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Juergens UR. Anti-infl ammation with 1,8-cineole … Drug Res
received 27 . 10 . 2013
accepted 18 . 03 . 2014
Bibliography
DOI http://dx.doi.org/
10.1055/s-0034-1372609
Published online: 2014
Drug Res
© Georg Thieme Verlag KG
Stuttgart · New York
ISSN 2194-9379
Correspondence
U. R. Juergens
Department of Pneumology
Allergology, Sleep Medicine
Medical Clinic II, Bonn
University Hospital
Sigmund-Freud-Strasse 25
D-53105 Bonn
G e r m a n y
Tel.: + 49/228/28715 052
Fax: + 49/228/455 193(priv.)
uwe.juergens@ukb.uni-bonn.de
juergens_uwe@t-online.de
Key words
●
▶
1,8-cineole
●
▶
superoxides
●
▶
infl ammatory mediators
●
▶
airway disease
●
▶
asthma
●
▶
COPD
Anti-infl ammatory Properties of the Monoterpene
1.8-cineole: Current Evidence for Co-medication in
Infl ammatory Airway Diseases
lier preclinical studies have demonstrated the
diff erent pharmacological eff ects on the respira-
tory tract. Clinical trials have confi rmed that
1,8-cineole improves ciliary beat frequency of
the mucus membrane, and exhibits secretolytic
and bronchospasmolytic properties [ 4 – 6 ] . Addi-
tional benefi ts during respiratory tract infections
have been known for many years due to the anti-
septic [ 7 ] and antimicrobial [ 8 ] properties of
1,8-cineole, shown in vitro. More recently, there
is increasing evidence of so far unknown anti-
oxidant and anti-infl ammatory effi cacy for
1,8-cineole from various in vitro studies with
human monocytes suggesting its long-term clini-
cal use for upper and lower infl ammatory airway
diseases as well. By these modes of actions a pro-
tective effi cacy of 1,8-cineole was shown at the
histoarchitectural level in various animal models
against hepatic necrosis [ 9 ] , ethanol-induced
gastric injury [ 10 ] or colonic damage in induced
colitis [ 11 ] . Following oral ingestion in gastric
resistant capsules, 1,8-cineole is resorbed in the
small intestine, then metabolized in the liver by
Introduction
▼
1,8-cineole is a saturated monoterpene (
●
▶
Fig. 1 ),
present in various plant species (e. g. Eucalyptus,
Rosmarinus, Psidium, Croton, and Salvia ), with
the main sources being eucalyptus leaves [ 1 ] .
Due to its natural source, 1,8-cineole is also
called eucalyptol, but it should not be con-
founded with eucalyptus oil, a mixture of many
other constituents [ 2 ] . Also, cineole should be
completely distinguished from natural mixtures
of various cell-activating and -inhibitory terpe-
nes known as essential oils. The content of cine-
ole in eucalyptus oil varies from species to
species [ 1 , 3 ] . High concentrations of 1,8-cineole
can be obtained from Eucalyptus nicholii ( > 80 %)
[ 1 ] . Based on its pleasant aroma and taste,
1,8-cineole is frequently used in food, fragrances,
and cosmetics.
Like many aromatic oils, the pure monoterpene
1,8-cineole is used for respiratory tract infec-
tions, such as common cold or bronchitis, and
also as an additional treatment for sinusitis. Ear-
Author U. R. Juergens
Affi liation
Department of Pneumology, Allergology, Sleep Medicine Medical Clinic II, Bonn University Hospital Bonn, Germany
Abstract
▼
1,8-cineole is a natural monoterpene, also
known as eucalyptol. It is a major compound
of many plant essential oils, mainly extracted
from Eucalyptus globulus oil. As an isolated
compound, 1,8-cineole is known for its muco-
lytic and spasmolytic action on the respiratory
tract, with proven clinical effi cacy. 1,8-cineole
has also shown therapeutic benefi ts in infl am-
matory airway diseases, such as asthma and
chronic obstructive pulmonary disease (COPD).
This clinical evidence refers to its anti-infl am-
matory and anti-oxidant mode of action, which
has been proven in numerous pre-clinical stud-
ies. In vitro studies found strong evidence that
1,8-cineole controls infl ammatory processes and
mediator production of infection- or infl amma-
tion-induced mucus hypersecretion by its action
as anti-infl ammatory modifi er rather than a
simple mucolytic agent. The aim of this review
is to present these preclinical studies performed
with the pure monoterpene, and to summarize
the current knowledge on the mode of action
of 1,8-cineole. The actual understanding of the
pure 1,8-cineole compared to mixtures of natu-
ral volatile oils containing 1,8-cineole as a major
compound and to mixtures of natural terpenes,
known as essential oils, will be discussed. Based
on the anti-oxidative and anti-infl ammatory
properties, recent clinical trials with 1,8-cineole
have shown fi rst evidence for the benefi cial use
of 1,8-cineole as long-term therapy in the pre-
vention of COPD-exacerbations and to improve
asthma control.
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Juergens UR. Anti-infl ammation with 1,8-cineole … Drug Res
human cytochrome P450 enzymes (CYPyp3A4/5) into its major
metabolites of 2alpha-hydroxy- and 3alpha-hydroxy-1,8-cine-
ole that are further excreted with the urine in humans [ 12 ] .
Besides its systemic availability in the blood, 1,8-cineole reaches
the lungs and is exhaled via the peripheral airways thereby
exposing its benefi cial eff ects to the entire airways including the
sinuses that are known as important source to promote infect-
induced exacerbations [ 13 ] .
