Immunology and Cell Biology (2001) 79, 170–177
Special Feature
New insights into the role of zinc in the respiratory epithelium
A I Q T RU O N G - T R A N , J OA N N E C A RT E R , R I C H A R D RU F F I N a n d P E T E R D Z A L E W S K I
Department of Medicine, University of Adelaide, The Queen Elizabeth Hospital, Woodville, South Australia,
Australia
Summary Over the past 30 years, many researchers have demonstrated the critical role of zinc (Zn), a group IIb
metal, in diverse physiological processes, such as growth and development, maintenance and priming of the
immune system, and tissue repair. This review will discuss aspects of Zn physiology and its possible beneficial role
in the respiratory epithelium. Here we have detailed the mechanisms by which Zn diversely acts as: (i) an antioxidant; (ii) an organelle stabilizer; (iii) an anti-apopototic agent; (iv) an important cofactor for DNA synthesis;
(v) a vital component for wound healing; and (vi) an anti-inflammatory agent. This paper will also review studies
from the authors’ laboratory concerning the first attempts to map Zn in the respiratory epithelium and to elucidate
its role in regulating caspase-3 activated apoptosis. We propose that Zn, being a major dietary anti-oxidant has a
protective role for the airway epithelium against oxyradicals and other noxious agents. Zn may therefore have
important implications for asthma and other inflammatory diseases where the physical barrier is vulnerable and
compromised.
Key words: anti-oxidant, epithelium, inflammation, respiratory, zinc.
Zinc
There have been numerous reviews focusing on the importance of vitamin C, vitamin E and selenium for respiratory
diseases such as asthma, but limited studies are available on
the role of dietary zinc (Zn). This paper will attempt to
review the current state of knowledge, while also proposing
the possible importance of Zn in the context of the respiratory system.
Zinc is a group IIb dietary metal required for the healthy
functioning of the body. The Australian recommended dietary
intake of Zn is approximately 12 mg/day and this is obtainable from protein-rich foods, such as red meats, seafood,
fresh fruit and vegetables, and dairy products. Over the past
30 years, many researchers have demonstrated the critical
role of Zn in a variety of physiological processes, including
growth and development, maintenance and priming of the
immune system and tissue repair and regeneration.1
As Zn is the most widely used biometal in biology, it can
be found in all organs, secretions, fluids and tissues of the
body and is transported via albumin in the circulation.1 Zinc
possesses two main properties, which make it an ideal participator in biological systems. First, Zn is virtually non-toxic
as the homeostatic mechanism by which it is regulated is so
efficient that no chronic disorders are known to be associated
with excessive accumulation.2 Second, its physical and chemical properties enable it to interact with a variety of enzymes
and other proteins that participate in cellular metabolism as
well as in the control of gene transcription.3
Correspondence: AQ Truong-Tran, Department of Medicine,
University of Adelaide, The Queen Elizabeth Hospital, Woodville,
South Australia 5011, Australia.
Email: [email protected]
Received 10 October 2000; accepted 10 October 2000.
In the body Zn exists in two main states: (i) a bound form
that is held on to tightly by metalloproteins and Zn finger
proteins; and (ii) a more loosely bound labile form that
participates in intracellular Zn fluxes and is readily depleted
in Zn deficiency. Although all organs contain labile intracellular Zn, the following tissues are particularly labile Zn
rich: hippocampus, testis and secretory cells (e.g. pancreatic
β cells and mast cells).4
Respiratory epithelium
The respiratory epithelium is a complex and highly-regulated
inert barrier separating the human airway from the external
environment and is therefore constantly exposed to a variety
of exogenous agents (e.g. allergens, inhaled pollutants and
viruses) capable of initiating an inflammatory reaction.
