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Airway-parenchymal interdependence in the lung slice
Abstract
The explanted lung slice has become a popular in vitro system for studying how airways contract. Because the forces of airway-parenchymal interdependence are such important modulators of airway narrowing, it is of significant interest to understand how the parenchyma around a constricting airway in a lung slice behaves. We have previously shown that the predictions of the 2-dimensional distortion field around a constricting airway are substantially different depending on whether the parenchyma is modeled as an elastic continuum versus a network of hexagonally arranged springs, which raises the question as to which model best explains the lung slice. We treated lung slices with methacholine and then followed the movement of a set of parenchymal landmarks around the airway as it narrowed. The resulting parenchymal displacement field was compared to the displacement fields predicted by the continuum and hexagonal spring network models. The predictions of the continuum model were much closer to the measured data than were those of the hexagonal spring network model, suggesting that the parenchyma in the lung slice behaves like an elastic continuum rather than a network of discrete springs. This may be because the alveoli of the lung slice are filled with agarose in order to provide structural stability, causing the parenchyma in the slice to act like a true mechanical continuum. How the air-filled parenchyma in the intact lung behave in vivo remains an open question.
... These datasets, however, contain a rich source of additional dynamic and spatial biomechanical data that heretofore have not been investigated. For example, a limited number of studies have utilized the PCLS to examine the mechanical interdependence between the constricting airway and the surrounding parenchyma (Adler et al., 1998;Brook et al., 2010;Ma et al., 2013). However, beyond the immediate vicinity of the contracting airway, the parenchyma contains other airways and arterioles which may themselves contract or even passively contribute to the effective material properties of surrounding tissues. ...
... To date, most studies using PCLS have simply monitored airway caliber. Although, a few studies have extracted some detailed strain data from PCLS (Adler et al., 1998;Brook et al., 2010;Ma et al., 2013), these have been obtained by tracking specific landmarks in the tissue. In this study, by contrast, we present a computational strain-mapping tool that is able to characterize heretofore inaccessible mechanical events that bear directly upon the physiology of airway narrowing. ...
... Injection of gelatin into the vasculature during lung harvesting may prevent this phenomenon (Perez and Sanderson, 2005;Wang et al., 2008). Additionally the presence of agarose in the parenchymal spaces will contribute viscoelastic components not ordinarily present in vivo (Brook et al., 2010;Ma et al., 2013) thus modifying effective mechanical properties and dynamic response of the parenchymal tissue. It is also vitally important to ensure that the edges of the PCLS during the contraction experiment are held down to prevent sliding of the slice and therefore control the boundary conditions of the system. ...
The precision-cut lung slice (PCLS) is a powerful tool for studying airway reactivity, but biomechanical measurements to date have largely focused on changes in airway caliber. Here we describe an image processing tool that reveals the associated spatio-temporal changes in airway and parenchymal strains. Displacements of sub-regions within the PCLS are tracked in phase-contrast movies acquired after addition of contractile and relaxing drugs. From displacement maps, strains are determined across the entire PCLS or along user-specified directions. In a representative mouse PCLS challenged with 10⁻⁴M methacholine, as lumen area decreased, compressive circumferential strains were highest in the 50 μm closest to the airway lumen while expansive radial strains were highest in the region 50–100 μm from the lumen. However, at any given distance from the airway the strain distribution varied substantially in the vicinity of neighboring small airways and blood vessels. Upon challenge with the relaxant agonist chloroquine, although most strains disappeared, residual positive strains remained a long time after addition of chloroquine, predominantly in the radial direction. Taken together, these findings establish strain mapping as a new tool to elucidate local dynamic mechanical events within the constricting airway and its supporting parenchyma.
... We have postulated previously (Ma and Bates, 2012) that the key to long-range force transmission in a network of elastic elements lies in its shear modulus, the modulus of a hexagonal network of springs being much lower than that of a triangular network. We investigated this concept in the present study by first adapting our previous 2D model of an airway embedded in a hexagonal network of elastic walls Bates, 2012, 2014;Ma et al., 2013b) so that it now includes an empirical mechanism for resisting a change in the shape of each hexagonal cell in the network. This mechanism is similar to that which we employed previously for the airway lumen (Ma and Bates, 2014) and is governed by a shape-restoring force applied to each spring junction (node) in addition to the elastic recoil forces exerted by the attaching springs. ...
... As in our previous studies Bates, 2012, 2014;Ma et al., 2013a;Ma et al., 2013b), the middle section of the network was removed to represent the airway lumen. The springs around the perimeter of the resulting hole represent the airway wall, and each has a stiffness that is ten times that of each of the springs in the parenchymal network, which themselves were assigned a stiffness of unity. ...
... The procedure we used for simulating airway contraction in both the 2D and 3D models was similar to that used in our previous studies Bates, 2012, 2014;Ma et al., 2013a;Ma et al., 2013b). The nodes around the outer boundary of the network were fixed in place such that the length of each spring in the network was 11% above its zero-load length, so the network began in a pre-stressed state. ...
We have recently shown that if the lung parenchyma is modeled in 2 dimensions as a network of springs arranged in a pattern of repeating hexagonal cells, the distortional forces around a contracting airway propagate much further from the airway wall than classic continuum theory predicts. In the present study we tested the hypothesis that this occurs because of the negligible shear modulus of a hexagonal spring network. We simulated the narrowing of an airway embedded in a hexagonal network of elastic alveolar walls when the hexagonal cells of the network offered some resistance to a change in shape. We found that as the forces resisting shape change approach about 10% of the forces resisting length change of an individual spring the range of distortional force propagation in the spring network fell of rapidly as in an elastic continuum. We repeated these investigations in a 3-dimensional spring network composed of space-filling polyhedral cells and found similar results. This suggests that force propagation away from a point of local parenchymal distortion also falls off rapidly in real lung tissue.
Copyright © 2015. Published by Elsevier B.V.
... This opposes the shortening of airway smooth muscle and so causes a strong inverse dependence of airway responsiveness on lung volume (6,9). By the same token, when an airway narrows, it distorts the surrounding parenchyma for some distance out from the airway wall (23). Any other airway within this parenchymal distortion field will then have its own forces of airway-parenchymal interdependence increased accordingly. ...
... The elastic elements were connected via frictionless pin joints. This representation has a long history of use as a model of mechanical interdependence and parenchymal stability (25,28), and we have used it recently in detailed investigations of airway-parenchymal interdependence (21)(22)(23). ...
