The Importance of Synergy between Deep Inspirations and Fluidization in Reversing Airway Closure

Deep inspirations (DIs) and airway smooth muscle fluidization are two widely studied phenomena in asthma research, particularly for their ability (or inability) to counteract severe airway constriction. For example, DIs have been shown effectively to reverse airway constriction in normal subjects, but this is impaired in asthmatics. Fluidization is a connected phenomenon, wherein the ability of airway smooth muscle (ASM, which surrounds and constricts the airways) to exert force is decreased by applied strain. A maneuver which sufficiently strains the ASM, then, such as a DI, is thought to reduce the force generating capacity of the muscle via fluidization and hence reverse or prevent airway constriction. Understanding these two phenomena is considered key to understanding the pathophysiology of asthma and airway hyper-responsiveness, and while both have been extensively studied, the mechanism by which DIs fail in asthmatics remains elusive. Here we show for the first time the synergistic interaction between DIs and fluidization which allows the combination to provide near complete reversal of airway closure where neither is effective alone. This relies not just on the traditional model of airway bistability between open and closed states, but also the critical addition of previously-unknown oscillatory and chaotic dynamics. It also allows us to explore the types of subtle change which can cause this interaction to fail, and thus could provide the missing link to explain DI failure in asthmatics.     

Responsiveness of the isolated airway during simulated deep inspirations: effect of airway smooth muscle stiffness and strain.

In vivo, breathing movements, including tidal and deep inspirations (DIs), exert a number of beneficial effects on respiratory system responsiveness in healthy humans that are diminished or lost in asthma, possibly as a result of reduced distension (strain) of airway smooth muscle (ASM). We used bronchial segments from pigs to assess airway responsiveness under static conditions and during simulated tidal volume oscillations with and without DI and to determine the roles of airway stiffness and ASM strain on responsiveness. To simulate airway dilations during breathing, we cycled the luminal volume of liquid-filled segments. Volume oscillations (15 cycles/min) were set so that, in relaxed airways, they produced a transmural pressure increase of approximately 5-10 cmH(2)O for tidal maneuvers and approximately 5-30 cmH(2)O for DIs. ACh dose-response curves (10(-7)-3 x 10(-3) M) were constructed under static and dynamic conditions, and maximal response and sensitivity were determined. Airway stiffness was measured from tidal trough-to-peak pressure and volume cycles. ASM strain produced by DI was estimated from luminal volume, airway length, and inner wall area. DIs produced substantial ( approximately 40-50%) dilation, reflected by a decrease in maximal response (P < 0.001) and sensitivity (P < 0.05). However, the magnitude of bronchodilation decreased significantly in proportion to airway stiffening caused by contractile activation and an associated reduction in ASM strain. Tidal oscillations, in comparison, had little effect on responsiveness. We conclude that DI regulates airway responsiveness at the airway level, but this is limited by airway stiffness due to reduced ASM strain.     

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.     

Maintenance of airway caliber in isolated airways by deep inspiration and tidal strains.

Deep inspirations (DIs) are large periodic breathing maneuvers that regulate airway caliber and prevent airway obstruction in vivo. This study characterized the intrinsic response of the intact airway to DI, isolated from parenchymal attachments and other in vivo interactions. Porcine isolated bronchial segments were constricted with carbachol and subjected to transmural pressures of 5-10 cmH2O at 0.25 Hz (tidal breathing) interspersed with single DIs of amplitude 5-20 cmH2O, 5-30 cmH2O, or 5-40 cmH2O (6-s duration) or DI of amplitude 5-30 cmH2O (30-s duration). Tidal breathing was ceased after DI in a subset of airways and in control airways in which no DI was performed. Luminal cross-sectional area was measured using a fiber-optic endoscope. Bronchodilation by DI was amplitude dependent; 5-20 cmH2O DIs produced less dilation than 5-30 cmH2O and 5-40 cmH2O DIs (P=0.003 and 0.012, respectively). Effects of DI duration were not significant (P=0.182). Renarrowing after DI followed a monoexponential decay function to pre-DI airway caliber with time constants between 27.4+/-4.3 and 36.3+/-6.9 s. However, when tidal breathing was ceased after DI, further bronchoconstriction occurred within 30s. This response was identical in both the presence and absence of DI (P=0.919). We conclude that the normal bronchodilatory response to DI occurs as a result of the direct mechanical effects of DI on activated ASM in the airway wall. Further bronchoconstriction occurs by altering the airway wall stress following DI, demonstrating the importance of continual transient strains in maintaining airway caliber.     

