Iran J Cancer Preven. 2015 June; 8(3):e2333.
Published online 2015 June 22. Research Article
The Eﬀect of Aerobic Exercise in Ambient Particulate Matter on Lung Tissue
Inﬂammation and Lung Cancer
; Hamid Agha Alinejad
; Hasan Asilian Mahabadi
Department of Physical Education and Sports Sciences, Tarbiat Modares University, Tehran, IR Iran
Deptartment of Occupational Health Engineering, Tarbiat Modares University, Tehran, IR Iran
*Corresponding author: Hamid Agha Alinejad, Department of Physical Education and Sports Sciences, Tarbiat Modares University, Tehran, IR Iran. Tel: +98-9124946181,
Received: January 14, 2015; Revised: January 20, 2015; Accepted: January 28, 2015
Background: Exposure to Air pollution PM10 results in lung inﬂammation increased risk of lung cancer. Regular aerobic exercise improves
the inﬂammatory status in diﬀerent lung diseases. However, the eﬀects of long-term aerobic exercise on the pulmonary response to PM10
have not been investigated.
Objectives: The present study evaluated the eﬀect of aerobic exercise on the lung inﬂammatory and risk of lung cancer of rat exposed to
PM10 carbon black.
Materials and Methods: Twenty four adult male Wistar rats were divided into 4 groups: A: control (without exposure PM10 and aerobic
exercise; n = 6), B: aerobic exercise (ﬁve times per week for 4 weeks; n = 6), C: exposure to PM10 carbon black (5 mg/m
; per rat; n = 6), D: and
aerobic exercise concomitantly with exposure to PM10 carbon black (n = 6). The gene expression of TLR4, NF-κB and TNF-α were analyzed
in lung tissue by Real time-PCR. In order to determine the signiﬁcant diﬀerences between groups, one way ANOVA and LSD post hoc and
Kruskal-Vallis test were used.
Results: Aerobic exercise inhibited the PM10 -induced increase in the gene expression of TLR4, NF-κB and TNF-α. But there was signiﬁcant
diﬀerent only between B and C groups for TNF-α and NF-κB (P = 0.047, 0.014 respectively).
Conclusions: We conclude that four week aerobic exercise presents protective eﬀects in a rat model of PM10 carbon black-induced lung
inﬂammation and risk of lung cancer. Our results indicate a need for human studies that evaluate the lung Responses to aerobic exercise
chronically performed in polluted areas.
Keywords: Lung Neoplasms; Inﬂammation; Aerobic Exercise; PM10
Copyright © 2015, Iranian Journal of Cancer Prevention. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCom-
mercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial us-
ages, provided the original work is properly cited.
Inhalation of particulate matter (PM) from fossil fuel
combustion is associated with adverse health eﬀects, in-
cluding reduced lung function (1) and increased mortal-
ity (2). Although the mechanism for PM-induced health
eﬀects is not fully deﬁned, animal models and in vitro
studies suggest that pro-inﬂammatory cytokine release
from airway cells is an important factor (3). Inﬂamma-
tion may play a role in the etiology of lung cancer. Envi-
ronmental agents associated with elevated lung cancer
risk, such as ambient particulate matter, may damage
the lung by inducing chronic inﬂammation. Lung can-
cer risk is elevated in individuals with emphysema (4, 5),
interstitial lung disease (6), and asthma (7), which could
similarly reﬂect eﬀects of the underlying inﬂammatory
Induction of pro-inﬂammatory mediators by alveolar
macrophages exposed to ambient air particulate matter
has been suggested to be a key factor in the pathogene-
sis of inﬂammatory and diseases in the lungs. However,
receptors and mechanisms underlying these responses
have not been fully elucidated. Diﬀerent contributing
physiological and psychosocial factors have been pro-
posed (8). A few prior studies have examined lung cancer
risk in relation to polymorphisms in the genes coding for
inﬂammation pathway signaling molecules, such as In-
terleukin 1β (IL1β) (9-11), IL1 receptor antagonist (IL1RN) (12,
13), IL6 (10, 14), IL10 (15), cyclooxygenase 2 (14), and tumor
necrosis factor α (16). These inﬂammatory cytokines are
regulated by the pro-inﬂammatory transcription factor,
nuclear factor NF-κB (8).
