Bronchodilatory Effect Of Deep Inspiration Research Articles

Inhibition of Rho-kinase improves response to deep inspiration in ovalbumin-sensitized guinea pigs.

Objective(s):The modulatory effect of deep inspiration (DI) on airway constriction is impaired in asthma. However, mechanisms underlying this impairment are not clear. Since there is evidence indicating that Rho-kinase activation mediates force maintenance under oscillatory strain, we investigated the impact of Rho-kinase inhibition on the bronchodilatory effect of DI in ovalbumin (OVA) sensitized guinea pigs.Materials and Methods:forty-eight male Dunkin Hartley guinea pigs were divided into 8 groups including saline/ constant, saline/DI, OVA/constant, OVA/DI, Rho-I/OVA/constant, Rho-I/OVA/DI, OVA-Rho-I/MCh/constant, and OVA-Rho-I/MCh/DI. Animals were subjected to 12 inhalations of OVA or saline aerosol. Guinea pigs in Rho-I/OVA/constant or DI groups were treated with the Rho-kinase inhibitor (Rho-I) (Y-27632, 1 mM aerosols) prior to the last 8 allergen inhalations and OVA-Rho-I/MCh/constant or DI groups received Y-27632 at the end of allergen sensitization protocol before methacholine challenge. The bronchodilatory effect of DI in guinea pigs that were exposed to methacholine was assessed by using an animal ventilator. The bronchodilatory effect was assessed using several parameters: the airway pressure maintenance, airway pressure recovery, and decline of airway pressure.Results:Results indicated that application of Y-27632 prior to methacholine challenge reduces the airway smooth muscle ability to maintain pressure and also causes further decline in airway pressure in OVA-sensitized animals undergone DI. However, the inhibition of Rho-kinase before OVA inhalations had minimal effect.Conclusion:We propose that alteration of Rho-kinase signaling pathway may be one of the mechanisms underlying the impairment of DI-induced bronchodilation in OVA-sensitized guinea pigs.

Prestrain and cholinergic receptor-dependent differential recruitment of mechanosensitive energy loss and energy release elements in airway smooth muscle.

We tested the hypothesis that oscillatory airway smooth muscle (ASM) mechanics is governed by mechanosensitive energy loss and energy release elements that can be recruited by prestrain and cholinergic stimulation. We measured mechanical energy loss and mechanical energy release in unstimulated and carbachol-stimulated bovine ASM held at prestrains ranging from 0.3 to 1.0 Lo (reference length) and subjected to sinusoidal length oscillation at 1 hz with oscillatory strain amplitudes ranging from 0.1 to 1.5% Lo. We found that oscillatory ASM mechanics during sinusoidal length oscillation is governed predominantly by one class of nonlinear mechanosensitive energy loss element and one class of nonlinear mechanosensitive energy release element with differential mechanosensitivities to oscillatory strain amplitude. The greater mechanosensitivity of the energy loss element than energy release element may explain the bronchodilatory effect of deep inspiration. Prestrain, an important determinant of ASM responsiveness, differentially increased energy loss and energy release in unstimulated and carbachol-stimulated ASM. Cholinergic stimulation, an important cause of bronchoconstriction and airway inflammation, also differentially increased energy loss and energy release. When prestrain and cholinergic stimulation were combined, we found that prestrain and cholinergic stimulation synergistically increased energy loss and energy release by ASM. The relationship between recruitment of energy loss elements and recruitment of energy release elements was nonlinear, suggesting that energy loss and energy release elements are not coupled in ASM cells. These findings imply that large lung volume and cholinergic ASM activation would synergistically increase mechanical energy expenditure during inspiration and mechanical recoil of ASM during expiration. NEW & NOTEWORTHY We report for the first time that oscillatory airway smooth muscle mechanics is governed predominantly by one class of nonlinear mechanosensitive energy loss element and one class of nonlinear mechanosensitive energy release element with differential mechanosensitivities to oscillatory strain amplitude. Prestrain and cholinergic stimulation synergistically and differentially recruit energy loss and energy release elements. The greater mechanosensitivity of the energy loss element than the energy release element may explain the bronchodilatory effect of deep inspiration.

More Relaxation by Deep Breath on Methacholine- Than on Exercise-Induced bronchoconstriction during the Routine Testing of Asthmatic Children.

