The multiple inert gas elimination technique (MIGET) provides a method for estimating the efficiency of alveolar gas exchange. Six soluble inert gases with blood solubility spanning six orders of magnitude are infused into a peripheral vein of an animal. After gas equilibration, the exhaled, venous, and arterial partial pressures of these six gases are measured and interpreted by using a mathematical model of alveolar gas exchange. MIGET has been very successful in improving our understanding of alveolar gas exchange in both health and disease.
Developed in the early 1970s, MIGET assumed that none of the six chosen gases exchanged with the airways. However, this assumption is no longer considered to be valid. Over the past 20 years, our experimental and theoretical investigations on airway gas exchange have shown that the location of gas exchange (airway versus alveoli) depends primarily on gas solubility in both blood and water (as measured by a partition coefficient). Gases with both blood-air and water-air partition coefficients greater than 10 exchange primarily in the airways. Meeting this criteria, two of the most soluble MIGET gases, ether and acetone, exchange primarily in the airways, violating a basic assumption for application of MIGET.
To examine the impact of airway gas exchange on the MIGET predictions, we replaced ether and acetone in the MIGET analysis with two gases of similar blood solubility but decreased water solubility (toluene for ether and m-DCB for acetone) and, thereby, theoretically minimized the influence of airway gas exchange on MIGET. A comparison of the MIGET predictions using ether and acetone versus using the two replacement gases provided a straightforward means for evaluating the effect of airway gas exchange on the MIGET predictions. We found that airway gas exchange mostly affects predictions of dead space, mean of the ventilation distribution and standard deviation of the ventilation distribution. We conclude that revision of the protocol for the MIGET method by substituting gases with lower water solubility would improve MIGET predictions.
The lung consists of myriad disparate components that interact in a rich variety of ways. Accordingly, a quantitative understanding of how the lung functions can be pursued at many levels of scale, from that of the molecule up to the whole organ. Importantly, however, a complete understanding of lung function at the organ level does not follow automatically from knowledge of the individual characteristics of its components. Indeed, understanding the components in isolation may not even constitute the major requirement for an understanding of the lung as a whole. This is because the lung is a complex system - something with emergent properties that arise from the way its components operate as an ensemble. Emergent properties in a complex system typically bear little qualitative relationship to the individual properties of the system components, yet somehow arise from these components and their interactions in frequently subtle ways. Prediction of emergence in complex systems is well known to physicists, as it constitutes the central paradigm of statistical mechanics that began with the kinetic theory of gases more than a century ago. Emergence has been formally embraced by the biomedical community only more recently, but it impacts the life of every scientist, whether they know it or not, through the Central Limit Theorem which provides a theoretical basis for the widespread appearance of the Gaussian distribution throughout the natural world. Even the ubiquity of power law processes in nature, which is now exciting a great deal of interest in biology and physics and makes its appearance in the lung, likely represents an emergent phenomenon. Understanding the genesis of emergent behavior, however, is frequently not straightforward. Highly nonlinear interactions between system components are typical of complex biological systems, which severely limits the use of analytical methods for predicting the emergent properties arising there from. The exploration of emergent behavior in the lung is thus going to be based on computational models based constructs such as cellular automata, artificial network networks, percolation networks, and distributed recruitment mechanisms. As specific examples, we will consider how percolation and recruitment mechanisms might be invoked to account for the bulk mechanical properties of lung tissue.
Detailed knowledge of aerosol particle deposition in the human respiratory tract is an important issue in understanding the effect of aerosol exposure whether this exposure results from atmospheric pollution, biological warfare, occupational factors or inhaled drug therapy. Information on lung deposition in humans is limited and mathematical models have often been used to complement experimental studies under different exposure conditions. Mathematical models not only help interpret experimental data but also allow predictions to be made for cases where experimental data are not available or ethically obtainable.
Early models of aerosol transport and deposition in the lung were based on a one-dimensional (1D) approach either by estimation of total deposition in a lung model made up of a discrete number of morphometric regions or by a continuous description of aerosol transport in the lung. However, the 1D models rest on the implicit assumptions that the radial diffusion of the aerosol can be dealt with by use of a single effective diffusion constant, and that velocity and aerosol concentration are uniform over the cross section of the airways; neither of which is valid in the complex structure of the lung.
