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Ginger ( Zingiber officinale ) prevents severe damage to the lungs due to hyperoxia and inflammation

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Background/aim: Hyperoxia- and inflammation-induced lung injury is an important cause of the development of bronchopulmonary dysplasia (BPD) in premature infants. We aimed to ascertain the beneficial effects of ginger ( Zingiber officinale ) on rat pups exposed to hyperoxia and inflammation. Materials and methods: Thirty-six newborn Wistar rats were randomly divided into 3 groups as the hyperoxia (95% O 2 ) + lipopolysaccharide (LPS) group, the hyperoxia + LPS + ginger-treated group, and the control/no treatment group (21% O 2 ). Pups in the hyperoxia + LPS + ginger group were administered oral ginger at a dose of 1000 mg/kg daily during the study period. Histopathologic, immunochemical (SMA and lamellar body), and biochemical evaluations including total antioxidant status (TAS), total oxidant status (TOS), malondialdehyde (MDA), myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and caspase-3 activities were performed. Results: Better weight gain and survival rates were shown in the hyperoxia + LPS + ginger group (P < 0.05). In the histopathologic and immunochemical evaluation, severity of lung damage was significantly reduced in the hyperoxia + LPS + ginger group, as well as decreased apoptosis (ELISA for caspase-3) (P < 0.05). Tissue TAS levels were significantly protected, and TOS, MDA, and MPO levels were significantly lower in the hyperoxia + LPS + ginger group (P < 0.05). Tissue TNF-α, IL-1β, and IL-6 concentrations were significantly decreased in the ginger-treated group (P < 0.05). Conclusion: Ginger efficiently reduced the lung damage and protected the lungs from severe damage due to hyperoxia and inflammation. Therefore, ginger may be an alternative option for the treatment of BPD.
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http://journals.tubitak.gov.tr/medical/
Turkish Journal of Medical Sciences
Turk J Med Sci
(2018) 48: 892-900
© TÜBİTAK
doi:10.3906/sag-1803-223
Ginger (Zingiber ocinale) prevents severe damage to the lungs due to hyperoxia and
inammation
Atilla ÇİFCİ1, Cüneyt TAYMAN2, Halil İbrahim YAKUT3, Halit HALİL4, Esra ÇAKIR5, Ufuk ÇAKIR2,*, Salih AYDEMİR6
1Department of Pediatrics, Faculty of Medicine, Yıldırım Beyazıt University, Ankara, Turkey
2Department of Neonatology, Zekai Tahir Burak Maternity Education and Research Hospital, Ankara, Turkey
3Department of Pediatrics, Ankara Childrens Hematology Oncology Education and Research Hospital, Ankara, Turkey
4Department of Pediatric Emergency Medicine, Dr. Sami Ulus Childrens Research Hospital, Ankara, Turkey
5Department of Anesthesiology and Clinical Critical Care, Ankara Numune Education and Research Hospital, Ankara, Turkey
6Department of Neonatology, Private Ege Yaşam Hospital, İzmir, Turkey
* Correspondence: drufukcakir@hotmail.com
1. Introduction
Bronchopulmonary dysplasia (BPD), also called neonatal
chronic lung disease, is an important cause of signicant
morbidity and mortality related to lung injury in preterm
newborns, leading to frequent hospitalizations, recurrent
respiratory exacerbations, exercise intolerance, and
adverse neurodevelopmental outcomes (1–4). e exact
pathogenic mechanisms underlying the development of
BPD are uncertain. However, recent evidence suggests
complex roles of pre- and postnatal factors in the
development of BPD. Prematurity is believed to be the
most important contributing factor, in addition to other
factors, including oxidative stress and inammation-
mediated lung injury (chorioamnionitis), hyperoxia/
value-barotrauma, and genetic factors (5,6). Treatment
strategies for the prevention of lung injury and appropriate
induction of lung growth to avoid the development of BPD
are still lacking (3,7). erefore, new treatment options
need to be identied for the prevention of severe injury to
the lungs in the course of BPD.
Ginger (Zingiber ocinale) is one of the most
commonly used spices all over the world. It is known
to have many health benets and is also applied to treat
respiratory diseases. Ginger contains more than 60 dierent
active ingredients, including volatile (hydrocarbons and
sesquiterpenes) and nonvolatile (gingerols, shogaols,
Background/aim: Hyperoxia- and inammation-induced lung injury is an important cause of the development of bronchopulmonary
dysplasia (BPD) in premature infants. We aimed to ascertain the benecial eects of ginger (Zingiber ocinale) on rat pups exposed to
hyperoxia and inammation.