Chronic airway diseases, such as asthma or chronic obstructive
pulmonary disease (COPD), are associated with infl ammatory
processes within the lower respiratory tract, that can be only
partially reached with standard inhalative medicines. During
asthma, immune cells as well as structural cells release various
cytokines responsible for the infl ammatory cascade [ 14 – 16 ] . In
this respect important cytokines are airway epithelial, mono-
cyte/macrophage and T cell-derived cytokines with pro-infl am-
matory and chemotactic activities, such as TNF-α, IL-1β, IL-6,
IL-8, as well as in allergic infl ammation IGE-inducing IL-4 and
chemotactic-activating IL-5 for eosinophiles. Part of the infl am-
matory cascade in asthma are the known pro-infl ammatory
metabolites of the arachidonic acid (AA) pathway. These infl am-
matory processes lead to the typical symptoms of asthma:
mucus/airway hypersecretion and bronchospasm, which cause
airfl ow obstruction and shortness of breath. Mucus hypersecre-
tion is linked to increases in airway infl ammation and became
also a marker for related frequent exacerbations in COPD, that
induce disease progression following increasingly recurrent
exacerbations with increased chemotaxis, primarily of reactive
oxygen species (ROS) releasing neutrophils that also induce ster-
oid-resistance in COPD [ 12 , 17 ] .
Currently, symptomatic therapies are considered the standard
treatment. Chronic infl ammatory airway diseases are typically
treated in relation to the degree of airway obstruction with
inhaled glucocorticoids (ICS) besides long-acting β
2 -symptho-
mimetics (LABA) and long-acting muscarinic receptor antago-
nists (LAMA). Adverse eff ects of locally applied glucocorticoids
are less pronounced than when applied systemically and are
recommended with increasing disease severity, starting in par-
tially controlled asthma and severe COPD (GOLD III, FEV1 < 60 %).
However, there are still various side eff ects of the locally applied
glucocorticoids [ 13 , 18 , 19 ] .
Actually, in a double-blind, placebo-controlled, multi-center-
study in patients with acute bronchitis 1,8-cineole signifi cantly
improved the Bronchitis Sum Score and particularly cough fre-
quency at day 4 [ 20 ] . Apart from proving effi cacy in the treat-
ment of bronchitis and sinusitis [ 4 – 6 , 21 ] , 1,8-cineole as
concomitant therapy has also demonstrated an ability to reduce
exacerbations in COPD as well to improve lung function and
health condition in asthma in randomized controlled clinical tri-
als [ 22 – 25 ] . In particular, preclinical data from our monocyte in
vitro model have shown strong inhibition of infl ammatory
mediator production and of oxygen radicals known as the pri-
mary cause of bronchial hypersecretion. These anti-oxidative
and anti-infl ammatory eff ects of cineole at the recommended
daily dose of 3 × 200 mg/day were shown in a randomized, pla-
cebo-controlled, double blind study to reduce signifi cantly sys-
temic corticosteroids use in patients with severe asthma in the
verum group by 3.75 mg/day as compared to placebo ( − 0.91 mg/
day) [ 23 ] . These data suggested a prednisolon equivalent anti-
infl ammatory activity of cineole of 3.8 mg in patients with
severe asthma, that are treated with prednisolon and co-medi-
cation cineole.
This clinical evidence of 1,8-cineole is potentially related to its
systemic and topical availability while being exhaled and its
anti-oxidant and anti-infl ammatory activity to improve sensi-
tivity of guideline medications, particularly of ICS.
Clinical effi cacy is further underlined by numerous pre-clinical
studies, which investigate the anti-infl ammatory mode of action
of 1,8-cineole. The aim of this review is to illustrate the mode of
action behind the therapeutic benefi t of 1,8-cineole. The phar-
macological properties of 1,8-cineole within the respiratory
tract, investigated in many in vitro and ex vivo studies, will be
illustrated in this review. The main focus will be on the anti-
oxidant and anti-infl ammatory eff ects of the isolated monoter-
pene and its mode of action.
Anti-oxidative and Anti-infl ammatory properties of
1,8-cineole
▼
Mainly in the last decade of the 20
th c e n t u r y t h e a n t i - i n fl amma-
tory properties of 1,8-cineole have been brought into focus by
the investigations of our laboratory. Other investigations fol-
lowed, further supporting the anti-infl ammatory action of
1,8-cineole (for summary see
●
▶
Table 1 ). Many of the below cited
in vitro and ex vivo studies were performed with the medicinal
product Soledum
® Kapseln (Cassella-med GmbH & Co.KG;
G e r m a n y ) c o n t a i n i n g p u r e i s o l a t e d m o n o t e r p e n e 1 , 8 - c i n e o l e .
In vitro studies
When isolated monocytes (10
5 /ml) from healthy human sub-
jects were challenged in vitro with lipopolysaccharides (LPS;
10 μg/ml/20 h), 1,8-cineole was able to inhibit dose-dependently
with a maximal eff ect in therapeutic dosages (1.5 μg/ml; 10
− 5 M )
the production of LTB
4 , PGE
2 and IL-1β [ 26 , 27 ] . This inhibitory
activity was comparable to the inhibitory eff ect of therapeutic
airway concentrations of budesonide (10
− 8 M ) . T h i s i n v e s t i g a -
tion showed anti-infl ammatory action of 1,8-cineole by 2 sepa-
rate mechanisms: inhibition of the AA-metabolism by reduction
of the 2 major AA-metabolites of the 5-lipoxygenase (LOX) and
cyclooxygenase (COX) pathways of LTB
4 and PGE
2 a s w e l l a s i n h i -
Fig. 1 C h e m i c a l
structure of isolated
1,8-cineole (C
10 H
18 O)
from eucalyptus spe-
cies
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Juergens UR. Anti-infl ammation with 1,8-cineole … Drug Res
Table 1 Preclinical studies, investigating the anti-infl ammatory and anti-oxidative capacity of 1,8-cineole.
Refere-
nce
Model system/Methods Measurement
parameter
Results
[ 22 ] Ex vivo study in asthma of the
anti-infl ammatory effi cacy of
therapeutically relevant cineole
concentrations (3 × 200 mg/day)
on Ca
2 + ionophore stimulated
monocytes by A23187 ex vivo.
