Human Lung Airway Research Articles

Occupational exposure to particulate matter during blackboard teaching and its deposition in the airways of human lungs.

This study aims to estimate the teachers' exposure to particulate matter (PM) during a chalk and talk class considering various exposure conditions and to determine the deposition pattern of PM in human airways. The study was carried out in three steps, viz., questionnaire survey, exposure measurement, and dosage calculation. Exposure to chalk dust during teaching was measured for 40 teachers in terms of PM of different size range (PM 10, PM 2.5, and PM 1) while using different brands of chalks. Deposition in lungs was determined using Multiple Path Dosimetry model for four subject categories, viz., adult men, elderly men, adult women, and elderly women. The average exposure during teaching activity was 498, 85, and 30µg/m3 of PM 10, PM 2.5, and PM 1, respectively. Chalks which are made of calcium carbonate with high density of packing emitted lesser PM 10. Results showed no significant difference in the exposure to PM by teachers while writing at different relative heights of the board. The highest total deposition of PM in lung was observed for elderly women. The deposited mass per unit area was the highest for adult women in all the three sizes of PM. This study showed that there was no significant difference in exposure to PM while using normal and dustless chalks. The exposure level suggests that there is a strong need to either shift to smart classes or to improve the technology in chalk production in such a way that it produces less dust and limit the exposure to teaching professionals.

Environmental organophosphate co‐exposure in pre‐existing systemic inflammation can Increase susceptibility to SARS‐COV‐2 infection in human lung epithelial cells

Environmental exposures from pollutants in air, water and food cause systemic inflammatory events to persist. Studies have shown that environmental co exposures alter the microbiome profile and cause long lasting systemic inflammation. This is common in the general population as well as a certain subsection of veterans having Gulf War Illness who were co exposed to organophosphates decades ago. With COVID19 pandemic claiming more than 335,000 deaths in USA alone, we aimed to study the susceptibility of SARS‐COV‐2 virus entry and its potential inflammatory mechanisms in the lung epithelial cells following co‐exposure to IL6 and pesticide chlorpyrifos. Notably, a recent report confirms more than 160,000 positive SARS‐COV‐2 cases of veterans with mortality rate of more than 4%. Recent studies from our laboratory and others suggested that pesticide exposure during war theater and increased IL‐6 in blood serum played pivotal role in physiological complications which include neurological and gastrointestinal disturbances. In the present report, we aim to identify whether pesticides and IL‐6 co‐exposure increases the risk of SARS‐COV‐2 infection by invitro studies with human lung airway epithelial cells. Cells were exposed to organophosphate Chlorpyriphos (20 µg/ml) or human recombinant IL‐6 (20 pg/ml) or with both for 6 h and treated with recombinant SARS‐COV‐2 spike protein (50 ng/ml) and observed for Angiotensin Converting Enzyme 2 expression (ACE2) on the apical or basolateral surface of airway epithelial cells. ACE‐2 has been identified as putative receptor for SARS‐COV‐2 entry where it's spike protein pivotal to the entry of viral particle in cells. With reports showing abundant expression of ACE2 receptor protein to apical surface of polarized epithelial cells might support viral entry and replication in host cells, we performed Immunofluorescence microscopy to study ACE 2 protein expression in Apical cell surface (FoxJ1) or in basolateral cell surface (Sodium‐Potassium ATPase 2). Results showed organophosphate and IL 6 exposure significantly increased ACE2 protein expression on the apical cell surface compared to when cells were unexposed or exposed with organophosphate alone. Furthermore, results showed that co exposure of IL 6 and organophosphate were instrumental in increased apoptosis of lung airway epithelial cells in presence of SARS‐COV‐2 spike protein compared to untreated cells. The following results though preliminary may pave the way for more mechanistic studies in rodent models to identify mechanisms of susceptibility of severe COVID19 outcomes in the general population and veterans who were co exposed to environmental agents in early life.

