Suppression of adenosine-activated chloride transport by ethanol in airway epithelia.

Directory of Open Access Journals (Sweden)

Sammeta V Raju

Full Text Available Alcohol abuse is associated with increased lung infections. Molecular understanding of the underlying mechanisms is not complete. Airway epithelial ion transport regulates the homeostasis of airway surface liquid, essential for airway mucosal immunity and lung host defense. Here, air-liquid interface cultures of Calu-3 epithelial cells were basolaterally exposed to physiologically relevant concentrations of ethanol (0, 25, 50 and 100 mM for 24 hours and adenosine-stimulated ion transport was measured by Ussing chamber. The ethanol exposure reduced the epithelial short-circuit currents (I(SC in a dose-dependent manner. The ion currents activated by adenosine were chloride conductance mediated by cystic fibrosis transmembrane conductance regulator (CFTR, a cAMP-activated chloride channel. Alloxazine, a specific inhibitor for A(2B adenosine receptor (A(2BAR, largely abolished the adenosine-stimulated chloride transport, suggesting that A(2BAR is a major receptor responsible for regulating the chloride transport of the cells. Ethanol significantly reduced intracellular cAMP production upon adenosine stimulation. Moreover, ethanol-suppression of the chloride secretion was able to be restored by cAMP analogs or by inhibitors to block cAMP degradation. These results imply that ethanol exposure dysregulates CFTR-mediated chloride transport in airways by suppression of adenosine-A(2BAR-cAMP signaling pathway, which might contribute to alcohol-associated lung infections.

CXCR3 surface expression in human airway epithelial cells: cell cycle dependence and effect on cell proliferation.

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Aksoy, Mark O; Yang, Yi; Ji, Rong; Reddy, P J; Shahabuddin, Syed; Litvin, Judith; Rogers, Thomas J; Kelsen, Steven G

2006-05-01

We recently demonstrated that human bronchial epithelial cells (HBEC) constitutively express the CXC chemokine receptor CXCR3, which when activated, induces directed cell migration. The present study in HBEC examined the relative expression of the CXCR3 splice variants CXCR3-A and -B, cell cycle dependence of CXCR3 expression, and the effects of the CXCR3 ligand, the interferon-gamma-inducible CXC chemokine I-TAC/CXCL11, on DNA synthesis and cell proliferation. Both CXCR3-A and -B mRNA, assessed by real-time RT-PCR, were expressed in normal HBEC (NHBEC) and the HBEC line 16-HBE. However, CXCR3-B mRNA was 39- and 6-fold greater than CXCR3-A mRNA in NHBEC and 16-HBE, respectively. Although most HBEC (>80%) assessed by flow cytometry and immunofluorescence microscopy contained intracellular CXCR3, only a minority (75%) were in the S + G(2)/M phases of the cell cycle. Stimulation of CXCR3 with I-TAC enhanced thymidine incorporation and cell proliferation and increased p38 and ERK1/2 phosphorylation. These data indicate that 1) human airway epithelial cells primarily express CXCR3-B mRNA, 2) surface expression of CXCR3 is largely confined to the S + G(2)/M phases of the cell cycle, and 3) activation of CXCR3 induces DNA synthesis, cell proliferation, and activation of MAPK pathways. We speculate that activation of CXCR3 exerts a mitogenic effect in HBEC, which may be important during airway mucosal injury in obstructive airway diseases such as asthma and chronic obstructive pulmonary disease.

The chemokine receptor CXCR3 and its splice variant are expressed in human airway epithelial cells.

Science.gov (United States)

Kelsen, Steven G; Aksoy, Mark O; Yang, Yi; Shahabuddin, Syed; Litvin, Judith; Safadi, Fayez; Rogers, Thomas J

2004-09-01

Activation of the chemokine receptor CXCR3 by its cognate ligands induces several differentiated cellular responses important to the growth and migration of a variety of hematopoietic and structural cells. In the human respiratory tract, human airway epithelial cells (HAEC) release the CXCR3 ligands Mig/CXCL9, IP-10/CXCL10, and I-TAC/CXCL11. Simultaneous expression of CXCR3 by HAEC would have important implications for the processes of airway inflammation and repair. Accordingly, in the present study we sought to determine whether HAEC also express the classic CXCR3 chemokine receptor CXCR3-A and its splice variant CXCR3-B and hence may respond in autocrine fashion to its ligands. We found that cultured HAEC (16-HBE and tracheocytes) constitutively expressed CXCR3 mRNA and protein. CXCR3 mRNA levels assessed by expression array were approximately 35% of beta-actin expression. In contrast, CCR3, CCR4, CCR5, CCR8, and CX3CR1 were <5% beta-actin. Both CXCR3-A and -B were expressed. Furthermore, tracheocytes freshly harvested by bronchoscopy stained positively for CXCR3 by immunofluorescence microscopy, and 68% of cytokeratin-positive tracheocytes (i.e., the epithelial cell population) were positive for CXCR3 by flow cytometry. In 16-HBE cells, CXCR3 receptor density was approximately 78,000 receptors/cell when assessed by competitive displacement of 125I-labeled IP-10/CXCL10. Finally, CXCR3 ligands induced chemotactic responses and actin reorganization in 16-HBE cells. These findings indicate constitutive expression by HAEC of a functional CXC chemokine receptor, CXCR3. Our data suggest the possibility that autocrine activation of CXCR3 expressed by HAEC may contribute to airway inflammation and remodeling in obstructive lung disease by regulating HAEC migration.

Neuronal NOS localises to human airway cilia.

Science.gov (United States)

Jackson, Claire L; Lucas, Jane S; Walker, Woolf T; Owen, Holly; Premadeva, Irnthu; Lackie, Peter M

2015-01-30

Airway NO synthase (NOS) isoenzymes are responsible for rapid and localised nitric oxide (NO) production and are expressed in airway epithelium. We sought to determine the localisation of neuronal NOS (nNOS) in airway epithelium due to the paucity of evidence. Sections of healthy human bronchial tissue in glycol methacrylate resin and human nasal polyps in paraffin wax were immunohistochemically labelled and reproducibly demonstrated nNOS immunoreactivity, particularly at the proximal portion of cilia; this immunoreactivity was blocked by a specific nNOS peptide fragment. Healthy human epithelial cells differentiated at an air-liquid interface (ALI) confirmed the presence of all three NOS isoenzymes by immunofluorescence labelling. Only nNOS immunoreactivity was specific to the ciliary axonemeand co-localised with the cilia marker β-tubulin in the proximal part of the ciliary axoneme. We report a novel localisation of nNOS at the proximal portion of cilia in airway epithelium and conclude that its independent and local regulation of NO levels is crucial for normal cilia function. Copyright © 2014 Elsevier Inc. All rights reserved.

Avian Influenza Virus Glycoproteins Restrict Virus Replication and Spread through Human Airway Epithelium at Temperatures of the Proximal Airways

OpenAIRE

Scull, Margaret A.; Gillim-Ross, Laura; Santos, Celia; Roberts, Kim L.; Bordonali, Elena; Subbarao, Kanta; Barclay, Wendy S.; Pickles, Raymond J.

2009-01-01

Transmission of avian influenza viruses from bird to human is a rare event even though avian influenza viruses infect the ciliated epithelium of human airways in vitro and ex vivo. Using an in vitro model of human ciliated airway epithelium (HAE), we demonstrate that while human and avian influenza viruses efficiently infect at temperatures of the human distal airways (37 degrees C), avian, but not human, influenza viruses are restricted for infection at the cooler temperatures of the human p...

Airway skills training using a human patient simulator

African Journals Online (AJOL)

Thesegan Moodley

2016-04-11

Apr 11, 2016 ... Airway management problems may be particularly challenging to junior doctors.1 ... They respond to real-time, real-life clinical ... Keywords: human patient simulator, simulation, airway management, psychomotor skills.

Secreted osteopontin is highly polymerized in human airways and fragmented in asthmatic airway secretions.

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Mehrdad Arjomandi

Full Text Available Osteopontin (OPN is a member of the small integrin-binding ligand N-linked glycoprotein (SIBLING family and a cytokine with diverse biologic roles. OPN undergoes extensive post-translational modifications, including polymerization and proteolytic fragmentation, which alters its biologic activity. Recent studies suggest that OPN may contribute to the pathogenesis of asthma.To determine whether secreted OPN (sOPN is polymerized in human airways and whether it is qualitatively different in asthma, we used immunoblotting to examine sOPN in bronchoalveolar lavage (BAL fluid samples from 12 healthy and 21 asthmatic subjects (and in sputum samples from 27 healthy and 21 asthmatic subjects. All asthmatic subjects had mild to moderate asthma and abstained from corticosteroids during the study. Furthermore, we examined the relationship between airway sOPN and cellular inflammation.We found that sOPN in BAL fluid and sputum exists in polymeric, monomeric, and cleaved forms, with most of it in polymeric form. Compared to healthy subjects, asthmatic subjects had proportionately less polymeric sOPN and more monomeric and cleaved sOPN. Polymeric sOPN in BAL fluid was associated with increased alveolar macrophage counts in airways in all subjects.These results suggest that sOPN in human airways (1 undergoes extensive post-translational modification by polymerization and proteolytic fragmentation, (2 is more fragmented and less polymerized in subjects with mild to moderate asthma, and (3 may contribute to recruitment or survival of alveolar macrophages.

Regional aerosol deposition in human upper airways

Energy Technology Data Exchange (ETDEWEB)

Swift, D.L.

1992-11-01

Laboratory experimental studies were carried out to investigate the factors influencing the deposition of aerosols ranging in size from 1 nm to 10 [mu]m in the human nasal, oral, pharyngeal and laryngeal airways. These experimental studies were performed in replicate upper airway physical models and in human volunteer subjects. New replicate models of the oral passage of an infant, the oral passage of an adult at two openings and the combined nasal and oral airways of an adult were constructed during the period, adding to the existing models of adult, child and infant nasal and oral airways models. Deposition studies in the adult oral and adult nasal models were performed under simulated cyclic flow conditions with 1 nm particles to compare with previously measured constant flow studies. Similar studies with inertial particles (1--10 [mu]m diameter) were performed with the adult nasal model; in both instances, results with cyclic flow were similar to constant flow results using a simple average flow rate based on inspiratory volume and time of inspiration. Human subject studies were performed with particle sizes 5--20 nm for nasal inspiration; preliminary analysis shows good agreement with model studies at several representative flow rates. Nasal inspiratory inertial deposition of 1--4 [mu]m diameter particles was measured in several adults as a function of airway dimensions; dimensional changes of the valve area by decongestion did not produce concomitant deposition changes.

Mediators on human airway smooth muscle.

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Armour, C; Johnson, P; Anticevich, S; Ammit, A; McKay, K; Hughes, M; Black, J

1997-01-01

1. Bronchial hyperresponsiveness in asthma may be due to several abnormalities, but must include alterations in the airway smooth muscle responsiveness and/or volume. 2. Increased responsiveness of airway smooth muscle in vitro can be induced by certain inflammatory cell products and by induction of sensitization (atopy). 3. Increased airway smooth muscle growth can also be induced by inflammatory cell products and atopic serum. 4. Mast cell numbers are increased in the airways of asthmatics and, in our studies, in airway smooth muscle that is sensitized and hyperresponsive. 5. We propose that there is a relationship between mast cells and airway smooth muscle cells which, once an allergic process has been initiated, results in the development of critical features in the lungs in asthma.

Orosomucoid-like 3 (ORMDL3) upregulates airway smooth muscle proliferation, contraction, and Ca2+ oscillations in asthma.

Science.gov (United States)

Chen, Jun; Miller, Marina; Unno, Hirotoshi; Rosenthal, Peter; Sanderson, Michael J; Broide, David H

2017-09-07

Airway hyperresponsiveness is a major feature of asthma attributed predominantly to an extrinsic immune/inflammatory response increasing airway smooth muscle (ASM) contractility. We investigated whether increased ASM expression of orosomucoid-like 3 (ORMDL3), a gene on chromosome 17q21 highly linked to asthma, induced increased ASM proliferation and contractility in vitro and influenced airway contractility and calcium flux in ASM in precision-cut lung slices (PCLSs) from wild-type and hORMDL3 Zp3-Cre mice (which express increased levels of human ORMDL3 [hORMDL3]). Levels of ASM proliferation and contraction were assessed in ASM cells transfected with ORMDL3 in vitro. In addition, airway contractility and calcium oscillations were quantitated in ASM cells in PCLSs derived from naive wild-type and naive hORMDL3 Zp3-Cre mice, which do not have a blood supply. Increased ASM expression of ORMDL3 in vitro resulted in increased ASM proliferation and contractility. PCLSs derived from naive hORMDL3 Zp3-Cre mice, which do not have airway inflammation, exhibit increased airway contractility with increased calcium oscillations in ASM cells. Increased ASM ORMDL3 expression increases levels of ASM sarcoplasmic reticulum Ca 2+ ATPase 2b (SERCA2b), which increases ASM proliferation and contractility. Overall, these studies provide evidence that an intrinsic increase in ORMDL3 expression in ASM can induce increased ASM proliferation and contractility, which might contribute to increased airway hyperresponsiveness in the absence of airway inflammation in asthmatic patients. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Common features of sexual dimorphism in the cranial airways of different human populations.

Science.gov (United States)

Bastir, Markus; Godoy, Paula; Rosas, Antonio

2011-11-01

Sexual dimorphism in the human craniofacial system is an important feature of intraspecific variation in recent and fossil humans. Although several studies have reported different morphological patterns of sexual dimorphism in different populations, this study searches for common morphological aspects related to functional anatomy of the respiratory apparatus. 3D geometric morphometrics were used to test the hypothesis that due to higher daily energy expenditure and associated greater respiratory air consumption as well as differences in body composition, males should have absolutely and relatively greater air passages in the bony cranial airways than females. We measured 25 3D landmarks in five populations (N = 212) of adult humans from different geographic regions. Male average cranial airways were larger in centroid sizes than female ones. Males tended to show relatively taller piriform apertures and, more consistently, relatively taller internal nasal cavities and choanae than females. Multivariate regressions and residual analysis further indicated that after standardizing to the same size, males still show relatively larger airway passages than females. Because the dimensions of the choanae are limiting factors for air transmission towards the noncranial part of the respiratory system, the identified sex-specific differences in cranial airways, possibly shared among human populations, may be linked with sex-specific differences in body size, composition, and energetics. These findings may be important to understanding trends in hominin facial evolution. Copyright © 2011 Wiley-Liss, Inc.

Airway skills training using a human patient simulator | Moodley ...

African Journals Online (AJOL)

... of airway management skills using the simulator. Participant satisfaction was much better in the simulator group. The importance of psychomotor reinforcement should be borne in mind when designing simulation courses. Keywords: human patient simulator, simulation, airway management, psychomotor skills ...

Human apolipoprotein E genotypes differentially modify house dust mite-induced airway disease in mice

DEFF Research Database (Denmark)

Yao, Xianglan; Dai, Cuilian; Fredriksson, Karin

2012-01-01

Apolipoprotein E (apoE) is an endogenous negative regulator of airway hyperreactivity (AHR) and mucous cell metaplasia in experimental models of house dust mite (HDM)-induced airway disease. The gene encoding human apoE is polymorphic, with three common alleles (e2, e3, and e4) reflecting single ...

Computational Thermodynamics Analysis of Vaporizing Fuel Droplets in the Human Upper Airways

Science.gov (United States)

Zhang, Zhe; Kleinstreuer, Clement

The detailed knowledge of air flow structures as well as particle transport and deposition in the human lung for typical inhalation flow rates is an important precursor for dosimetry-and-health-effect studies of toxic particles as well as for targeted drug delivery of therapeutic aerosols. Focusing on highly toxic JP-8 fuel aerosols, 3-D airflow and fluid-particle thermodynamics in a human upper airway model starting from mouth to Generation G3 (G0 is the trachea) are simulated using a user-enhanced and experimentally validated finite-volume code. The temperature distributions and their effects on airflow structures, fuel vapor deposition and droplet motion/evaporation are discussed. The computational results show that the thermal effect on vapor deposition is minor, but it may greatly affect droplet deposition in human airways.

Human airway epithelial cell cultures for modeling respiratory syncytial virus infection.

Science.gov (United States)

Pickles, Raymond J

2013-01-01

Respiratory syncytial virus (RSV) is an important human respiratory pathogen with narrow species tropism. Limited availability of human pathologic specimens during early RSV-induced lung disease and ethical restrictions for RSV challenge studies in the lower airways of human volunteers has slowed our understanding of how RSV causes airway disease and greatly limited the development of therapeutic strategies for reducing RSV disease burden. Our current knowledge of RSV infection and pathology is largely based on in vitro studies using nonpolarized epithelial cell-lines grown on plastic or in vivo studies using animal models semipermissive for RSV infection. Although these models have revealed important aspects of RSV infection, replication, and associated inflammatory responses, these models do not broadly recapitulate the early interactions and potential consequences of RSV infection of the human columnar airway epithelium in vivo. In this chapter, the pro et contra of in vitro models of human columnar airway epithelium and their usefulness in respiratory virus pathogenesis and vaccine development studies will be discussed. The use of such culture models to predict characteristics of RSV infection and the correlation of these findings to the human in vivo situation will likely accelerate our understanding of RSV pathogenesis potentially identifying novel strategies for limiting the severity of RSV-associated airway disease.

Morphology and Three-Dimensional Inhalation Flow in Human Airways in Healthy and Diseased Subjects

Science.gov (United States)

Van de Moortele, Tristan

We investigate experimentally the relation between anatomical structure and respiratory function in healthy and diseased airways. Computed Tomography (CT) scans of human lungs are analyzed from the data base of a large multi-institution clinical study on Chronic Obstructive Pulmonary Disease (COPD). Through segmentation, the 3D volumes of the airways are determined at total lung capacity. A geometric analysis provides data on the morphometry of the airways, including the length and diameter of branches, the child-to-parent diameter ratio, and branching angles. While several geometric parameters are confirmed to match past studies for healthy subjects, previously unreported trends are reported on the length of branches. Specifically, in most dichotomous airway bifurcation, the branch of smaller diameter tends to be significantly longer than the one of larger diameter. Additionally, the branch diameter tends to be smaller in diseased airways than in healthy airways up to the 7th generation of bronchial branching. 3D fractal analysis is also performed on the airway volume. Fractal dimensions of 1.89 and 1.83 are found for healthy non-smokers and declining COPD subjects, respectively, furthering the belief that COPD (and lung disease in general) significantly affects the morphometry of the airways already in early stages of the disease. To investigate the inspiratory flow, 3D flow models of the airways are generated using Computer Aided Design (CAD) software and 3D printed. Using Magnetic Resonance Velocimetry (MRV), 3-component 3D flow fields are acquired for steady inhalation at Reynolds number Re 2000 defined at the trachea. Analysis of the flow data reveals that diseased subjects may experience greater secondary flow strength in their conducting airways, especially in deeper generations.

Aldose reductase inhibition prevents allergic airway remodeling through PI3K/AKT/GSK3β pathway in mice.

Directory of Open Access Journals (Sweden)

Umesh C S Yadav

Full Text Available Long-term and unresolved airway inflammation and airway remodeling, characteristic features of chronic asthma, if not treated could lead to permanent structural changes in the airways. Aldose reductase (AR, an aldo-sugar and lipid aldehyde metabolizing enzyme, mediates allergen-induced airway inflammation in mice, but its role in the airway remodeling is not known. In the present study, we have examined the role of AR on airway remodeling using ovalbumin (OVA-induced chronic asthma mouse model and cultured human primary airway epithelial cells (SAECs and mouse lung fibroblasts (mLFs.Airway remodeling in chronic asthma model was established in mice sensitized and challenged twice a week with OVA for 6 weeks. AR inhibitor, fidarestat, was administered orally in drinking water after first challenge. Inflammatory cells infiltration in the lungs and goblet cell metaplasia, airway thickening, collagen deposition and airway hyper-responsiveness (AHR in response to increasing doses of methacholine were assessed. The TGFβ1-induced epithelial-mesenchymal transition (EMT in SAECs and changes in mLFs were examined to investigate AR-mediated molecular mechanism(s of airway remodeling.In the OVA-exposed mice for 6 wks inflammatory cells infiltration, levels of inflammatory cytokines and chemokines, goblet cell metaplasia, collagen deposition and AHR were significantly decreased by treatment with AR inhibitor, fidarestat. Further, inhibition of AR prevented TGFβ1-induced altered expression of E-cadherin, Vimentin, Occludin, and MMP-2 in SAECs, and alpha-smooth muscle actin and fibronectin in mLFs. Further, in SAECs, AR inhibition prevented TGFβ1- induced activation of PI3K/AKT/GSK3β pathway but not the phosphorylation of Smad2/3.Our results demonstrate that allergen-induced airway remodeling is mediated by AR and its inhibition blocks the progression of remodeling via inhibiting TGFβ1-induced Smad-independent and PI3K/AKT/GSK3β-dependent pathway.

Stochastic model of radon daughter deposition and clearance in human bronchial airways

International Nuclear Information System (INIS)

Hofmann, W.

1996-01-01

Morphometric measurements of human airway casts have repealed that the human bronchial tree is an asymmetrically dividing network, exhibiting individual variations of airway dimensions within a given airway generation Thus, a statistical correlation exists between the linear dimensions of a given parent airway and those of the asymmetrically dividing daughter branches. This statistical relationship, however, is constrained by correlations among various geometrical parameters. i.e., the human lung is not a fully stochastic system. From a statistical analysis of these morphometric data, the following geometrical parameters could be obtained for each airway generation or bifurcation: (i) probability distributions for diameters and lengths, ratios of parent cross section to the combined cross section of both daughters, ratios of major to minor daughter diameters, and branching angles for major and minor branches; (ii) correlations of diameters and lengths; and (iii) the probability of terminating the bronchial region as a function of both diameter and generation number. Since the original lung morphometry refers to total lung capacity, airway diameters and lengths were scaled down to functional residual capacity. (author)

Diacetyl and 2,3-pentanedione exposure of human cultured airway epithelial cells: Ion transport effects and metabolism of butter flavoring agents

Energy Technology Data Exchange (ETDEWEB)

Zaccone, Eric J. [Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV (United States); Goldsmith, W. Travis [Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, Morgantown, WV (United States); Shimko, Michael J. [Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV (United States); Wells, J.R.; Schwegler-Berry, Diane; Willard, Patsy A.; Case, Shannon L.; Thompson, Janet A. [Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, Morgantown, WV (United States); Fedan, Jeffrey S. [Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV (United States); Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, Morgantown, WV (United States)

2015-12-15

Inhalation of butter flavoring by workers in the microwave popcorn industry may result in “popcorn workers' lung.” In previous in vivo studies rats exposed for 6 h to vapor from the flavoring agents, diacetyl and 2,3-pentanedione, acquired flavoring concentration-dependent damage of the upper airway epithelium and airway hyporeactivity to inhaled methacholine. Because ion transport is essential for lung fluid balance, we hypothesized that alterations in ion transport may be an early manifestation of butter flavoring-induced toxicity. We developed a system to expose cultured human bronchial/tracheal epithelial cells (NHBEs) to flavoring vapors. NHBEs were exposed for 6 h to diacetyl or 2,3-pentanedione vapors (25 or ≥ 60 ppm) and the effects on short circuit current and transepithelial resistance (R{sub t}) were measured. Immediately after exposure to 25 ppm both flavorings reduced Na{sup +} transport, without affecting Cl{sup −} transport or Na{sup +},K{sup +}-pump activity. R{sub t} was unaffected. Na{sup +} transport recovered 18 h after exposure. Concentrations (100–360 ppm) of diacetyl and 2,3-pentanedione reported earlier to give rise in vivo to epithelial damage, and 60 ppm, caused death of NHBEs 0 h post-exposure. Analysis of the basolateral medium indicated that NHBEs metabolize diacetyl and 2,3-pentanedione to acetoin and 2-hydroxy-3-pentanone, respectively. The results indicate that ion transport is inhibited transiently in airway epithelial cells by lower concentrations of the flavorings than those that result in morphological changes of the cells in vivo or in vitro. - Highlights: • Butter flavoring vapor effects on human cultured airway epithelium were studied. • Na transport was reduced by a 6-h exposure to 25 ppm diacetyl and 2,3-pentanedione. • Na transport recovered 18 h after exposure. • > 60 ppm transepithelial voltage and resistance were abolished; cells were damaged. • Cells metabolized diacetyl and 2,3-pentanedione

Diacetyl and 2,3-pentanedione exposure of human cultured airway epithelial cells: Ion transport effects and metabolism of butter flavoring agents

International Nuclear Information System (INIS)

Zaccone, Eric J.; Goldsmith, W. Travis; Shimko, Michael J.; Wells, J.R.; Schwegler-Berry, Diane; Willard, Patsy A.; Case, Shannon L.; Thompson, Janet A.; Fedan, Jeffrey S.

2015-01-01

Inhalation of butter flavoring by workers in the microwave popcorn industry may result in “popcorn workers' lung.” In previous in vivo studies rats exposed for 6 h to vapor from the flavoring agents, diacetyl and 2,3-pentanedione, acquired flavoring concentration-dependent damage of the upper airway epithelium and airway hyporeactivity to inhaled methacholine. Because ion transport is essential for lung fluid balance, we hypothesized that alterations in ion transport may be an early manifestation of butter flavoring-induced toxicity. We developed a system to expose cultured human bronchial/tracheal epithelial cells (NHBEs) to flavoring vapors. NHBEs were exposed for 6 h to diacetyl or 2,3-pentanedione vapors (25 or ≥ 60 ppm) and the effects on short circuit current and transepithelial resistance (R t ) were measured. Immediately after exposure to 25 ppm both flavorings reduced Na + transport, without affecting Cl − transport or Na + ,K + -pump activity. R t was unaffected. Na + transport recovered 18 h after exposure. Concentrations (100–360 ppm) of diacetyl and 2,3-pentanedione reported earlier to give rise in vivo to epithelial damage, and 60 ppm, caused death of NHBEs 0 h post-exposure. Analysis of the basolateral medium indicated that NHBEs metabolize diacetyl and 2,3-pentanedione to acetoin and 2-hydroxy-3-pentanone, respectively. The results indicate that ion transport is inhibited transiently in airway epithelial cells by lower concentrations of the flavorings than those that result in morphological changes of the cells in vivo or in vitro. - Highlights: • Butter flavoring vapor effects on human cultured airway epithelium were studied. • Na transport was reduced by a 6-h exposure to 25 ppm diacetyl and 2,3-pentanedione. • Na transport recovered 18 h after exposure. • > 60 ppm transepithelial voltage and resistance were abolished; cells were damaged. • Cells metabolized diacetyl and 2,3-pentanedione into acetoin and 2-OH-3-pentanone.

Simulation of deposition and activity distribution of radionuclides in human airways

International Nuclear Information System (INIS)

Farkas, A.; Balashazy, I.; Szoke, I.; Hofmann, W.; Golser, R.

2002-01-01

The aim of our research activities is the modelling of the biological processes related to the development of lung cancer at the large central-airways observed in the case of uranium miners caused by the inhalation of radionuclides (especially alpha-emitting radon decay products). Statistical data show that at the uranium miners the lung cancer has developed mainly in the 3-4.-5. airway generations and especially in the right upper lobe. Therefore, it is rather important to study the physical and biological effects in this section of the human airways to find relations between the radiation dose and the adverse health effects. These results may provide useful information about the validity or invalidity of the currently used LNT (Linear-No-Threshold) dose-effect hypothesis at low doses

In vivo models of human airway epithelium repair and regeneration

Directory of Open Access Journals (Sweden)

C. Coraux

2005-12-01

Full Text Available Despite an efficient defence system, the airway surface epithelium, in permanent contact with the external milieu, is frequently injured by inhaled pollutants, microorganisms and viruses. The response of the airway surface epithelium to an acute injury includes a succession of cellular events varying from the loss of the surface epithelium integrity to partial shedding of the epithelium or even to complete denudation of the basement membrane. The epithelium has then to repair and regenerate to restore its functions. The in vivo study of epithelial regeneration in animal models has shown that airway epithelial cells are able to dedifferentiate, spread, migrate over the denuded basement membrane and progressively redifferentiate to reconstitute a functional respiratory epithelium after several weeks. Humanised tracheal xenograft models have been developed in immunodeficient nude and severe combined immunodeficient (SCID mice in order to mimic the natural regeneration process of the human airway epithelium and to analyse the cellular and molecular events involved during the different steps of airway epithelial reconstitution. These models represent very powerful tools for analysing the modulation of the biological functions of the epithelium during its regeneration. They are also very useful for identifying stem/progenitor cells of the human airway epithelium. A better knowledge of the mechanisms involved in airway epithelium regeneration, as well as the characterisation of the epithelial stem and progenitor cells, may pave the way to regenerative therapeutics, allowing the reconstitution of a functional airway epithelium in numerous respiratory diseases, such as asthma, chronic obstructive pulmonary diseases, cystic fibrosis and bronchiolitis.

Water permeability in human airway epithelium

DEFF Research Database (Denmark)

Pedersen, Peter Steen; Procida, Kristina; Larsen, Per Leganger

2005-01-01

Osmotic water permeability (P(f)) was studied in spheroid-shaped human airway epithelia explants derived from nasal polyps by the use of a new improved tissue collection and isolation procedure. The fluid-filled spheroids were lined with a single cell layer with the ciliated apical cell membrane ...

Mechanics of airflow in the human nasal airways.

Science.gov (United States)

Doorly, D J; Taylor, D J; Schroter, R C

2008-11-30

The mechanics of airflow in the human nasal airways is reviewed, drawing on the findings of experimental and computational model studies. Modelling inevitably requires simplifications and assumptions, particularly given the complexity of the nasal airways. The processes entailed in modelling the nasal airways (from defining the model, to its production and, finally, validating the results) is critically examined, both for physical models and for computational simulations. Uncertainty still surrounds the appropriateness of the various assumptions made in modelling, particularly with regard to the nature of flow. New results are presented in which high-speed particle image velocimetry (PIV) and direct numerical simulation are applied to investigate the development of flow instability in the nasal cavity. These illustrate some of the improved capabilities afforded by technological developments for future model studies. The need for further improvements in characterising airway geometry and flow together with promising new methods are briefly discussed.

Involvement of the MAPK and PI3K pathways in chitinase 3-like 1-regulated hyperoxia-induced airway epithelial cell death

Energy Technology Data Exchange (ETDEWEB)

Kim, Mi Na; Lee, Kyung Eun; Hong, Jung Yeon; Heo, Won Il; Kim, Kyung Won; Kim, Kyu Earn [Department of Pediatrics and Institute of Allergy, Severance Medical Research Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul (Korea, Republic of); Sohn, Myung Hyun, E-mail: mhsohn@yuhs.ac [Department of Pediatrics and Institute of Allergy, Severance Medical Research Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul (Korea, Republic of)

2012-05-18

Highlights: Black-Right-Pointing-Pointer Hyperoxia induces apoptosis and chitinase 3-like 1 expression in human airway epithelial cells. Black-Right-Pointing-Pointer Presence of chitinase 3-like 1 affects airway epithelial cell death after hyperoxic exposure. Black-Right-Pointing-Pointer Silencing chitinase 3-like 1 manipulate the phosphorylation of ERK, p38 and Akt. -- Abstract: Background: Exposure to 100% oxygen causes hyperoxic acute lung injury characterized by cell death and injury of alveolar epithelial cells. Recently, the role of chitinase 3-like 1 (CHI3L1), a member of the glycosyl hydrolase 18 family that lacks chitinase activity, in oxidative stress was demonstrated in murine models. High levels of serum CHI3L1 have been associated with various diseases of the lung, such as asthma, chronic obstructive pulmonary disease, and cancer. However, the role of CHI3L1 in human airway epithelial cells undergoing oxidative stress remains unknown. In addition, the signaling pathways associated with CHI3L1 in this process are poorly understood. Purpose: In this study, we demonstrate the role of CHI3L1, along with the MAPK and PI3K signaling pathways, in hyperoxia-exposed airway epithelial cells. Method: The human airway epithelial cell line, BEAS-2B, was exposed to >95% oxygen (hyperoxia) for up to 72 h. Hyperoxia-induced cell death was determined by assessing cell viability, Annexin-V FITC staining, caspase-3 and -7 expression, and electron microscopy. CHI3L1 knockdown and overexpression studies were conducted in BEAS-2B cells to examine the role of CHI3L1 in hyperoxia-induced apoptosis. Activation of the MAPK and PI3K pathways was also investigated to determine the role of these signaling cascades in this process. Results: Hyperoxia exposure increased CHI3L1 expression and apoptosis in a time-dependent manner. CHI3L1 knockdown protected cells from hyperoxia-induced apoptosis. In contrast, CHI3L1 overexpression promoted cell death after hyperoxia exposure. Finally

Airflow structures and nano-particle deposition in a human upper airway model

Science.gov (United States)

Zhang, Z.; Kleinstreuer, C.

2004-07-01

Considering a human upper airway model, or equivalently complex internal flow conduits, the transport and deposition of nano-particles in the 1-150 nm diameter range are simulated and analyzed for cyclic and steady flow conditions. Specifically, using a commercial finite-volume software with user-supplied programs as a solver, the Euler-Euler approach for the fluid-particle dynamics is employed with a low-Reynolds-number k- ω model for laminar-to-turbulent airflow and the mass transfer equation for dispersion of nano-particles or vapors. Presently, the upper respiratory system consists of two connected segments of a simplified human cast replica, i.e., the oral airways from the mouth to the trachea (Generation G0) and an upper tracheobronchial tree model of G0-G3. Experimentally validated computational fluid-particle dynamics results show the following: (i) transient effects in the oral airways appear most prominently during the decelerating phase of the inspiratory cycle; (ii) selecting matching flow rates, total deposition fractions of nano-size particles for cyclic inspiratory flow are not significantly different from those for steady flow; (iii) turbulent fluctuations which occur after the throat can persist downstream to at least Generation G3 at medium and high inspiratory flow rates (i.e., Qin⩾30 l/min) due to the enhancement of flow instabilities just upstream of the flow dividers; however, the effects of turbulent fluctuations on nano-particle deposition are quite minor in the human upper airways; (iv) deposition of nano-particles occurs to a relatively greater extent around the carinal ridges when compared to the straight tubular segments in the bronchial airways; (v) deposition distributions of nano-particles vary with airway segment, particle size, and inhalation flow rate, where the local deposition is more uniformly distributed for large-size particles (say, dp=100 nm) than for small-size particles (say, dp=1 nm); (vi) dilute 1 nm particle

Growth and characterization of different human rhinovirus C types in three-dimensional human airway epithelia reconstituted in vitro

International Nuclear Information System (INIS)

Tapparel, Caroline; Sobo, Komla; Constant, Samuel; Huang, Song; Van Belle, Sandra; Kaiser, Laurent

2013-01-01

New molecular diagnostic tools have recently allowed the discovery of human rhinovirus species C (HRV-C) that may be overrepresented in children with lower respiratory tract complications. Unlike HRV-A and HRV-B, HRV-C cannot be propagated in conventional immortalized cell lines and their biological properties have been difficult to study. Recent studies have described the successful amplification of HRV-C15, HRV-C11, and HRV-C41 in sinus mucosal organ cultures and in fully differentiated human airway epithelial cells. Consistent with these studies, we report that a panel of clinical HRV-C specimens including HRV-C2, HRV-C7, HRV-C12, HRV-C15, and HRV-C29 types were all capable of mediating productive infection in reconstituted 3D human primary upper airway epithelial tissues and that the virions enter and exit preferentially through the apical surface. Similar to HRV-A and HRV-B, our data support the acid sensitivity of HRV-C. We observed also that the optimum temperature requirement during HRV-C growth may be type-dependent. - Highlights: • A 3D human upper airway epithelia reconstituted in vitro supports HRV-C growth. • HRV-Cs enter and exit preferentially at the apical side of this ALI culture system. • HRV-Cs are acid sensitive. • Temperature sensitivity may be type-dependent for HRV-Cs

Growth and characterization of different human rhinovirus C types in three-dimensional human airway epithelia reconstituted in vitro

Energy Technology Data Exchange (ETDEWEB)

Tapparel, Caroline, E-mail: Caroline.Tapparel@hcuge.ch [Laboratory of Virology, Division of Infectious Diseases and Division of Laboratory Medicine, University of Geneva Hospitals, 4 Rue Gabrielle-Perret-Gentil, 1211 Geneva 14 (Switzerland); Sobo, Komla [Laboratory of Virology, Division of Infectious Diseases and Division of Laboratory Medicine, University of Geneva Hospitals, 4 Rue Gabrielle-Perret-Gentil, 1211 Geneva 14 (Switzerland); Constant, Samuel; Huang, Song [Epithelix sárl, 14 Chemin des Aulx, 1228 Plan les Ouates, Geneva (Switzerland); Van Belle, Sandra; Kaiser, Laurent [Laboratory of Virology, Division of Infectious Diseases and Division of Laboratory Medicine, University of Geneva Hospitals, 4 Rue Gabrielle-Perret-Gentil, 1211 Geneva 14 (Switzerland)

2013-11-15

New molecular diagnostic tools have recently allowed the discovery of human rhinovirus species C (HRV-C) that may be overrepresented in children with lower respiratory tract complications. Unlike HRV-A and HRV-B, HRV-C cannot be propagated in conventional immortalized cell lines and their biological properties have been difficult to study. Recent studies have described the successful amplification of HRV-C15, HRV-C11, and HRV-C41 in sinus mucosal organ cultures and in fully differentiated human airway epithelial cells. Consistent with these studies, we report that a panel of clinical HRV-C specimens including HRV-C2, HRV-C7, HRV-C12, HRV-C15, and HRV-C29 types were all capable of mediating productive infection in reconstituted 3D human primary upper airway epithelial tissues and that the virions enter and exit preferentially through the apical surface. Similar to HRV-A and HRV-B, our data support the acid sensitivity of HRV-C. We observed also that the optimum temperature requirement during HRV-C growth may be type-dependent. - Highlights: • A 3D human upper airway epithelia reconstituted in vitro supports HRV-C growth. • HRV-Cs enter and exit preferentially at the apical side of this ALI culture system. • HRV-Cs are acid sensitive. • Temperature sensitivity may be type-dependent for HRV-Cs.

Recombinant human DNase in children with airway malacia and lower respiratory tract infection.

NARCIS (Netherlands)

Boogaard, R.; Jongste, J.C. de; Vaessen-Verberne, A.A.; Hop, W.C.J.; Merkus, P.J.F.M.

2009-01-01

BACKGROUND: Children with airway malacia often have protracted courses of airway infections, because dynamic airway collapse during coughing results in impaired mucociliary clearance. The aim of this study was to determine the effect of the mucolytic drug recombinant human deoxyribonuclease

Human lung mast cells modulate the functions of airway smooth muscle cells in asthma.

Science.gov (United States)

Alkhouri, H; Hollins, F; Moir, L M; Brightling, C E; Armour, C L; Hughes, J M

2011-09-01

Activated mast cell densities are increased on the airway smooth muscle in asthma where they may modulate muscle functions and thus contribute to airway inflammation, remodelling and airflow obstruction. To determine the effects of human lung mast cells on the secretory and proliferative functions of airway smooth muscle cells from donors with and without asthma. Freshly isolated human lung mast cells were stimulated with IgE/anti-IgE. Culture supernatants were collected after 2 and 24 h and the mast cells lysed. The supernatants/lysates were added to serum-deprived, subconfluent airway smooth muscle cells for up to 48 h. Released chemokines and extracellular matrix were measured by ELISA, proliferation was quantified by [(3) H]-thymidine incorporation and cell counting, and intracellular signalling by phospho-arrays. Mast cell 2-h supernatants reduced CCL11 and increased CXCL8 and fibronectin production from both asthmatic and nonasthmatic muscle cells. Leupeptin reversed these effects. Mast cell 24-h supernatants and lysates reduced CCL11 release from both muscle cell types but increased CXCL8 release by nonasthmatic cells. The 24-h supernatants also reduced asthmatic, but not nonasthmatic, muscle cell DNA synthesis and asthmatic cell numbers over 5 days through inhibiting extracellular signal-regulated kinase (ERK) and phosphatidylinositol (PI3)-kinase pathways. However, prostaglandins, thromboxanes, IL-4 and IL-13 were not involved in reducing the proliferation. Mast cell proteases and newly synthesized products differentially modulated the secretory and proliferative functions of airway smooth muscle cells from donors with and without asthma. Thus, mast cells may modulate their own recruitment and airway smooth muscle functions locally in asthma. © 2011 John Wiley & Sons A/S.

Human airway organoid engineering as a step toward lung regeneration and disease modeling.

Science.gov (United States)

Tan, Qi; Choi, Kyoung Moo; Sicard, Delphine; Tschumperlin, Daniel J

2017-01-01

Organoids represent both a potentially powerful tool for the study cell-cell interactions within tissue-like environments, and a platform for tissue regenerative approaches. The development of lung tissue-like organoids from human adult-derived cells has not previously been reported. Here we combined human adult primary bronchial epithelial cells, lung fibroblasts, and lung microvascular endothelial cells in supportive 3D culture conditions to generate airway organoids. We demonstrate that randomly-seeded mixed cell populations undergo rapid condensation and self-organization into discrete epithelial and endothelial structures that are mechanically robust and stable during long term culture. After condensation airway organoids generate invasive multicellular tubular structures that recapitulate limited aspects of branching morphogenesis, and require actomyosin-mediated force generation and YAP/TAZ activation. Despite the proximal source of primary epithelium used in the airway organoids, discrete areas of both proximal and distal epithelial markers were observed over time in culture, demonstrating remarkable epithelial plasticity within the context of organoid cultures. Airway organoids also exhibited complex multicellular responses to a prototypical fibrogenic stimulus (TGF-β1) in culture, and limited capacity to undergo continued maturation and engraftment after ectopic implantation under the murine kidney capsule. These results demonstrate that the airway organoid system developed here represents a novel tool for the study of disease-relevant cell-cell interactions, and establishes this platform as a first step toward cell-based therapy for chronic lung diseases based on de novo engineering of implantable airway tissues. Copyright © 2016 Elsevier Ltd. All rights reserved.

Expression and function of human hemokinin-1 in human and guinea pig airways.

Science.gov (United States)

Grassin-Delyle, Stanislas; Naline, Emmanuel; Buenestado, Amparo; Risse, Paul-André; Sage, Edouard; Advenier, Charles; Devillier, Philippe

2010-10-07

Human hemokinin-1 (hHK-1) and endokinins are peptides of the tachykinin family encoded by the TAC4 gene. TAC4 and hHK-1 expression as well as effects of hHK-1 in the lung and airways remain however unknown and were explored in this study. RT-PCR analysis was performed on human bronchi to assess expression of tachykinin and tachykinin receptors genes. Enzyme immunoassay was used to quantify hHK-1, and effects of hHK-1 and endokinins on contraction of human and guinea pig airways were then evaluated, as well as the role of hHK-1 on cytokines production by human lung parenchyma or bronchi explants and by lung macrophages. In human bronchi, expression of the genes that encode for hHK-1, tachykinin NK1-and NK2-receptors was demonstrated. hHK-1 protein was found in supernatants from explants of human bronchi, lung parenchyma and lung macrophages. Exogenous hHK-1 caused a contractile response in human bronchi mainly through the activation of NK2-receptors, which blockade unmasked a NK1-receptor involvement, subject to a rapid desensitization. In the guinea pig trachea, hHK-1 caused a concentration-dependant contraction mainly mediated through the activation of NK1-receptors. Endokinin A/B exerted similar effects to hHK-1 on both human bronchi and guinea pig trachea, whereas endokinins C and D were inactive. hHK-1 had no impact on the production of cytokines by explants of human bronchi or lung parenchyma, or by human lung macrophages. We demonstrate endogenous expression of TAC4 in human bronchi, the encoded peptide hHK-1 being expressed and involved in contraction of human and guinea pig airways.

Expression and function of human hemokinin-1 in human and guinea pig airways

Directory of Open Access Journals (Sweden)

Sage Edouard

2010-10-01

Full Text Available Abstract Background Human hemokinin-1 (hHK-1 and endokinins are peptides of the tachykinin family encoded by the TAC4 gene. TAC4 and hHK-1 expression as well as effects of hHK-1 in the lung and airways remain however unknown and were explored in this study. Methods RT-PCR analysis was performed on human bronchi to assess expression of tachykinin and tachykinin receptors genes. Enzyme immunoassay was used to quantify hHK-1, and effects of hHK-1 and endokinins on contraction of human and guinea pig airways were then evaluated, as well as the role of hHK-1 on cytokines production by human lung parenchyma or bronchi explants and by lung macrophages. Results In human bronchi, expression of the genes that encode for hHK-1, tachykinin NK1-and NK2-receptors was demonstrated. hHK-1 protein was found in supernatants from explants of human bronchi, lung parenchyma and lung macrophages. Exogenous hHK-1 caused a contractile response in human bronchi mainly through the activation of NK2-receptors, which blockade unmasked a NK1-receptor involvement, subject to a rapid desensitization. In the guinea pig trachea, hHK-1 caused a concentration-dependant contraction mainly mediated through the activation of NK1-receptors. Endokinin A/B exerted similar effects to hHK-1 on both human bronchi and guinea pig trachea, whereas endokinins C and D were inactive. hHK-1 had no impact on the production of cytokines by explants of human bronchi or lung parenchyma, or by human lung macrophages. Conclusions We demonstrate endogenous expression of TAC4 in human bronchi, the encoded peptide hHK-1 being expressed and involved in contraction of human and guinea pig airways.

Computational Fluid Dynamics Modeling of Bacillus anthracis Spore Deposition in Rabbit and Human Respiratory Airways

Energy Technology Data Exchange (ETDEWEB)

Kabilan, Senthil; Suffield, Sarah R.; Recknagle, Kurtis P.; Jacob, Rick E.; Einstein, Daniel R.; Kuprat, Andrew P.; Carson, James P.; Colby, Sean M.; Saunders, James H.; Hines, Stephanie; Teeguarden, Justin G.; Straub, Tim M.; Moe, M.; Taft, Sarah; Corley, Richard A.

2016-09-30

Three-dimensional computational fluid dynamics and Lagrangian particle deposition models were developed to compare the deposition of aerosolized Bacillus anthracis spores in the respiratory airways of a human with that of the rabbit, a species commonly used in the study of anthrax disease. The respiratory airway geometries for each species were derived from computed tomography (CT) or µCT images. Both models encompassed airways that extended from the external nose to the lung with a total of 272 outlets in the human model and 2878 outlets in the rabbit model. All simulations of spore deposition were conducted under transient, inhalation-exhalation breathing conditions using average species-specific minute volumes. The highest exposure concentration was modeled in the rabbit based upon prior acute inhalation studies. For comparison, human simulation was also conducted at the same concentration. Results demonstrated that regional spore deposition patterns were sensitive to airway geometry and ventilation profiles. Due to the complex airway geometries in the rabbit nose, higher spore deposition efficiency was predicted in the upper conducting airways compared to the human at the same air concentration of anthrax spores. As a result, higher particle deposition was predicted in the conducting airways and deep lung of the human compared to the rabbit lung due to differences in airway branching pattern. This information can be used to refine published and ongoing biokinetic models of inhalation anthrax spore exposures, which currently estimate deposited spore concentrations based solely upon exposure concentrations and inhaled doses that do not factor in species-specific anatomy and physiology.

Overexpression of functional TrkA receptors after internalisation in human airway smooth muscle cells.

Science.gov (United States)

Freund-Michel, Véronique; Frossard, Nelly

2008-10-01

Trafficking of the TrkA receptor after stimulation by NGF is of emerging importance in structural cells in the context of airway inflammatory diseases. We have recently reported the expression of functional TrkA receptors in human airway smooth muscle cells (HASMC). We have here studied the TrkA trafficking mechanisms in these cells. TrkA disappearance from the cell membrane was induced within 5 min of NGF (3pM) stimulation. Co-immunoprecipitation of clathrin-TrkA was revealed, and TrkA internalisation inhibited either by clathrin inhibitors or by siRNA inducing downregulation of endogenous clathrin. TrkA internalised receptors were totally degraded in lysosomes, with no recycling phenomenon. Newly synthesized TrkA receptors were thereafter re-expressed at the cell membrane within 10 h. TrkA re-synthesis was inhibited by blockade of clathrin-dependent internalisation, but not of TrkA receptors lysosomal degradation. Finally, we observed that NGF multiple stimulations progressively increased TrkA expression in HASMC, which was associated with an increase in NGF/TrkA-dependent proliferation. In conclusion, we show here the occurrence of clathrin-dependent TrkA internalisation and lysosomal degradation in the airway smooth muscle, followed by upregulated re-synthesis of functional TrkA receptors and increased proliferative effect in the human airway smooth muscle. This may have pathophysiological consequences in airway inflammatory diseases.

Regional aerosol deposition in human upper airways

International Nuclear Information System (INIS)

Swift, D.L.

1989-01-01

During the report period significant progress on the quantitative understanding of regional upper airway deposition of airborne particle has been realized. Replicate models of the human upper airways obtained from post-mortem casting of the nasal, oral, pharyngeal, laryngeal and upper tracheal regions and in vivo magnetic resonance imaging (MRI) of the same regions of adults and children have been employed to determine the overall and local deposition characteristics of aerosols in the ultrafine (1--100 μm diameter) and fine (0.8--12 μm diameter) region. Studies have been carried out for both nasal and oral breathing during inspiratory and expiratory flow at constant flow rates representative of rest and states of exercise. The results of these investigations indicate that particles in the size range of ''unattached'' radon progeny (1--3 nm) are deposited in both the nasal and oral passages with high efficiency (60--80%) for both inspiration and expiration, with the nasal deposition being somewhat greater (5--10%) than oral deposition. The effect of flow rate on upper airway deposition for both pathways is not great; data analysis indicates that the deposition for all flow rates from 4--50 liters/minute can be grouped by plotting deposition vs Q- 1/8 , where Q is flow rate, a far weaker dependency than observed for inertial deposition. Diffusional transport is the primary mechanism of deposition, and size dependence can be accounted for by plotting, deposition percent vs D n where D is particle diffusion coefficient and n ranges from 0.5--0.66. 2 refs

Transport and deposition of cohesive pharmaceutical powders in human airway

Directory of Open Access Journals (Sweden)

Wang Yuan

2017-01-01

Full Text Available Pharmaceutical powders used in inhalation therapy are in the size range of 1-5 microns and are usually cohesive. Understanding the cohesive behaviour of pharmaceutical powders during their transportation in human airway is significant in optimising aerosol drug delivery and targeting. In this study, the transport and deposition of cohesive pharmaceutical powders in a human airway model is simulated by a well-established numerical model which combines computational fluid dynamics (CFD and discrete element method (DEM. The van der Waals force, as the dominant cohesive force, is simulated and its influence on particle transport and deposition behaviour is discussed. It is observed that even for dilute particle flow, the local particle concentration in the oral to trachea region can be high and particle aggregation happens due to the van der Waals force of attraction. It is concluded that the deposition mechanism for cohesive pharmaceutical powders, on one hand, is dominated by particle inertial impaction, as proven by previous studies; on the other hand, is significantly affected by particle aggregation induced by van der Waals force. To maximum respiratory drug delivery efficiency, efforts should be made to avoid pharmaceutical powder aggregation in human oral-to-trachea airway.

Transport and deposition of cohesive pharmaceutical powders in human airway

Science.gov (United States)

Wang, Yuan; Chu, Kaiwei; Yu, Aibing

2017-06-01

Pharmaceutical powders used in inhalation therapy are in the size range of 1-5 microns and are usually cohesive. Understanding the cohesive behaviour of pharmaceutical powders during their transportation in human airway is significant in optimising aerosol drug delivery and targeting. In this study, the transport and deposition of cohesive pharmaceutical powders in a human airway model is simulated by a well-established numerical model which combines computational fluid dynamics (CFD) and discrete element method (DEM). The van der Waals force, as the dominant cohesive force, is simulated and its influence on particle transport and deposition behaviour is discussed. It is observed that even for dilute particle flow, the local particle concentration in the oral to trachea region can be high and particle aggregation happens due to the van der Waals force of attraction. It is concluded that the deposition mechanism for cohesive pharmaceutical powders, on one hand, is dominated by particle inertial impaction, as proven by previous studies; on the other hand, is significantly affected by particle aggregation induced by van der Waals force. To maximum respiratory drug delivery efficiency, efforts should be made to avoid pharmaceutical powder aggregation in human oral-to-trachea airway.

Deposition and transport of linezolid mediated by a synthetic surfactant Synsurf® within a pressurized metered dose inhaler: a Calu-3 model

Science.gov (United States)

van Rensburg, Lyné; van Zyl, Johann M; Smith, Johan

2018-01-01

Background Previous studies in our laboratory demonstrated that a synthetic peptide containing lung surfactant enhances the permeability of chemical compounds through bronchial epithelium. The purpose of this study was to test two formulations of Synsurf® combined with linezolid as respirable compounds using a pressurized metered dose inhaler (pMDI). Methods Aerosolization efficiency of the surfactant-drug microparticles onto Calu-3 monolayers as an air interface culture was analyzed using a Next Generation Impactor™. Results The delivered particles and drug dose showed a high dependency from the preparation that was aerosolized. Scanning electron microscopy imaging allowed for visualization of the deposited particles, establishing them as liposomal-type structures (diameter 500 nm to 2 μm) with filamentous features. Conclusion The different surfactant drug combinations allow for an evaluation of the significance of the experimental model system, as well as assessment of the formulations providing a possible noninvasive, site-specific, delivery model via pMDI.

Computational fluid dynamics modeling of Bacillus anthracis spore deposition in rabbit and human respiratory airways

Energy Technology Data Exchange (ETDEWEB)

Kabilan, S.; Suffield, S. R.; Recknagle, K. P.; Jacob, R. E.; Einstein, D. R.; Kuprat, A. P.; Carson, J. P.; Colby, S. M.; Saunders, J. H.; Hines, S. A.; Teeguarden, J. G.; Straub, T. M.; Moe, M.; Taft, S. C.; Corley, R. A.

2016-09-01

Three-dimensional computational fluid dynamics and Lagrangian particle deposition models were developed to compare the deposition of aerosolized Bacillus anthracis spores in the respiratory airways of a human with that of the rabbit, a species commonly used in the study of anthrax disease. The respiratory airway geometries for each species were derived respectively from computed tomography (CT) and µCT images. Both models encompassed airways that extended from the external nose to the lung with a total of 272 outlets in the human model and 2878 outlets in the rabbit model. All simulations of spore deposition were conducted under transient, inhalation–exhalation breathing conditions using average species-specific minute volumes. Two different exposure scenarios were modeled in the rabbit based upon experimental inhalation studies. For comparison, human simulations were conducted at the highest exposure concentration used during the rabbit experimental exposures. Results demonstrated that regional spore deposition patterns were sensitive to airway geometry and ventilation profiles. Due to the complex airway geometries in the rabbit nose, higher spore deposition efficiency was predicted in the nasal sinus compared to the human at the same air concentration of anthrax spores. In contrast, higher spore deposition was predicted in the lower conducting airways of the human compared to the rabbit lung due to differences in airway branching pattern. This information can be used to refine published and ongoing biokinetic models of inhalation anthrax spore exposures, which currently estimate deposited spore concentrations based solely upon exposure concentrations and inhaled doses that do not factor in species-specific anatomy and physiology for deposition.

Oxytetracycline Inhibits Mucus Secretion and Inflammation in Human Airway Epithelial Cells.

Science.gov (United States)

Shah, Said Ahmad; Ishinaga, Hajime; Takeuchi, Kazuhiko

2017-01-01

Oxytetracycline is a broad-spectrum antibiotic, but its nonantibacterial effects in the human respiratory tract are unknown. In this study, the effects of oxytetracycline on mucus secretion and inflammation were examined by PCR and ELISA in the human airway epithelial cell line NCI-H292. Oxytetracycline (10 μg/mL) significantly inhibited TNF-α-induced MUC5AC gene expression and MUC5AC protein levels in NCI-H292 cells. It also downregulated IL-8 and IL-1β gene expression and IL-1β protein levels. Our findings demonstrated that oxytetracycline suppressed mucus production and inflammation in human respiratory epithelial cells, providing further evidence for the usefulness of oxytetracycline for human airway inflammatory diseases. © 2017 S. Karger AG, Basel.

Hold your horses: A comparison of human laryngomalacia with analogous equine airway pathology.

Science.gov (United States)

Lawrence, Rachael J; Butterell, Matthew J; Constable, James D; Daniel, Matija

2018-02-01

Laryngomalacia is the most common cause of stridor in infants. Dynamic airway collapse is also a well-recognised entity in horses and an important cause of surgical veterinary intervention. We compare the aetiology, clinical features and management of human laryngomalacia with equine dynamic airway collapse. A structured review of the PubMed, the Ovid Medline and the Cochrane Collaboration databases (Cochrane Central Register of Controlled Trials, Cochrane Database of Systemic Reviews). There are numerous equine conditions that cause dynamic airway collapse defined specifically by the anatomical structures involved. Axial Deviation of the Aryepiglottic Folds (ADAF) is the condition most clinically analogous to laryngomalacia in humans, and is likewise most prevalent in the immature equine airway. Both conditions are managed either conservatively, or if symptoms require it, with surgical intervention. The operative procedures performed for ADAF and laryngomalacia are technically comparable. Dynamic collapse of the equine larynx, especially ADAF, is clinically similar to human laryngomalacia, and both are treated in a similar fashion. Copyright © 2017 Elsevier B.V. All rights reserved.

Induction of human airway hyperresponsiveness by tumour necrosis factor-alpha.

Science.gov (United States)

Anticevich, S Z; Hughes, J M; Black, J L; Armour, C L

1995-09-15

Tumour necrosis factor-alpha (TNF alpha) is implicated in the pathogenesis of asthma; however, little is known of its direct effect on smooth muscle reactivity. We investigated the effect of TNF alpha on the responsiveness of human bronchial tissue to electrical field stimulation in vitro. Incubation of non-sensitized tissue with 1 nM, 3 nM and 10 nM TNF alpha significantly increased responsiveness to electrical field stimulation (113 +/- 8, 110 +/- 4 and 112 +/- 2% respectively) compared to control (99 +/- 2%) (P 0.05) nor were responses to exogenous acetylcholine (93 +/- 4% versus 73 +/- 7%, n = 3, P = 0.38). These results show that TNF alpha causes an increase in responsiveness of human bronchial tissue and that this occurs prejunctionally on the parasympathetic nerve pathway. This is the first report of a cytokine increasing human airway tissue responsiveness.

Human eosinophil–airway smooth muscle cell interactions

Directory of Open Access Journals (Sweden)

J. Margaret Hughes

2000-01-01

Full Text Available Eosinophils are present throughout the airway wall of asthmatics. The nature of the interaction between human airway smooth muscle cells (ASMC and eosinophils was investigated in this study. We demonstrated, using light microscopy, that freshly isolated eosinophils from healthy donors rapidly attach to ASMC in vitro. Numbers of attached eosinophils were highest at 2 h, falling to 50% of maximum by 20 h. Eosinophil attachment at 2 h was reduced to 72% of control by anti-VCAM-1, and to 74% at 20 h by anti-ICAM-1. Pre-treatment of ASMC for 24 h with TNF-α, 10 nM, significantly increased eosinophil adhesion to 149 and 157% of control after 2 and 20 h. These results provide evidence that eosinophil interactions with ASMC involve VCAM-1 and ICAM-1 and are modulated by TNF-α.

Development of a realistic human airway model.

Science.gov (United States)

Lizal, Frantisek; Elcner, Jakub; Hopke, Philip K; Jedelsky, Jan; Jicha, Miroslav

2012-03-01

Numerous models of human lungs with various levels of idealization have been reported in the literature; consequently, results acquired using these models are difficult to compare to in vivo measurements. We have developed a set of model components based on realistic geometries, which permits the analysis of the effects of subsequent model simplification. A realistic digital upper airway geometry except for the lack of an oral cavity has been created which proved suitable both for computational fluid dynamics (CFD) simulations and for the fabrication of physical models. Subsequently, an oral cavity was added to the tracheobronchial geometry. The airway geometry including the oral cavity was adjusted to enable fabrication of a semi-realistic model. Five physical models were created based on these three digital geometries. Two optically transparent models, one with and one without the oral cavity, were constructed for flow velocity measurements, two realistic segmented models, one with and one without the oral cavity, were constructed for particle deposition measurements, and a semi-realistic model with glass cylindrical airways was developed for optical measurements of flow velocity and in situ particle size measurements. One-dimensional phase doppler anemometry measurements were made and compared to the CFD calculations for this model and good agreement was obtained.

Novel 16-channel receive coil array for accelerated upper airway MRI at 3 Tesla.

Science.gov (United States)

Kim, Yoon-Chul; Hayes, Cecil E; Narayanan, Shrikanth S; Nayak, Krishna S

2011-06-01

Upper airway MRI can provide a noninvasive assessment of speech and swallowing disorders and sleep apnea. Recent work has demonstrated the value of high-resolution three-dimensional imaging and dynamic two-dimensional imaging and the importance of further improvements in spatio-temporal resolution. The purpose of the study was to describe a novel 16-channel 3 Tesla receive coil that is highly sensitive to the human upper airway and investigate the performance of accelerated upper airway MRI with the coil. In three-dimensional imaging of the upper airway during static posture, 6-fold acceleration is demonstrated using parallel imaging, potentially leading to capturing a whole three-dimensional vocal tract with 1.25 mm isotropic resolution within 9 sec of sustained sound production. Midsagittal spiral parallel imaging of vocal tract dynamics during natural speech production is demonstrated with 2 × 2 mm(2) in-plane spatial and 84 ms temporal resolution. Copyright © 2010 Wiley-Liss, Inc.

Extracellular acidification induces connective tissue growth factor production through proton-sensing receptor OGR1 in human airway smooth muscle cells

Energy Technology Data Exchange (ETDEWEB)

Matsuzaki, Shinichi [Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi 371-8511 (Japan); Ishizuka, Tamotsu, E-mail: tamotsui@showa.gunma-u.ac.jp [Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi 371-8511 (Japan); Yamada, Hidenori; Kamide, Yosuke; Hisada, Takeshi; Ichimonji, Isao; Aoki, Haruka; Yatomi, Masakiyo [Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi 371-8511 (Japan); Komachi, Mayumi [Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512 (Japan); Tsurumaki, Hiroaki; Ono, Akihiro; Koga, Yasuhiko [Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi 371-8511 (Japan); Dobashi, Kunio [Gunma University Graduate School of Health Sciences, Maebashi 371-8511 (Japan); Mogi, Chihiro; Sato, Koichi; Tomura, Hideaki [Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512 (Japan); Mori, Masatomo [Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi 371-8511 (Japan); Okajima, Fumikazu [Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512 (Japan)

2011-10-07

Highlights: {yields} The involvement of extracellular acidification in airway remodeling was investigated. {yields} Extracellular acidification alone induced CTGF production in human ASMCs. {yields} Extracellular acidification enhanced TGF-{beta}-induced CTGF production in human ASMCs. {yields} Proton-sensing receptor OGR1 was involved in acidic pH-stimulated CTGF production. {yields} OGR1 may play an important role in airway remodeling in asthma. -- Abstract: Asthma is characterized by airway inflammation, hyper-responsiveness and remodeling. Extracellular acidification is known to be associated with severe asthma; however, the role of extracellular acidification in airway remodeling remains elusive. In the present study, the effects of acidification on the expression of connective tissue growth factor (CTGF), a critical factor involved in the formation of extracellular matrix proteins and hence airway remodeling, were examined in human airway smooth muscle cells (ASMCs). Acidic pH alone induced a substantial production of CTGF, and enhanced transforming growth factor (TGF)-{beta}-induced CTGF mRNA and protein expression. The extracellular acidic pH-induced effects were inhibited by knockdown of a proton-sensing ovarian cancer G-protein-coupled receptor (OGR1) with its specific small interfering RNA and by addition of the G{sub q/11} protein-specific inhibitor, YM-254890, or the inositol-1,4,5-trisphosphate (IP{sub 3}) receptor antagonist, 2-APB. In conclusion, extracellular acidification induces CTGF production through the OGR1/G{sub q/11} protein and inositol-1,4,5-trisphosphate-induced Ca{sup 2+} mobilization in human ASMCs.

Extracellular acidification induces connective tissue growth factor production through proton-sensing receptor OGR1 in human airway smooth muscle cells

International Nuclear Information System (INIS)

Matsuzaki, Shinichi; Ishizuka, Tamotsu; Yamada, Hidenori; Kamide, Yosuke; Hisada, Takeshi; Ichimonji, Isao; Aoki, Haruka; Yatomi, Masakiyo; Komachi, Mayumi; Tsurumaki, Hiroaki; Ono, Akihiro; Koga, Yasuhiko; Dobashi, Kunio; Mogi, Chihiro; Sato, Koichi; Tomura, Hideaki; Mori, Masatomo; Okajima, Fumikazu

2011-01-01

Highlights: → The involvement of extracellular acidification in airway remodeling was investigated. → Extracellular acidification alone induced CTGF production in human ASMCs. → Extracellular acidification enhanced TGF-β-induced CTGF production in human ASMCs. → Proton-sensing receptor OGR1 was involved in acidic pH-stimulated CTGF production. → OGR1 may play an important role in airway remodeling in asthma. -- Abstract: Asthma is characterized by airway inflammation, hyper-responsiveness and remodeling. Extracellular acidification is known to be associated with severe asthma; however, the role of extracellular acidification in airway remodeling remains elusive. In the present study, the effects of acidification on the expression of connective tissue growth factor (CTGF), a critical factor involved in the formation of extracellular matrix proteins and hence airway remodeling, were examined in human airway smooth muscle cells (ASMCs). Acidic pH alone induced a substantial production of CTGF, and enhanced transforming growth factor (TGF)-β-induced CTGF mRNA and protein expression. The extracellular acidic pH-induced effects were inhibited by knockdown of a proton-sensing ovarian cancer G-protein-coupled receptor (OGR1) with its specific small interfering RNA and by addition of the G q/11 protein-specific inhibitor, YM-254890, or the inositol-1,4,5-trisphosphate (IP 3 ) receptor antagonist, 2-APB. In conclusion, extracellular acidification induces CTGF production through the OGR1/G q/11 protein and inositol-1,4,5-trisphosphate-induced Ca 2+ mobilization in human ASMCs.