Although this epithelium is fundamentally a protective
barrier, one of its important roles is to produce cytokines,
growth factors, nitric oxide, matrix metalloproteinases and
many pro- and anti-inflammatory substances.5 Hence the
potential for enhanced oxidative stress, due to the involvement of the epithelium in airway inflammation and continual
exposure to exogenous environmental agents, is greatly
enhanced in this tissue.6
Airway epithelial damage has been well reported in allergic diseases, such as asthma, where tissue injury leads to
epithelial desquamation and shedding. This is due to the
recruitment and activation of inflammatory cells, such as the
eosinophils, mast cells and neutrophils, which release tissuedamaging proteases, chemotactic cytokines and toxic reactive
oxygen species thereby exacerbating the allergic response.5
Why zinc may be beneficial for the respiratory tract
Zinc has been shown to be vital as an anti-oxidant, microtubule stabilizer, anti-apoptotic agent, growth cofactor and
Zinc and the respiratory epithelium
171
Figure 1 Zinc in the respiratory
epithelium. a) Potential target sites
for the beneficial effects of Zn in
the respiratory epithelium. This
image outlines some of the possible beneficial roles of Zn for the
respiratory epithelial cells. Zinc is
protective by virtue of being an
anti-oxidant, organelle stabilizer
and possessing anti-apoptotic
activity (as an inhibitor of caspase3 activation). Other important
functions include stimulation of
DNA synthesis and cell proliferation, tissue regeneration and
acting as an anti-inflammatory
agent. Finally, the demonstration
of Zn in cilia may indicate a hitherto unexpected role for this metal
ion in cilial function. b) Visualization of Zn in ciliated airway
epithelial cells. Left panel shows a
bright field UV laser confocal
image of two sheep tracheal ciliated cells and the right panel
shows the corresponding Zinquin
fluorescence demonstrating the
abundance of Zn in the apical
cytoplasm and cilia. BB, basal
bodies.
anti-inflammatory agent in a variety of tissues. We propose
that Zn is important in respiratory tract tissue as a cytoprotectant against toxins and inflammatory mediators in a similar
way to that reported for the endothelium.7,8 Figure 1 describes
the potential roles of Zn in the respiratory epithelium.
Zinc as an anti-oxidant
Zinc has been shown to be an important anti-oxidant as excellently reviewed by Powell,9 and this is best demonstrated in
animal studies where there is increased susceptibilty of
organs, such as the lung,10 liver11 and testes,12 to oxidative
injury in Zn deficient animals. Recent studies in a rat model
of Zn deficiency reported enhanced epithelial lesions in the
gastrointestinal epithelium, which were blocked by a nitric
oxide synthase inhibitor.13 Similar studies need to be performed in the conducting airways to determine if Zn is indeed
essential for maintaining the integrity of the airway epithelium and for providing protection in oxidative stress. This is
particularly important as oxidative stress is greatly increased
in the respiratory epithelium as a consequence of inflammation, exogenous exposure and leakage from actively respiring
mitochondria.14
Zinc can act as an anti-oxidant by a number of mechanisms, which may also be important in the respiratory
system. First, Zn ions can directly act as an anti-oxidant by
stabilizing and protecting sulfhydryl-containing proteins that
are important in lung function (e.g. ciliary tubulin, alany
transfer RNA (tRNA) synthetase and Zn finger transcription
factors). Zinc may protect these proteins from thiol oxidation
and disulphide formation. Zinc can stabilize sulfhydryl
groups by: (i) binding directly to the sulfhydryl groups;
(ii) binding to another protein site in close proximity to the
sulfhydryl groups and producing a steric hindrance to
oxyradicals; or (iii) binding to another site on the protein
resulting in a conformational change that results in a reduction in sulfhydryl reactivity.9 Second, Zn can displace Fe and
Cu from cell membranes and proteins,15 which can otherwise
cause lipid peroxidation and destruction of membrane protein
lipid organization due to their ability to promote the generation of hydroxyl ion (.OH) from H2O2 and superoxide via the
Fenton reaction.16 This is important as Zn has only one oxidation state (II) and therefore cannot undergo these redox
reactions. In addition, Zn can accept a spare pair of electrons
from oxidants, hence neutralizing their reactivity.17 Third, Zn
acts indirectly by inducing production of the anti-oxidant
172
AQ Truong-Tran et al.
metallothionein.18 Metallothionein can also release Zn under
high oxidative stress, which it can contribute to the antioxidant defense system.19 Finally, Zn is an important component of the major anti-oxidant enzyme Cu–Zn superoxide
dismutase (Cu–Zn SOD), which is found in the cytoplasm of
airway and alveolar epithelial cells. Cu–Zn SOD acts by
removing superoxide anions. Larsen and colleagues20
recently demonstrated the important protective effect of
Cu–Zn SOD in airway inflammation as transgenic mice with
elevated levels of Cu–Zn SOD in the lungs were found to be
more resistant to allergen-induced hyperresponsiveness than
their wild-type counterparts.
