Hyperresponsiveness: Relating the Intact Airway to the Whole Lung.

We relate changes of the airway wall to the response of the intact airway and the whole lung. We address how mechanical conditions and specific structural changes for an airway contribute to hyperresponsiveness resistant to deep inspiration. This review conveys that the origins of hyperresponsiveness do not devolve into an abnormality at single structural level but require examination of the complex interplay of all the parts.

A mechanical design principle for tissue structure and function in the airway tree.

With every breath, the dynamically changing mechanical pressures must work in unison with the cells and soft tissue structures of the lung to permit air to efficiently traverse the airway tree and undergo gas exchange in the alveoli. The influence of mechanics on cell and tissue function is becoming apparent, raising the question: how does the airway tree co-exist within its mechanical environment to maintain normal cell function throughout its branching structure of diminishing dimensions? We introduce a new mechanical design principle for the conducting airway tree in which mechanotransduction at the level of cells is driven to orchestrate airway wall structural changes that can best maintain a preferred mechanical microenvironment. To support this principle, we report in vitro radius-transmural pressure relations for a range of airway radii obtained from healthy bovine lungs and model the data using a strain energy function together with a thick-walled cylinder description. From this framework, we estimate circumferential stresses and incremental Young's moduli throughout the airway tree. Our results indicate that the conducting airways consistently operate within a preferred mechanical homeostatic state, termed mechanical homeostasis, that is characterized by a narrow range of circumferential stresses and Young's moduli. This mechanical homeostatic state is maintained for all airways throughout the tree via airway wall dimensional and mechanical relationships. As a consequence, cells within the airway walls throughout the airway tree experience similar oscillatory strains during breathing that are much smaller than previously thought. Finally, we discuss the potential implications of how the maintenance of mechanical homeostasis, while facilitating healthy tissue-level alterations necessary for maturation, may lead to airway wall structural changes capable of chronic asthma.

Elucidating the interaction between stretch and stiffness using an agent-based spring network model of progressive pulmonary fibrosis.

Pulmonary fibrosis is a deadly disease that involves the dysregulation of fibroblasts and myofibroblasts, which are mechanosensitive. Previous computational models have succeeded in modeling stiffness-mediated fibroblasts behaviors; however, these models have neglected to consider stretch-mediated behaviors, especially stretch-sensitive channels and the stretch-mediated release of latent TGF-ß. Here, we develop and explore an agent-based model and spring network model hybrid that is capable of recapitulating both stiffness and stretch. Using the model, we evaluate the role of mechanical signaling in homeostasis and disease progression during self-healing and fibrosis, respectively. We develop the model such that there is a fibrotic threshold near which the network tends towards instability and fibrosis or below which the network tends to heal. The healing response is due to the stretch signal, whereas the fibrotic response occurs when the stiffness signal overpowers the stretch signal, creating a positive feedback loop. We also find that by changing the proportional weights of the stretch and stiffness signals, we observe heterogeneity in pathological network structure similar to that seen in human IPF tissue. The system also shows emergent behavior and bifurcations: whether the network will heal or turn fibrotic depends on the initial network organization of the damage, clearly demonstrating structure's pivotal role in healing or fibrosis of the overall network. In summary, these results strongly suggest that the mechanical signaling present in the lungs combined with network effects contribute to both homeostasis and disease progression.

Factors determining airway caliber in asthma.

Airway hyperresponsiveness is a hallmark of asthma in which airways narrow excessively in response to an agonist, resulting in difficulty in breathing. Constriction of the smooth muscle that spirals around the airways is the principle cause of airway narrowing during an asthma attack. It is likely that several mechanisms are involved in the development of a hyperresponsive airway in asthma. In this review, we focus on the structural and functional aspects that govern the narrowing of a single airway within a lung, then we review the current understanding of how these factors become altered in a way that leads to the airway hyperresponsiveness observed in asthma. We first examine airway caliber as a simple equilibrium of forces favoring narrowing and the forces opposing this narrowing. We then review the role that the dynamic forces of tidal breathing and deep inspirations have across all length scales of the respiratory system; we describe an intriguing inconsistency that has arisen from these data. Finally, we examine the interaction between airway remodeling and inflammation and their roles in health and disease.