Materials and methods: irty-six newborn Wistar rats were randomly divided into 3 groups as the hyperoxia (95% O2) +
lipopolysaccharide (LPS) group, the hyperoxia + LPS + ginger-treated group, and the control/no treatment group (21% O2). Pups in the
hyperoxia + LPS + ginger group were administered oral ginger at a dose of 1000 mg/kg daily during the study period. Histopathologic,
immunochemical (SMA and lamellar body), and biochemical evaluations including total antioxidant status (TAS), total oxidant
status (TOS), malondialdehyde (MDA), myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β),
interleukin-6 (IL-6), and caspase-3 activities were performed.
Results: Better weight gain and survival rates were shown in the hyperoxia + LPS + ginger group (P < 0.05). In the histopathologic
and immunochemical evaluation, severity of lung damage was signicantly reduced in the hyperoxia + LPS + ginger group, as well
as decreased apoptosis (ELISA for caspase-3) (P < 0.05). Tissue TAS levels were signicantly protected, and TOS, MDA, and MPO
levels were signicantly lower in the hyperoxia + LPS + ginger group (P < 0.05). Tissue TNF-α, IL-1β, and IL-6 concentrations were
signicantly decreased in the ginger-treated group (P < 0.05).
Conclusion: Ginger eciently reduced the lung damage and protected the lungs from severe damage due to hyperoxia and inammation.
erefore, ginger may be an alternative option for the treatment of BPD.
Key words: Bronchopulmonary dysplasa, gnger, nammaton, newborn, oxygen-nduced lung njury, rat
Received: 27.03.2018 Accepted/Published Online: 04.07.2018 Final Version: 16.08.2018
Research Article
is work is licensed under a Creative Commons Attribution 4.0 International License.
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ÇİFCİ et al. / Turk J Med Sci
paradols, zingerone) compounds, in addition to various
minerals, vitamins, and enzymes (8–12). Some studies
have determined that the whole extract and dierent
separated compounds of ginger have antiinammatory
(8,9), antimicrobial (13), and antioxidant properties
(13,14), along with immunomodulatory (15), antibrotic
(16), and cytoprotective/regenerative actions on dierent
organ systems with a very low degree of toxicity (17).
However, the eects of ginger on lungs with BPD are not
yet known. erefore, we aimed to ascertain the eects
of ginger on the lungs of rat pups with BPD induced by
hyperoxia and lipopolysaccharide (LPS).
2. Materials and methods
2.1. Animal model
Ethical approval was obtained from the Experimental
Animal Ethics Committee of the Ankara Training and
Research Hospital (Ankara, Turkey). e National
Institutes of Health Guide for the Care and Use of
Laboratory Animals was followed. Five pregnant Wistar
rats were housed and cared for in individual cages with
12-h light/dark cycles. Laboratory food and water were
available ad libitum. For timed matings, embryonal day
0 was dened as the morning of vaginal plug discovery.
Pregnant rats were randomized into two groups: 1) no-
treatment group (n = 2); 2) intraamniotic LPS injection
group (n = 3). For the establishment of chorioamnionitis
in pregnant rats, the rats were anesthetized with sodium
pentobarbital injection (50 mg/kg intraperitoneal).
e abdominal wall was inltrated with 0.1–0.2 mL
of bupivacaine. A midline abdominal incision allowed
externalization of the uterine horns. Direct intraamniotic
injection of 1 µg of LPS (Escherichia coli serotype 0111:B4,
Sigma-Aldrich Chemical, Germany) solubilized in 0.1 mL
of normal saline or endotoxin-free saline, was injected into
the amniotic sacs of the pregnant rats on embryonal days
16 and 20 (18,19). Pregnant rats delivered spontaneously.
Pups were then pooled and randomized, and pups in the
LPS group were divided into two groups immediately aer
birth and returned to nursing dams. One group received
only LPS and the other received LPS plus ginger. Each
group consisted of 12 pups. e experiment began within
12 h aer birth and continued through postnatal day 14.
