Airway Distensibility Research Articles

A Quick Method to Assess Airway Distensibility in Mice

Airway distensibility is defined as the ease whereby airways are dilating in response to inflating lung pressure. If measured swiftly and accurately, airway distensibility would be a useful readout to parse the various elements contributing to airway wall stiffening, such as smooth muscle contraction, surface tension, and airway remodeling. The goal of the present study was to develop a method for measuring airway distensibility in mice. Lungs of BALB/c and C57BL/6 mice from either sex were subjected to stepwise changes in pressure. At each pressure step, an oscillometric perturbation was used to measure the impedance spectrum, on which the constant-phase model was fitted to deduce a surrogate for airway caliber called Newtonian conductance (GN). The change in GN over the change in pressure was subsequently used as an index of airway distensibility. An additional group of mice was infused with methacholine to confirm that smooth muscle contraction changes airway distensibility. GN increased with increasing steps in pressure, suggesting that the extent to which this occurs can be used as an index of airway distensibility. Airway distensibility was greater in BALB/c than C57BL/6 mice, and its variation by sex was mouse strain dependent, being greater in female than male in BALB/c mice with an inverse trend in C57BL/6 mice. Airway distensibility was also decreased by methacholine. This novel method swiftly measures airway distensibility in mice. Airway distensibility was also shown to vary with sex and mouse strain and to be sensitive to the contraction of smooth muscle.

Utilizing a Functional Lumen Imaging Probe for Evaluation of the Pediatric Airway, A Pilot Study.

Accurate and reproducible measurements of the pediatric airway are critical for diagnostic evaluation and management of subglottic and tracheal stenosis. The endoluminal functional lumen imaging probe (EndoFLIP) is a catheter-based imaging probe which utilizes impedance planimetry to calculate luminal parameters, including cross-sectional area and compliance. Herein, we demonstrate the feasibility of this system for multidimensional evaluation of the pediatric airway. 3D-printed pediatric laryngotracheal models were created based on computed tomography scans, then artificially deformed to simulate both circumferential and posterior subglottic stenosis. Two observers made six measurements of the minimum cross-sectional area (MCSA) and length of stenosis of each model with EndoFLIP. Agreement between observer measurements and model dimensions was evaluated using Lin's concordance correlation coefficient; inter-observer reliability was assessed using intraclass correlation. Four models were created: two without pathology (MCSA: 132.4, 44.3 mm2 ) and two with subglottic stenosis (MCSA: 28.7, 59.7 mm2 , stenotic length 27.8, 24.4 mm). Observer measurements of MCSA and length of stenosis demonstrated high concordance with the models (r = 0.99, 0.95, p < 0.001) with a mean error of 4.5% and 18.2% respectively. There was a low coefficient of variation (0.6%-2.8%) for measurements, indicating high precision. Interrater reliability was high for both MCSA and stenotic length (ICC: 0.99, 0.98). The EndoFLIP system allows for accurate and reproducible measurements of cross-sectional area and stenotic length in pediatric airway models. This method may provide further advantages in the evaluation of airway distensibility, as well as measurements of asymmetric airway pathology. NA Laryngoscope, 134:108-112, 2024.

Enhanced carbonic anhydrase expression with calcification and fibrosis in bronchial cartilage during COPD

