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Departments of 1 Medicine and 2 Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642-8692
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX A
APPENDIX B
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Human airways produce nitric oxide (NO), and
exhaled NO increases as expiratory flow rates fall. We show that mixing
during exhalation between the NO produced by the lower, alveolar
airways (
LNO)
and the upper conducting airways
(UNO)
explains this phenomenon and permits measurement of
LNO,
UNO,
and the NO diffusing capacity of the conducting airways
(DUNO).
After breath holding for 10-15 s the partial pressure of alveolar
NO (PA) becomes constant, and
during a subsequent exhalation at a constant expiratory flow rate the
alveoli will deliver a stable amount of NO to the conducting airways.
The conducting airways secrete NO into the lumen
(UNO),
which mixes with PA during
exhalation, resulting in the observed expiratory concentration of NO
(PE). At fast exhalations, PA makes a large contribution to
PE, and, at slow exhalations, NO
from the conducting airways predominates. Simple equations describing
this mixing, combined with measurements of
PE at several different
expiratory flow rates, permit calculation of
PA,
UNO, and DUNO.
LNO
is the product of PA and the
alveolar airway diffusion capacity for NO. In seven normal subjects,
PA = 1.6 ± 0.7 × 10
6 (SD) Torr,
LNO = 0.19 ± 0.07 µl/min,
UNO = 0.08 ± 0.05 µl/min, and
DUNO = 0.4 ± 0.4 ml · min1 · Torr1.
These quantitative measurements of
LNO
and
UNO
are suitable for exploring alterations in NO production at these sites
by diseases and physiological stresses.
nitric oxide diffusing capacity of airways; nitric oxide production by airways; lung nitric oxide; breath holding
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX A
APPENDIX B
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INCREASED EXHALED nitric oxide (NO) concentrations have
attracted interest as a means for detecting inflammation of the airways in asthma (17). NO production by the lungs may be abnormal in diseases
such as sepsis, cirrhosis, primary pulmonary hypertension, and
interstitial lung diseases (18, 21, 26, 27). The exhaled concentration
of NO (PE) increases as
expiratory flow rates
(
E) fall
(24), so E must be kept constant to
obtain reproducible measurements of
PE (Fig.
1). The reason for this flow dependence has
recently been elucidated by Tsoukias and co-workers (28, 29). They show
that during exhalation the mixing between NO from the lower alveolar
airways perfused by the pulmonary circulation (LNO)
with NO produced in the upper conducting airways
(UNO) perfused by the bronchial circulation explains this phenomenon. Simple
equations can describe this mixing. When combined with multiple
measurements of PE at different
E, these
equations permit calculation of
UNO
and the partial pressure of NO in the lower alveolar airways
(PA). In this report, we
describe an analysis of expired NO at different
E that also
permits calculation of the diffusing capacity of the upper airways
(DUNO)
and
LNO. LNO
is determined from the product of
PA and measurements of the
pulmonary diffusing capacity of the lower airways
(DLNO)
(12). Because diseases and physiological stress may cause changes in NO
production and diffusing capacity by the alveoli different from those
by the conducting airways, measurement of
LNO,
UNO, DLNO, and
DUNO may
provide new information about factors that alter NO production by the
lungs.
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Glossary
| DLNO | Diffusing capacity of the lower, alveolar airways recorded as milliliters of NO STPD moving from the air spaces into the tissues and blood per minute per Torr of NO in the air spaces |
| DUNO | Diffusing capacity of the upper, conducting airways recorded as milliliters of NO STPD moving from the air spaces into the tissues and blood per minute per Torr of NO in the air spaces |
| f | Small fraction of
DUNO,
PU, or
UNO
|
| FVC | Forced vital capacity |
| NO | Nitric oxide |
| PA | Partial pressure of NO in the alveoli |
| PB | Barometric pressure |
| PE | Partial pressure of NO in exhaled gas |
| PU | Partial pressure on NO in all or a segment of the upper conducting airway |
| E |
Expiratory flow rate |
| RV | Residual volume of gases in the lungs |
| TLC | Total capacity of gases in the lungs |
| LNO |
Rate of production of NO by the lower alveolar airways that enters the airways |
| UNO |
Rate of production of NO by the conducting airways that enters the airways |
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX A
APPENDIX B
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NO Exchange in the Alveolar Airways
The alveolar airways are defined as those tissues and air spaces well perfused by the pulmonary circulation, such as the alveoli, alveolar ducts, and respiratory bronchioles. In this zone, some of the NO produced by these lower airways diffuses into the air spaces. The fraction of the total NO produced in this alveolar compartment that enters the air spaces is calledLNO.
The NO in the alveoli can react with the surrounding tissues (16) or diffuse rapidly through the alveolar capillary membrane into the perfusing blood. After elimination of ventilation by breath holding for
10-15 s, a steady state will develop, and the amount of NO entering the alveoli
(LNO)
equals the amount of NO diffusing into the perfusing blood and
surrounding tissues (12) or
|
(1) |
LNO.
DLNO was
determined by a modification of the constant single exhalation
method for measuring the pulmonary carbon monoxide diffusing capacity
(DLCO)
described by Newth and co-workers (19) and Perillo and co-workers (20). Multiple values of
DLNO are
calculated during the exhalation and averaged.
NO Exchange in the Conducting Airways
The conducting airways are defined as those airways extending from the alveolar airways to the mouth. Strategies such as continuous positive pressure in the mouth (13, 24) or constant suction of gases from one nostril (9, 28, 29) can be used to avoid contamination of expired NO from the conducting airways by the much higher concentration in the nasopharynx (14). NO gas exchange in the conducting airways can be analyzed in the same manner as in the alveolar airways. Namely, a fraction of NO production by the conducting airways (UNO)
enters the lumen. Some of this NO can diffuse back into the tissues of
the conducting airways and enter the bronchial circulation in
proportion to the partial pressure of NO in the lumen of the conducting
airways (PU). If the bronchial
blood flow maintains the partial pressure of NO in the blood perfusing
the tissues of the conducting airways at a negligible level, the amount
of NO in the lumen that diffuses back into these tissues will equal
PU · DUNO.
With exhalation at a constant flow rate,
PU will reach a constant value,
and during this steady state
UNO
will equal the amount of NO diffusing back into the tissues or
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(2) |
UNO,
and DUNO
from multiple measurements of PE
performed at different constant
E.
Model 1.
Model 1 assumes a uniform
concentration of NO throughout the conducting airways (Fig.