Anti-inflammatory effects of embelin in A549 cells and human asthmatic airway epithelial tissues.

Science.gov (United States)

Lee, In-Seung; Cho, Dong-Hyuk; Kim, Ki-Suk; Kim, Kang-Hoon; Park, Jiyoung; Kim, Yumi; Jung, Ji Hoon; Kim, Kwanil; Jung, Hee-Jae; Jang, Hyeung-Jin

2018-02-01

Allergic asthma is the most common type in asthma, which is defined as a chronic inflammatory disease of the lung. In this study, we investigated whether embelin (Emb), the major component of Ardisia japonica BL. (AJB), exhibits anti-inflammatory effects on allergic asthma via inhibition of NF-κB activity using A549 cells and asthmatic airway epithelial tissues. Inflammation was induced in A549 cells, a human airway epithelial cell line, by IL-1β (10 ng/ml) treatment for 4 h. The effects of Emb on NF-κB activity and COX-2 protein expression in inflamed airway epithelial cells and human asthmatic airway epithelial tissues were analyzed via western blot. The secretion levels of NF-κB-mediated cytokines/chemokines, including IL-4, 6, 9, 13, TNF-α and eotaxin, were measured by a multiplex assay. Emb significantly blocked NF-κB activity in IL-1β-treated A549 cells and human asthmatic airway epithelial tissues. COX-2 expression was also reduced in both IL-1β-treated A549 cells and asthmatic tissues Emb application. Emb significantly reduced the secretion of IL-4, IL-6 and eotaxin in human asthmatic airway epithelial tissues by inhibiting activity of NF-κB. The results of this study suggest that Emb may be used as an anti-inflammatory agent via inhibition of NF-κB and related cytokines.

Iptakalim inhibits PDGF-BB-induced human airway smooth muscle cells proliferation and migration

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Liu, Wenrui; Kong, Hui; Zeng, Xiaoning; Wang, Jingjing; Wang, Zailiang; Yan, Xiaopei; Wang, Yanli; Xie, Weiping, E-mail: wpxie@njmu.edu.cn; Wang, Hong, E-mail: hongwang@njmu.edu.cn

2015-08-15

Chronic airway diseases are characterized by airway remodeling which is attributed partly to the proliferation and migration of airway smooth muscle cells (ASMCs). ATP-sensitive potassium (K{sub ATP}) channels have been identified in ASMCs. Mount evidence has suggested that K{sub ATP} channel openers can reduce airway hyperresponsiveness and alleviate airway remodeling. Opening K{sup +} channels triggers K{sup +} efflux, which leading to membrane hyperpolarization, preventing Ca{sup 2+}entry through closing voltage-operated Ca{sup 2+} channels. Intracellular Ca{sup 2+} is the most important regulator of muscle contraction, cell proliferation and migration. K{sup +} efflux decreases Ca{sup 2+} influx, which consequently influences ASMCs proliferation and migration. As a K{sub ATP} channel opener, iptakalim (Ipt) has been reported to restrain the proliferation of pulmonary arterial smooth muscle cells (PASMCs) involved in vascular remodeling, while little is known about its impact on ASMCs. The present study was designed to investigate the effects of Ipt on human ASMCs and the mechanisms underlying. Results obtained from cell counting kit-8 (CCK-8), flow cytometry and 5-ethynyl-2′-deoxyuridine (EdU) incorporation showed that Ipt significantly inhibited platelet-derived growth factor (PDGF)-BB-induced ASMCs proliferation. ASMCs migration induced by PDGF-BB was also suppressed by Ipt in transwell migration and scratch assay. Besides, the phosphorylation of Ca{sup 2+}/calmodulin-dependent kinase II (CaMKII), extracellular regulated protein kinases 1/2 (ERK1/2), protein kinase B (Akt), and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) were as well alleviated by Ipt administration. Furthermore, we found that the inhibition of Ipt on the PDGF-BB-induced proliferation and migration in human ASMCs was blocked by glibenclamide (Gli), a selective K{sub ATP} channel antagonist. These findings provide a strong evidence to support that Ipt

Sidestream smoke exposure increases the susceptibility of airway epithelia to adenoviral infection.

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Priyanka Sharma

Full Text Available Although significant epidemiological evidence indicates that cigarette smoke exposure increases the incidence and severity of viral infection, the molecular mechanisms behind the increased susceptibility of the respiratory tract to viral pathogens are unclear. Adenoviruses are non-enveloped DNA viruses and important causative agents of acute respiratory disease. The Coxsackievirus and adenovirus receptor (CAR is the primary receptor for many adenoviruses. We hypothesized that cigarette smoke exposure increases epithelial susceptibility to adenovirus infection by increasing the abundance of apical CAR.Cultured human airway epithelial cells (CaLu-3 were used as a model to investigate the effect of sidestream cigarette smoke (SSS, mainstream cigarette smoke (MSS, or control air exposure on the susceptibility of polarized respiratory epithelia to adenoviral infection. Using a Cultex air-liquid interface exposure system, we have discovered novel differences in epithelial susceptibility between SSS and MSS exposures. SSS exposure upregulates an eight-exon isoform of CAR and increases adenoviral entry from the apical surface whilst MSS exposure is similar to control air exposure. Additionally, the level of cellular glycogen synthase kinase 3β (GSK3β is downregulated by SSS exposure and treatment with a specific GSK3β inhibitor recapitulates the effects of SSS exposure on CAR expression and viral infection.This is the first time that SSS exposure has been shown to directly enhance the susceptibility of a polarized epithelium to infection by a common respiratory viral pathogen. This work provides a novel understanding of the impact of SSS on the burden of respiratory viral infections and may lead to new strategies to alter viral infections. Moreover, since GSK3β inhibitors are under intense clinical investigation as therapeutics for a diverse range of diseases, studies such as these might provide insight to extend the use of clinically relevant

Patient-specific three-dimensional explant spheroids derived from human nasal airway epithelium

DEFF Research Database (Denmark)

Marthin, June Kehlet; Stevens, Elizabeth Munkebjerg; Larsen, Lars Allan

2017-01-01

BACKGROUND: Three-dimensional explant spheroid formation is an ex vivo technique previously used in studies of airway epithelial ion and water transport. Explanted cells and sheets of nasal epithelium form fully differentiated spheroids enclosing a partly fluid-filled lumen with the ciliated apical...... surface facing the outside and accessible for analysis of ciliary function. METHODS: We performed a two-group comparison study of ciliary beat pattern and ciliary beat frequency in spheroids derived from nasal airway epithelium in patients with primary ciliary dyskinesia (PCD) and in healthy controls...... in the investigation of pathophysiological aspects and drug effects in human nasal airway epithelium....

CCL20 and Beta-Defensin 2 Production by Human Lung Epithelial Cells and Macrophages in Response to Brucella abortus Infection

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Fernández, Andrea G.; Bonetto, Josefina; Giambartolomei, Guillermo H.; Fossati, Carlos A.; Baldi, Pablo C.

2015-01-01

Both CCL20 and human β-defensin 2 (hBD2) interact with the same membrane receptor and display chemotactic and antimicrobial activities. They are produced by airway epithelia in response to infectious agents and proinflammatory cytokines. Whereas Brucella spp. can infect humans through inhalation, their ability to induce CCL20 and hBD2 in lung cells is unknown. Here we show that B. abortus induces CCL20 expression in human alveolar (A549) or bronchial (Calu-6) epithelial cell lines, primary alveolar epithelial cells, primary human monocytes, monocyte-derived macrophages and the monocytic cell line THP-1. CCL20 expression was mainly mediated by JNK1/2 and NF-kB in both Calu-6 and THP-1 cells. CCL20 secretion was markedly induced in A549, Calu-6 and THP-1 cells by heat-killed B. abortus or a model Brucella lipoprotein (L-Omp19) but not by the B. abortus lipopolysaccharide (LPS). Accordingly, CCL20 production by B. abortus-infected cells was strongly TLR2-dependent. Whereas hBD2 expression was not induced by B. abortus infection, it was significantly induced in A549 cells by conditioned media from B. abortus-infected THP-1 monocytes (CMB). A similar inducing effect was observed on CCL20 secretion. Experiments using blocking agents revealed that IL-1β, but not TNF-α, was involved in the induction of hBD2 and CCL20 secretion by CMB. In the in vitro antimicrobial assay, the lethal dose (LD) 50 of CCL20 for B. abortus (>50 μg/ml) was markedly higher than that against E. coli (1.5 μg/ml) or a B. abortus mutant lacking the O polysaccharide in its LPS (8.7 ug/ml). hBD2 did not kill any of the B. abortus strains at the tested concentrations. These results show that human lung epithelial cells secrete CCL20 and hBD2 in response to B. abortus and/or to cytokines produced by infected monocytes. Whereas these molecules do not seem to exert antimicrobial activity against this pathogen, they could recruit immune cells to the infection site. PMID:26448160

CXCR3 chemokine receptor-induced chemotaxis in human airway epithelial cells: role of p38 MAPK and PI3K signaling pathways.

Science.gov (United States)

Shahabuddin, Syed; Ji, Rong; Wang, Ping; Brailoiu, Eugene; Dun, Na; Yang, Yi; Aksoy, Mark O; Kelsen, Steven G

2006-07-01

Human airway epithelial cells (HAEC) constitutively express the CXC chemokine receptor CXCR3, which regulates epithelial cell movement. In diseases such as chronic obstructive pulmonary disease and asthma, characterized by denudation of the epithelial lining, epithelial cell migration may contribute to airway repair and reconstitution. This study compared the potency and efficacy of three CXCR3 ligands, I-TAC/CXCL11, IP-10/CXCL10, and Mig/CXCL9, as inducers of chemotaxis in HAEC and examined the underlying signaling pathways involved. Studies were performed in cultured HAEC from normal subjects and the 16-HBE cell line. In normal HAEC, the efficacy of I-TAC-induced chemotaxis was 349 +/- 88% (mean +/- SE) of the medium control and approximately one-half the response to epidermal growth factor, a highly potent chemoattractant. In normal HAEC, Mig, IP-10, and I-TAC induced chemotaxis with similar potency and a rank order of efficacy of I-TAC = IP-10 > Mig. Preincubation with pertussis toxin completely blocked CXCR3-induced migration. Of interest, intracellular [Ca(2+)] did not rise in response to I-TAC, IP-10, or Mig. I-TAC induced a rapid phosphorylation (5-10 min) of two of the three MAPKs, i.e., p38 and ERK1/2. Pretreatment of HAEC with the p38 inhibitor SB 20358 or the PI3K inhibitor wortmannin dose-dependently inhibited the chemotactic response to I-TAC. In contrast, the ERK1/2 inhibitor U0126 had no effect on chemotaxis. These data indicate that in HAEC, CXCR3-mediated chemotaxis involves a G protein, which activates both the p38 MAPK and PI3K pathways in a calcium-independent fashion.

Airway basement membrane perimeter in human airways is not a constant; potential implications for airway remodeling in asthma.

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McParland, Brent E; Paré, Peter D; Johnson, Peter R A; Armour, Carol L; Black, Judith L

2004-08-01

Many studies that demonstrate an increase in airway smooth muscle in asthmatic patients rely on the assumption that bronchial internal perimeter (P(i)) or basement membrane perimeter (P(bm)) is a constant, i.e., not affected by fixation pressure or the degree of smooth muscle shortening. Because it is the basement membrane that has been purported to be the indistensible structure, this study examines the assumption that P(bm) is not affected by fixation pressure. P(bm) was determined for the same human airway segment (n = 12) fixed at distending pressures of 0 cmH(2)O and 21 cmH(2)O in the absence of smooth muscle tone. P(bm) for the segment fixed at 0 cmH(2)O was determined morphometrically, and the P(bm) for the same segment, had the segment been fixed at 21 cmH(2)O, was predicted from knowing the luminal volume and length of the airway when distended to 21 cmH(2)O (organ bath-derived P(i)). To ensure an accurate transformation of the organ bath-derived P(i) value to a morphometry-derived P(bm) value, had the segment been fixed at 21 cmH(2)O, the relationship between organ bath-derived P(i) and morphometry-derived P(bm) was determined for five different bronchial segments distended to 21 cmH(2)O and fixed at 21 cmH(2)O (r(2) = 0.99, P < 0.0001). Mean P(bm) for bronchial segments fixed at 0 cmH(2)O was 9.4 +/- 0.4 mm, whereas mean predicted P(bm), had the segments been fixed at 21 cmH(2)O, was 14.1 +/- 0.5 mm (P < 0.0001). This indicates that P(bm) is not a constant when isolated airway segments without smooth muscle tone are fixed distended to 21 cmH(2)O. The implication of these results is that the increase in smooth muscle mass in asthma may have been overestimated in some previous studies. Therefore, further studies are required to examine the potential artifact using whole lungs with and without abolition of airway smooth muscle tone and/or inflation.

A Numerical Study of Water Loss Rate Distributions in MDCT-based Human Airway Models

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Wu, Dan; Miyawaki, Shinjiro; Tawhai, Merryn H.; Hoffman, Eric A.; Lin, Ching-Long

2015-01-01

Both three-dimensional (3D) and one-dimensional (1D) computational fluid dynamics (CFD) methods are applied to study regional water loss in three multi-detector row computed-tomography (MDCT)-based human airway models at the minute ventilations of 6, 15 and 30 L/min. The overall water losses predicted by both 3D and 1D models in the entire respiratory tract agree with available experimental measurements. However, 3D and 1D models reveal different regional water loss rate distributions due to the 3D secondary flows formed at bifurcations. The secondary flows cause local skewed temperature and humidity distributions on inspiration acting to elevate the local water loss rate; and the secondary flow at the carina tends to distribute more cold air to the lower lobes. As a result, the 3D model predicts that the water loss rate first increases with increasing airway generation, and then decreases as the air approaches saturation, while the 1D model predicts a monotonic decrease of water loss rate with increasing airway generation. Moreover, the 3D (or 1D) model predicts relatively higher water loss rates in lower (or upper) lobes. The regional water loss rate can be related to the non-dimensional wall shear stress (τ*) by the non-dimensional mass transfer coefficient (h0*) as h0* = 1.15 τ*0.272, R = 0.842. PMID:25869455

Influence of horse stable environment on human airways

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Pringle John

2009-05-01

Full Text Available Abstract Background Many people spend considerable amount of time each day in equine stable environments either as employees in the care and training of horses or in leisure activity. However, there are few studies available on how the stable environment affects human airways. This study examined in one horse stable qualitative differences in indoor air during winter and late summer conditions and assessed whether air quality was associated with clinically detectable respiratory signs or alterations to selected biomarkers of inflammation and lung function in stable personnel. Methods The horse stable environment and stable-workers (n = 13 in one stable were investigated three times; first in the winter, second in the interjacent late summer and the third time in the following winter stabling period. The stable measurements included levels of ammonia, hydrogen sulphide, total and respirable dust, airborne horse allergen, microorganisms, endotoxin and glucan. The stable-workers completed a questionnaire on respiratory symptoms, underwent nasal lavage with subsequent analysis of inflammation markers, and performed repeated measurements of pulmonary function. Results Measurements in the horse stable showed low organic dust levels and high horse allergen levels. Increased viable level of fungi in the air indicated a growing source in the stable. Air particle load as well as 1,3-β-glucan was higher at the two winter time-points, whereas endotoxin levels were higher at the summer time-point. Two stable-workers showed signs of bronchial obstruction with increased PEF-variability, increased inflammation biomarkers relating to reported allergy, cold or smoking and reported partly work-related symptoms. Furthermore, two other stable-workers reported work-related airway symptoms, of which one had doctor's diagnosed asthma which was well treated. Conclusion Biomarkers involved in the development of airway diseases have been studied in relation to

Influence of horse stable environment on human airways.

Science.gov (United States)

Elfman, Lena; Riihimäki, Miia; Pringle, John; Wålinder, Robert

2009-05-25

Many people spend considerable amount of time each day in equine stable environments either as employees in the care and training of horses or in leisure activity. However, there are few studies available on how the stable environment affects human airways. This study examined in one horse stable qualitative differences in indoor air during winter and late summer conditions and assessed whether air quality was associated with clinically detectable respiratory signs or alterations to selected biomarkers of inflammation and lung function in stable personnel. The horse stable environment and stable-workers (n = 13) in one stable were investigated three times; first in the winter, second in the interjacent late summer and the third time in the following winter stabling period. The stable measurements included levels of ammonia, hydrogen sulphide, total and respirable dust, airborne horse allergen, microorganisms, endotoxin and glucan. The stable-workers completed a questionnaire on respiratory symptoms, underwent nasal lavage with subsequent analysis of inflammation markers, and performed repeated measurements of pulmonary function. Measurements in the horse stable showed low organic dust levels and high horse allergen levels. Increased viable level of fungi in the air indicated a growing source in the stable. Air particle load as well as 1,3-beta-glucan was higher at the two winter time-points, whereas endotoxin levels were higher at the summer time-point. Two stable-workers showed signs of bronchial obstruction with increased PEF-variability, increased inflammation biomarkers relating to reported allergy, cold or smoking and reported partly work-related symptoms. Furthermore, two other stable-workers reported work-related airway symptoms, of which one had doctor's diagnosed asthma which was well treated. Biomarkers involved in the development of airway diseases have been studied in relation to environmental exposure levels in equine stables. Respirable dust and 1,3

Electronic cigarette liquid increases inflammation and virus infection in primary human airway epithelial cells.

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Wu, Qun; Jiang, Di; Minor, Maisha; Chu, Hong Wei

2014-01-01

The use of electronic cigarettes (e-cigarettes) is rapidly increasing in the United States, especially among young people since e-cigarettes have been perceived as a safer alternative to conventional tobacco cigarettes. However, the scientific evidence regarding the human health effects of e-cigarettes on the lung is extremely limited. The major goal of our current study is to determine if e-cigarette use alters human young subject airway epithelial functions such as inflammatory response and innate immune defense against respiratory viral (i.e., human rhinovirus, HRV) infection. We examined the effects of e-cigarette liquid (e-liquid) on pro-inflammatory cytokine (e.g., IL-6) production, HRV infection and host defense molecules (e.g., short palate, lung, and nasal epithelium clone 1, SPLUNC1) in primary human airway epithelial cells from young healthy non-smokers. Additionally, we examined the role of SPLUNC1 in lung defense against HRV infection using a SPLUNC1 knockout mouse model. We found that nicotine-free e-liquid promoted IL-6 production and HRV infection. Addition of nicotine into e-liquid further amplified the effects of nicotine-free e-liquid. Moreover, SPLUNC1 deficiency in mice significantly increased lung HRV loads. E-liquid inhibited SPLUNC1 expression in primary human airway epithelial cells. These findings strongly suggest the deleterious health effects of e-cigarettes in the airways of young people. Our data will guide future studies to evaluate the impact of e-cigarettes on lung health in human populations, and help inform the public about potential health risks of e-cigarettes.

Electronic cigarette liquid increases inflammation and virus infection in primary human airway epithelial cells.

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Qun Wu

Full Text Available The use of electronic cigarettes (e-cigarettes is rapidly increasing in the United States, especially among young people since e-cigarettes have been perceived as a safer alternative to conventional tobacco cigarettes. However, the scientific evidence regarding the human health effects of e-cigarettes on the lung is extremely limited. The major goal of our current study is to determine if e-cigarette use alters human young subject airway epithelial functions such as inflammatory response and innate immune defense against respiratory viral (i.e., human rhinovirus, HRV infection.We examined the effects of e-cigarette liquid (e-liquid on pro-inflammatory cytokine (e.g., IL-6 production, HRV infection and host defense molecules (e.g., short palate, lung, and nasal epithelium clone 1, SPLUNC1 in primary human airway epithelial cells from young healthy non-smokers. Additionally, we examined the role of SPLUNC1 in lung defense against HRV infection using a SPLUNC1 knockout mouse model. We found that nicotine-free e-liquid promoted IL-6 production and HRV infection. Addition of nicotine into e-liquid further amplified the effects of nicotine-free e-liquid. Moreover, SPLUNC1 deficiency in mice significantly increased lung HRV loads. E-liquid inhibited SPLUNC1 expression in primary human airway epithelial cells. These findings strongly suggest the deleterious health effects of e-cigarettes in the airways of young people. Our data will guide future studies to evaluate the impact of e-cigarettes on lung health in human populations, and help inform the public about potential health risks of e-cigarettes.

Directional secretory response of double stranded RNA-induced thymic stromal lymphopoetin (TSLP) and CCL11/eotaxin-1 in human asthmatic airways.

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Nino, Gustavo; Huseni, Shehlanoor; Perez, Geovanny F; Pancham, Krishna; Mubeen, Humaira; Abbasi, Aleeza; Wang, Justin; Eng, Stephen; Colberg-Poley, Anamaris M; Pillai, Dinesh K; Rose, Mary C

2014-01-01

Thymic stromal lymphoproetin (TSLP) is a cytokine secreted by the airway epithelium in response to respiratory viruses and it is known to promote allergic Th2 responses in asthma. This study investigated whether virally-induced secretion of TSLP is directional in nature (apical vs. basolateral) and/or if there are TSLP-mediated effects occurring at both sides of the bronchial epithelial barrier in the asthmatic state. Primary human bronchial epithelial cells (HBEC) from control (n = 3) and asthmatic (n = 3) donors were differentiated into polarized respiratory tract epithelium under air-liquid interface (ALI) conditions and treated apically with dsRNA (viral surrogate) or TSLP. Sub-epithelial effects of TSLP were examined in human airway smooth muscle cells (HASMC) from normal (n = 3) and asthmatic (n = 3) donors. Clinical experiments examined nasal airway secretions obtained from asthmatic children during naturally occurring rhinovirus-induced exacerbations (n = 20) vs. non-asthmatic uninfected controls (n = 20). Protein levels of TSLP, CCL11/eotaxin-1, CCL17/TARC, CCL22/MDC, TNF-α and CXCL8 were determined with a multiplex magnetic bead assay. Our data demonstrate that: 1) Asthmatic HBEC exhibit an exaggerated apical, but not basal, secretion of TSLP after dsRNA exposure; 2) TSLP exposure induces unidirectional (apical) secretion of CCL11/eotaxin-1 in asthmatic HBEC and enhanced CCL11/eotaxin-1 secretion in asthmatic HASMC; 3) Rhinovirus-induced asthma exacerbations in children are associated with in vivo airway secretion of TSLP and CCL11/eotaxin-1. There are virally-induced TSLP-driven secretory immune responses at both sides of the bronchial epithelial barrier characterized by enhanced CCL11/eotaxin-1 secretion in asthmatic airways. These results suggest a new model of TSLP-mediated eosinophilic responses in the asthmatic airway during viral-induced exacerbations.

Directional secretory response of double stranded RNA-induced thymic stromal lymphopoetin (TSLP and CCL11/eotaxin-1 in human asthmatic airways.

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Gustavo Nino

Full Text Available Thymic stromal lymphoproetin (TSLP is a cytokine secreted by the airway epithelium in response to respiratory viruses and it is known to promote allergic Th2 responses in asthma. This study investigated whether virally-induced secretion of TSLP is directional in nature (apical vs. basolateral and/or if there are TSLP-mediated effects occurring at both sides of the bronchial epithelial barrier in the asthmatic state.Primary human bronchial epithelial cells (HBEC from control (n = 3 and asthmatic (n = 3 donors were differentiated into polarized respiratory tract epithelium under air-liquid interface (ALI conditions and treated apically with dsRNA (viral surrogate or TSLP. Sub-epithelial effects of TSLP were examined in human airway smooth muscle cells (HASMC from normal (n = 3 and asthmatic (n = 3 donors. Clinical experiments examined nasal airway secretions obtained from asthmatic children during naturally occurring rhinovirus-induced exacerbations (n = 20 vs. non-asthmatic uninfected controls (n = 20. Protein levels of TSLP, CCL11/eotaxin-1, CCL17/TARC, CCL22/MDC, TNF-α and CXCL8 were determined with a multiplex magnetic bead assay.Our data demonstrate that: 1 Asthmatic HBEC exhibit an exaggerated apical, but not basal, secretion of TSLP after dsRNA exposure; 2 TSLP exposure induces unidirectional (apical secretion of CCL11/eotaxin-1 in asthmatic HBEC and enhanced CCL11/eotaxin-1 secretion in asthmatic HASMC; 3 Rhinovirus-induced asthma exacerbations in children are associated with in vivo airway secretion of TSLP and CCL11/eotaxin-1.There are virally-induced TSLP-driven secretory immune responses at both sides of the bronchial epithelial barrier characterized by enhanced CCL11/eotaxin-1 secretion in asthmatic airways. These results suggest a new model of TSLP-mediated eosinophilic responses in the asthmatic airway during viral-induced exacerbations.

Dysregulation of TIM-3-galectin-9 pathway in the cystic fibrosis airways.

LENUS (Irish Health Repository)

Vega-Carrascal, Isabel

2012-02-01

The T-cell Ig and mucin domain-containing molecules (TIMs) have emerged as promising therapeutic targets to correct abnormal immune function in several autoimmune and chronic inflammatory conditions. It has been reported that proinflammatory cytokine dysregulation and neutrophil-dominated inflammation are the main causes of morbidity in cystic fibrosis (CF). However, the role of TIM receptors in CF has not been investigated. In this study, we demonstrated that TIM-3 is constitutively overexpressed in the human CF airway, suggesting a link between CF transmembrane conductance regulator (CFTR) function and TIM-3 expression. Blockade of CFTR function with the CFTR inhibitor-172 induced an upregulation of TIM-3 and its ligand galectin-9 in normal bronchial epithelial cells. We also established that TIM-3 serves as a functional receptor in bronchial epithelial cells, and physiologically relevant concentrations of galectin-9 induced TIM-3 phosphorylation, resulting in increased IL-8 production. In addition, we have demonstrated that both TIM-3 and galectin-9 undergo rapid proteolytic degradation in the CF lung, primarily because of neutrophil elastase and proteinase-3 activity. Our results suggest a novel intrinsic defect that may contribute to the neutrophil-dominated immune response in the CF airways.

Dysregulation of TIM-3-galectin-9 pathway in the cystic fibrosis airways.

LENUS (Irish Health Repository)

Vega-Carrascal, Isabel

2011-03-01

The T-cell Ig and mucin domain-containing molecules (TIMs) have emerged as promising therapeutic targets to correct abnormal immune function in several autoimmune and chronic inflammatory conditions. It has been reported that proinflammatory cytokine dysregulation and neutrophil-dominated inflammation are the main causes of morbidity in cystic fibrosis (CF). However, the role of TIM receptors in CF has not been investigated. In this study, we demonstrated that TIM-3 is constitutively overexpressed in the human CF airway, suggesting a link between CF transmembrane conductance regulator (CFTR) function and TIM-3 expression. Blockade of CFTR function with the CFTR inhibitor-172 induced an upregulation of TIM-3 and its ligand galectin-9 in normal bronchial epithelial cells. We also established that TIM-3 serves as a functional receptor in bronchial epithelial cells, and physiologically relevant concentrations of galectin-9 induced TIM-3 phosphorylation, resulting in increased IL-8 production. In addition, we have demonstrated that both TIM-3 and galectin-9 undergo rapid proteolytic degradation in the CF lung, primarily because of neutrophil elastase and proteinase-3 activity. Our results suggest a novel intrinsic defect that may contribute to the neutrophil-dominated immune response in the CF airways.

Targeting Phosphoinositide 3-Kinase γ in Airway Smooth Muscle Cells to Suppress Interleukin-13-Induced Mouse Airway Hyperresponsiveness

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Jiang, Haihong; Xie, Yan; Abel, Peter W.; Toews, Myron L.; Townley, Robert G.; Casale, Thomas B.

2012-01-01

We recently reported that phosphoinositide 3-kinase γ (PI3Kγ) directly regulates airway smooth muscle (ASM) contraction by modulating Ca2+ oscillations. Because ASM contraction plays a critical role in airway hyperresponsiveness (AHR) of asthma, the aim of the present study was to determine whether targeting PI3Kγ in ASM cells could suppress AHR in vitro and in vivo. Intranasal administration into mice of interleukin-13 (IL-13; 10 μg per mouse), a key pathophysiologic cytokine in asthma, induced AHR after 48 h, as assessed by invasive tracheostomy. Intranasal administration of a broad-spectrum PI3K inhibitor or a PI3Kγ-specific inhibitor 1 h before AHR assessment attenuated IL-13 effects. Airway responsiveness to bronchoconstrictor agonists was also examined in precision-cut mouse lung slices pretreated without or with IL-13 for 24 h. Acetylcholine and serotonin dose-response curves indicated that IL-13-treated lung slices had a 40 to 50% larger maximal airway constriction compared with controls. Furthermore, acetylcholine induced a larger initial Ca2+ transient and increased Ca2+ oscillations in IL-13-treated primary mouse ASM cells compared with control cells, correlating with increased cell contraction. As expected, PI3Kγ inhibitor treatment attenuated IL-13-augmented airway contractility of lung slices and ASM cell contraction. In both control and IL-13-treated ASM cells, small interfering RNA-mediated knockdown of PI3Kγ by 70% only reduced the initial Ca2+ transient by 20 to 30% but markedly attenuated Ca2+ oscillations and contractility of ASM cells by 50 to 60%. This report is the first to demonstrate that PI3Kγ in ASM cells is important for IL-13-induced AHR and that acute treatment with a PI3Kγ inhibitor can ameliorate AHR in a murine model of asthma. PMID:22543031

Neurally mediated airway constriction in human and other species: a comparative study using precision-cut lung slices (PCLS.

Directory of Open Access Journals (Sweden)

Marco Schlepütz

Full Text Available The peripheral airway innervation of the lower respiratory tract of mammals is not completely functionally characterized. Recently, we have shown in rats that precision-cut lung slices (PCLS respond to electric field stimulation (EFS and provide a useful model to study neural airway responses in distal airways. Since airway responses are known to exhibit considerable species differences, here we examined the neural responses of PCLS prepared from mice, rats, guinea pigs, sheep, marmosets and humans. Peripheral neurons were activated either by EFS or by capsaicin. Bronchoconstriction in response to identical EFS conditions varied between species in magnitude. Frequency response curves did reveal further species-dependent differences of nerve activation in PCLS. Atropine antagonized the EFS-induced bronchoconstriction in human, guinea pig, sheep, rat and marmoset PCLS, showing cholinergic responses. Capsaicin (10 µM caused bronchoconstriction in human (4 from 7 and guinea pig lungs only, indicating excitatory non-adrenergic non-cholinergic responses (eNANC. However, this effect was notably smaller in human responder (30 ± 7.1% than in guinea pig (79 ± 5.1% PCLS. The transient receptor potential (TRP channel blockers SKF96365 and ruthenium red antagonized airway contractions after exposure to EFS or capsaicin in guinea pigs. In conclusion, the different species show distinct patterns of nerve-mediated bronchoconstriction. In the most common experimental animals, i.e. in mice and rats, these responses differ considerably from those in humans. On the other hand, guinea pig and marmoset monkey mimic human responses well and may thus serve as clinically relevant models to study neural airway responses.

Human mast cell and airway smooth muscle cell interactions: implications for asthma.

Science.gov (United States)

Page, S; Ammit, A J; Black, J L; Armour, C L

2001-12-01

Asthma is characterized by inflammation, hyperresponsiveness, and remodeling of the airway. Human mast cells (HMCs) play a central role in all of these changes by releasing mediators that cause exaggerated bronchoconstriction, induce human airway smooth muscle (HASM) cell proliferation, and recruit and activate inflammatory cells. Moreover, the number of HMCs present on asthmatic HASM is increased compared with that on nonasthmatic HASM. HASM cells also have the potential to actively participate in the inflammatory process by synthesizing cytokines and chemokines and expressing surface molecules, which have the capacity to perpetuate the inflammatory mechanisms present in asthma. This review specifically examines how the mediators of HMCs have the capacity to modulate many functions of HASM; how the synthetic function of HASM, particularly through the release and expression of stem cell factor, has the potential to influence HMC number and activation in an extraordinarily potent and proinflammatory manner; and how these interactions between HMCs and HASM have potential consequences for airway structure and inflammation relevant to the disease process of asthma.

Quantitative imaging of the human upper airway: instrument design and clinical studies

Science.gov (United States)

Leigh, M. S.; Armstrong, J. J.; Paduch, A.; Sampson, D. D.; Walsh, J. H.; Hillman, D. R.; Eastwood, P. R.

2006-08-01

Imaging of the human upper airway is widely used in medicine, in both clinical practice and research. Common imaging modalities include video endoscopy, X-ray CT, and MRI. However, no current modality is both quantitative and safe to use for extended periods of time. Such a capability would be particularly valuable for sleep research, which is inherently reliant on long observation sessions. We have developed an instrument capable of quantitative imaging of the human upper airway, based on endoscopic optical coherence tomography. There are no dose limits for optical techniques, and the minimally invasive imaging probe is safe for use in overnight studies. We report on the design of the instrument and its use in preliminary clinical studies, and we present results from a range of initial experiments. The experiments show that the instrument is capable of imaging during sleep, and that it can record dynamic changes in airway size and shape. This information is useful for research into sleep disorders, and potentially for clinical diagnosis and therapies.

Oscillatory flow in the human airways from the mouth through several bronchial generations

International Nuclear Information System (INIS)

Banko, Andrew J.; Coletti, Filippo; Elkins, Christopher J.; Eaton, John K.

2016-01-01

Highlights: • Oscillatory flow in the human airways is studied experimentally. • The realistic anatomy is obtained from the CT scan of a healthy adult. • Integral parameters are calculated to quantify streamwise and lateral dispersion. • Flow in real human anatomy is qualitatively different from idealized models. - Abstract: The time-varying flow is studied experimentally in an anatomically accurate model of the human airways from the mouth through several generations of bronchial branching. The airway geometry is obtained from the CT scan of a healthy adult male of normal height and build. The three-component, three-dimensional mean velocity field is obtained throughout the entire model using phase-locked Magnetic Resonance Velocimetry. A pulsatile pump drives a sinusoidal waveform (inhalation and exhalation) with frequency and stroke-length such that the mean trachea Reynolds number at peak inspiration is 4200 and the Womersley number is 7. Integral parameters are defined to quantify the degree of velocity profile non-uniformity (related to axial dispersion) and secondary flow strength (lateral dispersion). It is found that the extrathoracic airways significantly modify the tracheal flow and that the flow at the first bifurcation is highly asymmetric. The effect of flow oscillation is to produce time dependent flow features which are asymmetric with respect to the acceleration and deceleration periods surrounding peak inhalation and exhalation. This is most pronounced in regions of separation and on the secondary flow structure, which are sensitive to local attributes of the real anatomy. This is reflected in the integral parameters, which behave non-monotonically between successive bronchial generations. In general, the measured oscillatory flow in a realistic anatomy confirms many trends derived from idealized models but also possesses qualitatively different large scale flow structures as compared to idealized representations of the upper airways.

Airway remodeling and its reversibility in equine asthma

Directory of Open Access Journals (Sweden)

Jean-Pierre Lavoie

2017-06-01

Full Text Available Despite effective therapies for controlling its clinical manifestations, human asthma remains an incurable disease. It is now recognized that inflammation induced structural changes (remodeling of the airways are responsible for the progressive loss of lung function in asthmatic patients. However, the peripheral airways, where most of the remodeling occurs in severe asthmatic patients, cannot be safely sampled in humans, and therefore, little is known of the effects of current therapies at reversing the established asthmatic remodeling, especially those occurring in the peripheral airways. Animal models have been studied to unravel etiological, immunopathological, and genetic attributes leading to asthma. However, experiments in which the disease is artificially induced have been shown to have limited translational potential for humans. To the contrary, horses naturally suffer from an asthma-like condition which shares marked similarities with human asthma making this model unique to investigate the kinetics, reversibility, as well as the physiological consequences of tissue remodeling (Bullone and Lavoie 2015. We reported an increased deposition of smooth muscle, collagen and elastic fibers in the peripheral airways of affected horses, which was correlated with the lung function (Herszberg et al., 2006; Setlakwe et al., 2014. The airway subepithelial collagen depositions were almost completely reversed with 6 to 12 months of treatment with either antigen avoidance or inhaled corticosteroids (ICS administration, and there was a modest (30% on average decrease in airway smooth muscle (Leclere et al., 2011. A recent study also found that ICS combined with long-acting ß2-agonists drugs (LABA and ICS monotherapy similarly induced a 30% decrease of the airway smooth muscle mass at 3 months (Buollone, 2017. However, only ICS/LABA and antigen avoidance decreased airway luminal neutrophilia. The findings indicate the enhance therapeutic effect of ICS

Regional aerosol deposition in human upper airways. Progress report, March 1, 1992--February 28, 1993

Energy Technology Data Exchange (ETDEWEB)

Swift, D.L.

1992-11-01

Laboratory experimental studies were carried out to investigate the factors influencing the deposition of aerosols ranging in size from 1 nm to 10 {mu}m in the human nasal, oral, pharyngeal and laryngeal airways. These experimental studies were performed in replicate upper airway physical models and in human volunteer subjects. New replicate models of the oral passage of an infant, the oral passage of an adult at two openings and the combined nasal and oral airways of an adult were constructed during the period, adding to the existing models of adult, child and infant nasal and oral airways models. Deposition studies in the adult oral and adult nasal models were performed under simulated cyclic flow conditions with 1 nm particles to compare with previously measured constant flow studies. Similar studies with inertial particles (1--10 {mu}m diameter) were performed with the adult nasal model; in both instances, results with cyclic flow were similar to constant flow results using a simple average flow rate based on inspiratory volume and time of inspiration. Human subject studies were performed with particle sizes 5--20 nm for nasal inspiration; preliminary analysis shows good agreement with model studies at several representative flow rates. Nasal inspiratory inertial deposition of 1--4 {mu}m diameter particles was measured in several adults as a function of airway dimensions; dimensional changes of the valve area by decongestion did not produce concomitant deposition changes.

Screening of siRNA nanoparticles for delivery to airway epithelial cells using high-content analysis

LENUS (Irish Health Repository)

Hibbitts, Alan

2011-08-01

Aims: Delivery of siRNA to the lungs via inhalation offers a unique opportunity to develop a new treatment paradigm for a range of respiratory conditions. However, progress has been greatly hindered by safety and delivery issues. This study developed a high-throughput method for screening novel nanotechnologies for pulmonary siRNA delivery. Methodology: Following physicochemical analysis, the ability of PEI–PEG–siRNA nanoparticles to facilitate siRNA delivery was determined using high-content analysis (HCA) in Calu-3 cells. Results obtained from HCA were validated using confocal microscopy. Finally, cytotoxicity of the PEI–PEG–siRNA particles was analyzed by HCA using the Cellomics® multiparameter cytotoxicity assay. Conclusion: PEI–PEG–siRNA nanoparticles facilitated increased siRNA uptake and luciferase knockdown in Calu-3 cells compared with PEI–siRNA.

Genetic modification of adeno-associated viral vector type 2 capsid enhances gene transfer efficiency in polarized human airway epithelial cells.

Science.gov (United States)

White, April F; Mazur, Marina; Sorscher, Eric J; Zinn, Kurt R; Ponnazhagan, Selvarangan

2008-12-01

Cystic fibrosis (CF) is a common genetic disease characterized by defects in the expression of the CF transmembrane conductance regulator (CFTR) gene. Gene therapy offers better hope for the treatment of CF. Adeno-associated viral (AAV) vectors are capable of stable expression with low immunogenicity. Despite their potential in CF gene therapy, gene transfer efficiency by AAV is limited because of pathophysiological barriers in these patients. Although a few AAV serotypes have shown better transduction compared with the AAV2-based vectors, gene transfer efficiency in human airway epithelium has still not reached therapeutic levels. To engineer better AAV vectors for enhanced gene delivery in human airway epithelium, we developed and characterized mutant AAV vectors by genetic capsid modification, modeling the well-characterized AAV2 serotype. We genetically incorporated putative high-affinity peptide ligands to human airway epithelium on the GH loop region of AAV2 capsid protein. Six independent mutant AAV were constructed, containing peptide ligands previously reported to bind with high affinity for known and unknown receptors on human airway epithelial cells. The vectors were tested on nonairway cells and nonpolarized and polarized human airway epithelial cells for enhanced infectivity. One of the mutant vectors, with the peptide sequence THALWHT, not only showed the highest transduction in undifferentiated human airway epithelial cells but also indicated significant transduction in polarized cells. Interestingly, this modified vector was also able to infect cells independently of the heparan sulfate proteoglycan receptor. Incorporation of this ligand on other AAV serotypes, which have shown improved gene transfer efficiency in the human airway epithelium, may enhance the application of AAV vectors in CF gene therapy.

Translocation of SiO2-NPs across in vitro human bronchial epithelial monolayer

International Nuclear Information System (INIS)

George, I; Vranic, S; Boland, S; Borot, M C; Marano, F; Baeza-Squiban, A

2013-01-01

Safe development and application of nanotechnologies in many fields require better knowledge about their potential adverse effects on human health. Evidence of abilities of nanoparticles (NPs) to cross epithelial barriers and reach secondary organs via the bloodstream led us to investigate the translocation of SiO 2 NPs of 50 nm (50 nm-SiO 2 -NPs) across human bronchial epithelial cells that are primary targets after exposure to inhaled NPs. We quantified the translocation of fluorescently labelled SiO 2 NPs at non-cytotoxic concentrations (5 and 10 μg/cm 2 ) across Calu-3 epithelial monolayer. After 14 days in culture Calu-3 cells seeded onto 3 μm-polycarbonate Transwell membranes formed an efficient bronchial barrier assessed by measurement of the transepithelial electric resistance and quantification of the permeability of the monolayer. After 24 hours of exposure, we observed a significant translocation of NPs that was more important when the initial NP concentration decreased. Confocal microscopy observations revealed NP uptake by cells and an important NP retention inside the porous membrane. In conclusion, 50 nm-SiO 2 -NPs can cross the human bronchial epithelial barrier without affecting the integrity of the epithelial cell monolayer.

Selective response of human airway epithelia to luminal but not serosal solution hypertonicity. Possible role for proximal airway epithelia as an osmolality transducer

DEFF Research Database (Denmark)

Willumsen, Niels J.; Davis, C.W.; Boucher, R.C.

1994-01-01

exposure (10 min) to 430 mosM luminal solution elicited no regulation of any parameter. Optical measurements revealed a reduction in the thickness of preparations only in response to luminal hypertonic solutions. We conclude that (a) airway epithelial cells exhibit asymmetric water transport properties......- secretion; and (d) cell volume loss increases the resistance of the paracellular path. We speculate that these properties configure human nasal epithelium to behave as an osmotic sensor, transducing information about luminal solutions to the airway wall....

Semi-automated tabulation of the 3D topology and morphology of branching networks using CT: application to the airway tree

International Nuclear Information System (INIS)

Sauret, V.; Bailey, A.G.

1999-01-01

Detailed information on biological branching networks (optical nerves, airways or blood vessels) is often required to improve the analysis of 3D medical imaging data. A semi-automated algorithm has been developed to obtain the full 3D topology and dimensions (direction cosine, length, diameter, branching and gravity angles) of branching networks using their CT images. It has been tested using CT images of a simple Perspex branching network and applied to the CT images of a human cast of the airway tree. The morphology and topology of the computer derived network were compared with the manually measured dimensions. Good agreement was found. The airways dimensions also compared well with previous values quoted in literature. This algorithm can provide complete data set analysis much more quickly than manual measurements. Its use is limited by the CT resolution which means that very small branches are not visible. New data are presented on the branching angles of the airway tree. (author)

In vivo deposition of ultrafine aerosols in human nasal and oral airways

Energy Technology Data Exchange (ETDEWEB)

Yeh, Hsu-Chi; Swift, D.L. [John Hopkins Univ., Baltimore, MD (United States); Simpson, S.Q. [Univ. of New Mexico, Albuquerque, NM (United States)] [and others

1995-12-01

The extrathoracic airways, including the nasal passage, oral passage, pharynx, and larynx, are the first targets for inhaled particles and provide an important defense for the lung. Understanding the deposition efficiency of the nasal and oral passages is therefore crucial for assessing doses of inhaled particles to the extrathoracic airways and the lung. Significant inter-subject variability in nasal deposition has been shown in recent studies by Rasmussen, T.R. et al, using 2.6 {mu}m particles in 10 human subjects and in our preliminary studies using 0.004-0.15 {mu}m particles in four adult volunteers. No oral deposition was reported in either of these studies. Reasons for the intersubject variations have been frequently attributed to the geometry of the nasal passages. The aims of the present study were to measure in vivo the nasal airway dimensions and the deposition of ultrafine aerosols in both the nasal and oral passages, and to determine the relationship between nasal airway dimensions and aerosol deposition. A statistical procedure incorporated with the diffusion theory was used to model the dimensional features of the nasal airways which may be responsible for the biological variability in particle deposition. In summary, we have correlated deposition of particles in the size range of 0.004 to 0.15 {mu}m with the nasal dimensions of each subject.

In vivo deposition of ultrafine aerosols in human nasal and oral airways

International Nuclear Information System (INIS)

Yeh, Hsu-Chi; Swift, D.L.; Simpson, S.Q.

1995-01-01

The extrathoracic airways, including the nasal passage, oral passage, pharynx, and larynx, are the first targets for inhaled particles and provide an important defense for the lung. Understanding the deposition efficiency of the nasal and oral passages is therefore crucial for assessing doses of inhaled particles to the extrathoracic airways and the lung. Significant inter-subject variability in nasal deposition has been shown in recent studies by Rasmussen, T.R. et al, using 2.6 μm particles in 10 human subjects and in our preliminary studies using 0.004-0.15 μm particles in four adult volunteers. No oral deposition was reported in either of these studies. Reasons for the intersubject variations have been frequently attributed to the geometry of the nasal passages. The aims of the present study were to measure in vivo the nasal airway dimensions and the deposition of ultrafine aerosols in both the nasal and oral passages, and to determine the relationship between nasal airway dimensions and aerosol deposition. A statistical procedure incorporated with the diffusion theory was used to model the dimensional features of the nasal airways which may be responsible for the biological variability in particle deposition. In summary, we have correlated deposition of particles in the size range of 0.004 to 0.15 μm with the nasal dimensions of each subject

Lipids in airway secretions

International Nuclear Information System (INIS)

Bhaskar, K.R.; DeFeudis O'Sullivan, D.; Opaskar-Hincman, H.; Reid, L.M.

1987-01-01

Lipids form a significant portion of airway mucus yet they have not received the same attention that epithelial glycoproteins have. We have analysed, by thin layer chromatography, lipids present in airway mucus under 'normal' and hypersecretory (pathological) conditions.The 'normals' included (1) bronchial lavage obtained from healthy human volunteers and from dogs and (2) secretions produced ''in vitro'' by human (bronchial) and canine (tracheal) explants. Hypersecretory mucus samples included (1) lavage from dogs made bronchitic by exposure to SO 2 , (2) bronchial aspirates from acute and chronic tracheostomy patients, (3) sputum from patients with cystic fibrosis and chronic bronchitis and (4) postmortem secretions from patients who died from sudden infant death syndrome (SIDS) or from status asthmaticus. Cholesterol was found to be the predominant lipid in 'normal' mucus with lesser amounts of phospholipids. No glycolipids were detected. In the hypersecretory mucus, in addition to neutral and phospholipids, glycolipids were present in appreciable amounts, often the predominant species, suggesting that these may be useful as markers of disease. Radioactive precursors 14 C acetate and 14 C palmitate were incorporated into lipids secreted ''in vitro'' by canine tracheal explants indicating that they are synthesised by the airway. (author)

Direct numerical simulation of particle laden flow in a human airway bifurcation model

International Nuclear Information System (INIS)

Stylianou, Fotos S.; Sznitman, Josué; Kassinos, Stavros C.

2016-01-01

Highlights: • An anatomically realistic model of a human airway bifurcation is constructed. • Direct numerical simulations are used to study laminar and turbulent airflow. • Aerosol deposition in the bifurcation is studied with lagrangian particle tracking. • Carinal vortices forming during steady expiration are reported for the first time. • Stokes number determines deposition differences between inspiration and expiration. - Abstract: During the delivery of inhaled medicines, and depending on the size distribution of the particles in the formulation, airway bifurcations are areas of preferential deposition. Previous studies of laminar flow through airway bifurcations point to an interplay of inertial and centrifugal forces that leads to rich flow phenomena and controls particle deposition patterns. However, recent computational studies have shown that the airflow in the upper human airways is turbulent during much of the respiratory cycle. The question of how the presence of turbulence modifies these effects remains open. In this study, we perform for the first time Direct Numerical Simulations (DNS) of fully developed turbulent flow through a single human airway bifurcation model, emulating steady prolonged inspiration and expiration. We use the rich information obtained from the DNS in order to identify key structures in the flow field and scrutinize their role in determining deposition patterns in the bifurcation. We find that the vortical structures present in the bifurcation during expiration differ from those identified during inspiration. While Dean vortices are present in both cases, a set of three dimensional “carinal vortices” are identified only during expiration. A set of laminar simulations in the same geometries, but at lower Reynolds numbers, allow us to identify key differences in aerosol deposition patterns between laminar and turbulent respiration. We also report deposition fractions for representative Stokes numbers for both

Matrine suppresses airway inflammation by downregulating SOCS3 expression via inhibition of NF-κB signaling in airway epithelial cells and asthmatic mice

Energy Technology Data Exchange (ETDEWEB)

Sun, Daqing [Department of Respiration, Xi’an Children’s Hospital, Xi’an 710003 (China); Wang, Jing [Department of Neonatology, Xi’an Children’s Hospital, Xi’an 710003 (China); Yang, Niandi [Outpatient Department, School of Aerospace Engineering, Air Force Engineering University, Xi’an 710038 (China); Ma, Haixin, E-mail: drhaixinma@163.com [Department of Quality Control, Xi’an Children’s Hospital, Xi’an 710003 (China)

2016-08-12

Matrine has been demonstrated to attenuate allergic airway inflammation. Elevated suppressor of cytokine signaling 3 (SOCS3) was correlated with the severity of asthma. The aim of this study was to investigate the effect of matrine on SOCS3 expression in airway inflammation. In this study, we found that matrine significantly inhibited OVA-induced AHR, inflammatory cell infiltration, goblet cell differentiation, and mucous production in a dose-dependent manner in mice. Matrine also abrogated the level of interleukin (IL)-4 and IL-13, but enhanced interferon (IFN)-γ expression, both in BALF and in lung homogenates. Furthermore, matrine impeded TNF-α-induced the expression of IL-6 and adhesion molecules in airway epithelial cells (BEAS-2B and MLE-12). Additionally, we found that matrine inhibited SOCS3 expression, both in asthmatic mice and TNF-α-stimulated epithelial cells via suppression of the NF-κB signaling pathway by using pcDNA3.1-SOCS3 plasmid, SOCS3 siRNA, or nuclear factor kappa-B (NF-κB) inhibitor PDTC. Conclusions: Matrine suppresses airway inflammation by downregulating SOCS3 expression via inhibition of NF-κB signaling in airway epithelial cells and asthmatic mice. - Highlights: • Matrine attenuates asthmatic symptoms and regulates Th1/Th2 balance in vivo. • Matrine suppresses inflammation responses in vitro. • Matrine decreases SOCS3 expression both in vivo and in vitro. • Matrine inhibits SOCS3 expression by suppressing NF-κB signaling.

Divergent pro-inflammatory profile of human dendritic cells in response to commensal and pathogenic bacteria associated with the airway microbiota.

Science.gov (United States)

Larsen, Jeppe Madura; Steen-Jensen, Daniel Bisgaard; Laursen, Janne Marie; Søndergaard, Jonas Nørskov; Musavian, Hanieh Sadat; Butt, Tariq Mahmood; Brix, Susanne

2012-01-01

Recent studies using culture-independent methods have characterized the human airway microbiota and report microbial communities distinct from other body sites. Changes in these airway bacterial communities appear to be associated with inflammatory lung disease, yet the pro-inflammatory properties of individual bacterial species are unknown. In this study, we compared the immune stimulatory capacity on human monocyte-derived dendritic cells (DCs) of selected airway commensal and pathogenic bacteria predominantly associated with lungs of asthma or COPD patients (pathogenic Haemophillus spp. and Moraxella spp.), healthy lungs (commensal Prevotella spp.) or both (commensal Veillonella spp. and Actinomyces spp.). All bacteria were found to induce activation of DCs as demonstrated by similar induction of CD83, CD40 and CD86 surface expression. However, asthma and COPD-associated pathogenic bacteria provoked a 3-5 fold higher production of IL-23, IL-12p70 and IL-10 cytokines compared to the commensal bacteria. Based on the differential cytokine production profiles, the studied airway bacteria could be segregated into three groups (Haemophilus spp. and Moraxella spp. vs. Prevotella spp. and Veillonella spp. vs. Actinomyces spp.) reflecting their pro-inflammatory effects on DCs. Co-culture experiments found that Prevotella spp. were able to reduce Haemophillus influenzae-induced IL-12p70 in DCs, whereas no effect was observed on IL-23 and IL-10 production. This study demonstrates intrinsic differences in DC stimulating properties of bacteria associated with the airway microbiota.

Airway surface irregularities promote particle diffusion in the human lung

International Nuclear Information System (INIS)

Martonen, T.; North Carolina Univ., Chapel Hill, NC; Zhang, Z.; Yang, Y.; Bottei, G.

1995-01-01

Current NCRP and ICRP particle deposition models employed in risk assessment analyses treat the airways of the human lung as smooth-walled tubes. However, the upper airways of the tracheobronchial (TB) tree are line with cartilaginous rings. Recent supercomputer simulations of in vivo conditions (cited herein), where cartilaginous ring morphologies were based upon fibre-optic bronchoscope examinations, have clearly demonstrated their profound effects upon fluid dynamics. A physiologically based analytical model of fluid dynamics is presented, focusing upon applications to particle diffusion within the TB tree. The new model is the first to describe particle motion while simultaneously simulating effects of wall irregularities, entrance conditions and tube curvatures. This study may explain the enhanced deposition by particle diffusion detected in replica case experiments and have salient implications for the clinically observed preferential distributions of bronchogenic carcinomas associated with inhaled radionuclides. (author)

Exposure to ozone modulates human airway protease/antiprotease balance contributing to increased influenza A infection.

Directory of Open Access Journals (Sweden)

Matthew J Kesic

Full Text Available Exposure to oxidant air pollution is associated with increased respiratory morbidities and susceptibility to infections. Ozone is a commonly encountered oxidant air pollutant, yet its effects on influenza infections in humans are not known. The greater Mexico City area was the primary site for the spring 2009 influenza A H1N1 pandemic, which also coincided with high levels of environmental ozone. Proteolytic cleavage of the viral membrane protein hemagglutinin (HA is essential for influenza virus infectivity. Recent studies suggest that HA cleavage might be cell-associated and facilitated by the type II transmembrane serine proteases (TTSPs human airway trypsin-like protease (HAT and transmembrane protease, serine 2 (TMPRSS2, whose activities are regulated by antiproteases, such as secretory leukocyte protease inhibitor (SLPI. Based on these observations, we sought to determine how acute exposure to ozone may modulate cellular protease/antiprotease expression and function, and to define their roles in a viral infection. We utilized our in vitro model of differentiated human nasal epithelial cells (NECs to determine the effects of ozone on influenza cleavage, entry, and replication. We show that ozone exposure disrupts the protease/antiprotease balance within the airway liquid. We also determined that functional forms of HAT, TMPRSS2, and SLPI are secreted from human airway epithelium, and acute exposure to ozone inversely alters their expression levels. We also show that addition of antioxidants significantly reduces virus replication through the induction of SLPI. In addition, we determined that ozone-induced cleavage of the viral HA protein is not cell-associated and that secreted endogenous proteases are sufficient to activate HA leading to a significant increase in viral replication. Our data indicate that pre-exposure to ozone disrupts the protease/antiprotease balance found in the human airway, leading to increased influenza susceptibility.

Development of an in vitro cytotoxicity model for aerosol exposure using 3D reconstructed human airway tissue; application for assessment of e-cigarette aerosol.

Science.gov (United States)

Neilson, Louise; Mankus, Courtney; Thorne, David; Jackson, George; DeBay, Jason; Meredith, Clive

2015-10-01

Development of physiologically relevant test methods to analyse potential irritant effects to the respiratory tract caused by e-cigarette aerosols is required. This paper reports the method development and optimisation of an acute in vitro MTT cytotoxicity assay using human 3D reconstructed airway tissues and an aerosol exposure system. The EpiAirway™ tissue is a highly differentiated in vitro human airway culture derived from primary human tracheal/bronchial epithelial cells grown at the air-liquid interface, which can be exposed to aerosols generated by the VITROCELL® smoking robot. Method development was supported by understanding the compatibility of these tissues within the VITROCELL® system, in terms of airflow (L/min), vacuum rate (mL/min) and exposure time. Dosimetry tools (QCM) were used to measure deposited mass, to confirm the provision of e-cigarette aerosol to the tissues. EpiAirway™ tissues were exposed to cigarette smoke and aerosol generated from two commercial e-cigarettes for up to 6 h. Cigarette smoke reduced cell viability in a time dependent manner to 12% at 6 h. E-cigarette aerosol showed no such decrease in cell viability and displayed similar results to that of the untreated air controls. Applicability of the EpiAirway™ model and exposure system was demonstrated, showing little cytotoxicity from e-cigarette aerosol and different aerosol formulations when compared directly with reference cigarette smoke, over the same exposure time. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Staphylococcus aureus α-Toxin Induces Actin Filament Remodeling in Human Airway Epithelial Model Cells.

Science.gov (United States)

Ziesemer, Sabine; Eiffler, Ina; Schönberg, Alfrun; Müller, Christian; Hochgräfe, Falko; Beule, Achim G; Hildebrandt, Jan-Peter

2018-04-01

Exposure of cultured human airway epithelial model cells (16HBE14o-, S9) to Staphylococcus aureus α-toxin (hemolysin A, Hla) induces changes in cell morphology and cell layer integrity that are due to the inability of the cells to maintain stable cell-cell or focal contacts and to properly organize their actin cytoskeletons. The aim of this study was to identify Hla-activated signaling pathways involved in regulating the phosphorylation level of the actin-depolymerizing factor cofilin. We used recombinant wild-type hemolysin A (rHla) and a variant of Hla (rHla-H35L) that is unable to form functional transmembrane pores to treat immortalized human airway epithelial cells (16HBE14o-, S9) as well as freshly isolated human nasal tissue. Our results indicate that rHla-mediated changes in cofilin phosphorylation require the formation of functional Hla pores in the host cell membrane. Formation of functional transmembrane pores induced hypophosphorylation of cofilin at Ser3, which was mediated by rHla-induced attenuation of p21-activated protein kinase and LIM kinase activities. Because dephosphorylation of pSer3-cofilin results in activation of this actin-depolymerizing factor, treatment of cells with rHla resulted in loss of actin stress fibers from the cells and destabilization of cell shape followed by the appearance of paracellular gaps in the cell layers. Activation of protein kinase A or activation of small GTPases (Rho, Rac, Cdc42) do not seem to be involved in this response.

Unsteady flow characteristics through a human nasal airway.

Science.gov (United States)

Lee, Jong-Hoon; Na, Yang; Kim, Sung-Kyun; Chung, Seung-Kyu

2010-07-31

Time-dependent characteristics of the flow in a human nasal airway constructed from the CT image of a healthy volunteer were investigated using a computational fluid dynamics (CFD) technique. To capture the time-varying nature of the flow as well as pressure and temperature fields, the large eddy simulation (LES) technique instead of the RANS (Reynolds Averaged Navier-Stokes) approach was adopted. To make the present analysis more relevant to a real human breathing cycle, the flow was designed to be induced by the pressure difference and the time-varying pressure at the end of trachea was described to reproduce the flow rate data from the measurement. Comparison of the present results with those of typical steady simulations showed that the difference in flow characteristics is magnified in the expiration phase. This fact may suggest that the inertial effect associated with unsteady flow is more important during the expiration period. Also, the fact that the distribution of the flow rate in a given cross-section of the airway changes significantly with time implies the importance of unsteady data for clinical decision. The wall shear stress was found to have relatively high values at the locations near nasopharynx and larynx but the magnitude changes with time during the whole respiratory cycle. Analysis of the temperature field showed that most of the temperature change occurs in the nasal cavity when the air is incoming and thus, the nasal cavity acts as a very efficient heat exchanger during an inspiration period. Copyright 2010 Elsevier B.V. All rights reserved.

From single cilia to collective waves in human airway ciliated tissues

Science.gov (United States)

Cicuta, Pietro; Chioccioli, Maurizio; Feriani, Luigi; Pellicciotta, Nicola; Kotar, Jurij

I will present experimental results on activity of motile cilia on various scales: from waveforms on individual cilia to the synchronised motion in cilia carpets of airway cells. Model synthetic experiments have given us an understanding of how cilia could couple with each other through forces transmitted by the fluid, and thus coordinate to beat into well organized waves (previous work is reviewed in Annu. Rev. Condens. Matter Phys. 7, 1-26 (2016)). Working with live imaging of airway human cells at the different scales, we can now test whether the biological system satisfies the ``simple'' behavior expected of the fluid flow coupling, or if other factors of mechanical forces transmission need to be accounted for. In general being able to link from the scale of molecular biological activity up to the phenomenology of collective dynamics requires to understand the relevant physical mechanism. This understanding then allows informed diagnostics (and perhaps therapeutic) approaches to a variety of diseases where mucociliary clearance in the airways is compromised. We have started exploring particularly cystic fibrosis, where the rheological properties of the mucus are affected and prevent efficient cilia synchronization. ERC Grant HydroSync.

Detonation Nanodiamond Toxicity in Human Airway Epithelial Cells Is Modulated by Air Oxidation

Science.gov (United States)

Detonational nanodiamonds (DND), a nanomaterial with an increasing range of industrial and biomedical applications, have previously been shown to induce a pro-inflammatory response in cultured human airway epithelial cells (HAEC). We now show that surface modifications induced by...

DEPOSITION DISTRICUTION AMONG THE PARALLEL PATHWAYS IN THE HUMAN LUNG CONDUCTING AIRWAY STRUCTURE.

Science.gov (United States)

DEPOSITION DISTRIBUTION AMONG THE PARALLEL PATHWAYS IN THE HUMAN LUNG CONDUCTING AIRWAY STRUCTURE. Chong S. Kim*, USEPA National Health and Environmental Effects Research Lab. RTP, NC 27711; Z. Zhang and C. Kleinstreuer, Department of Mechanical and Aerospace Engineering, North C...

TRANSPORT AND DEPOSITION OF NANO-SIZE PARTICLES IN THE UPPER HUMAN RESPIRATORY AIRWAYS

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TRANSPORT AND DEPOSITION OF NANO-SIZE PARTICLES IN THE UPPER HUMAN RESPIRATORY AIRWAYS. Zhe Zhang*, Huawei Shi, Clement Kleinstreuer, Department of Mechanical and Aerospace Engineering, North Carolina State University, Raleigh, NC 27695-7910; Chong S. Kim, National Health and En...

Mucous solids and liquid secretion by airways: studies with normal pig, cystic fibrosis human, and non-cystic fibrosis human bronchi

Science.gov (United States)

Martens, Chelsea J.; Inglis, Sarah K.; Valentine, Vincent G.; Garrison, Jennifer; Conner, Gregory E.

2011-01-01

To better understand how airways produce thick airway mucus, nonvolatile solids were measured in liquid secreted by bronchi from normal pig, cystic fibrosis (CF) human, and non-CF human lungs. Bronchi were exposed to various secretagogues and anion secretion inhibitors to induce a range of liquid volume secretion rates. In all three groups, the relationship of solids concentration (percent nonvolatile solids) to liquid volume secretion rate was curvilinear, with higher solids concentration associated with lower rates of liquid volume secretion. In contrast, the secretion rates of solids mass and water mass as functions of liquid volume secretion rates exhibited positive linear correlations. The y-intercepts of the solids mass-liquid volume secretion relationships for all three groups were positive, thus accounting for the higher solids concentrations in airway liquid at low rates of secretion. Predictive models derived from the solids mass and water mass linear equations fit the experimental percent solids data for the three groups. The ratio of solids mass secretion to liquid volume secretion was 5.2 and 2.4 times higher for CF bronchi than for pig and non-CF bronchi, respectively. These results indicate that normal pig, non-CF human, and CF human bronchi produce a high-percent-solids mucus (>8%) at low rates of liquid volume secretion (≤1.0 μl·cm−2·h−1). However, CF bronchi produce mucus with twice the percent solids (∼8%) of pig or non-CF human bronchi at liquid volume secretion rates ≥4.0 μl·cm−2·h−1. PMID:21622844

Fetal human airway smooth muscle cell production of leukocyte chemoattractants is differentially regulated by fluticasone.

