Gene 678 (2018) 177–183

Contents lists available at ScienceDirect

Gene
journal homepage: www.elsevier.com/locate/gene

Review

Oxidative stress and bronchopulmonary dysplasia☆ T

⁎
Junyi Wang, Wenbin Dong
Department of Newborn Medicine, The Affiliated Hospital of Southwest Medical University, 25 Taiping Road, Luzhou, Sichuan 646000, People's Republic of China

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

Keywords: With the progress of modern medicine, oxygen therapy has become a crucial measure for the treatment of
Neonatal premature infants. As an environmental stimulus, in the normal development of lungs, oxygen plays a very
BPD important regulatory role. However, the problem is that long-term exposure to hyperoxia can interfere with the
Oxidative stress development of lungs, leading to irreversible developmental abnormalities. Now, the incidence of broncho-
pulmonary dysplasia (BPD) is increasing year by year. The existing related research shows that although BPD is a
multi-factor triggered disease, its main risk factors are the premature exposure to hyperoxia and the role of
reactive oxygen species (ROS). As for premature infants, especially very premature babies and those with very
low birth weight, prolonged exposure to high oxygen can affect and alter the normal developmental trajectories
of lung tissue and vascular beds, triggering developmental disorders, such as BPD. In the relevant studies about
human BPD, a large number of them support that ROS is associated with impaired lung development. Neonates,
due to the damage in the development of alveolar, are specific to hyperoxia-induced inflammatory damage. This
review while focusing on the role of oxidative stress in the pathogenesis of BPD, suggests that antioxidant
measures may be effective to guard against BPD of preterm infants.

1. Introduction hypertension in preterm infants with BPD is also relatively high.

Nowadays, thanks to the widespread use of oxygen therapy, the
survival rate of premature infants is increasing. As an environmental
stimulus, in the normal development of lungs, oxygen plays a very
important regulatory role, which may be related to the interaction
between oxygen and cells. However, the problem is that long-term
exposure to hyperoxia can interfere with the development of lungs,
leading to irreversible developmental abnormalities (Buczynski et al.,
2013; Saugstad et al., 2011).
Now, bronchopulmonary dysplasia (BPD) incidence is rising year by
year. Current research shows that (Carraro et al., 2013; O'Reilly and
Thébaud, 2013; Kotecha et al., 2013) although BPD is a multi-factor
disease, including premature lung development immature, infection,
nutrition, oxygen poisoning, volumetric injury during mechanical
ventilation, barotrauma and inflammatory factor response, etc., its
main risk factor is due to the exposure to hyperoxia and the role of
reactive oxygen species (ROS) on premature infants. Previous studies
have shown that children with BPD have a poor prognosis. They often
suffer repeated respiratory infections and re-hospitalization. In addi-
tion, they would suffer gradual decline of lung function with their age
increasing. The further risk of retinopathy, learning disabilities and
Although many pharmacological and non-pharmacological methods
have been proposed, there is no clear protocol for limiting or treating
BPD. Therefore, to explore the pathogenesis of BPD is an important
guide for early prevention. The purpose of this review is to summarize
the research progress in the role of oxidative stress during the devel-
opment of BPD, which proposes that anti-oxidative stress may be a key
link in the prevention and treatment of BPD.
2. BPD
2.1. The definition of BPD
Northern (Jr and Rosan, 1968) first reported BPD in 1967, defining
the typical BPD as a chronic lung injury caused by severe respiratory
distress syndrome. In the same year, BPD was reported to be closely
related to hyperoxia (Northway Jr and R., 1967). With the widespread
use of new treatments such as exogenous surfactants, mild ventilation
strategies and prenatal steroids, the description of traditional BPD has
been changed. A typical BPD characterized by wide-ranging and serious
inflammation in lung tissue and extensive fibrosis in various respiratory
tracts has slowly evolved into a new type of BPD: NICHD redefined BPD

☆
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
⁎
Corresponding author.
E-mail address: dongwenbin2000@163.com (W. Dong).

https://doi.org/10.1016/j.gene.2018.08.031
Received 10 April 2018; Received in revised form 30 July 2018; Accepted 6 August 2018
Available online 09 August 2018
0378-1119/ © 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
J. Wang, W. Dong
and its indexing standards in 2000. In terms of the “new BPD” char-
acterized by alveolar and pulmonary microvascular dysplasia, there
was no change in chest radiographs used as a basis for assessing BPD
severity (Pesce and Musi, 1996). Any newborn with oxygen dependence
(oxygen concentration > 21%) over 28 days can be diagnosed as “new
BPD”. Its characteristics include impaired lung function, mainly mani-
fested as airway hyperresponsiveness and airway obstruction, as well as
obstructive ventilation dysfunction (Niedermaier and Hilgendorff,
2015). Compared with traditional BPD (Jobe, 1999), its pathological
manifestations include less smooth muscle hyperplasia, lighter fibrosis,
rarely, severe squamous metaplasia, decreased alveolar number, in-
creased alveolar volume, and simple structure, pulmonary micro-
vascular dysplasia and increased elastic tissue. In terms of the new BPD,
the process of normal lung development is altered, leading to the de-
velopment of lungs in different orders and orientations.
2.2. Hyperoxia with lung injury
Previous studies have shown that (Dani et al., 2004) infants have a
partial increase in oxidative stress signs before birth and at birth, sug-
gesting an increase in its ability to resist oxidative stress, which may be
aimed at adapting to the increased level of oxidation due to the spon-
taneous inhalation of oxygen at birth. However, as for preterm children,
especially very premature ones and those with very low birth weight do
not have such response. Furthermore, due to its pulmonary in-
sufficiency, lack of alveolar surfactant, endogenous antioxidant en-
zymes system defects, the anti-oxidative stress system is imperfect.
Therefore, it is more likely to be exposed to hyperoxia. A very short
time of high oxygen exposure will trigger a cascade of oxidative stress,
thus leading to oxidative damage (Maltepe and Saugstad, 2009;
Kaarteenahowiik and Kinnula, 2004).
The lung injury caused by hyperoxia exposure mainly includes cell
necrosis or apoptosis in the alveolar epithelium and vascular en-
dothelium, resulting in the destruction of alveolar structure, increased
vascular permeability, and massive recruitment of inflammatory cells
(Balany and Bhandari, 2015), which would can delay the separation of
cystic alveoli with alveoli, inducing the proliferation of stromal cells,
thus leading to the persistence of inflammation, while blocking the
formation of capillaries in the distal lung tissue. That is how it can
eventually result in pulmonary hypertension (Warner et al., 1998).
Inflammatory cells cause damage to lung tissue by inducing in-
flammatory and vascular responses by producing cytokines and che-
motaxis. The relevant studies have shown that hyperoxia exposure in-
duces focal endothelial cell damage in the early stages of lung tissue,
which will leading to necrosis of epithelial cells if continued exposure to
hyperoxia still exists (Bhandari, 2010; Shyanne et al., 2016).
Hyperoxia would cause pulmonary dynamics changes, the destruc-
tion of alveolar capillary membrane would cause gas exchange dis-
orders, and pulmonary edema would cause pulmonary capillary per-
meability. All of them would eventually result in alveolar endothelial
and epithelial cell death, increased alveolar vascular permeability.
Moreover, ruptured capillaries would result in a loss of lung integrity.
However, pulmonary edema and concomitant inflammatory processes
decrease even with continued exposure to hyperoxia, but chronic lung
inflammation occurs after acute reactions. Hyperoxia lung injury of
neonates occurs during the developmental stage, and is influenced by a
variety of cytokines during hyperoxia-induced lung injury, thus forming
a characteristic pathological manifestation of BPD (Hellström et al.,
1990).
