Amina
Hamed Ahmad Al Obaidi
Abdul Ghani Mohamed
Al Samarai
Departments of
Biochemistry and Medicine
Tikrit University College of Medicine,
Tikrit, IRAQ
Email: aminahamed2006@yahoo.com
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ABSTRACT
Concurrent with the
use of acetaminophen, a large increase
in asthma, particularly in the pediatric
population, has been reported. The
impact of therapeutic doses of paracetamol
on serum total antioxidant capacity
(TAC) and malodialdehyde (MDA) levels
were studied in asthmatic patients.
A total of 43 asthmatic patients were
enrolled in the study; 24 of them
were afebrile and not receiving acetaminophen,
and 19 were febrile and received acetaminophen
3 gm / day from 0 - 7 days and 3 gm
/ day on 10th and 14th days. TAC serum
mean was significantly lower in asthmatic
patients receiving acetaminophen than
that in asthmatics not receiving the
drug and the control group. In contrast,
MDA mean serum level was significantly
higher in the asthma group receiving
acetaminophen than that in asthmatic
patients not receiving the drug and
the control group. Acetaminophen usage
led to a significant reduction in
FEV1 in asthmatic patients more than
in the control group and asthmatic
patients not receiving acetaminophen.
The above antioxidant activity of
acetaminophen was corrected following
administration of N acetylcystine.
In conclusion, acetaminophen usage
leads to a reduction in serum TAC
and an increase in lipid peroxidation
and consequently this oxidative stress
contributes to asthma progression
and decrease in lung function. N-acetylcystine
administration may restore these changes.
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The prevalence of asthma
in the United States has risen by 75% in
the last 3 decades, with a particularly
marked increase in children < 5 years
of age (160%). [1] The reason for the surge
in prevalence is unclear. A number of hypotheses
have been proposed, including increased
environmental exposures to "synthetic"
materials and indoor allergens, decreased
exposure to bacteria and childhood illnesses
(the "hygiene" hypothesis), the
increasing prevalence of obesity, changes
in diet and antioxidant intake, increased
exposure to cockroaches, changing meteorological
patterns, and decreased use of aspirin [2-8].
In addition, cytokine imbalance or dysregulation
occurring as a result of environmental exposures
during infancy and early childhood is hypothesized
to induce lifelong T-helper type 2 (allergic)
dominance over T-helper type 1 (nonallergic)
responses. T-helper type 2 dominance increases
the risk for atopic diseases, including
asthma. While most studies have focused
on the effects of these factors after birth,
some have suggested sensitization in utero
[6,7,9].
A link between acetaminophen
and bronchoconstriction was originally suggested
in a case report of an aspirin-intolerant
patient as early as 1967 by Chafee and Settipane
[10]. Recently, with the rise in asthma
prevalence, there has been renewed interest
in the role of acetaminophen [11]. Concurrent
with the use of acetaminophen, a large increase
in asthma, particularly in the pediatric
population, has been reported [11].
Various epidemiologic
and quasi experimental studies have suggested
a link between both therapeutic and overdose
ingestion of acetaminophen and bronchoconstriction
in certain individuals. Across European
countries, asthma rates ecologically associated
with acetaminophen use [12], have also been
seen at the individual level. In a large
population-based, case-control study [13]
of young adults, daily and weekly use of
acetaminophen was strongly associated with
asthma. The relationship was much stronger
for severe asthma. Aspirin avoidance did
not appear to account for the positive results,
as the association was found in those taking
only acetaminophen as well as in those taking
both analgesics.
A report found that increased
frequency of acetaminophen use in 1990 to
1992 was associated with a subsequent risk
of physician diagnosis of new-onset asthma
diagnosed between 1990 and 1996 [14]. The
risk of wheezing was increased twofold in
30-to 42-month-old children whose mothers
frequently used acetaminophen prenatally
during weeks 20 to 39 of gestation [15].
N-acetylcystine (NAC),
a precursor of reduced glutathione (GSH),
has been in clinical use for more than 30
years, primarily as mucolytic. In addition
to its mucolytic action, NAC is being studied
and utilized in conditions characterized
by decreased GSH or oxidative stress [16].
Because of its hepato-protective activity,
intravenous and oral administration of NAC
have been used extensively in the management
of acetaminophen poisoning [17].
NAC exhibits direct and
indirect antioxidant properties. Its free
thiol group is capable of interacting with
the electrophilic groups of ROS [18].
NAC reduced H2O2-induced
damage to epithelial cells in vitro [271]
and NF-kB activation in some cells [19].
In addition to its effects on PMNs, NAC
also influences the morphology and markers
of oxidative stress in red blood cells (RBCs)
[20]. Treatment with NAC may alter lung
oxidant/antioxidant imbalance and reduced
O2·- production by alveolar macrophages
and decreased BALF PMN chemiluminescence
in vitro [21]. Treatment with NAC resulted
in a considerable reduction in elastase
activity, in both the bronchoalveolar cavity
and plasma, related to its property of scavenging
HOCl [18].
Bleas et al [22] reported
that Oral NAC exerts an antioxidant protective
effect and attenuates pulmonary inflammation
induced by antigen exposure in experimental
asthma. In addition, oxidative stress stimulates
mucin synthesis in airways, a process that
is inhibited by NAC [23]. It has been reported
that oral NAC reduces BHR to 5- hydroxytriptamine
and the augmented eosinophil numbers elicited
by allergen exposure in actively sensitized
rats [22].