... Fi defined in this way is sensitive to changes in airway lumen shape but not to changes in area. As airway contraction occurs on a time scale of seconds to minutes (2,11,12,16,23), the deformation of the model due to airway contraction was regarded as a quasi-static process, and was calculated in a sequence of small time steps to produce a time course of change in airway area. Dynamic airway narrowing was achieved by having each wall spring follow the Hill hyperbolic relationship between force (F) and velocity (v) (6,11), thus: ...
The forces of mechanical interdependence between the airways and the parenchyma in the lung are powerful modulators of airways responsiveness. Little is known, however, about the extent to which adjacent airways affect each other's ability to narrow due to distortional forces generated within the intervening parenchyma. We developed a 2-dimensional computational model of two airways embedded in parenchyma. The parenchyma itself was modeled in three ways: 1) as a network of hexagonally arranged springs, 2) as a network of triangularly arranged springs, and 3) as an elastic continuum. In all cases, we determined how the narrowing of one airway was affected when the other airway was relaxed versus when it narrowed to the same extent as the first airway. For the continuum and triangular network models, interactions between airways were negligible unless the airways lay within about 2 relaxed diameters of each other, but even at this distance the interactions were small. By contrast, the hexagonal spring network model predicted that airway-airway interactions mediated by the parenchyma can be substantial for any degree of airway separation at intermediate values of airway contraction forces. Evidence to date suggests that the parenchyma may be better represented by the continuum model, which suggests that the parenchyma does not mediate significant interactions between narrowing airways.
... All theoretical studies to date have assumed the parenchyma to be homogeneous, yet it is well known that substantial heterogeneity and anisotropy can develop in the lung parenchyma in disease (Chapman et al., 2012;Ito et al., 2004;Ito et al., 2007;Kaczka et al., 2011). Indeed, even normal parenchyma is clearly inhomogeneous (Adler et al., 1998;Ma et al., 2013). This raises the important question as to whether our understanding of the nature of airway-parenchymal interdependence, which is currently based on the assumption of parenchymal homogeneity, might change significantly if heterogeneity is taken into account. ...
... Accordingly, the goal of the present study was to determine if regional heterogeneities in parenchymal mechanics have any important consequences for the forces of airwayparenchymal interdependence generated by airway narrowing. We performed this investigation using heterogeneous adaptations of computational models that we have investigated previously, namely a 2-dimensional circular airway embedded in homogeneous linear elastic parenchyma (Ma and Bates, 2012;Ma et al., 2013) and a 3-dimensional continuum model of a circular airway embedded in homogeneous nonlinear elastic parenchyma (Breen et al., 2012). ...
... We first modeled the parenchyma as a 2-dimensional network of nonlinear springs (Ma and Bates, 2012;Ma et al., 2013). The springs were connected to each other either in a hexagonal pattern or a triangular pattern. ...
To estimate the influence of parenchymal heterogeneities on airway-parenchymal interdependence, we considered a circular airway embedded within elastic parenchyma modeled as 1) a hexagonal spring network, 2) a triangular spring network, or 3) a continuum. The deformation in the parenchyma due to active airway contraction was simulated using the finite element method. Random perturbations of elastic moduli in the parenchyma did not significantly affect the overall pattern of force transmission. By contrast, when elastic moduli were increased along a path projecting radially outward from the airway, the hexagonal spring network model predicted significantly increased force along this line as the airway contracted, but this was not observed in other two models. These results indicate that tissue heterogeneities generally have minimal effect on the global nature of airway-parenchymal interdependence. However, in the exceptional circumstance of scar tissue aligned radially from the airway wall, parenchymal distortion forces may propagate much farther from the airway wall than was previously thought.
... The concentration of agarose is important as too low a percentage or alternative mediums that are soft do not allow for sufficient inherent recoil capacity to mediate airway relaxation after contraction (Sanderson, 2011). Agarose is retained within the alveoli after preparation of PCLS, and although this does not prevent airway contraction, it is likely to alter the parenchymal stiffness within a PCLS and should be considered when assessing lung mechanics (Ma et al., 2013). ...
Precision cut lung slices (PCLS) have emerged as powerful experimental tools for respiratory research. Pioneering studies using mouse PCLS to visualize intrapulmonary airway contractility have been extended to pulmonary arteries and for assessment of novel bronchodilators and vasodilators as therapeutics. Additional disease-relevant outcomes, including inflammatory, fibrotic, and regenerative responses, are now routinely measured in PCLS from multiple species, including humans. This review provides an overview of established and innovative uses of PCLS as an intermediary between cellular and organ-based studies and focuses on opportunities to increase their application to investigate mechanisms and therapeutic targets to oppose excessive airway contraction and fibrosis in lung diseases.
... However, the approximation that peribronchial pressure is equal to pleural pressure does not apply to hyperinflation nor to lungs with heterogeneous ventilation such as VDefs during asthma attacks. Additionally, airway narrowing during asthma attacks results in a deformation of the tissue surrounding the airway increasing the parenchymal tethering forces [9][10][11], and heterogeneity in airway geometry as well as asymmetry in airway branching affect bronchoconstriction [12][13][14]. Under these conditions, airway peribronchial pressures are different from the global average that the relationship between peribronchial and pleural pressure describes. ...
Airway transmural pressure in healthy homogeneous lungs with dilated airways is approximately equal to the difference between intraluminal and pleural pressure. However, bronchoconstriction causes airway narrowing, parenchymal distortion, dynamic hyperinflation, and the emergence of ventilation defects (VDefs) affecting transmural pressure. This study aimed to investigate the changes in transmural pressure caused by bronchoconstriction in a bronchial tree. Transmural pressures before and during bronchoconstriction were estimated using an integrative computational model of bronchoconstriction. Briefly, this model incorporates a 12-generation symmetric bronchial tree, and the Anafi and Wilson model for the individual airways of the tree. Bronchoconstriction lead to the emergence of VDefs and a relative increase in peak transmural pressures of up to 84% compared to baseline. The highest increase in peak transmural pressure occurred in a central airway outside of VDefs, and the lowest increase was 27% in an airway within VDefs illustrating the heterogeneity in peak transmural pressures within a bronchial tree. Mechanisms contributing to the increase in peak transmural pressures include increased regional ventilation and dynamic hyperinflation both leading to increased alveolar pressures compared to baseline. Pressure differences between intraluminal and alveolar pressure increased driven by the increased airway resistance and its contribution to total transmural pressure reached up to 24%. In conclusion, peak transmural pressure in lungs with VDefs during bronchoconstriction can be substantially increased compared to dilated airways in healthy homogeneous lungs and is highly heterogeneous. Further insights will depend on the experimental studies taking these conditions into account.