Multidimensional simulations have provided more detailed and realistic information on aerosol behavior in the human lung. Several authors have modeled aerosol transport in the conducting airways examining the effects of geometrical features of the upper respiratory tract; and by considering one, two, or more successive airway bifurcations. In all studies, the distribution of deposited particles showed significant inhomogeneities. Interestingly, comparison between planar and non-planar configurations of successive generations showed significant differences in both the distribution and the local concentrations of the deposited particles suggesting that the angle with respect to gravity of the bronchi cannot be ignored in a realistic model.
Detailed computations of intra-acinar aerosol transport were first performed in two-dimensional models and more recently in a three-dimensional model of a single bifurcation of alveolated ducts. All these studies showed that flow patterns were influenced by the geometric characteristics of the alveolar aperture; that the presence of the alveolar septa contributed to the penetration of the particles into the periphery of the lung; and that there were large inhomogeneities in deposition patterns within the acinar structure. More recent studies have focused on predicting aerosol transport in acinar models with moving walls. Flow patterns in an expanding structure differ substantially from that in a rigid-wall model allowing particles to penetrate the alveolar cavities not only as a result of their intrinsic motions (diffusion, sedimentation) but also by convective transport. The result is a much higher deposition in moving-wall models compared to rigid-wall models, demonstrating the importance of modeling the expansion and contraction of the alveolar structure.
With every beat of the heart, inflation of the lung, or peristalsis of the gut, cell types of diverse function are subjected to substantial stretch. New data show that cell responses to a transient stretch exhibit remarkable physical similarities to fluidization observed in jammed inert matter, including colloids, pastes, emulsions, and foams, and thus implicate mechanisms mediated not only by specific signaling intermediates, as is usually presumed, but also by nonspecific actions of a slowly evolving network of physical forces. These results support the idea that the cell interior is at once a crowded chemical space and a fragile soft material in which the effects of biochemistry, molecular crowding, and physical forces are complex and inseparable, yet conspire nonetheless to yield remarkably simple phenomenological laws. These laws appear to be universal and thus comprise a striking point of contact between the worlds of cell signaling biology and soft matter physics.
Asthma is a chronic disease that affects approximately 10% of the population in the United States. Although our understanding of underlying mechanisms (e.g., Th2 type inflammation) has continued to increase over the past several decades, the prevalence continues to rise. Furthermore, the mainstay of monitoring (spirometry) and therapy (anti-inflammation and -agonist bronchodilation) are essentially unchanged over the same time period. Over the past ten years, the interest in using exhaled nitric oxide as a non-invasive marker of inflammation has steadily increased despite a limited understanding of the cell and molecular mechanisms. More recently, the loss of naturally occurring NO-based bronchodilators (S-nitrosothiols or SNOs) in an animal model of asthma has sparked renewed interest in the key role of NO biochemistry in modulating asthma. Our group combines advanced primary cell culture techniques, direct measurement of gas phase NO release, quantitation of enzymatic activity, exhaled nitric oxide from human subjects, and mathematical models in an integrative fashion to understand how multiscale systems interact to influence NO storage and release in the lungs. We hope this approach will significantly improve our mechanistic understanding of NO metabolism and gas phase release, and thus non-invasive inflammatory monitoring of asthma.
Several respiratory disorders including infant RDS, adult RDS and acute lung injury, are characterized by the fluid-occlusion of small pulmonary airways and alveoli. The reopening of these fluid-filled structures involves the movement of air-liquid interfaces and the application of complex hydrodynamic and surface tension forces on the epithelial cells which line airway and alveolar walls. Although these fluid mechanical forces may contribute to ventilator-induced lung injury, the mechanism of cellular injury during these free-surface flows is not well established. Under these conditions, the amount of cellular deformation is not known a priori and may depend on several multi-scale factors including a) reopening dynamics, b) surfactant transport to the air-liquid interface, c) morphological and/or micro-mechanical properties of the epithelial cells and d) molecular interactions at focal adhesion sites. In addition, biochemical responses (i.e. protein/gene expression) to these different hydrodynamic conditions may also contribute to lung injury. Our laboratory utilizes a combination of in-vitro cell culture experiments, advanced imaging techniques and computational models to investigate the relative importance of these different factors. The goal is to obtain a better understanding of the biophysical and biological mechanisms of cell/tissue injury during the reopening of fluid-filled airways/alveoli.
