Content uploaded by Daniel Silveira Serra
Author content
All content in this area was uploaded by Daniel Silveira Serra on Sep 16, 2018
Content may be subject to copyright.
_____________________________________________________________________________________________________
*Corresponding author: E-mail: fladimirgondim@gmail.com, lima.gondim@aluno.uece.br;
European Journal of Medicinal Plants
25(1): 1-10, 2018; Article no.EJMP.43561
ISSN: 2231-0894, NLM ID: 101583475
Beneficial Effects of Eucalyptol in the
Pathophysiological Changes of the Respiratory
System: A Proposal for Alternative Pharmacological
Therapy for Individuals with COPD
Fladimir de Lima Gondim
1*
, Gilvan Ribeiro dos Santos
2
,
Igor Fernandes Maia Gomes do Nascimento
3
, Daniel Silveira Serra
2
and Francisco Sales Ávila Cavalcante
2
1
Institute of Biomedical Sciences, State University of Ceará, Ceará, Brazil.
2
Center of Technological Sciences, State University of Ceará, Ceará, Brazil.
3
University of Fortaleza, Ceará, Brazil.
Authors’ contributions
This work was carried out in collaboration between all authors. Authors FLG, GRS and IFMGN wrote
the first draft of the manuscript and managed the literature searches. Author DSS reviewed and edited
the manuscript. Author FSAC supervised the study. All authors read and approved the final
manuscript.
Article Information
DOI: 10.9734/EJMP/2018/43561
Editor(s):
(1)
Dr. Marcello Iriti, Professor, Plant Biology and Pathology, Department of Agricultural and Environmental Sciences,
Milan State University, Italy.
Reviewers:
(1)
A. Papazafiropoulou, Tzaneio General Hospital of Piraeus, Greece.
(2)
Laura Andrea Svetaz, National University of Rosario, Argentina.
(3)
Maricica Pacurari, Jackson State University, USA.
(4)
Antonio Belda Antolí, Universidad de Alicante, Spain.
Complete Peer review History:
http://www.sciencedomain.org/review-history/26249
Received 28
th
May 2018
Accepted 22
nd
August 2018
Published 15
th
September 2018
ABSTRACT
It is estimated that there will be an increase in the incidence of chronic obstructive pulmonary
disease (COPD) in the coming decades. Thus, the pharmacological attributes of products of plant
origin should be considered as an important economic and scientific strategy in the investigation of
therapeutic alternatives, since their experimental validations are indispensable to substantiate the
reliability of these products in the treatment of chronic diseases. Like biologically active compounds,
Review Article
Gondim et al.; EJMP, 25(1): 1-10, 2018; Article no.EJMP.43561
2
Eucalyptol, also known as 1,8- cineole, is the major constituent of the leaf oil of eucalyptus species,
such as Eucalyptus globulus and Eucalyptus tereticornis. It is a terpenoid oxide, free of steroid-like
side effects. This study is based on a review of the specialised literature with purpose to discuss the
biological effects of Eucalyptol in the respiratory system and its interaction with some of the most
promising targets in the treatment of COPD, such as: receivers and membrane channels, oxidative
stress, transcription and expression of cytokines, cell adhesion molecules and neutrophil
chemotaxis, proteases and remodeling.
Keywords: Anti-inflammatory; biological activity; COPD; eucalyptol; herbal medicine; respiratory
system; 1,8- cineole.
1. INTRODUCTION
Individuals with chronic physiologic dysfunctions
such as cancer, diabetes, cardiovascular
disease, asthma and chronic obstructive
pulmonary disease (COPD) are often affected by
a number of factors including irregular physical
activity, poor eating habits, smoking, and
environmental pollutants [1].
Although it is preventable and treatable, COPD is
still the fourth leading cause of death in the
world, and it is estimated that there will be an
increase in its incidence in the coming decades
due to population ageing and continuous
exposure to its risk factors [2]. In parallel, the
study of the pharmacological attributes of plant
origin products used for medicinal purposes
should be recognised as an important economic
and scientific strategy in the investigation of
therapeutic alternatives, since their experimental
validations are indispensable to base the
reliability of these products. With this motivation,
components derived from plant species have
been widely used in a wide variety of diseases,
including chronic diseases [3].
Like biologically active compounds, Eucalyptol,
also known as 1,8- cineole, is a major constituent
of the leaf oil of eucalyptus species, such as
Eucalyptus globulus Labill and Eucalyptus
tereticornis SM. It is classified as a terpenoid
oxide, compound responsible for fragrance and
pleasant taste, endowed with an immense variety
of structures and biological activities, free of
steroid-like side effects. Thus, systemic therapy
with Eucalyptol seems to be favourable in
relation to its lipophilicity related to the terpene
group, and its excretion predominant by
exhalation [4-6].
Such characteristics of this compound attribute
approval of Eucalyptol by the US Food and Drug
Administration (USFDA) for consumption as a
food additive and license as a medicinal product
(SoledumTM capsules, Cassella-med, Cologne,
Germany) in Germany [7]. In view of the above,
this review aims to describe the cell signalling
pathways and biological activities of Eucalyptol in
the respiratory system, to provide scientific
support on its efficacy as an alternative therapy
for the treatment of COPD.
