Effect of bronchial smooth muscle contraction on lung compliance WAYNE

MITZNER,

SANDRALEE

BLOSSER,

DEBORAH

YAGER,

AND ELIZABETH

WAGNER

Divisions of Physiology and Pulmonury Medicine, The Johns Hopkins Medical Institutions, Baltimore, Murylund 21205; and Department of Environmentul Science and Physiology, Harvard School of Public Health, Boston, Massachusetts 02115 MITZNER,WAYNE,SANDRALEEBLOSSER,DEBORAHYAGER, signed to evaluate AND ELIZABETH WAGNER. Effect of bronchial smooth muscle contraction on lung compliance. J. Appl. Physiol. 72(l): 158-167, 1992.-Lung complianceis generally consideredto represent a

blend of surfaceand tissueforces, and changesin compliancein vivo are commonly usedto indicate changesin surface forces. There are, however, theoretical arguments that would allow contraction of airway smooth muscleto affect substantially the elasticity of the lung. In the present study we evaluated the role of conducting airway contraction on lung compliancein vivo by infusing methacholine (MCh) at a constant rate into the bronchial circulation. With a steady-state MCh infusion of 2.4 pgl min into the bronchial perfusate (perfusateconcentration = 0.7 PM), there wasan approximate doubling of lung resistanceand a 50% fall in dynamic compliance. There were also significant decreasesin chord compliance measuredfrom the quasi-static pressure-volumecurves and in total lung capacity and residual volume. When the sameinfusion rate was administered into the pulmonary artery, no changesin lung mechanicswere observed.These results indicate that the conducting airways may have a major role in regulating lung elasticity. This linkage between airway contraction and lung compliance may account for the common observation that pharmacological challenges given to the lung usually result in similar changesin lung compliance and airway conductance. Our results also suggestthe possibility that the lung tissue resistance,which dominatesthe measurementof lung resistancein many species,might in fact reflect the physical properties of conducting airways. lung resistance;airway resistance;lung elasticity; surfactant; bronchial circulation; airway circulation; interdependence;airway closure;bronchial circulation THEREHASBEENCONSIDERABLE investigation,boththe-

oretical and experimental, of the effect of lung parenchyma on airway dimensions. As the lung inflates, the tension in the alveolar walls increases, and the forces of interdependence act to dilate the airways (23, 29). The converse situation, that is, how the airways might alter lung parenchymal tension and hence lung compliance, has received relatively scant attention. The air-filled pressure-volume (PV) curve is traditionally considered to represent a blend of surface and tissue forces, and changes in the PV curve of the lung have been commonly used to indicate changes in these forces (7, 13, 30). While there is little question that both surface and tissue forces at the alveolar level have important roles in parenchymal elasticity, the role of smooth muscle con-

traction is often overlooked. However, in studies de158

0161-7567192

$2.00

the pharmacological response of the airway smooth muscle, agonists that result in increases in lung resistance (RL) nearly always result in simultaneous decreases in dynamic compliance (Cdyn) (10, 18, 31). In this study, we will be concerned with determination of the mechanism of this decrease in compliance. It is our hypothesis that the observed changes in lung compliance result entirely from contraction of airway smooth muscle. This contraction can have two effects, with the first being a generalized contraction of airways that stiffens the lung parenchyma by virtue of interdependence forces. In the extreme, as was speculated by Macklin (26) many years ago, if all airways were completely rigid, inflation of the lung might be quite difficult. The second effect would arise from a more localized airway contraction that could result in the physical closure of airways and trapping of gas in alveoli. It has been difficult to obtain evidence for or against this hypothesis, because existing methods of challenging airways are not localized to specific airway regions. Both intravenous and aerosol challenges generally reach all airways and parenchyma. In addition neither the aerosol nor intravenous challenge route can be used to cause steady-state levels of airway constriction without significant systemic side effects. In the present study we were able to test the importance of a steady-state level of airway contraction in sheep by employing continuous infusion of agonist directly into the bronchial artery, In the sheep the bronchial artery joins the airway tree just below the carina. As discrete branches then follow along the branching tree, they give rise to both a peribronchial arterial plexus and a submucosal plexus (4,27). Thus, as illustrated schematically in Fig. 1, the airway smooth muscle is in intimate contact with this circulation. As the airways branch deeper in the lung, it is believed that the bronchial circulation continues to bathe the airways down to the level of the terminal bronchioles. At this level the capillaries of the bronchial circulation merge with vessels of the pulmonary circulation. There are also bronchial veins that drain a small fraction of the flow into the azygous vein. In our study, we maintain a stable concentration of agonist in the bronchial perfusate; this is maintained until the agonist in the bronchial circulation becomes diluted in the smallest airways by the much larger pulmonary blood flow. The normal pulmonary artery flow is ~100 times larger than the bronchial flow, so the con-

