Melatonin and Respiratory Diseases: A Review

Abstract

Melatonin is an indoleamine with potent multifunctional biological and pharmacological effects, both receptor dependent and receptor-independent effects, including antioxidant, anticancer, antitumor, anti-inflammatory, anti-aging, anti-diabetic, antiviral, neuroprotective activities. Melatonin mitigates tissue injury via modification of abnormalities in redox status and other biochemical markers. At the molecular level, the biological and pharmacological activities of melatonin are attributed to the inhibition of nuclear factor-ĸappa beta (NF-ĸB), c-Fos over expression and down-regulation of matrix metalloproteinases-3 (MMP-3), which are regulators of pro-inflammatory and pro-fibrotic cytokines. There are numerous scientific reports on the therapeutic potential of melatonin in treatment of asthma, respiratory diseases for infections, chronic obstructive pulmonary disease, lung cancer, pleural cavity diseases, as well as vascular pulmonary disease. In the present communication, we systematically review the therapeutic potential of melatonin in the treatment of respiratory diseases along with its molecular mechanism of actions.

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Current Topics in Medicinal Chemistry, 2017, 17, 1-22 1
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Melatonin and Respiratory Diseases: A Review
Seyed Fazel Nabavi1, Solomon Habtemariam2, Maria Daglia3, Antoni Sureda4,
Eduardo Sobarzo-Sánchez5, Zeliha Selamoglu6, Mehmet Fuat Gulhan6 and
Seyed Mohammad Nabavi1,*
1Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran; 2Pharmacognosy
Research Laboratories, Medway School of Science, University of Greenwich, Central Ave., Chatham-Maritime, Kent
ME4 4TB, United Kingdom; 3Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Sec-
tion, University of Pavia, Italy; 4Research Group on Community Nutrition and Oxidative Stress, Laboratory of Physical
Activity Sciences, IUNICS, University of Balearic Islands, Palma de Mallorca, IllesBalears, Spain; 5Laboratory of
Pharmaceutical Chemistry, Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compo-
stela, 15782 Santiago de Compostela, Spain; Dirección de Investigación y Postgrado, Universidad Central de Chile,
Santiago, Chile; 6Department of Biology, Faculty of Arts and Science, Nigde University, Nigde, Turkey
Abstract: Melatonin is an indoleamine with potent multifunctional biological and
pharmacological effects, both receptor dependent and receptor-independent effects,
including antioxidant, anticancer, antitumor, anti-inflammatory, anti-aging, anti-
diabetic, antiviral, neuroprotective activities. Melatonin mitigates tissue injury via
modification of abnormalities in redox status and other biochemical markers. At the
molecular level, the biological and pharmacological activities of melatonin are at-
tributed to the inhibition of nuclear factor-κappa beta (NF-κB), c-Fos over expres-
sion and down-regulation of matrix metalloproteinases-3 (MMP-3), which are regu-
lators of pro-inflammatory and pro-fibrotic cytokines. There are numerous scien-
tific reports on the therapeutic potential of melatonin in treatment of asthma, respir-
atory diseases for infections, chronic obstructive pulmonary disease, lung cancer, pleural cavity dis-
eases, as well as vascular pulmonary disease. In the present communication, we systematically review
the therapeutic potential of melatonin in the treatment of respiratory diseases along with its molecular
mechanism of actions.
A R T I C L E H I S T O R Y
Received: July 13, 2015
Revised: September 20, 2015
Accepted: December 13, 2015
DOI: 10.2174/1568026616666160824
120338
Keywords: Anti-inflammatory, Antioxidant, Lung disease, Melatonin, Pulmonary disease, Respiratory disorders.
INTRODUCTION
The main function of the lung is to transport exogenous
oxygen to blood and to release carbon dioxide from respira-
tory tree to the atmosphere [1]. Lung diseases are major
health issue and a leading cause of death worldwide [2]. The
term lung diseases includes different abnormalities which
affect the lungs and the respiratory tissues, such as infec-
tions, cancer, asthma, chronic obstructive pulmonary disease
(COPD), drug-induced injuries, etc. [3]. For example, acute
lung infection (pneumonia) is an important health problem in
developing countries that accounts for 30% of all deaths in
children under 5 years of age [4]. Also, lung cancer is known
as common types of cancer that is often accompanied by
long-term exposure to smoking [5, 6]. Other factors such as
genetics, air pollution, etc. play an important role in lung
*Address correspondence to this author at the Applied Biotechnology Re-
search Center, Baqiyatallah University of Medical Sciences, Tehran, Iran,
P.O. Box 19395-5487; Tel/Fax: +98 21 88617712;
E-mail: Nabavi208@gmail.com
cancer induction [7]. A close correlation between air pollu-
tion and mortality rates for lung diseases has been estab-
lished [8]. Asthma is a common airways inflammatory dis-
order [9] that is accompanied by symptoms such as difficulty
and shortness of breathing, chest tightness, wheezing, cough-
ing, and bronchospasm [10]. According to the World Health
Organization (WHO) report, about 235-330 million people
suffered from this lung disease in 2011 [11]. COPD is anoth-
er common type of lung disease is accompanied by emphy-
sema and chronic bronchitis [12] that leads to the blockade
of airflow causing breathing problems [13]. This is an im-
portant lung disease which causes of chronic morbidity and
mortality in the world [14]. The WHO Statistical data ac-
counted COPD as the third leading cause of death worldwide
[15]. Pulmonary vascular disease is a serious and fatal com-
plication of lung injury in congenital heart disease [16]
which affects the blood circulation in the lungs associated
with chest pain, shortness of breath, and fainting [17]. Also,
it has been reported that several drugs (such as bleomycin,
busulfan, chlorambucil, cyclophosphamide, methotrexate,
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2 Current Topics in Medicinal Chemistry, 2017, Vol. 17, No. 7 Nabavi et al.
mitomycin, nitrosoureas, nitrofurantoin, nilutamide, etc.) can
induce severe interstitial lung disorders during the first days
of pharmacotherapy [18]. Drug-induced interstitial lung dis-
orders can lead to respiratory injuries and acute respiratory
distress syndrome [19].
Melatonin, an indoleamine compound, is produced by the
pineal gland from the aminoacid tryptophan [20]. Its noctur-
nal production is high and daily production is low. Pineal
melatonin production is controlled by the suprachiasmatic
nucleus which sends neural information to the gland via the
autonomic nervous system [21]. In addition to the pineal
gland, melatonin is produced in other organs including the
retina, lens, ovary, gastrointestinal tract, etc. [22]. Some
types of cells such as bone marrow cells have high levels of
melatonin [23]. Furthermore, the bile and cerebrospinal fluid
levels of melatonin are much higher than in human blood
[24]. Melatonin has also been found in plants and microbes
[25-27]. It plays a pivotal role in body sleep cycles, and sev-
eral cellular, neuroendocrine, and physiological processes
[27, 28]. Melatonin is an important hormone involved in the
regulation of circadian rhythms [29]. The circadian rhythm
of sleep propensity and thermoregulation is correlated with
the rhythm of melatonin [29]. Hence, evening consumption
of melatonin elevates the sleep propensity and diminishes the
body temperature. This suggests that melatonin has a direct
role in circadian rhythm sleep cycles [30]. More than 150
clinical trials, including non-randomized phase II/III trials,
randomized double-blind placebo-controlled, etc. have fo-
cused on the promising role of melatonin on different human
diseases including autism, osteoporosis, ulcerative colitis,
epilepsy, schizophrenia, asthma, cancers, skin diseases, my-
ocardial infarction, blood pressure, chronic kidney disease,
stroke, mental disorders, gastro-esophageal reflux disease,
hypertension, sleep disorders, neurodegenerative disorders,
etc. (www.ClinicalTrials.gov), when given alone or in com-
bination with functional or therapeutic agents such as foods
or drugs. The results of the clinical and preclinical studies
suggest that melatonin exerts a variety of therapeutic actions
and is currently being considered for use in the treatment of
several diseases including cancers, depression, infections,
gastric diseases, immune diseases, metabolic diseases, cardi-
ovascular diseases, reproductive diseases and insomnia, etc.
The present summary was designed to critically review
scientific studies which demonstrate the therapeutic actions
of melatonin on respiratory diseases. The molecular aspects
of melatonin’s therapeutic potential is also discussed with
due reference to its chemical structure, molecular targets,
and pharmacological effects.
