Surfactant protein D attenuates sub-epithelial fibrosis in allergic airways disease through TGF-β.

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Ogawa, Hirohisa; Ledford, Julie G; Mukherjee, Sambuddho; Aono, Yoshinori; Nishioka, Yasuhiko; Lee, James J; Izumi, Keisuke; Hollingsworth, John W

2014-11-29

Surfactant protein D (SP-D) can regulate both innate and adaptive immunity. Recently, SP-D has been shown to contribute to the pathogenesis of airway allergic inflammation and bleomycin-induced pulmonary fibrosis. However, in allergic airways disease, the role of SP-D in airway remodeling remains unknown. The objective of this study was to determine the contribution of functional SP-D in regulating sub-epithelial fibrosis in a mouse chronic house dust mite model of allergic airways disease. C57BL/6 wild-type (WT) and SP-D-/- mice (C57BL/6 background) were chronically challenged with house dust mite antigen (Dermatophagoides pteronyssinus, Dp). Studies with SP-D rescue and neutralization of TGF-β were conducted. Lung histopathology and the concentrations of collagen, growth factors, and cytokines present in the airspace and lung tissue were determined. Cultured eosinophils were stimulated by Dp in presence or absence of SP-D. Dp-challenged SP-D-/- mice demonstrate increased sub-epithelial fibrosis, collagen production, eosinophil infiltration, TGF-β1, and IL-13 production, when compared to Dp-challenged WT mice. By immunohistology, we detected an increase in TGF-β1 and IL-13 positive eosinophils in SP-D-/- mice. Purified eosinophils stimulated with Dp produced TGF-β1 and IL-13, which was prevented by co-incubation with SP-D. Additionally, treatment of Dp challenged SP-D-/- mice with exogenous SP-D was able to rescue the phenotypes observed in SP-D-/- mice and neutralization of TGF-β1 reduced sub-epithelial fibrosis in Dp-challenged SP-D-/- mice. These data support a protective role for SP-D in the pathogenesis of sub-epithelial fibrosis in a mouse model of allergic inflammation through regulation of eosinophil-derived TGF-β.

The involvement of glycosaminoglycans in airway disease associated with cystic fibrosis.

LENUS (Irish Health Repository)

Reeves, Emer P

2012-02-01

Individuals with cystic fibrosis (CF) present with severe airway destruction and extensive bronchiectasis. It has been assumed that these structural airway changes have occurred secondary to infection and inflammation, but recent studies suggest that glycosaminoglycan (GAG) remodelling may be an important independent parallel process. Evidence is accumulating that not only the concentration, but also sulphation of GAGs is markedly increased in CF bronchial cells and tissues. Increased expression of GAGs and, in particular, heparan sulphate, has been linked to a sustained inflammatory response and neutrophil recruitment to the CF airways. This present review discusses the biological role of GAGs in the lung, as well as their involvement in CF respiratory disease, and their potential as therapeutic targets.

Diagnosis of bronchiectasis and airway wall thickening in children with cystic fibrosis. Objective airway-artery quantification

International Nuclear Information System (INIS)

Kuo, Wieying; Tiddens, Harm A.W.M.; Bruijne, Marleen de; Petersen, Jens; Nasserinejad, Kazem; Ozturk, Hadiye; Chen, Yong; Perez-Rovira, Adria

2017-01-01

To quantify airway and artery (AA)-dimensions in cystic fibrosis (CF) and control patients for objective CT diagnosis of bronchiectasis and airway wall thickness (AWT). Spirometer-guided inspiratory and expiratory CTs of 11 CF and 12 control patients were collected retrospectively. Airway pathways were annotated semi-automatically to reconstruct three-dimensional bronchial trees. All visible AA-pairs were measured perpendicular to the airway axis. Inner, outer and AWT (outer-inner) diameter were divided by the adjacent artery diameter to compute A in A-, A out A- and A WT A-ratios. AA-ratios were predicted using mixed-effects models including disease status, lung volume, gender, height and age as covariates. Demographics did not differ significantly between cohorts. Mean AA-pairs CF: 299 inspiratory; 82 expiratory. Controls: 131 inspiratory; 58 expiratory. All ratios were significantly larger in inspiratory compared to expiratory CTs for both groups (p<0.001). A out A- and A WT A-ratios were larger in CF than in controls, independent of lung volume (p<0.01). Difference of A out A- and A WT A-ratios between patients with CF and controls increased significantly for every following airway generation (p<0.001). Diagnosis of bronchiectasis is highly dependent on lung volume and more reliably diagnosed using outer airway diameter. Difference in bronchiectasis and AWT severity between the two cohorts increased with each airway generation. (orig.)

Diagnosis of bronchiectasis and airway wall thickening in children with cystic fibrosis. Objective airway-artery quantification

Energy Technology Data Exchange (ETDEWEB)

Kuo, Wieying; Tiddens, Harm A.W.M. [Erasmus MC - Sophia Children' s Hospital, Department of Pediatric Pulmonology and Allergology, Rotterdam (Netherlands); Erasmus MC, Department of Radiology, Rotterdam (Netherlands); Bruijne, Marleen de [Erasmus MC, Biomedical Imaging Group Rotterdam, Departments of Medical Informatics and Radiology, Rotterdam (Netherlands); University of Copenhagen, Department of Computer Science, Copenhagen (Denmark); Petersen, Jens [University of Copenhagen, Department of Computer Science, Copenhagen (Denmark); Nasserinejad, Kazem [Erasmus MC Cancer Institute, HOVON Data Center, Clinical Trial Center, Rotterdam (Netherlands); Erasmus MC, Department of Biostatistics, Rotterdam (Netherlands); Ozturk, Hadiye [Erasmus MC - Sophia Children' s Hospital, Department of Pediatric Pulmonology and Allergology, Rotterdam (Netherlands); Chen, Yong [General Hospital of Ningxia Medical University, Department of Radiology, Yinchuan (China); Perez-Rovira, Adria [Erasmus MC - Sophia Children' s Hospital, Department of Pediatric Pulmonology and Allergology, Rotterdam (Netherlands); Erasmus MC, Biomedical Imaging Group Rotterdam, Departments of Medical Informatics and Radiology, Rotterdam (Netherlands)

2017-11-15

To quantify airway and artery (AA)-dimensions in cystic fibrosis (CF) and control patients for objective CT diagnosis of bronchiectasis and airway wall thickness (AWT). Spirometer-guided inspiratory and expiratory CTs of 11 CF and 12 control patients were collected retrospectively. Airway pathways were annotated semi-automatically to reconstruct three-dimensional bronchial trees. All visible AA-pairs were measured perpendicular to the airway axis. Inner, outer and AWT (outer-inner) diameter were divided by the adjacent artery diameter to compute A{sub in}A-, A{sub out}A- and A{sub WT}A-ratios. AA-ratios were predicted using mixed-effects models including disease status, lung volume, gender, height and age as covariates. Demographics did not differ significantly between cohorts. Mean AA-pairs CF: 299 inspiratory; 82 expiratory. Controls: 131 inspiratory; 58 expiratory. All ratios were significantly larger in inspiratory compared to expiratory CTs for both groups (p<0.001). A{sub out}A- and A{sub WT}A-ratios were larger in CF than in controls, independent of lung volume (p<0.01). Difference of A{sub out}A- and A{sub WT}A-ratios between patients with CF and controls increased significantly for every following airway generation (p<0.001). Diagnosis of bronchiectasis is highly dependent on lung volume and more reliably diagnosed using outer airway diameter. Difference in bronchiectasis and AWT severity between the two cohorts increased with each airway generation. (orig.)

Abnormal ion content, hydration and granule expansion of the secretory granules from cystic fibrosis airway glandular cells

International Nuclear Information System (INIS)

Baconnais, S.; Delavoie, F.; Zahm, J.M.; Milliot, M.; Terryn, C.; Castillon, N.; Banchet, V.; Michel, J.; Danos, O.; Merten, M.; Chinet, T.; Zierold, K.; Bonnet, N.; Puchelle, E.; Balossier, G.

2005-01-01

The absence or decreased expression of cystic fibrosis transmembrane conductance regulator (CFTR) induces increased Na + absorption and hyperabsorption of the airway surface liquid (ASL) resulting in a dehydrated and hyperviscous ASL. Although the implication of abnormal airway submucosal gland function has been suggested, the ion and water content in the Cystic Fibrosis (CF) glandular secretory granules, before exocytosis, is unknown. We analyzed, in non-CF and CF human airway glandular cell lines (MM-39 and KM4, respectively), the ion content in the secretory granules by electron probe X-ray microanalysis and the water content by quantitative dark field imaging on freeze-dried cryosections. We demonstrated that the ion content (Na + , Mg 2+ , P, S and Cl - ) is significantly higher and the water content significantly lower in secretory granules from the CF cell line compared to the non-CF cell line. Using videomicroscopy, we observed that the secretory granule expansion was deficient in CF glandular cells. Transfection of CF cells with CFTR cDNA or inhibition of non-CF cells with CFTR inh -172, respectively restored or decreased the water content and granule expansion, in parallel with changes in ion content. We hypothesize that the decreased water and increased ion content in glandular secretory granules may contribute to the dehydration and increased viscosity of the ASL in CF

The airway microbiota in early cystic fibrosis lung disease.

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Frayman, Katherine B; Armstrong, David S; Grimwood, Keith; Ranganathan, Sarath C

2017-11-01

Infection plays a critical role in the pathogenesis of cystic fibrosis (CF) lung disease. Over the past two decades, the application of molecular and extended culture-based techniques to microbial analysis has changed our understanding of the lungs in both health and disease. CF lung disease is a polymicrobial disorder, with obligate and facultative anaerobes recovered alongside traditional pathogens in varying proportions, with some differences observed to correlate with disease stage. While healthy lungs are not sterile, differences between the lower airway microbiota of individuals with CF and disease-controls are already apparent in childhood. Understanding the evolution of the CF airway microbiota, and its relationship with clinical treatments and outcome at each disease stage, will improve our understanding of the pathogenesis of CF lung disease and potentially inform clinical management. This review summarizes current knowledge of the early development of the respiratory microbiota in healthy children and then discusses what is known about the airway microbiota in individuals with CF, including how it evolves over time and where future research priorities lie. © 2017 Wiley Periodicals, Inc.

Evolution and adaptation of Pseudomonas aeruginosa in cystic fibrosis airways

DEFF Research Database (Denmark)

Madsen Sommer, Lea Mette

of natural environments, the primary obstacle is re-sampling of the samepopulation over time, especially if the population is small.Nevertheless, it has been accomplished: Chronic airway infections of cystic fibrosis (CF) patients have offered a unique view into the adaptationand evolution of Pseudomonas...... to the CF airways. From this analysis we found common clonal lineages among the patients, evidence of patient-to-patient transmission, historic contingencies, and convergent evolution of 52 candidate pathoadaptive genes. By further genome sequencing 26 P. aeruginosa isolates from four Italian CF patients...

Inhibition of airway epithelial-to-mesenchymal transition and fibrosis by kaempferol in endotoxin-induced epithelial cells and ovalbumin-sensitized mice.

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Gong, Ju-Hyun; Cho, In-Hee; Shin, Daekeun; Han, Seon-Young; Park, Sin-Hye; Kang, Young-Hee

2014-03-01

Chronic airway remodeling is characterized by structural changes within the airway wall, including smooth muscle hypertrophy, submucosal fibrosis and epithelial shedding. Epithelial-to-mesenchymal transition (EMT) is a fundamental mechanism of organ fibrosis, which can be induced by TGF-β. In the in vitro study, we investigated whether 1-20 μM kaempferol inhibited lipopolysaccharide (LPS)-induced bronchial EMT in BEAS-2B cells. The in vivo study explored demoting effects of 10-20 mg/kg kaempferol on airway fibrosis in BALB/c mice sensitized with ovalbumin (OVA). LPS induced airway epithelial TGF-β1 signaling that promoted EMT with concurrent loss of E-cadherin and induction of α-smooth muscle actin (α-SMA). Nontoxic kaempferol significantly inhibited TGF-β-induced EMT process through reversing E-cadherin expression and retarding the induction of N-cadherin and α-SMA. Consistently, OVA inhalation resulted in a striking loss of epithelial morphology by displaying myofibroblast appearance, which led to bronchial fibrosis with submucosal accumulation of collagen fibers. Oral administration of kaempferol suppressed collagen deposition, epithelial excrescency and goblet hyperplasia observed in the lung of OVA-challenged mice. The specific inhibition of TGF-β entailed epithelial protease-activated receptor-1 (PAR-1) as with 20 μM kaempferol. The epithelial PAR-1 inhibition by SCH-79797 restored E-cadherin induction and deterred α-SMA induction, indicating that epithelial PAR-1 localization was responsible for resulting in airway EMT. These results demonstrate that dietary kaempferol alleviated fibrotic airway remodeling via bronchial EMT by modulating PAR1 activation. Therefore, kaempferol may be a potential therapeutic agent targeting asthmatic airway constriction.

The osmolyte xylitol reduces the salt concentration of airway surface liquid and may enhance bacterial killing

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Zabner, Joseph; Seiler, Michael P.; Launspach, Janice L.; Karp, Philip H.; Kearney, William R.; Look, Dwight C.; Smith, Jeffrey J.; Welsh, Michael J.

2000-10-01

The thin layer of airway surface liquid (ASL) contains antimicrobial substances that kill the small numbers of bacteria that are constantly being deposited in the lungs. An increase in ASL salt concentration inhibits the activity of airway antimicrobial factors and may partially explain the pathogenesis of cystic fibrosis (CF). We tested the hypothesis that an osmolyte with a low transepithelial permeability may lower the ASL salt concentration, thereby enhancing innate immunity. We found that the five-carbon sugar xylitol has a low transepithelial permeability, is poorly metabolized by several bacteria, and can lower the ASL salt concentration in both CF and non-CF airway epithelia in vitro. Furthermore, in a double-blind, randomized, crossover study, xylitol sprayed for 4 days into each nostril of normal volunteers significantly decreased the number of nasal coagulase-negative Staphylococcus compared with saline control. Xylitol may be of value in decreasing ASL salt concentration and enhancing the innate antimicrobial defense at the airway surface.

Measurement of the airway surface liquid volume with simple light refraction microscopy.

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Harvey, Peter R; Tarran, Robert; Garoff, Stephen; Myerburg, Mike M

2011-09-01

In the cystic fibrosis (CF) lung, the airway surface liquid (ASL) volume is depleted, impairing mucus clearance from the lung and leading to chronic airway infection and obstruction. Several therapeutics have been developed that aim to restore normal airway surface hydration to the CF airway, yet preclinical evaluation of these agents is hindered by the paucity of methods available to directly measure the ASL. Therefore, we sought to develop a straightforward approach to measure the ASL volume that would serve as the basis for a standardized method to assess mucosal hydration using readily available resources. Primary human bronchial epithelial (HBE) cells cultured at an air-liquid interface develop a liquid meniscus at the edge of the culture. We hypothesized that the size of the fluid meniscus is determined by the ASL volume, and could be measured as an index of the epithelial surface hydration status. A simple method was developed to measure the volume of fluid present in meniscus by imaging the refraction of light at the ASL interface with the culture wall using low-magnification microscopy. Using this method, we found that primary CF HBE cells had a reduced ASL volume compared with non-CF HBE cells, and that known modulators of ASL volume caused the predicted responses. Thus, we have demonstrated that this method can detect physiologically relevant changes in the ASL volume, and propose that this novel approach may be used to rapidly assess the effects of airway hydration therapies in high-throughput screening assays.

Adaptation of Pseudomonas aeruginosa to the cystic fibrosis airway: an evolutionary perspective

DEFF Research Database (Denmark)

Folkesson, Anders; Jelsbak, Lars; Yang, Lei

2012-01-01

evolves from a state of early, recurrent intermittent colonization of the airways of patients with CF to a chronic infection state, and how this process offers opportunities to study bacterial evolution in natural environments. We believe that such studies are valuable not only for our understanding......The airways of patients with cystic fibrosis (CF) are nearly always infected with many different microorganisms. This environment offers warm, humid and nutrient-rich conditions, but is also stressful owing to frequent antibiotic therapy and the host immune response. Pseudomonas aeruginosa...... is commonly isolated from the airways of patients with CF, where it most often establishes chronic infections that usually persist for the rest of the lives of the patients. This bacterium is a major cause of mortality and morbidity and has therefore been studied intensely. Here, we discuss how P. aeruginosa...

Hypertonic saline in treatment of pulmonary disease in cystic fibrosis.

LENUS (Irish Health Repository)

Reeves, Emer P

2012-01-01

The pathogenesis of lung disease in cystic fibrosis is characterised by decreased airway surface liquid volume and subsequent failure of normal mucociliary clearance. Mucus within the cystic fibrosis airways is enriched in negatively charged matrices composed of DNA released from colonizing bacteria or inflammatory cells, as well as F-actin and elevated concentrations of anionic glycosaminoglycans. Therapies acting against airway mucus in cystic fibrosis include aerosolized hypertonic saline. It has been shown that hypertonic saline possesses mucolytic properties and aids mucociliary clearance by restoring the liquid layer lining the airways. However, recent clinical and bench-top studies are beginning to broaden our view on the beneficial effects of hypertonic saline, which now extend to include anti-infective as well as anti-inflammatory properties. This review aims to discuss the described therapeutic benefits of hypertonic saline and specifically to identify novel models of hypertonic saline action independent of airway hydration.

Cyanide levels found in infected cystic fibrosis sputum inhibit airway ciliary function.

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Nair, Chandrika; Shoemark, Amelia; Chan, Mario; Ollosson, Sarah; Dixon, Mellissa; Hogg, Claire; Alton, Eric W F W; Davies, Jane C; Williams, Huw D

2014-11-01

We have previously reported cyanide at concentrations of up to 150 μM in the sputum of cystic fibrosis patients infected with Pseudomonas aeruginosa and a negative correlation with lung function. Our aim was to investigate possible mechanisms for this association, focusing on the effect of pathophysiologically relevant cyanide levels on human respiratory cell function. Ciliary beat frequency measurements were performed on nasal brushings and nasal air-liquid interface (ALI) cultures obtained from healthy volunteers and cystic fibrosis patients. Potassium cyanide decreased ciliary beat frequency in healthy nasal brushings (n = 6) after 60 min (150 μM: 47% fall, pcyanide as a key component inhibiting the ciliary beat frequency. If cyanide production similarly impairs mucocilliary clearance in vivo, it could explain the link with increased disease severity observed in cystic fibrosis patients with detectable cyanide in their airway. ©ERS 2014.

Altered Sputum Microstructure as a Marker of Airway Obstruction in Cystic Fibrosis Patients

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Duncan, Gregg; Jung, James; West, Natalie; Boyle, Michael; Suk, Jung Soo; Hanes, Justin

In the lungs of cystic fibrosis (CF) patients, highly viscoelastic mucus remains stagnant in the lung leading to obstructed airways prone to recurrent infections. Bulk-fluid rheological measurement is primarily used to assess the pathological features of mucus. However, this approach is limited in detecting microscopic properties on the length scale of pathogens and immune cells. We have shown in prior work based on the transport of muco-inert nanoparticles (MIP) in CF sputum that patients can carry significantly different microstructural properties. In this study, we aimed to determine the factors leading to variations between patients in sputum microstructure and their clinical implications. The microrheological properties of CF sputum were measured using multi-particle tracking experiments of MIP. MIP were made by grafting polyethylene glycol onto the surface of polystyrene nanoparticles which prior work has shown prevents adhesion to CF sputum. Biochemical analyses show that sputum microstructure was significantly altered by elevated mucin and DNA content. Reduction in sputum pore size is characteristic of patients with obstructed airways as indicated by measured pulmonary function tests. Our microstructural read-out may serve as a novel biomarker for CF.

Hypertonic Saline in Treatment of Pulmonary Disease in Cystic Fibrosis

Directory of Open Access Journals (Sweden)

Emer P. Reeves

2012-01-01

Full Text Available The pathogenesis of lung disease in cystic fibrosis is characterised by decreased airway surface liquid volume and subsequent failure of normal mucociliary clearance. Mucus within the cystic fibrosis airways is enriched in negatively charged matrices composed of DNA released from colonizing bacteria or inflammatory cells, as well as F-actin and elevated concentrations of anionic glycosaminoglycans. Therapies acting against airway mucus in cystic fibrosis include aerosolized hypertonic saline. It has been shown that hypertonic saline possesses mucolytic properties and aids mucociliary clearance by restoring the liquid layer lining the airways. However, recent clinical and bench-top studies are beginning to broaden our view on the beneficial effects of hypertonic saline, which now extend to include anti-infective as well as anti-inflammatory properties. This review aims to discuss the described therapeutic benefits of hypertonic saline and specifically to identify novel models of hypertonic saline action independent of airway hydration.

The microbial community of the cystic fibrosis airway is disrupted in early life.

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Julie Renwick

Full Text Available Molecular techniques have uncovered vast numbers of organisms in the cystic fibrosis (CF airways, the clinical significance of which is yet to be determined. The aim of this study was to describe and compare the microbial communities of the lower airway of clinically stable children with CF and children without CF.Bronchoalveolar lavage (BAL fluid and paired oropharyngeal swabs from clinically stable children with CF (n = 13 and BAL from children without CF (n = 9 were collected. DNA was isolated, the 16S rRNA regions amplified, fragmented, biotinylated and hybridised to a 16S rRNA microarray. Patient medical and demographic information was recorded and standard microbiological culture was performed.A diverse bacterial community was detected in the lower airways of children with CF and children without CF. The airway microbiome of clinically stable children with CF and children without CF were significantly different as measured by Shannon's Diversity Indices (p = 0.001; t test and Principle coordinate analysis (p = 0.01; Adonis test. Overall the CF airway microbial community was more variable and had a less even distribution than the microbial community in the airways of children without CF. We highlighted several bacteria of interest, particularly Prevotella veroralis, CW040 and a Corynebacterium, which were of significantly differential abundance between the CF and non-CF lower airways. Both Pseudomonas aeruginosa and Streptococcus pneumoniae culture abundance were found to be associated with CF airway microbial community structure. The CF upper and lower airways were found to have a broadly similar microbial milieu.The microbial communities in the lower airways of stable children with CF and children without CF show significant differences in overall diversity. These discrepancies indicate a disruption of the airway microflora occurring early in life in children with CF.

Aspergillus antigen induces robust Th2 cytokine production, inflammation, airway hyperreactivity and fibrosis in the absence of MCP-1 or CCR2

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Charo Israel F

2004-09-01

Full Text Available Abstract Background Asthma is characterized by type 2 T-helper cell (Th2 inflammation, goblet cell hyperplasia, airway hyperreactivity, and airway fibrosis. Monocyte chemoattractant protein-1 (MCP-1 or CCL2 and its receptor, CCR2, have been shown to play important roles in the development of Th2 inflammation. CCR2-deficient mice have been found to have altered inflammatory and physiologic responses in some models of experimental allergic asthma, but the role of CCR2 in contributing to inflammation and airway hyperreactivity appears to vary considerably between models. Furthermore, MCP-1-deficient mice have not previously been studied in models of experimental allergic asthma. Methods To test whether MCP-1 and CCR2 are each required for the development of experimental allergic asthma, we applied an Aspergillus antigen-induced model of Th2 cytokine-driven allergic asthma associated with airway fibrosis to mice deficient in either MCP-1 or CCR2. Previous studies with live Aspergillus conidia instilled into the lung revealed that MCP-1 and CCR2 play a role in anti-fungal responses; in contrast, we used a non-viable Aspergillus antigen preparation known to induce a robust eosinophilic inflammatory response. Results We found that wild-type C57BL/6 mice developed eosinophilic airway inflammation, goblet cell hyperplasia, airway hyperreactivity, elevations in serum IgE, and airway fibrosis in response to airway challenge with Aspergillus antigen. Surprisingly, mice deficient in either MCP-1 or CCR2 had responses to Aspergillus antigen similar to those seen in wild-type mice, including production of Th2 cytokines. Conclusion We conclude that robust Th2-mediated lung pathology can occur even in the complete absence of MCP-1 or CCR2.

Inflammation and airway microbiota during cystic fibrosis pulmonary exacerbations.

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Edith T Zemanick

Full Text Available Pulmonary exacerbations (PEx, frequently associated with airway infection and inflammation, are the leading cause of morbidity in cystic fibrosis (CF. Molecular microbiologic approaches detect complex microbiota from CF airway samples taken during PEx. The relationship between airway microbiota, inflammation, and lung function during CF PEx is not well understood.To determine the relationships between airway microbiota, inflammation, and lung function in CF subjects treated for PEx.Expectorated sputum and blood were collected and lung function testing performed in CF subjects during early (0-3d. and late treatment (>7d. for PEx. Sputum was analyzed by culture, pyrosequencing of 16S rRNA amplicons, and quantitative PCR for total and specific bacteria. Sputum IL-8 and neutrophil elastase (NE; and circulating C-reactive protein (CRP were measured.Thirty-seven sputum samples were collected from 21 CF subjects. At early treatment, lower diversity was associated with high relative abundance (RA of Pseudomonas (r = -0.67, p<0.001, decreased FEV(1% predicted (r = 0.49, p = 0.03 and increased CRP (r = -0.58, p = 0.01. In contrast to Pseudomonas, obligate and facultative anaerobic genera were associated with less inflammation and higher FEV₁. With treatment, Pseudomonas RA and P. aeruginosa by qPCR decreased while anaerobic genera showed marked variability in response. Change in RA of Prevotella was associated with more variability in FEV₁ response to treatment than Pseudomonas or Staphylococcus.Anaerobes identified from sputum by sequencing are associated with less inflammation and higher lung function compared to Pseudomonas at early exacerbation. CF PEx treatment results in variable changes of anaerobic genera suggesting the need for larger studies particularly of patients without traditional CF pathogens.

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

Evidence and Role for Bacterial Mucin Degradation in Cystic Fibrosis Airway Disease

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Flynn, Jeffrey M.; Niccum, David; Dunitz, Jordan M.

2016-01-01

Chronic lung infections in cystic fibrosis (CF) patients are composed of complex microbial communities that incite persistent inflammation and airway damage. Despite the high density of bacteria that colonize the lower airways, nutrient sources that sustain bacterial growth in vivo, and how those nutrients are derived, are not well characterized. In this study, we examined the possibility that mucins serve as an important carbon reservoir for the CF lung microbiota. While Pseudomonas aeruginosa was unable to efficiently utilize mucins in isolation, we found that anaerobic, mucin-fermenting bacteria could stimulate the robust growth of CF pathogens when provided intact mucins as a sole carbon source. 16S rRNA sequencing and enrichment culturing of sputum also identified that mucin-degrading anaerobes are ubiquitous in the airways of CF patients. The collective fermentative metabolism of these mucin-degrading communities in vitro generated amino acids and short chain fatty acids (propionate and acetate) during growth on mucin, and the same metabolites were also found in abundance within expectorated sputum. The significance of these findings was supported by in vivo P. aeruginosa gene expression, which revealed a heightened expression of genes required for the catabolism of propionate. Given that propionate is exclusively derived from bacterial fermentation, these data provide evidence for an important role of mucin fermenting bacteria in the carbon flux of the lower airways. More specifically, microorganisms typically defined as commensals may contribute to airway disease by degrading mucins, in turn providing nutrients for pathogens otherwise unable to efficiently obtain carbon in the lung. PMID:27548479

Archetypal analysis of diverse Pseudomonas aeruginosa transcriptomes reveals adaptation in cystic fibrosis airways

DEFF Research Database (Denmark)

Thøgersen, Juliane Charlotte; Mørup, Morten; Pedersen, Søren Damkiær

2013-01-01

is to introduce a method for DNA microarray analysis that provides an intuitive interpretation of data through dimension reduction and pattern recognition. We present the first “Archetypal Analysis” of global gene expression. The analysis is based on microarray data from five integrated studies of Pseudomonas...... aeruginosa isolated from the airways of cystic fibrosis patients. RESULTS: Our analysis clustered samples into distinct groups with comprehensible characteristics since the archetypes representing the individual groups are closely related to samples present in the data set. Significant changes in gene....... This suggests positive selection in the cystic fibrosis lung environment, and changes in gene expression for these isolates are therefore most likely related to adaptation of the bacteria. CONCLUSIONS: Archetypal analysis succeeded in identifying adaptive changes of P. aeruginosa. The combination of clustering...

Treatment response of airway clearance assessed by single-breath washout in children with cystic fibrosis.

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Abbas, Chiara; Singer, Florian; Yammine, Sophie; Casaulta, Carmen; Latzin, Philipp

2013-12-01

We studied the ability of 4 single-breath gas washout (SBW) tests to measure immediate effects of airway clearance in children with CF. 25 children aged 4-16 years with CF performed pulmonary function tests to assess short-term variability at baseline and response to routine airway clearance. Tidal helium and sulfur hexafluoride (double-tracer gas: DTG) SBW, tidal capnography, tidal and vital capacity nitrogen (N2) SBW and spirometry were applied. We analyzed the gasses' phase III slope (SnIII--normalized for tidal volume) and FEV1 from spirometry. SnIII from tidal DTG-SBW, SnIII from vital capacity N2-SBW, and FEV1 improved significantly after airway clearance. From these tests, individual change of SnIII from tidal DTG-SBW and FEV1 exceeded short-term variability in 10 and 6 children. With the tidal DTG-SBW, an easy and promising test for peripheral gas mixing efficiency, immediate pulmonary function response to airway clearance can be assessed in CF children. Copyright © 2013 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Airway Microbiota in Bronchoalveolar Lavage Fluid from Clinically Well Infants with Cystic Fibrosis.

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Theresa A Laguna

Full Text Available Upper airway cultures guide the identification and treatment of lung pathogens in infants with cystic fibrosis (CF; however, this may not fully reflect the spectrum of bacteria present in the lower airway. Our objectives were to characterize the airway microbiota using bronchoalveolar lavage fluid (BALF from asymptomatic CF infants during the first year of life and to investigate the relationship between BALF microbiota, standard culture and clinical characteristics.BALF, nasopharyngeal (NP culture and infant pulmonary function testing data were collected at 6 months and one year of age during periods of clinical stability from infants diagnosed with CF by newborn screening. BALF was analyzed for total bacterial load by qPCR and for bacterial community composition by 16S ribosomal RNA sequencing. Clinical characteristics and standard BALF and NP culture results were recorded over five years of longitudinal follow-up.12 BALF samples were collected from 8 infants with CF. Streptococcus, Burkholderia, Prevotella, Haemophilus, Porphyromonas, and Veillonella had the highest median relative abundance in infant CF BALF. Two of the 3 infants with repeat BALF had changes in their microbial communities over six months (Morisita-Horn diversity index 0.36, 0.38. Although there was excellent percent agreement between standard NP and BALF cultures, these techniques did not routinely detect all bacteria identified by sequencing.BALF in asymptomatic CF infants contains complex microbiota, often missed by traditional culture of airway secretions. Anaerobic bacteria are commonly found in the lower airways of CF infants.

The Role of Short-Chain Fatty Acids, Produced by Anaerobic Bacteria, in the Cystic Fibrosis Airway.

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Mirković, Bojana; Murray, Michelle A; Lavelle, Gillian M; Molloy, Kevin; Azim, Ahmed Abdul; Gunaratnam, Cedric; Healy, Fiona; Slattery, Dubhfeasa; McNally, Paul; Hatch, Joe; Wolfgang, Matthew; Tunney, Michael M; Muhlebach, Marianne S; Devery, Rosaleen; Greene, Catherine M; McElvaney, Noel G

2015-12-01

Anaerobic bacteria are present in large numbers in the airways of people with cystic fibrosis (PWCF). In the gut, anaerobes produce short-chain fatty acids (SCFAs) that modulate immune and inflammatory processes. To investigate the capacity of anaerobes to contribute to cystic fibrosis (CF) airway pathogenesis via SCFAs. Samples of 109 PWCF were processed using anaerobic microbiological culture with bacteria present identified by 16S RNA sequencing. SCFA levels in anaerobic supernatants and bronchoalveolar lavage (BAL) were determined by gas chromatography. The mRNA and/or protein expression of two SCFA receptors, GPR41 and GPR43, in CF and non-CF bronchial brushings and 16HBE14o(-) and CFBE41o(-) cells were evaluated using reverse transcription polymerase chain reaction, Western blot analysis, laser scanning cytometry, and confocal microscopy. SCFA-induced IL-8 secretion was monitored by ELISA. Fifty-seven (52.3%) of 109 PWCF were anaerobe positive. Prevalence increased with age, from 33.3% to 57.7% in PWCF younger (n = 24) and older (n = 85) than 6 years of age. All evaluated anaerobes produced millimolar concentrations of SCFAs, including acetic, propionic, and butyric acids. SCFA levels were higher in BAL samples of adults than in those of children. GPR41 levels were elevated in CFBE41o(-) versus 16HBE14o(-) cells; CF versus non-CF bronchial brushings; and 16HBE14o(-) cells after treatment with cystic fibrosis transmembrane conductance regulator inhibitor CFTR(inh)-172, CF BAL, or inducers of endoplasmic reticulum stress. SCFAs induced a dose-dependent and pertussis toxin-sensitive IL-8 response in bronchial epithelial cells, with a higher production of IL-8 in CFBE41o(-) than in 16HBE14o(-) cells. This study illustrates that SCFAs contribute to excessive production of IL-8 in CF airways colonized with anaerobes via up-regulated GPR41.

Cystic fibrosis: Beyond the airways. Report on the meeting of the basic science working group in Loutraki, Greece.

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Amaral, Margarida D; Boj, Sylvia F; Shaw, James; Leipziger, Jens; Beekman, Jeffrey M

2018-06-01

The European Cystic Fibrosis Society (ECFS) Basic Science Working Group (BSWG) organized a session on the topic "Cystic Fibrosis: Beyond the Airways", within the 15th ECFS Basic Science Conference which gathered around 200 researchers working in the basic science of CF. The session was organized and chaired by Margarida Amaral (BioISI, University of Lisboa, Portugal) and Jeffrey Beekman (University Medical Centre Utrecht, Netherlands) as Chair and Vice-Chair of the BSWG and its purpose was to bring attention of participants of the ECFS Basic Science Conference to "more forgotten" organs in CF disease. In this report we attempt to review and integrate the ideas that emerged at the session. Copyright © 2018 European Cystic Fibrosis Society. All rights reserved.

Benchmark Evaluation of True Single Molecular Sequencing to Determine Cystic Fibrosis Airway Microbiome Diversity

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Andrea Hahn

2018-05-01

Full Text Available Cystic fibrosis (CF is an autosomal recessive disease associated with recurrent lung infections that can lead to morbidity and mortality. The impact of antibiotics for treatment of acute pulmonary exacerbations on the CF airway microbiome remains unclear with prior studies giving conflicting results and being limited by their use of 16S ribosomal RNA sequencing. Our primary objective was to validate the use of true single molecular sequencing (tSMS and PathoScope in the analysis of the CF airway microbiome. Three control samples were created with differing amounts of Burkholderia cepacia, Pseudomonas aeruginosa, and Prevotella melaninogenica, three common bacteria found in cystic fibrosis lungs. Paired sputa were also obtained from three study participants with CF before and >6 days after initiation of antibiotics. Antibiotic resistant B. cepacia and P. aeruginosa were identified in concurrently obtained respiratory cultures. Direct sequencing was performed using tSMS, and filtered reads were aligned to reference genomes from NCBI using PathoScope and Kraken and unique clade-specific marker genes using MetaPhlAn. A total of 180–518 K of 6–12 million filtered reads were aligned for each sample. Detection of known pathogens in control samples was most successful using PathoScope. In the CF sputa, alpha diversity measures varied based on the alignment method used, but similar trends were found between pre- and post-antibiotic samples. PathoScope outperformed Kraken and MetaPhlAn in our validation study of artificial bacterial community controls and also has advantages over Kraken and MetaPhlAn of being able to determine bacterial strains and the presence of fungal organisms. PathoScope can be confidently used when evaluating metagenomic data to determine CF airway microbiome diversity.

Airway-centered interstitial fibrosis: etiology, clinical findings and prognosis.

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Kuranishi, Lilian Tiemi; Leslie, Kevin O; Ferreira, Rimarcs Gomes; Coletta, Ester Aparecida Ney; Storrer, Karin Mueller; Soares, Maria Raquel; de Castro Pereira, Carlos Alberto

2015-05-09

Airway-centered Interstitial Fibrosis (ACIF) is a common pathologic pattern observed in our practice. The objectives of this study are to describe the causes associated with ACIF in a large sample of patients and its effect on survival. A retrospective study in three centers of interstitial lung disease in São Paulo, between January of 1995 and December of 2012. The surgical lung biopsy specimens were reviewed by three pathologists. The clinical, functional and tomographic findings were analyzed by a standardized protocol. There were 68 cases of ACIF, most of them women. The mean age was 57 ± 12 yr. Dyspnea, cough, restrictive pattern at spirometry and oxygen desaturation at exercise were common. A reticular pattern with peribronchovascular infiltrates was found in 79% of the cases. The etiologies of ACIF were hypersensitivity pneumonitis in 29 (42.6%), gastroesophageal reflux disease in 17 (25.0%), collagen vascular disease in 4 (5.9%), a combination of them in 15 cases and idiopathic in 3 (4.4%). The median survival was 116 months (95% CI = 58.5 - 173.5). Lower values of oxygen saturation at rest, presence of cough and some histological findings--organizing tissue in the airways, fibroblastic foci and microscopic honeycombing--were predictors of worse survival. ACIF is an interstitial lung disease with a better survival when compared with IPF. The main etiologies are HP and GERD. The oxygen saturation at rest, the presence of cough and some histological findings are predictors of survival.

The effects of interleukin-8 on airway smooth muscle contraction in cystic fibrosis

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Safka Katherine

2008-12-01

Full Text Available Abstract Background Many cystic fibrosis (CF patients display airway hyperresponsiveness and have symptoms of asthma such as cough, wheezing and reversible airway obstruction. Chronic airway bacterial colonization, associated with neutrophilic inflammation and high levels of interleukin-8 (IL-8 is also a common occurrence in these patients. The aim of this work was to determine the responsiveness of airway smooth muscle to IL-8 in CF patients compared to non-CF individuals. Methods Experiments were conducted on cultured ASM cells harvested from subjects with and without CF (control subjects. Cells from the 2nd to 5th passage were studied. Expression of the IL-8 receptors CXCR1 and CXCR2 was assessed by flow cytometry. The cell response to IL-8 was determined by measuring intracellular calcium concentration ([Ca2+]i, cell contraction, migration and proliferation. Results The IL-8 receptors CXCR1 and CXCR2 were expressed in both non-CF and CF ASM cells to a comparable extent. IL-8 (100 nM induced a peak Ca2+ release that was higher in control than in CF cells: 228 ± 7 versus 198 ± 10 nM (p 20 in CF than in control cells. In addition, MLC20 expression was also increased in CF cells. Exposure to IL-8 induced migration and proliferation of both groups of ASM cells but was not different between CF and non-CF cells. Conclusion ASM cells of CF patients are more contractile to IL-8 than non-CF ASM cells. This enhanced contractility may be due to an increase in the amount of contractile protein MLC20. Higher expression of MLC20 by CF cells could contribute to airway hyperresponsiveness to IL-8 in CF patients.

