Acta Oto-Laryngologica, 2007; 127: 855
860

ORIGINAL ARTICLE

Experimentally induced acute sinusitis and efficacy of vitamin A

MEHMET GUVEN1, IBRAHIM ALADAG1, AHMET EYIBILEN1, NURPER ONUK FILIZ2,

HUSEYIN ÖZYURT3 & KÜRŞAT YELKEN1
1
Department of ORL, 2Department of Pathology and 3Department of Biochemistry, Faculty of Medicine, Gaziosmanpasa
University, Tokat, Turkey

Abstract
Conclusions. Although antibiotics are the mainstays for treatment of sinusitis, they do not specifically treat tissue damage due
to free radicals. We propose that antioxidant, anti-infective, immunomodulator vitamin A may be a useful addition in the
management of sinusitis. Objectives. Acute sinusitis is one of the most common diseases in humans. Vitamin A is a fat-
soluble vitamin and essential for immunity, cellular differentiation, and maintenance of respiratory and gastrointestinal
epithelial surfaces, growth, reproduction, and vision. The objective of this study was to investigate the therapeutic role of
vitamin A on healing of acute sinusitis. Materials and methods. This was a prospective controlled animal trial. Experimental
sinusitis was induced by blocking the right nose and inoculating Streptococcus pneumoniae into the right maxillary sinuses.
Left maxillary sinuses were used as controls. Rabbits were divided in to two groups. At 48 h after inoculation, group
I received only parenteral ampicillin-sulbactam (50 mg/kg), group II was treated with parenteral ampicillin-sulbactam
(50 mg/kg) and parenteral a dose of 100 000 IU vitamin A in palmitate form. All animals were sacrificed on the 10th day.
Mucosal samples were excised from the infected and control sinuses for histopathologic examination, for measurement of
activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT), and for evaluation of
levels of malondialdehyde (MDA) and nitric oxide (NO). Results. All the infected sinuses displayed signs of inflammation,
but there was no statistically significant difference between the study and control groups. In our study, epithelial integrity as
well as NO and MDA levels were better in the group receiving both antibiotic and vitamin A than the group receiving
antibiotic alone. Nevertheless, SOD activity was significantly increased in the group receiving only antibiotics, compared
with the control mucosal SOD activity. There was no difference between the groups as regards CAT and GSH activity.

Keywords: Acute sinusitis, vitamin A, free radicals, antioxidant enzymes

Introduction as intracellular messaging in the cell differentiation,

Acute sinusitis is a common health problem in both
children and adults. The treatment consists of anti-
biotic therapy and other therapies including topical
and systemic decongestants, corticosteroids, anti-
inflammatory agents, mucolytic agents, humidifica-
tion, and antihistamines. Conservative functional
endoscopic sinus surgery is reserved for refractory
cases. Despite appropriate treatment, prolonged and
excessive inflammation may cause chronic rhinosi-
nusitis or sinusitis complications in some cases.
Free radicals (FRs) including hydroxyl radicals,
superoxide anions, and hydrogen peroxide, which
are produced by activated granulocytes, play an
important role in many biochemical processes such
apoptosis, immunity, and defense against microor-
ganisms [1]. The shift of the delicate balance
between FRs and the cellular antioxidant defense
system in favor of FRs might lead to development of
oxidative stress [2]. Main targets of FRs are the
polyunsaturated fatty acids in cell membranes caus-
ing lipid peroxidation and malondialdehyde (MDA)
formation, which may lead to damage of the cell
structures and function [3]. Aerobic organisms are
protected against free radicals by enzymatic and
nonenzymatic antioxidant defense systems [1]. The
most important enzymatic antioxidants are super-
oxide dismutase (SOD), glutathione peroxidase
(GSH-Px), and catalase (CAT). Increased activity

Correspondence: Mehmet Güven, Department of Otorhinolaryngology, Gaziosmanpasa University Medical Faculty, Tokat, Turkey. Tel/Fax: /90 356 213 31
79. E-mail: guvenmehmet28@yahoo.com

(Received 18 August 2006; revised 21 September 2006; accepted 4 October 2006)