CHEMISTRY OF MELATONIN
Physicochemical Profile
Melatonin is a white to yellowish crystalline powder with
a molecular formula C13H16N2O2 (molecular weight: 232.3)
and melting point of 117°C (generally 116 -120 °C). Melato-
nin is also known by various trade names including Circadin,
Melatol, Melatonine, Melovine and Regulin. It derived from
an essential dietary amino acid, tryptophan, which is an in-
doleamine possessing polar and non-polar structural moieties
(Fig. 1). Although melatonin generally partitions in lipid
phases, it is also highly soluble in aqueous medium up to the
concentration of 5×10−3 M [31]. In fact, melatonin is an am-
phiphilic molecule with high lipid and water solubility and
suggests that it can easily moves across the cell membranes
and into various body fluids and is rapidly distributed to all
tissues. With a good UV chromophore showing two charac-
teristic absorption bands at λ223 and 278 nm and fluores-
cence properties, melatonin’s interaction with various sys-
tems can be monitored by spectroscopic methods.
Fig. (1). Chemical structure of melatonin. Structural components
shown in black are of tryptophan origin; the red part is from the
hydroxylation and methoxylation reactions, and the blue one is
originated from the acetylation reactions.
Biosynthesis
The pineal gland is regarded as a primary site of melato-
nin biosynthesis in vertebrates. In pineal tissue, tryptophan is
converted by tryptophan 5-hydroxylase to 5-
hydroxytryptophan. In the next step, serotonin is produced
through decaboxylation of 5-hydroxytryptophan by 5-
hydroxytryptophan decarboxylase. It has been widely recog-
nized that serotonin is stored in large amounts in the pineal
gland and its acetylation by the enzyme serotonin N-acetyl-
transferase to N-acetylserotonin is the rate limiting step in
melatonin biosynthesis [32, 33]. The rate limiting nature of
AANAT-catalyzed reaction has also shown to be attributed
to its de novo synthesis at night. The pineal gland receives a
sympathetic neuronal input during darkness which leads to
the release of norepinephrine and the subsequent cAMP-
coupled synthesis of AANAT. This rhythmic feature in the
synthesis of melatonin results in its highest nocturnal level
and low daily values [34]. Previous report demonstrated that
light exposure to even a brief period rapidly diminishes the
nocturnal AANAT activity and production [35]. The final
stage of melatonin synthesis involves methylation of N-
acetyl serotonin by the enzyme hydroxyindole-O-methyl
transferase to form melatonin (Fig. 2).
In vertebrate and invertebrate organisms the retina is an-
other melatonin source. The rhythmic productions of this
indolamine in the retina and the cAMP-dependent signaling
cascade have been well established [36, 37]. Moreover, mel-
atonin is known to be formed in various other organs such as
gut mucosa, Harderian gland, airway epithelium, cerebellum,
liver, kidney, adrenals, etc. and cellular components of the
immune system including natural killer cells, mast cells, eo-
sinophilic leukocytes, endothelial cells and platelets [38, 39].
Melatonin is also synthesized by plants to serve in a variety
of physiological conditions [26, 40-43].

Melatonin and Respiratory Diseases Current Topics in Medicinal Chemistry, 2017, Vol. 17, No. 7 3
Fig. (2). Biosynthethic route of melatonin.
Catabolism
The circulating melatonin in plasma is converted to 6-
hydroxy melatonin in the liver by cytochrome P450 1A2
monooxygenases, where over 90% of melatonoin clearance
takes place. Further catalysis of 6-hydroxymelatonin by
sulphotransferase ST1A3 yields the major by-product 6-
sulfatoxymelatonin while to a lesser extent, catalysis by
UDP-glucuronosyltransferase results in the formation of uri-
nary excretion product, 6-hydroxymelatonin glucuronide
[44] (Fig. 3). It has been reported that urinary level of 6-
sulfatoxymelatonin closely correlated with the plasma mela-
tonin concentrations [45]. Melatonin also is oxidized by
myeloperoxidase, 3-dioxygenase, and/or indoleamine-2, to
yield an unstable product, N1-acetyl-N2-formyl-5-
methoxykynurenine which is then de-formulated to generate
N1-acetyl-5-methoxy-kynurenine. Small (less than 1%)
amounts of melatonin are also excreted in the urine without
any alteration.
Melatonin Interaction with Nitrogenous and Reactive
Oxygen Species
Melatonin ability to up-regulation of several antioxida-
tive enzymes such as glutathione peroxidase, superoxide
dismutase, and glutathione reductase, down-regulation of the
pro-oxidative enzyme such as nitric oxide synthase has been
publicized [46-48]. As a powerful antioxidant, often claimed
to be far superior than vitamin E and C, melatonin can also
directly scavenge nitrogenous and reactive oxygen species
(ROS and RNS) such as H2O2, peroxinitrite anion (ONOO-),,
hydroxyl radical (OH·) singlet oxygen (1O2), (superoxide)
O2
·-, and peroxyl radical (ROO·) [49-51]. Structure-activity
relationship studies on ROS/RNS scavenging effect of mela-
tonin revealed that the indole moiety plays a central role in
the scavenging of free radicals, [52]. Being an electron-rich
molecule, melatonin can interact with free radicals through
donation of electrons to form melatoninyl cation radical.
Free radicals (such as OH·) can directly attack at C-3 posi-
tion to form cyclic 3-hydroxymelatonin which by itself is a
potent radical scavenging metabolite [53]. Hydrogen abstrac-
tion by radicals from the nitrogen atom or side chain substi-
tution at C2, C4 and C7 position as well as nitrosation are
also all implicated as possible routs of radical scavenging
reactions. Ultimately, melatonin undergoes consecutive reac-
tions to yield many stable secondary and tertiary metabolites
that are capable of free radical scavenging (Fig. 4). N-acetyl-
methoxykynuramine and N1-acetyl-N2-formyl-5-methoxyky-
nuramine are two good examples of melatonin metabolites
with antioxidant activities [54-57] possibly even better than
melatonin itself [58]. Many antioxidant compounds, such as
plant polyphenols and ascorbic acid have dual effects in that
they undergo both prooxidant and antioxidant reactions [59-
64]. In the absence of free phenolic hydroxyl group in mela-
tonin and the above mentioned stable intermediates, a proox-
idative mechanism is not for a common feature of melatonin.
MELATONIN IN PLANTS AND ANIMALS
Melatonin is a multifunctional molecule found wide-
spread in nature, being present in all taxa of organisms. In
plants, this molecule is present in roots, stems, flowers and

4 Current Topics in Medicinal Chemistry, 2017, Vol. 17, No. 7 Nabavi et al.
Fig. (3). Catabolism of melatonin.
seeds [65, 66]. Previous report shows that more than 20 di-
cotyledon and monocotyledon families of flowering plants
have melatonin with different [67, 68]. Moreover, it is be-
lieved that plants employ more complex biosynthetic to pro-
duce melatonin than animals [69]. The major role of melato-
nin in plants is as antioxidant to protect them from environ-
mental agents-induced oxidative damage [41, 70-72]. Free
radicals are marginal products of essential cellular metabo-
lisms such as cellular respiration and photosynthesis and
their excessive generation and accumulation in cells leads to
oxidative stress condition [73-75]. The protective activity of
melatonin against mitochondrial and chlorophyll oxidation
has been clearly evidenced [76-78]. Hence, previous studies
reported that some transgenic plants rich in melatonin have a
higher antioxidant capacity with lower oxidative damage,
when compared with non-transgenic plants [79].
In invertebrates, melatonin appears to be present and syn-
thesized rhythmically in neural or neurosensory structures
i.e., brain, cerebroid ganglia, eyes, optic lobes, it is also
found in circulating fluids such as hemolymph [80, 81]. Pho-
toperiod changes provoke some physiological reactions and
initiates special behaviors such as sexual behavior [82]. Mel-
atonin may participate in these processes acting in inverte-
brates as a transducer of photoperiodic information with a
similar role to that found in vertebrates [83, 84]. However,
the exact function of indoleamine in the behavior of inverte-
brates remains unknown.
Fig. (4). Major routes of melatonin oxidation by ROS and RNS.
