Respiratory flow in obstructed airways

Chronic obstructive pulmonary disease (COPD) is one of the most common diseases in human community. The COPD always results in inflammation that leads to narrowing and obstruction of the airways. The obstructive airways have significant effect on respiratory flow. In order to understand the flow phenomenon in such obstructive airways, four three-dimensional four-generation lung models based on the 23-generation model of Weibel [1963. Morphometry of the Human Lung. Springer, Academic Press, Berlin, New York] are generated. The fully three-dimensional incompressible laminar Navier-Stokes equations are solved using computational fluid dynamics (CFD) solver on unstructured tetrahedral meshes. Therein, a symmetric four-generation airway model is served as the reference, the other three models are considered to be obstructed at each generation, respectively. The calculation results show that the obstructive airway has significant influence on the air flow in both up- and down-stream airways and it even results in flow separation in the conjunction region. The re-circulation cell blocks the air from entering the downstream branches. This may be the reason why COPD patients should breathe gently, and this also provides some valuable information for medicine powder deposition.     

Computational analysis of flow structure and particle deposition in a single asthmatic human airway bifurcation

This paper aims to improve current understanding of flow structure and particle deposition in asthmatic human airways. A single, symmetric airway bifurcation, corresponding to generations 10–11 of Weibel’s model, is investigated through validated numerical simulations. The parent airway segment is modelled as a smooth circular tube. The child segments are considered asthmatic and their cross-section is modelled as a constricted tube with sinusoidal folds uniformly distributed along the circumference. The flow structure and particle deposition pattern for normal (i.e., healthy) and asthmatic airway bifurcations are compared and discussed. The numerical results reveal that the secondary flow in the asthmatic airway bifurcation is much stronger than in the healthy one, resulting in higher particle deposition. The effects of size of the lumen area and number of folds on particle deposition and pressure drop are also investigated. It is found that particle deposition efficiency is significantly affected by lumen area of the asthmatic segment (the smaller the lumen area, the higher the particle deposition efficiency). The effect of number of folds is small. Particle deposition efficiency also increases with Reynolds number. The pressure drop in the asthmatic airway bifurcation depends mainly on size of the lumen area. The effect of number of folds becomes important for strongly collapsed airways.     

Nicotine signals through muscle-type and neuronal nicotinic acetylcholine receptors in both human bronchial epithelial cells and airway fibroblasts

Chronic obstructive pulmonary disease (COPD) is a major global health problem and is predicted to become the third most common cause of death by 2020. Apart from the important preventive steps of smoking cessation, there are no other specific treatments for COPD that are as effective in reversing the condition, and therefore there is a need to understand the pathophysiological mechanisms that could lead to new therapeutic strategies. The development of experimental models will help to dissect these mechanisms at the cellular and molecular level. COPD is a disease characterized by progressive airflow obstruction of the peripheral airways, associated with lung inflammation, emphysema and mucus hypersecretion. Different approaches to mimic COPD have been developed but are limited in comparison to models of allergic asthma. COPD models usually do not mimic the major features of human COPD and are commonly based on the induction of COPD-like lesions in the lungs and airways using noxious inhalants such as tobacco smoke, nitrogen dioxide, or sulfur dioxide. Depending on the duration and intensity of exposure, these noxious stimuli induce signs of chronic inflammation and airway remodelling. Emphysema can be achieved by combining such exposure with instillation of tissue-degrading enzymes. Other approaches are based on genetically-targeted mice which develop COPD-like lesions with emphysema, and such mice provide deep insights into pathophysiological mechanisms. Future approaches should aim to mimic irreversible airflow obstruction, associated with cough and sputum production, with the possibility of inducing exacerbations.     

