Mechanical modulation of pressure-volume characteristics of contracted canine airways in vitro

In normal humans and dogs, the airways do not constrict to closure even when maximally stimulated. However, airway closure can be produced in isolated canine lobes and bronchial segments that are stimulated with maximal concentrations of bronchoconstrictors. These observations suggest that under normal conditions, physiological mechanisms to limit bronchoconstriction exist in vivo. In this investigation, we evaluated how mechanical factors that influence airway smooth muscle contractility contribute to the modulation of the pressure-volume characteristics of contracted canine intraparenchymal airways in vitro. Our results demonstrated that maximal and even submaximal contractile stimuli can produce airway closure in bronchi that are allowed to contract under isobaric conditions. However, the effectiveness of bronchoconstrictors is significantly reduced when the airways are subjected to tidal volume oscillations during contraction. In addition, airways contracted isovolumetrically at low volumes exhibit a markedly reduced sensitivity to submaximal concentrations of acetylcholine. This may limit bronchoconstriction at low lung volumes and transpulmonary pressures where the effectiveness of parenchymal stress in keeping the airways open is reduced. Together these factors could provide a mechanism by which bronchoconstriction is limited to low levels of airway resistance under normal conditions in vivo.     

Effect of Parenchymal Stiffness on Canine Airway Size with Lung Inflation

Although airway patency is partially maintained by parenchymal tethering, this structural support is often ignored in many discussions of asthma. However, agonists that induce smooth muscle contraction also stiffen the parenchyma, so such parenchymal stiffening may serve as a defense mechanism to prevent airway narrowing or closure. To quantify this effect, specifically how changes in parenchymal stiffness alter airway size at different levels of lung inflation, in the present study, we devised a method to separate the effect of parenchymal stiffening from that of direct airway narrowing. Six anesthetized dogs were studied under four conditions: baseline, after whole lung aerosol histamine challenge, after local airway histamine challenge, and after complete relaxation of the airways. In each of these conditions, we used High resolution Computed Tomography to measure airway size and lung volume at five different airway pressures (0, 12, 25, 32, and 45 cm H₂O). Parenchymal stiffening had a protective effect on airway narrowing, a fact that may be important in the airway response to deep inspiration in asthma. When the parenchyma was stiffened by whole lung aerosol histamine challenge, at every lung volume above FRC, the airways were larger than when they were directly challenged with histamine to the same initial constriction. These results show for the first time that a stiff parenchyma per se minimizes the airway narrowing that occurs with histamine challenge at any lung volume. Thus in clinical asthma, it is not simply increased airway smooth muscle contraction, but perhaps a lack of homogeneous parenchymal stiffening that contributes to the symptomatic airway hyperresponsiveness.     

Parenchymal interdependence and airway response to methacholine in excised dog lobes

The objective of this investigation was to determine the minimum transpulmonary pressure (PL) at which the forces of interdependence between the airways and the lung parenchyma can prevent airway closure in response to maximal stimulation of the airways in excised canine lobes. We first present an analysis of the relationship between PL and the transmural pressure (Ptm) that airway smooth muscle must generate to close the airways. This analysis predicts that airway closure can occur at PL less than or equal to 10 cmH2O with maximal airway stimulation. We tested this prediction in eight excised canine lobes by nebulizing 50% methacholine into the airways while the lobe was held at constant PL values ranging from 25 to 5 cmH2O. Airway closure was assessed by comparing changes in alveolar pressure (measured by an alveolar capsule technique) and pressure at the airway opening during low-amplitude oscillations in lobar volume. Airway closure occurred in two of the eight lobes at PL = 10 cmH2O; in an additional five it occurred at PL = 7.5 cmH2O. We conclude that the forces of parenchymal interdependence per se are not sufficient to prevent airway closure at PL less than or equal to 7.5 cmH2O in excised canine lobes.     

Parenchymal tethering, airway wall stiffness, and the dynamics of bronchoconstriction.