Invertebrates detect photoperiodic data through their reti-
na and then, by use of their pineal organ, they translate this
information to melatonin generation. Retinal melatonin plays

Melatonin and Respiratory Diseases Current Topics in Medicinal Chemistry, 2017, Vol. 17, No. 7 5
a role in improving the photo adaptation by the retina in all
studied species of vertebrates [85, 86]. Pineal melatonin is
first secreted into cerebrospinal fluid and then it enters blood
and is responsible for the time-keeping effects in the organ-
ism [86, 87]. Anatomical, structural and physiological stud-
ies have documented that the pineal organ of ectotherms has
direct photosensitivity, which acts as a luminance detector
[86, 88]. Mammals have secretory pineal gland which is one
of several sources of melatonin production and secretion. A
plethora of physiological and biological functions attributed
to this indole.
In animals, light reaches the pineal organ through com-
plex nervous pathways [89, 90] and helps them to organize
seasonal rhythms. The circadian production of melatonin
synthesis/secretion rhythm and is mainly synchronized by
the prevailing light/dark cycle [91]. The evolution process
has resulted in a complete loss of the direct photoreception
of the pineal gland. Other areas such as retina, gut, immune
competent cells, etc. can also produce melatonin. and acts
either in a paracrine or autocrine manner [28]. It is well
known that melatonin has potent antioxidant actions and
therefore it is thought that these organs produce melatonin in
order to protect themselves from oxidative damage [70, 92,
93].
In the humans, pineal gland is responsible of melatonin
production and secretion. It is well known as the chemical
expression of darkness because of its high generation during
night [94]. It is believed that its production and secretion
rhythm is initiated between 6-8 weeks of human life [95].
The nightly melatonin peak continuous to increase and
reaches to its highest values between 4-7 years after birth.
During aging melatonin levels decrease slowly so eventually
the night time rise is minimal daytime concentration after 70
years of age [96, 97]. In the suprachiasmatic nucleus melato-
nin acts as a circadian pacemaker, and perhaps it has a simi-
lar action in peripheral organs [98]. Melatonin is a key factor
in homeostatic functions in humans such as the control of
energy metabolism, physiological growth, differentiation,
and adaptive response to stress stimuli [98, 99]. In fact, mel-
atonin exhibits multifaceted functions of specific signaling
pathways and the transcription of metabolic and stress-
related genes [100-103].
MOLECULAR TARGETS
In recent years, melatonin has been used both for its
physiological effects (such as control of sleep/wake cycle,
sleep-promotion, seasonal adaptation, and reduction of jet
lag symptoms) and for its therapeutic activities on cardiovas-
cular and bone metabolisms, renal functions, gastrointestinal
system, anticancer effects. The wide range of applications of
melatonin in physiological and pathological processes is
connected to both independent actions as an antioxidant and
to the widespread distribution of melatonin receptors that are
localized in suprachiasmatic nuclei (SCN) and in many pe-
ripheral tissues. Melatonin receptors were first postulated by
Heward and Haley in 1975 [104], while the demonstration of
the two human best known melatonin membrane receptor
come 20 years later, when two G protein-coupled melatonin
receptors were discovered [105, 106]. The first receptor,
identified as Mel1a receptor, was found to be a protein of
350 amino acids (MW 39,374 Da) expressed in the hypophy-
sis and hypothalamic SCN. The second one (Mel1b) is a
proteins of 362 amino acids (MW 40,188 Da), 60% similar
in the amino acid level to Mel1a, expressed in retina and
brain, that shows functional characteristics close to those of
the Mel1a receptor. Mel1a (now called MT1) and Mel1b
(MT2) receptors are seven transmembrane proteins with the
amino group of the N-terminal amino acid in the extracellu-
lar surface and the carboxyl tail in the intracellular surface.
Melatonin in different concentrations is able to induce the
activation of the relative receptors, ranges from 30 to 400
pM. Therefore, the physiological concentration of blood
melatonin at night (ranging from 100 to 400 pM) may some-
times be higher than that necessary to activate the receptors,
whereas the blood melatonin concentrations during the day
light hours are not sufficient for the receptor activation
[107]. Also, it was demonstrated that chronic exposure to
melatonin could desensitize endogenous MT2 melatonin
receptors with a feedback mechanism without affecting the
sensitivity of endogenous MT1 receptors [108]. The above
reported data have served as the starting point for what is
known today as human melatonin receptors that are classi-
fied into two types (MT1 and MT2) on the basis of structural
finding related to amino acids sequence and functional in-
formation.
In adition to membrane melatonin receptors, nuclear
melatonin receptors have been proposed, they belong to the
subfamily of retinoid Z receptor (RZR) or retinoid orphan
receptors (ROR). These receptors are subdivided into differ-
ent receptor isoforms (ROR alpha (RORA), ROR beta
(RORB), and ROR gamma (RORC)) [109]. With regard to
their function, MT1 and MT2 melatonin receptors work in a
complementary way in SCN neurons to regulate the circadi-
an rhythms and many other functions. Genetic polymor-
phism of human MT1 and MT2 receptors were initially doc-
umented by Ebisawa et al. [110, 111], they found seven mu-
tations for MT1 and two variants for MT2. While MT1 vari-
ants were more common in non-24-h sleep-wake syndrome
subjects, compared with control subjects, the MT2 variants
were not located to patients with this circadian sleep disor-
der. These results seem to lead to the hypothesis that MT1
and MT2 plays different roles in this sleep disorders.
MT1 and MT2 receptors occurring in peripheral tissues
have different physiological roles, thus MT1 receptors are
responsible for modulation of arterial vasoconstriction, can-
cerous cell proliferation, as well as metabolic and reproduc-
tive functions, while MT2 receptors inhibit dopamine release
in retina, modulate vasodilation, and stimulate immune-
system.
In recent years many investigations have been carried out
to demonstrate the role of melatonin receptors in different
organs and tissues. Ekmekcioglu et al. showed that MT1
receptors expressed in human coronary arteries. Two years
later, the same authors showed the presence of MT2 recep-
tors also in left ventricles [112-116]. The protective activity
of melatonin in maintaining a healthy cardiovascular system
is coupled with activation of MT2 receptors on endothelial
cells [117], that induces nitric oxide (NO) production and
endothelium-dependent vasodilation [118, 119]. It was fur-
ther shown that melatonin supplementation induces a

6 Current Topics in Medicinal Chemistry, 2017, Vol. 17, No. 7 Nabavi et al.
Fig. (5). Schematic representation of the mechanisms of action associated to melatonin in the treatment of respiratory disorders. Abbrevia-
tions: glutathione peroxidase (GPX); immunoglobulin E (IgE); inducible nitric oxide synthase (iNOS); lipoxygenase (LOX); matrix metallo-
proteinase (MMP); nuclear factor erythroid (Nrf); nuclear factor kappa beta (NF-kb), superoxide dismutase (SOD); vascular endothelial
growth factor (VEGF).
reduction of blood pressure [119, 120], and variable effects
on myocardial contractility [121-126]. Moreover, reduced
melatonin levels associated with altered expression of MT2
receptors have been reported in various cardiovascular dis-
eases, such as ischemic heart disease [127] and myocardial
infarction [128].
High density of these receptors has been also reported in
human gastrointestinal (GI) tract, whereas the presence of
nuclear receptors has yet to be defined. Variable binding
density in different regions of the intestine has been noted
and the localization of MT1 is mainly in the sub-epithelial
layer, whereas the highest levels of MT2 receptors are in the
circular and longitudinal muscle layers, suggesting a poten-
tial role of MT2 receptors in intestinal motility [129]. Other
functions of melatonin are also suggested (such as GI secre-
tion, release of peptide YY, a gut hormone that is thought to
be a satiety signal [129]. Further research is needed to pro-
vide more data to support the role of melatonin in the GIT of
humans.
Growing scientific evidence also support the role of mel-
atonin in human reproductive function [130]. Melatonin was
first suggested to meddle in modulation of humans reproduc-
tion at the follicular level by Ronnberg and others [131].