This study is based on the reviews of the
specialised literatures, in which references were
collected from books and scientific articles
selected from electronic databases such as
Scielo, Medline, Pubmed and ScienceDirect. The
inclusion criteria for the studies found were the
therapeutic approaches in COPD, the biological
activity of Eucalyptol on the respiratory system,
as well as the cellular signalling pathways of this
constituent. We excluded studies that reported
aspects with an emphasis in another discussion
that the focus was not related to the respiratory
system or pharmacological properties of
Eucalyptol.
2. GLOBAL INITIATIVE PROJECT ON
COPD
It is estimated that there will be an increase in
the incidence of COPD in the coming decades.
Since 2001, the global strategy for the diagnosis,
management, and prevention of COPD has been
a valuable resource for professional health
promoters. Thus, the Global Initiative for Chronic
Obstructive Pulmonary Disease (GOLD) project
strives to improve prevention and care in COPD
worldwide. Its specific topics address diagnosis,
management of exacerbations in Asthma and
COPD, and means of treating the disease when
in its stable stage [2].
Despite current and future needs, the scientific
committee of the GOLD project, in its catalogue
of scientific papers suggested for reading and
deepening, explains the need for discussion,
elucidation and new research on the
pathophysiological factors involved in COPD,
such as: immune system, membrane specific
Gondim et al.; EJMP, 25(1): 1-10, 2018; Article no.EJMP.43561
3
receptors, gene transcription factors, cytokines,
chemokines, proteases, antiproteases [8-14] and
aggravating and/or causative agents of the
disease, which cause dysfunction in the airways
and pulmonary parenchyma, such as exposure
to cigarette smoke and environmental pollutants
[15-18].
A greater understanding of the inflammatory
mechanisms involved in COPD, achieved in the
last decades, has resulted in the identification of
several processes and goals for the development
of new anti-inflammatory treatments [19]. The
following topics bring a sequential approach to
the action of pathophysiological mediators
parallel to the regulation of these exerted by
Eucalyptol.
3. PHARMACOLOGICAL STUDIES
3.1 Receivers and Membrane Channels
Hypersecretion of mucus, one of the causes of
airflow limitation in COPD, is due to the increase
in the number of goblet cells and submucosal
glands, both due to chronic irritation in the
airways by noxious agents. In this situation,
many mediators stimulate mucus hypersecretion
exerting their effects through the activation of the
epidermal growth factor receptor (EGFR), whose
ligands, such as transforming growth factor alpha
(TGF-α), are produced by neutrophils and
macrophages [20-23].
Analyses were performed on bronchial biopsy
specimens obtained from asthmatic individuals
and patients with COPD. Results showed a
positive correlation between EGFR and mucin
MUC5AC expression [24,25], as EGFR acts as a
transcription factor that plays a regulatory role in
the expression of many genes important for
inflammation [26,27]. Zhou and collaborators
[28] performed a study to elucidate the
anti-inflammatory mechanisms in monocytes
obtained from asthmatic subjects incubated with
Eucalyptol thirty minutes before being stimulated
with lipopolysaccharides (LPS). In this work, it
was observed that Eucalyptol in a concentration-
dependent manner (1, 10, and 100 mg/L, 30 min)
was able to inhibit EGFR synthesis, providing an
evidence of the role of 1,8- cineole in the control
of inflammation and limitation to airway flow.
In a study conducted by Nascimento and
collaborators [29], 1,8- cineole reduced the
tracheobronchial resistance in vivo after
bronchospasm was induced by the challenge to
carbachol. A similar effect was seen when
compared to the response obtained with
fenoterol, a drug used in asthmatic crises and
exacerbation of COPD. In addition, it also directly
relaxed in vitro the airway smooth muscle
previously contracted with the induction of
carbachol, a high concentration of potassium and
histamine. Inhibition of phasic contractions
suggests that Eucalyptol has an antagonistic
action on the transmembrane influx of calcium or
its intracellular action as a second messenger.
Bastos and collaborators [30], in a model of
airway hyper reactivity with subsequent
treatment with a single dose of Eucalyptol
(1 mg/mL) administered by inhalation,
significantly developed lower tracheal ring
contractions when compared to the untreated
group. Specifically, we observed Eucalyptol's
preferential action on voltage-operated calcium
channels (VOCCs).
In accordance with such myorelaxant properties,
Soares and collaborators [31] have shown that
1,8- cineol could induce a negative inotropic
effect on rat heart tissues, while it blocked the
influx of Ca
2+
through the VOCCs located in the
sarcolemma of cardiac myocytes. Therefore, the
relaxation induced by Eucalyptol in the muscle
tissue of the trachea and bronchus in the murine
model may be related to its negative interference
in the influx of calcium through the cell
membrane.
Although it is still a question of transmembrane
proteins, it is important to note that a signalling
pathway associated with Toll-like 4 standard
recognition receptors (TLR4), such as the
activation of p38 mitogen-activated protein
kinase (MAPK p38), play a critical role in
inflammation allergic reaction [32]. Continuous
inhalation of irritants, such as cigarette smoke,
fossil fuel gases and environmental particles,
activate TLR4 [33,34]. This mechanism leads to
the propagation of an innate immune response,
with activation of airway epithelial cells and
secretion of mucus [35].
