Human Lung Airway Research Articles

비대칭 인체 기관지 분지관의 압력손실 특성

정밀한 물질분배기관인 인체 기관지의 기능을 이해하기 위해서는 호흡에서 발생하는 다양한 유동 및 형상 조건에서 압력손실특성을 파악하는 것이 필수적이다. 본 연구는 기관지 구조의 기본 단위인 분지관의 층류 흡기유동 압력손실을 수치해석을 통해 확인하였다. 인체 기관지에 대한 관찰에서 보고되는 비대칭 형상과 유량분배비율 범위 안에서 압력손실계수 K 는 Re 와 관의 길이만의 함수로 다음과 같이 표현이 가능하며 (수식) 이는 대칭 분지관의 관계식과 동일한 것이다. 연속분지로 입구 유속분포가 편향될 경우 분지관 압력손실의 변화는 4% 미만이었으며 분지가 반복될수록 그 차이는 줄어들어 무시할 만하였다.

The stationary flow in a heterogeneous compliant vessel network

We introduce a mathematical model of the hydrodynamic transport into systems consisting in a network of connected flexible pipes. In each pipe of the network, the flow is assumed to be steady and one-dimensional. The fluid-structure interaction is described through tube laws which relate the pipe diameter to the pressure difference across the pipe wall. We show that the resulting one-dimensional differential equation describing the flow in the pipe can be exactly integrated if one is able to estimate averages of the Reynolds number along the pipe. The differential equation is then transformed into a non linear scalar equation relating pressures at both ends of the pipe and the flow rate in the pipe. These equations are coupled throughout the network with mass conservation equations for the flow and zero pressure losses at the branching points of the network. This allows us to derive a general model for the computation of the flow into very large inhomogeneous networks consisting of several thousands of flexible pipes. This model is then applied to perform numerical simulations of the human lung airway system at exhalation. The topology of the system and the tube laws are taken from morphometric and physiological data in the literature. We find good qualitative and quantitative agreement between the simulation results and flow-volume loops measured in real patients. In particular, expiratory flow limitation which is an essential characteristic of forced expiration is found to be well reproduced by our simulations. Finally, a mathematical model of a pathology (Chronic Obstructive Pulmonary Disease) is introduced which allows us to quantitatively assess the influence of a moderate or severe alteration of the airway compliances.

NCS 613, a potent and specific PDE4 inhibitor, displays anti-inflammatory effects on human lung tissues

Chronic inflammation is a hallmark of pulmonary diseases, which leads to lung parenchyma destruction (emphysema) and obstructive bronchiolitis occurring in both chronic obstructive pulmonary disease and asthma. Inflammation is strongly correlated with low intracellular cAMP levels and increase in specific cAMP hydrolyzing activity. The aim of the present study was to investigate the role of the cyclic phosphodiesterase type 4 (PDE4) in human lung and to determine the effects of NCS 613, a new PDE4 inhibitor, on lung inflammation and bronchial hyperresponsiveness. High cAMP-PDE activities were found in the cytosoluble fractions from human lung parenchyma and distal bronchi. PDE4 (rolipram sensitive) represented 40% and 56% of total cAMP-PDE activities in the above-corresponding tissues. Moreover, PDE4A, PDE4B, PDE4C, and PDE4D isoforms were detected in all three subcellular fractions (cytosolic, microsomal, and nuclear) with differential distributions according to specific variants. Pharmacological treatments with NCS 613 significantly decreased PDE4 activity and reduced IκBα degradation in cultured parenchyma, both of which are usually correlated with a lower inflammation status. Moreover, NCS 613 pretreatment potentiated isoproterenol-induced relaxations in human distal bronchi, while reducing TNF-α-induced hyperresponsiveness in cultured bronchi, as assessed in the presence of methacholine, U-46619, or histamine. This reducing effect of NCS 613 on human bronchi hyperresponsiveness triggered by TNF-α was related to a lower expression level of PDE4B and PDE4C, as well as a downregulation of the phosphorylated forms of p38-MAPK, CPI-17, and MYPT-1, which are known to control tone. In conclusion, specific PDE4 inhibitors, such as NCS 613, may represent an alternative and isoform-specific approach toward reducing human lung inflammation and airway overreactivity.

