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Eosinophilic inflammation is primarily characterized by type 2 immune responses against parasitic organisms. In the contemporary human being especially in developed countries, eosinophilic inflammation is strongly associated with allergic/sterile inflammation, and constitutes an undesired immune reaction. This situation is in stark contrast to neutrophilic inflammation, which is indispensable for the host defense against bacterial infections. Among eosinophilic inflammatory disorders, massive accumulation of eosinophils within mucus is observed in certain cases, and is often linked to the distinctive clinical finding of mucus with high viscosity. Eosinophilic mucus is found in a variety of diseases, including chronic allergic keratoconjunctivitis, chronic rhinosinusitis encompassing allergic fungal sinusitis, eosinophilic otitis media, eosinophilic sialodochitis, allergic bronchopulmonary aspergillosis/mycosis, eosinophilic plastic bronchitis, and eosinophilic asthma. In these pathological conditions, chronic inflammation and tissue remodeling coupled with irreversible organ damage due to persistent adhesion of toxic substances and luminal obstruction may impose a significant burden on the body. Eosinophils aggregate in the hyperconcentrated mucus together with cell-derived crystals, macromolecules, and polymers, thereby affecting the biophysical properties of the mucus. This review focuses on the clinically significant challenges of mucus and discusses the consequences of activated eosinophils on the mucosal surface that impact mucus and persistent inflammation.

Asthma is a chronic inflammatory disease with many patients failing to respond appropriately to pharmacotherapy. Thus, virgin coconut oil (VCO) can be an alternative therapy. Guinea pigs were divided into control (Ctrl), chronic allergic lung inflammation (Asth), Asth treated with dexamethasone (Asth + dexa), and Asth supplemented with VCO (Asth + VCO4). The tested animals were sensitized and challenged with ovalbumin. Relaxation induced by arachidonic acid (AA) was impaired in Asth, and this reduction was prevented by VCO (p = 0.0004), indicating formation of relaxing prostanoids, or the decrease of cysteinyl-leukotrienes by VCO. Furthermore, a possible negative modulation of β receptors/BKCa pathway by TGF–β in Asth was prevented by VCO (p = 0.0073). Finally, in Asth, Masson’s trichrome staining revealed airway remodeling and immunohistochemistry showed increased TGF-β expression in the lungs of Asth (p

Background: Due to the complexity of airways and the limitation of experiments, the production mechanism of the lung sounds in airways has not been fully understood, which often confuses diagnosis. Method: A 3D geometrical model of human airways (G5-G8) has been developed based on Weibel's model. Simulation on transient airflow and the noise production during exhalation under different breathing intensities (Q = 15, 30, 45, 60, 75, 90 L/min) has been carried out with Direct Noise Computation (DNC) and Ffowcs Williams-Hawkings (FW-H) method. Results: (1) The junctions between airways are most likely to produce lung sounds, and the peak value is located in the junction between G7 and G6 at the middle of exhalation (about 0.75 s). (2) With the increase in breathing intensity, the average sound pressure level first increases, reaches the peak value at 70–75 L/min, and then drops. (3) Higher breathing intensity is helpful to produce the feature of wheezing, namely a comparatively higher sound pressure level in the range of 200–500 Hz. Moreover, this feature is prominent with the increase in breathing intensity.

Helminths are not usually considered important pathogens for birds of prey. There is a single published report of mortality in raptors due to an air sac trematode infection. We report a well-documented death case from massive infection by an air sac trematode of the family Cyclocoelidae in a wild-caught, juvenile male Snail Kite (Rostrhamus sociabilis) in Ecuador. The necropsy of a Snail Kite revealed more than 200 trematodes among air sacs, lungs, heart, gizzard, proventriculus, and liver. Within air sacs and lungs, mature flukes were associated with sacculitis, bronchitis, pneumonia, and atelectasis. Using an integrative taxonomic approach with morphological and molecular data, we identified the parasites as Bothrigaster variolaris (Trematoda: Cyclocoelidae: Ophthalmophaginae). This case provides the first evidence for the pathologic presence of air sac trematodes associated with morbidity in birds of prey in South America. Our results suggest that cyclocoelids may cause debilitation and significant clinical lesions in birds of prey, with potentially fatal consequences.

Background: Molecular pathways contributing to Cystic Fibrosis pathogenesis remain poorly understood. Epithelial-mesenchymal transition (EMT) has been recently observed in CF lungs and certain CFTR mutation classes may be more susceptible than others. No investigations of EMT processes in CF animal models have been reported., Aim: The aim of this study was to assess the expression of EMT-related markers in Phe508del and knockout (CFTR-KO) rat lung tissue and tracheal-derived basal epithelial stem cells, to determine whether CFTR dysfunction can produce an EMT state., Method: The expression of EMT-related markers in lung tissue and cultured tracheal basal epithelial stem cells from wildtype (WT), Phe508del, and CFTR-KO rats were assessed using qPCR and Western blots. Cell responses were evaluated in the presence of Rho-associated protein kinase (ROCK) inhibitor Y27632, which blocks EMT-pathways, or after treatment with TGFβ1 to stimulate EMT., Results: Different gene expression profiles were observed between Phe508del and CFTR-KO rat models compared to wild type. There was lower expression of type 1 collagen in KO lungs and primary cell cultures, while Phe508del lungs and cells had higher expression, particularly when treated with TGFβ1. The addition of Y27632 rescued changes in EMT related genes in Phe508del cells but not in KO cells., Conclusion: Our findings show the first evidence of upregulated EMT pathways in the lungs and airway cells of any CF animal model. Differences in the regulation of the EMT genes and proteins in the Phe508del and CFTR-KO cells suggest that the signalling pathways underlying EMT are CFTR mutation dependent., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