Zinc as a membrane and cytoskeletal stabilizer
In addition to its role as an anti-oxidant, Zn has other properties advantageous in cytoprotection as it can protect proteins and nucleic acids from degradation, while stabilizing
the microtubular cytoskeleton and cellular membranes.21
Similarly, Hennig et al.7 demonstrated the importance of Zn
in maintaining endothelial cell integrity and vascular barrier
function. Zinc may play a similar role in the respiratory
epithelium, which also acts as a physical barrier. Numerous
studies have reported that Zn deficiency alters the lipid
composition, enzyme activity and protein composition of the
plasma membrane skeleton thereby increasing membrane
permeability.21 Zinc is also important for tubulin assembly as
Zn deficiency causes disruption of microtubules.22 Therefore,
Zn may also be vital for maintaining the integrity and function of cilia in respiratory epithelial cells.
Zinc as an anti-apoptotic agent
Numerous in vivo studies have demonstrated the important
role of Zn in the regulation of apoptosis, noting an increase
in populations of apoptotic cells in a variety of tissues,
including the intestinal epithelium, skin, thymus, testis, retina
and pancreas, in Zn deficient animals.23 Similar increases in
apoptosis arose within the neuroepithelium of fetal rats
within 4 days of maternal Zn deficiency. This interfered with
neural closure and was associated with the presence of congenital abnormalities.24 Whether this applies in humans is not
known; however, one relevant study is that by Mori et al.25
who reported an increase in the apoptosis of keratinocytes
around vesicular lesions of patients with Zn deficiency.
Despite the extensive knowledge available there have been no
studies to date reporting on the susceptibility of the respiratory system to Zn deficiency induced apoptosis in vivo.
In vitro studies have advanced our understanding of the
biochemical mechanisms by which Zn deficiency triggers
apoptosis (Fig. 2). One of the earliest studies documenting
the involvement of Zn in suppressing apoptosis was performed by Cohen and Duke26 who found that Zn inhibited the
activity of Ca/Mg-dependent endonucleases responsible for
nuclear DNA fragmentation in thymocytes. Studies performed later, during the 1990s, found that micromolar concentrations of Zn were able to suppress the activation of
caspase-3 (see review by Truong-Tran et al.27). This is now
thought to be the principle mechanism by which Zn acts as an
anti-apoptotic agent. A possible mechanism by which Zn
suppresses caspase-3 activation includes the inhibition of
caspase-6. Caspase-6 not only cleaves the lamin proteins in
the nuclear membrane, inducing nuclear collapse, a distinguishing characteristic of apoptosis,28 but is also known to
cleave pro-caspase-3 into its activated form.29 Yet another
possible mechanism by which Zn suppresses apoptosis is by
increasing the B cell lymphoma-2 (Bcl-2)/Bax ratio, thereby
increasing the resistance of cells to apoptosis.30 Although
rates of apoptosis in different regions of the respiratory tract
have yet to be studied, it has recently been shown that total
caspase-3 protein by immunocytochemistry is much higher
in the bronchial epithelium compared to alveolar pneumocytes.31 Figure 2 is a schematic diagram summarizing the biochemical pathway of apoptosis and highlights the steps at
which Zn has been shown to have a suppressive effect.
Zinc is essential for DNA synthesis and cellular growth
Cell proliferation is important in the respiratory epithelium as
there is rapid cell turn over. Zinc is essential for DNA synthesis and cell growth and is therefore likely to be one of the
regulatory factors in airway cell homeostasis. One of the
most telling signs of Zn deficiency is growth retardation as
this metal is vital for pituitary growth hormone secretion and
function, and it is needed for hepatic insulin like growth
factor-1 (IGF-1). These requirements may be related to the
anorexia, decreased food intake and decreased growth,
observed in Zn deficient rats.32 Furthermore, MacDonald
et al.33 demonstrated that Zn is essential for IGF-1 mediated
stimulation of cell division. Thymidine uptake was greatly
enhanced when Swiss 3T3 cells were incubated with Zn in
combination with IGF-1, as compared to IGF-1 alone.