Enhancement of antioxidant
defense mechanisms, therefore, seems a rational
therapeutic option. Antioxidant therapy,
including NAC, has been reported to be useful
in the treatment of acute lung injury [24].
Understanding of the key elements of the
redox control mechanism of IL-1B induced
eotaxin and MCP-1 expression and production
by HASMC, may indicate a new strategy in
controlling airway inflammation [20,25].
Bleas et al [22] study provides some in
vitro evidence that NAC, an antioxidant
agent that has been used for many years
as mucolytic drug, could also be useful
in the treatment of more chronic inflammatory
diseases such as asthma. It is not known,
at the present time, whether NAC is capable
of producing a beneficial effect in controlling
the airways inflammation in-vivo. However,
if NAC, a relatively harmless molecule,
is able to exert an anti-inflammatory effect,
this can be used in combination with existing,
potent, but potentially more harmful , drugs.
This hypothesis, however, needs further
investigation [26]. Oxidative stress may
increase the risk of asthma, contribute
to asthma progression and decrease lung
function. Previous research suggests that
use of acetaminophen, which hypothesized
to reduce antioxidant capacity in the lung,
is associated with an increased risk of
asthma. The above research outcome measures
were epidemiological and clinical parameters.
The purpose of this study was to evaluate
the effect of acetaminophen on serum total
antioxidant capacity and lipid peroxidation
and the protective effect of N -acetylcystine
in asthma. The study was approved by the
ethics committee of our college, and written
consent was obtained from all participating
subjects.
Study Population:
The impact of therapeutic doses of paracetamol
(BP 500 mg tablet, SDI, Samara) on serum
total antioxidant capacity and malodialdehyde
levels, were studied in asthmatic patients.
A total of 43 asthmatic patients were enrolled
in the study; 24 of them were afebrile and
not receiving acetaminophen, and 19 were
febrile and received acetaminophen 3 gm/
day from 0 - 7 days and 3 gm / day on 10th
and 14th days. Venous blood samples collected
from all patients in the two groups on day
15th of their enrollment in the study. Serum
TAC and MDA were determined and compared
between the two groups and to healthy control
findings. N acetylcystine ( BP 600 mg tablet.
Azupharma, GmbH, Germany),
a drug with antioxidant properties, was
investigated for its beneficial therapeutic
effects in preventing oxidative stress induced
by acetaminophen in asthma. Thus the drug
was given in a dose of 600 mg twice daily
for 4 weeks to the above two groups and
at the end of treatment course serum collected
for determination of TAC and MDA.
The subjects included
in the study were outpatients from the Asthma
and Allergy Centre or Samara General Hospital
outpatients Clinic. The diagnosis of asthma
was performed by specialist physician and
was established according to the National
Heart Blood and Lung Institute / World Health
Organization (NHLBI/WHO) workshop on the
Global Strategy for Asthma [27]. Patients
were excluded if they were smokers, if they
had respiratory infection within the month
preceding the study, a rheumatological illness,
malignancy, diabetic, heart failure, history
of venous embolisms, coronary heart disease
and liver or kidney disease.
At enrollment, they all
underwent full clinical examination, pulmonary
function test, and blood sampling. Normal
volunteers were also enrolled in the study
as a healthy control. None of them had any
previous history of lung or allergic disease
and were not using any medication. They
had a normal lung function test (FEV1 >
80%) and negative skin allergy test. General
stool examination was performed for all
patients and control to exclude parasitic
infections. The sampling was performed during
the period from May 2004 to December 2005.
All samples were collected at morning following
overnight fasting.
The study was approved
by the ethics committee of our college and
written consent was obtained from all participating
subjects.
Determination of Total
Antioxidant Capacity (TAC):
The method for serum TAC determination was
as previously described by Kampa M et al
[28]. In brief, in each tube 400 µl
of crocin and 200 µl of serum sample
were pipetted. The reaction was initiated
with the addition of 400 µl of prewarmed
(370C) ABAP (5 mg/ml), and crocin bleaching
was made by incubating the plate in an oven
for 60 - 75 minutes. Blanks consist of crocin,
serum samples and phosphate buffer (400,
200, 400 µl respectively) were run
in parallel. The absorbance was measured
at 450 nm. A standard curve of the water
soluble synthetic antioxidant Trolox, prepared
prior to use, ranging from 0 - 10 µg/ml
was equally assayed under the same conditions.
Determination of Malodialdehyde:
As the index of lipid
peroxidation, serum MDA concentration was
determined by measuring the thiobarbituric
acid reactive substances (TBARS) according
to the spectrophotometric method of Janero
[29]. The TBARS was determined using OXITEK
TBARS Assay kit from Zeptometrix Company.
A 100 ul of sodium doedecyl
sulfate was added to the tubes that contain
either serum sample or standard and mixed
thoroughly. Then 2.5 ml of thiobarbituric
acid/ buffer reagent was added down the
side of each tube. The tube was covered
and incubated at 95 o C for 60 minutes.
The tube was then removed and cooled to
room temperature in an ice bath for 10 minutes.
After cooling the samples centrifuged at
3000 rpm for 15 minutes. The supernatant
was removed from samples for analysis. The
absorbance of supernatant was measured at
532 nm. Determination of MDA equivalent
in µmol/ l in samples was by interpretation
from standard curve.
Lung Function Test:
Computerised spirometer (Autosphiror, Discom-14,
Chest Corporation, Japan) was used for measurement
of FEV1 of the patients at their enrollment
in the study and when indicated according
to study design.