Models of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a major global health problem and is predicted to become the third most common cause of death by 2020. Apart from the important preventive steps of smoking cessation, there are no other specific treatments for COPD that are as effective in reversing the condition, and therefore there is a need to understand the pathophysiological mechanisms that could lead to new therapeutic strategies. The development of experimental models will help to dissect these mechanisms at the cellular and molecular level. COPD is a disease characterized by progressive airflow obstruction of the peripheral airways, associated with lung inflammation, emphysema and mucus hypersecretion. Different approaches to mimic COPD have been developed but are limited in comparison to models of allergic asthma. COPD models usually do not mimic the major features of human COPD and are commonly based on the induction of COPD-like lesions in the lungs and airways using noxious inhalants such as tobacco smoke, nitrogen dioxide, or sulfur dioxide. Depending on the duration and intensity of exposure, these noxious stimuli induce signs of chronic inflammation and airway remodelling. Emphysema can be achieved by combining such exposure with instillation of tissue-degrading enzymes. Other approaches are based on genetically-targeted mice which develop COPD-like lesions with emphysema, and such mice provide deep insights into pathophysiological mechanisms. Future approaches should aim to mimic irreversible airflow obstruction, associated with cough and sputum production, with the possibility of inducing exacerbations.     

Automated Measurement of Pulmonary Emphysema and Small Airway Remodeling in Cigarette Smoke-exposed Mice

COPD is projected to be the third most common cause of mortality world-wide by 2020⁽¹⁾. Animal models of COPD are used to identify molecules that contribute to the disease process and to test the efficacy of novel therapies for COPD. Researchers use a number of models of COPD employing different species including rodents, guinea-pigs, rabbits, and dogs⁽²⁾. However, the most widely-used model is that in which mice are exposed to cigarette smoke. Mice are an especially useful species in which to model COPD because their genome can readily be manipulated to generate animals that are either deficient in, or over-express individual proteins. Studies of gene-targeted mice that have been exposed to cigarette smoke have provided valuable information about the contributions of individual molecules to different lung pathologies in COPD^(3-5). Most studies have focused on pathways involved in emphysema development which contributes to the airflow obstruction that is characteristic of COPD. However, small airway fibrosis also contributes significantly to airflow obstruction in human COPD patients⁽⁶⁾, but much less is known about the pathogenesis of this lesion in smoke-exposed animals. To address this knowledge gap, this protocol quantifies both emphysema development and small airway fibrosis in smoke-exposed mice. This protocol exposes mice to CS using a whole-body exposure technique, then measures respiratory mechanics in the mice, inflates the lungs of mice to a standard pressure, and fixes the lungs in formalin. The researcher then stains the lung sections with either Gill’s stain to measure the mean alveolar chord length (as a readout of emphysema severity) or Masson’s trichrome stain to measure deposition of extracellular matrix (ECM) proteins around small airways (as a readout of small airway fibrosis). Studies of the effects of molecular pathways on both of these lung pathologies will lead to a better understanding of the pathogenesis of COPD.     

ASTHMA,CHRONIC BRONCHITIS AND EMPHYSEMA—The Use of Intermittent Positive Pressure Breathing with Inspiratory Flow Rate Control: A Review of the Literature

In chronic obstructive lung disease (asthma, chronic bronchitis, obstructive emphysema) there is a segmental reduction in the caliber of the airways, which always results in obstruction to air-flow. Increased airway resistance is a physiological expression of airway obstruction.The addition of inspiratory flow rate control to an intermittent positive pressure breathing device permits slow filling of a lung with obstructed airways, and is presented as a simple means of reducing the high pulmonary flow resistance and increasing the tidal volume.     

Aerosol deposition characteristics in distal acinar airways under cyclic breathing conditions

Although the major mechanisms of aerosol deposition in the lung are known, detailed quantitative data in anatomically realistic models are still lacking, especially in the acinar airways. In this study, an algorithm was developed to build multigenerational three-dimensional models of alveolated airways with arbitrary bifurcation angles and spherical alveolar shape. Using computational fluid dynamics, the deposition of 1- and 3-μm aerosol particles was predicted in models of human alveolar sac and terminal acinar bifurcation under rhythmic wall motion for two breathing conditions (functional residual capacity = 3 liter, tidal volume = 0.5 and 0.9 liter, breathing period = 4 s). Particles entering the model during one inspiration period were tracked for multiple breathing cycles until all particles deposited or escaped from the model. Flow recirculation inside alveoli occurred only during transition between inspiration and expiration and accounted for no more than 1% of the whole cycle. Weak flow irreversibility and convective transport were observed in both models. The average deposition efficiency was similar for both breathing conditions and for both models. Under normal gravity, total deposition was ~33 and 75%, of which ~67 and 96% occurred during the first cycle, for 1- and 3-μm particles, respectively. Under zero gravity, total deposition was ~2-5% for both particle sizes. These results support previous findings that gravitational sedimentation is the dominant deposition mechanism for micrometer-sized aerosols in acinar airways. The results also showed that moving walls and multiple breathing cycles are needed for accurate estimation of aerosol deposition in acinar airways.     