Fast and Accurate Multiscale Reduced-Order Model for Prediction of Multibreath Washout Curves of Human Respiratory System

The curve of exhaled inert gas concentration against exhaled volume is called gas washout curve. The slope at the end part of gas washout curve (Sₙ) is a measure of structural abnormalities. Sₙ depends on the spatial concentration distribution and dynamic of gas washout, which depends on several mechanisms including asymmetry of airways, nonhomogeneous ventilation, sequential emptying, and gas exchange with blood. Due to a large number of airways in human lungs, using simplified models is inevitable. On the other hand, these simplified models cannot capture some of the mentioned mechanisms and subsequently were not able to predict experimental trend of change in Sₙ with breath number in multibreath washout. The present study proposes a novel, accurate, and fast model of gas transport in human lungs, which can accurately predict this trend for the first time. The model consists of a proxy model of conducting airways and a reduced-order model of respiratory airways. A correlation is proposed for the estimation of model parameters, which are all functions of inert gas properties, ventilation, and structure of lung acini. The performance of the proposed model is validated in the prediction of Sₙ’s of various inert gases and lung clearance index. The obtained results show that the proposed model outperforms the previous ones based on both accuracy and required computational time. The effects of gas properties, functional residual capacity, and tidal volume on Sₙ are also investigated. The proposed model is fast where simulation of one breath nitrogen washout takes ∼0.18 s. Furthermore, it is flexible and can range from fully symmetric to detailed asymmetric airways.

Human lung-on-chips: Advanced systems for respiratory virus models and assessment of immune response.

Respiratory viral infections are leading causes of death worldwide. A number of human respiratory viruses circulate in all age groups and adapt to person-to-person transmission. It is vital to understand how these viruses infect the host and how the host responds to prevent infection and onset of disease. Although animal models have been widely used to study disease states, incisive arguments related to poor prediction of patient responses have led to the development of microfluidic organ-on-chip models, which aim to recapitulate organ-level physiology. Over the past decade, human lung chips have been shown to mimic many aspects of the lung function and its complex microenvironment. In this review, we address immunological responses to viral infections and elaborate on human lung airway and alveolus chips reported to model respiratory viral infections and therapeutic interventions. Advances in the field will expedite the development of therapeutics and vaccines for human welfare.

The effect of viscoelasticity in an airway closure model.

The closure of a human lung airway is modeled as a pipe coated internally with a liquid that takes into account the viscoelastic properties of mucus. For a thick enough coating, the Plateau-Rayleigh instability blocks the airway by the creation of a liquid plug, and the pre-closure phase is dominated by the Newtonian behavior of the liquid. Our previous study with a Newtonian-liquid model demonstrated that the bifrontal plug growth consequent to airway closure induces a high level of stress and stress gradients on the airway wall, which is large enough to damage the epithelial cells, causing sub-lethal or lethal responses. In this study, we explore the effect of the viscoelastic properties of mucus by means of the Oldroyd-B and FENE-CR model. Viscoelasticity is shown to be very relevant in the post-coalescence process, introducing a second peak of the wall shear stresses. This second peak is related to an elastic instability due to the presence of the polymeric extra stresses. For high-enough Weissenberg and Laplace numbers, this second shear stress peak is as severe as the first one. Consequently, a second lethal or sub-lethal response of the epithelial cells is induced.

Microbiota - The Unseen Players in Adult Asthmatic Airways.

Modulation of human lung airway physiology by commensal microbiota has become one of the key mechanisms involved in the pathogenesis of adult asthma. Recent evidence suggests that the composition of respiratory microbiota plays a significant role in the manifestation of adult asthma; however, scientific evidence about the relationship between airway microbial diversity and phenotypes of adult asthma is limited. Further research is needed to understand the interactions between the airway microbiota and host immune response to develop microbiota-based strategies in management of adult asthma. This study reviews the advances in culture-independent methods for detection of airway microbiome, the current data about airway microbiota in healthy individuals and in adult patients with asthma with a focus on bacterial communities, and the future research directions in airway microbiome.