Notch-Dependent Differentiation of Adult Airway Basal Stem Cells

The epithelium lining the airways of the adult human lung is composed of ciliated and secretory cells together with undifferentiated basal cells (BCs). The composition and organization of this epithelium is severely disrupted in many respiratory diseases. However, little is known about the mechanisms controlling airway homeostasis and repair after epithelial damage. Here, we exploit the mouse tracheobronchial epithelium, in which BCs function as resident stem cells, as a genetically tractable model of human small airways. Using a reporter allele we show that the low level of Notch signaling at steady state is greatly enhanced during repair and the generation of luminal progenitors. Loss-of-function experiments show that Notch signaling is required for the differentiation, but not self-renewal, of BCs. Moreover, sustained Notch activation in BCs promotes their luminal differentiation, primarily toward secretory lineages. We also provide evidence that this function of Notch signaling is conserved in BCs from human airways.

Deposition of silica agglomerates in a cast of human lung airways: Enhancement relative to spheres of equal mobility and aerodynamic diameter

This paper reports on an experimental study of the deposition of well-characterized silica agglomerates in a cast of a section of a human lung. Deposition of the agglomerates is compared with the deposition of oleic acid spheres and sodium chloride particles for a range of mobility sizes, agglomerate properties (primary particle size and mass–mobility exponent) and inspiratory flow rates. In most cases, agglomerate deposition was significantly greater than that of the oleic acid and sodium chloride particles. Deposition of agglomerates with a more open structure was greater than that of relatively more compact (but still non-spherical) agglomerates. Deposition also increased with the flow rate. Because of the large physical size of the agglomerates, as well as the crenulated flow path through the model and the flow rate dependence, it is likely that interception is responsible for the enhanced deposition of the agglomerates.

Effect of geometric variations on pressure loss for a model bifurcation of the human lung airway

Characteristics of pressure loss (ΔP) in human lung airways were numerically investigated using a realistic model bifurcation. Flow equations were numerically solved for the steady inspiratory condition with the tube length, the branching angle and flow velocity being varied over a wide range. In general, the ΔP coefficient K showed a power-law dependence on Reynolds number (Re) and length-to-diameter ratio with a different exponent for Re≥100 than for Re<100. The effect of different branching angles on pressure loss was very weak in the smooth-branching airways.

Computational Fluid Dynamics Simulations of Particle Deposition in Large-Scale, Multigenerational Lung Models

Computational fluid dynamics (CFD) has emerged as a useful tool for the prediction of airflow and particle transport within the human lung airway. Several published studies have demonstrated the use of Eulerian finite-volume CFD simulations coupled with Lagrangian particle tracking methods to determine local and regional particle deposition rates in small subsections of the bronchopulmonary tree. However, the simulation of particle transport and deposition in large-scale models encompassing more than a few generations is less common, due in part to the sheer size and complexity of the human lung airway. Highly resolved, fully coupled flowfield solution and particle tracking in the entire lung, for example, is currently an intractable problem and will remain so for the foreseeable future. This paper adopts a previously reported methodology for simulating large-scale regions of the lung airway (Walters, D. K., and Luke, W. H., 2010, "A Method for Three-Dimensional Navier-Stokes Simulations of Large-Scale Regions of the Human Lung Airway," ASME J. Fluids Eng., 132(5), p. 051101), which was shown to produce results similar to fully resolved geometries using approximate, reduced geometry models. The methodology is extended here to particle transport and deposition simulations. Lagrangian particle tracking simulations are performed in combination with Eulerian simulations of the airflow in an idealized representation of the human lung airway tree. Results using the reduced models are compared with those using the fully resolved models for an eight-generation region of the conducting zone. The agreement between fully resolved and reduced geometry simulations indicates that the new method can provide an accurate alternative for large-scale CFD simulations while potentially reducing the computational cost of these simulations by several orders of magnitude.