Some of the reasons why Zn is important for cell proliferation relate to its presence in the cell nucleus, nucleolus and
chromosomes, where it both stabilizes the structure of DNA
and RNA and acts as a vital cofactor of many enzymes
required for DNA and RNA synthesis (e.g. DNA polymerase,
RNA polymerase and reverse transcriptase). Zinc is also
important for Zn finger proteins, such as transcription factor
IIIA.34 Zinc finger proteins possess a folded domain in which
Zn binds to appropriately spaced cysteines and histidines
thereby facilitating the interaction between the transcription
factor and DNA specific sequences in the promoter/enhancer
regions of certain genes and promoting gene transcription.
Wound healing
Tissue damage to the respiratory epithelium can occur frequently as it is often exposed to toxic endogenous and exogenous substances resulting in varying degrees of damage,
from a slight enhancement of the epithelium’s permeability,
to a more drastic epithelial cell shedding or denuding of the
basement membrane. After an insult, the respiratory epithelium initiates a tissue-healing process that involves the rapid
re-epithelialization of the denuded area. Restoration of the
integrity of the epithelium is via the dedifferentiation, spread,
and rapid migration of the remaining viable epithelial cells
found at the edge of the wound over the denuded basement
membrane.35
The epithelium requires Zn and is sensitive to fluxes in
plasma Zn. Zinc deficient patients suffering poor healing of
skin lesions and wounds can be treated by increasing dietary
Zinc and the respiratory epithelium
173
Figure 2 Inhibitory effects of
Zn in apoptosis. There are many
input pathways that trigger cells
to die by apoptosis and these converge onto a central pathway that
is governed by the mitochondria
and associated proteins, such as the
anti-apoptotic B cell lymphoma-2
(Bcl-2) and the pro-apoptotic Bax.
The activation of caspases, a cysteine protease family of proteins,
results in the biochemical and
morphological characteristics of
apoptosis. Zinc is thought to act at
multiple sites by: (1) inhibiting
endonucleases responsible for
DNA fragmentation; (2) inhibiting
the activation of caspase-3 and 6,
the major executioner caspases;
and (3) increasing the Bcl-2 to
Bax ratio. CAD, calcium activated
DNase; P21, p21waf1/cip1 protein; Ps
flip, phosphatidyl-serine flip.
Zn intake or by the use of Zn-impregnated bandages. The
application of topical Zn to wounds and lesions produces
accelerated healing via enhanced re-epithelialization.1
Another study supporting the role of Zn in wound healing is
that of Cario et al.36 who found that physiological amounts of
exogenous Zn improved epithelial repair by promoting
intestinal epithelial wound healing at the initial step of
epithelial cell restitution.
The wound healing process in the respiratory epithelium
and other tissues is thought to be controlled by the upregulation of Zn dependent metalloproteinases (e.g. MMP-9 and
MMP-3).35 Metalloproteinases are responsible for the degradation of the extracellular matrix (i.e. collagenases,
stromelysins and gelatinases). These enzymes possess a catalytic mechanism that requires an active site Zn cation that
binds to a conserved histidine-containing domain.37
Anti-inflammatory effects of Zinc
Labile Zn plays a major role in the control of inflammation
via a number of mechanisms. First, many inflammatory
diseases, such as arthritis and asthma, are associated with
an increase in the inducible form of nitric oxide (NO)
synthase resulting in enhanced NO formation. Studies by
Abou-Mohamed et al.38 demonstrated that Zn is able to
inhibit lipopolysaccharide and interleukin-1β-induced NO
formation. Second, Zn is anti-inflammatory as it is also able
to inhibit the activation of NF-κβ, a transcription factor
implicated in the expression of many pro-inflammatory
genes. Zinc inhibits NF-κβ activation by blocking the phosphorylation and degradation of the inhibitory proteins ΙκΒ
and its multisubunit ΙκΒ kinase, essential reactions required
for the activation of NF-κβ.39
A switch from an initial cellular (Th1 predominance) to a
more humoral and more pro-inflammatory (Th2 mediated)
immune response is a feature of many inflammatory diseases,
such as asthma, rheumatoid arthritis and food allergies.40 The
same switch favouring the Th2 subset also occurs in Zn deficiency and can be reversed when patients are treated with Zn
supplements.41 This will be discussed later in the present
review in the context of a relationship between Zn deficiency
and asthma. Other mechanisms by which Zn may be antiinflammatory in the respiratory tract include: (i) blocking the
binding of leucocytes to endothelial cells via the interaction
between leucocyte associated antigen 1 and intercellular
adhesion molecule-1 (ICAM-1);42 (ii) blocking the docking
of human rhinovirus on ICAM-1 of somatic cells, thereby
preventing viral infections in the respiratory tract;42 and
174
Table 1
AQ Truong-Tran et al.
