Lung tissue behavior during methacholine challenge in rabbits in vivo P. V. ROMERO,

F. M. ROBATTO,

S. SIMARD,

Meakins-Christie Laboratories, Royal Victoria Canada; and Servicio de Neumologia, Hospital ROMERO, P.V.,F.M. ROBATTO, %SIMARD,AND M.S. LUDWIG.Lung tissue behavior during methacholine challenge in rabbits in vivo. J. Appl. Physiol. 73(l): 207-212, 1992.-Previous studies have shown that lung challenge with smooth muscle agonistsincreasestissue viscance (Vti), which is the pressure drop between the alveolus and the pleura divided by the flow. Passiveinflation alsoincreasesVti. The purposeof the present study was to measurethe changesin Vti during positive endexpiratory pressure- (PEEP) induced changesin lung volume and with a concentration-response curve to methacholine (MCh) in rabbits and to compare the effects of induced constriction vs. passive lung inflation on tissue mechanics.Measurementswere madein 10 anesthetized open-chestmechanically ventilated New Zealand male rabbits exposedfirst to increasinglevels of PEEP (3-12 cmH,O) and then to increasing concentrations of MCh aerosol (0.5-128 mg/ml). Lung elastance (EL), lung resistance(RL), and Vti were determined by adjusting the equation of motion to tracheal and alveolar pressuresduring tidal ventilation. Our results showthat under baseline conditions, Vti accounted for a major proportion of RL; during both passivelung inflation and MCh challengethis proportion increasedprogressively. For the samelevel of changein EL, however, the increase in Vti was larger during MCh challenge than during passive inflation; i.e., the relationship between energy storage and energy dissipation or hysteresivity was dramatically altered. These results are consistent with a MCh-induced change in the intrinsic rheological properties of lung tissuesunrelated to lung volume changeper se. Lung tissueconstriction is one possibleexplanation. alveolar pressure;lung tissue mechanics;hysteresivity RECENT STUDIES (3,6,12,14)

have shown that much of the resistive pressure drop across the lungs is attributable to the resistive pressure drop across the lung tissues. Moreover, tissue resistance or viscance (Vti) tends to increase with lung volume (6, 12). We have previously shown that increasing lung volume by 0.5 liter will essentially double tissue viscance in open-chest dogs. Gustin et al. (6) have reported similar data in calves. Vti also increases substantially after the administration of smooth muscle constrictors (12, 15) and decreases after the administration of smooth muscle relaxants (19, 20). It remains unclear, however, whether both mechanisms are related, i.e., if the increase in Vti after pharmacologically induced constriction is related to constriction-induced changes in lung volume or if it represents an actual change in the intrinsic viscoelastic properties of the lung parenchyma. The change in tissue viscance with constriction could

AND

M. S. LUDWIG

Hospital, McGill University, Montreal, de Bellvitge, 08907 Barcelona, Spain

Quebec H2X

2P2,

potentially result from changes in lung volume due to either air trapping or the effects of airway smooth muscle constriction and changes in airway caliber on the effective lung volume of the surrounding tethered parenchyma (16). If so, then changing lung volume directly should result in similar rheological changes in the lung tissues as those provoked by induced constriction. To test this hypothesis, we examined, in an in vivo rabbit model, the response of lung tissue to passive inflation effected by increasing end-expiratory pressure and compared this response with that obtained during constriction induced by inhalation of increasing concentrations of methacholine (MCh). To quantify the tissue response, we examined several parameters in addition to deriving values for tissue viscance and dynamic elastance. First, we determined the relationship between tissue viscance and dynamic elastance over the range of the induced responses. In addition, we calculated the constant k proposed by Hildebrandt and Bachofen (1,7,8), wh .ich rela .tes ene rgy dissipated . to energy stored. Finally we looked at the hysteresivity index (17)recently developed by Fredberg and Stamenovic (5), which links energy dissipation and storage in a more direct manner. The results of our analysis indicate that MCh induces a substantial change in the intrinsic viscoelastic properties of the lung parenchyma that is quite distinct from that induced by volume change alone. MATERIALS AND METHODS Animal preparation. We studied 10 adult male New Zealand White rabbits with a mean weight of 3.14 t 0.28 (SD) kg (range 2.50-3.45). Animals were anesthetized with urethan 50% by slow infusion of l-l.2 mg/kg in the marginal vein of the ear. Anesthesia was maintained by administration of 10% of the initial dose every l-l.5 h. After anesthesia was induced, the upper trachea was dissected and cut. A short T-shaped cannula was inserted into the trachea and tightly bound. Inside the lateral port of the tracheal connection a, piezoelectric microtransducer was inserted. A jugula r venous line w as placed for fluid and drug administration. Rabbits were paralyzed with pancuronium (2 mg) and ventilated with a Siemens 9OOC constant-flow servo-ventilator. A warming pad prevented cooling of the animal. Through an upper midline abdominal incision, the diaphragm was cut at the level of the ziphoid and a bilateral pneumothorax was introduced. The thorax was widely opened by a midline sternotomy and dissection of costal diaphragm inser-

