Effect of lung volume on plateau response of airways and tissue to methacholine in dogs F. M. ROBATTO,
S. SIMARD,
H. ORANA,
P. T. MACKLEM,
AND
M. S. LUDWIG
Meakins-Christie Laboratories, Royal Victoria Hospital, McGill University, Montreal, Quebec H2X 2P2; and Respiratory Health Network of Centers of Excellence, Montreal Chest Hospital Centre, Montreal, Quebec H2X 2P4, Canada ROBATTO, F. M., S. SIMARD, H. ORANA, P. T. MACKLEM, AND M. S. LUDWIG. Effect of lung volume on plateau response of airways and tissue to methacholine in dogs. J. Appl. Physiol. 73(5): 1908~1913,1992.-We have recently shown in dogs that much of the increase in lung resistance (RL) after induced constriction can be attributed to increases in tissue resistance, the pressure drop in phase with flow across the lung tissues (Rti). Rti is dependent on lung volume (VL) even after induced constriction. As maximal responses in RL to constrictor agonists can also be affected by changes in VL, we questioned whether changes in the plateau response with VL could be attributed in part to changes in the resistive properties of lung tissues. We studied the effect of changes in VL on RL, Rti, airway resistance (Raw), and lung elastance (EL) during maximal methacholine (MCh) -induced constriction in 8 anesthetized, paralyzed, openchest mongrel dogs. We measured tracheal flow and pressure (Ptr) and alveolar pressure (PA), the latter using alveolar capsules, during tidal ventilation [positive end-expiratory pressure (PEEP) = 5.0 cmHZO, tidal volume = 15 ml/kg, frequency = 0.3 Hz]. Measurements were recorded at baseline and after the aerosolization of increasing concentrations of MCh until a clear plateau response had been achieved. VL was then altered by changing PEEP to 2.5,7.5, and 10 cmH,O. RI, changed only when PEEP was altered from 5 to 10 cmH,O (P < 0.01). EL changed when PEEP was changed from 5 to 7.5 and 5 to 10 cmH,O (P < 0.05). Rti and Raw varied significantly with all three maneuvers (P < 0.05). Our data demonstrate that the effects of VL on the plateau response reflect a complex combination of changes in tissue resistance, airway caliber, and lung recoil. tissue resistance; airway resistance; mechanical interdependence LUNG TISSUES are generally modeled as passive mechanical structures. However, we (12) have recently shown, using the alveolar capsule technique, that much of the increase in lung resistance (RL) after induced constriction can be attributed to increases in the resistive pressure drop across lung tissues (Rti). These findings are consistent with the hypothesis that lung tissues are capable of responding to constrictor agonists (4417). In addition, we and others (3,12) have shown that Rti is dependent on lung volume; this dependence persists even after induced constriction (12). It has been demonstrated in both humans (5) and rats (2) that the maximal response in RL to a constrictor agonist can be modified by changes in lung volume. The usual interpretation of this finding has been that RL reflects airway resistance (Raw), and the amount that air1908
0161~X67/92
$2.00 Copyright
way caliber can decrease in response to constriction has been affected by alterations in the force opposing airway smooth muscle shortening. This hypothesis depends on the mechanical interdependence between airways and tissues (16) that occurs as the result of the radial connection of collagen and elastin fibers to the external perimeters of airways. With changes in lung volume the force exerted by such fibers on the airways is passively altered, and the degree that the airways can narrow during constriction is affected. However, if the parenchymal tissues are capable of active responses, i.e., if it is possible to modify tissue mechanical behavior with constrictor agonists, then the tissue reaction itself could be one of the factors modifying the effects of changing lung volume on the plateau response. Accordingly, we studied the plateau response to methacholine in dog lungs to which alveolar capsules had been applied so that resistive changes could be partitioned into airway and tissue components. End-expiratory lung volume was altered during the plateau response to change the relative resistance of airways and tissues and the forces of interaction between the two. In this way we attempted to examine the effects of changing lung volume on these mechanically interdependent structures during maximal methacholine-induced constriction. METHODS
Animal preparation. Experiments were done in eight mongrel male dogs ranging in weight from 15.5 to 20.0 kg [17.1 t 2.37 (SD) kg]. Dogs were anesthetized with pentobarbital sodium (30 mg/kg iv), and anesthesia was maintained by an intravenous injection of 10% of the initial dose every hour. Tracheostomy was performed, and a snugly fitting tracheal cannula with a side tap to measure tracheal pressure (Ptr) was inserted. A jugular venous line was placed. Dogs were paralyzed with 3 mg pancuronium iv; paralysis was maintained by intravenous administration of 1 mg/h. Dogs were ventilated with a volume ventilator (Harvard Apparatus) with a tidal volume of 15 ml/kg, 18 breaths/min, and at a positive end-expiratory pressure (PEEP) of 5 cmH,O. The temperature was kept constant with a heating pad placed below the animal. A midline sternotomy was performed, and the chest was widely retracted. Three alveolar capsules were applied to the pleural surface of the upper and/or the cardiac lobe with cyanoacrylate glue. The pleura underneath the capsule was punctured several times to a depth of a few millimeters
0 1992 the American Physiological
Society
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AIRWAY-TISSUE
