Adipose tissue in the small airways: How much is enough to drive functional changes?

Obesity is a contributing factor to asthma severity; while it has long been understood that obesity is related to greater asthma burden, the mechanisms though which this occurs have not been fully elucidated. One common explanation is that obesity mechanically reduces lung volume through accumulation of adipose tissue external to the thoracic cavity. However, it has been recently demonstrated that there is substantial adipose tissue within the airway wall itself, and that the presence of adipose tissue within the airway wall is related to body mass index. This suggests the possibility of an additional mechanism by which obesity may worsen asthma, namely by altering the behaviour of the airways themselves. To this end, we modify Anafi & Wilson's classic model of the bistable terminal airway to incorporate adipose tissue within the airway wall in order to answer the question of how much adipose tissue would be required in order to drive substantive functional changes. This analysis suggests that adipose tissue within the airway wall on the order of 1%-2% of total airway cross-sectional area could be sufficient to drive meaningful changes, and further that these changes may interact with volume effects to magnify the overall burden.

Bronchial Thermoplasty Improves Ventilation Heterogeneity Measured by Functional Respiratory Imaging in Severe Asthma.

Purpose: Bronchial thermoplasty (BT) is a bronchoscopic intervention for the treatment of severe asthma. Despite demonstrated symptomatic benefit, the underlying mechanisms by which this is achieved remain uncertain. We hypothesize that the effects of BT are driven by improvements in ventilation heterogeneity as assessed using functional respiratory imaging (FRI). Patient and Methods: Eighteen consecutive patients with severe asthma who underwent clinically indicated BT were recruited. Patients were assessed at baseline, 4-week after treatment of the left lung, and 12-month after treatment of the right lung. Data collected included short-acting beta-agonist (SABA) and oral prednisolone (OCS) use, asthma control questionnaire (ACQ-5) and exacerbation history. Patients also underwent lung function tests and chest computed tomography. Ventilation parameters including interquartile distance (IQD; measure of ventilation heterogeneity) were derived using FRI. Results: 12 months after BT, significant improvements were seen in SABA and OCS use, ACQ-5, and number of OCS-requiring exacerbations. Apart from pre-bronchodilator FEV1, no other significant changes were observed in lung function. Ventilation heterogeneity significantly improved after treatment of the left lung (0.18 ± 0.04 vs 0.20 ± 0.04, p=0.045), with treatment effect persisting up to 12 months later (0.18 ± 0.05 vs 0.20 ± 0.04, p=0.028). Ventilation heterogeneity also improved after treatment of the right lung, although this did not reach statistical significance (0.18 ± 0.05 vs 0.19 ± 0.04, p=0.06). Conclusion: Clinical benefits after BT are accompanied by improvements in ventilation heterogeneity, advancing our understanding of its mechanism of action. Beyond BT, FRI has the potential to be expanded into other clinical applications.

Which airways should we treat? Structure-function relationships and estimation of the singular input modes from the forward model alone.

Structure-function relationships occur throughout the sciences. Motivated by optimization of such systems, we develop a framework for estimating the input modes from the singular value decomposition from the action of the forward operator alone. These can then be used to determine the input (structure) changes, which induce the largest output (function) changes. The accuracy of the estimate is determined by reference to the method of snapshots. The proposed method is demonstrated on several example problems, and finally used to approximate the optimal airway treatment set for a problem in respiratory physiology.

Heterogeneity of Airway Smooth Muscle Remodeling in Asthma.

Rationale: Ventilatory defects in asthma are heterogeneous and may represent the distribution of airway smooth muscle (ASM) remodeling. Objectives: To determine the distribution of ASM remodeling in mild-severe asthma. Methods: The ASM area was measured in nine airway levels in three bronchial pathways in cases of nonfatal (n = 30) and fatal asthma (n = 20) and compared with control cases without asthma (n = 30). Correlations of ASM area within and between bronchial pathways were calculated. Asthma cases with 12 large and 12 small airways available (n = 42) were classified on the basis of the presence or absence of ASM remodeling (more than two SD of mean ASM area of control cases, n = 86) in the large or small airway or both. Measurements and Main Results: ASM remodeling varied widely within and between cases of nonfatal asthma and was more widespread and confluent and more marked in fatal cases. There were weak correlations of ASM between levels within the same or separate bronchial pathways; however, predictable patterns of remodeling were not observed. Using mean data, 44% of all asthma cases were classified as having no ASM remodeling in either the large or small airway despite a three- to 10-fold increase in the number of airways with ASM remodeling and 81% of asthma cases having ASM remodeling in at least one large and small airway. Conclusions: ASM remodeling is related to asthma severity but is heterogeneous within and between individuals and may contribute to the heterogeneous functional defects observed in asthma. These findings support the need for patient-specific targeting of ASM remodeling.

