Pulmonary Acinus Research Articles

A Semiautomatic Segmentation Algorithm for Extracting the Complete Structure of Acini from Synchrotron Micro-CT Images

Pulmonary acinus is the largest airway unit provided with alveoli where blood/gas exchange takes place. Understanding the complete structure of acinus is necessary to measure the pathway of gas exchange and to simulate various mechanical phenomena in the lungs. The usual manual segmentation of a complete acinus structure from their experimentally obtained images is difficult and extremely time-consuming, which hampers the statistical analysis. In this study, we develop a semiautomatic segmentation algorithm for extracting the complete structure of acinus from synchrotron micro-CT images of the closed chest of mouse lungs. The algorithm uses a combination of conventional binary image processing techniques based on the multiscale and hierarchical nature of lung structures. Specifically, larger structures are removed, while smaller structures are isolated from the image by repeatedly applying erosion and dilation operators in order, adjusting the parameter referencing to previously obtained morphometric data. A cluster of isolated acini belonging to the same terminal bronchiole is obtained without floating voxels. The extracted acinar models above 98% agree well with those extracted manually. The run time is drastically shortened compared with manual methods. These findings suggest that our method may be useful for taking samples used in the statistical analysis of acinus.

A first principles calculation of the oxygen uptake in the human pulmonary acinus at maximal exercise

It has recently been shown that the acinus can have a reduced efficiency due to a “screening effect” governed by the ratio of oxygen diffusivity to membrane permeability, the gas flow velocity, as well as the size and configuration of the acinus. We present here a top to bottom calculation of the functioning of a machine acinus at exercise that takes this screening effect into account. It shows that, given the geometry and the breathing dynamics of real acini, respiration can be correlated to a single equivalent parameter that we call the integrative permeability. In particular we find that both V˙O2,max and PAO2 depend on this permeability in a non-linear manner. Numerical solutions of dynamic convection–diffusion equations indicate that only a narrow range of permeability values is compatible with the experimental measurements of PAO2 and V˙O2,max. These permeability values are significantly smaller than those found in the literature. In a second step, we present a new type of evaluation of the diffusive permeability, yielding values compatible with the top to bottom approach, but smaller than the usual morphometric value.

Respiratory microflows in the pulmonary acinus

Over the past few decades, our understanding of the fluid mechanics characterizing the pulmonary acinus of the lungs has been fundamentally revisited. In the present paper, we review the current knowledge of acinar convective airflows and their role in determining the fate of inhaled aerosols in the distal regions of the lungs. We discuss the influential body of computational and experimental efforts following the revealing bolus studies initiated by Heyder et al. (1988) that have dramatically advanced our description of acinar flow phenomena. In particular, we characterize the range of complex flow topologies that exist locally in alveolar cavities and describe the ensuing convective mechanisms known to generate kinematic irreversibility in the acinus, despite low-Reynolds-number flows. By using dimensional analysis, we shed some light on the intimate coupling that arises in the pulmonary acinus between diffusive, convective and sedimentation mechanisms for aerosol deposition. Finally, we evoke some of the critical challenges that lie ahead in predicting accurately the deposition of inhaled particles across the acinar region and give a brief outlook toward novel approaches for resolving acinar flow dynamics at the real scale.

Assessment of morphometry of pulmonary acini in mouse lungs by nondestructive imaging using multiscale microcomputed tomography

Establishing the 3D architecture and morphometry of the intact pulmonary acinus is an essential step toward a more complete understanding of the relationship of lung structure and function. We combined a special fixation method with a unique volumetric nondestructive imaging technique and image processing tools to separate individual acini in the mouse lung. Interior scans of the parenchyma at a resolution of 2 µm enabled the reconstruction and quantitative study of whole acini by image analysis and stereologic methods, yielding data characterizing the 3D morphometry of the pulmonary acinus. The 3D reconstructions compared well with the architecture of silicon rubber casts of mouse acini. The image-based segmentation of individual acini allowed the computation of acinar volume and surface area, as well as estimation of the number of alveoli per acinus using stereologic methods. The acinar morphometry of male C57BL/6 mice age 12 wk and 91 wk was compared. Significant increases in all parameters as a function of age suggest a continuous change of the lung morphometry, with an increase in alveoli beyond what has been previously viewed as the maturation phase of the animals. Our image analysis methods open up opportunities for defining and quantitatively assessing the acinar structure in healthy and diseased lungs. The methods applied here to mice can be adjusted for the study of similarly prepared human lungs.