with an 18-gauge needle to bring the underlying alveoli into communication with the capsule chamber. Pressures in the capsules and in the tracheal cannula were measured with miniature piezoresistive pressure transducers (model 8507B, Endevco, San Juan Capistrano, CA) calibrated with a water manometer. The three capsule pressure transducers were then recalibrated in situ against the Ptr transducer so that all transducers registered the same pressure during quasi-static conditions. The technical details of the alveolar capsule technique and its validity as a means of measuring alveolar pressure (PA) have been well documented (6, 12, 15). It is readily apparent when airways subtending a region sampled by an alveolar capsule are closed (10,12). The corresponding PA signal no longer matches the Ptr signal, and PA may even decrease as Ptr increases (12). Flow at the trachea was measured with a heated pneumotachograph (Fleisch no. 2). A piezoresistive differential pressure transducer (Microswitch 163PCOlD36, Honeywell, Scarborough, Ontario, Canada), calibrated with a rotameter, measured the pressure drop across the pneumotachograph. Volume change was obtained by digital integration of the flow signal. ProtocoI. Complete concentration-response curves to inhaled methacholine were obtained. Before the concentration-response curve was begun one inspiratory capacity breath, defined as the volume excursion between PEEP and a peak Ptr = 30 cmH,O, was delivered to standardize volume history. Aerosols were generated by an ultrasonic nebulizer (DeVilbiss 1OOB) that produced particles with a mean aerodynamic diameter of 4.5-6.0 pm. Saline was administered initially, and then the agonist was delivered into the trachea through a side port in the tracheal cannula in progressively doubling concentrations (0.5-128 mg/ml) at a flow rate of 1 l/min for 2 min. Tidal ventilation was continued during delivery of the aerosol. We considered that a plateau had been achieved when at least three subsequent doses did not cause any further increase in end-inspiratory peak Ptr. Measurements were recorded during tidal ventilation at baseline, after saline aerosol, and 1 min after each dose of methacholine aerosol had been administered. In addition, we made measurements at different end-expiratory lung volumes once a plateau response had been achieved. We altered end-expiratory lung volume by randomly changing PEEP, which was controlled by a water valve, to levels of 2.5,7.5,and 10 cmH,O. The precise protocol was as follows: we made a measurement at PEEP = 5 cmH,O. PEEP was then changed to its new level, and, once PEEP was stable, usually within 2 min, a further measurement was made. PEEP was then returned to 5 cmHZO, and an additional 1 min of aerosol was delivered in an attempt to maintain a constant level of bronchoconstriction. A measurement at PEEP = 5 cmH,O was then repeated before adjusting PEEP again This procedure was repeated for all PEEP levels. Signal conditioning and collection. All collected signals (3 PA, Ptr, and flow) were amplified, low-pass filtered at 100 Hz, converted from analog to digital by a 12-bit analog-to-digital converter (DT=2801A, Data Translation, Marlborough, MA) using a sampling rate of 200 Hz, and stored on an IBM-compatible personal computer. Data analysis. Total RL and lung elastance (EL) were
1909
INTERACTIONS
calculated by multiple linear regression by digitally ting the 15-s segments of data to the equation
fit-
Ptr =~RL+VEL+K
(I)
where v is tracheal flow, V is volume change, and K is a constant with a value that was also estimated by multiple linear regression and a function that was to take into account that, in an open-chest animal, zero volume corresponded to 5 cmH,O in pressure. We calculated Rti for each PA by multiple linear regression from the equation
PA =VRti
+VEL+
K
(2)
The values so obtained from each alveolar were then meaned. Raw was obtained by subtraction
capsule
Raw = RL - Rti (3) We constructed methacholine dose-response curves for all the animals, plotting percent change from the saline baseline in RL, Raw, and Rti against concentration of methacholine. We calculated the concentration of methacholine necessary to elicit a twofold rise in RL above saline (EC,,,RL) by log linear interpolation. Corresponding quantities were calculated for Raw and Rti (EC,,,Raw and EC,,*Rti, respectively). Statistical analysis. We did linear regression analysis to compare percent change in Rti to percent change in Raw. Paired t test was used to compare the effect of changes in PEEP on Raw, RL, and Rti, using the preceding measurement at 5 cmH,O of PEEP as the control for the subsequent measurement at the new PEEP level. RESULTS
Baseline values of RL, Rti, Raw, and EL are given for all the dogs in Table 1. Mean RL was 1.23 t 0.15 (SE) cmH,O 1-l s under baseline conditions and increased to 6.18 t 2.77 cmH,O l 1-l. s after the plateau response was attained. Mean Raw was 0.31 t 0.08 cmH,O 01-l s at baseline and increased to 2.47t 1.024 cmH,O 1-l s after methacholine. Mean Rti was 0.92 t 0.10 cmH,O l 1-l s at baseline and increased to 13.54 t 2.77cmH,O 1-l s after methacholine. EL was 12.48 t 1.33 cmH,O/l at baseline and increased to 92.03 t 21.41 cmH,O/l after methacholine. A plateau in RL was obtained in all the animals. This is illustrated in Fig. 1, which shows individual methacholine concentration-response curves. It should be noted that we did not observe airway closure with any of the capsules in any of the dogs, even with PEEP = 2.5 cmH,O. The geometric mean EC,,RL was 0.15mg/ml, the geometric mean EC,,,Rti was 0.17 mg/ml, and the geometric mean EC,,,Raw was 0.17 mg/ml. There were no differences in sensitivity (the dose of agent at which the response occurred) between the airways and tissues. Figure 2 shows an identity plot of percent increase in Rti vs. percent increase in EL after methacholine. The correlation coefficient was 0.74 (P < 0.01,n = 67). Note that the correlation was of similar degree both before and after the plateau response. An identity plot of percent increase in Raw vs. percent increase in Rti after methacholine is shown in Fig. 3. The l
l
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l
l
l
l
l
l
1910 TABLE
AIRWAY-TISSUE
INTERACTIONS
1. Baseline values cm&O
Dog No.
wt, kg
RL
Rti
20.0 13.2
0.75 1.56 0.97 0.95 1.31 1.43 0.94 1.93
0.53 1.03 0.73 0.83 0.82 1.15 0.92 1.34
17.1 to.3
1.23 kO.15
0.92 :O.lO
16.8 18.6 16.8 20.0 15.5 15.5
Mean &SE
81-l
l
s EL, cmH,O/l
EC,RL
EC,Rti
E&,Raw
0.21 0.54 0.24 0.12 0.50 0.29 0.02 0.55
10.08 12.48 10.32 12.01 11.56 12.99 9.67 20.69
0.03 0.31 0.14 0.59 0.06 0.06 0.23 0.39
0.09 0.27 0.13 0.59 0.06 0.08 0.24 0.41
4.40 0.29 0.59 0.07 0.04 0.08 0.32
0.31 kO.08
12.48 tl.33
0.15
0.17
0.17
Raw
0.01
RL, lung resistance; Rti, tissue resistance; Raw, airway resistance; EL, lung elastance. Mean &fold effective concn (EC&J is a geometric mean.