In this instalment of the How I Do It series on severe asthma, we tackle the clinical conundrum of choosing the right biologic for the right patient with severe asthma. With 6 biologics now approved for use in this area comprising 4 different targeting strategies (anti-Ig E: omalizumab; anti-IL-5 and anti-IL-5-receptor: mepolizumab, reslizumab, and benralizumab; anti-IL-4-receptor: dupilumab; anti-thymic stromal lymphopoietin: tezepelumab), this question is increasingly complex. Recognizing that no head-to-head trial has compared biologics, we based our review on the expected effects of inhibiting different aspects of type 2 airway inflammation, supported whenever possible by clinical trial and real-world data. We use 4 variations of a case of severe uncontrolled asthma to develop concepts and considerations introduced in the previous installment ("Workup of Severe Asthma") and discuss pregnancy-related, biomarker-related, comorbidity-related, and corticosteroid dependency-related considerations when choosing a biologic. The related questions of deciding when, why, and how to switch from one biologic to another also are discussed. Overall, we consider that the choice of biologics should be based on the available clinical trial data for the desired efficacy outcomes, the biomarker profile of the patient, safety profiles (eg, when pregnancy is considered), and opportunities to target 2 comorbidities with 1 biologic. Using systemic and airway biomarkers (blood eosinophils and exhaled nitric oxide) and other phenotypic characteristics, we suggest a framework to facilitate therapeutic decision-making. Post hoc studies and new comparative studies are needed urgently to test this framework and to determine whether it allows us to make other clinically useful predictions., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: S. C. reports nonrestricted research grants from the NIHR Oxford BRC, the Quebec Respiratory Health Research Network, the Fondation Québécoise en Santé Respiratoire, AstraZeneca, bioMérieux, and Sanofi-Genyme-Regeneron; support as the Association Pulmonaire du Québec’s Research Chair in Respiratory Medicine and as a clinical research scholar of the Fonds de Recherche du Québec; speaker honoraria from AstraZeneca, GlaxoSmithKline, Sanofi-Regeneron, and Valeo Pharma; consultancy fees from FirstThought, AstraZeneca, GlaxoSmithKline, Sanofi-Regeneron, Access Biotechnology, and Access Industries; and sponsorship to attend or speak at international scientific meetings by or for AstraZeneca and Sanofi-Regeneron. He is an advisory board member and will have stock options for Biometry, Inc., a company that is developing an Feno device (myBiometry). He advised the Institut National d’Excellence en Santé et Services Sociaux for an update of the asthma general practice information booklet for general practitioners. D. J. J. has received advisory board and speaker’s fees from AstraZeneca, Boehringer Ingelheim, Novartis, Teva, GSK, Sanofi/Regeneron, and Chiesi outside of the submitted work. I. D. P. has received speaker’s honoraria for speaking at sponsored meetings from AstraZeneca, Boehringer Ingelheim, Aerocrine AB, Almirall, Novartis, Teva, Chiesi, Sanofi/Regeneron, Menarini, and GSK in the last 5 years and has received payments for organizing educational events from AstraZeneca, GSK, Sanofi/Regeneron, and Teva. He has received honoraria for attending advisory panels with Genentech, Sanofi/Regeneron, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Teva, Merck, Circassia, Chiesi, and Knopp and has received payments to support Food and Drug Administration approval meetings from GSK. He has received sponsorship to attend international scientific meetings from Boehringer Ingelheim, GSK, AstraZeneca, Teva, and Chiesi. He has received a grant from Chiesi to support a phase 2 clinical trial in Oxford. He is copatent holder of the rights to the Leicester Cough Questionnaire and has received payments for its use in clinical trials from Merck, Bayer, and Insmed. In 2014-2015 he was an expert witness for a patent dispute involving AstraZeneca and Teva. M. E. W. reports grants and personal fees from Novartis, Sanofi, GSK, and Cohero Health; personal fees from Regeneron, Genentech, Sentien, Restorbio, Equillium, and Genzyme; grants, personal fees, and nonfinancial support from Teva; personal fees and nonfinancial support from Boehringer Ingelheim; and grants, personal fees, and nonfinancial support from AstraZeneca., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Eosinophilic inflammation is primarily characterized by type 2 immune responses against parasitic organisms. In the contemporary human being especially in developed countries, eosinophilic inflammation is strongly associated with allergic/sterile inflammation, and constitutes an undesired immune reaction. This situation is in stark contrast to neutrophilic inflammation, which is indispensable for the host defense against bacterial infections. Among eosinophilic inflammatory disorders, massive accumulation of eosinophils within mucus is observed in certain cases, and is often linked to the distinctive clinical finding of mucus with high viscosity. Eosinophilic mucus is found in a variety of diseases, including chronic allergic keratoconjunctivitis, chronic rhinosinusitis encompassing allergic fungal sinusitis, eosinophilic otitis media, eosinophilic sialodochitis, allergic bronchopulmonary aspergillosis/mycosis, eosinophilic plastic bronchitis, and eosinophilic asthma. In these pathological conditions, chronic inflammation and tissue remodeling coupled with irreversible organ damage due to persistent adhesion of toxic substances and luminal obstruction may impose a significant burden on the body. Eosinophils aggregate in the hyperconcentrated mucus together with cell-derived crystals, macromolecules, and polymers, thereby affecting the biophysical properties of the mucus. This review focuses on the clinically significant challenges of mucus and discusses the consequences of activated eosinophils on the mucosal surface that impact mucus and persistent inflammation., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Musa paradisiaca L. (Musaceae), a tropical plant named banana is used as food and as medicine in Brazil. Banana inflorescence, popularly known as mangará, presents several biological activities including anti-inflammatory effects. Here, we demonstrated the immunomodulatory activity of banana inflorescence extract (HEM) on a mice model of combined allergic rhinitis and asthma syndrome (CARAS) and in human macrophages. The HEM inhibited the eosinophil migration, production of cytokines as IL-4, IL-5, IL-13, and IL-17A dependent on IFN-ɣ production in the airway. The mechanism of the extract was, in part, by the NF-κB signaling pathway inhibition. Besides, the HEM decreased expression of the CD86 and HLA-DR receptors on human M1 macrophages independently of M2 modulation. Therefore, we infer that the inflorescence, a disposable material from the banana crops, has anti-allergic property in the CARAS model and modulates the human macrophages, characterizing it as biologically important material for the production of phytomedicine.