Effect of Low-Dose, Long-Term Roxithromycin on Airway Inflammation and Remodeling of Stable Noncystic Fibrosis Bronchiectasis

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Jifeng Liu

2014-01-01

Full Text Available Background. Noncystic fibrosis bronchiectasis (NCFB is characterized by airway expansion and recurrent acute exacerbations. Macrolide has been shown to exhibit anti-inflammatory effects in some chronic airway diseases. Objective. To assess the efficacy of roxithromycin on airway inflammation and remodeling in patients with NCFB under steady state. Methods. The study involved an open-label design in 52 eligible Chinese patients with NCFB, who were assigned to control (receiving no treatment and roxithromycin (receiving 150 mg/day for 6 months groups. At baseline and 6 months, the inflammatory markers such as interleukin- (IL-8, neutrophil elastase (NE, matrix metalloproteinase- (MMP9, hyaluronidase (HA, and type IV collagen in sputum were measured, along with the detection of dilated bronchus by throat computed tomography scan, and assessed the exacerbation. Results. Forty-three patients completed the study. The neutrophil in the sputum was decreased in roxithromycin group compared with control (P<0.05. IL-8, NE, MMP-9, HA, and type IV collagen in sputum were also decreased in roxithromycin group compared with the control group (all P<0.01. Airway thickness of dilated bronchus and exacerbation were reduced in roxithromycin group compared with the control (all P<0.05. Conclusions. Roxithromycin can reduce airway inflammation and airway thickness of dilated bronchus in patients with NCFB.

Targeting miRNA-based medicines to cystic fibrosis airway epithelial cells using nanotechnology

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McKiernan PJ

2013-10-01

Full Text Available Paul J McKiernan,2 Orla Cunninghamm,1,2 Catherine M Greenem,2 Sally-Ann Cryan1,31School of Pharmacy, Royal College of Surgeons in Ireland, 2Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland Education and Research Centre, Beaumont Hospital, 3Trinity Centre for Bioengineering, Trinity College Dublin, Dublin, IrelandAbstract: Cystic fibrosis (CF is an inherited disorder characterized by chronic airway inflammation. microRNAs (miRNAs are endogenous small RNAs which act on messenger (mRNA at a post transcriptional level, and there is a growing understanding that altered expression of miRNA is involved in the CF phenotype. Modulation of miRNA by replacement using miRNA mimics (premiRs presents a new therapeutic paradigm for CF, but effective and safe methods of delivery to the CF epithelium are limiting clinical translation. Herein, polymeric nanoparticles are investigated for delivery of miRNA mimics into CF airway epithelial cells, using miR-126 as a proof-of-concept premiR cargo to determine efficiency. Two polymers, polyethyleneimine (PEI and chitosan, were used to prepare miRNA nanomedicines, characterized for their size, surface (zeta potential, and RNA complexation efficiency, and screened for delivery and cytotoxicity in CFBE41o- (human F508del cystic fibrosis transmembrane conductance regulator bronchial epithelial cells using a novel high content analysis method. RNA extraction was carried out 24 hours post transfection, and miR-126 and TOM1 (target of Myb1 expression (a validated miR-126 target was assessed. Manufacture was optimized to produce small nanoparticles that effectively complexed miRNA. Using high content analysis, PEI-based nanoparticles were more effective than chitosan-based nanoparticles in facilitating uptake of miRNA into CFBE41o- cells and this was confirmed in miR-126 assays. PEI-premiR-126 nanoparticles at low nitrogen/phosphate (N/P ratios resulted in significant knockdown of

Effect of Obstructive airway disease in patients with non-cystic fibrosis bronchiectasis

International Nuclear Information System (INIS)

Khalid, Mohammad; Saleemi, Sarfraz; Zeitouni, Mohammed; Al-Dammas, Saleh; Khaliq, Mohammad Rehan

2004-01-01

Extensive research has been devoted to cystic fibrosis-related brochiectasis compared with noncystic fibrosis brochiectasis but the latter is more common and results in significant morbidity and mortality. We assessed the relationship between pulmonary function test (PFT) findings and sputum bacteriology, blood gases, number of hospital admissions and mortality in patients with non-cystic fibrosis brochiectasis (NCFB). we conducted a retrospective review of 88 consecutive patients admitted with exacerbation of brochiectasis over 5 years from 1996 to 2001. Demographic and clinical data collected included gender, age, pulmonary functions, arterial blood gases, sputum bacteriology during stable and exacerbation periods and number of hospital admissions due to exacerbation of brochiectasis. A comparison was made between patients having obstructive airway disease (OAD group) and patients with normal or restrictive pulmonaru functions (non-OAD group). OAD patients with NCFB adversely affected clinical outcome.There was a significant increase in Pseuomonas colonization (60.3% vs. 16%; P<0.0003), hypercapnic respiratory failure (63.4% vs. 20%; P<0.0003) and mean number of admissons due to exacerbation (6 vs. 2; P<0.0001)in the OAD group as compared with the non OAD group, the difference was not statistically significant. Patients with NCFB who have OAD have a significantly higher rate of colonization with Pseuomonas aeruginosa (PSA) hypercapric respiratory failure, a greater number of hospital admissions due to exacerbation of brochiectasis and a a higher mortality compared with patients with restrictive or normal pulmonary functions. (author)

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.

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...

High rhinovirus burden in lower airways of children with cystic fibrosis.

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Kieninger, Elisabeth; Singer, Florian; Tapparel, Caroline; Alves, Marco P; Latzin, Philipp; Tan, Hui-Leng; Bossley, Cara; Casaulta, Carmen; Bush, Andrew; Davies, Jane C; Kaiser, Laurent; Regamey, Nicolas

2013-03-01

Rhinovirus (RV)-induced pulmonary exacerbations are common in cystic fibrosis (CF) and have been associated with impaired virus clearance by the CF airway epithelium in vitro. Here, we assess in vivo the association of RV prevalence and load with antiviral defense mechanisms, airway inflammation, and lung function parameters in children with CF compared with a control group and children with other chronic respiratory diseases. RV presence and load were measured by real-time reverse transcription-polymerase chain reaction in BAL samples and were related to antiviral and inflammatory mediators measured in BAL and to clinical parameters. BAL samples were obtained from children with CF (n = 195), non-CF bronchiectasis (n = 40), or asthma (n = 29) and from a control group (n = 35) at a median (interquartile range [IQR]) age of 8.2 (4.0-11.7) years. RV was detected in 73 samples (24.4%). RV prevalence was similar among groups. RV load (median [IQR] x 10(3) copies/mL) was higher in children with CF (143.0 [13.1-1530.0]), especially during pulmonary exacerbations, compared with children with asthma (3.0 [1.3-25.8], P = .006) and the control group (0.5 [0.3-0.5], P < .001), but similar to patients with non-CF bronchiectasis (122.1 [2.7-4423.5], P = not significant). In children with CF, RV load was negatively associated with interferon (IFN)- b and IFN- l , IL-1ra levels, and FEV 1 , and positively with levels of the cytokines CXCL8 and CXCL10. RV load in CF BAL is high, especially during exacerbated lung disease. Impaired production of antiviral mediators may lead to the high RV burden in the lower airways of children with CF. Whether high RV load is a cause or a consequence of inflammation needs further investigation in longitudinal studies.

Airway Surface Dehydration Aggravates Cigarette Smoke-Induced Hallmarks of COPD in Mice.

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Seys, Leen J M; Verhamme, Fien M; Dupont, Lisa L; Desauter, Elke; Duerr, Julia; Seyhan Agircan, Ayca; Conickx, Griet; Joos, Guy F; Brusselle, Guy G; Mall, Marcus A; Bracke, Ken R

2015-01-01

Airway surface dehydration, caused by an imbalance between secretion and absorption of ions and fluid across the epithelium and/or increased epithelial mucin secretion, impairs mucociliary clearance. Recent evidence suggests that this mechanism may be implicated in chronic obstructive pulmonary disease (COPD). However, the role of airway surface dehydration in the pathogenesis of cigarette smoke (CS)-induced COPD remains unknown. We aimed to investigate in vivo the effect of airway surface dehydration on several CS-induced hallmarks of COPD in mice with airway-specific overexpression of the β-subunit of the epithelial Na⁺ channel (βENaC). βENaC-Tg mice and wild-type (WT) littermates were exposed to air or CS for 4 or 8 weeks. Pathological hallmarks of COPD, including goblet cell metaplasia, mucin expression, pulmonary inflammation, lymphoid follicles, emphysema and airway wall remodelling were determined and lung function was measured. Airway surface dehydration in βENaC-Tg mice aggravated CS-induced airway inflammation, mucin expression and destruction of alveolar walls and accelerated the formation of pulmonary lymphoid follicles. Moreover, lung function measurements demonstrated an increased compliance and total lung capacity and a lower resistance and hysteresis in βENaC-Tg mice, compared to WT mice. CS exposure further altered lung function measurements. We conclude that airway surface dehydration is a risk factor that aggravates CS-induced hallmarks of COPD.

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

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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

Inhaled ENaC antisense oligonucleotide ameliorates cystic fibrosis-like lung disease in mice.

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Crosby, Jeff R; Zhao, Chenguang; Jiang, Chong; Bai, Dong; Katz, Melanie; Greenlee, Sarah; Kawabe, Hiroshi; McCaleb, Michael; Rotin, Daniela; Guo, Shuling; Monia, Brett P

2017-11-01

Epithelial sodium channel (ENaC, Scnn1) hyperactivity in the lung leads to airway surface dehydration and mucus accumulation in cystic fibrosis (CF) patients and in mice with CF-like lung disease. We identified several potent ENaC specific antisense oligonucleotides (ASOs) and tested them by inhalation in mouse models of CF-like lung disease. The inhaled ASOs distributed into lung airway epithelial cells and decreased ENaC expression by inducing RNase H1-dependent degradation of the targeted Scnn1a mRNA. Aerosol delivered ENaC ASO down-regulated mucus marker expression and ameliorated goblet cell metaplasia, inflammation, and airway hyper-responsiveness. Lack of systemic activity of ASOs delivered via the aerosol route ensures the safety of this approach. Our results demonstrate that antisense inhibition of ENaC in airway epithelial cells could be an effective and safe approach for the prevention and reversal of lung symptoms in CF and potentially other inflammatory diseases of the lung. Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Nebulisation of receptor-targeted nanocomplexes for gene delivery to the airway epithelium.

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Manunta, Maria D I; McAnulty, Robin J; Tagalakis, Aristides D; Bottoms, Stephen E; Campbell, Frederick; Hailes, Helen C; Tabor, Alethea B; Laurent, Geoffrey J; O'Callaghan, Christopher; Hart, Stephen L

2011-01-01

Gene therapy mediated by synthetic vectors may provide opportunities for new treatments for cystic fibrosis (CF) via aerosolisation. Vectors for CF must transfect the airway epithelium efficiently and not cause inflammation so they are suitable for repeated dosing. The inhaled aerosol should be deposited in the airways since the cystic fibrosis transmembrane conductance regulator gene (CFTR) is expressed predominantly in the epithelium of the submucosal glands and in the surface airway epithelium. The aim of this project was to develop an optimised aerosol delivery approach applicable to treatment of CF lung disease by gene therapy. The vector suspension investigated in this study comprises receptor-targeting peptides, cationic liposomes and plasmid DNA that self-assemble by electrostatic interactions to form a receptor-targeted nanocomplex (RTN) of approximately 150 nm with a cationic surface charge of +50 mV. The aerodynamic properties of aerosolised nanocomplexes produced with three different nebulisers were compared by determining aerosol deposition in the different stages of a Next Generation Pharmaceutical Impactor (NGI). We also investigated the yield of intact plasmid DNA by agarose gel electrophoresis and densitometry, and transfection efficacies in vitro and in vivo. RTNs nebulised with the AeroEclipse II BAN were the most effective, compared to other nebulisers tested, for gene delivery both in vitro and in vivo. The biophysical properties of the nanocomplexes were unchanged after nebulisation while the deposition of RTNs suggested a range of aerosol aerodynamic sizes between 5.5 µm-1.4 µm cut off (NGI stages 3-6) compatible with deposition in the central and lower airways. RTNs showed their ability at delivering genes via nebulisation, thus suggesting their potential applications for therapeutic interventions of cystic fibrosis and other respiratory disorders.

Nebulisation of receptor-targeted nanocomplexes for gene delivery to the airway epithelium.

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Maria D I Manunta

Full Text Available Gene therapy mediated by synthetic vectors may provide opportunities for new treatments for cystic fibrosis (CF via aerosolisation. Vectors for CF must transfect the airway epithelium efficiently and not cause inflammation so they are suitable for repeated dosing. The inhaled aerosol should be deposited in the airways since the cystic fibrosis transmembrane conductance regulator gene (CFTR is expressed predominantly in the epithelium of the submucosal glands and in the surface airway epithelium. The aim of this project was to develop an optimised aerosol delivery approach applicable to treatment of CF lung disease by gene therapy.The vector suspension investigated in this study comprises receptor-targeting peptides, cationic liposomes and plasmid DNA that self-assemble by electrostatic interactions to form a receptor-targeted nanocomplex (RTN of approximately 150 nm with a cationic surface charge of +50 mV. The aerodynamic properties of aerosolised nanocomplexes produced with three different nebulisers were compared by determining aerosol deposition in the different stages of a Next Generation Pharmaceutical Impactor (NGI. We also investigated the yield of intact plasmid DNA by agarose gel electrophoresis and densitometry, and transfection efficacies in vitro and in vivo.RTNs nebulised with the AeroEclipse II BAN were the most effective, compared to other nebulisers tested, for gene delivery both in vitro and in vivo. The biophysical properties of the nanocomplexes were unchanged after nebulisation while the deposition of RTNs suggested a range of aerosol aerodynamic sizes between 5.5 µm-1.4 µm cut off (NGI stages 3-6 compatible with deposition in the central and lower airways.RTNs showed their ability at delivering genes via nebulisation, thus suggesting their potential applications for therapeutic interventions of cystic fibrosis and other respiratory disorders.

Non-invasive ventilation used as an adjunct to airway clearance treatments improves lung function during an acute exacerbation of cystic fibrosis: a randomised trial

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Tiffany J Dwyer

2015-07-01

Full Text Available Question: During an acute exacerbation of cystic fibrosis, is non-invasive ventilation beneficial as an adjunct to the airway clearance regimen? Design: Randomised controlled trial with concealed allocation and intention-to-treat analysis. Participants: Forty adults with moderate to severe cystic fibrosis lung disease and who were admitted to hospital for an acute exacerbation. Intervention: Comprehensive inpatient care (control group compared to the same care with the addition of non-invasive ventilation during airway clearance treatments from Day 2 of admission until discharge (experimental group. Outcome measures: Lung function and subjective symptom severity were measured daily. Fatigue was measured at admission and discharge on the Schwartz Fatigue Scale from 7 (no fatigue to 63 (worst fatigue points. Quality of life and exercise capacity were also measured at admission and discharge. Length of admission and time to next hospital admission were recorded. Results: Analysed as the primary outcome, the experimental group had a greater rate of improvement in forced expiratory volume in 1 second (FEV1 than the control group, but this was not statistically significant (MD 0.13% predicted per day, 95% CI –0.03 to 0.28. However, the experimental group had a significantly higher FEV1 at discharge than the control group (MD 4.2% predicted, 95% CI 0.1 to 8.3. The experimental group reported significantly lower levels of fatigue on the Schwartz fatigue scale at discharge than the control group (MD 6 points, 95% CI 1 to 11. There was no significant difference between the experimental and control groups in subjective symptom severity, quality of life, exercise capacity, length of hospital admission or time to next hospital admission. Conclusion: Among people hospitalised for an acute exacerbation of cystic fibrosis, the use of non-invasive ventilation as an adjunct to the airway clearance regimen significantly improves FEV1 and fatigue. Trial

Archetypal analysis of diverse Pseudomonas aeruginosa transcriptomes reveals adaptation in cystic fibrosis airways

Science.gov (United States)

2013-01-01

Background Analysis of global gene expression by DNA microarrays is widely used in experimental molecular biology. However, the complexity of such high-dimensional data sets makes it difficult to fully understand the underlying biological features present in the data. The aim of this study is to introduce a method for DNA microarray analysis that provides an intuitive interpretation of data through dimension reduction and pattern recognition. We present the first “Archetypal Analysis” of global gene expression. The analysis is based on microarray data from five integrated studies of Pseudomonas aeruginosa isolated from the airways of cystic fibrosis patients. Results Our analysis clustered samples into distinct groups with comprehensible characteristics since the archetypes representing the individual groups are closely related to samples present in the data set. Significant changes in gene expression between different groups identified adaptive changes of the bacteria residing in the cystic fibrosis lung. The analysis suggests a similar gene expression pattern between isolates with a high mutation rate (hypermutators) despite accumulation of different mutations for these isolates. This suggests positive selection in the cystic fibrosis lung environment, and changes in gene expression for these isolates are therefore most likely related to adaptation of the bacteria. Conclusions Archetypal analysis succeeded in identifying adaptive changes of P. aeruginosa. The combination of clustering and matrix factorization made it possible to reveal minor similarities among different groups of data, which other analytical methods failed to identify. We suggest that this analysis could be used to supplement current methods used to analyze DNA microarray data. PMID:24059747

In vivo models of human airway epithelium repair and regeneration

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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.

Airway Clearance Devices for Cystic Fibrosis

Science.gov (United States)

2009-01-01

Executive Summary Objective The purpose of this evidence-based analysis is to examine the safety and efficacy of airway clearance devices (ACDs) for cystic fibrosis and attempt to differentiate between devices, where possible, on grounds of clinical efficacy, quality of life, safety and/or patient preference. Background Cystic fibrosis (CF) is a common, inherited, life-limiting disease that affects multiple systems of the human body. Respiratory dysfunction is the primary complication and leading cause of death due to CF. CF causes abnormal mucus secretion in the airways, leading to airway obstruction and mucus plugging, which in turn can lead to bacterial infection and further mucous production. Over time, this almost cyclical process contributes to severe airway damage and loss of respiratory function. Removal of airway secretions, termed airway clearance, is thus an integral component of the management of CF. A variety of methods are available for airway clearance, some requiring mechanical devices, others physical manipulation of the body (e.g. physiotherapy). Conventional chest physiotherapy (CCPT), through the assistance of a caregiver, is the current standard of care for achieving airway clearance, particularly in young patients up to the ages of six or seven. CF patients are, however, living much longer now than in decades past. The median age of survival in Canada has risen to 37.0 years for the period of 1998-2002 (5-year window), up from 22.8 years for the 5-year window ending in 1977. The prevalence has also risen accordingly, last recorded as 3,453 in Canada in 2002, up from 1,630 in 1977. With individuals living longer, there is a greater need for independent methods of airway clearance. Airway Clearance Devices There are at least three classes of airway clearance devices: positive expiratory pressure devices (PEP), airway oscillating devices (AOD; either handheld or stationary) and high frequency chest compression (HFCC)/mechanical percussion (MP

Quantitative computed tomography analysis of the airways in patients with cystic fibrosis using automated software: correlation with spirometry in the evaluation of severity

International Nuclear Information System (INIS)

Santos, Marcel Koenigkam; Cruvinel, Danilo Lemos; Menezes, Marcelo Bezerra de; Teixeira, Sara Reis; Vianna, Elcio de Oliveira; Elias Junior, Jorge; Martinez, Jose Antonio Baddini

2016-01-01

Objective: To perform a quantitative analysis of the airways using automated software, in computed tomography images of patients with cystic fibrosis, correlating the results with spirometric findings. Materials and methods: Thirty-four patients with cystic fibrosis were studied-20 males and 14 females; mean age 18 ± 9 years - divided into two groups according to the spirometry findings: group I (n = 21), without severe airflow obstruction (forced expiratory volume in first second [FEV1] > 50% predicted), and group II (n = 13), with severe obstruction (FEV1 ≤ 50% predicted). The following tracheobronchial tree parameters were obtained automatically: bronchial diameter, area, thickness, and wall attenuation. Results: On average, 52 bronchi per patient were studied. The number of bronchi analyzed was higher in group II. The correlation with spirometry findings, especially between the relative wall thickness of third to eighth bronchial generation and predicted FEV1, was better in group I. Conclusion: Quantitative analysis of the airways by computed tomography can be useful for assessing disease severity in cystic fibrosis patients. In patients with severe airflow obstruction, the number of bronchi studied by the method is higher, indicating more bronchiectasis. In patients without severe obstruction, the relative bronchial wall thickness showed a good correlation with the predicted FEV1. (author)

Quantitative computed tomography analysis of the airways in patients with cystic fibrosis using automated software: correlation with spirometry in the evaluation of severity

Energy Technology Data Exchange (ETDEWEB)

Santos, Marcel Koenigkam; Cruvinel, Danilo Lemos; Menezes, Marcelo Bezerra de; Teixeira, Sara Reis; Vianna, Elcio de Oliveira; Elias Junior, Jorge; Martinez, Jose Antonio Baddini, E-mail: marcelk46@yahoo.com.br [Universidade de Sao Paulo (HC/FMRP/USP), Ribeirao Preto, SP (Brazil). Faculdade de Medicina

2016-11-15

Objective: To perform a quantitative analysis of the airways using automated software, in computed tomography images of patients with cystic fibrosis, correlating the results with spirometric findings. Materials and methods: Thirty-four patients with cystic fibrosis were studied-20 males and 14 females; mean age 18 ± 9 years - divided into two groups according to the spirometry findings: group I (n = 21), without severe airflow obstruction (forced expiratory volume in first second [FEV1] > 50% predicted), and group II (n = 13), with severe obstruction (FEV1 ≤ 50% predicted). The following tracheobronchial tree parameters were obtained automatically: bronchial diameter, area, thickness, and wall attenuation. Results: On average, 52 bronchi per patient were studied. The number of bronchi analyzed was higher in group II. The correlation with spirometry findings, especially between the relative wall thickness of third to eighth bronchial generation and predicted FEV1, was better in group I. Conclusion: Quantitative analysis of the airways by computed tomography can be useful for assessing disease severity in cystic fibrosis patients. In patients with severe airflow obstruction, the number of bronchi studied by the method is higher, indicating more bronchiectasis. In patients without severe obstruction, the relative bronchial wall thickness showed a good correlation with the predicted FEV1. (author)

"Cystic fibrotics could survive cholera, choleraics could survive cystic fibrosis"; hypothesis that explores new horizons in treatment of cystic fibrosis.

Science.gov (United States)

Azimi, Arsalan

2015-12-01

Cystic fibrosis, the most common inherited disease of white population, is a disease of CFTR channels, in which mucosal function of many organs especially respiratory tract is impaired. Decreased mucociliary clearance and accumulation of mucus in airways facilitates colonization of infectious microorganisms, followed by infection. Following chronic infection, persistent inflammation ensues, which results in airway remodeling and deterioration of mucociliary clearance and result in a vicious cycle. Here, it is hypothesized that cholera toxin (CT) could ameliorate symptoms of cystic fibrosis as CT could dilute the thickened mucus, improve mucociliary clearance and alleviate airway obstruction. CT strengthens immunity of airway mucosa and it could attenuates bacterial growth and reduce persistency of infection. CT also modulates cellular immune response and it could decrease airway inflammation, hinder airway remodeling and prevent respiratory deterioration. Thereby it is hypothesized that CT could target and ameliorate many of pathophysiologic steps of the disease and it explores new horizons in treatment of CF. Copyright © 2015 Elsevier Ltd. All rights reserved.

Distinct patterns of inflammation in the airway lumen and bronchial mucosa of children with cystic fibrosis.

Science.gov (United States)

Regamey, Nicolas; Tsartsali, Lemonia; Hilliard, Tom N; Fuchs, Oliver; Tan, Hui-Leng; Zhu, Jie; Qiu, Yu-Sheng; Alton, Eric W F W; Jeffery, Peter K; Bush, Andrew; Davies, Jane C

2012-02-01

Studies in cystic fibrosis (CF) generally focus on inflammation present in the airway lumen. Little is known about inflammation occurring in the airway wall, the site ultimately destroyed in end-stage disease. To test the hypothesis that inflammatory patterns in the lumen do not reflect those in the airway wall of children with CF. Bronchoalveolar lavage (BAL) fluid and endobronchial biopsies were obtained from 46 children with CF and 16 disease-free controls. BAL cell differential was assessed using May-Gruenwald-stained cytospins. Area profile counts of bronchial tissue immunopositive inflammatory cells were determined. BAL fluid from children with CF had a predominance of neutrophils compared with controls (median 810×10(3)/ml vs 1×10(3)/ml, p<0.0001). In contrast, subepithelial bronchial tissue from children with CF was characterised by a predominance of lymphocytes (median 961 vs 717 cells/mm(2), p=0.014), of which 82% were (CD3) T lymphocytes. In chest exacerbations, BAL fluid from children with CF had more inflammatory cells of all types compared with those with stable disease whereas, in biopsies, only the numbers of lymphocytes and macrophages, but not of neutrophils, were higher. A positive culture of Pseudomonas aeruginosa was associated with higher numbers of T lymphocytes in subepithelial bronchial tissue (median 1174 vs 714 cells/mm(2), p=0.029), but no changes were seen in BAL fluid. Cell counts in BAL fluid and biopsies were positively correlated with age but were unrelated to each other. The inflammatory response in the CF airway is compartmentalised. In contrast to the neutrophil-dominated inflammation present in the airway lumen, the bronchial mucosa is characterised by the recruitment and accumulation of lymphocytes.

Inhibition of Toll-like receptor 2-mediated interleukin-8 production in Cystic Fibrosis airway epithelial cells via the alpha7-nicotinic acetylcholine receptor.

LENUS (Irish Health Repository)

Greene, Catherine M

2010-01-01

Cystic Fibrosis (CF) is an inherited disorder characterised by chronic inflammation of the airways. The lung manifestations of CF include colonization with Pseudomonas aeruginosa and Staphylococcus aureus leading to neutrophil-dominated airway inflammation and tissue damage. Inflammation in the CF lung is initiated by microbial components which activate the innate immune response via Toll-like receptors (TLRs), increasing airway epithelial cell production of proinflammatory mediators such as the neutrophil chemokine interleukin-8 (IL-8). Thus modulation of TLR function represents a therapeutic approach for CF. Nicotine is a naturally occurring plant alkaloid. Although it is negatively associated with cigarette smoking and cardiovascular damage, nicotine also has anti-inflammatory properties. Here we investigate the inhibitory capacity of nicotine against TLR2- and TLR4-induced IL-8 production by CFTE29o- airway epithelial cells, determine the role of alpha7-nAChR (nicotinic acetylcholine receptor) in these events, and provide data to support the potential use of safe nicotine analogues as anti-inflammatories for CF.

Exhaled nitric oxide in paediatric asthma and cystic fibrosis.

Science.gov (United States)

Lundberg, J O; Nordvall, S L; Weitzberg, E; Kollberg, H; Alving, K

1996-01-01

Nitric oxide (NO) is present in exhaled air of humans. This NO is mostly produced in the upper airways, whereas basal NO excretion in the lower airways is low. Children with Kartagener's syndrome have an almost total lack of NO in nasally derived air, whereas adult asthmatics have increased NO in orally exhaled air. NO excretion was measured in the nasal cavity and in orally exhaled air in 19 healthy children, in 36 age matched subjects with asthma, and in eight children with cystic fibrosis. NO levels in orally exhaled air were similar in controls and in children with cystic fibrosis, at 4.8 (SD 1.2) v 5.8 (0.8) parts per billion (ppb), but were increased in asthmatic children who were untreated or were being treated only with low doses of inhaled steroids (13.8 (2.5) ppb). Nasal NO levels were reduced by about 70% in children with cystic fibrosis compared to controls and asthmatics. Measurements of airway NO release in different parts of the airways may be useful in non-invasive diagnosis and monitoring of inflammatory airway diseases. PMID:8984919

Airway Clearance Techniques (ACTs)

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Full Text Available ... in CF Clinical Care Guidelines Cystic Fibrosis-Related Diabetes Clinical Care Guidelines Liver Disease Clinical Care Guidelines Respiratory Care Guidelines CF Airway Clearance Therapies Clinical Care Guidelines Chronic Medications to Maintain Lung ...

Airway Clearance Techniques (ACTs)

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Full Text Available ... a Family Parenting as an Adult With CF Treatments and Therapies People with cystic fibrosis are living ... to specialized CF care and a range of treatment options. Airway Clearance Active Cycle of Breathing Technique ...

Airway Clearance Techniques (ACTs)

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Full Text Available ... about the needs of people with cystic fibrosis so that they make smart decisions about CF-related ... then move the mucus out of the airways so it can be coughed out. These medications can ...

Airway Clearance Techniques (ACTs)

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Full Text Available ... huffing . Many of them use percussion (clapping) or vibration to loosen mucus from airway walls. See how ... What is CF? About Cystic Fibrosis CF Genetics Diagnosis Testing for CF Life With CF Caring for ...

Epigenetic dysregulation of interleukin 8 (CXCL8) hypersecretion in cystic fibrosis airway epithelial cells

Energy Technology Data Exchange (ETDEWEB)

Poghosyan, Anna, E-mail: pannagos@yahoo.com; Patel, Jamie K.; Clifford, Rachel L.; Knox, Alan J., E-mail: alan.knox@nottingham.ac.uk

2016-08-05

Airway epithelial cells in cystic fibrosis (CF) overexpress Interleukin 8 (CXCL8) through poorly defined mechanisms. CXCL8 transcription is dependent on coordinated binding of CCAAT/enhancer binding protein (C/EBP)β, nuclear factor (NF)-κB, and activator protein (AP)-1 to the promoter. Here we show abnormal epigenetic regulation is responsible for CXCL8 overexpression in CF cells. Under basal conditions CF cells had increased bromodomain (Brd)3 and Brd4 recruitment and enhanced NF-κB and C/EBPβ binding to the CXCL8 promoter compared to non-CF cells due to trimethylation of histone H3 at lysine 4 (H3K4me3) and DNA hypomethylation at CpG6. IL-1β increased NF-κB, C/EBPβ and Brd4 binding. Furthermore, inhibitors of bromodomain and extra-terminal domain family (BET) proteins reduced CXCL8 production in CF cells suggesting a therapeutic target for the BET pathway. -- Highlights: •A regulatory mechanism of CXCL8 transcriptional control in CF airways is proposed. •There was an increased binding of NF-κB and C/EBPβ transcription factors. •There was enhanced recruitment of BET proteins to the CXCL8 promoter. •Epigenetic modifications are responsible for the aberrant CXCL8 transcription.

Epigenetic dysregulation of interleukin 8 (CXCL8) hypersecretion in cystic fibrosis airway epithelial cells

International Nuclear Information System (INIS)

Poghosyan, Anna; Patel, Jamie K.; Clifford, Rachel L.; Knox, Alan J.

2016-01-01

Airway epithelial cells in cystic fibrosis (CF) overexpress Interleukin 8 (CXCL8) through poorly defined mechanisms. CXCL8 transcription is dependent on coordinated binding of CCAAT/enhancer binding protein (C/EBP)β, nuclear factor (NF)-κB, and activator protein (AP)-1 to the promoter. Here we show abnormal epigenetic regulation is responsible for CXCL8 overexpression in CF cells. Under basal conditions CF cells had increased bromodomain (Brd)3 and Brd4 recruitment and enhanced NF-κB and C/EBPβ binding to the CXCL8 promoter compared to non-CF cells due to trimethylation of histone H3 at lysine 4 (H3K4me3) and DNA hypomethylation at CpG6. IL-1β increased NF-κB, C/EBPβ and Brd4 binding. Furthermore, inhibitors of bromodomain and extra-terminal domain family (BET) proteins reduced CXCL8 production in CF cells suggesting a therapeutic target for the BET pathway. -- Highlights: •A regulatory mechanism of CXCL8 transcriptional control in CF airways is proposed. •There was an increased binding of NF-κB and C/EBPβ transcription factors. •There was enhanced recruitment of BET proteins to the CXCL8 promoter. •Epigenetic modifications are responsible for the aberrant CXCL8 transcription.

Airway Clearance Techniques (ACTs)

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Full Text Available ... people with cystic fibrosis so that they make smart decisions about CF-related research, treatment, and access ... Facebook Twitter YouTube Instagram Email DONATE Breadcrumb Navigation Home Life With CF Treatments and Therapies Airway Clearance ...

Airway Clearance Techniques (ACTs)

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Full Text Available ... a Family Parenting as an Adult With CF Treatments and Therapies People with cystic fibrosis are living longer and ... to specialized CF care and a range of treatment options. Airway Clearance Active Cycle of Breathing Technique ...

Cystic fibrosis: a mucosal immunodeficiency syndrome

Science.gov (United States)

Cohen, Taylor Sitarik; Prince, Alice

2013-01-01

Cystic fibrosis transmembrane conductance regulator (CFTR) functions as a channel that regulates the transport of ions and the movement of water across the epithelial barrier. Mutations in CFTR, which form the basis for the clinical manifestations of cystic fibrosis, affect the epithelial innate immune function in the lung, resulting in exaggerated and ineffective airway inflammation that fails to eradicate pulmonary pathogens. Compounding the effects of excessive neutrophil recruitment, the mutant CFTR channel does not transport antioxidants to counteract neutrophil-associated oxidative stress. Whereas mutant CFTR expression in leukocytes outside of the lung does not markedly impair their function, the expected regulation of inflammation in the airways is clearly deficient in cystic fibrosis. The resulting bacterial infections, which are caused by organisms that have substantial genetic and metabolic flexibility, can resist multiple classes of antibiotics and evade phagocytic clearance. The development of animal models that approximate the human pulmonary phenotypes—airway inflammation and spontaneous infection—may provide the much-needed tools to establish how CFTR regulates mucosal immunity and to test directly the effect of pharmacologic potentiation and correction of mutant CFTR function on bacterial clearance. PMID:22481418

Human airway epithelial cells investigated by atomic force microscopy: A hint to cystic fibrosis epithelial pathology

Energy Technology Data Exchange (ETDEWEB)

Lasalvia, Maria [Department of Clinical and Experimental Medicine, University of Foggia, Foggia (Italy); Istituto Nazionale di Fisica Nucleare, Sezione di Bari, Bari (Italy); Castellani, Stefano [Department of Medical and Surgical Sciences, University of Foggia, Foggia (Italy); D’Antonio, Palma [Department of Clinical and Experimental Medicine, University of Foggia, Foggia (Italy); Perna, Giuseppe [Department of Clinical and Experimental Medicine, University of Foggia, Foggia (Italy); Istituto Nazionale di Fisica Nucleare, Sezione di Bari, Bari (Italy); Carbone, Annalucia [Department of Medical and Surgical Sciences, University of Foggia, Foggia (Italy); Colia, Anna Laura; Maffione, Angela Bruna [Department of Clinical and Experimental Medicine, University of Foggia, Foggia (Italy); Capozzi, Vito [Department of Clinical and Experimental Medicine, University of Foggia, Foggia (Italy); Istituto Nazionale di Fisica Nucleare, Sezione di Bari, Bari (Italy); Conese, Massimo, E-mail: massimo.conese@unifg.it [Department of Medical and Surgical Sciences, University of Foggia, Foggia (Italy)

2016-10-15

The pathophysiology of cystic fibrosis (CF) airway disease stems from mutations in the CF Transmembrane Conductance Regulator (CFTR) gene, leading to a chronic respiratory disease. Actin cytoskeleton is disorganized in CF airway epithelial cells, likely contributing to the CF-associated basic defects, i.e. defective chloride secretion and sodium/fluid hypersorption. In this work, we aimed to find whether this alteration could be pointed out by means of Atomic Force Microscopy (AFM) investigation, as roughness and Young's elastic module. Moreover, we also sought to determine whether disorganization of actin cytoskeleton is linked to hypersoption of apical fluid. Not only CFBE41o- (CFBE) cells, immortalized airway epithelial cells homozygous for the F508del CFTR allele, showed a different morphology in comparison with 16HBE14o- (16HBE) epithelial cells, wild-type for CFTR, but also they displayed a lack of stress fibers, suggestive of a disorganized actin cytoskeleton. AFM measurements showed that CFBE cells presented a higher membrane roughness and decreased rigidity as compared with 16HBE cells. CFBE overexpressing wtCFTR became more elongated than the parental CFBE cell line and presented actin stress fibers. CFBE cells absorbed more fluid from the apical compartment. Study of fluid absorption with the F-actin-depolymerizing agent Latrunculin B demonstrated that actin cytoskeletal disorganization increased fluid absorption, an effect observed at higher magnitude in 16HBE than in CFBE cells. For the first time, we demonstrate that actin cytoskeleton disorganization is reflected by AFM parameters in CF airway epithelial cells. Our data also strongly suggest that the lack of stress fibers is involved in at least one of the early step in CF pathophysiology at the levels of the airways, i.e. fluid hypersorption. - Highlights: • CF bronchial epithelial (CFBE) cells show a disorganized actin cytoskeleton. • CFBE cells present high roughness and low rigidity in

Human airway epithelial cells investigated by atomic force microscopy: A hint to cystic fibrosis epithelial pathology

International Nuclear Information System (INIS)

Lasalvia, Maria; Castellani, Stefano; D’Antonio, Palma; Perna, Giuseppe; Carbone, Annalucia; Colia, Anna Laura; Maffione, Angela Bruna; Capozzi, Vito; Conese, Massimo

2016-01-01

The pathophysiology of cystic fibrosis (CF) airway disease stems from mutations in the CF Transmembrane Conductance Regulator (CFTR) gene, leading to a chronic respiratory disease. Actin cytoskeleton is disorganized in CF airway epithelial cells, likely contributing to the CF-associated basic defects, i.e. defective chloride secretion and sodium/fluid hypersorption. In this work, we aimed to find whether this alteration could be pointed out by means of Atomic Force Microscopy (AFM) investigation, as roughness and Young's elastic module. Moreover, we also sought to determine whether disorganization of actin cytoskeleton is linked to hypersoption of apical fluid. Not only CFBE41o- (CFBE) cells, immortalized airway epithelial cells homozygous for the F508del CFTR allele, showed a different morphology in comparison with 16HBE14o- (16HBE) epithelial cells, wild-type for CFTR, but also they displayed a lack of stress fibers, suggestive of a disorganized actin cytoskeleton. AFM measurements showed that CFBE cells presented a higher membrane roughness and decreased rigidity as compared with 16HBE cells. CFBE overexpressing wtCFTR became more elongated than the parental CFBE cell line and presented actin stress fibers. CFBE cells absorbed more fluid from the apical compartment. Study of fluid absorption with the F-actin-depolymerizing agent Latrunculin B demonstrated that actin cytoskeletal disorganization increased fluid absorption, an effect observed at higher magnitude in 16HBE than in CFBE cells. For the first time, we demonstrate that actin cytoskeleton disorganization is reflected by AFM parameters in CF airway epithelial cells. Our data also strongly suggest that the lack of stress fibers is involved in at least one of the early step in CF pathophysiology at the levels of the airways, i.e. fluid hypersorption. - Highlights: • CF bronchial epithelial (CFBE) cells show a disorganized actin cytoskeleton. • CFBE cells present high roughness and low rigidity in the

Airway Clearance Techniques (ACTs)

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Full Text Available ... Team Your cystic fibrosis care team includes a group of CF health care professionals who partner with ... Awards and Grants Career Development Awards Research Awards Training Awards CF ... Clearance Airway Clearance Techniques (ACTs) There are different ways to clear your ...