correlation coefficient (r) for the pooled data was 0.49 (P < 0.01, n = 67), and slope and intercept were 0.76 and 0.72, respectively. For the preplateau data points only, r was 0.68 (P < 0.01, n = 26), and slope and intercept were 1.01 and 0.01, respectively. The plateau data points showed no correlation (r = 0.28, n = 41, not significant). Figure 4 shows the change in RL, Rti, Raw, and EL with change in PEEP. There were no significant differences among the various PEEPS = 5 cmH,O for RL, Raw, and Rtii. EL at the different PEEPS = 5.0 cmH,O was significantly different (P < 0.05). RL varied significantly (P < 0.01, paired t test) when PEEP was changed from 5 to 10 cmH,O. Rti varied significantly (P < 0.05) with change of PEEP from 5 to 7.5 and from 5 to 10 cmH,O. Raw and EL varied significantly (P < 0.05) with all three maneuvers, i.e., changing PEEP from 5 to 2.5, 5 to 7.5, and 5 to 10 cmH,O (P < 0.05). The changes in Rti and Raw with lung volume were always in opposite directions, i.e,, when mean lung volume increased, Rti increased and Raw decreased. When mean lung volume decreased, Rti decreased and Raw increased (Fig. 4). The changes in RL were in the same direction as Rti when mean lung volume increased and in the same direction as Raw when mean lung volume decreased. DISCUSSION
Recently the alveolar capsule technique (6), which allows direct measurement of PA, has provided a new method for partitioning the changes in RL into Raw and Rti components. We and others (3, 12, 14) have shown that, in dogs, under baseline conditions, Rti is the predominant component of RL, accounting for -6O-80% of the resistive pressure drop. After induced constriction the increase in RL is, to a large extent, attributable to increases in Rti (13, 14). The data of the present study confirm those observations: Rti accounted for 75% and Raw for 25% of RL under control conditions and 85 and 15% after maximal levels of constriction had been induced, respectively. It should be noted that under the current experimental conditions (tidal volume = 15 ml/ kg, frequency = 0.3 Hz, and PEEP = 5 cmH,O) the contribution of quasi-static hysteresis to Rti is negligible (18). Changes in Rti were correlated with changes in Raw; we found a significant correlation (r = 0.49, P < 0.01; Fig. 3) between percentage change in Raw and percent
change in Rti, confirming previous observations in dogs (13) and in rabbits (19). When only the preplateau points were considered, the correlation was stronger (r = 0.68, P < O.Ol), and the regression line showed an intercept near zero (0.01) and a slope equal to one (1.01). These findings are consistent with either the hypothesis that for submaximal levels of constriction similar contractile elements are responding at both airway and tissue levels or that the contraction of airway smooth muscle alters the geometric configuration of the alveolar ducts and/or alveolar sacs, resulting in a change in the mechanical characteristics of lung tissues. On the other hand, at the plateau level the correlation between the percent change in airways and tissues was lost. One could hypothesize that at the plateau mechanical interdependence has become increasingly important and that “lung tissue contraction” limits airway narrowing. Alternatively, one could propose that alveolar ducts and/or alveolar sacs are deformed to the maximal extent and therefore they limit airway smooth muscle contraction in a more passive way. Previously we (19) have shown an inverse relationship between airway and tissue responses to inhaled methacholine at the level of the plateau response in rabbits. Our inability to find the same inverse correlation in this experiment (although we did lose the positive correlation between airway and tissue response seen prior to the plateau) could be explained by the small value of Raw in dogs compared with rabbits or by some other interspeties differences. Nevertheless we did observe in six dogs a progressive decrease in Raw after a peak value had been reached early in the concentration-response curves. The demonstration of a tissue response during constriction (12-14) suggests a reevaluation of the interaction between airways and tissues is warranted (2, 5, 16). Various authors (2,5,21) have shown that changing the force opposing airway smooth muscle shortening affects the level of maximal induced constriction. Ding et al. (5) measured RL in humans during tidal ventilation at different end-expiratory volumes during a methacholine challenge. They demonstrated that passive changes in lung volume affected the maximal response to methacholine and interpreted their data as consistent with the hypothesis that airway constriction was opposed by the tethering action of the surrounding parenchyma. The findings of Sly et al. (21) in cats were similar: alterations in lung volume affected the degree of airway constriction. Bellofiore et al. (2) showed in a rat model that changes in
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AIRWAY-TISSUE DOG
5000
1
0 RL
t
0
DUG
700
1
I
1
I
1
l
Rtl
A
Raw
I
1911
INTERACTIONS 2000
DUG
5
DOG
6
DOG
7
J
2
600 500 400
s H
m
3000
1200
/ P\
2500
6\”
800
2000
600
1500
400
1000
200
500
1000 0 :
0 DOG
2000
4
-A-A
I
I
8
16
I
I
I
J
. DOG 8
1200 1000
1500
800 1000
600 400
500 200 0
Bas Sal
0 0.5
1
2
4
ME’I’HACHOLINE
8
16
32
64
128
(mg/ml)
Bas Sal
0.5
1
2
4
32 64 128
METHACHOLINE(mg/ml)
1. Concentration-response curves for each individual dog. In all animals a plateau response in lung resistance is obtained. Rti, tissue resistance; Raw, airway resistance; EL, lung elastance; Bas, baseline; Sal, saline. %Saline, percentage of change relative to saline control value for each parameter. FIG.
(RL)
lung volume affected maximal constriction; in addition they demonstrated that inducing emphysema and thereby changing EL affected responsiveness. In all these studies, lung parenchyma was considered a passive element, but, as discussed above, lung tissues may be capable of active responses. Moreover, in two of these three studies, the authors measured RL and made inferences about Raw assuming that RL was an appropriate index of airway behavior. In the present protocol, in which airway and tissue components were partitioned, we confirmed that lung volume markedly affected the level of maximal bronchoconstriction, even after lung tissues were actively %onstricted.” The changes in Raw with PEEP were significant; Raw increased at the lower lung volumes and decreased at the higher lung volumes. The significance of
the change in Raw, as well as the direction, is consistent with the hypothesis that the degree of airway smooth muscle shortening is limited by the load against which the airway smooth muscle contracts (5). These forces opposing airway narrowing likely depend not only on passive interactions between airways and tissues as proposed by Mead et al. (16) and Ding et al. (5) but also on the state of activation of lung tissues. The direction of the Rti change deserves mention (Fig. 4). Increasing lung volume resulted in an increase in Rti, not a decrease as would be expected if constriction had been reversed due to the volume history effects of a deep inflation (12). Rather, what changed was airway diameter, which became larger at the higher lung volume as a consequence of mechanical interdependence. Gunst et al. (10) calculated the minimum transpul-
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1912
AIRWAY-TISSUE
INTERACTIONS 250.0
Preplateau Plateau
0
i
l
i
r
200.0 150.0 5 E z 100.0 2 0
0.0
-50.0
c I .
C
RL
l
Rti Raw
A
I
2.5
I
5.0
PEEP r = 0.74 n = 67 p < 0.01
I
t
I
t
III
lo3
E,
monary pressure at which the forces of interdependence between the airways and the lung parenchyma could prevent airway closure in response to maximal stimulation of the airway in excised canine diaphragmatic lobes. From their analysis these authors concluded that the forces of parenchymal interdependence per se are not sufficient to prevent airway closure if transpulmonary pressure is 17.5 cmH,O. In the present experiment, we found (Fig. 4) that with transpulmonary pressures of 7.5 and 10 cmH,O, during maximal induced constriction, Raw was significantly less than that measured at a PEEP lo4
0
i
I’ I, ,
Preplateau Plateau
0
II
,'
,'
I I , , I I I
3. * , I I
r = 0.49 n = 67 P < 0.01
I ,
II 8’ ,ol
,*'
10'
,’
,,
,, ,
I I’
I
,
(
,
,
,
,,,
I
lo*
IO3
I
104
(% saline) FIG. 3. Identity plot of percent increase in Raw vs. percent increase in Rti after methacholine. Dashed line is line of identity. Correlation was lost when only plateau points were considered. Rti
I
10.0
I
( cmH20)
FIG. 4. Changes in RL, Rti, Raw, and EL with changes in positive end-expiratory pressure (PEEP). Value of 5.0 refers to last data point of concentration-response curve. Data are expressed as percent of this maximum value. * Significantly different from value at PEEP = 5 cmH,O.