Predicting alveolar ventilation heterogeneity in pulmonary fibrosis using a non-uniform polyhedral spring network model.

Pulmonary Fibrosis (PF) is a deadly disease that has limited treatment options and is caused by excessive deposition and cross-linking of collagen leading to stiffening of the lung parenchyma. The link between lung structure and function in PF remains poorly understood, although its spatially heterogeneous nature has important implications for alveolar ventilation. Computational models of lung parenchyma utilize uniform arrays of space-filling shapes to represent individual alveoli, but have inherent anisotropy, whereas actual lung tissue is isotropic on average. We developed a novel Voronoi-based 3D spring network model of the lung parenchyma, the Amorphous Network, that exhibits more 2D and 3D similarity to lung geometry than regular polyhedral networks. In contrast to regular networks that show anisotropic force transmission, the structural randomness in the Amorphous Network dissipates this anisotropy with important implications for mechanotransduction. We then added agents to the network that were allowed to carry out a random walk to mimic the migratory behavior of fibroblasts. To model progressive fibrosis, agents were moved around the network and increased the stiffness of springs along their path. Agents migrated at various path lengths until a certain percentage of the network was stiffened. Alveolar ventilation heterogeneity increased with both percent of the network stiffened, and walk length of the agents, until the percolation threshold was reached. The bulk modulus of the network also increased with both percent of network stiffened and path length. This model thus represents a step forward in the creation of physiologically accurate computational models of lung tissue disease.

Multiscale stiffness of human emphysematous precision cut lung slices.

Emphysema is a debilitating disease that remodels the lung leading to reduced tissue stiffness. Thus, understanding emphysema progression requires assessing lung stiffness at both the tissue and alveolar scales. Here, we introduce an approach to determine multiscale tissue stiffness and apply it to precision-cut lung slices (PCLS). First, we established a framework for measuring stiffness of thin, disk-like samples. We then designed a device to verify this concept and validated its measuring capabilities using known samples. Next, we compared healthy and emphysematous human PCLS and found that the latter was 50% softer. Through computational network modeling, we discovered that this reduced macroscopic tissue stiffness was due to both microscopic septal wall remodeling and structural deterioration. Lastly, through protein expression profiling, we identified a wide spectrum of enzymes that can drive septal wall remodeling, which, together with mechanical forces, lead to rupture and structural deterioration of the emphysematous lung parenchyma.

A Personalized Spring Network Representation of Emphysematous Lungs From CT Images.

Emphysema is a progressive disease characterized by irreversible tissue destruction and airspace enlargement, which manifest as low attenuation area (LAA) on CT images. Previous studies have shown that inflammation, protease imbalance, extracellular matrix remodeling and mechanical forces collectively influence the progression of emphysema. Elastic spring network models incorporating force-based mechanical failure have been applied to investigate the pathogenesis and progression of emphysema. However, these models were general without considering the patient-specific information on lung structure available in CT images. The aim of this work was to develop a novel approach that provides an optimal spring network representation of emphysematous lungs based on the apparent density in CT images, allowing the construction of personalized networks. The proposed method takes into account the size and curvature of LAA clusters on the CT images that correspond to a pre-stressed condition of the lung as opposed to a naïve method that excludes the effects of pre-stress. The main findings of this study are that networks constructed by the new method 1) better preserve LAA cluster sizes and their distribution than the naïve method; and 2) predict different course of emphysema progression compared to the naïve method. We conclude that our new method has the potential to predict patient-specific emphysema progression which needs verification using clinical data.

Structure-function relations in an elastase-induced mouse model of emphysema.

Emphysema is a progressive disease characterized by the destruction of peripheral airspaces and subsequent decline in lung function. However, the relation between structure and function during disease progression is not well understood. The objective of this study was to assess the time course of the structural, mechanical, and remodeling properties of the lung in mice after elastolytic injury. At 2, 7, and 21 days after treatment with porcine pancreatic elastase, respiratory impedance, the constituents of lung extracellular matrix, and histological sections of the lung were evaluated. In the control group, no changes were observed in the structural or functional properties, whereas, in the treatment group, the respiratory compliance and its variability significantly increased by Day 21 (P < 0.001), and the difference in parameters decreased with increasing positive end-expiratory pressure. The heterogeneity of airspace structure gradually increased over time. Conversely, the relative amounts of elastin and type I collagen exhibited a peak (P < 0.01) at Day 2, but returned to baseline levels by Day 21. Structure-function relations manifested themselves in strong correlations between compliance parameters and both mean size and heterogeneity of airspace structure (r(2) > 0.9). Similar relations were also obtained in a network model of the parenchyma in which destruction was based on the notion that mechanical forces contribute to alveolar wall rupture. We conclude that, in a mouse model of emphysema, progressive decline in lung function is sensitive to the development of airspace heterogeneity governed by local, mechanical, force-induced failure of remodeled collagen.