Deep inspiration (DI) dilates normal airway precontracted with methacholine. The fact that this effect is diminished or absent in asthma could be explained by the presence of bronchial inflammation. The hypothesis was tested that DI induces more relaxation in methacholine induced bronchoconstriction—solely determined by the smooth muscle contraction—than in exercise induced bronchoconstriction, which is contributed to by both smooth muscle contraction and airway wall inflammation. The respiratory conductance (Grs) response to DI was monitored in asthmatic children presenting a moderately positive airway response to challenge by methacholine (n = 36) or exercise (n = 37), and expressed as the post- to pre-DI Grs ratio (GrsDI). Both groups showed similar change in FEV1 after challenge and performed a DI of similar amplitude. GrsDI however was significantly larger in methacholine than in exercise induced bronchoconstriction (p < 0.02). The bronchodilatory effect of DI is thus less during exercise- than methacholine-induced bronchoconstriction. The observation is consistent with airway wall inflammation—that characterizes exercise induced bronchoconstriction—rendering the airways less responsive to DI. More generally, it is surmised that less relief of bronchoconstriction by DI is to be expected during indirect than direct airway challenge. The current suggestion that airway smooth muscle constriction and airway wall inflammation may result in opposing effects on the bronchomotor action of DI opens important perspective to the routine testing of asthmatic children. New crossover research protocols comparing the mechanical consequences of the DI maneuver are warranted during direct and indirect bronchial challenges.

Bronchodilatory effect of deep inspiration in freshly isolated sheep lungs.

Taking a big breath is known to reverse bronchoconstriction induced by bronchochallenge in healthy subjects; this bronchodilatory effect of deep inspiration (DI) is diminished in asthmatics. The mechanism underlying the DI effect is not clear. Observations from experiments using isolated airway smooth muscle (ASM) preparations and airway segments suggest that straining of ASM due to DI could lead to bronchodilation, possibly due to strain-induced reduction in ASM contractility. However, factors external to the lung cannot be excluded as potential causes for the DI effect. Neural reflex initiated by stretch receptors in the lung are known to inhibit the broncho-motor tone and enhance vasodilatation; the former directly reduces airway resistance, and the latter facilitates removal of contractile agonists through the bronchial circulation. If the DI effect is solely mediated by factors extrinsic to the lung, the DI effect would be absent in isolated, nonperfused lungs. Here we examined the DI effect in freshly isolated, nonperfused sheep lungs. We found that imposition of DI on isolated lungs resulted in significant bronchodilation, that this DI effect was present only after the lungs were challenged with a contractile agonist (acetylcholine or histamine), and that the effect was independent of the difference in lung volume observed pre- and post-DI. We conclude that a significant portion of the bronchodilatory DI effect stems from factors internal to the lung related to the activation of ASM.

Enhanced airway dilation by positive-pressure inflation of the lungs compared with active deep inspiration in patients with asthma

Deep inspiration temporarily reduces induced airways obstruction in healthy subjects. This bronchodilatory effect of deep inspiration is impaired in asthma. Passive machine-assisted lung inflation may augment bronchodilation compared with an active deep inspiration in patients with asthma by either opening closed airways or by reducing fluid flux across the airway wall during deep inspiration, and thereby increasing the tethering forces on the airway wall. We recruited 24 patients with asthma [18-46 yr old, forced expiratory volume in 1 s (FEV(1)) > 70% predicted; provocative concentration of methacholine inducing a 20% fall in FEV(1) (PC(20)) < 8 mg/ml], with either an impaired (n = 12) or an intact (n = 12) bronchodilatory response to deep inspiration. Two methacholine challenges were performed on separate days. At a 50% increase in respiratory resistance (forced oscillation technique at 8 Hz), the change in resistance by a positive-pressure inflation (computer-driven syringe) or an active deep inspiration was measured in randomized order. The reduction in resistance by positive-pressure inflation was significantly greater than by active deep inspiration in the impaired deep inspiration response group (mean change +/- SE: -0.6 +/- 0.1 vs. -0.03 +/- 0.2 cmH(2)O.l(-1).s, P = 0.002). No significant difference was found between positive-pressure inflation and active deep inspiration in the intact deep inspiration response group (-0.6 +/- 0.2 vs. -1.0 +/- 0.3 cmH(2)O.l(-1).s, P = 0.18). Positive-pressure inflation of the lungs can significantly enhance deep inspiration-induced bronchodilation in patients with asthma.