(% Saline)
FIG. 2. Identity plot of percent increase in Rti vs. percent increase in EL after methacholine. Dashed line is line of identity. Correlation was similar before and after plateau response.
i
I
7.5
of 5.0 cmH,O and not significantly different from baseline values. Not only was airway closure not seen at these lung volumes, but the induced constriction was essentially reversed. Even at 2.5 cmH,O of PEEP, we did not observe airway closure. These data suggest that, in the current experiment, the load against which the airway smooth muscle contracted had become so great that the airways could hardly narrow at all. This discrepancy between our data and those of Gunst et al. (10) is likely attributable to differences in the experimental model utilized, i.e., excised vs. in situ lung. In fact, the same authors suggest in a subsequent study (9) that the effectiveness of bronchoconstrictors is significantly reduced when the airways are subjected to tidal volume oscillations during contraction, which is the case in an in vivo preparation. In the current study the direction of change in RL with lung volume was opposite to the direction reported by Ding et al. (5) and Bellofiore et al. (2). Specifically, we found that RL increased at higher lung volumes, whereas Ding et al. and Bellofiore et al. observed the opposite effect. We believe that this discrepancy is explained by the interspecies difference in the relative importance of Raw and Rti to the measurement of RL. In dogs Raw is small; conversely, Rti accounts for a disproportionately large amount of RL. Measuring RL as an index of bronchoconstriction during maximal induced constriction may be more appropriate when the contribution of Raw to RL is substantial. This was likely the case in the study of Ding et al., as their measurements were obtained in humans and included the upper airways. Bellofiore et al. (2) investigated rats, another species in which the contribution of Raw to RL is relatively high (20). In these latter experiments the effects of volume on RL are largely explained by the effects on Raw; in the current study the effects of volume on RL reflect the effects on Rti. Our data give some information regarding the site of Rti response. The observation that the maximal response of Rti increased with mean VL, whereas Raw decreased, suggests that increasing transpulmonary pressure does not change the load on the tissues in the same
Downloaded from www.physiology.org/journal/jappl at Midwestern Univ Lib (132.174.254.157) on February 12, 2019.
AIRWAY-TISSUE
way it does on the airways or, alternatively, that the tissues are load independent. If what we record as Rti was simply a measure of small airway or alveolar duct constriction, then Rti should behave like Raw in response to a change in lung volume. That it does not supports the hypothesis that Rti reflects an actual change in the mechanical behavior of the parenchymal tissues themselves. The precise mechanism governing tissue viscous behavior is not known. Classically, Rti has been regarded as a viscous energy dissipation inside lung tissues. Recently Fredberg and Stamenovic (7) have proposed that dissipative processes within lung tissue depend not only on the viscous stress but also on the elastic stress insofar as dissipation and elasticity are coupled at the level of the stress-bearing element. They called this the %tructural damping hypothesis.” We found a close correlation between Rti and EL (Fig. Z), consistent with their hypothesis. They suggested four processes to account for this coupling: the kinetics of cross-bridge attachment-detachment within contractile elements, the kinetics of surface active molecule adsorption-desorption from surface film, the kinetics of the fiber-fiber interactions within the connective tissue matrix, and the kinetics of alveolar recruitment and derecruitment. The action of contractile stimuli on lu .ng tissues could be due to a direct effect on one of these elements or, alternately, due to indirect effects. For example, on .e could hypothesize the presence of con tractile elements inside 1ung tissues that respond to constriction. Alternately, one could invoke changes in the geometric configuration of alveolar ducts or alveolar sacs after constriction that would affect the mechanical behavior of the tissues and/or of the air-liquid interface (I). There is evidence in the literature that supports both of these hypotheses. Kapanci et al. (11) described fibroblast-like contractile cells. Gil et al, (8) showed the presence of contractile structures inside interstitial cells. Nadel et al. (17) and Colebatch et al. (4) demonstrated that contraction of alveolar duct smooth muscle can markedly modify the architecture of the surrounding alveolar sacs (“pneumoconstriction”), reducing air space distensibility by either some direct mechanical effects or by changing the mechanical behavior of the surfactant layer. In conclusion, we have observed that lung volume markedly affects the degree of maximal induced bronchoconstriction. Whether these changes in airway caliber are reflected in the change in RL depends on the relative contributions of the airways and tissues to overall RL. RL as an index of Raw during maximal induced constriction may be appropriate only in an experimental model where the relative contribution of Raw is high. When the relative contribution is low, as in the dog, it is necessary to directly measure Raw to assess changes in ai.rway caliber. Nonetheless , our findings indicate that both Raw and Rti are sensitive to volume change after induced . constriction and that the effects of lung volume on the plateau response reflect a complex combination of changes in Rti, airway caliber, and lung recoil.
by a fellowship from the Royal Victoria Hospital Research Institute. Dr. M. S. Ludwig is a scholar of the Medical Research Council of Canada. Address for reprint requests: M. S. Ludwig, Meakins-Christie Laboratories, 3626 St. Urbain St., Montreal, Quebec H2X 2P2, Canada. Received 17 June 1991; accepted in final form 17 June 1992. REFERENCES
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work was supported by the J. T. Costello Memorial Research the Medical Research Council of Canada, and the Respiratory Health Network of Centers of Excellence. F. M. Robatto was supported
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815,1987. 13. LUDWIG,
M. S., P. V. ROMERO, AND J. H. T. BATES. A comparison of the dose-response behavior of canine airways and parenchymal tissues: a comparative study. J. Appl. Physiol. 67: 1220-1225,1989. 14. LUDWIG, M. S., S. A. SHORE, J. J. FREDBERG, AND J. M. DRAZEN. Differential responses of tissue viscance and collateral resistance to histamine and leukotriene Cd. J. Appl. Physiol. 65: 1424-1429, 1988. 15. MCNAMARA, J. J., R. G. CASTLE, G. M. GRASS, AND J. J. FREDBERG. Heterogeneous lung emptying during forced expiration. J. Appl. Physiol. 63: 1648-1657, 1987. 16. MEAD, J., T. TAKISHIMA, AND D. LEITH. Stress distribution in lungs: a model of pulmonary elasticity. J. Appl. Physiol. 28: 596608, 1970. 17. NADEL, J.
A., H. J. H. COLEBATCH, mechanism of airway constriction
AND C. R. OLSEN. Location and after barium sulfate microembo-
lism. J. Appl. Physiol. 19: 387-394, 1964. ROBATTO, F. M., P. V. ROMERO, J. J. FREDBERG, AND M. S. LUDWIG. Contribution of quasi-static tissue hysteresis to the dynamic alveolar pressure-volume loop. J. Appl. PhysioL. 70: 708-714, 1991. 19. ROMERO, P. V., AND M. S. LUDWIG. Maximal methacholine-in18.
duced constriction in rabbits lungs: interactions between airways and tissues? J. Appl. Physiol. 70: 1044-1050, 1991. 20. ROMERO, P. V., S. SAPIENZA, AND M. S. LUDWIG. Partitioning lung resistance into airway and tissue components in rats (Abstract). 21.
