Vol. 86, Issue 1, 306-312, January 1999
Acute response of the lung mechanics of the rabbit to hypoxia
H.
Sakai1,
M.
Fukui2,
Y.
Nakano1,
K.
Endo1,
T.
Hirai3,
Y.
Oku4, and
M.
Mishima5
Departments of 1 Experimental
Pathology and 4 Medical Systems
Control, Institute for Frontier Medical Sciences, and
5 Department of Physical
Therapeutics, Kyoto University Hospital, Kyoto University, Kyoto
606-8397; 2 Shiga Medical
Center for Adults, Shiga 524-0022, Japan; and
3 Meakins-Christie Laboratories,
McGill University, Montreal, Quebec, Canada H2X 2P2
 |
ABSTRACT |
We measured the
change in total lung resistance
(RL) and that in total lung
elastance (EL) induced by
hypoxia (n = 7) and compared the
results with those by intravenous histamine bolus (n = 5) at three different positive
end-expiratory pressure (PEEP) levels (2, 5, and 8 hPa) in open-chest
and vagotomized rabbits. The percent increase ratio of
RL
(PIRR) and
EL
(PIRE) was defined as the change
in RL and
EL, respectively, induced by
hypoxia compared with that in the normoxic condition, expressed as a
percentage. PIR values for the change in
RL and
EL induced by bolus injection of
histamine were also calculated. The
PIRR and
PIRE induced by hypoxia and by
histamine were positive by a statistically significant amount at every
PEEP level, except for the PIRE
value at 8-hPa PEEP in the hypoxic challenge. The
PIRE-to-PIRR
ratio values in the hypoxic challenge at 2-hPa PEEP were significantly
larger than those in the histamine challenge (hypoxia: 0.91 ± 0.23%; histamine: 0.37 ± 0.065%,
P < 0.05). The increase
in EL induced by histamine in
the acute phase has been reported to be mainly derived from tissue
distortion secondary to bronchial constriction. Thus our results
suggest that a part of the increase in
EL by hypoxia was originated in
different parenchymal responses from histamine and imply that this
hypoxic response of lung parenchyma is sensitive to the increase in
parenchymal tethering at high PEEP levels.
lung resistance; lung elastance; histamine
| |
INTRODUCTION |
PREVIOUS STUDIES on the mechanical change that occurs
in the lungs on exposure to hypoxic conditions have focused mainly on the response of the airway in terms of total lung resistance
(RL). Dewachter et al. (5)
reported that hypoxia causes bronchoconstriction in the rabbit.
However, Wetzel et al. (24) reported that hypoxia causes
bronchodilation in the pig. Previous studies have also reported
contradictory results of the change in
RL in response to hypoxia:
Goldstein et al. (10) reported that
RL increases, Loofbourrow et al.
(15) reported that RL decreases,
and Saunders et al. (21) reported that
RL remains the same. These
contradictory results may have been obtained because of the
considerable variability among different species and because different
experimental preparations were used. Most of the animal studies on
hypoxia have been done under closed-chest, nonvagotomized conditions
(4, 5, 10, 23, 24). However, Hantos et al. (11) reported that chest wall resistance makes up a substantial component of
RL in the rat. Iscoe and Fisher
(12) reported that vagal efferent activity contributes to the bronchial
smooth muscle tone by 50%.
On the other hand, there have been few reports showing whether hypoxia
alters total lung elastance
(EL). It is known that hypoxia
causes pulmonary parenchymal strips to contract (1, 8). Lung parenchyma
contains some contractile cells bearing prominent bundles of actin
filaments, such as contractile interstitial cells (CIC), as well as
pericytes and myocytes around small vessels and airways. Among them,
CIC have been a candidate for the hypoxia-evoked contraction of lung
parenchyma (13). Indeed, Fukui et al. (9) showed that CIC isolated from
bovine lung contract under hypoxic conditions in vitro. Because the
large, elongated CIC in vivo are interposed between the two adjacent
alveolar epithelia and their long cytoplasmic processes are widely
extended into the space between the alveolar epithelium and capillary
endothelium (8, 13), the hypoxic contraction of CIC would
increase the elastic recoil of the alveolar wall (1, 9).
