Acinar Airways Research Articles

Augmenting regional and targeted delivery in the pulmonary acinus using magnetic particles.

BackgroundIt has been hypothesized that by coupling magnetic particles to inhaled therapeutics, the ability to target specific lung regions (eg, only acinar deposition), or even more so specific points in the lung (eg, tumor targeting), can be substantially improved. Although this method has been proven feasible in seminal in vivo studies, there is still a wide gap in our basic understanding of the transport phenomena of magnetic particles in the pulmonary acinar regions of the lungs, including particle dynamics and deposition characteristics.MethodsHere, we present computational fluid dynamics-discrete element method simulations of magnetically loaded microdroplet carriers in an anatomically inspired, space-filling, multi-generation acinar airway tree. Breathing motion is modeled by kinematic sinusoidal displacements of the acinar walls, during which droplets are inhaled and exhaled. Particle dynamics are governed by viscous drag, gravity, and Brownian motion as well as the external magnetic force. In particular, we examined the roles of droplet diameter and volume fraction of magnetic material within the droplets under two different breathing maneuvers.Results and discussionOur results indicate that by using magnetic-loaded droplets, 100% of the particles that enter are deposited in the acinar region. This is consistent across all particle sizes investigated (ie, 0.5–3.0 µm). This is best achieved through a deep inhalation maneuver combined with a breath-hold. Particles are found to penetrate deep into the acinus and disperse well, while the required amount of magnetic material is maintained low (<2.5%). Although particles in the size range of ~90–500 nm typically show the lowest deposition fractions, our results suggest that this feature could be leveraged to augment targeted delivery.

Bronchodilator responsiveness of peripheral airways in smokers with normal spirometry.

Cigarette smoke exposure increases airway smooth muscle (ASM) contractility. Abnormalities in peripheral airway function in smokers with normal spirometry could be due to the effects of ASM tone. We aimed to determine the contribution of ASM tone to peripheral airway function in smokers with normal spirometry from the response to bronchodilator (BD). Ventilation heterogeneity in peripheral conductive (Scond) and acinar (Sacin) airways were measured in 50 asymptomatic smokers and 20 never-smokers using multiple breath nitrogen washout, before and 20 min after inhalation of 200 µg salbutamol and 80 µg ipratropium bromide. Z-scores were calculated to define abnormality in Sacin and Scond. Nineteen smokers had abnormal Sacin, and 12 had abnormal Scond; 7 had abnormalities in both. After BD, Sacin improved in smokers with normal Sacin (6.5 ± 15.9%, P = 0.02), smokers with abnormal Sacin (9.2 ± 16.9%, P = 0.03) and in control subjects (11.7 ± 18.2%, P = 0.01), with no differences in improvements between groups. Sacin remained abnormal in 15/19 smokers and their post-BD values correlated with smoking exposure (r = 0.53, P = 0.02). After BD, Scond improved in smokers with abnormal Scond (28.3 ± 15.9%, P = 0.002) and normalized in 9/12 subjects, but not in those with normal Scond (0.25 ± 32.7%, P = 0.44) or control subjects (-1.7 ± 21.2%, P = 0.64). In smokers with normal spirometry, abnormal conductive airway function could be attributed to increased bronchomotor tone. In contrast, bronchomotor tone in acinar airways is unaffected by smoking and functional abnormality. There may be different causal mechanisms underlying acinar and conductive airway abnormalities in smokers with normal spirometry.