Airway resistance at maximum inhalation as a marker of asthma and airway hyperresponsiveness.

BACKGROUND: Asthmatics exhibit reduced airway dilation at maximal inspiration, likely due to structural differences in airway walls and/or functional differences in airway smooth muscle, factors that may also increase airway responsiveness to bronchoconstricting stimuli. The goal of this study was to test the hypothesis that the minimal airway resistance achievable during a maximal inspiration (R(min)) is abnormally elevated in subjects with airway hyperresponsiveness. METHODS: The R(min) was measured in 34 nonasthmatic and 35 asthmatic subjects using forced oscillations at 8 Hz. R(min) and spirometric indices were measured before and after bronchodilation (albuterol) and bronchoconstriction (methacholine). A preliminary study of 84 healthy subjects first established height dependence of baseline R(min) values. RESULTS: Asthmatics had a higher baseline R(min) % predicted than nonasthmatic subjects (134 ± 33 vs. 109 ± 19 % predicted, p = 0.0004). Sensitivity-specificity analysis using receiver operating characteristic curves indicated that baseline R(min) was able to identify subjects with airway hyperresponsiveness (PC20 < 16 mg/mL) better than most spirometric indices (Area under curve = 0.85, 0.78, and 0.87 for R(min) % predicted, FEV1 % predicted, and FEF25-75 % predicted, respectively). Also, 80% of the subjects with baseline R(min) < 100% predicted did not have airway hyperresponsiveness while 100% of subjects with R(min) > 145% predicted had hyperresponsive airways, regardless of clinical classification as asthmatic or nonasthmatic. CONCLUSIONS: These findings suggest that baseline R(min), a measurement that is easier to perform than spirometry, performs as well as or better than standard spirometric indices in distinguishing subjects with airway hyperresponsiveness from those without hyperresponsive airways. The relationship of baseline R(min) to asthma and airway hyperresponsiveness likely reflects a causal relation between conditions that stiffen airway walls and hyperresponsiveness. In conjunction with symptom history, R(min) could provide a clinically useful tool for assessing asthma and monitoring response to treatment.

Inflation instability in the lung: an analytical model of a thick-walled alveolus with wavy fibres under large deformations.

Inflation of hollow elastic structures can become unstable and exhibit a runaway phenomenon if the tension in their walls does not rise rapidly enough with increasing volume. Biological systems avoid such inflation instability for reasons that remain poorly understood. This is best exemplified by the lung, which inflates over its functional volume range without instability. The goal of this study was to determine how the constituents of lung parenchyma determine tissue stresses that protect alveoli from instability-related overdistension during inflation. We present an analytical model of a thick-walled alveolus composed of wavy elastic fibres, and investigate its pressure-volume behaviour under large deformations. Using second-harmonic generation imaging, we found that collagen waviness follows a beta distribution. Using this distribution to fit human pressure-volume curves, we estimated collagen and elastin effective stiffnesses to be 1247 kPa and 18.3 kPa, respectively. Furthermore, we demonstrate that linearly elastic but wavy collagen fibres are sufficient to achieve inflation stability within the physiological pressure range if the alveolar thickness-to-radius ratio is greater than 0.05. Our model thus identifies the constraints on alveolar geometry and collagen waviness required for inflation stability and provides a multiscale link between alveolar pressure and stresses on fibres in healthy and diseased lungs.

Tracking respiratory mechanics around natural breathing rates via variable ventilation.