Emerging data from clinical studies have shown pro-inflammatory effects associated with e-cigarette use. Fractional exhaled nitric oxide (FeNO) is a biomarker of pulmonary type 2 (T2) inflammation. The effect of chronic e-cigarette use on FeNO is unclear. The aim of this study was to compare FeNO levels in COPD ex-smokers who use e-cigarettes (COPDE + e-cig) to COPDE ex-smokers (COPDE) and COPD current smokers (COPDS). FeNO levels were significantly higher in COPDE + e-cig (median 16.2 ppb) and COPDE (median 18.0 ppb) compared to COPDS (median 7.6 ppb) (p = 0.0003 and p < 0.0001 respectively). There was no difference in FeNO levels between COPDE + e-cig compared to COPDE (p > 0.9). The importance of our results is that electronic cigarette use does not alter the interpretation of FeNO results, and so does not interfere with the use of FeNO as a practical biomarker of T2 inflammation, unlike current cigarette smoking in COPD. Whilst the effect of electronic cigarette use on FeNO levels is not the same as cigarette smoke, this cannot be taken as evidence that electronic cigarettes are harmless. These differential pulmonary effects can be attributed to differences in the chemical composition of the two products., Competing Interests: Declaration of competing interest DS has received personal fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, Epidendo, Genentech, GlaxoSmithKline, Glenmark, Gossamerbio, Kinaset, Menarini, Novartis, Orion, Pulmatrix, Sanofi, Synairgen, Teva, Theravance and Verona. AH has received personal fees from Chiesi. AB has no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A multitude of conditions may cause acute and unexpected upper airway compromise in both children and adults. These include mechanical blockage of the airways either from internal obstructions due to inhaled food or foreign objects, or from external compression. In addition, kinking of the airway in cases of positional asphyxia may compromise aeration. Infections represent another cause of airway narrowing with the potential for occlusion. The case of a 64-year-old man with acute laryngo-epiglottitis is used to demonstrate that death may occur from infections in previously structurally-normal airways. Infections may compromise respiration due to acute airway occlusion from intraluminal material/mucus, mural abscesses or from acutely inflamed and oedematous mucosa with adherent tenacious mucopurulent secretions. External compression from nearby abscesses may also critically narrow air passages., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

A mathematical model of infection, inflammation and immune response in an idealized bronchial tree is developed. This work is based on a model from the literature that is extended to account for the propagation dynamics of an infection between the airways. The inflammation affects the size of the airways, the air flows distribution in the airway tree, and, consequently, the oxygen transfers to blood. We test different infections outcomes and propagation speed. In the hypotheses of our model, the inflammation can reduce notably and sometimes drastically the oxygen flow to blood. Our model predicts how the air flows and oxygen exchanges reorganize in the tree during an infection. Our results highlight the links between the localization of the infection and the amplitude of the loss of oxygen flow to blood. We show that a compensation phenomena due to the reorganization of the flow exists, but that it remains marginal unless the power produced the ventilation muscles is increased. Our model forms a first step towards a better understanding of the dynamics of bronchial infections., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Various structures in human physiology follow a treelike morphology, which often expresses complexity at very fine scales. Examples of such structures are intrathoracic airways, retinal blood vessels, and hepatic blood vessels. Large collections of 2D and 3D images have been made available by medical imaging modalities such as magnetic resonance imaging (MRI), computed tomography (CT), Optical coherence tomography (OCT) and ultrasound in which the spatial arrangement can be observed. Segmentation of these structures in medical imaging is of great importance since the analysis of the structure provides insights into disease diagnosis, treatment planning, and prognosis. Manually labelling extensive data by radiologists is often time-consuming and error-prone. As a result, automated or semi-automated computational models have become a popular research field of medical imaging in the past two decades, and many have been developed to date. In this survey, we aim to provide a comprehensive review of currently publicly available datasets, segmentation algorithms, and evaluation metrics. In addition, current challenges and future research directions are discussed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Lower airway cytology has been proposed as a complementary diagnostic method to confirm the presence and quantifying the severity of exercise-induced pulmonary hemorrhage (EIPH). Bronchoalveolar lavage is usually preferred over tracheal wash (TW), yet the need for sedation imposes as a limitation for active sport horses in addition to be a highly invasive technique. This study aims to evaluate the diagnostic value of TW with Total Hemosiderin Score (THS) for monitoring EIPH in active Thoroughbred racehorses. A sampling of 47 randomly selected Thoroughbreds were endoscopically examined for EIPH grading 30 to 60 minutes after competing in an official race and then classified as Group 1 (EIPH-negative), Group 2 (EIPH-positive) or Group 3 (furosemide users). Tracheal wash fluids (TWFs) were collected from 24 to 30 hours later and smears were stained for differential cell count and hemosiderophage grading and counting to calculate THS. Differential cell counts were compared by the median test. Comparisons between mean THS values by EIPH grade and by group were compared by the Mann-Whitney test and ANOVA, respectively. Test performance criteria were determined with a contingency table. It was not possible to establish a THS cut-off point but statistical results showed that, at THS stand view, all groups had similar results despite their EIPH grades. Most animals showed no signs of neutrophilic inflammation, but haemosiderophages were found even on a first-time runner from Group 1. Thus, TW can detect evidence of lung bleeding even on horses with no history of EIPH. The implementation of TW analysis to diagnose EIPH in racehorses is promising, as TW is both low-cost and a less invasive tool., (Copyright © 2022 Elsevier Inc. All rights reserved.)