Autoradiographic detection of radionuclides on the epithelial surfaces of pulmonary airways

International Nuclear Information System (INIS)

Pappin, J.L.; Filipy, R.E.; Madison, R.M.

1979-01-01

We are developing an autoradiographic method for detection of radionuclide deposition sites on the internal surfaces of pulmonary airways. The method is expected to generate information on the distribution as well as on the quantity of radionuclides deposited in pulmonary airways

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.

Bacteria isolated from the airways of paediatric patients with ...

African Journals Online (AJOL)

Knowledge of which bacteria are found in the airways of paediatric patients with bronchiectasis unrelated to cystic fibrosis. (CF) is important in defining empirical antibiotic guidelines for the treatment of acute infective exacerbations. Objective. To describe the bacteria isolated from the airways of children with non-CF ...

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

Directory of Open Access Journals (Sweden)

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.

Airway Clearance Techniques (ACTs)

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Full Text Available ... cystic fibrosis. CF CARE CENTER finder We provide funding for and accredit more than 120 care centers ... Community in Health Care Reform Milestones in Health Care Reform How Tax Reform Could Impact People With CF The ... Home Life With CF Treatments and Therapies Airway Clearance ...

Adult non-cystic fibrosis bronchiectasis is characterised by airway luminal Th17 pathway activation.

Directory of Open Access Journals (Sweden)

Alice C-H Chen

Full Text Available Non-cystic fibrosis (CF bronchiectasis is characterised by chronic airway infection and neutrophilic inflammation, which we hypothesised would be associated with Th17 pathway activation.Th17 pathway cytokines were quantified in bronchoalveolar lavage fluid (BALF, and gene expression of IL-17A, IL-1β, IL-8 and IL-23 determined from endobronchial biopsies (EBx in 41 stable bronchiectasis subjects and 20 healthy controls. Relationships between IL-17A levels and infection status, important clinical measures and subsequent Pseudomonas aeruginosa infection were determined.BALF levels of all Th17 cytokines (median (IQR pg/mL were significantly higher in bronchiectasis than control subjects, including IL-17A (1.73 (1.19, 3.23 vs. 0.27 (0.24, 0.35, 95% CI 1.05 to 2.21, p<0.0001 and IL-23 (9.48 (4.79, 15.75 vs. 0.70 (0.43, 1.79, 95% CI 4.68 to 11.21, p<0.0001. However, BALF IL-17A levels were not associated with clinical measures or airway microbiology, nor predictive of subsequent P. aeruginosa infection. Furthermore, gene expression of IL-17A in bronchiectasis EBx did not differ from control. In contrast, gene expression (relative to medians of controls in bronchiectasis EBx was significantly higher than control for IL1β (4.12 (1.24, 8.05 vs 1 (0.13, 2.95, 95% CI 0.05 to 4.07, p = 0.04 and IL-8 (3.75 (1.64, 11.27 vs 1 (0.54, 3.89, 95% CI 0.32 to 4.87, p = 0.02 and BALF IL-8 and IL-1α levels showed significant relationships with clinical measures and airway microbiology. P. aeruginosa infection was associated with increased levels of IL-8 while Haemophilus influenzae was associated with increased IL-1α.Established adult non-CF bronchiectasis is characterised by luminal Th17 pathway activation, however this pathway may be relatively less important than activation of non-antigen-specific innate neutrophilic immunity.

Surface Airways Observations (SAO) Hourly Data (1965-1981) (CDMP)

Data.gov (United States)

National Oceanic and Atmospheric Administration, Department of Commerce — The dataset consists primarily of U.S. surface airways observations (SAO) data beginning in 1965 and extending through 1981. Note that a few stations have already...

Surface Airways Observations (SAO) Hourly Data 1928-1948 (CDMP)

Data.gov (United States)

National Oceanic and Atmospheric Administration, Department of Commerce — The dataset consists of hourly U.S. surface airways observations (SAO). These observations extend as far back as 1928, from the time when commercial aviation began...

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

Science.gov (United States)

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

Cystic fibrosis lung disease: genetic influences, microbial interactions, and radiological assessment

International Nuclear Information System (INIS)

Moskowitz, Samuel M.; Gibson, Ronald L.; Effmann, Eric L.

2005-01-01

Cystic fibrosis (CF) is a multiorgan disease caused by mutation of the CF transmembrane conductance regulator (CFTR) gene. Obstructive lung disease is the predominant cause of morbidity and mortality; thus, most efforts to improve outcomes are directed toward slowing or halting lung-disease progression. Current therapies, such as mucolytics, airway clearance techniques, bronchodilators, and antibiotics, aim to suppress airway inflammation and the processes that stimulate it, namely, retention and infection of mucus plaques at the airway surface. New approaches to therapy that aim to ameliorate specific CFTR mutations or mutational classes by restoring normal expression or function are being investigated. Because of its sensitivity in detecting changes associated with early airway obstruction and regional lung disease, high-resolution CT (HRCT) complements pulmonary function testing in defining disease natural history and measuring response to both conventional and experimental therapies. In this review, perspectives on the genetics and microbiology of CF provide a context for understanding the increasing importance of HRCT and other imaging techniques in assessing CF therapies. (orig.)

Chronic respiratory aeroallergen exposure in mice induces epithelial-mesenchymal transition in the large airways.

Directory of Open Access Journals (Sweden)

Jill R Johnson

Full Text Available Chronic allergic asthma is characterized by Th2-polarized inflammation and leads to airway remodeling and fibrosis but the mechanisms involved are not clear. To determine whether epithelial-mesenchymal transition contributes to airway remodeling in asthma, we induced allergic airway inflammation in mice by intranasal administration of house dust mite (HDM extract for up to 15 consecutive weeks. We report that respiratory exposure to HDM led to significant airway inflammation and thickening of the smooth muscle layer in the wall of the large airways. Transforming growth factor beta-1 (TGF-β1 levels increased in mouse airways while epithelial cells lost expression of E-cadherin and occludin and gained expression of the mesenchymal proteins vimentin, alpha-smooth muscle actin (α-SMA and pro-collagen I. We also observed increased expression and nuclear translocation of Snail1, a transcriptional repressor of E-cadherin and a potent inducer of EMT, in the airway epithelial cells of HDM-exposed mice. Furthermore, fate-mapping studies revealed migration of airway epithelial cells into the sub-epithelial regions of the airway wall. These results show the contribution of EMT to airway remodeling in chronic asthma-like inflammation and suggest that Th2-polarized airway inflammation can trigger invasion of epithelial cells into the subepithelial regions of the airway wall where they contribute to fibrosis, demonstrating a previously unknown plasticity of the airway epithelium in allergic airway disease.

Efficacy and Safety of Inhaled Aztreonam Lysine for Airway Pseudomonas in Cystic Fibrosis

Science.gov (United States)

Retsch-Bogart, George Z.; Quittner, Alexandra L.; Gibson, Ronald L.; Oermann, Christopher M.; McCoy, Karen S.; Montgomery, A. Bruce; Cooper, Peter J.

2009-01-01

Background: We assessed the short-term efficacy and safety of aztreonam lysine for inhalation (AZLI [an aerosolized monobactam antibiotic]) in patients with cystic fibrosis (CF) and Pseudomonas aeruginosa (PA) airway infection. Methods: In this randomized, double-blind, placebo-controlled, international study (AIR-CF1 trial; June 2005 to April 2007), patients (n = 164; ≥ 6 years of age) with FEV1 ≥ 25% and ≤ 75% predicted values, and no recent use of antipseudomonal antibiotics or azithromycin were treated with 75 mg of AZLI (three times daily for 28 days) or placebo (1:1 randomization), then were monitored for 14 days after study drug completion. The primary efficacy end point was change in patient-reported respiratory symptoms (CF-Questionnaire-Revised [CFQ-R] Respiratory Scale). Secondary end points included changes in pulmonary function (FEV1), sputum PA density, and nonrespiratory CFQ-R scales. Adverse events and minimum inhibitory concentrations of aztreonam for PA were monitored. Results: After 28 days of treatment, AZLI improved the mean CFQ-R respiratory score (9.7 points; p < 0.001), FEV1 (10.3% predicted; p < 0.001), and sputum PA density (− 1.453 log10 cfu/g; p < 0.001), compared with placebo. Significant improvements in Eating, Emotional Functioning, Health Perceptions, Physical Functioning, Role Limitation/School Performance, and Vitality CFQ-R scales were observed. Adverse events were consistent with symptoms of CF lung disease and were comparable for AZLI and placebo except the incidence of “productive cough” was reduced by half in AZLI-treated patients. PA aztreonam susceptibility at baseline and end of therapy were similar. Conclusions: In patients with CF, PA airway infection, moderate-to-severe lung disease, and no recent use of antipseudomonal antibiotics or azithromycin, 28-day treatment with AZLI significantly improved respiratory symptoms and pulmonary function, and was well tolerated. Trial registration: Clinicaltrials

Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum.

Science.gov (United States)

Shak, S; Capon, D J; Hellmiss, R; Marsters, S A; Baker, C L

1990-12-01

Respiratory distress and progressive lung destruction in cystic fibrosis can be attributed to bacterial persistence and the accumulation of viscous purulent secretions in the airways. More than 30 yr ago it was suggested that the large amounts of DNA in purulent secretions contribute to its viscosity and that bovine pancreatic DNase I could reduce the viscosity. To evaluate the potential clinical utility of recombinant human DNase I (rhDNase) in the treatment of cystic fibrosis, we have cloned, sequenced, and expressed rhDNase. Catalytic amounts of rhDNase greatly reduce the viscosity of purulent cystic fibrosis sputum, transforming it within minutes from a nonflowing viscous gel to a flowing liquid. The reduction in viscosity is associated with a decrease in size of DNA in the sputum. Inhalation of a rhDNase aerosol may be a simple direct approach that will help individuals with cystic fibrosis and other patients with pneumonia or bronchitis to clear their airways of purulent secretions.

Multiple-Breath Washout Outcomes Are Sensitive to Inflammation and Infection in Children with Cystic Fibrosis.

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Ramsey, Kathryn A; Foong, Rachel E; Grdosic, Jasmine; Harper, Alana; Skoric, Billy; Clem, Charles; Davis, Miriam; Turkovic, Lidija; Stick, Stephen M; Davis, Stephanie D; Ranganathan, Sarath C; Hall, Graham L

2017-09-01

The lung clearance index is a measure of ventilation distribution derived from the multiple-breath washout technique. The lung clearance index is increased in the presence of lower respiratory tract inflammation and infection in infants with cystic fibrosis; however, the associations during the preschool years are unknown. We assessed the ability of the lung clearance index to detect the presence and extent of lower respiratory tract inflammation and infection in preschool children with cystic fibrosis. Ventilation distribution outcomes were assessed at 82 visits with 58 children with cystic fibrosis and at 38 visits with 31 healthy children aged 3-6 years. Children with cystic fibrosis also underwent bronchoalveolar lavage fluid collection for detection of lower respiratory tract inflammation and infection. Associations between multiple-breath washout indices and the presence and extent of airway inflammation and infection were assessed using linear mixed effects models. Lung clearance index was elevated in children with cystic fibrosis (mean [SD], 8.00 [1.45]) compared with healthy control subjects (6.67 [0.56]). In cystic fibrosis, the lung clearance index was elevated in individuals with lower respiratory tract infections (difference compared with uninfected [95% confidence interval], 0.62 [0.06, 1.18]) and correlated with the extent of airway inflammation. These data suggest that the lung clearance index may be a useful surveillance tool for monitoring the presence and extent of lower airway inflammation and infection in preschool children with cystic fibrosis.

Early adaptive developments of Pseudomonas aeruginosa after the transition from life in the environment to persistent colonization in the airways of human cystic fibrosis hosts

DEFF Research Database (Denmark)

Rau, Martin Holm; Hansen, Susse Kirkelund; Johansen, H. K.

2010-01-01

Pseudomonas aeruginosa is an opportunistic pathogen ubiquitous to the natural environment but with the capability of moving to the host environment. Long-term infection of the airways of cystic fibrosis patients is associated with extensive genetic adaptation of P. aeruginosa, and we have studied...... cases of the initial stages of infection in order to characterize the early adaptive processes in the colonizing bacteria. A combination of global gene expression analysis and phenotypic characterization of longitudinal isolates from cystic fibrosis patients revealed well-known characteristics...... such as conversion to a mucoid phenotype by mucA mutation and increased antibiotic resistance by nfxB mutation. Additionally, upregulation of the atu operon leading to enhanced growth on leucine provides a possible example of metabolic optimization. A detailed investigation of the mucoid phenotype uncovered profound...

Combination of hypothiocyanite and lactoferrin (ALX-109) enhances the ability of tobramycin and aztreonam to eliminate Pseudomonas aeruginosa biofilms growing on cystic fibrosis airway epithelial cells.

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Moreau-Marquis, Sophie; Coutermarsh, Bonita; Stanton, Bruce A

2015-01-01

Chelating iron may be a promising new therapy to eliminate Pseudomonas aeruginosa biofilms in the lungs of cystic fibrosis (CF) patients. Here, we investigate whether ALX-109 [a defined combination of an investigational drug containing lactoferrin (an iron-binding glycoprotein) and hypothiocyanite (a bactericidal agent)], alone and in combination with tobramycin or aztreonam, reduces P. aeruginosa biofilms grown on human CF airway epithelial cells. P. aeruginosa (PAO1 and six clinical isolates of Pseudomonas) biofilms grown at the apical surface of confluent monolayers of CF airway epithelial cells were treated with ALX-109, either alone or in combination with tobramycin or aztreonam. Bacterial cfu remaining after treatment were determined by plate counting. ALX-109 alone reduced PAO1 biofilm formation, but had no effect on established biofilms. ALX-109 enhanced the ability of tobramycin and aztreonam to inhibit PAO1 biofilm formation and to reduce established PAO1 biofilms. ALX-109 and tobramycin were additive in disrupting established biofilms formed by six clinical isolates of P. aeruginosa obtained from the sputum of CF patients. Mucoid P. aeruginosa isolates were most susceptible to the combination of ALX-109 and tobramycin. In addition, ALX-109 also enhanced the ability of aztreonam to reduce established PAO1 biofilms. Inhalation therapy combining hypothiocyanite and lactoferrin with TOBI(®) (tobramycin) or Cayston(®) (aztreonam) may be beneficial to CF patients by decreasing the airway bacterial burden of P. aeruginosa. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Airway clearance devices for cystic fibrosis: an evidence-based analysis.

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2009-01-01

The purpose of this evidence-based analysis is to examine the safety and efficacy of airway clearance devices (ACDs) for cystic fibrosis and attempt to differentiate between devices, where possible, on grounds of clinical efficacy, quality of life, safety and/or patient preference. Cystic fibrosis (CF) is a common, inherited, life-limiting disease that affects multiple systems of the human body. Respiratory dysfunction is the primary complication and leading cause of death due to CF. CF causes abnormal mucus secretion in the airways, leading to airway obstruction and mucus plugging, which in turn can lead to bacterial infection and further mucous production. Over time, this almost cyclical process contributes to severe airway damage and loss of respiratory function. Removal of airway secretions, termed airway clearance, is thus an integral component of the management of CF. A variety of methods are available for airway clearance, some requiring mechanical devices, others physical manipulation of the body (e.g. physiotherapy). Conventional chest physiotherapy (CCPT), through the assistance of a caregiver, is the current standard of care for achieving airway clearance, particularly in young patients up to the ages of six or seven. CF patients are, however, living much longer now than in decades past. The median age of survival in Canada has risen to 37.0 years for the period of 1998-2002 (5-year window), up from 22.8 years for the 5-year window ending in 1977. The prevalence has also risen accordingly, last recorded as 3,453 in Canada in 2002, up from 1,630 in 1977. With individuals living longer, there is a greater need for independent methods of airway clearance. AIRWAY CLEARANCE DEVICES: THERE ARE AT LEAST THREE CLASSES OF AIRWAY CLEARANCE DEVICES: positive expiratory pressure devices (PEP), airway oscillating devices (AOD; either handheld or stationary) and high frequency chest compression (HFCC)/mechanical percussion (MP) devices. Within these classes are

Dynamic in vivo mutations within the ica operon during persistence of Staphylococcus aureus in the airways of cystic fibrosis patients.

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Bianca Schwartbeck

2016-11-01

Full Text Available Cystic fibrosis (CF is associated with chronic bacterial airway infections leading to lung insufficiency and decreased life expectancy. Staphylococcus aureus is one of the most prevalent pathogens isolated from the airways of CF patients. Mucoid colony morphology has been described for Pseudomonas aeruginosa, the most common pathogen in CF, but not for S. aureus. From the airways of 8 of 313 CF patients (2.5% mucoid S. aureus isolates (n = 115 were cultured with a mean persistence of 29 months (range 1 month, 126 months. In contrast to non-mucoid S. aureus, mucoid isolates were strong biofilm formers. The upstream region of the ica operon, which encodes the proteins responsible for the synthesis of the polysaccharide intercellular adhesin (PIA, of mucoid isolates was sequenced. Spa-types of mucoid and non-mucoid strains were identical, but differed between patients. Mucoid isolates carried a 5 bp deletion in the intergenic region between icaR and icaA. During long-term persistence, from two patients subsequent non-mucoid isolates (n = 12 with 5 bp deletions were cultured, which did not produce biofilm. Sequencing of the entire ica operon identified compensatory mutations in various ica-genes including icaA (n = 7, icaD (n = 3 and icaC (n = 2. Six sequential isolates of each of these two patients with non-mucoid and mucoid phenotypes were subjected to whole genome sequencing revealing a very close relationship of the individual patient's isolates. Transformation of strains with vectors expressing the respective wild-type genes restored mucoidy. In contrast to the non-mucoid phenotype, mucoid strains were protected against neutrophilic killing and survived better under starvation conditions. In conclusion, the special conditions present in CF airways seem to facilitate ongoing mutations in the ica operon during S. aureus persistence.

Human airway xenograft models of epithelial cell regeneration

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Puchelle Edith

2000-10-01

Full Text Available Abstract Regeneration and restoration of the airway epithelium after mechanical, viral or bacterial injury have a determinant role in the evolution of numerous respiratory diseases such as chronic bronchitis, asthma and cystic fibrosis. The study in vivo 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 restore a functional respiratory epithelium after several weeks. Recently, human tracheal xenografts have been developed in immunodeficient severe combined immunodeficiency (SCID and nude mice. In this review we recall that human airway cells implanted in such conditioned host grafts can regenerate a well-differentiated and functional human epithelium; we stress the interest in these humanized mice in assaying candidate progenitor and stem cells of the human airway mucosa.

Maintaining Respiratory Health in Cystic Fibrosis Patients

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MR Modaresi

2014-04-01

Full Text Available Cystic fibrosis (CF is an inherited disease that primarily affects the lungs and the digestive system, however, it also affects a number of other organs and systems. More than 90% of mortality of  CF patients is due to lung complications.  Healthy lungs are important for a long life for people with CF, We will discuss two important topics for maintaining respiratory health. Chronic use of drugs for maintaining respiratory health There are a number of drugs available to keep CF lungs healthy. We will discuss the science behind the recommendations for use of: Inhaled antibiotics Dornase alfa Azithromycin Hypertonic saline High-dose ibuprofen Ivacaftor CF Airway Clearance Therapies Airway Clearance therapy is very important to keeping CF lungs healthy. Our discussions cover the following topics such as the: Daily airway clearance Different techniques of airway clearance Effect of aerobic exercise on airway clearance  

Bactericidal/Permeability-increasing protein fold-containing family member A1 in airway host protection and respiratory disease.

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Britto, Clemente J; Cohn, Lauren

2015-05-01

Bactericidal/permeability-increasing protein fold-containing family member A1 (BPIFA1), formerly known as SPLUNC1, is one of the most abundant proteins in respiratory secretions and has been identified with increasing frequency in studies of pulmonary disease. Its expression is largely restricted to the respiratory tract, being highly concentrated in the upper airways and proximal trachea. BPIFA1 is highly responsive to airborne pathogens, allergens, and irritants. BPIFA1 actively participates in host protection through antimicrobial, surfactant, airway surface liquid regulation, and immunomodulatory properties. Its expression is modulated in multiple lung diseases, including cystic fibrosis, chronic obstructive pulmonary disease, respiratory malignancies, and idiopathic pulmonary fibrosis. However, the role of BPIFA1 in pulmonary pathogenesis remains to be elucidated. This review highlights the versatile properties of BPIFA1 in antimicrobial protection and its roles as a sensor of environmental exposure and regulator of immune cell function. A greater understanding of the contribution of BPIFA1 to disease pathogenesis and activity may clarify if BPIFA1 is a biomarker and potential drug target in pulmonary disease.

Recent progress in translational cystic fibrosis research using precision medicine strategies.

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Cholon, Deborah M; Gentzsch, Martina

2018-03-01

Significant progress has been achieved in developing precision therapies for cystic fibrosis; however, highly effective treatments that target the ion channel, CFTR, are not yet available for many patients. As numerous CFTR therapeutics are currently in the clinical pipeline, reliable screening tools capable of predicting drug efficacy to support individualized treatment plans and translational research are essential. The utilization of bronchial, nasal, and rectal tissues from individual cystic fibrosis patients for drug testing using in vitro assays such as electrophysiological measurements of CFTR activity and evaluation of fluid movement in spheroid cultures, has advanced the prediction of patient-specific responses. However, for precise prediction of drug effects, in vitro models of CFTR rescue should incorporate the inflamed cystic fibrosis airway environment and mimic the complex tissue structures of airway epithelia. Furthermore, novel assays that monitor other aspects of successful CFTR rescue such as restoration of mucus characteristics, which is important for predicting mucociliary clearance, will allow for better prognoses of successful therapies in vivo. Additional cystic fibrosis treatment strategies are being intensively explored, such as development of drugs that target other ion channels, and novel technologies including pluripotent stem cells, gene therapy, and gene editing. The multiple therapeutic approaches available to treat the basic defect in cystic fibrosis combined with relevant precision medicine models provide a framework for identifying optimal and sustained treatments that will benefit all cystic fibrosis patients. Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Anaerobic Pseudomonas aeruginosa and other obligately anaerobic bacterial biofilms growing in the thick airway mucus of chronically infected cystic fibrosis patients: an emerging paradigm or "Old Hat"?

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Su, Shengchang; Hassett, Daniel J

2012-09-01

The cystic fibrosis (CF) airway mucus is an ideal niche in which many bacteria can develop antibiotic- and phagocyte-resistance in unique structures known as "mode II biofilms" where bacteria are embedded within the mucus, yet unattached to airway epithelial cells. Pseudomonas aeruginosa is the dominant CF pathogen, yet herein the authors provide burgeoning evidence that obligate anaerobic bacteria (e.g., Prevotella) actually thrive within the CF mucus, a paradigmatic shift that chronic CF is an "aerobic" disease. Interestingly, CF organisms repress virulence factor production (e.g., P. aeruginosa) while others (e.g., S. aureus) increase them under anaerobic conditions. The authors shed additional light on (i) the anoxic nature of the CF airway mucus, (ii) the relative commonality of anaerobic bacteria isolated from CF sputum, (iii) virulence factor production and cross-talk between obligate anaerobes and P. aeruginosa relative to disease progression/remission, (iv) the role of mucoidy in CF, and (v) the role of nitrosative stress in activation of bacteriophage and pyocins within biofilms. The authors conclude with insight as to how we might treat some CF bacteria during mode II biofilm infections that utilizes a metabolite of bacterial anaerobic respiration and an aerobic oxidation product of airway-generated NO, acidified NO(2)(-).

Impact of the CFTR-potentiator ivacaftor on airway microbiota in cystic fibrosis patients carrying a G551D mutation.

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Cédric Bernarde

Full Text Available Airway microbiota composition has been clearly correlated with many pulmonary diseases, and notably with cystic fibrosis (CF, an autosomal genetic disorder caused by mutation in the CF transmembrane conductance regulator (CFTR. Recently, a new molecule, ivacaftor, has been shown to re-establish the functionality of the G551D-mutated CFTR, allowing significant improvement in lung function.The purpose of this study was to follow the evolution of the airway microbiota in CF patients treated with ivacaftor, using quantitative PCR and pyrosequencing of 16S rRNA amplicons, in order to identify quantitative and qualitative changes in bacterial communities. Three G551D children were followed up longitudinally over a mean period of more than one year covering several months before and after initiation of ivacaftor treatment.129 operational taxonomy units (OTUs, representing 64 genera, were identified. There was no significant difference in total bacterial load before and after treatment. Comparison of global community composition found no significant changes in microbiota. Two OTUs, however, showed contrasting dynamics: after initiation of ivacaftor, the relative abundance of the anaerobe Porphyromonas 1 increased (p<0.01 and that of Streptococcus 1 (S. mitis group decreased (p<0.05, possibly in relation to the anti-Gram-positive properties of ivacaftor. The anaerobe Prevotella 2 correlated positively with the pulmonary function test FEV-1 (r=0.73, p<0.05. The study confirmed the presumed positive role of anaerobes in lung function.Several airway microbiota components, notably anaerobes (obligate or facultative anaerobes, could be valuable biomarkers of lung function improvement under ivacaftor, and could shed light on the pathophysiology of lung disease in CF patients.

Nebulized hypertonic saline decreases IL-8 in sputum of patients with cystic fibrosis.

LENUS (Irish Health Repository)

Reeves, Emer P

2011-06-01

Inflammation within the cystic fibrosis (CF) lung is mediated by inflammatory chemokines, such as IL-8. IL-8 is protected from proteolytic degradation in the airways by binding to glycosaminoglycans, while remaining active. Evidence that increased hypertonicity of airway secretions induced by hypertonic saline treatment alters levels of IL-8 is lacking.

Diversity of metabolic profiles of cystic fibrosis Pseudomonas aeruginosa during the early stages of lung infection

DEFF Research Database (Denmark)

Jørgensen, Karin Meinike; Wassermann, Tina; Johansen, Helle Krogh

2015-01-01

Pseudomonas aeruginosa is the dominant pathogen infecting the airways of cystic fibrosis (CF) patients. During the intermittent colonization phase, P. aeruginosa resembles environmental strains but later evolves to the chronic adapted phenotype characterized by resistance to antibiotics and mutat......Pseudomonas aeruginosa is the dominant pathogen infecting the airways of cystic fibrosis (CF) patients. During the intermittent colonization phase, P. aeruginosa resembles environmental strains but later evolves to the chronic adapted phenotype characterized by resistance to antibiotics...

Viral vectors for cystic fibrosis gene therapy: What does the future hold?

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Uta Griesenbach

2010-12-01

Full Text Available Uta Griesenbach1, Makoto Inoue2, Mamoru Hasegawa2, Eric WFW Alton11Department of Gene Therapy, Imperial College London, UK; The UK Cystic Fibrosis Gene Therapy Consortium; 2DNAVEC Corporation, Tsukuba, JapanAbstract: Gene transfer to the airway epithelium has been more difficult than originally anticipated, largely because of significant extra- and intracellular barriers in the lung. In general, viral vectors are more adapted to overcoming these barriers than nonviral gene transfer agents and are, therefore, more efficient in transferring genes into recipient cells. Viral vectors derived from adenovirus, adeno-associated virus, and Sendai virus, which all have a natural tropism for the airway epithelium, have been evaluated for cystic fibrosis (CF gene therapy. Although these vectors transduce airway epithelial cells efficiently, gene expression is transient and repeated administration is inefficient. They are, therefore, unlikely to be suitable for CF gene therapy. More recently, lentiviruses (LV have been assessed for lung gene transfer. In contrast to retroviruses, they transduce nondividing cells and randomly integrate into the genome. However, LVs do not have a natural tropism for the lung, and a significant amount of effort has been put into pseudotyping these vectors with proteins suitable for airway gene transfer. Several studies have shown that LV-mediated transduction leads to persistent gene expression (for the lifetime of the animal in the airways and, importantly, repeated administration is feasible. Thus, appropriately pseudotyped LV vectors are promising candidates for CF gene therapy. Here, we will review preclinical and clinical research related to viral CF gene therapy.Keywords: cystic fibrosis, gene therapy, adenovirus, AAV, lentivirus, Sendai virus

Magnetomotive optical coherence elastography for relating lung structure and function in cystic fibrosis

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Chhetri, Raghav K.; Carpenter, Jerome; Superfine, Richard; Randell, Scott H.; Oldenburg, Amy L.

2010-02-01

Cystic fibrosis (CF) is a genetic defect in the cystic fibrosis transmembrane conductance regulator protein and is the most common life-limiting genetic condition affecting the Caucasian population. It is an autosomal recessive, monogenic inherited disorder characterized by failure of airway host defense against bacterial infection, which results in bronchiectasis, the breakdown of airway wall extracellular matrix (ECM). In this study, we show that the in vitro models consisting of human tracheo-bronchial-epithelial (hBE) cells grown on porous supports with embedded magnetic nanoparticles (MNPs) at an air-liquid interface are suitable for long term, non-invasive assessment of ECM remodeling using magnetomotive optical coherence elastography (MMOCE). The morphology of ex vivo CF and normal lung tissues using OCT and correlative study with histology is also examined. We also demonstrate a quantitative measure of normal and CF airway elasticity using MMOCE. The improved understanding of pathologic changes in CF lung structure and function and the novel method of longitudinal in vitro ECM assessment demonstrated in this study may lead to new in vivo imaging and elastography methods to monitor disease progression and treatment in cystic fibrosis.

THE BUFFER CAPACITY OF AIRWAY EPITHELIAL SECRETIONS

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Dusik eKim

2014-06-01

Full Text Available The pH of airway epithelial secretions influences bacterial killing and mucus properties and is reduced by acidic pollutants, gastric reflux, and respiratory diseases such as cystic fibrosis (CF. The effect of acute acid loads depends on buffer capacity, however the buffering of airway secretions has not been well characterized. In this work we develop a method for titrating micro-scale (30 µl volumes and use it to study fluid secreted by the human airway epithelial cell line Calu-3, a widely used model for submucosal gland serous cells. Microtitration curves revealed that HCO3- is the major buffer. Peak buffer capacity (β increased from 17 to 28 mM/pH during forskolin stimulation, and was reduced by >50% in fluid secreted by cystic fibrosis transmembrane conductance regulator (CFTR-deficient Calu-3 monolayers, confirming an important role of CFTR in HCO3- secretion. Back-titration with NaOH revealed non-volatile buffer capacity due to proteins synthesized and released by the epithelial cells. Lysozyme and mucin concentrations were too low to buffer Calu-3 fluid significantly, however model titrations of porcine gastric mucins at concentrations near the sol-gel transition suggest that mucins may contribute to the buffer capacity of ASL in vivo. We conclude that CFTR-dependent HCO3- secretion and epithelially-derived proteins are the predominant buffers in Calu-3 secretions.

CFTR, Mucins, and Mucus Obstruction in Cystic Fibrosis

Science.gov (United States)

Kreda, Silvia M.; Davis, C. William; Rose, Mary Callaghan

2012-01-01

Mucus pathology in cystic fibrosis (CF) has been known for as long as the disease has been recognized and is sometimes called mucoviscidosis. The disease is marked by mucus hyperproduction and plugging in many organs, which are usually most fatal in the airways of CF patients, once the problem of meconium ileus at birth is resolved. After the CF gene, CFTR, was cloned and its protein product identified as a cAMP-regulated Cl− channel, causal mechanisms underlying the strong mucus phenotype of the disease became obscure. Here we focus on mucin genes and polymeric mucin glycoproteins, examining their regulation and potential relationships to a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR). Detailed examination of CFTR expression in organs and different cell types indicates that changes in CFTR expression do not always correlate with the severity of CF disease or mucus accumulation. Thus, the mucus hyperproduction that typifies CF does not appear to be a direct cause of a defective CFTR but, rather, to be a downstream consequence. In organs like the lung, up-regulation of mucin gene expression by inflammation results from chronic infection; however, in other instances and organs, the inflammation may have a non-infectious origin. The mucus plugging phenotype of the β-subunit of the epithelial Na+ channel (βENaC)-overexpressing mouse is proving to be an archetypal example of this kind of inflammation, with a dehydrated airway surface/concentrated mucus gel apparently providing the inflammatory stimulus. Data indicate that the luminal HCO3 − deficiency recently described for CF epithelia may also provide such a stimulus, perhaps by causing a mal-maturation of mucins as they are released onto luminal surfaces. In any event, the path between CFTR dysfunction and mucus hyperproduction has proven tortuous, and its unraveling continues to offer its own twists and turns, along with fascinating glimpses into biology. PMID:22951447

The impact of MRSA infection in the airways of children with cystic fibrosis; a case-control study.

LENUS (Irish Health Repository)

Cox, D W

2014-01-01

The prevalence of Methicillin Resistant Staphylococcus Aureus (MRSA) in patients with Cystic Fibrosis (CF) has risen dramatically over the past 10 years. The clinical significance of MRSA in CF patients remains undetermined. We conducted a review of patients with CF infected with MRSA over a 10 year period at Our Lady\\'s Children\\'s Hospital, Crumlin between 1999 and 2009. We collected data from 24 patients infected with MRSA and 24 control patients without MRSA There was a significant difference between the two groups in the rate of decline in percentage FEV1 two years after MRSA infection (Difference: -17.4, 95% CI: -30.48, -4.31, p = 0.01). A similar trend was seen for FVC% and FEF25-75% predicted. This study suggests that persistent MRSA infection in the airways of children with CF is associated with diminished lung function two years post acquisition, when compared to a matched control cohort without MRSA.

Hypertonic saline for cystic fibrosis: worth its salt?

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Goralski, Jennifer L; Donaldson, Scott H

2014-06-01

Airway dehydration in cystic fibrosis (CF) leads to chronic inflammation, ongoing infection and progressive lung disease. Restoration of airway hydration by inhalation of an osmotic agent (hypertonic saline) has been shown to be safe, effective and well-tolerated in adults with CF. Although the safety of hypertonic saline in infants and young children with CF has also been established, recent studies have reported inconclusive evidence about its efficacy. In this editorial, we discuss the evidence behind hypertonic saline use for adults, children and infants with CF.

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

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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.

Draft Genome Sequences of Pseudomonas aeruginosa B3 Strains Isolated from a Cystic Fibrosis Patient Undergoing Antibiotic Chemotherapy

DEFF Research Database (Denmark)

Marvig, Rasmus Lykke; Jochumsen, Nicholas; Johansen, Helle Krogh

2013-01-01

Pseudomonas aeruginosa frequently establishes chronic infections in the airways of patients suffering from cystic fibrosis (CF). Here, we report the draft genome sequences of four P. aeruginosa B3 strains isolated from a chronically infected CF patient undergoing antibiotic chemotherapy.......Pseudomonas aeruginosa frequently establishes chronic infections in the airways of patients suffering from cystic fibrosis (CF). Here, we report the draft genome sequences of four P. aeruginosa B3 strains isolated from a chronically infected CF patient undergoing antibiotic chemotherapy....

Personalized medicine for cystic fibrosis: establishing human model systems.

Science.gov (United States)

Mou, Hongmei; Brazauskas, Karissa; Rajagopal, Jayaraj

2015-10-01

With over 1,500 identifiable mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that result in distinct functional and phenotypical abnormalities, it is virtually impossible to perform randomized clinical trials to identify the best therapeutics for all patients. Therefore, a personalized medicine approach is essential. The only way to realistically accomplish this is through the development of improved in vitro human model systems. The lack of a readily available and infinite supply of human CFTR-expressing airway epithelial cells is a key bottleneck. We propose that a concerted two-pronged approach is necessary for patient-specific cystic fibrosis research to continue to prosper and realize its potential: (1) more effective culture and differentiation conditions for growing primary human airway and nasal epithelial cells and (2) the development of collective protocols for efficiently differentiating disease- and patient-specific induced pluripotent stem cells (iPSC) into pure populations of adult epithelial cells. Ultimately, we need a personalized human model system for cystic fibrosis with the capacity for uncomplicated bankability, widespread availability, and universal applicability for patient-specific disease modeling, novel pharmacotherapy investigation and screening, and readily executable genetic modification. © 2015 Wiley Periodicals, Inc.

Effects of airway surface liquid height on the kinetics of extracellular nucleotides in airway epithelia.

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Amarante, Tauanne D; da Silva, Jafferson K L; Garcia, Guilherme J M

2014-12-21

Experimental techniques aimed at measuring the concentration of signaling molecules in the airway surface liquid (ASL) often require an unrealistically large ASL volume to facilitate sampling. This experimental limitation, prompted by the difficulty of pipetting liquid from a very shallow layer (~15 μm), leads to dilution and the under-prediction of physiologic concentrations of signaling molecules that are vital to the regulation of mucociliary clearance. Here, we use a computational model to describe the effect of liquid height on the kinetics of extracellular nucleotides in the airway surface liquid coating respiratory epithelia. The model consists of a reaction-diffusion equation with boundary conditions that represent the enzymatic reactions occurring on the epithelial surface. The simulations reproduce successfully the kinetics of extracellular ATP following hypotonic challenge for ASL volumes ranging from 25 μl to 500 μl in a 12-mm diameter cell culture. The model reveals that [ATP] and [ADO] reach 1200 nM and 2200 nM at the epithelial surface, respectively, while their volumetric averages remain less than 200 nM at all times in experiments with a large ASL volume (500 μl). These findings imply that activation of P2Y2 and A2B receptors is robust after hypotonic challenge, in contrast to what could be concluded based on experimental measurements of volumetric concentrations in large ASL volumes. Finally, given the central role that ATP and ADO play in regulating mucociliary clearance, we investigated which enzymes, when inhibited, provide the greatest increase in ATP and ADO concentrations. Our findings suggest that inhibition of NTPDase1/highTNAP would cause the greatest increase in [ATP] after hypotonic challenge, while inhibition of the transporter CNT3 would provide the greatest increase in [ADO]. Copyright © 2014 Elsevier Ltd. All rights reserved.

Experimental pulmonary fibrosis in rats with chronic gastric acid reflux esophagitis.

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Shimazu, Rintaro; Aoki, Shigehisa; Kuratomi, Yuichiro

2015-10-01

To elucidate the association between gastric acid reflux and respiratory diseases by studying the histological changes of the lower airway in rats with chronic acid reflux esophagitis. An experimental rat model of chronic acid reflux esophagitis was surgically created. The lower airways of these rats were histologically observed for more than 50 weeks. Although there were no histological changes which induced gastric acid reflux at 10 weeks after surgery, thickening of the basal laminae and the proliferation of the collagenous fibers were observed in the alveolar epithelium at 20 weeks after surgery. At 50 weeks after surgery, the collagenous fibers obliterated the pulmonary alveoli and bronchial lumen. These findings observed in the GERD rats are similar to the pathological findings of human pulmonary fibrosis. In this study, we reported pathological changes in the lower airways of GERD rat models observed for more than 50 weeks. These results suggest that gastric acid reflux may be one of the pathogenic or exacerbating factors of pulmonary fibrosis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

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)

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...

miR-126 is downregulated in cystic fibrosis airway epithelial cells and regulates TOM1 expression.