Humidity was maintained at 50%, and environmental
temperature was maintained at 24 °C. Pups in the
hyperoxia group were exposed to 95% O2, while the pups
in the control group were cared for in room air (21%
O2). Nursing dams were rotated between hyperoxia and
room air-exposed litters every 24 h to prevent oxygen
toxicity in the dams. Continuous 95% O2 exposure was
achieved in a Plexiglas chamber (70 × 60 × 30 cm) by a
ow-through system, and CO2 was removed by soda lime
absorption. e oxygen level inside the Plexiglas chamber
was monitored continuously with a Ceramatec (MAXO2)
oxygen analyzer to maintain ≥95% O2 saturation. e pups
were weighed daily with scale sensitivity of 0.01 g and their
weights were recorded.
2.2. Preparation and dosage of ginger
Standardized ginger root capsules (SWH025, Swanson
Health Products, USA) were used. Capsules combined 250
mg of guaranteed-potency ginger extract (standardized
to 5% gingerols and 5% shogaols) with 250 mg of dried
ginger powder. Ginger was administered orally with a
feeding catheter (2 F) to each rat pup at a dose of 1000 mg/
kg through dissolved in 0.2 mL of distilled water (20,21).
Pups in the control group (21% O2 for 14 days + placebo)
and hyperoxia + LPS group (95% O2 for 14 days + placebo)
were administered oral saline (2 mL/kg), but pups in the
hyperoxia + LPS + ginger group (95% O2 for 14 days +
ginger) were treated once a day from the rst day of the
study to the end of the study. In the present experiment,
we used whole ginger since many dierent compounds in
ginger have been determined to act in a synergic manner
that suggests the importance of using whole ginger (8–17).
2.3. Preparation of lung tissue for histological and
biochemical analysis
At the end of the experiment, all pups were sacriced on the
14th day of the study under deep anesthesia by ketamine
and xylazine (100 and 10 mg/kg) intraperitoneally. e
thorax was then opened, and the lungs were resected
aer perfusion of the heart with normal saline. Aer a
tracheal cannula was placed, the lungs were excised and
perfused by normal saline. During perfusion, a constant
ination pressure of 5 cmH2O was maintained via the
tracheal catheter. e right main bronchus was then
ligated with a surgical suture, excised, and saved for later
biochemical analyses. e le lungs were xed by slowly
perfusing 0.1 M phosphate-buered saline (PBS) and 4%
paraformaldehyde (PFA). Upon completion of perfusion,
the trachea was ligated with a surgical suture, and the
lungs were incubated in fresh 4% PFA-PBS solution on ice
for 4–5 h. Following this incubation, PFA-PBS solution
was replaced with two quick changes of cold PBS to
remove exterior debris. e lungs were then transferred to
a ltered sterile PBS/30% sucrose solution and stored at 4
°C until fully equilibrated. e right lung tissues were kept
in PBS solution and stored at –80 °C until biochemical
analysis was performed.
e lungs were paran-embedded and these paran
blocks were sliced into sections of 4–5 µm. Sections
were chosen according to a systematic random sampling
procedure and then mounted onto poly-L-lysine-
coated slides (Histobond adhesion slides, Marienfeld,
Germany). Slides were stained for histopathologic
and immunohistochemical evaluations with standard
hematoxylin and eosin (H&E) and with the ABC technique
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for the lamellar body membrane protein and smooth muscle
actin (SMA) expression. Histopathologic examination and
immunohistochemical scoring were evaluated in a blinded
fashion by an experienced pathologist unaware of the
treatment group for each sample.
2.4. Histopathological examination
Paran blocks of the tissues were sliced into portions
of 4 µm and stained with H&E for histologic evaluation.
Ten H&E-stained sections of each time point for each rat
were randomly selected. Five elds for each section were
examined under a light microscope (200×) to observe
histological changes, estimate radical alveolar counts
(RACs), and calculate the mean value. Histopathologic
scoring was graded as follows: grade 1, normal histology;
grade 2, moderate leukocytic inltration; grade 3,
leukocytic inltration, edema, and partial destruction;
and grade 4, total destruction of the tissue. Sections
were evaluated for RAC through digital images for the
assessment of the alveolar development. Briey, a line
superimposed from the center of a respiratory bronchiole
to the nearest connective tissue septum at right angles
to the epithelium and the number of the alveolar septa
crossed by this line were counted on 3 or 4 sections for
each animal (22).