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PULM. a. FIG. 1. Schematic illustrati.ng stimulation of conducting airways with constant infusion rate (K) of methacholine (MCh) into bronchial artery. QBA, constant rate of bronchial blood flow set with perfusion pump.

centration of agonist beyond the level of the terminal bronchioles would be expected to be extremely attenuated. Thus with this preparation we are able to examine directly the effect on lung mechanics of contraction of airways larger than respiratory bronchioles. METHODS

We studied a total of eight young adult male sheep [mean wt 35.5 t 1.5 (SE) kg] initially anesthetized with ketamine (1 g im) and subsequently maintained with pentobarbital sodium (15 mg/kg loading dose, 20 mg/kg hourly dose). They were ventilated with a Harvard Apparatus ventilator at a rate of 12-15 breaths/min with a tidal volume of lo-12 ml/kg. Supplemental doses of anesthesia were delivered at hourly intervals. Using the method developed by Wagner et al. (36) as described briefly below, we cannulated and perfused the bronchial artery at a constant flow rate. The preparation ultimately established is shown in Fig. 2. The right femoral artery was cannulated for measurement of systemic arterial pressure (Pa) and sampling of arterial blood, and the left femoral vein was cannulated for administration of anesthetic. A Swan-Ganz catheter was inserted through the right femoral vein and floated into the pulmonary artery for measurement of pulmonary arterial pressure (Ppa) and infusion of the contractile agonist into the right atrium. The chest was opened with an incision in the fifth intercostal space on the left side. The bronchoesophageal artery was isolated, and all side branches of this vessel were ligated. The artery was then cannulated and connected to a roller pump; the inflow to this pump was from a catheter placed in the left femoral artery. Initial flow rate to the bronchial vasculature was set at 0.6 ml. min-l . kg-l. Measurement of pulmonary mechanical properties. Cdyn was calculated from the changes in lung volume and airway pressure at the points of zero flow. RL was measured by the method of forced oscillation (16). A gas volume of --30 ml was oscillated for 1.5 s at a frequency of 9 Hz after each tidal breath. Airway pressure was measured from a side arm in the tracheal cannula, and be-

cause the chest was widely opened, the airway pressure was equivalent to transpulmonary pressure (Ptp). A flow signal was obtained from a pneumotachograph positioned upstream from the cannula. Oscillatory signals were analyzed with an on-line computer that measured pressure at points of peak flow. An average resistance measurement was obtained over 8-10 oscillatory cycles. Although most traditional measurements of RL have a large component representing tissue resistance (25), it has been previously deduced that this forced oscillation measurement in sheep primarily represents airway resistance (35). This has recently been confirmed in dogs, where it was shown that RL measurements at a frequency of 10 Hz are dominated by the resistance of the airways (2) PV curves of the lungs were measured in vivo by inflation of the lungs with a calibrated air pump to a Ptp of 30 cmH,O [total lung capacity (TLC)] and then deflation of them to minimal or residual volume (RV). The lungs were reinflated to TLC and then deflated to 5 cmH,O, whereupon the absolute lung volume was measured by a lo-breath equilibration with 500-600 ml of helium. We then calculated the absolute TLC and RV. Inflation rate for these PV curves was such that the entire PV maneuver took -45 s. From the PV curves we measured a quasi-static compliance on the deflation limb as the slope of the curve between 5 and 10 cmH,O, and we refer to this as Cdef. A typical PV curve showing the variables measured is shown in Fig. 3. Experimental protocol. The experimental protocol used in six sheep is illustrated in Fig. 4. At least two sequential methacholine chloride (MCh) challenges were done in each animal. With constant bronchial blood flow (QBA), we infused MCh (J. T. Baker, Phillipsburg, NJ) directly into the bronchial artery at a constant rate (K). The steady-state molar concentration o< the bronchial perfusate can then be calculated as K/Q,, (Fig. 1). We had previously determined that a perfusate concentration of -0.7 PM would cause a doubling of the peak airway pressure, and this concentration was used in all protocols. Stable plateau values of RL and Cdyn occurred within 2 min of the start of the infusion and recovered spontanel

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L!