... Different degrees of narrowing depend on the level of inflammation and the airway diameter. This variation in narrowing, in turn, will also represent a varying airflow through the airway (3,5). ...
... Throughout, airway remodeling is a dynamic process that is active and potentially progressive, but that can be prevented by appropriate therapy [12]. So far, managements involve long-acting bronchodilators (LB), comprised of longacting beta2-agonists (LABA) and tiotropium, inhaled corticosteroid (ICS), phosphodiesterase, leukotriene antagonists, and so on [1,13]. However, they can only reduce the number and severity of exacerbation and established symptoms and have a limited effect on slowing down the progression of lung damage, inflammation, and airway remodeling [14]. ...
Background. Scutellaria baicalensis (SB) is commonly used in traditional Chinese medicine for chronic inflammatory diseases. This study aims to investigate the effects of the early intervention with SB on airway remodeling in a well-established rat model of COPD induced by cigarette smoking. Methods. COPD model in Sprague Dawley (SD) rats were established by exposing them to smoke for 6 days/week, for 12 weeks, 24 weeks, or 36 weeks. Meanwhile, rats were randomly divided into normal control group, model group, Budesonide (BUD) group, and the SB (low, middle, and high) dose groups with 8 rats in each group and 3 stages (12 weeks, 24 weeks, and 36 weeks). After treatment, the pulmonary function was evaluated by BUXCO system and the morphology changes of the lungs were observed with HE and Masson staining. The serum IL-6, IL-8, and IL-10 and TNF- α , TGF-beta (TGF- β 1), MMP-2, MMP-9, and TIMP-1 levels in BALF were detected by ELISA-kit assay. The protein expression levels of AKT and NF- κ B (p65) were determined by western blot (WB). Results. The oral of SB significantly improved pulmonary function (PF) and ameliorated the pathological damage and attenuated inflammatory cytokines infiltration into the lungs. Meanwhile, the levels of TGF- β , MMP-2, MMP-9, and TIMP-1 were partially significantly decreased. The levels of PI3K/AKT/NF- κ B pathway were also markedly suppressed by SB. Conclusions. SB could significantly improve the condition of airway remodeling by inhibiting airway inflammation and partially quenching TGF- β and MMPs via PI3K/AKT/NF- κ B pathway.
... There is evidence to suggest that this may be the case. For example, although qualitative quasi-linear viscoelastic behavior and PL stress relaxation arise naturally in models of lung tissue exhibiting sequentiality [16] , the predicted exponent in the PL relationship is much too large unless this mechanism is embedded in a multi-scale structure [16,153,154] . The same kind of behavior has been shown to occur in models comprised of fractal-like ladder networks of mechanical elements [103,104] . ...
This review provides the latest developments and trends in the application of fractional calculus (FC) in biomedicine and biology. Nature has often showed to follow rather simple rules that lead to the emergence of with complex phenomena as a result. Of these, the paper addresses the properties in respiratory lung tissue, whose natural solutions arise from the midst of FC in the form of non-integer differ-integral solutions and non-integer parametric models. Diffusion of substances in human body, e.g. drug diffusion, is also a phenomena well known to be captured with such mathematical models. FC has been employed in neuroscience to characterize the generation of action potentials ans spiking patters but also in charaterizing bio-systems (e.g. vegetable tissues). Despite the natural complexity, biological systems belong as well to this class of systems, where FC has offered parsimonious yet accurate models. This review paper is a collection of results and literature reports who are essential to any versed engineer with multidisciplinary applications and bio-medical in particular.
... Thus, developing pressure levels will be much higher in reality and viscoelastic tissue properties will both influence airflow and wall mechanics. Recently, more advanced boundary conditions have been proposed [14][15][16] also including the effects of airway flexibility and surrounding tissue [4,[17][18][19][20][21]. However, there is still no volumetric coupling between airflow and parenchyma mechanics available for fully resolved three-dimensional FSI models. ...
In this article, a novel approach is presented for combining standard fluid-structure interaction with additional volumetric constraints to model fluid flow into and from homogenised solid domains. The proposed algorithm is particularly interesting for investigations in the field of respiratory mechanics as it enables the mutual coupling of airflow in the conducting part and local tissue deformation in the respiratory part of the lung by means of a volume constraint. In combination with a classical monolithic fluid-structure interaction approach, a comprehensive model of the human lung can be established that will be useful to gain new insights into respiratory mechanics in health and disease. To illustrate the validity and versatility of the novel approach, three numerical examples including a patient-specific lung model are presented. The proposed algorithm proves its capability of computing clinically relevant airflow distribution and tissue strain data at a level of detail that is not yet achievable, neither with current imaging techniques nor with existing computational models. Copyright © 2016 John Wiley & Sons, Ltd.
... Several studies have demonstrated that the healthy lung is inherently inhomogeneous because of gravitational (Milic-Emili, 1986) and local forces (Ma et al., 2013). This results in vertical but opposing gradients of alveolar distension and relative ventilation (i.e., the ratio between ventilated gas and the volume of gas already present in a lung region) (Milic-Emili, 1966;Milic-Emili, 1986). ...
... Indeed, lung slices can be harvested from healthy or diseased specimen, are viable in vitro for several days and provide a natural co-culture, which preserves the native biochemical and mechanical interactions between cells of different types and their ECM. This integrative model of the airway system gives insights in the interplay occurring between the different compartments of the tissue, when contraction and relaxation are chemically induced either at rest (Konigshoff et al., 2011;Ma et al., 2013) or under oscillating stretch to account for the benefits of breathing (Lavoie et al., 2012). Despite the loss of three dimensional structures that may be important for the structural changes occurring during bronchoconstriction, the two dimensional character of the PCLS facilitates the use of many visualization techniques necessary to achieve a reasonable characterization of these changes. ...
Chronic obstructive pulmonary disease (COPD) is one of the most common lung diseases worldwide, and is characterized by airflow obstruction that is not fully reversible with treatment. Even though airflow obstruction is caused by airway smooth muscle contraction, the extent of airway narrowing depends on a range of other structural and functional determinants that impact on active and passive tissue mechanics. Cells and extracellular matrix in the airway and parenchymal compartments respond both passively and actively to the mechanical stimulation induced by smooth muscle contraction. In this review, we summarize the factors that regulate airway narrowing and provide insight into the relative contributions of different constituents of the extracellular matrix and their biomechanical impact on airway obstruction. We then review the changes in extracellular matrix composition in the airway and parenchymal compartments at different stages of COPD, and finally discuss how these changes impact airway narrowing and the development of airway hyperresponsiveness. Finally, we position these data in the context of therapeutic research focused on defective tissue repair. As a conclusion, we propose that future works should primarily target mild or early COPD, prior to the widespread structural changes in the alveolar compartment that are more characteristic of severe COPD.