Science.gov (United States)

Pearson, Helen; Britt, Rodney D; Pabelick, Christine M; Prakash, Y S; Amrani, Yassine; Pandya, Hitesh C

2015-12-01

Adult human airway smooth muscle (ASM) produce cytokines involved in recruitment and survival of leukocytes within airway walls. Cytokine generation by adult ASM is glucocorticoid-sensitive. Whether developing lung ASM produces cytokines in a glucocorticoid-sensitive fashion is unknown. Cultured fetal human ASM cells stimulated with TNF-α (0-20 ng/ml) were incubated with TNF-α receptor-blocking antibodies, fluticasone (1 and 100 nm), or vehicle. Supernatants and cells were assayed for the production of CCL5, CXCL10, and CXCL8 mRNA and protein and glucocorticoid receptor phosphorylation. CCL5, CXCL10, and CXCL8 mRNA and protein production by fetal ASM cell was significantly and dose-dependently following TNF-α treatment. Cytokine mRNA and protein production were effectively blocked by TNF-α R1 and R2 receptor neutralizing antibodies but variably inhibited by fluticasone. TNF-α-induced TNF-R1 and R2 receptor mRNA expression was only partially attenuated by fluticasone. Glucocorticoid receptor phosphorylation at serine (Ser) 211 but not at Ser 226 was enhanced by fluticasone. Production of CCL5, CXCL10, and CXCL8 by fetal ASM appears to involve pathways that are both qualitatively and mechanistically distinct to those described for adult ASM. The findings imply developing ASM has potential to recruit leukocyte into airways and, therefore, of relevance to childhood airway diseases.

Regional aerosol deposition in human upper airways: Progress report, June 1, 1988--February 28, 1989

International Nuclear Information System (INIS)

Swift, D.L.

1989-01-01

The objective of this research program is to elucidate important factors which influence overall and local deposition of aerosols in the human airways above the trachea, including nasal airways, oral passage, pharynx and larynx. The intent is to develop information which can be used for exposure models for radon from unattached radon progeny (/approximately/1nm) up to 10 μm. Special emphasis is upon flow rate and airway dimensions as influenced by age and respiratory condition, as no experimental data presently exist for age-related deposition. Because of ethical and practical considerations associated with measuring aerosol deposition in children and difficulties of measuring local deposition in vivo, our experimental approach is to construct faithful replicate models of the airways for several ages of humans in which detailed studies of deposition can be carried out with well-characterized aerosols. Initial studies of overall deposition of ultrafine aerosols in an adult model have been carried out using replicate nasal passage models provided from this laboratory. These studies demonstrate a significant deposition percent for particle sizes approaching that of unattached radon progeny (40--50%), decreasing as particle size approaches 0.1 μm. Studies of the effect of flow rate indicate that higher deposition percent is realized at lower flow rate over the range from 4--60 lmin -1

Treatment of severe porcine tracheomalacia with a 3-dimensionally printed, bioresorbable, external airway splint

Science.gov (United States)

Zopf, David A.; Flanagan, Colleen L.; Wheeler, Matthew; Hollister, Scott J.; Green, Glenn E.

2015-01-01

Importance The study demonstrates an application for 3-dimensional (3D) printing that may serve as an effective intervention for severe tracheobronchomalacia. Objective A novel 3D printed, bioresorbable airway splint is tested for efficacy in extending survival in an animal model of severe, life-threatening tracheobronchomalacia. Participants Evaluation of an external airway splint for severe, life-threatening tracheobronchomalacia in a porcine animal model. Setting Multi-institutional and multidisciplinary collaboration between biomedical engineering laboratories and an academic animal surgery center. Interventions Experimental analysis of a 3D printed, bioresorbable airway splint is assessed in a porcine animal model of life-threatening tracheobronchomalacia. The open-cylindrical, bellow shaped porous polycaprolactone splint is placed externally and designed to suspend the underlying collapsed airway. Control animals (n=3) undergoing tracheal cartilage division and inner tracheal lumen dissociation and experimental animals (n=3) receiving the same model with overlying placement of the newly developed airway splint were evaluated. Main Outcomes and Measures An animal model for severe, life-threatening tracheobronchomalacia is proposed. Complete or near complete tracheal lumen collapse was observed in each animal with resolution of symptoms in all of the experimental animals after splint placement. Using our severe tracheobronchomalacia animal model, survival was significantly longer in duration in the experimental group receiving the airway splint after model creation when compared to model creation alone (p = 0.0495). Mortality in the experimental group was related to infection. Conclusions A multidisciplinary effort producing a CAD/CAM, bioresorbable tracheobronchial splint was tested in a porcine model of severe tracheomalacia and was found to extend survival. PMID:24232078

Effects of epidermal growth factor, transferrin, and insulin on lipofection efficiency in human lung carcinoma cells.

Science.gov (United States)

Yanagihara, K; Cheng, H; Cheng, P W

2000-01-01

Poor transfection efficiency is the major drawback of lipofection. We showed previously that addition of transferrin (TF) to Lipofectin enhanced the expression of a reporter gene in HeLa cells by 120-fold and achieved close to 100% transfection efficiency. The purpose of this study was to determine whether TF and other ligands could improve the efficiency of lipofection in lung carcinoma cells. Confluent A549, Calu3, and H292 cells were transfected for 18 hours with a plasmid DNA (pCMVlacZ) using Lipofectin plus TF, insulin, or epidermal growth factor as the vector. The transfected cells were assessed for transfection efficiency by beta-galactosidase activity (light units/microg protein) and the percentage of blue cells following 5-bromo-4-chloro-3-indolyl beta-D-galactopyranoside staining. Lipofectin supplemented with epidermal growth factor yielded the largest enhancement of lipofection efficiency (lipofection efficiency in A549 and Calu3 cells but not in H292 cells, whereas TF showed significant lipofection efficiency-enhancing effect in Calu3 and H292 cells but not in A549 cells. The transfection efficiency correlated well with the amounts of DNA delivered to the nucleus as well as the amounts of the receptor. These results indicate that the gene delivery strategy employing ligand-facilitated lipofection can achieve high transfection efficiency in human lung carcinoma cells. In addition, enhancement of the expression of the receptor may be a possible strategy for increasing the efficiency of gene targeting.

Angiogenesis is induced by airway smooth muscle strain.

Science.gov (United States)

Hasaneen, Nadia A; Zucker, Stanley; Lin, Richard Z; Vaday, Gayle G; Panettieri, Reynold A; Foda, Hussein D

2007-10-01

Angiogenesis is an important feature of airway remodeling in both chronic asthma and chronic obstructive pulmonary disease (COPD). Airways in those conditions are exposed to excessive mechanical strain during periods of acute exacerbations. We recently reported that mechanical strain of human airway smooth muscle (HASM) led to an increase in their proliferation and migration. Sustained growth in airway smooth muscle in vivo requires an increase in the nutritional supply to these muscles, hence angiogenesis. In this study, we examined the hypothesis that cyclic mechanical strain of HASM produces factors promoting angiogenic events in the surrounding vascular endothelial cells. Our results show: 1) a significant increase in human lung microvascular endothelial cell (HMVEC-L) proliferation, migration, and tube formation following incubation in conditioned media (CM) from HASM cells exposed to mechanical strain; 2) mechanical strain of HASM cells induced VEGF expression and release; 3) VEGF neutralizing antibodies inhibited the proliferation, migration, and tube formations of HMVEC-L induced by the strained airway smooth muscle CM; 4) mechanical strain of HASM induced a significant increase in hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA and protein, a transcription factor required for VEGF gene transcription; and 5) mechanical strain of HASM induced HIF-1alpha/VEGF through dual phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and ERK pathways. In conclusion, exposing HASM cells to mechanical strain induces signal transduction pathway through PI3K/Akt/mTOR and ERK pathways that lead to an increase in HIF-1alpha, a transcription factor required for VEGF expression. VEGF release by mechanical strain of HASM may contribute to the angiogenesis seen with repeated exacerbation of asthma and COPD.

Divergent pro-inflammatory profile of human dendritic cells in response to commensal and pathogenic bacteria associated with the airway microbiota

NARCIS (Netherlands)

Larsen, J.M.; Steen-Jensen, D.B.; Laursen, J.M.; Sondergaard, J.N.; Musavian, H.S.; Butt, T.M.; Brix, S.

2012-01-01

Recent studies using culture-independent methods have characterized the human airway microbiota and report microbial communities distinct from other body sites. Changes in these airway bacterial communities appear to be associated with inflammatory lung disease, yet the pro-inflammatory properties

Cyclic mechanical strain-induced proliferation and migration of human airway smooth muscle cells: role of EMMPRIN and MMPs.

Science.gov (United States)

Hasaneen, Nadia A; Zucker, Stanley; Cao, Jian; Chiarelli, Christian; Panettieri, Reynold A; Foda, Hussein D

2005-09-01

Airway smooth muscle (ASM) proliferation and migration are major components of airway remodeling in asthma. Asthmatic airways are exposed to mechanical strain, which contributes to their remodeling. Matrix metalloproteinase (MMP) plays an important role in remodeling. In the present study, we examined if the mechanical strain of human ASM (HASM) cells contributes to their proliferation and migration and the role of MMPs in this process. HASM were exposed to mechanical strain using the FlexCell system. HASM cell proliferation, migration and MMP release, activation, and expression were assessed. Our results show that cyclic strain increased the proliferation and migration of HASM; cyclic strain increased release and activation of MMP-1, -2, and -3 and membrane type 1-MMP; MMP release was preceded by an increase in extracellular MMP inducer; Prinomastat [a MMP inhibitor (MMPI)] significantly decreased cyclic strain-induced proliferation and migration of HASM; and the strain-induced increase in the release of MMPs was accompanied by an increase in tenascin-C release. In conclusion, cyclic mechanical strain plays an important role in HASM cell proliferation and migration. This increase in proliferation and migration is through an increase in MMP release and activation. Pharmacological MMPIs should be considered in the pursuit of therapeutic options for airway remodeling in asthma.

Assessment of the storz video Macintosh laryngoscope for use in difficult airways: A human simulator study.

Science.gov (United States)

Bair, Aaron E; Olmsted, Kalani; Brown, Calvin A; Barker, Tobias; Pallin, Daniel; Walls, Ron M

2010-10-01

Video laryngoscopy has been shown to improve glottic exposure when compared to direct laryngoscopy in operating room studies. However, its utility in the hands of emergency physicians (EPs) remains undefined. A simulated difficult airway was used to determine if intubation by EPs using a video Macintosh system resulted in an improved glottic view, was easier, was faster, or was more successful than conventional direct laryngoscopy. Emergency medicine (EM) residents and attending physicians at two academic institutions performed endotracheal intubation in one normal and two identical difficult airway scenarios. With the difficult scenarios, the participants used video laryngoscopy during the second case. Intubations were performed on a medium-fidelity human simulator. The difficult scenario was created by limiting cervical spine mobility and inducing trismus. The primary outcome was the proportion of direct versus video intubations with a grade I or II Cormack-Lehane glottic view. Ease of intubation (self-reported via 10-cm visual analog scale [VAS]), time to intubation, and success rate were also recorded. Descriptive statistics as well as medians with interquartile ranges (IQRs) are reported where appropriate. The Wilcoxon matched pairs signed-rank test was used for comparison testing of nonparametric data. Participants (n = 39) were residents (59%) and faculty. All had human intubation experience; 51% reported more than 100 prior intubations. On difficult laryngoscopy, a Cormack-Lehane grade I or II view was obtained in 20 (51%) direct laryngoscopies versus 38 (97%) of the video-assisted laryngoscopies (p < 0.01). The median VAS score for difficult airways was 50 mm (IQR = 28–73 mm) for direct versus 18 mm (IQR = 9–50 mm) for video (p < 0.01). The median time to intubation in difficult airways was 25 seconds (IQR = 16–44 seconds) for direct versus 20 seconds (IQR = 12–35 seconds) for video laryngoscopy (p < 0.01). All intubations were successful without

MicroRNA Mediated Chemokine Responses in Human Airway Smooth Muscle Cells.

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Mythili Dileepan

Full Text Available Airway smooth muscle (ASM cells play a critical role in the pathophysiology of asthma due to their hypercontractility and their ability to proliferate and secrete inflammatory mediators. microRNAs (miRNAs are gene regulators that control many signaling pathways and thus serve as potential therapeutic alternatives for many diseases. We have previously shown that miR-708 and miR-140-3p regulate the MAPK and PI3K signaling pathways in human ASM (HASM cells following TNF-α exposure. In this study, we investigated the regulatory effect of these miRNAs on other asthma-related genes. Microarray analysis using the Illumina platform was performed with total RNA extracted from miR-708 (or control miR-transfected HASM cells. Inhibition of candidate inflammation-associated gene expression was further validated by qPCR and ELISA. The most significant biologic functions for the differentially expressed gene set included decreased inflammatory response, cytokine expression and signaling. qPCR revealed inhibition of expression of CCL11, CXCL10, CCL2 and CXCL8, while the release of CCL11 was inhibited in miR-708-transfected cells. Transfection of cells with miR-140-3p resulted in inhibition of expression of CCL11, CXCL12, CXCL10, CCL5 and CXCL8 and of TNF-α-induced CXCL12 release. In addition, expression of RARRES2, CD44 and ADAM33, genes known to contribute to the pathophysiology of asthma, were found to be inhibited in miR-708-transfected cells. These results demonstrate that miR-708 and miR-140-3p exert distinct effects on inflammation-associated gene expression and biological function of ASM cells. Targeting these miRNA networks may provide a novel therapeutic mechanism to down-regulate airway inflammation and ASM proliferation in asthma.

Reduced Airway Hyperresponsiveness by Phosphodiesterase 3 and 4 Inhibitors in Guinea-Pigs

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Nöella Germain

1999-01-01

Full Text Available The aim of the present study was to compare the effects of selective phosphodiesterase (PDE 3, 4 and 5 inhibitors on antigen-induced airway hyperresponsiveness in sensitized guinea-pigs. When the sensitized guinea-pigs were orally pre-treated with the selective PDE4 inhibitor, Ro 20-1724 (30 mg/kg, and studied 48 h after OA, a significant reduction (p<0.01 of the leftward shift of the dose-response curve to ACh was noted, whereas it was ineffective at the lower dose (10 mg/kg. Administration of the selective PDE3 inhibitor, milrinone (30 mg/kg also elicited a significant reduction (p<0.01 of the airway hyperresponsiveness, whereas the PDE5 inhibitor zaprinast (30 mg/kg was ineffective. These results show that both PDE3 and PDE4 inhibitors are able to inhibit the antigen-induced airway hyperresponsiveness in sensitized guinea-pigs and support the potential utility of selective PDE inhibitors in the treatment of asthma.

Differential transcriptional regulation of IL-8 expression by human airway epithelial cells exposed to diesel exhaust particles

International Nuclear Information System (INIS)

Tal, Tamara L.; Simmons, Steven O.; Silbajoris, Robert; Dailey, Lisa; Cho, Seung-Hyun; Ramabhadran, Ram; Linak, William; Reed, William; Bromberg, Philip A.; Samet, James M.

2010-01-01

Exposure to diesel exhaust particles (DEP) induces inflammatory signaling characterized by MAP kinase-mediated activation of NFkB and AP-1 in vitro and in bronchial biopsies obtained from human subjects exposed to DEP. NFkB and AP-1 activation results in the upregulation of genes involved in promoting inflammation in airway epithelial cells, a principal target of inhaled DEP. IL-8 is a proinflammatory chemokine expressed by the airway epithelium in response to environmental pollutants. The mechanism by which DEP exposure induces IL-8 expression is not well understood. In the current study, we sought to determine whether DEP with varying organic content induces IL-8 expression in lung epithelial cells, as well as, to develop a method to rapidly evaluate the upstream mechanism(s) by which DEP induces IL-8 expression. Exposure to DEP with varying organic content differentially induced IL-8 expression and IL-8 promoter activity human airway epithelial cells. Mutational analysis of the IL-8 promoter was also performed using recombinant human cell lines expressing reporters linked to the mutated promoters. Treatment with a low organic-containing DEP stimulated IL-8 expression by a mechanism that is predominantly NFkB-dependent. In contrast, exposure to high organic-containing DEP induced IL-8 expression independently of NFkB through a mechanism that requires AP-1 activity. Our study reveals that exposure to DEP of varying organic content induces proinflammatory gene expression through multiple specific mechanisms in human airway epithelial cells. The approaches used in the present study demonstrate the utility of a promoter-reporter assay ensemble for identifying transcriptional pathways activated by pollutant exposure.

Response of cultured human airway epithelial cells to X-rays and energetic α-particles

International Nuclear Information System (INIS)

Yang, T.C.; Holley, W.R.; Curtis, S.B.; Gruenert, D.C.; California Univ., San Francisco, CA

1990-01-01

Radon and its progeny, which emit α-particles during decay, may play an important role in inducing human lung cancer. To gain a better understanding of the biological effects of α-particles in human lung we studied the response of cultured human airway epithelial cells to X-rays and monoenergetic helium ions. Experimental results indicated that the radiation response of primary cultures was similar to that for airway epithelial cells that were transformed with a plasmid containing an origin-defective SV40 virus. The RBE for cell inactivation determined by the ratio of D 0 for X-rays to that for 8 MeV helium ions was 1.8-2.2. The cross-section for helium ions, calculated from the D 0 value, was about 24 μm 2 for cells of the primary culture. This cross-section is significantly smaller than the average geometric nuclear area (∼ 180 μm 2 ), suggesting that an average of 7.5 α-particles (8 MeV helium ions) per cell nucleus are needed to induce a lethal lesion. (author)

T cell subsets in human airways prior to and following endobronchial administration of endotoxin

DEFF Research Database (Denmark)

Ronit, Andreas; Plovsing, Ronni R; Gaardbo, Julie C

2015-01-01

BACKGROUND AND OBJECTIVES: Bronchial instillation of lipopolysaccharide (LPS) provides a reversible model of lung inflammation that may resemble early stages of acute respiratory distress syndrome (ARDS). We investigated the distributions of T-cell subsets in the human airways and sought to deter...

Airway Secretory microRNAome Changes during Rhinovirus Infection in Early Childhood.

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Maria J Gutierrez

Full Text Available Innate immune responses are fine-tuned by small noncoding RNA molecules termed microRNAs (miRs that modify gene expression in response to the environment. During acute infections, miRs can be secreted in extracellular vesicles (EV to facilitate cell-to-cell genetic communication. The purpose of this study was to characterize the baseline population of miRs secreted in EVs in the airways of young children (airway secretory microRNAome and examine the changes during rhinovirus (RV infection, the most common cause of asthma exacerbations and the most important early risk factor for the development of asthma beyond childhood.Nasal airway secretions were obtained from children (≤3 yrs. old during PCR-confirmed RV infections (n = 10 and age-matched controls (n = 10. Nasal EVs were isolated with polymer-based precipitation and global miR profiles generated using NanoString microarrays. We validated our in vivo airway secretory miR data in an in vitro airway epithelium model using apical secretions from primary human bronchial epithelial cells (HBEC differentiated at air-liquid interface (ALI. Bioinformatics tools were used to determine the unified (nasal and bronchial signature airway secretory miRNAome and changes during RV infection in children.Multiscale analysis identified four signature miRs comprising the baseline airway secretory miRNAome: hsa-miR-630, hsa-miR-302d-3p, hsa- miR-320e, hsa-miR-612. We identified hsa-miR-155 as the main change in the baseline miRNAome during RV infection in young children. We investigated the potential biological relevance of the airway secretion of hsa-mir-155 using in silico models derived from gene datasets of experimental in vivo human RV infection. These analyses confirmed that hsa-miR-155 targetome is an overrepresented pathway in the upper airways of individuals infected with RV.Comparative analysis of the airway secretory microRNAome in children indicates that RV infection is associated with airway

On the relation of nasal cycling with nasal airway dimensions

Energy Technology Data Exchange (ETDEWEB)

Guilmette, R A; Wolff, R K

1988-12-01

The size and configuration of the nasal airways of humans change with time as a result of the normal process of congestion/decongestion of the erectile tissue of the nasal mucosa. To determine the extent to which airway areas change in vivo, we used magnetic resonance imaging (MRI) to quantitate both the cross-sectional area and perimeter of coronal sections of the entire nasal airway of a human subject. Changes in airway size or patency were indexed to measured changes in unilateral nasal airway resistance determined by posterior rhino manometry. The results of this study in which two MRI scans were performed for presumed left-side patency and two for right-side patency, showed that changes in nasal airway resistance were difficult to ascribe to systematic changes In the sizes of the airways. (author)

On the relation of nasal cycling with nasal airway dimensions

International Nuclear Information System (INIS)

Guilmette, R.A.; Wolff, R.K.

1988-01-01

The size and configuration of the nasal airways of humans change with time as a result of the normal process of congestion/decongestion of the erectile tissue of the nasal mucosa. To determine the extent to which airway areas change in vivo, we used magnetic resonance imaging (MRI) to quantitate both the cross-sectional area and perimeter of coronal sections of the entire nasal airway of a human subject. Changes in airway size or patency were indexed to measured changes in unilateral nasal airway resistance determined by posterior rhino manometry. The results of this study in which two MRI scans were performed for presumed left-side patency and two for right-side patency, showed that changes in nasal airway resistance were difficult to ascribe to systematic changes In the sizes of the airways. (author)

Comparison of 3 airway access techniques during suspected spine injury management in American football.

Science.gov (United States)

Toler, Julianne D; Petschauer, Meredith A; Mihalik, Jason P; Oyama, Sakiko; Halverson, S Doug; Guskiewicz, Kevin M

2010-03-01

To determine how head movement and time to access airway were affected by 3 emergency airway access techniques used in American football. Prospective counterbalanced design. University research laboratory. Eighteen certified athletic trainers (ATCs) and 18 noncertified students (NCSs). Each participant performed 1 trial of each of the 3 after airway access techniques: quick release mechanism (QRM), cordless screwdriver (CSD), and pocket mask insertion (PMI). Time to task completion in seconds, head movement in each plane (sagittal, frontal, and transverse), maximum head movement in each plane, helmet movement in each plane, and maximum helmet movement in each plane. We observed a significant difference between all 3 techniques with respect to time required to achieve airway access (F(2,68) = 263.88; P football athlete experiencing respiratory arrest in the presence of a suspected cervical spine injury. In the event the athlete does not present with respiratory arrest, the facemask may be removed carefully with a pocket mask ready. Medical professionals must be familiar with differences in equipment and the effects these may have on the management of the spine-injured athlete.

Nogo-B regulates migration and contraction of airway smooth muscle cells by decreasing ARPC 2/3 and increasing MYL-9 expression

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Cai Zailong

2011-01-01

Full Text Available Abstract Background Abnormal proliferation, apoptosis, migration and contraction of airway smooth muscle (ASM cells in airway remodeling in asthma are basically excessive repair responses to a network of inflammatory mediators such as PDGF, but the mechanisms of such responses remain unclear. Nogo-B, a member of the reticulum family 4(RTN4, is known to play a key role in arteriogenesis and tissue repair. Further studies are needed to elucidate the role of Nogo-B in airway smooth muscle abnormalities. Methods A mouse model of chronic asthma was established by repeated OVA inhalation and subjected to Nogo-B expression analysis using immunohistochemistry and Western Blotting. Then, primary human bronchial smooth muscle cells (HBSMCs were cultured in vitro and a siRNA interference was performed to knockdown the expression of Nogo-B in the cells. The effects of Nogo-B inhibition on PDGF-induced HBSMCs proliferation, migration and contraction were evaluated. Finally, a proteomic analysis was conducted to unveil the underlying mechanisms responsible for the function of Nogo-B. Results Total Nogo-B expression was approximately 3.08-fold lower in chronic asthmatic mice compared to naïve mice, which was obvious in the smooth muscle layer of the airways. Interference of Nogo-B expression by siRNA resulted nearly 96% reduction in mRNA in cultured HBSMCs. In addition, knockdown of Nogo-B using specific siRNA significantly decreased PDGF-induced migration of HBSMCs by 2.3-fold, and increased the cellular contraction by 16% compared to negative controls, but had limited effects on PDGF-induced proliferation. Furthermore, using proteomic analysis, we demonstrate that the expression of actin related protein 2/3 complex subunit 5 (ARPC 2/3 decreased and, myosin regulatory light chain 9 isoform a (MYL-9 increased after Nogo-B knockdown. Conclusions These data define a novel role for Nogo-B in airway remodeling in chronic asthma. Endogenous Nogo-B, which may exert

Mechanism of mucosal permeability enhancement of CriticalSorb® (Solutol® HS15) investigated In Vitro in cell cultures.

OpenAIRE

Shubber, Saif; Vllasaliu, Driton; Rauch, Cyril; Jordan, Faron; Illum, Lisbeth; Stolnik, Snjezana

2015-01-01

Purpose CriticalSorb?, with the principal component Solutol? HS15, is a novel mucosal drug delivery system demonstrated to improve the bioavailability of selected biotherapeutics. The intention of this study is to elucidate mechanism(s) responsible for the enhancement of trans-mucosal absorption of biological drugs by Solutol? HS15. Methods Micelle size and CMC of Solutol? HS15 were determined in biologically relevant media. Polarised airway Calu-3 cell layers were used to measure the permeab...

Study of cyclic and steady particle motion in a realistic human airway model using phase-Doppler anemometry

Science.gov (United States)

Jedelský, Jan; Lízal, František; Jícha, Miroslav

2012-04-01

Transport and deposition of particles in human airways has been of research interest for many years. Various experimental methods such as constant temperature anemometry, particle image velocimetry and laser-Doppler based techniques were employed for study of aerosol transport in the past. We use Phase-Doppler Particle Analyser (P/DPA) for time resolved size and velocity measurement of liquid aerosol particles in a size range 1 to 8 μm. The di-2ethylhexyl sabacate (DEHS) particles were produced by condensation monodisperse aerosol generator. A thin-wall transparent model of human airways with non-symmetric bifurcations and non-planar geometry containing parts from throat to 3rd-4th generation of bronchi was fabricated for the study. Several cyclic (sinusoidal) breathing regimes were simulated using pneumatic breathing mechanism. Analogous steady-flow regimes were also investigated and used for comparison. An analysis of the particle velocity data was performed with aim to gain deeper understanding of the transport phenomena in the realistic bifurcating airway system. Flows of particles of different sizes in range 1 - 10 μm was found to slightly differ for extremely high Stokes numbers. Differences in steady and cyclic turbulence intensities were documented in the paper. Systematically higher turbulence intensity was found for cyclic flows and mainly in the expiration breathing phase. Negligible differences were found for behaviour of different particle size classes in the inspected range 1 to 8 μm. Possibility of velocity spectra estimation of air flow using the P/DPA data is discussed.

Study of cyclic and steady particle motion in a realistic human airway model using phase-Doppler anemometry

Directory of Open Access Journals (Sweden)

Jícha Miroslav

2012-04-01

Full Text Available Transport and deposition of particles in human airways has been of research interest for many years. Various experimental methods such as constant temperature anemometry, particle image velocimetry and laser-Doppler based techniques were employed for study of aerosol transport in the past. We use Phase-Doppler Particle Analyser (P/DPA for time resolved size and velocity measurement of liquid aerosol particles in a size range 1 to 8 μm. The di-2ethylhexyl sabacate (DEHS particles were produced by condensation monodisperse aerosol generator. A thin-wall transparent model of human airways with non-symmetric bifurcations and non-planar geometry containing parts from throat to 3rd-4th generation of bronchi was fabricated for the study. Several cyclic (sinusoidal breathing regimes were simulated using pneumatic breathing mechanism. Analogous steady-flow regimes were also investigated and used for comparison. An analysis of the particle velocity data was performed with aim to gain deeper understanding of the transport phenomena in the realistic bifurcating airway system. Flows of particles of different sizes in range 1 – 10 μm was found to slightly differ for extremely high Stokes numbers. Differences in steady and cyclic turbulence intensities were documented in the paper. Systematically higher turbulence intensity was found for cyclic flows and mainly in the expiration breathing phase. Negligible differences were found for behaviour of different particle size classes in the inspected range 1 to 8 μm. Possibility of velocity spectra estimation of air flow using the P/DPA data is discussed.

The classical Starling resistor model often does not predict inspiratory airflow patterns in the human upper airway.

Science.gov (United States)

Owens, Robert L; Edwards, Bradley A; Sands, Scott A; Butler, James P; Eckert, Danny J; White, David P; Malhotra, Atul; Wellman, Andrew

2014-04-15

The upper airway is often modeled as a classical Starling resistor, featuring a constant inspiratory airflow, or plateau, over a range of downstream pressures. However, airflow tracings from clinical sleep studies often show an initial peak before the plateau. To conform to the Starling model, the initial peak must be of small magnitude or dismissed as a transient. We developed a method to simulate fast or slow inspirations through the human upper airway, to test the hypothesis that this initial peak is a transient. Eight subjects [4 obstructive sleep apnea (OSA), 4 controls] slept in an "iron lung" and wore a nasal mask connected to a continuous/bilevel positive airway pressure machine. Downstream pressure was measured using an epiglottic catheter. During non-rapid eye movement (NREM) sleep, subjects were hyperventilated to produce a central apnea, then extrathoracic pressure was decreased slowly (∼2-4 s) or abruptly (resistor model, the upper airway exhibits marked NED in some subjects.

CD38/cADPR Signaling Pathway in Airway Disease: Regulatory Mechanisms

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Deepak A. Deshpande

2018-01-01

Full Text Available Asthma is an inflammatory disease in which proinflammatory cytokines have a role in inducing abnormalities of airway smooth muscle function and in the development of airway hyperresponsiveness. Inflammatory cytokines alter calcium (Ca2+ signaling and contractility of airway smooth muscle, which results in nonspecific airway hyperresponsiveness to agonists. In this context, Ca2+ regulatory mechanisms in airway smooth muscle and changes in these regulatory mechanisms encompass a major component of airway hyperresponsiveness. Although dynamic Ca2+ regulation is complex, phospholipase C/inositol tris-phosphate (PLC/IP3 and CD38-cyclic ADP-ribose (CD38/cADPR are two major pathways mediating agonist-induced Ca2+ regulation in airway smooth muscle. Altered CD38 expression or enhanced cyclic ADP-ribosyl cyclase activity associated with CD38 contributes to human pathologies such as asthma, neoplasia, and neuroimmune diseases. This review is focused on investigations on the role of CD38-cyclic ADP-ribose signaling in airway smooth muscle in the context of transcriptional and posttranscriptional regulation of CD38 expression. The specific roles of transcription factors NF-kB and AP-1 in the transcriptional regulation of CD38 expression and of miRNAs miR-140-3p and miR-708 in the posttranscriptional regulation and the underlying mechanisms of such regulation are discussed.

CD38/cADPR Signaling Pathway in Airway Disease: Regulatory Mechanisms

Science.gov (United States)

Deshpande, Deepak A.; Guedes, Alonso G. P.; Graeff, Richard; Dogan, Soner; Subramanian, Subbaya; Walseth, Timothy F.

2018-01-01

Asthma is an inflammatory disease in which proinflammatory cytokines have a role in inducing abnormalities of airway smooth muscle function and in the development of airway hyperresponsiveness. Inflammatory cytokines alter calcium (Ca2+) signaling and contractility of airway smooth muscle, which results in nonspecific airway hyperresponsiveness to agonists. In this context, Ca2+ regulatory mechanisms in airway smooth muscle and changes in these regulatory mechanisms encompass a major component of airway hyperresponsiveness. Although dynamic Ca2+ regulation is complex, phospholipase C/inositol tris-phosphate (PLC/IP3) and CD38-cyclic ADP-ribose (CD38/cADPR) are two major pathways mediating agonist-induced Ca2+ regulation in airway smooth muscle. Altered CD38 expression or enhanced cyclic ADP-ribosyl cyclase activity associated with CD38 contributes to human pathologies such as asthma, neoplasia, and neuroimmune diseases. This review is focused on investigations on the role of CD38-cyclic ADP-ribose signaling in airway smooth muscle in the context of transcriptional and posttranscriptional regulation of CD38 expression. The specific roles of transcription factors NF-kB and AP-1 in the transcriptional regulation of CD38 expression and of miRNAs miR-140-3p and miR-708 in the posttranscriptional regulation and the underlying mechanisms of such regulation are discussed. PMID:29576747

Arsenic compromises conducting airway epithelial barrier properties in primary mouse and immortalized human cell cultures.

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Cara L Sherwood

Full Text Available Arsenic is a lung toxicant that can lead to respiratory illness through inhalation and ingestion, although the most common exposure is through contaminated drinking water. Lung effects reported from arsenic exposure include lung cancer and obstructive lung disease, as well as reductions in lung function and immune response. As part of their role in innate immune function, airway epithelial cells provide a barrier that protects underlying tissue from inhaled particulates, pathogens, and toxicants frequently found in inspired air. We evaluated the effects of a five-day exposure to environmentally relevant levels of arsenic {<4μM [~300 μg/L (ppb] as NaAsO2} on airway epithelial barrier function and structure. In a primary mouse tracheal epithelial (MTE cell model we found that both micromolar (3.9 μM and submicromolar (0.8 μM arsenic concentrations reduced transepithelial resistance, a measure of barrier function. Immunofluorescent staining of arsenic-treated MTE cells showed altered patterns of localization of the transmembrane tight junction proteins claudin (Cl Cl-1, Cl-4, Cl-7 and occludin at cell-cell contacts when compared with untreated controls. To better quantify arsenic-induced changes in tight junction transmembrane proteins we conducted arsenic exposure experiments with an immortalized human bronchial epithelial cell line (16HBE14o-. We found that arsenic exposure significantly increased the protein expression of Cl-4 and occludin as well as the mRNA levels of Cl-4 and Cl-7 in these cells. Additionally, arsenic exposure resulted in altered phosphorylation of occludin. In summary, exposure to environmentally relevant levels of arsenic can alter both the function and structure of airway epithelial barrier constituents. These changes likely contribute to the observed arsenic-induced loss in basic innate immune defense and increased infection in the airway.

Hypercapnia modulates cAMP signalling and cystic fibrosis transmembrane conductance regulator‐dependent anion and fluid secretion in airway epithelia

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Turner, Mark J.; Saint‐Criq, Vinciane; Patel, Waseema; Ibrahim, Salam H.; Verdon, Bernard; Ward, Christopher; Garnett, James P.; Tarran, Robert; Cann, Martin J.

2015-01-01

Key points Raised arterial blood CO2 (hypercapnia) is a feature of many lung diseases.CO2 has been shown to act as a cell signalling molecule in human cells, notably by influencing the levels of cell signalling second messengers: cAMP and Ca2+.Hypercapnia reduced cAMP‐stimulated cystic fibrosis transmembrane conductance regulator‐dependent anion and fluid transport in Calu‐3 cells and primary human airway epithelia but did not affect cAMP‐regulated HCO3 − transport via pendrin or Na+/HCO3 − cotransporters.These results further support the role of CO2 as a cell signalling molecule and suggests CO2‐induced reductions in airway anion and fluid transport may impair innate defence mechanisms of the lungs. Abstract Hypercapnia is clinically defined as an arterial blood partial pressure of CO2 of above 40 mmHg and is a feature of chronic lung disease. In previous studies we have demonstrated that hypercapnia modulates agonist‐stimulated cAMP levels through effects on transmembrane adenylyl cyclase activity. In the airways, cAMP is known to regulate cystic fibrosis transmembrane conductance regulator (CFTR)‐mediated anion and fluid secretion, which contributes to airway surface liquid homeostasis. The aim of the current work was to investigate if hypercapnia could modulate cAMP‐regulated ion and fluid transport in human airway epithelial cells. We found that acute exposure to hypercapnia significantly reduced forskolin‐stimulated elevations in intracellular cAMP as well as both adenosine‐ and forskolin‐stimulated increases in CFTR‐dependent transepithelial short‐circuit current, in polarised cultures of Calu‐3 human airway cells. This CO2‐induced reduction in anion secretion was not due to a decrease in HCO3 − transport given that neither a change in CFTR‐dependent HCO3 − efflux nor Na+/HCO3 − cotransporter‐dependent HCO3 − influx were CO2‐sensitive. Hypercapnia also reduced the volume of forskolin‐stimulated fluid

Human factors in the development of complications of airway management: preliminary evaluation of an interview tool.

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Flin, R; Fioratou, E; Frerk, C; Trotter, C; Cook, T M

2013-08-01

The 4th National Audit Project of the Royal College of Anaesthetists and the Difficult Airway Society (NAP4) analysed reports of serious events arising from airway management during anaesthesia, intensive care and the emergency department. We conducted supplementary telephone interviews with 12 anaesthetists who had reported to NAP4, aiming to identify causal factors using a method based on the Human Factors Investigation Tool (HFIT). We identified contributing human factors in all cases (median [range] 4.5 [1-10] per case). The most frequent related to: situation awareness (failures to anticipate, wrong decision) (nine cases); job factors (e.g. task difficulty; staffing, time pressure) (eight cases); and person factors (e.g. tiredness, hunger, stress) (six cases). Protective factors, such as teamwork and communication, were also revealed. The post-report HFIT interview method identified relevant human factors and this approach merits further testing as part of the investigation of anaesthetic incidents. Anaesthesia © 2013 The Association of Anaesthetists of Great Britain and Ireland.

Computationally efficient analysis of particle transport and deposition in a human whole-lung-airway model. Part I: Theory and model validation.

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Kolanjiyil, Arun V; Kleinstreuer, Clement

2016-12-01

Computational predictions of aerosol transport and deposition in the human respiratory tract can assist in evaluating detrimental or therapeutic health effects when inhaling toxic particles or administering drugs. However, the sheer complexity of the human lung, featuring a total of 16 million tubular airways, prohibits detailed computer simulations of the fluid-particle dynamics for the entire respiratory system. Thus, in order to obtain useful and efficient particle deposition results, an alternative modeling approach is necessary where the whole-lung geometry is approximated and physiological boundary conditions are implemented to simulate breathing. In Part I, the present new whole-lung-airway model (WLAM) represents the actual lung geometry via a basic 3-D mouth-to-trachea configuration while all subsequent airways are lumped together, i.e., reduced to an exponentially expanding 1-D conduit. The diameter for each generation of the 1-D extension can be obtained on a subject-specific basis from the calculated total volume which represents each generation of the individual. The alveolar volume was added based on the approximate number of alveoli per generation. A wall-displacement boundary condition was applied at the bottom surface of the first-generation WLAM, so that any breathing pattern due to the negative alveolar pressure can be reproduced. Specifically, different inhalation/exhalation scenarios (rest, exercise, etc.) were implemented by controlling the wall/mesh displacements to simulate realistic breathing cycles in the WLAM. Total and regional particle deposition results agree with experimental lung deposition results. The outcomes provide critical insight to and quantitative results of aerosol deposition in human whole-lung airways with modest computational resources. Hence, the WLAM can be used in analyzing human exposure to toxic particulate matter or it can assist in estimating pharmacological effects of administered drug-aerosols. As a practical

Simulation of size-dependent aerosol deposition in a realistic model of the upper human airways

NARCIS (Netherlands)

Frederix, E.M.A.; Kuczaj, Arkadiusz K.; Nordlund, Markus; Belka, M.; Lizal, F.; Elcner, J.; Jicha, M.; Geurts, Bernardus J.

An Eulerian internally mixed aerosol model is used for predictions of deposition inside a realistic cast of the human upper airways. The model, formulated in the multi-species and compressible framework, is solved using the sectional discretization of the droplet size distribution function to

Nitric Oxide Synthase Enzymes in the Airways of Mice Exposed to Ovalbumin: NOS2 Expression Is NOS3 Dependent

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Jennifer M. Bratt

2010-01-01

Full Text Available Objectives and Design. The function of the airway nitric oxide synthase (NOS isoforms and the lung cell types responsible for its production are not fully understood. We hypothesized that NO homeostasis in the airway is important to control inflammation, which requires upregulation, of NOS2 protein expression by an NOS3-dependent mechanism. Materials or Subjects. Mice from a C57BL/6 wild-type, NOS1−/−, NOS2−/−, and NOS3−/− genotypes were used. All mice strains were systemically sensitized and exposed to filtered air or ovalbumin (OVA aerosol for two weeks to create a subchronic model of allergen-induced airway inflammation. Methods. We measured lung function, lung lavage inflammatory and airway epithelial goblet cell count, exhaled NO, nitrate and nitrite concentration, and airway NOS1, NOS2, and NOS3 protein content. Results. Deletion of NOS1 or NOS3 increases NOS2 protein present in the airway epithelium and smooth muscle of air-exposed animals. Exposure to allergen significantly reduced the expression of NOS2 protein in the airway epithelium and smooth muscle of the NOS3−/− strain only. This reduction in NOS2 expression was not due to the replacement of epithelial cells with goblet cells as remaining epithelial cells did not express NOS2. NOS1−/− animals had significantly reduced goblet cell metaplasia compared to C57Bl/6 wt, NOS2−/−, and NOS3−/− allergen-exposed mice. Conclusion. The airway epithelial and smooth muscle cells maintain a stable airway NO concentration under noninflammatory conditions. This “homeostatic” mechanism is unable to distinguish between NOS derived from the different constitutive NOS isoforms. NOS3 is essential for the expression of NOS2 under inflammatory conditions, while NOS1 expression contributes to allergen-induced goblet cell metaplasia.

Nitric Oxide Synthase Enzymes in the Airways of Mice Exposed to Ovalbumin: NOS2 Expression Is NOS3 Dependent

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Bratt, Jennifer M.; Williams, Keisha; Rabowsky, Michelle F.; Last, Michael S.; Franzi, Lisa M.; Last, Jerold A.; Kenyon, Nicholas J.

2010-01-01

Objectives and Design. The function of the airway nitric oxide synthase (NOS) isoforms and the lung cell types responsible for its production are not fully understood. We hypothesized that NO homeostasis in the airway is important to control inflammation, which requires upregulation, of NOS2 protein expression by an NOS3-dependent mechanism. Materials or Subjects. Mice from a C57BL/6 wild-type, NOS1−/−, NOS2−/−, and NOS3−/− genotypes were used. All mice strains were systemically sensitized and exposed to filtered air or ovalbumin (OVA) aerosol for two weeks to create a subchronic model of allergen-induced airway inflammation. Methods. We measured lung function, lung lavage inflammatory and airway epithelial goblet cell count, exhaled NO, nitrate and nitrite concentration, and airway NOS1, NOS2, and NOS3 protein content. Results. Deletion of NOS1 or NOS3 increases NOS2 protein present in the airway epithelium and smooth muscle of air-exposed animals. Exposure to allergen significantly reduced the expression of NOS2 protein in the airway epithelium and smooth muscle of the NOS3−/− strain only. This reduction in NOS2 expression was not due to the replacement of epithelial cells with goblet cells as remaining epithelial cells did not express NOS2. NOS1−/− animals had significantly reduced goblet cell metaplasia compared to C57Bl/6 wt, NOS2−/−, and NOS3−/− allergen-exposed mice. Conclusion. The airway epithelial and smooth muscle cells maintain a stable airway NO concentration under noninflammatory conditions. This “homeostatic” mechanism is unable to distinguish between NOS derived from the different constitutive NOS isoforms. NOS3 is essential for the expression of NOS2 under inflammatory conditions, while NOS1 expression contributes to allergen-induced goblet cell metaplasia. PMID:20953358

Endothelial MMP14 is required for endothelial-dependent growth support of human airway basal cells

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Ding, Bi-Sen; Gomi, Kazunori; Rafii, Shahin; Crystal, Ronald G.; Walters, Matthew S.

2015-01-01

ABSTRACT Human airway basal cells are the stem (or progenitor) population of the airway epithelium, and play a central role in anchoring the epithelium to the basement membrane. The anatomic position of basal cells allows for potential paracrine signaling between them and the underlying non-epithelial stromal cells. In support of this, we have previously demonstrated that endothelial cells support growth of basal cells during co-culture through vascular endothelial growth factor A (VEGFA)-mediated signaling. Building on these findings, we found, by RNA sequencing analysis, that basal cells expressed multiple fibroblast growth factor (FGF) ligands (FGF2, FGF5, FGF11 and FGF13) and that only FGF2 and FGF5 were capable of functioning in a paracrine manner to activate classical FGF receptor (FGFR) signaling. Antibody-mediated blocking of FGFR1 during basal-cell–endothelial-cell co-culture significantly reduced the endothelial-cell-dependent basal cell growth. Stimulation of endothelial cells with basal-cell-derived growth factors induced endothelial cell expression of matrix metallopeptidase 14 (MMP14), and short hairpin RNA (shRNA)-mediated knockdown of endothelial cell MMP14 significantly reduced the endothelial-cell-dependent growth of basal cells. Overall, these data characterize a new growth-factor-mediated reciprocal ‘crosstalk’ between human airway basal cells and endothelial cells that regulates proliferation of basal cells. PMID:26116571

Measuring the airway in 3 dimensions: a reliability and accuracy study.

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El, Hakan; Palomo, Juan Martin

2010-04-01

The aim of the study was to compare the reliability and accuracy of 3 commercially available digital imaging and communications in medicine (DICOM) viewers for measuring upper airway volumes. Thirty cone-beam computed tomography scans were randomly selected, and the upper airway volumes were calculated for both oropharynx and nasal passage. Dolphin3D (version 11, Dolphin Imaging & Management Solutions, Chatsworth, Calif), InVivoDental (version 4.0.70, Anatomage, San Jose, Calif), and OnDemand3D (version 1.0.1.8407, CyberMed, Seoul, Korea) were compared with a previously tested manual segmentation program called OrthoSegment (OS) (developed at the Department of Orthodontics at Case Western Reserve University, Cleveland, Ohio). The measurements were repeated after 2 weeks, and the ICC was used for the reliability tests. All commercially available programs were compared with the OS program by using regression analysis. The Pearson correlation was used to evaluate the correlation between the OS and the automatic segmentation programs. The reliability was high for all programs. The highest correlation found was between the OS and Dolphin3D for the oropharynx, and between the OS and InVivoDental for nasal passage volume. A high correlation was found for all programs, but the results also showed statistically significant differences compared with the OS program. The programs also had inconsistencies among themselves. The 3 commercially available DICOM viewers are highly reliable in their airway volume calculations and showed high correlation of results but poor accuracy, suggesting systematic errors. Copyright 2010 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.

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

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Luketich James D

2004-12-01

Full Text Available Abstract Background Non-neuronal cells, including those derived from lung, are reported to express nicotinic acetylcholine receptors (nAChR. We examined nAChR subunit expression in short-term cultures of human airway cells derived from a series of never smokers, ex-smokers, and active smokers. Methods and Results At the mRNA level, human bronchial epithelial (HBE cells and airway fibroblasts expressed a range of nAChR subunits. In multiple cultures of both cell types, mRNA was detected for subunits that constitute functional muscle-type and neuronal-type pentomeric receptors. Two immortalized cell lines derived from HBE cells also expressed muscle-type and neuronal-type nAChR subunits. Airway fibroblasts expressed mRNA for three muscle-type subunits (α1, δ, and ε significantly more often than HBE cells. Immunoblotting of HBE cell and airway fibroblast extracts confirmed that mRNA for many nAChR subunits is translated into detectable levels of protein, and evidence of glycosylation of nAChRs was observed. Some minor differences in nAChR expression were found based on smoking status in fibroblasts or HBE cells. Nicotine triggered calcium influx in the immortalized HBE cell line BEAS2B, which was blocked by α-bungarotoxin and to a lesser extent by hexamethonium. Activation of PKC and MAPK p38, but not MAPK p42/44, was observed in BEAS2B cells exposed to nicotine. In contrast, nicotine could activate p42/44 in airway fibroblasts within five minutes of exposure. Conclusions These results suggest that muscle-type and neuronal-type nAChRs are functional in airway fibroblasts and HBE cells, that prior tobacco exposure does not appear to be an important variable in nAChR expression, and that distinct signaling pathways are observed in response to nicotine.

GM-CSF production from human airway smooth muscle cells is potentiated by human serum

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Maria B. Sukkar

2000-01-01

Full Text Available Recent evidence suggests that airway smooth muscle cells (ASMC actively participate in the airway inflammatory process in asthma. Interleukin–1β (IL–1β and tumour necrosis factor–α (TNF–α induce ASMC to release inflammatory mediators in vitro. ASMC mediator release in vivo, however, may be influenced by features of the allergic asthmatic phenotype. We determined whether; (1 allergic asthmatic serum (AAS modulates ASMC mediator release in response to IL–1β and TNF–α, and (2 IL–1β/TNF–α prime ASMC to release mediators in response to AAS. IL–5 and GMCSF were quantified by ELISA in culture supernatants of; (1 ASMC pre-incubated with either AAS, non-allergic non-asthmatic serum (NAS or MonomedTM (a serum substitute and subsequently stimulated with IL–1β and TNF–α and (2 ASMC stimulated with IL–1β/TNF–α and subsequently exposed to either AAS, NAS or MonomedTM. IL-1g and TNF–α induced GM-CSF release in ASMC pre-incubated with AAS was not greater than that in ASMC pre-incubated with NAS or MonomedTM. IL–1β and TNF–α, however, primed ASMC to release GM-CSF in response to human serum. GM-CSF production following IL–1β/TNF–α and serum exposure (AAS or NAS was significantly greater than that following IL–1β /TNF–α and MonomedTM exposure or IL–1β/TNF–α exposure only. Whilst the potentiating effects of human serum were not specific to allergic asthma, these findings suggest that the secretory capacity of ASMC may be up-regulated during exacerbations of asthma, where there is evidence of vascular leakage.

Regulator of G-protein signaling 5 (RGS5) inhibits cell proliferation and enhances radiosensitivity of human lung cancer cells

International Nuclear Information System (INIS)

Xu Zumin; Wang Jin; Zuo Yufang; Yu Zhonghua; Peng Fang; Hu Xiao; Zhou Qichao; Ma Honglian; Bao Yong; Chen Ming

2014-01-01

Objective: To investigate the effects of regulator and the underlying molecular mechanisms of G-protein signaling 5 (RGS5) on radiation response in human lung cancer cells. Methods: The effects of RGS5 on viability were determined by MTT assay, and apoptosis rate was detected by flow cytometry, in human lung cancer cells. The combined effect of ionizing radiation and RGS5 on tumor cells was detected by colony formation assay. The protein expression was detected by Western blot. Results: RGS5 overexpression remarkably inhibited the survival of human lung cancer cells, and the growth inhibition rate of RGS5 overexpression on A549 and Calu-3 cells were 44.4% (F = 29.18, P < 0.05) and 39.27% (F = 23.04, P < 0.05) at 48 h, and 54.3%(F = 103.45, P < 0.05), 44.7%(F = 108.02, P < 0.05) at 72 h post-irradiation, respectively. RGS5 might exert its inhibitory effects on human lung cancer cells by inducing tumor cell apoptosis, while the apoptotic cells rate in A549 and Calu-3 cells in control group, pTRiEX group and pTRiEX-RGS5 group were (1.3±0.2)%, (3.4±0.6)%, (19.6±2.3)% (F = 86.62, P < 0.05), and (3.2±0.8)%, (3.0±0.9)%, (12.8±1.8)% (F = 28.80, P < 0.05) at 36 h post-irradiation, respectively. Furthermore, RGS5 could sensitize the lung cancer cells to radiation. Conclusions: RGS5 might play an inhibitory role in human lung cancer cell proliferation, which may explain the pathoclinical observation thet high expression of RGSS is a favorable prognostic factor in NSCLC patients. In addition, RGS5 also enhance the anti-tumor effects of radiation in human lung cancer cells. (authors)

TIM-3 is not essential for development of airway inflammation induced by house dust mite antigens

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Yoshihisa Hiraishi

2016-10-01

Conclusions: Our findings indicate that, in mice, TIM-3 is not essential for development of HDM-induced acute or chronic allergic airway inflammation, although it appears to be involved in reduced lymphocyte recruitment during HDM-induced chronic allergic airway inflammation.

Rule-based detection of intrathoracic airway trees

International Nuclear Information System (INIS)

Sonka, M.; Park, W.; Hoffman, E.A.

1996-01-01

New sensitive and reliable methods for assessing alterations in regional lung structure and function are critically important for the investigation and treatment of pulmonary diseases. Accurate identification of the airway tree will provide an assessment of airway structure and will provide a means by which multiple volumetric images of the lung at the same lung volume over time can be used to assess regional parenchymal changes. The authors describe a novel rule-based method for the segmentation of airway trees from three-dimensional (3-D) sets of computed tomography (CT) images, and its validation. The presented method takes advantage of a priori anatomical knowledge about pulmonary airway and vascular trees and their interrelationships. The method is based on a combination of 3-D seeded region growing that is used to identify large airways, rule-based two-dimensional (2-D) segmentation of individual CT slices to identify probable locations of smaller diameter airways, and merging of airway regions across the 3-D set of slices resulting in a tree-like airway structure. The method was validated in 40 3-mm-thick CT sections from five data sets of canine lungs scanned via electron beam CT in vivo with lung volume held at a constant pressure. The method's performance was compared with that of the conventional 3-D region growing method. The method substantially outperformed an existing conventional approach to airway tree detection

Estrogen receptor beta signaling inhibits PDGF induced human airway smooth muscle proliferation.

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Ambhore, Nilesh Sudhakar; Katragadda, Rathnavali; Raju Kalidhindi, Rama Satyanarayana; Thompson, Michael A; Pabelick, Christina M; Prakash, Y S; Sathish, Venkatachalem

2018-04-20

Airway smooth muscle (ASM) cell hyperplasia driven by persistent inflammation is a hallmark feature of remodeling in asthma. Sex steroid signaling in the lungs is of considerable interest, given epidemiological data showing more asthma in pre-menopausal women and aging men. Our previous studies demonstrated that estrogen receptor (ER) expression increases in asthmatic human ASM; however, very limited data are available regarding differential roles of ERα vs. ERβ isoforms in human ASM cell proliferation. In this study, we evaluated the effect of selective ERα and ERβ modulators on platelet-derived growth factor (PDGF)-stimulated ASM proliferation and the mechanisms involved. Asthmatic and non-asthmatic primary human ASM cells were treated with PDGF, 17β-estradiol, ERα-agonist and/or ERβ-agonist and/or G-protein-coupled estrogen receptor 30 (GPR30/GPER) agonist and proliferation was measured using MTT and CyQuant assays followed by cell cycle analysis. Transfection of small interfering RNA (siRNA) ERα and ERβ significantly altered the human ASM proliferation. The specificity of siRNA transfection was confirmed by Western blot analysis. Gene and protein expression of cell cycle-related antigens (PCNA and Ki67) and C/EBP were measured by RT-PCR and Western analysis, along with cell signaling proteins. PDGF significantly increased ASM proliferation in non-asthmatic and asthmatic cells. Treatment with PPT showed no significant effect on PDGF-induced proliferation, whereas WAY interestingly suppressed proliferation via inhibition of ERK1/2, Akt, and p38 signaling. PDGF-induced gene expression of PCNA, Ki67 and C/EBP in human ASM was significantly lower in cells pre-treated with WAY. Furthermore, WAY also inhibited PDGF-activated PCNA, C/EBP, cyclin-D1, and cyclin-E. Overall, we demonstrate ER isoform-specific signaling in the context of ASM proliferation. Activation of ERβ can diminish remodeling in human ASM by inhibiting pro-proliferative signaling pathways

IMAGE-BASED IN VIVO QUANTITATIVE ASSESSMENT OF HUMAN AIRWAY OPENING AND CONTRACTILITY BY FIBER OPTICAL NASOPHARYNGOSCOPY IN HEALTHY AND ASTHMATIC SUBJECTS

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LINHONG DENG

2013-04-01

Full Text Available Assessment of human airway lumen opening is important in diagnosing and understanding the mechanisms of airway dysfunctions such as the excessive airway narrowing in asthma and chronic obstructive pulmonary disease (COPD. Although there are indirect methods to evaluate the airway calibre, direct in vivo measurement of the airway calibre has not been commonly available. With recent advent of the flexible fiber optical nasopharyngoscope with video recording it has become possible to directly visualize the passages of upper and lower airways. However, quantitative analysis of the recorded video images has been technically challenging. Here, we describe an automatic image processing and analysis method that allows for batch analysis of the images recorded during the endoscopic procedure, thus facilitates image-based quantification of the airway opening. Video images of the airway lumen of volunteer subject were acquired using a fiber optical nasopharyngoscope, and subsequently processed using Gaussian smoothing filter, threshold segmentation, differentiation, and Canny image edge detection, respectively. Thus the area of the open airway lumen was identified and computed using a predetermined converter of the image scale to true dimension of the imaged object. With this method we measured the opening/narrowing of the glottis during tidal breathing with or without making "Hee" sound or cough. We also used this method to measure the opening/narrowing of the primary bronchus of either healthy or asthmatic subjects in response to histamine and/or albuterol treatment, which also provided an indicator of the airway contractility. Our results demonstrate that the image-based method accurately quantified the area change waveform of either the glottis or the bronchus as observed by using the optical nasopharygoscope. Importantly, the opening/narrowing of the airway lumen generally correlated with the airflow and resistance of the airways, and could

Pediatric Trainees Managing a Difficult Airway: Comparison of Laryngeal Mask Airway, Direct, and Video-Assisted Laryngoscopy

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Art Ambrosio MD

2017-05-01

Full Text Available Objective Difficult airway management is a key skill required by all pediatric physicians, yet training on multiple modalities is lacking. The objective of this study was to compare the rate of, and time to, successful advanced infant airway placement with direct laryngoscopy, video-assisted laryngoscopy, and laryngeal mask airway (LMA in a difficult airway simulator. This study is the first to compare the success with 3 methods for difficult airway management among pediatric trainees. Study Design Randomized crossover pilot study. Setting Tertiary academic medical center. Methods Twenty-two pediatric residents, interns, and medical students were tested. Participants were provided 1 training session by faculty using a normal infant manikin. Subjects then performed all 3 of the aforementioned advanced airway modalities in a randomized order on a difficult airway model of a Robin sequence. Success was defined as confirmed endotracheal intubation or correct LMA placement by the testing instructor in ≤120 seconds. Results Direct laryngoscopy demonstrated a significantly higher placement success rate (77.3% than video-assisted laryngoscopy (36.4%, P = .0117 and LMA (31.8%, P = .0039. Video-assisted laryngoscopy required a significantly longer amount of time during successful intubations (84.8 seconds; 95% CI, 59.4-110.1 versus direct laryngoscopy (44.9 seconds; 95% CI, 33.8-55.9 and LMA placement (36.6 seconds; 95% CI, 24.7-48.4. Conclusions Pediatric trainees demonstrated significantly higher success using direct laryngoscopy in a difficult airway simulator model. However, given the potential lifesaving implications of advanced airway adjuncts, including video-assisted laryngoscopy and LMA placement, more extensive training on adjunctive airway management techniques may be useful for trainees.

Integrated care pathways for airway diseases (AIRWAYS-ICPs)

DEFF Research Database (Denmark)

Bousquet, J; Addis, A; Adcock, I

2014-01-01

The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy...... and will add value to existing public health knowledge by: 1) proposing a common framework of care pathways for chronic respiratory diseases, which will facilitate comparability and trans-national initiatives; 2) informing cost-effective policy development, strengthening in particular those on smoking...... and environmental exposure; 3) aiding risk stratification in chronic disease patients, using a common strategy; 4) having a significant impact on the health of citizens in the short term (reduction of morbidity, improvement of education in children and of work in adults) and in the long-term (healthy ageing); 5...

Divergent pro-inflammatory profile of human dendritic cells in response to commensal and pathogenic bacteria associated with the airway microbiota

DEFF Research Database (Denmark)

Larsen, Jeppe Madura; Steen-Jensen, Daniel Bisgaard; Laursen, Janne Marie

2012-01-01

of individual bacterial species are unknown. In this study, we compared the immune stimulatory capacity on human monocyte-derived dendritic cells (DCs) of selected airway commensal and pathogenic bacteria predominantly associated with lungs of asthma or COPD patients (pathogenic Haemophillus spp. and Moraxella...... spp.), healthy lungs (commensal Prevotella spp.) or both (commensal Veillonella spp. and Actinomyces spp.). All bacteria were found to induce activation of DCs as demonstrated by similar induction of CD83, CD40 and CD86 surface expression. However, asthma and COPD-associated pathogenic bacteria...... provoked a 3-5 fold higher production of IL-23, IL-12p70 and IL-10 cytokines compared to the commensal bacteria. Based on the differential cytokine production profiles, the studied airway bacteria could be segregated into three groups (Haemophilus spp. and Moraxella spp. vs. Prevotella spp. and Veillonella...

VIRTUAL 3-D MODELLING OF AIRWAYS IN CONGENITAL HEART DEFECTS

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Simone Speggiorin

2016-10-01

Full Text Available The involvement of the airway is not uncommon in the presence of complex cardiovascular malformations. In these cases, a careful inspection of the relationship between the airway and the vasculature is paramount to plan the surgical procedure. Three-dimentional printing enhanced the visualization of the cardio-vascualr structure. Unfortunately IT does not allow to remove selected anatomy to improve the visualization of the surrounding ones. Computerized modelling (CM of has the potential to fill this gap by allowing a dynamic handling of different anatomies, increasing the exposure of vessels or bronchi to show their relationship.. We started to use this technique to plan the surgical repair in these complex cases where the airway is affected. This technique is routinely used in our Institution as an additional tool in the pre-surgical assessment. We report 4 cases in which the airways were compressed by vascular structures : ascending aorta in 1, left pulmonary artery sling in 1, Patent ductus arteriosus (PDA in 1 and major aorto-pulmonary collateral artery in 1. We believe this technique can enhance the understanding of the causes of airway involvement and facilitate the creation of an appropriate surgical plan.

The New Perilaryngeal Airway (CobraPLA™)1 Is as Efficient as the Laryngeal Mask Airway (LMA™)2, But Provides Better Airway Sealing Pressures

Science.gov (United States)

Akça, Ozan; Wadhwa, Anupama; Sengupta, Papiya; Durrani, Jaleel; Hanni, Keith; Wenke, Mary; Yücel, Yüksel; Lenhardt, Rainer; Doufas, Anthony G.; Sessler, Daniel I.

2006-01-01

The Laryngeal Mask Airway (LMA) is a frequently-used efficient airway device, yet it sometimes seals poorly, thus reducing the efficacy of positive-pressure ventilation. The Perilaryngeal Airway (CobraPLA) is a novel airway device with a larger pharyngeal cuff (when inflated). We tested the hypothesis that the CobraPLA was superior to LMA with regard to insertion time and airway sealing pressure and comparable to LMA in airway adequacy and recovery characteristics. After midazolam and fentanyl, 81 ASA I-II outpatients having elective surgery were randomized to receive an LMA or CobraPLA. Anesthesia was induced with propofol (2.5 mg/kg, IV), and the airway inserted. We measured 1) insertion time; 2) adequacy of the airway (no leak at 15-cm-H2O peak pressure or tidal volume of 5 ml/kg); 3) airway sealing pressure; 4) number of repositioning attempts; and 5) sealing quality (no leak at tidal volume of 8 ml/kg). At the end of surgery, gastric insufflation, postoperative sore throat, dysphonia, and dysphagia were evaluated. Data were compared with unpaired t-tests, chi-square tests, or Fisher’s Exact tests; P<0.05 was significant. Patient characteristics, insertion times, airway adequacy, number of repositioning attempts, and recovery were similar in each group. Airway sealing pressure was significantly greater with CobraPLA (23±6 cm H2O) than LMA (18±5 cm H2O, P<0.001). The CobraPLA has insertion characteristics similar to LMA, but better airway sealing capabilities. PMID:15281543

Airway smooth muscle cells : regulators of airway inflammation

NARCIS (Netherlands)

Zuyderduyn, Suzanne

2007-01-01

Airways from asthmatic subjects are more responsive to bronchoconstrictive stimuli than airways from healthy subjects. Airway smooth muscle (ASM) cells mediate contraction of the airways by responding to the bronchoconstrictive stimuli, which was thought to be the primary role of ASM cells. In this

Measuring three-dimensional flow structures in the conductive airways using 3D-PTV

Science.gov (United States)

Janke, Thomas; Schwarze, Rüdiger; Bauer, Katrin

2017-10-01

Detailed information about flow patterns and mass transport in the conductive airways is of crucial interest to improve ventilation strategies as well as targeted drug delivery. Despite a vast number of flow studies in this field, there is still a dearth in experimental data of three-dimensional flow patterns, in particular for the validation of numerical results. Therefore, oscillating flow within a realistic model of the upper human conductive airways is studied here experimentally. The investigated range of Reynolds numbers is Re = 250-2000 and the Womersley number is varied between α = 1.9-5.1, whereby physiological flow at rest conditions is included. In employing the three-dimensional particle tracking velocimetry measurement technique, we can directly visualize airway specific flow structures as well as examine Lagrangian trajectory statistics, which has not been covered to date. The systematic variation of characteristic flow parameters in combination with the advanced visualization technique sheds new light on the mechanisms of evolving flow patterns. By determining Lagrangian properties such as pathline curvature and torsion, we find that both strongly depend on the Reynolds number. Moreover, the probability density function of the curvature reveals a unique shape for certain flow regions and resembles a turbulent like behavior at the small scales.