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.     

Nonlinear Compliance Modulates Dynamic Bronchoconstriction in a Multiscale Airway Model

The role of breathing and deep inspirations (DI) in modulating airway hyperresponsiveness remains poorly understood. In particular, DIs are potent bronchodilators of constricted airways in nonasthmatic subjects but not in asthmatic subjects. Additionally, length fluctuations (mimicking DIs) have been shown to reduce mean contractile force when applied to airway smooth muscle (ASM) cells and tissue strips. However, these observations are not recapitulated on application of transmural pressure (P_TM) oscillations (that mimic tidal breathing and DIs) in isolated intact airways. To shed light on this paradox, we have developed a biomechanical model of the intact airway, accounting for strain-stiffening due to collagen recruitment (a large component of the extracellular matrix (ECM)), and dynamic actomyosin-driven force generation by ASM cells. In agreement with intact airway studies, our model shows that P_TM fluctuations at particular mean transmural pressures can lead to only limited bronchodilation. However, our model predicts that moving the airway to a more compliant point on the static pressure-radius relationship (which may involve reducing mean P_TM), before applying pressure fluctuations, can generate greater bronchodilation. This difference arises from competition between passive strain-stiffening of ECM and force generation by ASM yielding a highly nonlinear relationship between effective airway stiffness and P_TM, which is modified by the presence of contractile agonist. Effectively, the airway at its most compliant may allow for greater strain to be transmitted to subcellular contractile machinery. The model predictions lead us to hypothesize that the maximum possible bronchodilation of an airway depends on its static compliance at the P_TM about which the fluctuations are applied. We suggest the design of additional experimental protocols to test this hypothesis.     

Effect of airway smooth muscle tone on airway distensibility measured by the forced oscillation technique in adults with asthma

Airway distensibility appears to be unaffected by airway smooth muscle (ASM) tone, despite the influence of ASM tone on the airway diameter-pressure relationship. This discrepancy may be because the greatest effect of ASM tone on airway diameter-pressure behavior occurs at low transpulmonary pressures, i.e., low lung volumes, which has not been investigated. Our study aimed to determine the contribution of ASM tone to airway distensibility, as assessed via the forced oscillation technique (FOT), across all lung volumes with a specific focus on low lung volumes. We also investigated the accompanying influence of ASM tone on peripheral airway closure and heterogeneity inferred from the reactance versus lung volume relationship. Respiratory system conductance and reactance were measured using FOT across the entire lung volume range in 22 asthma subjects and 19 healthy controls before and after bronchodilator. Airway distensibility (slope of conductance vs. lung volume) was calculated at residual volume (RV), functional residual capacity (FRC), and total lung capacity. At baseline, airway distensibility was significantly lower in subjects with asthma at all lung volumes. After bronchodilator, distensibility significantly increased at RV (64.8%, P < 0.001) and at FRC (61.8%, P < 0.01) in subjects with asthma but not in control subjects. The increased distensibility at RV and FRC in asthma were not associated with the accompanying changes in the reactance versus lung volume relationship. Our findings demonstrate that, at low lung volumes, ASM tone reduces airway distensibility in adults with asthma, independent of changes in airway closure and heterogeneity.     

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.     

Partitioning of pulmonary resistance during constriction in the dog: effects of volume history

We assessed the relative changes in airways and lung tissue with bronchoconstriction, and the changes in each during and following a deep inhalation (DI). We partitioned pulmonary resistance (RL) into airway (Raw) and tissue (Vtis) components using alveolar capsules in 10 anesthetized, paralyzed, and open-chested dogs ventilated sinusoidally with 350-ml breaths at 1 Hz. We made measurements before and during bronchoconstriction induced by vagal stimulation or inhalation of histamine or prostaglandin F2 alpha (PGF2 alpha), each of which decreased dynamic compliance by approximately 40%. With histamine and PGF2 alpha the rise in RL was predominantly due to Vtis. With vagal stimulation there was a relatively greater increase in Raw than Vtis. At higher lung volumes, Vtis increases offset falls in Raw, producing higher RL at these volumes before and during constriction with PGF2 alpha and histamine. During constriction with vagal stimulation, the fall in Raw with inflation overrode the rise in Vtis, resulting in a lower RL at the higher compared with the lower lung volume. The changes seen after a DI in the control and constricted states were due to alterations in tissue properties, both viscous and elastic. However, the relative hysteresis of the airways and parenchyma were equal, since Raw, our index of airway size, was unchanged after a DI.     