Zhao and collaborators [36], investigated the
expression of these receptors in mice with LPS-
induced lung inflammation after treatment with
Eucalyptol. In this study, a single oral dose of
Eucalyptol (100 mg/kg) was found to decrease
TLR4 expression when compared to the non-
constituent group and the positive control group
treated with prednisone, a substance used in
anti-inflammatory drugs. Later, , the effects of
Eucalyptol in a model of solution-induced asthma
Gondim et al.; EJMP, 25(1): 1-10, 2018; Article no.EJMP.43561
4
composed of dust mites at home were
investigated by Lee and collaborators [37], where
TLR4 suppression and mitogen-activated protein
kinase p38 (MAPK p38) in mice was treated with
Eucalyptol (10 mg/mL), via nebulization, before
each exposure to the aggressive agent.
3.2 Oxidative Stress
The redox imbalance is also an important
mechanism of conduction in the pathophysiology
of chronic diseases and a crucial target for
therapies in COPD [38], because reactive
oxygen species (ROS) activate nuclear factor
kappa B (NF-κB) and MAPK p38, thus leading to
a further intensification of inflammatory genes
and inhibition of the activity of endogenous
antiproteases. This suggests that antioxidants
may be very useful in the treatment of COPD by
reducing the inflammatory process, as well as
repairing and reversing resistance to
corticosteroids [19].
The production of reactive oxygen species (ROS)
caused by smoking is linked to the
protease/antiprotease imbalance that contributes
to the development of COPD [39,40]. Kennedy-
Feitosa and collaborators [41], analysed the
efficacy of Eucalyptol against acute lung
inflammation caused by cigarette smoke (CF), in
which mice were exposed to CF and treated with
Eucalyptol (10 mg/mL) via inhalation 15 minutes
a day, for 5 days. In this protocol, it was
observed that the group treated with Eucalyptol,
when compared to the group exposed to smoke
and untreated, was able to reduce ROS levels,
confirmed by the reduction of the enzymatic
activities of catalase (CAT) and superoxide
dismutase (SOD). In parallel, the compound
reduced oxidative damage through lipid
peroxidation, evidenced by reduced levels of
malondialdehyde (MDA).
3.3 Transcription and Expression of
Cytokines
Both MAPK p38 and oxidative stress induce the
activation of NF-κB by promoting the
transcription of pro-inflammatory cytokines [42-
45], resulting in its translocation to the nucleus,
adhesion to DNA and effectuation of genetic
transcription. The pathway of activation of this
factor is associated with the transcription of
genes involved in the inflammatory process, such
as cytokines, chemokines and adhesion
molecules [46].
In a model of acute lung injury (IPA) induced by
LPS, BALB / C, mice were subjected to single
dose pre-treatment via intraperitoneal injection
with 400 mg/kg Eucalyptol, where it caused
a reduction in NF-κB expression and,
consequently, cytokines and proteinases [47].
Similar results in NF-kB suppression, compared
to Eucalyptol treatment, were also observed in
the IPA model caused by cigarette smoke [41]
and pneumonia model caused by influenza virus
infection (IFV), where BALB / C mice received
oral treatment at 120 mg/kg, two days prior to the
viral exposure [48]. In addition, Greiner and
collaborators [49], suggested a novel mode of
NF-kB blockade through inhibition of nuclear
translocation by the nuclear factor kappa B alpha
inhibitor (IκBα) and increased levels in response
to treatment with Eucalyptol after stimulation with
LPS.
As mentioned above, epithelial cell and
macrophage-activated NF-kB regulate the
secretion of many cytokines and chemokines in
both asthma and COPD, and these inflammatory
mediators play a potential role in the initiation
and perpetuation of airway mucus hypersecretion
in consequence to inflammatory stimuli
[45,50,51].
Under these conditions, cytokines are secreted
by the resident tissue cells, and also culminate in
the recruitment of leukocytes. Specifically, tumor
necrosis factor alpha (TNF-α), interleukin 1b (IL-
1β), interleukin-6 (IL-6), interleukin-8 (IL-8) and
interleukin-17 (IL-17) are documented for their
important roles in this process and are present in
high concentrations in bronchial, lung and
sputum biopsy samples of patients with COPD
[52-55]. Eucalyptol has been shown to be able to
reduce the number of macrophages, as well as
the expression of TNF-α, IL-1β, IL-6 and IL-17, is
responsible for the initiation and propagation of
inflammation [4,30,36,41,47,48,56].
Another property pertinent to the interaction with
these mediators, related to the biological
activities of Eucalyptol, relates to an increased
expression of interleukin 10 (IL-10) [30,36,48]
and cytokine that play an anti-inflammatory role
in the innate and adaptive response of the
immune system, with significantly lower
expression in sputum samples from patients with
asthma and COPD [57].
3.4 Cell Adhesion Molecules and
Neutrophil Chemotaxis
Some of these cytokines, such as TNF-α factor,
IL-1β, stimulate endothelial cells to express
intercellular adhesion molecule (ICAM) -1 and
Gondim et al.; EJMP, 25(1): 1-10, 2018; Article no.EJMP.43561
5
vascular cell adhesion molecule (VCAM) -1 in
bronchial vessels and alveoli, culminating in
leukocyte migration to the site of infection
[58,59]. In parallel, leukotrienes, a class of
eicosanoids present at high levels in asthma and
COPD [60], are also capable of inducing the
adhesion and activation of leukocytes in the
endothelium [61,62]. In contrast to the stimulation
of monocytes from asthmatic individuals,
Juergens and collaborators [63], observed
significant inhibition of cytokines, tramboxane B2
and leukotriene B4 (LTB4) after three days of
Eucalyptol therapy with daily doses of 600 mg (3
x 200 mg /day).