Pulmonary cartilage plays a crucial structural role determining the physiologic airway compressibility and distensibility, necessary for proper mechanical function. This functionality deteriorates with aging due to increased stiffness of both airway muscle and cartilage, as well as, decreased renewal capacity. Altered airway remodeling has been suggested as a pathogenic driver of chronic obstructive pulmonary disease (COPD) through mechanisms still incompletely understood. Using paraffin-embedded lung tissue sections from archived autopsy material from COPD with non-COPD age matched controls a histopathologic analysis focused on inflammation, fibrosis and calcification was performed with special stains (Masson’s trichrome and Von Kossa) and immunohistochemistry for carbonic anhydrase IV (CA IV) and Ki-67. COPD lung tissues showed increased peribronchial inflammation compared to the non-COPD. Coarse amphophilic crystalline deposits in bronchial cartilage were more frequently observed in COPD sections, which were compatible with early dystrophic calcification of the extracellular matrix and chondrocytes. Moreover, Von Kossa staining revealed a significant calcium deposition in the cartilages from COPD in comparison to the controls. Interestingly, Ki-67 immunostains demonstrated a higher overall proliferative rate, including epithelial cells, in COPD. Furthermore, Masson’s trichrome staining revealed relatively increased peribronchial collagen deposition associated with a fibrotic stromal response, which may be secondary to the inflammatory milieu in COPD. To further characterize the tissue microenvironment associated with dystrophic calcification, immunohistochemistry for CA IV was used, revealing significantly increased expression in chondrocytes and peribronchial tissue in COPD. Our findings demonstrate that dystrophic calcification of the extracellular matrix and chondrocytes can be linked to CA IV expression in COPD and suggest that pH changes in pulmonary tissue associated with inflammation and calcification may play an active role in COPD.

The application of statistical shape modeling for lung morphology in aerosol inhalation dosimetry

Even with the advance in medical imaging techniques such as CT/MRI, it is still challenging and time-consuming to reconstruct anatomically accurate lung geometries. It is even more challenging to study variability in inhalation dosimetry or pulmonary drug delivery, which requires a large cohort of lung models to ensure statistically significant results. This study used the statistical shape modeling (SSM) that bases on a limited number of lung models (40) to generate infinitely large numbers of parameterized models, which can span all major features inherent in the database of lung geometries. We demonstrated this model in lung models with more than 400 outlets (G9), which first identified the principal components (PCs) of base models, and then regenerated new models by systematically varying the mode (eigenvector) and its eigenvalues. The new models included airway remodeling at varying locations (left upper lobe and right lower lobe) and with varying levels of airway distensibility (compliance) and constriction (resistance). Airflow and aerosol dynamics within these lung geometries were numerically computed and compared. Results showed that even though the airway remodeling can be local, its influences on flow partition and deposition distribution can be global. Asthma-induced bronchiolar constriction, when severe, can strikingly alter the airflow and particle deposition mapping throughout the lungs. The highest deposition variability due to airway remodeling was found to come from particles of 4–10 μm in the upper lobes, and of 10–20 μm in the lower lobe. Statistical shape modeling is an imaging processing method that has often been used in computer sciences. This is the first study, to the author's knowledge, that SSM was applied in lung models with high complexity to quantify the resultant variances from these geometry remodeling. This method was also applied to lung models with 3000 outlets (G11) to generate diseased lung models at varying locations.

Impulse Oscillometry to Evaluate Lung Function in Young Children Under Five Years with Sickle Cell Disease