Our hypothesis is that hypoxia induces the stiffness of the lung tissue
through a mechanism involving parenchymal contractile elements, which
is different from the secondary tissue distortion caused by airway
constriction. To test this hypothesis, we performed experiments on two
groups of open-chest, paralyzed, vagotomized rabbits. In the first
group of rabbits, we measured the
RL and EL values in the normoxic and
hypoxic conditions at three different positive end-expiratory pressure
(PEEP) levels over time. In the second group of rabbits, we measured
the RL and
EL before and after an
intravenous injection of histamine. The administration of histamine
induced a change in EL, which
has been reported to be mainly derived from lung tissue distortion
secondary to airway constriction (2, 20). In the present study, we
compared the changes in RL and
EL induced by hypoxia and the
respective changes in RL and
EL induced by histamine. We also
compared the changes in RL and
EL between the two groups. With
these results, we attempted to assess the contribution of parenchymal
contraction to the mechanical change that occurs in the lung under
acute hypoxic conditions.
| |
METHODS |
Animal preparation.
This study was performed in 12 adult Japanese White rabbits that
weighed between 2.5 and 3.5 kg (4 male, 8 female). Seven rabbits were
placed in the hypoxia trial group, and five rabbits were placed in the
histamine trial group. In each rabbit, a catheter was inserted into a
marginal vein of the ear for drug injection. Each rabbit was
anesthetized with an initial intravenous injection of 30-50 mg/kg
of pentobarbital sodium. Thereafter, a dose of 15-20 mg/kg was
administered hourly to maintain anesthesia. The rabbits
were tracheostomized, and a cannula (4-mm ID) was inserted. The rabbits
were paralyzed with the administration of 1 mg of pancuronium bromide
every hour. They were mechanically ventilated with a tidal volume of 5 ml/kg at a frequency of 40 breaths/min. A 5.0-hPa baseline level of
PEEP was applied. A catheter was inserted into the left femoral artery
to monitor arterial blood gas. Another catheter was inserted into the
right jugular vein for the administration of histamine. A midline
sternotomy was performed to open the chest wall; a bilateral surgical
vagotomy was then performed. The rectal temperature was maintained at
38-39°C with an electric blanket.
Equipment.
Tracheal pressure (Ptr) was measured by using a piezoresistive
microtransducer (Fujikura FPM-05PG, Servoflo, Lexington, MA), which was
placed in the lateral port of the tracheal cannula. Tracheal flow
(
) was measured with a pneumotachograph (TV-241T, Fleisch No. 00; Nihon-Kohden, Kyoto, Japan) and a differential pressure
transducer (PX170-14DV, OMEGA). The pneumotachograph was placed
between the tracheal cannula and the mechanical ventilator (Harvard
Apparatus, South Natick, MA). Before the experiments were performed,
normoxic gas (25% O2 in
N2) was used to calibrate all of
the transducers. The normoxic gas and hypoxic gas (10% O2 in
N2) were produced by a gas mixer
(DNT 350, MERA, Calgary, Alberta) by using pure
O2 and
N2. All data were amplified,
low-pass filtered (20 Hz), and stored on a 486-based personal computer through a 12-bit analog-to-digital converter (DT2801-A, Data
Translation, Marlborough, MA), at a sampling rate of 100 Hz. The LABDAT
data-acquisition software package (RHT-Infodat, Montreal, Quebec) was
used to control the analog-to-digital conversion.
Measurement protocol.
To create a constant volume history, each trial was initiated with
inflation of the lungs to a Ptr of 30 hPa three times. The rabbits that
were in the hypoxia trial group were mechanically ventilated, first
with normoxic gas for 5 min, followed by hypoxic gas for 8 min, and
then normoxic gas again for 5 min at PEEP levels of 2, 5, and 8 hPa;
the order of the three different PEEP levels was randomly arranged for
each rabbit, with an interval of 10 min in between.
In each rabbit, arterial blood-gas analyses were performed three times
during the experiment. The first analysis was done 5 min before
impedance measurements were begun. From the results of this blood-gas
analysis, sodium bicarbonate was administered to the rabbit if
necessary, so that the HCO
3 level was
within the normal range (23-27 mM) in each rabbit. The second
arterial blood-gas analysis was performed 2 min after the start of
measurement of impedance in the normoxic condition (i.e., at the 2-min
measurement point within the total 18-min ventilation period). The
third analysis was performed 2 min after the switch to the hypoxic
condition. The results from the second arterial blood-gas analysis were
used as the values for the normoxic condition; the results from the
third analysis were used as the values for the hypoxic condition.