2.5. Immunohistochemical detection of lamellar body
membrane protein
For immunohistochemical detection of lamellar body
membrane protein, sections were subjected to rehydration
followed by treatment with 3% hydrogen peroxide for 30
min. Subsequently, sections were subjected to nonspecic
blocking with goat serum for 30 min, and sections were
then incubated with primary antibodies against lamellar
body membrane protein (1:100, Chemicon, AB3623-
rabbit, USA) overnight at 4 °C, followed by treatment
with biotinylated antirabbit secondary antibody (1:200,
Vector Laboratories, UK) for 30 min at room temperature.
Following the avidin-biotin complex treatment,
3,3’-diaminobenzidine (DAB; Vector Laboratories) was
used for color development. For negative control slides,
omission of the primary antibody was also done. e
tissue sections were examined using a light microscope
interfaced with a digital camera. Lamellar body-positive
cells (type II cells) in the alveolar area were counted ve
times on ten sections 25 µm apart for each animal. Data
were presented as number of lamellar body-positive cells
(type II cells)/mm2.
2.6. Immunohistochemistry for SMA expression
SMA expression was visualized using the avidin-biotin-
peroxidase method. Embedded lung tissues were
sectioned on poly-L-lysine-coated slides. e sections
were deparanized in xylene, rehydrated, and immersed
in distillate water. Endogenous peroxidase activity was
blocked using a 0.3% solution of hydrogen peroxidase
in PBS. e primary antibody against α-SMA (ready-to-
use, NeoMarkers, USA) was applied for 30 min at room
temperature and washed in PBS. Linking antibody and
streptavidin-peroxidase complex (NeoMarkers) were
added consecutively for 10 min at room temperature and
washed in PBS. e sections were stained using 3-amino-
9-ethylcarbazole (AEC) as a chromogen for 7 min for
immunohistochemical demonstration of actin. Finally, the
sections were counter-stained with Mayer’s hematoxylin
and the slides were dehydrated and mounted. Aer that,
tissue sections were examined using a light microscope
interfaced with a digital camera. Ten nonoverlapping
microscopic elds were selected at 10× magnication in
a random manner for immunohistochemical scoring.
e degree of positive staining was evaluated by a
semiquantitative scoring on a scale of 1–4 for intensity (I)
and distribution (D). Tissues with I × D less than or equal
to 4 were considered weakly positive, and those with I ×
D greater than 4 were designated as strongly positive (23).
2.7. Biochemical analysis
Tissues were homogenized in physiological saline (1 g in
5 mL) using a homogenizer (IKA T18 Basic Ultra-Turrax,
Germany) and centrifuged at 4000 × g for 20 min (NF 800
R Nuve). Clear supernatants were removed to be used
in the analyses. Protein levels were measured by using
Lowry’s method (24). Measurements were performed with
a spectrophotometer (UV Shimadzu 1700, Japan).
2.8. Measurement of TAS and TOS
TAS and TOS were determined using a novel automated
colorimetric measurement method developed by Erel (25).
e results are expressed as mmol Trolox equivalent/g
protein for TAS and µmol H2O2 equivalent/g protein for
TOS in the intestine tissue samples.
2.9. Determination of MDA activity
MDA levels were recognized as an index of lipid
peroxidation in the intestinal tissues. Tissue MDA levels
were determined by the method of Draper and Hadley
based on the reaction of MDA with thiobarbituric acid at
95 °C (26). Results were expressed as nmol/g protein.
2.10. Detection of MPO activity
is method is based on the principle that homogenate
containing MPO activity reduces o-dianisidine
dihydrochloride in the presence of H2O2, and this reduced
product gives absorbance at 460 nm. MPO activity was
computed using the o-dianisidine extinction quotient.
Results were stated as units per gram of wet tissue (U/g)
(27).
2.11. Determination of TNF-α, IL-1β, and IL-6
concentrations
Lung tissue TNF-α, IL-1β, and IL-6 concentrations were
measured in duplicate with a commercially available
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ÇİFCİ et al. / Turk J Med Sci
enzyme-linked immunosorbent assay kit (BioSource
Europe S.A., Belgium) according to the manufacturer’s
instructions. Results were expressed as pg/mg protein.
2.12. Caspase-3 detection
Lung tissue caspase-3 levels were measured with a
commercially available enzyme-linked immunosorbent
assay kit (rat CASP3, ELISA Kit, BioSource Europe S.A.)