BACKGROUND Young children with sickle cell disease (SCD) aged 2 - 5 years old are at the highest risk of acute chest syndrome (ACS), a leading cause of morbidity and mortality. In addition to severe forms of SCD (HbSS and HbSβ0 thalassemia), asthma and airway hyper-responsiveness are also known risk factors for ACS, and are three to five times more prevalent in older children and adults with SCD. However in SCD children under 5 years there are only a few studies describing airway function, due to limitations in spirometry and other common pulmonary function tests (PFTs). Impulse oscillometry, a passive, non-invasive technique to evaluate airway function via pulmonary resistance and reactance, has been validated in children as young as 3 years, but has not been used widely in children with SCD. OBJECTIVE We sought to describe baseline airway function in children under 5 years with SCD using impulse oscillometry, as part of an ongoing observational study to evaluate lung function in young SCD children over time. METHOD Following IRB approval, participation in the ongoing prospective study was offered to patients aged 3 - 5 years old with HbSS and HbSβ0 thalassemia followed at the Pediatric Sickle Cell Clinic at Augusta University. Parents of the consented patients completed a modified ISAAC questionnaire assessing reported asthma symptoms and tobacco smoke exposure. Baseline IOS was obtained within 6 months of consent, with other clinical data obtained from medical records. Airway function was assessed using airway resistance at 5Hz and 20Hz (R5, R20), and reactance at 5Hz (X5). Percent predicted values were computed using NHANES (National Health and Nutrition Examination Survey) reference criteria for age, height, gender and ethnicity. RESULTS Out of 9 consented patients, 7 completed the ISAAC questionnaire and 6 successfully performed IOS. One patient consented but deferred participation to next visit and 1 patient with HbSC was excluded from analysis. All remaining patients had sickle cell anemia (HbSS). Age range at study enrolment was 3.7 - 5.4 years (mean 4.6 years). All participants were African American, 4/7 were male. Four out of 7 survey participants were already on Hydroxyurea therapy for their disease with therapy duration ranging from 2 - 41 months. None had preceding history of ACS. One survey respondent reported asthma symptoms (wheezing, dry cough at night) in preceding 12 months and 1 reported passive tobacco exposure. None reported a prior asthma diagnosis. Of the 6 participants with PFT data, baseline percent-predicted values for IOS parameters R5 and R20 were 114.83 ± 22.37 and 97.83 ± 23.11 respectively. Baseline X5 (%pred) was 76.33 ± 48.59. DISCUSSION Our preliminary results show normal baseline airway function in this subset of young SCA patients, with R5 representing total airway resistance, and R20 representing resistance in large airways. Small airway function can be deduced from differences between R5 and R20. Airway resistance decreases with age, and early changes in small airway resistance can be seen in children with asthma and obstructive symptoms. Low frequency reactance serves as a measure of airway distensibility, especially in the distal airways. Therefore, conditions affecting lung elasticity would result in abnormal X5. Ongoing data collection and follow-up will help us study how airway function evolves in young children with SCA with or without underlying asthma. We will also assess the effects of Hydroxyurea and other disease-modifying therapies on airway function over time. Disclosures No relevant conflicts of interest to declare.

Bronchial thermoplasty increases airway volume measured by functional respiratory imaging

BackgroundThe purpose of this study was to use CT scanning with computational fluid dynamics to evaluate the mechanisms by which Bronchial Thermoplasty (BT) improves asthmatic symptoms.MethodsThe study was conducted in a university teaching hospital, experienced in performing BT. Imaging studies were performed before, and after, BT of the left lung, and prior to treatment of the right lung, which therefore acted as a control. On each occasion, two high-resolution CT scans were performed, one at full inspiration (TLC) and the other at Functional Residual Capacity (FRC). The study protocol was offered to 10 patients, all of whom met the definition of severe asthma, despite high dose inhaled corticosteroids and dual long acting bronchodilators.ResultsSignificant increases in airway luminal volume were observed on the treated side, compared with control, at both full inspiration (by 27%) and at FRC (by 17%). The ratio of distal airway volume to lung volume significantly increased on the treated side. The change in airway volume with inspiration from FRC increased by 48% on the treated side compared to 5% in the control lung, suggesting treatment increased airway distensibility. No effect was observed on airway wall thickness, nor air trapping. There was a trend towards correlation between the improvement in airway volume at TLC and improvement in symptoms.ConclusionThis study demonstrates that BT increases the luminal airway volume on the treated side compared to the control lung. We suggest that this is an important link between the airway smooth muscle atrophy demonstrated pathologically, and the improvement in symptoms observed clinically.

Pharyngeal distensibility during expiration is an independent predictor of the severity of obstructive sleep apnoea.