This Fund,
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INTERACTIONS
Physiologist 31: A221, 1988. SLY, P. D., K. A. BROWN, J. H. T. BATES, P. T. MACKLEM, J. MILIC-EMILI, AND J. G. MARTIN. Effect of lung volume on interrupter resistance in cats challenged with methacholine. J. Appl. Physiol. 64: 360-366, 1988.
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S. SIMARD,
H. ORANA,
P. T. MACKLEM,
AND
M. S. LUDWIG
Meakins-Christie Laboratories, Royal Victoria Hospital, McGill University, Montreal, Quebec H2X 2P2; and Respiratory Health Network of Centers of Excellence, Montreal Chest Hospital Centre, Montreal, Quebec H2X 2P4, Canada ROBATTO, F. M., S. SIMARD, H. ORANA, P. T. MACKLEM, AND M. S. LUDWIG. Effect of lung volume on plateau response of airways and tissue to methacholine in dogs. J. Appl. Physiol. 73(5): 1908~1913,1992.-We have recently shown in dogs that much of the increase in lung resistance (RL) after induced constriction can be attributed to increases in tissue resistance, the pressure drop in phase with flow across the lung tissues (Rti). Rti is dependent on lung volume (VL) even after induced constriction. As maximal responses in RL to constrictor agonists can also be affected by changes in VL, we questioned whether changes in the plateau response with VL could be attributed in part to changes in the resistive properties of lung tissues. We studied the effect of changes in VL on RL, Rti, airway resistance (Raw), and lung elastance (EL) during maximal methacholine (MCh) -induced constriction in 8 anesthetized, paralyzed, openchest mongrel dogs. We measured tracheal flow and pressure (Ptr) and alveolar pressure (PA), the latter using alveolar capsules, during tidal ventilation [positive end-expiratory pressure (PEEP) = 5.0 cmHZO, tidal volume = 15 ml/kg, frequency = 0.3 Hz]. Measurements were recorded at baseline and after the aerosolization of increasing concentrations of MCh until a clear plateau response had been achieved. VL was then altered by changing PEEP to 2.5,7.5, and 10 cmH,O. RI, changed only when PEEP was altered from 5 to 10 cmH,O (P < 0.01). EL changed when PEEP was changed from 5 to 7.5 and 5 to 10 cmH,O (P < 0.05). Rti and Raw varied significantly with all three maneuvers (P < 0.05). Our data demonstrate that the effects of VL on the plateau response reflect a complex combination of changes in tissue resistance, airway caliber, and lung recoil. tissue resistance; airway resistance; mechanical interdependence LUNG TISSUES are generally modeled as passive mechanical structures. However, we (12) have recently shown, using the alveolar capsule technique, that much of the increase in lung resistance (RL) after induced constriction can be attributed to increases in the resistive pressure drop across lung tissues (Rti). These findings are consistent with the hypothesis that lung tissues are capable of responding to constrictor agonists (4417). In addition, we and others (3,12) have shown that Rti is dependent on lung volume; this dependence persists even after induced constriction (12). It has been demonstrated in both humans (5) and rats (2) that the maximal response in RL to a constrictor agonist can be modified by changes in lung volume. The usual interpretation of this finding has been that RL reflects airway resistance (Raw), and the amount that air1908
0161~X67/92
$2.00 Copyright
way caliber can decrease in response to constriction has been affected by alterations in the force opposing airway smooth muscle shortening. This hypothesis depends on the mechanical interdependence between airways and tissues (16) that occurs as the result of the radial connection of collagen and elastin fibers to the external perimeters of airways. With changes in lung volume the force exerted by such fibers on the airways is passively altered, and the degree that the airways can narrow during constriction is affected. However, if the parenchymal tissues are capable of active responses, i.e., if it is possible to modify tissue mechanical behavior with constrictor agonists, then the tissue reaction itself could be one of the factors modifying the effects of changing lung volume on the plateau response. Accordingly, we studied the plateau response to methacholine in dog lungs to which alveolar capsules had been applied so that resistive changes could be partitioned into airway and tissue components. End-expiratory lung volume was altered during the plateau response to change the relative resistance of airways and tissues and the forces of interaction between the two. In this way we attempted to examine the effects of changing lung volume on these mechanically interdependent structures during maximal methacholine-induced constriction. METHODS
Animal preparation. Experiments were done in eight mongrel male dogs ranging in weight from 15.5 to 20.0 kg [17.1 t 2.37 (SD) kg]. Dogs were anesthetized with pentobarbital sodium (30 mg/kg iv), and anesthesia was maintained by an intravenous injection of 10% of the initial dose every hour. Tracheostomy was performed, and a snugly fitting tracheal cannula with a side tap to measure tracheal pressure (Ptr) was inserted. A jugular venous line was placed. Dogs were paralyzed with 3 mg pancuronium iv; paralysis was maintained by intravenous administration of 1 mg/h. Dogs were ventilated with a volume ventilator (Harvard Apparatus) with a tidal volume of 15 ml/kg, 18 breaths/min, and at a positive end-expiratory pressure (PEEP) of 5 cmH,O. The temperature was kept constant with a heating pad placed below the animal. A midline sternotomy was performed, and the chest was widely retracted. Three alveolar capsules were applied to the pleural surface of the upper and/or the cardiac lobe with cyanoacrylate glue. The pleura underneath the capsule was punctured several times to a depth of a few millimeters
0 1992 the American Physiological
Society
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AIRWAY-TISSUE