ISSN 0001-6489 print/ISSN 1651-2551 online # 2007 Taylor & Francis
DOI: 10.1080/00016480601053107
856 M. Guven et al.
of radical scavenger enzymes, such as CAT, SOD,
and GSH-Px, to prevent the detrimental effects of
oxidative stress in different organs, has been de-
scribed in recent reports [4]. FRs and lipid peroxides
have been implicated in the pathogenesis of many
diseases, including diabetes mellitus, cancer, rheu-
matoid arthritis, systemic lupus erythematosus,
Behcet’s disease, infectious diseases, arteriosclerosis,
and aging [5
7].
It is known that nitric oxide (NO) provides a first
line of defense against microorganisms through its
antiviral and antimicrobial activity and through its
up-regulation of ciliary motility. High NO concen-
trations were found in paranasal sinuses and it was
thought that the lack of NO may contribute to the
pathogenesis of sinusitis [8,9].
Vitamin A is a fat-soluble vitamin and essential for
immunity, cellular differentiation, maintenance of
respiratory and gastrointestinal epithelial surfaces,
growth, reproduction, and vision. Vitamin A defi-
ciency, recognized for its ocular complications, has
been shown to have systemic effects that increase
mortality and morbidity [10]. Although vitamin A
has been known as an anti-infective vitamin since the
1920s, only in the last several years have rigorous
clinical trials and appropriately designed experiments
in animals demonstrated that vitamin A enhances
immunity, thereby reducing childhood morbidity and
mortality from infectious diseases [10].
A similar report by Unal et al. [11] has examined
the effects of vitamin A on the improvement in acute
sinusitis via histopathologic evaluation. This study
did not assess NO and MDA levels and antioxidant
enzyme activities; however, we aimed to investigate
these missing points and to achieve a more compre-
hensive study on the therapeutic effects of vitamin A.
Materials and methods
Twenty New Zealand hybrid rabbits (weighing 2.3

3.4 kg) were used in the study. International
standards for the care of laboratory animals were
followed and the protocol of the study was approved
by the responsible local ethical committee. The
experimental method was adapted from the studies
of Cable et al. [12] and Unal et al. [11].
Right nares of rabbits were blocked unilaterally by
using merocel tamponade. On the following day, the
animals were anesthetized with an intramuscular
injection of ketamine HCI (50 mg/kg). Following
skin incision, superior parts of the maxillary sinuses
were exposed. The next day, 1 ml of type 1
Streptococcus pneumoniae solution, consisting of
107
109 pneumococci/ml, was inoculated into the
right maxillary sinuses. The same amount of phy-
siologic saline was similarly injected into the left
maxillary sinuses as a control agent. At 48 h after
maxillary sinus inoculation, a purulent nasal drai-
nage from the right nasal cavities was observed.
Then animals were randomly divided into two
groups: group I was treated with intramuscular
ampicillin-sulbactam (50 mg/kg) twice daily, group
II was treated with one intramuscular dose of
100 000 unit vitamin A (in palmitate form; Türk-
Roche, Istanbul, Turkey) in addition to intramuscu-
lar ampicillin-sulbactam. After 10 days, all animals
were sacrificed by using a lethal dose of intracardiac
sodium pentothal and maxillary sinuses were opened
immediately. All maxillary sinus mucosas were
removed. The removed mucosas were divided into
pairs for histopathologic evaluations and for bio-
chemical assessments.
Specimens were stained with hemotoxylin-eosin
and were examined using light microscopy. Histo-
pathologic analysis of the experimental side was
compared to the normal control sinuses. The exam-
iner (N.O.F.) was unaware of the groups. The
histopathologic analysis was scored for inflammation
and integrity of epithelium [12]. The severity of
grade of inflammation was assessed on a scale of
none, 0; minimal, 1 (rare individual inflammatory
cells within the mucosa and submucosa); mild, 2
(light infiltrate of individual and clusters of inflam-
matory cells); moderate, 3 (dense infiltrate of
inflammatory cells); and severe, 4 (inflammatory
infiltrate so dense as to obscure the normal archi-
tecture of the mucosa and submucosa). The integrity
of sinus epithelium was assessed on a scale of
complete, 0; focal epithelium lost but no vacuoliza-
tion and metaplasia, 1; focal epithelium lost and
vacuolization, 2; and focal epithelium lost and
epithelial metaplasia, 3.
Biochemical analyses
For biochemical analyses, maxillary sinus tissue was
separated and then stored at /708C until required
for analysis. After weighing the maxillary sinus
tissues, they were homogenized in five volumes of
ice-cold Tris-HCl buffer (50 mM, pH 7.4) contain-
ing 0.50 ml 11 Triton X-100 in a homogenizer
(IKA Ultra-Turrax t 25 Basic, Germany) for 2 min
at 13 000 rpm. All procedures were performed at
48C. Homogenate, supernatant, and extracted sam-
ples were prepared and the following determinations
were made on the samples using commercial chemi-
cals supplied by Sigma (St Louis, USA).
Mucosal tissue antioxidant enzyme analysis
Total (Cu
Zn and Mn) SOD (EC 1.15.1.1) activity
was determined according to the method of Sun
 Experimentally induced acute sinusitis and efficacy of vitamin A 857