Aif :::~:::::g P u m p ~:~:~~~:~ff 0 r :$i:i:g< PV Curves

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I MCI7 infusion

--

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FEMORAL

ARTERY

BRANCH

FIG. 2. Experimental preparation. A: animal’s trachea could be connected to conventional ventilator, oscillator for measurement of lung resistance, or air pump for pressure-volume (PV) curve measurement. Although shown schematically as mechanical rotating valve, actual setup utilized 3 solenoid valves that allowed any of 3 air pumps to be selected electronically. B: schematic illustrating setup for perfusion of bronchial vasculature with pump. Chest remained open during entire experimental procedure.

ously within 5 min after the infusion was stopped. After RL and Cdyn had plateaued, we obtained whole lung PV curves as described above at the time points illustrated by the arrows in Fig. 4. In each animal we also infused MCh at the same rate into the right atrium either before or after this protocol. This was done to determine if there was any direct effect of the MCh on the most peripheral airways, perfused primarily by the pulmonary circulation. In three additional animals we performed a similar protocol before and after vagotomy. In these animals, however, we did not measure PV curves. At the time of tracheostomy both vagus nerves were isolated. After completion of the above protocol, the nerves were cut, and the protocol was repeated after the systemic blood pressure had stabilized. MorphoZ~gicaZ analysis. To confirm that the very pe-

ripheral airways were not contracted with the MCh infusion into the bronchial artery, we prepared in two separate animals pieces of relaxed and contracted lung for morphological examination by low-temperature scanning electron microscopy (LTSEM). Samples of lung parenchyma were taken at end expiration from the periphery of either the left middle or upper lobe. This was accomplished by rapidly clamping a tip of the lobe with two rubber-covered hemostats, cutting between them, and then immersing the lung piece in liquid nitrogen. This sequence, from the initial clamping to immersion, took -30 s. In each animal a piece was taken under the following two conditions: 1) after a steady-state constriction had occurred as above during bronchial artery infusion of MCh and 2) near the peak constriction after an intravenous bolus injection of MCh (2.5 mg) that caused a comparable increase in peak airway pressure.

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IO

30

PTP kmH20)

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taken from the most peripheral lung regions, the largest airways that could be seen in these samples were -700 j4m. Airways seen in the LTSEM micrographs were quantified by measuring the length of the external border and the minimal internal diameter (d,). The internal border of the airway wall was defined by the lumenal epithelial edge and the external border by the outer edge of the smooth muscle, Airways were sized from the internal diameter assuming that noncircular cross sections resulted from oblique sections. Constriction is assumed to occur without changes in both internal perimeter and wall volume (21, 37), and the degree of constriction was expressed as a percent change in the length of the external circumference [AC/Co = 100 X (Co - C)/C,], where Co and C are the circumferences in the relaxed and contracted states, respectively. Statistical analysis. A one-way analysis of variance with repeated measures was used to assess significant differences between the lung mechanics variables during the sequential control and MCh challenges.

3. Representative pressure-volume curve from 1 sheep in conshowing measurements that were made. RV, residual volume (=minimal volume); TLC, total lung capacity (=volume at 30 cm&O transpulmonary pressure); Cdef, deflation limb compliance measured between 5 and 10 cmH,O.