A two‐grid fictitious domain method for direct simulation of flows involving non‐interacting particles of a very small size

AbstractThe full resolution of flows involving particles whose scale is hundreds or thousands of times smaller than the size of the flow domain is a challenging problem. A naive approach would require a tremendous number of degrees of freedom in order to bridge the gap between the two spatial scales involved. The approach used in the present study employs two grids whose grid size fits the two different scales involved, one of them (the micro‐scale grid) being embedded into the other (the macro‐scale grid). Then resolving first the larger scale on the macro‐scale grid, we transfer the so obtained data to the boundary of the micro‐scale grid and solve the smaller size problem. Since the particle is moving throughout the macro‐scale domain, the micro‐scale grid is fixed at the centroid of the moving particle and therefore moves with it. In this study we combine such an approach with a fictitious domain formulation of the problem resulting in a very efficient algorithm that is also easy to implement in an existing CFD code. We validate the method against existing experimental data for a sedimenting sphere, as well as analytical results for motion of an inertia‐less ellipsoid in a shear flow. Finally, we apply the method to the flow of a high aspect ratio ellipsoid in a model of a human lung airway bifurcation. Copyright © 2009 John Wiley &amp; Sons, Ltd.

A Method for Three-Dimensional Navier–Stokes Simulations of Large-Scale Regions of the Human Lung Airway

A new methodology for CFD simulation of airflow in the human bronchopulmonary tree is presented. The new approach provides a means for detailed resolution of the flow features via three-dimensional Navier–Stokes CFD simulation without the need for full resolution of the entire flow geometry, which is well beyond the reach of available computing power now and in the foreseeable future. The method is based on a finite number of flow paths, each of which is fully resolved, to provide a detailed description of the entire complex small-scale flowfield. A stochastic coupling approach is used for the unresolved flow path boundary conditions, yielding a virtual flow geometry that allows accurate statistical resolution of the flow at all scales for any set of flow conditions. Results are presented for multigenerational lung models based on the Weibel morphology and the anatomical data of Hammersley and Olson (1992, “Physical Models of the Smaller Pulmonary Airways,” J. Appl. Physiol., 72(6), pp. 2402–2414). Validation simulations are performed for a portion of the bronchiole region (generations 4–12) using the flow path ensemble method, and compared with simulations that are geometrically fully resolved. Results are obtained for three inspiratory flowrates and compared in terms of pressure drop, flow distribution characteristics, and flow structure. Results show excellent agreement with the fully resolved geometry, while reducing the mesh size and computational cost by up to an order of magnitude.

IL-33 synergizes with IgE-dependent and IgE-independent agents to promote mast cell and basophil activation

Mast cell and basophil activation contributes to inflammation, bronchoconstriction, and airway hyperresponsiveness in asthma. Because IL-33 expression is inflammation inducible, we investigated IL-33-mediated effects in concert with both IgE-mediated and IgE-independent stimulation. Because the HMC-1 mast cell line can be activated by GPCR and RTK signaling, we studied the effects of IL-33 on these pathways. The IL-33- and SCF-stimulated HMC-1 cells were co-cultured with human lung fibroblasts and airway smooth muscle cells in a collagen gel contraction assay. IL-33 effects on IgE-mediated activation were studied in primary mast cells and basophils. IL-33 synergized with adenosine, C5a, SCF, and NGF receptor activation. IL-33-stimulated and SCF-stimulated HMC-1 cells demonstrated enhanced collagen gel contraction when cultured with fibroblasts or smooth muscle cells. IL-33 also synergized with IgE receptor activation of primary human mast cells and basophils. IL-33 amplifies inflammation in both IgE-independent and IgE-dependent responses.

