Parenchymal Tethering Research Articles

Lung fibroblast-derived extracellular vesicles and soluble factors alleviate elastase-induced lung injury

One of the main pathological features of chronic obstructive pulmonary disease (COPD) is the loss of functional alveolar tissue as a consequence of impaired regenerative capacities (emphysema). Recent research suggests that the secretome from mesenchymal cells, particularly extracellular vesicles (EVs), may possess regenerative properties beneficial for lung repair. However, the regenerative potential of the soluble factors (SFs) within the secretome remains largely unexplored in COPD. To this extent, we purified EVs and SFs secreted by lung fibroblasts to generate EV-enriched and SF-enriched fractions, and evaluated their effects on elastase-induced lung injury in both precision-cut lung slices (PCLS) and a mouse model. EV- and SF-enriched fractions were concentrated and purified from the conditioned medium of cultured MRC-5 lung fibroblasts using a combination of ultrafiltration and size exclusion chromatography, and were subsequently characterized according to the MISEV guidelines. Treatment with EV- or SF-enriched concentrates prevented and improved elastase-induced emphysema in PCLS, leading to reduced lung injury and upregulated markers of alveolar epithelial cells (aquaporin 5 and surfactant protein C), indicating potential parenchymal regeneration. Accordingly, prophylactic intratracheal treatment with lung fibroblast-derived EV- and SF-enriched concentrates in vivo attenuated elastase-induced lung tissue destruction, improved lung function, and enhanced gene expression of alveolar epithelial cell markers. Here, alveolar repair not only serves the purpose of facilitating gas exchange, but also by reinstating the essential parenchymal tethering required for optimal airway mechanics. In conclusion, this study highlights the therapeutic potential of both lung fibroblast-derived EV- and SF-enriched concentrates for the treatment of lung injury and emphysema.

This Month in Anesthesiology

This Month in Anesthesiology

Perioperative Pulmonary Atelectasis: Part I. Biology and Mechanisms.

Pulmonary atelectasis is common in the perioperative period. Physiologically, it is produced when collapsing forces derived from positive pleural pressure and surface tension overcome expanding forces from alveolar pressure and parenchymal tethering. Atelectasis impairs blood oxygenation and reduces lung compliance. It is increasingly recognized that it can also induce local tissue biologic responses, such as inflammation, local immune dysfunction, and damage of the alveolar-capillary barrier, with potential loss of lung fluid clearance, increased lung protein permeability, and susceptibility to infection, factors that can initiate or exaggerate lung injury. Mechanical ventilation of a heterogeneously aerated lung (e.g., in the presence of atelectatic lung tissue) involves biomechanical processes that may precipitate further lung damage: concentration of mechanical forces, propagation of gas-liquid interfaces, and remote overdistension. Knowledge of such pathophysiologic mechanisms of atelectasis and their consequences in the healthy and diseased lung should guide optimal clinical management.

Surfactant-Mediated Airway and Acinar Interactions in a Multi-Scale Model of a Healthy Lung.

We present a computational multi-scale model of an adult human lung that combines dynamic surfactant physicochemical interactions and parenchymal tethering between ~16 generations of airways and subtended acini. This model simulates the healthy lung by modeling nonlinear stress distributions from airway/alveolar interdependency. In concert with multi-component surfactant transport processes, this serves to stabilize highly compliant interacting structures. This computational model, with ~10 k degrees of freedom, demonstrates physiological processes in the normal lung such as multi-layer surfactant transport and pressure–volume hysteresis behavior. Furthermore, this model predicts non-equilibrium stress distributions due to compliance mismatches between airway and alveolar structures. This computational model provides a baseline for the exploration of multi-scale interactions of pathological conditions that can further our understanding of disease processes and guide the development of protective ventilation strategies for the treatment of acute respiratory distress syndrome (ARDS).

A Physiologically Informed Strategy to Effectively Open, Stabilize, and Protect the Acutely Injured Lung.