with an 18-gauge needle to bring the underlying alveoli into communication with the capsule chamber. Pressures in the capsules and in the tracheal cannula were measured with miniature piezoresistive pressure transducers (model 8507B, Endevco, San Juan Capistrano, CA) calibrated with a water manometer. The three capsule pressure transducers were then recalibrated in situ against the Ptr transducer so that all transducers registered the same pressure during quasi-static conditions. The technical details of the alveolar capsule technique and its validity as a means of measuring alveolar pressure (PA) have been well documented (6, 12, 15). It is readily apparent when airways subtending a region sampled by an alveolar capsule are closed (10,12). The corresponding PA signal no longer matches the Ptr signal, and PA may even decrease as Ptr increases (12). Flow at the trachea was measured with a heated pneumotachograph (Fleisch no. 2). A piezoresistive differential pressure transducer (Microswitch 163PCOlD36, Honeywell, Scarborough, Ontario, Canada), calibrated with a rotameter, measured the pressure drop across the pneumotachograph. Volume change was obtained by digital integration of the flow signal. ProtocoI. Complete concentration-response curves to inhaled methacholine were obtained. Before the concentration-response curve was begun one inspiratory capacity breath, defined as the volume excursion between PEEP and a peak Ptr = 30 cmH,O, was delivered to standardize volume history. Aerosols were generated by an ultrasonic nebulizer (DeVilbiss 1OOB) that produced particles with a mean aerodynamic diameter of 4.5-6.0 pm. Saline was administered initially, and then the agonist was delivered into the trachea through a side port in the tracheal cannula in progressively doubling concentrations (0.5-128 mg/ml) at a flow rate of 1 l/min for 2 min. Tidal ventilation was continued during delivery of the aerosol. We considered that a plateau had been achieved when at least three subsequent doses did not cause any further increase in end-inspiratory peak Ptr. Measurements were recorded during tidal ventilation at baseline, after saline aerosol, and 1 min after each dose of methacholine aerosol had been administered. In addition, we made measurements at different end-expiratory lung volumes once a plateau response had been achieved. We altered end-expiratory lung volume by randomly changing PEEP, which was controlled by a water valve, to levels of 2.5,7.5,and 10 cmH,O. The precise protocol was as follows: we made a measurement at PEEP = 5 cmH,O. PEEP was then changed to its new level, and, once PEEP was stable, usually within 2 min, a further measurement was made. PEEP was then returned to 5 cmHZO, and an additional 1 min of aerosol was delivered in an attempt to maintain a constant level of bronchoconstriction. A measurement at PEEP = 5 cmH,O was then repeated before adjusting PEEP again This procedure was repeated for all PEEP levels. Signal conditioning and collection. All collected signals (3 PA, Ptr, and flow) were amplified, low-pass filtered at 100 Hz, converted from analog to digital by a 12-bit analog-to-digital converter (DT=2801A, Data Translation, Marlborough, MA) using a sampling rate of 200 Hz, and stored on an IBM-compatible personal computer. Data analysis. Total RL and lung elastance (EL) were
1909
INTERACTIONS
calculated by multiple linear regression by digitally ting the 15-s segments of data to the equation
fit-
Ptr =~RL+VEL+K
(I)
where v is tracheal flow, V is volume change, and K is a constant with a value that was also estimated by multiple linear regression and a function that was to take into account that, in an open-chest animal, zero volume corresponded to 5 cmH,O in pressure. We calculated Rti for each PA by multiple linear regression from the equation
PA =VRti
+VEL+
K
(2)
The values so obtained from each alveolar were then meaned. Raw was obtained by subtraction
capsule
Raw = RL - Rti (3) We constructed methacholine dose-response curves for all the animals, plotting percent change from the saline baseline in RL, Raw, and Rti against concentration of methacholine. We calculated the concentration of methacholine necessary to elicit a twofold rise in RL above saline (EC,,,RL) by log linear interpolation. Corresponding quantities were calculated for Raw and Rti (EC,,,Raw and EC,,*Rti, respectively). Statistical analysis. We did linear regression analysis to compare percent change in Rti to percent change in Raw. Paired t test was used to compare the effect of changes in PEEP on Raw, RL, and Rti, using the preceding measurement at 5 cmH,O of PEEP as the control for the subsequent measurement at the new PEEP level. RESULTS
Baseline values of RL, Rti, Raw, and EL are given for all the dogs in Table 1. Mean RL was 1.23 t 0.15 (SE) cmH,O 1-l s under baseline conditions and increased to 6.18 t 2.77 cmH,O l 1-l. s after the plateau response was attained. Mean Raw was 0.31 t 0.08 cmH,O 01-l s at baseline and increased to 2.47t 1.024 cmH,O 1-l s after methacholine. Mean Rti was 0.92 t 0.10 cmH,O l 1-l s at baseline and increased to 13.54 t 2.77cmH,O 1-l s after methacholine. EL was 12.48 t 1.33 cmH,O/l at baseline and increased to 92.03 t 21.41 cmH,O/l after methacholine. A plateau in RL was obtained in all the animals. This is illustrated in Fig. 1, which shows individual methacholine concentration-response curves. It should be noted that we did not observe airway closure with any of the capsules in any of the dogs, even with PEEP = 2.5 cmH,O. The geometric mean EC,,RL was 0.15mg/ml, the geometric mean EC,,,Rti was 0.17 mg/ml, and the geometric mean EC,,,Raw was 0.17 mg/ml. There were no differences in sensitivity (the dose of agent at which the response occurred) between the airways and tissues. Figure 2 shows an identity plot of percent increase in Rti vs. percent increase in EL after methacholine. The correlation coefficient was 0.74 (P < 0.01,n = 67). Note that the correlation was of similar degree both before and after the plateau response. An identity plot of percent increase in Raw vs. percent increase in Rti after methacholine is shown in Fig. 3. The l
l
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l
l
l
l
l
l
1910 TABLE
AIRWAY-TISSUE
INTERACTIONS
1. Baseline values cm&O
Dog No.
wt, kg
RL
Rti
20.0 13.2
0.75 1.56 0.97 0.95 1.31 1.43 0.94 1.93
0.53 1.03 0.73 0.83 0.82 1.15 0.92 1.34
17.1 to.3
1.23 kO.15
0.92 :O.lO
16.8 18.6 16.8 20.0 15.5 15.5
Mean &SE
81-l
l
s EL, cmH,O/l
EC,RL
EC,Rti
E&,Raw
0.21 0.54 0.24 0.12 0.50 0.29 0.02 0.55
10.08 12.48 10.32 12.01 11.56 12.99 9.67 20.69
0.03 0.31 0.14 0.59 0.06 0.06 0.23 0.39
0.09 0.27 0.13 0.59 0.06 0.08 0.24 0.41
4.40 0.29 0.59 0.07 0.04 0.08 0.32
0.31 kO.08
12.48 tl.33
0.15
0.17
0.17
Raw
0.01
RL, lung resistance; Rti, tissue resistance; Raw, airway resistance; EL, lung elastance. Mean &fold effective concn (EC&J is a geometric mean.