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

A108 肺細葉不均質構造モデルを用いた酸素拡散解析(A1-2 生体流体工学2)

A108 肺細葉不均質構造モデルを用いた酸素拡散解析(A1-2 生体流体工学2)

Morphometric changes in the human pulmonary acinus during inflation.

Despite decades of research into the mechanisms of lung inflation and deflation, there is little consensus about whether lung inflation occurs due to the recruitment of new alveoli or by changes in the size and/or shape of alveoli and alveolar ducts. In this study we use in vivo (3)He lung morphometry via MRI to measure the average alveolar depth and alveolar duct radius at three levels of inspiration in five healthy human subjects and calculate the average alveolar volume, surface area, and the total number of alveoli at each level of inflation. Our results indicate that during a 143 ± 18% increase in lung gas volume, the average alveolar depth decreases 21 ±5%, the average alveolar duct radius increases 7 ± 3%, and the total number of alveoli increases by 96 ± 9% (results are means ± SD between subjects; P < 0.001, P < 0.01, and P < 0.00001, respectively, via paired t-tests). Thus our results indicate that in healthy human subjects the lung inflates primarily by alveolar recruitment and, to a lesser extent, by anisotropic expansion of alveolar ducts.

Geometric Hysteresis of Alveolated Ductal Architecture

Low Reynolds number airflow in the pulmonary acinus and aerosol particle kinetics therein are significantly conditioned by the nature of the tidal motion of alveolar duct geometry. At least two components of the ductal structure are known to exhibit stress-strain hysteresis: smooth muscle within the alveolar entrance rings, and surfactant at the air-tissue interface. We hypothesize that the geometric hysteresis of the alveolar duct is largely determined by the interaction of the amount of smooth muscle and connective tissue in ductal rings, septal tissue properties, and surface tension-surface area characteristics of surfactant. To test this hypothesis, we have extended the well-known structural model of the alveolar duct by Wilson and Bachofen (1982, "A Model for Mechanical Structure of the Alveolar Duct," J. Appl. Physiol. 52(4), pp. 1064-1070) by adding realistic elastic and hysteretic properties of (1) the alveolar entrance ring, (2) septal tissue, and (3) surfactant. With realistic values for tissue and surface properties, we conclude that: (1) there is a significant, and underappreciated, amount of geometric hysteresis in alveolar ductal architecture; and (2) the contribution of smooth muscle and surfactant to geometric hysteresis are of opposite senses, tending toward cancellation. Quantitatively, the geometric hysteresis found experimentally by Miki et al. (1993, "Geometric Hysteresis in Pulmonary Surface-to-Volume Ratio during Tidal Breathing," J. Appl. Physiol. 75(4), pp. 1630-1636) is consistent with little or no smooth muscle tone in anesthetized rabbits in control conditions, and with substantial smooth muscle activation following methacholine challenge. The observed local hysteretic boundary motion of the acinar duct would result in irreversible acinar flow fields, which might be important mechanistic contributors to aerosol mixing and deposition deep in the lung.

RELATIONSHIPS AMONG SUBGROSS ANATOMY, COMPUTED TOMOGRAPHY, AND HISTOLOGIC FINDINGS IN DOGS WITH DISEASE LOCALIZED TO THE PULMONARY ACINI

During computed tomography (CT), the appearance of disease involving the pulmonary acinus may be described using terms such as atelectasis, ground-glass opacity, or consolidation. These CT signs, however, have not been correlated with histologic findings in canine pulmonary disease. To facilitate interpretation of lung diseases by CT signs, our goals were to review the morphologic organization of the lung and evaluate the medical records of four dogs with different types of pulmonary acinar disease. Anatomic review focused on understanding the pulmonary acinus and the secondary pulmonary lobule; the secondary pulmonary lobule is a fundamental unit for interpretation in people. All dogs had similar CT findings of fully expanded lungs with increased attenuation and partial-to-complete obscuring of the pulmonary blood vessels. Histologic findings varied between dogs and included partial-to-complete filling of airspaces with cells or fluid, interstitial thickening, increased capillary blood volume, or a combination of these findings. Final diagnoses were hemorrhagic pneumonia, bronchiolar carcinoma, metastatic mammary adenocarcinoma, and pulmonary edema. In summary, the morphologic organization of the lungs is complex and has implications for diagnostic interpretation needing further evaluation in dogs. In this study, increased lung attenuation during CT due to disease localized to the pulmonary acini was due to the displacement of air from the lungs and not to the microscopic distribution of lesions within the pulmonary acinus. Imaging descriptors that classify diseases according to structures larger than the pulmonary acini, for example, regions of the secondary pulmonary lobule or larger, may be appropriate for dogs.