Growth of the airway smooth muscle layer from late gestation to childhood is mediated initially by hypertrophy and subsequently hyperplasia.

BACKGROUND AND OBJECTIVE: The airway smooth muscle (ASM) layer thickens during development. Identifying the mechanism(s) for normal structural maturation of the ASM reveals pathways susceptible to disease processes. This study characterized thickening of the ASM layer from foetal life to childhood and elucidated the underlying mechanism in terms of hypertrophy, hyperplasia and extracellular matrix (ECM) deposition. METHODS: Airways from post-mortem cases were examined from seven different age groups: 22-24 weeks gestation, 25-31 weeks gestation, term (37-41 weeks gestation), <0.5 year, 0.5-1 year, 2-5 years and 6-10 years. The ASM layer area (thickness), the number and size of ASM cells and the volume fraction of ECM were assessed by planimetry and stereology. RESULTS: From late gestation to the first year of life, normalized ASM thickness more than doubled as a result of ASM hypertrophy. Thereafter, until childhood, the ASM layer grew in proportion to airway size, which was mediated by ASM hyperplasia. Hypertrophy and hyperplasia of ASM were accompanied by a proportional change in ECM such that the broad composition of the ASM layer was constant across age groups. CONCLUSION: These data suggest that the mechanisms of ASM growth from late gestation to childhood are temporally decoupled, with early hypertrophy and subsequent proliferation. We speculate that the developing airway is highly susceptible to ASM thickening in the first year of life and that the timing of an adverse event will determine structural phenotype.

Requirements and limitations of imaging airway smooth muscle throughout the lung in vivo.

Clinical visualization and quantification of the amount and distribution of airway smooth muscle (ASM) in the lungs of individuals with asthma has major implications for our understanding of airway wall remodeling as well as treatments targeted at the ASM. This paper theoretically investigates the feasibility of quantifying airway wall thickness (focusing on the ASM) throughout the lung in vivo by means of bronchoscopic polarization-sensitive optical coherence tomography (PS-OCT). Using extensive human biobank data from subjects with and without asthma in conjunction with a mathematical model of airway compliance, we define constraints that airways of various sizes pose to any endoscopic imaging technique and how this is impacted by physiologically relevant processes such as constriction, inflation and deflation. We identify critical PS-OCT system parameters and pinpoint parts of the airway tree that are conducive to successful quantification of ASM. We further quantify the impact of breathing and ASM contraction on the measurement error and recommend strategies for standardization and normalization.

Response of individual airways in vivo to bronchial thermoplasty.

Bronchial thermoplasty (BT) is a treatment for moderate-to-severe asthma, which generally improves quality-of-life scores but not conventional measures of lung function. Newer methodologies have begun to demonstrate the underlying physiological changes and elucidate the mechanism of action. We postulated that systematic, computed tomography (CT)-based assessment of the response of individual airways to BT is feasible, and our aim was to determine the distribution of these responses and the relationship with airway size. Twenty patients meeting the European Respiratory Society/American Thoracic Society (ERS/ATS) definition of severe asthma underwent BT and assessment including CT, Asthma Control Questionnaire (ACQ), and spirometry. Treatment was structured so that the left and right lungs are treated sequentially with a midtreatment assessment providing an internal control. Pairs of CT scans were analyzed using a new semiautomatic processing algorithm that matched individual segmented airways for quantitative comparison. Cross-sectional airway lumen area from matched airway pairs in treated lungs increased on average by 6.4% after BT (P < 0.02) but showed no change in the untreated lung. Matched airway length was also unchanged. Breakdown by airway size showed amplified response in more distal airways, with the smallest quintile of measured airways dilating by 13.2% (P < 0.001). ACQ improved from 3.5 ± 0.9 to 1.9 ± 1.2 (P < 0.001). These data show that the response to BT in individual airways can be assessed by CT and that dilation is heterogeneous and predominant in distal compared with proximal airways. A CT-based approach may further our understanding of the physiological changes in BT and aid in the development of refined and personalized versions of the therapy.NEW & NOTEWORTHY CT scanning was used to evaluate the response of individual airways in patients undergoing bronchial thermoplasty. Airways dilated after treatment by 6.4% on average with substantial heterogeneity and a greater response in the most distal airways measured.