Different effects of deep inspirations on central and peripheral airways in healthy and allergen-challenged mice

Directory of Open Access Journals (Sweden)

Dahlén Sven-Erik

2008-02-01

Full Text Available Abstract Background Deep inspirations (DI have bronchodilatory and bronchoprotective effects in healthy human subjects, but these effects appear to be absent in asthmatic lungs. We have characterized the effects of DI on lung mechanics during mechanical ventilation in healthy mice and in a murine model of acute and chronic airway inflammation. Methods Balb/c mice were sensitized to ovalbumin (OVA and exposed to nebulized OVA for 1 week or 12 weeks. Control mice were challenged with PBS. Mice were randomly selected to receive DI, which were given twice during the minute before assessment of lung mechanics. Results DI protected against bronchoconstriction of central airways in healthy mice and in mice with acute airway inflammation, but not when OVA-induced chronic inflammation was present. DI reduced lung resistance induced by methacholine from 3.8 ± 0.3 to 2.8 ± 0.1 cmH2O·s·mL-1 in healthy mice and 5.1 ± 0.3 to 3.5 ± 0.3 cmH2O·s·mL-1 in acute airway inflammation (both P P P P P Conclusion We have tested a mouse model of potential value for defining mechanisms and sites of action of DI in healthy and asthmatic human subjects. Our current results point to potent protective effects of DI on peripheral parts of chronically inflamed murine lungs and that the presence of DI may blunt airway hyperreactivity.

Anti-Cytotoxic and Anti-Inflammatory Effects of the Macrolide Antibiotic Roxithromycin in Sulfur Mustard-Exposed Human Airway Epithelial Cells

National Research Council Canada - National Science Library

Gao1, Radharaman Ray2, Yan Xiao3, Peter E. Barker3 and Prab, Xiugong

2006-01-01

.... In this study, the anti-cytotoxic and anti-inflammatory effects of a representative macrolide antibiotic, roxithromycin, were tested in vitro using SM-exposed normal human small airway epithelial (SAE...

Transient receptor potential ankyrin 1 channel localized to non-neuronal airway cells promotes non-neurogenic inflammation

DEFF Research Database (Denmark)

Nassini, Romina; Pedretti, Pamela; Moretto, Nadia

2012-01-01

The transient receptor potential ankyrin 1 (TRPA1) channel, localized to airway sensory nerves, has been proposed to mediate airway inflammation evoked by allergen and cigarette smoke (CS) in rodents, via a neurogenic mechanism. However the limited clinical evidence for the role of neurogenic...... inflammation in asthma or chronic obstructive pulmonary disease raises an alternative possibility that airway inflammation is promoted by non-neuronal TRPA1.By using Real-Time PCR and calcium imaging, we found that cultured human airway cells, including fibroblasts, epithelial and smooth muscle cells express...... functional TRPA1 channels. By using immunohistochemistry, TRPA1 staining was observed in airway epithelial and smooth muscle cells in sections taken from human airways and lung, and from airways and lung of wild-type, but not TRPA1-deficient mice. In cultured human airway epithelial and smooth muscle cells...

A novel animal model for hyperdynamic airway collapse.

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Tsukada, Hisashi; O'Donnell, Carl R; Garland, Robert; Herth, Felix; Decamp, Malcolm; Ernst, Armin

2010-12-01

Tracheobronchomalacia (TBM) is increasingly recognized as a condition associated with significant pulmonary morbidity. However, treatment is invasive and complex, and because there is no appropriate animal model, novel diagnostic and treatment strategies are difficult to evaluate. We endeavored to develop a reliable airway model to simulate hyperdynamic airway collapse in humans. Seven 20-kg male sheep were enrolled in this study. Tracheomalacia was created by submucosal resection of > 50% of the circumference of 10 consecutive cervical tracheal cartilage rings through a midline cervical incision. A silicone stent was placed in the trachea to prevent airway collapse during recovery. Tracheal collapsibility was assessed at protocol-specific time points by bronchoscopy and multidetector CT imaging while temporarily removing the stent. Esophageal pressure and flow data were collected to assess flow limitation during spontaneous breathing. All animals tolerated the surgical procedure well and were stented without complications. One sheep died at 2 weeks because of respiratory failure related to stent migration. In all sheep, near-total forced inspiratory airway collapse was observed up to 3 months postprocedure. Esophageal manometry demonstrated flow limitation associated with large negative pleural pressure swings during rapid spontaneous inhalation. Hyperdynamic airway collapse can reliably be induced with this technique. It may serve as a model for evaluation of novel diagnostic and therapeutic strategies for TBM.

Regulation of the cd38 promoter in human airway smooth muscle cells by TNF-α and dexamethasone

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Walseth Timothy F

2008-03-01

Full Text Available Abstract Background CD38 is expressed in human airway smooth muscle (HASM cells, regulates intracellular calcium, and its expression is augmented by tumor necrosis factor alpha (TNF-α. CD38 has a role in airway hyperresponsiveness, a hallmark of asthma, since deficient mice develop attenuated airway hyperresponsiveness compared to wild-type mice following intranasal challenges with cytokines such as IL-13 and TNF-α. Regulation of CD38 expression in HASM cells involves the transcription factor NF-κB, and glucocorticoids inhibit this expression through NF-κB-dependent and -independent mechanisms. In this study, we determined whether the transcriptional regulation of CD38 expression in HASM cells involves response elements within the promoter region of this gene. Methods We cloned a putative 3 kb promoter fragment of the human cd38 gene into pGL3 basic vector in front of a luciferase reporter gene. Sequence analysis of the putative cd38 promoter region revealed one NF-κB and several AP-1 and glucocorticoid response element (GRE motifs. HASM cells were transfected with the 3 kb promoter, a 1.8 kb truncated promoter that lacks the NF-κB and some of the AP-1 sites, or the promoter with mutations of the NF-κB and/or AP-1 sites. Using the electrophoretic mobility shift assays, we determined the binding of nuclear proteins to oligonucleotides encoding the putative cd38 NF-κB, AP-1, and GRE sites, and the specificity of this binding was confirmed by gel supershift analysis with appropriate antibodies. Results TNF-α induced a two-fold activation of the 3 kb promoter following its transfection into HASM cells. In cells transfected with the 1.8 kb promoter or promoter constructs lacking NF-κB and/or AP-1 sites or in the presence of dexamethasone, there was no induction in the presence of TNF-α. The binding of nuclear proteins to oligonucleotides encoding the putative cd38 NF-κB site and some of the six AP-1 sites was increased by TNF-α, and to

A hybrid method for airway segmentation and automated measurement of bronchial wall thickness on CT.

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Xu, Ziyue; Bagci, Ulas; Foster, Brent; Mansoor, Awais; Udupa, Jayaram K; Mollura, Daniel J

2015-08-01

Inflammatory and infectious lung diseases commonly involve bronchial airway structures and morphology, and these abnormalities are often analyzed non-invasively through high resolution computed tomography (CT) scans. Assessing airway wall surfaces and the lumen are of great importance for diagnosing pulmonary diseases. However, obtaining high accuracy from a complete 3-D airway tree structure can be quite challenging. The airway tree structure has spiculated shapes with multiple branches and bifurcation points as opposed to solid single organ or tumor segmentation tasks in other applications, hence, it is complex for manual segmentation as compared with other tasks. For computerized methods, a fundamental challenge in airway tree segmentation is the highly variable intensity levels in the lumen area, which often causes a segmentation method to leak into adjacent lung parenchyma through blurred airway walls or soft boundaries. Moreover, outer wall definition can be difficult due to similar intensities of the airway walls and nearby structures such as vessels. In this paper, we propose a computational framework to accurately quantify airways through (i) a novel hybrid approach for precise segmentation of the lumen, and (ii) two novel methods (a spatially constrained Markov random walk method (pseudo 3-D) and a relative fuzzy connectedness method (3-D)) to estimate the airway wall thickness. We evaluate the performance of our proposed methods in comparison with mostly used algorithms using human chest CT images. Our results demonstrate that, on publicly available data sets and using standard evaluation criteria, the proposed airway segmentation method is accurate and efficient as compared with the state-of-the-art methods, and the airway wall estimation algorithms identified the inner and outer airway surfaces more accurately than the most widely applied methods, namely full width at half maximum and phase congruency. Copyright © 2015. Published by Elsevier B.V.

Research of transport and deposition of aerosol in human airway replica

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Lizal, Frantisek; Jedelsky, Jan; Elcner, Jakub; Durdina, Lukas; Halasova, Tereza; Mravec, Filip; Jicha, Miroslav

2012-04-01

Growing concern about knowledge of aerosol transport in human lungs is caused by great potential of use of inhaled pharmaceuticals. Second substantial motive for the research is an effort to minimize adverse effects of particular matter emitted by traffic and industry on human health. We created model geometry of human lungs to 7th generation of branching. This model geometry was used for fabrication of two physical models. The first one is made from thin walled transparent silicone and it allows a measurement of velocity and size of aerosol particles by Phase Doppler Anemometry (PDA). The second one is fabricated by stereolithographic method and it is designed for aerosol deposition measurements. We provided a series of measurements of aerosol transport in the transparent model and we ascertained remarkable phenomena linked with lung flow. The results are presented in brief. To gather how this phenomena affects aerosol deposition in human lungs we used the second model and we developed a technique for deposition fraction and deposition efficiency assessment. The results confirmed that non-symmetric and complicated shape of human airways essentially affects transport and deposition of aerosol. The research will now focus on deeper insight in aerosol deposition.

Assessment of airway compression on chest radiographs in children with pulmonary tuberculosis

International Nuclear Information System (INIS)

Richter-Joubert, Lisel; Andronikou, Savvas; Workman, Lesley; Zar, Heather J.

2017-01-01

Because small, pliable paediatric airways are easily compressed by enlarged lymph nodes, detection of radiographic airway compression might be an objective criterion for diagnosing pulmonary tuberculosis. To investigate the frequency and inter-observer agreement of airway compression on chest radiographs in children with pulmonary tuberculosis compared to those with a different lower respiratory tract infection. Chest radiographs of children with suspected pulmonary tuberculosis were read by two readers according to a standardised format and a third reader when there was disagreement. Radiographs of children with proven pulmonary tuberculosis were compared to those with a different lower respiratory tract infection. We evaluated frequency and location of radiographic airway compression. Findings were correlated with human immunodeficiency virus (HIV) status and age. We assessed inter-observer agreement using kappa statistics. We reviewed radiographs of 505 children (median age 25.9 months, interquartile range [IQR] 14.3-62.2). Radiographic airway compression occurred in 54/188 (28.7%) children with proven pulmonary tuberculosis and in 24/317 (7.6%) children with other types of lower respiratory tract infection (odds ratio [OR] 4.9; 95% confidence interval [CI] 2.9-8.3). A higher frequency of radiographic airway compression occurred in infants (22/101, or 21.8%) compared to older children (56/404, or 13.9%; OR 1.7; 95% CI 1.0-3.0). We found no association between airway compression and HIV infection. Inter-observer agreement ranged from none to fair (kappa of 0.0-0.4). There is a strong association between airway compression on chest radiographs and confirmed pulmonary tuberculosis. However this finding's clinical use as an objective criterion for diagnosis of pulmonary tuberculosis in children is limited by poor inter-observer agreement. (orig.)

Assessment of airway compression on chest radiographs in children with pulmonary tuberculosis

Energy Technology Data Exchange (ETDEWEB)

Richter-Joubert, Lisel [Groote Schuur Hospital and University of Cape Town, Department of Radiology, Cape Town (South Africa); Andronikou, Savvas [Groote Schuur Hospital and University of Cape Town, Department of Radiology, Cape Town (South Africa); Bristol Royal Hospital for Children and the University of Bristol, Department of Paediatric Radiology, Bristol (United Kingdom); Workman, Lesley; Zar, Heather J. [University of Cape Town, Department of Paediatrics and Child Health and MRC Unit on Child and Adolescent Health, Red Cross War Memorial Children' s Hospital, Cape Town (South Africa)

2017-09-15

Because small, pliable paediatric airways are easily compressed by enlarged lymph nodes, detection of radiographic airway compression might be an objective criterion for diagnosing pulmonary tuberculosis. To investigate the frequency and inter-observer agreement of airway compression on chest radiographs in children with pulmonary tuberculosis compared to those with a different lower respiratory tract infection. Chest radiographs of children with suspected pulmonary tuberculosis were read by two readers according to a standardised format and a third reader when there was disagreement. Radiographs of children with proven pulmonary tuberculosis were compared to those with a different lower respiratory tract infection. We evaluated frequency and location of radiographic airway compression. Findings were correlated with human immunodeficiency virus (HIV) status and age. We assessed inter-observer agreement using kappa statistics. We reviewed radiographs of 505 children (median age 25.9 months, interquartile range [IQR] 14.3-62.2). Radiographic airway compression occurred in 54/188 (28.7%) children with proven pulmonary tuberculosis and in 24/317 (7.6%) children with other types of lower respiratory tract infection (odds ratio [OR] 4.9; 95% confidence interval [CI] 2.9-8.3). A higher frequency of radiographic airway compression occurred in infants (22/101, or 21.8%) compared to older children (56/404, or 13.9%; OR 1.7; 95% CI 1.0-3.0). We found no association between airway compression and HIV infection. Inter-observer agreement ranged from none to fair (kappa of 0.0-0.4). There is a strong association between airway compression on chest radiographs and confirmed pulmonary tuberculosis. However this finding's clinical use as an objective criterion for diagnosis of pulmonary tuberculosis in children is limited by poor inter-observer agreement. (orig.)

21 CFR 868.1780 - Inspiratory airway pressure meter.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Inspiratory airway pressure meter. 868.1780 Section 868.1780 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... meter. (a) Identification. An inspiratory airway pressure meter is a device used to measure the amount...

SLOWLY ADAPTING SENSORY UNITS HAVE MORE RECEPTORS IN LARGE AIRWAYS THAN IN SMALL AIRWAYS IN RABBITS

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Jun Liu

2016-12-01

Full Text Available Sensory units of pulmonary slowly adapting receptors (SARs are more active in large airways than in small airways. However, there is no explanation for this phenomenon. Although sensory structures in large airways resemble those in small airways, they are bigger and more complex. Possibly, a larger receptor provides greater surface area for depolarization, and thus has a lower activating threshold and/or a higher sensitivity to stretch, leading to more nerve electrical activities. Recently, a single sensory unit has been reported to contain multiple receptors. Therefore, sensory units in large airways may contain more SARs, which may contribute to high activities. To test this hypothesis, we used a double staining technique to identify sensory receptor sizes. We labeled the sensory structure with Na+/K+-ATPase antibodies and the myelin sheath with myelin basic protein (MBP antibodies. A SAR can be defined as the end formation beyond MBP labeling. Thus, we are able to compare sizes of sensory structures and SARs in large (trachea and bronchi vs small (bronchioles 0.05. However, the sensory structure contains more SARs in large airways than in small airways (9.6±0.6 vs 3.6±0.3; P<0.0001. Thus, our data support the hypothesis that greater numbers of SARs in sensory units of large airways may contribute to higher activities.

Human type II pneumocyte chemotactic responses to CXCR3 activation are mediated by splice variant A.

Science.gov (United States)

Ji, Rong; Lee, Clement M; Gonzales, Linda W; Yang, Yi; Aksoy, Mark O; Wang, Ping; Brailoiu, Eugen; Dun, Nae; Hurford, Matthew T; Kelsen, Steven G

2008-06-01

Chemokine receptors control several fundamental cellular processes in both hematopoietic and structural cells, including directed cell movement, i.e., chemotaxis, cell differentiation, and proliferation. We have previously demonstrated that CXCR3, the chemokine receptor expressed by Th1/Tc1 inflammatory cells present in the lung, is also expressed by human airway epithelial cells. In airway epithelial cells, activation of CXCR3 induces airway epithelial cell movement and proliferation, processes that underlie lung repair. The present study examined the expression and function of CXCR3 in human alveolar type II pneumocytes, whose destruction causes emphysema. CXCR3 was present in human fetal and adult type II pneumocytes as assessed by immunocytochemistry, immunohistochemistry, and Western blotting. CXCR3-A and -B splice variant mRNA was present constitutively in cultured type II cells, but levels of CXCR3-B greatly exceeded CXCR3-A mRNA. In cultured type II cells, I-TAC, IP-10, and Mig induced chemotaxis. Overexpression of CXCR3-A in the A549 pneumocyte cell line produced robust chemotactic responses to I-TAC and IP-10. In contrast, I-TAC did not induce chemotactic responses in CXCR3-B and mock-transfected cells. Finally, I-TAC increased cytosolic Ca(2+) and activated the extracellular signal-regulated kinase, p38, and phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B kinases only in CXCR3-A-transfected cells. These data indicate that the CXCR3 receptor is expressed by human type II pneumocytes, and the CXCR3-A splice variant mediates chemotactic responses possibly through Ca(2+) activation of both mitogen-activated protein kinase and PI 3-kinase signaling pathways. Expression of CXCR3 in alveolar epithelial cells may be important in pneumocyte repair from injury.

Bioaerosols from a Food Waste Composting Plant Affect Human Airway Epithelial Cell Remodeling Genes

Science.gov (United States)

Chang, Ming-Wei; Lee, Chung-Ru; Hung, Hsueh-Fen; Teng, Kuo-Sheng; Huang, Hsin; Chuang, Chun-Yu

2013-01-01

The composting procedure in food waste plants generates airborne bioaerosols that have the potential to damage human airway epithelial cells. Persistent inflammation and repair responses induce airway remodeling and damage to the respiratory system. This study elucidated the expression changes of airway remodeling genes in human lung mucoepidermoid NCI-H292 cells exposed to bioaerosols from a composting plant. Different types of microorganisms were detectable in the composting plant, using the agar culture method. Real-time polymerase chain reaction was used to quantify the level of Aspergillus fumigatus and the profile of remodeling genes. The real-time PCR results indicated that the amount of A. fumigatus in the composting hall was less than 102 conidia. The endotoxins in the field bioaerosols were determined using a limulus amebocyte lysate test. The endotoxin levels depended on the type of particulate matter (PM), with coarse particles (2.5–10 μm) having higher endotoxin levels than did fine particles (0.5–2.5 μm). After exposure to the conditioned medium of field bioaerosol samples, NCI-H292 cells showed increased pro-inflammatory interleukin (IL)-6 release and activated epidermal growth factor receptor (EGFR), transforming growth factor (TGF)-β1 and cyclin-dependent kinase inhibitor 1 (p21WAF1/CIP1) gene expression, but not of matrix metallopeptidase (MMP)-9. Airborne endotoxin levels were higher inside the composting hall than they were in other areas, and they were associated with PM. This suggested that airborne bioaerosols in the composting plant contained endotoxins and microorganisms besides A. fumigatus that cause the inflammatory cytokine secretion and augment the expression of remodeling genes in NCI-H292 cells. It is thus necessary to monitor potentially hazardous materials from bioaerosols in food composting plants, which could affect the health of workers. PMID:24368426

Bioaerosols from a food waste composting plant affect human airway epithelial cell remodeling genes.

Science.gov (United States)

Chang, Min-Wei; Lee, Chung-Ru; Hung, Hsueh-Fen; Teng, Kuo-Sheng; Huang, Hsin; Chuang, Chun-Yu

2013-12-24

The composting procedure in food waste plants generates airborne bioaerosols that have the potential to damage human airway epithelial cells. Persistent inflammation and repair responses induce airway remodeling and damage to the respiratory system. This study elucidated the expression changes of airway remodeling genes in human lung mucoepidermoid NCI-H292 cells exposed to bioaerosols from a composting plant. Different types of microorganisms were detectable in the composting plant, using the agar culture method. Real-time polymerase chain reaction was used to quantify the level of Aspergillus fumigatus and the profile of remodeling genes. The real-time PCR results indicated that the amount of A. fumigatus in the composting hall was less than 10(2) conidia. The endotoxins in the field bioaerosols were determined using a limulus amebocyte lysate test. The endotoxin levels depended on the type of particulate matter (PM), with coarse particles (2.5-10 μm) having higher endotoxin levels than did fine particles (0.5-2.5 μm). After exposure to the conditioned medium of field bioaerosol samples, NCI-H292 cells showed increased pro-inflammatory interleukin (IL)-6 release and activated epidermal growth factor receptor (EGFR), transforming growth factor (TGF)-β1 and cyclin-dependent kinase inhibitor 1 (p21 WAF1/CIP1) gene expression, but not of matrix metallopeptidase (MMP)-9. Airborne endotoxin levels were higher inside the composting hall than they were in other areas, and they were associated with PM. This suggested that airborne bioaerosols in the composting plant contained endotoxins and microorganisms besides A. fumigatus that cause the inflammatory cytokine secretion and augment the expression of remodeling genes in NCI-H292 cells. It is thus necessary to monitor potentially hazardous materials from bioaerosols in food composting plants, which could affect the health of workers.

Haemophilus influenzae genome evolution during persistence in the human airways in chronic obstructive pulmonary disease.

Science.gov (United States)

Pettigrew, Melinda M; Ahearn, Christian P; Gent, Janneane F; Kong, Yong; Gallo, Mary C; Munro, James B; D'Mello, Adonis; Sethi, Sanjay; Tettelin, Hervé; Murphy, Timothy F

2018-04-03

Nontypeable Haemophilus influenzae (NTHi) exclusively colonize and infect humans and are critical to the pathogenesis of chronic obstructive pulmonary disease (COPD). In vitro and animal models do not accurately capture the complex environments encountered by NTHi during human infection. We conducted whole-genome sequencing of 269 longitudinally collected cleared and persistent NTHi from a 15-y prospective study of adults with COPD. Genome sequences were used to elucidate the phylogeny of NTHi isolates, identify genomic changes that occur with persistence in the human airways, and evaluate the effect of selective pressure on 12 candidate vaccine antigens. Strains persisted in individuals with COPD for as long as 1,422 d. Slipped-strand mispairing, mediated by changes in simple sequence repeats in multiple genes during persistence, regulates expression of critical virulence functions, including adherence, nutrient uptake, and modification of surface molecules, and is a major mechanism for survival in the hostile environment of the human airways. A subset of strains underwent a large 400-kb inversion during persistence. NTHi does not undergo significant gene gain or loss during persistence, in contrast to other persistent respiratory tract pathogens. Amino acid sequence changes occurred in 8 of 12 candidate vaccine antigens during persistence, an observation with important implications for vaccine development. These results indicate that NTHi alters its genome during persistence by regulation of critical virulence functions primarily by slipped-strand mispairing, advancing our understanding of how a bacterial pathogen that plays a critical role in COPD adapts to survival in the human respiratory tract.

Randomized crossover comparison of the laryngeal mask airway classic with i-gel laryngeal mask airway in the management of difficult airway in post burn neck contracture patients

Directory of Open Access Journals (Sweden)

Jeevan Singh

2012-01-01

Full Text Available Purpose: The objective of the study was to compare the performance of i-gel supraglottic airway with cLMA in difficult airway management in post burn neck contracture patients and assess the feasibility of i-gel use for emergency airway management in difficult airway situation with reduced neck movement and limited mouth opening. Methods: Prospective, crossover, randomized controlled trial was performed amongst forty eight post burn neck contracture patients with limited mouth opening and neck movement. i-gel and cLMA were placed in random order in each patient. Primary outcome was overall success rate. Other measurements were time to successful ventilation, airway leak pressure, fiberoptic glottic view, visualization of square wave pattern. Results: Success rate for the i-gel was 91.7% versus 79.2% for the cLMA. i-gel required shorter insertion time (19.3 seconds vs. 23.5 seconds, P=0.000. Airway leak pressure difference was statistically significant (i-gel 21.2 cm H20; cLMA 16.9 cm H 2 0; P=0.00. Fiberoptic view through the i-gel showed there were less epiglottic downfolding and better fiberoptic view of the glottis than cLMA. Overall agreement in insertion outcome for i-gel was 22/24 (91.7% successes and 2/24(8.3% failure and for cLMA, 19/24 (79.16% successes and 5/24 (16.7% failure in the first attempt. Conclusion: The i-gel is cheap, effective airway device which is easier to insert and has better clinical performance in the difficult airway management of the airway in the post burn contracture of the neck. Our study shows that i-gel is feasible for emergency airway management in difficult airway situation with reduced neck movement and limited mouth opening in post burn neck.

Effect of Perinatal secondhand tobacco smoke exposure on in vivo and intrinsic airway structure/function in non-human primates

International Nuclear Information System (INIS)

Joad, Jesse P.; Kott, Kayleen S.; Bric, John M.; Peake, Janice L.; Pinkerton, Kent E.

2009-01-01

Infants exposed to second hand smoke (SHS) experience more problems with wheezing. This study was designed to determine if perinatal SHS exposure increases intrinsic and/or in vivo airway responsiveness to methacholine and whether potential structural/cellular alterations in the airway might explain the change in responsiveness. Pregnant rhesus monkeys were exposed to filtered air (FA) or SHS (1 mg/m 3 total suspended particulates) for 6 h/day, 5 days/week starting at 50 days gestational age. The mother/infant pairs continued the SHS exposures postnatally. At 3 months of age each infant: 1) had in vivo lung function measurements in response to inhaled methacholine, or 2) the right accessory lobe filled with agarose, precision-cut to 600 μm slices, and bathed in increasing concentrations of methacholine. The lumenal area of the central airway was determined using videomicrometry followed by fixation and histology with morphometry. In vivo tests showed that perinatal SHS increases baseline respiratory rate and decreases responsiveness to methacholine. Perinatal SHS did not alter intrinsic airway responsiveness in the bronchi. However in respiratory bronchioles, SHS exposure increased airway responsiveness at lower methacholine concentrations but decreased it at higher concentrations. Perinatal SHS did not change eosinophil profiles, epithelial volume, smooth muscle volume, or mucin volume. However it did increase the number of alveolar attachments in bronchi and respiratory bronchioles. In general, as mucin increased, airway responsiveness decreased. We conclude that perinatal SHS exposure alters in vivo and intrinsic airway responsiveness, and alveolar attachments

Local deposition patterns of inhaled radon progeny in human bronchial airways

International Nuclear Information System (INIS)

Heistracher, T.; Hofmann, W.; Balashazy, I.

1996-01-01

The local distribution of radon decay products deposited within bronchial bifurcations, particularly the formation of hot spots, may be more relevant for the determination of cellular doses in bronchial tissue than the commonly computed deposition efficiency, which is conceptually equivalent to the assumption of a uniform nuclide distribution. It is well known that the initial states of lung cancer in humans preferably occur in upper airways close to the cardinal location. In this study we use a recently developed geometric approach of a physiologically realistic bifurcation to demonstrate the site sensitivity of radon progeny deposition for two particle sizes, which are representative of the unattached and attached fraction of radon progeny

Three-dimensional segmentation and skeletonization to build an airway tree data structure for small animals

International Nuclear Information System (INIS)

Chaturvedi, Ashutosh; Lee, Zhenghong

2005-01-01

Quantitative analysis of intrathoracic airway tree geometry is important for objective evaluation of bronchial tree structure and function. Currently, there is more human data than small animal data on airway morphometry. In this study, we implemented a semi-automatic approach to quantitatively describe airway tree geometry by using high-resolution computed tomography (CT) images to build a tree data structure for small animals such as rats and mice. Silicon lung casts of the excised lungs from a canine and a mouse were used for micro-CT imaging of the airway trees. The programming language IDL was used to implement a 3D region-growing threshold algorithm for segmenting out the airway lung volume from the CT data. Subsequently, a fully-parallel 3D thinning algorithm was implemented in order to complete the skeletonization of the segmented airways. A tree data structure was then created and saved by parsing through the skeletonized volume using the Python programming language. Pertinent information such as the length of all airway segments was stored in the data structure. This approach was shown to be accurate and efficient for up to six generations for the canine lung cast and ten generations for the mouse lung cast

Human Lung Mast Cell Products Regulate Airway Smooth Muscle CXCL10 Levels.

Science.gov (United States)

Alkhouri, H; Cha, V; Tong, K; Moir, L M; Armour, C L; Hughes, J M

2014-01-01

In asthma, the airway smooth muscle (ASM) produces CXCL10 which may attract CXCR3(+) mast/T cells to it. Our aim was to investigate the effects of mast cell products on ASM cell CXCL10 production. ASM cells from people with and without asthma were stimulated with IL-1 β , TNF- α , and/or IFN γ and treated with histamine (1-100  μ M) ± chlorpheniramine (H1R antagonist; 1  μ M) or ranitidine (H2R antagonist; 50  μ M) or tryptase (1 nM) ± leupeptin (serine protease inhibitor; 50  μ M), heat-inactivated tryptase, or vehicle for 4 h or 24 h. Human lung mast cells (MC) were isolated and activated with IgE/anti-IgE and supernatants were collected after 2 h or 24 h. The supernatants were added to ASM cells for 48 h and ASM cell CXCL10 production detected using ELISA (protein) and real-time PCR (mRNA). Histamine reduced IL-1 β /TNF- α -induced CXCL10 protein, but not mRNA, levels independent of H1 and H2 receptor activation, whereas tryptase and MC 2 h supernatants reduced all cytokine-induced CXCL10. Tryptase also reduced CXCL10 levels in a cell-free system. Leupeptin inhibited the effects of tryptase and MC 2 h supernatants. MC 24 h supernatants contained TNF- α and amplified IFN γ -induced ASM cell CXCL10 production. This is the first evidence that MC can regulate ASM cell CXCL10 production and its degradation. Thus MC may regulate airway myositis in asthma.

Endogenous laminin is required for human airway smooth muscle cell maturation

Directory of Open Access Journals (Sweden)

Tran Thai

2006-09-01

Full Text Available Abstract Background Airway smooth muscle (ASM contraction underlies acute bronchospasm in asthma. ASM cells can switch between a synthetic-proliferative phenotype and a contractile phenotype. While the effects of extracellular matrix (ECM components on modulation of ASM cells to a synthetic phenotype have been reported, the role of ECM components on maturation of ASM cells to a contractile phenotype in adult lung is unclear. As both changes in ECM components and accumulation of contractile ASM are features of airway wall remodelling in asthma, we examined the role of the ECM protein, laminin, in the maturation of contractile phenotype in human ASM cells. Methods Human ASM cells were made senescence-resistant by stable expression of human telomerase reverse transcriptase. Maturation to a contractile phenotype was induced by 7-day serum deprivation, as assessed by immunoblotting for desmin and calponin. The role of laminin on ASM maturation was investigated by comparing the effects of exogenous laminin coated on culture plates, and of soluble laminin peptide competitors. Endogenous expression of laminin chains during ASM maturation was also measured. Results Myocyte binding to endogenously expressed laminin was required for ASM phenotype maturation, as laminin competing peptides (YIGSR or GRGDSP significantly reduced desmin and calponin protein accumulation that otherwise occurs with prolonged serum deprivation. Coating of plastic cell culture dishes with different purified laminin preparations was not sufficient to further promote accumulation of desmin or calponin during 7-day serum deprivation. Expression of α2, β1 and γ1 laminin chains by ASM cells was specifically up-regulated during myocyte maturation, suggesting a key role for laminin-2 in the development of the contractile phenotype. Conclusion While earlier reports suggest exogenously applied laminin slows the spontaneous modulation of ASM to a synthetic phenotype, we show for the

Airway distensibility in Chronic Obstructive Airway Disease

DEFF Research Database (Denmark)

Winkler Wille, Mathilde Marie; Pedersen, Jesper Holst; Dirksen, Asger

2013-01-01

Rationale – Chronic Obstructive Pulmonary Disease (COPD) is a combination of chronic bronchitis and emphysema, which both may lead to airway obstruction. Under normal circumstances, airway dimensions vary as a function of inspiration level. We aim to study the influence of COPD and emphysema......-20% (mild), 20%-30% (moderate) or >30% (severe). Spirometry was performed annually and participants were divided into severity groups according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Data were analysed in a mixed effects regression model with log(airway lumen diameter...... and emphysema, respectively. Conclusions – Airway distensibility decreases significantly with increasing severity of both GOLD status and emphysema, indicating that in COPD the dynamic change in airway calibre during respiration is compromised. Chronic bronchitis and emphysema appear to be interacting...

The actin regulator zyxin reinforces airway smooth muscle and accumulates in airways of fatal asthmatics.

Directory of Open Access Journals (Sweden)

Sonia R Rosner

Full Text Available Bronchospasm induced in non-asthmatic human subjects can be easily reversed by a deep inspiration (DI whereas bronchospasm that occurs spontaneously in asthmatic subjects cannot. This physiological effect of a DI has been attributed to the manner in which a DI causes airway smooth muscle (ASM cells to stretch, but underlying molecular mechanisms-and their failure in asthma-remain obscure. Using cells and tissues from wild type and zyxin-/- mice we report responses to a transient stretch of physiologic magnitude and duration. At the level of the cytoskeleton, zyxin facilitated repair at sites of stress fiber fragmentation. At the level of the isolated ASM cell, zyxin facilitated recovery of contractile force. Finally, at the level of the small airway embedded with a precision cut lung slice, zyxin slowed airway dilation. Thus, at each level zyxin stabilized ASM structure and contractile properties at current muscle length. Furthermore, when we examined tissue samples from humans who died as the result of an asthma attack, we found increased accumulation of zyxin compared with non-asthmatics and asthmatics who died of other causes. Together, these data suggest a biophysical role for zyxin in fatal asthma.

Difficult airway response team: a novel quality improvement program for managing hospital-wide airway emergencies.

Science.gov (United States)

Mark, Lynette J; Herzer, Kurt R; Cover, Renee; Pandian, Vinciya; Bhatti, Nasir I; Berkow, Lauren C; Haut, Elliott R; Hillel, Alexander T; Miller, Christina R; Feller-Kopman, David J; Schiavi, Adam J; Xie, Yanjun J; Lim, Christine; Holzmueller, Christine; Ahmad, Mueen; Thomas, Pradeep; Flint, Paul W; Mirski, Marek A

2015-07-01

Difficult airway cases can quickly become emergencies, increasing the risk of life-threatening complications or death. Emergency airway management outside the operating room is particularly challenging. We developed a quality improvement program-the Difficult Airway Response Team (DART)-to improve emergency airway management outside the operating room. DART was implemented by a team of anesthesiologists, otolaryngologists, trauma surgeons, emergency medicine physicians, and risk managers in 2005 at The Johns Hopkins Hospital in Baltimore, Maryland. The DART program had 3 core components: operations, safety, and education. The operations component focused on developing a multidisciplinary difficult airway response team, standardizing the emergency response process, and deploying difficult airway equipment carts throughout the hospital. The safety component focused on real-time monitoring of DART activations and learning from past DART events to continuously improve system-level performance. This objective entailed monitoring the paging system, reporting difficult airway events and DART activations to a Web-based registry, and using in situ simulations to identify and mitigate defects in the emergency airway management process. The educational component included development of a multispecialty difficult airway curriculum encompassing case-based lectures, simulation, and team building/communication to ensure consistency of care. Educational materials were also developed for non-DART staff and patients to inform them about the needs of patients with difficult airways and ensure continuity of care with other providers after discharge. Between July 2008 and June 2013, DART managed 360 adult difficult airway events comprising 8% of all code activations. Predisposing patient factors included body mass index >40, history of head and neck tumor, prior difficult intubation, cervical spine injury, airway edema, airway bleeding, and previous or current tracheostomy. Twenty

Effect of acute metabolic acid/base shifts on the human airway calibre.

NARCIS (Netherlands)

Brijker, F.; Elshout, F.J.J. van den; Heijdra, Y.F.; Bosch, F.H.; Folgering, H.T.M.

2001-01-01

Acute metabolic alkalosis (NaHCO(3)), acidosis (NH(4)Cl), and placebo (NaCl) were induced in 15 healthy volunteers (12 females, median age 34 (range 24-56) years) in a double blind, placebo controlled study to evaluate the presence of the effects on airway calibre. Acid-base shifts were determined

Increased airway reactivity in a neonatal mouse model of Continuous Positive Airway Pressure (CPAP)

OpenAIRE

Mayer, Catherine A.; Martin, Richard J.; MacFarlane, Peter M.

2015-01-01

Background Continuous positive airway pressure (CPAP) is a primary form of respiratory support used in the intensive care of preterm infants, but its long-term effects on airway (AW) function are unknown. Methods We developed a neonatal mouse model of CPAP treatment to determine whether it modifies later AW reactivity. Un-anesthetized spontaneously breathing mice were fitted with a mask to deliver CPAP (6cmH2O, 3hrs/day) for 7 consecutive days starting at postnatal day 1. Airway reactivity to...

Optimal surface segmentation using flow lines to quantify airway abnormalities in chronic obstructive pulmonary disease

DEFF Research Database (Denmark)

Petersen, Jens; Nielsen, Mads; Lo, Pechin Chien Pau

2014-01-01

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.......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...

Autoradiographic visualization of muscarinic receptor subtypes in human and guinea pig lung

International Nuclear Information System (INIS)

Mak, J.C.; Barnes, P.J.

1990-01-01

Muscarinic receptor subtypes have been localized in human and guinea pig lung sections by an autoradiographic technique, using [3H](-)quinuclidinyl benzilate [( 3H]QNB) and selective muscarinic antagonists. [3H]QNB was incubated with tissue sections for 90 min at 25 degrees C, and nonspecific binding was determined by incubating adjacent serial sections in the presence of 1 microM atropine. Binding to lung sections had the characterization expected for muscarinic receptors. Autoradiography revealed that muscarinic receptors were widely distributed in human lung, with dense labeling over submucosal glands and airway ganglia, and moderate labeling over nerves in intrapulmonary bronchi and of airway smooth muscle of large and small airways. In addition, alveolar walls were uniformly labeled. In guinea pig lung, labeling of airway smooth muscle was similar, but in contrast to human airways, epithelium was labeled but alveolar walls were not. The muscarinic receptors of human airway smooth muscle from large to small airways were entirely of the M3-subtype, whereas in guinea pig airway smooth muscle, the majority were the M3-subtype with a very small population of the M2-subtype present. In human bronchial submucosal glands, M1- and M3-subtypes appeared to coexist in the proportions of 36 and 64%, respectively. In human alveolar walls the muscarinic receptors were entirely of the M1-subtype, which is absent from the guinea pig lung. No M2-receptors were demonstrated in human lung. The localization of M1-receptors was confirmed by direct labeling with [3H]pirenzepine. With the exception of the alveolar walls in human lung, the localization of muscarinic receptor subtypes on structures in the lung is consistent with known functional studies

Research of transport and deposition of aerosol in human airway replica

Directory of Open Access Journals (Sweden)

Mravec Filip

2012-04-01

Full Text Available Growing concern about knowledge of aerosol transport in human lungs is caused by great potential of use of inhaled pharmaceuticals. Second substantial motive for the research is an effort to minimize adverse effects of particular matter emitted by traffic and industry on human health. We created model geometry of human lungs to 7th generation of branching. This model geometry was used for fabrication of two physical models. The first one is made from thin walled transparent silicone and it allows a measurement of velocity and size of aerosol particles by Phase Doppler Anemometry (PDA. The second one is fabricated by stereolithographic method and it is designed for aerosol deposition measurements. We provided a series of measurements of aerosol transport in the transparent model and we ascertained remarkable phenomena linked with lung flow. The results are presented in brief. To gather how this phenomena affects aerosol deposition in human lungs we used the second model and we developed a technique for deposition fraction and deposition efficiency assessment. The results confirmed that non-symmetric and complicated shape of human airways essentially affects transport and deposition of aerosol. The research will now focus on deeper insight in aerosol deposition.

Cigarette smoke modulates expression of human rhinovirus-induced airway epithelial host defense genes.

Directory of Open Access Journals (Sweden)

David Proud

Full Text Available Human rhinovirus (HRV infections trigger acute exacerbations of chronic obstructive pulmonary disease (COPD and asthma. The human airway epithelial cell is the primary site of HRV infection and responds to infection with altered expression of multiple genes, the products of which could regulate the outcome to infection. Cigarette smoking aggravates asthma symptoms, and is also the predominant risk factor for the development and progression of COPD. We, therefore, examined whether cigarette smoke extract (CSE modulates viral responses by altering HRV-induced epithelial gene expression. Primary cultures of human bronchial epithelial cells were exposed to medium alone, CSE alone, purified HRV-16 alone or to HRV-16+ CSE. After 24 h, supernatants were collected and total cellular RNA was isolated. Gene array analysis was performed to examine mRNA expression. Additional experiments, using real-time RT-PCR, ELISA and/or western blotting, validated altered expression of selected gene products. CSE and HRV-16 each induced groups of genes that were largely independent of each other. When compared to gene expression in response to CSE alone, cells treated with HRV+CSE showed no obvious differences in CSE-induced gene expression. By contrast, compared to gene induction in response to HRV-16 alone, cells exposed to HRV+CSE showed marked suppression of expression of a number of HRV-induced genes associated with various functions, including antiviral defenses, inflammation, viral signaling and airway remodeling. These changes were not associated with altered expression of type I or type III interferons. Thus, CSE alters epithelial responses to HRV infection in a manner that may negatively impact antiviral and host defense outcomes.

Phenotype and Functional Features of Human Telomerase Reverse Transcriptase Immortalized Human Airway Smooth Muscle Cells from Asthmatic and Non-Asthmatic Donors.

Science.gov (United States)

Burgess, J K; Ketheson, A; Faiz, A; Limbert Rempel, K A; Oliver, B G; Ward, J P T; Halayko, A J

2018-01-16

Asthma is an obstructive respiratory disease characterised by chronic inflammation with airway hyperresponsiveness. In asthmatic airways, there is an increase in airway smooth muscle (ASM) cell bulk, which differs from non-asthmatic ASM in characteristics. This study aimed to assess the usefulness of hTERT immortalisation of human ASM cells as a research tool. Specifically we compared proliferative capacity, inflammatory mediator release and extracellular matrix (ECM) production in hTERT immortalised and parent primary ASM cells from asthmatic and non-asthmatic donors. Our studies revealed no significant differences in proliferation, IL-6 and eotaxin-1 production, or CTGF synthesis between donor-matched parent and hTERT immortalised ASM cell lines. However, deposition of ECM proteins fibronectin and fibulin-1 was significantly lower in immortalised ASM cells compared to corresponding primary cells. Notably, previously reported differences in proliferation and inflammatory mediator release between asthmatic and non-asthmatic ASM cells were retained, but excessive ECM protein deposition in asthmatic ASM cells was lost in hTERT ASM cells. This study shows that hTERT immortalised ASM cells mirror primary ASM cells in proliferation and inflammatory profile characteristics. Moreover, we demonstrate both strengths and weaknesses of this immortalised cell model as a representation of primary ASM cells for future asthma pathophysiological research.

Integrated care pathways for airway diseases (AIRWAYS-ICPs)

NARCIS (Netherlands)

Bousquet, J.; Addis, A.; Adcock, I.; Agache, I.; Agusti, A.; Alonso, A.; Annesi-Maesano, I.; Anto, J. M.; Bachert, C.; Baena-Cagnani, C. E.; Bai, C.; Baigenzhin, A.; Barbara, C.; Barnes, P. J.; Bateman, E. D.; Beck, L.; Bedbrook, A.; Bel, E. H.; Benezet, O.; Bennoor, K. S.; Benson, M.; Bernabeu-Wittel, M.; Bewick, M.; Bindslev-Jensen, C.; Blain, H.; Blasi, F.; Bonini, M.; Bonini, S.; Boulet, L. P.; Bourdin, A.; Bourret, R.; Bousquet, P. J.; Brightling, C. E.; Briggs, A.; Brozek, J.; Buhl, R.; Bush, A.; Caimmi, D.; Calderon, M.; Calverley, P.; Camargos, P. A.; Camuzat, T.; Canonica, G. W.; Carlsen, K. H.; Casale, T. B.; Cazzola, M.; Cepeda Sarabia, A. M.; Cesario, A.; Chen, Y. Z.; Chkhartishvili, E.; Chavannes, N. H.; Chiron, R.; Chuchalin, A.; Chung, K. F.; Cox, L.; Crooks, G.; Crooks, M. G.; Cruz, A. A.; Custovic, A.; Dahl, R.; Dahlen, S. E.; de Blay, F.; Dedeu, T.; Deleanu, D.; Demoly, P.; Devillier, P.; Didier, A.; Dinh-Xuan, A. T.; Djukanovic, R.; Dokic, D.; Douagui, H.; Dubakiene, R.; Eglin, S.; Elliot, F.; Emuzyte, R.; Fabbri, L.; Fink Wagner, A.; Fletcher, M.; Fokkens, W. J.; Fonseca, J.; Franco, A.; Frith, P.; Furber, A.; Gaga, M.; Garcés, J.; Garcia-Aymerich, J.; Gamkrelidze, A.; Gonzales-Diaz, S.; Gouzi, F.; Guzmán, M. A.; Haahtela, T.; Harrison, D.; Hayot, M.; Heaney, L. G.; Heinrich, J.; Hellings, P. W.; Hooper, J.; Humbert, M.; Hyland, M.; Iaccarino, G.; Jakovenko, D.; Jardim, J. R.; Jeandel, C.; Jenkins, C.; Johnston, S. L.; Jonquet, O.; Joos, G.; Jung, K. S.; Kalayci, O.; Karunanithi, S.; Keil, T.; Khaltaev, N.; Kolek, V.; Kowalski, M. L.; Kull, I.; Kuna, P.; Kvedariene, V.; Le, L. T.; Lodrup Carlsen, K. C.; Louis, R.; MacNee, W.; Mair, A.; Majer, I.; Manning, P.; de Manuel Keenoy, E.; Masjedi, M. R.; Melen, E.; Melo-Gomes, E.; Menzies-Gow, A.; Mercier, G.; Mercier, J.; Michel, J. P.; Miculinic, N.; Mihaltan, F.; Milenkovic, B.; Molimard, M.; Momas, I.; Montilla-Santana, A.; Morais-Almeida, M.; Morgan, M.; N'Diaye, M.; Nafti, S.; Nekam, K.; Neou, A.; Nicod, L.; O'Hehir, R.; Ohta, K.; Paggiaro, P.; Palkonen, S.; Palmer, S.; Papadopoulos, N. G.; Papi, A.; Passalacqua, G.; Pavord, I.; Pigearias, B.; Plavec, D.; Postma, D. S.; Price, D.; Rabe, K. F.; Radier Pontal, F.; Redon, J.; Rennard, S.; Roberts, J.; Robine, J. M.; Roca, J.; Roche, N.; Rodenas, F.; Roggeri, A.; Rolland, C.; Rosado-Pinto, J.; Ryan, D.; Samolinski, B.; Sanchez-Borges, M.; Schünemann, H. J.; Sheikh, A.; Shields, M.; Siafakas, N.; Sibille, Y.; Similowski, T.; Small, I.; Sola-Morales, O.; Sooronbaev, T.; Stelmach, R.; Sterk, P. J.; Stiris, T.; Sud, P.; Tellier, V.; To, T.; Todo-Bom, A.; Triggiani, M.; Valenta, R.; Valero, A. L.; Valiulis, A.; Valovirta, E.; van Ganse, E.; Vandenplas, O.; Vasankari, T.; Vestbo, J.; Vezzani, G.; Viegi, G.; Visier, L.; Vogelmeier, C.; Vontetsianos, T.; Wagstaff, R.; Wahn, U.; Wallaert, B.; Whalley, B.; Wickman, M.; Williams, D. M.; Wilson, N.; Yawn, B. P.; Yiallouros, P. K.; Yorgancioglu, A.; Yusuf, O. M.; Zar, H. J.; Zhong, N.; Zidarn, M.; Zuberbier, T.

2014-01-01

The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will

Integrated care pathways for airway diseases (AIRWAYS-ICPs)

NARCIS (Netherlands)

Bousquet, J.; Addis, A.; Adcock, I.; Agache, I.; Agusti, A.; Alonso, A.; Annesi-Maesano, I.; Anto, J. M.; Bachert, C.; Baena-Cagnani, C. E.; Bai, C.; Baigenzhin, A.; Barbara, C.; Barnes, P. J.; Bateman, E. D.; Beck, L.; Bedbrook, A.; Bel, E. H.; Benezet, O.; Bennoor, K. S.; Benson, M.; Bernabeu-Wittel, M.; Bewick, M.; Bindslev-Jensen, C.; Blain, H.; Blasi, F.; Bonini, M.; Bonini, S.; Boulet, L. P.; Bourdin, A.; Bourret, R.; Bousquet, P. J.; Brightling, C. E.; Briggs, A.; Brozek, J.; Buh, R.; Bush, A.; Caimmi, D.; Calderon, M.; Calverley, P.; Camargos, P. A.; Camuzat, T.; Canonica, G. W.; Carlsen, K. H.; Casale, T. B.; Cazzola, M.; Sarabia, A. M. Cepeda; Cesario, A.; Chen, Y. Z.; Chkhartishvili, E.; Chavannes, N. H.; Chiron, R.; Chuchalin, A.; Chung, K. F.; Cox, L.; Crooks, G.; Crooks, M. G.; Cruz, A. A.; Custovic, A.; Dahl, R.; Dahlen, S. E.; De Blay, F.; Dedeu, T.; Deleanu, D.; Demoly, P.; Devillier, P.; Didier, A.; Dinh-Xuan, A. T.; Djukanovic, R.; Dokic, D.; Douagui, H.; Dubakiene, R.; Eglin, S.; Elliot, F.; Emuzyte, R.; Fabbri, L.; Wagner, A. Fink; Fletcher, M.; Fokkens, W. J.; Fonseca, J.; Franco, A.; Frith, P.; Furber, A.; Gaga, M.; Garces, J.; Garcia-Aymerich, J.; Gamkrelidze, A.; Gonzales-Diaz, S.; Gouzi, F.; Guzman, M. A.; Haahtela, T.; Harrison, D.; Hayot, M.; Heaney, L. G.; Heinrich, J.; Hellings, P. W.; Hooper, J.; Humbert, M.; Hyland, M.; Iaccarino, G.; Jakovenko, D.; Jardim, J. R.; Jeandel, C.; Jenkins, C.; Johnston, S. L.; Jonquet, O.; Joos, G.; Jung, K. S.; Kalayci, O.; Karunanithi, S.; Keil, T.; Khaltaev, N.; Kolek, V.; Kowalski, M. L.; Kull, I.; Kuna, P.; Kvedariene, V.; Le, L. T.; Carlsen, K. C. Lodrup; Louis, R.; MacNee, W.; Mair, A.; Majer, I.; Manning, P.; Keenoy, E. de Manuel; Masjedi, M. R.; Meten, E.; Melo-Gomes, E.; Menzies-Gow, A.; Mercier, G.; Mercier, J.; Michel, J. P.; Miculinic, N.; Mihaltan, F.; Milenkovic, B.; Molimard, M.; Mamas, I.; Montilla-Santana, A.; Morais-Almeida, M.; Morgan, M.; N'Diaye, M.; Nafti, S.; Nekam, K.; Neou, A.; Nicod, L.; O'Hehir, R.; Ohta, K.; Paggiaro, P.; Palkonen, S.; Palmer, S.; Papadopoulos, N. G.; Papi, A.; Passalacqua, G.; Pavord, I.; Pigearias, B.; Plavec, D.; Postma, D. S.; Price, D.; Rabe, K. F.; Pontal, F. Radier; Redon, J.; Rennard, S.; Roberts, J.; Robine, J. M.; Roca, J.; Roche, N.; Rodenas, F.; Roggeri, A.; Rolland, C.; Rosado-Pinto, J.; Ryan, D.; Samolinski, B.; Sanchez-Borges, M.; Schunemann, H. J.; Sheikh, A.; Shields, M.; Siafakas, N.; Sibille, Y.; Similowski, T.; Small, I.; Sola-Morales, O.; Sooronbaev, T.; Stelmach, R.; Sterk, P. J.; Stiris, T.; Sud, P.; Tellier, V.; To, T.; Todo-Bom, A.; Triggiani, M.; Valenta, R.; Valero, A. L.; Valiulis, A.; Valovirta, E.; Van Ganse, E.; Vandenplas, O.; Vasankari, T.; Vestbo, J.; Vezzani, G.; Viegi, G.; Visier, L.; Vogelmeier, C.; Vontetsianos, T.; Wagstaff, R.; Wahn, U.; Wallaert, B.; Whalley, B.; Wickman, M.; Williams, D. M.; Wilson, N.; Yawn, B. P.; Yiallouros, P. K.; Yorgancioglu, A.; Yusuf, O. M.; Zar, H. J.; Zhong, N.; Zidarn, M.; Zuberbier, T.

The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will

The contribution of airway smooth muscle to airway narrowing and airway hyperresponsiveness in disease.

Science.gov (United States)

Martin, J G; Duguet, A; Eidelman, D H

2000-08-01

Airway hyperresponsiveness (AHR), the exaggerated response to constrictor agonists in asthmatic subjects, is incompletely understood. Changes in either the quantity or properties of airway smooth muscle (ASM) are possible explanations for AHR. Morphometric analyses demonstrate structural changes in asthmatic airways, including subepithelial fibrosis, gland hyperplasia/hypertrophy, neovascularization and an increase in ASM mass. Mathematical modelling of airway narrowing suggests that, of all the changes in structure, the increase in ASM mass is the most probable cause of AHR. An increase in ASM mass in the large airways is more closely associated with a greater likelihood of dying from asthma than increases in ASM mass in other locations within the airway tree. ASM contraction is opposed by the elastic recoil of the lungs and airways, which appears to limit the degree of bronchoconstriction in vivo. The cyclical nature of tidal breathing applies stresses to the airway wall that enhance the bronchodilating influence of the lung tissues on the contracting ASM, in all probability by disrupting cross-bridges. However, the increase in ASM mass in asthma may overcome the limitation resulting from the impedances to ASM shortening imposed by the lung parenchyma and airway wall tissues. Additionally, ASM with the capacity to shorten rapidly may achieve shorter lengths and cause a greater degree of bronchoconstriction when stimulated to contract than slower ASM. Changes in ASM properties are induced by the process of sensitization and allergen-exposure such as enhancement of phospholipase C activity and inositol phosphate turnover, and increases in myosin light chain kinase activity. Whether changes in ASM mass or biochemical/biomechanical properties form the basis for asthma remains to be determined.

Aldose reductase regulates acrolein-induced cytotoxicity in human small airway epithelial cells.

Science.gov (United States)

Yadav, Umesh C S; Ramana, K V; Srivastava, Satish K

2013-12-01

Aldose reductase (AR), a glucose-metabolizing enzyme, reduces lipid aldehydes and their glutathione conjugates with more than 1000-fold efficiency (Km aldehydes 5-30 µM) relative to glucose. Acrolein, a major endogenous lipid peroxidation product as well as a component of environmental pollutants and cigarette smoke, is known to be involved in various pathologies including atherosclerosis, airway inflammation, COPD, and age-related disorders, but the mechanism of acrolein-induced cytotoxicity is not clearly understood. We have investigated the role of AR in acrolein-induced cytotoxicity in primary human small airway epithelial cells (SAECs). Exposure of SAECs to varying concentrations of acrolein caused cell death in a concentration- and time-dependent manner. AR inhibition by fidarestat prevented the low-dose (5-10 µM) but not the high-dose (>10 µM) acrolein-induced SAEC death. AR inhibition protected SAECs from low-dose (5 µM) acrolein-induced cellular reactive oxygen species (ROS). Inhibition of acrolein-induced apoptosis by fidarestat was confirmed by decreased condensation of nuclear chromatin, DNA fragmentation, comet tail moment, and annexin V fluorescence. Further, fidarestat inhibited acrolein-induced translocation of the proapoptotic proteins Bax and Bad from the cytosol to the mitochondria and that of Bcl2 and BclXL from the mitochondria to the cytosol. Acrolein-induced cytochrome c release from mitochondria was also prevented by AR inhibition. The mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinases 1 and 2, stress-activated protein kinase/c-Jun NH2-terminal kinase, and p38MAPK, and c-Jun were transiently activated in airway epithelial cells by acrolein in a concentration- and time-dependent fashion, which was significantly prevented by AR inhibition. These results suggest that AR inhibitors could prevent acrolein-induced cytotoxicity in the lung epithelial cells. Copyright © 2013 Elsevier Inc. All rights

Aldose reductase regulates acrolein-induced cytotoxicity in human small airway epithelial cells

Science.gov (United States)

Yadav, Umesh CS; Ramana, KV; Srivastava, SK

2013-01-01

Aldose reductase (AR), a glucose metabolizing enzyme, reduces lipid aldehydes and their glutathione conjugates with more than 1000-fold efficiency (Km aldehydes 5-30μM) than glucose. Acrolein, a major endogenous lipid peroxidation product as well as component of environmental pollutant and cigarette smoke, is known to be involved in various pathologies including atherosclerosis, airway inflammation, COPD, and age-related disorders but the mechanism of acrolein-induced cytotoxicity is not clearly understood. We have investigated the role of AR in acrolein-induced cytotoxicity in primary human small airway epithelial cells SAECs. Exposure of SAECs to varying concentrations of acrolein caused cell-death in a concentration- and time-dependent manner. AR inhibition by fidarestat prevented the low (5 to 10 μM) but not high (>10 μM) concentrations of acrolein-induced SAECs cell death. AR inhibition protected SAECs from low dose (5 μM) acrolein-induced cellular reactive oxygen species (ROS). Inhibition of acrolein-induced apoptosis by fidarestat was confirmed by decreased condensation of nuclear chromatin, DNA fragmentation, comet tail-moment, and annexin-V fluorescence. Further, fidarestat inhibited acrolein-induced translocation of pro-apoptotic proteins Bax and Bad from cytosol to the mitochondria, and that of Bcl2 and BclXL from mitochondria to cytosol. Acrolein-induced cytochrome c release from mitochondria was also prevented by AR inhibition. The mitogen-activated protein kinases (MAPK) such as extracellular signal-regulated kinases 1 and 2 (ERK1/2), stress-activated protein kinases/c-jun NH2-terminal kinases (SAPK/JNK) and p38MAPK, and c-jun were transiently activated in airway epithelial cells by acrolein in a concentration and time-dependent fashion, which were significantly prevented by AR inhibition. These results suggest that AR inhibitors could prevent acrolein-induced cytotoxicity in the lung epithelial cells. PMID:23770200

Histone deacetylase inhibitors up-regulate LL-37 expression independent of toll-like receptor mediated signalling in airway epithelial cells

OpenAIRE

Liu, Q.; Liu, J.; Roschmann, K.I.L.; Egmond, D. van; Golebski, K.; Fokkens, W.J.; Wang, D.; Drunen, C.M. van

2013-01-01

HDAC inhibitors have been proposed as anticancer agents. However, their roles in innate genes expression remain not well known. Cathelicidin LL-37 is one of the few human bactericidal peptides, but the regulation of histone acetylation on LL-37 expression in airway epithelium remains largely unknown. Therefore, we investigated the effects of two non-selective HDACi, trichostatin A (TSA) and sodium butyrate (SB), on the expression of the cathelicidin LL-37 in human airway epithelial cells. LL3...

Motile cilia of human airway epithelia contain hedgehog signaling components that mediate noncanonical hedgehog signaling.

Science.gov (United States)

Mao, Suifang; Shah, Alok S; Moninger, Thomas O; Ostedgaard, Lynda S; Lu, Lin; Tang, Xiao Xiao; Thornell, Ian M; Reznikov, Leah R; Ernst, Sarah E; Karp, Philip H; Tan, Ping; Keshavjee, Shaf; Abou Alaiwa, Mahmoud H; Welsh, Michael J

2018-02-06

Differentiated airway epithelia produce sonic hedgehog (SHH), which is found in the thin layer of liquid covering the airway surface. Although previous studies showed that vertebrate HH signaling requires primary cilia, as airway epithelia mature, the cells lose primary cilia and produce hundreds of motile cilia. Thus, whether airway epithelia have apical receptors for SHH has remained unknown. We discovered that motile cilia on airway epithelial cells have HH signaling proteins, including patched and smoothened. These cilia also have proteins affecting cAMP-dependent signaling, including Gα i and adenylyl cyclase 5/6. Apical SHH decreases intracellular levels of cAMP, which reduces ciliary beat frequency and pH in airway surface liquid. These results suggest that apical SHH may mediate noncanonical HH signaling through motile cilia to dampen respiratory defenses at the contact point between the environment and the lung, perhaps counterbalancing processes that stimulate airway defenses. Copyright © 2018 the Author(s). Published by PNAS.

Trefoil factor-2 reverses airway remodeling changes in allergic airways disease.

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Royce, Simon G; Lim, Clarice; Muljadi, Ruth C; Samuel, Chrishan S; Ververis, Katherine; Karagiannis, Tom C; Giraud, Andrew S; Tang, Mimi L K

2013-01-01

Trefoil factor 2 (TFF2) is a small peptide with an important role in mucosal repair. TFF2 is up-regulated in asthma, suggesting a role in asthma pathogenesis. Given its known biological role in promoting epithelial repair, TFF2 might be expected to exert a protective function in limiting the progression of airway remodeling in asthma. The contribution of TFF2 to airway remodeling in asthma was investigated by examining the expression of TFF2 in the airway and lung, and evaluating the effects of recombinant TFF2 treatment on established airway remodeling in a murine model of chronic allergic airways disease (AAD). BALB/c mice were sensitized and challenged with ovalbumin (OVA) or saline for 9 weeks, whereas mice with established OVA-induced AAD were treated with TFF2 or vehicle control (intranasally for 14 d). Effects on airway remodeling, airway inflammation, and airway hyperresponsiveness were then assessed, whereas TFF2 expression was determined by immunohistochemistry. TFF2 expression was significantly increased in the airways of mice with AAD, compared with expression levels in control mice. TFF2 treatment resulted in reduced epithelial thickening, subepithelial collagen deposition, goblet-cell metaplasia, bronchial epithelium apoptosis, and airway hyperresponsiveness (all P < 0.05, versus vehicle control), but TFF2 treatment did not influence airway inflammation. The increased expression of endogenous TFF2 in response to chronic allergic inflammation is insufficient to prevent the progression of airway inflammation and remodeling in a murine model of chronic AAD. However, exogenous TFF2 treatment is effective in reversing aspects of established airway remodeling. TFF2 has potential as a novel treatment for airway remodeling in asthma.

Pharyngeal airway changes following mandibular setback surgery

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Babu Ramesh

2005-01-01

Full Text Available Treatment of dentofacial deformities with jaw osteotomies has an effect on airway anatomy and therefore mandibular setback surgery has the potential to diminish airway size. The purpose of this study was to evaluate the effect of mandibular setback surgery on airway size. 8 consecutive patients were examined prospectively. All patients underwent mandibular setback surgery. Cephalometric analysis was performed preoperatively and 3 months post operatively with particular attention to pharyngeal airway changes. Pharyngeal airway size decreased considerably in all, patients thus predisposing to development of obstructive sleep apnea. Therefore, large anteroposterior discrepancies should be corrected by combined maxillary and mandibular osteotomies.

Deposition of inhaled radionuclides in bronchial airways: Implications for extrapolation modeling

International Nuclear Information System (INIS)

Balashazy, I.; Hofmann, W.; Heistracher, T.

1996-01-01

The laboratory rat has frequently been used as a human surrogate to estimate potential health effects following the inhalation of radioactive aerosol particles. Interspecies differences in biological response are commonly related to interspecies differences in particle deposition efficiencies. In addition, the documented site selectivity of bronchial carcinomas suggests that localized particle deposition patterns within bronchial airway bifurcations may have important implications for inhalation risk assessments. Interspecies differences in particle deposition patterns may be related primarily to differences in airway morphometries. Thus the validity of extrapolating rat deposition data to human inhalation conditions depends on their morphometric similarities and differences. It is well known that there are significant structural differences between the human - rather symmetric - and the rat - monopodial - airway systems. In the present approach, we focus on localized deposition patterns and deposition efficiencies in selected asymmetric bronchial airway bifurcations, whose diameters, lengths and branching angles were derived from the stochastic airway models of human and rat lungs (Koblinger and Hofmann, 1985;1988), which are based on the morphometric data of Raabe et al. (1976). The effects of interspecies differences in particle deposition patterns are explored in this study for two asymmetric bifurcation geometries in segmental bronchi and terminal bronchioles of both the human and rat lungs at different particle sizes. In order to examine the effect of flow rate on particle deposition in the human lung, we selected two different minute volumes, i.e., 10 and 60 1 min -1 , which are representative of low and heavy physical activity breathing conditions. In the case of the rat we used a minute volume of 0.234 1 min -1 (Hofmann et al., 1993)

Curcumin regulates airway epithelial cell cytokine responses to the pollutant cadmium

International Nuclear Information System (INIS)

Rennolds, Jessica; Malireddy, Smitha; Hassan, Fatemat; Tridandapani, Susheela; Parinandi, Narasimham; Boyaka, Prosper N.; Cormet-Boyaka, Estelle

2012-01-01

Highlights: ► Cadmium induces secretion of IL-6 and IL-8 by two distinct pathways. ► Cadmium increases NAPDH oxidase activity leading to Erk activation and IL-8 secretion. ► Curcumin prevents cadmium-induced secretion of both IL-6 and IL-8 by airway cells. ► Curcumin could be use to suppress lung inflammation due to cadmium inhalation. -- Abstract: Cadmium is a toxic metal present in the environment and its inhalation can lead to pulmonary disease such as lung cancer and chronic obstructive pulmonary disease. These lung diseases are characterized by chronic inflammation. Here we show that exposure of human airway epithelial cells to cadmium promotes a polarized apical secretion of IL-6 and IL-8, two pivotal pro-inflammatory cytokines known to play an important role in pulmonary inflammation. We also determined that two distinct pathways controlled secretion of these proinflammatory cytokines by human airway epithelial cells as cadmium-induced IL-6 secretion occurs via an NF-κB dependent pathway, whereas IL-8 secretion involves the Erk1/2 signaling pathway. Interestingly, the natural antioxidant curcumin could prevent both cadmium-induced IL-6 and IL-8 secretion by human airway epithelial cells. In conclusion, curcumin could be used to prevent airway inflammation due to cadmium inhalation.