Study on Flow Behavior of Parallel Lumped-Model under Constant Flow for Bronchial Tree

Redistribution of flow in the bronchial tree is an important factor that enhances gas exchange in the lungs, especially, in diseased lungs. The bifurcated bronchial tree is like an electric network in series and parallel. A lumped-model of parallel system for constant flow rate is solved analytically to demonstrate the intrinsic characteristics and the dynamic behavior of the system. Inertial and capacitive time constants are calculated for 19th generation airways of human lung to control the solution. The investigation revealed that (i) higher inertial force takes more time to maximize the inertial flow to steady state and more time to minimize the resistive flow to steady state and (ii) the compliant effect is negligible for a relatively higher inertial time constant, on the same experimental conditions. GANIT J. Bangladesh Math. Soc. 40.2 (2020) 86–94

ABCF1 Regulates dsDNA-induced Immune Responses in Human Airway Epithelial Cells.

Background: The airway epithelium represents a critical component of the human lung that helps orchestrate defenses against respiratory tract viral infections, which are responsible for more than 2.5 million deaths/year globally. Innate immune activities of the airway epithelium rely on Toll-like receptors (TLRs), nucleotide binding and leucine-rich-repeat pyrin domain containing (NLRP) receptors, and cytosolic nucleic acid sensors. ATP Binding Cassette (ABC) transporters are ubiquitous across all three domains of life—Archaea, Bacteria, and Eukarya—and expressed in the human airway epithelium. ABCF1, a unique ABC family member that lacks a transmembrane domain, has been defined as a cytosolic nucleic acid sensor that regulates CXCL10, interferon-β expression, and downstream type I interferon responses. We tested the hypothesis that ABCF1 functions as a dsDNA nucleic acid sensor in human airway epithelial cells important in regulating antiviral responses.Methods: Expression and localization experiments were performed using in situ hybridization and immunohistochemistry in human lung tissue, while confirmatory transcript and protein expression was performed in human airway epithelial cells. Functional experiments were performed with siRNA methods in a human airway epithelial cell line. Complementary transcriptomic analyses were performed to explore the contributions of ABCF1 to gene expression patterns.Results: Using archived human lung and human airway epithelial cells, we confirm expression of ABCF1 gene and protein expression in these tissue samples, with a role for mediating CXCL10 production in response to dsDNA viral mimic challenge. Although, ABCF1 knockdown was associated with an attenuation of select genes involved in the antiviral responses, Gene Ontology analyses revealed a greater interaction of ABCF1 with TLR signaling suggesting a multifactorial role for ABCF1 in innate immunity in human airway epithelial cells.Conclusion: ABCF1 is a candidate cytosolic nucleic acid sensor and modulator of TLR signaling that is expressed at gene and protein levels in human airway epithelial cells. The precise level where ABCF1 protein functions to modulate immune responses to pathogens remains to be determined but is anticipated to involve IRF-3 and CXCL10 production.

Controlled Release of Magnetic Particles for Drug Delivery in the Human Lung

Improving drug delivery to a specific site of body is an important issue. Magnetic drug targeting is an appropriate technique for drug delivery to a specified area. This method has been adopted in drug delivery to the lung tissues due to widespread outbreak of the lung cancer in the recent decades. Therefore, increasing the efficiency of drug delivery to the lung tissues is of paramount importance. In this article, controlled particle release from a determined area and magnetic drug targeting methods are used to deliver the drug to a tumor in the generation G2 of the human lung. Weibel model is used for modeling of the human lung airways, and particles are made of iron oxide magnetic cores and poly lactic coglycolic acid shell. Herein, two different methods of drug delivery are tested and compared. In the first method, controlled particle release in the absence of magnetic field is accomplished and in the second method, controlled particle release in the presence of magnetic field is performed for the first time. A coil is used to produce magnetic field. Comparison of the results obtained in this article with the previous results of the drug delivery to tumors by random particle release method (in the presence and absence of magnetic field) showed that controlled particle release method improves the deposition efficiency on the tumor surface and increases the efficiency from 0.09% (random particle release in the absence of magnetic field) and 5.69% (random particle release in the presence of magnetic field) for tumor with r/R = 1.5 to 87% and 100% in the controlled particle release without and with the presence of magnetic field, respectively. Consequently, the best method of drug targeting is controlled particle release in the presence of the magnetic field. Using the mentioned method, deposition efficiency reaches 100% for tumors with r/R values of 0.5, 1, and 1.5 in this article.