We do not yet have a good quantitative understanding of how the force-velocity properties of airway smooth muscle interact with the opposing loads of parenchymal tethering and airway wall stiffness to produce the dynamics of bronchoconstriction. We therefore developed a two-dimensional computational model of a dynamically narrowing airway embedded in uniformly elastic lung parenchyma and compared the predictions of the model to published measurements of airway resistance made in rats and rabbits during the development of bronchoconstriction following a bolus injection of methacholine. The model accurately reproduced the experimental time-courses of airway resistance as a function of both lung inflation pressure and tidal volume. The model also showed that the stiffness of the airway wall is similar in rats and rabbits, and significantly greater than that of the lung parenchyma. Our results indicate that the main features of the dynamical nature of bronchoconstriction in vivo can be understood in terms of the classic Hill force-velocity relationship operating against elastic loads provided by the surrounding lung parenchyma and an airway wall that is stiffer than the parenchyma.     

Effect of lung inflation in vivo on airways with smooth muscle tone or edema

Brown, Robert H., Wayne Mitzner, Yonca Bulut, and ElizabethM. Wagner. Effect of lung inflation in vivo on airways with smoothmuscle tone or edema. J. Appl.Physiol. 82(2): 491-499, 1997.Fibrousattachments to the airway wall and a subpleural surrounding pressurecan create an external load against which airway smooth muscle mustcontract. A decrease in this load has been proposed as a possible causeof increased airway narrowing in asthmatic individuals. To study theinteraction between the airways and the surrounding lung parenchyma, weinvestigated the effect of lung inflation on relaxed airways, airwayscontracted with methacholine, and airways made edematous by infusion ofbradykinin into the bronchial artery. Measurements were made inanesthetized sheep by using high-resolution computed tomography tovisualize changes in individual airways. During methacholine infusion,airway area was decreased but increased minimally with increases intranspulmonary pressure. Bradykinin infusion caused a 50% increase inairway wall area and a small decrease in airway luminal area. Incontrast to airways contracted with methacholine, the luminal areaafter bradykinin increased substantially with increases intranspulmonary pressure, reaching 99% of the relaxed area at totallung capacity. Thus airway edema by itself did not prevent fulldistension of the airway at lung volumes approaching total lungcapacity. Therefore, we speculate that if a deep inspiration fails torelieve airway narrowing in vivo, this must be a manifestation ofairway smooth muscle contraction and not airway wall edema.

     

Effect of resting smooth muscle length on contractile response in resistance airways

We studied the effect of resting smooth muscle length on the contractile response of the major resistance airways (generations 0-5) in 18 mongrel dogs in vivo using tantalum bronchography. Dose-response curves to 10(-10) to 10(-7) mol/kg methacholine (MCh) were generated [at functional residual capacity (FRC)] by repeated intravenous bolus administration using tantalum bronchography after each dose. Airway constriction varied substantially with dose-equivalent stimulation and varied sequentially from trachea (8.8 +/- 2.2% change in airway diam) to fifth-generation bronchus (49.8 +/- 3.0%; P less than 0.001). Length-tension curves were generated for each airway to determine the airway diameter (i.e., resting in situ smooth muscle length) at which maximal constriction was elicited using bolus intravenous injection of 10(-8) mol/kg MCh. A Frank-Starling relationship was obtained for each airway; the transpulmonary pressure at which maximal constriction was elicited increased progressively from 2.50 +/- 1.12 cmH2O for trachea (approximately FRC) to 18.3 +/- 1.05 cmH2O for fifth-generation airways (approximately 50% TLC) (P less than 0.001). A similar relationship was obtained when change in airway diameter was plotted as a function of airway radius. We demonstrate substantial heterogeneity in the lung volumes at which maximal constriction is elicited and in distribution of parasympathomimetic constriction within the first few generations of resistance bronchi. Our data also suggest that lung hyperinflation may lead to augmented airway contractile responses by shifting resting smooth muscle length toward optimum resting smooth muscle length.     

Effect of bronchomotor tone on work rate of breathing

We studied the optimal airway caliber for minimizing the work rate of breathing in the lung (W) with different bronchomotor tones in six normal subjects. The inhalation of methacholine contracted airway smooth muscle, and the inhalation of salbutamol relaxed it. To calculate W at a given alveolar ventilation (VA), anatomical dead space (VDanat), pulmonary resistance (RL), and dynamic compliance were measured simultaneously, breath by breath, during various breathing maneuvers. VDanat increased and RL decreased with both increased breathing frequency and tidal volume, even at a given airway tone. This suggests that the airway caliber varied even at a given bronchomotor tone. The minimum W at a given VA increased in constricted airways, but there was no significant difference between control airways after saline inhalation and relaxed airways. It has been suggested that airway smooth muscle tones at both control and relaxed conditions bring W to a minimum and that the airway smooth muscle tone existing in the control state acts to keep the airway caliber optimal in order to minimize the W and stabilize the airway mechanics.     