Li and collaborators [48], analysed the
expression of cell adhesion molecules on the cell
surface of mice in response to Influenza virus
infection, where positive regulation of ICAM-1
and VCAM-1 was observed, and a significant
reduction in the expression of these molecules in
the group receiving oral Eucalyptol (120 mg/kg)
before and after inoculation of the virus. The
results observed in the Eucalyptol treated group,
such as suppression of proinflammatory
cytokines, transcription factors and adhesion
molecules were similar to the positive control
group treated with Oseltamivir, the antiviral
substance commonly used against influenza
virus.
Chemokines, such as IL-8, exert their function by
coupling to the G protein of the receptor
expressed in inflammatory cells, regulating their
transit towards the pulmonary interstitium [64].
The level of IL-8 is related to the absolute
number of neutrophils in induced sputum in
individuals with COPD, in addition to being
increased in patients with α1- antiprotease
deficiency [44,65,66].
Both in vitro [4] and in vivo [37] experiments
demonstrated the efficacy of Eucalyptol in the
inhibition of IL-8, as well as the reduction in the
number of leukocytes in bronchoalveolar lavage
of mice induced to acute pulmonary inflammation
[41].
3.5 Proteases and Remodeling
It is known that neutrophils are implicated in the
release of inflammatory cytokines, lipid mediators
and enzymes capable of promoting tissue injury
[67]. Thus, constant inflammatory stimuli and a
growing influx of these leukocytes into the
pulmonary parenchyma cause a large release of
proteases by these cells, such as matrix
metalloproteinases (MMPs). Type 9 matrix
metalloprotease (MMP-9) is thought to be the
most promising target for drug development due
to its predominance in the degrading potential of
collagen fibres and elastin, causing pulmonary
emphysema and stimulation of mucus
hypersecretion, causing chronic bronchitis
[19,68-71].
Fig. 1. Schematic diagram, developed from the information collected in the present study, with
representation of biological components, which have functionality altered by inhaled irritants
(cigarette smoke, air pollutants, indoor dust), capable of interacting with Eucalyptol, such as
membrane proteins (EGFR, VOCCs and TLR4), proteins involved in the production of mucus
(MUC5AC), elements (TNF-α, IL-1β, IL-6, IL-8, IL-10, IL-17), transcriptional protein activators
(MAP38 p38 and ROS), transcriptional proteins (NF-kB), leukins (TNF-α, IL-1β, IL-6, IL-8, IL-10,
IL-17), cell adhesion molecules (VCAM, ICAM), LTB4 and MMP-9
Gondim et al.; EJMP, 25(1): 1-10, 2018; Article no.EJMP.43561
6
In a study conducted by Kim, Lee and Seol [47] it
was observed that pre-treatment with
Eucalyptol (400 mg/kg), injected intraperitoneally,
significantly attenuated the expression of MMP-9
and prevented the histopathological changes
caused by said proteolytic enzyme. These results
were also similar to the positive control of the
study, where dexamethasone was used because
it is a drug that has potential anti-inflammatory
effects.
Despite having properties that preserve the
histoarchitecture of lung tissue, there is a lack in
the literature of studies investigating the effects
of Eucalyptol in the functional mechanics of the
respiratory system. However, Worth et al. [72]
conducted a randomised, placebo-controlled
study of Eucalyptol (600 mg/kg/day, orally) over
6 months for patients with stable COPD using
concomitant pharmacological therapy (β-
agonists, anticholinergics and theophylline). In
the spirometric protocols, improvement of forced
expiratory volume in 1 second (FEV1), vital
capacity (CV) and reduction of exacerbations of
Eucalyptol-treated group disease in relation to
placebo was observed in the spirometric
protocols.
The literature review discussed in the present
study shows that the biological activities of
Eucalyptol when administered orally (100 to 600
mg/kg), intraperitoneal (400 mg/kg), or by
inhalation (1 to 10 mg/mL), involve various
stages and crucial molecules in the development
of the acute and chronic inflammatory process in
the respiratory system, as exemplified in Fig.1
4. CONCLUSION
The interaction of Eucalyptol in animal
experimental models with pathophysiological
mediators (oxidative stress, transcription
molecules of cytokines, pro-inflammatory cells
and proteases) identified in human respiratory
system affections show a relevant alternative
treatment option concomitant with the anti-
inflammatory drugs in asthma and COPD.
CONSENT
As per international standard or university
standard, patient’s written consent has been
collected and preserved by the authors.
ETHICAL APPROVAL
As per international standard or university
standard, written approval of Ethics committee
has been collected and preserved by the
authors.
COMPETING INTERESTS
Authors have declared that no competing
interests exist.
REFERENCES
1. Elwood P, Galante J, Pickering J, Palmer
S, Bayer A, Ben-Shlomo Y, Gallacher
J. Healthy lifestyles reduce the incidence
of chronic diseases and dementia:
Evidence from the Caerphilly cohort
study. PloS one. 2013;8(12):1-7.
doi: 10.1371/journal.pone.0081877
2. Global Strategy for the Diagnosis,
Management and Prevention of COPD,
Global Initiative for Chronic Obstructive
Lung Disease (GOLD); 2017.
Available: http://goldcopd.org
3. Greiner JFW, Müller J, Zeuner MT, Hauser
S, Seidel T, Klenke C, Kaltschmidt B. 1, 8-
Cineol inhibits nuclear translocation of NF-
κB p65 and NF-κB-dependent transcript-
tional activity. Biochimica et Biophysica
Acta (BBA)-Molecular Cell Research.