Determination of Infl ammatory
mediator production and lung-
function in asthmatic patients
(n = 12) and healthy volunteers
(n = 10) at day 4 and 4 days
after discontinuation (day 8)
Infl uence of cin-
eole on LTB
4 , PGE
2 ,
IL-1β production
in ex vivo stimu-
lated monocytes
at baseline (day
1), day 4 and after
discontinuation
(day 8) and on
forced expiratory
volume (FEV1) and
airway resistance
(RAW)
Spontaneous LTB
4 and PGE
2 production in monocytes of patients was lower than in
healthy volunteers. No signifi cant diff erences at LPS-stimulated baseline levels (day
1). Signifi cant suppression (p < 0.01) of LTB
4 and PGE
2 in ex vivo stimulated mono-
cytes of asthmatic patients ( − 40.3 %; − 31.4 %, respectively) and healthy subjects
( − 57.9 %; − 42.7 %, respectively) following cineole (day 4) and these eff ects subsided
at day 8. IL-1β remained suppressed in healthy subjects (n = 4) at day 8. Signifi cant im-
provement of FEV1 ( + 0.43 L, + 26.1 %) and RAW ( − 26.1 %) after discontinuation (day 8)
Addition of AA to cultured monocytes led to LTB
4 production of baseline values.
[ 26 ] In vitro study in isolated mono-
cytes from healthy subjects
to compare the mediator in-
hibitory activity of cineole and
budesonide on AA-metabolism
and cytokine production at
known plasma levels of cineole
Comparison of
inhibitory eff ects
of 1.8-cineole
with budesonide
on LPS-stimulated
production of
– LTB
4
– PGE
2
– IL-1β
in normal human
monocytes
No cytotoxicity for cineole and budesonide has been detected
Dose dependent inhibition of the LPS dependent stimulation of LTB
4 , PGE
2 and IL-1β.
Signifi cant inhibition of PGE
2 ( − 75.5 %) and IL-1ß ( − 84.2 %) at therapeutic dosages
of cineole (10
− 5 M = 1,5 μg/ml); signifi cant inhibition of LTB
4 ( − 27.9 %, p = 0.017) only
in dosages higher than therapeutic dosages of 10
− 4 M because of comparably low
production of LTB
4 after stimulation with LPS
Budesonid signifi cantly suppressed PGE
2 ( − 44 %) and IL-1β ( − 52 %) at therapeutic
airway concentrations (10
− 8 M) and showed comparably low inhibition of LTB
4 as well
Like cineole, the inhibition of IL-1β and PGE
2 production was stronger than the inhibi-
tion of LTB
4 production
Mediator inhibition by budesonide (10
− 8 M) was 100-fold stronger compared to cin-
eole, but equal at the therapeutic plasma concentration of cineole.
= > steroid-like anti-infl ammatory action of cineole
[ 27 ] In vitro study on the profi le
of infl ammatory mediator
inhibition by cineole in human
monocytes
Healthy volunteers as blood
donor
Isolated monocytes incubated
with cineole for 20 h, in the
presence of LPS or IL-1β
Cell viability
(trypan blue exclu-
sion and recovery
of cell function)
Production of
– TNF-α
– IL-1β
– LTB
4
– TxB
2
Concentration dependent inhibition of LPS-stimulated monocyte mediator production
Concentration dependent inhibition of the LPS or IL1β stimulated production of TNF-α
A n t i - i n fl ammatory profi le of mediator inhibition by cineole:
T N F - α ( − 98.8 %) > TxB
2 ( − 91 %) > IL-1β ( − 74 %) > LTB
4 ( − 47.6 %)
[28, 29] Blood donated from 9 healthy
volunteers:
– Isolation of lymphocytes
(containing 10 % monocytes):
– stimulation in vitro by iono-
mycin and PMA
– Isolation of monocytes:
– stimulation in vitro by LPS
Stimulation occurred with or
without cineole (20 h incuba-
tion)
Cell viability
(trypan blue exclu-
sion and LDH
activity)
Quantifi cation of
cytokine produc-
tion by ELISA
– TNF- α
– IL-1β
– IL-6
– IL-8 in mono-
cytes
and
– TNF-α
– IL-1β
– IL-4
IL-5 in lym-
phocytes
Cell viability
In therapeutic concentrations 1,8-cineole had no toxic eff ect
Eff ects without cineole:
Spontaneous cytokine production:
Unselected lymphocytes:
– production of IL-1β and TNF-α
– but not IL-4 or IL-5
Monocytes:
– p r o d u c t i o n o f I L - 1 β and TNF-α, but also IL-6 and IL-8
Cytokine production after stimulation at therapeutic
concentrations of cineole (1.5 μg/ml = 10
− 5 M)
LPS stimulated monocytes:
– TNF-α ( − 99 %) > IL-1β ( − 84 %) > IL-6 ( − 76 %) > IL-8 ( − 65 %)
Ionomycin/PMA stimulated lymphocytes:
– TNF-α ( − 92 %) ≥ IL-1β ( − 84 %) > IL-4 ( − 70 %) > IL-5 ( − 65 %)
Eff ects with cineole:
Ionomycin/PMA stimulated lymphocytes TH1:
– 10
− 6 M cineole signifi cantly inhibits TNF-α ( − 16 %) and IL-1β ( − 36 %) production
– Ionomycin/PMA stimulated lymphocytes TH2:
– 10
− 6 M cineole did not sign. inhibit IL-4 and IL-5 production
– However, increasing concentrations of cineole (10
− 5 M) inhibited production of
measured cytokines in a concentration dependent manner and to similar degree.
In LPS stimulated monocytes
– 10
− 6 M cineole inhibits TNF-α ( − 77 %) and IL-1β ( − 61 %) production (concentration
dependent), but not IL-6 or IL-8
– 10
− 5 M cineole inhibits also IL-6 or IL-8
= > in total stronger activity of cineole in monocytes than
in lymphocytes.
= > cineole is a strong inhibitor for IL-1β and TNF-α in stimulated monocytes and
lymphocytes
inhibitory activities are achieved by therapeutic blood concentrations of cineole
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Juergens UR. Anti-infl ammation with 1,8-cineole … Drug Res
bition of interleukin IL-1β production. Both, 1,8-cineole and glu-
cocorticoids, possess a terpene-like structure; therefore the
authors suggested a steroid-like mode of action of 1,8-cineole
that involve inhibition of phospholipase A2 and of COX-2, since
the inhibitory eff ect on COX-metabolites was almost twice as
much as compared to LTB
4 as the major 5-LOX-metabolite in
monocytes. Apart from the known inhibition of TNF-α, IL-1β,
and LTB
4 , a l s o t h r o m b o x a n e B 2 (TxB
2 ) inhibition has been
observed. Specifi cally, strong anti-infl ammatory action was
achieved by the inhibition of IL-1β induced TNF-α-production.