PGE 2 is a potent bronchodilator, but the mechanisms underlying this effect have not been fully elucidated. Acetylcholine-induced contractions of airway smooth muscle (ASM) are associated with the generation of repetitive Ca 2+ oscillations in airway smooth muscle cells (ASMC) and the force of contraction is positively correlated with the frequency of the underlying Ca 2+ oscillations. The purpose of the present study was to examine if carbachol-evoked Ca 2+ oscillations in isolated ASMC were inhibited by PGE 2 . Isolated murine ASMC loaded with fluo4-AM were imaged with a Nipkow spinning disk confocal microscope. Cells responded to application of CCh (1 μM) by generating an initial Ca 2+ transient followed by a series of Ca 2+ oscillations. This activity was abolished by PGE 2 (300 nM) and the EP 2 R agonist (R)-butaprost (3 μM) and the inhibitory effects of PGE 2 were reversed by application of the EP 2 R antagonist PF-04418948 (100 nM). Activation of adenylate cyclase using forskolin (1 μM) mimicked the effects of PGE 2 . The PKA activator, 6-MB-cAMP (300 μM) reduced the frequency of CCh-induced Ca 2+ oscillations by 33% and the PKA inhibitor Rp-8-CPT-cAMPs partially reversed the inhibitory effects of PGE 2 . The EPAC activator 007-AM (10 μM) reduced the frequency of the oscillations by 60% and joint application of 007-AM and 6-MB-cAMP reduced oscillation frequency by ∼85%. CCh-induced Ca 2+ oscillations were inhibited by 2-APB and tetracaine, but caffeine-evoked Ca 2+ transients were resistant to PGE 2 . These data suggest that PGE 2 inhibits CCh-induced Ca 2+ oscillations in murine ASMC via stimulation of EP 2 Rs and a mechanism involving activation of PKA and EPAC., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Airway function is under constant neurophysiological control, in order to maximize airflow and gas exchange and to protect the airways from aspiration, damage, and infection. There are multiple sensory nerve subtypes, whose disparate functions provide a wide array of sensory information into the CNS. Activation of these subtypes triggers specific reflexes, including cough and alterations in autonomic efferent control of airway smooth muscle, secretory cells, and vasculature. Importantly, every aspect of these reflex arcs can be impacted and altered by local inflammation caused by chronic lung disease such as asthma, bronchitis, and infections. Excessive and inappropriate activity in sensory and autonomic nerves within the airways is thought to contribute to the morbidity and symptoms associated with lung disease., (Copyright © 2022 Elsevier B.V. All rights reserved.)

A 56-year-old man has difficult-to-control asthma and a history of four exacerbations in the prior 12 months despite high-dose inhaled corticosteroids (ICS) and additional controller therapies. Is he suitable for more advanced therapeutic options? To address this query, we herein review the clinical assessment of a patient with suspected severe asthma and discuss factors contributing to poor asthma control and how biomarkers assist in disease investigation and stratification. The key components of our multidisciplinary approach are to confirm an asthma diagnosis and adherence to treatment, to assess any contributing comorbidities or confounding factors, and to stratify what type of asthma the patient has. The combination of spirometry and repeated measures of key biomarkers of type 2 airway inflammation-the blood eosinophil count and fractional exhaled nitric oxide-identifies whether poor disease control is driven by uncontrolled, ICS-resistant type 2 airway inflammation or ongoing airflow obstruction. A failure to elicit evidence of either suggests an alternative driver for the patient's symptoms, including chronic airway infection and non-asthma causes. Each phenotype represents a treatable trait that requires a specific targeted approach. Critically, steroids can cause harm, and their use should be guided by objective evidence of inflammation rather than symptoms alone. To conclude, after assessment of treatment adherence and exclusion of relevant comorbidities, the patient was found to have severe asthma with ICS-resistant type 2 airway inflammation. We will consider additional treatment options at our next appointment in part 2/2 of this How I Do It series., (Copyright © 2021. Published by Elsevier Inc.)