Acute respiratory distress syndrome (ARDS) causes a heterogeneous lung injury and remains a serious medical problem, with one of the only treatments being supportive care in the form of mechanical ventilation. It is very difficult, however, to mechanically ventilate the heterogeneously damaged lung without causing secondary ventilator-induced lung injury (VILI). The acutely injured lung becomes time and pressure dependent, meaning that it takes more time and pressure to open the lung, and it recollapses more quickly and at higher pressure. Current protective ventilation strategies, ARDSnet low tidal volume (LVt) and the open lung approach (OLA), have been unsuccessful at further reducing ARDS mortality. We postulate that this is because the LVt strategy is constrained to ventilating a lung with a heterogeneous mix of normal and focalized injured tissue, and the OLA, although designed to fully open and stabilize the lung, is often unsuccessful at doing so. In this review we analyzed the pathophysiology of ARDS that renders the lung susceptible to VILI. We also analyzed the alterations in alveolar and alveolar duct mechanics that occur in the acutely injured lung and discussed how these alterations are a key mechanism driving VILI. Our analysis suggests that the time component of each mechanical breath, at both inspiration and expiration, is critical to normalize alveolar mechanics and protect the lung from VILI. Animal studies and a meta-analysis have suggested that the time-controlled adaptive ventilation (TCAV) method, using the airway pressure release ventilation mode, eliminates the constraints of ventilating a lung with heterogeneous injury, since it is highly effective at opening and stabilizing the time- and pressure-dependent lung. In animal studies it has been shown that by “casting open” the acutely injured lung with TCAV we can (1) reestablish normal expiratory lung volume as assessed by direct observation of subpleural alveoli; (2) return normal parenchymal microanatomical structural support, known as alveolar interdependence and parenchymal tethering, as assessed by morphometric analysis of lung histology; (3) facilitate regeneration of normal surfactant function measured as increases in surfactant proteins A and B; and (4) significantly increase lung compliance, which reduces the pathologic impact of driving pressure and mechanical power at any given tidal volume.

Microscale to mesoscale analysis of parenchymal tethering: the effect of heterogeneous alveolar pressures on the pulmonary mechanics of compliant airways.

In the healthy lung, bronchi are tethered open by the surrounding parenchyma; for a uniform distribution of these peribronchial structures, the solution is well known. An open question remains regarding the effect of a distributed set of collapsed alveoli, as can occur in disease. Here, we address this question by developing and analyzing microscale finite-element models of systems of heterogeneously inflated alveoli to determine the range and extent of parenchymal tethering effects on a neighboring collapsible airway. This analysis demonstrates that micromechanical stresses extend over a range of ∼5 airway radii, and this behavior is dictated primarily by the fraction, not distribution, of collapsed alveoli in that region. A mesoscale analysis of the microscale data identifies an effective shear modulus, Geff, that accurately characterizes the parenchymal support as a function of the average transpulmonary pressure of the surrounding alveoli. We demonstrate the use of this formulation by analyzing a simple model of a single collapsible airway surrounded by heterogeneously inflated alveoli (a "pig-in-a-blanket" model), which quantitatively demonstrates the increased parenchymal compliance and reduction in airway caliber that occurs with decreased parenchymal support from hypoinflated obstructed alveoli. This study provides a building block from which models of an entire lung can be developed in a computationally tenable manner that would simulate heterogeneous pulmonary mechanical interdependence. Such multiscale models could provide fundamental insight toward the development of protective ventilation strategies to reduce the incidence or severity of ventilator-induced lung injury. NEW & NOTEWORTHY A destabilized lung leads to airway and alveolar collapse that can result in catastrophic pulmonary failure. This study elucidates the micromechanical effects of alveolar collapse and determines its range of influence on neighboring collapsible airways. A mesoscale analysis reveals a master relationship that can that can be used in a computationally efficient manner to quantitatively model alveolar mechanical heterogeneity that exists in acute respiratory distress syndrome (ARDS), which predisposes the lung to volutrauma and/or atelectrauma. This analysis may lead to computationally tenable simulations of heterogeneous organ-level mechanical interactions that can illuminate novel protective ventilation strategies to reduce ventilator-induced lung injury.

The influence of tethering and gravity on the stability of compliant liquid-lined airways

This study revolves around two simple questions: 1) how does pulmonary airway recruitment/de-recruitment (RecDer) depend on the tethering support provided by surrounding airways and alveoli, and 2) does airway angle of inclination (θ) influence airway stability? These two questions are critical to understanding the existence and prevention of atelectrauma, which may contribute to ventilator-induced lung injury (VILI). To address these questions, we develop PDMS 2mm ID compliant tubes that mimic pulmonary airways. Airway obstruction is modeled using silicone oil, and recruitment occurs through insufflation with a constant flow of air at Q=0.25ml/s. Parenchymal tethering is modeled through the use of a pressure chamber through which we independently establish the external pressure (Pext). Repetitive RecDer oscillation is observed as a function of Pext and θ. We find that airway collapse significantly increases the rate of instability, and this rate correlates strongly with the dimensionless film thickness (ε=h/R), where h is the film thickness and R is the transumural pressure dependent vessel radius. Furthermore, the angle of orientation influences RecDer oscillation, with stability decreased when airflow is directed in the upward direction. These results may provide insight into protective mechanical ventilation processes that can reduce the existence or severity of VILI.