Pharyngeal distensibility and collapsibility reflect the passive properties of tissue in the airway, are an indicator of the ease with which an airway can be deformed and are related to the severity of obstructive sleep apnoea (OSA). During normal tidal respiration, the collapsibility of the pharynx during expiration is passive without confounding by neuromuscular activation that occurs during inspiration. We evaluated the distensibility and collapsibility of the upper airway in subjects with OSA during wakefulness using sophisticated dynamic computed tomography (CT) imaging. We hypothesized that the dynamic changes of the upper airway during expiration would be related to the severity of OSA. Twenty-three patients with OSA and eight normal subjects underwent simultaneous measurement of respiratory flow and airway calibre using ultrafast CT. The change in pharyngeal cross-sectional area divided by the change in concomitant flow (as distensibility or collapsibility) was measured and compared across different severities of OSA. The slope of this relationship between delta area and delta flow during expiration was significantly higher in severe OSA when compared with normal controls and mild-moderate OSA. Differences in airway distensibility or collapsibility between severity groups were significant in expiration but not in inspiration. Distensibility or collapsibility contributed most to the apnoea-hypopnoea index in regression modelling. Age, gender, and body mass index (BMI) were not significant independent predictors. Our study demonstrates that airway distensibility during the expiratory phase of awake respiration is correlated with the severity of OSA.

The independent effects of vitamin D deficiency and house dust mite exposure on lung function are sex-specific

Vitamin D deficiency is increasing around the world and has been associated with the development of asthma. This study aims to evaluate the effect of dietary vitamin D deficiency at different life stages on lung function using a murine model of allergic airways disease. BALB/c mice were challenged intranasally with HDM or saline alone for 10 days. Twenty four hours after the last challenge, mice were anesthetized and lung function was measured using the forced oscillation technique (FOT). Mice were euthanized for assessment of inflammation in the bronchoalveolar lavage (BAL) and total collagen content in lung homogenates by ELISA. Vitamin D deficiency impaired lung function in both male and female mice, increasing tissue damping and elastance, however had no effect on HDM induced inflammation. The impact of vitamin D deficiency was more evident in females. HDM also decreased airway distensibility, but only in females and this response was not altered by vitamin D deficiency. Our data suggest that vitamin D deficiency and HDM exposure have independent effects on lung mechanics and that females are more susceptible to these effects. Vitamin D deficiency may exacerbate lung function deficits by having a direct, but independent, effect on parenchymal mechanics.

The effect of disease and respiration on airway shape in patients with moderate persistent asthma.

Computational models of gas transport and aerosol deposition frequently utilize idealized models of bronchial tree structure, where airways are considered a network of bifurcating cylinders. However, changes in the shape of the lung during respiration affect the geometry of the airways, especially in disease conditions. In this study, the internal airway geometry was examined, concentrating on comparisons between mean lung volume (MLV) and total lung capacity (TLC). A set of High Resolution CT images were acquired during breath hold on a group of moderate persistent asthmatics at MLV and TLC after challenge with a broncho-constrictor (methacholine) and the airway trees were segmented and measured. The airway hydraulic diameter (Dh) was calculated through the use of average lumen area (Ai) and average internal perimeter (Pi) at both lung volumes and was found to be systematically higher at TLC by 13.5±9% on average, with the lower lobes displaying higher percent change in comparison to the lower lobes. The average internal diameter (Din) was evaluated to be 12.4±6.8% (MLV) and 10.8±6.3% (TLC) lower than the Dh, for all the examined bronchi, a result displaying statistical significance. Finally, the airway distensibility per bronchial segment and per generation was calculated to have an average value of 0.45±0.28, exhibiting high variability both between and within lung regions and generations. Mixed constriction/dilation patterns were recorded between the lung volumes, where a number of airways either failed to dilate or even constricted when observed at TLC. We conclude that the Dh is higher than Din, a fact that may have considerable effects on bronchial resistance or airway loss at proximal regions. Differences in caliber changes between lung regions are indicative of asthma-expression variability in the lung. However, airway distensibility at generation 3 seems to predict distensibility more distally.