et al. [13]. The principle of the method is based on spectrophotometer at 545 nm. A standard curve was
inhibition of nitroblue tetrazolium (NBT) reduction established with a set of serial dilutions (108
103
by the xanthine
xanthine oxidase system as a super- mol/L) of sodium nitrite. Linear regression was
oxide generator. Activity was assessed in the ethanol carried out using the peak area from the nitrite
phase of the supernatant after 1.0 ml of ethanol
standard. The resulting equation was then used to
chloroform mixture (5:3, v/v) was added to the same calculate the unknown sample concentrations. Re-
volume of sample and centrifuged. One unit of SOD sults were expressed as mmol/g wet tissue.
was defined as the amount causing 50% inhibition in
the NBT reduction rate. The SOD activity is
expressed as U mg 1 protein. GSH-Px activity was Statistical methods
measured by the method of Paglia and Valentine Given as means9/standard error, data were analyzed
[14]. The enzymatic reaction in the tube
contain- by using the Statistical Package for Social Sciences
ing NADPH, reduced glutathione (GSH), sodium (SPSS) 12.0 for Windows software. Distribution of
azide and glutathione reductase
was initiated by the groups was assessed by the one-sample
addition of H2O2 and the change in absorbance at Kolmogrov
Smirnov test for biochemical para-
340 nm was monitored by a spectrophotometer. meters. All groups showed a normal distribution;
Activity is expressed as U mg 1 protein. CAT therefore parametrical statistical methods were used
activity was determined according to Aebi’s method to analyze the data. One-way analysis of variance
[15]. The principle of the method was based on (ANOVA) test was performed and post hoc multiple
determination of the rate constant k (s1) of the comparisons were done with least significant differ-
H2O2 decomposition at 240 nm. Results are ex- ences (LSD). p valuesB/0.05 were regarded as
pressed as k g1 protein. All samples were assayed in statistically significant.
duplicate. Histopathological semi-quantitative results were
analyzed by Kolmogrov Simirnov test for normality.
The differences among the groups were analyzed
Determination of thiobarbituric acid-reactive
with the nonparametric Kruskal-Wallis test and a
substance level
statistical difference between groups was defined
The tissue thiobarbituric acid-reactive substance using the nonparametric Mann-Whitney U test.
(TBARS) level was determined by the method of Critical p B/0.0083 adjusted for all histopathological
Esterbaur and Cheeseman [16], based on reaction comparisons.
with thiobarbituric acid (TBA) at 90
1008C. In the
TBA test reaction, MDA or MDA-like substances
and TBA react to produce a pink pigment with an Results
absorption maximum at 532 nm. The reaction was There was no inflammation in the control sinus
performed at pH 2
3 and 908C for 15 min. mucosas. All of the control specimens had normal
The sample was mixed with two volumes of cold sinus epithelium. A summary of histopathologic data
10% (w/v) trichloroacetic acid to precipitate the is presented in Table I. The epithelial integrity was
protein. The precipitate was pelleted by centrifuga- significantly better in group II than in group I
tion and an aliquot of the supernatant was reacted
with an equal volume of 0.67% (w/v) TBA in a Table I. Summary of the histopathologic results.
boiling water-bath for 10 min. After cooling, the
absorbance was read at 532 nm. Results were Group II
expressed as nmol per gram wet tissue, according Group I (antibiotics/
Parameter (antibiotics alone) vitamin A)
to the standard graphic prepared from measure-
ments with a standard solution (1,1,3,3-tetra- Inflammation
methoxypropane). None 2 2
Minimal 3 4
Mild 4 3
NO determination Moderate 1 1
Severe 0 0
NO measurement is very difficult in biological
Epithelium integrity
specimens, therefore tissue nitrite (NO2) and Complete 2 4
nitrate (NO3) were estimated as an index of Focal epithelium lost 4 5
NO production. Samples were initially deproteini- Focal epithelium lost 4 1
zed with Somogyi reagent. Total nitrite (nitrite/ with vacuolization
Focal epithelium lost 0 0