Statistical Analysis:
The values are reported as mean +/- SD and
95% confidence interval. For statistical
analysis between groups paired t test was
used. Pearson test was used for correlation
analysis. The levels of each marker were
compared between the study groups and control
group, using SPSS computer package. P values
of < 0.05 were considered significant.
TAC serum mean was significantly
lower in asthmatic patients receiving acetaminophen
(623 ± 216 µmol/l) than that
in asthmatics not receiving the drug (876
± 253 µmol/l; P< 0.005)
and control group (1074 ± 207 µmol/l;
P<0.0001)( Table 1).
MDA mean serum level was significantly higher
in the asthma group receiving acetaminophen
(7.23 ± 2.82 µmol/l) than that
in asthmatic patients not receiving the
drug (4.39 ±1.84 µmol/l; P<0.005)
and control group (2.24 ± 0.26 µmol/l;
P<0.0001). Acetaminophen usage led to
a significant reduction in FEV1 in asthmatic
patients (82 ± 6) more than in control
group (101±5; P<0.005) and asthmatic
patients not receiving acetaminophen (96
± 4; P<0.0001). (Table
1)
Thus acetaminophen usage
leads to reduction in serum TAC and increase
in lipid peroxidation and consequently this
oxidative stress contributes to asthma progression
and decrease in lung function. The oxidation
index was 11.61 in asthmatic patients receiving
acetaminophen and this was double that in
asthmatic patients not receiving the drug
(5) and about 6 times that of control group.
The chronic ingestion
of therapeutic doses of acetaminophen depletes
serum antioxidant capacity in asthmatic
patients as this study indicated. NAC has
antioxidant properties and was used effectively
for treatment of acetaminophen poisoning.
Thus in this study we investigated a possible
beneficial effect of NAC when combined with
acetaminophen in asthmatic patients. The
drug was given in a dose of 600 mg twice
daily for the previous two asthmatic groups
for 4 weeks and after that TAC and MDA were
measured (Table 2). The
results indicated that NAC led to a significant
increase in TAC (P<0.05) following the
treatment course in asthmatic patients not
receiving acetaminophen (986 ±118
µmol/l). However, the increase in
TAC serum levels was with higher significance
(P<0.025) in asthmatic patients group
receiving combined acetaminophen and NAC
(804 ± 294 µmol/l).
MDA serum levels decreased
significantly (P<0.0005) in asthmatic
groups receiving acetaminophen and NAC (4.62
± 1.14 µmol/l). However the
use of NAC by asthmatic patients not receiving
acetaminophen led to decrease of serum MDA,
but with lower significance (P<0.05).
Another interesting finding in this study
was that NAC led to significant increase
in FEV1 (P<0.0001) in asthmatic patients
receiving cetaminophen combined with NAC.
Oxidative index reduced to half (5.75) following
treatment with NAC in the acetaminophen
receiving group. However, NAC improved significantly
FEV1 (P<0.001) in asthmatic patients
not receiving acetaminophen. Thus NAC administration
to asthmatic patients effectively restores
serum TAC and MDA to nearly normal levels.
Therefore we suggest the use of combined
therapy of acetaminophen and NAC to reduce
the impact of acetaminophen on antioxidant
defense in asthmatic patients.
Asthma prevalence has
increased dramatically since the 1970s and
currently affects 5-8% 0f the population
[1]. Concurrent increases in asthma related
to hospitalization and mortality suggest
that the change in asthma prevalence did
not result from greater diagnosis and detection
alone [27], although, asthma related hospitalization
and mortality appear to have declined since
1995 with the more widespread use of inhaled
corticosteroids [30].
Various hypotheses have
been proposed to explain the rise in asthma
prevalence, including those relating to
changes in early life antigen exposure [31]
and to the obesity epidemic [32,33]. The
rise in the prevalence and severity of asthma,
however, also coincided with a large increase
in the use of acetaminophen in the 1970s
and 1980s [9].
This substitution of
acetaminophen for aspirin was not evaluated
inrandomized trials [14]. By contrast, ibuprofen
was recently compared with acetaminophen
for pediatric febrile illness in a large
randomized, double blind clinical trial
[34]. Among the subgroup of 1879 children
with asthma, asthma related outpatient visits
were significantly lower in the ibuprofen
arm, and asthma hospitalization was non
significantly reduced compared with the
acetaminophen [34]. The trial did not include
a placebo control, therefore it is uncertain
whether ibuprofen decreased or acetaminophen
increased asthma morbidity. Alternatively,
the finding may have been due to chance
[35].
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An increase in asthma
risk related to acetaminophen use, was suggested
by a population based case control study [13].
The study was limited, however, by the case
control design in which the diagnosis of asthma
preceded ascertainment of acetaminophen use
[35]. Recently, analysis of data from prospective
study, examined if acetaminophen use was associated
with a new physician diagnosis of asthma among
participants not previously diagnosed with
asthma [35]. They reported that their findings
confirm and extend the findings of prior cross
sectional studies of asthma and acetaminophen
use . In a cross countries trial in Europe,consumption
of acetaminophen was ecologically associated
with the prevalence of wheeze, diagnosed asthma
and BHR [12]. In addition, to the ecological
findings, a population based, case controlled
study from UK showed a dose dependent relationship
between acetaminophen use and asthma [13].
The association was much stronger for severe
asthma. Aspirin use was equally common among
cases and control subjects. Although, aspirin
avoidance was slightly more common among cases
than the control subjects, the magnitude of
the difference in that study was not large
enough to explain the association of acetaminophen
and asthma. Acetaminophen use in late pregnancy
was associated with an increased risk of wheeze
among offspring [13,35].