Modeling particle deposition in the Balb/c mouse respiratory tract

The mouse lung has become increasingly important as a surrogate of the human lung for inhalation risk assessment. The main structural difference between the two lungs is that the airway branching of the human lung is relatively symmetric, while that of the mouse lung is distinctly asymmetric or monopodial. The objectives of this study were to develop a stochastic, asymmetric particle deposition model for the Balb/c mouse and to compare predicted deposition patterns with those in the human lung. The asymmetric bronchial airway geometry of the Balb/c mouse was based on a statistical analysis of several lung casts, while, in the absence of pertinent data, the asymmetric acinar airway geometry was represented by an allometrically scaled-down version of the rat acinar region, assuming structural similarity. Deposition of inhaled particles in nasal, bronchial and acinar airways for mouse-specific breathing conditions was computed with the Monte Carlo deposition model IDEAL-mouse. While total deposition for submicron particles decreases with increasing diameter in a fashion similar to that in the human lung, the effect of inhalability and nasal pre-filtration significantly reduces total deposition in the mouse lung for particles with diameters greater than about 3 μm. The most notable difference between submicron particle deposition in the mouse and human airways is the shift of the deposition distribution from distal airway generations in the human lung to upper airway generations in the mouse lung. However, if plotted as a function of airway diameter, both deposition distributions are quite similar, indicating that airway diameter may be a more appropriate morphometric parameter for extrapolation purposes than airway generation.

Computational Models of Inhalation Therapy in Early Childhood: Therapeutic Aerosols in the Developing Acinus.

Inhalation therapy targeted to the deep alveolated regions holds great promise, specifically in pediatric populations. Yet, inhalation devices and medical protocols are overwhelmingly derived from adult guidelines, with very low therapeutic efficiency in young children. During the first years of life, airway remodeling and changing ventilation patterns are anticipated to alter aerosol deposition with underachieving outcomes in infants. As past research is still overwhelmingly focused on adults or limited to models of upper airways, a fundamental understanding of inhaled therapeutic transport and deposition in the acinar regions is needed to shed light on delivering medication to the developing alveoli. Using computational fluid dynamics (CFD), we simulated inhalation maneuvers in anatomically-inspired models of developing acinar airways, covering the distinct phases of lung development, from underdeveloped, saccular pulmonary architectures in infants, to structural changes in toddlers, ultimately mimicking space-filling morphologies of a young child, representing scaled-down adult lungs. We model aerosols whose diameters span the range of sizes acknowledged to reach the alveolar regions and examine the coupling between morphological changes, varying ventilation patterns and particle characteristics on deposition outcomes. Spatial distributions of deposited particles point to noticeable changes in the patterns of aerosol deposition with age, in particular in the youngest age group examined (3 month). Total deposition efficiency, as well as deposition dispersion, vary not only with the phases of lung development but also and critically with aerosol diameter. Given the various challenges when prescribing inhalation therapy to a young infant, our findings underline some mechanistic aspects to consider when targeting medication to the developing alveoli. Not only does the intricate coupling between acinar morphology and ventilation patterns need to be considered, but the physical properties (i.e., aerodynamic size) of therapeutic aerosols also closely affect the anticipated success rates of the inhaled medication.

Diffusion lung imaging with hyperpolarized gas MRI.

Lung imaging using conventional 1 H MRI presents great challenges because of the low density of lung tissue, lung motion and very fast lung tissue transverse relaxation (typical T2 * is about 1-2 ms). MRI with hyperpolarized gases (3 He and 129 Xe) provides a valuable alternative because of the very strong signal originating from inhaled gas residing in the lung airspaces and relatively slow gas T2 * relaxation (typical T2 * is about 20-30 ms). However, in vivo human experiments should be performed very rapidly - usually during a single breath-hold. In this review, we describe the recent developments in diffusion lung MRI with hyperpolarized gases. We show that a combination of the results of modeling of gas diffusion in lung airspaces and diffusion measurements with variable diffusion-sensitizing gradients allows the extraction of quantitative information on the lung microstructure at the alveolar level. From an MRI scan of less than 15 s, this approach, called in vivo lung morphometry, allows the provision of quantitative values and spatial distributions of the same physiological parameters as measured by means of 'standard' invasive stereology (mean linear intercept, surface-to-volume ratio, density of alveoli, etc.). In addition, the approach makes it possible to evaluate some advanced Weibel parameters characterizing lung microstructure: average radii of alveolar sacs and ducts, as well as the depth of their alveolar sleeves. Such measurements, providing in vivo information on the integrity of pulmonary acinar airways and their changes in different diseases, are of great importance and interest to a broad range of physiologists and clinicians. We also discuss a new type of experiment based on the in vivo lung morphometry technique combined with quantitative computed tomography measurements, as well as with gradient echo MRI measurements of hyperpolarized gas transverse relaxation in the lung airspaces. Such experiments provide additional information on the blood vessel volume fraction, specific gas volume and length of the acinar airways, and allow the evaluation of lung parenchymal and non-parenchymal tissue. Copyright © 2015 John Wiley & Sons, Ltd.