2), so
PU = PE. After breath holding for
10-15 s, a constant PA is
achieved (12), and subsequent exhalation at a steady flow rate
(E)
delivers a constant amount of NO to the conducting airways equal to
E[PA
/ (PB 
47)], where PB is the
barometric pressure, 47 is the partial pressure of water at body
temperature in Torr,
E is
expressed in milliliters per minute
STPD, and
PA is expressed in Torr. This NO
from the alveolar airways instantaneously mixes with NO in the
conducting airways, resulting in a uniform partial pressure of NO in
the conducting airways and the expired breath
(PE). The amount of NO exhaled
at any instant (STPD) equals
E[PE
/ (PB 47)].
This equals the contribution from the alveolar airways
{E[PA
/ (PB 47)]} plus
UNO
less the NO diffusing from the lumen of the conducting airways back
into the tissues and bronchial circulation of the conducting airways
(PE · DUNO)
or
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(3) |
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(4) |
E
provide the data needed to determine
PA,
UNO,
and DUNO in
Eqs. 3 and 4. First,
PA is determined graphically by
taking advantage of the following observation: At higher values of
E (i.e.,
>200 ml/s), PE is relatively
small and results in the term
PE · DUNO decreasing to <3% of
UNO.
If
PE · DUNO
is considered insignificant at such flow rates, Eq. 4 becomes
![P<SC>e</SC> = <FR><NU>1</NU><DE><A><AC>Q</AC><AC>˙</AC></A><SC>e</SC></DE></FR> [<A><AC>V</AC><AC>˙</AC></A><SC>u</SC><SUB>NO</SUB> (P<SC>b</SC> − 47)] + P<SC>a</SC>](/content/vol87/issue4/fulltext/1532/img005.gif)
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(5) |
E results
in PA at the
y-intercept when
1/E = 0, which is also the point where
E = 
. The
slope equals
UNO(PB 47). We therefore calculated
PA from the linear regression of
PE plotted vs.
1/E when
E > 200 ml/s (Fig. 3). If these data failed to result in a doubling of PE, data
at the next slower flow rate <200 ml/s were added until
PE doubled its lowest value.
This value of PA was combined
with all the measurements of PE
and E
collected at different constant
E to
calculate the remaining two variables, UNO
and DUNO,
with use of Eq. 4 with the assistance
of a curve-fitting program utilizing a quasi-Newton regression (8)
(Fig. 4). The program forced the fit
through the calculated value of
PA. To determine whether the
quasi-Newton regression-fitting algorithm supplied a unique solution
for
UNO
and DUNO,
we also calculated their values using the Newton and the steepest
descent-fitting algorithms for a representative subject. The three
algorithms yielded the same values for
UNO
and DUNO.
Therefore, the choice of curve-fitting algorithm does not influence
identification of the unique solutions from these data. The
curve-fitting program requires assumed starting values for
UNO
and DUNO.
These were arbitrarily chosen to be 0.1 µl/min and 0.3 ml · min1 · Torr1,
respectively. In a representative subject, these starting values could
be systematically varied 4- to 10-fold before deterioration of the
fitted curve became apparent. If a poor fit is obtained, starting
values would need to be changed to allow the program to identify a
reasonable fit to the data.
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UNO
was possible from just the faster values of
E used to
calculate PA, UNO
was also calculated from these data with Eq. 5 and compared with
UNO
determined with all values of
E by use of
Eq. 4.
This method for measuring PA,
UNO,
and DUNO
with model 1 assumes rapid arrival at
a new steady state when the NO coming from the alveolar airways mixes
with the NO in the conducting airways during exhalation.
APPENDIX A describes an equation for
calculating the changes in PE
during mixing and shows the amount of gas needed to be exhaled to reach
a steady state. The equation shows that once ~30% of the expiratory
vital capacity has been exhaled after the initial breath-holding
period, PE is within 99% of the
constant equilibrated value, so Eqs. 4 and 5 are valid for measuring
PA,
UNO,
and DUNO.
Model 2.
Model 2 assumes stratification of the
NO concentration in the conducting airways so the concentration
of NO can gradually increase as the expired gas moves through
the conducting airway (Fig. 5). In contrast
to model 1, the conducting airway is
considered to be a cylinder with a total volume K and an infinite
number of uniform segments. Each segment has an equal
fraction (f) of K, UNO,
and
DUNO, so
that the dimensions of any segment are fV,
fUNO,
and fDUNO.
At the start of exhalation at a constant E,
PA enters the first segment,
where
fUNO
adds NO and
fDUNO removes NO at a rate proportional to the partial pressure of NO in the
segment. The bronchial blood flow in the wall of the upper airway is
assumed to keep its partial pressure of NO at a negligible level. The
resultant partial pressure of NO in the lumen of the segment equals
PU1.
PU1 then
enters the next segment, and its fraction of
UNO
and DUNO
results in
PU2, and so
forth. At the proximal end of the conducting airway,
PU = PE.
|
47)]. It is
changed by the NO production
(fUNO)
entering the segment less the amount diffusing out
(PU · fDUNO)
or
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(6) |
|
(7) |
E, as
described above. With this value of
PA and all the measured pairs of
PE and
E,
UNO
and DUNO
are calculated using Eq. 7 with the
assistance of a curve-fitting program utilizing a quasi-Newton regression (8).