The myth of maximal airway responsiveness in vivo

A sine quanon of hyperresponsive airway disease in asthmatic subjects is the lackof a maximal response with increasing doses of aerosol agonistchallenge. Normal subjects, however, often appear toexhibit an airway response plateau effect even when challenged withhigh concentrations of agonist. To investigate this question of maximalnarrowing in individual airways in vivo, we used high-resolutioncomputed tomography to visualize canine airways narrowed by two routesof agonist challenge. We compared airway narrowing induced bymethacholine (MCh) via the conventional aerosol route to that caused bylocal atomization of MCh directly to individual airways. Our resultsshowed that, with aerosol challenge, airway responses never reached atruly flat plateau even at the highest possible nebulizerconcentrations. Airway closure was never observed. However, when MChwas delivered directly to the airway luminal surface, airways could beeasily narrowed to complete closure at modest (10 mg/ml) agonistconcentrations. Thus neither the elastic recoil of the lung norlimitations of smooth muscle shortening can be responsible for theapparent plateauing of dose-response curves. We suggest that theplateau results from limitations associated with the delivery of highconcentration of agonists via the aerosol route.

     

A disbalance between beta-adrenergic and muscarinic responses caused by hydrogen peroxide in rat airways in vitro

The effect of hydrogen peroxide on adrenergic and muscarinic responses of rat airway smooth muscle was studied. The trachea muscle and the lung parenchymal strip were contracted with methacholine and relaxed with (-)-isoprenaline. Recording of three (-)-isoprenaline curves on the trachea muscle and the lung parenchymal strip was followed by treatment for 30 min with hydrogen peroxide (H2O2) (1mM) after which a new dose response curve for (-)-isoprenaline was constructed. Using the trachea muscle this treatment with H2O2 resulted in a decrease of 61% of the maximum contraction by methacholine compared with the control and a complete inhibition of the relaxation by (-)-isoprenaline. In the lung parenchymal strip preparation we found, after the same treatment no reduction of the contraction by methacholine and 61% reduction of the relaxation by (-)-isoprenaline, compared with the control. The results demonstrate that the adrenergic response in rat airways is more susceptible to hydrogen peroxide than the muscarinic response.     

Airway closure on imaging relates to airway hyperresponsiveness and peripheral airway disease in asthma

The regional pattern and extent of airway closure measured by three-dimensional ventilation imaging may relate to airway hyperresponsiveness (AHR) and peripheral airways disease in asthmatic subjects. We hypothesized that asthmatic airways are predisposed to closure during bronchoconstriction in the presence of ventilation heterogeneity and AHR. Fourteen asthmatic subjects (6 women) underwent combined ventilation single photon emission computed tomography/computed tomography scans before and after methacholine challenge. Regional airway closure was determined by complete loss of ventilation following methacholine challenge. Peripheral airway disease was measured by multiple-breath nitrogen washout from which S(cond) (index of peripheral conductive airway abnormality) was derived. Relationships between airway closure and lung function were examined by multiple-linear regression. Forced expiratory volume in 1 s was 87.5 ± 15.8% predicted, and seven subjects had AHR. Methacholine challenge decreased forced expiratory volume in 1 s by 23 ± 5% and increased nonventilated volume from 16 ± 4 to 29 ± 13% of computed tomography lung volume. The increase in airway closure measured by nonventilated volume correlated independently with both S(cond) (partial R(2) = 0.22) and with AHR (partial R(2) = 0.38). The extent of airway closure induced by methacholine inhalation in asthmatic subjects is greater with increasing peripheral airways disease, as measured by ventilation heterogeneity, and with worse AHR.     

Desmin modulates lung elastic recoil and airway responsiveness

Desmin is a structural protein that is expressed in smooth muscle cells of both airways and alveolar ducts. Therefore, desmin could be well situated to participate in passive and contractile force transmission in the lung. We hypothesized that desmin modulates lung compliance, lung recoil pressure, and airway contractile response. To test this hypothesis, respiratory system complex impedance (Zin,rs) at different positive end-expiratory pressure (PEEP) levels and quasi-static pressure-volume data were obtained in desmin-null and wild-type mice at baseline and during methacholine administration. Airways and lung tissue properties were partitioned by fitting Zin,rs to a constant-phase model. Relative to controls, desmin-null mice showed 1) lower values for lung stiffness and recoil pressure at baseline and induced airway constriction, 2) greater negative PEEP dependence of H and airway resistance under baseline conditions and cholinergic stimulation, and 3) airway hyporesponsiveness. These results demonstrate that desmin is a load-bearing protein that stiffens the airways and consequently the lung and modulates airway contractile response.     