2.3. Relationship between hyperoxia exposure and BPD
Long-term hyperoxia exposure is the most important cause of BPD
pathogenesis (Kolls, 2017). A fetus relies on the placenta and the fetal
circulation in its mother's body to obtain oxygen for developing tissues
for growth maintenance in relatively hypoxic conditions. The oxygen
178
Gene 678 (2018) 177–183
concentration in the atmosphere at birth is also relatively high in
neonatal exposure. The relevant studies have shown that anti-oxidative
enzyme activity in the pre-natal level is significantly higher than in
early pregnancy, indicating a clear upward trend (such as superoxide
dismutase (SOD), catalase (CAT) and Glutathione peroxidase (GP)).
This change in regarding fetuses suggests that the defensive capacity of
the lungs in the defense of the uterus in the fetus is actually increasing,
which seems to be essential in the process of fetal maturation. The in-
crease of anti-oxidative enzyme activity before birth of fetuses con-
tributes to the smooth adaptation of lungs to a new respiratory en-
vironment, ensuring that a neonatal respiratory function can be
adapted at birth (Tsukahara, 2007). At the same time, the tolerance of
term infants to relatively high level of oxygen in air can be explained by
the level of high antioxidant enzyme activity in mature type II alveolar
cells. As the most important endothelial cells, type-II alveolar cells that
mediate the antioxidant capacity of the lungs are more likely to be
hypoplasia in preterm labor and have a higher likelihood of being
earlier. Therefore, as to premature children with weak resistance to
hyperoxia exposure, there is not enough anti-oxidation ability to pre-
vent exposure to hyperoxia damage (Frank and Groseclose, 1984).
3. Oxidative stress
3.1. ROS
Free radicals are defined as “any chemical that contains one or more
unpaired electrons and can stand alone” (Ryter and Choi, 2013). Free
electrons produced under the normal aerobic metabolism of cells are
readily accepted by oxygen to produce ROS, such as singlet oxygen,
superoxide (O2%) and oxygen-containing groups (hydroxyl, HO%) and
oxidant H2O2 (Winterbourn and Hampton, 2008). The role of ROS in
the body depends largely on the internal environment of the body in
which ROS exists, including location, time, concentration, proximity,
etc. (Auten and Davis, 2009). Current research suggests that ROS and its
reaction products can mediate cell signaling as signaling intermediates,
thus participating in adaptive or maladaptive molecular responses, in-
cluding cell growth, differentiation, apoptosis and necrosis (Saugstad,
2010). In general, antagonism of free radicals to the enzymes and an-
tioxidants in body at physiological states can maintain the balance of
ROS production and clearance. In terms of the mechanism of oxidative
stress reaction, any oxidant can induce oxidative stress reaction in an
excessive environment. ROS is the most important oxidant to initiate
oxidative stress reaction. Therefore, an overproduction of ROS under-
mines the oxidation-anti-oxidant balance and triggers an oxidative
stress response that can lead to inflammatory reaction and tissue da-
mage. ROS can cause damage to all biological molecules, while the
main targets of ROS in cells are proteins, nucleic acids, carbohydrates
and membrane lipids (Torres-Cuevas et al., 2016; Aparici et al., 2013;
Wiegman et al., 2014).
3.2. ROS with damage
The role of ROS in body is related to the environment it exists (Rees
et al., 2008). Physiologically, ROS induces an increase in specific types
of apoptosis. Therefore, under normal conditions, the synthesis of ROS
is essential for the normal development of embryo morphology. In
addition, ROS stimulates the growth factors of live cells, and eliminates
dysfunctional proteins through oxidation, playing a vital role in main-
taining the normal physiological functions of various organelles (Zuo
et al., 2015). In cells, mitochondria are the most important “factory” for
ROS (Quinlan et al., 2012; Parinandi et al., 2003; Carnesecchi et al.,
2009a) mainly through uncoupling of electron transport chains and
electron leaks. Other components that can produce ROS include (Auten
and Davis, 2009) cellular components, such as the plasma membrane
surface, endoplasmic reticulum-binding enzymes, and the cytosolic
enzyme system; activated multi-enzyme systems include inflammation-
J. Wang, W. Dong
associated synthase (COX and LOX), NOS, cytochrome oxidase, and
xanthine oxidoreductase. Hyperoxia, inflammation, ischemia-reperfu-
sion and antioxidant defensive decompensation/damage will lead to the
oxidative stress response of body tissue. In the early stage, over-
production of ROS results in the destruction of oxidative and anti-
oxidant balance in body and damage to tissue cells, especially the lung
tissue, which is mainly caused by inducing autotoxicity of lung epi-
thelial cells and endothelial cells concerning lung tissue damage
(Chuang et al., 2014).
ROS is a highly active oxidant that directly damages cellular
structures and can directly damage proteins, lipids and nucleic acids, as
well as cause cell death through a variety of pathways (Cadenas, 2018;
Richter et al., 2015; Sullivan and Chandel, 2014; Tann et al., 2011).
ROS can act on the biofilm to induce membrane lipid peroxidation.
Lipid peroxidation can activate sphingomyelinase and release large
amounts of ceramide to induce apoptosis (Tann et al., 2011; Sies, 2017;
Burgoyne et al., 2013). ROS can initiate protein oxidation processes and
nitrosylation processes, such as carbonylation, nitration and nitrotyr-
osine formation, thus affecting the biological activity and formation of
various enzymes, ultimately leading to significant cellular dysfunction.
In addition, ROS can act directly on oxidized nucleic acid which will
lead to DNA strand breaks, thereby inducing cell necrosis or apoptosis.
At the same time, ROS can activate multiple signal transduction path-
ways in cells, promoting the transmission of cytokines, growth factors
and calcium signals, and eventually leading to cell death (Tiganis,
2011; Barnes, 1990).
Oxidative stress triggered by hyperoxia exposure regulates the an-
tioxidant capacity in vivo, while the antioxidant enzyme system of
premature infants is dysplasia. Compared with those term infants,
premature infants suffer weak expression and activity of antioxidant
enzymes under hypoxic conditions. Therefore, poor tolerance to hy-
peroxia of preterm infants is also susceptible to ROS-mediated injury
and is more likely to cause lung injury and developmental block
(Kaarteenahowiik and Kinnula, 2004). Datta et al. (2015) believe that
the leakage of ROS in the matrix may be involved in the occurrence of
injury. Additionally, in the isolated pulmonary arterial smooth muscle
cells, it confirmed that the exposure to high oxygen concentration first
increased the production of ROS in mitochondria, followed by an in-
crease level of ROS in cytoplasm, eventually leading to oxidative stress
damage caused by the overload of ROS in cells. ROS is associated with
pathophysiological changes in many lung diseases, such as broncho-
pulmonary dysplasia (Djr et al., 2017; Domej et al., 2014; Hoffman
et al., 2015). In the relevant studies about of human BPD, a great
number of researches have shown that ROS is associated with ab-
normalities and injuries during lung maturation.