Acinar ventilation heterogeneity in COPD relates to diffusion capacity, resistance and reactance

The aim of this study was to investigate heterogenic ventilation in the acinar (Sacin) and conductive (Scond) airways of patients with varying chronic obstructive pulmonary disease (COPD) severity and how these relates to advanced lung function parameters, primarily measured by impulse oscillometry (IOS). A secondary aim was to investigate the effects of a short acting beta2-agonist and a muscarinic antagonist on the heterogenic ventilation.Eleven never smoking controls, 12 smoking controls, and 57 COPD patients (7 GOLD 1, 25 GOLD 2, 14 GOLD 3 and 11 GOLD 4) performed flow-volume spirometry, IOS, body plethysmography, single breath carbon monoxide diffusion, and N2-multiple breath washout. Six smoking controls and 13 of the COPD patients also performed double reversibility test by using salbutamol and its combination with ipratropium.Sacin was significantly higher in GOLD 2–4 compared to never smoking controls and smoking controls, but showed similar levels in GOLD 3 and 4. A factor analysis identified 4 components consisting of; 1) IOS parameters, 2) volume parameters, 3) diffusion parameters, Sacin and some IOS parameters and 4) Scond with central obstruction/air trapping. Salbutamol and its combination with ipratropium had no effect on Sacin and Scond.Increased Sacin in COPD was strongly related to diffusion capacity and lung volumes, but also weakly to resistance and reactance, showing a link between ventilation heterogeneity in the acinar airways and parameters measured by IOS.

Experimental evidence of age-related adaptive changes in human acinar airways.

The progressive decline of lung function with aging is associated with changes in lung structure at all levels, from conducting airways to acinar airways (alveolar ducts and sacs). While information on conducting airways is becoming available from computed tomography, in vivo information on the acinar airways is not conventionally available, even though acini occupy 95% of lung volume and serve as major gas exchange units of the lung. The objectives of this study are to measure morphometric parameters of lung acinar airways in living adult humans over a broad range of ages by using an innovative MRI-based technique, in vivo lung morphometry with hyperpolarized (3)He gas, and to determine the influence of age-related differences in acinar airway morphometry on lung function. Pulmonary function tests and MRI with hyperpolarized (3)He gas were performed on 24 healthy nonsmokers aged 19-71 years. The most significant age-related difference across this population was a 27% loss of alveolar depth, h, leading to a 46% increased acinar airway lumen radius, hence, decreased resistance to acinar air transport. Importantly, the data show a negative correlation between h and the pulmonary function measures forced expiratory volume in 1 s and forced vital capacity. In vivo lung morphometry provides unique information on age-related changes in lung microstructure and their influence on lung function. We hypothesize that the observed reduction of alveolar depth in subjects with advanced aging represents a remodeling process that might be a compensatory mechanism, without which the pulmonary functional decline due to other biological factors with advancing age would be significantly larger.

Characterization of acinar airspace involvement in asthmatic patients by using inert gas washout and hyperpolarized 3helium magnetic resonance

The multiple-breath inert gas washout parameter acinar ventilation heterogeneity (Sacin) is thought to be a marker of acinar airway involvement but has not been validated by using quantitative imaging techniques in asthmatic patients. We aimed to use hyperpolarized (3)He diffusion magnetic resonance at multiple diffusion timescales and quantitative computed tomographic (CT) densitometry to determine the nature of acinar airway involvement in asthmatic patients. Thirty-seven patients with asthma and 17 age-matched healthy control subjects underwent spirometry, body plethysmography, multiple-breath inert gas washout (with the tracer gas sulfur hexafluoride), and hyperpolarized (3)He diffusion magnetic resonance. Asubset of asthmatic patients (n= 27) underwent quantitative CT densitometry. Ninety-four percent (16/17) of patients with an increased Sacin had Global Initiative for Asthma treatment step 4 to 5 asthma, and 13 of 17 had refractory disease. The apparent diffusion coefficient (ADC) of (3)He at 1 second was significantly higher in patients with Sacin-high asthma compared with that in healthy control subjects (0.024 vs 0.017, P< .05). Sacin correlated strongly with ADCs at 1 second (R= 0.65, P< .001) but weakly with ADCs at 13 ms (R= 0.38, P< .05). ADCs at both 13 ms and 1 second correlated strongly with the mean lung density expiratory/inspiratory ratio, a CT marker of expiratory air trapping (R= 0.77, P< .0001 for ADCs at 13 ms; R=0.72,P<.001 for ADCs at 1 second). Sacin is associated with alterations in long-range diffusion within the acinar airways and gas trapping. The precise anatomic nature and mechanistic role in patients with severe asthma requires further evaluation.