Measuring respiratory resistance and elastance as a function of time, tidal volume, respiratory rate, and positive end-expiratory pressure can guide mechanical ventilation. However, current measurement techniques are limited since they are assessed intermittently at non-physiological frequencies or involve specialized equipment. To this end, we introduce ZVV, a practical approach to continuously track resistance and elastance during Variable Ventilation (VV), in which frequency and tidal volume vary from breath-to-breath. ZVV segments airway pressure and flow recordings into individual breaths, calculates resistance and elastance for each breath, bins them according to frequency or tidal volume and plots the results against bin means. ZVV's feasibility was assessed clinically in five human patients with acute lung injury, experimentally in five mice ventilated before and after lavage injury, and computationally using a viscoelastic respiratory model. ZVV provided continuous measurements in both settings, while the computational study revealed <2% estimation errors. Our findings support ZVV as a feasible technique to assess respiratory mechanics under physiological conditions. Additionally, in humans, ZVV detected a decrease in resistance and elastance with time by 12.8% and 6.2%, respectively, suggesting that VV can improve lung recruitment in some patients and can therefore potentially serve both as a dual diagnostic and therapeutic tool.

Probing airway conditions governing ventilation defects in asthma via hyperpolarized MRI image functional modeling.

Image functional modeling (IFM) has been introduced as a method to simultaneously synthesize imaging and mechanical data with computational models to determine the degree and location of airway constriction in asthma. Using lung imaging provided by hyperpolarized (3)He MRI, we advanced our IFM method to require matching not only to ventilation defect location but to specific ventilation throughout the lung. Imaging and mechanical data were acquired for four healthy and four asthmatic subjects pre- and postbronchial challenge. After provocation, we first identified maximum-size airways leading exclusively to ventilation defects and highly constricted them. Constriction patterns were then found for the remaining airways to match mechanical data. Ventilation images were predicted for each pattern, and visual and statistical comparisons were done with measured data. Results showed that matching of ventilation defects requires severe constriction of small airways. The mean constriction of such airways leading to the ventilation defects needed to be 70-80% rather than fully closed. Also, central airway constriction alone could not account for dysfunction seen in asthma, so small airways must be involved.

Maintenance of airway caliber in isolated airways by deep inspiration and tidal strains.

Deep inspirations (DIs) are large periodic breathing maneuvers that regulate airway caliber and prevent airway obstruction in vivo. This study characterized the intrinsic response of the intact airway to DI, isolated from parenchymal attachments and other in vivo interactions. Porcine isolated bronchial segments were constricted with carbachol and subjected to transmural pressures of 5-10 cmH2O at 0.25 Hz (tidal breathing) interspersed with single DIs of amplitude 5-20 cmH2O, 5-30 cmH2O, or 5-40 cmH2O (6-s duration) or DI of amplitude 5-30 cmH2O (30-s duration). Tidal breathing was ceased after DI in a subset of airways and in control airways in which no DI was performed. Luminal cross-sectional area was measured using a fiber-optic endoscope. Bronchodilation by DI was amplitude dependent; 5-20 cmH2O DIs produced less dilation than 5-30 cmH2O and 5-40 cmH2O DIs (P=0.003 and 0.012, respectively). Effects of DI duration were not significant (P=0.182). Renarrowing after DI followed a monoexponential decay function to pre-DI airway caliber with time constants between 27.4+/-4.3 and 36.3+/-6.9 s. However, when tidal breathing was ceased after DI, further bronchoconstriction occurred within 30s. This response was identical in both the presence and absence of DI (P=0.919). We conclude that the normal bronchodilatory response to DI occurs as a result of the direct mechanical effects of DI on activated ASM in the airway wall. Further bronchoconstriction occurs by altering the airway wall stress following DI, demonstrating the importance of continual transient strains in maintaining airway caliber.

Respiratory impedance measurements for assessment of lung mechanics: focus on asthma.