Fat Transfer for Breast Reconstruction

Sir: Fat grafting to the breast is an old concept. Czerny first described breast reconstruction by fat transfer in 1895.1 After a long and controversial history, fat grafting has become an invaluable tool in breast reconstruction. It is used for core reconstruction and as an ancillary technique after various procedures for breast reconstruction. Unfortunately, in many cases, the recipient area is deformed by previous oncologic surgery, radiotherapy, or other pathologic circumstances. To address this issue, we use the three-dimensional ligamentous band release technique, or “rigottomy.” This technique was first described by Gino Rigotti, who used a pickle fork to release heavily scarred, recipient-site–radiated tissue.2 Three-dimensional ligamentous band release followed by adipose tissue grafting can be used effectively in breast reconstructive surgery, breast augmentation, and for the treatment of Dupuytren contracture.3–5 Breast deformities due to internal ligamentous bands and extensive scars can be successfully treated percutaneously. Immediately before fat injections to the breast, an 18-gauge Tuohy needle is inserted into multiple sites to release parenchymal tethering and scars, thereby creating a matrix that is the scaffold that will better accept fat grafts. In fact, decreased interstitial pressure leads to increased tissue perfusion and more engraftment potential. At our institution, from September of 2011 to September of 2012, we performed 11 three-dimensional ligamentous band release procedures before fat grafting to the breast. Eight patients were treated after breast-conserving surgery and three patients after expander-implant breast reconstruction. The sequelae of breast-conserving surgery are a challenge for plastic surgeons. Fat grafting with the release of parenchymal tethering and constriction bands improves breast contour, which appears smoother and more harmonious after the procedure. Before fat injections, once adipose tissue has been harvested and purified, the skin of the breast is raised and placed under tension using two nylon stitches. Multiple breast puncture wounds are then made with a Tuohy epidural needle, and the constriction bands are progressively and extensively severed through slight transverse oscillations at each puncture point (Fig. 1). The 18-gauge Tuohy needle we use is 9 cm long and has a blunt bevel with a 30-degree curve at the tip. With its long and firm cannula, the Tuohy needle can be handled efficiently by the surgeon, allowing a stable hold. Tension is maintained by constantly stretching the skin of the breast using the nylon suture, as the ligamentous bands progressively give way. Frequently, it is necessary to replace the stitches during the procedure if the area to be addressed is wide. Residual parenchymal tethering and scars are localized by palpation and treated in the same fashion. We carefully avoid creating an empty space where the adipose-grafted tissue cannot be nourished. Otherwise, we mesh the ligamentous band in multiple levels and planes, converting the cicatrix into a three-dimensional matrix that subsequently will be filled by adipose tissue grafts. In our practice, we have found that percutaneous three-dimensional ligamentous band release is also very useful in expander-implant breast reconstruction, mostly for the treatment of acquired contour deformities due to cicatricial adhesions secondary to extensive postoperative scarring or radiotherapy. Constriction bands are broken up through slight transverse oscillations of a Tuohy needle under the scar, taking care not to damage the implant.Fig. 1: Three-dimensional ligamentous band release with a Tuohy needle, intraoperative view. Constriction bands are progressively severed in multiple planes through slight transverse oscillations at each puncture point.In conclusion, three-dimensional ligamentous band release with a Tuohy needle has dual beneficial effects: it allows the surgeon to break the constriction bands, and it increases parenchymal space, thereby reducing graft crowding and filling pressure. DISCLOSURE The authors have no financial interest to declare in relation to the content of this article.

A model of surfactant-induced surface tension effects on the parenchymal tethering of pulmonary airways

We developed a computational model of lung parenchyma, which is comprised of individual alveolar chamber models. Each alveolus is modeled by a truncated octahedron. Considering the force balance between the elastin and collagen fibers laying on the alveolar membrane and the pressures acting on the membrane, we computed the deformations of the parenchyma with a finite element method. We focused on the effect of surfactant on the force of parenchymal tethering an airway. As the lung inflates, the parenchyma becomes stiffer and the tethering force becomes stronger. As the alveolar surfactant concentration is reduced, the lung volume at a fixed alveolar pressure decreases, and thus, the tethering force becomes weaker. The distortion of parenchyma caused by the deformation of an airway extends widely around the airway. The displacement of parenchyma decays with distance from the airway wall, but deviates from the prediction based on a theory for a continuum material. Using results obtained from the present lung parenchyma model, we also developed a simple 1-dimensional model for parenchyma tethering force on an airway, which could be utilized for the analysis of liquid/gas transports in an axis-symmetric elastic airway. The effective shear modulus was calculated from the pressure–volume relation of parenchyma. By manipulating the pressure–volume curve, this simple model may be used to predict the parenchyma tethering force in diseased lungs.