Bronchodilatory effect of deep inspiration on the dynamics of bronchoconstriction in mice

We recently developed a computational model of an airway embedded in elastic parenchyma (Bates JH, Lauzon AM. J Appl Physiol 102: 1912-1920, 2007) that accurately mimics the time dependence of airway resistance on tidal volume and positive end-expiratory pressure (PEEP) following methacholine injection in normal animals. In the present study, we compared the model predictions of bronchodilation induced by a deep inflation (DI) of the lung following administration of the bronchial agonist methacholine to corresponding experimental measurements made in mice. We found that a DI in mice caused an immediate reduction in airway resistance when it was administered soon after intravenous injection of methacholine, while the airway smooth muscle was in the process of contracting. However, the magnitude of the reduction in resistance was greater and its subsequent rate of increase less than that predicted by the model. We found that this effect was most pronounced when the DI was given within approximately 3 s following methacholine injection, again in contrast to the predictions of the model. The reduction of airway resistance was virtually independent of the rate of lung inflation during the DI, however, which agrees with model predictions. We conclude that while the model accounts for a substantial fraction of the post-DI reduction in airway resistance seen experimentally, there remain important differences between prediction and experiment that suggest that the effects of a DI are not simply due to eccentric contraction of the airway smooth muscle.

Impaired Bronchodilatory Effect of Deep Inspiration With Increased Asthma Severity

RATIONALE: In healthy humans, deep inspiration (DI) induces bronchodilation. In mild asthmatics, this effect is minimally reduced (Scichilone et al. Am. J. Respir. Crit. Care Med. 163:413;2001). This study was conducted to examine whether DI-induced bronchodilation is impaired in more severe asthma.

Association between reduced bronchodilatory effect of deep inspiration and loss of alveolar attachments

BackgroundWe have previously shown that the bronchodilatory effect of deep inspiration is attenuated in individuals with COPD. This study was designed to investigate whether the impairment in this effect is associated with loss of alveolar attachments.MethodsWe measured deep inspiration (DI)-induced bronchodilation in 15 individuals with and without COPD (67 ± 2.2 yrs of age, mean ± SEM) undergoing lobar resection for peripheral pulmonary nodule. Prior to surgery, we measured TLCO and determined the bronchodilatory effect of deep inspiration after constricting the airways with methacholine. The number of destroyed alveolar attachments, as well as airway wall area and airway smooth muscle area, were determined in tumor-free, peripheral lung tissue.ResultsThe bronchodilatory effect of deep inspiration correlated inversely with the % destroyed attachments (r = -0.51, p = 0.05) and directly with the airway smooth muscle area (r = 0.59, p = 0.03), but not with the total wall area (r = 0.39, p = 0.15).ConclusionWe postulate that attenuation of airway stretch due to loss of alveolar attachments contributes to the loss of the bronchodilatory effect of lung inflation in COPD.

Alveolar Nitric Oxide and Effect of Deep Inspiration During Methacholine Challenge

To assess whether the dual anatomic origin of exhaled nitric oxide (NO), namely alveolar and bronchial, could explain the link between exhaled NO and airway responsiveness, and could participate in the bronchodilatory effect of deep inspiration (DI) that may be evidenced during methacholine challenge. Prospective study in a laboratory performing pulmonary function tests of an academic hospital. Patients underwent multiple flow analysis of exhaled NO, allowing calculation of total maximum airway NO flux (J'awno) and NO concentration of expansible compartment (CAno), and received a cumulative methacholine dose of 2,000 microg. DI effect was assessed by continuous measurement of the resistance of respiratory system using the forced oscillation technique before and after DI. In a first phase involving 23 patients, a positive correlation between log values of J'awno and CAno was demonstrated with the degree of airway responsiveness (percentage of FEV(1) decrease). In a second phase involving 38 patients, only log CAno was correlated with responsiveness, and no significant relationship was demonstrated between J'awno or CAno and the effect of DI. Patients with smaller airways and/or distal airflow limitation exhibited a constrictive response to DI. Airway responsiveness is mainly associated with an increase in distal origin of NO output, and no relationship between exhaled NO and the effect of DI was evidenced.