Measurement of NO
Details of methods for measuring NO have been recently published (9). Briefly, a rapidly responding chemiluminescence NO analyzer (Sievers NOA, model 270B, Sievers, Boulder, CO) operating at a sample rate of 250 ml/min measured exhaled levels of NO at the mouthpiece with a 150-cm-long, 1.6-mm-ID, 3.2-mm-OD Tygon inlet tube. Response time of the analyzer was <200 ms for a signal 90% of full scale. The analyzer was adjusted to provide 40 measurements of the NO concentration per second that could be averaged over any time interval. The NO analyzer was calibrated daily by serial dilutions of a gas containing 229 parts per billion (ppb) of NO. To obtain gas samples free of NO, air from a gas cylinder containing <2 ppb of NO (Scott Specialty Gases, Plumsteadville, PA) was passed through a filter constructed from a 5.8-cm-ID, 19-cm-long cylinder (Gas Drying Unit, VWR Scientific, Rochester, NY) packed with potassium permanganate (Purafil, Thermoenvironmental Instruments, Franklin, MA) (4).Because the air signal free of NO could drift as much as 2 ppb in 10 min, measurements of NO-free air were performed within 1 min before and
after each NO measurement from expired gas samples, and these values
were averaged to obtain the zero NO signal. The lag time between the
volume signal obtained from a potentiometer attached to the spirometer
and the change in the NO signal was determined daily and equaled 0.8 ± 0.1 (SD) s. Multiple repetitive measurements of gas mixtures of
2.8 and 8.2 × 106
Torr of NO showed a standard deviation of 0.09 × 106 Torr. We assumed that
the detection limit of our analyzer was two times the standard
deviation of these multiple measurements or 0.2 × 106 Torr. During gas
sampling the operator exhaled warm humidified gas from the mouth by the
inlet of the NO analyzer approximately every 5-10 min, so the
walls of the unheated inlet tubing were kept moist. This resulted in
all gases being considered measured at
ATPS. Measurements of NO in parts per
billion ATPS were converted to partial
pressure of NO in Torr BTPS as
follows: NO in Torr = (NO in ppb
ATPS)(PB)(PB 47) / (PB PH2O)(109),
where PH2O is
partial pressure of water at room temperature. For example, at
PB of 760 Torr and room temperature of 24°C where PH2O = 22.4 Torr, 1 ppb NO = 0.735 × 106 Torr of NO. The chart
recorder (MacLab Recording Instrument, AD Instruments, Castle Hill,
Australia) stored the volume signal and NO signal in a Macintosh LC
computer (Apple Computer, Cupertino, CA). To obtain a stable constant
value for the measurement of PE
after breath holding, we discarded an initial portion of the exhalate
equal to four times the sum of the subject's estimated anatomic dead
space and the instrument dead space of 100 ml, as well as the final
10% of the exhalate (Fig. 6). At flow
rates <45 ml/s, a constant value for
PE was obtained earlier during exhalation (APPENDIX A). At flow
rates >1,000 ml/s, a constant value for
PE was frequently not present
until 40-50% of the breath had been expired. In these cases, the
NO plateau level was determined by visual assessment of the NO signal
displayed on the computer.
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Maneuvers Used to Measure PE and
E
E. Each
subject performed measurements at seven different flow rates that were
as low as 6 ml/s and as high as 1,355 ml/s. Exhalations at each flow
rate were performed in triplicate, and the values for
PE and
E were averaged. PE was measured as
described above, and
E was
obtained from the spirometer's volume signal after the initial and
final 10% of the expired volume were discarded (Fig. 6). The entire experiment for each subject was completed within 4 h on the same day.
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Measurement of DLNO
DLNO for each subject was calculated from the expired NO concentration measured after inspiring 10 parts/million of NO in air placed in the bag in Fig. 7 from RV to TLC, breath holding for 5 s, and then exhaling to RV at a constant flow rate of 500 ml/s with a modification of the single-breath exhalation method for continuously measuring DLCO during exhalation described by Newth and co-workers (19) and Perillo and co-workers (20). Lung volume at any instant during exhalation used in the calculation of the multiple values of DLNO was obtained by adding the amount of exhaled gas remaining above RV recorded by the spirometer (Fig. 7) to the subject's RV. RV was obtained from the subject's functional residual capacity (FRC) measured with body plethysmography (5) by subtracting the expiratory reserve volume obtained from a spirometer (P. K. Morgan, Haverhill, MA) from FRC. The multiple measurements of DLNO during the exhalation were averaged and performed in triplicate, and the mean value was recorded.Subjects
PA,UNO,
and DUNO
were measured in seven healthy, nonsmoking, 31- to 72-yr-old (mean 46 ± 18 yr) subjects. Five were men and two were women. All subjects
were free of cardiopulmonary disease. Spirometry showed values >90%
of predicted for the forced expiratory volume in 1 s, with a mean value
of 104 ± 16 (SD)% (2). This study was approved by the University
of Rochester's committee for investigations involving human subjects.
Statistical Methods
Values are means ± SD. In experiments where subjects served as their own control, results were compared using a two-tailed paired t-test. Groups of subjects were compared with an unpaired t-test. P < 0.05 was required for statistical significance. Regression lines and curves were fitted to the experimental data by the line of least mean squares referenced to PE.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX A
APPENDIX B
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PA,
LNO,
and DLNO
E
(1/E) used
to determine PA from the faster
exhalations in the seven subjects. The linear regression of these
points extrapolated to infinite flow, where
1/E = 0, equals PA. The regression line fitted the data closely, with
r2 = 0.965-0.999. PA was 1.6 ± 0.7 × 106 (SD)
Torr. DLNO
was 123 ± 19 ml · min1 · Torr1.
LNO
(i.e.,
PA · DLNO)
was 0.19 ± 0.07 µl/min.
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UNO
and DUNO
E for all
exhalations by the seven subjects used to determine
UNO
and DUNO. E ranged
from 6 to 1,355 ml/s. For model 1,
UNO
was 0.077 ± 0.053 µl/min and
DUNO was
0.4 ± 0.4 ml · min1 · Torr1;
for model 2 the values were similar:
0.074 ± 0.052 µl/min and 0.5 ± 0.4 ml · min1 · Torr1, respectively. The
regression lines for both models fit the data closely, with
r2 > 0.998 in
all subjects. The value of
r2 for the two
models did not differ significantly: 0.9996 ± 0.0003 for
model 1 and 0.9994 ± 0.0006 for model 2 (P = 0.30).
UNO calculated with just the faster values of
E shown in
Fig. 8 with use of Eq. 4 was 0.070 ± 0.048 µl/min. Although this value is slightly lower than 0.077 ± 0.053 µl/min with model 1 and
0.074 ± 0.052 µl/min with model
2, the difference was not significant (P = 0.2).
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Comparison of
LNO
and
UNO
LNO
of 0.19 ± 0.07 µl/min was consistently greater than
UNO
of 0.077 ± 0.053 µl/min with use of model 1 (P < 0.01).
Calculating with model 2 gave similar
results.
LNO was 0.19 ± 0.07 µl/min compared with
UNO
of 0.074 ± 0.052 µl/min (P < 0.01).
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Comparison of DLNO and DUNO
Table 1 shows that DLNO is >100-fold greater than DUNO calculated with model 1 or model 2.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX A
APPENDIX B
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These data show that a model of the human airways where exhaled NO from
the alveoli mixes with the NO produced by the conducting airways
precisely predicts the PE
observed at different
E. Simple equations describing this mixing combined with values for
PE at different values of
E result in
measurements of
UNO,
DUNO, and
PA.