Complex airway behavior and paradoxical responses to bronchoprovocation.

Heterogeneity of airway constriction and regional ventilation in asthma are commonly studied under the paradigm that each airway's response is independent from other airways. However, some paradoxical effects and contradictions in recent experimental and theoretical findings suggest that considering interactions among serial and parallel airways may be necessary. To examine airway behavior in a bronchial tree with 12 generations, we used an integrative model of bronchoconstriction, including for each airway the effects of pressure, tethering forces, and smooth muscle forces modulated by tidal stretching during breathing. We introduced a relative smooth muscle activation factor (T(r)) to simulate increasing and decreasing levels of activation. At low levels of T(r), the model exhibited uniform ventilation and homogeneous airway narrowing. But as T(r) reached a critical level, the airway behavior suddenly changed to a dual response with a combination of constriction and dilation. Ventilation decreased dramatically in a group of terminal units but increased in the rest. A local increase of T(r) in a single central airway resulted in full closure, while no central airway closed under global elevation of T(r). Lung volume affected the response to both local and global stimulation. Compared with imaging data for local and global stimuli, as well as for the time course of airway lumen caliber during bronchoconstriction recovery, the model predictions were similar. The results illustrate the relevance of dynamic interactions among serial and parallel pathways in airway interdependence, which may be critical for the understanding of pathological conditions in asthma.     

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.     

An RGS4-mediated phenotypic switch of bronchial smooth muscle cells promotes fixed airway obstruction in asthma

In severe asthma, bronchodilator- and steroid-insensitive airflow obstruction develops through unknown mechanisms characterized by increased lung airway smooth muscle (ASM) mass and stiffness. We explored the role of a Regulator of G-protein Signaling protein (RGS4) in the ASM hyperplasia and reduced contractile capacity characteristic of advanced asthma. Using immunocytochemical staining, ASM expression of RGS4 was determined in endobronchial biopsies from healthy subjects and those from subjects with mild, moderate and severe asthma. Cell proliferation assays, agonist-induced calcium mobilization and bronchoconstriction were determined in cultured human ASM cells and in human precision cut lung slices. Using gain- and loss-of-function approaches, the precise role of RGS proteins was determined in stimulating human ASM proliferation and inhibiting bronchoconstriction. RGS4 expression was restricted to a subpopulation of ASM and was specifically upregulated by mitogens, which induced a hyperproliferative and hypocontractile ASM phenotype similar to that observed in recalcitrant asthma. RGS4 expression was markedly increased in bronchial smooth muscle of patients with severe asthma, and expression correlated significantly with reduced pulmonary function. Whereas RGS4 inhibited G protein-coupled receptor (GPCR)-mediated bronchoconstriction, unexpectedly RGS4 was required for PDGF-induced proliferation and sustained activation of PI3K, a mitogenic signaling molecule that regulates ASM proliferation. These studies indicate that increased RGS4 expression promotes a phenotypic switch of ASM, evoking irreversible airway obstruction in subjects with severe asthma.     

Cyclical elongation regulates contractile responses of isolated airways.

Bronchoconstrictor responses are quantitatively different when they are evoked under static conditions and during or after periods of deep inspiration. In vivo, deep inspirations produce bronchodilation and protect the lung from subsequent bronchoconstriction (termed bronchoprotection). These effects may be due in part to dynamic stretch on airways produced by cyclical expansion of airway diameter. However, airways also lengthen cyclically during breathing. The effects of cyclical airway elongation on evoked bronchoconstriction have not been examined. This study recorded evoked contractions of pig bronchial segments 1) at different airway lengths, 2) after a period of cyclical lengthening in relaxed airways, and 3) during cyclical lengthening in pretoned airways. Airway segments were mounted in organ baths and bathed in Krebs solution luminally and on the adventitia. Airways were cyclically lengthened by 5-30% of their deflated length at 0.5-2 Hz for 5 min. Contractions were evoked by electrical field stimulation or carbachol and were recorded under isovolumic conditions. Under static conditions, there was a blunt relationship between length and response to electrical field stimulation. After a period of airway length cycling, electrical field stimulation-induced contractions were increased. In airways pretoned with carbachol, cyclical lengthening produced a transient bronchodilation and a sustained increase in contraction. Contractile responses were not blocked by indomethacin. The results show that isolated airways respond actively to dynamic changes in length. Our results indicate that cyclical lengthening of airways could contribute to lung function in vivo but does not appear to account for the phenomenon of bronchoprotection.     