correlation coefficient (r) for the pooled data was 0.49 (P < 0.01, n = 67), and slope and intercept were 0.76 and 0.72, respectively. For the preplateau data points only, r was 0.68 (P < 0.01, n = 26), and slope and intercept were 1.01 and 0.01, respectively. The plateau data points showed no correlation (r = 0.28, n = 41, not significant). Figure 4 shows the change in RL, Rti, Raw, and EL with change in PEEP. There were no significant differences among the various PEEPS = 5 cmH,O for RL, Raw, and Rtii. EL at the different PEEPS = 5.0 cmH,O was significantly different (P < 0.05). RL varied significantly (P < 0.01, paired t test) when PEEP was changed from 5 to 10 cmH,O. Rti varied significantly (P < 0.05) with change of PEEP from 5 to 7.5 and from 5 to 10 cmH,O. Raw and EL varied significantly (P < 0.05) with all three maneuvers, i.e., changing PEEP from 5 to 2.5, 5 to 7.5, and 5 to 10 cmH,O (P < 0.05). The changes in Rti and Raw with lung volume were always in opposite directions, i.e,, when mean lung volume increased, Rti increased and Raw decreased. When mean lung volume decreased, Rti decreased and Raw increased (Fig. 4). The changes in RL were in the same direction as Rti when mean lung volume increased and in the same direction as Raw when mean lung volume decreased. DISCUSSION
Recently the alveolar capsule technique (6), which allows direct measurement of PA, has provided a new method for partitioning the changes in RL into Raw and Rti components. We and others (3, 12, 14) have shown that, in dogs, under baseline conditions, Rti is the predominant component of RL, accounting for -6O-80% of the resistive pressure drop. After induced constriction the increase in RL is, to a large extent, attributable to increases in Rti (13, 14). The data of the present study confirm those observations: Rti accounted for 75% and Raw for 25% of RL under control conditions and 85 and 15% after maximal levels of constriction had been induced, respectively. It should be noted that under the current experimental conditions (tidal volume = 15 ml/ kg, frequency = 0.3 Hz, and PEEP = 5 cmH,O) the contribution of quasi-static hysteresis to Rti is negligible (18). Changes in Rti were correlated with changes in Raw; we found a significant correlation (r = 0.49, P < 0.01; Fig. 3) between percentage change in Raw and percent
change in Rti, confirming previous observations in dogs (13) and in rabbits (19). When only the preplateau points were considered, the correlation was stronger (r = 0.68, P < O.Ol), and the regression line showed an intercept near zero (0.01) and a slope equal to one (1.01). These findings are consistent with either the hypothesis that for submaximal levels of constriction similar contractile elements are responding at both airway and tissue levels or that the contraction of airway smooth muscle alters the geometric configuration of the alveolar ducts and/or alveolar sacs, resulting in a change in the mechanical characteristics of lung tissues. On the other hand, at the plateau level the correlation between the percent change in airways and tissues was lost. One could hypothesize that at the plateau mechanical interdependence has become increasingly important and that “lung tissue contraction” limits airway narrowing. Alternatively, one could propose that alveolar ducts and/or alveolar sacs are deformed to the maximal extent and therefore they limit airway smooth muscle contraction in a more passive way. Previously we (19) have shown an inverse relationship between airway and tissue responses to inhaled methacholine at the level of the plateau response in rabbits. Our inability to find the same inverse correlation in this experiment (although we did lose the positive correlation between airway and tissue response seen prior to the plateau) could be explained by the small value of Raw in dogs compared with rabbits or by some other interspeties differences. Nevertheless we did observe in six dogs a progressive decrease in Raw after a peak value had been reached early in the concentration-response curves. The demonstration of a tissue response during constriction (12-14) suggests a reevaluation of the interaction between airways and tissues is warranted (2, 5, 16). Various authors (2,5,21) have shown that changing the force opposing airway smooth muscle shortening affects the level of maximal induced constriction. Ding et al. (5) measured RL in humans during tidal ventilation at different end-expiratory volumes during a methacholine challenge. They demonstrated that passive changes in lung volume affected the maximal response to methacholine and interpreted their data as consistent with the hypothesis that airway constriction was opposed by the tethering action of the surrounding parenchyma. The findings of Sly et al. (21) in cats were similar: alterations in lung volume affected the degree of airway constriction. Bellofiore et al. (2) showed in a rat model that changes in
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AIRWAY-TISSUE DOG
5000
1
0 RL
t
0
DUG
700
1
I
1
I
1
l
Rtl
A
Raw
I
1911
INTERACTIONS 2000
DUG
5
DOG
6
DOG
7
J
2
600 500 400
s H
m
3000
1200
/ P\
2500
6\”
800
2000
600
1500
400
1000
200
500
1000 0 :
0 DOG
2000
4
-A-A
I
I
8
16
I
I
I
J
. DOG 8
1200 1000
1500
800 1000
600 400
500 200 0
Bas Sal
0 0.5
1
2
4
ME’I’HACHOLINE
8
16
32
64
128
(mg/ml)
Bas Sal
0.5
1
2
4
32 64 128
METHACHOLINE(mg/ml)
1. Concentration-response curves for each individual dog. In all animals a plateau response in lung resistance is obtained. Rti, tissue resistance; Raw, airway resistance; EL, lung elastance; Bas, baseline; Sal, saline. %Saline, percentage of change relative to saline control value for each parameter. FIG.
(RL)
lung volume affected maximal constriction; in addition they demonstrated that inducing emphysema and thereby changing EL affected responsiveness. In all these studies, lung parenchyma was considered a passive element, but, as discussed above, lung tissues may be capable of active responses. Moreover, in two of these three studies, the authors measured RL and made inferences about Raw assuming that RL was an appropriate index of airway behavior. In the present protocol, in which airway and tissue components were partitioned, we confirmed that lung volume markedly affected the level of maximal bronchoconstriction, even after lung tissues were actively %onstricted.” The changes in Raw with PEEP were significant; Raw increased at the lower lung volumes and decreased at the higher lung volumes. The significance of
the change in Raw, as well as the direction, is consistent with the hypothesis that the degree of airway smooth muscle shortening is limited by the load against which the airway smooth muscle contracts (5). These forces opposing airway narrowing likely depend not only on passive interactions between airways and tissues as proposed by Mead et al. (16) and Ding et al. (5) but also on the state of activation of lung tissues. The direction of the Rti change deserves mention (Fig. 4). Increasing lung volume resulted in an increase in Rti, not a decrease as would be expected if constriction had been reversed due to the volume history effects of a deep inflation (12). Rather, what changed was airway diameter, which became larger at the higher lung volume as a consequence of mechanical interdependence. Gunst et al. (10) calculated the minimum transpul-
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1912
AIRWAY-TISSUE
INTERACTIONS 250.0
Preplateau Plateau
0
i
l
i
r
200.0 150.0 5 E z 100.0 2 0
0.0
-50.0
c I .
C
RL
l
Rti Raw
A
I
2.5
I
5.0
PEEP r = 0.74 n = 67 p < 0.01
I
t
I
t
III
lo3
E,
monary pressure at which the forces of interdependence between the airways and the lung parenchyma could prevent airway closure in response to maximal stimulation of the airway in excised canine diaphragmatic lobes. From their analysis these authors concluded that the forces of parenchymal interdependence per se are not sufficient to prevent airway closure if transpulmonary pressure is 17.5 cmH,O. In the present experiment, we found (Fig. 4) that with transpulmonary pressures of 7.5 and 10 cmH,O, during maximal induced constriction, Raw was significantly less than that measured at a PEEP lo4
0
i
I’ I, ,
Preplateau Plateau
0
II
,'
,'
I I , , I I I
3. * , I I
r = 0.49 n = 67 P < 0.01
I ,
II 8’ ,ol
,*'
10'
,’
,,
,, ,
I I’
I
,
(
,
,
,
,,,
I
lo*
IO3
I
104
(% saline) FIG. 3. Identity plot of percent increase in Raw vs. percent increase in Rti after methacholine. Dashed line is line of identity. Correlation was lost when only plateau points were considered. Rti
I
10.0
I
( cmH20)
FIG. 4. Changes in RL, Rti, Raw, and EL with changes in positive end-expiratory pressure (PEEP). Value of 5.0 refers to last data point of concentration-response curve. Data are expressed as percent of this maximum value. * Significantly different from value at PEEP = 5 cmH,O.