The effect of bronchial thermoplasty on airway volume measured 12†months post-procedure.

Bronchial thermoplasty induces atrophy of the airway smooth muscle layer, but the mechanism whereby this improves patient health is unclear. In this study, we use computed tomography (CT) to evaluate the effects of bronchial thermoplasty on airway volume 12 months post-procedure. 10 consecutive patients with severe asthma were evaluated at baseline by the Asthma Control Questionnaire (ACQ), and high-resolution CT at total lung capacity (TLC) and functional residual capacity (FRC). The CT protocol was repeated 4 weeks after the left lung had been treated by bronchial thermoplasty, but prior to right lung treatment, and then again 12 months after both lungs were treated. The CT data were also used to model the implications of including the right middle lobe (RML) in the treatment field. The mean patient age was 62.7±7.7 years and forced expiratory volume in 1 s (FEV1) 42.9±11.5% predicted. 12 months post-bronchial-thermoplasty, the ACQ improved, from 3.4±1.0 to 1.5±0.9 (p=0.001), as did the frequency of oral steroid-requiring exacerbations (p=0.008). The total airway volume increased 12 months after bronchial thermoplasty in both the TLC (p=0.03) and the FRC scans (p=0.02). No change in airway volume was observed in the untreated central airways. In the bronchial thermoplasty-treated distal airways, increases in airway volume of 38.4±31.8% at TLC (p=0.03) and 30.0±24.8% at FRC (p=0.01) were observed. The change in distal airway volume was correlated with the improvement in ACQ (r=-0.71, p=0.02). Modelling outputs demonstrated that treating the RML conferred no additional benefit. Bronchial thermoplasty induces long-term increases in airway volume, which correlate with symptomatic improvement.

Generalized distribution-moment approximation for kinetic theories of muscular contraction.

Crossbridge theory, originally developed by A.F. Huxley more than 60 years ago to explain the behaviour of striated muscle, has since evolved to encompass many different muscle types and behaviours. The governing equations are generally linear hyperbolic partial differential equations, or systems thereof, describing the evolution of probability density functions. Importantly, the macroscopic behaviour is often described not in terms of these distributions themselves, but rather in terms of their first few moments. Motivated by this observation, G.I. Zahalak proposed the distribution-moment approximation to describe the evolution of these moments alone. That work assumed a Gaussian underlying distribution, and was observed to provide reasonable approximation of the moments despite the non-Gaussian character of the underlying distribution. Here we propose two variations on the distribution-moment approximation: (i) a generalized N-moment approximation based on the Gram-Charlier A-series representation, and (ii) perhaps the simplest possible approximation based on a uniform distribution. Study of these variations suggests that Zahalak's original contention may be correct: approximations based on higher order moments may not be worth their complexity. However, the simplified variation shows more promise, with similar accuracy in approximating the moments yet reduced complexity in the derivation of the approximation.

Asthma: Pharmacological degradation of the airway smooth muscle layer.

Asthma: A disease characterised by excessive and variable airway narrowing, and pathologies of inflammation and remodelling, particularly thickening of the airway smooth muscle (ASM). Treatment approaches dilate narrowed airways and reduce inflammation; however, remodelling seems largely neglected. This review considers the evolution of remodelling in asthma and whether conventional hypotheses that inflammation causes ASM thickening has mislead the medical community into thinking that anti-inflammatories will remedy this ASM defect. There is instead reasonable evidence that ASM thickening occurs independently of inflammation, such that therapies should employ strategies to directly modify ASM growth. Lessons have been learned from the use of untargeted bronchial thermoplasty and there should also be consideration of pharmacological therapies to ablate ASM. We discuss several new approaches to target ASM remodelling in asthma. A major current obstacle is our inability to image the ASM layer and assess treatment response. In this regard, polarisation-sensitive optical coherence tomography offers future promise.