Aerosol transport and deposition in sequentially bifurcating airways

Deposition patterns and efficiencies of a dilute suspension of inhaled particles in three-dimensional double bifurcating airway models for both in-plane and 90 deg out-of-plane configurations have been numerically simulated assuming steady, laminar, constant-property air flow with symmetry about the first bifurcation. Particle diameters of 3, 5, and 7 microns were used in the simulation, while the inlet Stokes and Reynolds numbers varied from 0.037 to 0.23 and 500 to 2000, respectively. Comparisons between these results and experimental data based on the same geometric configuration showed good agreement. The overall trend of the particle deposition efficiency, i.e., an exponential increase with Stokes number, was somewhat similar for all bifurcations. However, the deposition efficiency of the first bifurcation was always larger than that of the second bifurcation, while in general the particle efficiency of the out-of-plane configuration was larger than that of the in-plane configuration. The local deposition patterns consistently showed that the majority of the deposition occurred in the carinal region. The distribution pattern in the first bifurcation for both configurations were symmetric about the carina, which was a direct result of the uniaxial flow at the inlet. The deposition patterns about the second carina showed increased asymmetry due to highly nonuniform flow generated by the first bifurcation and were extremely sensitive to bifurcation orientation. Based on the deposition variations between bifurcation levels and orientations, the use of single bifurcation models was determined to be inadequate to resolve the complex fluid-particle interactions that occur in multigenerational airways.     

Role of extracellular matrix and its regulators in human airway smooth muscle biology

Altered extracellular matrix (ECM) deposition contributing to airway wall remodeling is an important feature of asthma and chronic obstructive pulmonary disease (COPD). The molecular mechanisms of this process are poorly understood. One of the key pathological features of these diseases is thickening of airway walls. This thickening is largely to the result of airway smooth muscle (ASM) cell hyperplasia and hypertrophy as well as increased deposition of ECM proteins such as collagens, elastin, laminin, and proteoglycans around the smooth muscle. Many growth factors and cytokines, including fibroblast growth factor (FGF)-1, FGF-2, and transforming growth factor (TGF)-α₁, that are released from the airway wall have the potential to contribute to airway remodeling, revealed by enhanced ASM proliferation and increased ECM protein deposition. TGF-α₁ and FGF-1 stimulate mRNA expression of collagen I and III in ASM cells, suggesting their role in the deposition of extracellular matrix proteins by ASM cells in the airways of patients with chronic lung diseases. Focus is now on the bidirectional relationship between ASM cells and the ECM. In addition to increased synthesis of ECM proteins, ASM cells can be involved in downregulation of matrix metalloproteinases (MMPs) and upregulation of tissue inhibitors of metalloproteinases (TIMPs), thus eventually contributing to the alteration in ECM. In turn, ECM proteins promote the survival, proliferation, cytokine synthesis, migration, and contraction of human airway smooth muscle cells. Thus, the intertwined relationship of ASM and ECM and their response to stimuli such as chronic inflammation in diseases such as asthma and COPD contribute to the remodeling seen in airways of patients with these diseases.     

A new drift-flux model for particle transport and deposition in human airways

Particle deposition and transport in human airways isfrequently modeled numerically by the Lagrangian approach. Current formulations of such models always require some ad hoc assumptions, and they are computationally expensive. A new drift-flux model is developed and incorporated into a commercial finite volume code. Because it is Eulerian in nature, the model is able to simulate particle deposition patterns, distribution and transport both spatially and temporally. Brownian diffusion, gravitational settling, and electrostatic force are three major particle deposition mechanisms in human airways. The model is validated against analytical results for three deposition mechanisms in a straight tube prior to applying the method to a single bifurcation G3-G4. Two laminar flows with Reynolds numbers 500 and 2000 are simulated. Particle concentration contour deposition pattern, and enhancement factor are evaluated. To demonstrate how the diffusion and settling influence the deposition and transport along the bifurcation, particle sizes from 1 nm to 10 microm are studied. Different deposition mechanisms can be combined into the mass conversation equation. Combined deposition efficiency for the three mechanisms simultaneously was evaluated and compared with two commonly used empirical expressions.     