The level of airway constriction in thin slices of lung tissue is highly variable. Owing to the labor-intensive nature of these experiments, determining the number of airways to be analyzed in order to allocate a reliable value of constriction in one mouse is challenging. Herein, a new automated device for physiology and image analysis was used to facilitate high throughput screening of airway constriction in lung slices. Airway constriction was first quantified in slices of lungs from male BALB/c mice with and without experimental asthma that were inflated with agarose through the trachea or trans-parenchymal injections. Random sampling simulations were then conducted to determine the number of airways required per mouse to quantify maximal constriction. The constriction of 45 ± 12 airways per mouse in 32 mice were analyzed. Mean maximal constriction was 37.4 ± 32.0%. The agarose inflating technique did not affect the methacholine response. However, the methacholine constriction was affected by experimental asthma (p = 0.003), shifting the methacholine concentration–response curve to the right, indicating a decreased sensitivity. Simulations then predicted that approximately 35, 16 and 29 airways per mouse are needed to quantify the maximal constriction mean, standard deviation and coefficient of variation, respectively; these numbers varying between mice and with experimental asthma.
Precision Cut Lung Slices (PCLS) have emerged as a sophisticated and physiologically relevant ex vivo model for studying the intricacies of lung diseases, including fibrosis, injury, repair, and host defense mechanisms. This innovative methodology presents a unique opportunity to bridge the gap between traditional in vitro cell cultures and in vivo animal models, offering researchers a more accurate representation of the intricate microenvironment of the lung. PCLS require the precise sectioning of lung tissue to maintain its structural and functional integrity. These thin slices serve as invaluable tools for various research endeavors, particularly in the realm of airway diseases. By providing a controlled microenvironment, precision-cut lung slices empower researchers to dissect and comprehend the multifaceted interactions and responses within lung tissue, thereby advancing our understanding of pulmonary pathophysiology.
Despite being an essential life-support strategy in acute respiratory failure, mechanical ventilation can, if not optimally set and monitored, lead to injury of the lung parenchyma and diaphragm. These conditions are called ventilator-induced lung injury (VILI) and ventilator-induced diaphragmatic dysfunction (VIDD), respectively. Although substantial progress has been made in the ventilator management of lung-injured patients, we are still far from fully protective mechanical ventilation. It is questioned whether spontaneous breathing should be used in early acute respiratory distress syndrome (ARDS). Recent papers have reported concerns regarding spontaneous breathing, because of the potential of triggering so-called patient self-inflicted lung injury (P-SILI). Despite a clear improvement in ventilatory strategies, we still lack knowledge that could make spontaneous breathing fully protective. Assessment of potential parenchymal injury must take into account stress and strain as the real physical quantities acting on the lung structures. Moreover, the lack of information regarding regional lung mechanics and deformation at the acinar level is likely the main determinant of these unresolved issues.
The mammalian lung´s structural design is optimized to serve its main function: gas exchange. It takes place in the alveolar region (parenchyma) where air and blood are brought in close proximity over a large surface. Air reaches the alveolar lumen via a conducting airway tree. Blood flows in a capillary network embedded in inter-alveolar septa. The barrier between air and blood consists of a continuous alveolar epithelium (a mosaic of type I and type II alveolar epithelial cells), a continuous capillary endothelium and the connective tissue layer in-between. By virtue of its respiratory movements, the lung has to withstand mechanical challenges throughout life. Alveoli must be protected from over-distension as well as from collapse by inherent stabilizing factors. The mechanical stability of the parenchyma is ensured by two components: a connective tissue fiber network and the surfactant system. The connective tissue fibers form a continuous tensegrity (tension + integrity) backbone consisting of axial, peripheral and septal fibers. Surfactant (surface active agent) is the secretory product of type II alveolar epithelial cells and covers the alveolar epithelium as a biophysically active thin and continuous film. Here, we briefly review the structural components relevant for gas exchange. Then we describe our current understanding of how these components function under normal conditions and how lung injury results in dysfunction of alveolar micromechanics finally leading to lung fibrosis.
The lung is a delicately balanced and highly integrated mechanical system. Lung tissue is continuously exposed to the environment via the air we breathe, making it susceptible to damage. As a consequence, respiratory diseases present a huge burden on society and their prevalence continues to rise. Emergent function is produced not only by the sum of the function of its individual components but also by the complex feedback and interactions occurring across the biological scales - from genes to proteins, cells, tissue and whole organ - and back again. Computational modeling provides the necessary framework for pulling apart and putting back together the pieces of the body and organ systems so that we can fully understand how they function in both health and disease. In this review, we discuss models of lung tissue mechanics spanning from the protein level (the extracellular matrix) through to the level of cells, tissue and whole organ, many of which have been developed in isolation. This is a vital step in the process but to understand the emergent behavior of the lung, we must work towards integrating these component parts and accounting for feedback across the scales, such as mechanotransduction. These interactions will be key to unlocking the mechanisms occurring in disease and in seeking new pharmacological targets and improving personalized healthcare.
Understanding lung and airway behavior presents a number of challenges, both experimental and theoretical, but the potential rewards are great in terms of both potential treatments for disease and interesting biophysical phenomena. This presents an opportunity for modeling to contribute to greater understanding, and here, we focus on modeling efforts that work toward understanding the behavior of airways in vivo, with an emphasis on asthma. We look particularly at those models that address not just isolated airways but many of the important ways in which airways are coupled both with each other and with other structures. This includes both interesting phenomena involving the airways and the layer of airway smooth muscle that surrounds them, and also the emergence of spatial ventilation patterns via dynamic airway interaction. WIREs Syst Biol Med 2016, 8:459–467. doi: 10.1002/wsbm.1349
This article is categorized under:
• Analytical and Computational Methods > Dynamical Methods
• Models of Systems Properties and Processes > Mechanistic Models
• Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models
Mechanical ventilation is necessary for treatment of the acute respiratory distress syndrome but leads to overdistension of the open regions of the lung and produces further damage. Although we know that the excessive stresses and strains disrupt the alveolar epithelium, we know little about the relationship between epithelial strain and epithelial leak. We have developed a computational model of an epithelial monolayer to simulate leak progression due to overdistension and to explain previous experimental findings in mice with ventilator-induced lung injury. We found a nonlinear threshold-type relationship between leak area and increasing stretch force. After the force required to initiate the leak was reached, the leak area increased at a constant rate with further increases in force. Furthermore, this rate was slower than the rate of increase in force, especially at end-expiration. Parameter manipulation changed only the leak-initiating force; leak area growth followed the same trend once this force was surpassed. These results suggest that there is a particular force (analogous to ventilation tidal volume) that must not be exceeded to avoid damage and that changing cell physical properties adjusts this threshold. This is relevant for the development of new ventilator strategies that avoid inducing further injury to the lung.