Association between peripheral airway function and neutrophilic inflammation in asthma.

Small airway dysfunction is associated with asthma severity and control, but its association with airway inflammation is unknown. The aim was to determine the association between sputum inflammatory cells and the site of small airway dysfunction, measured by multiple breath nitrogen washout in convection-dependent (Scond) and more peripheral diffusion-dependent (Sacin) airways. Fifty-three (20-67 years) subjects with asthma on inhaled corticosteroid (ICS) treatment were characterized by spirometry, Scond, Sacin and induced sputum differential counts. %Predicted values for Scond and Sacin were calculated from published reference equations to adjust for the effects of age. Univariate correlations were assessed using the Spearman test. Multivariate linear regressions were performed to account for potential confounders, including age, gender, disease duration, body mass index and ICS dose. Sacin (%predicted) correlated significantly with neutrophil% (rs = 0.33, P = 0.02), ICS dose (rs = -0.28, P = 0.04) and age (rs = 0.27, P = 0.05). In multivariate analysis, Sacin related only to neutrophil% (adjusted R(2) = 0.18, P = 0.001). Scond (%predicted) correlated significantly only with eosinophil% (rs = 0.39, P = 0.004). There was a trend for a negative relationship with ICS dose (rs = -0.26, P = 0.06). In multivariate analysis, Scond related to eosinophil% and ICS dose independently (adjusted R(2) = 0.12, P = 0.02). Acinar and conductive airway dysfunction is associated with different inflammatory profiles in asthmatic airways, independently of the effects of age and disease duration. The association between acinar airway dysfunction and neutrophilic airway inflammation may have implications for asthma treatment.

Irreversible acinar airway abnormality in well controlled asthma

Even in stable asthma patients, acinar ventilation distribution can be abnormal, and we aimed to specifically maximize its reversibility by switching patients from a standard inhaled corticosteroid (iCS) to a fine particle iCS formulation. For this prospective double-blind double-dummy randomized study, 66 stable asthma patients under maintenance iCS (equivalent budesonide ≤ 800 μg/day) were screened for abnormal baseline acinar ventilation heterogeneity (Sacin). After a 3-week run-in period, 35 eligible patients were randomized to fine particle beclomethasone (HFA-BDP; Qvar Autohaler) or to budesonide (DPI-BUD; Pulmicort Turbohaler). Asthma Control Test (ACT) score and various lung function indices reflecting the small airways were obtained at baseline, after 6 and 12 weeks. Thirty one patients [age:52 ± 17(SD) years; FEV1:76 ± 19(SD)%pred] completed the study (DPI-BUD:n = 16; HFA-BDP:n = 15). After 6 and 12 weeks, there were no significant changes in acinar or conductive ventilation heterogeneity, nor in mid-expiratory flow, RV/TLC, closing capacity, impulse oscillometry indices (resistance, reactance), bronchial NO production or alveolar NO, in either treatment arm. Asthma control was maintained in both arms. In stable asthma patients with small airways dysfunction under maintenance therapy, there is a residual functional abnormality in the lung periphery which is probably not eosinophilic in origin and cannot be normalized with the iCS formulations under study. ISRCTN17195095.