Phenotype- and patient-specific modelling in asthma: Bronchial thermoplasty and uncertainty quantification.

Theoretical models can help to overcome experimental limitations to better our understanding of lung physiology and disease. While such efforts often begin in broad terms by determining the effect of a disease process on a relevant biological output, more narrowly defined simulations may inform clinical practice. Two such examples are phenotype-specific and patient-specific models, the former being specific to a group of patients with common characteristics, and the latter to an individual patient, in view of likely differences (heterogeneity) between patients. However, in order for such models to be useful, they must be sufficiently accurate, given the available data about the specific characteristics of the patient. We show that, for asthma in particular, this approach is promising: phenotype-specific targeting may be an effective way of selecting patients for treatment based on their airway remodelling phenotype, and patient-specific targeting may be viable with the use of a clinically-plausible dataset. Specifically we consider asthma and its treatment by bronchial thermoplasty, in which the airway smooth muscle layer is directly targeted by thermal energy. Patient-specific and phenotype-specific models in this context are considered using a combination of biobank data from ex vivo tissue samples, CT imaging, and optical coherence tomography which allows more detailed resolution of the airway wall structures.

Pharmacological ablation of the airway smooth muscle layer-Mathematical predictions of functional improvement in asthma.

Airway smooth muscle (ASM) plays a major role in acute airway narrowing and reducing ASM thickness is expected to attenuate airway hyper-responsiveness and disease burden. There are two therapeutic approaches to reduce ASM thickness: (a) a direct approach, targeting specific airways, best exemplified by bronchial thermoplasty (BT), which delivers radiofrequency energy to the airway via bronchoscope; and (b) a pharmacological approach, targeting airways more broadly. An example of the less well-established pharmacological approach is the calcium-channel blocker gallopamil which in a clinical trial effectively reduced ASM thickness; other agents may act similarly. In view of established anti-proliferative properties of the macrolide antibiotic azithromycin, we examined its effects in naive mice and report a reduction in ASM thickness of 29% (p < .01). We further considered the potential functional implications of this finding, if it were to extend to humans, by way of a mathematical model of lung function in asthmatic patients which has previously been used to understand the mechanistic action of BT. Predictions show that pharmacological reduction of ASM in all airways of this magnitude would reduce ventilation heterogeneity in asthma, and produce a therapeutic benefit similar to BT. Moreover there are differences in the expected response depending on disease severity, with the pharmacological approach exceeding the benefits provided by BT in more severe disease. Findings provide further proof of concept that pharmacological targeting of ASM thickness will be beneficial and may be facilitated by azithromycin, revealing a new mode of action of an existing agent in respiratory medicine.

Airway remodelling with spatial correlations: Implications for asthma pathogenesis.

Airway remodelling is a cardinal feature of asthma in which airways undergo structural changes - in particular, increased airway smooth muscle mass and total airway wall area. Remodelling has long been thought to have functional consequences in asthma due to geometric effects that can increase airway narrowing and luminal occlusion. Prior studies have examined the distribution of remodelling between and within patients, but none have yet considered the possibility for spatial correlations in airway remodelling. That is, is remodelling clustered locally, or interrelated along proximal and distal locations of the bronchial tree? In view of recent interest regarding airway remodelling produced by mechanical stimuli, we developed a mathematical model to examine whether spatial correlations in airway remodelling could arise due to cycles of bronchoconstriction and mechanotransduction. Further, we compared modelling predictions to the spatial distribution of airway remodelling in lungs from subjects with and without asthma. Results indicate that spatial correlations in airway remodelling do exist in vivo, and cycles of bronchoconstriction and mechanotransduction are one plausible mechanism for their origin. These findings offer insights into the evolution of airway remodelling in asthma, which may inform strategies for treatment and prevention.

Understanding the mechanism of bronchial thermoplasty using airway volume assessed by computed tomography.

High-resolution CT assessment of airway volumes after bronchial thermoplasty (BT), together with model predictions regarding the efficacy and underlying mechanism of action of the treatment, combine to help to elucidate the underlying mechanism of BT http://bit.ly/2WPHY6y.