Clustered ventilation defects are a hallmark of asthma, typically seen via imaging studies during asthma attacks. The mechanisms underlying the formation of these clusters is of great interest in understanding asthma. Because the clusters vary from event to event, many researchers believe they occur due to dynamic, rather than structural, causes. To study the formation of these clusters, we formulate and analyze a lattice-based model of the lung, considering both the role of airway bistability and a mechanism for organizing the spatial structure. Within this model we show how and why the homogeneous ventilation solution becomes unstable, and under what circumstances the resulting heterogeneous solution is a clustered solution. The size of the resulting clusters is shown to arise from structure of the eigenvalues and eigenvectors of the system, admitting not only clustered solutions but also (aphysical) checkerboard solutions. We also consider the breathing efficiency of clustered solutions in severely constricted lungs, showing that stabilizing the homogeneous solution may be advantageous in some circumstances. Extensions to hexagonal and cubic lattices are also studied.
Lung primordial specification as well as branching morphogenesis, and the formation of various pulmonary cell lineages, requires a specific interaction of the lung endoderm with its surrounding mesenchyme and mesothelium. Lung mesenchyme has been shown to be the source of inductive signals for lung branching morphogenesis. Epithelial-mesenchymal-mesothelial interactions are also critical to embryonic lung morphogenesis. Early embryonic lung organ culture is a very useful system to study epithelial-mesenchymal interactions. Both epithelial and mesenchymal morphogenesis proceed under specific conditions that can be readily manipulated in this system (in the absence of maternal influence and blood flow). More importantly this technique can be readily done in a serumless, chemically defined culture media. Gain and loss of function can be achieved using expressed proteins, recombinant viral vectors, and/or analysis of transgenic mouse strains, antisense RNA, as well as RNA interference gene knockdown. Additionally, to further study epithelial-mesenchymal interactions, the relative roles of epithelium versus mesenchyme signaling can also be determined using tissue recombination (e.g., epithelial and mesenchymal separation) and microbead studies.
This paper presents a modelling framework in which the local stress environment of airway smooth muscle (ASM) cells may be predicted and cellular responses to local stress may be investigated. We consider an elastic axisymmetric model of a layer of connective tissue and circumferential ASM fibres embedded in parenchymal tissue and model the active contractile force generated by ASM via a stress acting along the fibres. A constitutive law is proposed that accounts for active and passive material properties as well as the proportion of muscle to connective tissue. The model predicts significantly different contractile responses depending on the proportion of muscle to connective tissue in the remodelled airway. We find that radial and hoop-stress distributions in remodelled muscle layers are highly heterogenous with distinct regions of compression and tension. Such patterns of stress are likely to have important implications, from a mechano-transduction perspective, on contractility, short-term cytoskeletal adaptation and long-term airway remodelling in asthma.
The aim of the study was to determine whether the nonspecific in vivo airway hyperresponsiveness of the inbred Fisher F‐344 rat strain was associated with differences in the intrinsic contractile properties of tracheal smooth muscle (TSM) when compared with Lewis rats.
Isotonic and isometric contractile properties of isolated TSM from Fisher and Lewis rats (each n=10) were investigated, and myosin crossbridge (CB) number, force and kinetics in both strains were calculated using Huxley's equations adapted to nonsarcomeric muscles. Maximum unloaded shortening velocity and maximum extent of muscle shortening were higher in Fisher than in Lewis rats (∼46% and ∼42%, respectively), whereas peak isometric tension was similar.
The curvature of the hyperbolic force/velocity relationship did not differ between strains. Myosin CB number and unitary force were similar in both strains. The duration of CB detachment and attachment was shorter in Fisher than in Lewis rats (∼−46% and −34%, respectively).
In Fisher rats, these results show that inherited, genetically determined factors of airway hyperresponsiveness are associated with changes in crossbridge kinetics, contributing to an increased tracheal smooth muscle shortening capacity and velocity.
We recently developed a computational model of an airway embedded in elastic parenchyma (Bates JH, Lauzon AM. J Appl Physiol 102: 1912-1920, 2007) that accurately mimics the time dependence of airway resistance on tidal volume and positive end-expiratory pressure (PEEP) following methacholine injection in normal animals. In the present study, we compared the model predictions of bronchodilation induced by a deep inflation (DI) of the lung following administration of the bronchial agonist methacholine to corresponding experimental measurements made in mice. We found that a DI in mice caused an immediate reduction in airway resistance when it was administered soon after intravenous injection of methacholine, while the airway smooth muscle was in the process of contracting. However, the magnitude of the reduction in resistance was greater and its subsequent rate of increase less than that predicted by the model. We found that this effect was most pronounced when the DI was given within approximately 3 s following methacholine injection, again in contrast to the predictions of the model. The reduction of airway resistance was virtually independent of the rate of lung inflation during the DI, however, which agrees with model predictions. We conclude that while the model accounts for a substantial fraction of the post-DI reduction in airway resistance seen experimentally, there remain important differences between prediction and experiment that suggest that the effects of a DI are not simply due to eccentric contraction of the airway smooth muscle.
Airway hyper-responsiveness (AHR), a hallmark of asthma, is a highly complex phenomenon characterised by multiple processes manifesting over a large range of length and time scales. Multiscale computational models have been derived to embody the experimental understanding of AHR. While current models differ in their derivation, a common assumption is that the increase in parenchymal tethering pressure P(teth) during airway constriction can be described using the model proposed by Lai-Fook (1979), which is based on intact lung experimental data for elastic moduli over a range of inflation pressures. Here we reexamine this relationship for consistency with a nonlinear elastic material law that has been parameterised to the pressure-volume behaviour of the intact lung. We show that the nonlinear law and Lai-Fook's relationship are consistent for small constrictions, but diverge when the constriction becomes large.