慢性阻塞性肺病动物模型的研究进展

慢性阻塞性肺病(COPD)是一种严重的呼吸系统疾病,该病主要包括慢性肺气肿及慢性支气管炎,其发病率、死亡率高,医疗负担重。由于其发病机制、临床发展过程较为复杂,对COPD诊断、治疗的研究工作进展仍然相当缓慢。目前,国内外研究人员通过建立COPD动物模型对该病进行了大量研究工作。旨在对COPD动物模型的建立及评价方法进行总结,并对模型动物选择,评价方法的选择提出一点新的思路。     

Endoplasmic reticulum stress in chronic obstructive lung diseases

Chronic airway inflammation characterizes several airway diseases, including cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). The altered airway milieu that results from the pathogenic processes in these disorders affects the airway epithelia, leading to an up-regulation of their innate defense. In human airway epithelia, luminal inflammatory stimuli induce an adaptation characterized by an expansion of the endoplasmic reticulum (ER) and its Ca(2+) stores. This epithelial adaption mediates Ca(2+)-dependent "hyperinflammatory" responses, and recent studies have shown that activation of the unfolded protein response (UPR) by ER stress is involved in the process. The UPR is also known to be activated by cigarette smoke, the primary trigger for development of COPD. These studies illustrate the functional role of UPR pathways during airway inflammation and suggest that targeting the UPR may be a therapeutic strategy for obstructive airway diseases. This article reviews the link between airway epithelial inflammation and activation of the UPR, and discusses how UPR activation might be relevant for CF and COPD airways disease.     

Surfactant Protein A in Exhaled Endogenous Particles Is Decreased in Chronic Obstructive Pulmonary Disease (COPD) Patients: A Pilot Study

Background

Exhaled, endogenous particles are formed from the epithelial lining fluid in small airways, where surfactant protein A (SP-A) plays an important role in pulmonary host defense. Based on the knowledge that chronic obstructive pulmonary disease (COPD) starts in the small airway epithelium, we hypothesized that chronic inflammation modulates peripheral exhaled particle SP-A and albumin levels. The main objective of this explorative study was to compare the SP-A and albumin contents in exhaled particles from patients with COPD and healthy subjects and to determine exhaled particle number concentrations.

Methods

Patients with stable COPD ranging from moderate to very severe (n = 13), and healthy non-smoking subjects (n = 12) were studied. Subjects performed repeated breath maneuvers allowing for airway closure and re-opening, and exhaled particles were optically counted and collected on a membrane using the novel PExA^® instrument setup. Immunoassays were used to quantify SP-A and albumin.

Results

COPD patients exhibited significantly lower SP-A mass content of the exhaled particles (2.7 vs. 3.9 weight percent, p = 0.036) and lower particle number concentration (p<0.0001) than healthy subjects. Albumin mass contents were similar for both groups.

Conclusions

Decreased levels of SP-A may lead to impaired host defense functions of surfactant in the airways, contributing to increased susceptibility to COPD exacerbations. SP-A in exhaled particles from small airways may represent a promising non-invasive biomarker of disease in COPD patients.     

Comparison of theoretical and experimental particle diffusion data within human airway casts

The dose delivered to airway cells is a critical factor whether one is addressing the therapeutic (i.e., positive) effects of inhaled pharmacologic agents or the toxic (i.e., negative) effects of pollutants. In this study, theoretical models describing particle deposition have been compared with experimental data from the literature. In the simulations, airways can be either roughor smooth-walled to be consistent with human lungs which can be either lined by cartilaginous rings (i.e., rough) or muscle (i.e., smooth). Particle motion for rough-walled airways within generations I=1–6 is calculated using the formula proposed by Martonen et al. (1). For smooth-walled airways within generations I=7–10, particle motion is calculated using the formula proposed by Martonen et al. (2). Theoretical predictions of particle deposition efficiencies are not only in agreement with the overall best fit empirical correlation presented by Cohen and Asgharian (3) over a wide range of dimensionless diffusion parameters, but also match individual experimental measurements (only available in I=1–6) with regard to effects of the parameters of particle size, flow rate, and airway dimensions. The mean difference in the ratio of experimental-to-theoretical particle diffusion values is 0.9 for a flow rate of 18 L/min and 1.1 for a flow rate of 34 L/min (i.e., the difference is only about 10%) within the upper airways of the casts (airway generations I=1–6), the mean difference for the whole casts was much greater. This may be attributed to the uncertainty of flow conditions in the peripheral airways as a result of the trimmmed nature of the casts. Overall, the findings suggest that the model can be a valuable component of aerosol therapy and risk assessment protocols, especially to address effects of enhanced deposition of pharmacologic drugs and radionuclides at sites within the human tracheobronchial tree.     