Comparison of Zinc-dependent Zinquin fluorescence in A549 and NCI-H292 malignant cell lines
Zinc Status
Basal Zn levels
Zn supplementation
Zn depletion
A549 cells
Zinquin fluorescence
(pixels)*
n
NCI-H292 cells
Zinquin fluorescence
(pixels)*
n
11.78 ± 0.28a
59.86 ± 1.61c
7.22 ± 0.26e
192
307
187
23.14 ± 2.18b
95.10 ± 3.32d
9.70 ± 0.74a
29
58
28
*Zinquin fluorescence is expressed as average pixels ± SEM. Cells were loaded with exogenous Zn using sodium pyrithione, a Zn ionophore,
and depleted of Zn using TPEN, a membrane permeable Zn chelator.46
a–e
Values that share the same alphabetical superscript are not significantly different at the 5% level of confidence.
Table 2
Relationship between Zinc and asthma
Serum Zn
(µg/dL)
Author
Goldey et al. 198455
Di Toro et al. 198756
el-Kholy et al. 199057
Kadrabova et al. 199658
Hair Zn
(µg/gm)
Control
Asthma
Control
Asthma
83
n=8
NA
84
n=8
NA
169
n = 21
147 ± 9
n = 19
88.4 ± 11.0
n = 20
70.3 ± 13.2
n = 22
P ≤ 0.001
80 ± 1
n = 22
P ≤ 0.05
194.5 ± 18.6
n = 20
160
n = 29
99 ± 6
n = 43
P ≤ 0.05
167.5 ± 23.0
n = 22
P ≤ 0.001
NA
89 ± 2
n = 33
(iii) inhibiting the release of preformed mediators from mast
cells and basophils (e.g. histamine)43 and eosinophils (e.g.
eosinophil cationic protein).44
Localization of zinc in the respiratory epithelium
Studies by our laboratory have reported the first attempts to
localize Zn in the cells and tissues of the respiratory system
and to study the biochemical role of Zn in regulating apoptosis.45 Levels and distribution of intracellular labile Zn, were
determined using a novel UV-excitable Zn-specific fluorophore Zinquin, which has previously enabled the imaging
of distinct pools of labile Zn in a range of cell types and
tissues.46–49 By using Zinquin we have reported45 that: (i) the
malignant bronchial epithelial cell line NCI-H292 had twice
the Zinquin fluorescence of the malignant alveolar cell line
A549 (Table 1); (ii) airway epithelial cells were relatively rich
in labile Zn when compared with alveolar epithelial cells in
cryostat sections; (iii) labile Zn lines the apical and lumenal
side of the entire length of the conducting airways; and (iv)
this Zn is especially concentrated in the mitochondrial-rich,
apical cytoplasmic region, immediately below the cilia of
primary tracheobronchial epithelial cells (Fig. 1b).
There are several reasons why airway epithelial cells have
higher basal levels of intracellular Zn compared to alveolar
epithelial cells. First, upper airway epithelial cells are more
likely to be challenged or damaged by foreign pollutants due
to their positioning. Hence these cells may require higher Zn
NA
levels for protection and cellular repair. Second, upper
airway epithelial cells possess mucin-secreting granules that
are rich in carboxylated glycosaminoglycans that are largely
acidic in nature and can trap more positively charged labile
Zn within granules. Finally, these cells have a more rapid turn
over rate and thus will require higher intracellular Zn levels
for Zn-dependent DNA synthesis.