LENUS (Irish Health Repository)

Oglesby, Irene K

2010-02-15

Cystic fibrosis (CF) is one of the most common lethal genetic diseases in which the role of microRNAs has yet to be explored. Predicted to be regulated by miR-126, TOM1 (target of Myb1) has been shown to interact with Toll-interacting protein, forming a complex to regulate endosomal trafficking of ubiquitinated proteins. TOM1 has also been proposed as a negative regulator of IL-1beta and TNF-alpha-induced signaling pathways. MiR-126 is highly expressed in the lung, and we now show for the first time differential expression of miR-126 in CF versus non-CF airway epithelial cells both in vitro and in vivo. MiR-126 downregulation in CF bronchial epithelial cells correlated with a significant upregulation of TOM1 mRNA, both in vitro and in vivo when compared with their non-CF counterparts. Introduction of synthetic pre-miR-126 inhibited luciferase activity in a reporter system containing the full length 3\\'-untranslated region of TOM1 and resulted in decreased TOM1 protein production in CF bronchial epithelial cells. Following stimulation with LPS or IL-1beta, overexpression of TOM1 was found to downregulate NF-kappaB luciferase activity. Conversely, TOM1 knockdown resulted in a significant increase in NF-kappaB regulated IL-8 secretion. These data show that miR-126 is differentially regulated in CF versus non-CF airway epithelial cells and that TOM1 is a miR-126 target that may have an important role in regulating innate immune responses in the CF lung. To our knowledge, this study is the first to report of a role for TOM1 in the TLR2\\/4 signaling pathways and the first to describe microRNA involvement in CF.

Elective use of the Ventrain for upper airway obstruction during high-frequency jet ventilation.

Science.gov (United States)

Fearnley, Robert A; Badiger, Sheela; Oakley, Richard J; Ahmad, Imran

2016-09-01

The safety of high pressure source ventilation (jet ventilation) is dependent upon upper airway patency to facilitate adequate passive expiration and prevent increasing intrathoracic pressure and its associated deleterious sequelae. Distortions in airway anatomy may make passive expiration inadequate or impossible in some patients. We report the elective use of the Ventrain device to provide ventilation in a clinical setting of upper airway obstruction in a patient with post radiation fibrosis that had previously prevented passive expiration during attempted high pressure source ventilation. Copyright © 2016 Elsevier Inc. All rights reserved.

Adeno-associated virus for cystic fibrosis gene therapy

Directory of Open Access Journals (Sweden)

S.V. Martini

2011-11-01

Full Text Available Gene therapy is an alternative treatment for genetic lung disease, especially monogenic disorders such as cystic fibrosis. Cystic fibrosis is a severe autosomal recessive disease affecting one in 2500 live births in the white population, caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR. The disease is classically characterized by pancreatic enzyme insufficiency, an increased concentration of chloride in sweat, and varying severity of chronic obstructive lung disease. Currently, the greatest challenge for gene therapy is finding an ideal vector to deliver the transgene (CFTR to the affected organ (lung. Adeno-associated virus is the most promising viral vector system for the treatment of respiratory disease because it has natural tropism for airway epithelial cells and does not cause any human disease. This review focuses on the basic properties of adeno-associated virus and its use as a vector for cystic fibrosis gene therapy.

Link between vitamin D and airway remodeling

Directory of Open Access Journals (Sweden)

Berraies A

2014-04-01

Full Text Available Anissa Berraies, Kamel Hamzaoui, Agnes HamzaouiPediatric Respiratory Diseases Department, Abderrahmen Mami Hospital, Ariana, and Research Unit 12SP15 Tunis El Manar University, Tunis, TunisiaAbstract: In the last decade, many epidemiologic studies have investigated the link between vitamin D deficiency and asthma. Most studies have shown that vitamin D deficiency increases the risk of asthma and allergies. Low levels of vitamin D have been associated with asthma severity and loss of control, together with recurrent exacerbations. Remodeling is an early event in asthma described as a consequence of production of mediators and growth factors by inflammatory and resident bronchial cells. Consequently, lung function is altered, with a decrease in forced expiratory volume in one second and exacerbated airway hyperresponsiveness. Subepithelial fibrosis and airway smooth muscle cell hypertrophy are typical features of structural changes in the airways. In animal models, vitamin D deficiency enhances inflammation and bronchial anomalies. In severe asthma of childhood, major remodeling is observed in patients with low vitamin D levels. Conversely, the antifibrotic and antiproliferative effects of vitamin D in smooth muscle cells have been described in several experiments. In this review, we briefly summarize the current knowledge regarding the relationship between vitamin D and asthma, and focus on its effect on airway remodeling and its potential therapeutic impact for asthma.Keywords: vitamin D, asthma, airway remodeling, airway smooth muscle, supplementation

[Airway clearance techniques in chronic obstructive pulmonary syndrome : 2011 update].

Science.gov (United States)

Opdekamp, C

2011-09-01

For many years the airway clearance techniques used in chest physical therapy were assimilated with the singular technique of postural drainage, percussions and vibrations. However the side effects and counter indications and the lack of scientific proof regarding this technique have forced reflection and development of other techniques more comfortable and without deleterious effects. If all these techniques show a high efficiency in terms of improved mucociliary clearance, the literature is unanimous on how little effect these techniques have in the short and the long-term with regards to lung function and arterial blood gases. In view of the scientific literature, it is clear that the airway clearance techniques don't have the same recognition concerning their efficiency in all obstructive pulmonary diseases. As the cornerstone in the management of cystic fibrosis, the efficiency of the bronchial hygiene techniques are in general poorly documented in the management of the non-cystic fibrosis bronchiectasis, bronchitis or emphysema. The use of the chest physical therapy seems more to do with the interpretation of the imagery and symptomatology. The airway clearance techniques should be individualised according to symptoms, the amount of expectorated mucus and the objectives signs of secretions retention or subjective signs of difficulty expectorating secretions with progression of the disease.

Genetic Deletion and Pharmacological Inhibition of PI3Kγ Reduces Neutrophilic Airway Inflammation and Lung Damage in Mice with Cystic Fibrosis-Like Lung Disease

Directory of Open Access Journals (Sweden)

Maria Galluzzo

2015-01-01

Full Text Available Purpose. Neutrophil-dominated airway inflammation is a key feature of progressive lung damage in cystic fibrosis (CF. Thus, reducing airway inflammation is a major goal to prevent lung damage in CF. However, current anti-inflammatory drugs have shown several limits. PI3Kγ plays a pivotal role in leukocyte recruitment and activation; in the present study we determined the effects of genetic deletion and pharmacologic inhibition of PI3Kγ on airway inflammation and structural lung damage in a mouse model of CF lung disease. Methods. βENaC overexpressing mice (βENaC-Tg were backcrossed with PI3Kγ-deficient (PI3KγKO mice. Tissue damage was assessed by histology and morphometry and inflammatory cell number was evaluated in bronchoalveolar lavage fluid (BALF. Furthermore, we assessed the effect of a specific PI3Kγ inhibitor (AS-605240 on inflammatory cell number in BALF. Results. Genetic deletion of PI3Kγ decreased neutrophil numbers in BALF of PI3KγKO/βENaC-Tg mice, and this was associated with reduced emphysematous changes. Treatment with the PI3Kγ inhibitor AS-605240 decreased the number of neutrophils in BALF of βENaC-Tg mice, reproducing the effect observed with genetic deletion of the enzyme. Conclusions. These results demonstrate the biological efficacy of both genetic deletion and pharmacological inhibition of PI3Kγ in reducing chronic neutrophilic inflammation in CF-like lung disease in vivo.

Non-invasive airway health measurement using synchrotron x-ray microscopy of high refractive index glass microbeads

Energy Technology Data Exchange (ETDEWEB)

Donnelley, Martin, E-mail: martin.donnelley@adelaide.edu.au; Farrow, Nigel; Parsons, David [Respiratory & Sleep Medicine, Women’s and Children’s Hospital, North Adelaide, South Australia (Australia); Robinson Research Institute, University of Adelaide, South Australia (Australia); School of Paediatrics and Reproductive Health, University of Adelaide, South Australia (Australia); Morgan, Kaye; Siu, Karen [School of Physics, Monash University, Victoria (Australia)

2016-01-28

Cystic fibrosis (CF) is caused by a gene defect that compromises the ability of the mucociliary transit (MCT) system to clear the airways of debris and pathogens. To directly characterise airway health and the effects of treatments we have developed a synchrotron X-ray microscopy method that non-invasively measures the local rate and patterns of MCT behaviour. Although the nasal airways of CF mice exhibit the CF pathophysiology, there is evidence that nasal MCT is not altered in CF mice1. The aim of this experiment was to determine if our non-invasive local airway health assessment method could identify differences in nasal MCT rate between normal and CF mice, information that is potentially lost in bulk MCT measurements. Experiments were performed on the BL20XU beamline at the SPring-8 Synchrotron in Japan. Mice were anaesthetized, a small quantity of micron-sized marker particles were delivered to the nose, and images of the nasal airways were acquired for 15 minutes. The nasal airways were treated with hypertonic saline or mannitol to increase surface hydration and MCT. Custom software was used to locate and track particles and calculate individual and bulk MCT rates. No statistically significant differences in MCT rate were found between normal and CF mouse nasal airways or between treatments. However, we hope that the improved sensitivity provided by this technique will accelerate the ability to identify useful CF lung disease-modifying interventions in small animal models, and enhance the development and efficacy of proposed new therapies.

Non-invasive airway health measurement using synchrotron x-ray microscopy of high refractive index glass microbeads

Science.gov (United States)

Donnelley, Martin; Morgan, Kaye; Farrow, Nigel; Siu, Karen; Parsons, David

2016-01-01

Cystic fibrosis (CF) is caused by a gene defect that compromises the ability of the mucociliary transit (MCT) system to clear the airways of debris and pathogens. To directly characterise airway health and the effects of treatments we have developed a synchrotron X-ray microscopy method that non-invasively measures the local rate and patterns of MCT behaviour. Although the nasal airways of CF mice exhibit the CF pathophysiology, there is evidence that nasal MCT is not altered in CF mice1. The aim of this experiment was to determine if our non-invasive local airway health assessment method could identify differences in nasal MCT rate between normal and CF mice, information that is potentially lost in bulk MCT measurements. Experiments were performed on the BL20XU beamline at the SPring-8 Synchrotron in Japan. Mice were anaesthetized, a small quantity of micron-sized marker particles were delivered to the nose, and images of the nasal airways were acquired for 15 minutes. The nasal airways were treated with hypertonic saline or mannitol to increase surface hydration and MCT. Custom software was used to locate and track particles and calculate individual and bulk MCT rates. No statistically significant differences in MCT rate were found between normal and CF mouse nasal airways or between treatments. However, we hope that the improved sensitivity provided by this technique will accelerate the ability to identify useful CF lung disease-modifying interventions in small animal models, and enhance the development and efficacy of proposed new therapies.

[Airway management in a man with ankylosing spondylitis].

Science.gov (United States)

Gil, S; Jamart, V; Borrás, R; Miranda, A

2007-02-01

We report a case of difficult airway management in a 41-year-old man with ankylosing spondylitis who was scheduled for total left hip replacement surgery. After several failed attempts to achieve regional anesthesia, we converted to general anesthesia with orotracheal intubation using a fiberoptic bronchoscope. Ankylosing spondylitis leads to fibrosis, ossification, and ankylosis along the spinal column and sacroiliac articulations. Cervical column and atlantooccipital articulation mobility are reduced and in severe cases the cervical vertebrae become fixed in a flexed position. This portion of the spine is also the most susceptible to fracture, particularly in hyperextension, an event that could lead to damage to the cervical spinal cord during maneuvers to manage the airway. Patients with this condition may also have temporomandibular joint involvement, further complicating airway management. We report the case of a patient with ankylosing spondylitis with fixation along the entire spine. The airway was managed by intubation with a fiberoptic bronchoscope. Spontaneous ventilation was maintained during the maneuver, and sedation was achieved with perfusion of remifentanil as the only anesthetic agent following failure of intradural anesthesia.

Epidemiology of nontuberculous mycobacteria among patients with cystic fibrosis in Scandinavia

DEFF Research Database (Denmark)

Qvist, Tavs; Gilljam, Marita; Jönsson, Bodil

2015-01-01

BACKGROUND: Nontuberculous mycobacteria (NTM) are an emerging threat to cystic fibrosis (CF) patients but their epidemiology is not well described. METHODS: In this retrospective observational study we identified all Scandinavian CF patients with a positive NTM culture from airway secretions from...

Idiopathic pulmonary fibrosis. A rare cause of scintigraphic ventilation-perfusion mismatch

International Nuclear Information System (INIS)

Pochis, W.T.; Krasnow, A.Z.; Collier, B.D.; Mewissen, M.W.; Almagro, U.A.; Hellman, R.S.; Isitman, A.T.

1990-01-01

A case of idiopathic pulmonary fibrosis with multiple areas of mismatch on ventilation-perfusion lung imaging in the absence of pulmonary embolism is presented. Idiopathic pulmonary fibrosis is one of the few nonembolic diseases producing a pulmonary ventilation-perfusion mismatch. In this condition, chest radiographs may not detect the full extent of disease, and xenon-133 ventilation imaging may be relatively insensitive to morbid changes in small airways. Thus, when examining patients with idiopathic pulmonary fibrosis, one should be aware that abnormal perfusion imaging patterns without matching ventilation abnormalities are not always due to embolism. In this setting, contrast pulmonary angiography is often needed for accurate differential diagnosis

Idiopathic pulmonary fibrosis. A rare cause of scintigraphic ventilation-perfusion mismatch

Energy Technology Data Exchange (ETDEWEB)

Pochis, W.T.; Krasnow, A.Z.; Collier, B.D.; Mewissen, M.W.; Almagro, U.A.; Hellman, R.S.; Isitman, A.T. (Medical College of Wisconsin, Milwaukee (USA))

1990-05-01

A case of idiopathic pulmonary fibrosis with multiple areas of mismatch on ventilation-perfusion lung imaging in the absence of pulmonary embolism is presented. Idiopathic pulmonary fibrosis is one of the few nonembolic diseases producing a pulmonary ventilation-perfusion mismatch. In this condition, chest radiographs may not detect the full extent of disease, and xenon-133 ventilation imaging may be relatively insensitive to morbid changes in small airways. Thus, when examining patients with idiopathic pulmonary fibrosis, one should be aware that abnormal perfusion imaging patterns without matching ventilation abnormalities are not always due to embolism. In this setting, contrast pulmonary angiography is often needed for accurate differential diagnosis.

Simulation of the Cystic Fibrosis patient airway habitats using microfluidic devices

DEFF Research Database (Denmark)

Skolimowski, Maciej

2013-01-01

system tries to eradicate the infections, but with reduced success. This is due to the fact that the bacteria reside embedded in mucus and are more or less recalcitrant to the attack. Instead, the lung tissue is gradually damaged by the ongoing immunological exposure, eventually leading to massive...... are still not ideal, mainly because the immune response differs between man and e.g. mouse, and because the lung pathology after infection is very different in animals compared to humans. In flow cell based systems the bacteria are allowed to form a biofilm on the surface, as in the airways...... system in which the oxygen level can be regulated and the migration of cells between individual compartments can be controlled and monitored. Furthermore, the special conditions in the CF bronchi need to be mimicked as the thick mucus plug present there seems to be another essential factor in the failure...

Transcellular sodium transport in cultured cystic fibrosis human nasal epithelium

DEFF Research Database (Denmark)

Willumsen, Niels J.; Boucher, Richard C.

1991-01-01

Cystic fibrosis (CF) airway epithelia exhibit raised transepithelial Na+ transport rates, as determined by open-circuit isotope fluxes and estimates of the amiloride-sensitive equivalent short-circuit current (Ieq). To study the contribution of apical and basolateral membrane paths to raised Na+ ...

Native Small Airways Secrete Bicarbonate

OpenAIRE

Shamsuddin, A. K. M.; Quinton, Paul M.

2014-01-01

Since the discovery of Cl− impermeability in cystic fibrosis (CF) and the cloning of the responsible channel, CF pathology has been widely attributed to a defect in epithelial Cl− transport. However, loss of bicarbonate (HCO3−) transport also plays a major, possibly more critical role in CF pathogenesis. Even though HCO3− transport is severely affected in the native pancreas, liver, and intestines in CF, we know very little about HCO3− secretion in small airways, the principle site of morbidi...

Assessing idiopathic pulmonary fibrosis (IPF) with bronchoscopic OCT (Conference Presentation)

Science.gov (United States)

Hariri, Lida P.; Adams, David C.; Colby, Thomas V.; Tager, Andrew M.; Suter, Melissa J.

2016-03-01

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal form of fibrotic lung disease, with a 3 year survival rate of 50%. Diagnostic certainty of IPF is essential to determine the most effective therapy for patients, but often requires surgery to resect lung tissue and look for microscopic honeycombing not seen on chest computed tomography (CT). Unfortunately, surgical lung resection has high risks of associated morbidity and mortality in this patient population. We aim to determine whether bronchoscopic optical coherence tomography (OCT) can serve as a novel, low-risk paradigm for in vivo IPF diagnosis without surgery or tissue removal. OCT provides rapid 3D visualization of large tissue volumes with microscopic resolutions well beyond the capabilities of CT. We have designed bronchoscopic OCT catheters to effectively and safely access the peripheral lung, and conducted in vivo peripheral lung imaging in patients, including those with pulmonary fibrosis. We utilized these OCT catheters to perform bronchoscopic imaging in lung tissue from patients with pulmonary fibrosis to determine if bronchoscopic OCT could successfully visualize features of IPF through the peripheral airways. OCT was able to visualize characteristic features of IPF through the airway, including microscopic honeycombing (< 1 mm diameter) not visible by CT, dense peripheral fibrosis, and spatial disease heterogeneity. These findings support the potential of bronchoscopic OCT as a minimally-invasive method for in vivo IPF diagnosis. However, future clinical studies are needed to validate these findings.

Measuring surface temperature and grading pathological changes of airway tissue in a canine model of inhalational thermal injury.

Science.gov (United States)

Zhao, Ran; Di, La-na; Zhao, Xiao-zhuo; Wang, Cheng; Zhang, Guo-an

2013-06-01

Airway tissue shows unexpected invulnerability to heated air. The mechanisms of this phenomenon are open to debate. This study was designed to measure the surface temperatures at different locations of the airway, and to explore the relationship between the tissue's surface temperature and injury severity. Twenty dogs were randomly divided into four groups, including three experimental groups (six dogs in each) to inhale heated air at 70-80 °C (group I), 150-160 °C (group II) and 310-320 °C (group III) and a control group (two dogs, only for histological observation). Injury time was 20 min. Mucosal surface temperatures of the epiglottis (point A), cricoid cartilage (point B) and lower trachea (point C) were measured. Dogs in group I-III were divided into three subgroups (two in each), to be assayed at 12, 24 and 36 h after injury, respectively. For each dog, four tissue parts (epiglottis, larynx, lower trachea and terminal bronchiole) were microscopically observed and graded according to an original pathological scoring system (score range: 0-27). Surface temperatures of the airway mucosa increased slowly to 40.60±3.29 °C, and the highest peak temperature was 48.3 °C (group III, point A). The pathological score of burned tissues was 4.12±4.94 (0.0-18.0), suggesting slight to moderate injuries. Air temperature and airway location both influenced mucosal temperature and pathological scores very significantly, and there was a very significant positive correlation between tissue temperature and injury severity. Compared to the inhalational air hyperthermia, airway surface temperature was much lower, but was still positively correlated with thermal injury severity. Copyright © 2012 Elsevier Ltd and ISBI. All rights reserved.

Effects of inhaled high-molecular weight hyaluronan in inflammatory airway disease.

Science.gov (United States)

Lamas, Adelaida; Marshburn, Jamie; Stober, Vandy P; Donaldson, Scott H; Garantziotis, Stavros

2016-10-03

Cystic fibrosis (CF) is a chronic inflammatory disease that is affecting thousands of patients worldwide. Adjuvant anti-inflammatory treatment is an important component of cystic fibrosis treatment, and has shown promise in preserving lung function and prolonging life expectancy. Inhaled high molecular weight hyaluronan (HMW-HA) is reported to improve tolerability of hypertonic saline and thus increase compliance, and has been approved in some European countries for use as an adjunct to hypertonic saline treatment in cystic fibrosis. However, there are theoretical concerns that HMW-HA breakdown products may be pro-inflammatory. In this clinical pilot study we show that sputum cytokines in CF patients receiving HMW-HA are not increased, and therefore HMW-HA does not appear to adversely affect inflammatory status in CF airways.

Voice Disorder in Cystic Fibrosis Patients

Science.gov (United States)

Lourenço, Bruna Mendes; Costa, Kauê Machado; da Silva Filho, Manoel

2014-01-01

Cystic fibrosis is a common autosomal recessive disorder with drastic respiratory symptoms, including shortness of breath and chronic cough. While most of cystic fibrosis treatment is dedicated to mitigating the effects of respiratory dysfunction, the potential effects of this disease on vocal parameters have not been systematically studied. We hypothesized that cystic fibrosis patients, given their characteristic respiratory disorders, would also present dysphonic symptoms. Given that voice disorders can severely impair quality of life, the identification of a potential cystic fibrosis-related dysphonia could be of great value for the clinical evaluation and treatment of this disease. We tested our hypothesis by measuring vocal parameters, using both objective physical measures and the GRBAS subjective evaluation method, in male and female cystic fibrosis patients undergoing conventional treatment and compared them to age and sex matched controls. We found that cystic fibrosis patients had a significantly lower vocal intensity and harmonic to noise ratio, as well as increased levels of jitter and shimmer. In addition, cystic fibrosis patients also showed higher scores of roughness, breathiness and asthenia, as well as a significantly altered general grade of dysphonia. When we segregated the results according to sex, we observed that, as a group, only female cystic fibrosis patients had significantly lower values of harmonic to noise ratio and an abnormal general grade of dysphonia in relation to matched controls, suggesting that cystic fibrosis exerts a more pronounced effect on vocal parameters of women in relation to men. Overall, the dysphonic characteristics of CF patients can be explained by dysfunctions in vocal fold movement and partial upper airway obstruction, potentially caused by the accumulation of mucus and chronic cough characteristic of CF symptomatology. Our results show that CF patients exhibit significant dysphonia and suggest they may

Differential effects of allergen challenge on large and small airway reactivity in mice.

Directory of Open Access Journals (Sweden)

Chantal Donovan

Full Text Available The relative contributions of large and small airways to hyperresponsiveness in asthma have yet to be fully assessed. This study used a mouse model of chronic allergic airways disease to induce inflammation and remodelling and determine whether in vivo hyperresponsiveness to methacholine is consistent with in vitro reactivity of trachea and small airways. Balb/C mice were sensitised (days 0, 14 and challenged (3 times/week, 6 weeks with ovalbumin. Airway reactivity was compared with saline-challenged controls in vivo assessing whole lung resistance, and in vitro measuring the force of tracheal contraction and the magnitude/rate of small airway narrowing within lung slices. Increased airway inflammation, epithelial remodelling and fibrosis were evident following allergen challenge. In vivo hyperresponsiveness to methacholine was maintained in isolated trachea. In contrast, methacholine induced slower narrowing, with reduced potency in small airways compared to controls. In vitro incubation with IL-1/TNFα did not alter reactivity. The hyporesponsiveness to methacholine in small airways within lung slices following chronic ovalbumin challenge was unexpected, given hyperresponsiveness to the same agonist both in vivo and in vitro in tracheal preparations. This finding may reflect the altered interactions of small airways with surrounding parenchymal tissue after allergen challenge to oppose airway narrowing and closure.

Pilot trial of spirometer games for airway clearance practice in cystic fibrosis.

Science.gov (United States)

Bingham, Peter M; Lahiri, Thomas; Ashikaga, Taka

2012-08-01

Many children with cystic fibrosis (CF) adhere poorly to airway clearance techniques (ACTs), and would rather play video games that challenge their dexterity and visual tracking skills. We developed gaming technology that encourages forced expiratory maneuvers. Following interviews regarding recreational activities and subjects' practice of ACTs, we conducted a pilot trial of spirometer games in 13 adolescents with CF, to test the hypothesis that games could increase subjects' engagement with forced expiratory breathing maneuvers and improve pulmonary function tests (PFTs). After baseline PFTs, subjects were provided with digital spirometers and computers set up as "game only" or "control" devices. After the first of 2 periods (each > 2 weeks), the computer was set-up for the alternate condition for period 2. The t test and non-parametric correlation analyses examined use, number of expiratory high flow events (HFEs), and change in PFTs, identifying trends at P ≤ .1, significance at P games and control software a similar percentage of days during the game (26%) and control periods (32%). There was a trend toward more minutes with the game versus control setup (P = .07), though HFE count did not differ between the 2 conditions (P = .71). Game play showed no overall effect on FEV(1), though correlation analysis showed a modest relation between minutes of play and change in FEV(1) from baseline (r = 0.50, P = .09). The game period showed a trend to increased vital capacity (P = .05). Spirometer games elicit forced expiratory breath maneuvers in pediatric CF patients. Improvement in PFTs may be due to improved test performance technique, though improved obstructive/restrictive lung function due to game play cannot be excluded. A formal clinical trial of this approach is planned.

Nanostructured Surfaces for Drug Delivery and Anti-Fibrosis

Science.gov (United States)

Kam, Kimberly Renee

Effective and cost-efficient healthcare is at the forefront of public discussion; on both personal and policy levels, technologies that improve therapeutic efficacy without the use of painful hypodermic needle injections or the use of harsh chemicals would prove beneficial to patients. Nanostructured surfaces as structure-mediated permeability enhancers introduce a potentially revolutionary approach to the field of drug delivery. Parental administration routes have been the mainstay technologies for delivering biologics because these therapeutics are too large to permeate epithelial barriers. However, there is a significant patient dislike for hypodermic needles resulting in reduced patient compliance and poor therapeutic results. We present an alternative strategy to harness the body's naturally occurring biological processes and transport mechanisms to enhance the drug transport of biologics across the epithelium. Our strategy offers a paradigm shift from traditional biochemical drug delivery vehicles by using nanotopography to loosen the epithelial barrier. Herein, we demonstrate that nanotopographical cues can be used to enable biologics > 66 kDa to be transported across epithelial monolayers by increasing paracellular transport. When placed in contact with epithelial cells, nanostructured films significantly increase the transport of albumin, IgG, and a model therapeutic, etanercept. Our work highlights the potential to use drug delivery systems which incorporate nanotopographical cues to increase the transport of biologics across epithelial tissue. Furthermore, we describe current advancements in nano- and microfabrication for applications in anti-fibrosis and wound healing. Influencing cellular responses to biomaterials is crucial in the field of tissue engineering and regenerative medicine. Since cells are surrounded by extracellular matrix features that are on the nanoscale, identifying nanostructures for imparting desirable cellular function could greatly

Early experiences with crowdsourcing airway annotations in chest CT

DEFF Research Database (Denmark)

Cheplygina, Veronika; Perez-Rovira, Adria; Kuo, Wieying

2016-01-01

Measuring airways in chest computed tomography (CT) images is important for characterizing diseases such as cystic fibrosis, yet very time-consuming to perform manually. Machine learning algorithms offer an alternative, but need large sets of annotated data to perform well. We investigate whether...... a number of further research directions and provide insight into the challenges of crowdsourcing in medical images from the perspective of first-time users....

Next generation in vitro systems for biofilm studies - a cystic fibrosis patient airway perspective

DEFF Research Database (Denmark)

Weiss Nielsen, Martin

proven essential aspects on biofilm formations, however generates highly artificial biofilms that lack several CF airway scenarios. The driving force and the heart of this project has its origin in the study of the role played by P. aeruginosa in the CF airways. One of the aims of this thesis...

Impact of Aspergillus fumigatus in allergic airway diseases

Directory of Open Access Journals (Sweden)

Chaudhary Neelkamal

2011-06-01

Full Text Available Abstract For decades, fungi have been recognized as associated with asthma and other reactive airway diseases. In contrast to type I-mediated allergies caused by pollen, fungi cause a large number of allergic diseases such as allergic bronchopulmonary mycoses, rhinitis, allergic sinusitis and hypersensitivity pneumonitis. Amongst the fungi, Aspergillus fumigatus is the most prevalent cause of severe pulmonary allergic disease, including allergic bronchopulmonary aspergillosis (ABPA, known to be associated with chronic lung injury and deterioration in pulmonary function in people with chronic asthma and cystic fibrosis (CF. The goal of this review is to discuss new understandings of host-pathogen interactions in the genesis of allergic airway diseases caused by A. fumigatus. Host and pathogen related factors that participate in triggering the inflammatory cycle leading to pulmonary exacerbations in ABPA are discussed.

Cedecea davisae’s Role in a Polymicrobial Lung Infection in a Cystic Fibrosis Patient

Directory of Open Access Journals (Sweden)

Thayer G. Ismaael

2012-01-01

Full Text Available Chronic airway colonization and infection are the hallmark of cystic fibrosis (CF. Staphylococcus aureus, Pseudomonas aeruginosa, and Burkholderia cepacia are well-documented bacterial culprits in this chronic suppurative airway disease. Advanced molecular diagnostics have uncovered a possible role of a larger group of microorganisms in CF. Cedecea is a member of the family Enterobacteriaceae and is an emerging pathogen. We present a case of a polymicrobial healthcare-associated pneumonia in a CF patient caused by Cedecea davisae, among other bacteria.

High-dose ibuprofen therapy associated with esophageal ulceration after pneumonectomy in a patient with cystic fibrosis: a case report

Directory of Open Access Journals (Sweden)

Anbar Ran D

2004-09-01

Full Text Available Abstract Background Lung disease in patients with cystic fibrosis is thought to develop as a result of airway inflammation, infection, and obstruction. Pulmonary therapies for cystic fibrosis that reduce airway inflammation include corticosteroids, rhDNase, antibiotics, and high-dose ibuprofen. Despite evidence that high-dose ibuprofen slows the progression of lung disease in patients with cystic fibrosis, many clinicians have chosen not to use this therapy because of concerns regarding potential side effects, especially gastrointestinal bleeding. However, studies have shown a low incidence of gastrointestinal ulceration and bleeding in patients with cystic fibrosis who have been treated with high-dose ibuprofen. Case presentation The described case illustrates a life-threatening upper gastrointestinal bleed that may have resulted from high-dose ibuprofen therapy in a patient with CF who had undergone a pneumonectomy. Mediastinal shift post-pneumonectomy distorted the patient's esophageal anatomy and may have caused decreased esophageal motility, which led to prolonged contact of the ibuprofen with the esophagus. The concentrated effect of the ibuprofen, as well as its systemic effects, probably contributed to the occurrence of the bleed in this patient. Conclusions This report demonstrates that gastrointestinal tract anatomical abnormalities or dysmotility may be contraindications for therapy with high-dose ibuprofen in patients with cystic fibrosis.

Microbiology of airway disease in a cohort of patients with Cystic Fibrosis

Directory of Open Access Journals (Sweden)

Carnovale Vincenzo

2006-01-01

Full Text Available Abstract Background Recent reports document an increasing incidence of new Gram-negative pathogens such as Stenotrophomonas maltophilia and Alcaligenes xylosoxidans isolated from patients with Cystic Fibrosis, along with an increase in common Gram-negative pathogens such as Pseudomonas aeruginosa and Burkholderia cepacia complex. Furthermore, the increase in multidrug-resistance of such organisms makes the therapeutic management of these patients more problematic. Therefore, careful isolation and identification, and accurate studies of susceptibility to antibiotics are critical for predicting the spread of strains, improving therapeutic measures and facilitating our understanding of the epidemiology of emerging pathogens. The first aim of this study was to determine the incidence and the prevalence of colonization by Gram-negative organisms isolated from respiratory samples of Cystic Fibrosis patients in the Regional Referral Cystic Fibrosis Centre of Naples; the second was to evaluate the spectrum of multidrug-resistance of these organisms. Methods Patients (n = 300 attending the Regional Cystic Fibrosis Unit were enrolled in this study over 3 years. Sputum was processed for microscopic tests and culture. An automated system, Phoenix (Becton Dickinson, Sparks, Maryland, USA, was used for phenotypic identification of all strains; the API 20 NE identification system (bioMérieux, Marcy l'Etoile, France was used when the identification with the Phoenix system was inaccurate. A PCR-RFLP method was used to characterize the organisms in the Burkholderia cepacia complex. A chemosusceptibility test on microbroth dilutions (Phoenix was used. Primary outcomes such as FEV1 were correlate with different pathogens. Results During the period of study, 40% of patients was infected by Pseudomonas aeruginosa, 7% by Burkholderia cepacia complex, 11% by Stenotrophomonas maltophilia and 7% by Alcaligenes xylosoxidans. Of the strains isolated, 460 were multidrug

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

Automated measurement of pulmonary emphysema and small airway remodeling in cigarette smoke-exposed mice.

Science.gov (United States)

Laucho-Contreras, Maria E; Taylor, Katherine L; Mahadeva, Ravi; Boukedes, Steve S; Owen, Caroline A

2015-01-16

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

PRAGMA-CF. A quantitative structural lung disease CT outcome in young children with cystic fibrosis

DEFF Research Database (Denmark)

Rosenow, Tim; Oudraad, Merel C.J.; Murray, Conor P.

2015-01-01

RATIONALE: Chest computed tomography (CT) is the gold standard for demonstrating cystic fibrosis (CF) airways disease. However, there are no standardised outcome measures appropriate for children under 6 years. OBJECTIVES: We developed the Perth-Rotterdam Annotated Grid Morphometric Analysis for ...

Factors associated with worse lung function in cystic fibrosis patients with persistent staphylococcus aureus

NARCIS (Netherlands)

Junge, S. (Sibylle); Görlich, D. (Dennis); Reijer, M.D. (Martijn Den); B. Wiedemann (Baerbel); B. Tümmler (Burkhard); H. Ellemunter; Dübbers, A. (Angelika); Küster, P. (Peter); M. Ballmann; Koerner-Rettberg, C. (Cordula); Große-Onnebrink, J. (Jörg); Heuer, E. (Eberhardt); Sextro, W. (Wolfgang); Mainz, J.G. (Jochen G.); Hammermann, J. (Jutta); Riethmüller, J. (Joachim); Graepler-Mainka, U.M. (Ute M.); Staab, D. (Doris); Wollschläger, B. (Bettina); Szczepanski, R. (Rüdiger); A. Schuster (Antje); Tegtmeyer, F.-K. (Friedrich-Karl); Sutharsan, S. (Sivagurunathan); Wald, A. (Alexandra); Nofer, J.-R. (Jerzy-Roch); W.J.B. van Wamel (Willem); Becker, K. (Karsten); Peters, G. (Georg); Kahl, B.C. (Barbara C.)

2016-01-01

textabstractBackground Staphylococcus aureus is an important pathogen in cystic fibrosis (CF). However, it is not clear which factors are associated with worse lung function in patients with persistent S. aureus airway cultures. Our main hypothesis was that patients with high S. aureus density in

Decreased mucosal oxygen tension in the maxillary sinuses in patients with cystic fibrosis

DEFF Research Database (Denmark)

Aanæs, Kasper; Rickelt, Lars Fledelius; Johansen, Helle Krogh

2011-01-01

Pseudomonas aeruginosa in the sinuses plays a role in the lungs in cystic fibrosis (CF) patients, but little is known about the sinus environment where the bacteria adapt. Anoxic areas are found in the lower respiratory airways but it is unknown if the same conditions exist in the sinuses....

Imaging from cystic fibrosis

International Nuclear Information System (INIS)

Schmidt, H.; Posselt, H.G.

2008-01-01

Cystic fibrosis (CF) is the most frequent metabolic disorder with autosomal recessive inheritance in the Caucasian population. The gene defect is located on the long arm of chromosome 7. In Germany today, the actual median survival is 37 years. The genetic defect caused by chloride anion disturbances affects multiple body systems but the morbidity and mortality is due to lung disease. The secretion of highly viscous mucus promotes viral and bacterial pulmonary infections leading to airway obstruction and consecutive destruction of the lung parenchyma. This article will review and discuss both the clinical aspects of the disease and the diagnostic methods, referring in particular to new imaging strategies. (orig.)

Computed tomography dose and variability of airway dimension measurements: how low can we go?

International Nuclear Information System (INIS)

Jong, Pim A. de; Long, Frederick R.; Nakano, Yasutaka

2006-01-01

Quantitative CT shows promise as an outcome measure for cystic fibrosis (CF) lung disease in infancy, but must be accomplished at a dose as low as reasonably achievable. To determine the feasibility of ultra-low-dose CT for quantitative measurements of airway dimensions. Two juvenile pigs were anesthetized and their lungs scanned at 25 cm H 2 O face-mask pressure in apnoea using beam currents of 5, 10, 20, 40 and 100 mAs. The lumen diameters and wall thicknesses of matched airways (n=22) at each dose were measured by two observers using validated software. Measurement variability at each dose was compared to that at 100 mAs (reference dose) for large and small airways (lumen diameter <2.5 mm). Lowering CT dose (mAs) affected measurement variability for lumen diameter of small and large airways (P<0.001) and for wall thickness of small (P<0.001), but not large (P=0.63), airways. To obtain the same measurement variability at 5 mAs as at 100 mAs, four to six small airways or one to three large airways have to be measured and averaged. Quantitative airway measurements are feasible on images obtained at as low as 5 mAs, but more airways need to be measured to compensate for greater measurement variability. (orig.)

Pseudomonas aeruginosa host-adaptation in cystic fibrosis patients

DEFF Research Database (Denmark)

Rau, Martin Holm

Pseudomonas aeruginosa is an opportunistic pathogen capable of transition from an environmental lifestyle to a host-associated lifestyle, as exemplified in the life-long airway infection of cystic fibrosis (CF) patients. Long-term infection is associated with extensive genetic adaptation of P...... the framework upon which this thesis is based. Early P. aeruginosa colonization of the CF airways is the period in which the outcome of infection is determined, i.e. if the bacteria are eventually eradicated or persist. In three patient cases the evolutionary events from initiation of infection were explored...... to unravel the early adaptive processes possibly securing bacterial persistence. In this early stage, clinical isolates displayed few adaptive events however these included phenotypes often observed in late chronic infection isolates including the conversion to a mucoid phenotype and increased antibiotic...

Toll-like receptors as therapeutic targets in cystic fibrosis.

LENUS (Irish Health Repository)

Greene, Catherine M

2008-12-01

Background: Toll-like receptors (TLRs) are pattern recognition receptors that act as a first-line of defence in the innate immune response by recognising and responding to conserved molecular patterns in microbial factors and endogenous danger signals. Cystic fibrosis (CF)-affected airways represent a milieu potentially rich in TLR agonists and the chronic inflammatory phenotype evident in CF airway epithelial cells is probably due in large part to activation of TLRs. Objective\\/methods: To examine the prospects of developing novel therapies for CF by targeting TLRs. We outline the expression and function of TLRs and explore the therapeutic potential of naturally-occurring and synthetic TLR inhibitors for CF. Results\\/conclusion: Modulation of TLRs has therapeutic potential for the inflammatory lung manifestations of CF.