3.3. Oxidative stress with BPD
3.3.1. Oxidative stress with lung development
Many enzymes are capable of producing reactive oxygen species
(ROS) in human cells, but the NOX family is currently the only enzyme
that has been confirmed to produce ROS as its main function (Crosas-
Molist and Fabregat, 2015). Single Nucleotide Polymorphisms (SNPs) in
the NADPH oxidase (NOX) family are closely associated with oxidative
stress injury, especially in preterm infants (Huizing et al., 2017). The
mechanism by which the NOX enzyme catalyzes the production of su-
peroxide and free radicals is primarily operated by facilitating oxygen
molecules to receive electrons transferred from NADPH (Brandes et al.,
2014). NOX1, NOX3 and NOX5 produce superoxide, while NOX2 and
NOX4 mainly produce hydrogen peroxide (Bedard and Krause, 2007;
Takac et al., 2011). The increase number and over-activation of Nox1
during hyperoxia exposure is an important link leading to excessive
ROS production and destruction of the alveolar capillary barrier, and is
a participant in hyperoxia-induced acute oxidative stress injury
(Carnesecchi et al., 2009b). In contrast, Nox1 deficiency showed sig-
nificant protection against hyperoxia-induced lung injury of mice
179
Gene 678 (2018) 177–183
(Carnesecchi et al., 2011). Animal experiments has shown that O2 -
increases with the increase of NADPH oxidase in lambs with endothelial
dysfunction (Oishi et al., 2013). Similarly, endothelin-1 (ET-1) is an
important inflammatory mediator that is released by excessive ROS and
mediates increased NADPH oxidase activity and elevated O2 levels in
lung epithelial cells (Rafikova et al., 2013; Wedgwood et al., 2013).
Alveolar epithelial type-II cells (AEC II), as the most important stem
cells in lung tissue play a crucial role in the regulation of lung tissue
growth, maturation, wound-repair process and lung fluid homeostasis.
Proliferation and differentiation of AECIIs are the major factors which
regulate the post-injury repair of alveolar epithelial structures and
functions. As a stem cell, AECII can be converted to AECI, and can se-
crete a variety of bioactive substances to restore alveolar capillary
barrier integrity and maintain alveolar function, oxidative stress in-
duced by hyperoxia induces excessive apoptosis of AECII and inhibits
its proliferation, which is crucial for the development of BPD (Zhang
et al., 2014; Liu et al., 2014; Hou et al., 2015; Wu et al., 2018). Pul-
monary remodeling and vascular remodeling induced by hyperoxia are
the basis of BPD formation. Airway remodeling during lung develop-
ment is the result of the combination of pathological processes that
includes airway epithelial cells, smooth muscle cells, inflammatory cells
and ECM components. The main causes of airway remodeling include
airway epithelial damage, especially AECII repair abnormalities (Royce
et al., 2014; Shimoda and Laurie, 2013).
Cells under various harmful or stressful conditions will induce ab-
normal post-translational modifications of protein, resulting in a lot of
unfolded protein accumulation in cell and destroying the normal phy-
siological function of cell, Thus, eukaryotic cells would evolve into an
unfolded protein response (UPR) process to relieve unfolded protein
burden, including increasing protein folding capacity, degrading mis-
folded proteins and inhibiting protein translation (Lee et al., 2014;
Konsavage et al., 2012). During hyperoxia exposure, oxidative stress
promotes the increase of UPR (non-folded protein) and induces stronger
endoplasmic reticulum oxidative stress (ER) (Teng et al., 2017; Bai
et al., 2017), ER mediates apoptosis of AECII cells, oxidative stress, ROS
production and amplification of inflammation, leading to the apoptosis
in mitochondria-dependent and independent pathways, as well as the
alveolar growth retardation, which would damage the development of
lung morphology, and cause increased AECII apoptosis while mediating
impaired angiogenesis and vasodilation. Flodby et al. (2016) found that
ER-deficient mice stunted alveolar development, perinatal lung sur-
factant protein and type-I cell markers reduce, contributing to the oc-
currence of BPD.
3.3.2. Oxidative stress with vascular development
The process of normal lung maturation and the formation and ma-
turation of blood vessels are benefit from the presence of many kinds of
growth factors, such as FGF, TGF, HGF and VEG (Jin et al., 2016; Chen
et al., 2017b). VEGF has an effect in promoting endothelial growth and
remodeling lung tissue in endothelial cells, especially during normal
alveolar formation and vascular growth. The relevant studies have
shown that (Muramatsu et al., 2016) vascular endothelial growth factor
receptor 2 (VEGFR2) is very essential for maintaining the normal
structure and function of alveoli. The reduce of VEGFR2 activation level
is closely related to the stagnation of lung maturation, which can also
induce the apoptosis activity of endothelial cells and mesenchymal
cells. VEGF in allowing angiogenesis and alveolarization is a pre-
requisite for the remodeling and repair of lung injury during hyperoxia-
induced injury of microvasculature. There is a decrease tendency for
VEGF in human children with BPD and the use of VEGF antagonists in
neonatal rats resulted in significant impaired alveolar development
(Jiménez et al., 2018; Lingappan et al., 2016). Salaets et al. (2015) have
demonstrated the protective effect of VEGF on mesenchymal stem cells
in a hyperoxia-induced ALI rat model. The decreased expression of
VEGF results in the cessation of sprouting during development of lung
angiogenesis. Excessive ROS and nitrogenous substances can be
J. Wang, W. Dong
induced by oxidative stress and lead to apoptosis (Berger and Bhandari,
2014).
Inadequate angiogenesis, accompanied by hypoxia in local tissues,
leads to the dysplasia of blood vessels and alveoli and is an important
component of the mechanism of BPD. In addition, Zhang and Lingappan
(2017) have found that HUVECs (umbilical vein endothelial cells) of
female mice showed a better cell viability and angiogenesis compared
with male ones after hyperoxia exposure. In oxidative stress, male mice
produced more H2O2 with macrophages and neutrophil infiltration
increased more significantly. In addition, the number of pulmonary
vessels and the expression of angiogenic markers (PECAM1 and
VEGFR2) were more severely damaged.
3.3.3. Oxidative stress with inflammation
During hyperoxia exposure, the recruitment of inflammatory cells in
lung, which is caused by a large number of chemokines produced by
monocytes/macrophages, lymphocytes, epithelial cells, endothelial
cells and stroma, is the major mechanism leading to lung injury
(Bhandari, 2010; Thomas and Speer, 2014). NO is essential for main-
taining lung homeostasis. However, nitrification stress is activated and
enhanced by excessive NO, thus exerting pro-inflammatory effects. In-
flammatory stimuli, hypoxia and hyperoxia will lead to increased iNOS
expression in lungs. Reynolds et al. (2016) have found that Lung iNOS
protein expression in the hyperoxia models of mouse can serve as a
biomarker of inflammation, revealing that hyperoxia exposure leads to
potential lung inflammation.
Many kinds of proinflammatory cytokines are activated during
oxidative stress. Chemotactic inflammatory cells stimulate the synthesis
and secretion of inflammatory mediators, and enhance the in-
flammatory response (Anita et al., 2016; Yeh et al., 2016), such as IL-1,
IL-6, IL-17 (Lawrence et al., 2017), IL-8, CINC-1 and MCP-1. IL-1β was
demonstrated to be overexpressed in alveolar epithelial cells in the
model of neonatal mice with BPD (Rudloff et al., 2017). IL-6 was found
to be involved in the inflammatory cascade (Matsumura et al., 2017),
and was overexpressed in lung tissue exposed to hyperoxia. At the same
time, the relevant studies have shown that high levels of IL-6 are as-
sociated with more severe pulmonary edema and inflammatory re-
sponse during early exposure (Hsiao et al., 2017). Monocyte Chemo-
tactic Protein-1 (MCP-1), as a chemokine like CINC-1, has main target
cells of monocytes, lymphocytes and basophils (Kumar et al., 2016).
