Vol. 93, Issue 1, 189-194, July 2002
Ambient oxygen regulates epithelial metabolism and nitric
oxide production in the human nose
Hitoshi
Nakano1,
Hiroshi
Ide1,
Toshiyuki
Ogasa1,
Shinobu
Osanai1,
Masanobu
Imada2,
Satoshi
Nonaka2,
Kenjiro
Kikuchi1, and
Jun
Iwamoto3
1 First Department of Medicine,
2 Department of Otorhinolaryngology, and
3 Division of Applied Physiology, School of Nursing,
Asahikawa Medical College, Asahikawa 078-8510, Japan
 |
ABSTRACT |
The effects of ambient O2
tension on epithelial metabolism and nitric oxide (NO) production
(
NO) in the nasal airway were examined in nine
healthy volunteers. Nasal NO, O2
consumption (O2), and CO2
production (CO2) were measured during
normoxia followed by gradual hypoxia from 21 to 0% O2
concentration. Nasal O2,
CO2, and respiratory quotient during
normoxia were determined to be 1.19 ± 0.04 ml/min, 1.60 ± 0.04 ml/min, and 1.35 ± 0.04, respectively. Hypoxia exposure to
the nasal cavity significantly decreased both
CO2 and NO
[CO2: 1.60 ± 0.04 to 0.96 ± 0.03 ml/min (P < 0.01), NO:
530 ± 15 to 336 ± 9 nl/min (P < 0.01)]. NO was reduced commensurately with gradual decline
in O2 tension, and the apparent Km
value for O2 was determined to be 23.0 µM. These results
indicate that the nasal epithelial cells exchange O2 and
CO2 with ambient air in the course of their metabolism and
that nasal epithelial cells can synthesize NO by using ambient O2 as a substrate. We conclude that air-borne
O2 diffuses into the epithelium where it may be utilized
for either cell metabolism or NO synthesis.
airway epithelium; gas exchange
| |
INTRODUCTION |
THE SURFACE EPITHELIUM
OF airways has various physiological functions, including air
conditioning, mucociliary clearance, and acting as a barrier against
foreign bodies (28). In particular, ciliated cells, which
have a high content of ATPase within cilia, provide these functions
while consuming aerobic energy (27). Indeed, it has been
demonstrated that O2 concentration in the sinus falls when
the ostium is occluded in chronic sinusitis (2), suggesting that the sinus epithelium can continuously take up air-borne
O2 and excrete CO2; i.e., gas exchange occurs.
However, little is known of the metabolic properties and the source of O2 for epithelial metabolism.
Nitric oxide (NO), a highly diffusible gas, is synthesized
enzymatically by NO synthase (NOS) from L-arginine and
molecular O2, and it has various biological actions
(20). In the nose, NOS is located in the superficial
region of ciliated cells (7, 9, 25), and NO acts as an
upregulator of mucociliary motion (13, 26) and as a host
defense (3, 18). Extremely high concentrations of nasal NO
have been found in exhaled air from the normal human nasal cavity
(1, 17), but NO concentration is reduced in chronic
sinusitis (16). On the other hand, exhaled NO output is
reduced by hypoxia exposure in the human lower airways (6)
and in isolated perfused rabbit lungs (11, 21, 29). In the
human nasal cavity, NO output is depressed by hypoxia at O2
concentrations of <10% (8). However, the precise
mechanisms responsible for the reduced nasal NO output by hypoxia
remain unclear.
It has been demonstrated that cutaneous gas exchange of O2
and CO2 is a passive, diffusion-limited process in the
amphibian skin (22). Furthermore,
Km values for O2 have been
determined in three isoforms of NOS from isolated cell preparations,
suggesting that hypoxia limits the availability of substrate
O2 for NOS (24). Thus we hypothesized that
epithelial cell metabolism is associated with NO production and that
both of these processes are regulated by ambient O2
tension. In the present study, we measured concentrations of NO,
O2, and CO2 from the human nasal airway and
examined the effect of varying O2 tension on the nasal NO
and CO2 outputs.
| |
METHODS |
Subjects.