They found that melatonin concentration in human follicular
fluid is more than three fold higher than blood levels. Niles
and others [132] confirmed the presence of MT1and MT2 in
human granulosa cells using RT-PCR. Since then, numerous
published reports have shown that melatonin receptors are
present in the ovary, where exogenous melatonin acts via
receptors stimulating progesterone production [133], and
protect ovary from oxidative damages [134, 135]. More re-
cently, melatonin receptors have also been reported from the
placenta. During pregnancy, melatonin whose levels increase
in lae pregnancy, crosses the placenta, enters the amniotic
fluid and then the fetal circulation (included brain due the
fact that melatonin crosses blood-brain barrier), promoting
fetal development and neurogenesis [136-138]. It is notewor-
thy that lower melatonin receptors expression in placenta has
been found in preeclamptic women compared with normo-
tensive pregnant. The authors presumed that the decreased
levels of melatonin production in preeclamptic women in-
duces the down-regulation of melatonin receptor expression
and underlines the therapeutic role of melatonin system in
the pathogenesis of preeclampsia [139].
Melatonin is considered to be involved in suppression of
a number of tumors (breast, ovarian, prostate, and digestive
tract cancer and melanoma) and melatonin receptors have
been reported from a number of cancerous cell (e.g. breast
cancer cells) [140]. The mechanism of actions through which
melatonin exerts its oncostatic and antiproliferative effects
involved MT1 receptor activation that leads to suppression
of tumor initiation and growth in vivo. Also, MT2 and nucle-
ar receptor activation and non-receptor mechanisms, such as

Melatonin and Respiratory Diseases Current Topics in Medicinal Chemistry, 2017, Vol. 17, No. 7 7
apoptosis, immune-enhancement potential, antioxidant activ-
ity and antiangiogenic properties seem to be involved in
melatonin’s anticancer activity, but further researches are
needed to confirm its effect in humans [133, 141-145].
BIOLOGICAL AND PHARMACOLOGICAL ACTIVI-
TIES OF MELATONIN
Antioxidant Effects
It is believed that the electron rich indole moiety has cru-
cial role in antioxidant capacity of melatonin, inasmuch as its
high resonance stability and electroreactivity. However, oth-
er moieties such as amide chain and methoxy also have role
in antioxidant activity of melatonin [52]. Both plant and an-
imal kingdoms including insects, arthropods, etc., produce
melatonin [93, 146-149]. Melatonin in humans is an endoge-
nous antioxidant which is likely generated in a number of
organs: it also has an influence on the rhythms of various
hormones [124, 150]. There is some data indicating that
omega-3 fatty acids may have significant role in regulation
of the pineal gland [151]. The electron rich structure of mela-
tonin directly scavenges HO• and other ROS and RNS [152].
Melatonin is also up-regulates endogenous antioxidant de-
fense systems both enzymatic and non-enzymatic [46, 48,
153]. Specifically, it increases the activity of superoxide
dismutase and glutathione peroxidase and [154] although
there is one report claiming that melatonin is ineffective in
up-regulation of antioxidant enzyme activity [155]. Melato-
nin also dose-dependently quenches hydrogen peroxide; but
it is less effective as a peroxyl radicals and superoxide anion
scavenger [156]. A plethora of in vitro and in vivo works
have demonstrated that exogenous melatonin suppress oxida-
tive stress [157, 158]. It is well known that the promising
effect of N-acetyl serotonin and melatonin in stabilizing of
biological membrane structures are correlated with its capac-
ity to inhibit lipid peroxidation [159]. Also, melatonin ability
to protect polyunsaturated fatty acids in biological systems
against lipid peroxidation has been shown [160]. However,
there is also data on the capability of melatonin or its
analoges compound to suppress peroxidation of polyunsatu-
rated fatty acids (PUFAs) enriched liposomes [155]. It has
been documented that melatonin provoke an increased activi-
ty of γ-glutamylcysteine synthase while suppressing NO
synthase and lipoxygenase activities which results in in-
creased level of the non-enzymatic intracellular antioxidant
i.e. glutathione [161]. It is well known that melatonin admin-
istration helps to sustain microsomal membrane and miti-
gates oxidative injuries [162]. It is also reported that melato-
nin significantly suppress DNA damage and down regulates
8-hydroxy-2′-deoxyguanosine formation; in this capacity
melatonin is more 70 times more effective than vitamin C
and E [163].
There is a plethora of scientific reports on significant
therapeutics role of melatonin against different diseases such
as liver disease, kidney disease, diabetes, Alzheimer, Parkin-
son, etc. [164-167]. The antioxidant role of low levels of
melatonin occurs due to indirect up-regulation of glutathione
peroxidase expression, however in high concentration level,
it behaves as direct radical scavenger [168]. It has been re-
ported that the capacity of melatonin to up-regulate the anti-
oxidant enzymes includes both membrane and nuclear recep-
tors, and the induction of glutathione peroxidase by melato-
nin is a commonly reported action [58, 168].
Anticarcinogenic and Antitumoral Effects
Melatonin is protective against several forms of cancer
both in animal models and in vitro investigations [169].
There is evidence about suppressive functions of melatonin
on the progression of spontaneous and chemically-stimulated
carcinogenesis at different sites in experimental animals as
well as on the tumor growth in vitro [169]. Melatonin has
some beneficial effects in the care of advanced cancer pa-
tients [170]. Melatonin is also known as an effective anticar-
cinogen and antitumor molecule in other situations [171].
The function of the pineal gland in tumor development is
now widely studied [172]. It has been reported that cancer
progress is associated with melatonin reduction [173] and
mammary cancer progress is elevated by pinealectomy in
animal studied model [174]. Melatonin also suppresses
chromium and x-ray induced DNA damage, and mitigates
safrole induced DNA-adduct formation and cis-platinum
induced genetic damages [156, 175-177]. There is close cor-
relation between high levels of melatonin and a reduced risk
of breast cancer [178]. The promising effect of exogenous
melatonin on breast cancer has been reported previously
[179]. Several factors have been shown to link with reducing
of melatonin level including, increasing of age, obesity,
night working, etc. [180]. Respect to Humans inability to
produce tryptophan (melatonin precursor), they need to re-
ceive it via diet. Variation in melatonin may be due to con-
sumption of high tryptophan foods such as fish, nut, sesame
seeds, milk, etc.In fact, some studies have shown the nutri-
tion influences melatonin levels [181].
Blask and others [142] reported significant in vitro anti-
cancer effect of melatonin during different stages tu-
morogenesis. They showed that inhibition of tumor uptake of
linoleic acid and molecular signaling 13-
hydroxyoctadecadienoic acid plays crucial role in anticancer
effect of melatonin and melatonin receptor antagonist
S20928 inhibited this effect [142]. Also, there are numerous
evidence that there is a close correlation between increasing
nocturnal light exposing (decreasing of melatonin secretion)
and elevation of breast, colorectal and endometrial cancer
incidence rate [182, 183]. The most recent investigations
have demonstrated that melatonin has a significant oncostat-
ic character by changing the expression of anticancer cyto-
kines interleukin-2 and interleukin-12 in human neoplasms
[184]. It is believed that anticancer effect of melatonin
against breast cancer is mediated by MT1 receptors [144,
185]. Also, Schernhammer et al. [186] found that the risk of
colorectal cancer in nightshift nurses was higher than control
subject which was correlated to nocturnal light exposing-
induced diminishing of melatonin. Furthermore, Farriol et al.
[187] have found that melatonin suppresses the growth of
mourine colon carcinoma CT-26 cells line growth. The au-
thors emphasized that melatonin exerts its antiproliferative
role through a nonhormone-dependent action, because no
receptors were identified on the selected cell line [187].
It is reported that tryptophan can provoke melatonin pro-
duction and secretion in the gastrointestinal tract of rats and
chicks [188]. The concentration of daytime melatonin gastro-

8 Current Topics in Medicinal Chemistry, 2017, Vol. 17, No. 7 Nabavi et al.
intestinal tract is more than 10-100 times higher than blood
[189]. Melatonin accumulation has therapeutic role against
several diseases such as irritable bowel syndrome, colitis,
infantile colic, and gastric ulcers [190]. It has been also re-
ported that melatonin administration may prolong cellular
longevity [191]. It is believed that melatonin can control
some gonadal and pituitary hormones and inhibit mammary
carcinogenesis [192]. It also can supress cancer cell prolifer-
ation directly acting on tumor cell due to its antiestrogenic
effect [193]. Melatonin ability to induce apoptosis in cancer-
ous cells has been publicized [194, 195].