In the normal lung, breathing and deep inspirations potently antagonize bronchoconstriction, but in the asthmatic lung this salutary effect is substantially attenuated or even reversed. To explain these findings, the prevailing hypothesis focuses on contracting airway smooth muscle and posits a nonlinear dynamic interaction between actomyosin binding and the tethering forces imposed by tidally expanding lung parenchyma.
This hypothesis has never been tested directly in bronchial smooth muscle embedded within intraparenchymal airways. Our objective here is to fill that gap.
We designed a novel system to image contracting intraparenchymal human airways situated within near-normal lung architecture and subjected to dynamic parenchymal expansion that simulates breathing.
Reversal of bronchoconstriction depended on the degree to which breathing actually stretched the airway, which in turn depended negatively on severity of constriction and positively on the depth of breathing. Such behavior implies positive feedbacks that engender airway instability. OVERALL CONCLUSIONS: These findings help to explain heterogeneity of airflow obstruction as well as why, in people with asthma, deep inspirations are less effective in reversing bronchoconstriction.
The outward tethering forces exerted by the lung parenchyma on the airways embedded within it are potent modulators of the ability of the airway smooth muscle to shorten. Much of our understanding of these tethering forces is based on treating the parenchyma as an elastic continuum; yet, on a small enough scale, the lung parenchyma in two dimensions would seem to be more appropriately described as a discrete spring network. We therefore compared how the forces and displacements in the parenchyma surrounding a contracting airway are predicted to differ depending on whether the parenchyma is modeled as an elastic continuum or as a spring network. When the springs were arranged hexagonally to represent alveolar walls, the predicted parenchymal stresses and displacements propagated substantially farther away from the airway than when the springs were arranged in a triangular pattern or when the parenchyma was modeled as a continuum. Thus, to the extent that the parenchyma in vivo behaves as a hexagonal spring network, our results suggest that the range of interdependence forces due to airway contraction may have a greater influence than was previously thought.
The development of therapeutic approaches to treat lung disease requires an understanding of both the normal and disease physiology of the lung. Although traditional experimental approaches only address either organ or cellular physiology, the use of lung slice preparations provides a unique approach to investigate integrated physiology that links the cellular and organ responses. Living lung slices are robust and can be prepared from a variety of species, including humans, and they retain many aspects of the cellular and structural organization of the lung. Functional portions of intrapulmonary airways, arterioles and veins are present within the alveoli parenchyma. The dynamics of macroscopic changes of contraction and relaxation associated with the airways and vessels are readily observed with conventional low-magnification microscopy. The microscopic changes associated with cellular events, that determine the macroscopic responses, can be observed with confocal or two-photon microscopy. To investigate disease processes, lung slices can either be prepared from animal models of disease or animals exposed to disease invoking conditions. Alternatively, the lung slices themselves can be experimentally manipulated. Because of the ability to observe changes in cell physiology and how these responses manifest themselves at the level of the organ, lung slices have become a standard tool for the investigation of lung disease.
Understanding how tissue remodeling affects airway responsiveness is of key importance, but experimental data bearing on this issue remain scant. We used lung explants to investigate the effects of enzymatic digestion on the rate and magnitude of airway narrowing induced by acetylcholine. To link the observed changes in narrowing dynamics to the degree of alteration in tissue mechanics, we compared our experimental results with predictions made by a computational model of a dynamically contracting elastic airway embedded in elastic parenchyma. We found that treatment of explanted airways with two different proteases (elastase and collagenase) resulted in differential effects on the dynamics of airway narrowing following application of ACh. Histological corroboration of these different effects is manifest in different patterns of elimination of collagen and elastin from within the airway wall and the surrounding parenchyma. Simulations with a computational model of a dynamically contracting airway embedded in elastic parenchyma suggest that elastase exerts its functional effects predominately through a reduction in parenchymal tethering, while the effects of collagenase are more related to a reduction in airway wall stiffness. We conclude that airway and parenchymal remodeling as a result of protease activity can have varied effects on the loads opposing ASM shortening, with corresponding consequences for airway responsiveness.
Airway smooth muscle (ASM) is cyclically stretched during breathing, even in the active state, yet the factors determining its dynamic force-length behavior remain incompletely understood. We developed a model of the activated ASM strip and compared its behavior to that observed in strips of rat trachealis muscle stimulated with methacholine. The model consists of a nonlinear viscoelastic element (Kelvin body) in series with a force generator obeying the Hill force-velocity relationship. Isometric force in the model is proportional to the number of bound crossbridges, the attachment of which follows first-order kinetics. Crossbridges detach at a rate proportional to the rate of change of muscle length. The model accurately accounts for the experimentally observed transient and steady-state oscillatory force-length behavior of both passive and activated ASM. However, the model does not predict the sustained decrement in isometric force seen when activated strips of ASM are subjected briefly to large stretches. We speculate that this force decrement reflects some mechanism unrelated to the cycling of crossbridges, and which may be involved in the reversal of bronchoconstriction induced by a deep inflation of the lungs in vivo.
The pressure-diameter (PD) behavior of intact pulmonary vessels was measured roentgenographically at several fixed deflation transpulmonary pressures (Ptp). At any constant vascular pressure (Pv), the intact-vessel diameter was larger for higher Ptp. The behavior of the parenchyma was described by a nonlinear analysis. An excised-vessel PD behavior was computed which was consistent with both nonlinear parenchymal behavior and measured intact-vessel PD behavior. Estimates of Px', the difference between the perivascular pressure and the pleural pressure, as a function of Ptp and Pv were obtained. For physiological values of Pv, mean values of Px' for arteries were -1 cmH2O at Ptp of 4 cmH20 and decreased almost linearly to -15 cmH20 at Ptp of 25 cmH2O. Veins showed a similar behavior, but Px' was more positive. Increasing Pv raised Px' and decreasing Pv lowered Px' at all values of Ptp. These results indicate that the interdependence effect is small at functional residual capacity, increases with lung inflation, and is greater for arteries than veins.
At several transpulmonary pressures (Ptp), the pressure-diameter (PD) behavior of the largest intraparenchymal arterial segment in the isolated pig lung was compared with the behavior of the segment after its excision from the parenchyma and its extension to lengths equivalent to those in the intact state. For physiological changes in length, as may occur with lung inflation during Ptp changes from 4 to 25 cmH2O, excised-vessel diameters did not change significantly at a constant transmural pressure. The excised-vessel PD behavior was not significantly different from the intact-vessel PD behavior at a Ptp of 4 cmH2O. At any constant arterial pressure, intact-vessel diameters became larger as Ptp increased. Estimates of the perivascular pressure (Px) obtained by directly comparing intact-vessel and excised-vessel PD curves were as follows: 1) Px was equal to pleural pressure at a Ptp approximating the functional residual capacity; 2) Px decreased almost linearly as Ptp increased; and 3) Px decreased with a fall in arterial pressure. These results are consistent with direct measurements of the perivascular interstitial fluid pressure.