Levcromakalim- and isoprenaline-induced relaxation of human isolated airways--role of the epithelium and of K+ channel activation.

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Black, J L; Johnson, P R; McKay, K O; Carey, D; Armour, C L

1994-06-01

In this study we have investigated the mechanism of action of levcromakalim and isoprenaline in human isolated airways with respect to the K+ channels they activate and the possibility that these smooth muscle relaxants activate K+ channels on the airway epithelium. Mechanical removal of the epithelial layer (mean percentage of epithelium present 20 +/- 3%, n = 20 tissues) did not affect the relaxation responses to levcromakalim or isoprenaline, either in terms of maximal relaxation or sensitivity. Whilst having no effect on isoprenaline-induced relaxation, studied from basal tone, the ATP-sensitive K+ channel blocker BRL 31660 (10, 30 and 50 microM) reduced relaxation responses induced (from basal tone) by levcromakalim from 74 +/- 6% (of the maximal response to isoprenaline) to 48 +/- 12% (n = 7), 9 +/- 9% (n = 4) and 0 (n = 4), respectively. Charybdotoxin, a blocker of high conductance Ca(2+)-activated K+ channels, at concentrations of 30 and 100 nM, had no effect on either levcromakalim- or or isoprenaline-induced relaxation responses and yet charybdotoxin was active at KCa channels in outside-out patches of hippocampal granule cells. Moreover, tetraethylammonium (10 mM) inhibited neither isoprenaline- nor levcromakalim-induced relaxation. This study has demonstrated that the relaxation responses elicited in human bronchus to isoprenaline and levcromakalim are likely to be the result of direct effects on the smooth muscle with no contribution from epithelial receptors or K+ channels. The actions of levcromakalim appear to be mediated only via activation of KATP channels. Further, we have made the important observation that, under the experimental conditions of our study, isoprenaline does not activate the KCa channel to produce relaxation in human bronchus.

Critical Airway Team: A Retrospective Study of an Airway Response System in a Pediatric Hospital.

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Sterrett, Emily C; Myer, Charles M; Oehler, Jennifer; Das, Bobby; Kerrey, Benjamin T

2017-12-01

Objective Study the performance of a pediatric critical airway response team. Study Design Case series with chart review. Setting Freestanding academic children's hospital. Subjects and Methods A structured review of the electronic medical record was conducted for all activations of the critical airway team. Characteristics of the activations and patients are reported using descriptive statistics. Activation of the critical airway team occurred 196 times in 46 months (March 2012 to December 2015); complete data were available for 162 activations (83%). For 49 activations (30%), patients had diagnoses associated with difficult intubation; 45 (28%) had a history of difficult laryngoscopy. Results Activation occurred at least 4 times per month on average (vs 3 per month for hospital-wide codes). The most common reasons for team activation were anticipated difficult intubation (45%) or failed intubation attempt (20%). For 79% of activations, the team performed an airway procedure, most commonly direct laryngoscopy and tracheal intubation. Bronchoscopy was performed in 47% of activations. Surgical airway rescue was attempted 4 times. Cardiopulmonary resuscitation occurred in 41 activations (25%). Twenty-nine patients died during or following team activation (18%), including 10 deaths associated with the critical airway event. Conclusion Critical airway team activation occurred at least once per week on average. Direct laryngoscopy, tracheal intubation, and bronchoscopic procedures were performed frequently; surgical airway rescue was rare. Most patients had existing risk factors for difficult intubation. Given our rate of serious morbidity and mortality, primary prevention of critical airway events will be a focus of future efforts.

Test of the Starling resistor model in the human upper airway during sleep.

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Wellman, Andrew; Genta, Pedro R; Owens, Robert L; Edwards, Bradley A; Sands, Scott A; Loring, Stephen H; White, David P; Jackson, Andrew C; Pedersen, Ole F; Butler, James P

2014-12-15

The human pharyngeal airway during sleep is conventionally modeled as a Starling resistor. However, inspiratory flow often decreases with increasing effort (negative effort dependence, NED) rather than remaining fixed as predicted by the Starling resistor model. In this study, we tested a major prediction of the Starling resistor model--that the resistance of the airway upstream from the site of collapse remains fixed during flow limitation. During flow limitation in 24 patients with sleep apnea, resistance at several points along the pharyngeal airway was measured using a pressure catheter with multiple sensors. Resistance between the nose and the site of collapse (the upstream segment) was measured before and after the onset of flow limitation to determine whether the upstream dimensions remained fixed (as predicted by the Starling resistor model) or narrowed (a violation of the Starling resistor model). The upstream resistance from early to mid inspiration increased considerably during flow limitation (by 35 ± 41 cmH2O · liter(-1) · s(-1), P < 0.001). However, there was a wide range of variability between patients, and the increase in upstream resistance was strongly correlated with the amount of NED (r = 0.75, P < 0.001). Therefore, patients with little NED exhibited little upstream narrowing (consistent with the Starling model), and patients with large NED exhibited large upstream narrowing (inconsistent with the Starling model). These findings support the idea that there is not a single model of pharyngeal collapse, but rather that different mechanisms may dominate in different patients. These differences could potentially be exploited for treatment selection. Copyright © 2014 the American Physiological Society.

Chlamydophila spp. infection in horses with recurrent airway obstruction: similarities to human chronic obstructive disease

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Hotzel Helmut

2008-01-01

Full Text Available Abstract Background Recurrent airway obstruction (RAO in horses is a naturally occurring dust-induced disease mainly characterized by bronchiolitis which shows histological and pathophysiological similarities to human chronic obstructive pulmonary disease (COPD. In human COPD previous investigations indicated an association with Chlamydophila psittaci infection. The present study was designed (1 to clarify a possible role of this infectious agent in RAO and (2 to investigate the suitability of this equine disorder as a model for human COPD. Methods Clinico-pathological parameters of a total of 45 horses (25 horses with clinical signs of RAO and 20 clinically healthy controls were compared to histological findings in lung tissue samples and infection by Chlamydiaceae using light microscopy, immunohistochemistry, and PCR. Results Horses with clinical signs of RAO vs. controls revealed more inflammatory changes in histology (p = 0.01, and a higher detection rate of Chlamydia psittaci antigens in all cells (p OmpA sequencing identified Chlamydophila psittaci (n = 9 and Chlamydophila abortus (n = 13 in both groups with no significant differences. Within the group of clinically healthy horses subgroups with no changes (n = 15 and slight inflammation of the small airways (n = 5 were identified. Also in the group of animals with RAO subgroups with slight (n = 16 and severe (n = 9 bronchiolitis could be formed. These four subgroups can be separated in parts by the number of cells positive for Chlamydia psittaci antigens. Conclusion Chlamydophila psittaci or abortus were present in the lung of both clinically healthy horses and those with RAO. Immunohistochemistry revealed acute chlamydial infections with inflammation in RAO horses, whereas in clinically healthy animals mostly persistent chlamydial infection and no inflammatory reactions were seen. Stable dust as the known fundamental abiotic factor in RAO is comparable to smoking in human disease. These

Mechanical interactions between adjacent airways in the lung.

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Ma, Baoshun; Bates, Jason H T

2014-03-15

The forces of mechanical interdependence between the airways and the parenchyma in the lung are powerful modulators of airways responsiveness. Little is known, however, about the extent to which adjacent airways affect each other's ability to narrow due to distortional forces generated within the intervening parenchyma. We developed a two-dimensional computational model of two airways embedded in parenchyma. The parenchyma itself was modeled in three ways: 1) as a network of hexagonally arranged springs, 2) as a network of triangularly arranged springs, and 3) as an elastic continuum. In all cases, we determined how the narrowing of one airway was affected when the other airway was relaxed vs. when it narrowed to the same extent as the first airway. For the continuum and triangular network models, interactions between airways were negligible unless the airways lay within about two relaxed diameters of each other, but even at this distance the interactions were small. By contrast, the hexagonal spring network model predicted that airway-airway interactions mediated by the parenchyma can be substantial for any degree of airway separation at intermediate values of airway contraction forces. Evidence to date suggests that the parenchyma may be better represented by the continuum model, which suggests that the parenchyma does not mediate significant interactions between narrowing airways.

Lectin enhancement of the lipofection efficiency in human lung carcinoma cells.

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Yanagihara, K; Cheng, P W

1999-10-18

Poor transfection efficiency of human lung carcinoma cells by lipofection begs further development of more efficient gene delivery strategies. The purpose of this study was to determine whether lectins can improve the lipofection efficiency in lung carcinoma cells. A549, Calu3, and H292 cells grown to 90% confluence were transfected for 18 h with a plasmid DNA containing a beta-galactosidase reporter gene (pCMVlacZ) using lipofectin plus a lectin as the vector. Ten different lectins, which exhibit a wide range of carbohydrate-binding specificities, were examined for their abilities to enhance the efficiency of lipofection. The transfected cells were assessed for transfection efficiency by beta-galactosidase activity (units/microg protein) and % blue cells following X-Gal stain. Lipofectin supplemented with Griffonia simplicifolia-I (GS-I) yields largest enhancement of the lipofection efficiency in A549 and Calu3 cells (5.3- and 28-fold, respectively). Maackia amurensis gives the largest enhancement (6.5-fold) of lipofection efficiency in H292 cells. The transfection efficiency correlates with the amounts of DNA delivered to the nucleus. Binding of FITC-labeled GS-I and the enhancement of the lipofection efficiency by GS-I were inhibited by alpha-methyl-D-galactopyranoside, indicating an alpha-galactoside-mediated gene transfer to lung carcinoma cells. We conclude that lectin-facilitated lipofection is an efficient gene delivery strategy. Employment of cell type-specific lectins may allow for efficient cell type-specific gene targeting.

Stenting of major airway constriction

International Nuclear Information System (INIS)

Wu Xiaomei

2002-01-01

Objective: To investigate the correlated issues in the stenting treatment of major airway constriction. Methods: Nineteen cases of major airway stenting procedure were studied retrospectively. The clinical choice of stents of different advantages or deficiencies were discussed. The importance of intravenous anesthesia supporting, life-parameters monitoring during the procedures and the prevention of complications were analysed. Results: Under intravenous and local anesthesia, 19 Wallstents had been successively placed and relieved 19 cases of major airway constrictions due to malignant or benign diseases (15 of tumors, 3 of tuberculosis, 1 of tracheomalacia). Intravenous anesthesia and life-parameters monitoring had made the procedures more safe and precise. Conclusions: Major airway stenting is an reliable method for relieving tracheobronchial stenosis; and intravenous anesthesia supporting and life-parameters monitoring guarantee the satisfactions of procedures

Reliability and accuracy of three imaging software packages used for 3D analysis of the upper airway on cone beam computed tomography images.

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Chen, Hui; van Eijnatten, Maureen; Wolff, Jan; de Lange, Jan; van der Stelt, Paul F; Lobbezoo, Frank; Aarab, Ghizlane

2017-08-01

The aim of this study was to assess the reliability and accuracy of three different imaging software packages for three-dimensional analysis of the upper airway using CBCT images. To assess the reliability of the software packages, 15 NewTom 5G ® (QR Systems, Verona, Italy) CBCT data sets were randomly and retrospectively selected. Two observers measured the volume, minimum cross-sectional area and the length of the upper airway using Amira ® (Visage Imaging Inc., Carlsbad, CA), 3Diagnosys ® (3diemme, Cantu, Italy) and OnDemand3D ® (CyberMed, Seoul, Republic of Korea) software packages. The intra- and inter-observer reliability of the upper airway measurements were determined using intraclass correlation coefficients and Bland & Altman agreement tests. To assess the accuracy of the software packages, one NewTom 5G ® CBCT data set was used to print a three-dimensional anthropomorphic phantom with known dimensions to be used as the "gold standard". This phantom was subsequently scanned using a NewTom 5G ® scanner. Based on the CBCT data set of the phantom, one observer measured the volume, minimum cross-sectional area, and length of the upper airway using Amira ® , 3Diagnosys ® , and OnDemand3D ® , and compared these measurements with the gold standard. The intra- and inter-observer reliability of the measurements of the upper airway using the different software packages were excellent (intraclass correlation coefficient ≥0.75). There was excellent agreement between all three software packages in volume, minimum cross-sectional area and length measurements. All software packages underestimated the upper airway volume by -8.8% to -12.3%, the minimum cross-sectional area by -6.2% to -14.6%, and the length by -1.6% to -2.9%. All three software packages offered reliable volume, minimum cross-sectional area and length measurements of the upper airway. The length measurements of the upper airway were the most accurate results in all software packages. All

Phenotype and Functional Features of Human Telomerase Reverse Transcriptase Immortalized Human Airway Smooth Muscle Cells from Asthmatic and Non-Asthmatic Donors

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Burgess, J. K.; Ketheson, A.; Faiz, A.; Rempel, K. A. Limbert; Oliver, B. G.; Ward, J. P. T.; Halayko, A. J.

2018-01-01

Asthma is an obstructive respiratory disease characterised by chronic inflammation with airway hyperresponsiveness. In asthmatic airways, there is an increase in airway smooth muscle (ASM) cell bulk, which differs from non-asthmatic ASM in characteristics. This study aimed to assess the usefulness

Curcumin regulates airway epithelial cell cytokine responses to the pollutant cadmium

Energy Technology Data Exchange (ETDEWEB)

Rennolds, Jessica; Malireddy, Smitha; Hassan, Fatemat; Tridandapani, Susheela; Parinandi, Narasimham [Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, The Ohio State University, Columbus, OH 43210 (United States); Boyaka, Prosper N. [Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210 (United States); Cormet-Boyaka, Estelle, E-mail: Estelle.boyaka@osumc.edu [Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, The Ohio State University, Columbus, OH 43210 (United States)

2012-01-06

Highlights: Black-Right-Pointing-Pointer Cadmium induces secretion of IL-6 and IL-8 by two distinct pathways. Black-Right-Pointing-Pointer Cadmium increases NAPDH oxidase activity leading to Erk activation and IL-8 secretion. Black-Right-Pointing-Pointer Curcumin prevents cadmium-induced secretion of both IL-6 and IL-8 by airway cells. Black-Right-Pointing-Pointer Curcumin could be use to suppress lung inflammation due to cadmium inhalation. -- Abstract: Cadmium is a toxic metal present in the environment and its inhalation can lead to pulmonary disease such as lung cancer and chronic obstructive pulmonary disease. These lung diseases are characterized by chronic inflammation. Here we show that exposure of human airway epithelial cells to cadmium promotes a polarized apical secretion of IL-6 and IL-8, two pivotal pro-inflammatory cytokines known to play an important role in pulmonary inflammation. We also determined that two distinct pathways controlled secretion of these proinflammatory cytokines by human airway epithelial cells as cadmium-induced IL-6 secretion occurs via an NF-{kappa}B dependent pathway, whereas IL-8 secretion involves the Erk1/2 signaling pathway. Interestingly, the natural antioxidant curcumin could prevent both cadmium-induced IL-6 and IL-8 secretion by human airway epithelial cells. In conclusion, curcumin could be used to prevent airway inflammation due to cadmium inhalation.

Increased proinflammatory responses from asthmatic human airway smooth muscle cells in response to rhinovirus infection

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King Nicholas JC

2006-05-01

Full Text Available Abstract Background Exacerbations of asthma are associated with viral respiratory tract infections, of which rhinoviruses (RV are the predominant virus type. Airway smooth muscle is important in asthma pathogenesis, however little is known about the potential interaction of RV and human airway smooth muscle cells (HASM. We hypothesised that rhinovirus induction of inflammatory cytokine release from airway smooth muscle is augmented and differentially regulated in asthmatic compared to normal HASM cells. Methods HASM cells, isolated from either asthmatic or non-asthmatic subjects, were infected with rhinovirus. Cytokine production was assayed by ELISA, ICAM-1 cell surface expression was assessed by FACS, and the transcription regulation of IL-6 was measured by luciferase activity. Results RV-induced IL-6 release was significantly greater in HASM cells derived from asthmatic subjects compared to non-asthmatic subjects. This response was RV specific, as 5% serum- induced IL-6 release was not different in the two cell types. Whilst serum stimulated IL-8 production in cells from both subject groups, RV induced IL-8 production in only asthmatic derived HASM cells. The transcriptional induction of IL-6 was differentially regulated via C/EBP in the asthmatic and NF-κB + AP-1 in the non-asthmatic HASM cells. Conclusion This study demonstrates augmentation and differential transcriptional regulation of RV specific innate immune response in HASM cells derived from asthmatic and non-asthmatics, and may give valuable insight into the mechanisms of RV-induced asthma exacerbations.

Cigarette Smoke and Estrogen Signaling in Human Airway Smooth Muscle

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Venkatachalem Sathish

2015-06-01

Full Text Available Aims: Cigarette smoke (CS in active smokers and second-hand smoke exposure exacerbate respiratory disorders such as asthma and chronic bronchitis. While women are known to experience a more asthmatic response to CS than emphysema in men, there is limited information on the mechanisms of CS-induced airway dysfunction. We hypothesize that CS interferes with a normal (protective bronchodilatory role of estrogens, thus worsening airway contractility. Methods: We tested effects of cigarette smoke extract (CSE on 17β-estradiol (E2 signaling in enzymatically-dissociated bronchial airway smooth muscle (ASM obtained from lung samples of non-smoking female patients undergoing thoracic surgery. Results: In fura-2 loaded ASM cells, CSE increased intracellular calcium ([Ca2+]i responses to 10µM histamine. Acute exposure to physiological concentrations of E2 decreased [Ca2+]i responses. However, in 24h exposed CSE cells, although expression of estrogen receptors was increased, the effect of E2 on [Ca2+]i was blunted. Acute E2 exposure also decreased store-operated Ca2+ entry and inhibited stromal interaction molecule 1 (STIM1 phosphorylation: effects blunted by CSE. Acute exposure to E2 increased cAMP, but less so in 24h CSE-exposed cells. 24h CSE exposure increased S-nitrosylation of ERα. Furthermore, 24h CSE-exposed bronchial rings showed increased bronchoconstrictor agonist responses that were not reduced as effectively by E2 compared to non-CSE controls. Conclusion: These data suggest that CS induces dysregulation of estrogen signaling in ASM, which could contribute to increased airway contractility in women exposed to CS.

Airway structure and function in Eisenmenger's syndrome.

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McKay, K O; Johnson, P R; Black, J L; Glanville, A R; Armour, C L

1998-10-01

The responsiveness of airways from patients with Eisenmenger's syndrome (n = 5) was compared with that in airways from organ donors (n = 10). Enhanced contractile responses to cholinergic stimulation were found in airways from patients with Eisenmenger's syndrome. The maximal responses to acetylcholine, carbachol, and parasympathetic nerve stimulation in airway tissue from these patients were 221%, 139%, and 152%, respectively, of the maximal responses obtained in donor tissue. Further, relaxation responses to isoproterenol and levocromakalim were absent (n = 2) or markedly impaired (n = 3) in airways from patients with Eisenmenger's syndrome. This attenuated relaxation response was nonspecific in that it was also absent after vasoactive intestinal peptide, sodium nitroprusside, papaverine, and electrical field application. These observations can most likely be explained by a decrease in intrinsic smooth muscle tone, as precontraction of airways revealed relaxation responses that were equivalent to those obtained in donor tissues. Morphometric analysis of tissues used for the functional studies revealed no differences in the airway dimensions (internal perimeter) or airway wall components (e.g., smooth muscle, cartilage) or total area to explain these observations. Although the mechanism for this observed decrease in intrinsic airway smooth muscle tone is not certain, it may be due to alteration in the substructure of the airway wall or, alternatively, may result from the continued release of depressant factors in the vicinity of the smooth muscle which permanently alters smooth muscle responsiveness.

Protective effects of valproic acid against airway hyperresponsiveness and airway remodeling in a mouse model of allergic airways disease.

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Royce, Simon G; Dang, William; Ververis, Katherine; De Sampayo, Nishika; El-Osta, Assam; Tang, Mimi L K; Karagiannis, Tom C

2011-12-01

Airway remodeling and airway hyperresponsiveness are major aspects of asthma pathology that are not targeted optimally by existing anti-inflammatory drugs. Histone deacetylase inhibitors have a wide range of effects that may potentially abrogate aspects of remodeling. One such histone deacetylase inhibitor is valproic acid (2-propylvaleric acid). Valproic acid is used clinically as an anti-epileptic drug and is a potent inhibitor of class I histone deacetylases but also inhibits class II histone deacetylases. We used valproic acid as a molecular model of histone deacetylase inhibition in vivo in chronic allergic airways disease mice with airway remodeling and airway hyperresponsiveness. Wild-type Balb/c mice with allergic airways disease were treated with valproic acid or vehicle control. Airway inflammation was assessed by bronchoalveolar lavage fluid cell counts and examination of lung tissue sections. Remodeling was assessed by morphometric analysis of histochemically stained slides and lung function was assessed by invasive plethysmography measurement of airway resistance. Valproic acid treatment did not affect inflammation parameters; however, valproic acid treatment resulted in reduced epithelial thickness as compared to vehicle treated mice (p < 0.01), reduced subepithelial collagen deposition (p < 0.05) and attenuated airway hyperresponsiveness (p < 0.05 and p < 0.01 for the two highest doses of methacholine, respectively). These findings show that treatment with valproic acid can reduce structural airway remodeling changes and hyperresponsiveness, providing further evidence for the potential use of histone deacetylase inhibitors for the treatment of asthma.

Airway stents

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Keyes, Colleen

2018-01-01

Stents and tubes to maintain the patency of the airways are commonly used for malignant obstruction and are occasionally employed in benign disease. Malignant airway obstruction usually results from direct involvement of bronchogenic carcinoma, or by extension of carcinomas occurring in the esophagus or the thyroid. External compression from lymph nodes or metastatic disease from other organs can also cause central airway obstruction. Most malignant airway lesions are surgically inoperable due to advanced disease stage and require multimodality palliation, including stent placement. As with any other medical device, stents have significantly evolved over the last 50 years and deserve an in-depth understanding of their true capabilities and complications. Not every silicone stent is created equal and the same holds for metallic stents. Herein, we present an overview of the topic as well as some of the more practical and controversial issues surrounding airway stents. We also try to dispel the myths surrounding stent removal and their supposed use only in central airways. At the end, we come to the long-held conclusion that stents should not be used as first line treatment of choice, but after ruling out the possibility of curative surgical resection or repair. PMID:29707506

Educating the Educator: Teaching Airway Adjunct Techniques in Athletic Training

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Berry, David C.; Seitz, S. Robert

2011-01-01

The 5th edition of the "Athletic Training Education Competencies" ("Competencies") now requires athletic training educators (ATEs) to introduce into the curriculum various types of airway adjuncts including: (1) oropharyngeal airways (OPA), (2) nasopharyngeal airways (NPA), (3) supraglottic airways (SGA), and (4) suction. The addition of these…

Atopic asthmatic immune phenotypes associated with airway microbiota and airway obstruction.

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Benjamin A Turturice

Full Text Available Differences in asthma severity may be related to inflammation in the airways. The lower airway microbiota has been associated with clinical features such as airway obstruction, symptom control, and response to corticosteroids.To assess the relationship between local airway inflammation, severity of disease, and the lower airway microbiota in atopic asthmatics.A cohort of young adult, atopic asthmatics with intermittent or mild/moderate persistent symptoms (n = 13 were assessed via bronchoscopy, lavage, and spirometry. These individuals were compared to age matched non-asthmatic controls (n = 6 and to themselves after six weeks of treatment with fluticasone propionate (FP. Inflammation of the airways was assessed via a cytokine and chemokine panel. Lower airway microbiota composition was determined by metagenomic shotgun sequencing.Unsupervised clustering of cytokines and chemokines prior to treatment with FP identified two asthmatic phenotypes (AP, termed AP1 and AP2, with distinct bronchoalveolar lavage inflammatory profiles. AP2 was associated with more obstruction, compared to AP1. After treatment with FP reduced MIP-1β and TNF-α and increased IL-2 was observed. A module of highly correlated cytokines that include MIP-1β and TNF-α was identified that negatively correlated with pulmonary function. Independently, IL-2 was positively correlated with pulmonary function. The airway microbiome composition correlated with asthmatic phenotypes. AP2, prior to FP treatment, was enriched with Streptococcus pneumoniae. Unique associations between IL-2 or the cytokine module and the microbiota composition of the airways were observed in asthmatics subjects prior to treatment but not after or in controls.The underlying inflammation in atopic asthma is related to the composition of microbiota and is associated with severity of airway obstruction. Treatment with inhaled corticosteroids was associated with changes in the airway inflammatory response to

Antioxidant airway responses following experimental exposure to wood smoke in man

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Sehlstedt Maria

2010-08-01

Full Text Available Abstract Background Biomass combustion contributes to the production of ambient particulate matter (PM in rural environments as well as urban settings, but relatively little is known about the health effects of these emissions. The aim of this study was therefore to characterize airway responses in humans exposed to wood smoke PM under controlled conditions. Nineteen healthy volunteers were exposed to both wood smoke, at a particulate matter (PM2.5 concentration of 224 ± 22 μg/m3, and filtered air for three hours with intermittent exercise. The wood smoke was generated employing an experimental set-up with an adjustable wood pellet boiler system under incomplete combustion. Symptoms, lung function, and exhaled NO were measured over exposures, with bronchoscopy performed 24 h post-exposure for characterisation of airway inflammatory and antioxidant responses in airway lavages. Results Glutathione (GSH concentrations were enhanced in bronchoalveolar lavage (BAL after wood smoke exposure vs. air (p = 0.025, together with an increase in upper airway symptoms. Neither lung function, exhaled NO nor systemic nor airway inflammatory parameters in BAL and bronchial mucosal biopsies were significantly affected. Conclusions Exposure of healthy subjects to wood smoke, derived from an experimental wood pellet boiler operating under incomplete combustion conditions with PM emissions dominated by organic matter, caused an increase in mucosal symptoms and GSH in the alveolar respiratory tract lining fluids but no acute airway inflammatory responses. We contend that this response reflects a mobilisation of GSH to the air-lung interface, consistent with a protective adaptation to the investigated wood smoke exposure.

Candida spp. airway colonization: A potential risk factor for Acinetobacter baumannii ventilator-associated pneumonia.

Science.gov (United States)

Tan, Xiaojiang; Zhu, Song; Yan, Dongxing; Chen, Weiping; Chen, Ruilan; Zou, Jian; Yan, Jingdong; Zhang, Xiangdong; Farmakiotis, Dimitrios; Mylonakis, Eleftherios

2016-08-01

This retrospective study was conducted to identify potential risk factors for Acinetobacter baumannii (A. baumannii) ventilator-associated pneumonia (VAP) and evaluate the association between Candida spp. airway colonization and A. baumannii VAP. Intensive care unit (ICU) patients who were on mechanical ventilation (MV) for ≥48 hours were divided into the following groups: patients with and without Candida spp. airway colonization; colonized patients receiving antifungal treatment or not; patients with A. baumannii VAP and those without VAP. Logistic regression analysis and propensity score matching were used to identify factors independently associated with A. baumannii VAP. Among 618 eligible patients, 264 (43%) had Candida spp. airway colonization and 114 (18%) developed A. baumannii VAP. Along with MV for ≥7 days (adjusted odds ratio [aOR] 8.9, 95% confidence intervals [95% CI] 4.9-15.8) and presence of a central venous catheter (aOR 3.2, 95% CI 1.1-9), Candida spp. airway colonization (aOR 2.6, 95% CI 1.6-4.3) was identified as an independent risk factor for A. baumannii VAP. Patients with Candida spp. airway colonization were more likely to develop A. baumannii VAP than non-colonized patients (23% vs 15%, P=.01 and 34% vs. 15%, PCandida spp. airway colonization (43%) and A. baumannii VAP (18%) were common in ICU patients who were on mechanical ventilation for at least 48 hours. Candida spp. airway colonization was an independent risk factor for subsequent A. baumannii VAP. © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Incidence of unanticipated difficult airway using an objective airway score versus a standard clinical airway assessment

DEFF Research Database (Denmark)

Nørskov, Anders Kehlet; Rosenstock, Charlotte Valentin; Wetterslev, Jørn

2013-01-01

-specific assessment. Data from patients' pre-operative airway assessment are registered in the Danish Anaesthesia Database. Objective scores for intubation and mask ventilation grade the severity of airway managements. The accuracy of predicting difficult intubation and mask ventilation is measured for each group...... the examination and registration of predictors for difficult mask ventilation with a non-specified clinical airway assessment on prediction of difficult mask ventilation.Method/Design: We cluster-randomized 28 Danish departments of anaesthesia to airway assessment either by the SARI or by usual non...... that registration of the SARI and predictors for difficult mask ventilation are mandatory for the intervention group but invisible to controls....

Airway branching morphogenesis in three dimensional culture

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Gudjonsson Thorarinn

2010-11-01

form branching bronchioalveolar-like structures in 3-D culture. This novel model of human airway morphogenesis can be used to study critical events in human lung development and suggests a supportive role for the endothelium in promoting branching of airway epithelium.

Motorcycle exhaust particles induce airway inflammation and airway hyperresponsiveness in BALB/C mice.

Science.gov (United States)

Lee, Chen-Chen; Liao, Jiunn-Wang; Kang, Jaw-Jou

2004-06-01

A number of large studies have reported that environmental pollutants from fossil fuel combustion can cause deleterious effects to the immune system, resulting in an allergic reaction leading to respiratory tract damage. In this study, we investigated the effect of motorcycle exhaust particles (MEP), a major pollutant in the Taiwan urban area, on airway inflammation and airway hyperresponsiveness in laboratory animals. BALB/c mice were instilled intratracheally (i.t.) with 1.2 mg/kg and 12 mg/kg of MEP, which was collected from two-stroke motorcycle engines. The mice were exposed 3 times i.t. with MEP, and various parameters for airway inflammation and hyperresponsiveness were sequentially analyzed. We found that MEP would induce airway and pulmonary inflammation characterized by infiltration of eosinophils, neutrophils, lymphocytes, and macrophages in bronchoalveolar lavage fluid (BALF) and inflammatory cell infiltration in lung. In addition, MEP treatment enhanced BALF interleukin-4 (IL-4), IL-5, and interferon-gamma (IFN-gamma) cytokine levels and serum IgE production. Bronchial response measured by unrestrained plethysmography with methacholine challenge showed that MEP treatment induced airway hyperresponsiveness (AHR) in BALB/c mice. The chemical components in MEP were further fractionated with organic solvents, and we found that the benzene-extracted fraction exerts a similar biological effect as seen with MEP, including airway inflammation, increased BALF IL-4, serum IgE production, and induction of AHR. In conclusion, we present evidence showing that the filter-trapped particles emitted from the unleaded-gasoline-fueled two-stroke motorcycle engine may induce proinflammatory and proallergic response profiles in the absence of exposure to allergen.

Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin-1c.

Science.gov (United States)

Liu, Gang; Cooley, Marion A; Nair, Prema M; Donovan, Chantal; Hsu, Alan C; Jarnicki, Andrew G; Haw, Tatt Jhong; Hansbro, Nicole G; Ge, Qi; Brown, Alexandra C; Tay, Hock; Foster, Paul S; Wark, Peter A; Horvat, Jay C; Bourke, Jane E; Grainge, Chris L; Argraves, W Scott; Oliver, Brian G; Knight, Darryl A; Burgess, Janette K; Hansbro, Philip M

2017-12-01

Asthma is a chronic inflammatory disease of the airways. It is characterized by allergic airway inflammation, airway remodelling, and airway hyperresponsiveness (AHR). Asthma patients, in particular those with chronic or severe asthma, have airway remodelling that is associated with the accumulation of extracellular matrix (ECM) proteins, such as collagens. Fibulin-1 (Fbln1) is an important ECM protein that stabilizes collagen and other ECM proteins. The level of Fbln1c, one of the four Fbln1 variants, which predominates in both humans and mice, is increased in the serum and airways fluids in asthma but its function is unclear. We show that the level of Fbln1c was increased in the lungs of mice with house dust mite (HDM)-induced chronic allergic airway disease (AAD). Genetic deletion of Fbln1c and therapeutic inhibition of Fbln1c in mice with chronic AAD reduced airway collagen deposition, and protected against AHR. Fbln1c-deficient (Fbln1c -/- ) mice had reduced mucin (MUC) 5 AC levels, but not MUC5B levels, in the airways as compared with wild-type (WT) mice. Fbln1c interacted with fibronectin and periostin that was linked to collagen deposition around the small airways. Fbln1c -/- mice with AAD also had reduced numbers of α-smooth muscle actin-positive cells around the airways and reduced airway contractility as compared with WT mice. After HDM challenge, these mice also had fewer airway inflammatory cells, reduced interleukin (IL)-5, IL-13, IL-33, tumour necrosis factor (TNF) and CXCL1 levels in the lungs, and reduced IL-5, IL-33 and TNF levels in lung-draining lymph nodes. Therapeutic targeting of Fbln1c reduced the numbers of GATA3-positive Th2 cells in the lymph nodes and lungs after chronic HDM challenge. Treatment also reduced the secretion of IL-5 and IL-13 from co-cultured dendritic cells and T cells restimulated with HDM extract. Human epithelial cells cultured with Fbln1c peptide produced more CXCL1 mRNA than medium-treated controls. Our data show

The genes of all seven CYP3A isoenzymes identified in the equine genome are expressed in the airways of horses.

Science.gov (United States)

Tydén, E; Löfgren, M; Hakhverdyan, M; Tjälve, H; Larsson, P

2013-08-01

In the present study, we examined the gene expression of cytochrome P450 3A (CYP3A) isoenzymes in the tracheal and bronchial mucosa and in the lung of equines using TaqMan probes. The results show that all seven CYP3A isoforms identified in the equine genome, that is, CYP3A89, CYP3A93, CYP3A94, CYP3A95, CYP3A96, CYP3A97 and CYP3A129, are expressed in the airways of the investigated horses. Though in previous studies, CYP3A129 was found to be absent in equine intestinal mucosa and liver, this CYP3A isoform is expressed in the airways of horses. The gene expression of the CYP3A isoenzymes varied considerably between the individual horses studied. However, in most of the horses CYP3A89, CYP3A93, CYP3A96, CYP3A97 and CYP3A129 were expressed to a high extent, while CYP3A94 and CYP3A95 were expressed to a low extent in the different parts of the airways. The CYP3A isoenzymes present in the airways may play a role in the metabolic degradation of inhaled xenobiotics. In some instances, the metabolism may, however, result in bioactivation of the xenobiotics and subsequent tissue injury. © 2012 John Wiley & Sons Ltd.

Protective Roles for RGS2 in a Mouse Model of House Dust Mite-Induced Airway Inflammation.

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Tresa George

Full Text Available The GTPase-accelerating protein, regulator of G-protein signalling 2 (RGS2 reduces signalling from G-protein-coupled receptors (GPCRs that signal via Gαq. In humans, RGS2 expression is up-regulated by inhaled corticosteroids (ICSs and long-acting β2-adrenoceptor agonists (LABAs such that synergy is produced in combination. This may contribute to the superior clinical efficacy of ICS/LABA therapy in asthma relative to ICS alone. In a murine model of house dust mite (HDM-induced airways inflammation, three weeks of intranasal HDM (25 μg, 3×/week reduced lung function and induced granulocytic airways inflammation. Compared to wild type animals, Rgs2-/- mice showed airways hyperresponsiveness (increased airways resistance and reduced compliance. While HDM increased pulmonary inflammation observed on hematoxylin and eosin-stained sections, there was no difference between wild type and Rgs2-/- animals. HDM-induced mucus hypersecretion was also unaffected by RGS2 deficiency. However, inflammatory cell counts in the bronchoalveolar lavage fluid of Rgs2-/- animals were significantly increased (57% compared to wild type animals and this correlated with increased granulocyte (neutrophil and eosinophil numbers. Likewise, cytokine and chemokine (IL4, IL17, IL5, LIF, IL6, CSF3, CXCLl, CXCL10 and CXCL11 release was increased by HDM exposure. Compared to wild type, Rgs2-/- animals showed a trend towards increased expression for many cytokines/chemokines, with CCL3, CCL11, CXCL9 and CXCL10 being significantly enhanced. As RGS2 expression was unaffected by HDM exposure, these data indicate that RGS2 exerts tonic bronchoprotection in HDM-induced airways inflammation. Modest anti-inflammatory and anti-remodelling roles for RGS2 are also suggested. If translatable to humans, therapies that maximize RGS2 expression may prove advantageous.

Critical role of constitutive type I interferon response in bronchial epithelial cell to influenza infection.

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Alan C-Y Hsu

Full Text Available Innate antiviral responses in bronchial epithelial cells (BECs provide the first line of defense against respiratory viral infection and the effectiveness of this response is critically dependent on the type I interferons (IFNs. However the importance of the antiviral responses in BECs during influenza infection is not well understood. We profiled the innate immune response to infection with H3N2 and H5N1 virus using Calu-3 cells and primary BECs to model proximal airway cells. The susceptibility of BECs to influenza infection was not solely dependent on the sialic acid-bearing glycoprotein, and antiviral responses that occurred after viral endocytosis was more important in limiting viral replication. The early antiviral response and apoptosis correlated with the ability to limit viral replication. Both viruses reduced RIG-I associated antiviral responses and subsequent induction of IFN-β. However it was found that there was constitutive release of IFN-β by BECs and this was critical in inducing late antiviral signaling via type I IFN receptors, and was crucial in limiting viral infection. This study characterizes anti-influenza virus responses in airway epithelial cells and shows that constitutive IFN-β release plays a more important role in initiating protective late IFN-stimulated responses during human influenza infection in bronchial epithelial cells.

Safety and Efficacy of Thoracic External Beam Radiotherapy After Airway Stenting in Malignant Airway Obstruction

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Rochet, Nathalie, E-mail: nrochet@partners.org [Department of Radiation Oncology, University of Heidelberg, Heidelberg (Germany); Hauswald, Henrik; Schmaus, Martina; Hensley, Frank [Department of Radiation Oncology, University of Heidelberg, Heidelberg (Germany); Huber, Peter [Department of Radiotherapy, German Cancer Research Center, Heidelberg (Germany); Eberhardt, Ralf; Herth, Felix J. [Department of Pulmonology and Respiratory Care Medicine, Thoraxklinik at University of Heidelberg, Heidelberg (Germany); Debus, Juergen; Neuhof, Dirk [Department of Radiation Oncology, University of Heidelberg, Heidelberg (Germany)

2012-05-01

Purpose: We retrospectively evaluated the outcome and toxicity of external beam radiotherapy (EBRT) after airway stents were placed in patients treated for malignant airway obstruction. Methods and Materials: Between 2004 and 2009, we performed airway stenting followed by EBRT in 43 patients for symptomatic primary lung cancer (n = 31) or other thoracic malignancies (n = 12). The median time interval between stent placement and first irradiation was 14 days. A median total dose of 50 Gy was delivered. Sixty-seven percent of the patients had reduced performance status (Karnofsky performance score, {<=}70). Results: EBRT had to be stopped prematurely in 16 patients (37%), at a median total dose of 17 Gy, for various reasons. In this group of patients, the survival was poor, with a median overall survival (OS) of only 21 days. Twenty-seven patients (63%) completed radiotherapy as planned, with a median OS of 8.4 months. Fourteen of 43 patients (33%) developed at least one Common Terminology Criteria for Adverse Event of grade 3 to 5. The most common event was a malignant restenosis of the stent leading to asphyxia (n = 7), followed by fistula formation (n = 4), necrosis (n = 3), mediastinitis with abscess (n = 1), secondary nonmalignant airway stenosis (n = 1), and hemoptysis (n = 1). With the exception of one event, all events were associated with a local progression of the tumor. Conclusions: Although the long-term prognosis for patients with malignant airway obstruction is poor, airway stenting combined with EBRT offers a possible therapeutic option, achieving fast relief of acute respiratory distress with an associated antitumor effect, resulting in a potential survival benefit. However, due to local advanced tumor growth, increased rates of adverse events are to be expected, necessitating careful monitoring.

Safety and Efficacy of Thoracic External Beam Radiotherapy After Airway Stenting in Malignant Airway Obstruction

International Nuclear Information System (INIS)

Rochet, Nathalie; Hauswald, Henrik; Schmaus, Martina; Hensley, Frank; Huber, Peter; Eberhardt, Ralf; Herth, Felix J.; Debus, Juergen; Neuhof, Dirk

2012-01-01

Purpose: We retrospectively evaluated the outcome and toxicity of external beam radiotherapy (EBRT) after airway stents were placed in patients treated for malignant airway obstruction. Methods and Materials: Between 2004 and 2009, we performed airway stenting followed by EBRT in 43 patients for symptomatic primary lung cancer (n = 31) or other thoracic malignancies (n = 12). The median time interval between stent placement and first irradiation was 14 days. A median total dose of 50 Gy was delivered. Sixty-seven percent of the patients had reduced performance status (Karnofsky performance score, ≤70). Results: EBRT had to be stopped prematurely in 16 patients (37%), at a median total dose of 17 Gy, for various reasons. In this group of patients, the survival was poor, with a median overall survival (OS) of only 21 days. Twenty-seven patients (63%) completed radiotherapy as planned, with a median OS of 8.4 months. Fourteen of 43 patients (33%) developed at least one Common Terminology Criteria for Adverse Event of grade 3 to 5. The most common event was a malignant restenosis of the stent leading to asphyxia (n = 7), followed by fistula formation (n = 4), necrosis (n = 3), mediastinitis with abscess (n = 1), secondary nonmalignant airway stenosis (n = 1), and hemoptysis (n = 1). With the exception of one event, all events were associated with a local progression of the tumor. Conclusions: Although the long-term prognosis for patients with malignant airway obstruction is poor, airway stenting combined with EBRT offers a possible therapeutic option, achieving fast relief of acute respiratory distress with an associated antitumor effect, resulting in a potential survival benefit. However, due to local advanced tumor growth, increased rates of adverse events are to be expected, necessitating careful monitoring.

Culturing of respiratory viruses in well-differentiated pseudostratified human airway epithelium as a tool to detect unknown viruses

Science.gov (United States)

Jazaeri Farsani, Seyed Mohammad; Deijs, Martin; Dijkman, Ronald; Molenkamp, Richard; Jeeninga, Rienk E; Ieven, Margareta; Goossens, Herman; van der Hoek, Lia

2015-01-01

Background Currently, virus discovery is mainly based on molecular techniques. Here, we propose a method that relies on virus culturing combined with state-of-the-art sequencing techniques. The most natural ex vivo culture system was used to enable replication of respiratory viruses. Method Three respiratory clinical samples were tested on well-differentiated pseudostratified tracheobronchial human airway epithelial (HAE) cultures grown at an air–liquid interface, which resemble the airway epithelium. Cells were stained with convalescent serum of the patients to identify infected cells and apical washes were analyzed by VIDISCA-454, a next-generation sequencing virus discovery technique. Results Infected cells were observed for all three samples. Sequencing subsequently indicated that the cells were infected by either human coronavirus OC43, influenzavirus B, or influenzavirus A. The sequence reads covered a large part of the genome (52%, 82%, and 57%, respectively). Conclusion We present here a new method for virus discovery that requires a virus culture on primary cells and an antibody detection. The virus in the harvest can be used to characterize the viral genome sequence and cell tropism, but also provides progeny virus to initiate experiments to fulfill the Koch's postulates. PMID:25482367

Effect of airway acidosis and alkalosis on airway vascular smooth muscle responsiveness to albuterol.

Science.gov (United States)

Cancado, Jose E; Mendes, Eliana S; Arana, Johana; Horvath, Gabor; Monzon, Maria E; Salathe, Matthias; Wanner, Adam

2015-04-02

In vitro and animal experiments have shown that the transport and signaling of β2-adrenergic agonists are pH-sensitive. Inhaled albuterol, a hydrophilic β2-adrenergic agonist, is widely used for the treatment of obstructive airway diseases. Acute exacerbations of obstructive airway diseases can be associated with changes in ventilation leading to either respiratory acidosis or alkalosis thereby affecting albuterol responsiveness in the airway. The purpose of this study was to determine if airway pH has an effect on albuterol-induced vasodilation in the airway. Ten healthy volunteers performed the following respiratory maneuvers: quiet breathing, hypocapnic hyperventilation, hypercapnic hyperventilation, and eucapnic hyperventilation (to dissociate the effect of pH from the effect of ventilation). During these breathing maneuvers, exhaled breath condensate (EBC) pH and airway blood flow response to inhaled albuterol (ΔQ̇aw) were assessed. Mean ± SE EBC pH (units) and ΔQ̇aw (μl.min(-1).mL(-1)) were 6.4 ± 0.1 and 16.8 ± 1.9 during quiet breathing, 6.3 ± 0.1 and 14.5 ± 2.4 during eucapnic hyperventilation, 6.6 ± 0.2 and -0.2 ± 1.8 during hypocapnic hyperventilation (p = 0.02 and <0.01 vs. quiet breathing), and 5.9 ± 0.1 and 2.0 ± 1.5 during hypercapnic hyperventilation (p = 0.02 and <0.02 vs quiet breathing). Albuterol responsiveness in the airway as assessed by ΔQ̇aw is pH sensitive. The breathing maneuver associated with decreased and increased EBC pH both resulted in a decreased responsiveness independent of the level of ventilation. These findings suggest an attenuated response to hydrophilic β2-adrenergic agonists during airway disease exacerbations associated with changes in pH. Registered at clinicaltrials.gov: NCT01216748 .

Radioiodine plus recombinant human thyrotropin do not cause acute airway compression and are effective in reducing multinodular goiter

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Albino, C.C., E-mail: ccalbino@uol.com.b [Instituto de Diabetes e Endocrinologia de Maringa, PR (Brazil); Graf, H.; Paz-Filho, G. [Universidade Federal do Parana (UFPR), Curitiba, PR (Brazil). Hospital das Clinicas. Servico de Endocrinologia e Metabologia; Diehl, L.A. [Universidade Estadual de Londrina (UEL), PR (Brazil); Olandoski, M.; Sabbag, A. [Pontificia Univ. Catolica do Parana (PUCPR), Curitiba, PR (Brazil). Nucleo de Bioestatistica; Buchpiguel, C. [Universidade de Sao Paulo (USP), SP (Brazil). Dept. de Radiologia

2006-03-15

Recombinant human thyrotropin (rhTSH) reduces the activity of radioiodine required to treat multinodular goiter (MNG), but acute airway compression can be a life-threatening complication. In this prospective, randomized, double-blind, placebo-controlled study, we assessed the efficacy and safety (including airway compression) of different doses of rhTSH associated with a fixed activity of {sup 131}I for treating MNG. Euthyroid patients with MNG (69.3 +- 62.0 mL, 20 females, 2 males, 64 +- 7 years) received 0.1 mg (group I, N = 8) or 0.01 mg (group II, N = 6) rhTSH or placebo (group III, N = 8), 24 h before 1.11 GBq {sup 131}I. Radioactive iodine uptake was determined at baseline and 24 h after rhTSH and thyroid volume (TV, baseline and 6 and 12 months after treatment) and tracheal cross-sectional area (TCA, baseline and 2, 7, 180, and 360 days after rhTSH) were determined by magnetic resonance; antithyroid antibodies and thyroid hormones were determined at frequent intervals. After 6 months, TV decreased significantly in groups I (28.5 +- 17.6%) and II (21.6 +- 17.8%), but not in group III (2.7 +- 15.3%). After 12 months, TV decreased significantly in groups I (36.7 +- 18.1%) and II (37.4 +- 27.1%), but not in group III (19.0 +- 24.3%). No significant changes in TCA were observed. T3 and free T4 increased transiently during the first month. After 12 months, 7 patients were hypothyroid (N 3 in group I and N = 2 in groups II and III). rhTSH plus a 1.11-GBq fixed {sup 131}I activity did not cause acute or chronic changes in TCA. After 6 and 12 months, TV reduction was more pronounced among patients treated with rhTSH plus {sup 131}I (author)

Radioiodine plus recombinant human thyrotropin do not cause acute airway compression and are effective in reducing multinodular goiter

International Nuclear Information System (INIS)

Albino, C.C.; Graf, H.; Paz-Filho, G.; Olandoski, M.; Sabbag, A.; Buchpiguel, C.

2006-01-01

Recombinant human thyrotropin (rhTSH) reduces the activity of radioiodine required to treat multinodular goiter (MNG), but acute airway compression can be a life-threatening complication. In this prospective, randomized, double-blind, placebo-controlled study, we assessed the efficacy and safety (including airway compression) of different doses of rhTSH associated with a fixed activity of 131 I for treating MNG. Euthyroid patients with MNG (69.3 ± 62.0 mL, 20 females, 2 males, 64 ± 7 years) received 0.1 mg (group I, N = 8) or 0.01 mg (group II, N = 6) rhTSH or placebo (group III, N = 8), 24 h before 1.11 GBq 131 I. Radioactive iodine uptake was determined at baseline and 24 h after rhTSH and thyroid volume (TV, baseline and 6 and 12 months after treatment) and tracheal cross-sectional area (TCA, baseline and 2, 7, 180, and 360 days after rhTSH) were determined by magnetic resonance; antithyroid antibodies and thyroid hormones were determined at frequent intervals. After 6 months, TV decreased significantly in groups I (28.5 ± 17.6%) and II (21.6 ± 17.8%), but not in group III (2.7 ± 15.3%). After 12 months, TV decreased significantly in groups I (36.7 ± 18.1%) and II (37.4 ± 27.1%), but not in group III (19.0 ± 24.3%). No significant changes in TCA were observed. T3 and free T4 increased transiently during the first month. After 12 months, 7 patients were hypothyroid (N 3 in group I and N = 2 in groups II and III). rhTSH plus a 1.11-GBq fixed 131 I activity did not cause acute or chronic changes in TCA. After 6 and 12 months, TV reduction was more pronounced among patients treated with rhTSH plus 131 I (author)

The Tulip GT® airway versus the facemask and Guedel airway: a randomised, controlled, cross-over study by Basic Life Support-trained airway providers in anaesthetised patients.

Science.gov (United States)

Shaikh, A; Robinson, P N; Hasan, M

2016-03-01

We performed a randomised, controlled, cross-over study of lung ventilation by Basic Life Support-trained providers using either the Tulip GT® airway or a facemask with a Guedel airway in 60 anaesthetised patients. Successful ventilation was achieved if the provider produced an end-tidal CO2 > 3.5 kPa and a tidal volume > 250 ml in two of the first three breaths, within 60 sec and within two attempts. Fifty-seven (95%) providers achieved successful ventilation using the Tulip GT compared with 35 (58%) using the facemask (p Basic Life Support-trained airway providers. © 2015 The Association of Anaesthetists of Great Britain and Ireland.

Differential effects of airway anesthesia on ozone-induced pulmonary responses in human subjects.

Science.gov (United States)

Schelegle, E S; Eldridge, M W; Cross, C E; Walby, W F; Adams, W C

2001-04-01

We examined the effect of tetracaine aerosol inhalation, a local anesthetic, on lung volume decrements, rapid shallow breathing, and subjective symptoms of breathing discomfort induced by the acute inhalation of 0.30 ppm ozone for 65 min in 22 ozone-sensitive healthy human subjects. After 50 min of ozone inhalation FEV(1) was reduced 24%, breathing frequency was increased 40%, tidal volume was decreased 31%, and total subjective symptom score was increased (71.2, compared with 3.8 for filtered air exposure). Inhalation of tetracaine aerosol resulted in marked reductions in ozone-induced subjective symptoms of throat tickle and/or irritation (92.1%), cough (78.5%), shortness of breath (72.5%), and pain on deep inspiration (69.4%). In contrast, inhalation of tetracaine aerosol (mass median aerodynamic diameter of 3.52 microm with a geometric standard deviation of 1.92) resulted in only minor and inconsistent rectification of FEV(1) decrements (5.0%) and breathing frequency (-3.8%) that was not significantly different from that produced by saline aerosol alone (FEV(1), 5.1% and breathing frequency, -2.7%). Our data are consistent with afferent endings located within the large conducting airways of the tracheobronchial tree being primarily responsible for ozone-induced subjective symptoms and provides strong evidence that ozone-induced inhibition of maximal inspiratory effort is not dependent on conscious sensations of inspiratory discomfort.

Do indoor chemicals promote development of airway allergy?

DEFF Research Database (Denmark)

Nielsen, G D; Larsen, S T; Olsen, O

2007-01-01

in animal studies and allergy-promoting effects in humans. Quaternary ammonium compounds may possess adjuvant effects in animal studies and promoted sensitization in humans in occupational settings. The use of cleaning agents, anionic and non-ionic surfactants are not considered to possess an important...... products, the important question may be would it be profitable to look for lifestyle factors and non-chemical indoor exposures in order to abate airway allergy? PRACTICAL IMPLICATIONS: Indoor chemicals (pollutants) have been accused to promote development of airway allergy by adjuvant effects......Allergic asthma has increased worldwide in the industrialized countries. This review evaluates whether the major groups of indoor chemical exposures possess allergy-promoting (adjuvant) effects; formaldehyde was excluded, because of the size of the literature. Volatile organic compounds (VOCs...

Airway resistance at maximum inhalation as a marker of asthma and airway hyperresponsiveness

Directory of Open Access Journals (Sweden)

O'Connor George T

2011-07-01

Full Text Available Abstract Background Asthmatics exhibit reduced airway dilation at maximal inspiration, likely due to structural differences in airway walls and/or functional differences in airway smooth muscle, factors that may also increase airway responsiveness to bronchoconstricting stimuli. The goal of this study was to test the hypothesis that the minimal airway resistance achievable during a maximal inspiration (Rmin is abnormally elevated in subjects with airway hyperresponsiveness. Methods The Rmin was measured in 34 nonasthmatic and 35 asthmatic subjects using forced oscillations at 8 Hz. Rmin and spirometric indices were measured before and after bronchodilation (albuterol and bronchoconstriction (methacholine. A preliminary study of 84 healthy subjects first established height dependence of baseline Rmin values. Results Asthmatics had a higher baseline Rmin % predicted than nonasthmatic subjects (134 ± 33 vs. 109 ± 19 % predicted, p = 0.0004. Sensitivity-specificity analysis using receiver operating characteristic curves indicated that baseline Rmin was able to identify subjects with airway hyperresponsiveness (PC20 min % predicted, FEV1 % predicted, and FEF25-75 % predicted, respectively. Also, 80% of the subjects with baseline Rmin min > 145% predicted had hyperresponsive airways, regardless of clinical classification as asthmatic or nonasthmatic. Conclusions These findings suggest that baseline Rmin, a measurement that is easier to perform than spirometry, performs as well as or better than standard spirometric indices in distinguishing subjects with airway hyperresponsiveness from those without hyperresponsive airways. The relationship of baseline Rmin to asthma and airway hyperresponsiveness likely reflects a causal relation between conditions that stiffen airway walls and hyperresponsiveness. In conjunction with symptom history, Rmin could provide a clinically useful tool for assessing asthma and monitoring response to treatment.

PLGA/DPPC/trimethylchitosan spray-dried microparticles for the nasal delivery of ropinirole hydrochloride: in vitro, ex vivo and cytocompatibility assessment

Energy Technology Data Exchange (ETDEWEB)

Karavasili, Christina [Laboratory of Pharmaceutical Technology, Department of Pharmacy, Aristotle University of Thessaloniki, 54124 (Greece); Bouropoulos, Nikolaos [Department of Materials Science, University of Patras, 26504 Rio, Patras (Greece); Foundation for Research and Technology, Hellas-Institute of Chemical Engineering and High Temperature, P.O. Box 1414, 26504 Patras (Greece); Sygellou, Lamprini [Foundation for Research and Technology, Hellas-Institute of Chemical Engineering and High Temperature, P.O. Box 1414, 26504 Patras (Greece); Amanatiadou, Elsa P.; Vizirianakis, Ioannis S. [Laboratory of Pharmacology, Department of Pharmaceutical Sciences, Aristotle University of Thessaloniki, GR-54124 Thessaloniki (Greece); Fatouros, Dimitrios G., E-mail: dfatouro@pharm.auth.gr [Laboratory of Pharmaceutical Technology, Department of Pharmacy, Aristotle University of Thessaloniki, 54124 (Greece)

2016-02-01

In the present study we investigated polymer-lipid microparticles loaded with ropinirole hydrochloride (RH) for nasal delivery. RH microparticles were further evaluated by means of scanning electron microscopy (SEM), ζ-potential measurements, Fourier-transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS) and x-ray diffraction (XRD). In vitro release studies were performed in simulated nasal electrolyte solution (SNES) pH 5.5 at 35 °C. Ex vivo permeation studies were conducted across sheep nasal mucosa. Cytocompatibility was tested in cultured human airway epithelial cells (Calu-3). SEM studies revealed spheroid microparticles in the range of 2.09 μm to 2.41 μm. The presence of trimethylchitosan (TMC) induced a slight shift towards less negative ζ-potential values. Surface chemistry (XPS) revealed the presence of dipalmitoylphospatidylcholine (DPPC) and poly(lactic-co-glycolic acid) (PLGA) onto microparticles' surface, further corroborating the FT-IR and XRD findings. In vitro release studies showed that the microparticle composition can partly modulate the release of RH. Ex vivo studies demonstrated a 2.35-folded enhancement of RH permeation when RH was co-formulated with TMC of low molecular weight, compared to the control. All formulations tested were found to be non-toxic to cells. The results suggest that polymer-lipid microparticles may be a promising carrier for the nasal delivery of RH. - Highlights: • Development of microparticles comprising PLGA/DPPC/TMC for nasal drug delivery. • Physicochemical characterization showed that DPPC dominated microparticles' surface. • Microparticles enhanced permeation of ropinirole across sheep nasal epithelium. • The cytotoxicity assay with Calu-3 cells demonstrated satisfactory cell viability.

PLGA/DPPC/trimethylchitosan spray-dried microparticles for the nasal delivery of ropinirole hydrochloride: in vitro, ex vivo and cytocompatibility assessment

International Nuclear Information System (INIS)

Karavasili, Christina; Bouropoulos, Nikolaos; Sygellou, Lamprini; Amanatiadou, Elsa P.; Vizirianakis, Ioannis S.; Fatouros, Dimitrios G.

2016-01-01

In the present study we investigated polymer-lipid microparticles loaded with ropinirole hydrochloride (RH) for nasal delivery. RH microparticles were further evaluated by means of scanning electron microscopy (SEM), ζ-potential measurements, Fourier-transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS) and x-ray diffraction (XRD). In vitro release studies were performed in simulated nasal electrolyte solution (SNES) pH 5.5 at 35 °C. Ex vivo permeation studies were conducted across sheep nasal mucosa. Cytocompatibility was tested in cultured human airway epithelial cells (Calu-3). SEM studies revealed spheroid microparticles in the range of 2.09 μm to 2.41 μm. The presence of trimethylchitosan (TMC) induced a slight shift towards less negative ζ-potential values. Surface chemistry (XPS) revealed the presence of dipalmitoylphospatidylcholine (DPPC) and poly(lactic-co-glycolic acid) (PLGA) onto microparticles' surface, further corroborating the FT-IR and XRD findings. In vitro release studies showed that the microparticle composition can partly modulate the release of RH. Ex vivo studies demonstrated a 2.35-folded enhancement of RH permeation when RH was co-formulated with TMC of low molecular weight, compared to the control. All formulations tested were found to be non-toxic to cells. The results suggest that polymer-lipid microparticles may be a promising carrier for the nasal delivery of RH. - Highlights: • Development of microparticles comprising PLGA/DPPC/TMC for nasal drug delivery. • Physicochemical characterization showed that DPPC dominated microparticles' surface. • Microparticles enhanced permeation of ropinirole across sheep nasal epithelium. • The cytotoxicity assay with Calu-3 cells demonstrated satisfactory cell viability.

Effect of inhomogeneous activity distributions and airway geometry on cellular doses in radon lung dosimetry

International Nuclear Information System (INIS)

Szoke, Istvan; Balashazy, Imre; Farkas, Arpad; Hofmann, Werner

2007-01-01

The human tracheobronchial system has a very complex structure including cylindrical airway ducts connected by airway bifurcation units. The deposition of the inhaled aerosols within the airways exhibits a very inhomogeneous pattern. The formation of deposition hot spots near the carinal ridge has been confirmed by experimental and computational fluid and particle dynamics (CFPD) methods. In spite of these observations, current radon lung dosimetry models apply infinitely long cylinders as models of the airway system and assume uniform deposition of the inhaled radon progenies along the airway walls. The aim of this study is to investigate the effect of airway geometry and non-uniform activity distributions within bronchial bifurcations on cellular dose distributions. In order to answer these questions, the nuclear doses of the bronchial epithelium were calculated in three different irradiation situations. (1) First, CFPD methods were applied to calculate the distribution of the deposited alpha-emitting nuclides in a numerically constructed idealized airway bifurcation. (2) Second, the deposited radionuclides were randomly distributed along the surface of the above-mentioned geometry. (3) Finally, calculations were made in cylindrical geometries corresponding to the parent and daughter branches of the bifurcation geometry assuming random nuclide activity distribution. In all three models, the same 218 Po and 214 Po surface activities per tissue volumes were assumed. Two conclusions can be drawn from this analysis: (i) average nuclear doses are very similar in all three cases (minor differences can be attributed to differences in the linear energy transfer (LET) spectra) and (ii) dose distributions are significantly different in all three cases, with the highest doses at the carinal ridge in case 3. (authors)

Hypoxia-inducible factor-1 signalling promotes goblet cell hyperplasia in airway epithelium

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Polosukhin, Vasiliy V; Cates, Justin M; Lawson, William E; Milstone, Aaron P; Matafonov, Anton G; Massion, Pierre P; Lee, Jae Woo; Randell, Scott H; Blackwell, Timothy S

2018-01-01

Goblet cell hyperplasia is a common feature of chronic obstructive pulmonary disease (COPD) airways, but the mechanisms that underlie this epithelial remodelling in COPD are not understood. Based on our previous finding of hypoxia-inducible factor-1α (HIF-1α) nuclear localization in large airways from patients with COPD, we investigated whether hypoxia-inducible signalling could influence the development of goblet cell hyperplasia. We evaluated large airway samples obtained from 18 lifelong non-smokers and 13 former smokers without COPD, and 45 former smokers with COPD. In these specimens, HIF-1α nuclear staining occurred almost exclusively in COPD patients in areas of airway remodelling. In COPD patients, 93.2 ± 3.9% (range 65 – 100%) of goblet cells were HIF-1α positive in areas of goblet cell hyperplasia, whereas nuclear HIF-1α was not detected in individuals without COPD or in normal-appearing pseudostratified epithelium from COPD patients. To determine the direct effects of hypoxia-inducible signalling on epithelial cell differentiation in vitro, human bronchial epithelial cells (HBECs) were grown in air-liquid interface cultures under hypoxia (1% O2) or following treatment with a selective HIF-1α stabilizer, (2R)-[(4-biphenylylsulphonyl)amino]-N-hydroxy-3-phenyl-propionamide (BiPS). HBECs grown in hypoxia or with BiPS treatment were characterized by HIF-1α activation, carbonic anhydrase IX expression, mucus-producing cell hyperplasia and increased expression of MUC5AC. Analysis of signal transduction pathways in cells with HIF-1α activation showed increased ERK1/2 phosphorylation without activation of epidermal growth factor receptor, Ras, PI3K-Akt or STAT6. These data indicate an important effect of hypoxia-inducible signalling on airway epithelial cell differentiation and identify a new potential target to limit mucus production in COPD. PMID:21557221

Automated method for structural segmentation of nasal airways based on cone beam computed tomography

Science.gov (United States)

Tymkovych, Maksym Yu.; Avrunin, Oleg G.; Paliy, Victor G.; Filzow, Maksim; Gryshkov, Oleksandr; Glasmacher, Birgit; Omiotek, Zbigniew; DzierŻak, RóŻa; Smailova, Saule; Kozbekova, Ainur

2017-08-01

The work is dedicated to the segmentation problem of human nasal airways using Cone Beam Computed Tomography. During research, we propose a specialized approach of structured segmentation of nasal airways. That approach use spatial information, symmetrisation of the structures. The proposed stages can be used for construction a virtual three dimensional model of nasal airways and for production full-scale personalized atlases. During research we build the virtual model of nasal airways, which can be used for construction specialized medical atlases and aerodynamics researches.

Human airway eosinophils exhibit preferential reduction in STAT signaling capacity and increased CISH expression.