An investigation of the pro‐inflammatory effects of wood smoke on human lung airway epithelial cells.

Over two‐fifths of the world’s population uses solid biomass fuels such as animal dung, plastic, rubber or wood for the purpose of cooking and the heating of their homes. In some instances, especially in underdeveloped regions of the world, biomass smoke exposure can disproportionately impact women and children of color, as they are more than likely to be performing cooking duties and being exposed to this type indoor air pollution. Poor ventilation of homes can also contribute to poorer health outcomes associated with biomass smoke exposure. These individuals exposed to biomass smoke and particulate matter are also more likely to be suffer from negative health outcomes such as repeated, acute lower respiratory infections (ALRI) and asthma. The mechanisms by which biomass smoke exposure contributes to these pathologies of the lung remain largely unknown. The purpose of this research was to determine the general effects of woodsmoke on lung airway epithelial cells (A549). In this project, we are modeling the effects biomass smoke exposure using solubilized wood smoke. Biomass smoke is believed to have a significant impact on the innate immune system and the epithelial cells than line airways. To determine the pro‐inflammatory effects of woodsmoke, we used the polymerase chain reaction (PCR) to assess the expression of many pro‐inflammatory genes. Results thus far show that treated A549 cells displayed an increase in COX‐2 expression with increasing concentrations of woodsmoke. This induction of iNOS, TGF‐beta, and HO‐1 gene expression was also observed. The cytotoxicity of woodsmoke on A549 cells was also assessed using the lactate dehydrogenase assay (LDH) assay. Future studies are aimed at determining the impact of woodsmoke on cytokine secretion in A549 cells and whether smoke exposure is capable of inducing oxidative stress in these cells.Support or Funding InformationUniversity of Richmond’s Integrated and Inclusive Science Program

Biomimetic smoking robot for in vitro inhalation exposure compatible with microfluidic organ chips.

Exposure of lung tissues to cigarette smoke is a major cause of human disease and death worldwide. Unfortunately, adequate model systems that can reliably recapitulate disease biogenesis in vitro, including exposure of the human lung airway to fresh whole cigarette smoke (WCS) under physiological breathing airflow, are lacking. This protocol extension builds upon, and can be used with, our earlier protocol for microfabrication of human organs-on-chips. Here, we describe the engineering, assembly and operation of a microfluidically coupled, multi-compartment platform that bidirectionally 'breathes' WCS through microchannels of a human lung small airway microfluidic culture device, mimicking how lung cells may experience smoke in vivo. Several WCS-exposure systems have been developed, but they introduce smoke directly from above the cell cultures, rather than tangentially as naturally occurs in the lung due to lateral airflow. We detail the development of an organ chip-compatible microrespirator and a smoke machine to simulate breathing behavior and smoking topography parameters such as puff time, inter-puff interval and puffs per cigarette. Detailed design files, assembly instructions and control software are provided. This novel platform can be fabricated and assembled in days and can be used repeatedly. Moderate to advanced engineering and programming skills are required to successfully implement this protocol. When coupled with the small airway chip, this protocol can enable prediction of patient-specific biological responses in a matched-comparative manner. We also demonstrate how to adapt the protocol to expose living ciliated airway epithelial cells to smoke generated by electronic cigarettes (e-cigarettes) on-chip.