Particle deposition in a CT-scanned human lung airway

The particle deposition in a computerized tomography (CT)-scanned human lung was numerically investigated. The five-generation airway is extracted from the trachea to segmental bronchi of a 60-year-old Chinese male patient. Computations were carried out in the flow rate range of 210–630 ml/s (Reynolds number range of 1000–3000) and particle size of 2–10 μm (Stokes number range of 0.0007–0.049). To count the effect of laryngeal jet on trachea inlet, the trachea was extended and modified to simulate the larynx, consequently the inlet velocity profile is biased towards the rear wall. The laryngeal jet-induced turbulence was simulated using low Reynolds number (LRN) κ–ω turbulent model. Particle deposition patterns, deposition efficiency and deposition factor were studied in detail. The turbulent flow has significant effect on the particle deposition, and the present deposition factor is compared well with the available data.

Experimental analysis of oscillatory airflow in a bronchiole model with stenosis

As the mechanism of gas transport and exchange in human respiratory ventilation, the complicated processes of mixing and diffusion in airways of human lungs are considered. However the mechanism has not been clarified enough. On the other hand, the analysis of detailed mechanism in the case of artificial ventilation like HFOV (High Frequency Oscillatory Ventilation) is strongly required for the development of clinical treatments on patients with respiration disorder. In HFOV, it is considered that pendelluft becomes one of the important factors of gas transport and exchange because of high frequency ventilation in comparison with natural breathing. As increase of the frequency, the different time constants of lung units generate phase lag of ventilation in airways of lungs. The phase lag of ventilation causes to generate pendelluft. The time constant is determined by compliance and flow resistance of lung unit. In order to investigate the effect of the different time constants induced by the difference of flow resistance in a part of respiratory bronchiole of human lungs, the experimental study has been carried out by using multi-bifurcated micro channels as a model of bronchiole. The flow resistance in the model channels was produced by a stenosis. The velocity distributions of ventilation flows in the channels with and without the stenosis have been measured by using μ-PIV technique. The results obtained show the frequency effects on the flow pattern in the bronchiole model channels and the appearance of pendelluft.

An Adjustable Triple-Bifurcation Unit Model for Air-Particle Flow Simulations in Human Tracheobronchial Airways

A new methodology for a swift and accurate computer simulation of large segments of the human lung airways is presented. Focusing on a representative tracheobronchial (TB) region, i.e., G0-G15, nano- and micron particle transports have been simulated for Q(in)=30 lmin, employing an experimentally validated computer model. The TB tree was geometrically decomposed into triple-bifurcation units with kinematically adjusted multilevel outlet/inlet conditions. Deposition patterns and maximum concentrations differ greatly between nanoparticles (1< or =d(p)< or =150 nm) and micron particles (1< or =d(p)< or =10 microm), which may relate uniquely to health impacts. In comparison with semi-analytical particle deposition results, it is shown that such simple "lung models" cannot predict local deposition values but can match computer simulation results for the entire TB region within 2.5-26%. The present study revealed that turbulent air-particle flow may propagate to G5 for the assumed inhalation flow rate. Geometry and upstream effects are more pronounced for micron particle deposition than for nanoparticle deposition.

Modeling the bifurcating flow in a CT-scanned human lung airway

The inspiratory flow characteristics in a CT-scanned human lung model were numerically investigated using low Reynolds number (LRN) κ– ω turbulent model. The five-generation airway is extracted from the trachea to segmental bronchi of a 60-year-old Chinese male patient. Computations were carried out in the Reynolds number range of 900–2100, corresponding to mouth-air breathing rates of 190–440 ml/s. Flow patterns on the Re=2100 and flow rate distribution were presented. In this model, the flow pattern is very complex. To count the effect of laryngeal jet on trachea inlet, the trachea was extended and modified to simulate the larynx, consequently the inlet velocity profile is biased towards the rear wall. In the inferior lobar bronchi, there are two stems in which the axial velocity is stronger but secondary velocity is weaker. Secondary flow in the lateral bronchi is stronger than the medial ones. With increasing Re, the air flow increases in the middle, inferior lobes and left main bronchus, i.e., flow biases to left and downward.