Quantifying parenchymal tethering in a finite element simulation of a human lung slice under bronchoconstriction

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 Pteth 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.

Ventilation heterogeneity: small length scales, big challenges

the distribution of regional ventilation is heterogeneous in normal lung and increases dramatically under pathological conditions. This has been demonstrated both in humans and in animal models using a number of different imaging techniques. General anesthesia and mechanical ventilation can

Acute hemorrhagic shock decreases airway resistance in anesthetized rat

We studied the relation between changes in pulmonary and systemic hemodynamics to those in the airway resistance, respiratory tissue mechanics, and thoracic gas volume (TGV) following acute hemorrhage and blood reinfusion in rats. Forced oscillation technique was used to measure airway resistance (Raw), respiratory tissue damping, and elastance at baseline and after stepwise 1-ml blood withdrawals up to 5 ml total, followed by stepwise reinfusion up to full restoration. Mean systemic (Pam) and pulmonary arterial pressures and suprarenal aortic blood flow were measured at each step. In supplemental animals, plethysmographic TGV, Pam, and respiratory mechanics measurements were performed. Blood volume loss (BVL) led to proportional decreases in Raw (66.5 ± 8.8 vs. 44.8 ± 9.0 cmH(2)O·s·l(-1) with 5 ml, P < 0.001), Pam, and aortic blood flow. In contrast, tissue damping increased significantly (1,070 ± 91 vs. 1,235 ± 105 cmH(2)O/l, P = 0.009 with 5 ml BVL), whereas tissue elastance did not change significantly. TGV significantly increased with acute BVL (3.7 ± 0.2 vs. 4.2 ± 0.2 ml, P = 0.01). Stepwise reinfusions produced opposite changes in the above parameters, with Raw reaching a higher value than baseline (P = 0.001) upon full volume restoration. Both adrenalin (P = 0.015) and noradrenalin levels were elevated (P = 0.010) after 5-ml blood withdrawal. Our data suggest that the decreases in Raw following BVL may be attributed to the following: 1) an increased TGV enhancing airway parenchymal tethering forces; and 2) an increase in circulating catecholamines. The apparent beneficial effect of a reduction in Raw in acute hemorrhagic shock is counteracted by an increase in dead space and the appearance of peripheral mechanical heterogeneities due to de-recruitment of the pulmonary vasculature.

Influence of airway wall stiffness and parenchymal tethering on the dynamics of bronchoconstriction

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.

Effect of parenchymal stiffness on canine airway size with lung inflation.

Although airway patency is partially maintained by parenchymal tethering, this structural support is often ignored in many discussions of asthma. However, agonists that induce smooth muscle contraction also stiffen the parenchyma, so such parenchymal stiffening may serve as a defense mechanism to prevent airway narrowing or closure. To quantify this effect, specifically how changes in parenchymal stiffness alter airway size at different levels of lung inflation, in the present study, we devised a method to separate the effect of parenchymal stiffening from that of direct airway narrowing. Six anesthetized dogs were studied under four conditions: baseline, after whole lung aerosol histamine challenge, after local airway histamine challenge, and after complete relaxation of the airways. In each of these conditions, we used High resolution Computed Tomography to measure airway size and lung volume at five different airway pressures (0, 12, 25, 32, and 45 cm H2O). Parenchymal stiffening had a protective effect on airway narrowing, a fact that may be important in the airway response to deep inspiration in asthma. When the parenchyma was stiffened by whole lung aerosol histamine challenge, at every lung volume above FRC, the airways were larger than when they were directly challenged with histamine to the same initial constriction. These results show for the first time that a stiff parenchyma per se minimizes the airway narrowing that occurs with histamine challenge at any lung volume. Thus in clinical asthma, it is not simply increased airway smooth muscle contraction, but perhaps a lack of homogeneous parenchymal stiffening that contributes to the symptomatic airway hyperresponsiveness.