Healthy adult volunteers with prior experience in respiratory
physiology were recruited from hospital colleagues because the breathing maneuver required voluntary closure of the soft palate for
several minutes. Subjects had no history of a recent upper airway
infection or allergy. All subjects provided informed written consent.
The study was approved by the Human Ethics Committee of Asahikawa
Medical College.
Measurements of nasal NO, O2, and CO2.
Nasal aspiration technique from nasal passages in series with closed
soft palate was used to measure nasal NO, O2, and
CO2 (4, 19). A schematic representation of the
apparatus is shown in Fig. 1. In brief, a
polystyrene tube was tightly attached into the vestibulum of one
nostril to supply compressed NO-free air containing 21%
O2-0.03% CO2-78.97% N2. The other
nostril was connected to the same tube to draw gas inside the nose. To
prevent outward leaks at the nostrils, the connected site was securely
sealed with adhesive tape. Gas was aspirated from one side of the
nostril to the other in series at a fixed flow of 300 ml/min. NO
concentration was continuously measured by a chemiluminescence NO
analyzer (model NOA 270B, Sievers, Boulder, CO) at the proximal site of
the nasal orifice while O2 and CO2
concentrations were simultaneously monitored with a mass spectrometer
(model Arco-1000, Arco System, Kashiwa, Japan). Each analog
output of NO, O2, and CO2 has a signal-delay time that is caused by the response of machine and the dead space of
sampling tube. Thus we adjusted the delay by using a computerized analog-to-digital and digital-to-analog converting device developed in
our laboratory (12). The corrected signals were then
transferred to a data acquisition system (MacLab, ADInstruments, Castle
Hill, New South Wales, Australia) for real-time recordings and later analysis. Nasal NO production (NO) was calculated by
multiplying NO concentration [parts per billion (ppb)] by aspiration
flow rate. Nasal O2 consumption
(O2) and CO2 production
(CO2) were calculated from the
inflow-outflow O2 and CO2 differences
multiplied by the aspiration flow rate. All values are presented at
STPD conditions.
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Fig. 1.
Schematic representation of the apparatus. Gas inside the
nasal cavity was aspirated from one side of the nostril to the other in
series at a flow of 300 ml/min.
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Subjects rested in a sitting position during the measurement. To
isolate the nasal airway from the lower airway, the subject was
instructed to take a shallow breath and to close the soft palate while
watching a monitor displaying nasal CO2 concentration. When
the CO2 concentration decreased to <1%, the nasal NO
concentration reached a maximum steady plateau (Fig.
2). Inward leaks, produced by the opening
of the soft palate, resulted in an abrupt rise in CO2
concentration leaving the nose. When a leak was detected, the
measurement was interrupted and repeated afterward. Subjects who could
not close the soft palate were excluded from this experiment.
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Fig. 2.
Representative recordings of concentrations of nasal
nitric oxide (NO), O2, and CO2. To isolate the
nasal airway from the lower airway, the subject was instructed to close
the soft palate. Nasal NO concentration reached the maximum steady
plateau after closure of the soft palate. ppb, Parts/billion.
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After the steady plateau level of nasal NO concentration was observed,
100% N2 was slowly added to the inlet air while NO, O2, and CO2 concentrations were monitored. The
O2 concentration was gradually and progressively decreased
from 21 to 0% for 5 min followed by a rapid increase to 21% (Fig.
3). NO,
O2, and
CO2 were estimated during normoxic
ventilation and at the end point of gradual hypoxia. The measurement
was taken for one nostril and then for the contralateral nostril. Each
measurement was repeated twice, and the average value of the individual
measurements was used for further analysis.
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Fig. 3.
Representative recordings of the effect of gradual
hypoxia on both NO and CO2 concentrations; O2
concentration was gradually decreased by adding 100% N2
into the inlet air. Both NO and CO2 concentrations
decreased commensurately with a gradual reduction in O2
concentration. Please note that the scale of CO2
concentration is 10 times larger than that of Fig. 2.