Multiple roles of nicotine on cell proliferation and inhibition of apoptosis: Implications on lung carcinogenesis

The genotoxic effects of tobacco carcinogens have long been recognized, the contribution of tobacco components to cancerogenesis by cell surface receptor signaling is relatively unexplored. Nicotine, the principal tobacco alkaloid, acts through nicotinic acetylcholine receptor (nAChR). nAChR are functionally present on human lung airway epithelial cells, on lung carcinoma [SCLC and NSCLC] and on mesothelioma and build a part of an autocrine-proliferative network that facilitates the growth of neoplastic cells. Different nAChR subunit gene expression patterns are expressed between NSCLC from smokers and non-smokers. Although there is no evidence that nicotine itself could induce cancer, different studies established that nicotine promotes in vivo the growth of cancer cells and the proliferation of endothelial cells suggesting that nicotine might contribute to the progression of tumors already initiated. These observations led to the hypothesis that nicotine might be playing a direct role in the promotion and progression of human lung cancers. Here, we briefly overview the role and the effects of nicotine on pulmonary cell growth and physiology and its feasible implications in lung carcinogenesis.

TNF-α-induced up-regulation of intercellular adhesion molecule-1 is regulated by a Rac-ROS-dependent cascade in human airway epithelial cells

Up-regulation of intercellular adhesion molecule-1 (ICAM-1) in the lung airway epithelium is associated with the epithelium-leukocyte interaction, critical for the pathogenesis of various lung airway inflammatory diseases such as asthma. However, little is known about how ICAM-1 is up-regulated in human airway epithelial cells. In this study, we show that tumor TNF-alpha induces monocyte adhesion to A549 human lung airway epithelium and also up-regulation of ICAM-1 expression. These effects were significantly diminished by pre-treatment with diphenyliodonium (DPI), an inhibitor of NADPH oxidase-like flavoenzyme. In addition, the level of reactive oxygen species (ROS) was increased in response to TNF-alpha in A549 cells, suggesting a potential role of ROS in the TNF-alpha-induced signaling to ICAM-1 expression and monocyte adhesion to airway epithelium. Further, we found out that expression of RacN17, a dominant negative mutant of Rac1, suppressed TNF-alpha-induced ROS generation, ICAM-1 expression, and monocyte adhesion to airway epithelium. These findings suggest that Rac1 lies upstream of ROS generation in the TNF-alpha-induced signaling to ICAM-1 expression in airway epithelium. Finally, pretreatment with pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kappaB, reduced TNF-alpha-induced ICAM-1 expression and both DPI and RacN17 significantly diminished NF-kappaB activation in response to TNF-alpha. Together, we propose that Rac1-ROS-linked cascade mediate TNF-alpha-induced ICAM-1 up-regulation in the airway epithelium via NF-kappaB-dependent manner.

Inhibition of FcεRI-dependent mediator release and calcium flux from human mast cells by sialic acid–binding immunoglobulin-like lectin 8 engagement

Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of glycan-binding inhibitory receptors, and among them, Siglec-8 is selectively expressed on human eosinophils, basophils, and mast cells. On eosinophils, Siglec-8 engagement induces apoptosis, but its function on mast cells is unknown. We sought to study the effect of Siglec-8 engagement on human mast cell survival and mediator release responses. Human mast cells were generated from CD34+ precursors. Apoptosis was studied by using flow cytometry. Mast cell mediator release or human lung airway smooth muscle contraction was initiated by FcepsilonRI cross-linking with or without preincubation with Siglec-8 or control antibodies, and release of mediators was analyzed along with Ca++ flux. RBL-2H3 cells transfected with normal and mutated forms of Siglec-8 were used to study how Siglec-8 engagement alters mediator release. Siglec-8 engagement failed to induce human mast cell apoptosis. However, preincubation with Siglec-8 mAbs significantly (P < .05) inhibited FcepsilonRI-dependent histamine and prostaglandin D(2) release, Ca++ flux, and anti-IgE-evoked contractions of human bronchial rings. In contrast, release of IL-8 was not inhibited. Siglec-8 ligation was also shown to inhibit beta-hexosaminidase release and Ca++ flux triggered through FcepsilonRI in RBL-2H3 cells transfected with full-length human Siglec-8 but not in cells transfected with Siglec-8 containing a tyrosine to phenylalanine point mutation in the membrane-proximal immunoreceptor tyrosine-based inhibitory motif domain. These data represent the first reported inhibitory effects of Siglec engagement on human mast cells.

Mucus Flow in Human Lung Airways :A Planar Two Layer Steady State Mathematical Model

In this paper, a planar two-layer steady state mathematical model is presented to study mucus flow in human lung airways due to cilia beating and some immobile cilia forming porous matrix in serous sub layer in contact with epithelium as a highly viscous fluid. The effect of air-motion is considered by prescribing air velocity at the mucus-air interface. The effects of pressure drop and gravitational force are also considered in the model. It is shown that the mucus flow rate increases as pressure drop or gravitational force increases. It also increases as the air- velocity at the mucus air interface increases whereas it decreases as the viscosity of serous fluid or that of mucus increases.It is also shown that the increase in mucus viscosity at higher values do not have any significant effect on its transport rate.

Dynamic flow in a realistic model of the upper human lung airways

The objective of the study is an analysis of lung ventilation during breathing under rest conditions and for high frequency ventilation (HFV). The measurements include investigations of the flow using an endotracheal tube. A transparent model of the upper human lung airways down to the 6th generation was generated, and the oscillatory flow through the branching network was studied by DPIV. The method of refractive index matching of the fluid (water/glycerin) and the model (silicone) allows an unobstructed view into the internal flow network. The mass flow rate and the frequency were adapted to the characteristic flow parameters, the Reynolds- and the Womersley-number. The comparison of the results for normal breathing and HFV shows that a mass exchange occurs for higher frequencies known as Pendelluft, which could not be seen during normal breathing. This mass exchange between the daughter tubes is a consequence of the asymmetric impedance in the successive daughter branches. The lung topology determines the local pressure loss in the model and therefore the local mass flow direction of the Pendelluft. At higher frequencies we observed an increase in exchange between the daughter branches. The transformation of the velocity profiles between inspiration and expiration suggests a net mass flow which is created into the model along the centerline and the inner walls of the bifurcations. This flow is compensated with a net mass outflow to the trachea along the outer walls of the branches.

Simulation of airflow fields and microparticle deposition in realistic human lung airway models. Part II: Particle transport and deposition

In Part II, given the airflow fields discussed in Part I, microparticle deposition for a practical range of Stokes numbers, 0.025 ⩽ St ⩽ 0.102 , has been simulated and analyzed, comparing different temporal assumptions, inlet conditions and geometric configurations. The matching steady-state assumption with equivalent Reynolds and Stokes numbers achieves basically the same deposition fraction (DF) values as under transient inhalation conditions. When comparing parabolic vs. realistic inlet velocity profiles, total DF-values are higher for the parabolic inlet flow for all Stokes numbers. Geometric features, such as out-of-plane configurations and cartilaginous rings in the trachea, further change local deposited microparticle concentrations when compared with simple airway models. Furthermore, significant differences were recorded when comparing DFs in some branches of the present realistic model and the Weibel Type A model. For practical purposes, algebraic microparticle-deposition correlations, DF = DF ( Re , St ) , have been obtained for both the left and right upper lung airways. Based on current research results, the out-of-plane model with tracheal rings and realistic inlet condition is recommended for future work.