Reproducibility of airway luminal size in asthma measured by HRCT.

Brown RH, Henderson RJ, Sugar EA, Holbrook JT, Wise RA, on behalf of the American Lung Association Airways Clinical Research Centers. Reproducibility of airway luminal size in asthma measured by HRCT. J Appl Physiol 123: 876-883, 2017. First published July 13, 2017; doi:10.1152/japplphysiol.00307.2017.-High-resolution CT (HRCT) is a well-established imaging technology used to measure lung and airway morphology in vivo. However, there is a surprising lack of studies examining HRCT reproducibility. The CPAP Trial was a multicenter, randomized, three-parallel-arm, sham-controlled 12-wk clinical trial to assess the use of a nocturnal continuous positive airway pressure (CPAP) device on airway reactivity to methacholine. The lack of a treatment effect of CPAP on clinical or HRCT measures provided an opportunity for the current analysis. We assessed the reproducibility of HRCT imaging over 12 wk. Intraclass correlation coefficients (ICCs) were calculated for individual airway segments, individual lung lobes, both lungs, and air trapping. The ICC [95% confidence interval (CI)] for airway luminal size at total lung capacity ranged from 0.95 (0.91, 0.97) to 0.47 (0.27, 0.69). The ICC (95% CI) for airway luminal size at functional residual capacity ranged from 0.91 (0.85, 0.95) to 0.32 (0.11, 0.65). The ICC measurements for airway distensibility index and wall thickness were lower, ranging from poor (0.08) to moderate (0.63) agreement. The ICC for air trapping at functional residual capacity was 0.89 (0.81, 0.94) and varied only modestly by lobe from 0.76 (0.61, 0.87) to 0.95 (0.92, 0.97). In stable well-controlled asthmatic subjects, it is possible to reproducibly image unstimulated airway luminal areas over time, by region, and by size at total lung capacity throughout the lungs. Therefore, any changes in luminal size on repeat CT imaging are more likely due to changes in disease state and less likely due to normal variability.NEW & NOTEWORTHY There is a surprising lack of studies examining the reproducibility of high-resolution CT in asthma. The current study examined reproducibility of airway measurements. In stable well-controlled asthmatic subjects, it is possible to reproducibly image airway luminal areas over time, by region, and by size at total lung capacity throughout the lungs. Therefore, any changes in luminal size on repeat CT imaging are more likely due to changes in disease state and less likely due to normal variability.

Assessment of Airway Distensibility by the Forced Oscillation Technique: Reproducible and Potentially Simplifiable.

A non-invasive index of airway distensibility is required to track airway remodeling over time. The forced oscillation technique (FOT) provides such an index by measuring the change in respiratory system conductance at 5 Hz over the corresponding change in lung volume (ΔGrs5/ΔVL). To become useful clinically, this method has to be reproducible and easy to perform. The series of breathing maneuvers required to measure distensibility would be greatly facilitated if the difficulty of breathing below functional residual capacity (FRC) could be precluded and the number of maneuvers could be reduced. The distensibility at lung volumes below FRC is also reduced by several confounders, suggesting that excluding data points below FRC should provide a better surrogate for airway remodeling. The objectives of this study were to investigate the reproducibility of airway distensibility measured by FOT and to assess whether the method could be simplified to increase feasibility. Distensibility was measured at three separate occasions in 13 healthy volunteers. At each visit, three deflationary maneuvers were performed, each consisting of tidal breathing from total lung capacity (TLC) to residual volume by slowly decreasing the end-expiratory volume on each subsequent breath. Distensibility was calculated by using either all data points from TLC to residual volume (RV) or only data points from TLC to FRC for either all three or only the first two deflationary maneuvers. Intra-class correlation coefficients (ICC) were used to assess reproducibility and Bland-Altman analyses were used to assess the level of agreement between the differently calculated values of distensibility. The results indicate that distensibility calculated using all data points is reproducible (ICC = 0.64). Using data points from TLC to FRC slightly improved reproducibility (ICC = 0.68) and increased distensibility by 19.4%, which was expected as distensibility above FRC should not be affected by confounders. Using only data points within the first two maneuvers did not affect reproducibility when tested between TLC and FRC (ICC = 0.66). We conclude that a valuable measure of airway distensibility could potentially be obtained with only two deflationary maneuvers that do not require breathing below FRC. This simplified method would increase feasibility without compromising reproducibility.