A method that interrelates lung pressure-volume behavior, bronchial pressure-diameter behavior, and parenchymal shear modulus is presented. The method was used to predict changes in intraparenchymal bronchial diameter that occurred when lobe pressure-volume behavior and parenchymal shear modulus were markedly changed by inducing air trapping in isolated dog lobes. Predictions agreed with measurements, thereby supporting the general method. Measured values for the shear modulus were approximately 0.7 times the transpulmonary pressure for the control state. Estimated values for the peribronchial pressure difference from pleural pressure during a deflation pressure-volume maneuver for transpulmonary pressures below 12 cmH2O were small, approximately +/- 1 cmH2O, its sign being positive or negative, depending on whether the bronchus was dilated or contricted.
Spherical and cylindrical holes were cut in the parenchyma of isolated dog lung lobes. The holes were insufflated with tantalum dust and the hole diameters were measured along the deflation limb of the lobe pressure-volume curve from transpulmonary pressures of 20 to 0 cmH2O. Hole volume as a fraction of lobe volume was found to be independent of transpulmonary pressure. The hole volume relative to the amount of tissue removed was used to determine the displacement at the hole boundary. A comparison of this displacement with the displacement predicted by a continuum mechanics analysis provides evidence for the applicability of the methods of continuum mechanics and further evidence that the shear modulus of the parenchyma is relatively small.
The objective of this investigation was to determine the minimum transpulmonary pressure (PL) at which the forces of interdependence between the airways and the lung parenchyma can prevent airway closure in response to maximal stimulation of the airways in excised canine lobes. We first present an analysis of the relationship between PL and the transmural pressure (Ptm) that airway smooth muscle must generate to close the airways. This analysis predicts that airway closure can occur at PL less than or equal to 10 cmH2O with maximal airway stimulation. We tested this prediction in eight excised canine lobes by nebulizing 50% methacholine into the airways while the lobe was held at constant PL values ranging from 25 to 5 cmH2O. Airway closure was assessed by comparing changes in alveolar pressure (measured by an alveolar capsule technique) and pressure at the airway opening during low-amplitude oscillations in lobar volume. Airway closure occurred in two of the eight lobes at PL = 10 cmH2O; in an additional five it occurred at PL = 7.5 cmH2O. We conclude that the forces of parenchymal interdependence per se are not sufficient to prevent airway closure at PL less than or equal to 7.5 cmH2O in excised canine lobes.
We examined the effects of lung volume on the bronchoconstriction induced by inhaled aerosolized methacholine (MCh) in seven normal subjects. We constructed dose-response curves to MCh, using measurements of inspiratory pulmonary resistance (RL) during tidal breathing at functional residual capacity (FRC) and after a change in end-expiratory lung volume (EEV) to either FRC -0.5 liter (n = 5) or FRC +0.5 liter (n = 2). Aerosols of MCh were generated using a nebulizer with an output of 0.12 ml/min and administered for 2 min in progressively doubling concentrations from 1 to 256 mg/ml. After MCh, RL rose from a base-line value of 2.1 +/- 0.3 cmH2O. 1-1 X s (mean +/- SE; n = 7) to a maximum of 13.9 +/- 1.8. In five of the seven subjects a plateau response to MCh was obtained at FRC. There was no correlation between the concentration of MCh required to double RL and the maximum value of RL. The dose-response relationship to MCh was markedly altered by changing lung volume. The bronchoconstrictor response was enhanced at FRC - 0.5 liter; RL reached a maximum of 39.0 +/- 4.0 cmH2O X 1-1 X s. Conversely, at FRC + 0.5 liter the maximum value of RL was reduced in both subjects from 8.2 and 16.6 to 6.0 and 7.7 cmH2O X 1-1 X s, respectively. We conclude that lung volume is a major determinant of the bronchoconstrictor response to MCh in normal subjects. We suggest that changes in lung volume act to alter the forces of interdependence between airways and parenchyma that oppose airway smooth muscle contraction.
In the characterization of stress-strain relationships for the lung using solid continuum-mechanics analysis, the lung parenchyma
is assumed to be in a state of uniform expansion and nonhomogeneous deformations are considered from the uniform state. If
the nonhomogeneous deformations are small, nonhomogeneous lung deformation problems are reduced to those solvable using infinitesimal
elasticity, since only the small superimposed deformations are considered. Using this incremental approach, the relevant elastic
constants of lung parechyma have been measured and their applicability has been verified by comparing the results of the theoretical
analysis of several nonhomogeneous deformation problems with experimental data.
The bronchus and artery, embedded in the lung parenchyma, were modeled as adjoining cylindrical tubes in an elastic continuum. Solutions using finite-element analysis of nonuniform stress and strain occurring from an initial uniform state were computed for a reduction in arterial pressure. Maximal nonuniform principal and shear stresses in the parenchyma, equal to 2.5 times the mean periarterial stresses, occurred in the region adjacent to the bronchial-arterial joint. Bronchial cross section became oval and elongated along the line passing through the centers of the tubes, whereas arterial cross section elongated at right angles to this line. These predicted changes in shape of bronchus and artery were verified by radiographic measurements in isolated lobes, held at constant transpulmonary pressures of 4 and 25 cmH2O while arterial pressure was varied. Results suggest that peribronchovascular interstitial fluid pressure may be nonuniform and that the bronchial-arterial joint may be the preferential site for emphysematous perivascular lesions, which may occur on lung hyperinflation.