New perspectives on the mechanical basis for airway hyperreactivity and airway hypersensitivity in asthma.

We revisit the airway wall model of Lambert et. al. (Lambert RK, Wiggs BR, Kuwano K, Hogg JC, and Pare PD. J Appl Physiol 74: 2771-2781, 1993). We examine in detail the notion of a general airway bistability such that the airway lumen can suddenly decrease from a relatively open to a relatively closed condition without needing additional increase in active airway smooth muscle (ASM) tension during the stimulation. The onset of this bistability is an emergent consequence of the balance of forces associated with airway wall properties, parenchymal tissue properties, maximum lung elastic recoil, and the maximum stress that the ASM can generate. In healthy lungs, we find that all these properties reside in conditions that largely prevent the emergence of the bistability even during maximum ASM stimulation. In asthmatic airways, however, the airway wall and ASM remodeling conditions can tip the balance so as to promote the onset of the bistability at a lower dose of ASM stimulation (enhanced sensitivity) and then work to amplify the maximum constriction reached by each airway (enhanced reactivity). Hence, a larger fraction of asthmatic airways can display overall airway hyperreactivity. Simulations studies examine the role of increasing ASM maximum tension, airway wall stiffening, reduced lung volume, and decreased parenchymal tethering. Results predict that the single most important factor causing this airway hyperreactivity is amplified maximum ASM tension and not a thickening of the airway wall per se.     

Effect of bronchial smooth muscle contraction on lung compliance.

Lung compliance is generally considered to represent a blend of surface and tissue forces, and changes in compliance in vivo are commonly used to indicate changes in surface forces. There are, however, theoretical arguments that would allow contraction of airway smooth muscle to affect substantially the elasticity of the lung. In the present study we evaluated the role of conducting airway contraction on lung compliance in vivo by infusing methacholine (MCh) at a constant rate into the bronchial circulation. With a steady-state MCh infusion of 2.4 micrograms/min into the bronchial perfusate (perfusate concentration = 0.7 microM), there was an approximate doubling of lung resistance and a 50% fall in dynamic compliance. There were also significant decreases in chord compliance measured from the quasi-static pressure-volume curves and in total lung capacity and residual volume. When the same infusion rate was administered into the pulmonary artery, no changes in lung mechanics were 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 changes in lung compliance and airway conductance. Our results also suggest the possibility that the lung tissue resistance, which dominates the measurement of lung resistance in many species, might in fact reflect the physical properties of conducting airways.     

In vivo loads on airway smooth muscle: the role of noncontractile airway structures.

The degree of airway smooth muscle contraction and shortening that occurs in vivo is modified by many factors, including those that influence the degree of muscle activation, the resting muscle length, and the loads against which the muscle contracts. Canine trachealis muscle will shorten up to 70% of starting length from optimal length in vitro but will only shorten by around 30% in vivo. This limitation of shortening may be a result of the muscle shortening against an elastic load such as could be applied by tracheal cartilage. Limitation of airway smooth muscle shortening in smaller airways may be the result of contraction against an elastic load, such as could be applied by lung parenchymal recoil. Measurement of the elastic loads applied by the tracheal cartilage to the trachealis muscle and by lung parenchymal recoil to smooth muscle of smaller airways were performed in canine preparations. In both experiments the calculated elastic loads applied by the cartilage and the parenchymal recoil explained in part the limitation of maximal active shortening and airway narrowing observed. We conclude that the elastic loads provided by surrounding structures are important in determining the degree of airway smooth muscle shortening and the resultant airway narrowing.     

Small airway morphology and lung function in the transition from normality to chronic airway obstruction.