The rabbits in the histamine trial group were ventilated for 5 min with
normoxic gas. They were then injected with a bolus of 0.001 mg/kg
histamine in 1 ml of saline through the catheter in the right jugular
vein. Continuous histamine infusion caused irreversible lung damage,
which made repeated measurements at different PEEP levels impossible;
therefore, it was administered once as a bolus. The histamine dose to
be administered was determined so that it caused a change in
RL equivalent to that caused by hypoxia at 2-hPa PEEP. To prevent tachyphylaxis to histamine, an
indomethacin (5 mg/kg iv) mixture was administered 20 min before the
experiment was begun; this was followed by supplemental intravenous doses of 2 mg/kg every hour (2). This mixture contained indomethacin dissolved in saline and 0.05 g/ml of sodium bicarbonate (22). All
measurements in the histamine trial group were made at PEEP levels of
2, 5, and 8 hPa, the order of which was randomly arranged with an
interval of 10 min between trials.
Data analysis.
Each breathing cycle was defined as the interval between successive
peaks of the integrated . The
RL and
EL values for each breathing
cycle were estimated by multiple linear regression (3). The following
equation was fitted to the measurement of Ptr
|
(1)
|
where
t is time, V is volume, and
K is a constant.
The V was obtained by numerical integration of the adjusted value of
after offset adjustment to remove any drift in V
that might otherwise have occurred. K
is a constant that depends on the specific PEEP level; it includes both
the applied PEEP and any intrinsic PEEP.
An acryl tube, which connects the pneumotachograph to the trachea, had
an internal diameter of 0.4 cm and a length of 15 cm. The theoretical
resistance of the tracheal tube, based on the assumption of a laminar
flow, was calculated to be 7.86 hPa · s · l1,
whereas the measured value was 7.96 hPa · s · l1.
Therefore, in the data analysis, each calculated value of
RL was reduced by 7.96 hPa · s · l1.
Elimination of the trend in the
RL and
EL values obtained from rabbits in
the hypoxia trial group.
When the RL and
EL values over the 18-min time
course of the experiment in the hypoxia trial group were graphed, a
small, positive trend in both RL
and EL was noted (Fig.
1). This small, positive trend is
presumably due to microatelectasis (19). The trend values of
RL and
EL were calculated by linear
regression of the respective RL
and EL values during 1 min of
normoxia (between the 4- and 5-min measurement points) and 1 min of
hypoxia (between the 6- and 7-min measurement points). Figure
2 shows how each EL value was subtracted by the
mean trend value between the 4- and 5-min and the 6- and 7-min
measurement points.
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Fig. 1.
Values of total lung resistance
(RL) and elastance
(EL) of a representative case
in hypoxia trial group. Rabbit was exposed to normoxic gas for first 5 min, then to hypoxic gas for next 8 min, then to normoxic gas again for
5 min.
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Fig. 2.
Elimination of trend in EL
values in representative rabbit in hypoxia trial group. Small, positive
trend in EL over time was noted.
To negate effects of this trend, a formula that represents the trend
was calculated by linear regression. Small dotted and solid lines,
fitted profiles before and after trend was eliminated, respectively.
MNE and
MHE, average value of
EL during 1 min of normoxia
(between 4- and 5-min measurement points) and during 1 min of hypoxia
(between 6- and 7-min measurement points), respectively.
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|
Assessment of hypoxia- and histamine-evoked change.
To assess the mechanical change in the lung that had occurred because
of hypoxia, we developed the following equations, which indicate how
much the RL and
EL in the lungs of the rabbits
changed in response to hypoxia or in response to histamine
|
(2)
|
where
PIRR is the percent increase ratio
of RL; for the hypoxia trial
group, MNR is the average value of
RL during 1 min of the normoxic
condition (between the 4- and 5-min measurement points) of each rabbit;
and MHR is the average value of
RL during 1 min of the hypoxic
condition (between the 6- and 7-min measurement points).
A PIR for EL
(PIRE) was also calculated the
same as for RL, by using the
following equation
|
(3)
|
where
MNE is the average value of
EL during 1 min of the normoxic
condition (between the 4- and 5-min measurement points) of each rabbit,
and MHE is the average value of
EL during 1 min of the hypoxic condition.