nitrate) was measured after conversion of nitrate
and metaplasia
to nitrite by copperized cadmium granules by a
858 M. Guven et al.
Table II. Enzyme activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and tissue levels of
malondialdehyde (MDA) and nitric oxide (NO) in all experimental groups.
Experimental group SOD (U/mg prot) CAT (k/g prot) GSH-Px (U/mg prot) NO (mmol/g wet tissue) MDA (nmol/g wet tissue)
Group I 0.01349/0.001 0.0889/0.001
Group I control 0.03669/0.002 0.2289/0.006
Group II 0.01169/0.001 0.0979/0.003
Group II control 0.01189/0.001 0.2789/0.007
p values
I vs I control 0.001* 0.001*
II vs II control 0.858 0.001*
I vs II 0.324 0.165
Group I, animals receiving antibiotic only; Group II, animals receiving both antibiotic and vitamin A.
*Statistically significant.
(p/0.002), but there was no statistically significant
difference between groups as regards inflammation
(p/0.065).
Therapeutic effects of vitamin A on acute sinusitis
were examined by means of histopathologic exam-
inations as well as SOD, CAT, and GSH-Px enzyme
activities, and tissue levels of NO and MDA. The
results are presented in Table II.
SOD activity was significantly higher in group I,
compared with the paired samples of mucosa from
the contralateral control sinuses (p /0.001). On the
other hand, no significant difference was found in
SOD activity in group II, compared to control
group, and in group I compared to group II.
Compared with the control groups, CAT activity
was significantly lower in both groups (p/0.001),
but no difference was determined between group I
and group II (p/0.165).
A significant decrease in GSH-Px activity was
found in both groups compared with control mucosa
(p/0.001); however, the difference between group I
and group II was not significant (p /0.55).
In the evaluation of MDA, a statistically significant
increase in both groups compared with control
maxillary sinus mucosa was observed (p/0.001).
The mean rate of MDA in group II was significantly
lower than in the animals receiving antibiotic alone.
Compared with the control mocosa, the decrease
in NO was significant in both groups (p/0.001).
Mean rate of NO in group I was significantly lower
than the animals receiving both antibiotic and
vitamin A (p /0.01).
Discussion
Vitamin A is a micronutrient that is essential for
immunity, cellular differentiation, maintenance of
epithelial surfaces, growth, reproduction, and vision.
This fat-soluble substance is found in foods from
animal sources, including dairy products. It has been
known for more than a century that vitamin A
1.419/0.069 1.519/0.023 210.499/9.77
3.269/0.063 4.969/0.130 43.659/1.51
1.489/0.047 1.969/0.026 110.989/5.87
2.779/0.123 3.219/0.255 45.709/2.25
0.001* 0.001* 0.001*
0.001* 0.001* 0.001*
0.55 0.01* 0.005*
deficiency is more common during infection than
in its absence [17]. Acute measles is associated with
low serum levels of vitamin A [18]. Vitamin A
supplementation reduces severe morbidity and mor-
tality from infectious diseases in children [10]. The
administration of a high dose vitamin A supplement
to children with acute complicated measles reduces
mortality by 50% [18]. Previous attempts have been
made to extend these observations to children at
higher risk for respiratory infections [19,20].
Unal et al. [11] have hypothesized that vitamin A
is essential for immunity and respiratory epithelium,
hence to confirm this assumption they have studied
the therapeutic role of vitamin A in acute sinusitis
based on histopathologic examinations. However,
they could not find any significant difference be-
tween groups. In our study, although there was no
statistically significant difference between groups as
regards inflammation, epithelial integrity was found
to be better in the vitamin A supplemented group.
We believe that this point is very important for the
healing process of the infection.
FRs have potentially harmful effects and cause
oxidative stress on the metabolic events occurring in
molecules. The cellular antioxidant defense system
controls the effects of these species and this role is
carried out by FR scavenger enzymes, such as SOD,