This study investigated the relationships between pathological changes in small airways (<6 mm perimeter) and lung function in 22 nonasthmatic subjects (20 smokers) undergoing lung resection for peripheral lesions. Preoperative pulmonary function tests revealed airway obstruction [ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) < 70%] in 12 subjects and normal lung function in 10. When all subjects were considered together, total airway wall thickness was significantly correlated with FEV1/FVC (r2 = 0.25), reactivity to methacholine (r2 = 0.26), and slope of linear regression of FVC against FEV1 values recorded during the methacholine challenge (r2 = 0.56). Loss of peribronchiolar alveolar attachments was significantly associated (r2 = 0.25) with a bronchoconstrictor effect of deep inhalation, as assessed from a maximal-to-partial expiratory flow ratio <1, but not with airway responses to methacholine. No significant correlation was found between airway smooth muscle thickness and lung function measurements. In conclusion, this study suggests that thickening of the airway wall is a major mechanism for airway closure, whereas loss of airway-to-lung interdependence may contribute to the bronchoconstrictor effect of deep inhalation in the transition from normal lung function to airway obstruction in nonasthmatic smokers.     

Effects of lung volume, bronchoconstriction, and cigarette smoke on morphometric airway dimensions

To examine the role of airway wall thickening in the bronchial hyperresponsiveness observed after exposure to cigarette smoke, we compared the airway dimensions of guinea pigs exposed to smoke (n = 7) or air (n = 7). After exposure the animals were anesthetized with urethan, pulmonary resistance was measured, and the lungs were removed, distended with Formalin, and fixed near functional residual capacity. The effects of lung inflation and bronchoconstriction on airway dimensions were studied separately by distending and fixing lungs with Formalin at total lung capacity (TLC) (n = 3), 50% TLC (n = 3), and 25% TLC (n = 3) or near residual volume after bronchoconstriction (n = 3). On transverse sections of extraparenchymal and intraparenchymal airways the following dimensions were measured: the internal area (Ai) and internal perimeter (Pi), defined by the epithelium, and the external area (Ae) and external perimeter (Pe), defined by the outer border of smooth muscle. Airway wall area (WA) was then calculated, WA = Ae - Ai. Ai, Pe, and Ae decreased with decreasing lung volume and after bronchoconstriction. However, WA and Pi did not change significantly with lung volume or after bronchoconstriction. After cigarette smoke exposure airway resistance was increased (P less than 0.05); however, there was no difference in WA between the smoke- and air-exposed groups when the airways were matched by Pi. We conclude that Pi and WA are constant despite changes in lung volume and smooth muscle tone and that airway hyperresponsiveness induced by cigarette smoke is not mediated by increased airway wall thickness.     

The airway response to deep inspirations decreases with COPD severity and is associated with airway distensibility assessed by computed tomography.

In patients with mild chronic obstructive pulmonary disease (COPD), the effect of deep inspirations (DIs) to reverse methacholine-induced bronchoconstriction is largely attenuated. In this study, we tested the hypothesis that the effectiveness of DI is reduced with increasing disease severity and that this is associated with a reduction in the ability of DI to distend the airways. Fifteen subjects [Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I-II: n = 7; GOLD stage III-IV: n = 8] underwent methacholine bronchoprovocation in the absence of DI, followed by DI. The effectiveness of DI was assessed by their ability to improve inspiratory vital capacity and forced expiratory volume in 1 s (FEV(1)). To evaluate airway distensibility, two sets of high-resolution computed tomography scans [at residual volume (RV) and at total lung capacity] were obtained before the challenge. In addition, mean parenchymal density was calculated on the high-resolution computed tomography scans. We found a strong correlation between the response to DI and baseline FEV(1) %predicted (r(2) = 0.70, P < 0.0001) or baseline FEV(1)/forced vital capacity (r(2) = 0.57, P = 0.001). RV %predicted and functional residual capacity %predicted correlated inversely (r(2) = 0.33, P = 0.02 and r(2) = 0.32, P = 0.03, respectively), and parenchymal density at RV correlated directly (r(2) = 0.30, P = 0.03), with the response to DI. Finally, the effect of DI correlated to the change in large airway area from RV to total lung capacity (r(2) = 0.44, P = 0.01). We conclude that loss of the effects of DI is strongly associated with COPD severity and speculate that the reduction in the effectiveness of DI is due to the failure to expand the lungs because of the hyperinflated state and/or the parenchymal damage that prevents distension of the airways with lung inflation.     