A recently reported study
[15] is another development in the story
of how acetaminophen consumption may be
a potential risk factor for developing asthma
and atopy. The authors demonstrated a positive
association between acetaminophen use in
late pregnancy and subsequent asthma, wheezing
and elevated serum IgE antibodies in 6 year
old children. The data are consistent and
build upon earlier observation of the same
cohort demonstrating that frequent use of
acetaminophen in late pregnancy is associated
with increased risk of wheeze in the offspring
aged 3 years old [13].
Sheehan et al [15] adds
to the existing literature on acetaminophen
and asthma that has developed since the
report of the same research group in 2000
[13]. Another study reported from the USA,
which indicated that taking acetaminophen
for more than 14 days per month, had a 60%
greater risk of incident asthma than those
who never used acetaminophen [35]. Recently,
data from New Zealand again demonstrated
that current use of acetaminophen was associated
with two fold increase in the prevalence
of wheeze in children aged 6-7 years, with
a smaller increase in wheeze in children
who received acetaminophen in the first
year of their life [36].
Association between acetaminophen
consumption and asthma in adults may result
from aspirin avoidance, or from the use
of acetaminophen for asthma symptoms or
for symptoms arising from the use of asthma
medications [36]. The advantages of Sheehan
studies in which the association is between
maternal consumption and infant or child
symptoms is that these alternative explanations
are likely to operate [36]. Maternal asthma
or allergy may still confound the association,
as it may be associated with both asthma
in the child and preferential acetaminophen
use [36]. However, in the most recent study,
the relationship persists after adjustment
for maternal asthma [15].
All the above mentioned
studies that suggest a link between acetaminophen
use and development of asthma are epidemiologic
studies. To our knowledge, only one study
reported [37] that determines the effect
of regular intake of acetaminophen on serum
antioxidant capacity in healthy volunteers.
It reports that chronic ingestion of maximum
therapeutic doses of acetaminophen depletes
serum TAC in healthy volunteers in as few
as 14 days. It shows a trend toward reduced
TAC over time. Another study investigated
the effect of acetaminophen use on glutathione
and antioxidant status in febrile children
receiving repeated supra therapeutic doses
[38]. TAC of serum and erythrocyte glutathione
concentration were reduced in the group
receiving supra therapeutic acetaminophen
doses.
In the present study
the association between acetaminophen use
in asthmatic patients and changes in their
serum TAC and MDA as parameters of oxidative
stress was evaluated. Serum TAC significantly
lowers in asthmatic patients receiving acetaminophen
than in asthmatics not receiving the drug
and control subjects. In addition, MDA serum
levels were significantly higher in the
asthma group receiving the acetaminophen
than in asthmatics not receiving the drug
and the control group. FEV1 of asthmatic
patients reduced significantly after treatment
with acetaminophen and it was significantly
lower than that for asthmatic patients group
not receiving the drug and that of the control
group.
The acetaminophen use
in asthmatics as this study indicated, leads
to a reduction in serum TAC and increase
in lipid peroxidation and consequently these
oxidative stresses contribute to asthma
progression and decrease in lung function.
The oxidation index was two fold higher
in the asthmatic group receiving the drug
than in the asthmatic not receiving acetaminophen
and about six times than that of the control
group. Acetaminophen related brochospasm
has been reported for at least 39 years
in a subset of patients with asthma [10].
Acetaminophen provokes bronchospasm in up
to 35% of patients with stable, aspirin
sensitive asthma [11,39,40]. Reactions generally
are milder than seen after aspirin challenge
and occur with a high, but clinically relevant,
dose of acetaminophen. Acetaminophen related
bronchospasm also has been demonstrated
in some patients of no history of aspirin
sensitive asthma. The mechanism for this
phenomenon is unclear, but may involve glutathione
[11]. Acetaminophen decreases the level
of glutathione in the liver, kidneys and
lungs [41,42]. These decreases are dose
dependent. Overdose levels of acetaminophen
are cytotoxic to pneumocyte and cause acute
lung injury, whereas nontoxic, therapeutic
doses produce smaller, but significant,
reductions in glutathione levels in type
II pneumocytes and alveolar macrophages
[43].
Oxidative stress in asthma
occurs from the production of ROS in the
lung by inflammatory cells. ROS causes contraction
of airway smooth muscle and release of leukotrines
and other secondary inflammatory mediators,
leading to BHR and bronchoconstriction [44].
The importance of glutathione pathway in
asthma is reinforced by the finding that
polymorphisms in glutathione - s- transferase
are associated with increased susceptibility
to pediatric asthma and with slowed lung
function growth in childhood [45].
If the association between
acetaminophen consumption and asthma is
causal, then as well as identifying a new
risk factor for asthma, the proposed mechanism
of this biological effect provides further
support for the hypothesis that an imbalance
of oxidant / antioxidant equilibrium influences
susceptibility to developing asthma, with
glutathione metabolism [46] in particular
appearing to have a pivotal role. It is
hypothesized that the mechanism by which
acetaminophen would increase the risk of
asthma is through depletion of reduced glutathione
leading to a decrease in pulmonary antioxidant
defenses [14,15].
Evidence that administration
of therapeutic doses of acetaminophen can
influence oxidative status is available
with the finding of this study and the recent
reports of a decrease in TAC [37], and if
this effect is replicated in the lungs then
it is likely that they would be more susceptible
to oxidative insults [47].