In this presentation we will first present a brief overview of previous studies which have elucidated the multiphase fluid mechanics of airway/alveolar reopening. We will then present recent experimental data which demonstrate how changes in reopening dynamics, cellular morphology, cell mechanics and cytoskeletal structure influence cell injury during airway reopening. We will also discuss the development of multi-scale, computational models of cellular deformation during airway reopening. In addition to providing valuable insight into the mechanism of cell injury, these computational models have been used to explain several counter-intuitive experimental results including increased cell death at slow reopening velocities and decreased death in cells with a lower elastic modulus (i.e. a more flexible cell). Finally, we will discuss future challenges in modeling cellular responses to complex hydrodynamic and surface tension forces including the incorporation of realistic airway/cellular geometries, non-linear membrane mechanics, heterogeneous viscoelastic cell properties and molecular interactions at focal adhesion sites.
There has been no consensus how the alveolar shape changes during breathing due to difficulties in observing directly alveoli in vivo. A computational model of dynamical 3D model, that can be called a 4D model, would be useful for understanding such an invisible phenomenon. The living organ changes its shape during morphogenetic process as well as during physiologic motion. Therefore, an algorithm for constructing a 3D model of the organ should be consistent with its morphogenetic process, too. In other words, the fourth dimension of the organ model should possess both of physiological and morphogenetic time scales. The alveolar morphogenesis is roughly classified into four steps from a geometric point of view: formation of a fluid pathway, enlargement of intra-acinar pathway, bellows-like arrangement of primary septa by capillary invasions, and growth of secondary septa whose edges form alveolar mouths containing abundant elastin fibers. Those steps are accompanied with functional maturation: making a duct transport system, utilize full space in the organ, increasing surface area, and finally acquiring deformability. We have constructed a 4D alveolar model according to the above morphogenetic process, where the alveolar deformation is modeled by a combination of spring (elastin fibers at alveolar mouths) and hinge (septal junctions). The model includes a hypothesis that alveolar mouths are closed at minimum volume and that closed alveoli are stabilized by the alveolar lining liquid film containing surfactant. The validity of the model has been verified not fully but satisfactorily by comparing it with real experimental results; in vivo microscopic observation of subpleural alveoli (courtesy of Nieman, GF), histologic sections of rapidly frozen lungs (in literatures), and morphometric investigations by light scattering and intravascular fixation-dehydration method (in literatures).
In this presentation I will talk about the progress in developing a comprehensive computational fluid dynamic (CFD) model for pulmonary air flow which utilizes subject-specific airway geometries and employs a Computed Tomography (CT) data-driven, multi-stage approach to provide accurate predictions of regional ventilation and gas transport through the entire moving airway tree. The model is based up an in-house parallel characteristic Galerkin fractional four-step finite element method. Both direct numerical simulation (DNS) and large-eddy simulation (LES) techniques have been employed to simulate turbulent flow in the proximal conducting airways. A three-stage approach has been adopted to simulate air flow in the acinar airways. Due to the large mesh size, some CFD simulations have been carried on TeraGrid clusters. The effects of boundary conditions and subject-specific human airways on air flow have been assessed. The transient air flow in a CT-based monopodial sheep (ovine) tracheobronchial tree of up to 13 generations has also been studied numerically. Currently, a geometric model of 11 generations of human airways has been constructed and the preliminary CFD simulation has been successfully performed. The progress in developing an in-house mesh generation software which aims to create CFD mesh from the trachea to the terminal bronchioles will be reported. Toward modeling a breathing lung, the host-mesh technique in conjunction with 4D dynamic imaging, the model for soft tissue mechanics, and the fluid-structure interaction (FSI) technique have been or are being developed, which will be briefly discussed as well.
Behavior of complex systems is often better characterized by assessment of temporal variation and amplitude distribution properties rather than by current or average values. As an example, asthma has been postulated to be a disease arising from multiple acting influences to a complex, heterogeneous, nonlinear system. These influences include both endogenous and environmental factors that are thought to contribute to increase random fluctuations in symptoms and lung function. While increased fluctuations in peak expired flow in asthma are well established, recently it has been shown that the fluctuations are not entirely random, but show long range temporal correlations, indicative of fractal processes associated with complex systems.
While variation in lung function has been quantified over many months at long time scales, variability of airway function also occurs at short time scales, on the order of seconds and minutes. We and others have shown that short-term variation in airway resistance (like long-term variation in peak expired flow) is elevated in asthma and we will show that this measure is more sensitive to the effects of an inhaled bronchodilator than instantaneous measures such as FEV1.0, FEF25-75 and average airway resistance. We will also show that variation in airway resistance depends on diameter and lung volume due the inverse 4th power dependence of resistance on diameter and also depends on activation state and loading of the smooth muscle. Thus a bronchodilator appears to both relax airway smooth muscle leading to bronchodilation, and to quiet airway smooth muscle, with both effects leading to reduced variation in airway resistance.