RESULTS

After submersion in liquid nitrogen, tissue samples from the four lobes were studied in the frozen hydrated state by LTSEM as described previously (37). Briefly, 5 X 5 X lo-mm tissue blocks were cut from each lung piece such that one face contained one or more airways in cross section. Once secured in a brass sample holder with the chosen surface exposed, each block was first transferred into a biochamber for fracturing and evaporative gold coating and then directly shuttled into the attached LTSEM for study. To identify clear structural boundaries, the sample surface was radiant heat-etched before gold coating. At all times during specimen cutting, transfer, and study, the samples were held at liquid nitrogen temperature (-196°C). In addition, while in the biochamber and microscope they were also kept under a vacuum of 1O-5-lO-6 mmHg. Airways were imaged in the LTSEM at 10 kV, and micrographs were taken in stereo pairs for three-dimensional viewing. Because pieces were

Average values (*SE) of the cardiovascular variables measured before the first infusion of MCh were the following: Q,, = 20.8kO.4 ml/ min, Pa = 93.5 -t 10.3 mmHg, and Ppa = 12.7 t 1.8 mmHg. With infusion of MCh into the bronchial artery, there were negligible changes in systemic pressure and Ppa. Figure 5 summarizes the results from the six animals in which resistance, compliance, and PV curves were measured. Repeat MCh challenges caused significant (P < 0.01) reversible changes in RL, Cdyn, and Cdef. There were also statistically significant decreases in both RV and TLC; during the MCh infusions the average fall in TLC was 535 ml (30% of control, P < O.Ol), and in RV it was 98 ml (14% of control, P < 0.05). We also analyzed potential shape changes in the PV curves by measuring the percent volume remaining on deflation at 0,5, and 15 cmH,O (6). During the MCh infusion there were no significant changes in any of these percentage volumes. Thus, with bronchoconstriction, al-

FIG.

trol state

Contrcil

MCh

4--

t

(0.7pM)

Cm ml

t

t

TLC, FIG.

4. Experimental

taken

immediately

Control

T

f

6 min 4

PRESSURE-VOLUME

were

MCh (0.7pM)

MEASUREMENTS RV, C&f

protocol. Values of lung resistance (RL) and dynamic compliance (Cdyn) reported in Fig. 5 before pressure-volume measurements.

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c

MCh

MCh

6'

C

MCh

C

5. Summary of data for Cdyn, RL, Cdef, TLC, and RV. Abscissa represents sequential measurements made during control (C) and methacholine (MCh) challenges as illustrated in Fig. 4. Cdef, quasi-static compliance; VL, lung volume. Differences between control and MCh challenges were statistically significant at P c 0.01 for all variables, except for RV during 2nd MCh challenge (P < 0.05). FIG.

though there were changes in absolute lung volumes at given transpulmonary pressures, when expressed as fractions of TLC there were no changes. When the MCh was infused at the same constant rate directly into the pulmonary vasculature there were no detectable changes in either RL or Cdyn. In the three animals that were vagotomized, before vagotomy the MCh infusion caused a fall in Cdyn from 37 t 1.1 to 16 t 0.4 ml/cmH,O (56% fall). After vagotomy Cdyn fell from 43 t 1.5 to 18 + 0.3 ml/cmH,O (58% fall). In each of the animals the vagotomy itself caused the Cdyn to increase slightly and the RL to decrease more substantially. Before vagotomy, the MCh caused RL to increase from 1.5 + 0.2 to 6 + 0.7 cmH,O. ml-l amin (300% increase). After the vagotomy, RL fell from 1.4 t 0.2 to 0.73 +- 0.06 cmH,O. 1-l ss, but the MCh infusion then increased the RL to 2.8 t 0.7 cmH,O l 1-l. s (280% increase). Thus potential vagal reflexes had little influence on the response to MCh infusion through the bronchial arteries. In the lung contracted with a bronchial artery infusion of MCh, we were unable to observe any morphological evidence of airway constriction. Figure 6 shows one representative 700-pm airway. Thus it appears that the airways contracted with this challenge via the bronchial artery must be at least >700 pm. That this absence of contraction in the frozen lungs was not a result of some problem with the sampling and preparation procedures is confirmed by the clear evidence of airway contraction after an intravenous bolus. In airways between 500 and 700 pm, there was moderate to severe constriction, with AC/C0 ranging between 37 and 50%. Airways 400 pm showed minimal constriction. Figure 7 shows one representative 70O-pm airway given an intravenous challenge

that caused a similar change in Cdyn to that observed in the lung shown in Fig. 6. In this airway there was 37% constriction. This result confirms that the morphological method is sufficiently sensitive to detect constriction in this size airway. Thus we can conclude that when MCh is infused into the bronchial circulation, by the time it reaches the smallest airways it is sufficiently diluted that there is no detectable airway constriction. It is also clear that the same change in lung compliance can be caused with very peripheral airway constriction as can be caused by more central airway constriction with no peripheral constriction. DISCUSSION