Figure 3 illustrates the time course of
RL and
EL in a representative case of
the histamine trial group. We also calculated PIRR and
PIRE for the rabbits in the
histamine trial group to assess the mechanical change of the lung
induced by histamine. MNR and
MNE were assigned to be the average value
of RL and
EL, respectively, during the
15-s interval before histamine injection. MHR and MHE
were assigned to be the peak value of
RL and
EL, respectively, after
histamine injection (Fig. 3). In all of the histamine trial group
rabbits (n = 5), it took ~15 s to
reach the peak value of RL
and EL.
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Fig. 3.
Time course of RL and
EL in representative case of
histamine trial group. MNE was assigned
to be average value of EL during
15-s interval before histamine injection.
MHE was assigned to be peak value of
EL after histamine injection.
Analogously, MHR was assigned to be
average value of RL during 15-s
interval before histamine injection (hypoxia), and
MNR was assigned to be peak value of
RL after histamine injection
(normoxia). Peak value in EL and
RL occurred ~15 s after
histamine was injected.
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Correction of the difference in viscosity between the normoxic and
hypoxic gases.
As previously mentioned, all transducers were calibrated with normoxic
gas before the experiment. Because the viscosity of the hypoxic gas is
less than that of the normoxic gas, the differential pressure at the
pneumotachometer would consistently be lower in the hypoxic condition.
This situation leads to underestimation of the
in all of the measurements made under the
hypoxic condition. A test lung was used to study this effect on the
RL and
EL values. The test lung was
made of an acryl tube with a rubber balloon, and it had
RL and
EL values that were similar to
those in the rabbits. As can be seen in Fig.
4, the measured
EL increased in the hypoxic
condition; this increase is apparently due to underestimation of the
by the pneumotachometer. The
PIRR and
PIRE values of the test lung, were
0.031 ± 0.02 (SE) and 2.02 ± 0.02%, respectively (n = 6 trials).
The PIRE value in the hypoxic
condition with the use of the test lung is near the theoretical
PIRE value calculated, assuming the flow through the acryl tube is laminar (see
APPENDIX for detailed calculation). In
contrast, the RL value with the
use of the test lung remained constant through both the normoxic and
hypoxic conditions. The reason that
RL remains constant is that,
although the amount of is underestimated in the
hypoxic condition, airway resistance (i.e., the differential pressure)
also decreases in the hypoxic condition.
In the hypoxic condition, whether the
PIRR value and that of
PIRE were positive or negative was
evaluated by comparing MNE with
MHE. In the calculation of
PIRE, the value of
MHE was substituted with
MHE · (1 
0.0202), and the following equation was used to calculate
PIRE
![PIR<SUB>E</SUB> = 100 × [M<SUB>HE</SUB> ⋅ (1 − 0.0202) − M<SUB>NE</SUB>]/M<SUB>NE</SUB>](/content/vol86/issue1/fulltext/306/img004.gif)
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(4)
|
Statistical analysis.
Friedman's nonparametric two-way ANOVA was used to test whether the
difference between the EL and
RL values at the three PEEP levels was significant. If a significant difference for a group of
EL or
RL values was found by ANOVA,
then the statistical difference between each pair of values in that
group was tested by using Wilcoxon's signed-rank statistic. The
Mann-Whitney U statistic was used to
test whether the difference between a histamine trial group parameter
and the respective parameter in the hypoxia trial group was
significant. A P value <0.05 was
considered to be statistically significant. StatView (Abacus Concepts,
Berkeley, CA) software was used for all of the statistical analyses.
All data are expressed as means ± SE.
| |
RESULTS |
RL and
EL baseline values in the
hypoxia and histamine trial groups in the normoxic condition.
In the normoxic condition, the
RL and
EL values increased as the PEEP
was increased in the rabbits of both the hypoxia and histamine trial
groups (see Table 1). These results were
compatible with previous reports (3, 14). However, there was no
statistical difference between the
RL or
EL baseline value at a
particular PEEP level of the hypoxia trial group and the respective
baseline value of RL or
EL of the histamine trial group
at each PEEP level.
Arterial blood-gas parameters.
The results of arterial blood-gas analyses and acid-base parameters of
arterial blood in the normoxic and hypoxic conditions are given in
Table 2. The arterial
PO2 in the hypoxic condition was
significantly lower than the respective value in the normoxic condition
at all PEEP levels. The arterial PCO2 (PaCO2) at 2-hPa PEEP in the hypoxic
condition was significantly lower than that in the normoxic condition.