CAT, and GSH-PX [2]. When there is impairment
in the cellular antioxidant defense system and/or
reactive oxygen species (ROS) production exceeds
the ability of this defense system to scavenge these
species, oxidative stress occurs and ROS attack
polyunsaturated fatty acids found widely in cell
membranes. Lipid peroxidation develops in cell
membranes, which causes production of membrane
destruction products, such as MDA [3].
Excessive lipid peroxidation in the experimental
sinus mucosa can arise due to factors favoring the
formation of FRs. Parks et al. [21] demonstrated
that mucosal MDA level was increased in experi-
mental otitis media and FRs in mucosa of infected
 Experimentally induced acute sinusitis and efficacy of vitamin A
middle ear might cause damage by lipid peroxida-
tion. Döner et al. [22] reported that MDA levels of
serum and infected maxillary sinus mucosa were
significantly higher than those of controls. Although
our results are in accordance with the literature,
MDA levels in animals receiving both antibiotic and
vitamin A were significantly different from the
animals receiving only antibiotic.
Werspaget at al. [23] showed that the neutrophil
content of SOD was markedly diminished in
Crohn’s disease and ulcerative colitis compared
with a control group. When neutrophils accumulate,
however, they may produce local toxic levels of FRs
and cause an inflammatory process. We found that
tissue SOD activity in the maxillary sinus mucosa of
the rabbits that received antibiotic only was signifi-
cantly higher than in the control sinus mucosa,
whereas the increase in SOD activity in the group
that received both antibiotic and vitamin A was
nearly similar to that in the control group. Döner
et al. [22] reported increased SOD activity in the
serum and erythrocytes of rabbits with experimental
sinusitis. Parks and Haddad [24] have reported that
SOD activity is significantly higher in the infected
mucosa than in the normal mucosa.
GSH-Px and CAT levels were significantly lower
in the infected sinus mucosa compared with control
mucosa in both groups. This difference might be
explained by the fact that during inflammation an
increased oxidant production leads to consumption
of GSH-Px through direct scavenging of ROS.
GSH-Px and CAT levels did not differ significantly
between group I and group II.
Although it is known that NO concentration is
high in paranasal sinuses, recent evidence suggests
that the sinuses are not the site of nasal NO
production [9]. In a previous study it has been
shown that when all the sinus ostia are blocked, nasal
NO output is decreased by a mere 12% [25]. In
sinusitis, probably due to a decrease in the occlusion
of ostium, this low NO concentration affects bacter-
ial growth. In a study performed on children with
acute sinusitis, nasal NO level was found to be
decreased during illness and increased after anti-
biotic therapy [12]. In the present study, the NO
activity in group I was significantly lower than in
group II.
Whatever the cause, the inflammation of the
sinuses increases the level of FRs. FR level is
normally maintained at a steady state by antioxidant
enzymes. When the antioxidant defense system is
weakened, the increased FRs may contribute to
sinusitis formation. Although antibiotics are main-
stays for the treatment of sinusitis, they do not
specifically treat tissue damage due to FRs. Our
results may explain the rapid improvement in
859
sinusitis in the group treated with both antibiotic
and vitamin A.
Conclusion
In our study, epithelial integrity as well as NO and
MDA levels were better in the group receiving both
antibiotic and vitamin A than in the group receiving
antibiotics alone. Nevertheless, SOD activity was
significantly increased in the group receiving only
antibiotics, compared with the control mucosal SOD
activity. We propose that antioxidant, anti-infective,
immunomodulating vitamin A may be added to the
management of sinusitis. In conclusion, further
clinical studies are needed to evaluate the therapeu-
tic role of vitamin A in acute sinusitis in humans.
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