Table 1 Preclinical studies, investigating the anti-infl ammatory and anti-oxidative capacity of 1,8-cineole.
Refere-
nce
Model system/Methods Measurement
parameter
Results
[ 34 ] In vitro study on the anti-
oxidative eff ects of cineole on
isolated human monocytes
from healthy patients
Long term cultures of isolated
monocytes for 20 h with or
without 1,8-cineole
Stimulation of O
2
− production
(ROS), superoxide dismutase
(SOD)-activity, and H
2 O
2 pro-
duction by PMA/zymosan
Stimulation of 8-isoP produc-
tion by LPS for 20 h
A n t i o x i d a t i v e
activity of cineole
on the produc-
tion of:
– 0
2 −
– H
2 O
2
– 8-isoprostane
(8-isoP)
and (SOD) activity
Therapeutic concentrations of 1.8-cineole signifi cantly inhibited 8-isoP (-84.1 %) and
0
2 − (-52.6 %) production
SOD-activities were signifi cantly inhibited (-33.4 %) by 1.8-cineole, which further results
in an inhibition of the H
2 O
2 production
[ 35 ] Anti-oxidative eff ects of cineole
on isolated human monocytes
from healthy patients
Long term cultures of isolated
monocytes for 20 h with or
without 1,8-cineole
Stimulation of ROS production
by FCS after 20 h
E ff ect of cineole
vs. budesonide
on ROS produc-
tion in monocytes
(antioxidative
activity):
– 0
2 − production
– H
2 O
2
and superoxidase
dismutase (SOD)
activity
FCS stimulated dose-dependently production of SODs (H
2 O
2 > 0
2 − ) in cultures of normal
human monocytes
therapeutic concentrations of 1.8-cineole (6 × 10
− 6 M) showed signifi cant inhibitory
eff ects on ROS and H
2 O
2 production and smaller inhibitory eff ects on SOD activity
therapeutic concentrations of formoterol and budesonide demonstrated minor inhibi-
tory eff ects on ROS production
co-incubation of budesonide with 1.8-cineole increased the inhibitory eff ects of
budesonide
further, co-incubation of small concentrations of 1.8-cineole with budesonide increased
the suppression of LPS-stimulated IL-1β formation
[ 40 ] THP-1 cells incubated with 1,8
cineole prior to LPS stimulation
Localization of
Erg-1 protein and
NF-κB/p65 protein
expression in cells
by immunofl uo-
rescence
Measurement by
Western blot
1,8-cineole reduces LPS-induced Egr-1 expression in THP-1 cells; however does not
eff ect NF-κB expression
[ 41 ] In vitro smooth muscle rings
from guinea pig stomach:
– Stimulation of contraction by
10
− 8 M histamine
– O b s e r v a t i o n o f 1 . 8 - c i n e o l e
eff ects
I n v e s t i g a t i o n
of cineole on
the concentra-
tion dependent
inhibition of the
histamine induced
contrac tion
1,8-cineole inhibits the histamine induced contractions, probably by blocking the
histamine receptors,
cineole seems to be a competitive antagonist of the histamine receptor
[ 44 ] ovalbumin (OVA)-sensitized
guinea pigs (animal model for
asthma) are used to inhale a
single dose of 1,8-cineole for
15 min;
control animals inhaled saline
after treatment with cineol/
saline the animals were chal-
lenged with OVA/saline
Tracheal re-
sponsiveness to
carbachol
Bronchoalveolar
lavage fl uid (BALF)
Myeloperoxidase
Determination of
cytokines in BALF
(TNF-α, IL-1β,
IL-10)
Tracheal mucocili-
ary transport
Tracheal responsiveness to carbachol
Tracheal rings from animals prior treated with cineole did not develop after OVA chal-
lenge contractions higher than rings obtained from guinea pigs inhaled cineole and
challenged with saline
Bronchoalveolar lavage fl uid (BALF):
Without cineole: OVA challenge increased the number of infl ammatory cells such as
eosinophils and neutrophils
Cineole signifi cantly prevents the increase in
leucocytes due to OVA challenge
Myeloperoxidase (MPO)
Pre-treatment with cineole markedly impaired the increase of MPO activity induced by
OVA challenge
Determination of cytokines in BALF (TNF-α, IL-1β, IL-10)
Pre-treatment with cineole completely impaired the OVA challenge induced increase in
TNF-α and IL-1β and the decrease of IL-10
Tracheal mucociliary transport
Transport distance in untreated trachea after OVA challenge is signifi cant reduced
compared to control
Pretreatment with cineole did not cause signifi cant diff erences in transport distance
compared to control
Continued.
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Juergens UR. Anti-infl ammation with 1,8-cineole … Drug Res
Mounting evidence for the role of 1,8-cineole in cytokine inhibi-
tion was shown in vitro on isolated monocytes and unselected
lymphocytes. These cells were stimulated by LPS or ionomycin/
PMA in the presence or absence of cineole following incubation
for 20 h. In therapeutic concentrations, 1,8-cineole (10
− 5 M) sig-
nifi cantly inhibited cytokine production in lymphocytes and in
monocytes with the strongest degree of TNF-α inhibition (100 %)
(
●
▶
Table 1 ). By blocking the IL-4 and IL-5 production, cineole
may also exhibit inhibitory eff ects on Th2-lymphocytes and
anti-allergic activity [ 28 , 29 ] . These data have shown for the fi rst
time, that cineole may act in many cells non-specifi cally by con-
trolling infectious or allergic immune responses with a steroid-
like anti-infl ammatory profi le of infl ammatory mediator
inhibition, particularly with the strongest eff ect on TNF-α pro-
duction.
A p a r t f r o m i t s e s t a b l i s h e d a n t i - i n fl ammatory activity, recently
the anti-oxidative eff ects of cineole were investigated in vitro.