(sensitivity: 0.188 ng/mL, detection range: 0.313–20 ng/
mL) according to the manufacturer’s instructions. Results
were expressed as ng/g protein.
2.13. Statistical analysis
SPSS 16.0 (SPSS Inc., USA) was used for statistical
analysis. e Shapiro–Wilk test was used to examine the
normal distribution of values graphically. Descriptive
statistics were shown as median (IQR) and mean and
standard deviation (SD). ANOVA with the Bonferroni
test was performed for intergroup analysis for parametric
variables, but the Friedman test was used for intergroup
comparisons of nonparametric variables. e Wilcoxon
test with Bonferroni adjustment were applied for
comparisons of categorical variables for independent
groups. ANOVA with Bonferroni adjustment was used to
analyze independent data with a normal distribution, and
the Mann–Whitney U test was used in the comparison of
data without a normal distribution. Survival time analysis
was performed using the Kaplan–Meier method, and
statistical dierences were conrmed by log-rank test.
Power analysis was conducted. If 0.80 eect size, 0.05
alpha, and 0.20 beta were taken to obtain 80% power, 12
animals were found to be adequate in each group.
3. Results
At the end of the study, 4 (33.3%) rat pups in the hyperoxia
+ LPS and 1 (8.3%) rat pup in the hyperoxia + LPS + ginger
group had died. e survival rate was signicantly higher
in the hyperoxia + LPS + ginger group than the hyperoxia
+ LPS group (P < 0.05) (Table 1). e median survival
time in the hyperoxia + LPS group was 10.9 days (95%
condence interval: 10.2–12.9 days), and it was 13.9 days
(95% condence interval: 13.8–14.1 days) in the hyperoxia
+ LPS + ginger group (log rank P = 0.019) (Figure 1). ere
were no signicant dierences among the three groups in
terms of birth weight (P = 0.53). At the end of the study,
the mean body weight of the pups in the hyperoxia + LPS
+ ginger group was signicantly higher than those in the
hyperoxia + LPS group (P = 0.02) (Table 1).
In histopathological examination, severity of lung
damage was dened as grade 1 to grade 4. Less lung
damage was detected in the hyperoxia + LPS + ginger
group compared to the hyperoxia + LPS group (P = 0.002)
(Figures 2A–2C; Table 1). ickening of the alveolar septa
or cell inltration was not seen in the control group.
However, signicant changes in histological grading and
improvement were determined in the ginger-treated group
compared to the hyperoxia + LPS group (P < 0.05). Lung
tissue samples from the hyperoxia + LPS group displayed
abnormal alveolar structure, having enlarged alveoli with
decreased terminal air spaces and secondary septa (Figures
2A–2C). RACs revealed that the alveolar space count
was signicantly increased in the ginger-treated group
compared with the hyperoxia + LPS group (Figures 2A–
2C). ese data reect more intact alveoli in the ginger-
treated group (P < 0.05). We also examined lamellar body
protein-positive cells (type II cells) for each specimen and
a signicantly better density of lamellar body membrane
protein was observed in the ginger-treated group than the
hyperoxia + LPS group (P < 0.05) (Figures 3A–3C; Table
1). In addition, considerably decreased alveolar brosis
Table 1. Comparison of weight changes, histopathological evaluation, radial alveolar count, lamellar body protein levels, and mortality
of the study groups.
Variables
Control (n = 12),
mean ± SD,
median (IQR)
Hyperoxia
(n = 12/8),
mean ± SD,
median (IQR)
Hyperoxia + ginger
(n = 12/11),
mean ± SD,
median (IQR)
P
Birth weight (g) 5.3 ± 0.4 5.23 ± 0.5 5.25 ± 0.35 0.53
Weight on day 14 (g) 18.8 ± 3.5 13.7 ± 1.4 17.1 ± 1.3 0.02*
Death, n (%) 0 4 (33.3%) 1 (8.3%) 0.03*
Histopathologic examination 0 3.1 (1) 2 (1) 0.02*
Radial alveolar count 12 ± 3.5 6.2 ± 2.1 8.9 ± 1.5 0.03*
Lamellar body protein-positive cells/unit area 8 ± 2.2 2 ± 0.3 6 ± 1.5 <0.01*
*Signicant dierences among all groups (P < 0.05).
SD: Standard deviation; IQR: interquartile range.