Like long-term variation in lung function, we will show short-term variation in airway resistance also exhibits some long range-temporal correlations. And like long-term variation, we have found that short-term variation in airway resistance also depends on asthma therapy. We will discuss our measurements of short-term variation of airway resistance in asthma, and discuss if short-term variation in lung function could predict long term-variation and thus make predictions to the severity of the disease. Although the direct mechanisms may be different, variation in lung function extends from short to long time scales in asthma, and it is likely that both result from the interactions between environmental inputs and memory effects of the dynamic nonlinear system.
We present a theoretical model to quantify how alterations in the cross-bridge kinetics of airway smooth muscle (ASM) and in the airway wall remodeling affect the symptoms of asthma and chronic obstructive pulmonary disease (COPD). By taking into account the coupling between ASM contraction and the dynamics of breathing, the new model is able to predict the hyperreactivity of the asthmatic airways and their hypersensitivity to increasing doses of contractile agents. The latter could not be reproduced by previous models that considered static equilibrium between the isometric ASM force and the mean transpulmonary pressure. In the presented model the airway caliber - proportional to the ASM length - is dynamically determined from the instantaneous balance between airway wall reaction force (AWRF) and the ASM contractile force. The AWRF is derived from transmural pressure across the airway wall and the forces of parenchymal tethering: it is computed from the elasticity and geometry of the airway wall, the tethering of the airway to the lung parenchyma, and the state of lung inflation. The resulting force is equivalent to an instantaneous load acting on the ASM in situ. This force depends on the transpulmonary pressure variation and the pressure drop along the airway tree during breathing. The ASM contractile force and length are determined using Mijailovich's model, based on the perturbed equilibria of myosin binding. The instantaneous airway luminal area and resistance are obtained from the ASM length for each airway generation in Weibel's bronchial tree. The pressure drop along the tree is computed from the resistance and the instantaneous flow rate. The calculations include the effect of deep inspirations (DI) superimposed over quiet tidal breathing for normal, COPD, and asthmatic airways. Our results show that at low doses of histamine, ASM reaches dynamical equilibrium at long lengths, and the airways are completely open and compliant. However, at histamine doses above a "critical" value, the ASM drastically shortens, and the airways are severely constricted and stiff. In COPD and asthmatic airways the critical dose is significantly lower than in normal airways; above this dose the degree of ASM shortening, and therefore airway constriction, are both significantly greater than in normal airways. In this case, DI may not be sufficient to open the asthmatic airways. The agreement between the model predictions and clinical observations suggests that both the hyperreactivity and hypersensitivity observed in asthmatic and COPD airways can be explained by a single mechanism - perturbed equilibria of myosin binding.
Key words: Airway narrowing, airway resistance, lung mechanics, computational model, a multiscale model, smooth muscle, cross-bridge kinetics, obstructive disease, asthma.
The lung is an inflatable organ that must incorporate three separate tree structures. Thus, in order for the lung to inflate, all of these trees must stretch both axially and radially. Indeed, it was noted almost a century ago that if the airway tree could not lengthen, then the lung likely could not inflate. In this presentation we will discuss the first distensibility of airways, and then how this distensibility interacts with that of the surrounding lung parenchyma.
In modeling the lung an implicit assumption is often made that airway diameter varies as the cube root of lung volume. While there has been some published evidence to support this under certain conditions, the assumption is not supported by what is known about the airway structure. The role of the relatively nondistensible basement membrane is generally ignored. However, the fact that the length of this membrane is relatively fixed has been used histologically to compare airways of comparable size in asthmatic and normal subjects. So if the basement membrane is rigid, how can the airway diameter vary as the cube root of lung volume? Either this fixed length is larger than the largest size the airway ever achieves, or the assumption is wrong. We will show that the latter reason is the correct one.
We will show that pressure-area curves of relaxed airways in vivo are highly nonlinear, reaching a maximal size at a very low pressure (less than 10 cmH2O). The limit is consistent with a rigid basement membrane. With smooth muscle tone, the relation between airway area and pressure becomes highly variable depending on the level of tone and other uncertain factors. This variability in tone even under baseline conditions is what often causes misinterpretation of the nature of the distensibility. All dogs we have studied have a variable degree of baseline tone, averaging from 50-70% of maximally relaxed size. Although most clinical research suggests that there is little baseline tone in normal healthy subjects, this is not true. With sufficient relaxation of the airway smooth muscle, we can show that even normal humans also live with airways at about 705 of maximal size.