The level of MCP-1 is elevated in tracheal aspirates of hyperoxia-in-
duced premature infants with BPD, which is related to BPD. In the
animal model with BPD, the number of neutrophils in tracheal aspirate
and bronchoalveolar lavage fluid increased with the increasing level of
IL-8 protein, which was associated with infection. IL-8 protein con-
centrations in homogenates of pre-term explant culture of lung exposed
to hyperoxia were much higher than those of lungs of full-term babies
(Leroy et al., 2017). Tumor necrosis factor-α (TNF-α) (Ehrhardt et al.,
2016a; Ehrhardt et al., 2016b) can induce apoptosis due to the in-
flammation through death receptor signaling. It is mainly composed of
various activated immune cells, including macrophages, natural killer
(NK) cells, granulocytes, CD4 + lymphocytes, mast cells and eosino-
phils. The high level of TNF-α may promote chronic inflammation
leading to the development of BPD. Experiments in neonatal rats by
Oncel et al. (2015) have showed that the inhibition of TNF-α is bene-
ficial for alveolar and lung injury by reducing lung inflammation and
oxidative stress. Kaya et al. (2016) have indicate that the inhibition of
NF-κB and TNF-α in the BPD model of neonatal rats can decrease the
MDA level while increase the GSH-PX and SOD levels, which is helpful
for lung development and pulmonary vascularization. At the same time,
TNF-α activates NOX to generate excess ROS. Mitochondria-generated
ROS plays a signaling role in enhancing TGF signaling and promoting
fibrosis (Gonzalez-Gonzalez et al., 2017). NF-κB can be activated by
oxidative stress (Yu et al., 2015). Activated NF-κB mediates the pro-
duction and activation of many inflammatory factors with pro-in-
flammatory effect, and mediates the translocation of nuclear proteins,
180
Gene 678 (2018) 177–183
thus ultimately promoting apoptosis (Kawaguchi et al., 2017;
Lingappan et al., 2016).
Previous studies have shown that (Misra et al., 2015) sustained high
oxygen exposure can up-regulate CINC-1 in lung tissue. Administration
of anti-CINC-1 significantly reduced the neutrophils and myeloperox-
idase activities in the alveolar lavage fluid while preserving more al-
veolar volume and surface area. However, the inhibition of neutrophils
recruitment in lung tissue of neonatal rats exposed to hyperoxia has
been confirmed as an element which can reduce DNA-oxidation-in-
duced breakage and injury, and inhibit the HO% formation and O2%
accumulation. At the same time, it can enhance the alveolar develop-
ment. The LPA receptor (LPAR1-6), as a 7-transmembrane G protein-
coupled receptor, is associated with a variety of physiological and pa-
thological responses, including pulmonary fibrosis, LPS-related in-
flammation, bronchospasm, and airway hyperresponsiveness. Recently,
Shim et al. (2015) have demonstrated that compared with air control
group, young rat pups exposed to hyperoxia had an important increase
in enzyme production and activity to produce LPA and an increase in
LPA receptor LPAR1 and LPAR3 expression. Such data indicate that in
neonatal rats, LPA synthesis and secretion and signal transduction de-
pendent on LPA can be induced by hyperoxia. This process may be
related to the progression of BPD. Chen et al. (2017a) have found that
under hyperoxia exposure, the inhibition of LPAR1 has protective ef-
fects on lung injury and fibrosis associated with ROS and inflammation.
Sphingosine-1-phosphate (S1P) is a signaling molecule existing inside
and outside a cell, whose level is regulated by the synthesis of SphKs 1
and 2. Hyperoxia exposure may cause an increase in SphK1. Natarajan
et al. (2017) have demonstrated that a significant increase in S1P/
SphK1 signaling in neonatal lungs is associated with hyperoxia-induced
apoptosis, promoting gene expression, inflammation, extracellular
matrix remodeling, and cell proliferation arrest. LOOH (Lipid Hydrogen
Peroxide) is a special substance produced during lipid peroxidation
widely distributing in the whole body. Its production is dependent on
oxygen radicals peroxidation of unsaturated fatty acids (especially in
membrane phospholipids). LOOH has a strong destructive effect on
many biological macromolecules in cells. Fabiano et al. (2016) have
found that the level of LOOH in the alveolar lavage of children with
BPD increased, which may be related to ROS overload. At the same time
a large number of cytokines, proteins and enzymes are induced by the
oxidative stress of body and promote cell death, such as acetylated P53.
It has been reported that (Hori et al., 2013; Marcel et al., 2015) hy-
peroxia exposure can increase the transcriptional level of P53 and the
expression and activity of acetylated P53. HGF (hepatocyte growth
factor) (Seedorf et al., 2016) has been demonstrated to protect neonatal
lung tissue against hyperoxic-related injury in animal models under
hyperoxia exposure while improving the dysfunction and preventing
the alveolar development. However, the HGF level of premature infants
is low. HGF can not be protected from being up-regulated under hy-
peroxia exposure. The anti-oxidative damage is weak and alveolar de-
velopment is more easily inhibited.
As for adults and newborns, there is a significant difference in the
type and timing of cytokine synthesis and secretion in lung tissue
during hyperoxia exposure. Lung has a complex developmental and
cause mechanism for lung injury by hyperoxia of newborn infants,
especially preterm infants. Various cytokines would produce different
pro-inflammatory/anti-inflammatory effects. Inflammation triggered
by hyperoxia exposure erupts acutely in the early stages of acute injury,
followed by a reduction in acute and inflammatory responses to chronic
inflammation depending on the acute lung response to hyperoxia.
Neonates, however, are specific to hyperoxia-induced inflammatory
damage occurring in the alveolar development (Wollen et al., 2013;
Thomas and Speer, 2014; Wollen et al., 2014).
3.4. Oxidation with anti-oxidation
Redox potential is thought to be the key to many metabolic
J. Wang, W. Dong
pathways, including cell proliferation, differentiation and apoptosis.
Abnormalities of such pathways can lead to a characteristic block of
blood vessels and a stalled alveolus in BPD. Mohamed et al. (2015) have
found that the oxidative stress injury caused by the hyperoxia plays an
important role in the development of BPD. Antioxidant enzymes are
essential components of antioxidants in the whole body. The specific
distribution of antioxidant enzymes in cells determines the sensitivity of
tissues and cells to ROS-related injury, including superoxide dismutase,
catalase, glutathione peroxidase and peroxiredoxin. The major non-
enzymatic intracellular antioxidants are glutathione (GSH) (Sullivan
et al., 2013). The reduced glutathione can be oxidized by glutathione
peroxidase to reduce free radical activity and the production of H2O2
and lipid peroxidation products, or to stabilize electrophiles. Glu-
tathione reductase subsequently is mediated to restore reduced glu-
tathione by using electrons from NADPH. Immature and low activity of
the antioxidant enzyme system of preterm infants is a causing me-
chanism for lung injury by hyperoxia and lung development retardation
(Poggi and Dani, 2014). Extracellular superoxide dismutase (EC-SOD) is
one of the essential antioxidant enzymes, which is highly expressed in
lung tissue and vascular system, and can dissociate superoxide into
hydrogen peroxide and oxygen. Studies conducted by Cassidy et al.
(2015) has showed that under oxidative stress, mice lacking the EC-SOD
system had more-pronounced obstructive alveolar development, pul-
monary hypertension, and pulmonary vascular remodeling. Nrf2,
known as the “main helmsman” for antioxidant responses, stimulates
most of the gene expressions for antioxidant/detoxifying enzymes, with
antioxidants (SODs) and NQO1 induced (Loboda et al., 2016). NQO1 is
one of the important antioxidant enzymes through which the oxidative
stress induces NQO1 gene expression and regulates the synthesis of ROS
and other free radicals, thereby protecting cells from oxidative injury.