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Figure 1. Kaplan–Meier survival curve: median survival times of pups in the study groups.
Figure 2. Lung sections of rat pups stained with H&E. A) Control group exposed to room air; B) aer exposure to 95% oxygen and
LPS; C) exposed to 95% oxygen + LPS and treated with ginger. Microphotographs are representative and were obtained at the same
magnication (200×). Hyperoxia and LPS caused distal air space enlargement, and the alveolar architecture was simplied with
reduced RACs.
Figure 3. Representing the immunohistochemistry for the lamellar body membrane protein in each group (50 µm): A) control group
exposed to room air (21% oxygen); signicantly worse density of the lamellar body membrane protein in the hyperoxia + LPS group (B)
compared to the hyperoxia + LPS + ginger group (C).
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and decreased SMA immunostaining in smooth muscle
content were seen in the ginger-treated group compared
to the hyperoxia + LPS group (P < 0.05) (Table 2; Figures
4A–4C). In the harvested lung tissues, caspase-3 levels were
evaluated to determine apoptotic changes in all groups.
Caspase-3 levels were signicantly lower in the ginger-
treated group compared to the hyperoxia + LPS group (P
< 0.05) (Table 3).
In biochemical analysis, lung tissue TOS and MDA levels
were signicantly lower in the ginger-treated group than in
the hyperoxia + LPS group (P < 0.05). However, signicantly
lower TAS and higher MDA levels in the hyperoxia + LPS
group were seen, indicating decreased oxidative stress and
lower lipid peroxidation in the ginger-treated group (P
< 0.05) (Table 3). In the ginger-treated group, there was
signicantly reduced MPO activity in the lungs (P < 0.05).
Additionally, lung tissue TNF-α, IL-1β, and IL-6 levels were
signicantly decreased in the ginger-treated group (P < 0.05)
in contrast to the hyperoxia + LPS group. ese data suggest
that ginger treatment decreased lipid peroxidation due to
ROS as well as reduced neutrophil inltration/inammation
in rat lungs subjected to hyperoxia + LPS (P < 0.05) (Table 3).
4. Discussion
rough this study, the benecial eects of ginger on the
lungs were investigated in a model of experimental lung
injury that mirrors the ndings of BPD. Bronchopulmonary
dysplasia was created by hyperoxia and intrauterine LPS-
induced inammation as a model of chorioamnionitis.
We determined that use of whole ginger protected the
lungs from histopathological damage (parenchymal tissue
destruction, brosis, abnormal alveolar structure, and
cell apoptosis) as well as reduced ongoing tissue damage
in the lungs. Biochemical analysis of harvested lung
tissues revealed that factors playing important roles in
the pathogenesis of BPD such as neutrophil inltration,
inammation, oxidant stress, and lipid peroxidation were
reduced, in addition to increased antioxidant activities in
the injured lung tissues through the antiinammatory,
antioxidant, antibrotic, and antiapoptotic eects of ginger
on the lungs during the course of experimental BPD.
One of the most important risk factors in the
development of BPD is believed to be preterm birth (1–
6). Once a premature baby is born, he or she does not
have fully developed lungs to adapt to external life. ey
Table 2. Fibrosis and SMA immunostaining scores for all groups.
Fibrosis SMA immunostaining
Groups None We a k Moderate Severe None Weak Moderate Severe
1: Control (n = 12) 12 0 0 0 10 2 0 0
2: Hyperoxia (n = 8) 0 0 2 6 0 0 2 6
3: Hyperoxia + ginger (n = 11) 6 3 1 0 6 3 1 0
P-values
1 vs. 2
1 vs. 3
2 vs. 3
0.002*
0.021*
<0.001*
0.001*
0.12
0.002*
SMA: Smooth muscle actin. *Signicant dierences among all groups (P < 0.05).
Figure 4. Immunohistochemical α-SMA staining (α-SMA, original magnication 200×): A) minimal brosis could be seen in the group
exposed to room air; B) hyperoxia exposure increased local pulmonary interstitial brosis; C) the ginger-treated group had reduced
brosis.
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experience a pause in the development of the alveolar
epithelial, mesenchymal, and endothelial cell structures
(5). Furthermore, inammation has a considerable role in
the pathogenesis of BPD. Particularly, premature infants
have a high prevalence of inammatory conditions
such as chorioamnionitis during the perinatal period.