Angiogenesis is another crucial step in tumor develop-
ment stimulated by endothelin-1 synthesis in blood vessel
[196]. Endothelin-1 directly induces constriction by releas-
ing proangiogenic agents including vascular endothelial
growth factor (VEGF) [197]. Melatonin administration sig-
nificantly inhibits endothelin-1 synthesis through suppres-
sion of endothelin converting enzyme activity [198, 199] and
down regulation of HIF-1α expression level in prostatic can-
cer [200]. This ability melatonin is necessary to suppressing
of tumor angiogenesis.
Effects on Apoptotic Mechanism
Apoptosis or programmed cell death process, essential
for removing damaged, infected or potentially neoplastic
cells. This process is basically initiated by either the extrinsic
pathway, which is also known as the death receptor pathway,
exclusively controlled by caspases [201], or by the intrinsic
pathway, which influence cellular organelles, such as mito-
chondria, the endoplasmic reticulum, the nucleus and lyso-
somes [202]. Several chemotherapeutic drugs used in the
care of various cancers are known to up-regulate apoptosis
[203]. Many in vitro studies suggest that some antioxidants
have the potential to develop the clinical efficacy of selected
cytotoxic chemotherapeutics [204]. In vitro research has also
proved that antioxidants may increase the cytotoxic effects
of chemotherapeutic drug on cancerous cells [205]. Melato-
nin is noted to possess significant neuroendocrine and physi-
ological properties in humans [124]. It can enter subcellular
compartments and probably bind to some cytosolic proteins
[206]. The signaling of melatonin is performed through G-
protein coupled receptor or nuclear receptor activation [207].
As reported above, the melatonin receptors have been identi-
fied in some tissues such as brain, ovary, teeth and bone
[208, 209]. Melatonin binding sites have also been identified
in cells occurring in retina, blood lymphocytes, and platelets
[208]. Melatonin found that can trigger apoptosis through
elevation of ROS and oxidative stress, depolarization of mi-
tochondrial inner transmembrane potential and consequently
externalizing of internal phosphatidylserine and eventually
releasing apoptotic factor and apoptosis [210].
Melatonin administration in Alzheimer disease also sup-
presses beta amyloid peptide and ROS induced neural cell
apoptosis [211]. However, it may be less effective against N-
methyl-D-aspartate, ethylcholinazyridine or staurosporine
induced neural toxicity [212, 213].
It was shown that the suppressive role of melatonin on
neural cells apoptosis is mediated by suppression of glycoly-
sation derivative-induced necrosis [213]. Melatonin also can
prevent nitric oxide and ischemic stroke induced apoptosis
through up-regulation of antiapoptotic protein (BcL-2) ex-
pression level in PGT-beta immortalized pineal cells [214].
Previous study showed that consecutive 40 days melatonin
administration at 15 mg/l either mitigate oxidative stress
induced thymocyte apoptosis or up-regulate thymocyte pro-
liferation [215]. Melatonin administration at 20 mg/L signif-
icantly suppresses colon tumors in rats suffer from 1, 2-
dimethyl hydrazine induced colon cancer [216].
Melatonin also inhibits aflatoxin b1 induced caspase-3
activation and apoptosis in rat’s hepatic tissue through its
antioxidant effects [217]. Previous studies show that melato-
nin administration up-regulates the glutathione in liver and
brain when it is diminished by oxidative stress [218, 219].
Petrosillo et al. [220] have reported that melatonin suppress
cytochrome c releasing and mitochondrial permeability tran-
sition trough inhibition of calcium-dependent cardiolipin
peroxidation in mitochondria. It is interesting to note that
melatonin acts as double edge sword; an antiapoptotic mole-
cule in normal cell, and apoptosis inducer in cancerous cells
[221]. Most of the studies have established that melatonin
may reduce cancer cell proliferation and promote apoptotic
cancer cell death [210, 222, 223].
Anti-inflammatory Effect
Inflammation is a natural protective response to tissue in-
jury by physical, chemical or biological mechanisms [224].
As part of the acute and chronic inflammatory process of
tissue repair, activated inflammatory cells (e.g. leukocytes,
endothelial cells, etc.) release a plethora of mediators includ-
ing ROS/RNS and cytokines [224, 225]. Suppressing the
inflammatory process is one of the major strategies in com-
bating chronic inflammatory diseases such as arthritis, ather-
osclerosis, gout, chronic obstructive pulmonary disease, etc.
[226-229]. As a potent regulator of inflammation through
antioxidant ability, melatonin mitigates the chronic inflam-
mation induced oxidative stress and modulates of leukocyte
function and/or number, therefore it can be considered as a
valuable therapeutic agent [230, 231]. Early studies revealed
that nightly increased concentration of melatonin is needed
to suppress inflammation [157]. Previous report also proved
that supraphysiological concentration of melatonin provokes
inflammatory response via increasing of lymphocyte prolif-
eration and NK cell and up-regulate pro-inflammatory cyto-
kines and tumor necrosis factor α [232]. Melatonin is gener-
ally considered to have and anti-inflammatory actions which
regulate cellular pathways and protects against excitotoxicity
and other cell death processes [232]. It is believed that oxida-
tive stress and oxidative-mediated processes have a key role
in pathophysiology of the inflammatory diseases [20, 233,
234]. During phagocytosis, activated polymorphonuclear
neutrophils rapidly produce ROS as their important antimi-
crobial mechanism against invading microorganism [235].
This process so-called oxidative burst leads to concentration
gradient which direct leukocytes to damaged sites [236].
This oxidative stress also causes monocyte maturation and
increase leukocytes adhesion to endothelial cells [237].
ROS also up-regulate pro-inflammatory cytokines and
consequently triggers inflammatory response, mediated by
the redox sensitive transcription factors such as NF-κβ [238].
Any delay in treatment of injuries, elevates ROS production

Melatonin and Respiratory Diseases Current Topics in Medicinal Chemistry, 2017, Vol. 17, No. 7 9
and leukocyte recruitment in damaged tissue and lead to
chronic inflammation and may increase risk of cancer and/or
organ failure [239]. Inasmuch as explicit detrimental role of
excessive produced ROS in progression of chronic inflam-
mation, effective therapeutic protocol needs antioxidant to
restrict damage in inflammatory site [240, 241].
New trends and insights related to melatonin´s anti-
inflammatory character and molecular ability have been re-
cently shown [231]. It is well known that iNOS and cyto-
kines production are most important targets of melatonin
anti-inflammatory effect [231]. The safety of melatonin
makes this it interesting molecule for translate into the clinic
[231]. It has been showed that inflammatory cells produce
ROS and RNS, as well as pro-inflammatory cytokines [242].
Moreover these pro-inflammatory cytokines have several
detrimental effects on several tissues such as lung [243].
The ameliorative effects of antioxidants and iNOS inhibi-
tors against chemical-induced lung inflammation have been
publicized [244, 245]. Su and others have demonstrated that
the iNOS inhibitors suppress pro-inflammatory cytokines
production in endotoxin-induced acute pulmonary damages
[246]. Melatonin is a versatile antioxidant and anti-
inflammatory agent which directly neutralizes many
ROS/RNS and minimizes free radical production [247]. It
also up-regulates expression of other endogenous antioxidant
enzymes [247]. This molecule is known as potent iNOS in-
hibitor which can cross all biological membrane [248]. Due
to these specific characters; melatonin is capable to suppress
inflammation.
SAFETY OF MELATONIN
Although melatonin is a very popular natural food sup-
plement, there are a variety of reports related to its minimal
side effects although there are few studies on its long term
safety [249]. It has been reported that acute toxicity of mela-
tonin is extremely low according to both animal and human
studies [250]. Melatonin is safe and even 800 mg/kg b.w.
was not fatal and its LD50 is not established till now [251].
However, some minor side effects such as headache, upset
stomach, rash, sleep disorders have been reported in long-
term usage of melatonin [252]; these were similar to those
reported for the placebo. Human studies showed that long-
term consumption of different doses (between 1-6.6 g per
day) of melatonin did not caused abnormalities according to
the biochemical tests and all tested factors were at normal
range at the end of treatment period [252]. Although melato-
nin has effects on the regulation of seasonal reproduction in
photoperiod species, these actions do not occur after chronic
long-term administration of melatonin to humans [253].