UP-TO-DATE MANAGEMENT OF LUNG DISEASE IN CHILDREN AND ADOLESCENTS WITH CYSTIC FIBROSIS

Directory of Open Access Journals (Sweden)

Marina Praprotnik

2015-04-01

Full Text Available Cystic fibrosis (CF is a multi-organ disease,  affecting mostly lungs and gastrointestinal tract. Data from patient registries show that the survival of patients with CF has progressively improved over the past several decades, as a result of advances in antibiotic treatment, supplementation of pancreatic enzymes, better nutrition and a holistic approach to treatment in CF centres.The purpose of this review is to survey recent developments in the treatment of lung disease  in children and adolescents with CF.We describe newborn screening for CF.When chronic respiratory insufficiency occurs, lung transplantation becomes a very important issue.Lung disease is the most common cause of morbidity and mortality in CF patients. Emerging new therapies are targeted at all points in the pathogenesis of lung disease, from drugs that treat infection and inflammation in the airways to gene transfer studies  and to drugs that augment airway surface liquid height. A number of antibacterial agents formulated for inhalation are at various stages of study and there are several anti-inflammatory candidate drugs in  clinical trials.  The most important development  in the recent years is  modulation of the abnormal protein that causes CF, the cystic fibrosis transmembrane regulator (CFTR, where drugs are targeted at specific defects in the transcription, processing or functioning.When chronic respiratory insufficiency occurs, lung transplantation becomes a very important issue. The role of the CF nurse, who has responsibilities in educating and teaching clinical skills to patients and families, is described.

Antioxidant supplementation for lung disease in cystic fibrosis

DEFF Research Database (Denmark)

Ciofu, Oana; Lykkesfeldt, Jens

2014-01-01

BACKGROUND: Airway infection leads to progressive damage of the lungs in cystic fibrosis and oxidative stress has been implicated in the etiology. Supplementation of antioxidant micronutrients (vitamin E, vitamin C, ß-carotene and selenium) or glutathione may therefore potentially help maintain...... COLLECTION AND ANALYSIS: Two authors independently selected studies, extracted data and assessed the risk of bias in the included studies. We contacted trial investigators to obtain missing information. Primary outcomes are lung function and quality of life; secondary outcomes are oxidative stress...... or by inhalation) appears to improve lung function in some cases and decrease oxidative stress; however, due to the very intensive antibiotic treatment and other treatments that cystic fibrosis patients receive, the beneficial effect of antioxidants is very difficult to assess in patients with chronic infection...

Opening up of plasmalemma type-1 VDAC to form apoptotic "find me signal" pathways is essential in early apoptosis - evidence from the pathogenesis of cystic fibrosis resulting from failure of apoptotic cell clearance followed by sterile inflammation.

Science.gov (United States)

Thinnes, Friedrich P

2014-04-01

Cell membrane-standing type-1 VDAC is involved in cell volume regulation and thus apoptosis. The channel has been shown to figure as a pathway for osmolytes of varying classes, ATP included. An early event in apoptotic cell death is the release of "find me signals" by cells that enter the apoptotic process. ATP is one of those signals. Apoptotic cells this way attract phagocytes for an immunologically silent cell clearance. Thus, whenever apoptosis fails by a blockade of plasmalemma type-1 VDAC processes of sterile inflammation must be assumed for cell elimination. This is evident from a close look on the pathogenetic process of cystic fibrosis (CF). However, in normal airway epithelia two different anion channels cooperate to guarantee an appropriate volume of airway surface liquid (ASL) necessary for surface clearing: the cystic fibrosis conductance regulator (CFTR) and the outwardly rectifying chloride channel (ORCC) complex also called "alternate chloride channel" and under the control of the CFTR. There are arguments, that type-1 VDAC forms the channel part of the ORCC complex, and it has been shown that CFTR and type-1 VDAC co-localize in the apical membranes of human surface respiratory epithelium. In cystic fibrosis, the central cAMP-dependent regulation of ion and water transport via functional CFTR is lost. Here, CFTR molecules do not reach the apical membranes of airway epithelia anymore or work in an insufficient way, respectively. In addition, type-1 VDAC is no longer available to work as a "find me signal" pathway. In consequence, clearing away of apoptotic cells is blocked. There are experimental data on the channel characteristics of type-1 VDAC under the anion channel blocker DIDS (4,4-diisothiocyanato-stilbenedisulphonic acid) that argue in favor of this hypothesis. Together, type-1 VDAC should be kept as a "find me signal" pathway, which may give way to several classes of such signals. Copyright © 2014 Elsevier Inc. All rights reserved.

In Vitro Activities against Cystic Fibrosis Pathogens of Synthetic Host Defence Propeptides Processed by Neutrophil Elastase.

LENUS (Irish Health Repository)

Desgranges, Stephane

2011-02-22

The antimicrobial and haemolytic activities of a host defence peptide can be controlled by modification as a propeptide of reduced net charge which can be processed by neutrophil elastase, a serine protease involved in chronic airway inflammation and infections associated with cystic fibrosis.

Antimicrobial resistance, respiratory tract infections and role of biofilms in lung infections in cystic fibrosis patients

DEFF Research Database (Denmark)

Ciofu, Oana; Tolker-Nielsen, Tim; Jensen, Peter Østrup

2015-01-01

Lung infection is the main cause of morbidity and mortality in patients with cystic fibrosis and is mainly dominated by Pseudomonas aeruginosa. The biofilm mode of growth makes eradication of the infection impossible, and it causes a chronic inflammation in the airways. The general mechanisms...

Idiopathic Pulmonary Fibrosis: A Genetic Disease That Involves Mucociliary Dysfunction of the Peripheral Airways

Science.gov (United States)

Evans, Christopher M.; Fingerlin, Tasha E.; Schwarz, Marvin I.; Lynch, David; Kurche, Jonathan; Warg, Laura; Yang, Ivana V.; Schwartz, David A.

2016-01-01

Idiopathic pulmonary fibrosis (IPF) is an incurable complex genetic disorder that is associated with sequence changes in 7 genes (MUC5B, TERT, TERC, RTEL1, PARN, SFTPC, and SFTPA2) and with variants in at least 11 novel loci. We have previously found that 1) a common gain-of-function promoter variant in MUC5B rs35705950 is the strongest risk factor (genetic and otherwise), accounting for 30-35% of the risk of developing IPF, a disease that was previously considered idiopathic; 2) the MUC5B promoter variant can potentially be used to identify individuals with preclinical pulmonary fibrosis and is predictive of radiologic progression of preclinical pulmonary fibrosis; and 3) MUC5B may be involved in the pathogenesis of pulmonary fibrosis with MUC5B message and protein expressed in bronchiolo-alveolar epithelia of IPF and the characteristic IPF honeycomb cysts. Based on these considerations, we hypothesize that excessive production of MUC5B either enhances injury due to reduced mucociliary clearance or impedes repair consequent to disruption of normal regenerative mechanisms in the distal lung. In aggregate, these novel considerations should have broad impact, resulting in specific etiologic targets, early detection of disease, and novel biologic pathways for use in the design of future intervention, prevention, and mechanistic studies of IPF. PMID:27630174

Blunted perception of neural respiratory drive and breathlessness in patients with cystic fibrosis

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Charles C. Reilly

2016-03-01

Full Text Available The electromyogram recorded from the diaphragm (EMGdi and parasternal intercostal muscle using surface electrodes (sEMGpara provides a measure of neural respiratory drive (NRD, the magnitude of which reflects lung disease severity in stable cystic fibrosis. The aim of this study was to explore perception of NRD and breathlessness in both healthy individuals and patients with cystic fibrosis. Given chronic respiratory loading and increased NRD in cystic fibrosis, often in the absence of breathlessness at rest, we hypothesised that patients with cystic fibrosis would be able to tolerate higher levels of NRD for a given level of breathlessness compared to healthy individuals during exercise. 15 cystic fibrosis patients (mean forced expiratory volume in 1 s (FEV1 53.5% predicted and 15 age-matched, healthy controls were studied. Spirometry was measured in all subjects and lung volumes measured in the cystic fibrosis patients. EMGdi and sEMGpara were recorded at rest and during incremental cycle exercise to exhaustion and expressed as a percentage of maximum (% max obtained from maximum respiratory manoeuvres. Borg breathlessness scores were recorded at rest and during each minute of exercise. EMGdi % max and sEMGpara % max and associated Borg breathlessness scores differed significantly between healthy subjects and cystic fibrosis patients at rest and during exercise. The relationship between EMGdi % max and sEMGpara % max and Borg score was shifted to the right in the cystic fibrosis patients, such that at comparable levels of EMGdi % max and sEMGpara % max the cystic fibrosis patients reported significantly lower Borg breathlessness scores compared to the healthy individuals. At Borg score 1 (clinically significant increase in breathlessness from baseline corresponding levels of EMGdi % max (20.2±12% versus 32.15±15%, p=0.02 and sEMGpara % max (18.9±8% versus 29.2±15%, p=0.04 were lower in the healthy individuals compared to the cystic

Changes of Proteases, Antiproteases, and Pathogens in Cystic Fibrosis Patients’ Upper and Lower Airways after IV-Antibiotic Therapy

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Ulrike Müller

2015-01-01

Full Text Available Background. In cystic fibrosis (CF the upper (UAW and lower airways (LAW are reservoirs for pathogens like Pseudomonas aeruginosa. The consecutive hosts’ release of proteolytic enzymes contributes to inflammation and progressive pulmonary destruction. Objectives were to assess dynamics of protease : antiprotease ratios and pathogens in CF-UAW and LAW sampled by nasal lavage (NL and sputum before and after intravenous- (IV- antibiotic therapy. Methods. From 19 IV-antibiotic courses of 17 CF patients NL (10 mL/nostril and sputum were collected before and after treatment. Microbiological colonization and concentrations of NE/SLPI/CTSS (ELISA and MMP-9/TIMP-1 (multiplex bead array were determined. Additionally, changes of sinonasal symptoms were assessed (SNOT-20. Results. IV-antibiotic treatment had more pronounced effects on inflammatory markers in LAW, whereas trends to decrease were also found in UAW. Ratios of MMP-9/TIMP-1 were higher in sputum, and ratios of NE/SLPI were higher in NL. Remarkably, NE/SLPI ratio was 10-fold higher in NL compared to healthy controls. SNOT-20 scores decreased significantly during therapy (P=0.001. Conclusion. For the first time, changes in microbiological patterns in UAW and LAW after IV-antibiotic treatments were assessed, together with changes of protease/antiprotease imbalances. Delayed responses of proteases and antiproteases to IV-antibiotic therapy were found in UAW compared to LAW.

Effects of puberty on cystic fibrosis related pulmonary exacerbations in women versus men.

Science.gov (United States)

Sutton, Shelby; Rosenbluth, Daniel; Raghavan, Deepa; Zheng, Jie; Jain, Raksha

2014-01-01

Epidemiologic data from studies of airway diseases, such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis indicate a gender disparity where women have worse outcomes. The explanation for this is largely unknown. We hypothesize that female sex hormones play a role in this gender disparity, predisposing women to more exacerbations and decreased lung function post-puberty. In Cystic Fibrosis, to determine if puberty marks a point of increasing exacerbations and decreasing lung function in women relative to men. Using the United States Cystic Fibrosis Foundation Patient Registry, we used linear regression to compare lung function and rate of pulmonary exacerbations in men versus women before and after puberty. Of 5,137 subjects who met inclusion criteria, 2,689 were male and 2,448 were female. Average age of puberty was found to be 13.2 ± 2.2 years in men and 11.2 ± 2.0 years of age in women. Percent predicted FEV1 pre- and post-puberty were no different between males versus females (P = 0.44 pre-puberty and P = 0.16 post-puberty). In contrast, women had a significantly higher rate of pulmonary exacerbations post-puberty than men (1.17 ± 1.35 exacerbations per year in women versus 0.95 ± 1.27 in men; P puberty, the rate of pulmonary exacerbations increased in adolescent women relative to men with cystic fibrosis, supporting a role for sex hormones in the disease process. Further understanding of the mechanisms that modulate sex hormone receptors in airway disease may serve as future targets for therapy. © 2013 Wiley Periodicals, Inc.

Nebulized hypertonic saline via positive expiratory pressure versus via jet nebulizer in patients with severe cystic fibrosis.

LENUS (Irish Health Repository)

O'Connell, Oisin J

2011-06-01

Nebulized hypertonic saline is a highly effective therapy for patients with cystic fibrosis (CF), yet 10% of patients are intolerant of hypertonic saline administered via jet nebulizer. Positive expiratory pressure (PEP) nebulizers splint open the airways and offers a more controlled rate of nebulization.

Claremount Nursing Home, Claremount, Claremorris, Mayo.

LENUS (Irish Health Repository)

Reeves, Emer P

2012-01-01

The pathogenesis of lung disease in cystic fibrosis is characterised by decreased airway surface liquid volume and subsequent failure of normal mucociliary clearance. Mucus within the cystic fibrosis airways is enriched in negatively charged matrices composed of DNA released from colonizing bacteria or inflammatory cells, as well as F-actin and elevated concentrations of anionic glycosaminoglycans. Therapies acting against airway mucus in cystic fibrosis include aerosolized hypertonic saline. It has been shown that hypertonic saline possesses mucolytic properties and aids mucociliary clearance by restoring the liquid layer lining the airways. However, recent clinical and bench-top studies are beginning to broaden our view on the beneficial effects of hypertonic saline, which now extend to include anti-infective as well as anti-inflammatory properties. This review aims to discuss the described therapeutic benefits of hypertonic saline and specifically to identify novel models of hypertonic saline action independent of airway hydration.

Adare and District Nursing Home, Croagh, Limerick.

LENUS (Irish Health Repository)

Reeves, Emer P

2012-01-01

The pathogenesis of lung disease in cystic fibrosis is characterised by decreased airway surface liquid volume and subsequent failure of normal mucociliary clearance. Mucus within the cystic fibrosis airways is enriched in negatively charged matrices composed of DNA released from colonizing bacteria or inflammatory cells, as well as F-actin and elevated concentrations of anionic glycosaminoglycans. Therapies acting against airway mucus in cystic fibrosis include aerosolized hypertonic saline. It has been shown that hypertonic saline possesses mucolytic properties and aids mucociliary clearance by restoring the liquid layer lining the airways. However, recent clinical and bench-top studies are beginning to broaden our view on the beneficial effects of hypertonic saline, which now extend to include anti-infective as well as anti-inflammatory properties. This review aims to discuss the described therapeutic benefits of hypertonic saline and specifically to identify novel models of hypertonic saline action independent of airway hydration.

Time for a change: is idiopathic pulmonary fibrosis still idiopathic and only fibrotic?

Science.gov (United States)

Wolters, Paul J; Blackwell, Timothy S; Eickelberg, Oliver; Loyd, James E; Kaminski, Naftali; Jenkins, Gisli; Maher, Toby M; Molina-Molina, Maria; Noble, Paul W; Raghu, Ganesh; Richeldi, Luca; Schwarz, Marvin I; Selman, Moises; Wuyts, Wim A; Schwartz, David A

2018-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and typically fatal lung disease characterised by subpleural fibrosis, subepithelial fibroblast foci, and microscopic honeycombing. Although understanding of the pathogenic mechanisms continues to evolve, evidence indicates that distal airway and alveolar epithelial cells are central drivers of the disease. In this Viewpoint, we review the history of naming and classifications used to define the disease now referred to as IPF, in the context of understanding the clinical presentation, causes, and pathogenesis of the disease. We aim to generate discussion on whether, given the substantial progress made in understanding the clinical, genetic, cellular, and molecular mechanisms involved in the development of IPF, a change of name should be considered. To initiate this discussion, we offer new suggestions to update the name of this disease and new approaches to classify all forms of pulmonary fibrosis. PMID:29413083

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.

In Vitro Microfluidic Models of Mucus-Like Obstructions in Small Airways

Science.gov (United States)

Mulligan, Molly K.; Grotberg, James B.; Sznitman, Josué

2012-11-01

Liquid plugs can form in the lungs as a result of a host of different diseases, including cystic fibrosis and chronic obstructive pulmonary disease. The existence of such fluid obstructions have been found as far down in the bronchiole tree as the sixteenth generation, where bronchiole openings have diameters on the order of a hundred to a few hundred microns. Understanding the propagation of liquid plugs within the bifurcating branches of bronchiole airways is important because their presence in the lungs, and their rupture and break-up, can cause injury to the epithelial cells lining the airway walls as a result of high wall shear stresses. In particular, liquid plug rupture and break-up frequently occurs at airway bifurcations. Until present, however, experimental studies of liquid plugs have generally been restricted to Newtonian fluids that do not reflect the actual pseudoplastic properties of lung mucus. The present work attempts to uncover the propagation, rupture and break-up of mucus-like liquid plugs in the lower generations of the airway tree using microfluidic models. Our approach allows the dynamics of mucus-like plug break-up to be studied in real-time, in a one-to-one in vitro model, as a function of mucus rheology and bronchial tree geometry.

The fate of inhaled antibiotics after deposition in cystic fibrosis: How to get drug to the bug?

Science.gov (United States)

Bos, Aukje C; Passé, Kimberly M; Mouton, Johan W; Janssens, Hettie M; Tiddens, Harm A W M

2017-01-01

Chronic airway infections in patients with cystic fibrosis (CF) are most often treated with inhaled antibiotics of which deposition patterns have been extensively studied. However, the journey of aerosol particles does not end after deposition within the bronchial tree. To review how local conditions affect the clinical efficacy of antibiotic aerosol particles after deposition in the airways of patients with CF. Electronic databases were searched from inception to September 2015. Original studies describing the effect of CF sputum or bacterial factors on antibiotic efficacy and formulations to increase efficacy were included. 35 articles were included which mostly described in vitro studies and mainly investigated aminoglycosides. After deposition, diffusion through the mucus layer was reduced for aminoglycosides, β-lactam antibiotics and fluoroquinolones. Within CF mucus, low oxygen tension adversely affected aminoglycosides, β-lactam antibiotics, and chloramphenicol; and molecules inactivated aminoglycosides but not β-lactam antibiotics. Finally, the alginate layer surrounding Pseudomonas aeruginosa was an important factor in the resistance against all antibiotics. After deposition in the airways, the local efficacy of inhaled antibiotics can be reduced by molecules within CF mucus and the alginate layer surrounding P. aeruginosa. Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

CYSTIC FIBROSIS: MICROBIOLOGY AND HOST RESPONSE

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Zemanick, Edith T.

2016-01-01

THE EARLIEST DESCRIPTIONS OF LUNG DISEASE IN PEOPLE WITH CYSTIC FIBROSIS (CF) DEMONSTRATED THE INVOLVEMENT OF THREE INTERACTING PATHOPHYSIOLOGICAL ELEMENTS IN CF AIRWAYS: MUCUS OBSTRUCTION, INFLAMMATION, AND INFECTION. OVER THE PAST 7 DECADES, OUR UNDERSTANDING OF CF RESPIRATORY MICROBIOLOGY AND INFLAMMATION HAS EVOLVED WITH THE INTRODUCTION OF NEW TREATMENTS, WITH INCREASED LONGEVITY, AND WITH INCREASINGLY SOPHISTICATED LABORATORY TECHNIQUES. IN THIS CHAPTER, WE WILL REVIEW THE CURRENT STATE OF UNDERSTANDING OF THE ROLES OF INFECTION AND INFLAMMATION AND THEIR ROLES IN DRIVING LUNG DISEASE. WE WILL ALSO DISCUSS HOW THIS CONSTANTLY EVOLVING INFORMATION IS USED TO INFORM CURRENT THERAPEUTIC STRATEGIES, MEASURES AND PREDICTORS OF DISEASE SEVERITY, AND RESEARCH PRIORITIES. PMID:27469179

Innovating cystic fibrosis clinical trial designs in an era of successful standard of care therapies.

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VanDevanter, Donald R; Mayer-Hamblett, Nicole

2017-11-01

Evolving cystic fibrosis 'standards of care' have influenced recent cystic fibrosis clinical trial designs for new therapies; care additions/improvements will require innovative trial designs to maximize feasibility and efficacy detection. Three cystic fibrosis therapeutic areas (pulmonary exacerbations, Pseudomonas aeruginosa airway infections, and reduced cystic fibrosis transmembrane conductance regulator [CFTR] protein function) differ with respect to the duration for which recognized 'standards of care' have been available. However, developers of new therapies in all the three areas are affected by similar challenges: standards of care have become so strongly entrenched that traditional placebo-controlled studies in cystic fibrosis populations likely to benefit from newer therapies have become less and less feasible. Today, patients/clinicians are more likely to entertain participation in active-comparator trial designs, that have substantial challenges of their own. Foremost among these are the selection of 'valid' active comparator(s), estimation of a comparator's current clinical efficacy (required for testing noninferiority hypotheses), and effective blinding of commercially available comparators. Recent and future cystic fibrosis clinical trial designs will have to creatively address this collateral result of successful past development of effective cystic fibrosis therapies: patients and clinicians are much less likely to accept simple, placebo-controlled studies to evaluate future therapies.

B cell activating factor is central to bleomycin- and IL-17-mediated experimental pulmonary fibrosis.

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François, Antoine; Gombault, Aurélie; Villeret, Bérengère; Alsaleh, Ghada; Fanny, Manoussa; Gasse, Paméla; Adam, Sylvain Marchand; Crestani, Bruno; Sibilia, Jean; Schneider, Pascal; Bahram, Seiamak; Quesniaux, Valérie; Ryffel, Bernhard; Wachsmann, Dominique; Gottenberg, Jacques-Eric; Couillin, Isabelle

2015-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive devastating, yet untreatable fibrotic disease of unknown origin. We investigated the contribution of the B-cell activating factor (BAFF), a TNF family member recently implicated in the regulation of pathogenic IL-17-producing cells in autoimmune diseases. The contribution of BAFF was assessed in a murine model of lung fibrosis induced by airway administered bleomycin. We show that murine BAFF levels were strongly increased in the bronchoalveolar space and lungs after bleomycin exposure. We identified Gr1(+) neutrophils as an important source of BAFF upon BLM-induced lung inflammation and fibrosis. Genetic ablation of BAFF or BAFF neutralization by a soluble receptor significantly attenuated pulmonary fibrosis and IL-1β levels. We further demonstrate that bleomycin-induced BAFF expression and lung fibrosis were IL-1β and IL-17A dependent. BAFF was required for rIL-17A-induced lung fibrosis and augmented IL-17A production by CD3(+) T cells from murine fibrotic lungs ex vivo. Finally we report elevated levels of BAFF in bronchoalveolar lavages from IPF patients. Our data therefore support a role for BAFF in the establishment of pulmonary fibrosis and a crosstalk between IL-1β, BAFF and IL-17A. Copyright © 2014 Elsevier Ltd. All rights reserved.

Functional and prognostic effects when emphysema complicates idiopathic pulmonary fibrosis.

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Jacob, Joseph; Bartholmai, Brian J; Rajagopalan, Srinivasan; Kokosi, Maria; Maher, Toby M; Nair, Arjun; Karwoski, Ronald; Renzoni, Elisabetta; Walsh, Simon L F; Hansell, David M; Wells, Athol U

2017-07-01

This study aimed to investigate whether the combination of fibrosis and emphysema has a greater effect than the sum of its parts on functional indices and outcome in idiopathic pulmonary fibrosis (IPF), using visual and computer-based (CALIPER) computed tomography (CT) analysis.Consecutive patients (n=272) with a multidisciplinary IPF diagnosis had the extent of interstitial lung disease (ILD) scored visually and by CALIPER. Visually scored emphysema was subcategorised as isolated or mixed with fibrotic lung. The CT scores were evaluated against functional indices forced vital capacity (FVC), diffusing capacity of the lungs for carbon monoxide ( D LCO ), transfer coefficient of the lung for carbon monoxide ( K CO ), composite physiologic index (CPI)) and mortality.The presence and extent of emphysema had no impact on survival. Results were maintained following correction for age, gender, smoking status and baseline severity using D LCO , and combined visual emphysema and ILD extent. Visual emphysema quantitation indicated that relative preservation of lung volumes (FVC) resulted from tractionally dilated airways within fibrotic lung, ventilating areas of admixed emphysema (pemphysema. Conversely, only isolated emphysema (pemphysema in IPF, beyond that explained by the additive extents of both fibrosis and emphysema. With respect to the location of pulmonary fibrosis, emphysema distribution determines the functional effects of emphysema. Copyright ©ERS 2017.

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.

Sputum Candida albicans presages FEV₁ decline and hospital-treated exacerbations in cystic fibrosis.

LENUS (Irish Health Repository)

Chotirmall, Sanjay H

2010-11-01

The role of Candida albicans in the cystic fibrosis (CF) airway is underexplored. Considered a colonizer, few question its pathogenic potential despite high isolation frequencies from sputum culture. We evaluated the frequency and identified the strongest predictors of C albicans colonization in CF. Independent associations of colonization with clinical outcomes were determined, and the longitudinal effects of C albicans acquisition on BMI and FEV₁ were evaluated.

[Normal lung volumes in patients with idiopathic pulmonary fibrosis and emphysema].

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Casas, Juan Pablo; Abbona, Horacio; Robles, Adriana; López, Ana María

2008-01-01

Pulmonary function tests in idiopathic pulmonary fibrosis characteristically show a restrictive pattern, resulting from reduction of pulmonary compliance due to diffuse fibrosis. Conversely, an obstructive pattern with hyperinflation results in emphysema by loss of elastic recoil, expiratory collapse of the peripheral airways and air trapping. Previous reports suggest that when both diseases coexist, pulmonary volumes are compensated and a smaller than expected reduction or even normal lung volumes can be found. We report 4 male patients of 64, 60, 73 and 70 years, all with heavy cigarette smoking history and progressive breathlessness. Three of them had severe limitation in their quality of life. All four showed advanced lung interstitial involvement, at high resolution CT scan, fibrotic changes predominantly in the subpleural areas of lower lung fields and concomitant emphysema in the upper lobes. Emphysema and pulmonary fibrosis was confirmed by open lung biopsy in one patient. The four patients showed normal spirometry and lung volumes with severe compromise of gas exchange and poor exercise tolerance evaluated by 6 minute walk test. Severe pulmonary arterial hypertension was also confirmed in three patients. Normal lung volumes does not exclude diagnosis of idiopathic pulmonary fibrosis in patients with concomitant emphysema. The relatively preserved lung volumes may underestimate the severity of idiopathic pulmonary fibrosis and attenuate its effects on lung function parameters.

Evolution and Pathoadaptation of Pseudomonas aeruginosa in Cystic Fibrosis Patients

DEFF Research Database (Denmark)

Marvig, Rasmus Lykke

, which is a transmissible clone isolated from chronically infected Danish CF patients over a period of 38 years. Whole-genome analysis of DK2 isolates enabled a finegrained reconstruction of the recent evolutionary history of the DK2 lineage and an identification of bacterial genes targeted by mutations...... to optimize pathogen fitness. The identification of such pathoadaptive genes gives new insight into how the pathogen evolves under the selective pressures of the host immune system and drug therapies. Furthermore, isolates with increased rates of mutation (hypermutator phenotype) emerged in the DK lineage...... is the dominating pathogen of chronic airway infections in patients with cystic fibrosis (CF), and the bacterial long-term persistence in CF hosts involves mutation and selection of genetic variants with increased fitness in the CF airways. We performed a retrospective study of the P. aeruginosa DK2 clone type...

Effective silencing of ENaC by siRNA delivered with epithelial-targeted nanocomplexes in human cystic fibrosis cells and in mouse lung.

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Tagalakis, Aristides D; Munye, Mustafa M; Ivanova, Rositsa; Chen, Hanpeng; Smith, Claire M; Aldossary, Ahmad M; Rosa, Luca Z; Moulding, Dale; Barnes, Josephine L; Kafetzis, Konstantinos N; Jones, Stuart A; Baines, Deborah L; Moss, Guy W J; O'Callaghan, Christopher; McAnulty, Robin J; Hart, Stephen L

2018-05-10

Loss of the cystic fibrosis transmembrane conductance regulator in cystic fibrosis (CF) leads to hyperabsorption of sodium and fluid from the airway due to upregulation of the epithelial sodium channel (ENaC). Thickened mucus and depleted airway surface liquid (ASL) then lead to impaired mucociliary clearance. ENaC regulation is thus a promising target for CF therapy. Our aim was to develop siRNA nanocomplexes that mediate effective silencing of airway epithelial ENaC in vitro and in vivo with functional correction of epithelial ion and fluid transport. We investigated translocation of nanocomplexes through mucus and their transfection efficiency in primary CF epithelial cells grown at air-liquid interface (ALI).Short interfering RNA (SiRNA)-mediated silencing was examined by quantitative RT-PCR and western analysis of ENaC. Transepithelial potential (V t ), short circuit current (I sc ), ASL depth and ciliary beat frequency (CBF) were measured for functional analysis. Inflammation was analysed by histological analysis of normal mouse lung tissue sections. Nanocomplexes translocated more rapidly than siRNA alone through mucus. Transfections of primary CF epithelial cells with nanocomplexes targeting αENaC siRNA, reduced αENaC and βENaC mRNA by 30%. Transfections reduced V t , the amiloride-sensitive I sc and mucus protein concentration while increasing ASL depth and CBF to normal levels. A single dose of siRNA in mouse lung silenced ENaC by approximately 30%, which persisted for at least 7 days. Three doses of siRNA increased silencing to approximately 50%. Nanoparticle-mediated delivery of ENaCsiRNA to ALI cultures corrected aspects of the mucociliary defect in human CF cells and offers effective delivery and silencing in vivo. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

The HDAC inhibitor SAHA does not rescue CFTR membrane expression in Cystic Fibrosis.

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Bergougnoux, Anne; Petit, Aurélie; Knabe, Lucie; Bribes, Estelle; Chiron, Raphaël; De Sario, Albertina; Claustres, Mireille; Molinari, Nicolas; Vachier, Isabelle; Taulan-Cadars, Magali; Bourdin, Arnaud

2017-07-01

The development of suitable Cystic Fibrosis (CF) models for preclinical bench tests of therapeutic candidates is challenging. Indeed, the validation of molecules to rescue the p.Phe508del-CFTR channel (encoded by the Cystic Fibrosis Transmembrane conductance Regulator gene carrying the p.Phe508del mutation) requires taking into account their overall effects on the epithelium. Suberoylanilide Hydroxamic Acid (SAHA), a histone deacetylase inhibitor (HDACi), was previously shown to be a CFTR corrector via proteostasis modulation in CFTR-deficient immortalized cells. Here, we tested SAHA effects on goblet cell metaplasia using an ex vivo model based on the air-liquid interface (ALI) culture of differentiated airway epithelial cells obtained by nasal scraping from CF patients and healthy controls. Ex vivo epithelium grew successfully in ALI cultures with significant rise in the expression of CFTR and of markers of airway epithelial differentiation compared to monolayer cell culture. SAHA decreased CFTR transcript and protein levels in CF and non-CF epithelia. Whereas SAHA induced lysine hyperacetylation, it did not change histone modifications at the CFTR promoter. SAHA reduced MUC5AC and MUC5B expression and inhibited goblet epithelial cell differentiation. Similar effects were obtained in CF and non-CF epithelia. All the effects were fully reversible within five days from SAHA withdrawal. We conclude that, ex vivo, SAHA modulate the structure of airway epithelia without specific effect on CFTR gene and protein suggesting that HDACi cannot be useful for CF treatment. Copyright © 2017. Published by Elsevier Ltd.

Bergamot (Citrus bergamia Risso) fruit extracts and identified components alter expression of interleukin 8 gene in cystic fibrosis bronchial epithelial cell lines

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2011-01-01

Background Cystic fibrosis (CF) airway pathology is a fatal, autosomal, recessive genetic disease characterized by extensive lung inflammation. After induction by TNF-α, elevated concentrations of several pro-inflammatory cytokines (i.e. IL-6, IL-1β) and chemokines (i.e. IL-8) are released from airway epithelial cells. In order to reduce the excessive inflammatory response in the airways of CF patients, new therapies have been developed and in this respect, medicinal plant extracts have been studied. In this article we have investigated the possible use of bergamot extracts (Citrus bergamia Risso) and their identified components to alter the expression of IL-8 associated with the cystic fibrosis airway pathology. Methods The extracts were chemically characterized by 1H-NMR (nuclear magnetic resonance), GC-FID (gas chromatography-flame ionization detector), GC-MS (gas chromatography-mass spectrometry) and HPLC (high pressure liquid chromatography). Both bergamot extracts and main detected chemical constituents were assayed for their biological activity measuring (a) cytokines and chemokines in culture supernatants released from cystic fibrosis IB3-1 cells treated with TNF-α by Bio-Plex cytokine assay; (b) accumulation of IL-8 mRNA by real-time PCR. Results The extracts obtained from bergamot (Citrus bergamia Risso) epicarps contain components displaying an inhibitory activity on IL-8. Particularly, the most active molecules were bergapten and citropten. These effects have been confirmed by analyzing mRNA levels and protein release in the CF cellular models IB3-1 and CuFi-1 induced with TNF-α or exposed to heat-inactivated Pseudomonas aeruginosa. Conclusions These obtained results clearly indicate that bergapten and citropten are strong inhibitors of IL-8 expression and could be proposed for further studies to verify possible anti-inflammatory properties to reduce lung inflammation in CF patients. PMID:21496221

Cordyceps sinensis inhibits airway remodeling in rats with chronic obstructive pulmonary disease.

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Yang, Lei; Jiao, Xingai; Wu, Jinxiang; Zhao, Jiping; Liu, Tian; Xu, Jianfeng; Ma, Xiaohui; Cao, Liuzao; Liu, Lin; Liu, Yahui; Chi, Jingyu; Zou, Minfang; Li, Shuo; Xu, Jiawei; Dong, Liang

2018-03-01

Cordyceps sinensis is a traditional Chinese herbal medicine that has been used for centuries in Asia as a tonic to soothe the lung for the treatment of respiratory diseases. The aim of the present study was to determine the effects of C. sinensi s on airway remodeling in chronic obstructive pulmonary disease (COPD) and investigate the underlying molecular mechanisms. Rats with COPD were orally administered C. sinensis at low, moderate or high doses (2.5, 5 or 7.5 g/kg/day, respectively) for 12 weeks. Airway tissue histopathology, lung inflammation and airway remodeling were evaluated. C. sinensis treatment significantly ameliorated airway wall thickening, involving collagen deposition, airway wall fibrosis, smooth muscle hypertrophy and epithelial hyperplasia in model rats with COPD. Additionally, C. sinensis administration in rats with COPD reduced inflammatory cell accumulation and decreased inflammatory cytokine production, including tumor necrosis factor-α, interleukin-8 and transforming growth factor (TGF)-β1 in bronchoalveolar lavage fluid. Meanwhile, the increased levels of α-smooth muscle actin and collagen I in the COPD group were also markedly decreased by C. sinensis treatment. Furthermore, compared with untreated rats with COPD, C. sinensis reduced the expression level of phosphorylated (p)-Smad2, p-Smad3, TGF-β1 and its receptors, with the concomitant increased expression of Smad7 in the lungs of rats with COPD. These results indicated that treatment with C. sinensis may be a useful approach for COPD therapy.

Tissue engineering and the use of stem/progenitor cells for airway epithelium repair

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GM Roomans

2010-06-01

Full Text Available Stem/progenitor cells can be used to repair defects in the airway wall, resulting from e.g., tumors, trauma, tissue reactions following long-time intubations, or diseases that are associated with epithelial damage. Several potential sources of cells for airway epithelium have been identified. These can be divided into two groups. The first group consists of endogenous progenitor cells present in the respiratory tract. This group can be subdivided according to location into (a a ductal cell type in the submucosal glands of the proximal trachea, (b basal cells in the intercartilaginous zones of the lower trachea and bronchi, (c variant Clara cells (Clarav-cells in the bronchioles and (d at the junctions between the bronchioles and the alveolar ducts, and (e alveolar type II cells. This classification of progenitor cell niches is, however, controversial. The second group consists of exogenous stem cells derived from other tissues in the body. This second group can be subdivided into: (a embryonic stem (ES cells, induced pluripotent stem (iPS cells, or amniotic fluid stem cells, (b side-population cells from bone marrow or epithelial stem cells present in bone marrow or circulation and (c fat-derived mesenchymal cells. Airway epithelial cells can be co-cultured in a system that includes a basal lamina equivalent, extracellular factors from mesenchymal fibroblasts, and in an air-liquid interface system. Recently, spheroid-based culture systems have been developed. Several clinical applications have been suggested: cystic fibrosis, acute respiratory distress syndrome, chronic obstructive lung disease, pulmonary fibrosis, pulmonary edema, and pulmonary hypertension. Clinical applications so far are few, but include subglottic stenosis, tracheomalacia, bronchiomalacia, and emphysema.

From single cilia to collective waves in human airway ciliated tissues

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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.

A novel telomerase activator suppresses lung damage in a murine model of idiopathic pulmonary fibrosis.

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Le Saux, Claude Jourdan; Davy, Philip; Brampton, Christopher; Ahuja, Seema S; Fauce, Steven; Shivshankar, Pooja; Nguyen, Hieu; Ramaseshan, Mahesh; Tressler, Robert; Pirot, Zhu; Harley, Calvin B; Allsopp, Richard

2013-01-01

The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2-4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L), a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC) or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis.

Characteristic patterns in the fibrotic lung. Comparing idiopathic pulmonary fibrosis with chronic lung allograft dysfunction.

Science.gov (United States)

Fernandez, Isis E; Heinzelmann, Katharina; Verleden, Stijn; Eickelberg, Oliver

2015-03-01

Tissue fibrosis, a major cause of death worldwide, leads to significant organ dysfunction in any organ of the human body. In the lung, fibrosis critically impairs gas exchange, tissue oxygenation, and immune function. Idiopathic pulmonary fibrosis (IPF) is the most detrimental and lethal fibrotic disease of the lung, with an estimated median survival of 50% after 3-5 years. Lung transplantation currently remains the only therapeutic alternative for IPF and other end-stage pulmonary disorders. Posttransplant lung function, however, is compromised by short- and long-term complications, most importantly chronic lung allograft dysfunction (CLAD). CLAD affects up to 50% of all transplanted lungs after 5 years, and is characterized by small airway obstruction with pronounced epithelial injury, aberrant wound healing, and subepithelial and interstitial fibrosis. Intriguingly, the mechanisms leading to the fibrotic processes in the engrafted lung exhibit striking similarities to those in IPF; therefore, antifibrotic therapies may contribute to increased graft function and survival in CLAD. In this review, we focus on these common fibrosis-related mechanisms in IPF and CLAD, comparing and contrasting clinical phenotypes, the mechanisms of fibrogenesis, and biomarkers to monitor, predict, or prognosticate disease status.