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Burnham, Mandy E; Koziol-White, Cynthia J; Esnault, Stephane; Bates, Mary E; Evans, Michael D; Bertics, Paul J; Denlinger, Loren C

2013-09-15

Allergic asthma, a chronic respiratory disorder marked by inflammation and recurrent airflow obstruction, is associated with elevated levels of IL-5 family cytokines and elevated numbers of eosinophils (EOS). IL-5 family cytokines elongate peripheral blood EOS (EOS(PB)) viability, recruit EOS(PB) to the airways, and, at higher concentrations, induce degranulation and reactive oxygen species generation. Although airway EOS (EOS(A)) remain signal ready in that GM-CSF treatment induces degranulation, treatment of EOS(A) with IL-5 family cytokines no longer confers a survival advantage. Because the IL-5 family receptors have common signaling capacity, but are uncoupled from EOS(A) survival, whereas other IL-5 family induced endpoints remain functional, we tested the hypothesis that EOS(A) possess a JAK/STAT-specific regulatory mechanism (because JAK/STAT signaling is critical to EOS survival). We found that IL-5 family-induced STAT3 and STAT5 phosphorylation is attenuated in EOS(A) relative to blood EOS from airway allergen-challenged donors. However, IL-5 family-induced ERK1/2 phosphorylation is not altered between EOS(A) and EOS from airway allergen-challenged donors. These observations suggest EOS(A) possess a regulatory mechanism for suppressing STAT signaling distinct from ERK1/2 activation. Furthermore, we found, in EOS(PB), IL-5 family cytokines induce members of the suppressors of cytokine signaling (SOCS) genes, CISH and SOCS1. Additionally, following allergen challenge, EOS(A) express significantly more CISH and SOCS1 mRNA and CISH protein than EOS(PB) counterparts. In EOS(PB), long-term pretreatment with IL-5 family cytokines, to varying degrees, attenuates IL-5 family-induced STAT5 phosphorylation. These data support a model in which IL-5 family cytokines trigger a selective downregulation mechanism in EOS(A) for JAK/STAT pathways.

Acoustic rhinometry (AR): An Alternative Method to Image Nasal Airway Geometry

DEFF Research Database (Denmark)

Straszek, Sune; Pedersen, O.F.

  ACOUSTIC RHINOMETRY (AR): AN ALTERNATIVE METHOD TO IMAGE NASAL AIRWAY GEOMETRY.  INTRODUCTION AND BACKGROUND:  In human studies the acoustic reflection technique was first applied to describe the area-distance relationship of the lower airways, but later the acoustic reflection technique appeared...... to be of more use in the description of nasal cavity geometry. Applied to human subjects AR has been applied to monitor the effect of corrective surgery and mucosal effects of pharmacological interventions. In recent years, however, AR has found use also in pharmacological studies in animals ranging in size...

Comparison of vectorial ion transport in primary murine airway and human sinonasal air-liquid interface cultures, models for studies of cystic fibrosis, and other airway diseases.

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Zhang, Shaoyan; Fortenberry, James A; Cohen, Noam A; Sorscher, Eric J; Woodworth, Bradford A

2009-01-01

The purpose of this study was to compare vectorial ion transport within murine trachea, murine nasal septa, and human sinonasal cultured epithelium. Our hypothesis is that murine septal epithelium, rather than trachea, will more closely mimic the electrophysiology properties of human sinonasal epithelium. Epithelium from murine trachea, murine septa, and human sinonasal tissue were cultured at an air-liquid interface to confluence and full differentiation. A limited number of homozygous dF508 epithelia were also cultured. Monolayers were mounted in modified Ussing chambers to investigate pharmacologic manipulation of ion transport. The change in forskolin-stimulated current (delta-I(SC), expressed as micro-A/cm(2)) in murine septal (n = 19; 16.84 +/- 2.09) and human sinonasal (n = 18; 12.15 +/- 1.93) cultures was significantly increased over murine tracheal cultures (n = 15; 6.75 +/- 1.35; p = 0.035 and 0.0005, respectively). Forskolin-stimulated I(SC) was inhibited by the specific cystic fibrosis transmembrane regulator (CFTR) inhibitor INH-172 (5 microM). No forskolin-stimulated I(SC) was shown in cultures of dF508 homozygous murine septal epithelium (n = 3). Murine septal I(SC) was largely inhibited by amiloride (12.03 +/- 0.66), whereas human sinonasal cultures had a very limited response (0.70 +/- 0.47; p < 0.0001). The contribution of CFTR to stimulated chloride current as measured by INH-172 was highly significantly different between all groups (murine septa, 19.51 +/- 1.28; human sinonasal, 11.12 +/- 1.58; murine trachea, 4.85 +/- 0.49; p < 0.0001). Human sinonasal and murine septal epithelial cultures represent a useful model for studying CFTR activity and may provide significant advantages over lower airway tissues for investigating upper and lower respiratory pathophysiology.

Peripherally Generated Foxp3+ Regulatory T Cells Mediate the Immunomodulatory Effects of IVIg in Allergic Airways Disease.

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Massoud, Amir H; Kaufman, Gabriel N; Xue, Di; Béland, Marianne; Dembele, Marieme; Piccirillo, Ciriaco A; Mourad, Walid; Mazer, Bruce D

2017-04-01

IVIg is widely used as an immunomodulatory therapy. We have recently demonstrated that IVIg protects against airway hyperresponsiveness (AHR) and inflammation in mouse models of allergic airways disease (AAD), associated with induction of Foxp3 + regulatory T cells (Treg). Using mice carrying a DTR/EGFP transgene under the control of the Foxp3 promoter (DEREG mice), we demonstrate in this study that IVIg generates a de novo population of peripheral Treg (pTreg) in the absence of endogenous Treg. IVIg-generated pTreg were sufficient for inhibition of OVA-induced AHR in an Ag-driven murine model of AAD. In the absence of endogenous Treg, IVIg failed to confer protection against AHR and airway inflammation. Adoptive transfer of purified IVIg-generated pTreg prior to Ag challenge effectively prevented airway inflammation and AHR in an Ag-specific manner. Microarray gene expression profiling of IVIg-generated pTreg revealed upregulation of genes associated with cell cycle, chromatin, cytoskeleton/motility, immunity, and apoptosis. These data demonstrate the importance of Treg in regulating AAD and show that IVIg-generated pTreg are necessary and sufficient for inhibition of allergen-induced AAD. The ability of IVIg to generate pure populations of highly Ag-specific pTreg represents a new avenue to study pTreg, the cross-talk between humoral and cellular immunity, and regulation of the inflammatory response to Ags. Copyright © 2017 by The American Association of Immunologists, Inc.

Upper airway morphology in Down Syndrome patients under dexmedetomidine sedation

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Rajeev Subramanyam

Full Text Available Abstract Background and objectives: Children with Down Syndrome are vulnerable to significant upper airway obstruction due to relative macroglossia and dynamic airway collapse. The objective of this study was to compare the upper airway dimensions of children with Down Syndrome and obstructive sleep apnea with normal airway under dexmedetomidine sedation. Methods: IRB approval was obtained. In this retrospective study, clinically indicated dynamic sagittal midline magnetic resonance images of the upper airway were obtained under low (1 mcg/kg/h and high (3 mcg/kg/h dose dexmedetomidine. Airway anteroposterior diameters and sectional areas were measured as minimum and maximum dimensions by two independent observers at soft palate (nasopharyngeal airway and at base of the tongue (retroglossal airway. Results and conclusions: Minimum anteroposterior diameter and minimum sectional area at nasopharynx and retroglossal airway were significantly reduced in Down Syndrome compared to normal airway at both low and high dose dexmedetomidine. However, there were no significant differences between low and high dose dexmedetomidine in both Down Syndrome and normal airway. The mean apnea hypopnea index in Down Syndrome was 16 ± 11. Under dexmedetomidine sedation, children with Down Syndrome and obstructive sleep apnea when compared to normal airway children show significant reductions in airway dimensions most pronounced at the narrowest points in the nasopharyngeal and retroglossal airways.

Upper airway morphology in Down Syndrome patients under dexmedetomidine sedation.

Science.gov (United States)

Subramanyam, Rajeev; Fleck, Robert; McAuliffe, John; Radhakrishnan, Rupa; Jung, Dorothy; Patino, Mario; Mahmoud, Mohamed

2016-01-01

Children with Down Syndrome are vulnerable to significant upper airway obstruction due to relative macroglossia and dynamic airway collapse. The objective of this study was to compare the upper airway dimensions of children with Down Syndrome and obstructive sleep apnea with normal airway under dexmedetomidine sedation. IRB approval was obtained. In this retrospective study, clinically indicated dynamic sagittal midline magnetic resonance images of the upper airway were obtained under low (1mcg/kg/h) and high (3mcg/kg/h) dose dexmedetomidine. Airway anteroposterior diameters and sectional areas were measured as minimum and maximum dimensions by two independent observers at soft palate (nasopharyngeal airway) and at base of the tongue (retroglossal airway). Minimum anteroposterior diameter and minimum sectional area at nasopharynx and retroglossal airway were significantly reduced in Down Syndrome compared to normal airway at both low and high dose dexmedetomidine. However, there were no significant differences between low and high dose dexmedetomidine in both Down Syndrome and normal airway. The mean apnea hypopnea index in Down Syndrome was 16±11. Under dexmedetomidine sedation, children with Down Syndrome and obstructive sleep apnea when compared to normal airway children show significant reductions in airway dimensions most pronounced at the narrowest points in the nasopharyngeal and retroglossal airways. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.

[Upper airway morphology in Down Syndrome patients under dexmedetomidine sedation].

Science.gov (United States)

Subramanyam, Rajeev; Fleck, Robert; McAuliffe, John; Radhakrishnan, Rupa; Jung, Dorothy; Patino, Mario; Mahmoud, Mohamed

2016-01-01

Children with Down Syndrome are vulnerable to significant upper airway obstruction due to relative macroglossia and dynamic airway collapse. The objective of this study was to compare the upper airway dimensions of children with Down Syndrome and obstructive sleep apnea with normal airway under dexmedetomidine sedation. IRB approval was obtained. In this retrospective study, clinically indicated dynamic sagittal midline magnetic resonance images of the upper airway were obtained under low (1mcg/kg/h) and high (3mcg/kg/h) dose dexmedetomidine. Airway anteroposterior diameters and sectional areas were measured as minimum and maximum dimensions by two independent observers at soft palate (nasopharyngeal airway) and at base of the tongue (retroglossal airway). Minimum anteroposterior diameter and minimum sectional area at nasopharynx and retroglossal airway were significantly reduced in Down Syndrome compared to normal airway at both low and high dose dexmedetomidine. However, there were no significant differences between low and high dose dexmedetomidine in both Down Syndrome and normal airway. The mean apnea hypopnea index in Down Syndrome was 16±11. Under dexmedetomidine sedation, children with Down Syndrome and obstructive sleep apnea when compared to normal airway children show significant reductions in airway dimensions most pronounced at the narrowest points in the nasopharyngeal and retroglossal airways. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

Eosinophilic airway inflammation in asthmatic patients is associated with an altered airway microbiome

DEFF Research Database (Denmark)

Sverrild, Asger; Kiilerich, Pia; Brejnrod, Asker Daniel

2017-01-01

BACKGROUND: Asthmatic patients have higher microbiome diversity and an altered composition, with more Proteobacteria and less Bacteroidetes compared with healthy control subjects. Studies comparing airway inflammation and the airway microbiome are sparse, especially in subjects not receiving anti......-inflammatory treatment. OBJECTIVE: We sought to describe the relationship between the airway microbiome and patterns of airway inflammation in steroid-free patients with asthma and healthy control subjects. METHODS: Bronchoalveolar lavage fluid was collected from 23 steroid-free nonsmoking patients with asthma and 10...... and AHR to mannitol but not airway neutrophilia. The overall composition of the airway microbiome of asthmatic patients with the lowest levels of eosinophils but not asthmatic patients with the highest levels of eosinophils deviated significantly from that of healthy subjects. Asthmatic patients...

Role of Aquaporin Water Channels in Airway Fluid Transport, Humidification, and Surface Liquid Hydration

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Song, Yuanlin; Jayaraman, Sujatha; Yang, Baoxue; Matthay, Michael A.; Verkman, A.S.

2001-01-01

Several aquaporin-type water channels are expressed in mammalian airways and lung: AQP1 in microvascular endothelia, AQP3 in upper airway epithelia, AQP4 in upper and lower airway epithelia, and AQP5 in alveolar epithelia. Novel quantitative methods were developed to compare airway fluid transport–related functions in wild-type mice and knockout mice deficient in these aquaporins. Lower airway humidification, measured from the moisture content of expired air during mechanical ventilation with dry air through a tracheotomy, was 54–56% efficient in wild-type mice, and reduced by only 3–4% in AQP1/AQP5 or AQP3/AQP4 double knockout mice. Upper airway humidification, measured from the moisture gained by dry air passed through the upper airways in mice breathing through a tracheotomy, decreased from 91 to 50% with increasing ventilation from 20 to 220 ml/min, and reduced by 3–5% in AQP3/AQP4 knockout mice. The depth and salt concentration of the airway surface liquid in trachea was measured in vivo using fluorescent probes and confocal and ratio imaging microscopy. Airway surface liquid depth was 45 ± 5 μm and [Na+] was 115 ± 4 mM in wild-type mice, and not significantly different in AQP3/AQP4 knockout mice. Osmotic water permeability in upper airways, measured by an in vivo instillation/sample method, was reduced by ∼40% by AQP3/AQP4 deletion. In doing these measurements, we discovered a novel amiloride-sensitive isosmolar fluid absorption process in upper airways (13% in 5 min) that was not affected by aquaporin deletion. These results establish the fluid transporting properties of mouse airways, and indicate that aquaporins play at most a minor role in airway humidification, ASL hydration, and isosmolar fluid absorption. PMID:11382807

Difficult Airway Response Team: A Novel Quality Improvement Program for Managing Hospital-Wide Airway Emergencies

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Mark, Lynette J.; Herzer, Kurt R.; Cover, Renee; Pandian, Vinciya; Bhatti, Nasir I.; Berkow, Lauren C.; Haut, Elliott R.; Hillel, Alexander T.; Miller, Christina R.; Feller-Kopman, David J.; Schiavi, Adam J.; Xie, Yanjun J.; Lim, Christine; Holzmueller, Christine; Ahmad, Mueen; Thomas, Pradeep; Flint, Paul W.; Mirski, Marek A.

2015-01-01

Background Difficult airway cases can quickly become emergencies, increasing the risk of life-threatening complications or death. Emergency airway management outside the operating room is particularly challenging. Methods We developed a quality improvement program—the Difficult Airway Response Team (DART)—to improve emergency airway management outside the operating room. DART was implemented by a team of anesthesiologists, otolaryngologists, trauma surgeons, emergency medicine physicians, and risk managers in 2005 at The Johns Hopkins Hospital in Baltimore, Maryland. The DART program had three core components: operations, safety, and education. The operations component focused on developing a multidisciplinary difficult airway response team, standardizing the emergency response process, and deploying difficult airway equipment carts throughout the hospital. The safety component focused on real-time monitoring of DART activations and learning from past DART events to continuously improve system-level performance. This objective entailed monitoring the paging system, reporting difficult airway events and DART activations to a web-based registry, and using in situ simulations to identify and mitigate defects in the emergency airway management process. The educational component included development of a multispecialty difficult airway curriculum encompassing case-based lectures, simulation, and team building/communication to ensure consistency of care. Educational materials were also developed for non-DART staff and patients to inform them about the needs of patients with difficult airways and ensure continuity of care with other providers after discharge. Results Between July 2008 and June 2013, DART managed 360 adult difficult airway events comprising 8% of all code activations. Predisposing patient factors included body mass index > 40, history of head and neck tumor, prior difficult intubation, cervical spine injury, airway edema, airway bleeding, and previous

Automatic airway-artery analysis on lung CT to quantify airway wall thickening and bronchiectasis

DEFF Research Database (Denmark)

Perez-Rovira, Adria; Kuo, Wieying; Petersen, Jens

2016-01-01

Purpose: Bronchiectasis and airway wall thickening are commonly assessed in computed tomography (CT) by comparing the airway size with the size of the accompanying artery. Thus, in order to automate the quantification of bronchiectasis and wall thickening following a similar principle......, and pairs airway branches with the accompanying artery, then quantifies airway wall thickening and bronchiectasis by measuring the wall-artery ratio (WAR) and lumen and outer wall airway-artery ratio (AAR). Measurements that do not use the artery size for normalization are also extracted, including wall...... area percentage (WAP), wall thickness ratio (WTR), and airway diameters. Results: The method was thoroughly evaluated using 8000 manual annotations of airway-artery pairs from 24 full-inspiration pediatric CT scans (12 diseased and 12 controls). Limits of agreement between the automatically...

Biosignature for airway inflammation in a house dust mite-challenged murine model of allergic asthma

Directory of Open Access Journals (Sweden)

Hadeesha Piyadasa

2016-02-01

Full Text Available House dust mite (HDM challenge is commonly used in murine models of allergic asthma for preclinical pathophysiological studies. However, few studies define objective readouts or biomarkers in this model. In this study we characterized immune responses and defined molecular markers that are specifically altered after HDM challenge. In this murine model, we used repeated HDM challenge for two weeks which induced hallmarks of allergic asthma seen in humans, including airway hyper-responsiveness (AHR and elevated levels of circulating total and HDM-specific IgE and IgG1. Kinetic studies showed that at least 24 h after last HDM challenge results in significant AHR along with eosinophil infiltration in the lungs. Histologic assessment of lung revealed increased epithelial thickness and goblet cell hyperplasia, in the absence of airway wall collagen deposition, suggesting ongoing tissue repair concomitant with acute allergic lung inflammation. Thus, this model may be suitable to delineate airway inflammation processes that precede airway remodeling and development of fixed airway obstruction. We observed that a panel of cytokines e.g. IFN-γ, IL-1β, IL-4, IL-5, IL-6, KC, TNF-α, IL-13, IL-33, MDC and TARC were elevated in lung tissue and bronchoalveolar fluid, indicating local lung inflammation. However, levels of these cytokines remained unchanged in serum, reflecting lack of systemic inflammation in this model. Based on these findings, we further monitored the expression of 84 selected genes in lung tissues by quantitative real-time PCR array, and identified 31 mRNAs that were significantly up-regulated in lung tissue from HDM-challenged mice. These included genes associated with human asthma (e.g. clca3, ear11, il-13, il-13ra2, il-10, il-21, arg1 and chia1 and leukocyte recruitment in the lungs (e.g. ccl11, ccl12 and ccl24. This study describes a biosignature to enable broad and systematic interrogation of molecular mechanisms and intervention

A study of airway smooth muscle in asthmatic and non-asthmatic airways using PS-OCT (Conference Presentation)

Science.gov (United States)

Adams, David C.; Holz, Jasmin A.; Szabari, Margit V.; Hariri, Lida P.; Harris, R. Scott; Cho, Jocelyn L.; Hamilos, Daniel L.; Luster, Andrew D.; Medoff, Benjamin D.; Suter, Melissa J.

2016-03-01

Present understanding of the pathophysiological mechanisms of asthma has been severely limited by the lack of an imaging modality capable of assessing airway conditions of asthma patients in vivo. Of particular interest is the role that airway smooth muscle (ASM) plays in the development of asthma and asthma related symptoms. With standard Optical Coherence Tomography (OCT), imaging ASM is often not possible due to poor structural contrast between the muscle and surrounding tissues. A potential solution to this problem is to utilize additional optical contrast factors intrinsic to the tissue, such as birefringence. Due to its highly ordered structure, ASM is strongly birefringent. Previously, we demonstrated that Polarization Sensitive OCT(PS-OCT) has the potential to be used to visualize ASM as well as easily segment it from the surrounding (weakly) birefringent tissue by exploiting a property which allows it to discriminate the orientation of birefringent fibers. We have already validated our technology with a substantial set of histological comparisons made against data obtained ex vivo. In this work we present a comprehensive comparison of ASM distributions in asthmatic and non-asthmatic human volunteers. By isolating the ASM we parameterize its distribution in terms of both thickness and band width, calculated volumetrically over centimeters of airway. Using this data we perform analyses of the asthmatic and non-asthmatic airways using a broad number and variety and subjects.

Airway Clearance Techniques (ACTs)

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Full Text Available ... Treatments and Therapies Airway Clearance Airway Clearance Techniques (ACTs) There are different ways to clear your airways. ... or caregiver. Older kids and adults can choose ACTs that they can do on their own. Share ...

Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients.

Science.gov (United States)

Silkoff, Philip E; Laviolette, Michel; Singh, Dave; FitzGerald, J Mark; Kelsen, Steven; Backer, Vibeke; Porsbjerg, Celeste M; Girodet, Pierre-Olivier; Berger, Patrick; Kline, Joel N; Chupp, Geoffrey; Susulic, Vedrana S; Barnathan, Elliot S; Baribaud, Frédéric; Loza, Matthew J

2017-09-01

The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects. We explored this data set to define type 2 inflammation based on airway mucosal IL-13-driven gene expression and how this related to clinically accessible biomarkers. IL-13-driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (Feno) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression. Expression of airway mucosal CCL26, periostin, and IL-13-IVS all facilitated segregation of subjects into type 2-high and type 2-low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had Feno values (≥35 ppb) and/or high bEOS counts (≥300 cells/mm 3 ) compared with a minority (36%) of subjects with low airway mucosal CCL26 expression. A combination of Feno values, bEOS counts, and serum CCL17 and CCL26 expression had 100% positive predictive value and 87% negative predictive value for airway mucosal CCL26-high status. Clinical variables did not differ between subjects with type 2-high and type 2-low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression. A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13-IVS gene expression. Use of Feno values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient

Characteristics of turbulent particle transport in human airways under steady and cyclic flows

International Nuclear Information System (INIS)

Jedelsky, Jan; Lizal, Frantisek; Jicha, Miroslav

2012-01-01

Highlights: ► PDA data allow to estimate PSD of particle velocity fluctuations in realistic model. ► PSD of micron-sized particles is independent of their size up to 700 Hz. ► Such particles follow air flow and turb. diffusion contributes to their deposition. ► Cyclic flow PSDs contain more TKE at high freq. than equivalent steady-flow PSDs. ► Exp. breathing phase differs from insp. phase at high frequency part of the spectra. - Abstract: Motion of monodispersed aerosol particles suspended in air flow has been studied on realistic transparent model of human airways using Phase Doppler Particle Analyser (P/DPA). Time-resolved velocity data for particles in size range 1–8 μm were processed using Fuzzy Slotting Technique to estimate the power spectral density (PSD) of velocity fluctuations. The optimum processing setup for our data was found and recommendations for future experiments to improve PSD quality were suggested. Typical PSD plots at mainstream positions of the trachea and the upper bronchi are documented and differences among (1) steady-flow regimes and equivalent cyclic breathing regimes, (2) inspiration and expiration breathing phase and (3) behaviour of particles of different sizes are described in several positions of the airway model. Systematically higher level of velocity fluctuations in the upper part of the frequency range (30–500 Hz) was found for cyclic flows in comparison with corresponding steady flows. Expiratory flows in both the steady and cyclic cases produce more high-frequency fluctuations compared to inspiratory flows. Negligible differences were found for flow of particles in the inspected size range 1–8 μm at frequencies below 500 Hz. This finding was explained by Stokes number analysis. Implied match of the air and particle flows thereby indicates turbulent diffusion as important deposition mechanism and confirms the capability to use the P/DPA data as the air flow velocity estimate.

Equine recurrent airway obstruction

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Artur Niedźwiedź

2014-10-01

Full Text Available Equine Recurrent Airway Obstruction (RAO, also known as heaves or broken wind, is one of the most common disease in middle-aged horses. Inflammation of the airway is inducted by organic dust exposure. This disease is characterized by neutrophilic inflammation, bronchospasm, excessive mucus production and pathologic changes in the bronchiolar walls. Clinical signs are resolved in 3-4 weeks after environmental changes. Horses suffering from RAO are susceptible to allergens throughout their lives, therefore they should be properly managed. In therapy the most importanthing is to eliminate dustexposure, administration of corticosteroids and use bronchodilators to improve pulmonary function.

Effect of titanium dioxide nanoparticles (TiO2 NPs) on the expression of mucin genes in human airway epithelial cells.

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Kim, Gui Ok; Choi, Yoon Seok; Bae, Chang Hoon; Song, Si-Youn; Kim, Yong-Dae

2017-01-01

Titanium dioxide nanoparticles (TiO 2 NPs) are utilized with growing frequency for a wide variety of industrial applications. Recently, acute and chronic exposures to TiO 2 NPs have been found to induce inflammatory response in the human respiratory tract. However, the effect and mechanism underlying the induction of major airway mucins by TiO 2 NPs have not been elucidated. This study was conducted to characterize the effect of TiO 2 NPs, and the mechanism involved, on the expressions of airway mucins in human airway epithelial cells. In NCI-H292 cells and primary cultures of normal nasal epithelial cells, the effects of TiO 2 NPs and signaling pathway for airway mucin genes were investigated by reverse transcriptase-polymerase chain reaction (RT-PCR), real-time PCR, enzyme immunoassays and immunoblot analysis using several specific inhibitors and small interfering RNAs (siRNAs). TiO 2 NPs increased MUC5B expression and activated the phosphorylations of extracellular signal-related kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK). U0126 (an ERK1/2 MAPK inhibitor) and SB203580 (a p38 MAPK inhibitor) inhibited TiO 2 NPs-induced MUC5B expression. And knockdown of ERK1, ERK2 and p38 MAPK using siRNAs significantly blocked TiO 2 NPs-induced MUC5B mRNA expression. Furthermore, Toll-like receptor 4 (TLR4) mRNA expression was increased by TiO 2 NPs, and knockdown by TLR4 siRNA significantly attenuated TiO 2 NPs-induced MUC5B mRNA expression and the TiO 2 NPs-induced phosphorylations of ERK1/2 and p38 MAPK. These results demonstrate for the first time that TiO 2 NPs induce MUC5B expression via TLR4-dependent ERK1/2 and p38 MAPK signaling pathways in respiratory epithelium.

Airway Clearance Techniques (ACTs)

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Full Text Available ... to loosen mucus from airway walls. See how different airway clearance techniques work to help you clear the thick, sticky mucus ... Offer their tips for fitting ACTs into daily life Airway Clearance Techniques | Webcast ... Facebook Twitter ...

Adrenomedullin stimulates cyclic AMP production in the airway epithelial cells of guinea-pigs and in the human epithelial cell line

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Takashi Kawaguchi

1999-01-01

Full Text Available This study was designed to examine the effects of adrenomedullin (AM on airway epithelial cells. Primary cultures of guinea-pig tracheal epithelial cells and the human bronchiolar epithelial cell line NCI-H441 were used. Intracellular cyclic adenosine monophosphate (cAMP, cyclic guanosine monophosphate (cGMP, prostaglandin E2 (PGE2, and stable end-products of nitric oxide were assayed. Adrenomedullin (10−6 mol/L stimulated cAMP production in guinea-pig epithelial cells. Indomethacin (10−5 mol/L significantly decreased the basal level of intracellular cAMP in guinea-pig epithelial cells, but not in NCI-H441 cells. However, AM did not stimulate production of PGE2, a major product that can increase cAMP formation. In the case of NCI-H441 cells, AM (10−8 – 10−6 mol/L did not significantly affect intracellular cGMP levels or nitrite content in conditioned medium. Adrenomedullin and calcitonin gene-related peptide (CGRP each stimulated cAMP production in NCI-H441 cells, but AM-stimulated cAMP production was antagonized by the CGRP fragment CGRP8–37. These findings suggest that AM stimulates cAMP production and functionally competes with CGRP for binding sites in airway epithelial cells, at least in human epithelial cells, but that it does not stimulate the release of PGE2 and nitric oxide. Though cyclooxygenase products contribute to some extent to cAMP formation in guinea-pigs, AM independently stimulates intracellular cAMP formation in airway epithelial cells.

Effect of Class III bone anchor treatment on airway.

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Nguyen, Tung; De Clerck, Hugo; Wilson, Michael; Golden, Brent

2015-07-01

To compare airway volumes and minimum cross-section area changes of Class III patients treated with bone-anchored maxillary protraction (BAMP) versus untreated Class III controls. Twenty-eight consecutive skeletal Class III patients between the ages of 10 and 14 years (mean age, 11.9 years) were treated using Class III intermaxillary elastics and bilateral miniplates (two in the infra-zygomatic crests of the maxilla and two in the anterior mandible). The subjects had cone beam computed tomographs (CBCTs) taken before initial loading (T1) and 1 year out (T2). Twenty-eight untreated Class III patients (mean age, 12.4 years) had CBCTs taken and cephalograms generated. The airway volumes and minimum cross-sectional area measurements were performed using Dolphin Imaging 11.7 3D software. The superior border of the airway was defined by a plane that passes through the posterior nasal spine and basion, while the inferior border included the base of the epiglottis to the lower border of C3. From T1 to T2, airway volume from BAMP-treated subjects showed a statistically significant increase (1499.64 mm(3)). The area in the most constricted section of the airway (choke point) increased slightly (15.44 mm(2)). The airway volume of BAMP patients at T2 was 14136.61 mm(3), compared with 14432.98 mm(3) in untreated Class III subjects. Intraexaminer correlation coefficients values and 95% confidence interval values were all greater than .90, showing a high degree of reliability of the measurements. BAMP treatment did not hinder the development of the oropharynx.

In vitro assessment of human airway toxicity from major aldehydes in automotive emissions

Energy Technology Data Exchange (ETDEWEB)

Grafstroem, R.C. [Karolinska Inst., Stockholm (Sweden). Inst. of Environmental Medicine

1997-09-01

Automotive exhausts can significantly contribute to the levels of reactive aldehydes, including formaldehyde, acetaldehyde and acrolein, in urban air. The use of alcohols as an alternative fuel for gasoline or diesel may further increase these emissions. Since it is unclear if aldehyde inhalation may induce pathological states, including cancer, in human airways, the toxic properties of the above-mentioned aldehydes were studied in cultured target cell types. Each aldehyde modified vital cellular functions in a dose-dependent manner, and invariably inhibited growth and induced abnormal terminal differentiation. Decreases of cellular thiols and increases of intracellular Ca{sup 2+} were observed, and moreover, variable types and amounts of short-lived or persistent genetic damage were induced. The concentrations required for specified levels of a particular type of injury varied up to 10000-fold among the aldehydes. Overall, distinctive patterns of cytopathological activity were observed, which differed both qualitatively and quantitatively among the aldehydes. Finally, aldehydes inhibited DNA repair processes and increased cytotoxicity and mutagenesis in synergy with other known toxicants, indicating that aldehydes may also enhance damage by other constituents in automotive exhausts. In summary, the aldehydes, notably {sup m}u{sup M}-mM formaldehyde, caused pathological effects and induced mechanisms that relate to acute toxicity and cancer development in airway epithelial cells. Since `no-effect` levels may not exist for carcinogenic agents, the overall results support a need for elimination of aldehydes in automotive exhausts. 41 refs

Imaging software accuracy for 3-dimensional analysis of the upper airway.

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Weissheimer, André; Menezes, Luciane Macedo de; Sameshima, Glenn T; Enciso, Reyes; Pham, John; Grauer, Dan

2012-12-01

The aim of this study was to compare the precision and accuracy of 6 imaging software programs for measuring upper airway volumes in cone-beam computed tomography data. The sample consisted of 33 growing patients and an oropharynx acrylic phantom, scanned with an i-CAT scanner (Imaging Sciences International, Hatfield, Pa). The known oropharynx acrylic phantom volume was used as the gold standard. Semi-automatic segmentations with interactive and fixed threshold protocols of the patients' oropharynx and oropharynx acrylic phantom were performed by using Mimics (Materialise, Leuven, Belgium), ITK-Snap (www.itksnap.org), OsiriX (Pixmeo, Geneva, Switzerland), Dolphin3D (Dolphin Imaging & Management Solutions, Chatsworth, Calif), InVivo Dental (Anatomage, San Jose, Calif), and Ondemand3D (CyberMed, Seoul, Korea) software programs. The intraclass correlation coefficient was used for the reliability tests. A repeated measurements analysis of variance (ANOVA) test and post-hoc tests (Bonferroni) were used to compare the software programs. The reliability was high for all programs. With the interactive threshold protocol, the oropharynx acrylic phantom segmentations with Mimics, Dolphin3D, OsiriX, and ITK-Snap showed less than 2% errors in volumes compared with the gold standard. Ondemand3D and InVivo Dental had more than 5% errors compared with the gold standard. With the fixed threshold protocol, the volume errors were similar (-11.1% to -11.7%) among the programs. In the oropharynx segmentation with the interactive protocol, ITK-Snap, Mimics, OsiriX, and Dolphin3D were statistically significantly different (P 0.05) was found between InVivo Dental and OnDemand3D. All 6 imaging software programs were reliable but had errors in the volume segmentations of the oropharynx. Mimics, Dolphin3D, ITK-Snap, and OsiriX were similar and more accurate than InVivo Dental and Ondemand3D for upper airway assessment. Copyright © 2012 American Association of Orthodontists. Published by

Numerical modelling of local deposition patients, activity distributions and cellular hit probabilities of inhaled radon progenies in human airways

International Nuclear Information System (INIS)

Farkas, A.; Balashazy, I.; Szoeke, I.

2003-01-01

The general objective of our research is modelling the biophysical processes of the effects of inhaled radon progenies. This effort is related to the rejection or support of the linear no threshold (LNT) dose-effect hypothesis, which seems to be one of the most challenging tasks of current radiation protection. Our approximation and results may also serve as a useful tool for lung cancer models. In this study, deposition patterns, activity distributions and alpha-hit probabilities of inhaled radon progenies in the large airways of the human tracheobronchial tree are computed. The airflow fields and related particle deposition patterns strongly depend on the shape of airway geometry and breathing pattern. Computed deposition patterns of attached an unattached radon progenies are strongly inhomogeneous creating hot spots at the carinal regions and downstream of the inner sides of the daughter airways. The results suggest that in the vicinity of the carinal regions the multiple hit probabilities are quite high even at low average doses and increase exponentially in the low-dose range. Thus, even the so-called low doses may present high doses for large clusters of cells. The cell transformation probabilities are much higher in these regions and this phenomenon cannot be modeled with average burdens. (authors)

Efficacy of Surgical Airway Plasty for Benign Airway Stenosis.

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Tsukioka, Takuma; Takahama, Makoto; Nakajima, Ryu; Kimura, Michitaka; Inoue, Hidetoshi; Yamamoto, Ryoji

2016-01-01

Long-term patency is required during treatment for benign airway stenosis. This study investigated the effectiveness of surgical airway plasty for benign airway stenosis. Clinical courses of 20 patients, who were treated with surgical plasty for their benign airway stenosis, were retrospectively investigated. Causes of stenosis were tracheobronchial tuberculosis in 12 patients, post-intubation stenosis in five patients, malacia in two patients, and others in one patient. 28 interventional pulmonology procedures and 20 surgical plasty were performed. Five patients with post-intubation stenosis and four patients with tuberculous stenosis were treated with tracheoplasty. Eight patients with tuberculous stenosis were treated with bronchoplasty, and two patients with malacia were treated with stabilization of the membranous portion. Anastomotic stenosis was observed in four patients, and one to four additional treatments were required. Performance status, Hugh-Jones classification, and ventilatory functions were improved after surgical plasty. Outcomes were fair in patients with tuberculous stenosis and malacia. However, efficacy of surgical plasty for post-intubation stenosis was not observed. Surgical airway plasty may be an acceptable treatment for tuberculous stenosis. Patients with malacia recover well after surgical plasty. There may be untreated patients with malacia who have the potential to benefit from surgical plasty.

Sex, stress and sleep apnoea: Decreased susceptibility to upper airway muscle dysfunction following intermittent hypoxia in females.

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O'Halloran, Ken D; Lewis, Philip; McDonald, Fiona

2017-11-01

Obstructive sleep apnoea syndrome (OSAS) is a devastating respiratory control disorder more common in men than women. The reasons for the sex difference in prevalence are multifactorial, but are partly attributable to protective effects of oestrogen. Indeed, OSAS prevalence increases in post-menopausal women. OSAS is characterized by repeated occlusions of the pharyngeal airway during sleep. Dysfunction of the upper airway muscles controlling airway calibre and collapsibility is implicated in the pathophysiology of OSAS, and sex differences in the neuro-mechanical control of upper airway patency are described. It is widely recognized that chronic intermittent hypoxia (CIH), a cardinal feature of OSAS due to recurrent apnoea, drives many of the morbid consequences characteristic of the disorder. In rodents, exposure to CIH-related redox stress causes upper airway muscle weakness and fatigue, associated with mitochondrial dysfunction. Of interest, in adults, there is female resilience to CIH-induced muscle dysfunction. Conversely, exposure to CIH in early life, results in upper airway muscle weakness equivalent between the two sexes at 3 and 6 weeks of age. Ovariectomy exacerbates the deleterious effects of exposure to CIH in adult female upper airway muscle, an effect partially restored by oestrogen replacement therapy. Intriguingly, female advantage intrinsic to upper airway muscle exists with evidence of substantially greater loss of performance in male muscle during acute exposure to severe hypoxic stress. Sex differences in upper airway muscle physiology may have relevance to human OSAS. The oestrogen-oestrogen receptor α axis represents a potential therapeutic target in OSAS, particularly in post-menopausal women. Copyright © 2016 Elsevier B.V. All rights reserved.

Clearance patterns for 111In-oxide particles deposited in specific airways of beagle dogs

International Nuclear Information System (INIS)

Snipes, M.B.; Muggenburg, B.A.; Griffith, W.C.; Guilmette, R.A.

1994-01-01

The International Commission on Radiological Protection (ICRP) has incorporated long-term retention of radioactive particles in conducting airways into its newly approved respiratory tract dosimetry model. This model is purported to provide a better basis for assessing risk associated with human inhalation exposures to radioactive particles. However, applying the new model requires an understanding of particle retention patterns in conducting airways of the lung. Studies are being conducted at ITRI to quantify long-term retention patterns for particles deposited at specific sites in conducting airways of Beagle dogs. The dog was selected as a model because long-term retention and clearance patterns for particles deposited in the lungs of dogs and humans are similar

Impact of varying physical activity levels on airway sensitivity and bronchodilation in healthy humans.

Science.gov (United States)

Smith, Joshua R; Kurti, Stephanie P; Johnson, Ariel M; Kolmer, Sarah A; Harms, Craig

2015-12-01

The purpose of this study was to determine if the amount of physical activity influences airway sensitivity and bronchodilation in healthy subjects across a range of physical activity levels. Thirty healthy subjects (age, 21.9 ± 2.6 years; 13 men/17 women) with normal pulmonary function reported to the laboratory on 2 separate occasions where they were randomized to breathe either hypertonic saline (HS) (nebulized hypertonic saline (25%) for 20 min) or HS followed by 5 deep inspirations (DIs), which has been reported to bronchodilate the airways. Pulmonary function tests (PFTs) were performed prior to both conditions and following the HS breathing or 5 DIs. Moderate to vigorous physical activity (MVPA) level was measured via accelerometer worn for 7 days. Following the HS breathing, forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) significantly decreased from baseline by -11.8% ± 8.4% and -9.3% ± 6.7%, respectively. A 2-segment linear model determined significant relationships between MVPA and percent change in FEV1 (r = 0.50) and FVC (r = 0.55). MVPA above ∼497 and ∼500 min/week for FEV1 and FVC, respectively, resulted in minor additional improvements (p > 0.05) in PFTs following the HS breathing. Following the DIs, FEV1 and FVC decreased (p 0.05) to MVPA. In conclusion, these data demonstrate that higher MVPA levels attenuated airway sensitivity but not bronchodilation in healthy subjects.

New frontiers in CT imaging of airway disease

International Nuclear Information System (INIS)

Grenier, Philippe A.; Beigelman-Aubry, Catherine; Fetita, Catalin; Preteux, Francoise; Brauner, Michel W.; Lenoir, Stephane

2002-01-01

Combining helical volumetric CT acquisition and thin-slice thickness during breath hold provides an accurate assessment of both focal and diffuse airway diseases. With multiple detector rows, compared with single-slice helical CT, multislice CT can cover a greater volume, during a simple breath hold, and with better longitudinal and in-plane spatial resolution and improved temporal resolution. The result in data set allows the generation of superior multiplanar and 3D images of the airways, including those obtained from techniques developed specifically for airway imaging, such as virtual bronchography and virtual bronchoscopy. Complementary CT evaluation at suspended or continuous full expiration is mandatory to detect air trapping that is a key finding for depicting an obstruction on the small airways. Indications for CT evaluation of the airways include: (a) detection of endobronchial lesions in patients with an unexplained hemoptysis; (b) evaluation of extent of tracheobronchial stenosis for planning treatment and follow-up; (c) detection of congenital airway anomalies revealed by hemoptysis or recurrent infection; (d) detection of postinfectious or postoperative airway fistula or dehiscence; and (e) diagnosis and assessment of extent of bronchiectasis and small airway disease. Improvement in image analysis technique and the use of spirometrically control of lung volume acquisition have made possible accurate and reproducible quantitative assessment of airway wall and lumen areas and lung density. This contributes to better insights in physiopathology of obstructive lung disease, particularly in chronic obstructive pulmonary disease and asthma. (orig.)

Lentiviral Vector Gene Transfer to Porcine Airways

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Patrick L Sinn

2012-01-01

Full Text Available In this study, we investigated lentiviral vector development and transduction efficiencies in well-differentiated primary cultures of pig airway epithelia (PAE and wild-type pigs in vivo. We noted gene transfer efficiencies similar to that observed for human airway epithelia (HAE. Interestingly, feline immunodeficiency virus (FIV-based vectors transduced immortalized pig cells as well as pig primary cells more efficiently than HIV-1–based vectors. PAE express TRIM5α, a well-characterized species-specific lentiviral restriction factor. We contrasted the restrictive properties of porcine TRIM5α against FIV- and HIV-based vectors using gain and loss of function approaches. We observed no effect on HIV-1 or FIV conferred transgene expression in response to porcine TRIM5α overexpression or knockdown. To evaluate the ability of GP64-FIV to transduce porcine airways in vivo, we delivered vector expressing mCherry to the tracheal lobe of the lung and the ethmoid sinus of 4-week-old pigs. One week later, epithelial cells expressing mCherry were readily detected. Our findings indicate that pseudotyped FIV vectors confer similar tropisms in porcine epithelia as observed in human HAE and provide further support for the selection of GP64 as an appropriate envelope pseudotype for future preclinical gene therapy studies in the porcine model of cystic fibrosis (CF.

Airway inflammation in chronic obstructive pulmonary disease (COPD): a true paradox.

Science.gov (United States)

Eapen, Mathew Suji; Myers, Stephen; Walters, Eugene Haydn; Sohal, Sukhwinder Singh

2017-10-01

Chronic obstructive pulmonary disease (COPD) is primarily an airway condition, which mainly affects cigarette smokers and presents with shortness of breath that is progressive and poorly reversible. In COPD research, there has been a long held belief that airway disease progression is due to inflammation. Although this may be true in the airway lumen with innate immunity activated by the effect of smoke or secondary to infection, the accurate picture of inflammatory cells in the airway wall, where the pathophysiological COPD remodeling occurs, is uncertain and debatable. Areas covered: The current review provides a comprehensive literature survey of the changes in the main inflammatory cells in human COPD patients and focuses on contrarian views that affect the prevailing dogma on inflammation. The review also delves into the role of oxidative stress and inflammasomes in modulating the immune response in COPD. Further, the effects of inflammation in affecting the epithelium, fibroblasts, and airway remodeling are discussed. Expert commentary: Inflammation as a driving force for airway wall damage and remodelling in early COPD is at the very least 'oversimplified' and is likely to be misleading. This has serious implications for rational thinking about the illness, including pathogenesis and designing therapy.

Adam8 Limits the Development of Allergic Airway Inflammation in Mice

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Knolle, Martin D.; Nakajima, Takahiro; Hergrueter, Anja; Gupta, Kushagra; Polverino, Francesca; Craig, Vanessa J.; Fyfe, Susanne E.; Zahid, Muhammad; Permaul, Perdita; Cernadas, Manuela; Montano, Gilbert; Tesfaigzi, Yohannes; Sholl, Lynette; Kobzik, Lester; Israel, Elliot; Owen, Caroline A.

2013-01-01

To determine whether a disintegrin and a metalloproteinase-8 (Adam8) regulates allergic airway inflammation (AAI) and airway hyper-responsiveness (AHR), we compared AAI and AHR in wild type (WT) versus Adam8−/− mice in different genetic backgrounds sensitized and challenged with ovalbumin (OVA) or house dust mite protein extract (HDM). OVA- and HDM-treated Adam8−/− mice had higher lung leukocyte counts, more airway mucus metaplasia, greater lung levels of some TH2 cytokines, and higher methacholine-induced increases in central airway resistance than allergen-treated WT mice. Studies of OVA-treated Adam8 bone marrow chimeric mice confirmed that leukocyte-derived Adam8 predominantly mediated Adam8’s anti-inflammatory activities in murine airways. Airway eosinophils and macrophages both expressed Adam8 in WT mice with AAI. Adam8 limited AAI and AHR in mice by reducing leukocyte survival because: 1) Adam8−/− mice with AAI had fewer apoptotic eosinophils and macrophages in their airways than WT mice with AAI; and 2) Adam8−/− macrophages and eosinophils had reduced rates of apoptosis compared with WT leukocytes when the intrinsic (but not the extrinsic) apoptosis pathway was triggered in the cells in vitro. ADAM8 was robustly expressed by airway granulocytes in lung sections from human asthma patients but, surprisingly, airway macrophages had less ADAM8 staining than airway eosinophils. Thus, ADAM8 has anti-inflammatory activities during AAI in mice by activating the intrinsic apoptosis pathway in myeloid leukocytes. Strategies that increase ADAM8 levels in myeloid leukocytes may have therapeutic efficacy in asthma. PMID:23670189

Extraglottic airway devices: technology update

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Sharma B

2017-08-01

Full Text Available Bimla Sharma, Chand Sahai, Jayashree Sood Department of Anaesthesiology, Pain and Perioperative Medicine, Sir Ganga Ram Hospital, New Delhi, India Abstract: Extraglottic airway devices (EADs have revolutionized the field of airway management. The invention of the laryngeal mask airway was a game changer, and since then, there have been several innovations to improve the EADs in design, functionality, safety and construction material. These have ranged from changes in the shape of the mask, number of cuffs and material used, like rubber, polyvinylchloride and latex. Phthalates, which were added to the construction material in order to increase device flexibility, were later omitted when this chemical was found to have serious adverse reproductive outcomes. The various designs brought out by numerous companies manufacturing EADs resulted in the addition of several devices to the airway market. These airway devices were put to use, many of them with inadequate or no evidence base regarding their efficacy and safety. To reduce the possibility of compromising the safety of the patient, the Difficult Airway Society (DAS formed the Airway Device Evaluation Project Team (ADEPT to strengthen the evidence base for airway equipment and vet the new extraglottic devices. A preuse careful analysis of the design and structure may help in better understanding of the functionality of a particular device. In the meantime, the search for the ideal EAD continues. Keywords: extraglottic airway devices, laryngeal mask airway, other extraglottic airway devices, safety, technology update

Magnetic resonance imaging of the pediatric airway

International Nuclear Information System (INIS)

Auringer, S.T.; Bisset, G.S. III; Myer, C.M.

1991-01-01

Evaluation of the pediatric airway is often complex and may require multiple imaging techniques and invasive procedures. We performed magnetic resonance (MR) imaging of the airway in 34 children with clinical evidence of chronic airway obstruction and compared MR findings with those obtained by surgery and/or endoscopy. MR diagnoses included vascular compression in 15 patients, primary tracheomalacic states in 12 patients, and mediastinal masses in 4 patients. Findings were normal for 3 patients. The MR findings were in agreement with the endoscopic findings in 25 to 28 cases and in agreement with the surgical findings in 21 to 21 cases. (orig./GDG)

Airway management after maxillectomy with free flap reconstruction.

Science.gov (United States)

Brickman, Daniel S; Reh, Douglas D; Schneider, Daniel S; Bush, Ben; Rosenthal, Eben L; Wax, Mark K

2013-08-01

Maxillectomy defects require complex 3-dimensional reconstructions often best suited to microvascular free tissue transfer. Postoperative airway management during this procedure has little discussion in the literature and is often dictated by surgical dogma. The purpose of this article was to review our experience in order to evaluate the effect of airway management on perioperative outcomes in patients undergoing maxillectomy with free flap reconstruction. A retrospective chart review was performed on patients receiving maxillectomy with microvascular reconstruction at 2 institutions between 1999 and 2011. Patient's airways were managed with or without elective tracheotomy at the surgical team's discretion and different perioperative outcomes were measured. The primary outcome was incidence of airway complication including pneumonia and need for further airway intervention. Secondary outcome was measured as factors leading to perioperative performance of the tracheotomy. Seventy-nine of 143 patients received elective tracheotomy perioperatively. The incidence of airway complication was equivalent between groups (10.1% vs 9.4%; p = .89). Patients with cardiopulmonary comorbidities were more likely to receive perioperative tracheotomy (74.1% vs 50.9%; p = .03) without a difference in airway complications. Other patient cofactors did not have an impact on perioperative tracheotomy or airway complication rate. Elective tracheotomy may safely be avoided in a subset of patients undergoing maxillectomy with microvascular reconstruction. Elective tracheotomy should be considered in patients with cardiopulmonary risk factors. Copyright © 2012 Wiley Periodicals, Inc.

Propagation of respiratory viruses in human airway epithelia reveals persistent virus-specific signatures.

Science.gov (United States)

Essaidi-Laziosi, Manel; Brito, Francisco; Benaoudia, Sacha; Royston, Léna; Cagno, Valeria; Fernandes-Rocha, Mélanie; Piuz, Isabelle; Zdobnov, Evgeny; Huang, Song; Constant, Samuel; Boldi, Marc-Olivier; Kaiser, Laurent; Tapparel, Caroline

2018-06-01

The leading cause of acute illnesses, respiratory viruses, typically cause self-limited diseases, although severe complications can occur in fragile patients. Rhinoviruses (RVs), respiratory enteroviruses (EVs), influenza virus, respiratory syncytial viruses (RSVs), and coronaviruses are highly prevalent respiratory pathogens, but because of the lack of reliable animal models, their differential pathogenesis remains poorly characterized. We sought to compare infections by respiratory viruses isolated from clinical specimens using reconstituted human airway epithelia. Tissues were infected with RV-A55, RV-A49, RV-B48, RV-C8, and RV-C15; respiratory EV-D68; influenza virus H3N2; RSV-B; and human coronavirus (HCoV)-OC43. Replication kinetics, cell tropism, effect on tissue integrity, and cytokine secretion were compared. Viral adaptation and tissue response were assessed through RNA sequencing. RVs, RSV-B, and HCoV-OC43 infected ciliated cells and caused no major cell death, whereas H3N2 and EV-D68 induced ciliated cell loss and tissue integrity disruption. H3N2 was also detected in rare goblet and basal cells. All viruses, except RV-B48 and HCoV-OC43, altered cilia beating and mucociliary clearance. H3N2 was the strongest cytokine inducer, and HCoV-OC43 was the weakest. Persistent infection was observed in all cases. RNA sequencing highlighted perturbation of tissue metabolism and induction of a transient but important immune response at 4 days after infection. No majority mutations emerged in the viral population. Our results highlight the differential in vitro pathogenesis of respiratory viruses during the acute infection phase and their ability to persist under immune tolerance. These data help to appreciate the range of disease severity observed in vivo and the occurrence of chronic respiratory tract infections in immunocompromised hosts. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Effects of Human Parvovirus B19 and Bocavirus VP1 Unique Region on Tight Junction of Human Airway Epithelial A549 Cells

Science.gov (United States)

Chiu, Chun-Ching; Shi, Ya-Fang; Yang, Jiann-Jou; Hsiao, Yuan-Chao; Tzang, Bor-Show; Hsu, Tsai-Ching

2014-01-01

As is widely recognized, human parvovirus B19 (B19) and human bocavirus (HBoV) are important human pathogens. Obviously, both VP1 unique region (VP1u) of B19 and HBoV exhibit the secreted phospholipase A2 (sPLA2)-like enzymatic activity and are recognized to participate in the pathogenesis of lower respiratory tract illnesses. However, exactly how, both VP1u from B19 and HBoV affect tight junction has seldom been addressed. Therefore, this study investigates how B19-VP1u and HBoV-VP1u may affect the tight junction of the airway epithelial A549 cells by examining phospholipase A2 activity and transepithelial electrical resistance (TEER) as well as performing immunoblotting analyses. Experimental results indicate that TEER is more significantly decreased in A549 cells by treatment with TNF-α (10 ng), two dosages of B19-VP1u and BoV-VP1u (400 ng and 4000 ng) or bee venom PLA2 (10 ng) than that of the control. Accordingly, more significantly increased claudin-1 and decreased occludin are detected in A549 cells by treatment with TNF-α or both dosages of HBoV-VP1u than that of the control. Additionally, more significantly decreased Na+/K+ ATPase is observed in A549 cells by treatment with TNF-α, high dosage of B19-VP1u or both dosages of BoV-VP1u than that of the control. Above findings suggest that HBoV-VP1u rather than B19 VP1u likely plays more important roles in the disruption of tight junction in the airway tract. Meanwhile, this discrepancy appears not to be associated with the secreted phospholipase A2 (sPLA2)-like enzymatic activity. PMID:25268969

Prolonged ozone exposure in an allergic airway disease model: Adaptation of airway responsiveness and airway remodeling

Directory of Open Access Journals (Sweden)

Park Chang-Soo

2006-02-01

Full Text Available Abstract Background Short-term exposure to high concentrations of ozone has been shown to increase airway hyper-responsiveness (AHR. Because the changes in AHR and airway inflammation and structure after chronic ozone exposure need to be determined, the goal of this study was to investigate these effects in a murine model of allergic airway disease. Methods We exposed BALB/c mice to 2 ppm ozone for 4, 8, and 12 weeks. We measured the enhanced pause (Penh to methacholine and performed cell differentials in bronchoalveolar lavage fluid. We quantified the levels of IL-4 and IFN-γ in the supernatants of the bronchoalveolar lavage fluids using enzyme immunoassays, and examined the airway architecture under light and electron microscopy. Results The groups exposed to ozone for 4, 8, and 12 weeks demonstrated decreased Penh at methacholine concentrations of 12.5, 25, and 50 mg/ml, with a dose-response curve to the right of that for the filtered-air group. Neutrophils and eosinophils increased in the group exposed to ozone for 4 weeks compared to those in the filtered-air group. The ratio of IL-4 to INF-γ increased significantly after exposure to ozone for 8 and 12 weeks compared to the ratio for the filtered-air group. The numbers of goblet cells, myofibroblasts, and smooth muscle cells showed time-dependent increases in lung tissue sections from the groups exposed to ozone for 4, 8, and 12 weeks. Conclusion These findings demonstrate that the increase in AHR associated with the allergic airway does not persist during chronic ozone exposure, indicating that airway remodeling and adaptation following repeated exposure to air pollutants can provide protection against AHR.

General anesthetic octanol and related compounds activate wild-type and delF508 cystic fibrosis chloride channels.

Science.gov (United States)

Marcet, Brice; Becq, Frédéric; Norez, Caroline; Delmas, Patrick; Verrier, Bernard

2004-03-01

1. Cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel is defective during cystic fibrosis (CF). Activators of the CFTR Cl(-) channel may be useful for therapy of CF. Here, we demonstrate that a range of general anesthetics like normal-alkanols (n-alkanols) and related compounds can stimulate the Cl(-) channel activity of wild-type CFTR and delF508-CFTR mutant. 2. The effects of n-alkanols like octanol on CFTR activity were measured by iodide ((125)I) efflux and patch-clamp techniques on three distinct cellular models: (1). CFTR-expressing Chinese hamster ovary cells, (2). human airway Calu-3 epithelial cells and (3). human airway JME/CF15 epithelial cells which express the delF508-CFTR mutant. 3. Our data show for the first time that n-alkanols activate both wild-type CFTR and delF508-CFTR mutant. Octanol stimulated (125)I efflux in a dose-dependent manner in CFTR-expressing cells (wild-type and delF508) but not in cell lines lacking CFTR. (125)I efflux and Cl(-) currents induced by octanol were blocked by glibenclamide but insensitive to 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, as expected for a CFTR Cl(-) current. 4. CFTR activation by octanol was neither due to cell-to-cell uncoupling properties of octanol nor to an intracellular cAMP increase. CFTR activation by octanol requires phosphorylation by protein kinase-A (PKA) since it was prevented by H-89, a PKA inhibitor. 5. n-Alkanols chain length was an important determinant for channel activation, with rank order of potencies: 1-heptanoloctanoloctanol<1-decanol. Our findings may be of valuable interest for developing novel therapeutic strategies for CF.

Airway management in neuroanesthesiology.

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Aziz, Michael

2012-06-01

Airway management for neuroanesthesiology brings together some key principles that are shared throughout neuroanesthesiology. This article appropriately targets the cervical spine with associated injury and the challenges surrounding airway management. The primary focus of this article is on the unique airway management obstacles encountered with cervical spine injury or cervical spine surgery, and unique considerations regarding functional neurosurgery are addressed. Furthermore, topics related to difficult airway management for those with rheumatoid arthritis or pituitary surgery are reviewed. Copyright © 2012 Elsevier Inc. All rights reserved.

Roxithromycin inhibits VEGF-induced human airway smooth muscle cell proliferation: Opportunities for the treatment of asthma

International Nuclear Information System (INIS)

Pei, Qing-Mei; Jiang, Ping; Yang, Min; Qian, Xue-Jiao; Liu, Jiang-Bo; Kim, Sung-Ho

2016-01-01

Asthma is a chronic respiratory disease characterized by reversible airway obstruction with persistent airway inflammation and airway remodelling, which is associated with increased airway smooth muscle (ASM) mass. Roxithromycin (RXM) has been widely used in asthma treatment; however, its mechanism of action is poorly understood. Vascular endothelial growth factor (VEGF) has been implicated in inflammatory and airway blood vessel remodelling in patients with asthma, and shown to promote ASM cell proliferation. Here, we investigated the effect of RXM on VEGF-induced ASM cell proliferation and attempted to elucidate the underlying mechanisms of action. We tested the effect of RXM on proliferation and cell cycle progression, as well as on the expression of phospho-VEGF receptor 2 (VEGFR2), phospho-extracellular signal-regulated kinase 1/2 (ERK1/2), phospho-Akt, and caveolin-1 in VEGF-stimulated ASM cells. RXM inhibited VEGF-induced ASM cell proliferation and induced cell cycle arrest. Additionally, VEGF-induced ASM cell proliferation was suppressed by inhibiting the activity of ERK1/2, but not that of Akt. Furthermore, RXM treatment inhibits VEGF-induced activation of VEGFR2 and ERK and downregulation of caveolin-1 in a dose-dependent manner. RXM also inhibited TGF-β-induced VEGF secretion by ASM cells and BEAS-2B cells. Collectively, our findings suggest that RXM inhibits VEGF-induced ASM cell proliferation by suppression of VEGFR2 and ERK1/2 activation and caveolin-1 down-regulation, which may be involved in airway remodelling. Further elucidation of the mechanisms underlying these observations should enable the development of treatments for smooth muscle hyperplasia-associated diseases of the airway such as asthma. - Highlights: • RXM inhibited VEGF-induced ASM cell proliferation and induced cell cycle arrest. • VEGF-induced cell proliferation was suppressed by inhibiting the activity of ERK1/2. • RXM inhibits activation of VEGFR2 and ERK and downregulation

Roxithromycin inhibits VEGF-induced human airway smooth muscle cell proliferation: Opportunities for the treatment of asthma

Energy Technology Data Exchange (ETDEWEB)

Pei, Qing-Mei, E-mail: 34713316@qq.com [Department of Radiology, Tianjin Hospital of Integrated Traditional Chinese and Western Medicine, Tianjin (China); Jiang, Ping, E-mail: jiangping@163.com [Department of Respiration, Tianjin First Central Hospital, Tianjin (China); Yang, Min, E-mail: YangMin@163.com [Department of Respiration, Tianjin First Central Hospital, Tianjin (China); Qian, Xue-Jiao, E-mail: qianxuejiao@163.com [Department of Respiration, Tianjin First Central Hospital, Tianjin (China); Liu, Jiang-Bo, E-mail: LJB1984@163.com [Department of Respiration, Tianjin First Central Hospital, Tianjin (China); Kim, Sung-Ho, E-mail: chenghao0726@hotmail.com [Department of Respiration, Tianjin First Central Hospital, Tianjin (China)

2016-10-01

Asthma is a chronic respiratory disease characterized by reversible airway obstruction with persistent airway inflammation and airway remodelling, which is associated with increased airway smooth muscle (ASM) mass. Roxithromycin (RXM) has been widely used in asthma treatment; however, its mechanism of action is poorly understood. Vascular endothelial growth factor (VEGF) has been implicated in inflammatory and airway blood vessel remodelling in patients with asthma, and shown to promote ASM cell proliferation. Here, we investigated the effect of RXM on VEGF-induced ASM cell proliferation and attempted to elucidate the underlying mechanisms of action. We tested the effect of RXM on proliferation and cell cycle progression, as well as on the expression of phospho-VEGF receptor 2 (VEGFR2), phospho-extracellular signal-regulated kinase 1/2 (ERK1/2), phospho-Akt, and caveolin-1 in VEGF-stimulated ASM cells. RXM inhibited VEGF-induced ASM cell proliferation and induced cell cycle arrest. Additionally, VEGF-induced ASM cell proliferation was suppressed by inhibiting the activity of ERK1/2, but not that of Akt. Furthermore, RXM treatment inhibits VEGF-induced activation of VEGFR2 and ERK and downregulation of caveolin-1 in a dose-dependent manner. RXM also inhibited TGF-β-induced VEGF secretion by ASM cells and BEAS-2B cells. Collectively, our findings suggest that RXM inhibits VEGF-induced ASM cell proliferation by suppression of VEGFR2 and ERK1/2 activation and caveolin-1 down-regulation, which may be involved in airway remodelling. Further elucidation of the mechanisms underlying these observations should enable the development of treatments for smooth muscle hyperplasia-associated diseases of the airway such as asthma. - Highlights: • RXM inhibited VEGF-induced ASM cell proliferation and induced cell cycle arrest. • VEGF-induced cell proliferation was suppressed by inhibiting the activity of ERK1/2. • RXM inhibits activation of VEGFR2 and ERK and downregulation

Phase-contrast MRI and CFD modeling of apparent 3He gas flow in rat pulmonary airways

Science.gov (United States)

Minard, Kevin R.; Kuprat, Andrew P.; Kabilan, Senthil; Jacob, Richard E.; Einstein, Daniel R.; Carson, James P.; Corley, Richard A.

2012-08-01

Phase-contrast (PC) magnetic resonance imaging (MRI) with hyperpolarized 3He is potentially useful for developing and testing patient-specific models of pulmonary airflow. One challenge, however, is that PC-MRI provides apparent values of local 3He velocity that not only depend on actual airflow but also on gas diffusion. This not only blurs laminar flow patterns in narrow airways but also introduces anomalous airflow structure that reflects gas-wall interactions. Here, both effects are predicted in a live rat using computational fluid dynamics (CFD), and for the first time, simulated patterns of apparent 3He gas velocity are compared with in vivo PC-MRI. Results show (1) that correlations (R2) between measured and simulated airflow patterns increase from 0.23 to 0.79 simply by accounting for apparent 3He transport, and (2) that remaining differences are mainly due to uncertain airway segmentation and partial volume effects stemming from relatively coarse MRI resolution. Higher-fidelity testing of pulmonary airflow predictions should therefore be possible with future imaging improvements.

Paediatric airway management: basic aspects

DEFF Research Database (Denmark)

Holm-Knudsen, R J; Rasmussen, L S

2009-01-01

Paediatric airway management is a great challenge, especially for anaesthesiologists working in departments with a low number of paediatric surgical procedures. The paediatric airway is substantially different from the adult airway and obstruction leads to rapid desaturation in infants and small...... children. This paper aims at providing the non-paediatric anaesthesiologist with a set of safe and simple principles for basic paediatric airway management. In contrast to adults, most children with difficult airways are recognised before induction of anaesthesia but problems may arise in all children...

A confocal microscopic study of solitary pulmonary neuroendocrine cells in human airway epithelium

Directory of Open Access Journals (Sweden)

Sparrow Malcolm P

2005-10-01

Full Text Available Abstract Background Pulmonary neuroendocrine cells (PNEC are specialized epithelial cells that are thought to play important roles in lung development and airway function. PNEC occur either singly or in clusters called neuroepithelial bodies. Our aim was to characterize the three dimensional morphology of PNEC, their distribution, and their relationship to the epithelial nerves in whole mounts of adult human bronchi using confocal microscopy. Methods Bronchi were resected from non-diseased portions of a lobe of human lung obtained from 8 thoracotomy patients (Table 1 undergoing surgery for the removal of lung tumors. Whole mounts were stained with antibodies to reveal all nerves (PGP 9.5, sensory nerves (calcitonin gene related peptide, CGRP, and PNEC (PGP 9.5, CGRP and gastrin releasing peptide, GRP. The analysis and rendition of the resulting three-dimensional data sets, including side-projections, was performed using NIH-Image software. Images were colorized and super-imposed using Adobe Photoshop. Results PNEC were abundant but not homogenously distributed within the epithelium, with densities ranging from 65/mm2 to denser patches of 250/mm2, depending on the individual wholemount. Rotation of 3-D images revealed a complex morphology; flask-like with the cell body near the basement membrane and a thick stem extending to the lumen. Long processes issued laterally from its base, some lumenal and others with feet-like processes. Calcitonin gene-related peptide (CGRP was present in about 20% of PNEC, mainly in the processes. CGRP-positive nerves were sparse, with some associated with the apical part of the PNEC. Conclusion Our 3D-data demonstrates that PNEC are numerous and exhibit a heterogeneous peptide content suggesting an active and diverse PNEC population.