However, recently, Gavrili et al. (2015) found that the NQO1 variant
genotype may increase the risk of BPD.
Other antioxidants include NO, CO, AM, etc. During normal alveolar
development, endogenous NO signaling is enhanced, thereby sig-
nificantly improving the oxygenation response while reducing the lung
oxidation (Davis, 2002; Tsukahara, 2014). CO is a gaseous signal mo-
lecule that has a powerful protective activity on tissues and cells during
oxidative stress (Anyanwu et al., 2014). Adrenomedullin (AM) belongs
181
Gene 678 (2018) 177–183
to the calcitonin family, the normal physiological functions of en-
dothelial cells depends on the action of AM. Zhang et al. (2015) have
demonstrated that AM can reduce oxidative stress, inflammation and
cytotoxicity induced by hyperoxia by activating Akt or protein kinase B
(Akt/PKB). Calcitonin gene-related peptide (CGRP) is a 37-amino acid
neuropeptide. It is an important biomarker for pain control and is
closely related to the embryonic development and cell proliferation
(Azuma et al., 2016; Dang et al., 2012). In lung tissue, AECII cells can
secrete CGRP and mainly distribute in nerve fibers around vascular
smooth muscle and airway mucosa. Recent studies have shown (Fu
et al., 2010; Yu et al., 2015; Li and Wang, 2006) that CGRP can improve
hyperoxia-induced oxidative stress and inflammatory response, thus
preventing hyperoxia-induced apoptosis and destruction of lung struc-
ture by inhibiting the production of ROS. The decompensation of en-
dogenous antioxidant system may lead to the redox function and induce
the oxidative stress injury, which can induce the transcription of genes
that inhibiting the progression of cell cycle (Schieber and Chandel,
2014). However, there has been some controversy in the recent use of
antioxidants. The relevant literature has suggested that antioxidants
may play a dual role in promoting the survival rate of cancer cells.
Moreover, the efficacy of antioxidants is positively correlated with the
drug concentration in target organs. Therefore, targeted administration
is also important in clinical application of antioxidants (Saeidnia and
Abdollahi, 2013).
In summary, the oxidative stress response plays an important role in
the causing mechanism regarding hyperoxia-induced BPD. The oxida-
tion/antioxidant balance can be broken by many factors. Oxidative
stress can induce an oxidative stress response, which can lead to cas-
cade reactions, inducing cell death and further resulting in acute lung
injury. Under the condition of hyperoxia exposure, continuous oxida-
tion can affect the process of lung development, alveolar development
and angiogenesis, eventually leading to BPD. In addition, inflammation,
infection, genetic susceptibility and any other iatrogenic injuries and
factors concerning the pathogenesis of BPD mechanism are still needed
further study. The study on the action mechanism of oxidative stress
plays an important guiding role in the control of clinical use of oxygen
therapy, early detection and prevention of oxidative injury and im-
provement of the prognosis of BPD.
J. Wang, W. Dong
References
Anita, B., Christopher, C., Vineet, B., 2016. BPD following preterm birth: a model for
chronic lung disease and a substrate for ARDS in childhood. Front. Pediatr. 4(3).
Anyanwu, A.C., Bentley, J.K., Popova, A.P., et al., 2014. Suppression of inflammatory cell
trafficking and alveolar simplification by the heme oxygenase-1 product carbon
monoxide. Am. J. Physiol. Lung Cell. Mol. Physiol. 306 (8), L749.
Aparici, S., Martorell, L., Codoñer-Franch, P., 2013. Role of oxidative stress in preterm
infants with bronchopulmonary dysplasia after exposure to chorioamnionitis. J.
Pediatr. Biochem. 03 (03), 143–153.
Auten, R.L., Davis, J.M., 2009. Oxygen toxicity and reactive oxygen species: the devil is in
the details. Pediatr. Res. 66 (2), 121–127.
Azuma, Y., Miwa, Y., Sato, I., 2016. Expression of CGRP in embryonic mouse masseter
muscle. Ann. Anat. 206, 34–47.
Bai, Y.X., Fang, F., Jiang, J.L., 2017. Extrinsic calcitonin gene-related peptide inhibits
hyperoxia-induced alveolar epithelial type II cells apoptosis, oxidative stress, and
reactive oxygen species (ROS) production by enhancing notch 1 and homocysteine-
induced endoplasmic reticulum protein (HERP) expression. Med. Sci. Monit. 23,
5774–5782.
Balany, J., Bhandari, V., 2015. Understanding the impact of infection, inflammation, and
their persistence in the pathogenesis of bronchopulmonary dysplasia. Front. Med. 2
(3), 90.
Barnes, P.J., 1990. Reactive oxygen species and airway inflammation. Free Radic. Biol.
Med. 9 (3), 235–243.
Bedard, K., Krause, K.H., 2007. The NOX family of ROS-generating NADPH oxidases:
physiology and pathophysiology. Physiol. Rev. 87 (1), 245.
Berger, J., Bhandari, V., 2014. Animal models of bronchopulmonary dysplasia. The term
mouse models. Am. J. Physiol. Lung Cell. Mol. Physiol. 307 (12), 936–947.
Bhandari, V., 2010. Hyperoxia-derived lung damage in preterm infants. Semin. Fetal
Neonatal Med. 15 (4), 223.
Brandes, R.P., Norbert, W., Katrin, S., 2014. Nox family NADPH oxidases: molecular
mechanisms of activation. Free Radic. Biol. Med. 76, 208–226.
Buczynski, B.W., Maduekwe, E.T., O'Reilly, M.A., 2013. The role of hyperoxia in the
pathogenesis of experimental BPD. Semin. Perinatol. 37 (2), 69–78.
Burgoyne, J.R., Oka, S., Aleagha, N., et al., 2013. Hydrogen peroxide sensing and sig-
naling by protein kinases in the cardiovascular system. Antioxid. Redox Signal. 18
(9), 1042.
Cadenas, S., 2018. ROS and redox signaling in myocardial ischemia-reperfusion injury
and cardioprotection. Free Radic. Biol. Med. 117, 76–89.
Carnesecchi, S., Deffert, C., Pagano, A., et al., 2009a. NOX1 plays a crucial role in hy-
peroxia-induced acute lung injury in mice. Am. J. Respir. Crit. Care Med. 180 (10),
972–981.
Carnesecchi, S., Deffert, C., Pagano, A., et al., 2009b. NADPH oxidase-1 plays a crucial
role in hyperoxia-induced acute lung injury in mice. Am. J. Respir. Crit. Care Med.
180 (10), 972–981.
Carnesecchi, S., Dunandsauthier, I., Singovsky, G., et al., 2011. NADPH oxidase isoform 1
is expressed in lung tissue of ARDS patients and decreases hyperoxia-induced ROS
production and cell death in pulmonary type II epithelial cells. Eur. Respir. J. (Suppl.
55), 2942.
Carraro, S., Filippone, M., Da, D.L., et al., 2013. Bronchopulmonary dysplasia: the earliest
and perhaps the longest lasting obstructive lung disease in humans. Early Hum. Dev.
89 (5), S3.
Cassidy, D., Wright, R.H., Tang, J.R., et al., 2015. Lack of EC-SOD worsens alveolar and
vascular development in a neonatal mouse model of bleomycin-induced broncho-
pulmonary dysplasia and pulmonary hypertension. Pediatr. Res. 78 (6), 634–640.