Given the close interaction between the external en-
vironment and the lung, TLRs have been implicated in
lung-associated immune responses, including airway
hyper responsiveness (AHR) and allergic asthma (17). Dys-
function and unregulated activation of the TLR pathway
can contribute to decreased lung function and the patho-
genesis of acute and chronic lung inﬂammatory diseases
(18). TLR activation, can occur via two pathways: 1- the
Myeloid Diﬀerentiation primary-response protein 88
(MyD88)-dependent pathway, and 2- the MyD88-indepen-
dent pathway. These two pathways correspond to early
and late-phase NF-κB signaling and pathway-speciﬁc in-
Fashi M et al.
Iran J Cancer Preven. 2015;8(3):e23332
duction of pro-inﬂammatory cytokines and chemokines
(19, 20). Inﬂammation play an important role in the etiol-
ogy of lung cancer.
Regular aerobic exercise results in multiple health ben-
eﬁts, including improvement of cardiorespiratory ﬁtness
and quality of life, reduction of obesity and blood pres-
sure, and increased longevity (21, 22). When performed
chronically on a regular basis, aerobic exercise also re-
duces oxidative stress systemically (23) in diﬀerent dis-
eases, such as heart diseases, type 2 diabetes, rheumatic
arthritis, and alzheimer and parkinson diseases (23) , as
well as in the airway epithelial cells of animals with long-
term allergic lung inﬂammation (24). Chronic practice
of regular exercise exerts a marked anti-inﬂammatory
eﬀect in diﬀerent models of pulmonary diseases, such
as in asthma models (25-28), acute respiratory distress
syndrome (29, 30), and chronic obstructive pulmonary
Studies that have investigated the eﬀects of exposure to
air pollutants during exercise have suggested that peo-
ple exercising in polluted environments are at increased
risk of respiratory and cardiovascular morbidity related
to air pollution owing to an exercise-induced ampliﬁca-
tion in respiratory uptake, lung deposition, and toxicity
of inhaled pollutants (32-35). Exercise may increase the
likelihood of an adverse eﬀect by increasing the dose of
pollutants delivered to target sites in the lungs as venti-
lation increases to meet metabolic demands (36). How-
ever, these studies do not take into account the potential
anti-inﬂammatory and health eﬀects of exercising in air
pollution (37), which could inhibit the pro-inﬂammatory
events induced by air pollution.
Therefore, the aim of this study was to investigate the
eﬀects of 4 weeks of aerobic exercise performed in asso-
ciation with carbon black PM10 exposure on lung tissue
inﬂammation and lung cancer.
3. Materials and Methods
In all experiments, the Tarbiat Modares university
guidelines for animal care was followed. This study was
approved by the Tarbiat Modares University of Tehran
(code number: 62.2987).
Twenty four adult male Wistar rats aged 8 weeks were
obtained from Pasteur Institute of Iran and randomly di-
vided into the 4 groups: A; control (without exposure car-
bon black PM10 and aerobic exercise; n = 6), B; aerobic ex-
ercise (ﬁve times per week for 4 weeks; n = 6), C; exposure
to carbon black PM10 (5 mg/m
; per rat; n = 6), D; aerobic
exercise concomitantly with exposure to carbon black
PM10 (n = 6). Rats were housed in cages under controlled
environment (23°C and 12 hour light-dark cycle) with free
access to normal chow and tap water.
3.2. Exposure to Carbon Black PM10
Figure 1 shows the inhalation chamber at the labora-
tory of Tarbiat Modares university (Falonak) where inha-
lation exposure was carried out. Carbon black dust (38)
obtained from Iran-carbon factory. Rats in groups of C
and D were exposed to carbon black in the inhalation
chamber at nominal concentrations of 5 mg/m
for 2 h/
day, 5 days per week for a total of 4 weeks. The control rats
were exposed to clean, ﬁltered air containing no carbon
black for the same period. The concentrations, size and
shape of CB particle were monitored once time weekly by
Grimm Aerosol Technique (GmbH and Co. KG. Dorfstraße
9 - 83404 Ainring-Germany (and light microscope (Acc.V-
Spot magn. 25.0 KV 3.4. 5000 x) respectively.