Why chaotic mixing of particles is inevitable in the deep lung

Fine/ultrafine particles can easily reach the pulmonary acinus, where gas is exchanged, but they need to mix with alveolar residual air to land on the septal surface. Classical fluid mechanics theory excludes flow-induced mixing mechanisms because of the low Reynolds number nature of the acinar flow. For more than a decade, we have been challenging this classical view, proposing the idea that chaotic mixing is a potent mechanism in determining the transport of inhaled particles in the pulmonary acinus. We have demonstrated this in numerical simulations, experimental studies in both physical models and in animals, and mathematical modeling. However, the mathematical theory that describes chaotic mixing in small airways and alveoli is highly complex; it not readily accessible by non-mathematicians. The purpose of this paper is to make the basic mechanisms that operate in acinar chaotic mixing more accessible, by translating the key mathematical ideas into physics-oriented language. The key to understanding chaotic mixing is to identify two types of frequency in the system, each of which is induced by a different mechanism. The way in which their interplay creates chaos is explained with instructive illustrations but without any equations. We also explain why self-similarity occurs in the alveolar system and was indeed observed as a fractal pattern deep in rat lungs (Proc. Natl. Acad. Sci. USA. 99:10173-10178, 2002).

Clinicoradiological diagnosis of respiratory infections: estimate of pathogens by radiological findings and the strategy for treatment

This review discusses the clinicoradiological findings of pulmonary tuberculosis as well as non-tuberculous mycobacteria. To make a differential diagnosis between pneumonia and mycobacterial infections, it is very important to analyze the radiological findings of inflammatory lung diseases based on normal anatomical structures. If clinicoradiological analyses could make these differentiations, the appropriate treatment strategy for respiratory infections could be established. To accomplish this, exact orientations of pulmonary lobulus, acinus, and respiratory bronchioles is very important. Then, through analyzing chest CT findings and distribution patterns based on normal anatomical structures. estimation of causative pathogens could be possible. To differentiate infections caused by Mycobacterium tuberculosis from non-tuberculous mycobacteria, several important criteria have been demonstrated. Briefly, in MAC respiratory infection, right middle lobe and left lingula are frequently involved and centrilobular nodules and diffuse bronchiectases are characteristic radiological findings.

Evidence for minimal oxygen heterogeneity in the healthy human pulmonary acinus

It has been suggested that the human pulmonary acinus operates at submaximal efficiency at rest due to substantial spatial heterogeneity in the oxygen partial pressure (Po(2)) in alveolar air within the acinus. Indirect measurements of alveolar air Po(2) could theoretically mask significant heterogeneity if intra-acinar perfusion is well matched to Po(2). To investigate the extent of intra-acinar heterogeneity, we developed a computational model with anatomically based structure and biophysically based equations for gas exchange. This model yields a quantitative prediction of the intra-acinar O(2) distribution that cannot be measured directly. Temporal and spatial variations in Po(2) in the intra-acinar air and blood are predicted with the model. The model, representative of a single average acinus, has an asymmetric multibranching respiratory airways geometry coupled to a symmetric branching conducting airways geometry. Advective and diffusive O(2) transport through the airways and gas exchange into the capillary blood are incorporated. The gas exchange component of the model includes diffusion across the alveolar air-blood membrane and O(2)-hemoglobin binding. Contrary to previous modeling studies, simulations show that the acinus functions extremely effectively at rest, with only a small degree of intra-acinar Po(2) heterogeneity. All regions of the model acinus, including the peripheral generations, maintain a Po(2) >100 mmHg. Heterogeneity increases slightly when the acinus is stressed by exercise. However, even during exercise the acinus retains a reasonably homogeneous gas phase.

Visualization of respiratory flows from 3D reconstructed alveolar airspaces using X-ray tomographic microscopy

A deeper knowledge of the three-dimensional (3D) structure of the pulmonary acinus has direct applications in studies on acinar fluid dynamics and aerosol kinematics. To date, however, acinar flow simulations have been often based on geometrical models inspired by morphometrical studies; limitations in the spatial resolution of lung imaging techniques have prevented the simulation of acinar flows using 3D reconstructions of such small structures. In the present study, we use high-resolution, synchrotron radiation-based X-ray tomographic microscopy (SRXTM) images of the pulmonary acinus of a mouse to reconstruct 3D alveolar airspaces and conduct computational fluid dynamic (CFD) simulations mimicking rhythmic breathing motion. Respiratory airflows and Lagrangian (massless) particle tracking are visualized in two examples of acinar geometries with varying size and complexity, representative of terminal sacculi including their alveoli. The present CFD simulations open the path towards future acinar flow and aerosol deposition studies in complete and anatomically realistic multi-generation acinar trees using reconstructed 3D SRXTM geometries.