Models of human lung airways and their application to inhaled particle deposition

Models of the human respiratory tract were developed based on detailed morphometric measurements of a silicone rubber cast of the human tracheobronchial airways. Emphasis was placed on the “Typical Path Lung Model” which used one typical pathway to represent a portion of the lung, such as a lobe, or to represent the whole lung. The models contain geometrical parameters, including airway segment diameters, lengths, branching angles and angles of inclination to gravity, which are needed for estimating inhaled particle deposition. Aerosol depositions for various breathing patterns and particle sizes were calculated using these lung models and the modified Findeisen-Landahl computational scheme. The results agree reasonably well with recent experimental data. Regional deposition, including lobar deposition fractions, are also calculated and compared with results based on the ICRP lung deposition model.     

Tenascin-C and alpha-smooth muscle actin positive cells are increased in the large airways in patients with COPD

Background

Chronic obstructive pulmonary disease (COPD) is characterized by inflammation and remodeling of the lungs. This results in alterations in extracellular matrix (ECM) and structural changes leading to airflow obstruction. We studied the expression of tenascin-C (Tn-C) and alpha smooth muscle actin (α-SMA), which act as a marker of myofibroblasts, in large airways from COPD patients. Our aim was to elucidate whether this expression correlated with smoking or with disease development.

Methods

Bronchoscopy was performed on 20 COPD patients (mean age 56 years; range 39-61; FEV1/FVC < 70% and FEV1 median 53% (range 33-69) of predicted). Age and smoking matched smokers (S) without COPD (n = 13) and age matched non-smokers (NS) (n = 14) served as controls. Bronchial mucosal biopsies were analyzed by immunohistochemistry. The distribution of Tn-C expression was assessed and graded in three levels, and the number of spindle shaped cells staining positive for α-SMA were counted.

Results

Biopsies from COPD patients had more (P < 0.001) Tn-C expression than the two control groups. A significantly (P < 0.05) increased number of spindle shaped cells expressing α-SMA was observed in COPD patients compared with the controls. Smokers and nonsmokers did not differ in this respect. The expression of Tn-C correlated positively (P < 0.001) to the number of α-SMA positive cells.

Conclusions

We demonstrate increased expression of Tn-C and α-SMA positive cells in the large airways in COPD. This was not associated to smoking per se, but to the presence of airway obstruction. Our findings add new information regarding remodeling characteristics and highlight the large airways as a potential site for airways obstruction in COPD.     

A two-component theory of aerosol deposition in lung airways

The deposition of aerosol particles in the human lung airways is due to two distinct mechanisms. One is by direct deposition resulting from diffusion, sedimentation and impaction as the aerosol moves in and out of the lung. The other is an indirect mechanism by which particles are transported mechanically from the tidal air to the residential air and eventually captured by the airways due to intrinsic particle motion. This last mechanism is not well understood at present. Using a trumpet airway model constructed from Weibel's data, a two-component theory is developed. In this theory, the particle concentrations in the airways and the alveoli at a given airway depth are considered to be quantitatively different. This difference in concentrations will cause a net mixing between the tidal and residential aerosol as the aerosol is breathed in and out. A distribution parameter is then introduced to account for the distribution of ventilation. The effect of intrinsic particle motion on the aerosol mixing is also included. From this theory, total and regional deposition in the lung at the steady mouth breathing without pause is calculated for several different respiratory cycles. The results agree reasonably well with the experimental data.     