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Statistics.
The differences in NO or
CO2 between normoxia and hypoxia were
analyzed by ANOVA followed by a Scheffé's post hoc
t-test. The relationship between NO and
ambient O2 level, which obeyed the Michaelis-Menten
kinetics, was analyzed by the double-reciprocal method
(Lineweaver-Burke plots) with linear least squares regression. In
all cases, a P value < 0.05 was considered
statistically significant. Data are presented as means ± SE.
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RESULTS |
Fourteen subjects (11 men and 3 women) attempted the experiment.
However, five subjects failed to complete it because they were unable
to maintain closure of their soft palate. Nine subjects (age range,
26-48 yr; all men) were successful.
When the nasal cavity was completely isolated from the lower airway, we
found that O2 concentrations in nasal outflow were decreased compared with those in inflow, whereas CO2
concentrations in outflow were increased. From these results, we
calculated nasal O2 and
O2 during normoxia to be 1.19 ± 0.04 and 1.60 ± 0.04 ml/min, respectively (Table
1). In addition, the respiratory quotient
(RQ) was >1 (1.35 ± 0.04).
Figure 3 illustrates representative recordings of the effects of
gradual hypoxia on both NO and CO2 concentrations. Please note that the scale of CO2 concentration in Fig. 3 is 10 times larger than that of Fig. 2. NO concentration decreased
commensurately with a gradual reduction in O2 concentration
as well as CO2 concentration.
As shown in Fig. 4, NO
significantly decreased from 530 ± 15 nl/min during normoxia to
336 ± 9 nl/min (63% of control) at the end point of hypoxia
(P < 0.01), and CO2
significantly decreased from 1.60 ± 0.04 ml/min during normoxia
to 0.96 ± 0.03 ml/min (60% of control) at the end point of
hypoxia (P < 0.01).
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Fig. 4.
Nasal NO production (NO) and carbon
dioxide production (CO2) during normoxia
and at the end of hypoxia. Bars, mean value. Both NO
and CO2 are significantly decreased by
hypoxia exposure (P < 0.01).
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In Fig. 5, the mean values of
NO are plotted against varying O2
concentrations, revealing a curvilinear relationship between NO and O2 concentration. The shape of
the curve resembles closely the plot for enzyme-substrate reaction that
obeys Michaelis-Menten kinetics although NO did not
fall to zero at 0% O2. To analyze this relationship, we
subtracted 336 nl/min (the mean NO value at 0%
O2) from all the NO values and then
replotted the data with the Lineweaver-Burke double-reciprocal method,
which demonstrated a strong linear correlation (r = 0.989) between 1/O2 and 1/NO (Fig.
6). From this analysis, the apparent
Km value for O2 was estimated to be
23.0 µM, which corresponds to ~18 Torr of
PO2, and Vmax was 228.2 nl/min.
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Fig. 5.
Nasal NO responses to varying
O2 concentrations. Mean values of NO
decreased along with a reduction in O2 concentration from
21 to 0%. Shape of the curve closely resembles the plot for
enzyme-substrate reaction that obeys Michaelis-Menten kinetics. Values
are means ± SE.
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Fig. 6.
Lineweaver-Burke double-reciprocal plots between
O2 tension and nasal NO. Apparent
Km value and Vmax are
also shown. Error bars are omitted.
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DISCUSSION |
Nasal O2 and CO2 metabolism.
We found that the nasal epithelium takes up ambient O2 and
excretes CO2 under normoxic conditions; i.e., epithelial
gas exchange occurs. It has been reported that O2 is taken
up by the sinus mucosa (2). However, little is known of
the properties of cutaneous gas exchange in the nasal epithelium. In
the present study, the nasal O2 was
determined to be 1.19 ml/min out of a body metabolic rate of ~250
ml/min, or 0.5% of total body metabolism. By comparison, Kelley and
DuBois (15) demonstrated that nasal superficial capillary blood flow was 13-16 ml/min out of a cardiac output of ~5,000 ml/min, or 0.3% of cardiac output. Although the tissue metabolism is
not necessarily proportional to the local blood flow, the higher percentage of the nasal metabolism than the blood flow indicates that,
in addition to the O2 supplied from the blood, the nasal epithelium may consume much more O2 from the ambient air.