Particle Deposition in Human Lung Airways: Effects of Airflow, Particle Size, and Mechanisms

Characterizing particle deposition in the airways of the human lungs is essential to evaluate the health effects of particulate air pollution. However, lung deposition is rather complicated, and its main influencing factors remain unclear. Hence, this study applied computational fluid dynamics (CFD) to investigate the roles of airflow (Reynolds number [Re] = 100–2000) and particle size (1–10 µm) in deposition using a human tracheobronchial airway model (G3–G6). We calculated the deposition efficiency (DE) based on two mechanisms, inertial impaction (DEi) and gravitational sedimentation (DEg), which produced hot spots around the bifurcations and uniform distributions along the tube, respectively. Furthermore, as the particle size increased, DEi grew rapidly, whereas DEg grew log-linearly. Particles that were less than 2 µm in diameterµ only penetrated deep in the lungs where the airflow rate was low, but 3 µm particles were more likely to settle in this region owing to the combination of gravitational sedimentation and inertial impaction. Larger particles, on the other hand, mainly deposited in the proximal bifurcations as a result of inertial impaction. Additionally, the deposition due to inertial impaction and that due to gravitational sedimentation primarily depended on the Stokes number (St) and the ratio of St to Re2, respectively. The orientation of the human body was another potential factor in the pattern of deposition, although the upright and lateral positions exhibited similar deposition efficiencies for 3 µm particles regardless of Re. These findings identify the critical Reynolds number at which the particle deposition mechanism for a specific size shifts from gravitation to inertia.

Liquid plug formation in an airway closure model.

The closure of a human lung airway is modeled as an instability of a two-phase flow in a pipe coated internally with a Newtonian liquid. For a thick enough coating, the Plateau-Rayleigh instability creates a liquid plug which blocks the airway, halting distal gas exchange. Owing to a bi-frontal plug growth, this airway closure flow induces high stress levels on the wall, which is the location of airway epithelial cells. A parametric numerical study is carried out simulating relevant conditions for human lungs, either in ordinary or pathological situations. Our simulations can represent the physical process from pre- to post-coalescence phases. Previous studies have been limited to pre-coalescence only. The topological change during coalescence induces a high level of stress and stress gradients on the epithelial cells, which are large enough to damage them, causing sub-lethal or lethal responses. We find that post-coalescence wall stresses can be in the range of 300% to 600% greater than pre-coalescence values, so introduce a new important source of mechanical perturbation to the cells.

XBP1S Regulates MUC5B in a Promoter Variant-Dependent Pathway in Idiopathic Pulmonary Fibrosis Airway Epithelia.

Rationale: The goal was to connect elements of idiopathic pulmonary fibrosis (IPF) pathogenesis, including chronic endoplasmic reticulum stress in respiratory epithelia associated with injury/inflammation and remodeling, distal airway mucus obstruction and honeycomb cyst formation with accumulation of MUC5B (mucin 5B), and associations between IPF risk and polymorphisms in the MUC5B promoter. Objectives: To test whether the endoplasmic reticulum (ER) stress sensor protein ERN2 (ER-to-nucleus signaling 2) and its downstream effector, the spliced form of XBP1S (X-box-binding protein 1), regulate MUC5B expression and differentially activate the MUC5B promoter variant in respiratory epithelia. Methods: Primary human airway epithelial (HAE) cells, transgenic mouse models, human IPF lung tissues, and cell lines expressing XBP1S and MUC5B promoters were used to explore relationships between the ERN2/XBP1S pathway and MUC5B. An inhibitor of the pathway, KIRA6, and XBP1 CRISPR-Cas9 were used in HAE cells to explore therapeutic potential. Measurements and Main Results: ERN2 regulated MUC5B and MUC5AC mRNAs. Downstream XBP1S selectively promoted MUC5B expression in vitro and in distal murine airway epithelia in vivo. XBP1S bound to the proximal region of the MUC5B promoter and differentially upregulated MUC5B expression in the context of the MUC5B promoter rs35705950 variant. High levels of ERN2 and XBP1S were associated with excessive MUC5B mRNAs in distal airways of human IPF lungs. Cytokine-induced MUC5B expression in HAE cells was inhibited by KIRA6 and XBP1 CRISPR-Cas9. Conclusions: A positive feedback bistable ERN2-XBP1S pathway regulates MUC5B-dominated mucus obstruction in IPF, providing an unfolded protein response-dependent mechanism linking the MUC5B promoter rs35705950 polymorphism with IPF pathogenesis. Inhibiting ERN2-dependent pathways/elements may provide a therapeutic option for IPF.