Zinc suppresses caspase activation and apoptosis in
respiratory epithelial cells
In order to determine the importance of labile intracellular Zn
in the survival of respiratory epithelial cells we have previously investigated the role of this Zn in regulating oxyradicalinduced apoptosis.45 It is interesting to note that our observed
distribution of labile Zn in these cells closely matches that of
the inactive form of the major executioner enzyme in apoptosis, caspase-3, as detected by immunocytochemistry in
human tracheobronchial epithelium.31
The zinc status of malignant NCI-H292 and A549 and
primary ciliated airway epithelial cells from sheep was
manipulated using a membrane permeable Zn chelator TPEN
(N,N,N′,N′-tetrakis-{2-pyridylmethyl}-ethylenediamine),
which binds tightly to labile pools of Zn making it functionally Zn deficient, and the Zn ionophore sodium pyrithione,
which has a supplementary effect by transporting exogenous
Zn into cells. We have found that Zn is clearly an important
factor for the survival of these cells as chelation of labile Zn
Zinc and the respiratory epithelium
resulted in the rapid activation of caspase-3-like activity and
down stream events of apoptosis. Furthermore, in primary
sheep ciliated tracheal epithelial cells, H2O2 gave an increase
over the control in DEVD-caspase activity of 1.24 ± 0.12
units/µg protein/h; TPEN gave an increase of 0.52 ± 0.14
units/µg protein/h, while the two in combination gave a synergistic increase of 2.58 ± 0.53 units/µg protein/h (P ≤ 0.05).45
Hence Zn depletion not only results in the rapid activation of
caspase-3-like activity, but also greatly increases respiratory
epithelial cell susceptibility to oxyradical induced apoptosis.
Alternatively Zn supplementation via 1 µmol/L sodium
pyrithione and 25 µmol/L exogenous ZnSO4 resulted in a
59.3% inhibition of H2O2-induced DEVD-caspase activation
(P ≤ 0.005) and thus suppression of apoptosis in primary
sheep ciliated tracheal epithelial cells.45
Is zinc beneficial or detrimental for respiratory
diseases?
Excessive inhalation of zinc salts, such as zinc oxide, has
previously been implicated in causing metal fume fever, an
influenza-like illness that results from an acute or subacute
respiratory tract inflammation (mild interstitial pneumonia)
and is characterized by bronchial hyper-responsiveness,
myalgias and fever. If left untreated or undetected fume fever
can also lead to occupational asthma.50
In contrast brief exposures to zinc sulphate aerosols have
been shown to protect against allergic bronchoconstriction in
guinea pigs, possibly by blocking histamine release from
mast cells.51 Zinc has also been shown to directly decrease
the incidence of respiratory infections in young children from
developing countries. It has been reported that there was a
45% decrease in the incidence and prevalence of acute lower
respiratory infection in children of 6–35 months of age
receiving 10 mg of supplemental Zn daily.52
Similarly, Zn may be beneficial in reducing the severity of
symptoms of the common cold. However, there has been
conflicting data arguing the pros and cons of Zn lozenges in
the treatment of colds. One recent randomized, double
blinded, placebo-controlled study by Prasad et al.53 supportive of Zn, reported a shorter mean overall duration of cold
symptoms (4.5 vs 8.1 days), cough (3.1 vs 6.3 days), and
nasal discharge (4.1 vs 5.8 days) when compared with the
placebo group. It has been proposed that Zn acts by preventing viral docking, capsid formation and replication in the
respiratory epithelium.42,53 Several factors, such as the
dosage, route of administration and the form of Zn salts
given, may influence the outcome of whether Zn is good or
bad for the respiratory system. Another issue which needs to
be taken into account is whether certain diseases have an
underlying hypozincaemia, for example, in chronic inflammatory diseases such as rheumatoid arthritis39 and asthma.
This may influence the recovery rate when supplemented
with exogenous Zn.
Is there a relationship between asthma and zinc
deficiency?