Bronchodilation response to deep inspirations in asthma is dependent on airway distensibility and air trapping

In healthy individuals, deep inspirations (DIs) have a potent bronchodilatory ability against methacholine (MCh)-induced bronchoconstriction. This is variably attenuated in asthma. We hypothesized that inability to bronchodilate with DIs is related to reduced airway distensibility. We examined the relationship between DI-induced bronchodilation and airway distensibility in 15 asthmatic individuals with a wide range of baseline lung function [forced expired volume in 1 s (FEV(1)) = 60-99% predicted]. After abstaining from DIs for 20 min, subjects received a single-dose MCh challenge and then asked to perform DIs. The effectiveness of DIs was assessed by the ability of the subjects to improve FEV(1). The same subjects were studied by two sets of high-resolution CT scans, one at functional residual capacity (FRC) and one at total lung capacity (TLC). In each subject, the areas of 21-41 airways (0.8-6.8 mm diameter at FRC) were matched and measured, and airway distensibility (increase in airway diameter from FRC to TLC) was calculated. The bronchodilatory ability of DIs was significantly lower in individuals with FEV(1) <75% predicted than in those with FEV(1) ≥75% predicted (15 ± 11% vs. 46 ± 9%, P = 0.04) and strongly correlated with airway distensibility (r = 0.57, P = 0.03), but also with residual volume (RV)/TLC (r = -0.63, P = 0.01). In multiple regression, only RV/TLC was a significant determinant of DI-induced bronchodilation. These relationships were lost when the airways were examined after maximal bronchodilation with albuterol. Our data indicate that the loss of the bronchodilatory effect of DI in asthma is related to the ability to distend the airways with lung inflation, which is, in turn, related to the extent of air trapping and airway smooth muscle tone. These relationships only exist in the presence of airway tone, indicating that structural changes in the conducting airways visualized by high-resolution CT do not play a pivotal role.     

Mechanical response to methacholine and deep inspiration in supine men.

The effects of supine posture on airway responses to inhaled methacholine and deep inspiration (DI) were studied in seven male volunteers. On a control day, subjects were in a seated position during both methacholine inhalation and lung function measurements. On a second occasion, the whole procedure was repeated with the subjects lying supine for the entire duration of the study. On a third occasion, methacholine was inhaled from the seated position and measurements were taken in a supine position. Finally, on a fourth occasion, methacholine was inhaled from the supine position and measurements were taken in the seated position. Going from sitting to supine position, the functional residual capacity decreased by approximately 1 liter in all subjects. When lung function measurements (pulmonary resistance, dynamic elastance, residual volume, and maximal flows) were taken in supine position, the response to methacholine was greater than at control, and this was associated with a greater dyspnea and a faster recovery of dynamic elastance after DI. By contrast, when methacholine was inhaled in supine position but measurements were taken in sitting position, the response to methacholine was similar to control day. These findings document the potential of the decrease in the operational lung volumes in eliciting or sustaining airflow obstruction in nocturnal asthma. It is speculated that the exaggerated response to methacholine in the supine posture may variably contribute to airway smooth muscle adaptation to short length, airway wall edema, and faster airway renarrowing after a large inflation.     

Airway remodeling in asthma amplifies heterogeneities in smooth muscle shortening causing hyperresponsiveness.

Although airway remodeling and inflammation in asthma can amplify the constriction response of a single airway, their influence on the structural changes in the whole airway network is unknown. We present a morphometric model of the human lung that incorporates cross-sectional wall areas corresponding to the adventitia, airway smooth muscle (ASM), and mucosa for healthy and mildly and severely asthmatic airways and the influence of parenchymal tethering. A heterogeneous ASM percent shortening stimulus is imposed, causing distinct constriction patterns for healthy and asthmatic airways. We calculate lung resistance and elastance from 0.1 to 5 Hz. We show that, for a given ASM stimulus, the distribution of wall area in asthmatic subjects will amplify not only the mean but the heterogeneity of constriction in the lung periphery. Moreover, heterogeneous ASM shortening that would produce only mild changes in the healthy lung can cause hyperresponsive changes in lung resistance and elastance at typical breathing rates in the asthmatic lung, even with relatively small increases in airway resistance. This condition arises when airway closures occur randomly in the lung periphery. We suggest that heterogeneity is a crucial determinant of hyperresponsiveness in asthma and that acute asthma is more a consequence of extensive airway wall inflammation and remodeling, predisposing the lung to produce an acute pattern of heterogeneous constriction.