Our results indicate that contraction of airways larger than terminal bronchioles causes a substantial decrease in lung Cdyn. This dynamic stiffening is associated with a decrease in the quasi-static deflation compliance and a decrease in TLC. This change in lung elasticity resulted only from conducting airway contraction and not contraction of more peripheral airways, alveolar ducts, or other elements in the alveolar wall. By the time the MCh reaches these more peripheral airways it is substantially diluted by the pulmonary circulation. That this degree of dilution is adequate was shown first by the fact that, if the MCh was infused directly into the pulmonary circulation (thereby resulting in the same dilution), there was no effect, and second by the absence of observable peripheral airway constriction in the fixed lung. We also used an infusion rate of MCh that was sufficiently low to have no observable systemic effects. Despite this low rate, however, we could still achieve relatively high steadystate con centrations in the bronchial perfusate in vivo.

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In several of the previous relevant experimental studies that will be discussed subsequently, relatively large bolus injections were frequently used, causing substantial alterations in systemic blood pressure that may have confounded the direct changes in lung mechanics. Mechanisms. There are two possible mechanisms that can account for this effect of conducting airway contraction. One mechanism involves airway closure and the other is related to interdependence forces between airways and parenchyma. Airway closure could cause changes in resistance and compliance because of changes in the extent of lung being ventilated. For example, if the MCh caused half the airways to close off, one would expect the Cdyn to be half. Additionally, temporary airway closure on expiration could increase the end-expiratory alveolar pressure above the airway pressure. If these airways could then be opened with each inspiration, the end-inspiratory airway pressure would have to be increased, and one would measure a decreased Cdyn. However, there are several reasons why airway closure seems an unlikely mechanism. First, the hyperinflation to 30 cmH,O should have opened the airways and recruited more lung volume. Thus, if there were airway closure we would not have expected to measure such a large decrease in TLC. For a similar reason the hyperinflation also should have increased the deflation limb compliance, thereby restoring it to control values. That we found similar changes in Cdyn and Cdef argues against this explanation. One could argue that the airways close off so strongly that they remain closed even when the lung is inflated to a Ptp of 30 cmH,O. If this were the case, then our He dilution lung volume measured on the deflation limb would not measure all the gas volume. While this possibility cannot be ruled out with our present data, it does not seem very likely. A 50% fall in deflation limb compliance would require that half the airways of the lung remain closed after inflation to 30 cmH,O. Yet when the MCh infusion was stopped, resistance and compliance spontaneously returned to baseline within 5 min. Closed airways would not be expected to open in such a short time period without hyperinflation (1). It thus seems more likely that interdependence between conducting airways and alveolar walls causes the changes in lung elasticity. Interdependence could act to decrease lung compliance by virtue of the contracted airways increasing parenchymal stresses in a radial direction around airways. Contracted airways could also increase axial-oriented stresses, thereby restricting the airway lengthening that is required for lung inflation (26). This latter mechanism was considered on a theoretical and experimental basis by Hoppin et al. (19). They showed a strong interaction between the lung parenchyma and axial stiffness of the larger airways. The force required to lengthen the airways in situ was -20 times FIG. 6. Micrographs of frozen-hydrated airway from 1 lung that received bronchial artery injection of methacholine (675 grn ID). A: light micrograph of radiant heat-etched airway before gold coating and further study by low-temperature scanning electron microscopy (LTSEM). Bar, 200 pm. B: LTSEM micrograph of same airway. Bar, 100 pm. C: LTSEM of region indicated by arrow in B. Bar, 20 pm. D: sketch of structures seen in C. White arrows match same location in each micrograph. bv, blood vessel.