Chorioamnionitis seems to be another important risk factor
for the development of BPD by inducing inammation in
the lungs (5,6,28). During the inammation process, several
dierent proinammatory cytokines are synthesized and
released from alveolar macrophages, broblasts, type II
pneumocytes, and endothelial cells through stimulation
of hyperoxia, endotoxins, and other bacterial products
(5,6). Additionally, there is an imbalance between pro-
and antiinammatory cytokines in the pulmonary
tissue of preterm infants due to an inability to regulate
inammation in the lung (29,30). Increased levels of some
proinammatory cytokines such as IL-1β, IL-6, and TNF
have been determined in the tracheal aspirate and serum
of premature infants with BPD, and those with respiratory
distress syndrome who subsequently developed BPD
(31,32). In the present experiment, tissue levels of IL-1β,
IL-6, and TNF-α were found to be reduced in the lungs
of ginger-treated pups. Some experimental and clinical
studies have reported that ginger extract diminishes
acute and chronic inammation through decreasing
overexpression of proinammatory cytokines in the
lungs (8–11). Aer proinammatory cytokines increase,
inammatory cells are attracted and inux into the lung.
ese cells are dominated by alveolar macrophages and
neutrophils, leading to the persistence of the inammation
by the production of further proinammatory cytokines
(5,6). During the inammation process, neutrophil
migration and inltration into the lungs can be determined
by measuring MPO activity in the lung tissues (33). MPO,
a peroxidase enzyme, is specic for neutrophils and is
expressed in neutrophil lysosomes (34). However, our
results showed that MPO activity in the lungs was reduced
with ginger treatment. erefore, we suggest that ginger
has antiinammatory properties by decreasing neutrophil
activation and migration into the lungs with evidence of
reduced MPO activity in the lungs (9,11).
Oxygen toxicity has a key role in the development of
BPD (1–7). High concentrations of inspired oxygen can
damage lung cells by the overproduction of cytotoxic
reactive oxygen species (ROS) such as superoxide free
radical, hydrogen peroxide, and hydroxyl free radical.
Aer hyperoxia, additional chemotactic eects of oxygen
on inammatory cells occur as well as the eects of
cytokines and chemotactic factors. Inammatory cells,
neutrophils, and macrophages migrate to the lungs and
are activated by hyperoxia, and ROS are produced by the
cellular metabolism of molecular oxygen (35). ROS cause
oxidative stress by oxidation of lipids, proteins, and DNA
at the cellular level (36,37). Moreover, preterm infants
are very prone to oxidative stress. ey have immature
and inadequate antioxidant enzyme system activity,
such as superoxide dismutase, catalase, and glutathione
peroxidase, as well as nutrient deciencies such as vitamins
A and E, iron, copper, zinc, and selenium (36–38). us,
ROS overwhelm the neonate’s immature antioxidant
system and cause lung damage (36). Premature infants
Table 3. Biochemical and apoptosis analysis of groups, including TAS, TOS, MDA, MPO, TNF-α, IL-1β, IL-6, and caspase-3 activities
of the studied groups.
Variables
Control
(n = 12),
mean ± SD,
median (IQR)
Hyperoxia
(n = 8),
mean ± SD,
median (IQR)
Hyperoxia + ginger
(n = 11),
mean ± SD,
median (IQR)
P
TAS (mmol Trolox equivalent/g protein) 9.43 ± 2.12 5.23 ± 0.34 7.13 ± 0.78 <0.05*
TOS (µmol H2O2 equivalent/g protein) 5.89 ± 1.5 63.34 ± 21.42 18.56 ± 7.41 <0.05*
MDA (nmol/g protein) 5.78 (0.64) 52.33 (15.34) 14.57 (4.12) <0.05*
MPO (U/g protein) 49.34 (8.58) 174.61 (37.15) 78.59 (15.61) <0.05*
TNF-α (pg/mg protein) 3.8 ± 2.2 12.2 ± 2.9 5.3 ± 2.4 <0.05*
IL-1β (pg/mg protein) 5.1 ± 1.8 12.9 6.3 ± 1.3 <0.05*
IL-6 (pg/mg protein) 48. ± 14.8 303.6 ± 24.3 157.3 ± 18.4 <0.05*
Caspase-3 (ng/g protein) 4.6 ± 0.3 24.3 ± 0.5 10.5 ± 0.6 <0.05*
*Signicant dierences among all groups (P < 0.05).