Chen, X., Walther, F.J., Laghmani, E.H., et al., 2017a. Adult lysophosphatidic acid re-
ceptor 1-deficient rats with hyperoxia-induced neonatal chronic lung disease are
protected against lipopolysaccharide-induced acute lung injury. Front. Physiol. 8.
Chen, X.Q., Wu, S.H., Luo, Y.Y., et al., 2017b. Lipoxin A4 attenuates bronchopulmonary
dysplasia via upregulation of let-7c and downregulation of TGF-β1 signaling
pathway. Inflammation 40 (6), 1–15.
Chuang, C.Y., Degendorfer, G., Davies, M.J., 2014. Oxidation and modification of ex-
tracellular matrix and its role in disease. Free Radic. Res. 48 (9), 970–989.
Crosas-Molist, E., Fabregat, I., 2015. Role of NADPH oxidases in the redox biology of liver
fibrosis. Redox Biol. 6, 106–111.
Dang, H., Yang, L., Wang, S., et al., 2012. Calcitonin gene-related peptide ameliorates
hyperoxia-induced lung injury in neonatal rats. Tohoku J. Exp. Med. 227 (2), 129.
Dani, C., Cecchi, A., Bertini, G., 2004. Role of oxidative stress as physiopathologic factor
in the preterm infant. Minerva Pediatr. 56 (4), 381–394.
Datta, A., Kim, G.A., Taylor, J.M., et al., 2015. Mouse lung development and NOX1 in-
duction during hyperoxia are developmentally regulated and mitochondrial ROS
dependent. Am. J. Phys. Lung Cell. Mol. Phys. 309 (4), 369–377.
Davis, J.M., 2002. Role of oxidant injury in the pathogenesis of neonatal lung disease.
Acta Paediatr. 91 (s437), 23–25.
Djr, F., Li, X., Bordan, Z., et al., 2017. Reactive oxygen and nitrogen species in the de-
velopment of pulmonary hypertension. Antioxidants 6 (3), 54.
Domej, W., Oettl, K., Renner, W., 2014. Oxidative stress and free radicals in
COPD—implications and relevance for treatment. Int. J. Chron. Obstruct. Pulmon.
Dis. 9 (9), 1207–1224.
Ehrhardt, H., Pritzke, T., Oak, P., et al., 2016a. Absence of TNF-α enhances inflammatory
response in the newborn lung undergoing mechanical ventilation. Am. J. Phys. Lung
Cell. Mol. Phys. 310 (10), L909.
Ehrhardt, H., Pritzke, T., Oak, P., et al., 2016b. Biomarkers in lung diseases: from pa-
thogenesis to prediction to new therapies: absence of TNF-α enhances inflammatory
response in the newborn lung undergoing mechanical ventilation. Am. J. Phys. Lung
182
Gene 678 (2018) 177–183
Cell. Mol. Phys. 310 (10), L909.
Fabiano, A., Gavilanes, A.W.D., Zimmermann, L.J.I., et al., 2016. The development of
lung biochemical monitoring can play a key role in the early prediction of bronch-
opulmonary dysplasia. Acta Paediatr. 105 (5), 535–541.
Flodby, P., Li, C., Liu, Y., et al., 2016. GRP78 regulates ER homeostasis and distal epi-
thelial cell survival during lung development. Am. J. Respir. Cell Mol. Biol. 55 (1),
135.
Frank, L., Groseclose, E.E., 1984. Preparation for birth into an O2-rich environment: the
antioxidant enzymes in the developing rabbit lung. Pediatr. Res. 18 (3), 240–244.
Fu, H.M., Li, L., Wang, Y.J., et al., 2010. The proliferation-promoting effects of calcitonin
gene-related peptide on type II alveolar epithelial cell exposed to hyperoxia mediated
by protein kinase C alpha pathway. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 22 (5),
263–266.
Gavrili, S., Zachaki, S., Daraki, A., et al., 2015. Association of C609T-inborn poly-
morphism of NAD(P)H: quinone oxidoreductase 1 with the risk of bronchopulmonary
dysplasia in preterm neonates. Am. J. Perinatol. 33 (06), 535–539.
Gonzalez-Gonzalez, F.J., Chandel, N.S., Jain, M., 2017. Reactive oxygen species as sig-
naling molecules in the development of lung fibrosis. Transl. Res. 190, 61–68.
https://doi.org/10.1016/j.trsl.2017.09.005.
Hellström, A., Smith, L.E., Dammann, O., 1990. Retinopathy of prematurity. Dev. Med.
Child Neurol. 32 (5), 377–378.
Hoffman, S., Nolin, J., Mcmillan, D., et al., 2015. Thiol redox chemistry: role of protein
cysteine oxidation and altered redox homeostasis in allergic inflammation and
asthma. J. Cell. Biochem. 116 (6), 884.
Hori, Y.S., Kuno, A., Hosoda, R., et al., 2013. Regulation of FOXOs and p53 by SIRT1
modulators under oxidative stress. PLoS One 8 (9), e73875.
Hou, A., Fu, J., Yang, H., et al., 2015. Hyperoxia stimulates the transdifferentiation of
type II alveolar epithelial cells in newborn rats. Am. J. Physiol. Lung Cell. Mol.
Physiol. 308 (9), L861.
Hsiao, C.C., Chang, J.C., Tsao, L.Y., et al., 2017. Correlates of elevated interleukin-6 and
8-hydroxy-2′-deoxyguanosine levels in tracheal aspirates from very low birth weight
infants who develop bronchopulmonary dysplasia. Pediatr. Neonatol. 58 (1), 63–69.
https://doi.org/10.1016/j.pedneo.2016.01.004.
Huizing, M.J., Cavallaro, G., Moonen, R.M., et al., 2017. Is the C242T polymorphism of
the CYBA gene linked with oxidative stress-associated complications of prematurity?
Antioxid. Redox Signal. 27, 1432–1438. https://doi.org/10.1089/ars.2017.7042.
Jiménez, J., Lesage, F., Richter, J., et al., 2018. Upregulation of vascular endothelial
growth factor in amniotic fluid stem cells enhances their potential to attenuate lung
injury in a preterm rabbit model of bronchopulmonary dysplasia. Neonatology 113
(3), 275–285.
Jin, Meihua, Lee, Juyoung, Lee, 等, Kyung-yup, 2016. Alteration of TGF-Î2-ALK-Smad
signaling in hyperoxia-induced bronchopulmonary dysplasia model of newborn rats.
Exp. Lung Res. 42 (7), 1.
Jobe, A.J., 1999. The new BPD: an arrest of lung development. Pediatr. Res. 46 (6),
641–643.
Jr, W.H.N., Rosan, R.C., 1968. Radiographic features of pulmonary oxygen toxicity in the
newborn: bronchopulmonary dysplasia1. Radiology 91 (1), 49–58.
Kaarteenahowiik, R., Kinnula, V.L., 2004. Distribution of antioxidant enzymes in devel-
oping human lung, respiratory distress syndrome, and bronchopulmonary dysplasia.
J. Histochem. Cytochem. 52 (9), 1231–1240.
Kawaguchi, T., Yanagihara, T., Yokoyama, T., et al., 2017. Probucol attenuates hyper-
oxia-induced lung injury in mice. PLoS One 12 (4), e0175129.
Kaya, G., Saldir, M., Polat, A., et al., 2016. Evaluation of etanercept treatment in newborn
rat model with hyperoxic lung injury. Pediatr. Pathol. 35 (5), 327–338.
Kolls, Jay K., 2017. Commentary: understanding the impact of infection, inflammation
and their persistence in the pathogenesis of bronchopulmonary dysplasia. Front.
Med. 4.