2013;1833(12):2866-2878.
DOI: 10.1016/J.BBAMCR.2013.07.001
4. Juergens UR, Engelen T, Racké K, Stöber
M, Gillissen A, Vetter H. Inhibitory activity
of 1, 8-cineol (Eucalyptol) on cytokine
production in cultured human lymphocytes
and monocytes. Pulmonary pharmacology
& therapeutics. 2004;17(5):281-287.
DOI: 10.1016/J.PUPT.2004.06.002
5. Aparicio S, Alcalde R, Dávila MJ, García B,
Leal JM. Properties of 1,8-cineole: A
thermophysical and theoretical study. The
Journal of Physical Chemistry B. 2007;
111(12):3167-3177.
DOI: 10.1021/jp067405b
6. Liu CH, Chang FY. Development
and characterization of Eucalyptol
microemulsions for topic delivery of
curcumin. Chemical and Pharmaceutical
Bulletin. 2011;59(2):172-178.
DOI: 10.1248/CPB.59.172
7. Barceloux DG. Medical toxicology of
natural substances: Foods, fungi,
medicinal herbs, plants, and venomous
animals. John Wiley & Sons; 2012.
8. Ansarin K, Rashidi F, Namdar H, Ghaffari
M, Sharifi A. Echocardiographic Evaluation
of the Relationship Between inflammatory
factors (IL6, TNFα, hs-CRP) and
secondary pulmonary hypertension in
Gondim et al.; EJMP, 25(1): 1-10, 2018; Article no.EJMP.43561
7
patients with COPD. A cross sectional
study. Pneumologia (Bucharest, Romania).
2015;64(3):31-35.
9. Brill SE, Law M, El-Emir E, Allinson JP,
James P, Maddox V, Nazareth I. Effects of
different antibiotic classes on airway
bacteria in stable COPD using culture and
molecular techniques: A randomised
controlled trial. Thorax. Thoraxjnl; 2015.
DOI: 10.1136/thoraxjnl-2015-207194
10. Chillappagari S, Preuss J, Licht S, Müller
C, Mahavadi P, Sarode G, Henke MO.
Altered protease and antiprotease balance
during a COPD exacerbation contributes to
mucus obstruction. Respiratory Research.
2015;16(1):85.
doi: 10.1186/s12931-015-0247-x
11. Esther Jr CR, Coakley RD, Henderson
AG, Zhou YH, Wright FA, Boucher
RC. Metabolomic evaluation of
neutrophilic airway inflammation in cystic
fibrosis. CHEST Journal. 2015;148(2):507-
515.
DOI: 10.1378/chest.14-1800
12. Gane JM, Stockley RA, Sapey E. The
rs361525 polymorphism does not increase
production of tumor necrosis factor alpha
by monocytes from alpha-1 antitrypsin
deficient subjects with chronic obstructive
pulmonary disease-a pilot study. Journal of
Negative Results in Biomedicine. 2015;
14(1):20.
DOI: 10.1186/s12952-015-0039-3
13. Wells JM, Jackson PL, Viera L, Bhatt SP,
Gautney J, Handley G, Dransfield MT. A
randomized, placebo-controlled trial of
roflumilast. Effect on proline-glycine-proline
and neutrophilic inflammation in chronic
obstructive pulmonary disease. American
Journal of Respiratory and Critical Care
Medicine. 2015;192(8):934-942.
DOI: 10.1164/rccm.201503-0543oc
14. YUN CM, SANG XY. Role of proteinase-
activated receptor-1 gene polymorphisms
in susceptibility to chronic obstructive
pulmonary disease. Genetics and
Molecular Research. 2015;14(4):13215-
13220.
DOI: 10.4238/2015.October.26.18
15. Cortez-Lugo M, Ramírez-Aguilar M, Pérez-
Padilla, R, Sansores-Martínez R, Ramírez-
Venegas A, Barraza-Villarreal A. Effect of
personal exposure to PM2.5 on respiratory
health in a Mexican panel of patients with
COPD. International Journal of
Environmental Research and Public
Health. 2015;12(9):10635-10647.
DOI: 10.3390/ijerph120910635
16. Minakata Y, Morishita Y, Ichikawa T,
Akamatsu K, Hirano T, Nakanishi M,
Ichinose M. Effects of pharmacologic
treatment based on airflow limitation and
breathlessness on daily physical activity in
patients with chronic obstructive pulmonary
disease. International Journal of Chronic
Obstructive Pulmonary Disease. 2015;10:
1275.
DOI: 10.2147/COPD.S84134
17. Topalovic M, Derom E, Osadnik CR,
Troosters T, Decramer M, Janssens W.
Airways resistance and specific
conductance for the diagnosis of
obstructive airways diseases. Respiratory
Research. 2015;16(1):88.
DOI: 10.1186/S12931-015-0252-0
18. Wei J, Zhao H, Fan G, Li J. Bilirubin
treatment suppresses pulmonary
inflammation in a rat model of smoke-
induced emphysema. Biochemical and
Biophysical Research Communications.
2015;465(2):180-187.
DOI: 10.1016/j.bbrc.2015.07.133
19. Barnes PJ. New anti-inflammatory targets
for chronic obstructive pulmonary
disease. Nature Reviews Drug Discovery.
2013;12(7):543-559.