The human cathelicidin LL-37 enhances airway mucus production in chronic obstructive pulmonary disease

Airway mucus overproduction is a distinguishing feature of chronic obstructive pulmonary disease (COPD). LL-37 is the only member of human cathelicidins family of antimicrobial peptides and plays a central role in many immune and inflammatory reactions. Increasing evidence suggests the involvement of LL-37 in the pathogenesis of COPD. Here, we investigated the effects of LL-37 on airway mucus overproduction in COPD. We observed overexpression of both LL-37 and MUC5AC mucin (a major mucin component of mucus) in airways of COPD patients and found a correlation between them. We showed in vitro that LL-37 induces MUC5AC mucin production by airway epithelial NCI-H292 cells in the absence and presence of cigarette smoke extract, with TNF-α converting enzyme (TACE)–EGFR–ERK1/2 pathway and IL-8 required for the induction. Therefore, we concluded that LL-37 enhances the mucus production in COPD airways, thus contributing to the progression of COPD.     

Patient-Specific Modeling of Regional Antibiotic Concentration Levels in Airways of Patients with Cystic Fibrosis: Are We Dosing High Enough?

Background

Pseudomonas aeruginosa (Pa) infection is an important contributor to the progression of cystic fibrosis (CF) lung disease. The cornerstone treatment for Pa infection is the use of inhaled antibiotics. However, there is substantial lung disease heterogeneity within and between patients that likely impacts deposition patterns of inhaled antibiotics. Therefore, this may result in airways below the minimal inhibitory concentration of the inhaled agent. Very little is known about antibiotic concentrations in small airways, in particular the effect of structural lung abnormalities. We therefore aimed to develop a patient-specific airway model to predict concentrations of inhaled antibiotics and to study the impact of structural lung changes and breathing profile on local concentrations in airways of patients with CF.

Methods

In- and expiratory CT-scans of children with CF (5–17 years) were scored (CF-CT score), segmented and reconstructed into 3D airway models. Computational fluid dynamic (CFD) simulations were performed on 40 airway models to predict local Aztreonam lysine for inhalation (AZLI) concentrations. Patient-specific lobar flow distribution and nebulization of 75 mg AZLI through a digital Pari eFlow model with mass median aerodynamic diameter range were used at the inlet of the airway model. AZLI concentrations for central and small airways were computed for different breathing patterns and airway surface liquid thicknesses.

Results

In most simulated conditions, concentrations in both central and small airways were well above the minimal inhibitory concentration. However, small airways in more diseased lobes were likely to receive suboptimal AZLI. Structural lung disease and increased tidal volumes, respiratory rates and larger particle sizes greatly reduced small airway concentrations.

Conclusions

CFD modeling showed that concentrations of inhaled antibiotic delivered to the small airways are highly patient specific and vary throughout the bronchial tree. These results suggest that anti-Pa treatment of especially the small airways can be improved.     

Early detection of upper airway obstructions by analysis of acoustical respiratory input impedance

Repetitive occurrence of partial or total upper airway obstruction characterizes several respiratory dysfunctions such as the obstructive sleep apnea syndrome (OSAS). In OSAS patients, pharyngeal collapses are linked to a decrease in upper airway muscle activity during sleep which causes decreased upper airway wall stiffness. Continuous positive airway pressure (CPAP) is recommended as the treatment of choice. Advancements in CPAP therapy require early detection of respiratory events in real time to adapt the level of the applied pressure to airway collapsibility. The forced oscillation technique (FOT) is a noninvasive method which reflects patients' airway patency by measuring respiratory impedance. The aim of this study was to evaluate by a mathematical model of the respiratory system if FOT can provide an early detection index of total or partial upper airway obstruction. Furthermore, the simulation should suggest which characteristic features are relevant for early apnea detection in measured clinical data. The respiratory system has been treated as a series of cylindrical segments. The oropharynx analog of the model allows simulation of upper airway collapse, mimicking the situation in patients with OSAS. We calculated the input impedance for different degrees of upper airway obstruction ranging from unobstructed airways to total occlusion. Furthermore, we simulated different upper airway wall compliances. We compared the simulation with real data. The results of the study suggest that FOT is a valuable tool for assessing the degree of upper airway obstruction in patients with OSAS. Especially, the phase angle of the impedance seems to be a potentially useful tool for early apnea detection by assessing the upper airway wall collapsibility. Received: 23 July 1998 / Accepted in revised form: 26 January 1999