There is may be some correlation between high level of mel-
atonin with puberty delay and with hypo-gonadism [134,
254]. In women, melatonin has been tested as a contraceptive
substance [255], but this action of melatonin is no longer
considers viable. Also, melatonin consumption reportedly a
negative effect on autoimmune diseases [256], but, again,
this has not been considered. A report showed that melatonin
increased neurological abnormalities in a patient who suffer
from multiple sclerosis [257]. But all other studies show that
melatonin is neuroprotective. Melatonin consumption in-
creased seizures in neurological disabled children [258], but
in other cases it inhibits seizures [259]. According to animal
studies, high doses of melatonin increase the light-induced
retinal photoreceptors injuries and aortic atherosclerosis in
hyper-cholesterolemic rats [260, 261] however, there are
many studies that indicate the contrary melatonin has been
widely used for two decades by human and no untoward
unsequences have been reported.
MELATONIN AND LUNG DISEASES
Infection
Respiratory tract infections are most common infective
disorders in the world which causes considerable morbidity
and complications [262]. Respiratory tract infections, which
have different etiologies, from bacterial infections to viral
infections, and other infective agents [263], are generally
classified into two major groups, i.e. upper respiratory tract
infections and lower respiratory tract infections [264]. The
upper respiratory tract infections (such as the common cold)
area are very common viral disease that affects all people
globally [265]. According to statistics, young children are
the most susceptible to upper respiratory infections [266].
Common cold is usually associated with different symptoms
such as cough, runny and/or stuffy nose, nasal congestion,
nasal pain, sneezing, headache, sore throat, fatigue, and fever
[267, 268]. Lower respiratory tract infections are generic
infections of trachea, airways and lungs [269]. There are
numerous infections which can affect the lower respiratory
tract such as bronchitis, pneumonia, and tuberculosis, which
are the most common types of lower respiratory tract infec-
tions [270, 271]. Major symptoms of lower respiratory tract
infections are shortness of breath, breathlessness, wheezing,
coughing, high fever, weakness, and fatigue [272]. Lower
respiratory tract infections are important health problem due
to their high prevalence, morbidity and mortality rates [273].
Huang et al., [274] reported that syncytial virus infection
up-regulates oxidative stress in the lung tissues and melato-
nin mitigates syncytial virus infection-induced oxidative
stress and lung inflammation via decreasing of the levels of
malondialdehyde, NO, and OH·, as well as increasing of the
glutathione and superoxide dismutase activity (Table 1).
They also found that melatonin inhibits the pro-
inflammatory cytokines production such as TNFα production
and from this way; they suggested that melatonin can be
used as a new therapeutic strategy for viral infection [275].
Huang et al. [275] examined the molecular mechanisms of
the inhibitory effect of melatonin against respiratory syncyti-
al virus infection in the RAW264.7 macrophages via exami-
nation of the Toll-like receptor 3 signaling pathways. They
found that downstream Toll-like receptor signaling pathway
leads to interferon regulatory factor-3 activation, as well as
nuclear factor kappa-β and other pro-inflammatory cytokines
and chemokines [275]. Huang et al. [275] found that melato-
nin modulate Toll-like receptor 3-mediated inflammatory
genes via inhibition of NF-κβ activity in the RAW264.7
macrophages. Castro-Silva et al. [276] performed a random-
ized, double-blind placebo-controlled study on the beneficial
role of this indolamine in the improvement of sleep quality
and mitigation of inflammation and oxidative stress in 20
patients suffered from cystic fibrosis. They used actigraphy
and determined isoprostane and nitrite levels in cystic

10 Current Topics in Medicinal Chemistry, 2017, Vol. 17, No. 7 Nabavi et al.
Table 1. Studies investigating the effect of melatonin on respiratory diseases.
Studied model
Disease
Main findings
References
Human
Syncytial virus infection
Mitigation of infection-induced oxidative stress and lung inflammation.
Inhibition the pro-inflammatory cytokines.
[274]; [275]
Human
Cystic fibrosis
Improved sleep quality and decreased nitrite level in exhaled breath con-
densate
[276]
Human
Respiratory distress syn-
drome in preterm infants
Reduced oxidative stress, inhibited the increase of pro-inflammatory cyto-
kines and lowered nitrite/nitrate levels.
[284]; [285]
Human
Female asthmatic patients
Improved sleep quality.
[300]
Human
Chronic obstructive pulmo-
nary disease
Ameliorated oxidative stress and improved dyspnea. Improved sleep quali-
ty, sleep latency, sleep efficacy, and sleep duration No effects on lung
function and the exercise capacity.
[309]; [310]; [311];
[311]
Human
Advanced non-small lung
cancer
Increased the tumor regression rate, prolonged patient survival time, in-
creased the efficacy of chemotherapy and reduced of chemotherapeutic
toxicity.
[323]; [324]; [325];
[326]; [328]
Human
Inoperable lung cancer
No evidence of mitigation against myelotoxicity induced by carboplatin
and etoposide.
[327]
Human
Metastatic cancer patients
Decreased vascular endothelial growth factor secretion.
[330]
Rat
Pleurisy induced by carre-
genan
Reduced inflammation of pleura and increased mitochondrial function and
levels of NAD+ in macrophages
[277]
Rat
Bronchial asthma induced by
ovalbumin
Inhibited the expression of nuclear factor-kappa β and the inducible NO
synthesis.
Restored the airway inflammation and immunoglobulin E levels.
[296]; [299]
Rat
Chronic obstructive pulmo-
nary disease
Reduced of airway oxidative stress, increased antioxidant enzymes and
mitigated histopathological abnormalities in the bronchial walls and lung
tissues.
[308]
Rat
Pulmonary hypertension
Pulmonary hypertension development was associated with the loss of the
vasorelaxant influence of melatonin.
[340]
Rat
Pulmonary arterial hyperten-
sion
Improved cardiac functions
[341]
Mice
Bronchial asthma induced by
ovalbumin
Suppression of airway inflammation via up-regulation of STAT4 gene.
Inhibition connective tissue growth factor expression and reduced mucus
area.
[297]; [298]
Cell culture
IMR90 normal lung cells and
A549 human lung cancer
cells
Preventive role against adverse effects of chemotherapy by inhibiting dox-
orubicin-induced cellular premature senescence.
[329]
fibrosis patients at both baseline and after melatonin treat-
ment. They found that although melatonin does not affect
isoprostane levels at low dose, it improved sleep quality and
decreases nitrite level in exhaled breath condensate in cystic
fibrosis patients [276].
Pleurisy is an inflammation of pleura, which is common-
ly caused by viral infections [277]. Cuzzocrea et al. [278]
studied the promising role of intraperitoneally administration
of melatonin at 15 mg/kg in carrageenan-induced pleurisy in
rat. They found that melatonin mitigated carrageenan-
induced pleurisy via decreasing of peroxynitrite formation,
myeloperoxidase activity, lipid peroxidation levels, and
DNA damage in the lung tissues as well as increasing in the
mitochondrial function and cellular levels of NAD+ in mac-
rophages [278]. In addition to these studies, there are numer-
ous scientific reports about the role of oxidative stress in
different types of lung infections such as influenza [279,
280], pneumonia [281], etc. Also, it has been reported that
lung infections are associated with the increasing in the lev-
els of different pro-inflammatory cytokines and chemokines
such as interleukin-6, interleukin-1beta, and TNFα in the
lung tissues [282, 283]. Therefore, it can be hypothesized
that melatonin may reduce the oxidative stress and inhibits
the increase of pro-inflammatory cytokines and chemokines
levels in the lung tissues and from this way reduces the se-
verity of lung infections [284, 285].