A Three-Dimensional Model of Human Lung Airway Tree to Study Therapeutics Delivery in the Lungs.

Surfactant instillation into the lungs is used to treat several respiratory disorders such as neonatal respiratory distress syndrome (NRDS). The success of the treatments significantly depends on the uniformity of distribution of the instilled surfactant in airways. This is challenging to directly evaluate due to the inaccessibility of lung airways and great difficulty with imaging them. To tackle this problem, we developed a 3D physical model of human lung airway tree. Using a defined set of principles, we first generated computational models of eight generations of neonates' tracheobronchial tree comprising the conducting zone airways. Similar to native lungs, these models contained continuously-branching airways that rotated in the 3D space and reduced in size with increase in the generation number. Then, we used additive manufacturing to generate physical airway tree models that precisely replicated the computational designs. We demonstrated the utility of the physical models to study surfactant delivery in the lungs and showed the effect of orientation of the airway tree in the gravitational field on the distribution of instilled surfactant between the left and right lungs and within each lung. Our 3D lung airway tree model offers a novel tool for quantitative studies of therapeutics delivery.

Optimal diameter reduction ratio of acinar airways in human lungs.

In the airway network of a human lung, the airway diameter gradually decreases through multiple branching. The diameter reduction ratio of the conducting airways that transport gases without gas exchange is 0.79, but this reduction ratio changes to 0.94 in acinar airways beyond transitional bronchioles. While the reduction in the conducting airways was previously rationalized on the basis of Murray’s law, our understanding of the design principle behind the acinar airways has been far from clear. Here we elucidate that the change in gas transfer mode is responsible for the transition in the diameter reduction ratio. The oxygen transfer rate per unit surface area is maximized at the observed geometry of acinar airways, which suggests the minimum cost for the construction and maintenance of the acinar airways. The results revitalize and extend the framework of Murray’s law over an entire human lung.

Experimental and numerical investigation on inspiration and expiration flows in a three-generation human lung airway model at two flow rates

The respiration flow pattern plays a key role in fluid flow, heat and mass transfer in human lung airway. To reveal the complex flow pattern within human lung multiple-generation airway, both the steady inspiration and expiration flows are comprehensively studied using laser Doppler velocimetry technique and computational fluid dynamics method for an idealized human tracheobronchial three-generation airway model at two flow rates, corresponding to an adult male breathing under light activity and moderate exercise conditions, respectively. The comparison of mainstream velocity between the measurements and simulations are generally good. Both of the inspiration and expiration flows are heavily influenced by the combination of geometrical bifurcating/merging, local wall curvature, limited generation length and multi-generation interaction. The mainstream flow is non-uniform and behaves as skewed, double-peaked and M-shaped patterns. The secondary flow is complex and characteristic of Dean-type two-vortex, four-vortex, six-vortex and eight-vortex patterns. This work is of scientific significance for a deep understanding of respiratory flow physics and of certain application values for clinical diagnosis and remedy of respiratory deceases.

Short-chain fatty acids increase TNFα-induced inflammation in primary human lung mesenchymal cells through the activation of p38 MAPK.