Activation of angiotensin-converting enzyme 2 (ACE2) attenuates allergic airway inflammation in rat asthma model

International Nuclear Information System (INIS)

Dhawale, Vaibhav Shrirang; Amara, Venkateswara Rao; Karpe, Pinakin Arun; Malek, Vajir; Patel, Deep; Tikoo, Kulbhushan

2016-01-01

Angiotensin-I converting enzyme (ACE) is positively correlated to asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and is highly expressed in lungs. ACE2, the counteracting enzyme of ACE, was proven to be protective in pulmonary, cardiovascular diseases. In the present study we checked the effect of ACE2 activation in animal model of asthma. Asthma was induced in male wistar rats by sensitization and challenge with ovalbumin and then treated with ACE2 activator, diminazene aceturate (DIZE) for 2 weeks. 48 h after last allergen challenge, animals were anesthetized, blood, BALF, femoral bone marrow lavage were collected for leucocyte count; trachea for measuring airway responsiveness to carbachol; lungs and heart were isolated for histological studies and western blotting. In our animal model, the characteristic features of asthma such as altered airway responsiveness to carbachol, eosinophilia and neutrophilia were observed. Western blotting revealed the increased pulmonary expression of ACE1, IL-1β, IL-4, NF-κB, BCL2, p-AKT, p-p38 and decreased expression of ACE2 and IκB. DIZE treatment prevented these alterations. Intraalveolar interstitial thickening, inflammatory cell infiltration, interstitial fibrosis, oxidative stress and right ventricular hypertrophy in asthma control animals were also reversed by DIZE treatment. Activation of ACE2 by DIZE conferred protection against asthma as evident from biochemical, functional, histological and molecular parameters. To the best of our knowledge, we report for the first time that activation of ACE2 by DIZE prevents asthma progression by altering AKT, p38, NF-κB and other inflammatory markers. - Highlights: • Diminazene aceturate (DIZE), an ACE2 activator prevents ovalbumin-induced asthma. • DIZE acted by upregulating ACE2, downregulating ACE1, MAPKs, markers of inflammation, apoptosis. • DIZE reduced airway inflammation, fibrosis, right ventricular hypertrophy and

Activation of angiotensin-converting enzyme 2 (ACE2) attenuates allergic airway inflammation in rat asthma model

Energy Technology Data Exchange (ETDEWEB)

Dhawale, Vaibhav Shrirang; Amara, Venkateswara Rao; Karpe, Pinakin Arun; Malek, Vajir; Patel, Deep; Tikoo, Kulbhushan, E-mail: tikoo.k@gmail.com

2016-09-01

Angiotensin-I converting enzyme (ACE) is positively correlated to asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and is highly expressed in lungs. ACE2, the counteracting enzyme of ACE, was proven to be protective in pulmonary, cardiovascular diseases. In the present study we checked the effect of ACE2 activation in animal model of asthma. Asthma was induced in male wistar rats by sensitization and challenge with ovalbumin and then treated with ACE2 activator, diminazene aceturate (DIZE) for 2 weeks. 48 h after last allergen challenge, animals were anesthetized, blood, BALF, femoral bone marrow lavage were collected for leucocyte count; trachea for measuring airway responsiveness to carbachol; lungs and heart were isolated for histological studies and western blotting. In our animal model, the characteristic features of asthma such as altered airway responsiveness to carbachol, eosinophilia and neutrophilia were observed. Western blotting revealed the increased pulmonary expression of ACE1, IL-1β, IL-4, NF-κB, BCL2, p-AKT, p-p38 and decreased expression of ACE2 and IκB. DIZE treatment prevented these alterations. Intraalveolar interstitial thickening, inflammatory cell infiltration, interstitial fibrosis, oxidative stress and right ventricular hypertrophy in asthma control animals were also reversed by DIZE treatment. Activation of ACE2 by DIZE conferred protection against asthma as evident from biochemical, functional, histological and molecular parameters. To the best of our knowledge, we report for the first time that activation of ACE2 by DIZE prevents asthma progression by altering AKT, p38, NF-κB and other inflammatory markers. - Highlights: • Diminazene aceturate (DIZE), an ACE2 activator prevents ovalbumin-induced asthma. • DIZE acted by upregulating ACE2, downregulating ACE1, MAPKs, markers of inflammation, apoptosis. • DIZE reduced airway inflammation, fibrosis, right ventricular hypertrophy and

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

Aerosolized recombinant human DNase I for the treatment of cystic fibrosis.

Science.gov (United States)

Shak, S

1995-02-01

Respiratory symptoms, recurrent infectious exacerbations, and progressive lung destruction in cystic fibrosis can be attributed to bacterial persistence and the accumulation of viscous purulent secretions in the airways. Purulent secretions contain high concentrations of extracellular DNA, a viscous material released by leukocytes. To evaluate the potential clinical utility of recombinant human DNase I (rhDNase or Pulmozyme), the human enzyme was cloned, sequenced, and expressed. In in vitro studies, rhDNase has been shown to reduce the viscoelasticity, reduce the adhesiveness, and improve the mucociliary transportability of cystic fibrosis sputum. In short-term phase 1 and phase 2 clinical trials, rhDNase has been shown to be safely tolerated and to improve the FEV1, FVC, and symptoms of dyspnea. A long-term placebo-controlled phase 3 study was performed in 968 adults and children (> or = 5 years) with cystic fibrosis to determine the effect of rhDNase on the risk of respiratory exacerbations requiring parenteral antibiotics and on the FEV1. Compared with placebo-treated patients, patients treated with rhDNase once daily or twice daily experienced a reduced risk of respiratory exacerbations by 28% (p = 0.04) and 37% (p = 0.01), respectively, and had a mean improvement in FEV1 of 5.8% (p < 0.01) and 5.6% (p < 0.01), respectively. Compared with placebo-treated patients, patients treated with rhDNase spent 2.7 fewer days receiving parenteral antibiotics (p = 0.04) and spent 1.3 fewer days in the hospital (p = 0.06) over the 6-month treatment period. Inhalation of rhDNase did not cause anaphylaxis but was associated with upper airway symptoms (ie, voice alteration, hoarseness, pharyngitis) that were generally mild and transient. In conclusion, aerosol administration of rhDNase was safely tolerated, reduced the risk of infectious exacerbations requiring parenteral antibiotics, and improved pulmonary function and patient well-being.

Molecular epidemiology of Aspergillus collected from cystic fibrosis patients.

Science.gov (United States)

Sabino, Raquel; Ferreira, Jose A G; Moss, Richard B; Valente, Joana; Veríssimo, Cristina; Carolino, Elisabete; Clemons, Karl V; Everson, Cassie; Banaei, Niaz; Penner, John; Stevens, David A

2015-07-01

Aspergillus respiratory infection is a common complication in cystic fibrosis (CF) and is associated with loss of pulmonary function and allergic disease. Fifty-three Aspergillus isolates recovered from CF patients were identified to species by Internal Transcribed Spacer Region (ITS), β-tubulin, and calmodulin sequencing. Three species complexes (Terrei, Nigri, and Fumigati) were found. Identification to species level gave a single Aspergillus terreus sensu stricto, one Aspergillus niger sensu stricto and 51 Aspergillus fumigatus sensu stricto isolates. No cryptic species were found. To our knowledge, this is the first prospective study of Aspergillus species in CF using molecular methods. The paucity of non-A. fumigatus and of cryptic species of A. fumigatus suggests a special association of A. fumigatus sensu stricto with CF airways, indicating it likely displays unique characteristics making it suitable for chronic residence in that milieu. These findings could refine an epidemiologic and therapeutic approach geared to this pathogen. Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

[Manual airway clearance techniques in adults and adolescents: What level of evidence?

Science.gov (United States)

Cabillic, Michel; Gouilly, Pascal; Reychler, Gregory

2016-04-13

The aim of this systematic literature review was to grade the levels of evidence of the most widely used manual airway clearance techniques. A literature search was conducted over the period 1995-2014 from the Medline, PEDro, ScienceDirect, Cochrane Library, REEDOC and kinedoc databases, with the following keywords: "postural drainage", "manual vibrations", "manual chest percussion", "directed cough", "increased expiratory flow", "ELTGOL", "autogenic drainage" and "active cycle of breathing technique". Two-hundred and fifty-six articles were identified. After removing duplicates and reading the titles and abstracts, 63 articles were selected, including 9 systematic reviews. This work highlights the lack of useful scientific data and the difficulty of determining levels of evidence for manual airway clearance techniques. Techniques were assessed principally with patients with sputum production (cystic fibrosis, DDB, COPD, etc.). It also shows the limited pertinence of outcome measures to quantify congestion and hence the efficacy of airway clearance techniques. The 1994 consensus conference summary table classifying airway clearance techniques according to physical mechanism provides an interesting tool for assessment, grouping together techniques having identical mechanisms of action. From the findings of the present systematic review, it appears that only ELTGOL, autogenic drainage and ACBT present levels of evidence "B". All other techniques have lower levels of evidence. II. Copyright © 2016. Published by Elsevier Masson SAS.

Factors associated with worse lung function in cystic fibrosis patients with persistent staphylococcus aureus

OpenAIRE

Junge, S. (Sibylle); Görlich, D. (Dennis); Reijer, M.D. (Martijn Den); Wiedemann, Baerbel; Tümmler, Burkhard; Ellemunter, H.; Dübbers, A. (Angelika); Küster, P. (Peter); Ballmann, M.; Koerner-Rettberg, C. (Cordula); Große-Onnebrink, J. (Jörg); Heuer, E. (Eberhardt); Sextro, W. (Wolfgang); Mainz, J.G. (Jochen G.); Hammermann, J. (Jutta)

2016-01-01

textabstractBackground Staphylococcus aureus is an important pathogen in cystic fibrosis (CF). However, it is not clear which factors are associated with worse lung function in patients with persistent S. aureus airway cultures. Our main hypothesis was that patients with high S. aureus density in their respiratory specimens would more likely experience worsening of their lung disease than patients with low bacterial loads. Methods Therefore, we conducted an observational prospective longitudi...

Volumetric capnography for the evaluation of pulmonary disease in adult patients with cystic fibrosis and noncystic fibrosis bronchiectasis.

Science.gov (United States)

Veronez, L; Moreira, M M; Soares, S T P; Pereira, M C; Ribeiro, M A G O; Ribeiro, J D; Terzi, R G G; Martins, L C; Paschoal, I A

2010-06-01

This study was designed to use volumetric capnography to evaluate the breathing pattern and ventilation inhomogeneities in patients with chronic sputum production and bronchiectasis and to correlate the phase 3 slope of the capnographic curve to spirometric measurements. Twenty-four patients with cystic fibrosis (CF) and 21 patients with noncystic fibrosis idiopathic bronchiectasis (BC) were serially enrolled. The diagnosis of cystic fibrosis was based on the finding of at least two abnormal sweat chloride concentrations (iontophoresis sweat test). The diagnosis of bronchiectasis was made when the patient had a complaint of chronic sputum production and compatible findings at high-resolution computed tomography (HRCT) scan of the thorax. Spirometric tests and volumetric capnography were performed. The 114 subjects of the control group for capnographic variables were nonsmoker volunteers, who had no respiratory symptoms whatsoever and no past or present history of lung disease. Compared with controls, patients in CF group had lower SpO(2) (P volumes normalized for weight (V(E)/kg) (P volume (P3Slp/V(E)) (P capacities and both groups had very similar abnormalities. The capnographic variables in the patient group suggest a restrictive respiratory pattern (greater respiratory rates, smaller expiratory times and expiratory volumes, normal peak expiratory flows). Both groups of patients showed increased phase III slopes compared with controls, which probably indicates the presence of diffuse disease of small airways in both conditions leading to inhomogeneities of ventilation.

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.

Science.gov (United States)

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.

Rnaseq As A Method To Study Microbial Interactions Arising In The Cystic Fibrosis Airways

DEFF Research Database (Denmark)

Amador Hierro, Cristina Isabel; Jelsbak, Lars

2015-01-01

Introduction: In previous studies from our laboratory, a Pseudomonas aeruginosa lineage, named DK2, has been identified and characterized as highly successful, transmissible and persistent over four decades in cystic fibrosis (CF) patients. This lineage underwent substantial phenotypic and geneti...

Gene therapy in cystic fibrosis.

Science.gov (United States)

Flotte, T R; Laube, B L

2001-09-01

Theoretically, cystic fibrosis transmembrane conductance regulator (CFTR) gene replacement during the neonatal period can decrease morbidity and mortality from cystic fibrosis (CF). In vivo gene transfers have been accomplished in CF patients. Choice of vector, mode of delivery to airways, translocation of genetic information, and sufficient expression level of the normalized CFTR gene are issues that currently are being addressed in the field. The advantages and limitations of viral vectors are a function of the parent virus. Viral vectors used in this setting include adenovirus (Ad) and adeno-associated virus (AAV). Initial studies with Ad vectors resulted in a vector that was efficient for gene transfer with dose-limiting inflammatory effects due to the large amount of viral protein delivered. The next generation of Ad vectors, with more viral coding sequence deletions, has a longer duration of activity and elicits a lesser degree of cell-mediated immunity in mice. A more recent generation of Ad vectors has no viral genes remaining. Despite these changes, the problem of humoral immunity remains with Ad vectors. A variety of strategies such as vector systems requiring single, or widely spaced, administrations, pharmacologic immunosuppression at administration, creation of a stealth vector, modification of immunogenic epitopes, or tolerance induction are being considered to circumvent humoral immunity. AAV vectors have been studied in animal and human models. They do not appear to induce inflammatory changes over a wide range of doses. The level of CFTR messenger RNA expression is difficult to ascertain with AAV vectors since the small size of the vector relative to the CFTR gene leaves no space for vector-specific sequences on which to base assays to distinguish endogenous from vector-expressed messenger RNA. In general, AAV vectors appear to be safe and have superior duration profiles. Cationic liposomes are lipid-DNA complexes. These vectors generally have been

Factors Associated with Worse Lung Function in Cystic Fibrosis Patients with Persistent Staphylococcus aureus

OpenAIRE

Junge, Sibylle; G?rlich, Dennis; den Reijer, Martijn; Wiedemann, B?rbel; T?mmler, Burkhard; Ellemunter, Helmut; D?bbers, Angelika; K?ster, Peter; Ballmann, Manfred; Koerner-Rettberg, Cordula; Gro?e-Onnebrink, J?rg; Heuer, Eberhardt; Sextro, Wolfgang; Mainz, Jochen G.; Hammermann, Jutta

2016-01-01

Background Staphylococcus aureus is an important pathogen in cystic fibrosis (CF). However, it is not clear which factors are associated with worse lung function in patients with persistent S. aureus airway cultures. Our main hypothesis was that patients with high S. aureus density in their respiratory specimens would more likely experience worsening of their lung disease than patients with low bacterial loads. Methods Therefore, we conducted an observational prospective longitudinal multi-ce...

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...

Serelaxin as a novel therapeutic opposing fibrosis and contraction in lung diseases.

Science.gov (United States)

Lam, Maggie; Royce, Simon G; Samuel, Chrishan S; Bourke, Jane E

2018-07-01

The most common therapies for asthma and other chronic lung diseases are anti-inflammatory agents and bronchodilators. While these drugs oppose disease symptoms, they do not reverse established structural changes in the airways and their therapeutic efficacy is reduced with increasing disease severity. The peptide hormone, relaxin, is a Relaxin Family Peptide Receptor 1 (RXFP1) receptor agonist with unique combined effects in the lung that differentiates it from these existing therapies. Relaxin has previously been reported to have cardioprotective effects in acute heart failure as well anti-fibrotic actions in several organs. This review focuses on recent experimental evidence of the beneficial effects of chronic relaxin treatment in animal models of airways disease demonstrating inhibition of airway hyperresponsiveness and reversal of established fibrosis, consistent with potential therapeutic benefit. Of particular interest, accumulating evidence demonstrates that relaxin can also acutely oppose contraction by reducing the release of mast cell-derived bronchoconstrictors and by directly eliciting bronchodilation. When used in combination, chronic and acute treatment with relaxin has been shown to enhance responsiveness to both glucocorticoids and β 2 -adrenoceptor agonists respectively. While the mechanisms underlying these beneficial actions remain to be fully elucidated, translation of these promising combined preclinical findings is critical in the development of relaxin as a novel alternative or adjunct therapeutic opposing multiple aspects of airway pathology in lung diseases. Copyright © 2018 Elsevier Inc. All rights reserved.

Airway ciliary dysfunction and respiratory symptoms in patients with transposition of the great arteries.

Science.gov (United States)

Zahid, Maliha; Bais, Abha; Tian, Xin; Devine, William; Lee, Dong Ming; Yau, Cyrus; Sonnenberg, Daniel; Beerman, Lee; Khalifa, Omar; Lo, Cecilia W

2018-01-01

Our prior work on congenital heart disease (CHD) with heterotaxy, a birth defect involving randomized left-right patterning, has shown an association of a high prevalence of airway ciliary dysfunction (CD; 18/43 or 42%) with increased respiratory symptoms. Furthermore, heterotaxy patients with ciliary dysfunction were shown to have more postsurgical pulmonary morbidities. These findings are likely a reflection of the common role of motile cilia in both airway clearance and left-right patterning. As CHD comprising transposition of the great arteries (TGA) is commonly thought to involve disturbance of left-right patterning, especially L-TGA with left-right ventricular inversion, we hypothesize CHD patients with transposition of great arteries (TGA) may have high prevalence of airway CD with increased respiratory symptoms. We recruited 75 CHD patients with isolated TGA, 28% L and 72% D-TGA. Patients were assessed using two tests typically used for evaluating airway ciliary dysfunction in patients with primary ciliary dyskinesia (PCD), a recessive sinopulmonary disease caused by respiratory ciliary dysfunction. This entailed the measurement of nasal nitric oxide (nNO), which is typically low with PCD. We also obtained nasal scrapes and conducted videomicroscopy to assess respiratory ciliary motion (CM). We observed low nNO in 29% of the patients, and abnormal CM in 57%, with 22% showing both low nNO and abnormal CM. No difference was observed for the prevalence of either low nNO or abnormal ciliary motion between patients with D vs. L-TGA. Respiratory symptoms were increased with abnormal CM, but not low nNO. Sequencing analysis showed no compound heterozygous or homozygous mutations in 39 genes known to cause PCD, nor in CFTR, gene causing cystic fibrosis. As both are recessive disorders, these results indicate TGA patients with ciliary dysfunction do not have PCD or cystic fibrosis (which can cause low nNO or abnormal ciliary motion). TGA patients have high

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

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.

Science.gov (United States)

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.

Simvastatin Inhibits Goblet Cell Hyperplasia and Lung Arginase in a Mouse Model of Allergic Asthma: A Novel Treatment for Airway Remodeling?

Science.gov (United States)

Zeki, Amir A.; Bratt, Jennifer M.; Rabowsky, Michelle; Last, Jerold A.; Kenyon, Nicholas J.

2010-01-01

Airway remodeling in asthma contributes to airway hyperreactivity, loss of lung function, and persistent symptoms. Current therapies do not adequately treat the structural airway changes associated with asthma. The statins are cholesterol-lowering drugs that inhibit the enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase, the rate-limiting step of cholesterol biosynthesis in the mevalonate pathway. These drugs have been associated with improved respiratory health and ongoing clinical trials are testing their therapeutic potential in asthma. We hypothesized that simvastatin treatment of ovalbumin-exposed mice would attenuate early features of airway remodeling, by a mevalonate-dependent mechanism. BALB/c mice were initially sensitized to ovalbumin, and then exposed to 1% ovalbumin aerosol for 2 weeks after sensitization for a total of six exposures. Simvastatin (40 mg/kg) or simvastatin plus mevalonate (20 mg/kg) were injected intraperitoneally before each ovalbumin exposure. Treatment with simvastatin attenuated goblet cell hyperplasia, arginase-1 protein expression, and total arginase enzyme activity, but did not alter airway hydroxyproline content or transforming growth factor-β1. Inhibition of goblet cell hyperplasia by simvastatin was mevalonate-dependent. No appreciable changes to airway smooth muscle cells were observed in any of the control or treatment groups. In conclusion, in an acute mouse model of allergic asthma, simvastatin inhibited early hallmarks of airway remodeling, indicators that can lead to airway thickening and fibrosis. Statins are potentially novel treatments for airway remodeling in asthma. Further studies utilizing sub-chronic or chronic allergen exposure models are needed to extend these initial findings. PMID:21078495

Comparison of quiet breathing and controlled ventilation in the high-resolution CT assessment of airway disease in infants with cystic fibrosis

Energy Technology Data Exchange (ETDEWEB)

Long, Frederick R.; Adler, Brent H. [Children' s Radiological Institute, Children' s Hospital, Columbus, OH (United States); Williams, Roger S. [Christiana Hospitals, Department of Radiology, Newark, DE (United States); Castile, Robert G. [Children' s Hospital, Section of Pulmonary Medicine, Department of Pediatrics, Columbus, OH (United States)

2005-11-01

Respiratory motion and low lung volumes limit the quality of HRCT examinations in infants and young children. To assess the effects of respiratory motion and lung inflation on the ability to diagnose airway abnormalities and air trapping (AT) using HRCT in infants with cystic fibrosis (CF). HRCT images of the lungs were obtained at four anatomical levels in 16 sedated children (age 2.4{+-}1.1 years, mean{+-}SD) with CF using controlled ventilation at full lung inflation (CVCT-I), at resting end exhalation (CVCT-E), and during quiet breathing (CT-B). Two blinded reviewers independently and then by consensus scored all images for the presence or absence of bronchiectasis (BE), bronchial wall thickening (BWT), and AT. Of the 64 images evaluated, BE was identified in 19 (30%) of the CVCT-I images compared to 6 (9%) of the CVCT-E images (P=0.006) and 4 (6%) of the CT-B images (P=0.044). AT was seen in 29 (45%) of the CVCT-E images compared to 14 (22%) of the CVCT-I images (P=0.012) and 12 (19%) of the CT-B images (P=0.012). There were no significant differences in the detection of BWT among the three methods. Summary: In infants with CF, fully inflating the lung improved the ability to diagnose early BE, and obtaining motion-free images at end exhalation enhanced the detection of AT. (orig.)

Positive signature-tagged mutagenesis in Pseudomonas aeruginosa: tracking patho-adaptive mutations promoting airways chronic infection.

Directory of Open Access Journals (Sweden)

Irene Bianconi

2011-02-01

Full Text Available The opportunistic pathogen Pseudomonas aeruginosa can establish life-long chronic infections in the airways of cystic fibrosis (CF patients. Persistent lifestyle is established with P. aeruginosa patho-adaptive variants, which are clonal with the initially-acquired strains. Several reports indicated that P. aeruginosa adapts by loss-of-function mutations which enhance fitness in CF airways and sustain its clonal expansion during chronic infection. To validate this model of P. aeruginosa adaptation to CF airways and to identify novel genes involved in this microevolution, we designed a novel approach of positive-selection screening by PCR-based signature-tagged mutagenesis (Pos-STM in a murine model of chronic airways infection. A systematic positive-selection scheme using sequential rounds of in vivo screenings for bacterial maintenance, as opposed to elimination, generated a list of genes whose inactivation increased the colonization and persistence in chronic airways infection. The phenotypes associated to these Pos-STM mutations reflect alterations in diverse aspects of P. aeruginosa biology which include lack of swimming and twitching motility, lack of production of the virulence factors such as pyocyanin, biofilm formation, and metabolic functions. In addition, Pos-STM mutants showed altered invasion and stimulation of immune response when tested in human respiratory epithelial cells, indicating that P. aeruginosa is prone to revise the interaction with its host during persistent lifestyle. Finally, sequence analysis of Pos-STM genes in longitudinally P. aeruginosa isolates from CF patients identified signs of patho-adaptive mutations within the genome. This novel Pos-STM approach identified bacterial functions that can have important clinical implications for the persistent lifestyle and disease progression of the airway chronic infection.

The development of bronchiectasis on chest computed tomography in children with cystic fibrosis: can pre-stages be identified?

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Tepper, Leonie A. [Sophia Children' s Hospital, Department of Pediatric Pulmonology, Erasmus MC, Rotterdam (Netherlands); Sophia Children' s Hospital, Department of Radiology, Erasmus MC, Rotterdam (Netherlands); Caudri, Daan [Sophia Children' s Hospital, Department of Pediatric Pulmonology, Erasmus MC, Rotterdam (Netherlands); Perez Rovira, Adria [Sophia Children' s Hospital, Department of Pediatric Pulmonology, Erasmus MC, Rotterdam (Netherlands); Erasmus MC, Biomedical Imaging Group Rotterdam, Departments of Radiology and Medical Informatics, Rotterdam (Netherlands); Tiddens, Harm A.W.M. [Sophia Children' s Hospital, Department of Pediatric Pulmonology, Erasmus MC, Rotterdam (Netherlands); Sophia Children' s Hospital, Department of Radiology, Erasmus MC, Rotterdam (Netherlands); Sophia Children' s Hospital, Department of Pediatric Pulmonology and Radiology, Erasmus Medical Center, Rotterdam (Netherlands); Bruijne, Marleen de [Erasmus MC, Biomedical Imaging Group Rotterdam, Departments of Radiology and Medical Informatics, Rotterdam (Netherlands); University of Copenhagen, Department of Computer Science, Copenhagen (Denmark)

2016-12-15

Bronchiectasis is an important component of cystic fibrosis (CF) lung disease but little is known about its development. We aimed to study the development of bronchiectasis and identify determinants for rapid progression of bronchiectasis on chest CT. Forty-three patients with CF with at least four consecutive biennial volumetric CTs were included. Areas with bronchiectasis on the most recent CT were marked as regions of interest (ROIs). These ROIs were generated on all preceding CTs using deformable image registration. Observers indicated whether: bronchiectasis, mucus plugging, airway wall thickening, atelectasis/consolidation or normal airways were present in the ROIs. We identified 362 ROIs on the most recent CT. In 187 (51.7 %) ROIs bronchiectasis was present on all preceding CTs, while 175 ROIs showed development of bronchiectasis. In 139/175 (79.4 %) no pre-stages of bronchiectasis were identified. In 36/175 (20.6 %) bronchiectatic airways the following pre-stages were identified: mucus plugging (17.7 %), airway wall thickening (1.7 %) or atelectasis/consolidation (1.1 %). Pancreatic insufficiency was more prevalent in the rapid progressors compared to the slow progressors (p = 0.05). Most bronchiectatic airways developed within 2 years without visible pre-stages, underlining the treacherous nature of CF lung disease. Mucus plugging was the most frequent pre-stage. (orig.)

The development of bronchiectasis on chest computed tomography in children with cystic fibrosis: can pre-stages be identified?

International Nuclear Information System (INIS)

Tepper, Leonie A.; Caudri, Daan; Perez Rovira, Adria; Tiddens, Harm A.W.M.; Bruijne, Marleen de

2016-01-01

Bronchiectasis is an important component of cystic fibrosis (CF) lung disease but little is known about its development. We aimed to study the development of bronchiectasis and identify determinants for rapid progression of bronchiectasis on chest CT. Forty-three patients with CF with at least four consecutive biennial volumetric CTs were included. Areas with bronchiectasis on the most recent CT were marked as regions of interest (ROIs). These ROIs were generated on all preceding CTs using deformable image registration. Observers indicated whether: bronchiectasis, mucus plugging, airway wall thickening, atelectasis/consolidation or normal airways were present in the ROIs. We identified 362 ROIs on the most recent CT. In 187 (51.7 %) ROIs bronchiectasis was present on all preceding CTs, while 175 ROIs showed development of bronchiectasis. In 139/175 (79.4 %) no pre-stages of bronchiectasis were identified. In 36/175 (20.6 %) bronchiectatic airways the following pre-stages were identified: mucus plugging (17.7 %), airway wall thickening (1.7 %) or atelectasis/consolidation (1.1 %). Pancreatic insufficiency was more prevalent in the rapid progressors compared to the slow progressors (p = 0.05). Most bronchiectatic airways developed within 2 years without visible pre-stages, underlining the treacherous nature of CF lung disease. Mucus plugging was the most frequent pre-stage. (orig.)

Bolus Weekly Vitamin D3 Supplementation Impacts Gut and Airway Microbiota in Adults With Cystic Fibrosis: A Double-Blind, Randomized, Placebo-Controlled Clinical Trial.

Science.gov (United States)

Kanhere, Mansi; He, Jiabei; Chassaing, Benoit; Ziegler, Thomas R; Alvarez, Jessica A; Ivie, Elizabeth A; Hao, Li; Hanfelt, John; Gewirtz, Andrew T; Tangpricha, Vin

2018-02-01

Disruption of gut microbiota may exacerbate severity of cystic fibrosis (CF). Vitamin D deficiency is a common comorbidity in patients with CF that may influence composition of the gut microbiota. Compare microbiota of vitamin D-sufficient and -insufficient CF patients and assess impact of a weekly high-dose vitamin D3 bolus regimen on gut and airway microbiome in adults with CF and vitamin D insufficiency (25-hydroxyvitamin D Gut microbiota differed significantly based on vitamin D status with Gammaproteobacteria, which contain numerous, potentially pathogenic species enriched in the vitamin D-insufficient group. Principal coordinates analysis showed differential gut microbiota composition within the vitamin D-insufficient patients following 12 weeks treatment with placebo or vitamin D3 (permutation multivariate analysis of variance = 0.024), with Lactococcus significantly enriched in subjects treated with vitamin D3, whereas Veillonella and Erysipelotrichaceae were significantly enriched in patients treated with placebo. This exploratory study suggests that vitamin D insufficiency is associated with alterations in microbiota composition that may promote inflammation and that supplementation with vitamin D has the potential to impact microbiota composition. Additional studies to determine the impact of vitamin D on microbiota benefit clinical outcomes in CF are warranted. Copyright © 2017 Endocrine Society

Airway epithelial cell exposure to distinct e-cigarette liquid flavorings reveals toxicity thresholds and activation of CFTR by the chocolate flavoring 2,5-dimethypyrazine.

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Sherwood, Cara L; Boitano, Scott

2016-05-17

that the increases in ion conductance evoked by 2,5-dimethylpyrazine were largely attributed to a protein kinase A-dependent (PKA) activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel. Data from our high-capacity screening assays demonstrates that individual e-cigarette liquid flavoring chemicals vary in their cytotoxicity profiles and that some constituents evoke a cellular physiological response on their own independent of cell death. The activation of CFTR by 2,5-dimethylpyrazine may have detrimental consequences for airway surface liquid homeostasis in individuals that use e-cigarettes habitually.

A new compound heterozygous CFTR mutation in a Chinese family with cystic fibrosis.

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Xie, Yingjun; Huang, Xueqiong; Liang, Yujian; Xu, Lingling; Pei, Yuxin; Cheng, Yucai; Zhang, Lidan; Tang, Wen

2017-11-01

Cystic fibrosis (CF) is the most common autosomal recessive disease among Caucasians but is rarer in the Chinese population, because mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. To elucidate the causative role of a novel compound heterozygous mutation of CF. In this study, clinical samples were obtained from two siblings with recurrent airway infections, clubbed fingers, salt-sweat and failure to gain weight in a non-consanguineous Chinese family. Next-generation sequencing was performed on the 27 coding exons of CFTR in both children, with confirmation by Sanger sequencing. Next-generation sequencing showed the same compound heterozygous CFTR mutation (c.865A>T p.Arg289X and c.3651_3652insAAAT p.Tyr1219X) in both children. As this mutation is consistent with the clinical manifestations of CF and no other mutations were detected after scanning the gene sequence, we suggest that the CF phenotype is caused by compound heterozygosity for c.865A>T and c.3651_3652insAAAT. As c865A>T is not currently listed in the "Cystic Fibrosis Mutation Database", this information about CF in a Chinese population is of interest. © 2015 John Wiley & Sons Ltd.

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.

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)

Therapeutic flexible bronchoscopy in child with cystic fibrosis

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Amina Selimović

2008-05-01

Full Text Available The report deals with the case of a 10-year-old girl with chronic cystic fibrosis. She has been repeatedly treated at the hospital. She has been hospitalized due to respiratory deterioration. Cystic fibrosis is a rare disease, inherited autosomaly recessively, but is very complex in terms of diagnostic and treatment (2. The diagnosis is confirmed based on a clinical picture of the child, measure of Chloride in the sweat, chest X-ray, CT thorax, laboratory findings--genetic confirmation CFTR ( cystic fibrosis transmembrane conductance regulator genes (3, which result in the production of hyper-viscous mucus and chloride malabsorption in the sweat glands ducts (5,6. Bronchial thickening and plugging and ring shadows suggesting bronchiectasis, segmental or lobar atelectasis are often. Computer tomography of the chest can be used to detect and localize thickening of bronchial airways walls, mucus plugging, hyperinflation and early bronchieactasiae. Pulmonary therapy: the object is to clear secretions from airways and to control infection (7. The diagnosis is originally set when she was 4 years old. She is now admitted due to a deterioration of the main disease. Day before admission in the hospital had a higher bodily temperature, cough and difficult breathing. She already treated conservatively (Ceftazidim, Ceftriakson, Kloksacillin Since the girl is a chronic patient with bronchiectasie chronic walls of bronchi changes full of the mucus, who is not responding to conservative treatment (antibiotics, therapeutic and diagnostic flexible bronchoscopy had to be performed, resulting in a gram-negative bacteria pseudomonas aeruginosa--a typical bacteria for chronically sick C. F.PATIENT:A pseudomonas therapy was prescribed according to the sensitive antibiogram, during which bronchoscopy was given locally on changes mucous pulmozyme and garamycin. Flexible bronchoscopy was performed as therapeutic. Local

Effect of chlorhexidine on oral airway biofilm formation of Staphylococcus epidermidis

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Ünase Büyükkoçak

2015-12-01

Full Text Available Objective: Biofilm formation of microorganisms on the surface of airways may lead to supraglottic colonization that may cause lower respiratuar tract infections. Studies searching the efficiency of local disinfectants on biofilm formation are limited. The aim of this study was to investigate the effects of chlorhexidine coated airways on biofilm formation of Staphylococcus epidermidis. Methods: Culture and electron microscopy methods were used for biofilm assessment. Airways were divided into two groups to investigate the effects of chlorhexidine on number of bacteria attached to the airway and biofilm formation. Group 1(control: naive material, S. epidermidis, Group 2: chlorhexidine coated material, S. epidermidis. No process was applied in Group 1. Chlorhexidine gluconate (0.2% was sprayed on the surface of naive material for four seconds and then left to dry in air, in Group to. Number of bacteria attached to the airway were counted by microbiological methods and biofilm formation was shown by Scanning Electron Microscope (SEM. Mann-Whitney u test was performed for statistical analyses. Results: In Group 2, bacteria numbers were 1x102-8x102 cfu/ml, whereas they were 3x103-1x104 cfu/ml in Group 1. Chlorhexidine decreased number of microorganisms attached to the airways with statistical significance (p=0.04. The results of the electron microscopic evaluation were in accordance with the acteriological findings. Conclusion: This study has shown that chlorhexidine coating can successfully reduce the number of adhered bacteria and biofilm formation on airways. J Microbiol Infect Dis 2015;5(4: 162-166

Raman spectroscopy as a new tool for early detection of bacteria in patients with cystic fibrosis

Science.gov (United States)

Rusciano, Giulia; Capriglione, Paola; Pesce, Giuseppe; Abete, Pasquale; Carnovale, Vincenzo; Sasso, Antonio

2013-07-01

Respiratory infections represent a major threat for people affected by cystic fibrosis, leading to pulmonary deterioration and lung transplantation as a therapeutic option for end-stage patients. A fast and correct identification of pathogens in airway fluid of these patients is crucial to establish appropriate therapies, to prevent cross-infections and, ultimately, to preserve lung function. In this study, we used Raman spectroscopy to reveal bacteria in the sputa of patients such as Pseudomonas aeruginosa and Staphylococcus aureus, which are among the earliest and the most frequent bacteria affecting cystic fibrosis patients. We found that Raman analysis, combined with principal component analysis, is able to provide a correct identification of these bacteria, with a global accuracy higher than 95%. Interestingly, bacterial identification is performed by analysing patients’ sputa as a whole, avoiding, therefore, time-consuming procedures involving bacterial isolation or even bacterial cultures. This study suggests that Raman spectroscopy could be a suitable candidate for the development of innovative and non-invasive procedures for a fast and reliable identification of respiratory infections in cystic fibrosis patients.

Raman spectroscopy as a new tool for early detection of bacteria in patients with cystic fibrosis

International Nuclear Information System (INIS)

Rusciano, Giulia; Capriglione, Paola; Pesce, Giuseppe; Sasso, Antonio; Abete, Pasquale; Carnovale, Vincenzo

2013-01-01

Respiratory infections represent a major threat for people affected by cystic fibrosis, leading to pulmonary deterioration and lung transplantation as a therapeutic option for end-stage patients. A fast and correct identification of pathogens in airway fluid of these patients is crucial to establish appropriate therapies, to prevent cross-infections and, ultimately, to preserve lung function. In this study, we used Raman spectroscopy to reveal bacteria in the sputa of patients such as Pseudomonas aeruginosa and Staphylococcus aureus, which are among the earliest and the most frequent bacteria affecting cystic fibrosis patients. We found that Raman analysis, combined with principal component analysis, is able to provide a correct identification of these bacteria, with a global accuracy higher than 95%. Interestingly, bacterial identification is performed by analysing patients’ sputa as a whole, avoiding, therefore, time-consuming procedures involving bacterial isolation or even bacterial cultures. This study suggests that Raman spectroscopy could be a suitable candidate for the development of innovative and non-invasive procedures for a fast and reliable identification of respiratory infections in cystic fibrosis patients. (letter)

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

Science.gov (United States)

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

The Importance of the 6 Minute Walk test in the assessment of Romanian teenagers with cystic fibrosis

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Ornela O. Cluci

2012-06-01

Full Text Available The measurement of lung function is the central part of the patients with cystic fibrosis assessment but we consider that exercise testing become an important tool in the continuous evaluation which is an indicative of prognosis and functional capacity and care of these patients. The 6 minute walk test is used to assess the individual’s response to exercise. The aim of the study is to design an exercise training program, based on 6 minute walk test and to evaluate the effects of this complex protocol including incentive therapy, individualized supervised training program: swimming, trampoline, walking, jogging, aerobic gymnastic, cycling 3 times per week and airway clearance techniques. Material and method: We conducted a 6-month study, on 20 patients from the Romanian National Cystic Fibrosis Center, aged between 12 and 18. The inclusion criteria were: FEV1 or FVC lower than 60% of predicted, SpO2 lower than 94% at rest. Results and discussions: The initial assessment showed limitations of exercise due to poor skeletal muscle mass, pulmonary status and respiratory muscle strength. After combining airway clearance techniques, incentive therapy and individualized physical training, we observed improvements regarding pulmonary function, ease of breathing and significant increased of fitness (6 minutes walking distance increased from 518.2±108.9 meters to 604.9±68 meters. A positive correlation was observed between skeletal muscle mass and distance achieved to 6 minute walk test, at the end of the study. Conclusion: The proposed rehabilitation protocol of young cystic fibrosis patients is efficient and creates pleasure and joy during physiotherapy which enhanced the patient’s adherence to the program.

Effects of Autogenic Drainage on Sputum Recovery and Pulmonary Function in People with Cystic Fibrosis: A Systematic Review.