Effects of pollen season on central and peripheral nitric oxide production in subjects with pollen asthma

Pollen exposure of allergic subjects with asthma causes increased nitric oxide (NO) in exhaled air (FENO) suggestive of increased airway inflammation. It is, however, unclear to what extent NO production in peripheral airways and alveoli are involved. The aim of the present investigation was to analyze the relationship between central and peripheral components of FENO to clarify the distribution of pollen induced inflammation in asthma. 13 pollen allergic non-smoking subjects with mild-intermittent asthma and 12 healthy non-smoking control subjects were examined with spirometry and FENO at flows between 50 and 270mL/s during and out of pollen season. Spirometry was normal and unaffected by season in subjects with asthma as well as controls. Out of season subjects with asthma had significantly higher FENO, elevated airway production (JáwNO) and preacinar/acinar production (CANO) than controls. Pollen exposure resulted in significantly increased FENO and JáwNO but not CANO. FENO among controls were not affected by season. Individual results showed, however, that CANO increased substantially in a few subjects with asthma. The increased CANO in subjects with asthma may be explained by increased NO production in preacinar/acinar airways and back diffusion towards the alveoli. The findings may indicate that subjects with allergic asthma have airway inflammation without alveolar involvement outside the pollen season and pollen exposure causes a further increase of airway inflammation and in a few subjects obstruction of intra acinar airways causing impeded back diffusion. Increased NO production in central airways, unassociated with airway obstruction could be an alternative explanation. These effects were not disclosed by spirometry.

Efficient estimation of the total number of acini in adult rat lung.

Pulmonary airways are subdivided into conducting and gas‐exchanging airways. An acinus is defined as the small tree of gas‐exchanging airways, which is fed by the most distal purely conducting airway. Until now a dissector of five consecutive sections or airway casts were used to count acini. We developed a faster method to estimate the number of acini in young adult rats. Right middle lung lobes were critical point dried or paraffin embedded after heavy metal staining and imaged by X‐ray micro‐CT or synchrotron radiation‐based X‐rays tomographic microscopy. The entrances of the acini were counted in three‐dimensional (3D) stacks of images by scrolling through them and using morphological criteria (airway wall thickness and appearance of alveoli). Segmentation stopper were placed at the acinar entrances for 3D visualizations of the conducting airways. We observed that acinar airways start at various generations and that one transitional bronchiole may serve more than one acinus. A mean of 5612 (±547) acini per lung and a mean airspace volume of 0.907 (±0.108) μL per acinus were estimated. In 60‐day‐old rats neither the number of acini nor the mean acinar volume did correlate with the body weight or the lung volume.

Probing lung microstructure with hyperpolarized 3He gradient echo MRI.

In this paper we demonstrate that gradient echo MRI with hyperpolarized (3)He gas can be used for simultaneously extracting in vivo information about lung ventilation properties, alveolar geometrical parameters, and blood vessel network structure. This new approach is based on multi-gradient-echo experimental measurements of hyperpolarized (3)He gas MRI signal from human lungs and a proposed theoretical model of this signal. Based on computer simulations of (3)He atoms diffusing in the acinar airway tree in the presence of an inhomogeneous magnetic field induced by the susceptibility differences between lung tissue (alveolar septa, blood vessels) and lung airspaces, we derive analytical expressions relating the time-dependent MR signal to the geometrical parameters of acinar airways and the blood vessel network. Data obtained on eight healthy volunteers are in good agreement with literature values. This information is complementary to the information obtained by means of the in vivo lung morphometry technique with hyperpolarized 3He diffusion MRI previously developed by our group, and opens new opportunities to study lung microstructure in health and disease.