DOI: 10.1038/nrd4025
20. Global initiative for chronic obstructive lung
disease. Global strategy for the diagnosis,
management, and prevention of copd;
2017.
Available:http://goldcopd.org/global-
strategy-diagnosis-management-
prevention-copd-2016/
21. Burgel PR, Nadel JA. Epidermal growth
factor receptor-mediated innate immune
responses and their roles in airway
diseases. European Respiratory Journal.
2008;32(4):1068-1081.
DOI: 10.1183/09031936.00172007
22. Calafat J, Janssen H, Zuurbier AE, Knol
EF, Egesten A. Human monocytes and
neutrophils store transforming growth
factor-α in a subpopulation of cytoplasmic
granules. Blood. 1997;90(3):1255-1266.
23. Rumelhard M, Ramgolam K, Hamel
R, Marano F, Baeza- Squiban A.
Expression and role of EGFR ligands
induced in airway cells by PM2.5
and its components. European Respiratory
Journal. 2007;30(6):1064-1073.
DOI: 10.1183/09031936.00085907
24. Takeyama K, Fahy JV, Nadel JA.
Relationship of epidermal growth factor
Gondim et al.; EJMP, 25(1): 1-10, 2018; Article no.EJMP.43561
8
receptors to goblet cell production in
human bronchi. American Journal of
Respiratory and Critical Care Medicine.
2001;163(2):511-516.
DOI: 10.1164/AJRCCM.163.2.2001038
25. O’donnell RA, Richter A, Ward J, Angco G,
Mehta A, Rousseau K, Wilson SJ.
Expression of ErbB receptors and mucins
in the airways of long term current
smokers. Thorax. 2004;59(12):1032-1040.
DOI: 10.1136/THX.2004.028043
26. Liu L, Tsa, JC, Aird, William C. Egr-1 gene
is induced by the systemic administration
of the vascular endothelial growth factor
and the epidermal growth factor. Blood.
2000;96(5):1772-1781.
27. Cho SJ, Kang MJ, Homer RJ, Kang
HR, Zhang X, Lee PJ, Lee CG. Role
of early growth response-1 (Egr-1)
in interleukin-13-induced inflammation
and remodeling. Journal of Biological
Chemistry. 2006;281(12):8161-8168.
28. Zhou X, Dai Q, Huang X. Neutrophils in
acute lung injury. Frontiers in bioscience
(Landmark edition). 2011;17:2278-2283.
29. Nascimento NRF, Refosco RMDC,
Vasconcelos ECF, Kerntopf MR, Santos
CF, Batista, FJA, Fonteles MC. 1,
8‐Cineole induces relaxation in rat and
guinea‐pig airway smooth muscle. Journal
of Pharmacy and Pharmacology. 2009;
61(3):361-366.
DOI: 10.1211/JPP.61.03.0011
30. Bastos VP, Gomes AS, Lima FJ, Brito TS,
Soares PM, Pinho JP, Magalhães PJ.
Inhaled 1, 8‐cineole reduces inflammatory
parameters in airways of
Ovalbumin‐challenged Guinea Pigs. Basic
& Clinical Pharmacology & Toxicology.
2011;108(1):34-39.
DOI: 10.1111/J.1742-7843.2010.00622.X
31. Soares MCMS, Damiani CEN, Moreira
CM, Stefanon I, Vassallo DV. Eucalyptol,
an essential oil, reduces contractile activity
in rat cardiac muscle. Brazilian Journal of
Medical and Biological Research. 2005;
38(3):453-461.
DOI: 10.1590/S0100-79X2005000300017
32. Jarvis D, Zock JP, Heinrich J, Svanes C,
Verlato G, Olivieri M, Dahlman-Hoglund A.
Cat and dust mite allergen levels, specific
IgG and IgG 4 and respiratory symptoms in
adults. Journal of allergy and clinical
immunology. 2007;119(3):697-704.
DOI: 10.1016/J.JACI.2006.10.042
33. Freeman CM, Martinez FJ, Han MK,
Washko GR, McCubbrey AL, Chensue
SW, Curtis JL. Lung CD8+ T cells in COPD
have increased expression of bacterial
TLRs. Respiratory Research. 2013;14(1):
13.
DOI: 10.1186/1465-9921-14-13
34. Nadigel J, Préfontaine D, Baglole CJ,
Maltais F, Bourbeau J, Eidelman DH,
Hamid Q. Cigarette smoke increases
TLR4 and TLR9 expression and induces
cytokine production from CD8+ T cells in
chronic obstructive pulmonary disease.
Respiratory Research. 2011;12(1):149.
DOI: 10.1186/1465-9921-12-149
35. Vassallo R, Walters PR, Lamont J, Kottom
TJ, Eunhee SY, Limper AH. Cigarette
smoke promotes dendritic cell
accumulation in COPD; a Lung Tissue
Research Consortium study. Respiratory
Research. 2010;11(1):45.
DOI: 10.1186/1465-9921-11-45
36. Zhao C, Sun J, Fang C, Tang F. 1, 8-cineol
attenuates LPS-induced acute pulmonary
inflammation in mice. Inflammation. 2014;
37(2):566-572.
DOI: 10.1007/s10753-013-9770-4
37. Lee HS, Park DE, Song WJ, Park
HW, Kang HR, Cho SH, Sohn SW. Effect
of 1.8-cineole in dermatophagoides
pteronyssinus- stimulated bronchial
epithelial cells and mouse model of
asthma. Biological and Pharmaceutical
Bulletin. 2016;39(6):946-952.