Contribution of serial and parallel microperfusion to spatial variability in pulmonary inter- and intra-acinar blood flow.

This study presents a theoretical model of combined series and parallel perfusion in the human pulmonary acinus that maintains computational simplicity while capturing some important features of acinar structure. The model provides a transition between existing models of perfusion in the large pulmonary blood vessels and the pulmonary microcirculation. Arterioles and venules are represented as distinct elastic vessels that follow the branching structure of the acinar airways. These vessels are assumed to be joined at each generation by capillary sheets that cover the alveoli present at that generation, forming a "ladderlike" structure. Compared with a model structure in which capillary beds connect only the most distal blood vessels in the acinus, the model with combined serial and parallel perfusion provides greater capacity for increased blood flow in the lung via capillary recruitment when the blood pressure is elevated. Stratification of acinar perfusion emerges in the model, with red blood cell transit time significantly larger in the distal portion of the acinus compared with the proximal portion. This proximal-to-distal pattern of perfusion may act in concert with diffusional screening to optimize the potential for gas exchange.

The effects of geometry on airflow in the acinar region of the human lung

Understanding flow phenomena in the pulmonary acinus is important for predicting particle transport and deposition and hence, in designing effective drug delivery strategies for the lung. In the current study, a three-dimensional honeycomb-like geometry involving a central airspace and surrounding alveoli is used to represent an alveolar duct and sacs. Numerical results predict that flow in the presence of wall motion is characterized by the presence of a developing recirculation region within the cavity and by a flow entrainment region indicative of the weak nature of interaction between duct and cavity. Under the normal breathing condition (2.5 s) and volumetric expansion (∼25%) considered here, recirculation disappears for Re<0.6. Alveolar flow in higher generations (at lower Reynolds number) results from significantly higher entrainment of the ductal flow, and does not exhibit any recirculation. In an asymmetric arrangement of the alveolar cluster, topological differences in cavity result in significant differences in the size of recirculation and the size of entrainment region within the alveoli of the same acinar generation, indicative of a non-uniform alveolar ventilation. The flow in the terminal alveolar sac is non-recirculating and not affected by variation in geometrical features.

Hémorragies alvéolaires en dehors des situations d’immunodépression : prise en charge diagnostique et thérapeutique

Diffuse alveolar hemorrhage is a bleeding originating from the pulmonary acinus. Number of causes are possible, that can be divided in immune and non immune causes. Immune mediated diffuse alveolar hemorrhages are mainly due to small vessels vasculitis (Wegener granulomatosis, microscopic polyangiitis), systemic lupus erythematosus and antiglomerular basement membrane antibody disease. Early immunosuppressive treatment is required, mostly with pulse methylprednisolone and cyclophosphamide. Plasmapheresis are added in antiglomerular basement membrane antibody disease and refractory systemic lupus erythematosus. Non immune mediated diffuse alveolar hemorrhages are mainly due to cardiac failure, severe dyscrasia and idiopathic diffuse alveolar hemorrhage. Barotrauma, cancer microangiopathy, toxic or drug-induced diffuse alveolar hemorrhage are other rare causes. Whatever is the cause, diffuse alveolar hemorrhage is an emergency associated with an intrahospital mortality rate of approximately 20 percent.

Convective gas transport in the pulmonary acinus: Comparing roles of convective and diffusive lengths

To investigate the relative importance of convection and diffusion in the transport of oxygen in the pulmonary acinus, it is often useful to locate the transition from convection-dominated to diffusion-dominated transport. Traditionally, this is done by estimating the values of a Peclet number. This dimensionless number compares the bulk ductal flow velocity at an acinar generation with a diffusion velocity over a characteristic length scale. Here, we revisit the convection–diffusion transition by comparing the relative importance of convective and diffusive lengths. We introduce the ratio of such lengths ( L conv / L diff ) to quantify the extent of convective transport in the acinus over an inhalation phase. We distinguish between convection along the acinar airways and within alveoli, respectively. Results for L conv / L diff suggest that convection in acinar ducts may play a potential role in more peripheral airways compared with values obtained for a Peclet number. Within alveoli, however, independent of acinar depth, oxygen transport is governed by diffusion as soon as molecules enter within alveolar cavities.