3.3. Exercise Treadmill Test and Training
Animals in B and D groups were adapted to the tread-
mill for rat (will running treadmill, Lafayette American)
training for 3 days (15 minutes, 20 m/min). On the fourth
day, the individual maximal exercise capacity test was
performed with a 5-minute warm-up (6 m/min) and fol-
lowed by an increase in treadmill speed (3 m/min every
3 minutes) until animal exhaustion (i.e., when they were
not able to run voluntarily after 3 mechanical stimuli)
(24, 27, 28). The maximal exercise capacity (100%) was
deﬁned as the maximum speed reached by each animal.
The physical test was performed for each rat individually.
The speed average of each group was calculated, and then
the rats were submitted to treadmill training as a mean
speed of the group workload. rats were trained at low
intensity, corresponding to 50% of the initial maximal
speed obtained in the exercise test, for 60 minutes, ﬁve
times per week, as previously described (24, 27, 28).
3.4. Analysis of mRNA Expression TLR4, NF-κB and
TNF-α by RT-PCR
After sacriﬁced rat and total lung tissue, RNA was isolat-
ed using Trizolereagent (Qiagen, Germany), according to
Figure 1. Inhalation Chamber Used for Whole-Body Inhalation Exposure
to Carbon Black PM10
Fashi M et al.
Iran J Cancer Preven. 2015;8(3):e2333
the manufacturer’s instructions. The RNA samples were-
subjected to reverse transcription using thermo scien-
tiﬁc revert aid ﬁrst strand cDNA synthesis kit (Feremen-
tase). In the subsequent step, the cDNAs were used as
templates to perform real-time PCR using SYBR green PCR
master mix (SYBR green I,) by step one ABI system (Ap-
plied Biosystem).The crossing threshold values assessed
by the real-time PCR were evaluated for the transcripts
and normalized to the results for GAPDH mRNA. The cor-
responding primer pairs for TLR4, NF-κB, and TNF-α and
GAPDH (housekeeping gene) were listed in Table 1.
3.5. Real-Time PCR
All of the tests were repeated two times in each group.
The threshold cycle (Ct) for each speciﬁc gene, corre-
sponding housekeeping gene (GAPDH) and their diﬀer-
ences (ΔCt) were determined and then evaluated gene
expression changes using ∆∆CT formula.
3.6. Statistical Analysis
Results are expressed as Mean ± SD. Diﬀerences in body
weight between pre and post interventions were exam-
ined by 2-tailed t-test. In order to determine the signiﬁcant
diﬀerences between groups one way ANOVA and LSD post
hoc test and Kruskal-Vallis test after examined normal dis-
tribution of data by Kolmogorov-Smirnov test were used. P
< 0.05 were considered statistically signiﬁcant.
Body weight: There were signiﬁcant diﬀerences among
the A (control) and C (PM10 exposure only) groups in
body weight pre and post interventions. The mean of in-
crease in body weight in C group was higher than A, B and
D groups (Table 2).
4.1. Eﬀects of Aerobic Exercise and Carbon Black
PM10 Exposure on Gene Expression TLR4. NF-κB
Presented data in Figure 2 demonstrate that PM10 car-
bon black exposure increased the gene expression TLR4,
NF-κB and TNF-α in lung tissue compared with all of the
other groups (P ≤ 0.05) and that aerobic exercise in
carbon black PM10 exposure decreased the expression
of these cytokine compared with the carbon black PM10
exposure group (P ≤ 0.05). 0ne way ANOVA also dem-
onstrated that carbon black PM10 exposure presented a
signiﬁcant eﬀect on the TNF-α (P = 0.047) and NF-κB (P =
0.014). No signiﬁcant eﬀect was observed on the gene ex-
pression TLR4 by Kruskal-Vallis test (P = 0.325).
Table 1. Primer Sequences Used in Real-Time PCR
Gene Primer Sequence
Forward 5´-AATCCCTGCATAGAGGTACTTCCTAAT -3´
Reverse 5´-CTCAGATCTAGGTTCTTGGTTGAATAAG -3´
Forward 5´-AACACTGCCGAGCTCAAGAT -3´
Reverse 5´-CATCGGCTTGAGAAAAGGAG -3´
Forward 5´-GACCCTCACACTCAGATCATCTTC -3´
Reverse 5´-TGCTACGACGTGGGCTACG -3´
Forward 5´-GACATGCCGCCTGGAGAAAC -3´
Reverse 5´-AGCCCAGGATGCCCTTTAGT -3´
Table 2. Body Weight of Animal’s Pre and Post Intervention
Groups Initial Test Final Test Final-Initial Test P Value
A, Control 285.83 ± 25.55 324.33 ± 27.12 38.50 ± 1.57 0.045
B, Exercise 279.17 ± 32.55 304.33 ± 43.31 25.16 ± 10.76 0.090
C, PM10 270.50 ± 27.12 311.17 ± 36.66 40.67 ± 9.54 0.023
D, exe+PM10 281.67 ± 22.73 315.67 ± 33.23 34.00 ± 10.50 0.101
Data are presented as mean ± SD.