With regard to the nasal CO2 production, 60% of control
value was observed after 100% N2 exposure, suggesting that
this CO2 may come from the O2 supplied from the
blood in the course of ATP turn over rather than from the
O2 from the ambient air.
On the other hand, the value of RQ we found in the nasal cavity
(~1.35) is higher than that for the gas exchange of the mammalian lung; it is consistent with the value obtained for cutaneous
respiration in amphibians (23). Hence, the human nasal
epithelium may have metabolic functions similar to amphibian skin. It
has been demonstrated that cutaneous gas exchange of O2 and
CO2 is a passive, diffusion-limited process that is
determined by the PO2 and
PCO2 gradients across the skin
(22). Thus, in the present study, a marked
decrease in nasal CO2 during hypoxia may
be secondary to a metabolic downregulation due to diffusion limitation
of O2.
Nasal NO.
Most of the nasal lumen is covered by densely ciliated columnar cells.
This epithelium rests on a layer of collagen fibrils called the
basement membrane. Beneath the basement membrane, there is the
submucosa, which is rich in blood vessels. Because NO produced under
the basement membrane would be trapped by hemoglobin circulating in
blood vessels, it is likely that most of the NO excreted into the nasal
cavity originates from the surface epithelium, which stains
immunologically for NOS (7). In addition, NO concentration in the sinuses is extremely high and the sinus NO continues to diffuse
into the nasal cavity (17). To estimate the net NO
production in the nose, it is necessary to take into account the amount
of NO removed by the processes of absorption and/or chemical reaction. As expected, according to the analysis by Dubois et al.
(5), the amount of NO absorbed on the way through the nose
was small in the present study because the gas flow rate we used was
sufficiently high (300 ml/min).
In the present study, ventilation with 100% N2 gas in the
nasal cavity elicited 37% suppression in NO output, with the remainder being 63%. In our previous study, however, inhalation of 100% N2 gas almost completely suppressed exhaled NO output in
isolated perfused rabbit lungs (11). The most likely
reason why 100% N2 did not fully eliminate nasal NO
production could be that NO remained to diffuse into the nasal cavity
from the sinuses, even during 100% N2 exposure, because
O2 concentration in the sinuses was not decreased enough as
a result of poor ventilation of the sinuses. Another possible
explanation is that the blood-borne O2, which is required
for tissue metabolism, may, in part, contribute to the remaining NO
output. In support of this, both nasal vasoconstriction induced by a
topical decongestant xylometazoline and reductions in the blood
O2 content by maximal breath holding-elicited decreases in
baseline levels of nasal NO output (8).