Objective: The bronchodilatory effect of hydro-ethanolic extract of Z. multiflora was examined in asthmatic patients., Design: Pulmonary function tests (PFTs) were measured before and 15, 30, 60, 90, 120, 150, and 180 min after administration of the extract (20 mg/kg) in 18 asthmatics and after theophylline syrup (6 mg/kg) in 12 patients., Main Outcome Measures: The extract of Z. multiflora significantly increased all PFT values, 30 to 180 min post-administration similar to the effect of theophylline (all, p<0.001). Increased PFT values due to the extract were significantly declined 180 min but the effects of theophylline were declined 150 min after administration (p<0.05 to p<0.001). Values of PFTs at baseline, 30 and 180 min after drugs administration were not singnificantly different between the extract and theophylline., Conclusions: Z. multiflora showed a bronchodilatory effect in asthmatic patients comparable to theophylline effect but with a longer duration of action., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Neonates and infants are susceptible to hypoxaemia in the perioperative period. The aim of this study was to analyse interventions related to anaesthesia tracheal intubations in this European cohort and identify their clinical consequences., Methods: We performed a secondary analysis of tracheal intubations of the European multicentre observational trial (NEonate and Children audiT of Anaesthesia pRactice IN Europe [NECTARINE]) in neonates and small infants with difficult tracheal intubation. The primary endpoint was the incidence of difficult intubation and the related complications. The secondary endpoints were the risk factors for severe hypoxaemia attributed to difficult airway management, and 30 and 90 day outcomes., Results: Tracheal intubation was planned in 4683 procedures. Difficult tracheal intubation, defined as two failed attempts of direct laryngoscopy, occurred in 266 children (271 procedures) with an incidence (95% confidence interval [CI]) of 5.8% (95% CI, 5.1-6.5). Bradycardia occurred in 8% of the cases with difficult intubation, whereas a significant decrease in oxygen saturation (SpO 2 <90% for 60 s) was reported in 40%. No associated risk factors could be identified among co-morbidities, surgical, or anaesthesia management. Using propensity scoring to adjust for confounders, difficult anaesthesia tracheal intubation did not lead to an increase in 30 and 90 day morbidity or mortality., Conclusions: The results of the present study demonstrate a high incidence of difficult tracheal intubation in children less than 60 weeks post-conceptual age commonly resulting in severe hypoxaemia. Reassuringly, the morbidity and mortality at 30 and 90 days was not increased by the occurrence of a difficult intubation event., Clinical Trial Registration: NCT02350348., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pulmonary disease is known to cause remodeling of tissue structure, resulting in altered viscoelastic properties; yet the foundation for understanding this phenomenon is still nascent and will enable scientific insights regarding lung functionality. In order to characterize the viscoelastic response of pulmonary airways, uniaxial tensile experiments are conducted on porcine extra- and intra-parenchymal bronchial regions, measuring both axially and circumferentially oriented tissue. Anisotropic and heterogeneous effects on preconditioning and hysteresis are substantial, linking to energy dissipation expectancies. Stress relaxation is rheologically modeled using several classical configurations of discrete spring and dashpot elements; among them, Standard Linear Solid (SLS) and Maxwell-Weichart exhibit better fit performance. Enhanced fractional order derivative SLS (FSLS) model is also evaluated through use of a hybrid spring-pot of order α. FSLS outperforms the conventional models, demonstrating superior representation of the stress-relaxation curve's initial value and non-linear asymptotic decent. FSLS parameters exhibit notable orientation- and region-specific values, trending with observed tissue structural constituents, such as glycosaminoglycan and collagen. To the best of our knowledge, this work is the first to characterize proximal and distal bronchial energy efficiency and contextualize tissue biochemical composition in view of experimental measures and viscoelastic trends. Results provide a foundation for future investigations, particularly for understanding the role of viscoelasticity in diseased states., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Graph refinement, or the task of obtaining subgraphs of interest from over-complete graphs, can have many varied applications. In this work, we extract trees or collection of sub-trees from image data by, first deriving a graph-based representation of the volumetric data and then, posing the tree extraction as a graph refinement task. We present two methods to perform graph refinement. First, we use mean-field approximation (MFA) to approximate the posterior density over the subgraphs from which the optimal subgraph of interest can be estimated. Mean field networks (MFNs) are used for inference based on the interpretation that iterations of MFA can be seen as feed-forward operations in a neural network. This allows us to learn the model parameters using gradient descent. Second, we present a supervised learning approach using graph neural networks (GNNs) which can be seen as generalisations of MFNs. Subgraphs are obtained by training a GNN-based graph refinement model to directly predict edge probabilities. We discuss connections between the two classes of methods and compare them for the task of extracting airways from 3D, low-dose, chest CT data. We show that both the MFN and GNN models show significant improvement when compared to one baseline method, that is similar to a top performing method in the EXACT'09 Challenge, and a 3D U-Net based airway segmentation model, in detecting more branches with fewer false positives., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aim Determine changes in the expressions of the ion channel-TRPV1-and neuropeptides-NKA, NKB, calcitonin gene-related peptide (CGRP), and SP-in 14-, 21-, and 42-day-old rats after inhaling 1.5% and 2.6% sevoflurane., Main Methods: A small in-house inhalation anesthesia chamber was designed to allow 14-, 21-, and 42-day-old rats inhale 1.5% and 2.6% sevoflurane, and rats in the control group inhaled carrier gas(1 L/min air +1 L/min O 2 ). In addition, 14- and 21-day-old rats were pretreated with capsazepine, followed by inhalation of 1.5% and 2.6% sevoflurane or the carrier gas. The expression of TRPV1 in lung tissues was detected by Western blotting, whereas the expressions of NKA, NKB, CGRP, and SP in the trachea were detected by immunohistochemistry., Key Findings: After inhalation of 1.5% sevoflurane, the expression of TRPV1 in the lung tissues of 14- and 21-day-old rats was significantly increased compared with that in the control group, which was antagonized by capsazepine pretreatment. Moreover, inhalation of 1.5% sevoflurane markedly increased the expressions of NKA, NKB, CGRP, and SP in the trachea of 21-day-old rats and of NKB, CGRP, and SP in the trachea of 14-day-old rats. The expressions of these molecules were antagonized by capsazepine pretreatment. Conversely, inhalation of 2.6% sevoflurane decreased the expressions of NKA and NKB in the trachea of 42-day-old rats., Significance: Sevoflurane did not upregulate the expression of TRPV1 in the airways of late-developing rats. This anesthetic may have a two-way effect on airways, resulting in considerable effects in pediatric clinical anesthesia management., Competing Interests: Declaration of competing interest None., (Copyright © 2020. Published by Elsevier Inc.)

Adamts18 encodes a secreted metalloprotease restricted to branch-tip progenitor pools directing the morphogenesis of multiple mammalian organs. Adamts18 was targeted to explore a potential role in branching morphogenesis. In the kidney, an arborized collecting system develops through extensive branching morphogenesis of an initial epithelial outgrowth of the mesonephric duct, the ureteric bud. Adamts18 mutants displayed a weakly penetrant phenotype: duplicated ureteric outgrowths forming enlarged, bi-lobed kidneys with an increased nephron endowment. In contrast, Adamts18 mutants showed a fully penetrant lung phenotype: epithelial growth was markedly reduced and early secondary branching scaled to the reduced length of the primary airways. Furthermore, there was a pronounced delay in the appearance of differentiated cell types in both proximal and distally positions of the developing airways. Adamts18 is closely related to Adamts16. In the kidney but not the lung, broad epithelial Adamts16 expression overlaps Adamts18 in branch tips. However, compound Adamts16/18 mutants displayed a comparable low penetrance duplicated ureteric phenotype, ruling out a possible role for Adamts16 as a functional modifier of the Adamts18 kidney phenotype. Given the predicted action of secreted Adamts18 metalloprotease, and broad expression of Adamts18 in branching organ systems, these findings suggest distinct requirements for matrix modelling in the morphogenesis of epithelial networks., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The incidence and severity of asthma preponderate in women versus men. Leukotrienes (LTs) are lipid mediators involved in asthma pathogenesis, and sex disparities in LT biosynthesis and anti-LT pharmacology in inflammation have recently emerged. Here, we report on sex dimorphism in LT production during allergen sensitization and its correlation to lung function. While high plasma levels of IgE, as sensitization index, were elevated in both sexes, LT levels increased only in lungs of female ovalbumin-sensitized BALB/c mice. Sex-dependent elevated LT levels strictly correlated to an enhanced airway hyperreactivity, pulmonary inflammation and mast cell infiltration/activation in female mice. Importantly, this sex bias was coupled to superior therapeutic efficacy of different types of clinically used LT modifiers like zileuton, MK886 and montelukast in female animals. Our findings reveal sex-dependent LT production as a basic mechanism of sex dimorphism in allergic asthma, and suggest that women might benefit more from anti-LT asthma therapy., (Copyright © 2018. Published by Elsevier Ltd.)