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greater than that required after the airways were excised, suggesting that the lung parenchyma is a primary determinant of airway lengths. Experimental evidence in dogs supporting the absence of changes in axial dimensions during MCh-induced airway constriction was presented by Shoiya et al. (33). Thus if there were an axial component to the airway contraction in sheep caused by MCh, it would likely have to be quite substantial before the whole lung elasticity were affected. Kallok et al. (22) and Smith et al. (34) considered this problem from a more theoretical basis. Kallok et al. used a continuum mechanics model of lung elasticity to show that shear stresses at the airway-parenchymal boundary calculated from the analysis predict quite well the measured axial displacements. Smith et al. modeled the effect of both axial and radial constriction of airways on lung elasticity. Consistent with the above argument, they concluded that axial contraction could have only a trivial effect on lung elastic recoil. Given this conclusion one would have to conclude further that the mechanism of our observed decrease in lung compliance with bronchial artery infusion of MCh must be related to radial contraction of airways. However, the model of Smith et al. predicted that a reasonable limit on the maximal amount of change in lung recoil would be --O-20%. Anything larger, they argued, would be due to muscle activation at the level of the alveolar duct. However, in the present study this explanation would not apply, because we did not observe any morphological evidence of alveolar duct constriction. Furthermore, because we report 50% changes in the present data, and with greater MCh concentrations we could readily decrease compliance 75%, it would seem that one or more of the assumptions made in the model by Smith et al. needs to be revised. This model was based on the continuum mechanics analysis of lung interdependence (24). One of the key assumptions of this model is that the lung behaves as an isotropic medium, that is, that the lung looks the same regardless of the direction from which it is viewed. However, while this may be true on certain dimensional levels, it is clearly not true for the whole lung. Specifically, it makes a considerable difference how one looks at the airway tree. The muscular or cartilaginous walls of the airways have different physical properties from the septal walls, and the airways are connected together in a very nonrandom structured manner. The continuous branching tree terminates in individual alveolar ducts, which then butt up against other ducts or conducting airways. Thus in this regard, the airway tree structure is not like a botanical tree, to which it is commonly compared. In a botanical tree the energy-producing and gas-exchanging units are located primarily at the periphery. However, the lung airways and ducts are space filling, and as such they must

FIG. 7. Micrographs of constricted frozen-hydrated airway from 1 lung that received intravenous bolus of methacholine (700 pm ID, cir-

cumference in contracted state/circumference in relaxed state = 37%; see text). A: light micrograph of radiant heat-etched airway before gold coating and further study by LTSEM. Note thickened wall with gross indication of epithelial folding. Bar, 200 pm. B: LTSEM micrograph of same airway. Bar, 50 pm. C: LTSEM of region indicated by arrow in B. Note details of rosette pattern formed by epithelial folding in response to smooth muscle contraction. Bar, 20 pm. D: sketch of structures seen in C. White arrows match same location in each micrograph. Ip, lamina propria.

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coil back on themselves, ultimately connecting back to the walls of airways. This situation was emphasized by von Hayek (17), who noted that with seven successive branches from a ronchiole to alveolus, the branches would describe 1.5 circular turns. With lung inflation there must be some degree of uncoiling of the airway tree, and we suggest that airway smooth muscle contraction restricts this process. Both radially and axially oriented forces might be important, but until a theoretical analysis of this mechanism is done, it is not possible to estimate its quantitative influence on lung compliance. Related ex~erirne~taz work. Several experimental studeen concerned with differential effects of contraction of conducting and peripheral airways. Colebatch et al. (IO) defined peripheral airways as consisting of the respiratory bronchioles and alveolar ducts; the conducting airways then consist of all other airways down to and including the terminal bronchioles. Within this framework, the bronchial arteries would perfuse exclusively the conducting airways. With injections of histamine or acetylcholine (ACh) into the pulmonary artery, they observed changes in Rr, and Cdyn that were well correlated. With injections into the aorta they observed similar, but much smaller, changes and argued that the pulmonary effects occurred by recirculation back through the pulmonary artery. With pulmonary artery injection of histamine they also showed histological evidence of alveolar duct constriction, with slight narrowing of respiratory bronchioles. Why there was such a good correlation between RL and Cdyn was not adequately addressed, but because the total ai .rflow resistance of the respiratory bronchioles and alveolar ducts is trivial, it now seems clear that changes in their measurement of RL were primarily reflecting changes in lung tissue resistance. The effect of bronchoconstriction on PV curves of lungs was studied by several investigators (7, 8, 15, 32, 38). Although Radford and Lefcoe (32) concluded that bronchoconstriction has little direct effect on lung elastic recoil, with a different interpretation their data are in fact consistent with the results found here. They found in liquid-filled lungs that ACh caused a rightward shift of the PV curve. Had they carried out the PV curves to the same Ptp in control and constricted lungs, they would also have found a decrease in TLC in the constricted lungs. Similar shifts caused by histamine in the liquidfilled PV curves of lungs from dogs and cats were observed by Colebatch and Mitchell (9), and this effect of histamine was also foun in air-filled cat lungs in vivo (7, 10). However, the above studies concluded that the effect on the PV curve resulted from constriction of alveolar duct smooth muscle, and that ‘“constriction of conducting airways cannot contribute appreciably to constriction of the lung” (7). Our results clearly do not support this conclusion. Yoshida (38) studi PV curves during ACh and histamine infusion into e canine bronchial arteries. He found that bronc striction caused a rightward shift in the inflation li of the PV curve up to a pressure of ssures were increased above this (to the control and constricted curves ent. He concluded that the major effect of bronchoconstriction was a derecruitment of