In the normoxic condition, the PaCO2 at
2 hPa was higher than that at 5 hPa. The pH values at 2- and 5-hPa PEEP
in the hypoxic condition were significantly higher than the respective
values in the normoxic condition. However, there were no differences in
any of the HCO3 levels among any of
the PEEP levels nor between hypoxia and normoxia within a given PEEP
level.
Hypoxia trial.
No statistical difference existed among the trend values in each of the
seven rabbits. A graph of the PIRR
and PIRE values at each PEEP level
in the hypoxia trial group is shown in Fig. 5. The
PIRR values at all PEEP levels
were statistically positive. However, the differences between pairs of
PIRR values at the three PEEP
levels were not statistically significant. The
PIRR values were 7.57 ± 1.78, 5.70 ± 1.04, and 7.22 ± 1.78% at 2-, 5-, and 8-hPa
PEEP, respectively.
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Fig. 5.
Percent increase ratio (PIR) of
RL
(PIRR) and
EL
(PIRE) at different positive
end-expiratory pressure (PEEP) levels in hypoxia trial group.
PIRR and
PIRE values were calculated for
each of the 7 rabbits in hypoxia trial group. Graph shows average
PIRR and average
PIRE at 2-, 5-, and 8-hPa PEEP.
Values are means ± SE. * Hypoxic condition value is
significantly different from respective normoxic condition value,
P < 0.05 (Wilcoxon's signed-rank
test). ** PIRE values at 2 and 8 hPa are significantly different,
P < 0.05 (Wilcoxon's signed-rank
test).
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The PIRE values were statistically
positive at 2- and 5-hPa PEEP. However, there was no significant change
in EL at 8-hPa PEEP. The
PIRE values were 8.07 ± 4.22 (P < 0.05, compared with the
PIRE value at 8 hPa), 3.14 ± 1.44, and 1.73 ± 0.78% at 2-, 5-, and 8-hPa PEEP, respectively.
Histamine trial.
The PIRR and
PIRE values at each PEEP level in
the histamine trial group are shown in Fig.
6. At 2-, 5-, and 8-hPa PEEP, the values of
PIRR were statistically positive.
However, a statistically significant difference between pairs of
PIRR values did not exist. The
PIRR values were 12.95 ± 2.47, 12.97 ± 3.48, and 14.36 ± 1.62% at 2-, 5-, and 8-hPa PEEP,
respectively.
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Fig. 6.
PIRR and
PIRE at different PEEP levels in
the 5 rabbits of histamine trial group. Values are means ± SE.
* Hypoxic condition value is significantly different from
respective normoxic condition value, P < 0.05 (Wilcoxon's signed-rank test).
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In the histamine trial group, the
PIRE values of all three PEEP
levels were statistically positive. However, a statistically significant difference was not found among the
PIRE values at the three PEEP
levels. The PIRE values were 4.30 ± 0.50, 4.78 ± 0.85, and 3.49 ± 0.85% at 2-, 5-, and 8-hPa
PEEP, respectively.
Values of the
PIRE-to-PIRR
ratio.
The ratios of PIRE to
PIRR
(PIRE/PIRR)
for each rabbit in the hypoxia trial group and each rabbit in the
histamine trial group were calculated.
As can be seen in Fig. 7, in the hypoxia
trial group, as the PEEP was increased, the
PIRE/PIRR
values decreased. The
PIRE/PIRR values in the hypoxia trial group were 0.91 ± 0.23 (P < 0.05, compared with the
respective values at 5 and 8 hPa), 0.52 ± 0.23, and 0.23 ± 0.11 at 2-, 5-, and 8-hPa PEEP, respectively .
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Fig. 7.
Ratio of
PIRE/PIRR
at different PEEP levels in hypoxia (n = 7) and histamine trial groups (n = 5). Values are means ± SE.
* P < 0.05 (Mann-Whitney's
U-test);
** P < 0.05 (Wilcoxon's
signed-rank test).