Bronchodilatory Effect of Deep Inspiration Is Absent in Subjects With Mild COPD

To investigate whether the bronchodilatory effect of deep inspiration is impaired in subjects with COPD. We measured deep inspiration-induced bronchodilation in 19 patients with COPD and 17 healthy subjects (mean age, 67.8 +/- 7.1 years vs 62.5 +/- 9.3 years, respectively [+/- SEM]). Each subject underwent a series of single-dose methacholine provocations to induce at least a 15% reduction in inspiratory vital capacity (IVC). When this was achieved, subjects were asked to perform four consecutive deep inspirations, after which the IVC measurement was repeated and the percentage of bronchodilation by deep inspiration was calculated. The percentage of reduction in IVC from baseline prior to the deep inspirations did not differ between the two groups (COPD, 20.1 +/- 1.6%; healthy, 22.7 +/- 2.4%; p = 0.38); median single methacholine doses employed were 20 mg/mL (range, 0.025 to 75 mg/mL) and 25 mg/mL (range, 10 to 75 mg/mL), respectively (p = 0.19). Deep inspirations were not able to reverse bronchoconstriction in patients with COPD (bronchodilation, 3.9 +/- 2.6%; p = 0.15 by one-sample t test). Bronchodilation by deep inspiration was present in healthy subjects (13.7 +/- 3.0%, p = 0.0003), and was significantly higher than that of patient with COPD (p = 0.02). In patients with COPD, deep inspiration-induced bronchodilation correlated with the percentage of predicted transfer factor of the lung for carbon monoxide (r = 0.53, p = 0.05), but not with airway obstruction, as assessed by FEV(1) or FEV(1)/FVC. The bronchodilatory ability of deep inspiration is lost in mild COPD. We speculate that the absence of deep inspiration-induced bronchodilation contributes to the development and severity of chronic respiratory symptoms in patients with COPD.

The bronchodilatory effect of deep inspiration diminishes with aging

Deep inspirations have the ability to dilate constricted airways. The impairment of this function has been associated with the occurrence of asthmatic symptoms. We evaluated whether the bronchodilatory effect of deep inspiration (DI) is affected by aging. We tested 25 healthy subjects (median age: 54 yrs, range: 25–83 yrs). Single dose methacholine (Mch) provocations were performed in the absence of DI, which induced at least 15% reduction in inspiratory vital capacity (IVC) from baseline. The post-Mch IVC measurement was followed by 4 DIs and by another IVC (post-DI IVC). The fractional difference between post-DI IVC and post-Mch IVC represented the % bronchodilation by DI. The % bronchodilation significantly diminished with aging ( r=0.65, P=0.0005). The bronchodilatory ability of DI was also positively associated with the degree of Mch-induced reduction in IVC ( r=0.84, P<0.0001). In multiple regression analysis, where % bronchodilation was the dependent variable, both % reduction in IVC ( P<0.0001) and age ( P=0.02) entered the model. Our data raise the hypothesis that aging is associated with reduction in DI-induced bronchodilation.

The role of lung inflation in airway hyperresponsiveness and in asthma

Airway hyperresponsiveness (AHR) is a fundamental phenomenon in asthma that can explain many aspects of the clinical manifestations of the disease. Several theories on the mechanisms of AHR have been proposed, but the true nature of this problem is yet to be defined. During the past decade, the role of lung inflation in airway physiology and its relationship to AHR have attracted major attention. Deep inspirations are known to exert strong beneficial effects on the airways of healthy humans. These effects appear to be of dual nature: bronchoprotective and bronchodilatory. The bronchoprotective effect of deep inspiration is lost in asthma, even in mild disease. It is also lost in individuals with rhinitis and AHR, but no asthma. Therefore, the loss of bronchoprotection is related to AHR. The bronchodilatory effect of deep inspiration is somewhat reduced in mild asthma and is only lost in severe disease, in the presence of significant airway obstruction. Current research is focused on the elucidation of the physiologic mechanisms behind lung inflation-induced bronchoprotection and bronchodilation and on the causes of their loss. This information could open new horizons in asthma therapy and prevention.

Stress distribution in lungs: a model of pulmonary elasticity.

MEAD, JERE, TAMOTSU TAKISHIMA, AND DAVID LEITH. Stress distribution in lungs: a model of pulmonary elasticity. J. Appl. Physiol. 28(5) : 596-608. 1970.Although lungs are exposed to transpulmonary pressure, the air spaces within are distended solely by forces applied from surrounding tissues. By relating these forces to the areas on which they operate, we derive the effective pressure distending air spaces. In uniformly expanded lungs this pressure probably approximates transpulmonary pressure. In nonuniformly expanded lungs the effective distending pressure differs from transpulmonary pressure, and in the appropriate sign to reduce the nonuniformity. This interdependence of air-space distention bears on a number of aspects of pulmonary function, including the size of air spaces which may be expanded from the gas-free state, the static and dynamic stability of air spaces, the dryness of air spaces, the forces distending airways and blood vessels within lungs, and the distribution of pulmonary edema. The principal function of the mechanical interdependence would appear to be to support uniform expansion of air spaces. The principal functional risk that it entails is increase in capillary transmural pressure in regions which become subjected to abnormally high outward-acting stress.