Airway response to deep inspiration: role of inflation pressure.

Deep inspirations (DIs) have been shown to have both bronchoprotective and bronchodilator effects in healthy subjects; however, the bronchodilator effects of a DI appear to be impaired in asthmatic compared with healthy subjects. Because the ability to generate high transpulmonary pressures at total lung capacity depends on both the lung properties and voluntary effort, we wondered how the response of airways to DI might be altered if the maneuver were done with less than maximal inflation. The present work was undertaken to examine the effects of varying the magnitude of lung inflation during the DI maneuver on subsequent airway caliber. In five anesthetized and ventilated dogs during methacholine infusion, changes in airway size after DIs of increasing magnitude were measured over the subsequent 5-min period using high-resolution computed tomography. Results show that the magnitude of lung inflation is extremely important, leading to a qualitative change in the airway response. A large DI (45 cmH(2)O airway pressure) caused subsequent airway dilation, whereas smaller DIs (< or =35 cmH(2)O) caused bronchoconstriction. The precise mechanism underlying these observations is uncertain, but it seems to be related to an interaction between intrinsic properties of the contracted airway smooth muscle and the response to mild stretch.     

Airway stability and heterogeneity in the constricted lung.

The effect of bronchoconstriction on airway resistance is known to be spatially heterogeneous and dependent on tidal volume. We present a model of a single terminal airway that explains these features. The model describes a feedback between flow and airway resistance mediated by parenchymal interdependence and the mechanics of activated smooth muscle. The pressure-tidal volume relationship for a constricted terminal airway is computed and shown to be sigmoidal. Constricted terminal airways are predicted to have two stable states: one effectively open and one nearly closed. We argue that the heterogeneity of whole lung constriction is a consequence of this behavior. Airways are partitioned between the two states to accommodate total flow, and changes in tidal volume and end-expiratory pressure affect the number of airways in each state. Quantitative predictions for whole lung resistance and elastance agree with data from previously published studies on lung impedance.     

Substance P-inducing massive postmortem bronchoconstriction in guinea pig lungs

To further examine the role that substance P plays in initiating the observed massive postmortem bronchoconstriction in guinea pig lungs and to explore the role of neural reflex in this airway spasm, six groups of animals were employed: control (n = 6), morphine (n = 6), substance P (n = 5), chronic capsaicin pretreatment + substance P (n = 5), tetrodotoxin (TTX) + acute capsaicin (n = 4), and chlorisondamine + acute capsaicin (n = 5). Pressure-volume curves were performed prior to and following the initiation of artificial pulmonary perfusion with 1% bovine serum albumin and 5% dextran in Tyrode's solution. A decrease in inflation volume (the lung volume between transpulmonary pressure of 0 and 30 cmH2O during inflation) was used as an index of bronchoconstriction. In control animals, inflation volume decreased to 20-30% of the base-line value at 15-30 min of perfusion, indicating massive bronchial constriction during this time period. Morphine (an agent inhibiting substance P release) significantly attenuated the spasm, whereas the presence of substance P in the perfusate markedly enhanced the constriction. Depletion of endogenous substance P by chronic capsaicin pretreatment did not affect exogenous substance P-induced spasm. Acute capsaicin-induced bronchoconstriction was significantly attenuated by TTX but was not affected by the ganglionic blocking agent, chlorisondamine. These data suggest that substance P initiates the massive postmortem bronchoconstriction in guinea pig lungs and that substance P is released by local stimulation of sensory nerve endings via axonal reflex.     

Differences in airway structure in immature and mature rabbits.