Melatonin and Respiratory Diseases Current Topics in Medicinal Chemistry, 2017, Vol. 17, No. 7 11
Asthma
Asthma is a highly prevalent and the most common long-
term inflammatory disease which affects airways mucosa via
activation of different inflammatory cytokines and chemo-
kines [9, 286]. Wheezing, breathless, coughing, tight chest,
and difficulty breathing are the most common symptoms of
asthma in patients [287]. It has been reported that the anti-
gen-specific T!helper cell type 2 has key role in the patho-
physiology of allergic asthma [288]. It has been shown that
targeting the T!helper cell type 2-driven airway inflamma-
tion emerges as new therapeutic strategy for treatment of
asthma [289]. Mast cells mediate an important role in or-
chestrating asthma through the production of a host of auta-
coid mediators, cytokines, and chemokines [290]. In asthma,
epithelial cells mediate a pivotal role in inducing the in-
flammation via activation of different cytokines (such as
SCF, TSLP), and chemokines which activate eosinophils
through CCR3 activation [291, 292]. During asthma, Th2
cells induce the inflammatory response via producing of IL-
4, IL-13, IL-5, and IL-9 [293]. According to statistical re-
ports, in developed countries, asthma affects 10% of people
[294]. Although the prevalence of asthma in developing
countries is lower than that of developed countries, it is in-
creasing rapidly [295]. Intraperitoneally administration of
melatonin at 10 mg/kg significantly inhibit the expression of
NF-κβ and down-regulate the inducible NO synthesis activi-
ty in the lung tissues, and also significantly reduce the NO
production in bronchoalveolar lavage fluid in an experi-
mental animal model of bronchial asthma [296]. They con-
cluded that melatonin may decrease the airway hyper re-
sponsiveness and inflammation in ovalbumin model of bron-
chial asthma [296]. Melatonin administration up-regulated
STAT4 gene expression in asthmatic mice leads to suppres-
sion of airway inflammation [297]. The same authors in a
later study found that the melatonin significantly inhibits the
expression of connective tissue growth factor and reduces
mucus area in ovalbumin model of asthmatic mice, with an
activity similar to that exerted by dexamethasone [298].
Wang et al. [299] also reported that there is a negative corre-
lation between CD4+CD25+ regulatory T/ CD4+T cell ratio
and eosinophil counts around the airway and also with the
bronchoalveolar lavage fluid total leukocytes counts. They
observed that CD4+CD25+ regulatory T/ CD4+T cell ratio
increased in the asthmatic rats and melatonin significantly
reduce the eosinophils in peripheral blood and around the
airway and bronchoalveolar lavage fluid total leukocytes
counts as well as serum immunoglobulin E in ovalbumin-
induced asthma in rat. They concluded that melatonin can
significantly restore the airway inflammation and immuno-
globulin E level via down-regulation of CD4+CD25+ regula-
tory T [299]. Moreover, Campos et al. [300] performed a
double-blind, randomized, placebo-controlled study on the
effect of 4 weeks consumption of melatonin at 3 mg on sleep
in 22 female asthmatic patients by employing Pittsburgh
sleep quality index (for sleep quality), the Epworth sleepi-
ness scale (for daytime somnolence), and spirometry (for
pulmonary function). They reported that melatonin con-
sumption significantly improved sleep quality in comparison
with the placebo group [300].
Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease (COPD) is known
as one of the most common lung disease and a leading cause
of death worldwide which affect 10% of people worldwide
[301, 302]. Its prevalence is influenced by lifestyle factors,
such as smoking [302]. In the industrial countries, COPD is
the fourth leading cause of chronic mortality [302, 303]. Ir-
reversible airflow obstruction is main characterstic of COPD
[304] and is associated with lung inflammation induced by
toxic materials as well as gases [12]. Tobacco smoking and
burning biomass are the most important risk factors of
chronic obstructive pulmonary disease [305]. Major breath-
ing-related symptoms of chronic obstructive pulmonary dis-
ease are chronic coughing (associated with large amount of
mucus), wheezing, chest tightness, exertional dyspnea, and
shortness of breath [306, 307].
Jun-wei [308] observed that intraperitoneal administra-
tion of melatonin at 10 mg/kg significantly reduced total
white blood cells, neutrophils, NO and malondialdehyde in
the bronchial alveolar lavage fluid and also decrease the
monocyte-macrophage ratio. He found that superoxide dis-
mutase and glutathione superoxide were significantly in-
creased in the bronchial alveolar lavage fluid of melatonin
treated rats and also reported that melatonin mitigates histo-
pathological abnormalities in the bronchial walls and lung
tissues [308]. He concluded that melatonin mitigates the de-
velopment of chronic obstructive pulmonary disease via re-
ducing of airway oxidative stress in experimental animals
[308]. De Matos Cavalcante et al. [309] performed a ran-
domized, double-blind, placebo-controlled study on the ther-
apeutic effects of melatonin in 36 patients who suffered from
COPD. They showed that 3 months of therapy with melato-
nin (3 mg) significantly reduce the level of8-isoprostane and
improve dyspnea in patients who suffered from chronic ob-
structive pulmonary disease [309]. However, De Matos Cav-
alcante et al. [309] showed that there is no significant differ-
ence between the melatonin effects on lung function and the
exercise capacity versus placebo group. They concluded that
the treatment with melatonin significantly ameliorates oxida-
tive stress and improves dyspnea and suggested that it can be
used for ameliorating the severity of COPD [309].
Another randomized, double-blind, placebo-controlled
trial study on 54 patients demonstrated that the treatment
with melatonin at 3 mg (1 hour prior to bedtime) significant-
ly improves sleep quality, sleep latency, sleep efficacy, and
sleep duration in the patients with chronic obstructive pul-
monary disease [310]. However, they found that there is no
significant therapeutic action on daytime sleepiness, lung
function and oxygenation in melatonin treated patients. Also,
Shilo et al. [311] performed a double-blind, placebo-
controlled study to find the promising effect of melatonin on
the sleep quality on 8 patients who suffered from COPD.
They found that the treatment with 3 mg of melatonin im-
proves sleep duration and sleep quality in patients [311].
Moreover, Nunes et al. [312] performed another randomized,
double-blind, placebo-controlled study to explore the effects
of melatonin on sleep in 30 patients with COPD. They
demonstrated that orally administration of melatonin at 3 mg
for 21 consecutive days significantly enhanced sleep quality,
sleep latency, sleep efficacy, and sleep duration in COPD

12 Current Topics in Medicinal Chemistry, 2017, Vol. 17, No. 7 Nabavi et al.
patients [312]. However, they also found that there is no sig-
nificant difference in daytime sleepiness, lung function and
functional exercise in melatonin treated patients [312].
Lung Cancer
Lung cancer is a highly prevalent form of cancer in both
sexes and is one of the leading causes of cancer-related
deaths worldwide [313]. It has been reported that genetic and
epigenetic factors (such as smoking, environmental pollu-
tion, etc.) play a crucial role in the initiation and develop-
ment of lung cancer [314]. Lung cancers are generally classi-
fied into two major types, including small-cell lung cancer
and non–small-cell lung cancer [315], with approximately
over than 85% being non–small-cell lung cancer [316]. Non-
small-cell cancer is classified into three groups, namely
squamous-cell carcinoma, adenocarcinoma, and large-cell
lung cancer [317]. Although there are numerous available
early diagnosis methods and effective therapeutic procedures
for lung cancer, it is usually detected at advanced stages and
therefore the treatment efficacy is low [318]. Despite the
treatment of lung cancer is a major health problem world-
wide; it can be improved via the finding of its exact molecu-
lar mechanisms as well as causative agents of this disease
[319]. There is a close correlation between smoking with
squamous-cell carcinoma and small-cell lung cancer [320,
321], however adenocarcinoma usually occurs in non-
smoking patients [322].
There are some studies that demonstrate the ameliorative
effect of melatonin on lung cancers, especially non-small
lung cancer [323-325]. Lissoni et al. [323] performed a ran-
domized clinical trial on the comparison of chemotherapy
alone (with three day consumption of cisplatin at 20 mg/m2
per day and three day consumption of etoposide at 100
mg/m2 per day) or chemotherapy plus orally consumption of
20 mg/day of melatonin on 70 patients who suffer from ad-
vanced non-small lung cancer. The authors reported that
melatonin significantly prolonged patient survival time and
concluded that concomitant consumption of melatonin may-
be useful for the increase of survival time in chemotherapy,
and also for the reduction of chemotherapeutic toxicity
[323].
Another randomized clinical trial by Lissoni et al. [326]
showed that immunotherapy including 6 days of subcutane-
ous administration of interleukin-2 at 3 million IU/day plus
orally administration of melatonin at 40 mg/day (started one
week prior to interleukin-2) was more effective than chemo-
therapy including cisplatin in 60 advanced non-small cell
lung cancer patients. Lissoni et al. [325] also performed a
randomized clinical trial to examine 5-year survival results
of chemotherapy alone (containing of cisplatin and etopo-
side) and the same chemotherapy and melatonin (orally ad-
ministered at 20 mg/day) on 100 non-small cell lung cancer
patients. They found that chemotherapy and melatonin sig-
nificantly increase the tumor regression rate and prolong
survival time in non-small cell lung cancer patients. They
also found that melatonin significantly increases the efficacy
of chemotherapy and so, concluded that chemotherapy plus
melatonin should be used as new therapeutic strategy for
non-small cell lung cancer [325].