As the purpose of the
lungs is to permit transfer of gases including
oxygen, they are exposed to higher concentrations
of oxygen than other tissues, and hence
are more at risk of oxidant induced injury
and thus require antioxidant defenses to
prevent permanent tissue damage [47]. The
data from the present study and Shaheen
et al [15] contribute to the hypothesis
that oxidant / antioxidant equilibrium is
important with regard to asthma, a concept
that has developed over the past 20 years.
The extent to which a high oxidant load
is causally associated with asthma rather
than being a secondary consequence of the
inflammatory processes that accompany asthma
remain unclear [47]. However, the data from
the aforementioned perspective studies that
exposure to a drug with pro - oxidant qualities
such as acetaminophen increases the risk
of subsequent asthma, are supportive of
the more general hypothesis that a greater
oxidative burden has a causal role in the
pathogenesis of asthma [47].
Host antioxidant defenses may also be modified
by the environment and are also considered
potentially important with regards to asthma
[48]. Those with lower endogenous antioxidant
capacity as assessed by dietary intake [49],
or serum markers of dietary antioxidants
[2] are more likely to have incident or
prevalent asthma, although studies have
been inconsistent. The more pertinent measurement
of lung antioxidant status has proven to
be difficult to measure, but the non invasive
measurement such as the use of exhaled markers
of pulmonary disease [50] have also demonstrated
increased oxidative activity in those with
asthma compared with those without. . More
invasive techniques such as BAL have demonstrated
reduced levels of antioxidants such as vitamin
C, vitamin E and urate, with higher concentrations
of glutathione in those with asthma compared
with those without the disease [51,52].
One interpretation of these observations
is that the increased oxidative burden associated
with asthma results in a reactive increase
in the lung antioxidant capacity in the
form of increased pulmonary glutathione
[50], while subsequently depleting systemic
antioxidant reserves as reflected in lower
levels in the blood.
In vitro studies demonstrating
that oxidative stress results in increased
expression of the pro inflammatory transcription
factors, nuclear factor KB and activator
protein-1, provide one possible mechanism
of how oxidative stress may promote an inflammatory
condition such as asthma at cellular level
[47].
As the concept that oxidant
/ antioxidant balance may influence the
development of asthma becomes more established,
the potential for prevention and therapeutic
intervention needs to be established. These
would aim to reduce the risk of developing
asthma or modify the severity of the disease.
As reported there was a link between frequent
use of acetaminophen and asthma incidence
and severity [15]. In addition, administration
of the drug to normal individuals, led to
reduction in TAC [37]. In febrile non-asthmatic
children acetaminophen administration reduced
TAC, GSH, SOD and increased aspartate aminotransferase
activity significantly [38]. Although, the
chronic ingestion of therapeutic dose of
acetaminophen in asthmatic patients depletes
serum TAC, as this study indicated.
N acetylcystine is an
antioxidant drug commonly used in clinical
practice [53], especially for the treatment
of acetaminophen poisoning. On the basis
of the above mentioned facts the time has
come to evaluate the use of combination
of NAC with acetaminophen in asthmatic patients.
Thus their combination leads to a significant
increased in serum TAC, accompanied with
significant reduction in MDA serum levels.
Also, the combination of both drugs cause
significant improvement of FEV1 and reduction
of oxidation index. Two possible antioxidant
mechanisms have been proposed for this thiol
containing antioxidant [53]. Firstly, NAC
may have direct free radical scavenging
properties. ROS may react with NAC resulting
in the formation of NAC disulphide [18,40].
Secondly, and of more importance, NAC may
also exert its antioxidant effects indirectly
by facilitating GSH biosynthesis [21].
A reduction in the levels of various markers
of inflammatory activity, such as ECP, lactoferrin
and antitrypsin was found after administration
of NAC [54]. Treatment with NAC resulted
in a considerable reduction in elastase
activity, in both the BAL fluid and plasma,
related to its property of scavenging HOCl
[18].
Oral administration
of NAC before antigen exposure of a sensitized
rat, a widely used experimental model for
asthma, resulted in attenuation of antigen
induced augmented lipid peroxidation and
altered glutathione status, suppression
of the nuclear factor Alfa levels and enhanced
inducible nitric oxide synthase, intracellular
adhesion molecule - 1, and mucin MUC5AC
expression that follows allergen exposure
and a marked decrease in airway hyperresponsiveness,
bronchoalveolar lavage fluid eosinophil
number and exudation after antigen challenge
[22]. Other animal studies [55,56] reported
that NAC administration reduces serum and
plasma MDA levels, plasma NO and increases
plasma SOD, CAT, GSH and GPX. In addition,
NAC administration was with modulatory effect
on genes [19,57].
Reactive oxygen species
are involved in the activation of several
mitogen activated protein kinases (MAPK),
key players in the production of several
cytokines [54]. NAC decreased the expression
of eotoxin and monocyte chemotactic protein
-1 in human airway smooth muscle cells.
Also NAC decreased the IL-1B induced production
of ROS, as suggested by a reduction in the
8- isoprostan production [54]. The potential
therapeutic value of antioxidants including
NAC awaits support from controlled clinical
trials that evaluate oral versus inhaler
route of administration.