Respiratory Flow Phenomena and Gravitational Deposition in a Three-Dimensional Space-Filling Model of the Pulmonary Acinar Tree

The inhalation of micron-sized aerosols into the lung's acinar region may be recognized as a possible health risk or a therapeutic tool. In an effort to develop a deeper understanding of the mechanisms responsible for acinar deposition, we have numerically simulated the transport of nondiffusing fine inhaled particles (1 mum and 3 microm in diameter) in two acinar models of varying complexity: (i) a simple alveolated duct and (ii) a space-filling asymmetrical acinar branching tree following the description of lung structure by Fung (1988, "A Model of the Lung Structure and Its Validation," J. Appl. Physiol., 64, pp. 2132-2141). Detailed particle trajectories and deposition efficiencies, as well as acinar flow structures, were investigated under different orientations of gravity, for tidal breathing motion in an average human adult. Trajectories and deposition efficiencies inside the alveolated duct are strongly related to gravity orientation. While the motion of larger particles (3 microm) is relatively insensitive to convective flows compared with the role of gravitational sedimentation, finer 1 microm aerosols may exhibit, in contrast, complex kinematics influenced by the coupling between (i) flow reversal due to oscillatory breathing, (ii) local alveolar flow structure, and (iii) streamline crossing due to gravity. These combined mechanisms may lead to twisting and undulating trajectories in the alveolus over multiple breathing cycles. The extension of our study to a space-filling acinar tree was well suited to investigate the influence of bulk kinematic interaction on aerosol transport between ductal and alveolar flows. We found the existence of intricate trajectories of fine 1 microm aerosols spanning over the entire acinar airway network, which cannot be captured by simple alveolar models. In contrast, heavier 3 microm aerosols yield trajectories characteristic of gravitational sedimentation, analogous to those observed in the simple alveolated duct. For both particle sizes, however, particle inhalation yields highly nonuniform deposition. While larger particles deposit within a single inhalation phase, finer 1 microm particles exhibit much longer residence times spanning multiple breathing cycles. With the ongoing development of more realistic models of the pulmonary acinus, we aim to capture some of the complex mechanisms leading to deposition of inhaled aerosols. Such models may lead to a better understanding toward the optimization of pulmonary drug delivery to target specific regions of the lung.

Hamiltonian Chaos in a Model Alveolus

In the pulmonary acinus, the airflow Reynolds number is usually much less than unity and hence the flow might be expected to be reversible. However, this does not appear to be the case as a significant portion of the fine particles that reach the acinus remains there after exhalation. We believe that this irreversibility is at large a result of chaotic mixing in the alveoli of the acinar airways. To test this hypothesis, we solved numerically the equations for incompressible, pulsatile, flow in a rigid alveolated duct and tracked numerous fluid particles over many breathing cycles. The resulting Poincare sections exhibit chains of islands on which particles travel. In the region between these chains of islands, some particles move chaotically. The presence of chaos is supported by the results of an estimate of the maximal Lyapunov exponent. It is shown that the streamfunction equation for this flow may be written in the form of a Hamiltonian system and that an expansion of this equation captures all the essential features of the Poincare sections. Elements of Kolmogorov-Arnol'd-Moser theory, the Poincare-Birkhoff fixed-point theorem, and associated Hamiltonian dynamics theory are then employed to confirm the existence of chaos in the flow in a rigid alveolated duct.

Finite element 3D reconstruction of the pulmonary acinus imaged by synchrotron X-ray tomography.

The alveolated structure of the pulmonary acinus plays a vital role in gas exchange function. Three-dimensional (3D) analysis of the parenchymal region is fundamental to understanding this structure-function relationship, but only a limited number of attempts have been conducted in the past because of technical limitations. In this study, we developed a new image processing methodology based on finite element (FE) analysis for accurate 3D structural reconstruction of the gas exchange regions of the lung. Stereologically well characterized rat lung samples (Pediatr Res 53: 72-80, 2003) were imaged using high-resolution synchrotron radiation-based X-ray tomographic microscopy. A stack of 1,024 images (each slice: 1024 x 1024 pixels) with resolution of 1.4 mum(3) per voxel were generated. For the development of FE algorithm, regions of interest (ROI), containing approximately 7.5 million voxels, were further extracted as a working subunit. 3D FEs were created overlaying the voxel map using a grid-based hexahedral algorithm. A proper threshold value for appropriate segmentation was iteratively determined to match the calculated volume density of tissue to the stereologically determined value (Pediatr Res 53: 72-80, 2003). The resulting 3D FEs are ready to be used for 3D structural analysis as well as for subsequent FE computational analyses like fluid dynamics and skeletonization.