Konsavage, W.M., Zhang, L., Wu, Y., et al., 2012. Hyperoxia-induced activation of the
integrated stress response in the newborn rat lung. Am. J. Physiol. Lung Cell. Mol.
Physiol. 302 (1), L27.
Kotecha, S.J., Edwards, M.O., Watkins, W.J., et al., 2013. Effect of preterm birth on later
FEV1: a systematic review and meta-analysis. Thorax 68 (8), 760–766.
Kumar, V.H.S., Lakshminrusimha, S., Kishkurno, S., et al., 2016. Neonatal hyperoxia in-
creases airway reactivity and inflammation in adult mice. Pediatr. Pulmonol. 51 (11),
1131–1141.
Lawrence, S.M., Ruoss, J.L., Wynn, J.L., 2017. IL-17 in neonatal health and disease. Am.
J. Reprod. Immunol.(1 Pt 1).
Lee, D., Sun, S., Ho, A.S., et al., 2014. Hyperoxia resensitizes chemoresistant glioblastoma
cells to temozolomide through unfolded protein response. Anticancer Res. 34 (6),
2957–2966.
Leroy, S., Caumette, E., Waddington, C., et al., 2017. A time-based analysis of in-
flammation in infants at risk of bronchopulmonary dysplasia. J. Pediatr. 192.
Li, W.J., Wang, T.K., 2006. Calcitonin gene-related peptide inhibits interleukin-1beta-
induced interleukin-8 secretion in human type II alveolar epithelial cells. Acta
Pharmacol. Sin. 27 (10), 1340.
Lingappan, K., Jiang, W., Wang, L., et al., 2016. Sex-specific differences in neonatal hy-
peroxic lung injury. Am. J. Physiol. Lung Cell. Mol. Physiol. 311 (2), L481.
Liu, G., Zhang, J., Chen, H., et al., 2014. Effects and mechanisms of alveolar type II
epithelial cell apoptosis in severe pancreatitis-induced acute lung injury. Exp. Ther.
Med. 7 (3), 565.
Loboda, A., Damulewicz, M., Pyza, E., et al., 2016. Role of Nrf2/HO-1 system in devel-
opment, oxidative stress response and diseases: an evolutionarily conserved me-
chanism. Cell. Mol. Life Sci. 73 (17), 3221–3247.
Maltepe, E., Saugstad, O.D., 2009. Oxygen in health and disease: regulation of oxygen
homeostasis-clinical implications. Pediatr. Res. 65 (3), 261–268.
Marcel, V., Catez, F., Diaz, J.J., 2015. p53, a translational regulator: contribution to its
J. Wang, W. Dong
tumour-suppressor activity. Oncogene 34 (44), 5513.
Matsumura, H., Ichiba, H., Ohnishi, S., et al., 2017. Histologic chorioamnionitis, amniotic
fluid interleukin 6, Krebs von den Lungen 6, and transforming growth factor β1 for
the development of neonatal bronchopulmonary dysplasia. Jpn. Clin. Med. 8,
1179066017696076.
Misra, R.S., Shah, S., Fowell, D.J., et al., 2015. Preterm cord blood CD4+, T cells exhibit
increased IL-6 production in chorioamnionitis and decreased CD4+, T cells in
bronchopulmonary dysplasia. Hum. Immunol. 76 (5), 329–338.
Mohamed, I., Elremaly, W., Rouleau, T., et al., 2015. Oxygen and parenteral nutrition two
main oxidants for extremely preterm infants: ‘It all adds up’. J. Neonatal-Perinatal
Med. 8 (3), 189–197.
Muramatsu, Y., Ito, M., Oshima, T., et al., 2016. Hydrogen-rich water ameliorates
bronchopulmonary dysplasia (BPD) in newborn rats. Pediatr. Pulmonol. 51 (9),
928–935.
Natarajan, V., Ha, A.W., Dong, Y., et al., 2017. Expression profiling of genes regulated by
sphingosine kinase1 signaling in a murine model of hyperoxia induced neonatal
bronchopulmonary dysplasia. BMC Genomics 18 (1), 664.
Niedermaier, S., Hilgendorff, A., 2015. Bronchopulmonary dysplasia - an overview about
pathophysiologic concepts. Mol. Cell. Pediatr. 2 (1), 1–7.
Northway Jr., W.H., R., C., 1967. Pulmonary disease following respiratory therapy of
hyaline-membrane disease. N. Engl. J. Med. 276, 357–368.
Oishi, P.E., Sharma, S., Datar, S.A., et al., 2013. Rosiglitazone preserves pulmonary
vascular function in lambs with increased pulmonary blood flow. Pediatr. Res. 73
(1), 54.
Oncel, M.Y., Yurttutan, S., Alyamac, D.E., et al., 2015. Beneficial effect of etanercept on
hyperoxic lung injury model in neonatal rats. J. Investig. Surg. 29 (1), 1–5.
O'Reilly, M., Thébaud, B., 2013. The promise of stem cells in bronchopulmonary dys-
plasia. [C]//seminars in perinatology. Semin. Perinatol. 79–84.
Parinandi, N.L., Kleinberg, M.A., Usatyuk, P.V., et al., 2003. Hyperoxia-induced NAD(P)H
oxidase activation and regulation by MAP kinases in human lung endothelial cells.
Am. J. Phys. Lung Cell. Mol. Phys. 284 (1), 26–38.
Pesce, C., Musi, L., 1996. Progress in the surgical treatment of congenital and acquired
broncho-pulmonary pathology. Pediatr. Med. Chir. 18 (5), 451–461.
Poggi, C., Dani, C., 2014. Antioxidant strategies and respiratory disease of the preterm
newborn: an update. Oxidative Med. Cell. Longev. 2014 (5), 721043.
Quinlan, C.L., Orr, A.L., Perevoshchikova, I.V., et al., 2012. Mitochondrial complex II can
generate reactive oxygen species at high rates in both the forward and reverse re-
actions. J. Biol. Chem. 287 (32), 27255–27264.
Rafikova, O., Rafikov, R., Kumar, S., et al., 2013. Bosentan inhibits oxidative and ni-
trosative stress and rescues occlusive pulmonary hypertension. Free Radic. Biol. Med.
56 (2), 28–43.
Rees, M., Kennett, E.J., Davies, M., 2008. Oxidative damage to extracellular matrix and its
role in human pathologies. Free Radic. Biol. Med. 44 (12), 1973–2001.
Reynolds, C.L., Zhang, S., Shrestha, A.K., et al., 2016. Phenotypic assessment of pul-
monary hypertension using high-resolution echocardiography is feasible in neonatal
mice with experimental bronchopulmonary dysplasia and pulmonary hypertension: a
step toward preventing chronic obstructive pulmonary disease. Int. J. Chron.
Obstruct. Pulmon. Dis. 11 (Issue 1), 1597.
Richter, K., Konzack, A., Pihlajaniemi, T., et al., 2015. Redox-fibrosis: impact of TGFβ1 on
ROS generators, mediators and functional consequences. Redox Biol. 6, 344–352.
Royce, S.G., Li, X., Tortorella, S., et al., 2014. Mechanistic insights into the contribution of
epithelial damage to airway remodeling novel therapeutic targets for asthma. Am. J.
Respir. Cell Mol. Biol. 50 (1), 180–192. https://doi.org/10.1165/rcmb.2013-
0008OC.
Rudloff, I., Cho, S.X., Bui, C.B., et al., 2017. Refining anti-inflammatory therapy strategies
for bronchopulmonary dysplasia. J. Cell. Mol. Med. 21 (6), 1128–1138.