Acute administration of ivacaftor to people with cystic fibrosis and a G551D-CFTR mutation reveals smooth muscle abnormalities.

Airflow obstruction is common in cystic fibrosis (CF), yet the underlying pathogenesis remains incompletely understood. People with CF often exhibit airway hyperresponsiveness, CF transmembrane conductance regulator (CFTR) is present in airway smooth muscle (ASM), and ASM from newborn CF pigs has increased contractile tone, suggesting that loss of CFTR causes a primary defect in ASM function. We hypothesized that restoring CFTR activity would decrease smooth muscle tone in people with CF. To increase or potentiate CFTR function, we administered ivacaftor to 12 adults with CF with the G551D-CFTR mutation; ivacaftor stimulates G551D-CFTR function. We studied people before and immediately after initiation of ivacaftor (48 hours) to minimize secondary consequences of CFTR restoration. We tested smooth muscle function by investigating spirometry, airway distensibility, and vascular tone. Ivacaftor rapidly restored CFTR function, indicated by reduced sweat chloride concentration. Airflow obstruction and air trapping also improved. Airway distensibility increased in airways less than 4.5 mm but not in larger-sized airways. To assess smooth muscle function in a tissue outside the lung, we measured vascular pulse wave velocity (PWV) and augmentation index, which both decreased following CFTR potentiation. Finally, change in distensibility of <4.5-mm airways correlated with changes in PWV. Acute CFTR potentiation provided a unique opportunity to investigate CFTR-dependent mechanisms of CF pathogenesis. The rapid effects of ivacaftor on airway distensibility and vascular tone suggest that CFTR dysfunction may directly cause increased smooth muscle tone in people with CF and that ivacaftor may relax smooth muscle. This work was funded in part from an unrestricted grant from the Vertex Investigator-Initiated Studies Program.

Frictional resistance sheds light on the multicomponent nature of nasal obstruction: A combined in vivo and computational fluid dynamics study

Exploring nasal flow contributes to better understanding of pathophysiological functions of nasal cavities. We combined the rhinomanometry measurements of 11 patients and computational fluid dynamics (CFD) simulations in 3 nasal airway models to dissect the complex mechanisms that determine nasal flow obstruction: spatial complexity and pressure-dependent deformability of nasal airways. We quantified spatial complexity by calculating longitudinal variations of hydraulic diameter, perimeter and area of nasal cavities, and their impact on flow characteristics by examining the longitudinal variations of the kinetic energy coefficient and the kinetic to potential energy ratio. Airway distensibility variably affected in vivo pressure–flow relationships through the appearance of flow-limitation patterns characterized by maximum flow and/or flow plateau. We quantified deformability and spatial complexity effects on nasal airway resistance by normalizing all data with averaged reference parameters. The results show that discrepancies in nasal flow resistances reflect airway deformability and geometrical complexity, and thereby constitute a framework to better characterize nasal obstruction.