N acetycystine is a thiol
compound with antioxidant properties [89]
that reduces the lung damage produced by
oxidant stress in different experimental
models and exerts beneficial effects in
pulmonary diseases in which oxidant stress
appears pathogeneticaly relevant [26]. In
experimental models of allergic asthma,
antioxidant, and anti inflammatory and anti
hyperresponsiveness effect of oral NAC was
observed [22,58]. Allergen challenge of
the peripheral airways in atopic asthmatics
has been demonstrated to produce immediately,
significant amounts of ROS released locally
from eosinophils and other inflammatory
cells [59]. Blesa et al [22] reported that
antigen challenge causes increase in lipid
peroxidation levels and decreased GSH/GSSH
ratio, confirming the existence of oxidative
stress. An increase in GSSH and decrease
in GSH level in epithelial lining fluid
early after antigen challenge has been reported
recently in asthmatics [60]. Oral treatment
with NAC is efficient at attenuating the
augmented lipid peroxidation and GSSH levels,
and reversing the decreased GSH/GSSH ratio,
confirming its antioxidant properties in
this animal model [22].
Since the presence of
oxidative stress was demonstrated for rat
models of allergic asthma, activation of
a number of inflammatory elements reported
to be oxidant sensitive, including transcription
factors like NF-kB and cytokines such as
TNF Alfa; and expression of gene like iNOS,
intracellular adhesion molecule -1 (ICAM-1)
and MUC5AC were sought [17,19,22,25,57,61].
Furthermore, treatment with an antioxidant
should attenuate these activated factors
as well as prove beneficial against the
typical features of experimental asthma
such as airway hyper-responsiveness, eoisinophilia
and exudation.
NF- kB is considered
as a pivotal transcription factor in chronic
inflammatory diseases and very sensitive
to oxidants as well as other stimuli [19].
Augmented activation of NF-kB has been demonstrated
in the airways and inflammatory cells of
asthmatic patients as well as in experimental
asthma [19]. The antioxidant properties
of NAC may contribute directly to its inhibitory
effects on NF-kB activation [22]. Alternatively,
NF-kB activation may result from the release
of TNF Alfa, which induces generation of
ROS [50].
TNF Alfa is a proinflammatory
cytokines that has been implicated in the
pathogenesis of asthma and considered a
potential target for therapeutic intervention.
This increased TNF Alfa level was attenuated
in NAC treated animals, a finding consistent
with the suggestion that GSH status regulates
TNF Alfa production in vivo and with the
inhibition by NAC of the increase in TNF
Alfa observed in various studies [17,19].
The ICAM-1 gene contains NF-kB binding sites
and its expression is oxidant sensitive
[57]. The expression or airway and endothelial
ICAM-1 are enhanced by TNF Alfa and other
inflammatory cytokines [57]. Therefore,
various elements may contribute to the enhanced
expression reported by Blesa et al [22]
and the inhibition found for NAC would be
consistent with other reports [62,63].
Mucus overproduction
is often observed in airway inflammation
and contributes to airway obstruction in
asthma. Recent work indicates that
oxidative stress stimulates mucin synthesis
in airways particularly synthesis of MUC5AC
[23]. Treatment with NAC blocked this early
expression of MUC5AC. These results confirm
that oxidative stress appears important
in the excessive production of mucin airways,
and antioxidants are effective at suppressing
the enhanced expression of mucin genes in
experimental asthma [58].
Consequential to these
inhibitory effects of antioxidant treatment
on treanscription factors, inflammatory
cytokines and genes, there should be experimental
evidence of beneficial effects of NAC on
characteristic features of allergic asthma.
NAC was effective at reducing both BHR and
the elevated BALF eosinophil numbers [22].
Several lines of evidence suggest that the
production of oxygen radicals is implicated
in the airway response to allergen [46].
Thus the antigen induced hyper-responsiveness
was found to correlate significantly with
the increases in oxygen radicals release
from BALF cells in sensitized animals [48].
The oxidant transcription
factor NF-kB appears relevant to eosinophilia
in allergic asthma [19]. Also, cell trafficking
into inflammatory sites depends on the sequential
expression of cell adhesion molecules, which
are modulated by oxidant species; in particular,
ICAM-1 is important for induction of BHR
in vivo as well as eosinophil migration
into inflamed lung [57]. Therefore, the
reduced BHR and eosinophilia produced by
NAC may also be related to its antioxidant
properties.
In conclusion, oral administration
of NAC attenuates the oxidative stress induced
by acetaminophen in asthmatic patients.
In keeping with these results the reported
findings from several studies in animal
models indicated that NAC 1) attenuate antigen
induced lipid peroxidatin and altered glutathione
status,;2) suppression of NF-kB activation,
mucin MUC5AC expressions, ICAM-1,elevated
tumor necrosis factor Alfa levels, 3) a
marked decrease in BHR and BALF eosinophil
number and exudation after allergen challenge.
These results confirm that oxidative stress
may contribute to the pathogenesis of asthma.
The potential therapeutic value of antioxidant
including NAC awaits support from controlled
clinical trials.
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- Burr ML, Wat D, Evans
C, et al. Asthma prevalence in 1973,1988
and 2003 . Thorax 2006;61:296-299.
- Misso NL, Brooks J,
Ray S, Vally H, Thompson PJ. Plasma concentrations
of dietary and nondietary antioxidants
are low in severe asthma. Eur Respir J
2005;26:257-264.
- Broide DH. Molecular
and cellular mechanisms of allergic disease.
J Allergy Clin Immunol 2001;108: S65-
S71.
- Weiss ST. Eat dirt
- The hygiene hypothesis of allergic diseases.
N Eng J Med 2002;347:930-31.
- Sporik R, Holgate
ST, Platts-Mills TAE, Cogswell JJ. Exposure
to house-dust mite allergen (Der p I)
and the development of asthma in childhood.
N Eng J Med 1990; 323: 502-507.