Signiﬁcantly Diﬀerent at P ≤ 0.05.
Figure 2. Eﬀects of Aerobic Exercise and Carbon Black PM10 Exposure on Gene Expression TLR4, NF- κB and TNF-α
Asterisk Indicates Treatments That are Signiﬁcantly Diﬀerent at P ≤ 0.05 Compared With all of the Groups.
Fashi M et al.
Iran J Cancer Preven. 2015;8(3):e23334
In the present study, we demonstrated that aerobic ex-
ercise inhibits lung inﬂammation and pro-inﬂammatory
cytokine release in lung tissue in an experimental model
of PM10 carbon black-induced lung inﬂammation.
Considerable epidemiological and toxicological stud-
ies have established a clear link between exposure to air
pollution particles and adverse pulmonary health eﬀects.
Several experimental and human studies have demon-
strated that increased levels of air pollution associated
with pulmonary inﬂammation (37, 38). The association
between ambient air pollution particles exposure and
lung cancer risk has been investigated in prospective
studies and the results are generally consistent, indicat-
ing that long-term exposure to air pollution may cause
Gene expression analysis identiﬁed the association
with the eﬀect of PM10 carbon black on the innate im-
mune response. PM10 carbon black exposure increased
the gene expression TLR4, NF-κB and TNF-α in lung tissue.
TLR4 activation is corresponded to NF-κB signaling and
pathway-speciﬁc induction of pro-inﬂammatory cyto-
kines and chemokines or interferon signaling (39).
An extensive research in recent years has been indicated
that chronic inﬂammation leads to various chronic dis-
orders associated with cancer (40-42). A central role in
the induction of chronic inﬂammation is played by a set
of genes encoding pro-inﬂammatory cytokines such as
IL-1, IL-2, IL-6, and TNF-α and monocyte chemotactic Pro-
tein 1 that are regulated by the transcription factor (NF-
Particulate matter exposure could eﬀect on Obesity
(46). These conditions are associated with derangements
in the interplay between metabolic and immune process-
es and inﬂammation (47). The authors observed signiﬁ-
cant increase in body weight with PM10 carbon black ex-
posure which could explain the increased inﬂammation
can be caused by PM10 exposure.
Studies have suggested that potential anti-inﬂamma-
tory eﬀects of aerobic exercise could inhibit the pro-
inﬂammatory events induced by air pollution. The anti-
inﬂammatory eﬀects of exercise (48-50) have focused on
three possible mechanisms: the reduction in visceral fat
mass; increased production and release of anti-inﬂam-
matory cytokines from contracting skeletal muscle (such
molecules are termed myokines (48-51); and reduced ex-
pression of Toll-like receptors (TLRs) on monocytes and
macrophages (52). In the present study, aerobic exercise
in PM10 carbon black exposure decreased the gene ex-
pression TLR4, NF-κB and TNF-α in lung tissue and also
body weight of animals. Although this change in gene ex-
pression was slight, however this result can be clinically
We conclude that low-intensity aerobic exercise pres-
ents protective eﬀects from PM10 carbon black-induced
lung inﬂammation. Future studies should therefore
be directed towards better deﬁning the mechanism in-
volved in the induction of symptoms by inﬂammatory
molecules and risk of cancer in exposure to air pollution
We would like to thank the members of this research for
their assistance in conducting this study. Special thanks
to Amir Abbas Moﬁdi for assistance in construct chamber
and PM10 simulator system.
Mohamad Fashi designed and wrote this article and col-
lected and analyzed the data, with Dr. Hamid Agha Aline-
jad and Dr. Hasan Asilian Mahabadi. All authors read and
approved the ﬁnal manuscript.
The authors have no conﬂict of interest in this study.
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