The constriction of pulmonary airways is limited by the tethering effect exerted by parenchymal attachments. To characterize this tethering effect at the scale of intraparenchymal airways, we studied the pattern of parenchymal distortion due to bronchoconstriction in a rat lung explant system. First, we measured the elastic modulus under tension for 2% (wt/vol) agarose alone (37.6 +/- 1.5 kPa) and for agarose-filled lung (5.7 +/- 1.3 kPa). The latter is similar to the elastic modulus of air-filled lung at total lung capacity (4.5-6 kPa) (S. J. Lai-Fook, T. A. Wilson, R. E. Hyatt, and J. R. Rodarte. J. Appl. Physiol. 40: 508-513, 1976), suggesting that explants can be used as a model of lung tissue distortion. Subsequently, confocal microscopic images of fluorescently labeled 0.5-mm-thick explants prepared from agarose-filled rat lungs inflated to total lung capacity (48 ml/kg) were acquired. Images were taken before and after airway constriction was induced by direct application of 10 mM methacholine, and the pattern of parenchymal distortion was measured from the displacement of tissue landmarks identified in each image for 14 explants. The magnitude of the radial component of tissue displacement was calculated as a function of distance from the airway wall and characterized by a parameter, b, describing the rate at which tissue movement decreased with radial distance. The parameter b was 0.994 +/- 0.19 (SE), which is close to the prediction of b = 1 of micromechanical modeling (T. A. Wilson. J. Appl. Physiol. 33: 472-478, 1972). There was significant variability in b, however, which was correlated with the fractional reduction in airway diameter (r = 0.496). Additionally, parenchymal distortion showed significant torsion with respect to the radial direction. This torsion was similar in concentric zones around the airway, suggesting that it originates from inhomogeneity in the parenchyma rather than inhomogeneous airway constriction. Our results demonstrate the significance of the nonlinear mechanical properties of alveolar walls and the anisotropy of the parenchyma in determining the nature of airway-parenchymal interdependence.
When strips of activated airway smooth muscle are stretched cyclically, they exhibit force-length loops that vary substantially in both position and shape with the amplitude and frequency of the stretch. This behavior has recently been ascribed to a dynamic interaction between the imposed stretch and the number of actin-myosin interactions in the muscle. However, it is well known that the passive rheological properties of smooth muscle have a major influence on its mechanical properties. We therefore hypothesized that these rheological properties play a significant role in the force-length dynamics of activated smooth muscle. To test the plausibility of this hypothesis, we developed a model of the smooth muscle strip consisting of a force generator in series with an elastic component. Realistic steady-state force-length loops are predicted by the model when the force generator obeys a hyperbolic force-velocity relationship, the series elastic component is highly nonlinear, and both elastic stiffness and force generation are adjusted so that peak loop force equals isometric force. We conclude that the dynamic behavior of airway smooth muscle can be ascribed in large part to an interaction between connective tissue rheology and the force-velocity behavior of contractile proteins.
To investigate the phenomenon of Ca(2+) sensitization, we developed a new intact airway and arteriole smooth muscle cell (SMC) "model" by treating murine lung slices with ryanodine-receptor antagonist, ryanodine (50 microM), and caffeine (20 mM). A sustained elevation in intracellular Ca(2+) concentration ([Ca(2+)](i)) was induced in both SMC types by the ryanodine-caffeine treatment due to the depletion of internal Ca(2+) stores and the stimulation of a persistent influx of Ca(2+). Arterioles responded to this sustained increase in [Ca(2+)](i) with a sustained contraction. By contrast, airways responded to sustained high [Ca(2+)](i) with a transient contraction followed by relaxation. Subsequent exposure to methacholine (MCh) induced a sustained concentration-dependent contraction of the airway without a change in the [Ca(2+)](i). During sustained MCh-induced contraction, Y-27632 (a Rho-kinase inhibitor) and GF-109203X (a protein kinase C inhibitor) induced a concentration-dependent relaxation without changing the [Ca(2+)](i). The cAMP-elevating agents, forskolin (an adenylyl cyclase activator), IBMX (a phosphodiesterase inhibitor), and caffeine (also acting as a phosphodiesterase inhibitor), exerted similar relaxing effects. These results indicate that 1) ryanodine-caffeine treatment is a valuable tool for investigating the contractile mechanisms of SMCs while avoiding nonspecific effects due to cell permeabilization, 2) in the absence of agonist, sustained high [Ca(2+)](i) has a differential time-dependent effect on the Ca(2+) sensitivity of airway and arteriole SMCs, 3) MCh facilitates the contraction of airway SMCs by inducing Ca(2+) sensitization via the activation of Rho-kinase and protein kinase C, and 4) cAMP-elevating agents contribute to the relaxation of airway SMCs through Ca(2+) desensitization.
We do not yet have a good quantitative understanding of how the force-velocity properties of airway smooth muscle interact with the opposing loads of parenchymal tethering and airway wall stiffness to produce the dynamics of bronchoconstriction. We therefore developed a two-dimensional computational model of a dynamically narrowing airway embedded in uniformly elastic lung parenchyma and compared the predictions of the model to published measurements of airway resistance made in rats and rabbits during the development of bronchoconstriction following a bolus injection of methacholine. The model accurately reproduced the experimental time-courses of airway resistance as a function of both lung inflation pressure and tidal volume. The model also showed that the stiffness of the airway wall is similar in rats and rabbits, and significantly greater than that of the lung parenchyma. Our results indicate that the main features of the dynamical nature of bronchoconstriction in vivo can be understood in terms of the classic Hill force-velocity relationship operating against elastic loads provided by the surrounding lung parenchyma and an airway wall that is stiffer than the parenchyma.
mphysematous and fibrotic remodelling of lung tissue associated with chronic obstructive pulmonary disease (COPD) is known to alter the mechanical properties of the parenchyma and the airways, as well as the mechanical interdependence between them. This is thought to contribute to increased airway resistance in COPD (1). Due to its dynamic nature, attempts to directly characterise the in vivo airway- parenchyma interaction have yet to produce satisfactory results. Although some airways can be visualised (and their lumen areas quantified) in vivo with high-resolution computed tomography (HRCT) (2, 3), the time resolution of HRCT is inadequate to capture rapid events associated with the airway- parenchyma interaction in the dynamic lung environment. In addition, the spatial resolution of HRCT precludes it from imaging sub-millimeter airways. In vitro studies of airway
Allergic inflammation is known to cause airway hyperresponsiveness in mice. However, it is not known whether inflammation affects the stiffness of the airway wall, which would alter the load against which the circumscribing smooth muscle shortens when activated. Accordingly, we measured the time course of airway resistance immediately following intravenous methacholine injection in acutely and chronically allergically inflamed mice. We estimated the effective stiffness of the airway wall in these animals by fitting to the airway resistance profiles a computational model of a dynamically narrowing airway embedded in elastic parenchyma. Effective airway wall stiffness was estimated from the model fit and was found not to change from control in either the acute or chronic inflammatory groups. However, the acutely inflamed mice were hyperresponsive compared with controls, which we interpret as reflecting increased delivery of methacholine to the airway smooth muscle through a leaky pulmonary endothelium. These results support the notion that acutely inflamed BALB/c mice represent an animal model of functionally normal airway smooth muscle in a transiently abnormal lung.