Overproduction of reactive oxygen species (ROS) is involved in
COPD and asthma and particularly in acute COPD exacerbations
or non-controlled asthma requiring systemic corticosteroids
[ 30 , 31 ] . Of major importance for our understanding of the ther-
apeutic activity of cineole is the fact that oxygen radicals, mainly
from cigarette smoke, have become known as strongest inducers
of mucus hypersecretion, inhibitors of histone deacetylase-2
(HDAC) causing corticosteroid resistance, and further as bron-
choconstrictors and activators of nuclear factor κB (NFκB) that
stimulate TNF-α and related IL-8 production for neutrophil
recruitment and emphysema development following inhibition
of anti-proteases [ 32 , 33 ] . Therefore, antioxidative capacity of
1,8-cineole was investigated in vitro [ 34 , 35 ] . Monocytes from
healthy humans were kept in culture incubated at medium
plasma concentration (6 × 10
− 6 M) or without 1,8-cineole. After
stimulation with FCS, the production of SOD, H
2 0
2 , and O
2 −
increased in a dose-dependent manner. 1,8-cineole signifi cantly
inhibited production of ROS and H
2 O
2 , and, to a smaller extent,
SOD activity (
●
▶
Table 1 ). When compared to cineole alone, ther-
apeutic concentrations of budesonide demonstrated only minor
inhibitory eff ects on ROS production. However, co-incubation of
budesonide with 1,8-cineole increased the inhibitory eff ect. The
combination of cineole and budesonide led to a synergistic
inhibitory eff ect of oxygen radicals suggesting that cineole
increases the low anti-oxidative activity of ICS. In a previous
experiment, isolated human monocytes were stimulated by LPS
after incubation with cineole [ 27 ] . Therapeutic concentrations
of cineole signifi cantly inhibit 8-isoprostane (IsoP), a known
marker of total anti-oxidative activity, and 0
2 − production. Fur-
ther, SOD activity was inhibited with no dose-dependency by
around 30 %, which led to a reduced production of H
2 O
2 i n t h i s
culture system [ 34 ] . These investigations increased tremen-
dously our knowledge on the anti-oxidative action of cineole,
that strongly blocks oxygen radicals and furthermore their
transformation into cytokine inducing H
2 O
2 by partial blockade
of SODs. For this reason high therapeutic concentrations of cin-
eole (1.5 μg/mL, 10
− 5 M) with the strongest ROS inhibition in the
presence of partial SOD-inhibition led to decreasing inhibitory
eff ects on H
2 O
2 , potentially by reduced substrate supply for H
2 O
2
production, that was, however strongly inhibited by lower ther-
apeutic concentrations of cineole. Further eff ects on the down-
stream of H
2 O
2 have not yet been investigated.
To summarize, this interference of cineole with the oxidative
mediator production by its oxygen species scavenging activity
with the strongest inhibition of oxygen radicals is considered a
new mode of action, and potentially also contributes to the anti-
infl ammatory abilities of cineole and suggests long-term co-
medication in COPD and asthma to prevent exacerbation and
probably also disease progression. For this reason, these results
suggest, that cineole controls mucus hypersecretion by direct
inhibition of mucus inducing mediators, mainly of ROS and
potentially prostanoids, such as PGE
2 , and is therefore no more
considered as simple mucolytic or secretolytic agent.
Furthermore, new perspectives arise for the use of cineole by the
fact, that vitamin D (VD) became known to control infl ammation
and Th2-cell dependent IGE production in COPD and asthma,
that both are mostly known as VD insuffi cient or defi cient air-
way diseases. Since typically hypersecretion inducing mediators,
such as PGE
2 and ROS and also H
2 O
2 , down-regulate VD-receptor
(VDR) expression [ 36 , 37 ] , cineole is expected to improve the
infl ammatory state of airways by inhibition of these mediators
and to partially compensate increased disease exacerbations at
low VD levels, particularly in winter times. Furthermore, in a
model of cystic fi brosis, known for severe VD-defi ciency, using
epithelial cell lines exposed to pseudomonas aeruginosa VDR-
agonists, such as 1,25-DOH D3, signifi cantly inhibited LPS-stim-
ulated IL-6 and IL-8 protein secretion in the presence of
decreased Iκbα phosphorylation and induced total cellular Iκbα
[ 38 ] . A most recent publication by Greiner, Kaltschmidt et al.
highlights our actual understanding on the anti-infl ammatory
mode of action of 1,8-cineole by reporting increased protein
levels of IκBα, inhibition of nuclear NF-κB activity and decreased
levels of proinfl ammmatory NF-κB target genes in LPS-stimu-
lated human cell lines U373 and HeLa [ 39 ] .
The mode of action of 1,8-cineole was further investigated on
the sub-cellular level [ 40 ] . The THP-1 cell line was used as a
model system for macrophages, which are known to be involved
in airway infl ammatory disorders. Prior to the in vitro LPS chal-
lenge, the cells were incubated with high concentrations 1,8-cin-
eole (1 mg/L, 10 mg/L, or 100 mg/L) for 30 min. LPS challenge
increases early growth response factor 1 (Egr-1) protein expres-
sion in the nucleus, the perinuclear and whole cell localization.
This could be markedly reduced by pretreatment with cineole.
Egr-1 is a transcription factor that regulates many genes involved
in infl ammatory processes. Some of the target genes are
cytokines, chemokines, cell adhesion molecules and immune
receptors. 1,8-cineole may suppress the expression of pro-
infl ammatory genes by inhibiting the Egr-1 transcription factor
synthesis. The expression of NF-κB/p65 was not altered by
1,8-cineole in this model. Taken together, the anti-infl ammatory
abilities of 1,8-cineole are mediated by inhibition of Egr-1 syn-
thesis and nuclear internalization [ 40 ] .