0161-7567192 $2.00 Copyright 0 1992 the American Physiological Society

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208

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DURING

tions. Basal mechanical ventilation was set at a frequency of 60 breaths per minute, a tidal volume (VT) of 5 ml/kg, positive end-expiratory pressure (PEEP) of 5 cmH,O, and a duty cycle ratio of 0.33. Two alveolar capsules were glued to the pleural surface with cyanoacrylate (4). The capsules were placed on the anterior (ventral) part of the lower lobes in both lungs. Through the central port of the capsule two small shallow holes were made in the pleura puncturing it gently to a depth of 25% change in Vti), and a progressive shift in the Vti vs. EL relationship is seen. Vti is higher for any given value of EL than during passive inflation. This shift is greater as the tissue reaction to the agonist increases as evidenced by the nonlinear concave upward relationship between Vti and EL. The dashed line shows the second-order fit to the MCh data using the least-squares method (P < 0.001, with the quadratic term accounting for the significance). Figures 4 and 5 show the values of k and 7, respectively, after changes in PEEP and after the administration of increasing concentrations of MCh aerosol. Again there are different values obtained for these two parameters when passive inflation is compared with induced constriction. We compared dry-to-wet weight ratios for four of the experimental animals vs. six matched controls (i.e., animals in which no MCh concentration-response curve was performed) using standard techniques. This was done in an effort to evaluate whether edema was present in the constricted animals. The results are shown in Table 1. In addition, there was no histological evidence of alveolar or interstitial edema in the constricted animals. Finally, Fig. 6 shows data from the plethysmograph experiment. The increase in end-expiratory volume is plotted against increasing MCh concentration. Note that the increase in volume is 25% increase above baseline in tissue viscance was obtained are included. Linear adjustment (solid line) to passive inflation and second-order polynominal adjustment (dashed line) to methacholine data.

0.0

,

0

I I

I I

5

10

I I

A

I’itssure

I I

(CI&O,

I I

I I

I

25

30

35

FIG. 4. Application of Bachofen and Hildebrandt’s model (1) to data. Constant (k) vs. Apressure (between 0 flow at end expiration and end inspiration) during changes in positive end-expiratory pressure in (closed circles) and during methacholine challenge (open circles). Latter includes only those data points where change in tissue viscance of >25% above baseline was obtained.

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LUNG TISSUE

0.6

I

BEHAVIOR

DURING

METHACHOLINE

211

CHALLENGE

U

0 0 00

-30 10 A

15 Pressure

20 (cmH20)

25

30

5. Application of Fredberg and Stamenovic’s model (5) to data. -Hysteresivity (q) vs. Apressure during changes in positive end-expiratory pressure (closed circles) and during methacholine challenge (open circles). Latter includes only those data points where change in tissue viscance of >25% above baseline was obtained. FIG.

behavior of the lung tissues. However, we cannot completely rule out the possibility that the relationship between Vti and EL with passive inflation changes in some way after induced constriction and that this contributes in some measure to the shift in the Vti/EL curve observed during MCh administration. Alternately, the type of tissue distortion caused by constriction of the airways during MCh administration may be different from the tissue distortion caused by the airways during passive inflation. Hildebrandt and colleagues (1, 7, 8) developed an approach to the dynamic behavior of lung parenchyma relating energy dissipation by cycle (kinetic energy) to total energy stored in the system (potential energy) by a conWlU=

k

where W is the dissipated energy (work) and U is the stored or potential energy. The hysteresis area of the 1. Dry-to-wet weight ratios in control and constricted animals TABLE

DryW kg

Wet

Wt, kg

Dry/Wet

Control

0.937

4.613

1.341 1.160 1.755

6.545 5.570 8.300 7.550 4.640

1.639 1.094

Mean tSD

1.321 kO.293

6.203

t1.396

0.203 0.205 0.208 0.211 0.217 0.236 0.213

kO.011

Methacholine

1.820 1.560 2.065 1.530

Mean 1.815 +SD kO.206

7.789 7.220 7.844 7.070

0.234 0.216 0.263 0.216

7.618 to.282

to.019

Dry-to-wet weight ratios are for 4 experimental matched controls.

