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Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of Public Health, Baltimore, MD 21205, USA.
Journal of Applied Physiology (Impact Factor: 3.06). 06/2008; 104(5):1381-6. DOI: 10.1152/japplphysiol.01348.2007
Source: PubMed


Previous work showed that individual airway size, before any spasmogen, varied widely in the same animals on different days. The effect of this variable baseline size on the airway response to a subsequent challenge is unknown. The present study examined how the variability in individual airway baseline size in dogs was related to that after methacholine challenge on 4 different days using high-resolution computed tomography scans. Dogs were anesthetized and ventilated, and on 4 separate days randomly varying between 1 and 8 wk apart, baseline scans were acquired, followed by a continuous intravenous infusion of methacholine at three rates in increasing order (17, 67, and 200 microg/min). As the measure of variability, we used the coefficient of variation (CV) of the four airway luminal measurements of each airway at baseline and at each dose of methacholine. For most airways, there was wide variability both between and within dogs in the response to a given dose of methacholine (CV = 33-38%). Airways with any level of methacholine stimulation had greater variability than those at baseline. The airway variability was greatest at the lowest dose of methacholine administered but was elevated at all the doses. In conclusion, there was substantial day-to-day variability in baseline airway size. Most importantly, the same dose of methacholine to the same individual airway showed even greater variability than that at baseline. If we consider that increased heterogeneity may potentiate clinical symptoms, then airway response variability may play an important role in the manifestation of airway disease.

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Available from: David W. Kaczka, Sep 30, 2015
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    • "We previously demonstrated that airways with any level of Mch stimulation had greater temporal variability than without Mch.15 Our current results also demonstrate that the temporal variability of the airways decreased after the deep inspiration both at baseline and during low concentrations of Mch stimulation, but this beneficial effect of a deep inspiration was lost at higher concentrations of Mch. "
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    ABSTRACT: In healthy individuals, a DI can reverse (bronchodilation) or prevent (bronchoprotection) induced airway constriction. For individuals with asthma or COPD, these effects may be attenuated or absent. Previous work showed that the size and duration of a DI affected the subsequent response of the airways. Also, increased airway tone lead to increased airway size variability. The present study examined how a DI affected the temporal variability in individual airway baseline size and after methacholine challenge in dogs using High-Resolution Computed Tomography. Dogs were anesthetized and ventilated, and on 4 separate days, HRCT scans were acquired before and after a DI at baseline and during a continuous intravenous infusion of methacholine (Mch) at 3 dose rates (17, 67, and 200 μg/min). The Coefficient of Variation was used as an index of temporal variability in airway size. We found that at baseline and the lowest dose of Mch, variability decreased immediately and 5 minutes after the DI (P < 0.0001). In contrast, with higher doses of Mch, the DI caused a variable response. At a rate of 67 μg/min of Mch, the temporal variability increased after 5 minutes, while at a rate of 200 μg/min of Mch, the temporal variability increased immediately after the DI. Increased airway temporal variability has been shown to be associated with asthma. Although the mechanisms underlying this temporal variability are poorly understood, the beneficial effects of a DI to decrease airway temporal variability was eliminated when airway tone was increased. If this effect is absent in asthmatics, this may suggest a possible mechanism for the loss of bronchoprotective and bronchodilatory effects after a DI in asthma.
    Clinical Medicine Insights: Circulatory, Respiratory and Pulmonary Medicine 02/2011; 5:7-15. DOI:10.4137/CCRPM.S6531
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    • "Incorporating this model into a network of ventilation simulating imaging patterns observed in asthmatics, Venegas et al. (2005) documented that local interactions between airway wall and surrounding parenchyma caused by increasing airway smooth muscle tone or decreasing ventilation yielded a bimodal ventilation distribution, with some airways closing or approaching closure while others opening at the same time. These data would suggest that the interactions between operational lung volumes, tidal breathing, and airway smooth muscle tone is so potent to generate heterogeneous bronchoconstriction that may largely overcome the effects of any other source of heterogeneity , such as anatomical, neural, functional, and distribution of the constrictor agents (Brown et al., 2008). Decrements in lung volumes and ventilation could have contributed to cause heterogeneous and thus exaggerated airway narrowing in our study by two mechanisms. "
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    ABSTRACT: Chest wall strapping has been recently shown to be associated with an increase in airway responsiveness to methacholine. To investigate whether this is the result of the decreased lung volume or an increased heterogeneity due to chest wall distortion, ten healthy volunteers underwent a methacholine challenge at control conditions and after selective strapping of the rib cage, the abdomen or the whole chest wall resulting in similar decrements of functional residual capacity and total lung capacity but causing different distribution of the bronchoconstrictor. Methacholine during strapping reduced forced expiratory flow, dynamic compliance, and reactance at 5Hz and increased pulmonary resistance and respiratory resistance at 5Hz that were significantly greater than at control and associated with a blunted bronchodilator effect of the deep breath. However, no significant differences were observed between selective and total chest wall strapping, suggesting that the major mechanism for increasing airway responsiveness with chest wall strapping is the breathing at low lung volume rather than regional heterogeneities.
    Respiratory Physiology & Neurobiology 04/2009; 166(1):47-53. DOI:10.1016/j.resp.2009.01.006 · 1.97 Impact Factor
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    ABSTRACT: Obstructive lung diseases are often characterized by heterogeneous patterns of bronchoconstriction, although specific relationships between structural heterogeneity and lung function have yet to be established. We measured respiratory input impedance (Zrs) in eight anesthetized dogs using broadband forced oscillations at baseline and during intravenous methacholine (MCh) infusion. We also obtained high-resolution computed tomographic (HRCT) scans in 4 dogs and identified 20-30 individual airway segments in each animal. The Zrs spectra and HRCT images were obtained before and 5 min following a deep inspiration (DI) to 35 cmH(2)O. Each Zrs spectrum was fitted with two different models of the respiratory system: 1) a lumped airways model consisting of a single airway compartment, and 2) a distributed airways model incorporating a continuous distribution of airway resistances. For the latter, we found that the mean level and spread of airway resistances increased with MCh dose. Whereas a DI had no effect on average airway resistance during MCh infusion, it did increase the level of airway heterogeneity. At baseline and low-to-moderate doses of MCh, the lumped airways model was statistically more appropriate to describe Zrs in the majority of dogs. At the highest doses of MCh, the distributed airways model provided a superior fit in half of the dogs. There was a significant correlation between heterogeneity assessed with inverse modeling and the standard deviation of airway diameters obtained from HRCT. These data demonstrate that increases in airway heterogeneity as assessed with forced oscillations and inverse modeling can be linked to specific structural alterations in airway diameters.
    Journal of Applied Physiology 11/2008; 106(2):520-30. DOI:10.1152/japplphysiol.90576.2008 · 3.06 Impact Factor
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