The release of histamine by mast cells causes several allergic
symptoms and contributes to the infl ammatory response. It
causes constriction of smooth muscle cells, leading to contrac-
tion within the respiratory tract. 1,8-cineole is able to interfere
with the histamine-induced contraction. In vitro , cineole inhib-
its contractions of the smooth muscles even in the presence of
histamine, leading to the assumption that 1,8-cineole is also a
competitive histamine receptor antagonist [ 41 ] . These data
could partially explain the spasmolytic and secretolytic eff ects
of cineole in the airway system. The spasmolytic ability of cine-
ole is not restricted to histamine-induced contractions. Contrac-
tions of tracheal smooth muscles by K
+ were also inhibited by
1,8-cineole [ 42 ] . These fi ndings were confi rmed on non-sensi-
tized or ovalbumin-sensitized airway smooth muscle cells [ 43 ] .
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Juergens UR. Anti-infl ammation with 1,8-cineole … Drug Res
Ex vivo studies
I n a n e x v i v o s t u d y , t h e a n t i - i n fl ammatory eff ect of 1,8-cineole
(3 × 200 mg/day) on monocyte AA-metabolism in patients with
partially controlled bronchial asthma (n = 10) and healthy sub-
jects (n = 12) was investigated and in correlation to improvement
of lung-function tests in asthmatics [ 22 ] . Monocytes from bron-
chial asthma patients and healthy volunteers where isolated on
day 4 from blood before and after a 3 day treatment, as well as
after a 4 day displacement of 1,8-cineole. The isolated mono-
cytes were stimulated ex vivo with the Ca
2 + ionophore to induce
LTB
4 a n d P G E 2 production and in a subgroup of healthy subjects
(n = 4) also IL-1β was determined. Orally taken cineole signifi -
cantly inhibited the LTB
4 , PGE
2 and IL-1β production in mono-
cytes ex vivo, from both asthma patients and healthy subjects
(
●
▶
Table 1 ). Interestingly, in partially controlled asthma cineole
had a strong and signifi cant eff ect to improve lung-function.
Since mediator production in peripheral blood monocytes at
baseline was not diff erent in both groups with no evidence of
systemic infl ammation in studied asthmatics, the bronchodila-
tatory eff ects of orally taken and exhaled cineole may be caused
by mediator inhibition in lower airways. This study once more
supports the previous fi ndings that 1,8-cineole inhibits metabo-
lites of the AA-pathway [ 22 ] . When comparing the degree of
LPS-stimulated mediator inhibition of PGE
2 ( − 75.5 %) in vitro
[ 26 ] the ex vivo eff ect ( − 42.7 %) in Ca
+ + -ionophore stimulated
mediator production was smaller, mainly due to the diff erent
culture models [ 22 ] (
●
▶
Table 1 ). This investigation identifi ed the
fi rst mechanistic insights of the anti-infl ammatory action of
1,8-cineole, namely the inhibition of the AA metabolism, in
asthmatic patients.
In vivo studies
Investigations performed with an animal model for asthma
showed that 1,8-cineole prevents airway hyper-responsiveness
[ 44 ] . In guinea pigs, sensitized with ovalbumin, inhalation of
1,8-cineole prior to the ovalbumin challenge reduced the levels
of pro-infl ammatory cytokines TNF-α and IL-1β and prevented
the decrease of the anti-infl ammatory cytokine IL-10 in the
bronchoalveolar fl uid. The reduction of mucociliary clearance
was prevented by cineole. 1.8-cineole was able to restore ciliary
transport velocity. An anti-infl ammatory eff ect was also shown
on the cellular level in this animal model: Treatment with cine-
ole reduces the number of pro-infl ammatory cells and macro-
phages as well as myeloperoxidase (MPO) activity, a marker for
neutrophil infi ltration. Antioxidative properties of 1,8-cineole
were also shown in rats. There, chemically induced oxidative
stress on rat liver was reduced by cineole treatment [ 45 ] .
1,8-Cineole: Combined mode of action on airways
(
●
▶
Table 1 )
▼
In general, the ability to induce infl ammation is important for
our immune system to defend against infections and injuries. In
case of excessive or inappropriate infl ammation, as observed in
allergic and chronic infl ammatory airway diseases, the benefi t
of infl ammation is less than the detriment. These excessive
immunoreactions have to be stopped. In most cases, patients
with asthma or other chronic infl ammatory airway diseases are
treated with combined therapies of LABA + ICS.
1,8-cineole, a pure monoterpene, has shown very promising
results in reducing excessive immune reactions in various pre-
clinical investigations. Due to the lipophilic properties of cine-
ole, a transitory accumulation within in the phospholipids of the
monocyte cell membrane can be expected. This might possibly
interfere with the release of AA-substrate [ 22 ] . Several ways of
interference with the AA-metabolism by 1,8-cineole have been
identifi ed. Cineole can inhibit prostaglandins such as PGE
2 and
TxB
2
, as shown in many studies by our working group. Further
the inhibition of leucotrienes produced via 5-lipoxygenase such
as LTB
4 has been demonstrated [ 22 ] . Numerous of these AA-
derived metabolites are involved in asthma [ 16 ] . Prostagland-
ines are involved in airway mucus secretion, bronchoconstriction,
induction of infl ammatory mediators from other cells, or induc-
tion of cough [ 14 ] . LTB
4 is a chemo-attractant for neutrophils/
leukocytes, constitutes the major 5-LOX metabolite in mono-
cytes/macrophages, and its inhibition correlates in the men-
tioned cell culture systems with 5-LOX activity and total
LT-production. It attracts these immune cells and leads to adhesion
of these cells to the vascular endothelium [ 15 , 16 ] , increasing the
infl ammatory reactions and leading to broncho constriction. The
role of LTB
4 in asthma is not fully understood, however, it seems to
be critical especially during sensitization [ 46 , 47 ] .
The production of prostaglandins via COX1/2 is stimulated by
interleukins, mainly TNF-α, IL-1β [ 16 ] . Numerous in vitro and
ex vivo experiments demonstrated that 1,8-cineole is able to
strongly reduce the production of pro-infl ammatory cytokines,
namely TNF-α, IL-1β, IL-4, IL-5 IL-6, IL-8 (
●
▶
Table 1 ). Therefore,
cytokine inhibition will further contribute to the reduction of
pro-infl ammatory COX1/2 metabolites and recent data from our
laboratory (not published) also suggested selective partial
(around 30 %) COX-II inhibition to explain the greater impact of
mediator inhibition in the COX-pathway by cineole.