PA multiplied by a separate
measurement of
DLNO gives a measurement of
LNO.
Besides these separate quantitative measurements of
LNO
and
UNO,
this model provides a reasonable physiological explanation for the rise
in expired NO with slower
E and helps define the physiological basis for observed values of expired NO
reported by many investigators (6, 13, 17, 24, 29).
Common practice is to measure expired NO at a single relatively slow
E on the order
of 100-250 ml/s (13). The resultant observed values of
PE are three to five times
PA and, therefore, predominantly
represent
UNO.
Although these measurements at single relatively slow
E values
provide a useful index of
UNO, they are at a disadvantage for detecting changes in
PA and
LNO.
A number of studies suggest that the mechanisms altering
UNO
and
LNO
may be different. The large increases in
PE seen in bronchial asthma
likely come from upregulation of inducible NO synthase in the
conducting airways (11, 30). Endothelial-derived NO synthase is
reported to be located in the alveolar capillary membrane (10) and is
upregulated in a rat model of the hepatopulmonary syndrome (7). This
upregulation could explain the high levels of exhaled NO observed in
some patients with cirrhosis and the hepatopulmonary syndrome (18).
Downregulation of endothelial-derived NO synthase may account for the
low levels of expired NO reported in primary pulmonary hypertension (3,
21). The technique described in this report for measuring
UNO
and
LNO
should provide a quantitative method to localize alteration in NO
production to the alveoli or the conducting airways. Such measurements
may result in more precision in the use of exhaled NO to assess lung injury or alterations in regulation of NO production by the lungs than
that obtained with observations at a single
E.
Choice of Lung Models to Explain the Change in
PE With Different Values of
E
E, with
r2 > 0.998 in
all subjects. The multicompartment model of the conducting airways
(model 2), with the more realistic
assumption that NO concentration in the conducting airways gradually
approaches PE during exhalation,
does not provide a better fit to the observed data. We also performed
theoretical calculations to see if measurements of
PE at
E in humans as
low as the practical limit of ~5 ml/s can be used to distinguish
between the two models. These models generate different values for
PE shown in Fig.
11 for the same assumed values of
PA,
UNO,
and DUNO.
Fitting the equation of one model to the data generated by the
other model results in a very tight fit, with
r2 > 0.999 (Fig. 12). Therefore, observed values of
PE measured over a wide spectrum
of E values
cannot be expected to distinguish which model provides a more realistic
prediction of the observed data.
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Models 1 and
2 have limitations in their assumed
dimensions, because the conducting airways must contain multiple
compartments where the ratio of the surface area of the conducting
airways that secretes NO into the gas volume in the lumen decreases as exhaled gas moves from the alveoli through the trachea (6, 23, 31).
This anatomy results in uneven distribution between UNO,
DUNO, and
conducting airway gas volume. Because the simple one-compartment model
of the conducting airways so accurately predicts
PE at different values of
E, use of more
realistic models of the conducting airways is not likely to result in a better measurable prediction of the experimental data.
Lung Model Where NO Production Is Uniformly Distributed Throughout the Walls of the Conducting Airways
Tsoukias and George (28) reported what may be a more realistic model of the dynamics of pulmonary NO exchange in the conducting and alveolar airways. They define NO production as taking place uniformly throughout the walls of the lungs' tissues. From the differential mass balance of NO in the tissue, they derive a second-order partial differential equation (Eq. 1 in Ref. 28) that allows determination of the changes in PE by interventions such as varying breath-holding time before exhalation, accelerating or slowing flow rates during exhalation, and varying the inspired NO concentration. Their experimental data obtained by measuring expired NO concentrations in seven normal subjects at different constantE levels
result in a fit close to their model, similar to that obtained using models 1 and
2 described above. Therefore, expired
NO concentrations collected at different
E in normal
subjects unfortunately do not provide a means to determine which of
these various models most closely accounts for the observed profiles of
expired NO concentration.
Potential Errors in
LNO
Calculated With Eq. 2 With the Assumption That
DLNO Is Constant
LNO
might be falsely high when values for
DLNO
obtained at high lung volumes are used and falsely low when
measurements of
DLNO
measured at low lung volumes are used. In the calculation of
LNO
with Eq. 2, we used a mean value of
DLNO
obtained from
DLNO
continuously calculated from the expired NO concentration recorded
during expiration. The calculation started at a maximum volume equal to
the subject's TLC less four times the subject's estimated anatomic
dead space and ended when the subject reached a volume equal to the RV
plus 15% of the forced vital capacity (19, 20). Newth and co-workers
(19) reported that
DLCO
measured with this method was unchanged as lung volume decreased.
Preliminary measurements in nine subjects (20) showed that
DLNO
decreased 9% over this volume interval, but this change did not reach
statistical significance (P = 0.3).
Therefore, the change in
DLNO with
different lung volumes with use of the continuously calculated values
during exhalation appears modest and would not be expected to result in
large errors in
LNO.
However, use of single-breath measurements of
DLNO
obtained at TLC could result in overestimation of
LNO.
Fraction of Total
LNO
and
UNO
Measured From Analyses of PE
LNO
and
UNO
assumes that NO produced in the tissues enters the air
spaces and then diffuses into the surrounding tissues and
perfusing blood. Some of the NO produced in the alveoli and the
conducting airways will react with the tissues and blood and never
enter the air spaces (16). This NO will not be measured by analyses of
NO in the airways; therefore, LNO
and
UNO
are likely underestimates of the true amount of NO produced by the
alveoli and conducting airways. We are unaware of methods that can
measure the fraction of NO that does not communicate with
airways, and its size may be increased by diseases that impair diffusion of NO from the tissues into the air spaces.
Comparison to Estimates of
LNO
and PA From Data of Others
E of 1,550 ml/s preceded by a 30-s breath hold and obtained a
PE of 2.4 ± 1.0 × 106 Torr. With use of their
mean data for PE at slower
E,
extrapolation of their data to an infinite value for
E gives
PA of 1.9 ± 0.8 × 106 Torr, which is in close
agreement with our value of 1.6 ± 0.7 × 106 Torr observed in our
seven subjects.