These results stress the importance of understanding the link between airway structure and their functional distensibility. The way airways respond to inflation may have important clinical manifestations in the asthmatic pathology.
Gas entering the lung encounters a rapidly dividing network of airways with a total cross-sectional area that increases extremely rapidly from a few cm2 in the trachea, to an area of 50-100 m2 at the gas exchange surface. As a consequence, the forward velocity of the inspired gas falls precipitously as the airway tree is traversed, and in the periphery of the lung, diffusion is the dominant gas transport process.
Understanding gas transport in the periphery of the lung rests on modeling the interaction between diffusive and convective transport processes. Extensive modeling studies have shown that asymmetry in the vicinity of the acinar entrance, results in an inhomogeneous distribution of gas within the lung, even if the lung expands homogeneously. This degree of structural asymmetry in the lung at the point at which convective transport and diffusive transport are of a similar magnitude greatly affects the behavior of the exhaled gas profile. Further, variability in the degree of structural asymmetry is a critical component of how inhomogeneously inspired gas is distributed within the lung.
By using gases of different diffusivity (typically He and SF6), studies of gas mixing in the periphery of the lung may be performed, since the convective component of the transport is largely the same for both gases. When these studies were performed in sustained microgravity, the difference in Phase III slope between SF6 and He (normally positive in ground studies) was abolished. These results suggested a change in the conformation of the acinus of the lung (the functional gas exchange unit of the lung). Identical studies performed in the transient microgravity of parabolic flight produced different results to those in sustained microgravity, showing that the time constant of the changes in conformation was relatively long. Ground-based studies suggest that changes in the amount of extra-vascular water in the pulmonary interstitium, the early stages of pulmonary edema, may be responsible.
Acute lung injury (ALI) and the adult respiratory distress syndrome (ARDS) are syndromes of respiratory failure with mortality in excess of 30% affecting an estimated 25-50 patients per 100,000 per year worldwide. While there are a variety of initiating events, the final common pathway is characterized by hypoxemic respiratory failure with a heterogeneous loss of aerated lung volume and reduced compliance due to flooding and collapse, surfactant inactivation, increased dead space, and inflammation. Clinical management is currently limited to supportive measures, primarily low tidal volume mechanical ventilation with positive end-expiratory pressure (PEEP), in an attempt to recruit the poorly aerated lung while reducing injurious cyclic end-expiratory airspace opening and closing and end-inspiratory regional overdistension. Many other therapeutic approaches, including pharmacologic therapy to reduce edema formation or inflammation or improve perfusion distribution, exogenous surfactant treatment, and novel mechanical ventilation strategies, have been tried or are in development but none have yet been shown to improve outcome.
Modeling of ALI/ARDS pathophysiology to date has been focused on the quasi-static pressure-volume properties of the injured lungs, primarily in an attempt to predict recruitment and optimal mechanical ventilation strategies, but these approaches have had limited success, possibly because they do not adequately reflect the very different dynamic operating conditions of the injured lung. Opportunities for modeling to contribute to improved understanding of ALI pathophysiology and management abound. Better characterization of the dynamic mechanical properties of the lung, particularly the distributed regional contributions, non-linear effects over the tidal breathing cycle, and a focus on heterogeneity may help optimize mechanical ventilation management strategies. Next, the consequences of these interventions on ventilation and perfusions distributions and matching, dead space, and vascular regulation are important in translating mechanics to improved physiology and effective gas exchange. Novel therapies such as high-frequency oscillatory ventilation, airway pressure-release ventilation (APRV), and "noisy" ventilation need to be understood in terms of their mechanisms of gas exchange and effects on lung mechanics and V/Q. ALI/ARDS represents an area in which there is an opportunity for model-based advances to very rapidly achieve translation to the clinical arena and thus have great potential to improve patient care and outcomes.