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However, in the histamine trial group, the
PIRE/PIRR
values at the three PEEP levels did not differ significantly. The
PIRE/PIRR values in the histamine trial group were 0.37 ± 0.065, 0.42 ± 0.062, and 0.21 ± 0.052 at 2-, 5-, and 8-hPa PEEP, respectively. The
PIRE/PIRR
value at 2-hPa PEEP in the hypoxia trial group was significantly larger
than the respective value in the histamine trial group (0.91 ± 0.23 vs. 0.37 ± 0.065; P < 0.05).
| |
DISCUSSION |
The first finding in the present study is that, at 2-hPa PEEP, the
PIRE/PIRR
values of the rabbits in the hypoxic trial group were significantly
higher than those of the rabbits that received a histamine injection
(Fig. 7). The increase in
EL induced by histamine
injection is assumed to be derived mainly from tissue distortion
secondary to bronchial constriction (2, 20). Thus our results suggest
that the increase in EL on
exposure to hypoxic conditions at low PEEP includes a second tissue
response, such as the contraction of CIC, that is independent of the
response involving tissue distortion secondary to bronchial
constriction. The second finding is that, as the PEEP was increased in
the hypoxia trial group rabbits, the
PIRE/PIRR
value, as well as the PIRE value,
decreased (Figs. 5 and 7). This implies that the parenchymal tethering
may become increasingly important in the response of the lung tissue to
hypoxia at higher PEEP levels.
In previous reports, evaluation of the change in
EL because of hypoxia has not
been performed properly because the difference in the viscosity of
normoxic gas and that of hypoxic gas has not been taken into account.
In the present study, the influence from the difference in viscosity
between the normoxic and hypoxic gases was corrected after the
RL and
EL values were measured. The
correction values were set to be 0 and 2.02%, respectively, according
to the results from the test lung. However,
RL of the lung itself also
contains lung tissue resistance
(Rti,L), which is closely coupled with EL (7) and airway
resistance. If the hysteresivity is assumed to be 0.1 under normoxic
conditions, we calculated that the contribution of
Rti,L to the value of
RL would be 30% at 2-hPa PEEP
(7). At higher PEEP or in hypoxic conditions, the contribution of
Rti,L to
RL may be greater. Therefore,
the practical correction value of
RL would be between 0 and 2.02, and the actual value of PIRR may
be smaller. However, the
PIRE/PIRR value would be larger, and our results should be the same even if we
correct the value of RL for
Rti,L.
Another option for removing the influence of the difference in
viscosity between the normoxic and hypoxic gases from the results of RL and
EL is to use different
calibration factors in each condition. This may lead to a direct
estimation of EL. However, the
values of RL in the hypoxic
condition would be smaller, whereas the values of
RL in the normoxic condition
would be as measured, even if the size of the airway caliber is kept
constant. In such case, the
PIRE/PIRR
value would be larger, and our results should again be the same even if
different calibration factors are used.
The PaCO2 at 2-hPa PEEP under hypoxic
conditions was significantly smaller than the respective value under
normoxic conditions. It has been reported that hypercapnia enhances the
response of the lung to hypoxia (5, 12, 18). Therefore, the increase in
RL and
EL that we obtained at 2-hPa
PEEP in the hypoxia trial group may be underestimated.
Continuous infusion of histamine showed an irreversible change in the
values of RL and the
EL, probably due to lung damage. This made repeated measurements at different PEEP levels impossible. For this reason, histamine was administered in a bolus. However, preliminary measurements of continuous infusion of histamine (0.00033 mg · kg1 · min1)
at 2-hPa PEEP (n = 2) were made. The
PIRE,
PIRR, and
PIRE/PIRR values obtained from the continuous infusion of histamine and the
respective values obtained when a bolus of histamine was administered were similar.
The
PIRE/PIRR
value at 2-hPa PEEP in the histamine study was ~0.3. This value is
similar to the previously reported value (2). However, it has also been
reported that a negative PEEP dependency exists in both
PIRR and
PIRE (2, 17); this differs from
our results. The tracheal caliber size and the rabbit lung size are
much smaller than those in the canine. The relationship between the
response of the canine lung to histamine and the PEEP level may be
different from that in the rabbit; there may be species differences
that may have an influence on the outcomes of the various studies
addressing RL and
EL. The very small dose of
histamine used in our study may be another explanation. The histamine
dose in our study was very small compared with that administered in a
previous histamine challenge used in canines (2, 14). The PIR value in
canines from the previous histamine challenge is over ten times larger
than that obtained in the present study. Balassy et al. (2) suggested
that the negative PEEP dependency of the increased
RL seen at the histamine
injection is due to an increase in the degree of parenchymal tethering,
which supports the airway caliber. However, this mechanism
may not be applied in the case of the low-dose histamine, especially at
the high PEEP level. In our study, there was actually a lack of PEEP
dependency on the PIRE values in
the histamine challenge, because the response of
EL to histamine was mainly
secondary to changes in RL, and there was a lack of PEEP dependency on the
PIRR values. On the other hand,
the negative PEEP dependency of
PIRE was shown in our hypoxic
trials despite the fact that there was a lack of PEEP dependency on the
PIRR values. Therefore, these
results suggest the existence of a lung parenchymal response to hypoxia
that is much more sensitive to the PEEP level and that is independent of airway constriction.