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lung volume. Our present results do not support this conclusion. As already mentioned, the acute reversibility of the change in Cdyn would make airway closure a very unlikely mechanism. Additionally, it may be that the PV curves of Yoshida’s study are not really that different from those found here. In his study he did not measure absolute lung volume; the volume axis is expressed as volume introduced. Thus if the absolute lung volume is decreased with bronchoconstriction as we found, his curves will be artificially elevated, thereby masking the true ch.anges in the curves. When we express our curves in an analogous manner (i.e., as percent maximal volume), we too find no difference during constriction. Gold et al. (15) measured deflation PV curves in asthmatic subjects before and after histamine aerosol challenge. In the four patients studied they observed no changes in the PV curve, It is possibl .e that the effect of bronchoconstriction on lung elasticity is different in sheep and humans, but additional studies are required to evaluate the response in humans. One problem in this study of Gold et al. is that the aerosol challenges are not sustained and may in fact be reversed by the hyperinflation to TLC. These authors concluded that it was difficult to be certain that bronchoconstriction existed during the recording of the deflation PV curves. However, Colebatch et al. (8) found that there was a decreased quasistatic compliance in asthmatic subjects concomitant with a shift of the PV curve to the left--This may indicate some degree of airway closure9 and the situation in asthmatic subjects may be more complex than simply increased airway tone. A more recent study by Crawford et al. (11) in normal human subjects suggested that normal bronchomotor tone causes a parallel shift of the quasistatic PV curve to the right, that is, increased elastic recoil with no change in compliance. The mechanical properti .es that would allow such changes with increased are not obvious. DeKock et al. (12) employed a complex surgical approach in dogs to isolate the segment of aorta from which the multiple bronchial arteries in this species arise. They were thus able to contract the conducting airways in a manner similar to that used by Yoshida (38) and in the present study. In many of their experiments interpretation of the effects of bolus histamine injection into the bronchial arteries on Cdyn and RL was muddled by relatively large simultaneous decreases in systemic arterial pressure. In one of their dogs that did not show a decrease in blood pressure, DeKock et al. showed a decrease in Cdyn and an increase in RL as was found in sheep in the present study. However, several of their other observations in the dog were not reproduced in the present work, perhaps because of differences in species or actions of histamine and MCh. They found that the decrease in Cdyn with bronchial artery injection was abolished by vagotomy. They also found an even greater decrease in Cdyn when the histamine was given in the right atrium, whereas in the present study, with continuous infusion of MCh into the right atrium, we found no change in Cdyn. A similar in vivo isolation of the segment of canine aorta from which the bronchial arteries arise was described previously by Martinez et al. (28). These investi-