Airway Distensibility by HRCT in Asthmatics and COPD with Comparable Airway Obstruction

Introduction: Decreased airway distensibility (AD) in response to deep inspirations, as assessed by HRCT, has been associated with the severity of asthma and COPD. Aims: The current study was designed to compare the magnitude of AD by HRCT in individuals with asthma and COPD with comparable degrees of bronchial obstruction, and to explore factors that may influence it. Results: We enrolled a total of 12 asthmatics (M/F:7/5) and 8 COPD (7/1) with comparable degree of bronchial obstruction (FEV1% predicted mean±SEM: 69.1 ± 5.2% and 61.2 ± 5.0%, respectively; p = 0.31). Each subject underwent chest HRCT at FRC and at TLC. A total of 701 airways (range 20 to 38 airway per subject; 2.0 to 23.1 mm in diameter) were analyzed. AD did not differ between asthmatics and COPD (mean ± SEM: 14 ± 3.5% and 17 ± 4.3%, respectively; p = 0.58). In asthmatics, AD was significantly associated with FEV1% predicted (r2 = 0.45, p = 0.018). We found a significant correlation between the change in lung volume and the change in AD by HRCT (r2 = 0.64, p = 0.002). In COPD, we found significant correlations between AD and the RV% predicted (r2 = 0.51, p = 0.046) and the RV/TLC (r2 = 0.68, p = 0.01). Conclusions: AD was primarily affected by the dynamic ability to change lung volumes in asthmatics, and by static lung volumes in COPD.

Airway distensibility with lung inflation after allogeneic haematopoietic stem-cell transplantation

The ability to reverse induced-bronchoconstriction by deep-inhalation increases after allogeneic haematopoietic stem-cell transplantation (HSCT), despite a decreased total lung capacity (TLC). We hypothesized that this effect may be due to an increased airway distensibility with lung inflation, likely related to an increment in lung stiffness. We studied 28 subjects, 2 weeks before and 2 months after HSCT. Within-breath respiratory system conductance (Grs) at 5, 11 and 19Hz was measured by forced oscillation technique (FOT) at functional residual capacity (FRC) and TLC. Changes in conductance at 5Hz (Grs5) were related to changes in lung volume (ΔGrs5/ΔVL) to estimate airway distensibility. Grs at FRC showed a slight but significant increase at all forcing frequencies by approximately 12–16%. TLC decreased after HSCT whereas the ΔGrs5/ΔVL ratio became higher after than before HSCT and was positively correlated (R2=0.87) with lung tissue density determined by quantitative CT scanning.We conclude that airway caliber and distensibility with lung inflation are increased after HSCT. This effect seems to be related to an increase in lung stiffness and must be taken into account when interpreting lung function changes after HSCT.

Passive stiffness of airway smooth muscle: The next target for improving airway distensibility and treatment for asthma?

Reduced airway distensibility due to increased airway stiffness is a characteristic of asthma. Airway stiffness is determined by the property and structural organization of the various elements of the airway wall, and is often divided into active and passive components. Active stiffness is thought to be associated with activation of muscle cells in the airway wall. This component of stiffness can be inhibited when active force produced by the muscle is abolished. Passive stiffness, on the other hand, is thought to stem from non-muscle component of the airway wall, especially the collagen/elastin fibrous network of the extracellular matrix within which the muscle cells are embedded. In this brief review, the notion that passive stiffness is exclusively extracellular in origin is challenged. Recent evidence suggests that a substantial portion of the passive stiffness of an in vitro preparation of tracheal smooth muscle is calcium sensitive and is regulated by Rho-kinase, although the underlying mechanism and the details of regulation for the development of this intracellular passive stiffness are still largely unknown. To reduce airway stiffness different lines of attack must be tailored to different components of the stiffness. The regulatable passive stiffness is distinct from the relatively permanent stiffness of the extracellular matrix and the stiffness associated with active muscle contraction. To improve airway distensibility during asthma exacerbation, a comprehensive approach to reduce overall airway stiffness should therefore include a strategy for targeting the regulatable passive stiffness.