+--

35

0.238

animals vs. 6

FIG. 6. Absolute change in end-expiratory volume compa red with baseline during methacholine challenge. Values are means k SE.

alveolar pressure-volume loop amounts to the total energy dissipated. Potential energy, i.e. the total energy stored in the system during a cycle, is the product of VT times the pressure difference between end inspiration and end expiration; thus AI(VTAP)

= k

According to Hoppin et al. (9) k has a value of -0.12 for air, regardless of the species studied. Furthermore, k shows very little interindividual variability. In the nonconstricted state we obtain similar values for k (Fig. 4). The dispersion is very small and only noticeable for PEEP values 4 cmH,O. At this low level of lung inflation, recruitment is probably masking the assessment of the dynamic behavior of lung tissue (18). After MCh-induced constriction however, we found a marked change in the value of k. Moreover, this change seemed to be proportional to the degree of tissue reaction. Such a change in the energetic behavior of the lung parenchyma should be possible only if an important alteration in the intrinsic properties of the lung tissues had occurred. More recently, Fredberg and Stamenovic (5) further refined an approach to the assessment of lung tissue behavior, one in which energy dissipation and energy storage are directly linked. This relationship is defined by a parameter, v, that they label hysteresivity. In a recent review, Fredberg and Stamenovic give values for hysteresivity ranging from 0.12 to 0.20 for lungs of several different species ventilated with air in the basal physiological state. We obtain values of r) in the nonconstricted state as shown in Fig. 5. If we apply the equation q = Vtiw/Edyn to the slope of the unconstricted Vti/EL relationship in Fig. 3 (i.e., closed circles), we get a mean value of 0.11. These values are in agreement with those previously reported and demonstrate that changes in lung volume do not substantially alter hysteresivity, i.e., the relationship between energy stored and energy dissipated. Of note, v seems to decrease somewhat at higher lung volumes (Fig. 5). This is consistent with Fredberg and Stamenovic’s interpretation of Hildebrandt’s data, which show a decrease in 7 measured in cat lungs at the higher of two

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different lung volumes. In addition, our data show that at the lowest lung volumes hysteresivity is increased; this probably represents energy dissipation related to airway closure and subsequent cyclic recruitment and derecruitment (18) as commented on previously. After MCh-induced constriction, the value of 7 increased relative to the nonconstricted state. In a previous study where a single dose of constrictor agonist was delivered (13, 7 also increased. According to Fredberg and Stamenovic (5), the degree to which v changes reflects a change in the relationship between energy dissipation and storage at the level of the stress-bearing element. The complexity and heterogeneity of the system make it difficult, however, to identify a single concrete anatomic element responsible for this behavior. Possibilities include contractile elements in the lung parenchyma, the air-liquid interface, and the collagen-elastin matrix. Moreover, changes in the mechanical interactions between the different structures that comprise lung parenchyma might be responsible for changes in 7j. Nonetheless, Vti, 12,and q increase with the administration of MCh, indicating some sort of activation of a contractile constituent of the lung tissue. This element must be responsible for the changes observed either by its own contraction or by a secondary indirect effect on associated structures. The parenchyma itself has contractile structures: Kapanci et al. (11) described fibroblast-like cells containing actin fibrils in the interstitium of several animal species. These cells were thought to have some role in the regulation of the ventilation-perfusion ratio; it would also be possible for these elements to be implicated in some way in the regulation of the mechanical behavior of the lung parenchyma. Alveolar ducts contain a variable amount of smooth muscle. Their contraction could change tissue hysteretic properties in two ways: directly by increasing cross-bridge forces that oppose tissue stretching or deformation or indirectly by changing the architectural structure of alveolar spaces and acting on the balance of tissue and/or surface forces at this level (2). While the precise element(s) in the lung tissues responding to smooth muscle constrictors and relaxants is not yet known, the observation that the hysteretic behavior of the tissues is altered so markedly with constriction is clear. Changes in lung volume could explain a part of the change observed in tissue hysteresis with constriction. However, our data that show such a marked change in the relationship of stored to dissipated energy at the tissue level during induced constriction implicate a change in the basic structural elements comprising lung tissue. The authors thank D. Sepulveda for technical assistance. This work was supported by the J. T. Costello Memorial Research Fund and a grant from the Medical Research Council of Canada. M. S. Ludwig is a scholar of the Medical Research Council of Canada. P. V. Romero was supported by a grant from the Fondo de Investigaciones Sanitarias of Spain. F. M. Robatto is supported by a research fellowship from the Canadian Lung Association and the Royal Victoria Hospital Research Institute.

METHACHOLINE

CHALLENGE

Address for reprint requests: P. V. Romero, Servicio de Neumologia, Hospital de Bellvitge, Calle Feixa Llarga s/n, Hospitalet de Llobregat, 08907 Barcelona, Spain. Received 4 June 1991; accepted in final form 7 February 1992. REFERENCES 1. BACHOFEN, H., AND J. HILDEBRANDT. Area analysis of pressurevolume hysteresis in mammalian lungs. J. Appl. Physiol. 30: 439497,197l.

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Lung tissue behavior during methacholine challenge in rabbits in vivo.

Previous studies have shown that lung challenge with smooth muscle agonists increases tissue viscance (Vti), which is the pressure drop between the al...
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