TAS: Total antioxidant status; TOS: total oxidant status; MDA: malondialdehyde; MPO: myeloperoxidase; TNF-α: tumor necrosis
factor-alpha; IL-1β: interleukin-1 beta, IL-6: interleukin-6.
899
ÇİFCİ et al. / Turk J Med Sci
with BPD also have increased lipid peroxidation. MDA, a
reliable marker of lipid peroxidation and oxidative stress
in the tissues, is the breakdown product of oxidation of
polyunsaturated fatty acids by ROS (26,25). erefore,
ROS can be evaluated by the measurement of MDA
and TAS/TOS levels in tissues (25,26,33). Ginger can be
considered as a storehouse of antioxidants. e bioactive
ingredients of ginger such as gingerols, shogaols, and
zingerone have been shown to have antioxidant activity
by inhibiting oxidase enzymes such as xanthine oxidase
(8,9). Additionally, ginger enhances the activities of
antioxidant enzymes and reduces the lipid peroxidation of
cell membranes via ROS scavenging properties (35,39,40).
In the present study, treatment with ginger resulted in
decreased levels of MDA in addition to increased levels of
TAS and reduced levels of TOS in the rat pups subjected to
hyperoxia. ese data showed that ginger reduces oxidative
stress and lipid peroxidation, and enhances endogenous
antioxidant systems in the lungs.
In premature infants, characteristic pathological
changes seen in the lungs aer BPD formation can be
characterized by decreased alveolarization and alveolar
hypoplasia leading to fewer and larger alveoli, as shown
by decreased RAC and thickening of alveolar septa with
signicantly increased brosis. Moreover, surfactant
deciency plays an important role in the pathogenesis
of BPD. In pathologic specimens, a reduced lamellar
body expression pattern indicates severe lung injury
that demonstrates decreased type II cells (33,41). In the
current study, increased RAC and decreased thickness of
the alveolar septa with remarkably reduced brosis and
decreased SMA immunostaining, as well as better density
of the lamellar body protein staining pattern, were present
in the ginger-treated group (9–17,42). Additionally,
during the BPD process, increased apoptosis in lung tissue
cells has been demonstrated (43). In the present study,
apoptosis was evaluated by measuring tissue caspase-3
levels, and ginger administration reduced cell apoptosis.
Consequently, ginger protected lung injury with better
alveolarization and decreased brosis and apoptosis.
In conclusion, our results determined for the rst
time that ginger signicantly attenuated lung damage via
inhibition of oxidative stress as well as augmentation of
endogenous antioxidants, suppression of proinammatory
mediators and inammation, institution of better
alveolarization, and reduction of brosis and apoptosis.
erefore, ginger with its fewer side eects may be
a promising candidate agent for maintaining greater
functional lung activity of preterm infants aicted with
BPD. However, further studies are warranted to evaluate
the ecacy of ginger in the prevention of lung injury prior
to any clinical application.
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Ginger (Zingiber officinale) is a globally marketed flavoring agent and cooking spice with a long history of human health benefits. The fungicide carbendazim (CBZ) is often detected in fruits and vegetables for human nutrition and has been reported to elicit toxic effects in different experimental animal models. The present study investigated the protective effects of 6-Gingerol-rich fraction (6-GRF) from ginger on hematotoxicity and hepatorenal damage in rats exposed to CBZ. CBZ was administered at a dose of 50 mg/kg alone or simultaneously administered with 6-GRF at 50, 100, and 200 mg/kg, whereas control rats received corn oil alone at 2 mL/kg for 14 days. Hematological examination showed that CBZ-mediated toxicity to the total white blood cell (WBC), neutrophils, lymphocytes, and platelets counts were normalized to the control values in rats cotreated with 6-GRF. Moreover, administration of CBZ significantly decreased the activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione S-transferase as well as glutathione level in the livers and kidneys of rats compared with control. However, the levels of hydrogen peroxide (H2O2) and malondialdehyde were markedly elevated in kidneys and livers of CBZ-treated rats compared with control. The significant elevation in the plasma indices of renal and hepatic dysfunction in CBZ-treated rats was confirmed by light microscopy. Coadministration of 6-GRF exhibited chemoprotection against CBZ-mediated hematotoxicity, augmented antioxidant status, and prevented oxidative damage in the kidney and liver of rats.
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