Abnormal Small Airways Function in Children With Mild Asthma

Small airways disease is a hallmark in adults with persistent asthma, but little is known about small airways function in children with mild asthma and normal spirometry. We assessed ventilation heterogeneity, a marker of small airways function, with an easy tidal breath single-breath washout (SBW) technique in school-aged children with mild asthma and normal FEV1 and healthy age-matched control subjects. The primary outcome was the double-tracer gas phase III slope (SDTG), an index of ventilation heterogeneity in acinar airways derived from the tidal double-tracer gas SBW test. The second outcome was the nitrogen phase III slope (SN2), an index of global ventilation heterogeneity derived from the tidal nitrogen SBW test using pure oxygen. Triplicate SBW and spirometry tests were performed in healthy children (n=35) and children with asthma (n=31) at baseline and in children with asthma after bronchodilation. Acinar (SDTG) but not global (SN2) ventilation heterogeneity was significantly increased in asthma despite normal FEV1. Of the 31 children with asthma, abnormal results were found for SDTG (≤-2 z scores) in 11; forced expiratory flow, midexpiratory phase (FEF25%-75%) in three; and FEV1 in zero. After bronchodilation, SDTG, SN2, FEF25%-75%, and FEV1 significantly changed (mean [95% CI] change from baseline, 36% [15%-56%], 38% [18%-58%], 17% [9-25%], and 6% [3%-9%], respectively). Abnormal acinar ventilation heterogeneity in one-third of the children suggests that small airways disease may be present despite rare and mild asthma symptoms and normal spirometry. The easy tidal SBW technique has considerable potential as a clinical and research outcome in children with asthma.

Response to Commentary on “The influence of lung airways branching structure and diffusion time on measurements and models of short-range 3He gas MR diffusion”

Our extensive investigation of the cylinder model theory through numerical modelling and purpose-designed experiments has demonstrated that it does produce inaccurate estimates of airway dimensions at all diffusion times currently used. This is due to a variety of effects: incomplete treatment of non-Gaussian effects, finite airway size, branching geometry, background susceptibility gradients and diffusion time dependence of the 3He MR diffusion behaviour in acinar airways. The cylinder model is a good starting point for the development of a lung morphometry technique from 3He diffusion MR but its limitations need to be understood and documented in the interest of reliable clinical interpretation.

S120 Hyperpolarised 3HE diffusion MRI and multiple breath inert gas washout in patients with asthma

BackgroundMultiple breath inert gas washout (MBW) is a technique for detecting abnormal ventilation distribution in patients with asthma and other airway diseases. Scond and Sacin are measures of convective-dependent inhomogeneity...

Positive Expiratory Pressure via Mask Does Not Improve Ventilation Inhomogeneity More than Huffing and Coughing in Individuals with Stable Chronic Obstructive Pulmonary Disease and Chronic Sputum Expectoration

Background: Positive expiratory pressure (PEP) has been used to promote airway clearance in individuals with chronic obstructive pulmonary disease (COPD) for many years; however, its mechanism of action and benefits are unclear. Previous authors have suggested that PEP improves collateral ventilation via changes in lung volumes. Objectives: It was the aim of this study to determine whether PEP improves ventilation inhomogeneity more than controlled huffing and coughing in individuals with stable COPD. Methods: Twelve participants with COPD (mean forced expiratory volume in 1 s 45% predicted) and chronic sputum expectoration performed PEP therapy (10-20 cm H₂O) or controlled huffing and coughing in random order on alternate study days with a 48-hour washout. Measures of acinar and conductive airway ventilation (S_acin, S_cond), lung volumes, spirometry and sputum wet weight were recorded before, immediately after and 90 min following treatment. Ease of expectoration [visual analogue scale (VAS)] and oxyhaemoglobin saturation were assessed immediately following treatment. Results: There were no significant differences between the effect of either test condition at any time point for any test parameter. Mean S_acin immediately following PEP and control conditions was 0.465 and 0.438 litre^-1, respectively (p = 0.45 for comparison between conditions) and mean S_cond was 0.042 and 0.039 litre^-1 (p = 0.55). PEP therapy did not significantly enhance total mean sputum expectoration compared to controlled huffing and coughing (7.06 vs. 6.15 g; p = 0.51) and did not improve ease of expectoration (VAS PEP 4.8 cm vs. control 4.1 cm; p = 0.53). Conclusion: Any therapeutic benefits of PEP in individuals with COPD and chronic sputum expectoration are unlikely to be mediated by improvements in ventilation or lung volumes.