Ryter, S.W., Choi, A.M., 2013. Regulation of autophagy in oxygen-dependent cellular
stress. Curr. Pharm. Des. 19 (15), 2747–2756.
Saeidnia, S., Abdollahi, M., 2013. Toxicological and pharmacological concerns on oxi-
dative stress and related diseases. Toxicol. Appl. Pharmacol. 273 (3), 442–455.
Salaets, T., Richter, J., Brady, P., et al., 2015. Transcriptome analysis of the preterm
rabbit lung after seven days of hyperoxic exposure. PLoS One 10 (8), e0136569.
Saugstad, O.D., 2010. Oxygen and oxidative stress in bronchopulmonary dysplasia. J.
Perinat. Med. 38 (6), 571–577.
Saugstad, O.D., Speer, C.P., Halliday, H.L., 2011. Oxygen saturation in immature babies:
revisited with updated recommendations. Neonatology 100 (3), 217–218.
Schieber, M., Chandel, N.S., 2014. ROS function in redox signaling and oxidative stress.
Curr. Biol. 24 (10), 453–462.
Seedorf, G.J., Metoxen, A.J., Rock, R., et al., 2016. Hepatocyte growth factor as a
downstream mediator of vascular endothelial growth factor-dependent preservation
of growth in the developing lung. Am. J. Physiol. Lung Cell. Mol. Physiol. 310 (11)
(ajplung.00423.2015).
183
Gene 678 (2018) 177–183
Shim, G.H., Kim, H.S., Kim, E.S., et al., 2015. Expression of autotaxin and lysopho-
sphatidic acid receptors 1 and 3 in the developing rat lung and in response to hy-
peroxia. Free Radic. Res. 49 (11), 1362–1370.
Shimoda, L.A., Laurie, S.S., 2013. Vascular remodeling in pulmonary hypertension. J.
Mol. Med. 91 (3), 297–309.
Shyanne, P., Alli, M., Al-Ahmad, A.J., 2016. Cerebral hypoxia/ischemia selectively dis-
rupts tight junctions complexes in stem cell-derived human brain microvascular en-
dothelial cells. Fluids Barriers Cns 13 (1), 16.
Sies, H., 2017. Hydrogen peroxide as a central redox signaling molecule in physiological
oxidative stress: oxidative eustress. Redox Biol. 11 (C), 613.
Sullivan, L.B., Chandel, N.S., 2014. Mitochondrial reactive oxygen species and cancer.
Cardiovasc. Ultrasound 2 (1), 1–12 (2,1(2014-11-28)).
Sullivan, L.B., Martinez-Garcia, E., Nguyen, H., et al., 2013. The proto-oncometabolite
fumarate binds glutathione to amplify ROS-dependent signaling. Mol. Cell 51 (2),
236–248.
Takac, I., Schröder, K., Zhang, L., et al., 2011. The E-loop is involved in hydrogen per-
oxide formation by the NADPH oxidase Nox4. J. Biol. Chem. 286 (15), 13304.
Tann, A.W., Boldogh, I., Meiss, G., et al., 2011. Apoptosis induced by persistent single-
strand breaks in mitochondrial genome. J. Biol. Chem. 286 (37), 31975–31983.
Teng, R.J., Jing, X., Michalkiewicz, T., et al., 2017. Attenuation of endoplasmic reticulum
stress by caffeine ameliorates hyperoxia-induced lung injury. Am. J. Physiol. Lung
Cell. Mol. Physiol. 312 (5), L586.
Thomas, W., Speer, C.P., 2014. Chorioamnionitis is essential in the evolution of
bronchopulmonary dysplasia – the case in favour. Paediatr. Respir. Rev. 15 (1),
49–52.
Tiganis, T., 2011. Reactive oxygen species and insulin resistance: the good, the bad and
the ugly. Trends Pharmacol. Sci. 32 (2), 82–89.
Torres-Cuevas, I., Cernada, M., Nuñez, A., et al., 2016. Oxygen Modulation and
Bronchopulmonary Dysplasia: Delivery Room and Beyond[M]//Bronchopulmonary
Dysplasia. Springer International Publishing.
Tsukahara, H., 2007. Biomarkers for oxidative stress: clinical application in pediatric
medicine. Curr. Med. Chem. 14 (3).
Tsukahara, H., 2014. Oxidative Stress Biomarkers in Pediatric Medicine – A 2013 Update.
pp. 689–715.
Warner, B.B., Stuart, L.A., Papes, R.A., et al., 1998. Functional and pathological effects of
prolonged hyperoxia in neonatal mice. Am. J. Phys. 275 (1), 110–117.
Wedgwood, S., Lakshminrusimha, S., Czech, L., et al., 2013. Increased p22phox/Nox4
expression is involved in remodeling through hydrogen peroxide signaling in ex-
perimental persistent pulmonary hypertension of the newborn. Antioxid. Redox
Signal. 18 (14), 1765.
Wiegman, C.H., Li, F., Clarke, C.J., et al., 2014. A comprehensive analysis of oxidative
stress in the ozone-induced lung inflammation mouse model. Clin. Sci. 126 (6),
425–440.
Winterbourn, C.C., Hampton, M.B., 2008. Thiol chemistry and specificity in redox sig-
naling. Free Radic. Biol. Med. 45 (5), 549–561.
Wollen, E.J., Sejersted, Y., Wright, M.S., et al., 2013. Transcriptome profiling of the
newborn mouse lung after hypoxia and reoxygenation: hyperoxic reoxygenation af-
fects mTOR signaling pathway, DNA repair, and JNK-pathway regulation. Pediatr.
Res. 74 (5), 536.
Wollen, E.J., Sejersted, Y., Wright, M.S., et al., 2014. Transcriptome profiling of the
newborn mouse brain after hypoxia-reoxygenation: hyperoxic reoxygenation induces
inflammatory and energy failure responsive genes. Pediatr. Res. 75 (4), 517–526.
Wu, D., Liang, M., Dang, H., et al., 2018. Hydrogen protects against hyperoxia-induced
apoptosis in type II alveolar epithelial cells via activation of PI3K/Akt/Foxo3a sig-
naling pathway. Biochem. Biophys. Res. Commun. 495 (2), 1620–1627.
Yeh, T.F., Chen, C.M., Wu, S.Y., et al., 2016. Intratracheal administration of budesonide/
surfactant to prevent bronchopulmonary dysplasia. Am. J. Respir. Crit. Care Med.
193 (1), 86–95.
Yu, S., Shi, M., Liu, C., et al., 2015. Time course changes of oxidative stress and in-
flammation in hyperoxia-induced acute lung injury in rats. Iran. J. Basic Med. Sci. 18
(1), 98–103.
Zhang, Y., Lingappan, K., 2017. Differential sex-specific effects of oxygen toxicity in
human umbilical vein endothelial cells. Biochem. Biophys. Res. Commun. 486 (2),
431–437.
Zhang, Q., Jianhua, F.U., Xue, X., 2014. Expression and function of aquaporin-1 in hy-
peroxia-exposed alveolar epithelial type II cells. Exp. Ther. Med. 8 (2), 493–498.
Zhang, S., Patel, A., Moorthy, B., et al., 2015. Adrenomedullin deficiency potentiates
hyperoxic injury in fetal human pulmonary microvascular endothelial cells. Biochem.
Biophys. Res. Commun. 464 (4), 1048.
Zuo, L., Zhou, T., Pannell, B.K., et al., 2015. Biological and physiological role of reactive
oxygen species—the good, the bad and the ugly. Acta Physiol. 214 (3), 329–348.