Paradoxically, the vast majority of research models intended to understand the relationship between exogenous exposures and lung disease are reduced to a single inhalant. This approach is understandable given the practical challenges of investigation, but it is problematic in terms of translation to the real-world human condition. Furthermore, use of data from such models can lead to underestimation of effect, which may adversely influence regulatory imperatives to protect public health based on the most robust information. Efforts to incrementally introduce layers of complexity to observational and experimental systems have revealed pathophysiology previously "hidden" within simplified models. Capturing the effects of co-exposure to traffic-related air pollution and allergens is a paradigmatic example and illustrates the influence of co-exposures across a plethora of clinical and subclinical end points within the respiratory tract. From DNA methylation in the epithelium, to inflammatory mediators and allergen-specific antibodies in the airway, to airflow limitation and symptoms, the addition of a common second exposure induces profound changes. In addition, genetic variation significantly alters the product of these relationships, and capturing multidimensional interactions may reveal susceptible populations who are particularly affected by these exposures and may merit focused measures for protection. Collectively, better modeling, and ultimately deeper knowledge, of these complex relationships has important implications for personalized health and prevention, development and refinement of pharmacologic agents, and public health responses to climate change and the staggering burden of pollution-driven disease worldwide., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Scavenger receptors class B (SR-B) are multifunctional transmembrane proteins, which in vertebrates participate in lipid transport, pathogen clearance, lysosomal delivery and intracellular sorting. Drosophila has 14 SR-B members whose functions are still largely unknown. Here, we reveal a novel role for the SR-B family member Debris buster (Dsb) in Drosophila airway physiology. Larvae lacking dsb show yeast avoidance behavior, hypoxia, and severe growth defects associated with impaired elongation and integrity along the airways. Furthermore, in dsb mutant embryos, the barrier function of the posterior spiracles, which are critical for gas exchange, is not properly established and liquid clearance is locally impaired at the spiracular lumen. We found that Dsb is specifically expressed in a group of distal epithelial cells of the posterior spiracle organ and not throughout the entire airways. Furthermore, tissue-specific knockdown and rescue experiments demonstrate that Dsb function in the airways is only required in the posterior spiracles. Dsb localizes in intracellular vesicles, and a subset of these associate with lysosomes. However, we found that depletion of proteins involved in vesicular transport to the apical membrane, but not in lysosomal function, causes dsb-like airway elongation defects. We propose a model in which Dsb sorts components of the apical extracellular matrix which are essential for airway physiology. Since SR-B LIMP2-deficient mice show reduced expression of several apical plasma membrane proteins, sorting of proteins to the apical membrane is likely an evolutionary conserved function of Dsb and LIMP2. Our data provide insights into a spatially confined function of the SR-B Dsb in intracellular trafficking critical for the physiology of the whole tubular airway network., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: We sought to describe the characteristics of adult patients with bronchiectasis enrolled in the US Bronchiectasis Research Registry (BRR)., Methods: The BRR is a database of patients with non-cystic-fibrosis bronchiectasis (NCFB) enrolled at 13 sites in the United States. Baseline demographic, spirometric, imaging, microbiological, and therapeutic data were entered into a central Internet-based database. Patients were subsequently analyzed by the presence of NTM., Results: We enrolled 1,826 patients between 2008 and 2014. Patients were predominantly women (79%), white (89%), and never smokers (60%), with a mean age of 64 ± 14 years. Sixty-three percent of the patients had a history of NTM disease or NTM isolated at baseline evaluation for entry into the BRR. Patients with NTM were older, predominantly women, and had bronchiectasis diagnosed at a later age than those without NTM. Gastroesophageal reflux disease (GERD) was more common in those with NTM, whereas asthma, primary immunodeficiency, and primary ciliary dyskinesia were more common in those without NTM. Fifty-one percent of patients had spirometric evidence of airflow obstruction. Patients with NTM were more likely to have diffusely dilated airways and tree-in-bud abnormalities. Pseudomonas and Staphylococcus aureus isolates were cultured less commonly in patients with NTM. Bronchial hygiene measures were used more often in those with NTM, whereas antibiotics used for exacerbations, rotating oral antibiotics, steroid use, and inhaled bronchodilators were more commonly used in those without NTM., Conclusions: Adult patients with bronchiectasis enrolled in the US BRR are described, with differences noted in demographic, radiographic, microbiological, and treatment variables based on stratification of the presence of NTM., (Copyright © 2016. Published by Elsevier Inc.)