Ghielmini et al. [327] examined the myeloprotective ef-
fect of melatonin against carboplatin and etoposide-induced
myelotoxicity on 20 lung cancer patients. According to their
double-blind randomized study, orally administration of
melatonin at 40 mg/day for 21 days does not provide mitiga-
tion against myelotoxicity induced by carboplatin and etopo-
side in lung cancer patients [327]. Fic et al. [328] reported
that melatonin significantly intensify the cytotoxicity of
doxorubicin in non-small cell lung cancer via decreasing cell
counts and intensifying the apoptosis in dose-dependent
manner.
Recently, Song et al. [329] reported that melatonin sig-
nificantly inhibits the doxorubicin-induced cellular prema-
ture senescence in IMR90 normal lung cells and A549 hu-
man lung cancer cells. In this study, melatonin does not af-
fect on doxorubicin-induced cell cycle arrest at G2/M phase
and down regulation of cdc2/cyclin B expression induced by
doxorubicin. Moreover, melatonin decreases the intracellular
levels of ROS which play an important role for cellular
premature senescence [329]. Also, they reported that melato-
nin significantly inhibits doxorubicin-induced mitochondrial
dysfunction. This investigation concluded that melatonin
have a preventive role against adverse effects of chemother-
apy [329]. Lissoni et al. [330] performed another clinical
trial to assess the anti-angiogenic effects of 20 mg/day of
melatonin for at least 2 months on metastatic cancer patients.
The serum levels of vascular endothelial growth factor,
which is one of the most important angiogenic factor in the
metastatic cancer patients was detected [330]. They observed
that melatonin decreases vascular endothelial growth factor
secretion and from this results they suggest that melatonin
can be used for inhibition and/or control of tumor growth in
cancer patients [330].
Pulmonary Vascular Diseases
Pulmonary vascular diseases are a class of diseases
which affect pulmonary blood circulation [331]. Pulmonary
hypertension is one of the most common pulmonary vascular
diseases which resulted from pulmonary arteries occlusion
[332]. In fact, pulmonary hypertension is caused by high
blood pressure in pulmonary arteries (≥25 mmHg at rest) and
vascular resistance and leads to right-sided heart failure and
from this way decreases life quality and increases mortality
rates [333]. Pulmonary embolism is another type of pulmo-
nary vascular diseases which is a blockage in one or more
pulmonary arteries [334]. Pulmonary embolism is induced
by a substance (emboli) which is traveled through blood-
stream [335]. Although pulmonary embolism is well known
causes of death, its diagnosis is very difficult and therefore it
is often undiagnosed [336]. Major symptoms of pulmonary
embolism are chest pain, shortness of breath, sudden cough,
rapid and difficult breathing, and palpitations [337].
Weekley [338] examined the effects of melatonin on
pulmonary and coronary circulation systems via study on
isolated vessels of experimental pigs. The biophysical re-
sponses of pulmonary and coronary circulation systems to
melatonin were determined and from this way, the authors
observed that melatonin induced a dose-dependent relaxation
in the pulmonary arteries and a dose-dependent contraction
in the coronary arteries. So, they concluded that melatonin

Melatonin and Respiratory Diseases Current Topics in Medicinal Chemistry, 2017, Vol. 17, No. 7 13
shows different activity in the pulmonary and coronary cir-
culation systems [338]. In another study, Weekley [339]
found that melatonin administration causes relaxation in the
isolated bovine pulmonary vascular systems and induces a
small contractile response in the isolated bovine bronchial
smooth muscle at dose-dependent manner. In this study,
melatonin treatment was hypothesized to affect the circadian
rhythm of lung function in the some lung diseases such as
chronic asthma [339]. Das et al. [340] performed an animal
study to examine the effects of chronic hypoxia on antihy-
pertensive activity of melatonin in the rat model of pulmo-
nary hypertension. In the rat pulmonary trunk, melatonergic
receptors were discovered and so the researchers reported
that NO pathway not involved in the melatonin effect on the
vasoreactivity of rat pulmonary artery. Also, they concluded
that there is an inverse correlation between the development
of pulmonary hypertension and vasorelaxant effects of mela-
tonin [340].
Recently, Maarman et al. [341] reported that melatonin
reduced cardiac dysfunction in monocrotaline-induced pul-
monary arterial hypertension. They founded that daily con-
sumption of melatonin at 75ng/L, 4x106ng/L or 6x106ng/L
for the 28 days, significantly decreased fractional shortening
in male long Evans rats. Maarman et al. [341] concluded that
melatonin improves cardiac functions in the rat model of
pulmonary arterial hypertension and also suggested that mel-
atonin can be served as a new therapeutic strategy for pul-
monary arterial hypertension.
Although the therapeutic role of melatonin for treatment
of pulmonary embolism not has been assessed till now, it can
be hypothesized [341]. In fact, pulmonary embolism is asso-
ciate with the increase in the matrix metalloproteinase-2
(MMP-2) and matrix metalloproteinase-9 (MMP-9) [342,
343] and expression of CXC and C-C chemokines genes in
the lung tissues [344, 345]. Also, it has been reported that
pulmonary embolism significantly increases the level of
malondialdehyde [346], ROS [347], myeloperoxidase en-
zyme [348] and decreases the levels of reduced glutathione
and plasma protein sulfhydryl groups [347]. Inasmuch as the
role of melatonin on the regulation of inflammation-related
genes, especially the CXC and C-C chemokines [349] as
well as matrix metalloproteinase-2 and matrix metallopro-
teinase-9* [350], it can be hypothesized that melatonin can
improve lung function in pulmonary embolism. On the other
side, melatonin is a well-known antioxidant agent [244]
which can mitigates pulmonary embolism-induced oxidative
stress in lung tissues.
CONCLUSION
Melatonin has positive effects on the mitigation of
abovementioned lung diseases i.e. asthma, lung infection,
lung cancer, COPD, and pulmonary vascular disorders. Mo-
lecularly, melatonin mitigates lung diseases via its antioxi-
dant actions and regulation of inflammation-related genes
and profibrotic cytokines and chemokines in lung tissues,
which have pivotal role in pathophysiology of lung diseases.
In the lung infections, the melatonin ability as a potent
antioxidant and anti-inflammatory agent has key roles in the
mitigation of oxidative stress and the excessive production of
pro-inflammatory cytokines and chemokines in lung tissues.
In the case of asthma, melatonin improves lung functions via
mitigation of the airway inflammation as well as restoration
of immunoglobulin E level through down-regulation of
CD4+CD25+ regulatory T. Also, it can be hypothesized that
melatonin reduces the severity of chronic asthma via inhibi-
tion of different pro-inflammatory cytokines and chemokines
such as IL-4, IL-5, IL-13, as well as IL-9. In COPD, it has
been well shown that there is systemic oxidative stress and
from this way, antioxidant therapeutic targets are suggested
for the improvement of lung function in COPD patients. In
lung cancer, melatonin reduces the adverse effects of chemo-
therapy and anticancer drugs and also mitigates oxidative
stress in lung tissues. It has been well documented that mela-
tonin suppresses vascular endothelial growth factor secretion
in the patients with lung cancer. In the case of pulmonary
vascular diseases, melatonin reduces the severity of these
diseases via its anti-inflammatory and inhibitory actions on
the expression of pro-inflammatory cytokines and chemo-
kines such as CXC and C-C chemokines and also reduction
of MMP-2 and MMP-9 expressions in the lung tissues. Also,
the antioxidant activity of melatonin has promising effect on
pulmonary vascular disorders.
The below recommendations are important for future
studies about the utilization of melatonin for the treatment of
lung diseases.
• It can be recommended that people with lung diseases
should use melatonin and melatonin-rich foods such as
rice, banana, pineapple, orange, cherries, etc.
• More basic and clinical studies on the anti-infective ef-
fects of melatonin against different types of lung infec-
tions are needed.
• More basic and clinical studies aimed to find the exact
mechanisms of the ameliorative effects of melatonin in
the different types of lung cancer should be performed.
• More clinical studies aimed to ascertain the best effective
dose for amelioration of lung diseases are needed.
• It can be recommended that melatonin should be used for
the treatment of pulmonary embolism.
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
Declared none.
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PMID: 27558675