- Platts-Mills TAE,
Vaughan J, Squillace SP, Woodfolk JA,
Sporik R. Sensitisation, asthma, and a
modified Th2 response in children exposed
to cat allergen: a population-based cross-sectional
study. Lancet 2001; 357: 752-756.
- Sporik R, Squillace
SP, Ingram JM, Rakes G, Honsinger W, Platts-Mills
TAE. Mite, cat, and cockroach exposure,
allergen sensitisation, and asthma in
children: a case-control study of three
schools. Thorax 1999; 54: 675-680.
- Camargo C Jr,, Weiss
ST, Zhang Z, Willett WC, Speizer FE. Prospective
study of body mass index, weight change,
and risk of adult-onset asthma in women.
Arch Intern Med 1999; 159: 2582-2588
- Varner AE, Busse WW,
Lemanske RF Jr. Hypothesis: decreased
use of pediatric aspirin has contributed
to the increasing prevalence of childhood
asthma. Ann Allergy Asthma Immunol 1998;
81:347-351
- Chafee FH, Settipane
GA. Asthma caused by FD&C approved
dyes. J Allergy 1967; 40:65-72
- Eneli I, Sadrik K,
Camargo C, Barr G. Acetaminophen and risk
of asthma. Chest 2005;127:604-612.
- Newson RB, Shaheen
SO, Chinn S, et al. Paracetamol sales
and atopic disease in children and adults:
an ecological analysis. Eur Respir J 2000;
16:817-823
- Shaheen SO, Sterne
JA, Songhurst CE, et al. Frequent paracetamol
use and asthma in adults. Thorax 2000;
55:266-270
- Barr RG, Wentowski
CC, Curhan GC, et al. Prospective study
of acetaminophen use and newly diagnosed
asthma among women. Am J Respir Crit Care
Med 2004; 169:836-841
- Shaheen SO, Newson
RB, Sherriff A, et al. Paracetamol use
in pregnancy and wheezing in early childhood.
Thorax 2002; 57:958-963
- Kelly GS. Clinical
applications of N acetylcystine. Alternative
Medicine Review 1998;3:114-127.
- Hoffer E, Baum Y,
Tabak A, Taitelman U. N acetylcysteine
increases the glutathione content and
protects rat alveolar type II cells against
paraquat induced cytotoxicity. Toxicol
Lett 1996;84:7-12.
- Aruoma OI, Halliwell
B, Hoey BM, Buttler J. The antioxidant
action of N acetylcysteine . Free Radic
Biol Med 1989;6:593-597.
- Schreck R, Albermann
K, Baeuerle PA. Nuclear factor B: an oxidative
stress-responsive transcription factor
of eukaryotic cells (a review). Free Radic
Res Commun 1992;17:221-237.
- Wilmer WA, Tan LC,
Dickerson JA, Danne M, Rovin BH. Interleukin
-1beta induction of mitogen activated
protein kinases in human mesangial cells.
Role of oxidation. J Biol Chem 1997;272:10877-10881.
- Dekhuijzen PNR. Antioxidant
properties of N acetylcysteine. Eur Respir
J 2004;23:629-636.
- Blesa S, Cortijo
J, Mata M, et al. Oral N acetylcysteine
attenuate the rat pulmonary inflammatory
response to antigen. Eur Respir J2003;21:394-400.
- Takeyama K, Dabbagh
K, Shim JJ, Dao-Pick T, Ueki IF, Nadel
JA. Oxidative stress causes mucin synthesis
via transactivation of epidermal growth
factor receptor: role of neutrophils.
J Immunol 2000;164:1546-1552.
- Barnes PJ, Chung KF,
Page CP. Inflammatory mediators in asthma:
an update. Pharmacol Rev 1998;50:515-96.
- Wuyts WA, Pype JL,
Verleden GM. Modulation IL-1B induced
MCP-1, MCP-3 and eotaxin expression in
human airway smooth muscle cells.Am J
Respir Crit Care Med 2001;161:A594.
- Cotgreave IA. N Acetylcystine
: Pharmacological considerations and experimental
and clinical implications. Adv Pharmacol
1997;38:205-227.
- Global Initiative
for Asthma. Global strategy for asthma
management and prevention. NHLBI/WHO Workshop
Report. NIH Publication 02-3659. Bethesda,
MD: NHLBI, 2002.
- Kampa M, Nistikaki
A, Tsaousis V, Maliaraki N, Notas G, Gastonas
E. A new automated method for the determination
of TAC of human plasma based on crocin
bleaching assay. BMC Clin Pathol 2002;2:3-21.
- Janero D. Malondialdehyde
and thiobarbituric acid reactivity as
diagnostic indicies of lipid peroxidationand
peroxidative tissue injury. Free Rad Bio
Med 1998;9:515-540.
- Ernest P. Inhaled
corticosteroids moderate lung function
decline in adults with asthma. Thorax
2006; 61:93-94.
- Brusse JE, Smit HA,
Van Strien RT, et al. Allergen exposure
in infancy and the development of sensitizer
wheeze and asthma at 4 years. J Allergy
Clin Immunol 2005;115:946-952.
- Hallstrand TS, Fischer
ME, Wurfel MM, et al. Genetic pleotropy
between asthma and obesity in a community
based sample of twins. J Allergy Clin
Immunol 2005;116:1235-1241.
- Ford ES. The epidemiology
of obesity and asthma. J Allergy Clin
Immunol 2005;115:897-909.
- Lesko SM, Mitchell
AA. The safety of acetaminophen and ibuprofen
among children younger than two years
old. Pediatrics 1999; 104:e39
- Fallier CJ. Emergent
asthma : endogenous, exogenous or iatrogenous.