It has been speculated that the inhibition of IL-1β by 1,8-cineole
might be attributed to the inhibition of the NF-κB activation
[ 22 ] . However, this has been contradicted by [ 40 ] , who identi-
fi ed another transcription factor, Egr-1, which was suppressed
by cineole. Egr-1 seems not to be involved in early infl ammatory
response but in sustained expression of infl ammatory media-
tors. TNF-α gene expression is at least partially regulated by
Egr-1 [ 48 ] . The production of TNF-α in monocytes is probably
suppressed by 1,8-cineole via the inhibition control of the Egr-1
transcription factor and NF-κB [ 39 ] .
N e w e r t h e r a p e u t i c a p p r o a c h e s f o r a s t h m a i n v e s t i g a t e t h e i n h i b i -
tion of cytokine production or cytokine receptor antagonists.
However, inhibiting only a single cytokine or cytokine pathway
is insuffi cient due to adaptive mechanisms [ 14 ] . Therefore an
expanded inhibition of these mediators is advisable. 1,8-cineole
has been shown by its nonspecifi c mode of action to interfere
with a number of these cytokines by various mechanisms, and is
therefore a very good candidate for interfering with cytokine
overproduction.
The positive eff ects of 1,8-cineole on infl ammatory airway dis-
eases are further supported by its anti-oxidative activity. Cine-
ole reduces the formation of ROS [ 34 , 35 ] . Many activated
infl ammatory cells in the asthmatic airways produce ROS. O
2 −
ions are converted to H
2 O
2 by SODs. O
2 - and H
2 O
2 are involved in
the formation of further ROS. Apart from direct damage to the
airway system, ROS induce smooth muscle constriction and
increased bronchoconstriction. Oxidative stress is known to
increase mucus secretion [ 22 ] . Cineole reduces O
2 − ion forma-
tion and also formation of H
2 O
2 by inhibiting SODs [ 34 , 35 ] .
Further, it has been shown that 1,8-cineole inhibits some of the
histamine reactions, probably by acting as a competitive antago-
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Juergens UR. Anti-infl ammation with 1,8-cineole … Drug Res
nist of the histamine receptor [ 41 ] . This may have an additional
positive and non specifi c impact on allergic reaction due to IgE-
mediated histamine and further infl ammatory mediator release.
In summary, the anti-oxidative and anti-infl ammatory action of
cineole diminishes attraction and migration of immune cells
from blood and surrounding tissue into the infl amed bronchial
tissue. This in turn leads to attenuation of the local infl amma-
tion, leading to reduced swelling and dilatation of the bronchial
muscles, followed by reduced secretion of mucus. But there is
also increasing evidence that due to its systemic availability
1,8-cineole may also control systemic infl ammation, particular ly
in COPD, by controlling progression of arteriosclerocis via
reversal of cholesterin transport in macrophages as shown by
reduced lipogenesis in hepatocytes [ 49 ] , prevention of nicotine-
induced hypertension [ 50 ] , management and/or prevention of
type-2-diabetes [ 51 ] .
Diff erence between pure 1,8-cineole and natural
mixture of volatile oils
1,8-cineole, especially when called “eucalyptol”, is often con-
founded with Eucalyptus oil. This however, is critical since the
eff ects of pure 1,8-cineole, even though a main compound of
eucalyptus oil, are not comparable to eucalyptus oil.
1,8-cineole is a well-characterized isolated natural compound,
whereas the composition of eucalyptus oil, even when standard-
ized to at least 70–85 % cineole, as required by the European
pharmacopoeia, may vary from batch to batch. The characteriza-
tion of such natural oil mixtures is extremely challenging, in
particular with regard to natural essential oils. Studies per-
formed with the isolated compound cineole are reproducible,
which must be questioned in case of natural mixtures of volatile
oils. Studies performed with the pure substance cineole are not
comparable to natural volatile oil mixtures.
Eucalyptus oil contains various terpenes, including unsaturated
compounds (e. g. α-pinene, piperiton, and α-phellandren).
Adverse reactions to eucalyptus oil are probably related to dou-
ble-bindings in the unsaturated components of the mixture
[ 52 , 53 ] . These substances tend to bind oxygen and form
hydroperoxides. During enzymatic reduction of these sub-
stances, oxygen radicals may be formed, which leads to tissue
damage and further pro-infl ammatory mediators (summarized
in [ 33 ] ). Therefore it is not surprising that mixtures of volatile oil
may have more often negative eff ects in asthmatic patients, that are
particularly known in patients with allergies to perfume [ 54 ] .
It has been shown that oral ingestion of eucalyptus oil may very
rarely cause neurological symptoms and seizures. Even though
its dermal use is presumed safe, dermal exposure to eucalyptus
oil can lead to neurological symptoms in children [ 54 ] . Further,
for α-pinene, another component of eucalyptus oil, allergic
potential [ 55 ] as well as contraction enhancing and tissue irri-
tant abilities have been reported (summarized in [ 22 ] ). In con-
trast, cineole, due to its saturated structure, is very well tolerated,
as shown by many investigations [ 23 – 25 , 43 – 45 ] and is therefore
preferable to multi-component formulations.
Essential oils are natural mixtures of various monoterpenes,
some known for their overwhelming cell activating properties.
They stimulate the production of infl ammatory mediators, lead-
ing to increased mucus and airway hypersecretion, which was
one of the major side eff ects if asthmatic patients were treated
by such oils [ 43 ] . In sensitive persons, stimulation of prostaglan-
din production may cause bronchospastic reactions [ 43 , 56 ] . No
cell activating properties of cineole have been found [ 43 ] . There-
fore, the use of pure cineole should be preferred [ 26 , 29 ] .
Based on these diff erences, the results obtained by investiga-
tions with pure 1,8-cineole cannot be transferred to other vola-
tile oils containing cineole or eucalyptus oil.