Exposure to welding fumes and lower airway infection with Streptococcus pneumoniae.

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Suri, Reetika; Periselneris, Jimstan; Lanone, Sophie; Zeidler-Erdely, Patti C; Melton, Geoffrey; Palmer, Keith T; Andujar, Pascal; Antonini, James M; Cohignac, Vanessa; Erdely, Aaron; Jose, Ricardo J; Mudway, Ian; Brown, Jeremy; Grigg, Jonathan

2016-02-01

Welders are at increased risk of pneumococcal pneumonia. The mechanism for this association is not known. The capacity of pneumococci to adhere to and infect lower airway cells is mediated by host-expressed platelet-activating factor receptor (PAFR). We sought to assess the effect of mild steel welding fumes (MS-WF) on PAFR-dependent pneumococcal adhesion and infection to human airway cells in vitro and on pneumococcal airway infection in a mouse model. The oxidative potential of MS-WF was assessed by their capacity to reduce antioxidants in vitro. Pneumococcal adhesion and infection of A549, BEAS-2B, and primary human bronchial airway cells were assessed by means of quantitative bacterial culture and expressed as colony-forming units (CFU). After intranasal instillation of MS-WF, mice were infected with Streptococcus pneumoniae, and bronchoalveolar lavage fluid (BALF) and lung CFU values were determined. PAFR protein levels were assessed by using immunofluorescence and immunohistochemistry, and PAFR mRNA expression was assessed by using quantitative PCR. PAFR was blocked by CV-3988, and oxidative stress was attenuated by N-acetylcysteine. MS-WF exhibited high oxidative potential. In A549 and BEAS-2B cells MS-WF increased pneumococcal adhesion and infection and PAFR protein expression. Both CV-3988 and N-acetylcysteine reduced MS-WF-stimulated pneumococcal adhesion and infection of airway cells. MS-WF increased mouse lung PAFR mRNA expression and increased BALF and lung pneumococcal CFU values. In MS-WF-exposed mice CV-3988 reduced BALF CFU values. Hypersusceptibility of welders to pneumococcal pneumonia is in part mediated by the capacity of welding fumes to increase PAFR-dependent pneumococcal adhesion and infection of lower airway cells. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. All rights reserved.

The potassium channel KCa3.1 as new therapeutic target for the prevention of obliterative airway disease

DEFF Research Database (Denmark)

Hua, Xiaoqin; Deuse, Tobias; Chen, Yi-Je

2013-01-01

The calcium-activated potassium channel KCa3.1 is critically involved in T-cell activation as well as in the proliferation of smooth muscle cells and fibroblasts. We sought to investigate whether KCa3.1 contributes to the pathogenesis of obliterative airway disease (OAD) and whether knockout or p...

Airway management in trauma.

Science.gov (United States)

Langeron, O; Birenbaum, A; Amour, J

2009-05-01

Maintenance of a patent and prevention of aspiration are essential for the management of the trauma patient, that requires experienced physicians in airway control techniques. Difficulties of the airway control in the trauma setting are increased by the vital failures, the risk of aspiration, the potential cervical spine injury, the combative patient, and the obvious risk of difficult tracheal intubation related to specific injury related to the trauma. Endotracheal intubation remains the gold standard in trauma patient airway management and should be performed via the oral route with a rapid sequence induction and a manual in-line stabilization maneuver, to decrease the risks previously mentioned. Different techniques to control the airway in trauma patients are presented: improvement of the laryngoscopic vision, lighted stylet tracheal intubation, retrograde technique for orotracheal intubation, the laryngeal mask and the intubating laryngeal mask airways, the combitube and cricothyroidotomy. Management of the airway in trauma patients requires regular training in these techniques and the knowledge of complementary techniques allowing tracheal intubation or oxygenation to overcome difficult intubation and to prevent major complications as hypoxemia and aspiration.

Physiologic correlates of airspace size and airway remodeling in the smoke exposed guinea pig model

NARCIS (Netherlands)

Wright, J. L.; Postma, D. S.; Kerstjens, H. A. M.; Timens, W.; Whittaker, P.; Churg, A.

2007-01-01

Although small airway remodeling (SAR) leading to airflow obstruction is a common consequence of human cigarette smoking, the airways have been largely ignored in animal models of chronic obstructive pulmonary disease ( COPD). We examined lung structure in a guinea pig model of chronic cigarette

Airway status in civilian maxillofacial gunshot Injuries in ...

African Journals Online (AJOL)

The airway was threatened in 20/92 cases at admission; 12/20 cases were treated with oro-or nasotracheal intubation, and 9/12 later had elective tracheostomies; 8/20 needed immediate surgical airways, 5 tracheostomies and 3 cricothyroidotomies (all later converted to tracheostomies). Three of thirty-seven patients with ...

The Laryngeal Mask Airway (LMA) as an alternative to airway ...

African Journals Online (AJOL)

Background: To evaluate the possibility of airway management using a laryngeal mask airway (LMA) during dental procedures on mentally retarded (MR) patients and patients with genetic diseases. Design: A prospective pilot study. Setting: University Hospital. Methods: A pilot study was designed to induce general ...

Airway necrosis after salvage esophagectomy

International Nuclear Information System (INIS)

Tanaka, Norimitsu; Hokamura, Nobukazu; Tachimori, Yuji

2010-01-01

Salvage esophagectomy is the sole curative intent treatment for patients with persistent or recurrent locoregional disease after definitive chemoradiotherapy (CRT) for esophageal carcinoma. However, salvage esophagectomy is a very high-risk operation, and airway necrosis is a fatal complication. Between 1997 and 2007, 49 patients with thoracic esophageal cancer underwent salvage esophagectomy after definitive CRT. We retrospectively compared patients with and without airway necrosis, and investigated operative procedures related to airway necrosis. Airway necrosis occurred in five patients (10.2%), of four patients (80%) died during their hospitalization. Airway necrosis seemed to be closely related to operative procedures, such as resection of bronchial artery and cervical and subcarinal lymph node dissection. Bronchogastric fistula following necrosis of gastric conduit occured in 2 patients reconstructed through posterior mediastinal route. Airway necrosis is a highly lethal complication after salvage esophagectomy. It is important in salvage esophagectomy to take airway blood supply into consideration sufficiently and to reconstruct through retrosternal route to prevent bronchogastric fistula. (author)

Randomised comparison of the effectiveness of the laryngeal mask airway supreme, i-gel and current practice in the initial airway management of prehospital cardiac arrest (REVIVE-Airways): a feasibility study research protocol.

Science.gov (United States)

Benger, Jonathan Richard; Voss, Sarah; Coates, David; Greenwood, Rosemary; Nolan, Jerry; Rawstorne, Steven; Rhys, Megan; Thomas, Matthew

2013-01-01

Effective cardiopulmonary resuscitation with appropriate airway management improves outcomes following out-of-hospital cardiac arrest (OHCA). Historically, tracheal intubation has been accepted as the optimal form of OHCA airway management in the UK. The Joint Royal Colleges Ambulance Liaison Committee recently concluded that newer supraglottic airway devices (SADs) are safe and effective devices for hospital procedures and that their use in OHCA should be investigated. This study will address an identified gap in current knowledge by assessing whether it is feasible to use a cluster randomised design to compare SADs with current practice, and also to each other, during OHCA. The primary objective of this study is to assess the feasibility of a cluster randomised trial to compare the ventilation success of two newer SADs: the i-gel and the laryngeal mask airway supreme to usual practice during the initial airway management of OHCA. The secondary objectives are to collect data on ventilation success, further airway interventions required, loss of a previously established airway during transport, airway management on arrival at hospital (or termination of the resuscitation attempt), initial resuscitation success, survival to intensive care admission, survival to hospital discharge and patient outcome at 3 months. Ambulance paramedics will be randomly allocated to one of the three methods of airway management. Adults in medical OHCA attended by a trial paramedic will be eligible for the study. Approval for the study has been obtained from a National Health Service Research Ethics Committee with authority to review proposals for trials of a medical device in incapacitated adults. The results will be made publicly available on an open access website, and we will publish the findings in appropriate journals and present them at national and international conferences relevant to the subject field. ISRCTN: 18528625.

Microbial ecology and adaptation in cystic fibrosis airways

DEFF Research Database (Denmark)

Yang, Lei; Jelsbak, Lars; Molin, Søren

2011-01-01

Chronic infections in the respiratory tracts of cystic fibrosis (CF) patients are important to investigate, both from medical and from fundamental ecological points of view. Cystic fibrosis respiratory tracts can be described as natural environments harbouring persisting microbial communities...... constitute the selective forces that drive the evolution of the microbes after they migrate from the outer environment to human airways. Pseudomonas aeruginosa adapts to the new environment through genetic changes and exhibits a special lifestyle in chronic CF airways. Understanding the persistent...... colonization of microbial pathogens in CF patients in the context of ecology and evolution will expand our knowledge of the pathogenesis of chronic infections and improve therapeutic strategies....

Bronchoscopic management of patients with symptomatic airway stenosis and prognostic factors for survival.

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Okiror, Lawrence; Jiang, Li; Oswald, Nicola; Bille, Andrea; Rajesh, Pala; Bishay, Ehab; Steyn, Richard; Naidu, Babu; Kalkat, Maninder

2015-05-01

Interventional bronchoscopy is effective in the management of patients with symptomatic airway obstruction for both malignant and benign conditions. The main aim of this study is to report our experience with emergency interventional bronchoscopy in patients with symptomatic airway obstruction and identify prognostic factors for survival. This is a retrospective observational study of patients undergoing emergency interventional bronchoscopy over a 4-year period. Survival times were analyzed separately for patients with benign and malignant airway obstruction by the Kaplan-Meier method. Between June 2009 and July 2013, 168 emergency interventional bronchoscopies were performed in 112 patients for airway obstruction. The median age was 63 years (range, 20 to 86), and 91 patients (54%) patients were female. Seventy-two cases (43%) had airway obstruction due to malignant disease. There were 3 in-hospital deaths (2.7%). Median survival of the study population was 5.6 months (range, 0 to 51) with a median follow-up of 7.3 months (range, 0 to 51). Median survival for patients with malignant airway obstruction was 3.5 months (range, 0 to 21), and 9.8 months (range, 0.1 to 51) for those with benign disease. Airway intervention facilitated palliative chemotherapy in 32 patients (44%) of those with malignant airway obstruction. At multivariate analysis in patients with malignant airway obstruction, presence of stridor (hazard ratio 1.919, 95% confidence interval: 1.082 to 3.404, p = 0.026) and not receiving postprocedure chemotherapy (hazard ratio 2.05, 95% confidence interval: 1.156 to 3.636, p = 0.014) were independent prognostic factors for death. Emergency interventional bronchoscopy for airway obstruction is safe, relieved symptoms, and facilitated palliative chemotherapy, which improved survival. Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Relapsing polychondritis and airway involvement.

Science.gov (United States)

Ernst, Armin; Rafeq, Samaan; Boiselle, Phillip; Sung, Arthur; Reddy, Chakravarthy; Michaud, Gaetane; Majid, Adnan; Herth, Felix J F; Trentham, David

2009-04-01

To assess the prevalence and characteristics of airway involvement in relapsing polychondritis (RP). Retrospective chart review and data analysis of RP patients seen in the Rheumatology Clinic and the Complex Airway Center at Beth Israel Deaconess Medical Center from January 2004 through February 2008. RP was diagnosed in 145 patients. Thirty-one patients had airway involvement, a prevalence of 21%. Twenty-two patients were women (70%), and they were between 11 and 61 years of age (median age, 42 years) at the time of first symptoms. Airway symptoms were the first manifestation of disease in 17 patients (54%). Dyspnea was the most common symptom in 20 patients (64%), followed by cough, stridor, and hoarseness. Airway problems included the following: subglottic stenosis (n = 8; 26%); focal and diffuse malacia (n = 15; 48%); and focal stenosis in different areas of the bronchial tree in the rest of the patients. Twelve patients (40%) required and underwent intervention including balloon dilatation, stent placement, tracheotomy, or a combination of the above with good success. The majority of patients experienced improvement in airway symptoms after intervention. One patient died during the follow-up period from the progression of airway disease. The rest of the patients continue to undergo periodic evaluation and intervention. In this largest cohort described in the English language literature, we found symptomatic airway involvement in RP to be common and at times severe. The nature of airway problems is diverse, with tracheomalacia being the most common. Airway intervention is frequently required and in experienced hands results in symptom improvement.

The effect of body weight on distal airway function and airway inflammation.

Science.gov (United States)

van de Kant, Kim D G; Paredi, Paolo; Meah, Sally; Kalsi, Harpal S; Barnes, Peter J; Usmani, Omar S

Obesity is a global health problem that adversely influences the respiratory system. We assessed the effects of body mass index (BMI) on distal airway function and airway inflammation. Impulse oscillometry (IOS) as a measure of distal airway function, together with spirometry, were assessed in adults with a range of different BMIs. Airway inflammation was assessed with the fraction of exhaled nitric oxide (FeNO) and participants exhaled at various exhalation flows to determine alveolar and bronchial NO. In total 34 subjects were enrolled in the study; 19 subjects had a normal BMI (18.50-24.99), whilst 15 subjects were overweight (BMI 25.00-29.99), or obese (BMI ≥30). All subjects had normal spirometry. However, IOS measures of airway resistance (R) at 5Hz, 20Hz and frequency dependence (R 5-20 ) were elevated in overweight/obese individuals, compared to subjects with a normal BMI (median (interquartile range)); 5Hz: 0.41 (0.37, 0.45) vs. 0.32 (0.30, 0.37)kPa/l/s; 20Hz: 0.34 (0.30, 0.37) vs. 0.30 (0.26, 0.33)kPa/l/s; R 5-20 : 0.06 (0.04, 0.11) vs. 0.03 (0.01, 0.05)kPa/l/s; plimitation) and FeNO inflammatory measures, did not differ between groups (p>0.05). Being overweight has significant effects on distal and central airway function as determined by IOS, which is not detected by spirometry. Obesity does not influence airway inflammation as measured by FeNO. IOS is a reliable technique to identify airway abnormalities in the presence of normal spirometry in overweight people. Copyright © 2015 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Comparison of airway responses in sheep of different age in precision-cut lung slices (PCLS.

Directory of Open Access Journals (Sweden)

Verena A Lambermont

Full Text Available Animal models should display important characteristics of the human disease. Sheep have been considered particularly useful to study allergic airway responses to common natural antigens causing human asthma. A rationale of this study was to establish a model of ovine precision-cut lung slices (PCLS for the in vitro measurement of airway responses in newborn and adult animals. We hypothesized that differences in airway reactivity in sheep are present at different ages.Lambs were delivered spontaneously at term (147d and adult sheep lived till 18 months. Viability of PCLS was confirmed by the MTT-test. To study airway provocations cumulative concentration-response curves were performed with different allergic response mediators and biogenic amines. In addition, electric field stimulation, passive sensitization with house dust mite (HDM and mast cells staining were evaluated.PCLS from sheep were viable for at least three days. PCLS of newborn and adult sheep responded equally strong to methacholine and endothelin-1. The responses to serotonin, leukotriene D4 and U46619 differed with age. No airway contraction was evoked by histamine, except after cimetidine pretreatment. In response to EFS, airways in PCLS from adult and newborn sheep strongly contracted and these contractions were atropine sensitive. Passive sensitization with HDM evoked a weak early allergic response in PCLS from adult and newborn sheep, which notably was prolonged in airways from adult sheep. Only few mast cells were found in the lungs of non-sensitized sheep at both ages.PCLS from sheep lungs represent a useful tool to study pharmacological airway responses for at least three days. Sheep seem well suited to study mechanisms of cholinergic airway contraction. The notable differences between newborn and adult sheep demonstrate the importance of age in such studies.

Assessment of airway lesion in obstructive lung diseases by CT

International Nuclear Information System (INIS)

Niimi, Akio; Matsumoto, Hisako; Ueda, Tetsuya; Mishima, Michiaki

2002-01-01

Airway lesion in obstructive pulmonary diseases, such as asthma or chronic obstructive pulmonary disease (COPD), has recently been assessed quantitatively. Especially in asthma, wall thickening of central airways, and its relation to the severity of disease or airflow obstruction has been clarified. Pathophysiologic importance of peripheral airway lesion has also been highlighted by pathologic or physiologic studies. However, direct evaluation of peripheral airway lesion is beyond resolutional limitation of CT. To assess airway trapping, an indirect CT finding of peripheral airway disease, by quantitative and semiquantitative measures and compare them with clinical indices such as pulmonary function, airway responsiveness, or airway inflammation. Patients with stable asthma (n=20) were studied. HRCT at 3 levels of both lungs were scanned. Low attenuation area (LAA)% and mean lung density were quantitatively assessed by an automatic method. Distribution of mosaic pattern was visually scored semiquantitatively. LAA% and mean lung density at full expiratory phase correlated with the degree of airflow obstruction. Mosaic score at full inspiratory phase correlated with the severity of disease and airflow obstruction. Expiratory/inspiratory ratio of mean lung density was also associated with airway responsiveness or residual volume/total lung capacity (RV/TLC). These CT findings may be useful as markers of asthma pathophysiology. (author)

Defective Resensitization in Human Airway Smooth Muscle Cells Evokes β-Adrenergic Receptor Dysfunction in Severe Asthma.

Directory of Open Access Journals (Sweden)

Manveen K Gupta

Full Text Available β2-adrenergic receptor (β2AR agonists (β2-agonist are the most commonly used therapy for acute relief in asthma, but chronic use of these bronchodilators paradoxically exacerbates airway hyper-responsiveness. Activation of βARs by β-agonist leads to desensitization (inactivation by phosphorylation through G-protein coupled receptor kinases (GRKs which mediate β-arrestin binding and βAR internalization. Resensitization occurs by dephosphorylation of the endosomal βARs which recycle back to the plasma membrane as agonist-ready receptors. To determine whether the loss in β-agonist response in asthma is due to altered βAR desensitization and/or resensitization, we used primary human airway smooth muscle cells (HASMCs isolated from the lungs of non-asthmatic and fatal-asthmatic subjects. Asthmatic HASMCs have diminished adenylyl cyclase activity and cAMP response to β-agonist as compared to non-asthmatic HASMCs. Confocal microscopy showed significant accumulation of phosphorylated β2ARs in asthmatic HASMCs. Systematic analysis of desensitization components including GRKs and β-arrestin showed no appreciable differences between asthmatic and non-asthmatic HASMCs. However, asthmatic HASMC showed significant increase in PI3Kγ activity and was associated with reduction in PP2A activity. Since reduction in PP2A activity could alter receptor resensitization, endosomal fractions were isolated to assess the agonist ready β2ARs as a measure of resensitization. Despite significant accumulation of β2ARs in the endosomes of asthmatic HASMCs, endosomal β2ARs cannot robustly activate adenylyl cyclase. Furthermore, endosomes from asthmatic HASMCs are associated with significant increase in PI3Kγ and reduced PP2A activity that inhibits β2AR resensitization. Our study shows that resensitization, a process considered to be a homeostasis maintaining passive process is inhibited in asthmatic HASMCs contributing to β2AR dysfunction which may underlie

Airway malacia in children with achondroplasia.

Science.gov (United States)

Dessoffy, Kimberly E; Modaff, Peggy; Pauli, Richard M

2014-02-01

This study was undertaken to assess the frequency of airway malacia in infants and young children with achondroplasia, a population well known to be at risk for a variety of respiratory problems. We also wished to evaluate what, if any, contribution airway malacia makes to the complex respiratory issues that may be present in those with achondroplasia. Retrospective chart review of all infants and young children with achondroplasia who were assessed through the Midwest Regional Bone Dysplasia Clinics from 1985 through 2012 (n = 236) was completed. Records of comprehensive clinical examinations, polysomnographic assessments, and airway visualization were reviewed and abstracted using a data collection form. Analyses were completed comparing the group with and those without evidence for airway malacia. Thirteen of 236 patients (5.5%) were found to have airway malacia. Most of those affected had lower airway involvement (9/13). The presence of airway malacia was correlated with an increased occurrence of obstructive sleep apnea as well as need for oxygen supplementation, airway surgeries and tracheostomy placement. Although estimates of the frequency of airway malacia in the general population are limited, its frequency in children with achondroplasia appears to be much higher than any published general population estimate. The presence of airway malacia appears to confound other breathing abnormalities in this population and results in the need for more invasive airway treatments. © 2013 Wiley Periodicals, Inc.

Effects of Ginger and Its Constituents on Airway Smooth Muscle Relaxation and Calcium Regulation

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Siviski, Matthew E.; Zhang, Yi; Xu, Carrie; Hoonjan, Bhupinder; Emala, Charles W.

2013-01-01

The prevalence of asthma has increased in recent years, and is characterized by airway hyperresponsiveness and inflammation. Many patients report using alternative therapies to self-treat asthma symptoms as adjuncts to short-acting and long-acting β-agonists and inhaled corticosteroids (ICS). As many as 40% of patients with asthma use herbal therapies to manage asthma symptoms, often without proven efficacy or known mechanisms of action. Therefore, investigations of both the therapeutic and possible detrimental effects of isolated components of herbal treatments on the airway are important. We hypothesized that ginger and its active components induce bronchodilation by modulating intracellular calcium ([Ca2+]i) in airway smooth muscle (ASM). In isolated human ASM, ginger caused significant and rapid relaxation. Four purified constituents of ginger were subsequently tested for ASM relaxant properties in both guinea pig and human tracheas: [6]-gingerol, [8]-gingerol, and [6]-shogaol induced rapid relaxation of precontracted ASM (100–300 μM), whereas [10]-gingerol failed to induce relaxation. In human ASM cells, exposure to [6]-gingerol, [8]-gingerol, and [6]-shogaol, but not [10]-gingerol (100 μM), blunted subsequent Ca2+ responses to bradykinin (10 μM) and S-(−)-Bay K 8644 (10 μM). In A/J mice, the nebulization of [8]-gingerol (100 μM), 15 minutes before methacholine challenge, significantly attenuated airway resistance, compared with vehicle. Taken together, these novel data show that ginger and its isolated active components, [6]-gingerol, [8]-gingerol, and [6]-shogaol, relax ASM, and [8]-gingerol attenuates airway hyperresponsiveness, in part by altering [Ca2+]i regulation. These purified compounds may provide a therapeutic option alone or in combination with accepted therapeutics, including β2-agonists, in airway diseases such as asthma. PMID:23065130

Characterizing adult human nasal airway dimensions

International Nuclear Information System (INIS)

Guilmette, R.A.; Griffith, W.C.

1994-01-01

Respiratory tract models used in calculating radiation dose from exposure to inhaled radioactive aerosols have only recently focused attention on the importance of the nasal airways (NAs). Because the NAs are the first tissues of the respiratory tract available for aerosol deposition in normally nose-breathing people, any deposition of aerosol in this anatomical structure will reduce the amounts available to be deposited in the remainder of the respiratory tract. Thus, uncertainties in estimating the deposition fractions in the NAs will propagate throughout the remainder of the respiratory tract, creating errors in the calculated dose estimates. Additionally, there is evidence that the NAs are also at risk for induction of cancer from exposure to certain occupational aerosols such as wood dust, leather dust, chromium, and nickel. The purpose of this investigation was to conduct an anatomical study to assess the variabilities in NA dimensions

Relationship between airway pathophysiology and airway inflammation in older asthmatics

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Porsbjerg, Celeste M; Gibson, Peter G; Pretto, Jeffrey J

2013-01-01

-dose ratio (%fall in forced expiratory volume in 1 s (FEV1 )/mg saline). Airway closure was assessed during bronchoconstriction percent change in forced vital capacity (FVC)/percent change in FEV1 (i.e. Closing Index). Airway inflammation was assessed by induced sputum and exhaled nitric oxide (eNO). RESULTS...

Airway accidents in critical care unit: A 3-year retrospective study in a Public Teaching Hospital of Eastern India

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Dasgupta, Sugata; Singh, Shipti Shradha; Chaudhuri, Arunima; Bhattacharya, Dipasri; Choudhury, Sourav Das

2016-01-01

Background: Although tracheal tubes are essential devices to control and protect airway in a critical care unit (CCU), they are not free from complications. Aims: To document the incidence and nature of airway accidents in the CCU of a government teaching hospital in Eastern India. Methods: Retrospective analysis of all airway accidents in a 5-bedded (medical and surgical) CCU. The number, types, timing, and severity of airway accidents were analyzed. Results: The total accident rate was 19 in 233 intubated and/or tracheostomized patients over 1657 tube days (TDs) during 3 years. Fourteen occurred in 232 endotracheally intubated patients over 1075 endotracheal tube (ETT) days, and five occurred in 44 tracheostomized patients over 580 tracheostomy TDs. Fifteen accidents were due to blocked tubes. Rest four were unplanned extubations (UEs), all being accidental extubations. All blockages occurred during night shifts and all UEs during day shifts. Five accidents were mild, the rest moderate. No major accident led to cardiorespiratory arrest or death. All blockages occurred after 7th day of intubation. The outcome of accidents were more favorable in tracheostomy group compared to ETT group (P = 0.001). Conclusions: The prevalence of airway accidents was 8.2 accidents per 100 patients. Blockages were the most common accidents followed by UEs. Ten out of the 15 blockages and all 4 UEs were in endotracheally intubated patients. Tracheostomized patients had 5 blockages and no UEs. PMID:27076709

Fiberoptic intubation through laryngeal mask airway for management of difficult airway in a child with Klippel-Feil syndrome

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Ravi Bhat

2014-01-01

Full Text Available The ideal airway management modality in pediatric patients with syndromes like Klippel-Feil syndrome is a great challenge and is technically difficult for an anesthesiologist. Half of the patients present with the classic triad of short neck, low hairline, and fusion of cervical vertebra. Numerous associated anomalies like scoliosis or kyphosis, cleft palate, respiratory problems, deafness, genitourinary abnormalities, Sprengel′s deformity (wherein the scapulae ride high on the back, synkinesia, cervical ribs, and congenital heart diseases may further add to the difficulty. Fiberoptic bronchoscopy alone can be technically difficult and patient cooperation also becomes very important, which is difficult in pediatric patients. Fiberoptic bronchoscopy with the aid of supraglottic airway devices is a viable alternative in the management of difficult airway in children. We report a case of Klippel-Feil syndrome in an 18-month-old girl posted for cleft palate surgery. Imaging of spine revealed complete fusion of the cervical vertebrae with hypoplastic C3 and C6 vertebrae and thoracic kyphosis. We successfully managed airway in this patient by fiberoptic intubation through classic laryngeal mask airway (LMA. After intubation, we used second smaller endotracheal tube (ETT to stabilize and elongate the first ETT while removing the LMA.

Design, characterization and use of replicate human upper airways for radon dosimetry studies

International Nuclear Information System (INIS)

Swift, D.L.; Cheng, Y.S.; Su, Y.F.; Yeh, H.C.

1992-01-01

The size distribution of inhaled radon progeny aerosols is a significant factor in dosimetry. The role of the airways above the trachea is an important determinant of the respiratory distribution of both attached and unattached progeny aerosols. In order to provide information on the effect of particle size and breathing conditions on the overall and local deposition, we have developed a method to produce a replicate airway model from an in vivo magnetic resonance imaging coronal scan. The model consists of a sandwich of methacrylate elements, each element having the thickness of the scan interval. The transition between successive scan outlines traced on the front and back surfaces of each element is handsculpted in the plastic. The hollow model of the nasal passages thus produced has been characterized both morphologically and fluid-mechanically and has a flow resistance typical of a normal adult. The model has several distinct advantages for studies of radon progeny aerosol deposition. After exposure to a radioaerosol (or to an aerosol of an otherwise measurable substance) the individual elements can be separated to determine local deposition. The dimensions of specific upper-airway regions can be changed by replacing a small number of elements. The model has been incorporated in an exposure system for determining overall nandregional deposition of aerosols whose median diameter is approximately 1.7 nm. Measurements at several flow rates are presented to demonstrate use of the model in radon dosimetry. The model should also be useful for determining the airway deposition of other environmental aerosols

Impending Airway Compromise due to Cystic Hygroma

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Itai Shavit

2011-05-01

Full Text Available We report on a 3-month-old infant, who arrived in the pediatric emergency department (ED with a cervical cystic hygroma causing an impending compromise of the airway. We recognize that such a lesion can rapidly progress, and the judicious use of imaging in the ED may help to avoid airway compromise and possibly fatal complications. [West J Emerg Med. 2011;12(4:368–369.

Interleukin (IL) 36 gamma induces mucin 5AC, oligomeric mucus/gel-forming expression via IL-36 receptor-extracellular signal regulated kinase 1 and 2, and p38-nuclear factor kappa-light-chain-enhancer of activated B cells in human airway epithelial cells.

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Bae, Chang Hoon; Choi, Yoon Seok; Na, Hyung Gyun; Song, Si-Youn; Kim, Yong-Dae

2018-03-01

Mucin 5AC, oligomeric mucus/gel-forming (MUC5AC) expression is significantly increased in allergic and inflammatory airway diseases. Interleukin (IL) 36 gamma is predominantly expressed in airway epithelial cells and plays an important role in innate and adaptive immune responses. IL-36 gamma is induced by many inflammatory mediators, including cytokines and bacterial and viral infections. However, the association between IL-36 gamma and mucin secretion in human airway epithelial cells has not yet been fully investigated. The objective of this study was to determine whether IL-36 gamma might play a role in the regulation of mucin secretion in airway epithelial cells. We investigated the effect and brief signaling pathway of IL-36 gamma on MUC5AC expression in human airway epithelial cells. Enzyme immunoassay, immunoblot analysis, immunofluorescence staining, reverse transcriptase-polymerase chain reaction (PCR), and real-time PCR were performed in mucin-producing human airway epithelial NCI-H292 cells and in human nasal epithelial cells after pretreatment with IL-36 gamma, several specific inhibitors, or small interfering RNAs (siRNA). IL-36 gamma induced MUC5AC expression and activated the phosphorylation of extracellular signal regulated kinase (ERK) 1 and 2, p38, and nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-kappa B). IL-36 receptor antagonist significantly attenuated these effects. The specific inhibitor and siRNA of ERK1, ERK2, p38, and NF-kappa B significantly attenuated IL-36 gamma induced MUC5AC expression. These results indicated that IL-36 gamma induced MUC5AC expression via the IL-36 receptor-mediated ERK1/2 and p38/NF-kappa B pathway in human airway epithelial cells.

Induction of Activating Transcription Factor 3 Is Associated with Cisplatin Responsiveness in Non–Small Cell Lung Carcinoma Cells

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Jair Bar

2016-09-01

Full Text Available Non–small cell lung carcinoma (NSCLC is the most common cause of cancer deaths, with platin-based combination chemotherapy the most efficacious therapies. Gains in overall survival are modest, highlighting the need for novel therapeutic approaches including the development of next-generation platin combination regimens. The goal of this study was to identify novel regulators of platin-induced cytotoxicity as potential therapeutic targets to further enhance platin cytotoxicity. Employing RNA-seq transcriptome analysis comparing two parental NSCLC cell lines Calu6 and H23 to their cisplatin-resistant sublines, Calu6cisR1 and H23cisR1, activating transcription factor 3 (ATF3 was robustly induced in cisplatin-treated parental sensitive cell lines but not their resistant sublines, and in three of six tumors evaluated, but not in their corresponding normal adjacent lung tissue (0/6. Cisplatin-induced JNK activation was a key regulator of this ATF3 induction. Interestingly, in both resistant sublines, this JNK induction was abrogated, and the expression of an activated JNK construct in these cells enhanced both cisplatin-induced cytotoxicity and ATF3 induction. An FDA-approved drug compound screen was employed to identify enhancers of cisplatin cytotoxicity that were dependent on ATF3 gene expression. Vorinostat, a histone deacetylase inhibitor, was identified in this screen and demonstrated synergistic cytotoxicity with cisplatin in both the parental Calu6 and H23 cell lines and importantly in their resistant sublines as well that was dependent on ATF3 expression. Thus, we have identified ATF3 as an important regulator of cisplatin cytotoxicity and that ATF3 inducers in combination with platins are a potential novel therapeutic approach for NSCLC.

Dioscorin pre-treatment protects A549 human airway epithelial cells from hydrogen peroxide-induced oxidative stress.

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Hsu, Jeng-Yuan; Chu, Jao-Jia; Chou, Ming-Chih; Chen, Ya-Wen

2013-10-01

Hydrogen peroxide (H(2)O(2)) is a highly reactive oxygen species involved in lung and bronchial epithelium injury. Increased H(2)O(2) levels have been reported in expired breath condensates of patients with inflammatory airway diseases such as chronic obstructive pulmonary disease. Protecting airway epithelial cells from oxidative stress is an important task in the prevention and management of airway diseases. Previous studies demonstrate that yam (Dioscorea batatas Decne) has antioxidant and anti-trypsin activities. This study evaluated the validity of dioscorin in vitro. The results showed that dioscorin attenuated the alteration of H(2)O(2) on G2/M cell cycle arrest. This might be associated with the activation of IκB and subsequent inactivation of NF-κB. Furthermore, dioscorin suppressed IL-8 secretion and reduced changes of adhesion molecule expressions in H(2)O(2)-injured A549 cells. These results help in understanding the potential of traditional Chinese herbal medicine as treatment for airway inflammatory diseases.

Clinical review: Management of difficult airways

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Langeron, Olivier; Amour, Julien; Vivien, Benoît; Aubrun, Frédéric

2006-01-01

Difficulties or failure in airway management are still important factors in morbidity and mortality related to anesthesia and intensive care. A patent and secure airway is essential to manage anesthetized or critically ill patients. Oxygenation maintenance during tracheal intubation is the cornerstone of difficult airway management and is always emphasized in guidelines. The occurrence of respiratory adverse events has decreased in claims for injuries due to inadequate airway management mainly at induction of anesthesia. Nevertheless, claim reports emphasize that airway emergencies, tracheal extubation and/or recovery of anesthesia phases are still associated with death or brain damage, indicating that additional educational support and management strategies to improve patient safety are required. The present brief review analyses specific problems of airway management related to difficult tracheal intubation and to difficult mask ventilation prediction. The review will focus on basic airway management including preoxygenation, and on some oxygenation and tracheal intubation techniques that may be performed to solve a difficult airway. PMID:17184555

Clinical review: management of difficult airways.

Science.gov (United States)

Langeron, Olivier; Amour, Julien; Vivien, Benoît; Aubrun, Frédéric

2006-01-01

Difficulties or failure in airway management are still important factors in morbidity and mortality related to anesthesia and intensive care. A patent and secure airway is essential to manage anesthetized or critically ill patients. Oxygenation maintenance during tracheal intubation is the cornerstone of difficult airway management and is always emphasized in guidelines. The occurrence of respiratory adverse events has decreased in claims for injuries due to inadequate airway management mainly at induction of anesthesia. Nevertheless, claim reports emphasize that airway emergencies, tracheal extubation and/or recovery of anesthesia phases are still associated with death or brain damage, indicating that additional educational support and management strategies to improve patient safety are required. The present brief review analyses specific problems of airway management related to difficult tracheal intubation and to difficult mask ventilation prediction. The review will focus on basic airway management including preoxygenation, and on some oxygenation and tracheal intubation techniques that may be performed to solve a difficult airway.

Manipulation of Cell Physiology Enables Gene Silencing in Well-differentiated Airway Epithelia

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Sateesh Krishnamurthy

2012-01-01

Full Text Available The application of RNA interference-based gene silencing to the airway surface epithelium holds great promise to manipulate host and pathogen gene expression for therapeutic purposes. However, well-differentiated airway epithelia display significant barriers to double-stranded small-interfering RNA (siRNA delivery despite testing varied classes of nonviral reagents. In well-differentiated primary pig airway epithelia (PAE or human airway epithelia (HAE grown at the air–liquid interface (ALI, the delivery of a Dicer-substrate small-interfering RNA (DsiRNA duplex against hypoxanthine–guanine phosphoribosyltransferase (HPRT with several nonviral reagents showed minimal uptake and no knockdown of the target. In contrast, poorly differentiated cells (2–5-day post-seeding exhibited significant oligonucleotide internalization and target knockdown. This finding suggested that during differentiation, the barrier properties of the epithelium are modified to an extent that impedes oligonucleotide uptake. We used two methods to overcome this inefficiency. First, we tested the impact of epidermal growth factor (EGF, a known enhancer of macropinocytosis. Treatment of the cells with EGF improved oligonucleotide uptake resulting in significant but modest levels of target knockdown. Secondly, we used the connectivity map (Cmap database to correlate gene expression changes during small molecule treatments on various cells types with genes that change upon mucociliary differentiation. Several different drug classes were identified from this correlative assessment. Well-differentiated epithelia treated with DsiRNAs and LY294002, a PI3K inhibitor, significantly improved gene silencing and concomitantly reduced target protein levels. These novel findings reveal that well-differentiated airway epithelia, normally resistant to siRNA delivery, can be pretreated with small molecules to improve uptake of synthetic oligonucleotide and RNA interference (RNAi responses.

Serum IgE Induced Airway Smooth Muscle Cell Remodeling Is Independent of Allergens and Is Prevented by Omalizumab

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Roth, Michael; Zhao, Feng; Zhong, Jun; Lardinois, Didier; Tamm, Michael

2015-01-01

Background Airway wall remodeling in allergic asthma is reduced after treatment with humanized anti-IgE-antibodies. We reported earlier that purified IgE, without the presence of allergens, is sufficient to induce airway wall remodeling due to airway smooth muscle cell (ASMC) activity deposing extracellular matrix. Objective We postulate that IgE contained in serum of allergic asthma patients, in the absence of allergens, stimulates ASMC remodeling activities and can be prevented by anti-IgE antibodies. Methods Isolated human ASMC were exposed to serum obtained from: (i) healthy controls, or patients with (ii) allergic asthma, (iii) non-allergic asthma, and (iv) atopic non-asthma patients. Proliferation and the deposition of collagens and fibronectin were determined after 3 and 5 days. Results Serum from patients with allergies significantly stimulated: (i) ASMC proliferation, (ii) deposition of collagen type-I (48 hours) and (iii) of fibronectin (24 hours). One hour pre-incubation with Omalizumab prevented these three effects of allergic serum, but had no significant effect on serum from healthy donors or non-allergic asthma patients. Interestingly, the addition of allergens did not further increase any of the IgE effects. Conclusion and Clinical Relevance Our data provides experimental evidence that the beneficial effect of Omalizumab on airway wall remodeling and improved lung function may be due to its direct action on IgE bound ASMC. PMID:26332463

Serum IgE Induced Airway Smooth Muscle Cell Remodeling Is Independent of Allergens and Is Prevented by Omalizumab.

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Michael Roth

Full Text Available Airway wall remodeling in allergic asthma is reduced after treatment with humanized anti-IgE-antibodies. We reported earlier that purified IgE, without the presence of allergens, is sufficient to induce airway wall remodeling due to airway smooth muscle cell (ASMC activity deposing extracellular matrix.We postulate that IgE contained in serum of allergic asthma patients, in the absence of allergens, stimulates ASMC remodeling activities and can be prevented by anti-IgE antibodies.Isolated human ASMC were exposed to serum obtained from: (i healthy controls, or patients with (ii allergic asthma, (iii non-allergic asthma, and (iv atopic non-asthma patients. Proliferation and the deposition of collagens and fibronectin were determined after 3 and 5 days.Serum from patients with allergies significantly stimulated: (i ASMC proliferation, (ii deposition of collagen type-I (48 hours and (iii of fibronectin (24 hours. One hour pre-incubation with Omalizumab prevented these three effects of allergic serum, but had no significant effect on serum from healthy donors or non-allergic asthma patients. Interestingly, the addition of allergens did not further increase any of the IgE effects.Our data provides experimental evidence that the beneficial effect of Omalizumab on airway wall remodeling and improved lung function may be due to its direct action on IgE bound ASMC.

Airway Management in a Patient with Wolf-Hirschhorn Syndrome.

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Gamble, John F; Kurian, Dinesh J; Udani, Andrea G; Greene, Nathaniel H

2016-01-01

We present a case of a 3-month-old female with Wolf-Hirschhorn syndrome (WHS) undergoing general anesthesia for laparoscopic gastrostomy tube placement with a focus on airway management. WHS is a rare 4p microdeletion syndrome resulting in multiple congenital abnormalities, including craniofacial deformities. Microcephaly, micrognathia, and glossoptosis are common features in WHS patients and risk factors for a pediatric airway that is potentially difficult to intubate. We discuss anesthesia strategies for airway preparation and management in a WHS patient requiring general anesthesia with endotracheal intubation.

Airway epithelial NF-κB activation promotes Mycoplasma pneumoniae clearance in mice.

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Di Jiang

Full Text Available Respiratory infections including atypical bacteria Mycoplasma pneumoniae (Mp contribute to the pathobiology of asthma and chronic obstructive pulmonary disease (COPD. Mp infection mainly targets airway epithelium and activates various signaling pathways such as nuclear factor κB (NF-κB. We have shown that short palate, lung, and nasal epithelium clone 1 (SPLUNC1 serves as a novel host defense protein and is up-regulated upon Mp infection through NF-κB activation in cultured human and mouse primary airway epithelial cells. However, the in vivo role of airway epithelial NF-κB activation in host defense against Mp infection has not been investigated. In the current study, we investigated the effects of in vivo airway epithelial NF-κB activation on lung Mp clearance and its association with airway epithelial SPLUNC1 expression.Non-antimicrobial tetracycline analog 9-t-butyl doxycycline (9-TB was initially optimized in mouse primary tracheal epithelial cell culture, and then utilized to induce in vivo airway epithelial specific NF-κB activation in conditional NF-κB transgenic mice (CC10-(CAIKKβ with or without Mp infection. Lung Mp load and inflammation were evaluated, and airway epithelial SPLUNC1 protein was examined by immunohistochemistry. We found that 9-TB treatment in NF-κB transgene positive (Tg+, but not transgene negative (Tg- mice significantly reduced lung Mp load. Moreover, 9-TB increased airway epithelial SPLUNC1 protein expression in NF-κB Tg+ mice.By using the non-antimicrobial 9-TB, our study demonstrates that in vivo airway epithelial NF-κB activation promotes lung bacterial clearance, which is accompanied by increased epithelial SPLUNC1 expression.

Covered Balloon-Expanding Stents in Airway Stenosis.

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Majid, Adnan; Kheir, Fayez; Chung, Jey; Alape, Daniel; Husta, Bryan; Oh, Scott; Folch, Erik

2017-04-01

The balloon-expanding stents are widely available but rarely described for use within the tracheobronchial tree. This report describes our experience with these stents in airway stenosis particularly as a lobar salvage therapy. This was a retrospective review of all records in which the balloon-expanding stents were used at a tertiary medical center. Ages, sex, location of stenosis, etiology of stenosis, stent size, duration of stent placement and associated interventions for airway stenosis were recorded. Patient's self-reported respiratory symptoms, dyspnea scale, and radiographic imaging at baseline and after stent placement were also reported. Twenty-one Atrium iCAST stents were inserted in 18 patients with malignant and benign airway disease. The median age was 69.5 years (interquartile range, 53.5 to 74). Most stents (n=20, 95%) were deployed in the lobar airways. There was a significant improvement in the modified Medical Research Council dyspnea scale from median of 3 to 2 (Pstent placement was achieved in 15 patients (83%). No deaths were related to airway stenting complications. Adverse events related to stents included migration (n=2, 9.5%), granulation tissue formation (n=2, 9.5%) and mucus plugging (n=1, 4.8%). Lobar stenting with balloon-expanding metallic stents appears feasible, safe and improves symptoms as well as radiographic atelectasis in patients with lobar airway stenosis in this small case series. Larger studies are needed to confirm this observation and to address long-term safety.

Particle deposition in human and canine tracheobronchial casts: Annual progress report

International Nuclear Information System (INIS)

Cohen, B.S.

1987-01-01

This work measures deposition patterns and efficiencies of aerosols within realistic, physical models of the tracheobronchial airways of humans and experimental animals over a range of particle sizes from 0.01 to 1.0 μm, for a variety of respiratory modes and rates. Full morphometric and flow distribution measurements were completed on casts of human and canine tracheobronchial airways, which extend from just below the larynx to airways 1 mm in diameter. They show basic similarities in the distribution of airflow, but also species differences which must be considered. The distribution of airflow was measured for minute volumes equivalent to 6, 11, 17 and 22 L min -1 for the human and 3, 6, 8 and 11 L min -1 for the canine for both constant and pulsatile inspiratory flow. Inertance was found to carry more of the flow to airways of the lower lobes at higher flow rates. Basic differences in airway branching pattern result in a more distinct change in airflow distribution as flow rate changes for the canine cast as compared with the human cast. These differences will contribute to differing patterns of mass transfer of inhaled particles in central airways of the two species. 8 refs., 2 figs., 5 tabs

Anatomic and physiopathologic changes affecting the airway of the elderly patient: implications for geriatric-focused airway management

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Johnson KN

2015-12-01

Full Text Available Kathleen N Johnson,1 Daniel B Botros,1 Leanne Groban,1–4 Yvon F Bryan11Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA; 2Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA; 3Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, NC, USA; 4Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston-Salem, NC, USAAbstract: There are many anatomical, physiopathological, and cognitive changes that occur in the elderly that affect different components of airway management: intubation, ventilation, oxygenation, and risk of aspiration. Anatomical changes occur in different areas of the airway from the oral cavity to the larynx. Common changes to the airway include tooth decay, oropharyngeal tumors, and significant decreases in neck range of motion. These changes may make intubation challenging by making it difficult to visualize the vocal cords and/or place the endotracheal tube. Also, some of these changes, including but not limited to, atrophy of the muscles around the lips and an edentulous mouth, affect bag mask ventilation due to a difficult face-mask seal. Physiopathologic changes may impact airway management as well. Common pulmonary issues in the elderly (eg, obstructive sleep apnea and COPD increase the risk of an oxygen desaturation event, while gastrointestinal issues (eg, achalasia and gastroesophageal reflux disease increase the risk of aspiration. Finally, cognitive changes (eg, dementia not often seen as related to airway management may affect patient cooperation, especially if an awake intubation is required. Overall, degradation of the airway along with other physiopathologic and cognitive changes makes the elderly population more prone to complications related to airway management. When deciding which airway devices and techniques to use for intubation, the clinician should also consider the

Bronchoscopic assessment of airway retention time of aerosolized xylitol

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Durairaj, Lakshmi; Neelakantan, Srividya; Launspach, Janice; Watt, Janet L; Allaman, Margaret M; Kearney, William R; Veng-Pedersen, Peter; Zabner, Joseph

2006-01-01

Background Human airway surface liquid (ASL) has abundant antimicrobial peptides whose potency increases as the salt concentration decreases. Xylitol is a 5-carbon sugar that has the ability to lower ASL salt concentration, potentially enhancing innate immunity. Xylitol was detected for 8 hours in the ASL after application in airway epithelium in vitro. We tested the airway retention time of aerosolized iso-osmotic xylitol in healthy volunteers. Methods After a screening spirometry, volunteers received 10 ml of nebulized 5% xylitol. Bronchoscopy was done at 20 minutes (n = 6), 90 minutes (n = 6), and 3 hours (n = 5) after nebulization and ASL was collected using microsampling probes, followed by bronchoalveolar lavage (BAL). Xylitol concentration was measured by nuclear magnetic resonance spectroscopy and corrected for dilution using urea concentration. Results All subjects tolerated nebulization and bronchoscopy well. Mean ASL volume recovered from the probes was 49 ± 23 μl. The mean ASL xylitol concentration at 20, 90, and 180 minutes was 1.6 ± 1.9 μg/μl, 0.6 ± 0.6 μg/μl, and 0.1 ± 0.1 μg/μl, respectively. Corresponding BAL concentration corrected for dilution was consistently lower at all time points. The terminal half-life of aerosolized xylitol obtained by the probes was 45 minutes with a mean residence time of 65 minutes in ASL. Corresponding BAL values were 36 and 50 minutes, respectively. Conclusion After a single dose nebulization, xylitol was detected in ASL for 3 hours, which was shorter than our in vitro measurement. The microsampling probe performed superior to BAL when sampling bronchial ASL. PMID:16483382

Vessel-guided airway tree segmentation

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Lo, Pechin Chien Pau; Sporring, Jon; Ashraf, Haseem

2010-01-01

This paper presents a method for airway tree segmentation that uses a combination of a trained airway appearance model, vessel and airway orientation information, and region growing. We propose a voxel classification approach for the appearance model, which uses a classifier that is trained to di...

Gamma-aminobutyric acid, a potential tumor suppressor for small airway-derived lung adenocarcinoma.

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Schuller, Hildegard M; Al-Wadei, Hussein A N; Majidi, Mourad

2008-10-01

Pulmonary adenocarcinoma (PAC) is the leading type of lung cancer in smokers and non-smokers that arises in most cases from small airway epithelial cells. PAC has a high mortality due to its aggressive behavior and resistance to cancer therapeutics. We have shown previously that the proliferation of human PAC cells NCI-H322 and immortalized human small airway epithelial cells HPL1D is stimulated by cyclic adenosine monophosphate (cAMP)/protein kinase A-dependent phosphorylation of cyclic adenosine monophosphate response element-binding (CREB) protein and transactivation of the epidermal growth factor receptor and that this pathway is activated by beta-1-adrenoreceptors (beta(1)-ARs) and the non-genomic estrogen receptor beta. Our current in vitro studies with HPL1D and NCI-H322 cells showed that signaling via the gamma-amino butyric acid receptor (GABA(B)R) strongly inhibited base level and isoproterenol-induced cAMP, p-CREB, cyclic adenosine monophosphate response element-luciferase activity and p-extracellular regulated kinase-1 (ERK1)/2 and effectively blocked DNA synthesis and cell migration. The inhibitory effects of gamma-amino butyric acid (GABA) were disinhibited by the GABA(B)R antagonist CGP-35348 or GABA(B)R knockdown. Immunohistochemical investigation of hamster lungs showed significant underexpression of GABA in animals with small airway-derived PACs induced by the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These findings suggest that GABA may have tumor suppressor function in small airway epithelia and the PACs derived from them and that downregulation of GABA by NNK may contribute to the development of this cancer in smokers. Our findings suggest that marker-guided treatment with GABA or a GABA(B)R agonist of individuals with downregulated pulmonary GABA may provide a novel targeted approach for the prevention of PAC in smokers.

Bronchoscopic guidance of endovascular stenting limits airway compression.

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Ebrahim, Mohammad; Hagood, James; Moore, John; El-Said, Howaida

2015-04-01

Bronchial compression as a result of pulmonary artery and aortic arch stenting may cause significant respiratory distress. We set out to limit airway narrowing by endovascular stenting, by using simultaneous flexible bronchoscopy and graduated balloon stent dilatation, or balloon angioplasty to determine maximum safe stent diameter. Between August 2010 and August 2013, patients with suspected airway compression by adjacent vascular structures, underwent CT or a 3D rotational angiogram to evaluate the relationship between the airway and the blood vessels. If these studies showed close proximity of the stenosed vessel and the airway, simultaneous bronchoscopy and graduated stent re-dilation or graduated balloon angioplasty were performed. Five simultaneous bronchoscopy and interventional catheterization procedures were performed in four patients. Median age/weight was 33 (range 9-49) months and 14 (range 7.6-24) kg, respectively. Three had hypoplastic left heart syndrome, and one had coarctation of the aorta (CoA). All had confirmed or suspected left main stem bronchial compression. In three procedures, serial balloon dilatation of a previously placed stent in the CoA was performed and bronchoscopy was used to determine the safest largest diameter. In the other two procedures, balloon testing with simultaneous bronchoscopy was performed to determine the stent size that would limit compression of the adjacent airway. In all cases, simultaneous bronchoscopy allowed selection of an ideal caliber of the stent that optimized vessel diameter while minimizing compression of the adjacent airway. In cases at risk for airway compromise, flexible bronchoscopy is a useful tool to guide endovascular stenting. Maximum safe stent diameter can be determined without risking catastrophic airway compression. © 2014 Wiley Periodicals, Inc.

A prospective study to evaluate and compare laryngeal mask airway ProSeal and i-gel airway in the prone position.

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Taxak, Susheela; Gopinath, Ajith; Saini, Savita; Bansal, Teena; Ahlawat, Mangal Singh; Bala, Manju

2015-01-01

Prone position is commonly used to provide surgical access to a variety of surgeries. In view of the advantages of induction of anesthesia in the prone position, we conducted a randomized study to evaluate and compare ProSeal laryngeal mask airway (LMA) and i-gel in the prone position. Totally, 40 patients of either sex as per American Society of Anesthesiologists physical status I or II, between 16 and 60 years of age, scheduled to undergo surgery in prone position were included in the study. After the patients positioned themselves prone on the operating table, anesthesia was induced by the standard technique. LMA ProSeal was used as an airway conduit in group 1 while i-gel was used in group 2. At the end of surgery, the airway device was removed in the same position. Insertion of airway device was successful in first attempt in 16, and 17 cases in ProSeal laryngeal mask airway (PLMA) and i-gel groups, respectively. A second attempt was required to secure the airway in 4 and 3 patients in PLMA and i-gel groups, respectively. The mean insertion time was 21.8 ± 2.70 s for group 1 and 13.1 ± 2.24 s for group 2, the difference being statistically significant (P position. The PLMA has a better seal while insertion is easier with i-gel.

MicroRNA-20b-5p inhibits platelet-derived growth factor-induced proliferation of human fetal airway smooth muscle cells by targeting signal transducer and activator of transcription 3.

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Tang, Jin; Luo, Lingying

2018-06-01

Pediatric asthma is still a health threat to the pediatric population in recent years. The airway remodeling induced by abnormal airway smooth muscle (ASM) cell proliferation is an important cause of asthma. MicroRNAs (miRNAs) are important regulators of ASM cell proliferation. Numerous studies have reported that miR-20b-5p is a critical regulator for cell proliferation. However, whether miR-20b-5p is involved in regulating ASM cell proliferation remains unknown. In this study, we aimed to investigate the potential role of miR-20b-5p in regulating the proliferation of fetal ASM cell induced by platelet-derived growth factor (PDGF). Here, we showed that miR-20b-5p was significantly decreased in fetal ASM cells treated with PDGF. Biological experiments showed that the overexpression of miR-20b-5p inhibited the proliferation while miR-20b-5p inhibition markedly promoted the proliferation of fetal ASM cells. Bioinformatics analysis and luciferase reporter assay showed that miR-20b-5p directly targeted the 3'-UTR of signal transducer and activator of transcription 3 (STAT3). Further data showed that miR-20b-5p negatively regulated the expression of STAT3 in fetal ASM cells. Moreover, miR-20b-5p regulates the transcriptional activity of STAT3 in fetal ASM cells. Overexpression of STAT3 reversed the inhibitory effect of miR-20b-5p overexpression on fetal ASM cell proliferation while the knockdown of STAT3 abrogated the promoted effect of miR-20b-5p inhibition on fetal ASM cell proliferation. Overall, our results show that miR-20b-5p impedes PDGF-induced proliferation of fetal ASM cells through targeting STAT3. Our study suggests that miR-20b-5p may play an important role in airway remodeling during asthma and suggests that miR-20b-5p may serve as a potential therapeutic target for pediatric asthma. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Electrostatic Charge Effects on Pharmaceutical Aerosol Deposition in Human Nasal–Laryngeal Airways

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Jinxiang Xi

2014-01-01

Full Text Available Electrostatic charging occurs in most aerosol generation processes and can significantly influence subsequent particle deposition rates and patterns in the respiratory tract through the image and space forces. The behavior of inhaled aerosols with charge is expected to be most affected in the upper airways, where particles come in close proximity to the narrow turbinate surface, and before charge dissipation occurs as a result of high humidity. The objective of this study was to quantitatively evaluate the deposition of charged aerosols in an MRI-based nasal–laryngeal airway model. Particle sizes of 5 nm–30 µm and charge levels ranging from neutralized to ten times the saturation limit were considered. A well-validated low Reynolds number (LRN k–ω turbulence model and a discrete Lagrangian tracking approach that accounted for electrostatic image force were employed to simulate the nasal airflow and aerosol dynamics. For ultrafine aerosols, electrostatic charge was observed to exert a discernible but insignificant effect. In contrast, remarkably enhanced depositions were observed for micrometer particles with charge, which could be one order of magnitude larger than no-charge depositions. The deposition hot spots shifted towards the anterior part of the upper airway as the charge level increased. Results of this study have important implications for evaluating nasal drug delivery devices and for assessing doses received from pollutants, which often carry a certain level of electric charges.

Airway Management in a Patient with Wolf-Hirschhorn Syndrome

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John F. Gamble

2016-01-01

Full Text Available We present a case of a 3-month-old female with Wolf-Hirschhorn syndrome (WHS undergoing general anesthesia for laparoscopic gastrostomy tube placement with a focus on airway management. WHS is a rare 4p microdeletion syndrome resulting in multiple congenital abnormalities, including craniofacial deformities. Microcephaly, micrognathia, and glossoptosis are common features in WHS patients and risk factors for a pediatric airway that is potentially difficult to intubate. We discuss anesthesia strategies for airway preparation and management in a WHS patient requiring general anesthesia with endotracheal intubation.

Small airways disease: time for a revisit?

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Stockley JA

2017-08-01

Full Text Available James A Stockley,1 Brendan G Cooper,1 Robert A Stockley,2 Elizabeth Sapey3 1Department of Lung Function and Sleep, 2Department of Respiratory Medicine, University Hospital Birmingham, 3Institute of Inflammation and Ageing, Centre for Translational Inflammation Research, University of Birmingham, Edgbaston, Birmingham, UK Abstract: It is increasingly acknowledged that delays in the diagnosis of chronic inflammatory lung conditions have hampered our understanding of pathogenesis and thus our ability to design efficacious therapies. This is particularly true for COPD, where most patients are diagnosed with moderate-to-severe airflow obstruction and little is known about the inflammatory processes present in early disease. There is great interest in developing screening tests that can identify those most at risk of developing COPD before airflow obstruction has developed for the purpose of research and clinical care. Landmark pathology studies have suggested that damage to the small airways precedes the development of airflow obstruction and emphysema and, thus, presents an opportunity to identify those at risk of COPD. However, despite a number of physiological tests being available to assess small airways function, none have been adopted into routine care in COPD. The reasons that tests of small airways have not been utilized widely include variability in test results and a lack of validated reference ranges from which to compare results for some methodologies. Furthermore, population studies have not consistently demonstrated their ability to diagnose disease. However, the landscape may be changing. As the equipment that delivers tests of small airways become more widely available, reference ranges are emerging and newer methodologies specifically seek to address variability and difficulty in test performance. Moreover, there is evidence that while tests of small airways may not be helpful across the full range of established disease severity

PPARγ as a Potential Target to Treat Airway Mucus Hypersecretion in Chronic Airway Inflammatory Diseases

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Yongchun Shen

2012-01-01

Full Text Available Airway mucus hypersecretion (AMH is a key pathophysiological feature of chronic airway inflammatory diseases such as bronchial asthma, cystic fibrosis, and chronic obstructive pulmonary disease. AMH contributes to the pathogenesis of chronic airway inflammatory diseases, and it is associated with reduced lung function and high rates of hospitalization and mortality. It has been suggested that AMH should be a target in the treatment of chronic airway inflammatory diseases. Recent evidence suggests that a key regulator of airway inflammation, hyperresponsiveness, and remodeling is peroxisome proliferator-activated receptor gamma (PPARγ, a ligand-activated transcription factor that regulates adipocyte differentiation and lipid metabolism. PPARγ is expressed in structural, immune, and inflammatory cells in the lung. PPARγ is involved in mucin production, and PPARγ agonists can inhibit mucin synthesis both in vitro and in vivo. These findings suggest that PPARγ is a novel target in the treatment of AMH and that further work on this transcription factor may lead to new therapies for chronic airway inflammatory diseases.

Composition and Predicted Metabolic Capacity of Upper and Lower Airway Microbiota of Healthy Dogs in Relation to the Fecal Microbiota.

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Ericsson, Aaron C; Personett, Alexa R; Grobman, Megan E; Rindt, Hansjorg; Reinero, Carol R

2016-01-01

The upper and lower airways of healthy humans are reported to harbor stable and consistent bacterial populations, and the composition of these communities is altered in individuals affected with several respiratory diseases. Data regarding the presence of airway microbiota in other animals are scant and a better understanding of the composition and metabolic function of such bacterial populations is essential for the development of novel therapeutic and diagnostic modalities for use in both veterinary and human medicine. Based on targeted next-generation sequencing of feces and samples collected at multiple levels of the airways from 16 healthy female dogs, we demonstrate that canine airways harbor a topographically continuous microbiota with increasing relative abundance of proteobacterial species from the upper to lower airways. The lung-associated microbiota, as assessed via bronchoalveolar lavage fluid (BALF), was the most consistent between dogs and was dominated by three distinct taxa, two of which were resolved to the species level and one to the level of family. The gene content of the nasal, oropharyngeal, and lung-associated microbiota, predicted using the Phylogenetic Investigations into Communities by Reconstruction of Unobserved States (PICRUSt) software, provided information regarding the glyoxylate and citrate cycle metabolic pathways utilized by these bacterial populations to colonize such nutrient-poor, low-throughput environments. These data generated in healthy subjects provide context for future analysis of diseased canine airways. Moreover, as dogs have similar respiratory anatomy, physiology, and immune systems as humans, are exposed to many of the same environmental stimuli, and spontaneously develop similar respiratory diseases, these data support the use of dogs as a model species for prospective studies of the airway microbiota, with findings translatable to the human condition.

Mucociliary clearance, airway inflammation and nasal symptoms in urban motorcyclists

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Tereza C.S. Brant

2014-01-01

Full Text Available OBJECTIVES: There is evidence that outdoor workers exposed to high levels of air pollution exhibit airway inflammation and increased airway symptoms. We hypothesized that these workers would experience increased airway symptoms and decreased nasal mucociliary clearance associated with their exposure to air pollution. METHODS: In total, 25 non-smoking commercial motorcyclists, aged 18-44 years, were included in this study. These drivers work 8-12 hours per day, 5 days per week, driving on urban streets. Nasal mucociliary clearance was measured by the saccharine transit test; airway acidification was measured by assessing the pH of exhaled breath condensate; and airway symptoms were measured by the Sino-nasal Outcome Test-20 questionnaire. To assess personal air pollution exposure, the subjects used a passive-diffusion nitrogen dioxide (NO2 concentration-monitoring system during the 14 days before each assessment. The associations between NO2 and the airway outcomes were analyzed using the Mann-Whitney test and the Chi-Square test. Clinicaltrials.gov: NCT01976039. RESULTS: Compared with clearance in healthy adult males, mucociliary clearance was decreased in 32% of the motorcyclists. Additionally, 64% of the motorcyclists had airway acidification and 92% experienced airway symptoms. The median personal NO2 exposure level was 75 mg/m3 for these subjects and a significant association was observed between NO2 and impaired mucociliary clearance (p = 0.036. CONCLUSION: Non-smoking commercial motorcyclists exhibit increased airway symptoms and airway acidification as well as decreased nasal mucociliary clearance, all of which are significantly associated with the amount of exposure to air pollution.

Obstetric airway management

African Journals Online (AJOL)

of stomach contents into the lungs during obstetric anesthesia.8 ... Both of the mortalities occurred secondary to solid ... The large number of deaths ... subcategories of patients as a first-line airway device, and are increasingly being ... outline the problems with obstetric airway management, and then focus on a few of the ...

Individual canine Airway Response Variability to a Deep Inspiration

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Robert H. Brown

2011-01-01

Full Text Available In healthy individuals, a DI can reverse (bronchodilation or prevent (bronchoprotection induced airway constriction. For individuals with asthma or COPD, these effects may be attenuated or absent. Previous work showed that the size and duration of a DI affected the subsequent response of the airways. Also, increased airway tone lead to increased airway size variability. The present study examined how a DI affected the temporal variability in individual airway baseline size and after methacholine challenge in dogs using High-Resolution Computed Tomography. Dogs were anesthetized and ventilated, and on 4 separate days, HRCT scans were acquired before and after a DI at baseline and during a continuous intravenous infusion of methacholine (Mch at 3 dose rates (17, 67, and 200 μg/mm. The Coefficient of Variation was used as an index of temporal variability in airway size. We found that at baseline and the lowest dose of Mch, variability decreased immediately and 5 minutes after the DI ( P < 0.0001. In contrast, with higher doses of Mch, the DI caused a variable response. At a rate of 67 μg/min of Mch, the temporal variability increased after 5 minutes, while at a rate of 200 μg/min of Mch, the temporal variability increased immediately after the DI. Increased airway temporal variability has been shown to be associated with asthma. Although the mechanisms underlying this temporal variability are poorly understood, the beneficial effects of a DI to decrease airway temporal variability was eliminated when airway tone was increased. If this effect is absent in asthmatics, this may suggest a possible mechanism for the loss of bronchoprotective and bronchodilatory effects after a DI in asthma.

Endotracheal tube connector defect causing airway obstruction in an ...

African Journals Online (AJOL)

detected during routine visual inspection before their use, while some go unnoticed during such inspection and can lead to partial or complete airway obstruction in intubated patients. We report one case of partial airway obstruction resulting from manufacturing defect in the ET connector. A 3-month-old infant girl weighing 5 ...