tone

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gators did not partition the bronchoconstriction into Cdyn and RL, but they did study the effect of vagotomy. In contrast to the results of DeKock et al. (12), Martinez et al. did not find that vagotomy abolished the observed bronchoconstriction induced by bronchial artery injection of histamine. It did, however, abolish the observed systemic hypotension and bradycardia, suggesting that afferent nerves adjacent to the bronchial vessels were initiating some reflex activity. More recently Munoz et al. (31) separately perfused the bronchial and pulmonary circulations in isolated rat lungs. The bronchial perfusion was done by isolating the segment of aorta from which the bronchial arteries arise, as described by Martinez et al. (28). Analogous to the results found in the present work, Munoz et al. observed significant changes in Cdyn when ACh was given into the bronchial circulation. Unfortunately, they made no comment and offered no discussion as to why such contraction of large conducting airways should decrease lung compliance. In fact the magnitude of the change in Cdyn they observed would probably have been much greater if all the ACh injected had gone to the airways, but in their study it is likely that most of the ACh went through other vascular pathways. This reasoning follows from the fact that the magnitudes of their bronchial flows were -100 times predicted normal flows, suggesting that their isolation procedure was not nearly complete. ImpZications. Our results also raise an important issue relative to the anatomy of the bronchial circulation and its anastomosis with the pulmonary circulation. On the basis of anatomic studies in the sheep (4, 27), we would have predicted that 700-pm airways should be supplied primarily by the bronchial circulation. Although it is not clear at precisely what size terminal bronchioles begin in the sheep, airways of this size in the dog are at about the ninth generation (20) and would not be considered terminal bronchioles. The fact that we observed constriction of this size airway only when the MCh was given into the pulmonary circulation highlights an inconsistency between our understanding of the anatomy and physiology of the bronchial circulation. Finally, it is important to note one implication of our present results with regard to interpretations of the differences between airway resistance and RL. As mentioned previously, there has been considerable discussion recently regarding the effect of lung tissue resistance on the measurement of RL (3,25). However, exactly where the tissue viscous elements are structurally located has not been clearly identified. Our results suggest the possibility that the lung tissue resistance resides in the airways themselves. If conducting airway contraction can decrease the tissue compliance, there is no reason not to expect that it might also increase the tissue viscous resistance. Thus even the direct measurement of alveolar pressure with the alveolar capsule technique may still include a pressure component related to the viscosity of the airway tree. The recent analysis of lung elasticity by Fredberg et al. (14) provides a theoretical linkage between the viscous resistance and compliance. If the lung tissue resistance does indeed have a major component associated with smooth muscle contraction in the con-

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ducting airways, then changes in RL might primarily reflect contraction in airways after all. Conclusion. In this study we have found that substantial changes in lung elasticity result from contraction of airways. This linkage between airway contraction and lung compliance may account for the common observation that pharmacological challenges given to the lung commonly result in similar changes in lung compliance and airway conductance. Our findings thus offer empirical support for the use of changes in lung compliance to assess in a simple manner changes in airway reactivity. They also suggest the possibility that the lung tissue resistance, which dominates the measurement of RL in many species, might in fact reflect the physical properties of conducting airways. Address for reprint requests: W. Mitzner, Div. of Physiology, The Johns Hopkins University School of Hygiene and Public Health, 615 N. Wolfe St., Baltimore, MD 21205. Received 4 March 1991; accepted in final form 14 August 1991. REFERENCES 1. AIVTHONISEN, N. R. Changes in compliance in rabbits subjected to acute bronchoconstriction. J. Appl. Physiol. 18: 539-543, 1963. 2. BATES, J, H. T., B. DAROCZY, AND Z. HANTOS. A comparison of interrupted and forced oscillation measurements of respiratory system resistance in dogs (Abstract). FANG3 J. 5: Al136, 1991. 3. BRUSASCO, V.,D.O. WARNER, K.C. 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. CHARAN, N. B., G. M. TURK, AND R. DHAND. Gross and subgross anatomy of bronchial circulation in sheep. J. Appl. Physiol. 57: 658-664,1984. 5. CHRISTMAN, B. W.,P.L. LEFFERTS,AND J.R. SNAPPER. Effect of platelet-activating factor on aerosol histamine responsiveness in awake sheep. Am. Rev. Respir. Dis. 13: 1267-1270,1987. 6. CLEMENTS, J. A., E. S. BROWN, AND R. P. JOHNSON. Pulmonary surface tension and the mucus lining of the lungs: some theoretical considerations. J. Appl. Physiol. 12: 262-268, 1958. 7. COLEBATCH, H. J. H., AND L. A. ENGEL. Constriction of the lung by histamine before and after adrenalectomy in cats. J. Appl. PhysioZ. 37: 798~805,1974.

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