Short-chain fatty acids (SCFAs), produced as by-products of dietary fiber metabolism by gut bacteria, have anti-inflammatory properties and could potentially be used for the treatment of inflammatory diseases, including asthma. The direct effects of SCFAs on inflammatory responses in primary human lung mesenchymal cells have not been assessed. We investigated whether SCFAs can protect against tumor necrosis factor (TNF)α-induced inflammation in primary human lung fibroblasts (HLFs) and airway smooth muscle (ASM) cells in vitro. HLFs and ASM cells were exposed to SCFAs, acetate (C2:0), propionate (C3:0), and butyrate (C4:0) (0.01-25 mM) with or without TNFα, and the release of proinflammatory cytokines, IL-6, and CXCL8 was measured using ELISA. We found that none of the SCFAs suppressed TNFα-induced cytokine release. On the contrary, challenge with supraphysiological concentrations (10-25 mM), as might be used therapeutically, of propionate or butyrate in combination with TNFα resulted in substantially greater IL-6 and CXCL8 release from HLFs and ASM cells than challenge with TNFα alone, demonstrating synergistic effects. In ASM cells, challenge with acetate also enhanced TNFα-induced IL-6, but not CXCL8 release. Synergistic upregulation of IL-6 and CXCL8 was mediated through the activation of free fatty acid receptor (FFAR)3, but not FFAR2. The signaling pathways involved were further examined using specific inhibitors and immunoblotting, and responses were found to be mediated through p38 MAPK signaling. This study demonstrates that proinflammatory, rather than anti-inflammatory effects of SCFAs are evident in lung mesenchymal cells.

Quantifying Ciliary Dynamics during Assembly Reveals Stepwise Waveform Maturation in Airway Cells.

Motile cilia are essential for clearance of particulates and pathogens from airways. For effective transport, ciliary motor proteins and axonemal structures interact to generate the rhythmic, propulsive bending, but the mechanisms that produce a dynamic waveform remain incompletely understood. Biomechanical measures of human ciliary motion and their relationships to ciliary assembly are needed to illuminate the biophysics of normal ciliary function and to quantify dysfunction in ciliopathies. To these ends, we analyzed ciliary motion by high-speed video microscopy of ciliated cells sampled from human lung airways compared with primary culture cells that undergo ciliogenesis in vitro. Quantitative assessment of waveform parameters showed variations in waveform shape between individual cilia; however, general trends in waveform parameters emerged, associated with progression of cilia length and stage of differentiation. When cilia emerged from cultured cells, beat frequency was initially elevated, then fell and remained stable as cilia lengthened. In contrast, the average bending amplitude and the ability to generate force gradually increased and eventually approached values observed in ex vivo samples. Dynein arm motor proteins DNAH5, DNAH9, DNAH11, and DNAH6 were localized within specific regions of the axoneme in the ex vivo cells; however, distinct stages of in vitro waveform development identified by biomechanical features were associated with the progressive movement of dyneins to the appropriate proximal or distal sections of the cilium. These observations suggest that the stepwise variation in waveform development during ciliogenesis is dependent on cilia length and potentially on outer dynein arm assembly.

A Quasi-3D compartmental multi-scale approach to detect and quantify diseased regional lung constriction using spirometry data.

Spirometry is a widely used pulmonary function test to detect the airflow limitations associated with various obstructive lung diseases, such as asthma, chronic obstructive pulmonary disease, and even obesity-related complications. These conditions arise due to the change in the airway resistance, alveolar compliance, and inductance values. Currently, zero-dimensional compartmental models are commonly used for calibrating these resistance, compliance, and inductance values, ie, solving the inverse spirometry problem. However, zero-dimensional compartments cannot capture the flow physics or the spatial geometry effects, thereby generating a low fidelity prediction of the diseased lung. Computational fluid dynamics (CFD) models offer higher fidelity solutions but may be impractical for certain applications due to the duration of these simulations. Recently, a novel, fast-running, and robust Quasi-3D (Q3D) wire model for simulating the airflow in the human lung airway was developed by CFD Research Corporation. This Q3D method preserved the 3D spatial nature of the airways and was favorably validated against CFD solutions. In the present study, the Q3D compartmental multi-scale combination is further improved to predict regional lung constriction of diseased lungs using spirometry data. The Q3D mesh is resolved up to the eighth lung airway generation. The remainder of the airways and the alveoli sections are modeled using a compartmental approach. The Q3D geometry is then split into different spatial sections, and the resistance values in these regions are obtained using parameter inversion. Finally, the airway diameter values are then reduced to create the actual diseased lung model, corresponding to these resistance values. This diseased lung model can be used for patient-specific drug deposition predictions and the subsequent optimization of the orally inhaled drug products.