Purpose: Newborns with Pierre Robin sequence (PRS) and syndromic micrognathia show microgenia and glossoptosis, which cause reduction of the airway and breathing difficulty from birth. Our goal is to analyze quantitative and qualitative volumetric changes before and after fast and early mandibular osteodistraction (FEMOD) and to compare radiological data., Methods: The sample was composed of 4 patients, who satisfied inclusion criteria for completeness of data. Computed tomography pre- and post-operation were performed, then a volumetric assessment was made with Dolphin Imaging. Polysomnography was performed before and after FEMOD., Results: Pre- and post-operative CT scan data were compared. The analysis of all three sections showed a significant increase of volumetric parameters. The retroglossal volume average increase was 346%, and the retropalatal volume average increase was 169%. These data matched the improvement recorded by polysomnography., Conclusions: The data confirm FEMOD as an efficient treatment to improve airways and breathing problem in patients affected by Pierre Robin sequence and syndromic micrognathia. The three-dimensional volume rendering could be a useful method to evaluate and quantify the increase in airways volume., (Copyright © 2016 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Caffeine, theophylline and theobromine are the most known methylxanthines as they are present in coffee, tea and/or chocolate. In the last decades, a huge experimental effort has been devoted to get insight into the variety of actions that these compounds exert in humans. From such knowledge it is known that methylxanthines have a great potential in prevention, therapy and/or management of a variety of diseases. The benefits of methylxanthine-based therapies in the apnea of prematurity and their translational potential in pediatric affections of the respiratory tract are here presented., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Diisocyanate chemicals essential to polyurethane production are a well-recognized cause of occupational asthma. The pathogenesis of diisocyanate-induced asthma, including the pathways by which the chemical is taken up and its distribution in exposed tissue, especially the lung, remains unclear. We developed an antiserum with specificity for methylene diphenyl diisocyanate (MDI) the most abundantly produced and utilized diisocyanate world-wide, and established its ability to detect MDI in situ. Polyclonal MDI-specific IgG was induced by immunizing rabbits with MDI-conjugated to keyhole limpet hemocyanin (KLH) emulsified in complete Freund's adjuvant, followed by two booster injections with incomplete Freund's adjuvant. The antiserum contains IgG that recognize a variety of different MDI conjugated proteins, but not unconjugated or mock exposed proteins by dot blot analysis. The antiserum further demonstrates specificity for proteins conjugated with MDI, but not other commonly used diisocyanates. Immunochemical studies with cytospun airway cells and formalin-fixed paraffin embedded lung tissue sections from mice intranasally exposed to MDI (as reversibly reactive glutathione conjugates, e.g. GSH-MDI) demonstrated the antiserum's ability to detect MDI in tissue samples. The data demonstrate penetration of MDI into the lower airways, localized deposition in the epithelial region surrounding airways, and uptake by alveolar macrophages. The new immunochemical reagent should be useful for further studies delineating the uptake and tissue distribution of MDI, especially as it relates to adverse health effects from exposure., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The dynamics of unsteady flow in the human large airways during a rapid inhalation were investigated using highly detailed large-scale computational fluid dynamics on a subject-specific geometry. The simulations were performed to resolve all the spatial and temporal scales of the flow, thanks to the use of massive computational resources. A highly parallel finite element code was used, running on two supercomputers, solving the transient incompressible Navier-Stokes equations on unstructured meshes. Given that the finest mesh contained 350 million elements, the study sets a precedent for large-scale simulations of the respiratory system, proposing an analysis strategy for mean flow, fluctuations and wall shear stresses on a rapid and short inhalation (a so-called sniff). The geometry used encompasses the exterior face and the airways from the nasal cavity, through the trachea and up to the third lung bifurcation; it was derived from a contrast-enhanced computed tomography (CT) scan of a 48-year-old male. The transient inflow produces complex flows over a wide range of Reynolds numbers (Re). Thanks to the high fidelity simulations, many features involving the flow transition were observed, with the level of turbulence clearly higher in the throat than in the nose. Spectral analysis revealed turbulent characteristics persisting downstream of the glottis, and were captured even with a medium mesh resolution. However a fine mesh resolution was found necessary in the nasal cavity to observe transitional features. This work indicates the potential of large-scale simulations to further understanding of airway physiological mechanics, which is essential to guide clinical diagnosis; better understanding of the flow also has implications for the design of interventions such as aerosol drug delivery., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Cystic fibrosis (CF)-related diabetes (CFRD) is associated with faster pulmonary function decline. Thus, we evaluated the impact of hyperglycemia on airway epithelial repair and transepithelial ion transport, which are critical in maintaining lung integrity and function., Methods: Non-CF and CF airway epithelial cells were exposed to low (LG) or high (HG) glucose before ion current and wound repair rate measurements., Results: CFTR and K+ currents decreased after HG treatments. HG also reduced the wound healing rates of non-CF and CF cell monolayers. Although CFTR correction with VRT-325 accelerated the healing rates of CF cells monolayers under LG conditions, this improvement was significantly abrogated under HG conditions., Conclusions: Our data highlights a deleterious impact of hyperglycemia on ion transport and epithelial repair functions, which could contribute to the deterioration in lung function in CFRD patients. HG may also interfere with the beneficial effects of CFTR rescue on airway epithelial repair., (Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Airway epithelial cells (AEC) are the first line of defense against airborne infectious microbes and play an important role in regulating the local immune response. However, the interplay of epithelial cells and professional immune cells during both homeostasis and infection has only been partially studied. The present study was performed to determine how bronchial epithelial cells affect the activation of monocytes. Under healthy conditions, AECs were shown to inhibit reactivity of monocytes. We hypothesized that upon infection, monocytes might be released from inhibition by AECs. We report that direct contact of monocytes with unstimulated BEAS2B epithelial cells results in inhibition of TNF secretion by activated monocytes. In addition to the known soluble modulators, we show that cell contacts between epithelial cells and monocytes or macrophages also contribute to homeostatic inhibitory actions. We find AECs to express the inhibitory molecule PD-L1 and blockade of PD-L1 results in increased secretion of pro-inflammatory cytokines from monocytes. Contrary to the inhibitory activities during homeostasis, epithelial cells infected with Respiratory Syncitial Virus (RSV) induce a significant release of inhibition. However, release of inhibition was not due to modulation of PD-L1 expression in AECs. We conclude that airway epithelial cells control the reactivity of monocytes through direct and indirect interactions; however tonic inhibition can be reverted upon stimulation of AECs with RSV and thereof derived molecular patterns. The study confirms the important role of airway epithelial cells for local immune reactions., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Tracheobronchomalacia is a common congenital defect in which the walls of the trachea and bronchi lack of adequate cartilage required for support of the airways. Deletion of Wls, a cargo receptor mediating Wnt ligand secretion, in the embryonic endoderm using ShhCre mice inhibited formation of tracheal-bronchial cartilaginous rings. The normal dorsal-ventral patterning of tracheal mesenchyme was lost. Smooth muscle cells, identified by Acta2 staining, were aberrantly located in ventral mesenchyme of the trachea, normally the region of Sox9 expression in cartilage progenitors. Wnt/β-catenin activity, indicated by Axin2 LacZ reporter, was decreased in tracheal mesenchyme of Wls(f/f);Shh(Cre/+) embryos. Proliferation of chondroblasts was decreased and reciprocally, proliferation of smooth muscle cells was increased in Wls(f/f);Shh(Cre/+) tracheal tissue. Expression of Tbx4, Tbx5, Msx1 and Msx2, known to mediate cartilage and muscle patterning, were decreased in tracheal mesenchyme of Wls(f/f);Shh(Cre/+) embryos. Ex vivo studies demonstrated that Wnt7b and Wnt5a, expressed by the epithelium of developing trachea, and active Wnt/β-catenin signaling are required for tracheal chondrogenesis before formation of mesenchymal condensations. In conclusion, Wnt ligands produced by the tracheal epithelium pattern the tracheal mesenchyme via modulation of gene expression and cell proliferation required for proper tracheal cartilage and smooth muscle differentiation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