This review discusses the history and current state of the art of the forced oscillation technique (FOT) to measure respiratory impedance. We focus on how the FOT and its interaction with models have emerged as a powerful method to extract out not only clinically relevant information, but also to advance insight on the mechanisms and structures responsible for human lung diseases, especially asthma. We will first provide a short history of FOT for basic clinical assessment either directly from the data or in concert with lumped element models to extract out specific effective properties. We then spend several sections on the more exciting recent advances of FOT to probe the relative importance of tissue versus airway changes in disease, the impact of the disease on heterogeneous lung function, and the relative importance of small airways via synthesis of FOT with imaging. Most recently, the FOT approach has been able to directly probe airway caliber in humans and the distinct airway properties of asthmatics that seem to be required for airway hyperresponsiveness. We introduce and discuss the mechanism and clinical implications of this approach, which may be substantial for treatment assessment. Finally, we highlight important future directions for the FOT, particularly its use to probe specific lung components (e.g., isolated airways, isolated airway smooth muscle, etc.) and relate such data to the whole lung. The intent is to substantially advance an integrated understanding of structure-function relationships in the lung.

Comparison of a micro-electro-mechanical system airflow sensor with the pneumotach in the forced oscillation technique.

PURPOSE: This study supports the use of thin-film micro-electro-mechanical system (MEMS) airflow sensors in the forced oscillation technique. MATERIALS AND METHODS: The study employed static testing using air flow standards and computer-controlled sound attenuations at 8 Hz. Human feasibility studies were conducted with a testing apparatus consisting of a pneumotach and thin-film MEMS air flow sensors in series. Short-time Fourier transform spectra were obtained using SIGVIEW software. RESULTS: Three tests were performed, and excellent correlations were observed between the probes. The thin-film MEMS probe showed superior sensitivity to higher frequencies up to 200 Hz. CONCLUSION: The results suggest that lower-cost thin-film MEMS can be used for forced oscillation technique applications (including home care devices) that will benefit patients suffering from pulmonary diseases such as asthma, COPD, and cystic fibrosis.

Effects of heterogeneities on the partitioning of airway and tissue properties in normal mice.

We measured the mechanical properties of the respiratory system of C57BL/6 mice using the optimal ventilation waveform method in closed- and open-chest conditions at different positive end-expiratory pressures. The tissue damping (G), tissue elastance (H), airway resistance (Raw), and hysteresivity were obtained by fitting the impedance data to three different models: a constant-phase model by Hantos et al. (Hantos Z, Daroczy B, Suki B, Nagy S, Fredberg JJ. J Appl Physiol 72: 168-178, 1992), a heterogeneous Raw model by Suki et al. (Suki B, Yuan H, Zhang Q, Lutchen KR. J Appl Physiol 82: 1349-1359, 1997), and a heterogeneous H model by Ito et al. (Ito S, Ingenito EP, Arold SP, Parameswaran H, Tgavalekos NT, Lutchen KR, Suki B. J Appl Physiol 97: 204-212, 2004). Both in the closed- and open-chest conditions, G and hysteresivity were the lowest and Raw the highest in the heterogeneous Raw model, and G and H were the largest in the heterogeneous H model. Values of G, Raw, and hysteresivity were significantly higher in the closed-chest than in the open-chest condition. However, H was not affected by the conditions. When the tidal volume of the optimal ventilation waveform was decreased from 8 to 4 ml/kg in the closed-chest condition, G and hysteresivity significantly increased, but there were smaller changes in H or Raw. In summary, values of the obtained mechanical properties varied among these models, primarily due to heterogeneity. Moreover, the mechanical parameters were significantly affected by the chest wall and tidal volume in mice. Contribution of the chest wall and heterogeneity to the mechanical properties should be carefully considered in physiological studies in which partitioning of airway and tissue properties are attempted.

Dynamic lung mechanics in late-stage emphysema before and after lung volume reduction surgery.

This study evaluated the effects of lung volume reduction surgery (LVRS) on the heterogeneity of lung function in awake, late-stage emphysema patients with measurements taken before and after full recovery from LVRS. We assessed standard clinical measures of lung function and functional heterogeneity in six awake, late-stage emphysema patients before and 6 months after LVRS. Functional heterogeneity was quantified by measuring dynamic inspiratory resistance (R(L)(insp)) and elastance (E(L)(insp)) over a frequency range that included normal breathing ( approximately 0.33-8 Hz). Since LVRS involves targeted resection of emphysematous regions of the lung, we hypothesized that emphysema patients would be functionally more homogeneous post-LVRS. We also compared our measures of functional heterogeneity with indices of anatomic heterogeneity and severity using high-resolution computed tomography (HRCT). After LVRS, 6 min walk distance increased by 22% (940+/-91 versus 1158+/-299, p=0.031) and recoil pressure at TLC increased (9.0+/-2.0 versus 14+/-5, p=0.031), but changes in R(L)(insp) and E(L)(insp) varied greatly between subjects. A measure of anatomic severity quantified using HRCT positively correlated with airway resistance (r(s)=0.89, p=0.048). These results suggest that subjects with more severe disease as assessed by HRCT criteria had reduced overall effective airway caliber consequent to active airway constriction, reduced parenchymal tethering, and/or loss of parallel lung units. Furthermore, LVRS may not necessarily improve lung function via a substantial reduction in mechanical heterogeneity.