Chest 2005;127:427-429.
- Cohet C, Cheng S,
MacDonald D, et al. Infections, medication
use and the prevalence of symptoms of
asthma, rhinitis and eczema in childhood
. J Epidemiol Comm Health 2004;58:852-857.
- Nuttal S, Khan J,
Thorpe G, Langford N, Kendall M. The impact
of therapeutic doses of paracetamol on
serum total antioxidant capacity. J Clin
Pharmacol Ther 2003;28:289-294.
- Kozer E, Evans S,
Barr J, et al. Glutathione, glutathione
dependent enztymes and antioxidant status
in erythrocytes from children treated
with high dose paracetamol. Br J Clin
Pharmacol 2003;55:234-240.
- Delaney JC. The diagnosis
of aspirin idiosyncrasy by analgesic challenge
. Clin Allergy 1977;6:177-181.
- Moldeus P, Cotgreave
IA, Berggren M. Lung protection by a thiol-containing
antioxidant: N-acetylcysteine. Respiration
1986;50:31-42.
- Chen TS, Richie JP
Jr, Lang CA. Life span profiles of glutathione
and acetaminophen detoxification. Drug
Metab Dispos 1990:18:882-887
- Micheli L, Cerretani
D, Fiaschi AI, Giorgei G, Romeo MR, Runci
FM. Effect of paracetol on glutathione
levels in rats testis and lung. Env health
Perspect 1994;102:63-64.
- Dimova S, Hoet PH,
Nemery B. Paracetamol cytotoxicity in
rat type II pneumocytes and alveolar macrophages
in vitro. Biochem Pharmacol 2000;59:1467-1475.
- Seroogy CM, Gern J.
The role of T regulatory cells in asthma.
J Allergy Clin Immunol 2005;116:996-9.
- Gilliland FD, Li YF,
Dubeau L, et al. Effect of GST M1, maternal
smoking during pregnancy and environmental
tobacco smoke on asthma and wheezing in
children . Am J Respir Crit Care Med 2002;166:457-463.
- Dworski R. Oxidative
stress in asthma. Thorax 2000;55:S51-3.
- Fogarty A, Davey G.
Paracetol, antioxidants and asthma. Clin
Exp allergy 2005;35:700-702.
- Bowler RP. Oxidative
stress in the pathogenesis of asthma.
Current Allergy Asthma Reports 2004;4:116-122.
- Cheung MC, Austin
MA, Moulin P, et al. Effects of pravastatin
on apolipoprotein-specific high density
lipoprotein subpopulations and low density
lipoprotein subclass phenotypes in patients
with primary hypercholesterolemia. Atherosclerosis.
1993;102:107-119
- Rahman I, Morrison
D, Donaldson K, MacNee W. Systemic oxidative
stress in asthma. Am J respire Crit Care
Med 1996;154:1055-1060.
- Kelly FJ, Mudway I,
Blomberg A, Frew A, Sandstrom T. Altered
lung antioxidant status in patients with
mild asthma. Lancet 1999;354:482-483.
- Mak JC, Leung HC,
Ho SP, et al. Systemic oxidative and antioxidative
status in Chinese patients with asthma.
J Allergy Clin Immunol 2004;114:260-264.
- Heunks LMA, Dekhuijzen
PNR. Respiratory muscle functions and
free radicals. Thorax 200;55:704-716.
- Wuyts WA, Vanaudenaerde
BM, Dupont LJ, Demedets MG, Verleden GM.
N acetylcysteine reduces chemokines release
via inhibition of P38 MAPK in human airway
smooth muscle cells. Eur respire J 2003;22:43-49.
- Aydin S, Ozaras R,
Uzun H, et al. N acetylcystenine reduced
the effect of ethanol on antioxidant system
in rat plasma and brain tissue. Tohoku
J Exp Med 2002;198:71-77.
- Ozaras R, Tahan V,
Aydin S, Uzun H, Kaya S, Senturk H. N
acetylcystine attenuates alcohol induced
oxidative stress in rats. World J Gastroenterol
2003;9:791-794.
- Marui N, Offermann
MK, Swerlick R, et al. Vascular cell adhesion
molecule-1 (VCAM-1) gene transcription
and expression are regulated through an
antioxidant-sensitive mechanism in human
vascular endothelial cells. J Clin Invest
1993;92:1866-1874.
- Blesa S, Cortijo J,
Martinize- Losa M, et al. Effectiveness
of oral N acetycysteine in a rat experimental
model of asthma. Pharmacol Res 2002;45:135-140.
- Henricks PA, Nijkamp
FP. Reactive oxygen species as mediators
in asthma. Pulm Pharmacol Ther 2001;14:409-20.
- Comhair SA, Erzurum
SC. Antioxidant responses to oxidant-mediated
lung diseases. Am J Physiol Lung Cell
Mol Physiol 2002;283:L246-55.
- Pype JL, Dupont LJ,
Menten P et al. Expression of monocyte
chemotactic protein (MCP)-1, MCP-2 and
MCP-3 by human airway smooth muscle cells.
Modulation by corticosteroids and
T helper 2 cytokines. Am J Respir Cell
Mol Biol 1999;21:528-536.
- Pratt
S, Ioannides C. Mechanism of the protective
action of N acetylcysteine and methionine
against paracetol toxicity in the hamster.
Arch Toxicol 1985;57:173-177.
- Borgstrom L, Kagedal
B, Paulsen O. Pharmacokinetics of N-acetylcysteine
in man. Eur J Clin Pharmacol 1986;31:217-222.
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