Spi2 gene polymorphism is not associated with recurrent airway obstruction and inflammatory airway disease in thoroughbred horses

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Aline Correa da Silva

2011-01-01

Full Text Available The aim was to detect the presence of polymorphisms at exons 1, 2, 3 and 4 of the Spi2 gene, and evaluate a possible association between them and recurrent airway obstruction (RAO or inflammatory airway disease (IAD in thoroughbred horses, through single-strand conformational-polymorphism (SSCP screening. Although polymorphism was not detected in exons 1, 2 and 3, three alleles and six genotypes were identified in exon 4. The frequencies of allele A (0.6388 and genotype AA (0.3888 were higher in horses affected by RAO, although no association was found between polymorphism and horses with either RAO or IAD.

Lipopolysaccharide does not alter small airway reactivity in mouse lung slices.

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Donovan, Chantal; Royce, Simon G; Vlahos, Ross; Bourke, Jane E

2015-01-01

The bacterial endotoxin, lipopolysaccharide (LPS) has been associated with occupational airway diseases with asthma-like symptoms and in acute exacerbations of COPD. The direct and indirect effects of LPS on small airway reactivity have not been fully elucidated. We tested the hypothesis that both in vitro and in vivo LPS treatment would increase contraction and impair relaxation of mouse small airways. Lung slices were prepared from naïve Balb/C mice and cultured in the absence or presence of LPS (10 μg/ml) for up to 48 h for measurement of TNFα levels in conditioned media. Alternatively, mice were challenged with PBS or LPS in vivo once a day for 4 days for preparation of lung slices or for harvest of lungs for Q-PCR analysis of gene expression of pro-inflammatory cytokines and receptors involved in airway contraction. Reactivity of small airways to contractile agonists, methacholine and serotonin, and bronchodilator agents, salbutamol, isoprenaline and rosiglitazone, were assessed using phase-contrast microscopy. In vitro LPS treatment of slices increased TNFα release 6-fold but did not alter contraction or relaxation to any agonists tested. In vivo LPS treatment increased lung gene expression of TNFα, IL-1β and ryanodine receptor isoform 2 more than 5-fold. However there were no changes in reactivity in lung slices from these mice, even when also incubated with LPS ex vivo. Despite evidence of LPS-induced inflammation, neither airway hyperresponsiveness or impaired dilator reactivity were evident. The increase in ryanodine receptor isoform 2, known to regulate calcium signaling in vascular smooth muscle, warrants investigation. Since LPS failed to elicit changes in small airway reactivity in mouse lung slices following in vitro or in vivo treatment, alternative approaches are required to define the potential contribution of this endotoxin to altered small airway reactivity in human lung diseases.

Lipopolysaccharide does not alter small airway reactivity in mouse lung slices.

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Chantal Donovan

Full Text Available The bacterial endotoxin, lipopolysaccharide (LPS has been associated with occupational airway diseases with asthma-like symptoms and in acute exacerbations of COPD. The direct and indirect effects of LPS on small airway reactivity have not been fully elucidated. We tested the hypothesis that both in vitro and in vivo LPS treatment would increase contraction and impair relaxation of mouse small airways. Lung slices were prepared from naïve Balb/C mice and cultured in the absence or presence of LPS (10 μg/ml for up to 48 h for measurement of TNFα levels in conditioned media. Alternatively, mice were challenged with PBS or LPS in vivo once a day for 4 days for preparation of lung slices or for harvest of lungs for Q-PCR analysis of gene expression of pro-inflammatory cytokines and receptors involved in airway contraction. Reactivity of small airways to contractile agonists, methacholine and serotonin, and bronchodilator agents, salbutamol, isoprenaline and rosiglitazone, were assessed using phase-contrast microscopy. In vitro LPS treatment of slices increased TNFα release 6-fold but did not alter contraction or relaxation to any agonists tested. In vivo LPS treatment increased lung gene expression of TNFα, IL-1β and ryanodine receptor isoform 2 more than 5-fold. However there were no changes in reactivity in lung slices from these mice, even when also incubated with LPS ex vivo. Despite evidence of LPS-induced inflammation, neither airway hyperresponsiveness or impaired dilator reactivity were evident. The increase in ryanodine receptor isoform 2, known to regulate calcium signaling in vascular smooth muscle, warrants investigation. Since LPS failed to elicit changes in small airway reactivity in mouse lung slices following in vitro or in vivo treatment, alternative approaches are required to define the potential contribution of this endotoxin to altered small airway reactivity in human lung diseases.

Airway Obstruction Among Latino Poultry Processing Workers in North Carolina

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MIRABELLI, MARIA C.; CHATTERJEE, ARJUN B.; MORA, DANA C.; ARCURY, THOMAS A.; BLOCKER, JILL N.; CHEN, HAIYING; GRZYWACZ, JOSEPH G.; MARÍN, ANTONIO J.; SCHULZ, MARK R.; QUANDT, SARA A.

2015-01-01

This analysis was conducted to evaluate the prevalence of airway obstruction among Latino poultry processing workers. Data were collected from 279 poultry processing workers and 222 other manual laborers via spirometry and interviewer-administered questionnaires. Participants employed in poultry processing reported the activities they perform at work. Participants with forced expiratory volume in 1 second (FEV1) or FEV1/forced expiratory volume (FVC) below the lower limits of normal were categorized as having airway obstruction. Airway obstruction was identified in 13% of poultry processing workers and 12% of the comparison population. Among poultry processing workers, the highest prevalence of airway obstruction (21%) occurred among workers deboning chickens (prevalence ratio: 1.75; 95% confidence interval: 0.97, 3.15). These findings identify variations in the prevalence of airway obstruction across categories of work activities. PMID:24965321

Absence of Foxp3+ regulatory T cells during allergen provocation does not exacerbate murine allergic airway inflammation.

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Abdul Mannan Baru

Full Text Available Regulatory T cells (Tregs play a non-redundant role in maintenance of immune homeostasis. This is achieved by suppressing both, priming of naïve cells and effector cell functions. Although Tregs have been implicated in modulating allergic immune responses, their influence on distinct phases of development of allergies remains unclear. In this study, by using bacterial artificial chromosome (BAC-transgenic Foxp3-DTR (DEREG mice we demonstrate that the absence of Foxp3(+ Tregs during the allergen challenge surprisingly does not exacerbate allergic airway inflammation in BALB/c mice. As genetic disposition due to strain specificity may contribute significantly to development of allergies, we performed similar experiment in C57BL/6 mice, which are less susceptible to allergy in the model of sensitization used in this study. We report that the genetic background does not influence the consequence of this depletion regimen. These results signify the temporal regulation exerted by Foxp3(+ Tregs in limiting allergic airway inflammation and may influence their application as potential therapeutics.

Innate lymphoid cells contribute to allergic airway disease exacerbation by obesity.

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Everaere, Laetitia; Ait-Yahia, Saliha; Molendi-Coste, Olivier; Vorng, Han; Quemener, Sandrine; LeVu, Pauline; Fleury, Sebastien; Bouchaert, Emmanuel; Fan, Ying; Duez, Catherine; de Nadai, Patricia; Staels, Bart; Dombrowicz, David; Tsicopoulos, Anne

2016-11-01

Epidemiologic and clinical observations identify obesity as an important risk factor for asthma exacerbation, but the underlying mechanisms remain poorly understood. Type 2 innate lymphoid cells (ILC2s) and type 3 innate lymphoid cells (ILC3s) have been implicated, respectively, in asthma and adipose tissue homeostasis and in obesity-associated airway hyperresponsiveness (AHR). We sought to determine the potential involvement of innate lymphoid cells (ILCs) in allergic airway disease exacerbation caused by high-fat diet (HFD)-induced obesity. Obesity was induced by means of HFD feeding, and allergic airway inflammation was subsequently induced by means of intranasal administration of house dust mite (HDM) extract. AHR, lung and visceral adipose tissue inflammation, humoral response, cytokines, and innate and adaptive lymphoid populations were analyzed in the presence or absence of ILCs. HFD feeding exacerbated allergic airway disease features, including humoral response, airway and tissue eosinophilia, AHR, and T H 2 and T H 17 pulmonary profiles. Notably, nonsensitized obese mice already exhibited increased lung ILC counts and tissue eosinophil infiltration compared with values in lean mice in the absence of AHR. The numbers of total and cytokine-expressing lung ILC2s and ILC3s further increased in HDM-challenged obese mice compared with those in HDM-challenged lean mice, and this was accompanied by high IL-33 and IL-1β levels and decreased ILC markers in visceral adipose tissue. Furthermore, depletion of ILCs with an anti-CD90 antibody, followed by T-cell reconstitution, led to a profound decrease in allergic airway inflammatory features in obese mice, including T H 2 and T H 17 infiltration. These results indicate that HFD-induced obesity might exacerbate allergic airway inflammation through mechanisms involving ILC2s and ILC3s. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Computer simulation of airflow through a multi-generation tracheobronchial conducting airway

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Fan, B.; Cheng, Yung-Sung; Yeh, Hsu-Chi

1995-12-01

Knowledge of airflow patterns in the human lung is important for an analysis of lung diseases and drug delivery of aerosolized medicine for medical treatment. However, very little systematic information is available on the pattern of airflow in the lung and on how this pattern affects the deposition of toxicants in the lung, and the efficacy of aerosol drug therapy. Most previous studies have only considered the airflow through a single bifurcating airway. However, the flow in a network of more than one bifurcation is more complicated due to the effect of interrelated lung generations. Because of the variation of airway geometry and flow condition from generation to generation, a single bifurcating airway cannot be taken as a representative for the others in different generations. The flow in the network varies significantly with airway generations because of a redistribution of axial momentum by the secondary flow motions. The influence of the redistribution of flow is expected in every generation. Therefore, a systematic information of the airflow through a multi-generation tracheobronchial conducting airway is needed, and it becomes the purpose of this study. This study has provided information on airflow in a lung model which is necessary to the study of the deposition of toxicants and therapeutic aerosols.

Computer simulation of airflow through a multi-generation tracheobronchial conducting airway

International Nuclear Information System (INIS)

Fan, B.; Cheng, Yung-Sung; Yeh, Hsu-Chi.

1995-01-01

Knowledge of airflow patterns in the human lung is important for an analysis of lung diseases and drug delivery of aerosolized medicine for medical treatment. However, very little systematic information is available on the pattern of airflow in the lung and on how this pattern affects the deposition of toxicants in the lung, and the efficacy of aerosol drug therapy. Most previous studies have only considered the airflow through a single bifurcating airway. However, the flow in a network of more than one bifurcation is more complicated due to the effect of interrelated lung generations. Because of the variation of airway geometry and flow condition from generation to generation, a single bifurcating airway cannot be taken as a representative for the others in different generations. The flow in the network varies significantly with airway generations because of a redistribution of axial momentum by the secondary flow motions. The influence of the redistribution of flow is expected in every generation. Therefore, a systematic information of the airflow through a multi-generation tracheobronchial conducting airway is needed, and it becomes the purpose of this study. This study has provided information on airflow in a lung model which is necessary to the study of the deposition of toxicants and therapeutic aerosols

Downregulation of SLC7A7 Triggers an Inflammatory Phenotype in Human Macrophages and Airway Epithelial Cells

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Bianca Maria Rotoli

2018-03-01

Full Text Available Lysinuric protein intolerance (LPI is a recessively inherited aminoaciduria caused by mutations of SLC7A7, the gene encoding y+LAT1 light chain of system y+L for cationic amino acid transport. The pathogenesis of LPI is still unknown. In this study, we have utilized a gene silencing approach in macrophages and airway epithelial cells to investigate whether complications affecting lung and immune system are directly ascribable to the lack of SLC7A7 or, rather, mediated by an abnormal accumulation of arginine in mutated cells. When SLC7A7/y+LAT1 was silenced in human THP-1 macrophages and A549 airway epithelial cells by means of short interference RNA (siRNA, a significant induction of the expression and release of the inflammatory mediators IL1β and TNFα was observed, no matter the intracellular arginine availability. This effect was mainly regulated at transcriptional level through the activation of NFκB signaling pathway. Moreover, since respiratory epithelial cells are the important sources of chemokines in response to pro-inflammatory stimuli, the effect of IL1β has been addressed on SLC7A7 silenced A549 cells. Results obtained indicated that the downregulation of SLC7A7/y+LAT1 markedly strengthened the stimulatory effect of the cytokine on CCL5/RANTES expression and release without affecting the levels of CXCL8/IL8. Consistently, also the conditioned medium of silenced THP-1 macrophages activated airway epithelial cells in terms of CCL5/RANTES expression due to the presence of elevated amount of proinflammatory cytokines. In conclusion, our results point to a novel thus far unknown function of SLC7A7/y+LAT1, that, under physiological conditions, besides transporting arginine, may act as a brake to restrain inflammation.

Aspergillus in chronic lung disease: Modeling what goes on in the airways.

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Takazono, Takahiro; Sheppard, Donald C

2017-01-01

Aspergillus species cause a range of respiratory diseases in humans. While immunocompromised patients are at risk for the development of invasive infection with these opportunistic molds, patients with underlying pulmonary disease can develop chronic airway infection with Aspergillus species. These conditions span a range of inflammatory and allergic diseases including Aspergillus bronchitis, allergic bronchopulmonary aspergillosis, and severe asthma with fungal sensitization. Animal models are invaluable tools for the study of the molecular mechanism underlying the colonization of airways by Aspergillus and the host response to these non-invasive infections. In this review we summarize the state-of-the-art with respect to the available animal models of noninvasive and allergic Aspergillus airway disease; the key findings of host-pathogen interaction studies using these models; and the limitations and future directions that should guide the development and use of models for the study of these important pulmonary conditions. © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Predominant constitutive CFTR conductance in small airways

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Lytle Christian

2005-01-01

Full Text Available Abstract Background The pathological hallmarks of chronic obstructive pulmonary disease (COPD are inflammation of the small airways (bronchiolitis and destruction of lung parenchyma (emphysema. These forms of disease arise from chronic prolonged infections, which are usually never present in the normal lung. Despite the fact that primary hygiene and defense of the airways presumably requires a well controlled fluid environment on the surface of the bronchiolar airway, very little is known of the fluid and electrolyte transport properties of airways of less than a few mm diameter. Methods We introduce a novel approach to examine some of these properties in a preparation of minimally traumatized porcine bronchioles of about 1 mm diameter by microperfusing the intact bronchiole. Results In bilateral isotonic NaCl Ringer solutions, the spontaneous transepithelial potential (TEP; lumen to bath of the bronchiole was small (mean ± sem: -3 ± 1 mV; n = 25, but when gluconate replaced luminal Cl-, the bionic Cl- diffusion potentials (-58 ± 3 mV; n = 25 were as large as -90 mV. TEP diffusion potentials from 2:1 NaCl dilution showed that epithelial Cl- permeability was at least 5 times greater than Na+ permeability. The anion selectivity sequence was similar to that of CFTR. The bionic TEP became more electronegative with stimulation by luminal forskolin (5 μM+IBMX (100 μM, ATP (100 μM, or adenosine (100 μM, but not by ionomycin. The TEP was partially inhibited by NPPB (100 μM, GlyH-101* (5–50 μM, and CFTRInh-172* (5 μM. RT-PCR gave identifying products for CFTR, α-, β-, and γ-ENaC and NKCC1. Antibodies to CFTR localized specifically to the epithelial cells lining the lumen of the small airways. Conclusion These results indicate that the small airway of the pig is characterized by a constitutively active Cl- conductance that is most likely due to CFTR.

Reverse-phase phosphoproteome analysis of signaling pathways induced by Rift valley fever virus in human small airway epithelial cells.

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Taissia G Popova

Full Text Available Rift valley fever virus (RVFV infection is an emerging zoonotic disease endemic in many countries of sub-Saharan Africa and in Egypt. In this study we show that human small airway epithelial cells are highly susceptible to RVFV virulent strain ZH-501 and the attenuated strain MP-12. We used the reverse-phase protein arrays technology to identify phosphoprotein signaling pathways modulated during infection of cultured airway epithelium. ZH-501 infection induced activation of MAP kinases (p38, JNK and ERK and downstream transcriptional factors [STAT1 (Y701, ATF2 (T69/71, MSK1 (S360 and CREB (S133]. NF-κB phosphorylation was also increased. Activation of p53 (S15, S46 correlated with the increased levels of cleaved effector caspase-3, -6 and -7, indicating activation of the extrinsic apoptotic pathway. RVFV infection downregulated phosphorylation of a major anti-apoptotic regulator of survival pathways, AKT (S473, along with phosphorylation of FOX 01/03 (T24/31 which controls cell cycle arrest downstream from AKT. Consistent with this, the level of apoptosis inhibitor XIAP was decreased. However, the intrinsic apoptotic pathway marker, caspase-9, demonstrated only a marginal activation accompanied by an increased level of the inhibitor of apoptosome formation, HSP27. Concentration of the autophagy marker, LC3B, which often accompanies the pro-survival signaling, was decreased. Cumulatively, our analysis of RVFV infection in lung epithelium indicated a viral strategy directed toward the control of cell apoptosis through a number of transcriptional factors. Analyses of MP-12 titers in challenged cells in the presence of MAPK inhibitors indicated that activation of p38 represents a protective cell response while ERK activation controls viral replication.

Automated quantification of bronchiectasis, airway wall thickening and lumen tapering in chest CT

DEFF Research Database (Denmark)

Perez-Rovira, Adria; Kuo, Wieying; Petersen, Jens

thickness and accompanying artery radius), and inter-branch Lumen-Ratio (LR, ratio between a branch's lumen and its parent branch lumen radius, a tapering measurement) were computed. Because CF-related structural abnormalities only affect a portion of branches, the 75th percentile was used as summarising......Purpose: To automatically quantify airway structural properties visualised on CT in children with cystic fibrosis (CF) and controls, including: bronchiectasis, airway wall thickening, and lumen tapering. Methods and materials: The 3D surface of the airway lumen, outer wall, and bronchial arteries...... were obtained using a fully automatic, in-house developed, segmentation method. Subsequently, for each detected airway branch, the Airway-Artery Ratio (AAR, ratio between airway outer wall and accompanying artery radius, a bronchiectasis measurement), Wall-Artery Ratio (WAR, ratio between airway wall...

Airway Clearance Techniques (ACTs)

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Full Text Available ... specialized CF care and a range of treatment options. Airway Clearance Active Cycle of Breathing Technique Airway ... on their own. Share Facebook Twitter Email More options Print Share Facebook Twitter Email Print Permalink All ...

Airway Clearance Techniques (ACTs)

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Full Text Available ... Physical Therapy Coughing and Huffing High-Frequency Chest Wall Oscillation Positive Expiratory Pressure Clinical Trials Clinical Trials ... clapping) or vibration to loosen mucus from airway walls. See how different airway clearance techniques work to ...

Airway Clearance Techniques (ACTs)

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Full Text Available ... D Structure Consortium CFTR Folding Consortium Epithelial Stem Cell Consortium Mucociliary Clearance Consortium SUCCESS WITH THERAPIES RESEARCH ... clapping) or vibration to loosen mucus from airway walls. See how different airway clearance techniques work to ...

Airway Clearance Techniques (ACTs)

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Full Text Available ... ACTs involve coughing or huffing . Many of them use percussion (clapping) or vibration to loosen mucus from airway walls. See how different airway clearance techniques work to help you clear the thick, sticky mucus ...

Airway Clearance Techniques (ACTs)

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Full Text Available ... today. ANNUAL FUND Become a Corporate Supporter Cause Marketing Make a Charitable Gift Our Corporate Supporters Workplace ... Clearance Airway Clearance Techniques (ACTs) There are different ways to clear your airways. Most are easy to ...

Airway Clearance Techniques (ACTs)

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Full Text Available ... a range of treatment options. Airway Clearance Active Cycle of Breathing Technique Airway Clearance Techniques Autogenic Drainage ... LEGACY GIFT Sponsor a Participant CF Climb CF Cycle for Life Great Strides Xtreme Hike Participate In ...

Clinical review: Management of difficult airways

OpenAIRE

Langeron, Olivier; Amour, Julien; Vivien, Benoît; Aubrun, Frédéric

2006-01-01

Difficulties or failure in airway management are still important factors in morbidity and mortality related to anesthesia and intensive care. A patent and secure airway is essential to manage anesthetized or critically ill patients. Oxygenation maintenance during tracheal intubation is the cornerstone of difficult airway management and is always emphasized in guidelines. The occurrence of respiratory adverse events has decreased in claims for injuries due to inadequate airway management mainl...

The effect of inhaled menthol on upper airway resistance in humans: A randomized controlled crossover study

Directory of Open Access Journals (Sweden)

Effie J Pereira

2013-01-01

Full Text Available BACKGROUND: Menthol (l-menthol is a naturally-occurring cold receptor agonist commonly used to provide symptomatic relief for upper airway congestion. Menthol can also reduce the sensation of dyspnea. It is unclear whether the physiological action of menthol in dyspnea reduction is through its cold receptor agonist effect or whether associated mechanical changes occur in the upper airway.

Interaction of Mycobacterium leprae with human airway epithelial cells: adherence, entry, survival, and identification of potential adhesins by surface proteome analysis.

Science.gov (United States)

Silva, Carlos A M; Danelishvili, Lia; McNamara, Michael; Berredo-Pinho, Márcia; Bildfell, Robert; Biet, Franck; Rodrigues, Luciana S; Oliveira, Albanita V; Bermudez, Luiz E; Pessolani, Maria C V

2013-07-01

This study examined the in vitro interaction between Mycobacterium leprae, the causative agent of leprosy, and human alveolar and nasal epithelial cells, demonstrating that M. leprae can enter both cell types and that both are capable of sustaining bacterial survival. Moreover, delivery of M. leprae to the nasal septum of mice resulted in macrophage and epithelial cell infection in the lung tissue, sustaining the idea that the airways constitute an important M. leprae entry route into the human body. Since critical aspects in understanding the mechanisms of infection are the identification and characterization of the adhesins involved in pathogen-host cell interaction, the nude mouse-derived M. leprae cell surface-exposed proteome was studied to uncover potentially relevant adhesin candidates. A total of 279 cell surface-exposed proteins were identified based on selective biotinylation, streptavidin-affinity purification, and shotgun mass spectrometry; 11 of those proteins have been previously described as potential adhesins. In vitro assays with the recombinant forms of the histone-like protein (Hlp) and the heparin-binding hemagglutinin (HBHA), considered to be major mycobacterial adhesins, confirmed their capacity to promote bacterial attachment to epithelial cells. Taking our data together, they suggest that the airway epithelium may act as a reservoir and/or portal of entry for M. leprae in humans. Moreover, our report sheds light on the potentially critical adhesins involved in M. leprae-epithelial cell interaction that may be useful in designing more effective tools for leprosy control.

Respiratory syncytial virus infection induces higher Toll-like receptor-3 expression and TNF-α production than human metapneumovirus infection.

Directory of Open Access Journals (Sweden)

Ying Dou

Full Text Available Respiratory syncytial virus (RSV and human metapneumovirus (hMPV are common causes of respiratory infections in children. Diseases caused by hMPV are generally considered to be less severe than those caused by RSV; the underlying mechanisms, however, remain unknown. In the present study, the expressions of TLRs in airway epithelial cells and lungs of BALB/c mice infected by hMPV or RSV were measured in an attempt to explore the differences in the airway inflammation caused by the two viruses. Our results demonstrate that both hMPV and RSV infection upregulated the expressions of TLRs and inflammatory cytokines. Specifically, the TLR3 expression was revealed to be elevated in vitro and in mouse lungs. IFN-α produced by A549 cells after RSV or hMPV infection remained undistinguishable, whereas production of TNF-α was significantly higher after RSV infection than hMPV infection either in the presence or absence of Poly I:C. This study provides a clue that more severe clinical syndrome of RSV infection may be due to the greater magnitude of induction of airway inflammation by RSV involving TLR3 activation and production of TNF-α.

Airway Clearance Techniques (ACTs)

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Full Text Available ... Make a Charitable Gift Our Corporate Supporters Workplace Engagement DONATE YOUR PROPERTY eCards for a Cure About ... airway walls. See how different airway clearance techniques work to help you clear the thick, sticky mucus ...

Composition and Predicted Metabolic Capacity of Upper and Lower Airway Microbiota of Healthy Dogs in Relation to the Fecal Microbiota.

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Aaron C Ericsson

Full Text Available The upper and lower airways of healthy humans are reported to harbor stable and consistent bacterial populations, and the composition of these communities is altered in individuals affected with several respiratory diseases. Data regarding the presence of airway microbiota in other animals are scant and a better understanding of the composition and metabolic function of such bacterial populations is essential for the development of novel therapeutic and diagnostic modalities for use in both veterinary and human medicine. Based on targeted next-generation sequencing of feces and samples collected at multiple levels of the airways from 16 healthy female dogs, we demonstrate that canine airways harbor a topographically continuous microbiota with increasing relative abundance of proteobacterial species from the upper to lower airways. The lung-associated microbiota, as assessed via bronchoalveolar lavage fluid (BALF, was the most consistent between dogs and was dominated by three distinct taxa, two of which were resolved to the species level and one to the level of family. The gene content of the nasal, oropharyngeal, and lung-associated microbiota, predicted using the Phylogenetic Investigations into Communities by Reconstruction of Unobserved States (PICRUSt software, provided information regarding the glyoxylate and citrate cycle metabolic pathways utilized by these bacterial populations to colonize such nutrient-poor, low-throughput environments. These data generated in healthy subjects provide context for future analysis of diseased canine airways. Moreover, as dogs have similar respiratory anatomy, physiology, and immune systems as humans, are exposed to many of the same environmental stimuli, and spontaneously develop similar respiratory diseases, these data support the use of dogs as a model species for prospective studies of the airway microbiota, with findings translatable to the human condition.

Semi-Automatic Measurement of the Airway Dimension by Computed Tomography Using the Full-With-Half- Maximum Method: a Study of the Measurement Accuracy according to the Orientation of an Artificial Airway

International Nuclear Information System (INIS)

Kim, Nam Kug; Seo, Joon Beom; Song, Koun Sik; Chae, Eun Jin; Kang, Suk Ho

2008-01-01

To develop an algorithm to measure the dimensions of an airway oriented obliquely on a volumetric CT, as well as assess the effect of the imaging parameters on the correct measurement of the airway dimension. An airway phantom with 11 poly-acryl tubes of various lumen diameters and wall thicknesses was scanned using a 16-MDCT (multidetector CT) at various tilt angles (0, 30, 45, and 60 ). The CT images were reconstructed at various reconstruction kernels and thicknesses. The axis of each airway was determined using the 3D thinning algorithm, with images perpendicular to the axis being reconstructed. The luminal radius and wall thickness was measured by the full-width-half-maximum method. The influence of the CT parameters (the size of the airways, obliquity on the radius and wall thickness) was assessed by comparing the actual dimension of each tube with the estimated values. The 3D thinning algorithm correctly determined the axis of the oblique airway in all tubes (mean error: 0.91 ± 0.82 .deg. ). A sharper reconstruction kernel, thicker image thickness and larger tilt angle of the airway axis resulted in a significant decrease of the measured wall thickness and an increase of the measured luminal radius. Use of a standard kernel and a 0.75-mm slice thickness resulted in the most accurate measurement of airway dimension, which was independent of obliquity. The airway obliquity and imaging parameters have a strong influence on the accuracy of the airway wall measurement. For the accurate measurement of airway thickness, the CT images should be reconstructed with a standard kernel and a 0.75 mm slice thickness

Efficient Gene Delivery to Pig Airway Epithelia and Submucosal Glands Using Helper-Dependent Adenoviral Vectors

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Huibi Cao

2013-01-01

Full Text Available Airway gene delivery is a promising strategy to treat patients with life-threatening lung diseases such as cystic fibrosis (CF. However, this strategy has to be evaluated in large animal preclinical studies in order to translate it to human applications. Because of anatomic and physiological similarities between the human and pig lungs, we utilized pig as a large animal model to examine the safety and efficiency of airway gene delivery with helper-dependent adenoviral vectors. Helper-dependent vectors carrying human CFTR or reporter gene LacZ were aerosolized intratracheally into pigs under bronchoscopic guidance. We found that the LacZ reporter and hCFTR transgene products were efficiently expressed in lung airway epithelial cells. The transgene vectors with this delivery can also reach to submucosal glands. Moreover, the hCFTR transgene protein localized to the apical membrane of both ciliated and nonciliated epithelial cells, mirroring the location of wild-type CF transmembrane conductance regulator (CFTR. Aerosol delivery procedure was well tolerated by pigs without showing systemic toxicity based on the limited number of pigs tested. These results provide important insights into developing clinical strategies for human CF lung gene therapy.

Supplemental Carbon Dioxide Stabilizes the Upper Airway in Volunteers Anesthetized with Propofol.

Science.gov (United States)

Ruscic, Katarina Jennifer; Bøgh Stokholm, Janne; Patlak, Johann; Deng, Hao; Simons, Jeroen Cedric Peter; Houle, Timothy; Peters, Jürgen; Eikermann, Matthias

2018-05-10

Propofol impairs upper airway dilator muscle tone and increases upper airway collapsibility. Preclinical studies show that carbon dioxide decreases propofol-mediated respiratory depression. We studied whether elevation of end-tidal carbon dioxide (PETCO2) via carbon dioxide insufflation reverses the airway collapsibility (primary hypothesis) and impaired genioglossus muscle electromyogram that accompany propofol anesthesia. We present a prespecified, secondary analysis of previously published experiments in 12 volunteers breathing via a high-flow respiratory circuit used to control upper airway pressure under propofol anesthesia at two levels, with the deep level titrated to suppression of motor response. Ventilation, mask pressure, negative pharyngeal pressure, upper airway closing pressure, genioglossus electromyogram, bispectral index, and change in end-expiratory lung volume were measured as a function of elevation of PETCO2 above baseline and depth of propofol anesthesia. PETCO2 augmentation dose-dependently lowered upper airway closing pressure with a decrease of 3.1 cm H2O (95% CI, 2.2 to 3.9; P < 0.001) under deep anesthesia, indicating improved upper airway stability. In parallel, the phasic genioglossus electromyogram increased by 28% (23 to 34; P < 0.001). We found that genioglossus electromyogram activity was a significant modifier of the effect of PETCO2 elevation on closing pressure (P = 0.005 for interaction term). Upper airway collapsibility induced by propofol anesthesia can be reversed in a dose-dependent manner by insufflation of supplemental carbon dioxide. This effect is at least partly mediated by increased genioglossus muscle activity.

Early treatment of chlorine-induced airway hyperresponsiveness and inflammation with corticosteroids

Energy Technology Data Exchange (ETDEWEB)

Jonasson, Sofia, E-mail: sofia.jonasson@foi.se [Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå (Sweden); Wigenstam, Elisabeth [Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå (Sweden); Department of Public Health and Clinical Medicine, Unit of Respiratory Medicine, Umeå University, Umeå (Sweden); Koch, Bo [Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå (Sweden); Bucht, Anders [Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå (Sweden); Department of Public Health and Clinical Medicine, Unit of Respiratory Medicine, Umeå University, Umeå (Sweden)

2013-09-01

Chlorine (Cl{sub 2}) is an industrial gas that is highly toxic and irritating when inhaled causing tissue damage and an acute inflammatory response in the airways followed by a long-term airway dysfunction. The aim of this study was to evaluate whether early anti-inflammatory treatment can protect against the delayed symptoms in Cl{sub 2}-exposed mice. BALB/c mice were exposed by nose-only inhalation using 200 ppm Cl{sub 2} during 15 min. Assessment of airway hyperresponsiveness (AHR), inflammatory cell counts in bronchoalveolar lavage, occurrence of lung edema and lung fibrosis were analyzed 24 h or 14 days post-exposure. A single dose of the corticosteroid dexamethasone (10 or 100 mg/kg) was administered intraperitoneally 1, 3, 6, or 12 h following Cl{sub 2} exposure. High-dose of dexamethasone reduced the acute inflammation if administered within 6 h after exposure but treated animals still displayed a significant lung injury. The effect of dexamethasone administered within 1 h was dose-dependent; high-dose significantly reduced acute airway inflammation (100 mg/kg) but not treatment with the relatively low-dose (10 mg/kg). Both doses reduced AHR 14 days later, while lung fibrosis measured as collagen deposition was not significantly reduced. The results point out that the acute inflammation in the lungs due to Cl{sub 2} exposure only partly is associated with the long-term AHR. We hypothesize that additional pathogenic mechanisms apart from the inflammatory reactions contribute to the development of long-term airway dysfunction. By using this mouse model, we have validated early administration of corticosteroids in terms of efficacy to prevent acute lung injury and delayed symptoms induced by Cl{sub 2} exposure. - Highlights: • Inhalation of Cl{sub 2} may lead to a long-standing airway hyperresponsiveness. • The symptoms in Cl{sub 2}-exposed mice are similar to those described for RADS in humans. • Corticosteroids prevent delayed symptoms such as AHR in

Comparison of the Force Required for Dislodgement Between Secured and Unsecured Airways.

Science.gov (United States)

Davenport, Curtis; Martin-Gill, Christian; Wang, Henry E; Mayrose, James; Carlson, Jestin N

2018-05-01

Airway device placement and maintenance are of utmost importance when managing critically ill patients. The best method to secure airway devices is currently unknown. We sought to determine the force required to dislodge 4 types of airways with and without airway securing devices. We performed a prospective study using 4 commonly used airway devices (endotracheal tube [ETT], laryngeal mask airway [LMA], King laryngeal tube [King], and iGel) performed on 5 different mannequin models. All devices were removed twice per mannequin in random order, once unsecured and once secured as per manufacturers' recommendations; Thomas Tube Holder (Laerdal, Stavanger, Norway) for ETT, LMA, and King; custom tube holder for iGel. A digital force measuring device was attached to the exposed end of the airway device and gradually pulled vertically and perpendicular to the mannequin until the tube had been dislodged, defined as at least 4 cm of movement. Dislodgement force was reported as the maximum force recorded during dislodgement. We compared the relative difference in the secured and unsecured force for each device and between devices using a random-effects regression model accounting for variability in the manikins. The median dislodgment forces (interquartile range [IQR]) in pounds for each secured device were: ETT 13.3 (11.6, 14.1), LMA 16.6 (13.9, 18.3), King 21.7 (16.9, 25.1), and iGel 8 (6.8, 8.3). The median dislodgement forces for each unsecured device were: ETT 4.5 (4.3, 5), LMA 8.4 (6.8, 10.7), King 10.6 (8.2, 11.5), and iGel 3.9 (3.2, 4.2). The relative difference in dislodgement forces (95% confidence intervals) were higher for each device when secured: ETT 8.6 (6.2 to 11), LMA 8.8 (4.6 to 13), King 12.1 (7.2 to 16.6), iGel 4 (1.1 to 6.9). When compared to secured ETT, the King required greater dislodgement force (relative difference 8.6 [4.5-12.7]). The secured iGel required less force than the secured ETT (relative difference -4.8 [-8.9 to -0.8]). Compared with a

Inhibition of aldose reductase prevents experimental allergic airway inflammation in mice.

Directory of Open Access Journals (Sweden)

Umesh C S Yadav

2009-08-01

Full Text Available The bronchial asthma, a clinical complication of persistent inflammation of the airway and subsequent airway hyper-responsiveness, is a leading cause of morbidity and mortality in critically ill patients. Several studies have shown that oxidative stress plays a key role in initiation as well as amplification of inflammation in airways. However, still there are no good anti-oxidant strategies available for therapeutic intervention in asthma pathogenesis. Most recent studies suggest that polyol pathway enzyme, aldose reductase (AR, contributes to the pathogenesis of oxidative stress-induced inflammation by affecting the NF-kappaB-dependent expression of cytokines and chemokines and therefore inhibitors of AR could be anti-inflammatory. Since inhibitors of AR have already gone through phase-III clinical studies for diabetic complications and found to be safe, our hypothesis is that AR inhibitors could be novel therapeutic drugs for the prevention and treatment of asthma. Hence, we investigated the efficacy of AR inhibition in the prevention of allergic responses to a common natural airborne allergen, ragweed pollen that leads to airway inflammation and hyper-responsiveness in a murine model of asthma.Primary Human Small Airway Epithelial Cells (SAEC were used to investigate the in vitro effects of AR inhibition on ragweed pollen extract (RWE-induced cytotoxic and inflammatory signals. Our results indicate that inhibition of AR prevents RWE -induced apoptotic cell death as measured by annexin-v staining, increase in the activation of NF-kappaB and expression of inflammatory markers such as inducible nitric oxide synthase (iNOS, cycloxygenase (COX-2, Prostaglandin (PG E(2, IL-6 and IL-8. Further, BALB/c mice were sensitized with endotoxin-free RWE in the absence and presence of AR inhibitor and followed by evaluation of perivascular and peribronchial inflammation, mucin production, eosinophils infiltration and airway hyperresponsiveness. Our results

Airway, responsiveness and inflammation in adolescent elite swimmers

DEFF Research Database (Denmark)

Pedersen, Lise; Lund, T.K.; Barnes, P.J.

2008-01-01

Background: Whereas increased airway hyperresponsiveness (AHR) and airway inflammation are well documented in adult elite athletes, it remains uncertain whether the same airway changes are present in adolescents involved in elite sport. Objective: To investigate airway responsiveness and airway....... There was no difference in FeNO, cellular composition of sputum, airway reactivity, or prevalence of having AHR to methacholine and/or EVH between swimmers with and without respiratory symptoms. Conclusion: Adolescent elite swimmers do not have significant signs of airway damage after only a few years of intense training...... and competition. This leads us to believe that elite swimmers do not have particularly susceptible airways when they take up competitive swimming when young, but that they develop respiratory symptoms, airway inflammation, and AHR during their swimming careers Udgivelsesdato: 2008/8...

The operative cooperation and nursing in performing airway stent placement under DSA guidance for treating airway stenosis

International Nuclear Information System (INIS)

Yan Baojun; Wu Gang; Han Xinwei; Wang Nan; Shi Jin; Si Wenfeng; Wang Kai; Su Ning; Liu Jia; Hai Dandan

2011-01-01

Objective: To discuss the key points of the nursing care for effectively performing airway stent placement under DSA monitoring for airway stenosis. Methods: Corresponding nursing care measures were carried out for 118 patients with airway stenosis who were treated with airway stent placement. Results: The symptom of dyspnea was markedly relieved after stent implantation in all 118 patients with airway stenosis. Conclusion: To strengthen the preoperative psychological nursing and operative posture training, to make close postoperative watch on vital signs, to adopt some prevention measures for possible complications and to give necessary medical advises at the time of discharge are very helpful for patient's recovery after the surgery. (authors)

Analysis of airways in computed tomography

DEFF Research Database (Denmark)

Petersen, Jens

Chronic Obstructive Pulmonary Disease (COPD) is major cause of death and disability world-wide. It affects lung function through destruction of lung tissue known as emphysema and inflammation of airways, leading to thickened airway walls and narrowed airway lumen. Computed Tomography (CT) imaging...

A 'Good' muscle in a 'Bad' environment: the importance of airway smooth muscle force adaptation to airway hyperresponsiveness.

Science.gov (United States)

Bossé, Ynuk; Chapman, David G; Paré, Peter D; King, Gregory G; Salome, Cheryl M

2011-12-15

Asthma is characterized by airway inflammation, with a consequent increase in spasmogens, and exaggerated airway narrowing in response to stimuli, termed airway hyperresponsiveness (AHR). The nature of any relationship between inflammation and AHR is less clear. Recent ex vivo data has suggested a novel mechanism by which inflammation may lead to AHR, in which increased basal ASM-tone, due to the presence of spasmogens in the airways, may "strengthen" the ASM and ultimately lead to exaggerated airway narrowing. This phenomenon was termed "force adaptation" [Bossé, Y., Chin, L.Y., Paré, P.D., Seow, C.Y., 2009. Adaptation of airway smooth muscle to basal tone: relevance to airway hyperresponsiveness. Am. J. Respir. Cell Mol. Biol. 40, 13-18]. However, it is unknown whether the magnitude of the effect of force adaptation ex vivo could contribute to exaggerated airway narrowing in vivo. Our aim was to utilize a computational model of ASM shortening in order to quantify the potential effect of force adaptation on airway narrowing when all other mechanical factors were kept constant. The shortening in the model is dictated by a balance between physiological loads and ASM force-generating capacity at different lengths. The results suggest that the magnitude of the effect of force adaptation on ASM shortening would lead to substantially more airway narrowing during bronchial challenge at any given airway generation. We speculate that the increased basal ASM-tone in asthma, due to the presence of inflammation-derived spasmogens, produces an increase in the force-generating capacity of ASM, predisposing to AHR during subsequent challenge. Copyright © 2011 Elsevier B.V. All rights reserved.

Acrolein stimulates eicosanoid release from bovine airway epithelial cells

International Nuclear Information System (INIS)

Doupnik, C.A.; Leikauf, G.D.

1990-01-01

Injury to the airway mucosa after exposure to environmental irritants is associated with pulmonary inflammation and bronchial hyperresponsiveness. To better understand the relationships between mediator release and airway epithelial cell injury during irritant exposures, we studied the effects of acrolein, a low-molecular-weight aldehyde found in cigarette smoke, on arachidonic acid metabolism in cultured bovine tracheal epithelial cells. Confluent airway epithelial cell monolayers, prelabeled with [3H]arachidonic acid, released significant levels of 3H activity when exposed (20 min) to 100 microM acrolein. [3H]arachidonic acid products were resolved using reverse-phase high-performance liquid chromatography. Under control conditions the released 3H activity coeluted predominantly with the cyclooxygenase product, prostaglandin (PG) E2. After exposure to acrolein, significant peaks in 3H activity coeluted with the lipoxygenase products 12-hydroxyeicosatetraenoic acid (HETE) and 15-HETE, as well as with PGE2, PGF2 alpha, and 6-keto-PGF1 alpha. Dose-response relationships for acrolein-induced release of immunoreactive PGF2 alpha and PGE2 from unlabeled epithelial monolayers demonstrated 30 microM acrolein as the threshold dose, with 100 microM acrolein inducing nearly a fivefold increase in both PGF2 alpha and PGE2. Cellular viability after exposure to 100 microM acrolein, determined by released lactate dehydrogenase activity, was not affected until exposure periods were greater than or equal to 2 h. These results implicate the airway epithelial cell as a possible source of eicosanoids after exposure to acrolein

Emergency surgical airway management in Denmark

DEFF Research Database (Denmark)

Rosenstock, C V; Nørskov, A K; Wetterslev, J

2016-01-01

for difficult airway management. RESULTS: In the DAD cohort 27 out of 452 461 patients had an ESA representing an incidence of 0.06 events per thousand (95% CI; 0.04 to 0.08). A total of 12 149/452 461 patients underwent Ear-Nose and Throat (ENT) surgery, giving an ESA incidence among ENT patients of 1.6 events...... of which three failed. Reviewers evaluated airway management as satisfactory in 10/27 patients. CONCLUSIONS: The incidence of ESA in the DAD cohort was 0.06 events per thousand. Among ENT patients, the ESA Incidence was 1.6 events per thousand. Airway management was evaluated as satisfactory for 10......BACKGROUND: The emergency surgical airway (ESA) is the final option in difficult airway management. We identified ESA procedures registered in the Danish Anaesthesia Database (DAD) and described the performed airway management. METHODS: We extracted a cohort of 452 461 adult patients undergoing...

Generation of Distal Airway Epithelium from Multipotent Human Foregut Stem Cells.

Science.gov (United States)

Hannan, Nicholas R F; Sampaziotis, Fotios; Segeritz, Charis-Patricia; Hanley, Neil A; Vallier, Ludovic

2015-07-15

Collectively, lung diseases are one of the largest causes of premature death worldwide and represent a major focus in the field of regenerative medicine. Despite significant progress, only few stem cell platforms are currently available for cell-based therapy, disease modeling, and drug screening in the context of pulmonary disorders. Human foregut stem cells (hFSCs) represent an advantageous progenitor cell type that can be used to amplify large quantities of cells for regenerative medicine applications and can be derived from any human pluripotent stem cell line. Here, we further demonstrate the application of hFSCs by generating a near homogeneous population of early pulmonary endoderm cells coexpressing NKX2.1 and FOXP2. These progenitors are then able to form cells that are representative of distal airway epithelium that express NKX2.1, GATA6, and cystic fibrosis transmembrane conductance regulator (CFTR) and secrete SFTPC. This culture system can be applied to hFSCs carrying the CFTR mutation Δf508, enabling the development of an in vitro model for cystic fibrosis. This platform is compatible with drug screening and functional validations of small molecules, which can reverse the phenotype associated with CFTR mutation. This is the first demonstration that multipotent endoderm stem cells can differentiate not only into both liver and pancreatic cells but also into lung endoderm. Furthermore, our study establishes a new approach for the generation of functional lung cells that can be used for disease modeling as well as for drug screening and the study of lung development.

Innate immune receptors in human airway smooth muscle cells: activation by TLR1/2, TLR3, TLR4, TLR7 and NOD1 agonists.

Directory of Open Access Journals (Sweden)

Anne Månsson Kvarnhammar

Full Text Available BACKGROUND: Pattern-recognition receptors (PRRs, including Toll-like receptors (TLRs, NOD-like receptors (NLRs and RIG-I-like receptors (RLRs, recognize microbial components and trigger a host defense response. Respiratory tract infections are common causes of asthma exacerbations, suggesting a role for PRRs in this process. The present study aimed to examine the expression and function of PRRs on human airway smooth muscle cells (HASMCs. METHODS: Expression of TLR, NLR and RLR mRNA and proteins was determined using real-time RT-PCR, flow cytometry and immunocytochemistry. The functional responses to ligand stimulation were investigated in terms of cytokine and chemokine release, cell surface marker expression, proliferation and proteins regulating the contractile state. RESULTS: HASMCs expressed functional TLR2, TLR3, TLR4, TLR7 and NOD1. Stimulation with the corresponding agonists Pam3CSK4, poly(I:C, LPS, R-837 and iE-DAP, respectively, induced IL-6, IL-8 and GM-CSF release and up-regulation of ICAM-1 and HLA-DR, while poly(I:C also affected the release of eotaxin and RANTES. The proliferative response was slightly increased by LPS. Stimulation, most prominently with poly(I:C, down-regulated myosin light chain kinase and cysteinyl leukotriene 1 receptor expression and up-regulated β2-adrenoceptor expression. No effects were seen for agonist to TLR2/6, TLR5, TLR8, TLR9, NOD2 or RIG-I/MDA-5. CONCLUSION: Activation of TLR2, TLR3, TLR4, TLR7 and NOD1 favors a synthetic phenotype, characterized by an increased ability to release inflammatory mediators, acquire immunomodulatory properties by recruiting and interacting with other cells, and reduce the contractile state. The PRRs might therefore be of therapeutic use in the management of asthma and infection-induced disease exacerbations.

Effects of concentrated ambient particles on normal and hypersecretory airways in rats.

Science.gov (United States)

Harkema, Jack R; Keeler, Gerald; Wagner, James; Morishita, Masako; Timm, Edward; Hotchkiss, Jon; Marsik, Frank; Dvonch, Timothy; Kaminski, Norbert; Barr, Edward

2004-08-01

Epidemiological studies have reported that elevated levels of particulate air pollution in urban communities are associated with increases in attacks of asthma based on evidence from hospital admissions and emergency department visits. Principal pathologic features of chronic airway diseases, like asthma, are airway inflammation and mucous hypersecretion with excessive amounts of luminal mucus and increased numbers of mucus-secreting cells in regions of the respiratory tract that normally have few or no mucous cells (ie, mucous cell metaplasia). The overall goal of the present project was to understand the adverse effects of urban air fine particulate matter (PM2.5; pollutants in the outdoor air of a local Detroit community with a high incidence of childhood asthma; (2) determine the effects of this community-based PM2.5 on the airway epithelium in normal rats and rats compromised with preexisting hypersecretory airway diseases (ie, animal models of human allergic airway disease--asthma and chronic bronchitis); and (3) identify the chemical or physical components of PM2.5 that are responsible for PM2.5 -induced airway inflammation and epithelial alterations in these animal models. Two animal models of airway disease were used to examine the effects of PM2.5 exposure on preexisting hypersecretory airways: neutrophilic airway inflammation induced by endotoxin challenge in F344 rats and eosinophilic airway inflammation induced by ovalbumin (OVA) challenge in BN rats. A mobile air monitoring and exposure laboratory equipped with inhalation exposure chambers for animal toxicology studies, air pollution monitors, and particulate collection devices was used in this investigation. The mobile laboratory was parked in a community in southwestern Detroit during the summer months when particulate air pollution is usually high (July and September 2000). We monitored the outdoor air pollution in this community daily, and exposed normal and compromised rats to concentrated PM2

Development and characterization of a 3D multicell microtissue culture model of airway smooth muscle.

Science.gov (United States)

West, Adrian R; Zaman, Nishat; Cole, Darren J; Walker, Matthew J; Legant, Wesley R; Boudou, Thomas; Chen, Christopher S; Favreau, John T; Gaudette, Glenn R; Cowley, Elizabeth A; Maksym, Geoffrey N

2013-01-01

Airway smooth muscle (ASM) cellular and molecular biology is typically studied with single-cell cultures grown on flat 2D substrates. However, cells in vivo exist as part of complex 3D structures, and it is well established in other cell types that altering substrate geometry exerts potent effects on phenotype and function. These factors may be especially relevant to asthma, a disease characterized by structural remodeling of the airway wall, and highlights a need for more physiologically relevant models of ASM function. We utilized a tissue engineering platform known as microfabricated tissue gauges to develop a 3D culture model of ASM featuring arrays of ∼0.4 mm long, ∼350 cell "microtissues" capable of simultaneous contractile force measurement and cell-level microscopy. ASM-only microtissues generated baseline tension, exhibited strong cellular organization, and developed actin stress fibers, but lost structural integrity and dissociated from the cantilevers within 3 days. Addition of 3T3-fibroblasts dramatically improved survival times without affecting tension development or morphology. ASM-3T3 microtissues contracted similarly to ex vivo ASM, exhibiting reproducible responses to a range of contractile and relaxant agents. Compared with 2D cultures, microtissues demonstrated identical responses to acetylcholine and KCl, but not histamine, forskolin, or cytochalasin D, suggesting that contractility is regulated by substrate geometry. Microtissues represent a novel model for studying ASM, incorporating a physiological 3D structure, realistic mechanical environment, coculture of multiple cells types, and comparable contractile properties to existing models. This new model allows for rapid screening of biochemical and mechanical factors to provide insight into ASM dysfunction in asthma.

Awake Craniotomy: A New Airway Approach.

Science.gov (United States)

Sivasankar, Chitra; Schlichter, Rolf A; Baranov, Dimitry; Kofke, W Andrew

2016-02-01

Awake craniotomies have been performed regularly at the University of Pennsylvania since 2004. Varying approaches to airway management are described for this procedure, including intubation with an endotracheal tube and use of a laryngeal mask airway, simple facemask, or nasal cannula. In this case series, we describe the successful use (i.e., no need for endotracheal intubation related to inadequate gas exchange) of bilateral nasopharyngeal airways in 90 patients undergoing awake craniotomies. The use of nasopharyngeal airways can ease the transition between the asleep and awake phases of the craniotomy without the need to stimulate the airway. Our purpose was to describe our experience and report adverse events related to this technique.

Pediatric supraglottic airway devices in clinical practice: A prospective observational study.

Science.gov (United States)

Kleine-Brueggeney, Maren; Gottfried, Anne; Nabecker, Sabine; Greif, Robert; Book, Malte; Theiler, Lorenz

2017-09-02

Supraglottic airway devices (SGA) are commonly used in pediatric anesthesia and serve as primary or back-up devices for difficult airway management. Most SGA are marketed without proper clinical evaluation. The purpose of this study was to evaluate the performance of the pediatric LMA Supreme™, Air-Q® and Ambu® Aura-i™. This prospective observational study was performed at Bern University Hospital, Switzerland. With ethics committee approval and a waiver for written informed consent 240 children undergoing elective surgery with an ASA class I-III and a weight of 5-30 kg were included. Three different pediatric supraglottic airway devices were assessed: The LMA Supreme™, Air-Q® and Ambu® Aura-i™. Primary outcome parameter was airway leak pressure. Secondary outcome parameters included first attempt and overall success rate, insertion time, fiberoptic view through the SGA, and adverse events. The primary hypothesis was that the mean airway leak pressure of each tested SGA was 20 cmH 2 O ± 10%. None of the SGA showed a mean airway leak pressure of 20 cmH 2 O ± 10%, but mean airway leak pressures differed significantly between devices [LMA Supreme™ 18.0 (3.4) cmH 2 O, Air-Q® 15.9 (3.2) cmH 2 O, Ambu® Aura-i™ 17.3 (3.7) cmH 2 O, p < 0.001]. First attempt success rates (LMA Supreme™ 100%, Air-Q® 90%, Ambu® Aura-i™ 91%, p = 0.02) and overall success rates (LMA Supreme™ 100%, Air-Q® 91%, Ambu® Aura-i™ 95%, p = 0.02) also differed significantly. Insertion times ranged from 20 (7) seconds (Air-Q®) to 24 (6) seconds (LMA Supreme™, Airway leak pressures ranged from 16 to 18 cmH 2 O, enabling positive pressure ventilation with all successful SGA. The highest success rates were achieved by the LMA Supreme™, which was also

Acute lung injury and persistent small airway disease in a rabbit model of chlorine inhalation

Energy Technology Data Exchange (ETDEWEB)

Musah, Sadiatu; Schlueter, Connie F.; Humphrey, David M. [Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, KY (United States); Powell, Karen S. [Research Resource Facilities, University of Louisville, Louisville, KY (United States); Roberts, Andrew M. [Department of Physiology, University of Louisville, Louisville, KY (United States); Hoyle, Gary W., E-mail: Gary.Hoyle@louisville.edu [Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, KY (United States)

2017-01-15

Chlorine is a pulmonary toxicant to which humans can be exposed through accidents or intentional releases. Acute effects of chlorine inhalation in humans and animal models have been well characterized, but less is known about persistent effects of acute, high-level chlorine exposures. In particular, animal models that reproduce the long-term effects suggested to occur in humans are lacking. Here, we report the development of a rabbit model in which both acute and persistent effects of chlorine inhalation can be assessed. Male New Zealand White rabbits were exposed to chlorine while the lungs were mechanically ventilated. After chlorine exposure, the rabbits were extubated and were allowed to survive for up to 24 h after exposure to 800 ppm chlorine for 4 min to study acute effects or up to 7 days after exposure to 400 ppm for 8 min to study longer term effects. Acute effects observed 6 or 24 h after inhalation of 800 ppm chlorine for 4 min included hypoxemia, pulmonary edema, airway epithelial injury, inflammation, altered baseline lung mechanics, and airway hyperreactivity to inhaled methacholine. Seven days after recovery from inhalation of 400 ppm chlorine for 8 min, rabbits exhibited mild hypoxemia, increased area of pressure–volume loops, and airway hyperreactivity. Lung histology 7 days after chlorine exposure revealed abnormalities in the small airways, including inflammation and sporadic bronchiolitis obliterans lesions. Immunostaining showed a paucity of club and ciliated cells in the epithelium at these sites. These results suggest that small airway disease may be an important component of persistent respiratory abnormalities that occur following acute chlorine exposure. This non-rodent chlorine exposure model should prove useful for studying persistent effects of acute chlorine exposure and for assessing efficacy of countermeasures for chlorine-induced lung injury. - Highlights: • A novel rabbit model of chlorine-induced lung disease was developed. �

Endobronchial Ultrasound Reliably Quantifies Airway Smooth Muscle Remodeling in an Equine Asthma Model.

Directory of Open Access Journals (Sweden)

Michela Bullone

Full Text Available Endobronchial ultrasonography (EBUS revealed differences in the thickness of the layer representing subepithelial tissues (L2 between human asthmatics and controls, but whether this measurement correlates with airway smooth muscle (ASM remodeling in asthma is unknown. In this study, we sought to determine the ability of EBUS to predict histological ASM remodeling in normal and equine asthmatic airways. We studied 109 isolated bronchi from the lungs of 13 horses. They underwent EBUS examination using a 30 MHz radial probe before being processed for histology. ASM remodeling parameters were evaluated in EBUS images (L2 thickness, L2 area, L2 area/internal perimeter [Pi] and L2 area/Pi2 and histological cuts (ASM area/Pi2, and compared. EBUS was then performed ex vivo on the lungs of 4 horses with heaves, an asthma-like condition of horses, and 7 controls to determine whether central bronchial remodeling could be detected with this technique. An optimized approach was developed based on data variability within airways, subjects, and groups, and then validated in 7 horses (3 controls, 4 with heaves that underwent EBUS in vivo. L2 area was significantly associated to ASM area in isolated lungs (p<0.0001, in the absence of significant bias related to the airway size. Bronchial size significantly affected EBUS ASM-related parameters, except for L2 area/Pi2. L2 area/Pi2 was increased in the airways of asthmatic horses compared to controls, both ex vivo and in vivo (p<0.05. Bronchial histology confirmed our findings (AASM/Pi2 was increased in asthmatic horses compared to controls, p<0.05. In both horses with heaves and controls, L2 was composed of ASM for the outer 75% of its thickness and by ECM for the remaining inner 25%. In conclusion, EBUS reliably allows assessment of asthma-associated ASM remodeling of central airways in a non-invasive way.

Anticholinergic treatment in airways diseases.

LENUS (Irish Health Repository)

Flynn, Robert A

2009-10-01

The prevalence of chronic airways diseases such as chronic obstructive pulmonary disease and asthma is increasing. They lead to symptoms such as a cough and shortness of breath, partially through bronchoconstriction. Inhaled anticholinergics are one of a number of treatments designed to treat bronchoconstriction in airways disease. Both short-acting and long-acting agents are now available and this review highlights their efficacy and adverse event profile in chronic airways diseases.

Multiscale Vessel-guided Airway Tree Segmentation

DEFF Research Database (Denmark)

Lo, Pechin Chien Pau; Sporring, Jon; de Bruijne, Marleen

2009-01-01

This paper presents a method for airway tree segmentation that uses a combination of a trained airway appearance model, vessel and airway orientation information, and region growing. The method uses a voxel classification based appearance model, which involves the use of a classifier that is trai...

A 3D human tissue-engineered lung model to study influenza A infection.

Science.gov (United States)

Bhowmick, Rudra; Derakhshan, Mina; Liang, Yurong; Ritchey, Jerry; Liu, Lin; Gappa-Fahlenkamp, Heather

2018-05-05

Influenza A virus (IAV) claims approximately 250,000-500,000 lives annually worldwide. Currently, there are a few in vitro models available to study IAV immunopathology. Monolayer cultures of cell lines and primary lung cells (2D cell culture) is the most commonly used tool, however, this system does not have the in vivo-like structure of the lung and immune responses to IAV as it lacks the three-dimensional (3D) tissue structure. To recapitulate the lung physiology in vitro, a system that contains multiple cell types within a 3D environment that allows cell movement and interaction, would provide a critical tool. In this study, as a first step in designing a 3D-Human Tissue-Engineering Lung Model (3D-HTLM), we described the 3D culture of primary human small airway epithelial cells (HSAEpCs), and determined the immunophenotype of this system in response to IAV infections. We constructed a 3D chitosan-collagen scaffold and cultured HSAEpCs on these scaffolds at air-liquid interface (ALI). These 3D cultures were compared with 2D-cultured HSAEpCs for viability, morphology, marker protein expression, and cell differentiation. Results showed that the 3D-cultured HSAEpCs at ALI yielded maximum viable cells and morphologically resembled the in vivo lower airway epithelium. There were also significant increases in aquaporin-5 and cytokeratin-14 expression for HSAEpCs cultured in 3D compared to 2D. The 3D culture system was used to study the infection of HSAEpCs with two major IAV strains, H1N1 and H3N2.The HSAEpCs showed distinct changes in marker protein expression, both at mRNA and protein levels, and the release of proinflammatory cytokines. This study is the first step in the development of the 3D-HTLM, which will have wide applicability in studying pulmonary pathophysiology and therapeutics development.

Prenatal MRI Findings of Fetuses with Congenital High Airway Obstruction Sequence

Energy Technology Data Exchange (ETDEWEB)

Guimaraes, Carolina V. A.; Linam, Leann E.; Kline-Fath, Beth M. [Cincinnati Children' s Hospital Medical Center, Cincinnati (United States)] (and others)

2009-04-15

To define the MRI findings of congenital high airway obstruction sequence (CHAOS) in a series of fetuses. Prenatal fetal MR images were reviewed in seven fetuses with CHAOS at 21 to 27 weeks of gestation. The MRI findings were reviewed. The MRI parameters evaluated included the appearance of the lungs and diaphragm, presence or absence of hydrops, amount of amniotic fluid, airway appearance, predicted level of airway obstruction, and any additional findings or suspected genetic syndromes. All the fetuses viewed (7 of 7) demonstrated the following MRI findings: dilated airway below the level of obstruction, increased lung signal, markedly increased lung volumes with flattened or inverted hemidiaphragms, massive ascites, centrally positioned and compressed heart, as well as placentomegaly. Other frequent findings were anasarca (6 of 7) and polyhydramnios (3 of 7). MRI identified the level of obstruction as laryngeal in five cases and tracheal in two cases. In four of the patients, surgery or autopsy confirmed the MRI predicted level of obstruction. Associated abnormalities were found in 4 of 7 (genetic syndromes in 2). Postnatal radiography (n = 3) showed markedly hyperinflated lungs with inverted or flattened hemidiaphragms, strandy perihilar opacities, pneumothoraces and tracheotomy. Two fetuses were terminated and one fetus demised in utero. Four fetuses were delivered via ex utero intrapartum treatment procedure. MRI shows a consistent pattern of abnormalities in fetuses with CHAOS, accurately identifies the level of airway obstruction, and helps differentiate from other lung abnormalities such as bilateral congenital pulmonary airway malformation by demonstrating an abnormally dilated airway distal to the obstruction.

Relationship of airway dimensions with airflow limitation or lung volumes in chronic obstructive pulmonary disease (COPD

Directory of Open Access Journals (Sweden)

Masaru Hasegawa

2006-12-01

Full Text Available We have recently developed new software to obtain longitudinal images and accurate short axis images of airways with an inner diameter > 2 mm located anywhere in the lung, using curved multiplanar reconstruction. Using this software, we demonstrated in patients with COPD that FEV1 (%predicted was highly correlated with airway dimensions and the correlation coefficients improved as the airway became smaller in size (3. In this study, our aims are to further confirm the significant relationship between airway dimensions and airflow limitation in larger number of subjects, and to examine the relationship of airway dimensions with lung volumes in 95 patients with COPD (stage 0, 10; stage I, 23; stage II, 35; stage III, 24; stage IV, 3. We analyzed the airway dimensions from the 3rd to the 6th generations of the apical bronchus (B1 of the right upper lobe and the anterior basal bronchus (B8 of the right lower lobe. Lung volumes were measured by the helium closed circuit method. Both airway luminal area (Ai and wall area percent (WA% of all the generations, except a few, from the two bronchi were significantly correlated with RV and RV/TLC, but not with TLC or FRC. More importantly, the correlation coefficients (r between airway dimensions and RV/TLC improved as the airways became smaller in size from the 3rd to 6th generations in both bronchi (r = –0.483, –0482, –0.553, –0.624 for Ai of B8; r = 0.316, 0.380, 0.499, 0.551 for WA% of B8. These findings provide further evidence that distal (small airways rather than proximal (large airways are the determinants for airflow limitation in COPD.

Orofacial-cervical alterations in individuals with upper airway resistance syndrome

Directory of Open Access Journals (Sweden)

Pedro Wey Barbosa de Oliveira

Full Text Available ABSTRACT INTRODUCTION: Studies that assess the upper airways in sleep-related breathing disorders have been performed only in patients with obstructive sleep apnea syndrome who seek medical attention. Therefore, in addition to the need for population studies, there are no data on the orofacial-cervical physical examination in subjects with upper airway resistance syndrome. OBJECTIVES: To compare the orofacial-cervical examination between volunteers with upper airway resistance syndrome and without sleep-related breathing disorders. METHODS: Through questionnaires, physical measurements, polysomnography, and otorhinolaryngological evaluation, this study compared the orofacial-cervical physical examination, through a systematic analysis of the facial skeleton, mouth, throat, and nose, between volunteers with upper airway resistance syndrome and volunteers without sleep-related breathing disorders in a representative sample of the adult population of the city of São Paulo. RESULTS: There were 1042 volunteers evaluated; 49 subjects (5% were excluded as they did not undergo otorhinolaryngological evaluation, 381 (36% had apnea-hypopnea index > 5 events/hour, and 131 (13% had oxyhemoglobin saturation < 90%. Among the remaining 481 subjects (46%, 30 (3% met the criteria for the upper airway resistance syndrome definition and 53 (5% met the control group criteria. At the clinical evaluation of nasal symptoms, the upper airway resistance syndrome group had more oropharyngeal dryness (17% vs. 29.6%; p = 0.025 and septal deviation grades 1-3 (49.1% vs. 57.7%; p = 0.025 when compared to controls. In the logistic regression model, it was found that individuals from the upper airway resistance syndrome group had 15.6-fold higher chance of having nose alterations, 11.2-fold higher chance of being hypertensive, and 7.6-fold higher chance of complaining of oropharyngeal dryness when compared to the control group. CONCLUSION: Systematic evaluation of the facial

Current Practice of Airway Stenting in the Adult Population in Europe

DEFF Research Database (Denmark)

Dutau, Hervé; Breen, David; Bugalho, Antonio