Science.gov (United States)

Morgan, Kimbly; Osterling, Kristin; Gilbert, Robert; Dechman, Gail

2015-01-01

To determine the effects of short- and long-term use of autogenic drainage (AD) on pulmonary function and sputum recovery in people with cystic fibrosis (CF). The authors conducted a systematic review of randomized and quasi-randomized clinical trials in which participants were people with CF who use AD as their sole airway clearance technique. Searches in 4 databases and secondary sources using 5 key terms yielded 735 articles, of which 58 contained the terms autogenic drainage and cystic fibrosis. Ultimately, 4 studies, 2 of which were long term, were included. All measured forced expiratory volume in 1 second (FEV1) and found no change. The long-term studies were underpowered to detect change in FEV1; however, the short-term studies found a clinically significant sputum yield (≥4 g). AD has been shown to produce clinically significant sputum yields in a limited number of investigations. The effect of AD on the function of the pulmonary system remains uncertain, and questions have emerged regarding the appropriateness of FEV1 as a valid measure of airway clearance from peripheral lung regions. Further consideration should be given to the use of FEV1 as a primary measure of the effect of AD.

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

Novel short chain fatty acids restore chloride secretion in cystic fibrosis

International Nuclear Information System (INIS)

Nguyen, Toan D.; Kim, Ug-Sung; Perrine, Susan P.

2006-01-01

Phenylalanine deletion at position 508 of the cystic fibrosis transmembrane conductance regulator (ΔF508-CFTR), the most common mutation in cystic fibrosis (CF), causes a misfolded protein exhibiting partial chloride conductance and impaired trafficking to the plasma membrane. 4-Phenylbutyrate corrects defective ΔF508-CFTR trafficking in vitro, but is not clinically efficacious. From a panel of short chain fatty acid derivatives, we showed that 2,2-dimethyl-butyrate (ST20) and α-methylhydrocinnamic acid (ST7), exhibiting high oral bioavailability and sustained plasma levels, correct the ΔF508-CFTR defect. Pre-incubation (≥6 h) of CF IB3-1 airway cells with ≥1 mM ST7 or ST20 restored the ability of 100 μM forskolin to stimulate an 125 I - efflux. This efflux was fully inhibited by NPPB, DPC, or glibenclamide, suggesting mediation through CFTR. Partial inhibition by DIDS suggests possible contribution from an additional Cl - channel regulated by CFTR. Thus, ST7 and ST20 offer treatment potential for CF caused by the ΔF508 mutation

Degrees of reality: airway anatomy of high-fidelity human patient simulators and airway trainers.

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Schebesta, Karl; Hüpfl, Michael; Rössler, Bernhard; Ringl, Helmut; Müller, Michael P; Kimberger, Oliver

2012-06-01

Human patient simulators and airway training manikins are widely used to train airway management skills to medical professionals. Furthermore, these patient simulators are employed as standardized "patients" to evaluate airway devices. However, little is known about how realistic these patient simulators and airway-training manikins really are. This trial aimed to evaluate the upper airway anatomy of four high-fidelity patient simulators and two airway trainers in comparison with actual patients by means of radiographic measurements. The volume of the pharyngeal airspace was the primary outcome parameter. Computed tomography scans of 20 adult trauma patients without head or neck injuries were compared with computed tomography scans of four high-fidelity patient simulators and two airway trainers. By using 14 predefined distances, two cross-sectional areas and three volume parameters of the upper airway, the manikins' similarity to a human patient was assessed. The pharyngeal airspace of all manikins differed significantly from the patients' pharyngeal airspace. The HPS Human Patient Simulator (METI®, Sarasota, FL) was the most realistic high-fidelity patient simulator (6/19 [32%] of all parameters were within the 95% CI of human airway measurements). The airway anatomy of four high-fidelity patient simulators and two airway trainers does not reflect the upper airway anatomy of actual patients. This finding may impact airway training and confound comparative airway device studies.

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....

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

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Hadeesha Piyadasa

2016-02-01

strategies for airway inflammation pertinent to allergic asthma that precedes and possibly potentiates airway remodeling and fibrosis.

Variants in the interleukin 8 gene and the response to inhaled bronchodilators in cystic fibrosis.

Science.gov (United States)

Furlan, Larissa Lazzarini; Ribeiro, José Dirceu; Bertuzzo, Carmen Sílvia; Salomão Junior, João Batista; Souza, Dorotéia Rossi Silva; Marson, Fernando Augusto Lima

Interleukin 8 protein promotes inflammatory responses, even in airways. The presence of interleukin 8 gene variants causes altered inflammatory responses and possibly varied responses to inhaled bronchodilators. Thus, this study analyzed the interleukin 8 variants (rs4073, rs2227306, and rs2227307) and their association with the response to inhaled bronchodilators in cystic fibrosis patients. Analysis of interleukin 8 gene variants was performed by restriction fragment length polymorphism of polymerase chain reaction. The association between spirometry markers and the response to inhaled bronchodilators was evaluated by Mann-Whitney and Kruskal-Wallis tests. The analysis included all cystic fibrosis patients, and subsequently patients with two mutations in the cystic fibrosis transmembrane conductance regulator gene belonging to classes I to III. This study included 186 cystic fibrosis patients. There was no association of the rs2227307 variant with the response to inhaled bronchodilators. The rs2227306 variant was associated with FEF 50% in the dominant group and in the group with two identified mutations in the cystic fibrosis transmembrane conductance regulator gene. The rs4073 variant was associated with spirometry markers in four genetic models: co-dominant (FEF 25-75% and FEF 75% ), dominant (FEV 1 , FEF 50% , FEF 75% , and FEF 25-75% ), recessive (FEF 75% and FEF 25-75% ), and over-dominant (FEV 1 /FVC). This study highlighted the importance of the rs4073 variant of the interleukin 8 gene, regarding response to inhaled bronchodilators, and of the assessment of mutations in the cystic fibrosis transmembrane conductance regulator gene. Copyright © 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Challenges with current inhaled treatments for chronic Pseudomonas aeruginosa infection in patients with cystic fibrosis.

LENUS (Irish Health Repository)

Greally, Peter

2012-06-01

Pseudomonas aeruginosa (Pa) is the predominant pathogen infecting the airways of patients with cystic fibrosis (CF). Initial colonization is usually transient and associated with non-mucoid strains, which can be eradicated if identified early. This strategy can prevent, or at least delay, chronic Pa infection, which eventually develops in the majority of patients by their late teens or early adulthood. This article discusses the management and latest treatment developments of Pa lung infection in patients with CF, with a focus on nebulized antibiotic therapy.

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.

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.

Interleukin-17A induces bicarbonate secretion in normal human bronchial epithelial cells

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Kreindler, James L.; Bertrand, Carol A.; Lee, Robert J.; Karasic, Thomas; Aujla, Shean; Pilewski, Joseph M.; Frizzell, Raymond A.; Kolls, Jay K.

2009-01-01

The innate immune functions of human airways include mucociliary clearance and antimicrobial peptide activity. Both functions may be affected by changes in epithelial ion transport. Interleukin-17A (IL-17A), which has a receptor at the basolateral membrane of airway epithelia, is a T cell cytokine that has been shown to increase mucus secretion and antimicrobial peptide production by human bronchial epithelial (HBE) cells. Furthermore, IL-17A levels are increased in sputum from patients during pulmonary exacerbations of cystic fibrosis. Therefore, we investigated the effects of IL-17A on basal, amiloride-sensitive, and forskolin-stimulated ion transport in mature, well-differentiated HBE cells. Exposure of HBE monolayers to IL-17A for 48 h induced a novel forskolin-stimulated bicarbonate secretion in addition to forskolin-stimulated chloride secretion and resulted in alkalinization of liquid on the mucosal surface of polarized cells. IL-17A-induced bicarbonate secretion was cystic fibrosis transmembrane conductance regulator (CFTR)-dependent, mucosal chloride-dependent, partially Na+-dependent, and sensitive to serosal, but not mucosal, stilbene inhibition. These data suggest that IL-17A modulates epithelial bicarbonate secretion and implicate a mechanism by which airway surface liquid pH changes may be abnormal in cystic fibrosis. PMID:19074559

Cystic Fibrosis Transmembrane Conductance Regulator Attaches Tumor Suppressor PTEN to the Membrane and Promotes Anti Pseudomonas aeruginosa Immunity.

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Riquelme, Sebastián A; Hopkins, Benjamin D; Wolfe, Andrew L; DiMango, Emily; Kitur, Kipyegon; Parsons, Ramon; Prince, Alice

2017-12-19

The tumor suppressor PTEN controls cell proliferation by regulating phosphatidylinositol-3-kinase (PI3K) activity, but the participation of PTEN in host defense against bacterial infection is less well understood. Anti-inflammatory PI3K-Akt signaling is suppressed in patients with cystic fibrosis (CF), a disease characterized by hyper-inflammatory responses to airway infection. We found that Ptenl -/- mice, which lack the NH 2 -amino terminal splice variant of PTEN, were unable to eradicate Pseudomonas aeruginosa from the airways and could not generate sufficient anti-inflammatory PI3K activity, similar to what is observed in CF. PTEN and the CF transmembrane conductance regulator (CFTR) interacted directly and this interaction was necessary to position PTEN at the membrane. CF patients under corrector-potentiator therapy, which enhances CFTR transport to the membrane, have increased PTEN amounts. These findings suggest that improved CFTR trafficking could enhance P. aeruginosa clearance from the CF airway by activating PTEN-mediated anti-bacterial responses and might represent a therapeutic strategy. Published by Elsevier Inc.

Bacteria isolated from the airways of paediatric patients with bronchiectasis according to HIV status

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Charl Verwey

2017-05-01

Full Text Available Background. Knowledge of which bacteria are found in the airways of paediatric patients with bronchiectasis unrelated to cystic fibrosis (CF is important in defining empirical antibiotic guidelines for the treatment of acute infective exacerbations. Objective. To describe the bacteria isolated from the airways of children with non-CF bronchiectasis according to their HIV status. Methods. Records of children with non-CF bronchiectasis who attended the paediatric pulmonology clinic at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa, from April 2011 to March 2013, or were admitted to the hospital during that period, were reviewed. Data collected included patient demographics, HIV status, and characteristics of the airway samples and types of bacteria isolated. Results. There were 66 patients with non-CF bronchiectasis over the 2-year study period. The median age was 9.1 years (interquartile range 7.2 - 12.1. The majority of patients (78.8% were HIV-infected. A total of 134 samples was collected (median 1.5 per patient, range 1 - 7, of which 81.3% were expectorated or induced sputum samples. Most bacteria were Gram negatives (72.1%. Haemophilus influenzae was the most common bacterium identified (36.0%, followed by Streptococcus pneumoniae (12.6%, Moraxella catarrhalis (11.1% and Staphylococcus aureus (10.6%. There were no differences between HIV-infected and uninfected patients in prevalence or type of pathogens isolated. Conclusion. Bacterial isolates from the airways of children with non-CF bronchiectasis were similar to those in other paediatric populations and were not affected by HIV status.

Air pollution induces enhanced mitochondrial oxidative stress in cystic fibrosis airway epithelium.

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Kamdar, O; Le, Wei; Zhang, J; Ghio, A J; Rosen, G D; Upadhyay, D

2008-10-29

We studied the effects of airborne particulate matters (PM) on cystic fibrosis (CF) epithelium. We noted that PM enhanced human CF bronchial epithelial apoptosis, activated caspase-9 and PARP-1; and reduced mitochondrial membrane potential. Mitochondrial inhibitors (4,4-diisothiocyanatostilbene-2,2'disulfonic acid, rotenone and thenoyltrifluoroacetone) blocked PM-induced generation of reactive oxygen species and apoptosis. PM upregulated pro-apoptotic Bad, Bax, p53 and p21; and enhanced mitochondrial localization of Bax. The anti-apoptotic Bcl-2, Bcl-xl, Mcl-1 and Xiap remained unchanged; however, overexpression of Bcl-xl blocked PM-induced apoptosis. Accordingly, we provide the evidence that PM enhances oxidative stress and mitochondrial signaling mediated apoptosis via the modulation of Bcl family proteins in CF.

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

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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.

Elevated expression of NEU1 sialidase in idiopathic pulmonary fibrosis provokes pulmonary collagen deposition, lymphocytosis, and fibrosis.

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Luzina, Irina G; Lockatell, Virginia; Hyun, Sang W; Kopach, Pavel; Kang, Phillip H; Noor, Zahid; Liu, Anguo; Lillehoj, Erik P; Lee, Chunsik; Miranda-Ribera, Alba; Todd, Nevins W; Goldblum, Simeon E; Atamas, Sergei P

2016-05-15

Idiopathic pulmonary fibrosis (IPF) poses challenges to understanding its underlying cellular and molecular mechanisms and the development of better therapies. Previous studies suggest a pathophysiological role for neuraminidase 1 (NEU1), an enzyme that removes terminal sialic acid from glycoproteins. We observed increased NEU1 expression in epithelial and endothelial cells, as well as fibroblasts, in the lungs of patients with IPF compared with healthy control lungs. Recombinant adenovirus-mediated gene delivery of NEU1 to cultured primary human cells elicited profound changes in cellular phenotypes. Small airway epithelial cell migration was impaired in wounding assays, whereas, in pulmonary microvascular endothelial cells, NEU1 overexpression strongly impacted global gene expression, increased T cell adhesion to endothelial monolayers, and disrupted endothelial capillary-like tube formation. NEU1 overexpression in fibroblasts provoked increased levels of collagen types I and III, substantial changes in global gene expression, and accelerated degradation of matrix metalloproteinase-14. Intratracheal instillation of NEU1 encoding, but not control adenovirus, induced lymphocyte accumulation in bronchoalveolar lavage samples and lung tissues and elevations of pulmonary transforming growth factor-β and collagen. The lymphocytes were predominantly T cells, with CD8(+) cells exceeding CD4(+) cells by nearly twofold. These combined data indicate that elevated NEU1 expression alters functional activities of distinct lung cell types in vitro and recapitulates lymphocytic infiltration and collagen accumulation in vivo, consistent with mechanisms implicated in lung fibrosis.

Modeling airflow and particle transport/deposition in pulmonary airways.

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Kleinstreuer, Clement; Zhang, Zhe; Li, Zheng

2008-11-30

A review of research papers is presented, pertinent to computer modeling of airflow as well as nano- and micron-size particle deposition in pulmonary airway replicas. The key modeling steps are outlined, including construction of suitable airway geometries, mathematical description of the air-particle transport phenomena and computer simulation of micron and nanoparticle depositions. Specifically, diffusion-dominated nanomaterial deposits on airway surfaces much more uniformly than micron particles of the same material. This may imply different toxicity effects. Due to impaction and secondary flows, micron particles tend to accumulate around the carinal ridges and to form "hot spots", i.e., locally high concentrations which may lead to tumor developments. Inhaled particles in the size range of 20nm< or =dp< or =3microm may readily reach the deeper lung region. Concerning inhaled therapeutic particles, optimal parameters for mechanical drug-aerosol targeting of predetermined lung areas can be computed, given representative pulmonary airways.

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

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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.

Introduction to Pulmonary Fibrosis

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... page: Introduction to Pulmonary Fibrosis What Is Pulmonary Fibrosis? Pulmonary fibrosis is a disease where there is scarring ... of pulmonary fibrosis. Learn more How Is Pulmonary Fibrosis Diagnosed? Pulmonary fibrosis can be difficult to diagnose, so it ...

Pulmonary Fibrosis Foundation

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... submissions. MORE We Imagine a World Without Pulmonary Fibrosis The Pulmonary Fibrosis Foundation mobilizes people and resources to provide ... its battle against the deadly lung disease, pulmonary fibrosis (PF). PULMONARY FIBROSIS WALK SURPASSES PARTICIPATION AND FUNDRAISING GOALS Nearly ...

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

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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

Radionuclide assessment of the effects of chest physical therapy on ventilation in cystic fibrosis

International Nuclear Information System (INIS)

DeCesare, J.A.; Babchyck, B.M.; Colten, H.R.; Treves, S.

1982-01-01

This study assesses the use of /sup 81m/Kr scintigraphy as a measurement tool in evaluating the effectiveness of bronchial drainage with percussion and vibration on peripheral ventilation in patients with cystic fibrosis. Ten patients with cystic fibrosis participated. Each patient underwent a /sup 81m/Kr ventilation study and traditional pulmonary function tests. Forty-five minutes later, these studies were repeated before and after a chest physical therapy treatment. Each patient acted as his own control. All /sup 81m/Kr scintiscans were recorded and analyzed visually and numerically using a digital computer to assess distribution of ventilation. Visual analysis of the scintiscans indicated individual variation in treatment response: in some patients ventilation improved with therapy; in others, no change was noted; still others had changes independent of treatment. Numerical data derived from the scintiscans and pulmonary function tests showed no important differences among the three studies of each patient. Airway abnormalities characteristic of cystic fibrosis, progression of the disease, sputum production, or a combination of these factors may account for the individual variation in response to treatment. /sup 81m/Kr scintigraphy is a reliable measure of regional ventilation and should be useful for assessing the efficacy of chest physical therapy because of the consistent, high quality visual data retrieved

Sarcoidosis with Major Airway, Vascular and Nerve Compromise

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Hiroshi Sekiguchi

2013-01-01

Full Text Available The present report describes a 60-year-old Caucasian woman who presented with progressive dyspnea, cough and wheeze. A computed tomography scan of the chest showed innumerable bilateral inflammatory pulmonary nodules with bronchovascular distribution and a mediastinal and hilar infiltrative process with calcified lymphadenopathy leading to narrowing of lobar bronchi and pulmonary arteries. An echocardiogram revealed pulmonary hypertension. Bronchoscopy showed left vocal cord paralysis and significant narrowing of the bilateral bronchi with mucosal thickening and multiple nodules. Transbronchial biopsy was compatible with sarcoidosis. Despite balloon angioplasty of the left lower lobe and pulmonary artery, and medical therapy with oral corticosteroids, her symptoms did not significantly improve. To the authors’ knowledge, the present report describes the first case of pulmonary sarcoidosis resulting in major airway, vascular and nerve compromise due to compressive lymphadenopathy and suspected concurrent granulomatous infiltration. Its presentation mimicked idiopathic mediastinal fibrosis.

The effects of exogenous lipid on THP-1 cells: an in vitro model of airway aspiration?

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Yvette A. Hayman

2017-03-01

Full Text Available Chronic inflammatory diseases of the airways are associated with gastro-oesophageal reflux (GOR and aspiration events. The observation of lipid-laden macrophages (LLMs within the airway may indicate aspiration secondary to GOR. The proposed mechanism, that lipid droplets from undigested or partially digested food are aspirated leading to accumulation in scavenging macrophages, led us to hypothesise that an activated population of LLMs could interact with other immune cells to induce bronchial inflammation. To test this, we generated an in vitro model using differentiated THP-1 cells, which were treated with a high-fat liquid feed. Here, we show that THP-1 cells can take up lipid from the high-fat feed independent of actin polymerisation or CD36-dependent phagocytosis. These cells did not exhibit M1 or M2 polarisation. Gene array analysis confirmed over 8000 genes were upregulated by at least twofold following high fat exposure, and IL-8 was the most upregulated gene. Pathway analysis revealed upregulation of genes known to be involved in chronic obstructive pulmonary disease (COPD pathophysiology. We suggest that aspiration and macrophage phagocytosis may be important mechanisms in the aetiology of diseases such as COPD and cystic fibrosis that are characterised by high levels of IL-8 within the airways.

The effects of exogenous lipid on THP-1 cells: an in vitro model of airway aspiration?

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Hayman, Yvette A; Sadofsky, Laura R; Williamson, James D; Hart, Simon P; Morice, Alyn H

2017-01-01

Chronic inflammatory diseases of the airways are associated with gastro-oesophageal reflux (GOR) and aspiration events. The observation of lipid-laden macrophages (LLMs) within the airway may indicate aspiration secondary to GOR. The proposed mechanism, that lipid droplets from undigested or partially digested food are aspirated leading to accumulation in scavenging macrophages, led us to hypothesise that an activated population of LLMs could interact with other immune cells to induce bronchial inflammation. To test this, we generated an in vitro model using differentiated THP-1 cells, which were treated with a high-fat liquid feed. Here, we show that THP-1 cells can take up lipid from the high-fat feed independent of actin polymerisation or CD36-dependent phagocytosis. These cells did not exhibit M1 or M2 polarisation. Gene array analysis confirmed over 8000 genes were upregulated by at least twofold following high fat exposure, and IL-8 was the most upregulated gene. Pathway analysis revealed upregulation of genes known to be involved in chronic obstructive pulmonary disease (COPD) pathophysiology. We suggest that aspiration and macrophage phagocytosis may be important mechanisms in the aetiology of diseases such as COPD and cystic fibrosis that are characterised by high levels of IL-8 within the airways.

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

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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...

Extraluminal biodegradable splint to treat upper airway anterior malacia: A preclinical proof of principle.

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Gorostidi, François; Courbon, Cécile; Burki, Marco; Reinhard, Antoine; Sandu, Kishore

2018-02-01

Upper airway malacia highly complicates the treatment of benign laryngotracheal stenosis, and no ideal option is available to date. We here explore the use of extraluminal biodegradable splints in an animal model of long-segment anterior tracheomalacia (TM). We show the efficacy, as well as the tissue tolerance, of a custom-made biodegradable extraluminal device surgically inserted around the trachea. Preclinical animal study. Anterior TM was induced in rabbits through an anterior neck approach by removing eight consecutive anterior tracheal rings without damaging the underlying mucosa. Malacia was corrected during the same surgery by pexy sutures, suspending the tracheal mucosa to an experimental biodegradable device. Symptoms, survival, and tissue reaction were compared to healthy and sham surgery controls. The model induced death by respiratory failure within minutes. Ten animals received the experimental treatment, and those who survived the perioperative period remained asymptomatic with a maximum follow-up of 221 days. Histological studies at programmed euthanasia showed complete degradation of the prosthesis, with significant remnant fibrosis around the trachea. However, the tracheal stiffness of test segments was comparatively less than that of control segments. Extraluminal biodegradable splints rescued animals with a condition otherwise incompatible with life. It was well tolerated, leaving peritracheal fibrosis that was not as stiff as normal trachea. The external tracheal stiffening was sufficient for the test animals to live through the phase of severe acute hypercollapsibility. This represents a valid option to help pediatric patients with laryngotracheal stenosis and associated cartilaginous airway malacia. NA. Laryngoscope, 128:E53-E58, 2018. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

Quantitative analysis of airway abnormalities in CT

DEFF Research Database (Denmark)

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

2010-01-01

A coupled surface graph cut algorithm for airway wall segmentation from Computed Tomography (CT) images is presented. Using cost functions that highlight both inner and outer wall borders, the method combines the search for both borders into one graph cut. The proposed method is evaluated on 173 ...

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

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

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...

Inhaled antibiotics for lower airway infections.

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Quon, Bradley S; Goss, Christopher H; Ramsey, Bonnie W

2014-03-01

Inhaled antibiotics have been used to treat chronic airway infections since the 1940s. The earliest experience with inhaled antibiotics involved aerosolizing antibiotics designed for parenteral administration. These formulations caused significant bronchial irritation due to added preservatives and nonphysiologic chemical composition. A major therapeutic advance took place in 1997, when tobramycin designed for inhalation was approved by the U.S. Food and Drug Administration (FDA) for use in patients with cystic fibrosis (CF) with chronic Pseudomonas aeruginosa infection. Attracted by the clinical benefits observed in CF and the availability of dry powder antibiotic formulations, there has been a growing interest in the use of inhaled antibiotics in other lower respiratory tract infections, such as non-CF bronchiectasis, ventilator-associated pneumonia, chronic obstructive pulmonary disease, mycobacterial disease, and in the post-lung transplant setting over the past decade. Antibiotics currently marketed for inhalation include nebulized and dry powder forms of tobramycin and colistin and nebulized aztreonam. Although both the U.S. Food and Drug Administration and European Medicines Agency have approved their use in CF, they have not been approved in other disease areas due to lack of supportive clinical trial evidence. Injectable formulations of gentamicin, tobramycin, amikacin, ceftazidime, and amphotericin are currently nebulized "off-label" to manage non-CF bronchiectasis, drug-resistant nontuberculous mycobacterial infections, ventilator-associated pneumonia, and post-transplant airway infections. Future inhaled antibiotic trials must focus on disease areas outside of CF with sample sizes large enough to evaluate clinically important endpoints such as exacerbations. Extrapolating from CF, the impact of eradicating organisms such as P. aeruginosa in non-CF bronchiectasis should also be evaluated.

Thoracic findings in pediatric patiens with cystic fibrosis

International Nuclear Information System (INIS)

Wunsch, R.; Wunsch, C.

2003-01-01

Cystic fibrosis is the most common autosomal recessive metabolic disease in Europe with an incidence of 1:2500. The severity of the lung disease is the most important factor of morbidity and mortality in CF-patients. Because of the better diagnostic and therapeutic modalities life expectancy has increased significantly. The underlying pathology is a defect of chromosome 7, which encodes the regulation of the fluid balance across the cell membrane which effects chloride as well as sodium. The exocrine glands produce a viscous mucus which obstructs the airways and promotes infections. The result is the destruction of lung parenchyma. In daily routine, chest x-ray is still the most important radiological tool, although computed tomography depicts changes in morphology earlier and more exactly. Recent research studies show that MRI has - because of its additional functional options - interesting aspects for the future. (orig.) [de

Regional quantification of lung function in cystic fibrosis using hyperpolarized xenon-129 and chemical shift imaging

OpenAIRE

Fernandes, Carolina Campanha

2012-01-01

Tese de mestrado em Engenharia Biomédica e Biofísica (Radiações em Diagnóstico e Terapia), apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2012 Cystic fibrosis (CF) is a genetic disorder in which the defective gene causes the production of unusually thick and viscous mucus that builds-up in the airways, leading to impaired ventilation and infection of lung structures. Currently, there is a lack of methods capable of routinely assessing, in a regional manner, basic p...

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 ...

Morin Attenuates Ovalbumin-Induced Airway Inflammation by Modulating Oxidative Stress-Responsive MAPK Signaling

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Yuan Ma

2016-01-01

Full Text Available Asthma is one of the most common inflammatory diseases characterized by airway hyperresponsiveness, inflammation, and remodeling. Morin, an active ingredient obtained from Moraceae plants, has been demonstrated to have promising anti-inflammatory activities in a range of disorders. However, its impacts on pulmonary diseases, particularly on asthma, have not been clarified. This study was designed to investigate whether morin alleviates airway inflammation in chronic asthma with an emphasis on oxidative stress modulation. In vivo, ovalbumin- (OVA- sensitized mice were administered with morin or dexamethasone before challenge. Bronchoalveolar lavage fluid (BALF and lung tissues were obtained to perform cell counts, histological analysis, and enzyme-linked immunosorbent assay. In vitro, human bronchial epithelial cells (BECs were challenged by tumor necrosis factor alpha (TNF-α. The supernatant was collected for the detection of the proinflammatory proteins, and the cells were collected for reactive oxygen species (ROS/mitogen-activated protein kinase (MAPK evaluations. Severe inflammatory responses and remodeling were observed in the airways of the OVA-sensitized mice. Treatment with morin dramatically attenuated the extensive trafficking of inflammatory cells into the BALF and inhibited their infiltration around the respiratory tracts and vessels. Morin administration also significantly suppressed goblet cell hyperplasia and collagen deposition/fibrosis and dose-dependently inhibited the OVA-induced increases in IgE, TNF-α, interleukin- (IL- 4, IL-13, matrix metalloproteinase-9, and malondialdehyde. In human BECs challenged by TNF-α, the levels of proteins such as eotaxin-1, monocyte chemoattractant protein-1, IL-8 and intercellular adhesion molecule-1, were consistently significantly decreased by morin. Western blotting and the 2′,7′-dichlorofluorescein assay revealed that the increases in intracellular ROS and MAPK phosphorylation were

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 ...

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....

Role of Interaction and Nucleoside Diphosphate Kinase B in Regulation of the Cystic Fibrosis Transmembrane Conductance Regulator Function by cAMP-Dependent Protein Kinase A.

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Lee A Borthwick

Full Text Available Cystic fibrosis results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR, a cAMP-dependent protein kinase A (PKA and ATP-regulated chloride channel. Here, we demonstrate that nucleoside diphosphate kinase B (NDPK-B, NM23-H2 forms a functional complex with CFTR. In airway epithelia forskolin/IBMX significantly increases NDPK-B co-localisation with CFTR whereas PKA inhibitors attenuate complex formation. Furthermore, an NDPK-B derived peptide (but not its NDPK-A equivalent disrupts the NDPK-B/CFTR complex in vitro (19-mers comprising amino acids 36-54 from NDPK-B or NDPK-A. Overlay (Far-Western and Surface Plasmon Resonance (SPR analysis both demonstrate that NDPK-B binds CFTR within its first nucleotide binding domain (NBD1, CFTR amino acids 351-727. Analysis of chloride currents reflective of CFTR or outwardly rectifying chloride channels (ORCC, DIDS-sensitive showed that the 19-mer NDPK-B peptide (but not its NDPK-A equivalent reduced both chloride conductances. Additionally, the NDPK-B (but not NDPK-A peptide also attenuated acetylcholine-induced intestinal short circuit currents. In silico analysis of the NBD1/NDPK-B complex reveals an extended interaction surface between the two proteins. This binding zone is also target of the 19-mer NDPK-B peptide, thus confirming its capability to disrupt NDPK-B/CFTR complex. We propose that NDPK-B forms part of the complex that controls chloride currents in epithelia.

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.

Impaired Lymphocyte Profile in Schistosomiasis Patients with Periportal Fibrosis

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Luciana Santos Cardoso

2013-01-01

Full Text Available The Th2 immune response in chronic schistosomiasis is associated with the development of periportal fibrosis. However, little is known about the phenotype and activation status of T cells in the process. Objective. To evaluate the profile of T cells in schistosomiasis patients with periportal fibrosis. Methods. It was a cross-sectional study, conducted in the village of Agua Preta, Bahia, Brazil, which included 37 subjects with periportal fibrosis determined by ultrasound. Peripheral blood mononuclear cells were obtained by the Ficcol-hypaque gradient and the frequency of T cells expressing the surface markers CD28, CD69, CD25, and CTLA-4 was determined by flow cytometry. Results. The frequency of CD4+CD28+ T lymphocytes was higher in individuals with moderate to severe fibrosis compared to patients with incipient fibrosis. We did not observe any significant difference in the frequency of CD4+ T cells expressing CD69 among groups of individuals. There was also no significant difference in the frequency of CD8+ T cells expressing CD28 or CD69 among the studied groups. Individuals with moderate to severe fibrosis presented a lower frequency of CD8+ T cells, CD4+CD25high T cells, and CD4+CTLA-4+ T cells when compared to patients without fibrosis or incipient fibrosis. The frequency of CD4+CD25low cells did not differ between groups. Conclusion. The high frequency of activated T cells coinciding with a low frequency of putative Treg cells may account for the development of periportal fibrosis in human schistosomiasis.

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

TALENs Facilitate Single-step Seamless SDF Correction of F508del CFTR in Airway Epithelial Submucosal Gland Cell-derived CF-iPSCs

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Shingo Suzuki

2016-01-01

Full Text Available Cystic fibrosis (CF is a recessive inherited disease associated with multiorgan damage that compromises epithelial and inflammatory cell function. Induced pluripotent stem cells (iPSCs have significantly advanced the potential of developing a personalized cell-based therapy for diseases like CF by generating patient-specific stem cells that can be differentiated into cells that repair tissues damaged by disease pathology. The F508del mutation in airway epithelial cell-derived CF-iPSCs was corrected with small/short DNA fragments (SDFs and sequence-specific TALENs. An allele-specific PCR, cyclic enrichment strategy gave ≃100-fold enrichment of the corrected CF-iPSCs after six enrichment cycles that facilitated isolation of corrected clones. The seamless SDF-based gene modification strategy used to correct the CF-iPSCs resulted in pluripotent cells that, when differentiated into endoderm/airway-like epithelial cells showed wild-type (wt airway epithelial cell cAMP-dependent Cl ion transport or showed the appropriate cell-type characteristics when differentiated along mesoderm/hematopoietic inflammatory cell lineage pathways.

TRPV1 inhibition attenuates IL-13 mediated asthma features in mice by reducing airway epithelial injury.

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Rehman, Rakhshinda; Bhat, Younus Ahmad; Panda, Lipsa; Mabalirajan, Ulaganathan

2013-03-01

Even though neurogenic axis is well known in asthma pathogenesis much attention had not been given on this aspect. Recent studies have reported the importance of TRP channels, calcium-permeable ion channels and key molecules in neurogenic axis, in asthma therapeutics. The role of TRPV1 channels has been underestimated in chronic respiratory diseases as TRPV1 knockout mice of C57BL/6 strains did not attenuate the features of these diseases. However, this could be due to strain differences in the distribution of airway capsaicin receptors. Here, we show that TRPV1 inhibition attenuates IL-13 induced asthma features by reducing airway epithelial injury in BALB/c mice. We found that IL-13 increased not only the lung TRPV1 levels but also TRPV1 expression in bronchial epithelia in BALB/c rather than in C57BL/6 mice. TRPV1 knockdown attenuated airway hyperresponsiveness, airway inflammation, goblet cell metaplasia and subepithelial fibrosis induced by IL-13 in BALB/c mice. Further, TRPV1 siRNA treatment reduced not only the cytosolic calpain and mitochondrial calpain 10 activities in the lung but also bronchial epithelial apoptosis indicating that TRPV1 siRNA might have corrected the intracellular and intramitochondrial calcium overload and its consequent apoptosis. Knockdown of IL-13 in allergen induced asthmatic mice reduced TRPV1, cytochrome c, and activities of calpain and caspase 3 in lung cytosol. Thus, these findings suggest that induction of TRPV1 with IL-13 in bronchial epithelia could lead to epithelial injury in in vivo condition. Since TRPV1 expression is correlated with human asthma severity, TRPV1 inhibition could be beneficial in attenuating airway epithelial injury and asthma features. Copyright © 2013 Elsevier B.V. All rights reserved.

Relative contribution of Prevotella intermedia and Pseudomonas aeruginosa to lung pathology in airways of patients with cystic fibrosis

DEFF Research Database (Denmark)

Ulrich, Martina; Beer, Isabelle; Braitmaier, Peter

2010-01-01

Patients with cystic fibrosis (CF) with Pseudomonas aeruginosa lung infections produce endobronchial mucus plugs allowing growth of obligate anaerobes including Prevotella spp. Whether obligate anaerobes contribute to the pathophysiology of CF lung disease is unknown....

Effect of enterovirus D68 on Lung Clearance Index in patients with cystic fibrosis: A case report

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Danielle M. Goetz

2015-01-01

Full Text Available Cystic fibrosis (CF causes airways obstruction and a decline in percent predicted forced expiratory volume in 1 s (FEV1%. FEV1% is an objective measure of a pulmonary exacerbation of CF; improvement in FEV1% is the endpoint used often to determine success of treatment of these acute declines in pulmonary health. Lung Clearance Index (LCI, derived from multiple breath inert gas washout (MBW test, measures ventilation inhomogeneity and small airways dysfunction. In the United States in 2014–2015, enterovirus D68 (EV-D68, a novel virus, led to hospitalizations in children because of respiratory distress. This report describes 2 patients with CF admitted for pulmonary exacerbations who were enrolled in an inpatient study to assess patient satisfaction and utility of MBW to measure LCI. Diagnostic testing indicated that these patients were infected with EV-D68. Although their FEV1% improved to their previous baseline following treatment for pulmonary exacerbation, it was discordant with LCI. We discuss LCI as a novel measure of pulmonary function and hypothesize that, based on these cases, it may be a more sensitive indicator of ongoing post-viral airways dysfunction as compared to FEV1%.

PAI-1 gain-of-function genotype, factors increasing PAI-1 levels, and airway obstruction: The GALA II Cohort.

Science.gov (United States)

Sherenian, M G; Cho, S H; Levin, A; Min, J-Y; Oh, S S; Hu, D; Galanter, J; Sen, S; Huntsman, S; Eng, C; Rodriguez-Santana, J R; Serebrisky, D; Avila, P C; Kalhan, R; Smith, L J; Borrell, L N; Seibold, M A; Keoki Williams, L; Burchard, E G; Kumar, R

2017-09-01

PAI-1 gain-of-function variants promote airway fibrosis and are associated with asthma and with worse lung function in subjects with asthma. We sought to determine whether the association of a gain-of-function polymorphism in plasminogen activator inhibitor-1 (PAI-1) with airway obstruction is modified by asthma status, and whether any genotype effect persists after accounting for common exposures that increase PAI-1 level. We studied 2070 Latino children (8-21y) with genotypic and pulmonary function data from the GALA II cohort. We estimated the relationship of the PAI-1 risk allele with FEV1/FVC by multivariate linear regression, stratified by asthma status. We examined the association of the polymorphism with asthma and airway obstruction within asthmatics via multivariate logistic regression. We replicated associations in the SAPPHIRE cohort of African Americans (n=1056). Secondary analysis included the effect of the at-risk polymorphism on postbronchodilator lung function. There was an interaction between asthma status and the PAI-1 polymorphism on FEV 1 /FVC (P=.03). The gain-of-function variants, genotypes (AA/AG), were associated with lower FEV 1 /FVC in subjects with asthma (β=-1.25, CI: -2.14,-0.35, P=.006), but not in controls. Subjects with asthma and the AA/AG genotypes had a 5% decrease in FEV 1 /FVC (P<.001). In asthmatics, the risk genotype (AA/AG) was associated with a 39% increase in risk of clinically relevant airway obstruction (OR=1.39, CI: 1.01, 1.92, P=.04). These associations persisted after exclusion of factors that increase PAI-1 including tobacco exposure and obesity. The decrease in the FEV 1 /FVC ratio associated with the risk genotype was modified by asthma status. The genotype increased the odds of airway obstruction by 75% within asthmatics only. As exposures known to increase PAI-1 levels did not mitigate this association, PAI-1 may contribute to airway obstruction in the context of chronic asthmatic airway inflammation. © 2017

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

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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.

Airway management in neuroanesthesiology.

Science.gov (United States)

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.

What did we learn from two decades of chest computed tomography in cystic fibrosis?

International Nuclear Information System (INIS)

Tiddens, Harm A.W.M.; Rosenow, Tim

2014-01-01

Despite our current treatment, many cystic fibrosis (CF) patients still show progressive bronchiectasis and small airways disease. Adequate detection and monitoring of progression of these structural abnormalities is needed to personalize treatment to the severity of CF lung disease of the patient. Chest computed tomography (CT) is the gold standard to diagnose and monitor bronchiectasis. Many studies have been done to validate the role of chest CT in CF and to improve the protocols. From these studies it became clear that for correct interpretation of the severity of bronchiectasis and small airways disease standardization of lung volume for the inspiratory and expiratory CT scan acquisition is needed. The risk related to the radiation exposure of a chest CT scan every second year is considered low. Automated and quantitative image analysis systems are developed to improve the reliability and sensitivity of assessments of structural lung changes in CF, particularly in early life. In this paper an overview is given of the lessons learned from two decades of monitoring CF lung disease using chest CT. (orig.)

What did we learn from two decades of chest computed tomography in cystic fibrosis?