Our laboratory has previously demonstrated that maximal bronchoconstriction produces a greater degree of airway narrowing in immature than in mature rabbit lungs (33). To determine whether these maturational differences could be related to airway structure, we compared the fraction of the airway wall occupied by airway smooth muscle (ASM) and cartilage, the proportion of wall area internal to ASM, and the number of alveolar attachments to the airways, from mature and immature (6-mo- and 4-wk-old, respectively) rabbit lungs that were formalin fixed at total lung capacity. The results demonstrate that the airway walls of immature rabbits had a greater percentage of smooth muscle, a lower percentage of cartilage, and fewer alveolar attachments compared with mature rabbit airways; however, we did not find maturational differences in the airway wall thickness relative to airway size. We conclude that structural differences in the airway wall may contribute to the greater airway narrowing observed in immature rabbits during bronchoconstriction.     

Analysis of bronchial mechanics and density dependence of maximal expiratory flow

The computational model for expiratory flow in humans of Lambert and associates (J. Appl. Physiol. Respirat. Environ. Exercise Physiol. 52: 44-56, 1982) was used to investigate the effect of bronchial constrictions in three airway zones on the density dependence of maximal expiratory flow. It was found that constriction of the peripheral airways (less than 2 mm diam) reduced density dependence and increased the volume of isoflow. Constriction of the larger intraparenchymal airways resulted in increased density dependence at low lung volumes and essentially normal values at other volumes. The volume of isoflow was reduced. Extraparenchymal (but intrathoracic) airway constriction caused no change in the volume of isoflow but caused increased density dependence at the higher lung volumes. It was shown that in these model simulations the addition of extraparenchymal constriction to intraparenchymal constriction causes essentially no changes in density dependence. An increased volume of isoflow and significantly decreased density dependence at 50 and 25% vital capacity were produced by simulated constrictions only in the peripheral airways.     

Impaired response to deep inspiration in obesity

Deep inspirations modulate airway caliber and airway closure and their effects are impaired in asthma. The association between asthma and obesity raises the question whether the deep inspiration (DI) effect is also impaired in the latter condition. We assessed the DI effects in obese and nonobese nonasthmatics. Thirty-six subjects (17 obese, 19 nonobese) underwent routine methacholine (Mch) challenge and 30 of them also had a modified bronchoprovocation in the absence of DIs. Lung function was monitored with spirometry and forced oscillation (FO) [resistance (R) at 5 Hz (R5), at 20 Hz (R20), R5-R20 and the integrated area of low-frequency reactance (AX)]. The response to Mch, assessed with area under the dose-response curves (AUC), was consistently greater in the routine challenge in the obese (mean ± SE, obese vs. nonobese AUC: R5: 15.7 ± 2.3 vs. 2.4 ± 2.0, P < 0.0005; R20: 5.6 ± 1.4 vs. 1.4 ± 1.2, P = 0.027; R5-R20: 10.2 ± 1.6 vs. 0.9 ± 0.1.4, P < 0.0005; AX: 115.6 ± 22.0 vs. 1.5 ± 18.9, P < 0.0005), but differences between groups in the modified challenge were smaller, indicating reduced DI effects in obesity. Given that DI has bronchodilatory and bronchoprotective effects, we further assessed these components separately. In the obese subjects, DI prior to Mch enhanced Mch-induced bronchoconstriction, but DI after Mch resulted in bronchodilation that was of similar magnitude as in the nonobese. We conclude that obesity is characterized by increased Mch responsiveness, predominantly of the small airways, due to a DI effect that renders the airways more sensitive to the stimulus.     

Bronchoprotective and bronchodilatory effects of deep inspiration in rabbits subjected to bronchial challenge.

The effect of deep inspiration (DI) on airway responsiveness differs in asthmatic and normal human subjects. The mechanism for the effects of DI on airway responsiveness in vivo has not been identified. To elucidate potential mechanisms, we compared the effects of DI imposed before or during induced bronchoconstriction on the airway response to methacholine (MCh) in rabbits. The changes in airway resistance in response to intravenous MCh were continuously monitored. DI depressed the maximum response to MCh when imposed before or during the MCh challenge; however, the inhibitory effect of DI was greater when imposed during bronchoconstriction. Because immature rabbits have greater airway reactivity than mature rabbits, we compared the effects of DI on their airway responses. No differences were observed. Our results suggest that the mechanisms by which DI inhibits airway responsiveness do not depend on prior activation of airway smooth muscle (ASM). These results are consistent with the possibility that reorganization of the contractile apparatus caused by stretch of ASM during DI contributes to depression of the airway response.