Kapanci et al. (13) found that alveolar interstitial cells, which
occupy 42% of the total interstitial volume of the alveolar wall,
possess contractile properties and named them CIC. Fukui et al. (9)
purified and cultured CIC from the bovine lung and reported that
isolated CIC contract when exposed to hypoxic conditions. Because CIC
in the lung are closely associated with the adjacent capillaries,
hypoxia-induced contraction of CIC would reduce the patency of the
adjacent capillary lumen and increase the vascular resistance at the
alveolar capillary level. Additionally, the cell body and the long
cytoplasmic processes of CIC are also in close contact with the
epithelia of two adjacent alveoli and collagen fibers in the alveolar
interstitium (8, 13). Thus the contraction of CIC could induce a change
in the elastic recoil of the alveolar wall. Furthermore, it may be
expected that the mechanical properties of CIC could be largely
influenced by the PEEP level. It remains to be explored whether other
contractile cells such as pericytes and myocytes around small pulmonary
vessels and airways are also involved in the hypoxia-induced changes in
EL.
The limitation of our study is that we assumed that contraction of CIC
under hypoxic conditions would increase
EL because of their location and
mechanical properties. We could speculate that CIC located in the
parenchyma are influenced by the degree of parenchymal tethering
induced by the PEEP and could make the parenchyma stiff under hypoxic
conditions. This assumption is supported by a histological study that
demonstrated an increase in the depth of alveolar wall pleats in lung
tissue exposed to hypoxia, suggesting hypoxia-induced contraction of
the alveolar structure (16). However, further investigation of these
phenomena is needed with electron micrographs and histochemical analyses.
The role that contractile elements play in the response of the entire
lung to hypoxia was unclear. Our finding that the mechanical change of
the lung due to hypoxia includes a contractile mechanism of the lung
tissue, which is independent of the tissue distortion caused by airway
constriction, has an important physiological implication. In view of
the dynamic gas distribution, it has been suggested that the alveolar
O2 tension on the surface of an
acinus varies, because anatomic asymmetry of the acinus gives rise to the variable convective and diffusive gas transport on its surface (6).
The response of the lung tissue to hypoxia may enable fine regulation
of the ventilation-to-perfusion ratio under the variable
O2 tension on the surface of each alveolus.
| |
APPENDIX |
The pressure difference (Pd) during laminar flow is expressed by the
following equation: Pd = 8 · µ · L · 
1 · r4 · V1,
where µ is the viscosity of the gas,
L is the length of the tube, and
r is the radius of the tube. In our
experiment, we assigned normoxic gas to be 25%
O2 in
N2 and hypoxic gas to be 10%
O2 in N2. Assuming that the temperature
is 37°C and atmospheric pressure is 1,013 hPa, the viscosity of the
gas (µ) under the normoxic and hypoxic conditions is 1.82 and 1.78 N · s · m2,
respectively. According to the above-mentioned definition and data, the
theoretical value of PIR in the hypoxic condition under laminar flow
was calculated to be 2.01 with the use of the following equation
| |
ACKNOWLEDGEMENTS |
The authors thank Drs. K. Kuno, M. Ohi, K. Chin, and S. Muro of
Kyoto University for continued encouragement and suggestions during
this investigation. We are indebted to Dr. Chang-Wen Chen of National
Cheng Kung University for suggestions and technical support for our experiments.
| |
FOOTNOTES |
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: H. Sakai, Dept. of Experimental
Pathology, Institute for Frontier Medical Sciences, Kyoto Univ., 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8397, Japan (E-mail:
sakai{at}frontier.kyoto-u.ac.jp).
Received 1 June 1998; accepted in final form 18 September 1998.
| |
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Abstract
Introduction
![= 100 × [Pd(25%O<SUB>2</SUB>) − Pd(10%O<SUB>2</SUB>)]/Pd(10%O<SUB>2</SUB>)](/content/vol86/issue1/fulltext/306/img006.gif)