The role of heterogeneity in asthma: a structure-to-function perspective.

A number of methods have evolved through the years in probing the dysfunction that impacts mechanics and ventilation in asthma. What has been consistently found is the notion of heterogeneity that is not only captured in the frequency dependence of lung mechanics measurements but also rendered on imaging as patchy diffuse areas of ventilation defects. The degree of heterogeneity has been linked to airway hyperresponsiveness, a hallmark feature of asthma. How these heterogeneous constriction patterns lead to functional impairment in asthma have only been recently explored using computational airway tree models. By synthesizing measurements of lung mechanics and advances in imaging, computational airway tree models serve as a powerful engine to accelerate our understanding of the physiologic changes that occur in asthma. This review will be focused on the current state of investigational work on the role of heterogeneity in asthma, specifically exploring the structural and functional relationships.

Spatial distribution of airway wall displacements during breathing and bronchoconstriction measured by ultrasound elastography using finite element image registration.

With every breath, the airways within the lungs are strained. This periodic stretching is thought to play an important role in determining airway caliber in health and disease. Particularly, deep breaths can mitigate excessive airway narrowing in healthy subjects, but this beneficial effect is absent in asthmatics, perhaps due to an inability to stretch the airway smooth muscle (ASM) embedded within an airway wall. The heterogeneous composition throughout an airway wall likely modulates the strain felt by the ASM but the magnitude of ASM strain is difficult to measure directly. In this study, we optimized a finite element image registration method to measure the spatial distribution of displacements and strains throughout an airway wall during pressure inflation within the physiological breathing range before and after induced narrowing with acetylcholine (ACh). The method was shown to be repeatable, and displacements estimated from different image sequences of the same deformation agreed to within 5.3µm (0.77%). We found the magnitude and spatial distribution of displacements were radially and longitudinally heterogeneous. The region in the middle layer of the airway experienced the largest radial strain due to a transmural pressure (Ptm) increase simulating tidal breathing and a deep inspiration (DI), while the region containing the ASM (i.e., closest to the lumen) strained least. During induced narrowing with ACh, we observed temporal longitudinal heterogeneity of the airway wall. After constriction, the displacements and strain are much smaller than the relaxed airway and the pattern of strains changed, suggesting the airway stiffened heterogeneously.

New perspectives on the mechanical basis for airway hyperreactivity and airway hypersensitivity in asthma.

We revisit the airway wall model of Lambert et. al. (Lambert RK, Wiggs BR, Kuwano K, Hogg JC, and Pare PD. J Appl Physiol 74: 2771-2781, 1993). We examine in detail the notion of a general airway bistability such that the airway lumen can suddenly decrease from a relatively open to a relatively closed condition without needing additional increase in active airway smooth muscle (ASM) tension during the stimulation. The onset of this bistability is an emergent consequence of the balance of forces associated with airway wall properties, parenchymal tissue properties, maximum lung elastic recoil, and the maximum stress that the ASM can generate. In healthy lungs, we find that all these properties reside in conditions that largely prevent the emergence of the bistability even during maximum ASM stimulation. In asthmatic airways, however, the airway wall and ASM remodeling conditions can tip the balance so as to promote the onset of the bistability at a lower dose of ASM stimulation (enhanced sensitivity) and then work to amplify the maximum constriction reached by each airway (enhanced reactivity). Hence, a larger fraction of asthmatic airways can display overall airway hyperreactivity. Simulations studies examine the role of increasing ASM maximum tension, airway wall stiffening, reduced lung volume, and decreased parenchymal tethering. Results predict that the single most important factor causing this airway hyperreactivity is amplified maximum ASM tension and not a thickening of the airway wall per se.