Association Between Airway Caliber Changes With Lung Inflation and Emphysema Assessed by Volumetric CT Scan in Subjects With COPD

An increase in airway caliber (airway distensibility) with lung inflation is attenuated in COPD. Furthermore, some subjects have a decrease in airway caliber with lung inflation. We aimed to test the hypothesis that airway caliber increases are lower in subjects with emphysema-predominant (EP) compared with airway-predominant (AP) CT scan subtypes. Additionally, we compared clinical and CT scan features of subjects with (airway constrictors) and without a decrease in airway caliber. Based on GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages and CT scan subtypes, we created a control group (n = 46) and the following matched COPD groups (n = 23 each): GOLD-2-AP, GOLD-2-EP, GOLD-4-AP, and GOLD-4-EP. From the CT scans of all 138 subjects, we measured emphysema, lung volumes, and caliber changes in the third and fourth airway generations of two bronchi. We expressed airway distensibility (ratio of airway lumen diameter change to lung volume change from end tidal breathing to full inspiration) as a global or lobar measure based on normalization by whole-lung or lobar volume changes. Global distensibility in the third and fourth airway generations was significantly lower in the GOLD-2-EP and GOLD-4-EP groups than in control subjects. In GOLD-2 subjects, lobar distensibility of the right-upper-lobe fourth airway generation was significantly lower in those with EP than in those with AP. In multivariate analysis, emphysema was an independent determinant of global and lobar airway distensibility. Compared with nonconstrictors, airway constrictors experienced more dyspnea, were more hyperinflated, and had a higher percentage of emphysema. Distensibility of large- to medium-sized airways is reduced in subjects with an EP CT scan subtype. Emphysema seems to alter airway-parenchyma interdependence. ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov.

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.

Evaluation of the trachea and intrathoracic airways by the acoustic reflection method in children with cystic fibrosis

Tracheomalacia has been observed in older patients with cystic fibrosis (CF). The acoustic reflection method (ARM) allows a noninvasive calculation of the longitudinal cross-sectional area of the trachea (MTAv) and the airway resistance (Raw). ARM measurements were performed in 20 CF children and 20 controls during spontaneous breathing (SB), forced inspiration (FI), and forced expiration (FE). The mean MTAv value was comparable in the CF patients and the control subjects during SB, FI, and FE. The Raw was also comparable during SB and FI. However, the Raw during FE was higher in the CF patients than in the control subjects (7.9±2.3 vs. 5.0±1.5 cm H2O l(-1) s(-1), respectively, p<0.001). In the patients with CF, only the Raw during FE correlated with the predicted forced expiratory volume in 1s (R2=0.37, p=0.04). The tracheal cross-sectional area measured by the ARM is normal in children with CF but the increase in Raw during FE suggests an increase in intrathoracic airway distensibility.

Influence of inspiration level on bronchial lumen measurements with computed tomography

Bronchial dimensions measured in CT images generally do not take inspiration level into consideration. However, some studies showed that the bronchial membrane is distensible with airway inflation. Therefore, re-examination of the elasticity of bronchi is needed. To assess the influence of respiration on bronchial lumen area (defined as distensibility) in different segmental bronchi and to explore the correlations between distensibility and both lung function and emphysema severity. In 44 subjects with COPD related to alpha-1-antitrypsin deficiency (AATD), bronchial lumen area was measured in CT images, acquired at different inspiration levels. Measurements were done at matched locations in one apical and two basal segmental airways (RB1, RB10 and LB10). Airway distensibility was calculated as lumen area difference divided by lung volume difference. Bronchial lumen area in the lower lobes (RB10 and LB10) correlated positively with FEV(1)%predicted (p=0.027 for RB10; and p=0.037 for LB10, respectively). Lumen area is influenced by respiration (p=0.006, p=0.045, and, p=0.005 for RB1, RB10 and LB10, respectively). Airway distensibility was different between upper and lower bronchi (p<0.001), but it was not correlated with lung function. Lumen area of third generation bronchi is dependent on inspiration level and this distensibility is different between bronchi in the upper and lower lobes. Therefore, changes in lumen area over time should be studied whilst accounting for the lung volume changes, in order to estimate the progression of bronchial disease while excluding the effects of hyperinflation.