In the nasal airway, NOS has been identified in the epithelium close to
the ciliated surface and within the lamina propria in nerves and
vascular endothelium (7, 9, 25). Furthermore, NO is
synthesized enzymatically by NOS from L-arginine and
molecular O2 (20). It has been clearly
demonstrated that NO production is regulated by ambient O2
tension through a mechanism that obeys Michaelis-Menten kinetics in the
human lower airways (6) and in isolated perfused rabbit
lungs (11, 29). In the human nasal cavity, NO output was
depressed by hypoxia at O2 concentrations of <10%
(8). In the present study, we found that nasal NO output was dependent on luminal O2 concentrations over the range
from 0 to 21%. To estimate the NO kinetics, we simply analyzed the suppressed components of NO output by hypoxia because the remaining NO
components seemed to account for NO from the sinuses or NO originated
from the blood-borne O2 as mentioned previously. As a
result, we could determine the apparent Km value
for O2 to be 23.0 µM. These results indicate that the
nasal epithelial cells take up ambient O2 and excrete NO
into the nasal cavity in proportion to nasal O2 tension. It
has been shown that there is an O2 gradient from the
extracellular medium to the cytoplasm (14) and the plasma
membrane acts as a minimal barrier to O2 diffusion
(10). Nevertheless, the Lineweaver-Burke plot between
nasal NO and O2 concentration displayed
a linear relationship, indicating that nasal NO is synthesized by using
the ambient O2 molecules as a substrate and that hypoxia
limits the O2 available to NOS. The Km value obtained from the present study is
close to the values (14.4 and 24.1 µM) obtained from isolated
perfused rabbit lungs (11, 29) and the value
(7.7 ± 1.6 µM) from cultured bovine aortic endothelial cells
(24), suggesting that there are not huge species
differences in the availability of O2 for NOS. In contrast to these values, Dweik et al. (6) estimated
the Km value to be 190 µM in the human lower
airways. We, however, speculate that this higher
Km value than we reported in the present study may have resulted from these investigators failing to measure NO output
(nl/min) and the fact that they obtained only a few data points below
21% O2.
Significance of nasal NO and metabolism.
The apical region of the ciliated cell is filled with abundant
mitochondria to supply energy for motion of cilia, and the dynein arm
of cilia contains high content of ATPase to support its motility
(27). NOS is located superficially within ciliated cells
(25), and ciliary beat frequency is upregulated by NO (13, 26). Furthermore, NO exerts protective effects
against viral and bacterial infections (3, 18). Thus it is
likely that O2 demand and NO production are closely
associated with both mucociliary function and host defense. In the
present study, we found that hypoxia equally suppressed nasal
CO2 and NO to 60%
vs. 63% of control, respectively. With regard to structure and
function considerations, both aerobic metabolism and NO production are
limited by diffusion of O2, suggesting that mitochondrial respiration and NO synthesis in the epithelium require air-borne O2.
In chronic sinusitis, O2 tension in the sinus falls as a
result of ostial dysfunction (2) while nasal NO levels are
also markedly reduced (16). Therefore, it is likely that
impaired ventilation through the ostium would lead to an O2
deficiency followed by a decline in NO production, resulting in
disrupted mitochondrial respiration, mucociliary dysfunction, and
bacterial infection, thereby bringing about epithelial damage. On the
other hand, because not only the nasal cavity but also the lower
respiratory tracts are covered with ciliated cells, epithelial
metabolism and NO production in the entire airways are likely regulated
as functions of ambient O2 levels. Indeed, it has been
shown that exhaled NO from the lower airways is reduced by hypoxic gas
inhalation in humans (6) and in isolated perfused rabbit
lungs (11, 21, 29). Thus air-borne O2 may play
an important role in both epithelial metabolism and airway function via NO.
In conclusion, we have demonstrated that nasal NO production is, in
part, regulated by ambient O2 tension and that gaseous hypoxia in the nose diminishes epithelial cell metabolism. From these
results, we conclude that air-borne O2 is taken up through the surface of nasal epithelia where it may be utilized for either cell
metabolism or NO synthesis.
| |
ACKNOWLEDGEMENTS |
The authors express their sincere thanks to Dr. John A. Krasney
from the Department of Physiology and Biophysics, the State University
of New York at Buffalo, for comments on the manuscript.
| |
FOOTNOTES |
This work was supported in part by Grants 07670077 and 08670643 from
Scientific Research from the Ministry of Education and Science, Japan.
Address for reprint requests and other correspondence: J. Iwamoto, School of Nursing, Asahikawa Medical College, 2-1-1-1, Midorigaoka-Higashi, Asahikawa 078-8510, Japan (E-mail:
j1103{at}asahikawa-med.ac.jp).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published March 15, 2002;10.1152/japplphysiol.00096.2002
Received 5 February 2002; accepted in final form 14 March 2002.
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ABSTRACT
INTRODUCTION