Recently, Tsoukias and co-workers (28, 29) published a similar
two-compartment model consisting of a nonexpansile compartment representing the conducting airways and an expansile compartment representing the alveolar region of the lungs. In their seven normal
subjects, they determined PA
from 8-12 measurements of PE and
E performed at
constant values of
E that varied
from 175 to 600 ml/s. With an equation equivalent to
Eq. 3, they calculated PA and the flux of NO from the
tissues of the conducting airways to the lumen. For
model 1, flux equals
UNO (PE · DUNO).
By plotting
E[PE
/ (PB 47)]
on the vertical axis vs.
E on the horizontal axis, the intercept on the vertical axis equals flux and the
slope equals PA /
(PB 47). Their values of
PA of 4.1 ± 2.3 × 106 Torr were significantly
greater than 1.6 ± 0.7 × 106 Torr obtained in our
seven normal subjects (P = 0.025). We
have no explanation for the higher values of
PA obtained by Tsoukias and
co-workers. However, their flow rates ranged from only 175 to 600 ml/s,
whereas E for
the subjects of Silkoff et al. (24) and our subjects varied from 4 ml/s
to as high as 1,550 ml/s. This greater range in
E may provide
more precision in determining PA.
Comparison to Estimates of
UNO
and DUNO From Data of
Others
E
that permit calculation of
UNO
or DUNO. Silkoff and co-workers (24) reported
PE at nine different values of
E between 4.2 and 1,550 ml/s in 10 subjects. Their data shown in Fig.
13 permit calculation of
UNO
and DUNO by
use of Eq. 4 or
7. Note the similarity of their data
to the findings in our subjects shown in Fig. 9. Model
1 closely fit the data of Silkoff and co-workers, with
a mean r2 of
0.996 for their 10 subjects.
UNO
from their data was 0.061 ± 0.056 µl/min compared with 0.076 ± 0.053 µl/min in our subjects and did not differ significantly
(P = 0.22).
DUNO in
their subjects was 0.4 ± 0.3 ml · min1 · Torr1
compared with 0.4 ± 0.4 ml · min1 · Torr1
in our subjects (P = 0.61).
Model 2 gave similar results with a
close fit to the data
(r2 = 0.995).
UNO
was 0.053 ± 0.039 µl/min compared with 0.074 ± 0.052 µl/min
in our subjects (P = 0.20),
and DUNO
was 0.5 ± 0.3 ml · min1 · Torr1
vs. 0.5 ± 0.4 ml · min1 · Torr1
in our subjects (P = 0.46). The data
of Silkoff and co-workers and our data show a wide scatter for the
values of
UNO
and DUNO in
normal subjects, with coefficients of variation (CV) ranging from 60 to
90%. PA and
LNO
show less scatter, with a CV on the order of 40%.
|
Tsoukias and co-workers (28, 29) calculated flux from the data in their
seven subjects, as described above. With use of representative values
of PE in our subjects at
E of
175-600 ml/s used by Tsoukias and co-workers, their values of flux
would only be ~1-3% smaller than
UNO.
Flux in their subjects was 0.043 ± 0.015 µl/min and did not
significantly differ from the values of
UNO
of 0.070 ± 0.048 µl/min in our subjects with use of the faster
E shown in
Fig. 8 (P = 0.20) or 0.077 ± 0.053 µl/min with model 1 (P = 0.16) or 0.074 ± 0.52 µl/min with model 2 (P = 0.18) with use of faster and
slower
E.
Evaluation of a Simplified Method to Measure
UNO
by Use of Only Faster
E
UNO
with E > 80-100 ml/s would have the advantage of fewer measurements of
PE and elimination of the slow exhalations that are more difficult to perform because expiration must
be continued for 25-150 s. The disadvantage is that
DUNO cannot
be measured with any precision, because its accuracy requires the
higher concentrations of NO in the conducting airways achieved with
low values for
E. In our
subjects,
UNO
calculated with only the faster
E shown in
Fig. 8 with use of Eq. 4 was 0.070 ± 0.048 µl/min compared with 0.077 ± 0.053 µl/min for
model 1 and 0.074 ± 0.052 µl/min
for model 2 by use of all the values of PE and
E shown in
Fig. 9. The three values did not differ significantly
(P = 0.2) and have similar CVs of
~70%. Measuring UNO
with the useful expediency of using only faster
E provides acceptable values for
UNO
but at the expense of measurements of
DUNO.
Choice of Analytic Method to Determine
PA,
UNO,
and DUNO From
Measurements of PE and
E Performed at
Different Constant
E
E and
PE /
(PB 47) vs.
E, so that
the slope of the graph equaled
PA /
(PB 47) and the
intercept equaled flux (Eq. 3). We
rearranged Eq. 3 to the form in
Eqs. 4 and 5 and plotted
PE vs.
1/E so that
E
did not appear on both axes, thus eliminating potential errors of
mathematical coupling that can lead to erroneous conclusions (1, 22).
However, in our normal subjects the two analytic techniques provide
essentially the same values for UNO
or flux and PA. For example, the
data using the higher values of
E shown in
Fig. 8 with the analytic technique applied by Tsoukias and co-workers
(28, 29) using Eq. 3 resulted in flux of 0.065 ± 0.045 µl/min compared with
UNO
of 0.070 ± 0.048 µl/min by use of Eq. 5 (P = 0.21).
PA was 1.78 ± 0.77 × 106 Torr with the method of
Tsoukias and co-workers compared with 1.60 ± 0.72 × 106 Torr with Eq. 6
(P = 0.14). Calculations with all
seven sets of values of
E and
PE resulted in flux of 0.067 ± 0.046 µl/min with the method of Tsoukias and co-workers with
use of Eq. 3 compared with
UNO
of 0.077 ± 0.053 µl/min with Eq. 4. Therefore, in normal subjects the two analytic
methods result in similar data. Measurements in less well-trained
subjects are prone to greater variations in
PE and
E; therefore,
it may be wise to analyze data with both methods to determine whether
mathematical coupling is influencing the results.
Alternate Models to Explain Expired NO Levels at Different
E
|
(8) |
|
(9) |
UNO
/ DUNO.
Because all the other terms in Eqs. 7 and 9 are identical, Pti in this model
must equal
UNO
/ DUNO
in model 2 described above. Because
the two models result in identical solutions, the only difference in
the models is the terminology assigned to the measured constants. For
example, if the model with constant NO concentration in the wall of
the conducting airways (Pti) is preferred, the value for Pti
is readily determined by dividing
UNO
by DUNO
obtained with model 1 or
model 2. In our subjects this value
was 562 ± 798 and 313 ± 437 × 106 Torr for
models 1 and
2, respectively. In the 10 subjects of Silkoff et al. (24) shown in Fig. 13, this value was 573 ± 798 and
289 ± 531 × 106
Torr for models 1 and
2, respectively.