Antimicrobial Activity of 1,8-Cineole
▼
Cineole inhibited 16 out of 18 bacterial strains tested, including
Staphylococcus aureus, Bacillus sp., Citrobacter sp., Escherichia
coli, Klebsiella sp., Salmonella sp., Vibrio cholera strains, in a
standardized disc diff usion method and a dilution method. The
minimum inhibitory concentration (MIC) of cineole against
most of the pathogens was 6.7 μl/ml. Only against 2 P. aeruginosa
strains no inhibition zone could be produced by cineole, MIC
values were > 13.3 μl/ml [ 8 ] .
The antibacterial activity of cineole and other terpenes was
assayed against the human pathogenic bacteria Bacillus subtilis,
Enterobacter cloacae, Escherichia coli O157:H7, Micrococcus fl a-
vus, Proteus mirabilis, Pseudomonas aeruginosa, Salmonella
enteritidis, S. epidermidis, S. typhimurium and Staphylococcus
aureus, in a concentration of 1.0 μg/ml in the disc-diff usion
method [ 57 ] . Linalyl acetate and limonene showed the lowest
antibacterial activity among the components tested, with inhi-
bition zones 6.0–12.0 mm; α-pinene and β-pinene possessed
almost the same activity, with inhibition zones 8.0–16.0 mm.
These components were not eff ective against P. aeruginosa and
P. mirabilis. Cineole showed broader inhibition with zones of
10.0–20.0 mm and was active against all tested bacteria. Inhibi-
tion zones of the control substance streptomycin were
0–20.0 mm, with no eff ect against L. monocytogenes, P. mirabilis
and P. aeruginosa. In the microdilution method 1,8-cineole
showed bacteriostatic activity at 4.0–7.0 μg/ml and was bacteri-
cidal at 4.0–9.0 μg/ml [ 57 ] .
Anti-IBV (infectious bronchitis virus, IBV Gray strain) activity of
cineole was studied by MTT assay in Vero-E6 (African green
monkey kidney cells) [ 56 ] . The CC
50 of 1,8-cineole was above
10 mM, the maximum noncytotoxic concentration of cineole
was determined to be 3.90 ± 0.22 mM, which was much higher
than that of ribavirin (0.78 ± 0.15 mM). Thus, the growth of Vero
cells was not aff ected by cineole and its antiviral eff ects were not
due to any cytotoxicity. Cineole could inhibit IBV with an IC
50 of
0.61 mM. MTT assay showed that the inhibition of IBV by cineole
appears to occur moderately before entering the cell but much
stronger after penetration of the virus into the cell. In silico sim-
ulations indicated that the binding site of cineole was located at
the N-terminus of phosphorylated nucleocapsid (N) protein. The
residues TyrA92, ProA134, PheA137, AspA138 and TyrA140 had
important roles during the binding process and are fully or par-
tially conserved in various IBV strains which indicates that cin-
eole not only inhibits the N-protein of IBV Gray strain, but also
other known virus strains. As cineole interferes with the binding
between RNA and IBV N-protein it can be concluded that cineole
possesses anti-IBV properties.
In summary, conclusive evidence can be provided in vitro of
antimicrobial eff ects of cineole which can be evaluated as valu-
able addition to the known pharmacological eff ects of cineole
(
●
▶
Table 2 ).
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Juergens UR. Anti-infl ammation with 1,8-cineole … Drug Res
Summary
▼
The results clearly indicate that 1,8-cineole is more than just a
mucolytic and spasmolytic agent. It exhibits strong anti-oxida-
tive and anti-infl ammatory eff ects. Cineole inhibits the produc-
tion of oxygen radicals and various cytokines and other
infl ammatory mediators, involved in mucus hypersecretion and
infl ammation in airway diseases, via several mechanisms. These
benefi cial eff ects have been confi rmed in clinical trials on
patients with bronchitis, sinusitis, COPD, and asthma.
A s a c o n c u r r e n t m e d i c a t i o n i n a s t h m a t i c p a t i e n t s , c i n e o l e t r e a t -
ment signifi cantly reduces the daily oral steroid dosage, which con-
fi rms the synergistic eff ects with synthetic glucocorticosteroids. In
actual controlled clinical trials co-medication corresponding to
guideline recommended therapies has shown improvement of
asthma control and surprisingly strong eff ects on exacerbation
reductions in moderate to severe COPD. Therefore, cineole was
shown as effi cient co-medication to improve standard treatments
for asthma, COPD or other infl ammatory airway diseases.
In many chronic VD-defi cient infl ammatory diseases, cytokines
are considered to play a crucial role and actually pro-secretory
mediators, such as oxygen radicals and PGE
2 , being inhibited by
cineole, became known to down-regulate vitamin D receptors
(VDR). As new perspective, to be proven in further controlled
studies, 1,8-cineole has been found to exhibit anti-oxidative and
anti-infl ammatory eff ects. Also, beyond the airway system it
potentially controls systemic infl ammation in COPD and may
increase VDR-expression and, thus may have been used so far for
unknown compensation of the anti-infl ammatory eff ect of low
VD3 supplying states in airway diseases by its potentially, syner-
gistic eff ect together with VD3 on the induction of IκBα, since all
reported indications of cineole, such as respiratory infections,
COPD and asthma, are known as VD-defi cient diseases. In vivo,
cineole has shown to be well tolerated, to possess gastro-intesti-
nal and hepatoprotective as well as analgesic and anti-nocicep-
tive properties. Furthermore, in vitro antimicrobial eff ects of
cineole have been proven as well.
It might be further interesting to elucidate if the anti-oxidative
and anti-infl ammatory eff ects of 1,8-cineole, proven for the air-
way system, will increase the effi cacy of current guideline medi-
cations and could also be transferable to other systemic
infl ammatory diseases, such as infl ammatory bowel disease.
Acknowledgement
▼
The author is very thankful to the support of Cassella-med Inc.,
Cologne, Germany, for the assistance in preparing the manuscript.
Confl ict of Interest
▼
Prof. Juergens is member of the advisory board at Cassella-med
Inc., Cologne, Germany.
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Property Mediated by reference
A n t i - i n fl ammatory Inhibition of the AA pathway (steroid like inhibition) via
– Interference with 5-LOX pathway metabolites = > inhibition
of LTB
4 production
– Probably via inhibition of cyclooxygenase
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