The increase in prevalence of asthma is strongly dependent
on environmental factors including diet. Numerous studies
have suggested that significant decreases in the intake of
175
dietary anti-oxidants may be an important contributing factor
to the increasing incidence of asthma over the last three
decades.54
The first consistent study investigating the Zn status of
bronchial asthmatics was that of Goldey et al. in 198455
(Table 2) who reported a reduction in the Zn content of hair
in asthmatics, but due to a limited sample size these results
were not considered statistically significant. However in
1987, a larger study by Di Toro and colleagues56 reported a
significant decrease in Zn hair status in allergic and asthmatic
children, suggesting that asthmatic children were at risk of Zn
deficiency. Further adding to these findings, el-Kholy and
colleagues57 and Kadrabova et al.58 reported similar results,
but extended the observations to show a significant drop in
serum Zn levels. It was proposed that adequate dietary intake
and Zn supplementation may decrease the severity of asthmatic attacks by correcting this underlying hypozincaemia.57
Of particular relevance to Westernized countries, Schwartz
and Weiss59 conducted a large scale American study
(n = 9074) that found a negative relationship between wheezing and serum zinc:copper ratio. Furthermore, Soutar et al.54
investigated the relationship between allergic diseases and
dietary anti-oxidants and noted that there was an increase in
the presence of atopy, bronchial reactivity and the risk of
allergic-type symptoms in adults with the lowest intake of
dietary Zn.58
Despite these studies, the significance of these correlations between the severity of asthmatic symptoms and low Zn
levels is not yet fully understood. Hence, future studies are
required to fully appreciate the importance of varying Zn
status and its effect on the clinical symptoms and pathological changes noted in asthma.
Possible mechanisms of zinc deficiency in asthma
While acknowledging that dietary changes over the past
several decades have resulted in a decreased intake of fresh
foods containing anti-oxidants, we propose that several
intrinsic factors may contribute to a low Zn status in asthmatics. First, like other inflammatory diseases, a redistribution in plasma Zn to the liver can occur during excessive
stress. This has been attributed to the release of leucocyte
endogenous mediator from activated phagocytes, which then
stimulates movement of Zn from plasma to hepatocytes in
allergic reactions.57 Second, the immune system is extremely
dependent on the availability of Zn for maintaining its
homeostasis. Inflammatory diseases can cause an increase in
the demand for Zn as: (i) Zn is essential for producing the
thymic hormone thymulin necessary for regulating T-cell
development and activation; and (ii) Zn is crucial for the
activation of natural killer cells, phagocytic cells and for
granulocytes, such as mast cells and eosinophils.60 As a
result, greater demand for Zn by the immune system could be
a contributing factor to the Zn deficiency noted in inflammatory diseases. Zinc deficiency itself is detrimental for
inflammation as it results in dramatic increases in the
number, size and activation state of mast cells.60 This further
exacerbates damage via increasing chemotaxis of eosinophils
and neutrophils, which creates a continuous cycle of oxidative damage. Zinc deficiency can also cause a premature
switch from the Th1 dependent cellular immune response to
176
AQ Truong-Tran et al.
a Th2 dependent pro-inflammatory humoral response.41 This
shift in the Th1/Th2 balance promotes enhanced levels of
IL-4, IL-5, leukotriene B4 (LTB4) and prostaglandin E2
(PGE2) release, all of which have been implicated in promoting the pathogenesis of allergic diseases such as asthma.60
Third, although reactive oxygen species are formed as a
normal component of cellular respiration, in asthma there is
a reported imbalance between the flux of oxidants generated
and the presence and/or activation of cellular anti-oxidant
defence mechanisms. This especially relates to Cu-Zn SOD,
which is normally required to detoxify superoxide anions.60
At least three studies have demonstrated a significant
decrease in Cu-Zn SOD activity in erythrocytes61 and respiratory epithelial cells.62,63 One possible explanation for the
decrease in activity of Cu-Zn SOD may be that in order for
the body to compensate for increased oxidative stress, it must
upregulate its anti-oxidant production, hence increasing its
need for biochemically active Zn. Therefore, if a hypozincaemia exists and tissue Zn becomes limiting during
inflammation, the activity of Cu-Zn SOD may be compromised. Finally, because the respiratory epithelial cells are rich
in Zn their loss, through shedding into the airways during
asthmatic episodes, will further deplete Zn reserves.
Conclusions
This review has attempted to integrate the available information concerning Zn physiology and the structure and function
of the respiratory system, an area which to date has been
poorly studied. The advent of new technologies, such as the
visualization of labile pools of Zn by Zn fluorophores, will
enable new insights into the functionality of Zn in the respiratory tract, and its relevance to inflammatory diseases such as
asthma. We believe that a full understanding into the relevance of Zn for the respiratory system can only be achieved
once this information is acquired. Analogies can be drawn
with the gastrointestinal system where Zn has been clearly
shown to have protective effects against ulcers, diarrhoea and
mucosal damage.13
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