Lutein has been shown to have protective effects in retinal
disease by increasing the density of macular pigment, which could
absorb harmful blue light and protect photoreceptors from damage
[68]. As a common pigment found in plants, anthocyanin pigments are
important to improve visual ability by reducing inflammation and
oxidative damage, inhibiting lipid peroxidation, and preventing the
impairment of photoreceptor cell function during retinal inflammation
[69,70]. Additionally, plant extract, as potential medicine, has been
consumed to prevent eye diseases. Curcumin is an active component
obtained from the root of the plant Curcuma longa Linn. Curcumin has
demonstrated protective effect against blue light irradiation in RPE cells
by decreasing ROS levels and increasing VEGF, GSH, and GSH-Px levels
[71,72].
Prunella vulgaris can protect retinal degeneration from blue light-
induced oxidative stress through the Nrf2/HO-1 signaling pathway,
inhibition of NF-κB, and inflammatory factors [73]. Furthermore, βE2
has a strong therapeutic effect on neurodegenerative diseases, mainly
via its anti-oxidant activities [74]. The molecular mechanisms include
increasing the expression of p-AKT and Bcl-2, decreasing the expression
of caspase-3 and Bax, weakening the cytotoxic effect mediated by H2O2,
and enhancing autophagy.
4.2. Anti-VEGF therapy
The imbalance of PEDF and VEGF caused by blue light damage is
associated with diabetic retinopathy. Thus far, clinical therapy involves
injecting an anti-VEGF drug into the vitreous body to prevent the
progression of diabetic retinopathy [75]. MSC-derived exosomes (MSC-
Exos) were reported to play crucial roles in VEGF inhibition [76]. The
transplantation of MSC-Exos is a new type of treatment method with
distinct advantages, such as self-renewal, multidirectional differentia-
tion, and easy sampling.
6
Biomedicine & Pharmacotherapy 130 (2020) 110577
4.3. Anti-inflammatory drugs
Previous studies have shown the critical role of inflammation in the
pathogenesis of blue light hazard, suggesting that inflammatory factors
may be a target to treat eye diseases. The recruitment and activation of
microglial cells were inhibited in CCR2-knockout mice after blue light
exposure [31]. The inhibition of CCR3 in RPE cells decreased the rate of
cell death induced by decreasing the ROS levels and inhibiting caspase-
3/7 activation. Thus, CCR2 and CCR3 may be targeted for the treatment
of blue light hazard. Silibinin significantly protects RGCs from blue
light damage through the activation of MEK/ERK/CREB pathways [77].
4.4. Gene therapy
Ciliary neurotrophic factor (CNTF) has demonstrated protective
effects in retinal disease by reducing cell apoptosis, activating Müller
cells, and secreting neurotrophic factors. Injection of CNTF into the
vitreous cavity can significantly delay the degeneration and necrosis of
retinal photoreceptor cells caused by light [78]. The differentiation of
bone marrow mesenchymal stem cells modified with the CNTF gene
exhibited potent efficacy in the treatment of blue light-induced optic
nerve injury. CNTF-BMSCs can increase the antioxidant capacity of the
retina by reducing the MDA and VEGF levels, increasing the SOD level,
and enhancing retinal autophagy [79]. Panax notoginsenoside saponins
(PNS) protected against photoreceptor loss, attenuated retinal oxidative
stress and inflammatory changes, and promoted the expression of miR-
155 and SHIP1 in the retina after blue light exposure [80].
4.5. Blue light filtering intraocular lens
Cataract is the main cause of vision loss in the elderly. Effective
treatment is to replace the cloudy lens with intraocular lens. After
cataract surgery, the cloudy lens is removed, and the light that reaches
the retina increases; however, this light is more likely to cause blue
light hazard. Clinical tests have revealed that blue light-filtering in-
traocular lens can partially filter high-energy short-wave light and
shows great significance to protect the retinal fundus and retina of
cataract patients [81,82].
5. Discussion
Thus far, the upsurge in manufactured light sources has raised a
range of public concerns about blue light hazard. Blue light has been
recognized to affect the function of the eye through photochemical
damage only above the threshold. However, the threat of blue light to
the eye should not be underestimated for special groups. For example,
high-power LED irradiation for vital tooth bleaching is a threat to the
retina of dentists [83]. Dentists should control the frequency and
duration of irradiation or use radiation-filtering protection goggles to
prevent blue light hazard. In this review, we describe the primary
mechanisms of blue light hazard on eye and the strategy and treatment
to prevent blue light hazard.
It is widely recognized that blue light is the most harmful to the
retina and ocular surface. The mechanisms involved in blue light injury
mainly include the oxidative stress response, mitochondrial apoptosis,
inflammatory apoptosis, mitochondrial apoptosis, and DNA damage.
Additionally, blue light affects optical nerve conduction by inhibiting
mitochondrial activity. Lipofuscin and rhodopsin are important media
in RPE and photoreceptor cell light damage [42–47]. Blue light upre-
gulates ROS production, causes mitochondrial and lysosomal dysfunc-
tion and disrupts the epithelial barrier, resulting in apoptosis
[32–43,60]. The activation of the mitochondria-dependent apoptosis
pathway, caspase-dependent apoptotic pathway, p53 pathway, and the
ER stress (ERS) and unfolded protein response (UPR) signaling path-
ways play a major role in blue light damage [53–58]. These patholo-
gical changes may result in various eye diseases, such as diabetic
X. Ouyang, et al.
retinopathy, glaucoma, and dry diseases. Many studies have established
that the ultraviolet (UV) component of light is the major environmental
cause of skin aging [84,85]. However, the blue light of visible light has
been demonstrated to have deleterious effects on skin through oxidative
stress and destruction of endogenous flavin chromophores [86]. Frances
Rucker [87] and Min Wang [88] reported that blue light has a sup-
pressive effect on the development of myopia in chickens. The me-
chanisms are unclear, but they may be associated with higher retinal
dopamine release.
Several strategies have been used to protect against blue light ha-
zard based on the findings that blue light leads to ocular diseases, such
as wearing anti-blue light glasses to filter out the harmful light or
controlling the emission spectrum from smartphones and visual dis-
plays to attenuate the transmission of blue light. Additionally, topical or
oral antioxidants [70–74] and injected anti-VEGF reagents [73,76]
have shown promise to improve visual quality. Retinal transplantation,
gene therapy, neurotrophic factor intervention, and blue light-filtering
lens implantation also demonstrated good effects in clinical studies
[78,79]. However, these methods cannot completely cure the diseases.
With the progress of science, research on the mechanism of blue light
damage will identify potential therapeutic targets and continue to im-
prove visual quality in individuals.
Declaration of Competing Interest
There are none.
Acknowledgments
This study was supported by the Natural Science Foundation of
Shandong Province China (ZR2019MA018) and the National Natural
Science Foundation of China (11802209) and the Shandong Project for
Talents Introduction and development on Youth Innovation Team of
Higher Education.
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