Investigation of Hyperpolarized 3He Magnetic Resonance Imaging Utility in Examining Human Airway Diameter Behavior in Asthma Through Comparison with High-Resolution Computed Tomography

Application of a previously developed model-based algorithm on hyperpolarized (HP) (3)He magnetic resonance (MR) dynamic projection images of phantoms was extended to investigate the utility of HP (3)He MR imaging (MRI) in quantifying airway caliber changes associated with asthma. Airways of seven volunteers were imaged and measured using HP (3)He MRI and multidetector-row computed tomography (MDCT) before and after a methacholine (MCh) challenge. MDCT data were obtained at functional residual capacity and 1 L above functional residual capacity. Comparison of the resultant data showed that HP (3)He MRI did not match MDCT in measuring the ratios of airway calibers before and after the MCh challenge in 37% to 43% of the airways from the first six generations at the two lung volumes tested. However, MDCT did yield the observation that 49% to 69% of these airways displayed bronchodilation following MCh challenge. The current implementation of HP (3)He MRI did not match the MCh-induced postchallenge-to-prechallenge airway caliber ratios as measured with MDCT. Elevated parenchymal tethering due to bronchoconstriction-induced hyperinflation was proposed as a possible explanation for this airway dilation.

How should airway smooth muscle be punished for causing asthma?

asthma is a complex disease that has varied manifestations, is often difficult to treat, and indeed is even a challenge to define. Nevertheless, there are some features of asthma that are characteristic. Key among these is airways hyperresponsiveness (AHR), defined as an abnormally large mechanical

Airway Hyperresponsiveness, Remodeling, and Smooth Muscle Mass

We quantified the effects of airway wall remodeling upon airway smooth muscle (ASM) shortening. Isolated ASM from sheep was attached to a servo-controller that applied a physiologic load. This load could be altered to reflect specified changes of airway wall geometry, elasticity, parenchymal tethering, transpulmonary pressure (P(L)), and fluctuations in P(L) associated with breathing. Starting at a reference length (L(ref)), ASM was stimulated with acetlycholine and held at constant P(L) of 4 cm H(2)O for 2 h. When all compartments were thickened to simulate the asthmatic airway but P(L) was held fixed, ASM shortened much more than that in the normal airway (to 0.52 L(ref) versus 0.66 L(ref)). When breathing with deep inspirations (DIs) was initiated, within the first three DIs the ASM in the normal airway lengthened to 0.84 L(ref), whereas that in the asthmatic airway remained stuck at 0.53 L(ref). Thickening of the smooth muscle layer alone produced the greatest muscle shortening (to 0.47 L(ref)) when compared with thickening of only submucosal (to 0.67 L(ref)) or only adventitial (to 0.62 L(ref)) compartments. With increased ASM mass, the ASM failed to lengthen in response to DIs, whereas in the airway with thickened submucosal and adventitial layers ASM lengthened dramatically (to 0.83 L(ref)). These findings confirm the long-held conclusion that increased muscle mass is the functionally dominant derangement, but mechanisms accounting for this conclusion differ dramatically from those previously presumed. Furthermore, increased ASM mass explained both hyperresponsiveness and the failure of a DI to relax the asthmatic airway.

Parenchymal tethering, airway wall stiffness, and the dynamics of bronchoconstriction

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.

Deep Inhalation and Airway Patency in Children

Deep inhalation (DI) induces changes in airway calibre that may last beyond the manoeuvre itself. The mechanisms involve mechanical interaction between conducting airways subjected to parenchymal tethering and lung parenchyma itself. Healthy children usually show small bronchodilation after DI. Increased airway calibre after DI has been documented in wheezy preschool children with mild airway obstruction and, after methacholine challenge, in preschool and school children with normal lung function but has not yet been demonstrated in infants. The DI also induces bronchodilation in children with mild exercise induced airway obstruction. In the presence of severe airway obstruction, the bronchodilatory effect of DI may be blunted or reversed. The bronchodilatory effect of DI appears to be larger in children and adults than infants and elderly and larger in girls than boys. It is inversely related to the degree of airway hyperresponsiveness and the blunted bronchodilatory response to DI in acute or severe asthma is restored by steroid therapy or allergen avoidance. The airway effects of DI may in the future prove a valuable tool in assessing the mechanisms of airway obstruction and reactivity in children. Keywords: Conducting airways, lung parenchyma, respiratory or airway resistance, methacholine, exercise, asthma, bronchodilation, bronchoconstriction, airway responsiveness, lung volume

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.