(% Saline)
FIG. 2. Identity plot of percent increase in Rti vs. percent increase in EL after methacholine. Dashed line is line of identity. Correlation was similar before and after plateau response.
i
I
7.5
of 5.0 cmH,O and not significantly different from baseline values. Not only was airway closure not seen at these lung volumes, but the induced constriction was essentially reversed. Even at 2.5 cmH,O of PEEP, we did not observe airway closure. These data suggest that, in the current experiment, the load against which the airway smooth muscle contracted had become so great that the airways could hardly narrow at all. This discrepancy between our data and those of Gunst et al. (10) is likely attributable to differences in the experimental model utilized, i.e., excised vs. in situ lung. In fact, the same authors suggest in a subsequent study (9) that the effectiveness of bronchoconstrictors is significantly reduced when the airways are subjected to tidal volume oscillations during contraction, which is the case in an in vivo preparation. In the current study the direction of change in RL with lung volume was opposite to the direction reported by Ding et al. (5) and Bellofiore et al. (2). Specifically, we found that RL increased at higher lung volumes, whereas Ding et al. and Bellofiore et al. observed the opposite effect. We believe that this discrepancy is explained by the interspecies difference in the relative importance of Raw and Rti to the measurement of RL. In dogs Raw is small; conversely, Rti accounts for a disproportionately large amount of RL. Measuring RL as an index of bronchoconstriction during maximal induced constriction may be more appropriate when the contribution of Raw to RL is substantial. This was likely the case in the study of Ding et al., as their measurements were obtained in humans and included the upper airways. Bellofiore et al. (2) investigated rats, another species in which the contribution of Raw to RL is relatively high (20). In these latter experiments the effects of volume on RL are largely explained by the effects on Raw; in the current study the effects of volume on RL reflect the effects on Rti. Our data give some information regarding the site of Rti response. The observation that the maximal response of Rti increased with mean VL, whereas Raw decreased, suggests that increasing transpulmonary pressure does not change the load on the tissues in the same
Downloaded from www.physiology.org/journal/jappl at Midwestern Univ Lib (132.174.254.157) on February 12, 2019.
AIRWAY-TISSUE
way it does on the airways or, alternatively, that the tissues are load independent. If what we record as Rti was simply a measure of small airway or alveolar duct constriction, then Rti should behave like Raw in response to a change in lung volume. That it does not supports the hypothesis that Rti reflects an actual change in the mechanical behavior of the parenchymal tissues themselves. The precise mechanism governing tissue viscous behavior is not known. Classically, Rti has been regarded as a viscous energy dissipation inside lung tissues. Recently Fredberg and Stamenovic (7) have proposed that dissipative processes within lung tissue depend not only on the viscous stress but also on the elastic stress insofar as dissipation and elasticity are coupled at the level of the stress-bearing element. They called this the %tructural damping hypothesis.” We found a close correlation between Rti and EL (Fig. Z), consistent with their hypothesis. They suggested four processes to account for this coupling: the kinetics of cross-bridge attachment-detachment within contractile elements, the kinetics of surface active molecule adsorption-desorption from surface film, the kinetics of the fiber-fiber interactions within the connective tissue matrix, and the kinetics of alveolar recruitment and derecruitment. The action of contractile stimuli on lu .ng tissues could be due to a direct effect on one of these elements or, alternately, due to indirect effects. For example, on .e could hypothesize the presence of con tractile elements inside 1ung tissues that respond to constriction. Alternately, one could invoke changes in the geometric configuration of alveolar ducts or alveolar sacs after constriction that would affect the mechanical behavior of the tissues and/or of the air-liquid interface (I). There is evidence in the literature that supports both of these hypotheses. Kapanci et al. (11) described fibroblast-like contractile cells. Gil et al, (8) showed the presence of contractile structures inside interstitial cells. Nadel et al. (17) and Colebatch et al. (4) demonstrated that contraction of alveolar duct smooth muscle can markedly modify the architecture of the surrounding alveolar sacs (“pneumoconstriction”), reducing air space distensibility by either some direct mechanical effects or by changing the mechanical behavior of the surfactant layer. In conclusion, we have observed that lung volume markedly affects the degree of maximal induced bronchoconstriction. Whether these changes in airway caliber are reflected in the change in RL depends on the relative contributions of the airways and tissues to overall RL. RL as an index of Raw during maximal induced constriction may be appropriate only in an experimental model where the relative contribution of Raw is high. When the relative contribution is low, as in the dog, it is necessary to directly measure Raw to assess changes in ai.rway caliber. Nonetheless , our findings indicate that both Raw and Rti are sensitive to volume change after induced . constriction and that the effects of lung volume on the plateau response reflect a complex combination of changes in Rti, airway caliber, and lung recoil.
by a fellowship from the Royal Victoria Hospital Research Institute. Dr. M. S. Ludwig is a scholar of the Medical Research Council of Canada. Address for reprint requests: M. S. Ludwig, Meakins-Christie Laboratories, 3626 St. Urbain St., Montreal, Quebec H2X 2P2, Canada. Received 17 June 1991; accepted in final form 17 June 1992. REFERENCES
1. BACHOFEN, H., S. SCHURCH, M. URBINELLI, AND E. R. WEIBEL. Relations among alveolar surface tension, surface area, volume, and recoil pressure. J. Appl. Physiol. 62: 1878-1887, 1987. 2. BELLOFIORE, S., D. H. EIDELMAN, P. T. MACKLEM, AND J. G. MARTIN. Effects of elastase-induced emphysema on airway responsiveness to methacholine in rats. J. Appl. Physiol. 66: 606-612, 1989. 3. BRUSASCO, V., D. 0. WARNER, K. E. BECK, J. R. RODARTE, AND K. REHDER. Partitioning of pulmonary resistance in dogs: effect of tidal volume and frequency. J. Appl. Physiol. 66: 1190-1196, 1989. 4. COLEBATCH, J. H., C. R. OLSEN, AND J. A. NADEL. Effect of histamine, serotonin, and acetylcholine on the peripheral airways. J. 1968, Appl. Physiol. 21: 296-301, AND P. T. MACKLEM. Effects of lung 5. DING, D. J., J. G. MARTIN, volume on maximal methacholine-induced bronchoconstriction in normal humans. J. Appl. Physiol. 62: 1324-1330, 1987. 6. FREDBERG, J. J., D. H. KEEFE, G. M. GLASS, R, G. CASTILE, AND I. D. FRANTZ III. Alveolar pressure nonhomogeneity during smallamplitude high-frequency oscillation. J. Appl. Physiol. 57: 788-800, 1984. 7. FREDBERG, 8.
9.
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work was supported by the J. T. Costello Memorial Research the Medical Research Council of Canada, and the Respiratory Health Network of Centers of Excellence. F. M. Robatto was supported
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