DOI: 10.1248/BPB.B15-00876
38. Kirkham PA, Caramori G, Casolari P, Papi
AA, Edwards M, Shamji B, Heinemann L.
Oxidative stress–induced antibodies to
carbonyl-modified protein correlate with
severity of chronic obstructive pulmonary
disease. American journal of Respiratory
and Critical Care Medicine. 2011;184(7):
796-802.
DOI: 10.1164/Rccm.201010-1605oc
39. Pourazar J, Blomberg A, Kelly FJ, Davies
DE, Wilson SJ, Holgate ST, Sandström, T.
Diesel exhaust increases EGFR and
phosphorylated cterminal Tyr 1173 in the
bronchial epithelium. Particle and Fibre
Toxicology. 2008;5(1):1-9.
DOI: 10.1186/1743-8977-5-8
40. Rahman I, Biswas SK, Jimenez LA, Torres
M, Forman HJ. Glutathione, stress
responses, and redox signaling in lung
inflammation. Antioxidants & Redox
Signaling. 2005;7(1-2):42-59.
DOI: 10.1089/ARS.2005.7.42
41. Kennedy-Feitosa E, Okuro, RT, Ribeiro
VP, Lanzetti M, Barroso MV, Zin, WA,
Gondim et al.; EJMP, 25(1): 1-10, 2018; Article no.EJMP.43561
9
Valenca SS. Eucalyptol attenuates
cigarette smoke-induced acute lung
inflammation and oxidative stress in the
mouse. Pulmonary Pharmacology &
Therapeutics. 2016;41:11-18.
DOI: 10.1016/J.PUPT.2016.09.004
42. Carpentier I, Declercq W, Malinin NL,
Wallach D, Fiers W, Beyaert R. TRAF2
plays a dual role in NF-κB-dependent gene
activation by mediating the TNF-induced
activation of p38 MAPK and IκB kinase
pathways. Febs Letters. 1998;425(2):195-
198.
DOI: 10.1016/S0014-5793(98)00226-9
43. Saatian B, Yutong ZY, He D, Georas
SN, Watkins T, Spannhake E, Natarajan
V. Transcriptional regulation of
lysophosphatidic acid-induced interleukin-8
expression and secretion by p38 MAPK
and JNK in human bronchial epithelial
cells. Biochemical Journal. 2006;393(3):
657-668.
DOI: 10.1042/bj20050791
44. Pourazar J, Mudway IS, Samet JM,
Helleday R, Blomberg A, Wilson SJ,
Sandstrom T. Diesel exhaust activates
redox-sensitive transcription factors and
kinases in human airways. American
Journal of Physiology-Lung Cellular and
Molecular Physiology. 2005;289(5):L724-
L730.
DOI: 10.1152/AJPLUNG.00055.2005
45. Khansari N, Shakiba Y, Mahmoudi M.
Chronic inflammation and oxidative stress
as a major cause of age-related diseases
and cancer. Recent Patents on
Inflammation & Allergy Drug Discovery.
2009;3(1):73-80.
DOI: 10.2174/187221309787158371
46. Karin M, Yamamoto Y, Wang QM. The IKK
NF-κB system: A treasure trove for drug
development. Nature Reviews Drug
Discovery. 2004;3(1):17-26.
DOI: 10.1038/NRD1279
47. Kim KY, Lee HS, Seol GH. Eucalyptol
suppresses matrix metalloproteinase‐9
expression through an extracellular
signal‐regulated kinase‐dependent nuclear
factor‐kappa B pathway to exert
anti‐inflammatory effects in an acute lung
inflammation model. Journal of Pharmacy
and Pharmacology. 2015;67(8):1066-1074.
DOI: 10.1111/JPHP.12407
48. Li, Y, Lai Y, Wang Y, Liu N, Zhang F, Xu P.
1, 8-Cineol protect against influenza-virus-
induced pneumonia in mice. Inflammation.
2016;39(4):1582-1593.
DOI: 10.1007/s10753-016-0394-3
49. Greiner JFW, Müller J, Zeuner MT,
Hauser S, Seidel T, Klenke C, Kaltschmidt
B. 1, 8-Cineol inhibits nuclear translocation
of NF-κB p65 and NF-κB-dependent
transcriptional activity. Biochimica et
Biophysica Acta (BBA)-Molecular Cell
Research. 2013;1833(12):2866-2878.
DOI: 10.1016/J.BBAMCR.2013.07.001
50. Lundgren JD, Shelhamer JH.
Pathogenesis of airway mucus hyper-
secretion. Journal of allergy and clinical
immunology. 1990;85(2):399-417.
DOI: 10.1016/0091-6749(90)90147-V
51. Caramori G, Casolari P, Adcock I. Role of
transcription factors in the pathogenesis of
asthma and COPD. Cell Communication &
Adhesion. 2013;20(1-2):21-40.
DOI: 10.3109/141961.2013.775257
52. Ricci M, Matucci A, Rossi O. Recent
advances in the pathogenetic mechanisms
and genetic aspects of atopic
diseases. Allergy Clin Immunol News.
1994;6:103-8.
53. Di Stefano A, Caramori G, Gnemmi I,
Contoli M, Vicari C, Capelli A, Casolari P.
T helper type 17‐related cytokine
expression is increased in the bronchial
mucosa of stable chronic obstructive
pulmonary disease patients. Clinical &
Experimental Immunology. 2009;157(2):
316-324.