Probing lung microstructure with hyperpolarized noble gas diffusion MRI: theoretical models and experimental results

The introduction of hyperpolarized gases ((3)He and (129)Xe) has opened the door to applications for which gaseous agents are uniquely suited-lung MRI. One of the pulmonary applications, diffusion MRI, relies on measuring Brownian motion of inhaled hyperpolarized gas atoms diffusing in lung airspaces. In this article we provide an overview of the theoretical ideas behind hyperpolarized gas diffusion MRI and the results obtained over the decade-long research. We describe a simple technique based on measuring gas apparent diffusion coefficient (ADC) and an advanced technique, in vivo lung morphometry, that quantifies lung microstructure both in terms of Weibel parameters (acinar airways radii and alveolar depth) and standard metrics (mean linear intercept, surface-to-volume ratio, and alveolar density) that are widely used by lung researchers but were previously available only from invasive lung biopsy. This technique has the ability to provide unique three-dimensional tomographic information on lung microstructure from a less than 15 s MRI scan with results that are in good agreement with direct histological measurements. These safe and sensitive diffusion measurements improve our understanding of lung structure and functioning in health and disease, providing a platform for monitoring the efficacy of therapeutic interventions in clinical trials.

Effect of methacholine on peripheral lung mechanics and ventilation heterogeneity in asthma

The forced oscillation technique (FOT) and multiple-breath nitrogen washout (MBNW) are noninvasive tests that are potentially sensitive to peripheral airways, with MBNW indexes being especially sensitive to heterogeneous changes in ventilation. The objective was to study methacholine-induced changes in the lung periphery of asthmatic patients and determine how changes in FOT variables of respiratory system reactance (Xrs) and resistance (Rrs) and frequency dependence of resistance (Rrs5-Rrs19) can be linked to changes in ventilation heterogeneity. The contributions of air trapping and airway closure, as extreme forms of heterogeneity, were also investigated. Xrs5, Rrs5, Rrs19, Rrs5-Rrs19, and inspiratory capacity (IC) were calculated from the FOT. Ventilation heterogeneity in acinar and conducting airways, and trapped gas (percent volume of trapped gas at functional residual capacity/vital capacity), were calculated from the MBNW. Measurements were repeated following methacholine. Methacholine-induced airway closure (percent change in forced vital capacity) and hyperinflation (change in IC) were also recorded. In 40 mild to moderate asthmatic patients, increase in Xrs5 after methacholine was predicted by increases in ventilation heterogeneity in acinar airways and forced vital capacity (r(2) = 0.37, P < 0.001), but had no correlation with ventilation heterogeneity in conducting airway increase or IC decrease. Increases in Rrs5 and Rrs5-Rrs19 after methacholine were not correlated with increases in ventilation heterogeneity, trapped gas, hyperinflation, or airway closure. Increased reactance in asthmatic patients after methacholine was indicative of heterogeneous changes in the lung periphery and airway closure. By contrast, increases in resistance and frequency dependence of resistance were not related to ventilation heterogeneity or airway closure and were more indicative of changes in central airway caliber than of heterogeneity.

The influence of lung airways branching structure and diffusion time on measurements and models of short-range 3He gas MR diffusion

Hyperpolarized 3He diffusion experiments have been shown to be sensitive to changes in acinar structure due to emphysematous lung disease. Extracting quantitative information about lung microstructure from the diffusion signal is complicated due its dependence on a number of factors including diffusion time and the complex branching acinar geometry. A theoretical model (cylinder model) has been proposed as a means of estimating acinar airway dimensions from measured diffusivities. This model assumes that the effects of acinar branching geometry and finite airway length upon 3He diffusion behaviour are negligible. In this work, we use finite element simulations of diffusion in a model of branching alveolar ducts to investigate in detail the effects of acinar branching structure and finite airway length on short-range 3He diffusion measurements. The results show that branching effects have a significant influence upon 3He diffusivity, even at short diffusion times. The expressions of the cylinder model theory do not account for significant dependences upon diffusion time, branching geometry and airway length, as a consequence of the oversimplified geometrical model used. The effect of diffusion time on 3He ADC was also investigated through experiments with healthy human volunteers. The results demonstrate that the cylinder model can produce inaccurate estimates of the airway dimensions as a consequence of incompletely accounting for the diffusion-time dependence in the model equations and confirmed the predicted limitations of the cylinder model for reliable lung morphometry measurements. The results and models presented in this work may help in the development of a more realistic theoretical framework for ‘in vivo lung morphometry’ using 3He diffusion MR.