In conclusion, these experiments show that NO production into the
lungs' airways can be measured and divided into contributions from the
alveoli
(LNO)
and the conducting airways
(UNO).
LNO shows less scatter in measurements in normal subjects and is two- to
fourfold greater than
UNO.
DLNO is
>100-fold greater than DUNO.
Because diffusion and control of NO production in the alveoli and
conducting airways are likely governed by different mechanisms, this
technique may provide new information about processes that control and
alter NO production by the lungs.
| |
APPENDIX A |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX A
APPENDIX B
|
|---|
Rate of Mixing of Alveolar Airway NO With Conducting Airway NO in a Two-compartment Model
Model 1 assumes that, at the initiation of expiration at a constant flow rate, NO in the conducting airways rapidly arrives at a constant value that is maintained throughout expiration. To determine the time required to reach this constant value, we calculated the rate of change of NO in the conducting airways (PE) as NO enters from the alveolar airways. This instantaneous rate of change in the amount of NO in the conducting airways equals d/dt[(PE · K)/(PB 47)], where K is the volume of gas in the conducting
airways and PE is the partial
pressure of NO in the conducting airways. In this model,
PE is determined by four
variables: 1) NO from the alveoli
entering the conducting airways at a constant flow rate
[E · PA
/ (PB 47)],
2) NO produced in the conducting airway that enters its lumen
(UNO),
3) NO diffusing out of the lumen
of the conducting airway into the surrounding tissues
(PE · DUNO),
and 4) NO leaving the conducting
airway via exhalation [E · PE
/ (PB 47)].
Therefore
|
|
(A1) |
![<FR><NU>dP<SC>e</SC></NU><DE>d<IT>t</IT></DE></FR> = <FR><NU>1</NU><DE>K</DE></FR> (<A><AC>Q</AC><AC>˙</AC></A><SC>e</SC> ⋅ P<SC>a</SC> + <A><AC>V</AC><AC>˙</AC></A><SC>u</SC><SUB>NO</SUB>[P<SC>b</SC> − 47])](/content/vol87/issue4/fulltext/1532/img012.gif)
|
![− P<SC>e</SC> ⋅ <FR><NU>1</NU><DE>K</DE></FR>[<A><AC>Q</AC><AC>˙</AC></A><SC>e</SC> + D<SC>u</SC><SUB>NO</SUB>(P<SC>b</SC> − 47)]](/content/vol87/issue4/fulltext/1532/img013.gif)
|
(A2) |
bx, the solution of which is
x = (a/b)(1 ebt)
or
![P<SC>e</SC> = <FR><NU><A><AC>Q</AC><AC>˙</AC></A><SC>e</SC> ⋅ P<SC>a</SC> + <A><AC>V</AC><AC>˙</AC></A><SC>u</SC><SUB>NO</SUB> (P<SC>b</SC> − 47)</NU><DE><A><AC>Q</AC><AC>˙</AC></A><SC>e</SC> + D<SC>u</SC><SUB>NO</SUB> (P<SC>b</SC> − 47)</DE></FR> <FENCE>1 − <IT>e</IT><SUP>−<SUP> <FR><NU>[<A><AC>Q</AC><AC>˙</AC></A><SC>e</SC> ⋅ D<SC>u</SC><SUB>NO</SUB> (P<SC>b</SC> − 47)]<IT>t</IT></NU><DE>K</DE></FR></SUP></SUP> </FENCE>](/content/vol87/issue4/fulltext/1532/img014.gif)
|
(A3) |
E · PA + UNO(PB 47)]/[E + DUNO(PB 47)] in Eq. A3 equals
the value of PE when mixing is
complete (PE = ),
Eq. A3 can be written as
![<FR><NU>P<SC>e</SC><SUB><IT>t</IT></SUB></NU><DE>P<SC>e</SC><SUB>∞</SUB></DE></FR> = 1 − <IT>e</IT><SUP>−<SUP> <FR><NU>[<A><AC>Q</AC><AC>˙</AC></A><SC>e</SC> ⋅ D<SC>u</SC><SUB>NO</SUB> (P<SC>b</SC> − 47)]<IT>t</IT></NU><DE>K</DE></FR></SUP></SUP>](/content/vol87/issue4/fulltext/1532/img015.gif)
|
(A4) |
1 · Torr1
and the measured half time to reach a steady state during exhalation at
E = 250 ml/min that equaled 0.25 min measured in one of the subjects. Then,
according to Eq. A4
![1 ÷ 2 = 1 − <IT>e</IT><SUP>−<SUP> <FR><NU>[250 + 0.5 (P<SC>b</SC> − 47)]0.25</NU><DE>K</DE></FR></SUP></SUP> or K = 220 ml](/content/vol87/issue4/fulltext/1532/img016.gif)
|
E, the time
to reach a specified ratio of PE
to PE
can be calculated. For example, if
E
is 1,000 ml/s (60,000 ml/min),
PB = 760 Torr, and the time to
reach 99% equilibrium is desired, Eq. A4 becomes
![<FR><NU>99</NU><DE>100</DE></FR> = 1 − <IT>e</IT><SUP>−<SUP> <FR><NU>[60,000 + 0.5(713)]<IT>t</IT></NU><DE>220</DE></FR></SUP></SUP> or <IT>t</IT> = 1.01 s](/content/vol87/issue4/fulltext/1532/img017.gif)
|
E of 1,000 ml/s, total time to exhale the breath is 3,500 / 1,000 or 3.5 s.