Lung parenchyma is a tensed stress-supported structure. The key distending stress, transpulmonary pressure, is transmitted by a tensed parenchymal lattice composed of the extracellular matrix (ECM), surface film and the contractile apparatus. This stress confers, in a nearly direct proportion, the parenchymal shear modulus and the associated forces of elastic interdependence that are critical in maintaining the shape of organ, region, vessel and alveolus. At each of these levels, this distending stress is essential for lung function, including stability of airspaces, distributions of ventilation and perfusion, fluid balance, and expiratory flow limitation. In the normal lung, the tensed ECM is the scaffold to which many pulmonary cells adhere. These cells use their contractile apparatus to probe their mechanical microenvironment in order to orient, spread, contract, remodel, differentiate and proliferate. Force transmission between cells and the ECM is bidirectional. Contractile stress, generated within the cytoskeletal lattice, is transmitted to the ECM via focal adhesions. In turn, focal adhesions transmit the distending stress of the ECM into the cytoskeleton (CSK). By utilizing similar mechanisms as the parenchyma, the cytoskeletal distending stress confers, in nearly direct proportion, shear modulus to the cell stabilizing thereby cell's shape. The distending stress of the CSK is a result of the interplay between the stress generated by contractile apparatus and the stress generated by distension of the ECM. At low to moderate levels of ECM distension, these two stresses work in concert, but at higher levels of ECM distension, contractile force generation may be hampered and thus cell stiffness reduced. Nevertheless, even if contractile apparatus is inhibited, the ECM distension can confer shear modulus to the cell through the passive component of the cytoskeletal distending stress. In summary, in the lung at each level - the ECM, surface film, the contractile apparatus, and the CSK - the distending stress emerges as a recurring and unifying agent. Its role is to confer stability to each of these levels, which is essential for normal function of the lung.
The lung tissue is constantly under a preexisting tensile stress also called prestress which results from the distension of the lung by the transpulmonary pressure. The regional distribution of the prestress is determined by the hydrostatic pressure in the pleural space and the shape of the lung. Superimposed on this prestress are additional stresses due to breathing which change cyclically and irregularly. The prestress in the alveolar wall is transferred through the extracellular matrix (ECM) to the adhering cells with important consequences on cellular biophysics, biochemistry and phenotype which can modulate connective tissue homeostasis itself. The interaction between the ECM and cellular biochemistry also has important implications for the biomechanical properties of the connective tissues of the lung. Recently, we have argued that collagen plays a major role in transmitting the transpulmonary pressure to lung cells in the alveolar septa through a hierarchical transmission of mechanical stimuli from the level of the whole lung down to single cells with various possible feedback loops controlling ECM remodeling and ultimately organ level mechanics. In this multiple loop system, the alveolar wall network plays an important role since it must respond to any changes in local stiffness. We will discuss several general modeling approaches that are appropriate to describe this hierarchical force transmission in the normal and diseased lungs. As specific examples, we will describe several models of the parenchyma using two- or three-dimensional spring networks. By connecting different length scales, these models are able to account for many functional properties of the normal and the emphysematous lung including remodeling due to stretch, the deterioration of lung function due to rupture of the alveolar septa, or the effects of lung volume reduction surgery on survival rate. Finally, based on the results, we will speculate on how small- and large-scale heterogeneities necessarily develop during the progression of emphysema and possibly other diseases.
Heterogeneity in airway constriction and in ventilation are cardinal features of asthma and understanding them is important as they affect overall mechanical obstruction, gas exchange efficiency, intrapulmonary delivery of therapeutic agents, and interpretation of diagnostic tests.
The current paradigm in asthma research assumes that knowledge about individual components of the lung (airways, tissues, or cells) can be extrapolated to predict full organ behavior. This approach is of limited quantitative value when complex interactions amongst components of the system are involved. In this presentation we will review experimental data challenging the current appraoch and will present modeling results demonstrating that interdependence amongst lung components may be the cause for those experimental findings
Using an integrative model of the airway tree we have demonstrate that, smooth muscle activation cause heterogeneous ventilation characterized by large and contiguous clusters of highly constricted terminal bronchioles similar to ventilation defects observed with MRI, and PET. The heterogeneous behavior of the model is remarkable because it is exhibited by a virtually symmetric airway tree, with uniform parameters at each generation and homogeneous smooth muscle activation.
In this report we evaluate the interdependent behavior amongst the airways of such a model and present the following results: 1) Smooth muscle activation above a critical level yields a heterogeneous response of the airways including dilation of some and constriction of others. 2) A reduction of end-expiratory lung volume during breathing reduces the critical level of smooth muscle activation triggering clusters of severe constriction. 3) Smooth muscle activation of a single central airway leads to its full closure although stronger but uniform activation of the fill tree does not. And 4) A progressive relaxation from maximal smooth muscle activation leads to a progressive reduction in the extent of ventilation defects and a simultaneous constriction of central airways.
We postulate that these results are manifestations of interdependent behavior in a complex system which may explain apparently paradoxical experimental findings.