This paper puts forward a new hypothesis to interpret the high carrier frequency of CFTR mutations in individuals of European descent. The proposed heterozygote advantage factor is related to the specific climate conditions in Europe during the last 50 ky that might have heavily compromised the respiratory function of our ancestors in Eurasia. A large part of the last 50 ky was cold, and the coldest period was the Last Glacial Maximum (LGM) (26.5 to 19 kya). The global climate was dry with a dust-laden atmosphere (20 to 25 times more dust than the present level). High levels of atmospheric dust started more than 40 kya and ended less than 10 kya. Secretion of airway fluid is usually related to the submucosal tissue hydration, while salt reabsorption relies on activation of CFTRs that allow ENaCs to absorb salt and water. The water loss by evaporation depends on the air humidity and flow rate. Salt accumulation in the mucus is normally prevented by reabsorption of Na(+) and Cl(-) by epithelial cells if the presence of functional CFTRs is normal. If one gene for CFTR is mutated, the number of functional CFTRs is reduced and this limits the capacity of salt reabsorption by epithelial cells. This means that evaporation makes the airway fluid more hypertonic, and osmotic forces bring more water from the interstitial space, thus leading to a new balance in mucosal fluid traffic. Increased osmolarity and volume of airway fluid can be more moveable in cases when evaporation and dust exposure is increased. If both CFTR genes are mutated, low number of functional CFTRs diminishes salt resorption of epithelial cells. Salt accumulated in the mucous fluid within respiratory ducts, as previously described. The hypertonic ductal content forces more water and some electrolytes to enter the airway fluid from the interstitial fluid, and evaporation leads to further concentration of thick immobile mucus. The proposed interpretation is that CFTR mutations have spread among our ancestors that roamed the central Eurasia after the LGM. The heterozygote individuals might have benefitted from the limited water resorption in their respiratory mucosa that allowed improved airway cleansing., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The nanomechanical assessment of collagen fibrils via atomic force microscopy (AFM) is of increasing interest within the biomedical research community. In contrast to conventional nanoindentation there exists no common standard for conducting experiments and analysis of data. Currently used analysis approaches vary between studies and validation of quantitative results is usually not performed, which makes comparison of data from different studies difficult. Also there are no recommendations with regards to the maximum indentation depth that should not be exceeded to avoid substrate effects. Here we present a methodology and analysis approach for AFM cantilever-based nanoindentation experiments that allows efficient use of captured data and relying on a reference sample for determination of tip shape. Further we show experimental evidence that maximum indentation depth on collagen fibrils should be lower than 10-15% of the height of the fibril to avoid substrate effects and we show comparisons between our and other approaches used in previous works. While our analysis approach yields similar values for indentation modulus compared to the Oliver-Pharr method we found that Hertzian analysis yielded significantly lower values. Applying our approach we successfully and efficiently indented collagen fibrils from human bronchi, which were about 30 nm in size, considerably smaller compared to collagen fibrils obtained from murine tail-tendon. In addition, derived mechanical parameters of collagen fibrils are in agreement with data previously published. To establish a quantitative validation we compared indentation results from conventional and AFM cantilever-based nanoindentation on polymeric samples with known mechanical properties. Importantly we can show that our approach yields similar results when compared to conventional nanoindentation on polymer samples. Introducing an approach that is reliable, efficient and taking into account the AFM tip shape, we anticipate that the present work may act as a guideline for conducting AFM cantilever-based nanoindentation of collagen fibrils. This may aid understanding of collagen-related diseases such as asthma, lung fibrosis or bone disease with potential alterations of collagen fibril mechanics., (Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.)

Cancer patients often suffer from dyspnea the pathogenesis of which is incompletely understood. Both dyspnea and pulmonary diseases are closely linked to airway innervation. Recently, it was shown that Lewis lung carcinoma induces cardiac hypoinnervation in the mouse. We hypothesized that airway innervation undergoes similar changes as myocardial innervation and that this effect occurs in different mouse models of cancer. C57Bl6 mice were randomly assigned to subcutaneous injection of Lewis lung carcinoma cells (LLC, n=6), B16 melanoma cells (B16, n=6), or saline (control group, C, n=10). After 16 or 21 days, respectively, the trachea was processed for light and electron microscopic design-based stereology and the volume, surface area and length of axons ramifying in the tracheal wall were estimated. Body weight was reduced both in LLC and B16 vs. C. Hypoinnervation was present in both tumor groups compared to controls as volume and surface area of axons were significantly reduced in LLC and B16. However, the total length of tracheal axons and the mean number of axons per nerve fiber were reduced only in LLC but not in B16 compared to C indicating a differentially pronounced effect of cancer on tracheal innervation. In conclusion, reduced innervation of the trachea was observed in two different murine tumor models. These findings add to the pathophysiological concepts explaining cancer-related dyspnea and open new perspectives of treating this symptom., (Copyright © 2014 Elsevier B.V. All rights reserved.)

This paper introduces a graph construction method for multi-dimensional and multi-surface segmentation problems. Such problems can be solved by searching for the optimal separating surfaces given the space of graph columns defined by an initial coarse surface. Conventional straight graph columns are not well suited for surfaces with high curvature, we therefore propose to derive columns from properly generated, non-intersecting flow lines. This guarantees solutions that do not self-intersect. The method is applied to segment human airway walls in computed tomography images in three-dimensions. Phantom measurements show that the inner and outer radii are estimated with sub-voxel accuracy. Two-dimensional manually annotated cross-sectional images were used to compare the results with those of another recently published graph based method. The proposed approach had an average overlap of 89.3±5.8%, and was on average within 0.096±0.097mm of the manually annotated surfaces, which is significantly better than what the previously published approach achieved. A medical expert visually evaluated 499 randomly extracted cross-sectional images from 499 scans and preferred the proposed approach in 68.5%, the alternative approach in 11.2%, and in 20.3% no method was favoured. Airway abnormality measurements obtained with the method on 490 scan pairs from a lung cancer screening trial correlate significantly with lung function and are reproducible; repeat scan R(2) of measures of the airway lumen diameter and wall area percentage in the airways from generation 0 (trachea) to 5 range from 0.96 to 0.73., (Copyright © 2014 Elsevier B.V. All rights reserved.)