Therefore, in this subject, 99% equilibrium in
PE is reached when 1.01 /
3.5 or 29% of the breath has been exhaled. Figure
14 shows the required percentage of the
breath exhaled to reach 99% and 99.9% equilibrium at different E with use
of the above representative values for
DUNO of 0.5 ml · min1 · Torr1
and K of 220 ml in our subjects. At
E 
80 ml/s, 29% of the breath must be exhaled to achieve 99% mixing and
43% must be exhaled for 99.9% mixing. At slower flow rates, mixing is
achieved at progressively smaller fractions of the exhaled breath,
because PA is a smaller fraction
of the higher levels of NO present in the conducting airways with slow
exhalations. In summary, this analysis shows that stable values for
PE can be expected once 30-40% of the expiratory vital capacity is exhaled.
|
| |
APPENDIX B |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX A
APPENDIX B
|
|---|
Determination of PE in a Two-compartment Model of the Airways with Stratification of the Concentration of NO Along the Lumen of the Conducting Airways
In any segment of the conducting airways illustrated in Fig. 5
|
(B1) |
UNO
is the same small fraction of UNO,
fDUNO is
the same small fraction of
DUNO, and
PU1 is the partial pressure of NO in the segment. The ratio of fK,
fUNO, and fDUNO
is assumed constant throughout the conducting airways. As this volume
of gas moves to the next segment,
fUNO
will add NO and NO will be removed at a rate equal to
fDUNO · PU2,
where PU2
is the partial pressure of NO in the next segment that resulted from
residence in the previous segment. In Eq. B1, the term f cancels out, because each segment is
defined as containing an equal fraction f of K,
UNO,
and
DUNO.
Rearranging gives
|
(B2) |
bx. If the initial value of
PU is assumed to be zero, this
type of equation has the solution
|
|
(B3) |
E or
|
(B4) |
E approaches
zero, PE reaches a maximum value
of
UNO
/ DUNO.
This value results because when there is no flow in the upper airways,
the amount of NO entering (UNO)
will equal the amount leaving, which equals
PE · DUNO or
UNO = PE · DUNO.
Rearranging, PE = UNO
/ DUNO
when E = 0. When E is
very fast, Eq. B4 states that
PE approaches zero. However,
unlike Eq. B3, a finite concentration
of NO equal to PA is entering
the conducting airways from the alveoli, so when
E is
infinitely fast, PE equals
PA, not zero. Therefore, the
correct limits for PE are as
follows: PA when
E approaches
infinity and
UNO
/ DUNO
when E
approaches zero. Equation B4 can
therefore be expanded to
|
(B5) |
| |
ACKNOWLEDGEMENTS |
|---|
The authors thank Dr. Phillip E. Silkoff for providing the values of expired NO at different expiratory flow rates previously reported in Ref. 24 and illustrated in Fig. 13. Ann Bauman contributed expert editorial assistance.
| |
FOOTNOTES |
|---|
This study was supported by National Institutes of Health Grants R01-HL-51701, R01-ES-02679, and T32-HL-07216.
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: A. P. Pietropaoli, Pulmonary and Critical Care Unit, University of Rochester Medical Center, 601 Elmwood Ave., Box 692, Rochester, NY 14642-8692 (E-mail: anthony_pietropaoli{at}urmc.rochester.edu).
Received 12 January 1999; accepted in final form 14 June 1999.
| |
REFERENCES |
|---|
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX A
APPENDIX B
|
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 K. Roy, Z. L. Borrill, C. Starkey, A. L. Hazel, J. Morris, J. Vestbo, and D. Singh Use of different exhaled nitric oxide multiple flow rate models in COPD Eur. Respir. J., April 1, 2007; 29(4): 651 - 659. [Abstract] [Full Text] [PDF]
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P. Condorelli, H.-W. Shin, A. S. Aledia, P. E. Silkoff, and S. C. George A simple technique to characterize proximal and peripheral nitric oxide exchange using constant flow exhalations and an axial diffusion model J Appl Physiol, January 1, 2007; 102(1): 417 - 425. [Abstract] [Full Text] [PDF]
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 H.-W. Shin, C. D. Schwindt, A. S. Aledia, C. M. Rose-Gottron, J. K. Larson, R. L. Newcomb, D. M. Cooper, and S. C. George Exercise-induced bronchoconstriction alters airway nitric oxide exchange in a pattern distinct from spirometry Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2006; 291(6): R1741 - R1748. [Abstract] [Full Text] [PDF]
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 I. van der Lee, P. Zanen, J. C. Grutters, R. J. Snijder, and J. M.M. van den Bosch Diffusing capacity for nitric oxide and carbon monoxide in patients with diffuse parenchymal lung disease and pulmonary arterial hypertension. Chest, February 1, 2006; 129(2): 378 - 383. [Abstract] [Full Text] [PDF]
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H.-W. Shin, P. Condorelli, and S. C. George Examining axial diffusion of nitric oxide in the lungs using heliox and breath hold J Appl Physiol, February 1, 2006; 100(2): 623 - 630. [Abstract] [Full Text] [PDF]
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 ATS Workshop Proceedings: Exhaled Nitric Oxide and Nitric Oxide Oxidative Metabolism in Exhaled Breath Condensate. Proceedings of the ATS, January 1, 2006; 3(2): 131 - 145. [Full Text] [PDF]
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B. L. Rottier, J. Cohen, T. W. van der Mark, W. R. Douma, E. J. Duiverman, N. H. T. ten Hacken, and S. C. George A different analysis applied to a mathematical model on output of exhaled nitric oxide J Appl Physiol, July 1, 2005; 99(1): 378 - 380. [Abstract] [Full Text] [PDF]
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R Ratnawati and P S Thomas Exhaled nitric oxide in paediatric asthma Chronic Respiratory Disease, July 1, 2005; 2(3): 163 - 174. [Abstract] [PDF]
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H.-W. Shin, P. Condorelli, and S. C. George A new and more accurate technique to characterize airway nitric oxide using different breath-hold times J Appl Physiol, May 1, 2005; 98(5): 1869 - 1877. [Abstract] [Full Text] [PDF]
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 ATS/ERS Recommendations for Standardized Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide, 2005 Am. J. Respir. Crit. Care Med., April 15, 2005; 171(8): 912 - 930. [Full Text] [PDF]
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I. van der Lee, P. Zanen, and G. S. Zavorsky Diffusion Capacity for Nitric Oxide and Carbon Monoxide Chest, November 1, 2004; 126(5): 1708 - 1710. [Full Text] [PDF]