DOI: 10.1111/j.1365-2249.2009.03965.x
54. Pridgeon C, Bugeon L, Donnelly L,
Straschil U, Tudhope SJ, Fenwick P,
Dallman MJ. Regulation of IL-17 in chronic
inflammation in the human lung. Clinical
Science.2011;120(12):515-524.
DOI: 10.1042/cs20100417
55. Marumo S, Hoshino Y, Kiyokawa H,
Tanabe N, Sato A, Ogawa E, Mishima M.
p38 mitogen-activated protein kinase
determines the susceptibility to cigarette
smoke-induced emphysema in mice. BMC
pulmonary medicine. 2014;14(1):79.
DOI: 10.1186/1471-2466-14-79
56. Sadlon AE, Lamson DW. Immune-
modifying and antimicrobial effects of
Eucalyptus oil and simple inhalation
devices. Alternative Medicine Review.
2010;15(1):33-43.
57. Takanashi S, Hasegawa Y, Kanehira Y,
Yamamoto K, Fujimoto K, Satoh K,
Okamura K. Interleukin‐10 level in sputum
is reduced in bronchial asthma, COPD and
in smokers. European Respiratory Journal.
1999;14(2):309-314.
Gondim et al.; EJMP, 25(1): 1-10, 2018; Article no.EJMP.43561
10
58. Tosi MF, Stark JM, Smith C, Hamedani A,
Gruenert D, Infeld MD. Induction of ICAM-
1 expression on human airway epithelial
cells by inflmmatory cytokines: Effect of
neutrophil-epithelial cells adhesion. Am J
Respir Cell Mol Biol. 1992;7:214-21.
DOI: 10.1165/ajrcmb/7.2.214
59. Kumar V, Cotran RS, Robbins SL.
Patologia humana. Elsevier Health
Sciences; 2008.
60. Boyce JA. Eicosanoids in asthma,
allergic inflammation, and host defense.
Current molecular medicine. 2008;8(5):
335-349.
DOI: 10.2174/156652408785160989
61. Goetzl EJ, PICKETT WC. The human
PMN leukocyte chemotactic activity of
complex hydroxy-eicosatetraenoic acids
(HETEs). The Journal of Immunology.
1980;125(4):1789-1791.
62. Mayes PA, Botham KM. Metabolism
of unsaturated fatty acids and eicosanoids.
Harper’s Illustrated Biochemistry, 26
th
Ed.
(Lange Medical Books, New York). 2003;
190-196.
63. Juergens UR, Stöber M, Vetter H.
Inhibition of cytokine production and
arachidonic acid metabolism by Eucalyptol
(1.8-cineole) in human blood monocytes in
vitro. European Journal of Medical
Research. 1998;3(11):508-510.
64. Yamagata T, Ichinose M. Agents against
cytokine synthesis or receptors. European
Journal of Pharmacology. 2006;533(1):
289-301.
DOI: 10.1016/j.ejphar.2005.12.046
65. Woolhouse IS, Bayley DL, Stockley RA.
Sputum chemotactic activity in chronic
obstructive pulmonary disease: Effect of
α1–antitrypsin deficiency and the role of
leukotriene B4 and interleukin 8. Thorax.
2002;57(8):709-714.
DOI: 10.1136/THORAX.57.8.709
66. Rufino R, Costa CHD, Souza HSPD, Madi
K, Silva JRL. Induced sputum and
peripheral blood cell profile in chronic
obstructive pulmonary disease. Journal
Brasileiro de Pneumologia. 2007;33(5):
510-518.
DOI: 10.1590/S1806-37132007000500005
67. Holz O, Seiler T, Karmeier A, Fraedrich
J, Leiner H, Magnussen H, Welker
L. Assessing airway inflammation in
clinical practice–experience with
spontaneous sputum analysis. BMC
Pulmonary Medicine. 2008;8(1):5.
DOI: 10.1186/1471-2466-8-5
68. Parks WC, Wilson CL, López-Boado YS.
Matrix metalloproteinases as modulators of
inflammation and innate immunity. Nature
Reviews Immunology. 2004;4(8):617-629.
DOI: 10.1038/NRI1418
69. Macnee W. Pathogenesis of chronic
obstructive pulmonary disease.
Proceedings of the American Thoracic
Society. 2005;2(4):258-266.
DOI: 10.1513/pats.200504-045SR
70. Valença SS, Porto LC. Immuno-
histochemical study of lung remodeling in
mice exposed to cigarette smoke. Journal
Brasileiro de Pneumologia. 2008;34(10):
787-795.
DOI: 10.190/S1806-37132008001000006
71. Grzela K, Litwiniuk M, Zagorska W, Grzela
T. Airway remodeling in chronic obstructive
pulmonary disease and asthma: The
role of matrix metalloproteinase-9.
Archivum Immunologiae et Therapiae
Experimentalis. 2016;64(1):47-55.
DOI: 10.1007/s00005-015-0345-y
72. Worth H, Schacher C, Dethlefsen U.
Concomitant therapy with Cineole
(Eucalyptole) reduces exacerbations in
COPD: A placebo-controlled double-blind
trial. Respiratory Research. 2009;10(1):69.
DOI: 10.1186/1465-9921-10-69
_________________________________________________________________________________
© 2018 Gondim et al.; This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.
Peer-review history:
The peer review history for this paper can be accessed here:
http://www.sciencedomain.org/review-history/26249