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A. F. Gelb, C. F. Taylor, E. Nussbaum, C. Gutierrez, A. Schein, C. M. Shinar, M. J. Schein, J. D. Epstein, and N. Zamel Alveolar and Airway Sites of Nitric Oxide Inflammation in Treated Asthma Am. J. Respir. Crit. Care Med., October 1, 2004; 170(7): 737 - 741. [Abstract] [Full Text] [PDF]
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H.-W. Shin, P. Condorelli, C. M. Rose-Gottron, D. M. Cooper, and S. C. George Probing the impact of axial diffusion on nitric oxide exchange dynamics with heliox J Appl Physiol, September 1, 2004; 97(3): 874 - 882. [Abstract] [Full Text] [PDF]
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P. Condorelli, H.-W. Shin, and S. C. George Characterizing airway and alveolar nitric oxide exchange during tidal breathing using a three-compartment model J Appl Physiol, May 1, 2004; 96(5): 1832 - 1842. [Abstract] [Full Text] [PDF]
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S. C. George, M. Hogman, S. Permutt, and P. E. Silkoff Modeling pulmonary nitric oxide exchange J Appl Physiol, March 1, 2004; 96(3): 831 - 839. [Abstract] [Full Text] [PDF]
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B. Mahut, C. Delacourt, F. Zerah-Lancner, J. De Blic, A. Harf, and C. Delclaux Increase in Alveolar Nitric Oxide in the Presence of Symptoms in Childhood Asthma Chest, March 1, 2004; 125(3): 1012 - 1018. [Abstract] [Full Text] [PDF]
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H.-W. Shin, C. M. Rose-Gottron, D. M. Cooper, R. L. Newcomb, and S. C. George Airway diffusing capacity of nitric oxide and steroid therapy in asthma J Appl Physiol, January 1, 2004; 96(1): 65 - 75. [Abstract] [Full Text] [PDF]
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T. Martinez, A. Weist, T. Williams, C. Clem, P. Silkoff, and R. S. Tepper Assessment of exhaled nitric oxide kinetics in healthy infants J Appl Physiol, June 1, 2003; 94(6): 2384 - 2390. [Abstract] [Full Text] [PDF]
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C. C. W. Hsia, X. Yan, D. M. Dane, and R. L. Johnson Jr. Density-dependent reduction of nitric oxide diffusing capacity after pneumonectomy J Appl Physiol, May 1, 2003; 94(5): 1926 - 1932. [Abstract] [Full Text] [PDF]
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 D. J. Vaughan, T. V. Brogan, M. E. Kerr, S. Deem, D. L. Luchtel, and E. R. Swenson Contributions of nitric oxide synthase isozymes to exhaled nitric oxide and hypoxic pulmonary vasoconstriction in rabbit lungs Am J Physiol Lung Cell Mol Physiol, May 1, 2003; 284(5): L834 - L843. [Abstract] [Full Text] [PDF]
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A. Van Muylem, C. Noel, and M. Paiva Modeling of impact of gas molecular diffusion on nitric oxide expired profile J Appl Physiol, January 1, 2003; 94(1): 119 - 127. [Abstract] [Full Text] [PDF]
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H.-W. Shin and S. C. George Impact of axial diffusion on nitric oxide exchange in the lungs J Appl Physiol, December 1, 2002; 93(6): 2070 - 2080. [Abstract] [Full Text] [PDF]
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M. Shinkai, S. Suzuki, A. Miyashita, H. Kobayashi, T. Okubo, and Y. Ishigatsubo Analysis of Exhaled Nitric Oxide by the Helium Bolus Method* Chest, June 1, 2002; 121(6): 1847 - 1852. [Abstract] [Full Text] [PDF]
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C. DELCLAUX, B. MAHUT, F. ZERAH-LANCNER, C. DELACOURT, S. LAOUD, D. CHERQUI, C. DUVOUX, A. MALLAT, and A. HARF Increased Nitric Oxide Output from Alveolar Origin during Liver Cirrhosis versus Bronchial Source during Asthma Am. J. Respir. Crit. Care Med., February 1, 2002; 165(3): 332 - 337. [Abstract] [Full Text] [PDF]
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H.-W. SHIN, C. M. ROSE-GOTTRON, R. S. SUFI, F. PEREZ, D. M. COOPER, A. F. WILSON, and S. C. GEORGE Flow-independent Nitric Oxide Exchange Parameters in Cystic Fibrosis Am. J. Respir. Crit. Care Med., February 1, 2002; 165(3): 349 - 357. [Abstract] [Full Text] [PDF]
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R. M. Tamhane, R. L. Johnson Jr., and C. C. W. Hsia Pulmonary Membrane Diffusing Capacity and Capillary Blood Volume Measured During Exercise From Nitric Oxide Uptake Chest, December 1, 2001; 120(6): 1850 - 1856. [Abstract] [Full Text] [PDF]
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I. B. Perillo, R. W. Hyde, A. J. Olszowka, A. P. Pietropaoli, L. M. Frasier, A. Torres, P. T. Perkins, R. E. Forster II, M. J. Utell, and M. W. Frampton Chemiluminescent measurements of nitric oxide pulmonary diffusing capacity and alveolar production in humans J Appl Physiol, November 1, 2001; 91(5): 1931 - 1940. [Abstract] [Full Text] [PDF]
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H.-W. Shin, C. M. Rose-Gottron, F. Perez, D. M. Cooper, A. F. Wilson, and S. C. George Flow-independent nitric oxide exchange parameters in healthy adults J Appl Physiol, November 1, 2001; 91(5): 2173 - 2181. [Abstract] [Full Text] [PDF]
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J. T. Sylvester and S. Permutt Exhaled NO: first, hold your breath J Appl Physiol, July 1, 2001; 91(1): 474 - 476. [Full Text] [PDF]
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N. M. Tsoukias, H.-W. Shin, A. F. Wilson, and S. C. George A single-breath technique with variable flow rate to characterize nitric oxide exchange dynamics in the lungs J Appl Physiol, July 1, 2001; 91(1): 477 - 487. [Abstract] [Full Text] [PDF]
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H.-W. Shin and S. C. George Microscopic modeling of NO and S-nitrosoglutathione kinetics and transport in human airways J Appl Physiol, March 1, 2001; 90(3): 777 - 788. [Abstract] [Full Text] [PDF]
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H. DUPLAIN, C. SARTORI, M. LEPORI, M. EGLI, Y. ALLEMANN, P. NICOD, and U. SCHERRER Exhaled Nitric Oxide in High-Altitude Pulmonary Edema . Role in the Regulation of Pulmonary Vascular Tone and Evidence for a Role against Inflammation Am. J. Respir. Crit. Care Med., July 1, 2000; 162(1): 221 - 224. [Abstract] [Full Text]
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A. P. Pietropaoli, P. T. Perkins, I. B. Perillo, R. W. Hyde, U. Scherrer, C. Sartori, H. Duplain, and T. Busch Am. J. Respir. Crit. Care Med., June 1, 2000; 161(6): 2113 - 2114. [Full Text]
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