Energy Technology Data Exchange (ETDEWEB)

Tiddens, Harm A.W.M. [Erasmus MC-Sophia Children' s Hospital, Department of Pediatric Pulmonology, Rotterdam (Netherlands); Erasmus MC, Department of Radiology, Rotterdam (Netherlands); Rosenow, Tim [Erasmus MC-Sophia Children' s Hospital, Department of Pediatric Pulmonology, Rotterdam (Netherlands); The University of Western Australia, Telethon Institute for Child Health Research, Perth (Australia); The University of Western Australia, School of Paediatrics and Child Health Research, Perth (Australia)

2014-12-15

Despite our current treatment, many cystic fibrosis (CF) patients still show progressive bronchiectasis and small airways disease. Adequate detection and monitoring of progression of these structural abnormalities is needed to personalize treatment to the severity of CF lung disease of the patient. Chest computed tomography (CT) is the gold standard to diagnose and monitor bronchiectasis. Many studies have been done to validate the role of chest CT in CF and to improve the protocols. From these studies it became clear that for correct interpretation of the severity of bronchiectasis and small airways disease standardization of lung volume for the inspiratory and expiratory CT scan acquisition is needed. The risk related to the radiation exposure of a chest CT scan every second year is considered low. Automated and quantitative image analysis systems are developed to improve the reliability and sensitivity of assessments of structural lung changes in CF, particularly in early life. In this paper an overview is given of the lessons learned from two decades of monitoring CF lung disease using chest CT. (orig.)

Asthma and cystic fibrosis: a tangled web.

Science.gov (United States)

Kent, Brian D; Lane, Stephen J; van Beek, Edwin J; Dodd, Jonathan D; Costello, Richard W; Tiddens, Harm A W M

2014-03-01

Successfully diagnosing concomitant asthma in people with cystic fibrosis (CF) is a challenging proposition, and the utility of conventional diagnostic criteria of asthma in CF populations remains uncertain. Nonetheless, the accurate identification of individuals with CF and asthma allows appropriate tailoring of therapy, and should reduce the unnecessary use of asthma medication in broader CF cohorts. In this review, we discuss the diagnostic challenge posed by asthma in CF, both in terms of clinical evaluation, and of interpretation of pulmonary function testing and non-invasive markers of airway inflammation. We also examine how the role of cross-sectional thoracic imaging in CF and asthma can assist in the diagnosis of asthma in these patients. Finally, we critically appraise the evidence base behind the use of asthma medications in CF populations, with a particular focus on the use of inhaled corticosteroids and bronchodilators. As shall be discussed, the gaps in the current literature make further high-quality research in this field imperative. © 2014 Wiley Periodicals, Inc.

Cysteamine re-establishes the clearance of Pseudomonas aeruginosa by macrophages bearing the cystic fibrosis-relevant F508del-CFTR mutation.

Science.gov (United States)

Ferrari, Eleonora; Monzani, Romina; Villella, Valeria R; Esposito, Speranza; Saluzzo, Francesca; Rossin, Federica; D'Eletto, Manuela; Tosco, Antonella; De Gregorio, Fabiola; Izzo, Valentina; Maiuri, Maria C; Kroemer, Guido; Raia, Valeria; Maiuri, Luigi

2017-01-12

Cystic fibrosis (CF), the most common lethal monogenic disease in Caucasians, is characterized by recurrent bacterial infections and colonization, mainly by Pseudomonas aeruginosa, resulting in unresolved airway inflammation. CF is caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which functions as a chloride channel in epithelial cells, macrophages, and other cell types. Impaired bacterial handling by macrophages is a feature of CF airways, although it is still debated how defective CFTR impairs bacterial killing. Recent evidence indicates that a defective autophagy in CF macrophages leads to alterations of bacterial clearance upon infection. Here we use bone marrow-derived macrophages from transgenic mice to provide the genetic proof that defective CFTR compromises both uptake and clearance of internalized Pseudomonas aeruginosa. We demonstrate that the proteostasis regulator cysteamine, which rescues the function of the most common F508del-CFTR mutant and hence reduces lung inflammation in CF patients, can also repair the defects of CF macrophages, thus restoring both bacterial internalization and clearance through a process that involves upregulation of the pro-autophagic protein Beclin 1 and re-establishment of the autophagic pathway. Altogether these results indicate that cysteamine restores the function of several distinct cell types, including that of macrophages, which might contribute to its beneficial effects on CF.

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...

Familial Pulmonary Fibrosis

Science.gov (United States)

... Education & Training Home Conditions Familial Pulmonary Fibrosis Familial Pulmonary Fibrosis Make an Appointment Find a Doctor Ask a ... more members within the same family have Idiopathic Pulmonary Fibrosis (IPF) or any other form of Idiopathic Interstitial ...

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...

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.

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)

Inefficient cationic lipid-mediated siRNA and antisense oligonucleotide transfer to airway epithelial cells in vivo

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Hu Jim

2006-02-01

Full Text Available Abstract Background The cationic lipid Genzyme lipid (GL 67 is the current "gold-standard" for in vivo lung gene transfer. Here, we assessed, if GL67 mediated uptake of siRNAs and asODNs into airway epithelium in vivo. Methods Anti-lacZ and ENaC (epithelial sodium channel siRNA and asODN were complexed to GL67 and administered to the mouse airway epithelium in vivo Transfection efficiency and efficacy were assessed using real-time RT-PCR as well as through protein expression and functional studies. In parallel in vitro experiments were carried out to select the most efficient oligonucleotides. Results In vitro, GL67 efficiently complexed asODNs and siRNAs, and both were stable in exhaled breath condensate. Importantly, during in vitro selection of functional siRNA and asODN we noted that asODNs accumulated rapidly in the nuclei of transfected cells, whereas siRNAs remained in the cytoplasm, a pattern consistent with their presumed site of action. Following in vivo lung transfection siRNAs were only visible in alveolar macrophages, whereas asODN also transfected alveolar epithelial cells, but no significant uptake into conducting airway epithelial cells was seen. SiRNAs and asODNs targeted to β-galactosidase reduced βgal mRNA levels in the airway epithelium of K18-lacZ mice by 30% and 60%, respectively. However, this was insufficient to reduce protein expression. In an attempt to increase transfection efficiency of the airway epithelium, we increased contact time of siRNA and asODN using the in vivo mouse nose model. Although highly variable and inefficient, transfection of airway epithelium with asODN, but not siRNA, was now seen. As asODNs more effectively transfected nasal airway epithelial cells, we assessed the effect of asODN against ENaC, a potential therapeutic target in cystic fibrosis; no decrease in ENaC mRNA levels or function was detected. Conclusion This study suggests that although siRNAs and asODNs can be developed to inhibit

Microtubules Enable the Planar Cell Polarity of Airway Cilia

Science.gov (United States)

Vladar, Eszter K.; Bayly, Roy D.; Sangoram, Ashvin; Scott, Matthew P.; Axelrod, Jeffrey D.

2012-01-01

Summary Background Airway cilia must be physically oriented along the longitudinal tissue axis for concerted, directional motility that is essential for proper mucociliary clearance. Results We show that Planar Cell Polarity (PCP) signaling specifies directionality and orients respiratory cilia. Within all airway epithelial cells a conserved set of PCP proteins shows interdependent, asymmetric junctional localization; non-autonomous signaling coordinates polarization between cells; and a polarized microtubule (MT) network is likely required for asymmetric PCP protein localization. We find that basal bodies dock after polarity of PCP proteins is established, are polarized nearly simultaneously, and refinement of basal body/cilium orientation continues during airway epithelial development. Unique to mature multiciliated cells, we identify PCP-regulated, planar polarized MTs that originate from basal bodies and interact, via their plus ends, with membrane domains associated with the PCP proteins Frizzled and Dishevelled. Disruption of MTs leads to misoriented cilia. Conclusions A conserved PCP pathway orients airway cilia by communicating polarity information from asymmetric membrane domains at the apical junctions, through MTs, to orient the MT and actin based network of ciliary basal bodies below the apical surface. PMID:23122850

Relapsing polychondritis and airway involvement.

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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.

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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.

Cohort Study of Airway Mycobiome in Adult Cystic Fibrosis Patients: Differences in Community Structure between Fungi and Bacteria Reveal Predominance of Transient Fungal Elements

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Sauer-Heilborn, Annette; Welte, Tobias; Guzman, Carlos A.; Abraham, Wolf-Rainer; Höfle, Manfred G.

2015-01-01

The respiratory mycobiome is an important but understudied component of the human microbiota. Like bacteria, fungi can cause severe lung diseases, but their infection rates are much lower. This study compared the bacterial and fungal communities of sputum samples from a large cohort of 56 adult patients with cystic fibrosis (CF) during nonexacerbation periods and under continuous antibiotic treatment. Molecular fingerprinting based on single-strand conformation polymorphism (SSCP) analysis revealed fundamental differences between bacterial and fungal communities. Both groups of microorganisms were taxonomically classified by identification of gene sequences (16S rRNA and internal transcript spacer), and prevalences of single taxa were determined for the entire cohort. Major bacterial pathogens were frequently observed, whereas fungi of known pathogenicity in CF were detected only in low numbers. Fungal species richness increased without reaching a constant level (saturation), whereas bacterial richness showed saturation after 50 patients were analyzed. In contrast to bacteria, a large number of fungal species were observed together with high fluctuations over time and among patients. These findings demonstrated that the mycobiome was dominated by transient species, which strongly suggested that the main driving force was their presence in inhaled air rather than colonization. Considering the high exposure of human airways to fungal spores, we concluded that fungi have low colonization abilities in CF, and colonization by pathogenic fungal species may be considered a rare event. A comprehensive understanding of the conditions promoting fungal colonization may offer the opportunity to prevent colonization and substantially reduce or even eliminate fungus-related disease progression in CF. PMID:26135861

Endoscopic diode-laser applications in airway surgery

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Pankratov, Michail M.; Wang, Zhi; Rebeiz, Elie E.; Perrault, Donald F., Jr.; Shapshay, Stanley M.; Gleich, Lyon L.

1994-09-01

A technique was developed to secure small mucosal grafts onto the airway wound with fibrin/albumin tissue adhesive mixed with ICG dye and irradiated with a 810 nm diode laser. An in vitro study of the tensile strength produced strong mucosal soldering which was adequate to fix grafts in place. In vivo studies showed that wounds with mucosal grafts were completely covered by regenerated squamous cells in 1 week and by ciliated epithelium in 2 weeks. Excellent healing was observed at 6 and 14 days postoperatively and the histology at 28 days found normal epithelium over the vocal cord lesion. This soldering technique is a less traumatic treatment for patients with extensive lesions of the larynx of various origin. Diode laser soldering with ICG-doped fibrin tissue adhesive was evaluated in tracheal anastomosis as a substitute for absorbable sutures. In vitro studies demonstrated strong anastomoses with minimal tissue damage. In vivo animal study showed that these anastomoses had less fibrosis and tissue damage than control animals repaired with sutures only.

Muc5b is required for airway defence

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Roy, Michelle G.; Livraghi-Butrico, Alessandra; Fletcher, Ashley A.; McElwee, Melissa M.; Evans, Scott E.; Boerner, Ryan M.; Alexander, Samantha N.; Bellinghausen, Lindsey K.; Song, Alfred S.; Petrova, Youlia M.; Tuvim, Michael J.; Adachi, Roberto; Romo, Irlanda; Bordt, Andrea S.; Bowden, M. Gabriela; Sisson, Joseph H.; Woodruff, Prescott G.; Thornton, David J.; Rousseau, Karine; de La Garza, Maria M.; Moghaddam, Seyed J.; Karmouty-Quintana, Harry; Blackburn, Michael R.; Drouin, Scott M.; Davis, C. William; Terrell, Kristy A.; Grubb, Barbara R.; O'Neal, Wanda K.; Flores, Sonia C.; Cota-Gomez, Adela; Lozupone, Catherine A.; Donnelly, Jody M.; Watson, Alan M.; Hennessy, Corinne E.; Keith, Rebecca C.; Yang, Ivana V.; Barthel, Lea; Henson, Peter M.; Janssen, William J.; Schwartz, David A.; Boucher, Richard C.; Dickey, Burton F.; Evans, Christopher M.

2014-01-01

Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them through mucociliary clearance (MCC). However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus. Genetic variants are linked to diverse lung diseases, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that mouse Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally. Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL-23) production was reduced in Muc5b-/- mice. By contrast, in mice that transgenically overexpress Muc5b, macrophage functions improved. Existing dogma defines mucous phenotypes in asthma and chronic obstructive pulmonary disease (COPD) as driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%. By distinguishing a specific role for Muc5b in MCC, and by determining its impact on bacterial infections and inflammation in mice, our results provide a refined framework for designing targeted therapies to control mucin secretion and restore MCC.

Intrapulmonary Versus Nasal Transduction of Murine Airways With GP64-pseudotyped Viral Vectors

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Mayumi Oakland

2013-01-01

Full Text Available Persistent viral vector-mediated transgene expression in the airways requires delivery to cells with progenitor capacity and avoidance of immune responses. Previously, we observed that GP64-pseudotyped feline immunodeficiency virus (FIV-mediated gene transfer was more efficient in the nasal airways than the large airways of the murine lung. We hypothesized that in vivo gene transfer was limited by immunological and physiological barriers in the murine intrapulmonary airways. Here, we systematically investigate multiple potential barriers to lentiviral gene transfer in the airways of mice. We show that GP64-FIV vector transduced primary cultures of well-differentiated murine nasal epithelia with greater efficiency than primary cultures of murine tracheal epithelia. We further demonstrate that neutrophils, type I interferon (IFN responses, as well as T and B lymphocytes are not the major factors limiting the transduction of murine conducting airways. In addition, we observed better transduction of GP64-pseudotyped vesicular stomatitis virus (VSV in the nasal epithelia compared with the intrapulmonary airways in mice. VSVG glycoprotein pseudotyped VSV transduced intrapulmonary epithelia with similar efficiency as nasal epithelia. Our results suggest that the differential transduction efficiency of nasal versus intrapulmonary airways by FIV vector is not a result of immunological barriers or surface area, but rather differential expression of cellular factors specific for FIV vector transduction.

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.

Cationic Amphiphiles Increase Activity of Aminoglycoside Antibiotic Tobramycin in the Presence of Airway Polyelectrolytes

International Nuclear Information System (INIS)

Purdy Drew, Kirstin R.; Sanders, Lori K.; Culumber, Zachary W.; Zribi, Olena; Wong, Gerard C.L.

2009-01-01

It is empirically known that anionic polyelectrolytes present in cystic fibrosis (CF) airways due to bacterial infection significantly decrease the activity of cationic antimicrobials via electrostatic binding. In this work, we use synchrotron small-angle X-ray scattering to investigate the interaction between tobramycin, an aminoglycoside antibiotic commonly administered to CF patients via inhalation, with DNA, which is found in high concentrations in the CF airway. We find that interactions between DNA and tobramycin are significantly modified by the presence of mixtures of amphiphilic molecules. We measure a hierarchy of self-assembled structures formed between tobramycin, DNA, and the amphiphile mixtures and show how interactions between these components can be controlled. Results indicate that mixtures of cationic and negative curvature amphiphiles optimized for DNA binding via charge matching and curvature matching can competitively displace bound tobramycin from DNA and thereby drastically suppress tobramycin-DNA binding and resultant antimicrobial inactivation. Growth inhibition assays confirm the increased activity of tobramycin in the presence of DNA with the addition of the amphiphiles. These results suggest that optimized cationic amphiphile solutions have the potential to enhance antimicrobial function in highly infected environments that contain increased concentrations of anionic inflammatory polymers.

Cationic Amphiphiles Increase Activity of Aminoglycoside Antibiotic Tobramycin in the Presence of Airway Polyelectrolytes

International Nuclear Information System (INIS)

Drew, K.R.Purdy; Sanders, L.K.; Culumber, Z.W.; Zribi, O.; Wong, G.C.L.

2009-01-01

It is empirically known that anionic polyelectrolytes present in cystic fibrosis (CF) airways due to bacterial infection significantly decrease the activity of cationic antimicrobials via electrostatic binding. In this work, we use synchrotron small-angle X-ray scattering to investigate the interaction between tobramycin, an aminoglycoside antibiotic commonly administered to CF patients via inhalation, with DNA, which is found in high concentrations in the CF airway. We find that interactions between DNA and tobramycin are significantly modified by the presence of mixtures of amphiphilic molecules. We measure a hierarchy of self-assembled structures formed between tobramycin, DNA, and the amphiphile mixtures and show how interactions between these components can be controlled. Results indicate that mixtures of cationic and negative curvature amphiphiles optimized for DNA binding via charge matching and curvature matching can competitively displace bound tobramycin from DNA and thereby drastically suppress tobramycin-DNA binding and resultant antimicrobial inactivation. Growth inhibition assays confirm the increased activity of tobramycin in the presence of DNA with the addition of the amphiphiles. These results suggest that optimized cationic amphiphile solutions have the potential to enhance antimicrobial function in highly infected environments that contain increased concentrations of anionic inflammatory polymers

Airway Clearance Techniques (ACTs)

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Sound transmission in porcine thorax through airway insonification.

Science.gov (United States)

Peng, Ying; Dai, Zoujun; Mansy, Hansen A; Henry, Brian M; Sandler, Richard H; Balk, Robert A; Royston, Thomas J

2016-04-01

Many pulmonary injuries and pathologies may lead to structural and functional changes in the lungs resulting in measurable sound transmission changes on the chest surface. Additionally, noninvasive imaging of externally driven mechanical wave motion in the chest (e.g., using magnetic resonance elastography) can provide information about lung structural property changes and, hence, may be of diagnostic value. In the present study, a comprehensive computational simulation (in silico) model was developed to simulate sound wave propagation in the airways, lung, and chest wall under normal and pneumothorax conditions. Experiments were carried out to validate the model. Here, sound waves with frequency content from 50 to 700 Hz were introduced into airways of five porcine subjects via an endotracheal tube, and transmitted waves were measured by scanning laser Doppler vibrometry at the chest wall surface. The computational model predictions of decreased sound transmission with pneumothorax were consistent with experimental measurements. The in silico model can also be used to visualize wave propagation inside and on the chest wall surface for other pulmonary pathologies, which may help in developing and interpreting diagnostic procedures that utilize sound and vibration.

Sound transmission in porcine thorax through airway insonification

Science.gov (United States)

Dai, Zoujun; Mansy, Hansen A.; Henry, Brian M.; Sandler, Richard H.; Balk, Robert A.; Royston, Thomas J.

2015-01-01

Many pulmonary injuries and pathologies may lead to structural and functional changes in the lungs resulting in measurable sound transmission changes on the chest surface. Additionally, noninvasive imaging of externally driven mechanical wave motion in the chest (e.g., using magnetic resonance elastography) can provide information about lung structural property changes and, hence, may be of diagnostic value. In the present study, a comprehensive computational simulation (in silico) model was developed to simulate sound wave propagation in the airways, lung, and chest wall under normal and pneumothorax conditions. Experiments were carried out to validate the model. Here, sound waves with frequency content from 50 to 700 Hz were introduced into airways of five porcine subjects via an endotracheal tube, and transmitted waves were measured by scanning laser Doppler vibrometry at the chest wall surface. The computational model predictions of decreased sound transmission with pneumothorax were consistent with experimental measurements. The in silico model can also be used to visualize wave propagation inside and on the chest wall surface for other pulmonary pathologies, which may help in developing and interpreting diagnostic procedures that utilize sound and vibration. PMID:26280512

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.

MUCOCILIARY DYSFUNCTION IN HIV AND SMOKED SUBSTANCE ABUSE

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Srinivasan eChinnapaiyan

2015-10-01

Full Text Available Impaired mucociliary clearance (MCC is a hallmark of acquired chronic airway diseases like chronic bronchitis associated with chronic obstructive pulmonary disease (COPD and asthma. This manifests as microbial colonization of the lung consequently leading to recurrent respiratory infections. People living with HIV demonstrate increased incidence of these chronic airway diseases. Bacterial pneumonia continues to be an important comorbidity in people living with HIV even though anti-retroviral therapy has succeeded in restoring CD4+ cell counts. People living with HIV demonstrate increased microbial colonization of the lower airways. The microbial flora is similar to that observed in diseases like cystic fibrosis and COPD suggesting that mucociliary dysfunction could be a contributing factor to the increased incidence of chronic airway diseases in people living with HIV. The three principal components of the MCC apparatus are, a mucus layer, ciliary beating and a periciliary airway surface liquid (ASL layer that facilitates ciliary beating. Cystic fibrosis transmembrane conductance regulator (CFTR plays a pivotal role in regulating the periciliary airway surface liquid. HIV proteins can suppress all the components of the MCC apparatus by increasing mucus secretion and suppressing CFTR function. This can decrease ASL height leading to suppressed ciliary beating. The effects of HIV on MCC are exacerbated when combined with other aggravating factors like smoking or inhaled substance abuse, which by themselves can suppress one or more components of the MCC system. This review discusses the pathophysiological mechanisms that lead to MCC suppression in people living with HIV who also smoke tobacco or abuse illicit drugs.

Relationship between airway pathophysiology and airway inflammation in older asthmatics

DEFF Research Database (Denmark)

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...

Distribution of airway narrowing responses across generations and at branching points, assessed in vitro by anatomical optical coherence tomography

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Eastwood Peter R

2010-01-01

Full Text Available Abstract Background Previous histological and imaging studies have shown the presence of variability in the degree of bronchoconstriction of airways sampled at different locations in the lung (i.e., heterogeneity. Heterogeneity can occur at different airway generations and at branching points in the bronchial tree. Whilst heterogeneity has been detected by previous experimental approaches, its spatial relationship either within or between airways is unknown. Methods In this study, distribution of airway narrowing responses across a portion of the porcine bronchial tree was determined in vitro. The portion comprised contiguous airways spanning bronchial generations (#3-11, including the associated side branches. We used a recent optical imaging technique, anatomical optical coherence tomography, to image the bronchial tree in three dimensions. Bronchoconstriction was produced by carbachol administered to either the adventitial or luminal surface of the airway. Luminal cross sectional area was measured before and at different time points after constriction to carbachol and airway narrowing calculated from the percent decrease in luminal cross sectional area. Results When administered to the adventitial surface, the degree of airway narrowing was progressively increased from proximal to distal generations (r = 0.80 to 0.98, P Conclusions Our findings demonstrate that the bronchial tree expresses intrinsic serial heterogeneity, such that narrowing increases from proximal to distal airways, a relationship that is influenced by the route of drug administration but not by structural variations accompanying branching sites.

[Indoor fungal exposure: What impact on clinical and biological status regarding Aspergillus during cystic fibrosis].

Science.gov (United States)

Pricope, D; Deneuville, E; Frain, S; Chevrier, S; Belaz, S; Roussey, M; Gangneux, J-P

2015-06-01

The sources of exposure during diseases due to Aspergillus fungi in cystic fibrosis patients are still poorly explored. We assessed home fungal exposure in patients suffering from cystic fibrosis and analysed its impact on the presence of Aspergillus biological markers, the colonisation of airways, as well as the sensitization and Aspergillus serology. Between March 2012 and August 2012, 34 patients benefited from a visit performed by a home environment medical adviser including sampling for mycological analysis. The number of colonies of Aspergillus was not significantly different in the various sampling sites (P=0.251), but the number of non-Aspergillus colonies was much higher in the kitchen (P=0.0045). Subsequently, home fungal exposure was compared between the groups "absence of Aspergillus-related markers" and "presence of Aspergillus-related markers". Home exposure to Aspergillus (P=0.453) and non-Aspergillus (P=0.972) flora was not significant between the 2 groups. Within this series of 34 patients that should be expanded, we note an absence of clear relationship between home exposure and the Aspergillus-linked markers in patients suffering from cystic fibrosis. This result should be taken into account regarding too restrictive hygiene advices provided to families, given the fact that fungal exposure can also results from activities performed away from home. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

In vivo micro-CT assessment of airway remodeling in a flexible OVA-sensitized murine model of asthma.

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Mathieu Lederlin

Full Text Available Airway remodeling is a major pathological feature of asthma. Up to now, its quantification still requires invasive methods. In this study, we aimed at determining whether in vivo micro-computed tomography (micro-CT is able to demonstrate allergen-induced airway remodeling in a flexible mouse model of asthma. Sixty Balb/c mice were challenged intranasally with ovalbumin or saline at 3 different endpoints (Days 35, 75, and 110. All mice underwent plethysmography at baseline and just prior to respiratory-gated micro-CT. Mice were then sacrificed to assess bronchoalveolar lavage and lung histology. From micro-CT images (voxel size = 46×46×46 µm, the numerical values of total lung attenuation, peribronchial attenuation (PBA, and PBA normalized by total lung attenuation were extracted. Each parameter was compared between OVA and control mice and correlation coefficients were calculated between micro-CT and histological data. As compared to control animals, ovalbumin-sensitized mice exhibited inflammation alone (Day 35, remodeling alone (Day 110 or both inflammation and remodeling (Day 75. Normalized PBA was significantly greater in mice exhibiting bronchial remodeling either alone or in combination with inflammation. Normalized PBA correlated with various remodeling markers such as bronchial smooth muscle size or peribronchial fibrosis. These findings suggest that micro-CT may help monitor remodeling non-invasively in asthmatic mice when testing new drugs targeting airway remodeling in pre-clinical studies.

Cystic fibrosis airway secretions exhibit mucin hyperconcentration and increased osmotic pressure

Science.gov (United States)

Henderson, Ashley G.; Ehre, Camille; Button, Brian; Abdullah, Lubna H.; Cai, Li-Heng; Leigh, Margaret W.; DeMaria, Genevieve C.; Matsui, Hiro; Donaldson, Scott H.; Davis, C. William; Sheehan, John K.; Boucher, Richard C.; Kesimer, Mehmet

2014-01-01

The pathogenesis of mucoinfective lung disease in cystic fibrosis (CF) patients likely involves poor mucus clearance. A recent model of mucus clearance predicts that mucus flow depends on the relative mucin concentration of the mucus layer compared with that of the periciliary layer; however, mucin concentrations have been difficult to measure in CF secretions. Here, we have shown that the concentration of mucin in CF sputum is low when measured by immunologically based techniques, and mass spectrometric analyses of CF mucins revealed mucin cleavage at antibody recognition sites. Using physical size exclusion chromatography/differential refractometry (SEC/dRI) techniques, we determined that mucin concentrations in CF secretions were higher than those in normal secretions. Measurements of partial osmotic pressures revealed that the partial osmotic pressure of CF sputum and the retained mucus in excised CF lungs were substantially greater than the partial osmotic pressure of normal secretions. Our data reveal that mucin concentration cannot be accurately measured immunologically in proteolytically active CF secretions; mucins are hyperconcentrated in CF secretions; and CF secretion osmotic pressures predict mucus layer–dependent osmotic compression of the periciliary liquid layer in CF lungs. Consequently, mucin hypersecretion likely produces mucus stasis, which contributes to key infectious and inflammatory components of CF lung disease. PMID:24892808

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. 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.

Airway Clearance Techniques (ACTs)

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Full Text Available ... X close ABOUT CYSTIC FIBROSIS Learn about cystic fibrosis, a genetic disorder that affects the lungs, pancreas, and other organs, and how to treat ... Bone Disease in CF Clinical Care Guidelines Cystic Fibrosis-Related Diabetes Clinical Care ... to Maintain Lung Health Clinical Care Guidelines Lung Transplants Clinical Care ...

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)

Eosinophilic Angiocentric Fibrosis as a Stenosing Lesion in the Subglottis

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Ivan Keogh

2017-01-01

Full Text Available Subglottic Eosinophilic Angiocentric Fibrosis (EAF is an extremely rare disease of an elusive aetiology. It is chronically progressive benign condition that causes narrowing of the subglottic region leading to dysphonia and airway compromise. The diagnosis is historical and imaging is nonspecific. We report a case xc of 56-year-old lady referred to our institution with globus sensation, hoarseness, and mild stridor. Incidental subglottic mass was found at time of diagnostic microlaryngoscopy and biopsy confirmed subglottic EAF. All laboratory investigations were unremarkable. Lesion was removed with laryngeal microdebrider and three courses of intravenous dexamethasone were administered. Patient’s postoperative period was uneventful and had remained disease free for 1 year. To date, no consensus has been reached on the optimal treatment of subglottic EAF. We recommend regular follow-up to detect early recurrence.

Vessel-guided airway tree segmentation

DEFF Research Database (Denmark)

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...

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

Science.gov (United States)

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.

Cystic Fibrosis (CF): Chloride Sweat Test

Science.gov (United States)

... on this topic for: Parents Kids Teens Cystic Fibrosis Cystic Fibrosis and Nutrition Cystic Fibrosis (CF) Respiratory Screen: Sputum Cystic Fibrosis: Diet and Nutrition Cystic Fibrosis Cystic Fibrosis: Diet and Nutrition View more Partner Message ...

Quantitative study of the penetration of insoluble particles into the tissue of the conducting airways

Energy Technology Data Exchange (ETDEWEB)

Gore, D J; Patrick, G [Medical Research Council, Harwell (UK). Radiobiological Research Unit

1982-01-01

A quantitative study is presented of the spatial distribution of both inhaled UO/sub 2/ particles and intra-tracheally administered BaSO/sub 4/ particles in the wall of the airways in the rat. The results show that in the intrapulmonary airways between 7 and 17 days after inhalation, UO/sub 2/ particles are situated most frequently at a depth of 8-10 ..mu..m from the luminal surface. At 24 h in the trachea, BaSO/sub 4/ particles concentrate between 10 and 15 ..mu..m beneath the surface, corresponding to the zone immediately beneath the basement membrane; by 7 days the distribution is broader but otherwise similar. This pattern of retention should assist in assessing the dose from radioactive particles absorbed by the basal cells of the epithelium, which are likely to be the origin of carcinoma of the airways.

The human airway epithelial basal cell transcriptome.

Directory of Open Access Journals (Sweden)

Neil R Hackett

2011-05-01

Full Text Available The human airway epithelium consists of 4 major cell types: ciliated, secretory, columnar and basal cells. During natural turnover and in response to injury, the airway basal cells function as stem/progenitor cells for the other airway cell types. The objective of this study is to better understand human airway epithelial basal cell biology by defining the gene expression signature of this cell population.Bronchial brushing was used to obtain airway epithelium from healthy nonsmokers. Microarrays were used to assess the transcriptome of basal cells purified from the airway epithelium in comparison to the transcriptome of the differentiated airway epithelium. This analysis identified the "human airway basal cell signature" as 1,161 unique genes with >5-fold higher expression level in basal cells compared to differentiated epithelium. The basal cell signature was suppressed when the basal cells differentiated into a ciliated airway epithelium in vitro. The basal cell signature displayed overlap with genes expressed in basal-like cells from other human tissues and with that of murine airway basal cells. Consistent with self-modulation as well as signaling to other airway cell types, the human airway basal cell signature was characterized by genes encoding extracellular matrix components, growth factors and growth factor receptors, including genes related to the EGF and VEGF pathways. Interestingly, while the basal cell signature overlaps that of basal-like cells of other organs, the human airway basal cell signature has features not previously associated with this cell type, including a unique pattern of genes encoding extracellular matrix components, G protein-coupled receptors, neuroactive ligands and receptors, and ion channels.The human airway epithelial basal cell signature identified in the present study provides novel insights into the molecular phenotype and biology of the stem/progenitor cells of the human airway epithelium.

Exposure of neonates to Respiratory Syncytial Virus is critical in determining subsequent airway response in adults

Directory of Open Access Journals (Sweden)

Daly Melissa

2006-08-01

Full Text Available Abstract Background Respiratory syncytial virus (RSV is the most common cause of acute bronchiolitis in infants and the elderly. Furthermore, epidemiological data suggest that RSV infection during infancy is a potent trigger of subsequent wheeze and asthma development. However, the mechanism by which RSV contributes to asthma is complex and remains largely unknown. A recent study indicates that the age of initial RSV infection is a key factor in determining airway response to RSV rechallenge. We hypothesized that severe RSV infection during neonatal development significantly alters lung structure and the pulmonary immune micro-environment; and thus, neonatal RSV infection is crucial in the development of or predisposition to allergic inflammatory diseases such as asthma. Methods To investigate this hypothesis the present study was conducted in a neonatal mouse model of RSV-induced pulmonary inflammation and airway dysfunction. Seven-day-old mice were infected with RSV (2 × 105 TCID50/g body weight and allowed to mature to adulthood. To determine if neonatal RSV infection predisposed adult animals to enhanced pathophysiological responses to allergens, these mice were then sensitized and challenged with ovalbumin. Various endpoints including lung function, histopathology, cytokine production, and cellularity in bronchoalveolar lavage were examined. Results RSV infection in neonates alone led to inflammatory airway disease characterized by airway hyperreactivity, peribronchial and perivascular inflammation, and subepithelial fibrosis in adults. If early RSV infection was followed by allergen exposure, this pulmonary phenotype was exacerbated. The initial response to neonatal RSV infection resulted in increased TNF-α levels in bronchoalveolar lavage. Interestingly, increased levels of IL-13 and mucus hyperproduction were observed almost three months after the initial infection with RSV. Conclusion Neonatal RSV exposure results in long term

Nebulized hypertonic saline decreases IL-8 in sputum of patients with cystic fibrosis.

LENUS (Irish Health Repository)

Reeves, Emer P

2012-02-01

RATIONALE: Inflammation within the cystic fibrosis (CF) lung is mediated by inflammatory chemokines, such as IL-8. IL-8 is protected from proteolytic degradation in the airways by binding to glycosaminoglycans, while remaining active. Evidence that increased hypertonicity of airway secretions induced by hypertonic saline treatment alters levels of IL-8 is lacking. OBJECTIVES: To investigate the antiinflammatory effect of hypertonic saline (HTS) treatment within the CF lung by focusing on IL-8. METHODS: Degradation of IL-8 in CF lung secretions after treatment with glycosaminoglycan lyases and HTS was analyzed by Western blot analysis and ELISA. The ex vivo chemotactic activity of purified neutrophils in response to CF airway secretions was evaluated post nebulization of HTS (7% saline). MEASUREMENTS AND MAIN RESULTS: In vivo CF bronchoalveolar lavage fluid (BALF) IL-8 levels were significantly higher than the control group (P < 0.05). Digesting glycosaminoglycans in CF BALF displaced IL-8 from glycosaminoglycan matrices, rendering the chemokine susceptible to proteolytic cleavage. High sodium concentrations also liberate IL-8 in CF BALF in vitro, and in vivo in CF sputum from patients receiving aerosolized HTS, resulting in degradation of IL-8 and decreased neutrophil chemotactic efficiency. CONCLUSIONS: Glycosaminoglycans possess the ability to influence the chemokine profile of the CF lung by binding and stabilizing IL-8, which promotes neutrophil chemotaxis and activation. Nebulized hypertonic saline treatment disrupts the interaction between glycosaminoglycans and IL-8, rendering IL-8 susceptible to proteolytic degradation with subsequent decrease in neutrophil chemotaxis, thereby facilitating resolution of inflammation.

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 ...

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

Directory of Open Access Journals (Sweden)

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.

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.

Mediators on human airway smooth muscle.

Science.gov (United States)

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.

Asthma and cystic fibrosis: A tangled web.

LENUS (Irish Health Repository)

Kent, Brian D

2014-03-01

Successfully diagnosing concomitant asthma in people with cystic fibrosis (CF) is a challenging proposition, and the utility of conventional diagnostic criteria of asthma in CF populations remains uncertain. Nonetheless, the accurate identification of individuals with CF and asthma allows appropriate tailoring of therapy, and should reduce the unnecessary use of asthma medication in broader CF cohorts. In this review, we discuss the diagnostic challenge posed by asthma in CF, both in terms of clinical evaluation, and of interpretation of pulmonary function testing and non-invasive markers of airway inflammation. We also examine how the role of cross-sectional thoracic imaging in CF and asthma can assist in the diagnosis of asthma in these patients. Finally, we critically appraise the evidence base behind the use of asthma medications in CF populations, with a particular focus on the use of inhaled corticosteroids and bronchodilators. As shall be discussed, the gaps in the current literature make further high-quality research in this field imperative. Pediatr Pulmonol. 2014; 49:205-213. © 2014 Wiley Periodicals, Inc.

Avian Influenza virus glycoproteins restrict virus replication and spread through human airway epithelium at temperatures of the proximal airways.

Directory of Open Access Journals (Sweden)

Margaret A Scull

2009-05-01

Full Text Available 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 proximal airways (32 degrees C. These data support the hypothesis that avian influenza viruses, ordinarily adapted to the temperature of the avian enteric tract (40 degrees C, rarely infect humans, in part due to differences in host airway regional temperatures. Previously, a critical residue at position 627 in the avian influenza virus polymerase subunit, PB2, was identified as conferring temperature-dependency in mammalian cells. Here, we use reverse genetics to show that avianization of residue 627 attenuates a human virus, but does not account for the different infection between 32 degrees C and 37 degrees C. To determine the mechanism of temperature restriction of avian influenza viruses in HAE at 32 degrees C, we generated recombinant human influenza viruses in either the A/Victoria/3/75 (H3N2 or A/PR/8/34 (H1N1 genetic background that contained avian or avian-like glycoproteins. Two of these viruses, A/Victoria/3/75 with L226Q and S228G mutations in hemagglutinin (HA and neuraminidase (NA from A/Chick/Italy/1347/99 and A/PR/8/34 containing the H7 and N1 from A/Chick/Italy/1347/99, exhibited temperature restriction approaching that of wholly avian influenza viruses. These data suggest that influenza viruses bearing avian or avian-like surface glycoproteins have a reduced capacity to establish productive infection at the temperature of the human proximal airways. This temperature restriction may limit zoonotic transmission of avian influenza viruses and

Mechanical interactions between adjacent airways in the lung.

Science.gov (United States)

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.

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.

RAGE: a new frontier in chronic airways disease

Science.gov (United States)

Sukkar, Maria B; Ullah, Md Ashik; Gan, Wan Jun; Wark, Peter AB; Chung, Kian Fan; Hughes, J Margaret; Armour, Carol L; Phipps, Simon

2012-01-01

Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous inflammatory disorders of the respiratory tract characterized by airflow obstruction. It is now clear that the environmental factors that drive airway pathology in asthma and COPD, including allergens, viruses, ozone and cigarette smoke, activate innate immune receptors known as pattern-recognition receptors, either directly or indirectly by causing the release of endogenous ligands. Thus, there is now intense research activity focused around understanding the mechanisms by which pattern-recognition receptors sustain the airway inflammatory response, and how these mechanisms might be targeted therapeutically. One pattern-recognition receptor that has recently come to attention in chronic airways disease is the receptor for advanced glycation end products (RAGE). RAGE is a member of the immunoglobulin superfamily of cell surface receptors that recognizes pathogen- and host-derived endogenous ligands to initiate the immune response to tissue injury, infection and inflammation. Although the role of RAGE in lung physiology and pathophysiology is not well understood, recent genome-wide association studies have linked RAGE gene polymorphisms with airflow obstruction. In addition, accumulating data from animal and clinical investigations reveal increased expression of RAGE and its ligands, together with reduced expression of soluble RAGE, an endogenous inhibitor of RAGE signalling, in chronic airways disease. In this review, we discuss recent studies of the ligand–RAGE axis in asthma and COPD, highlight important areas for future research and discuss how this axis might potentially be harnessed for therapeutic benefit in these conditions. PMID:22506507

Glucocorticoids can affect Pseudomonas aeruginosa (ATCC 27853) internalization and intracellular calcium concentration in cystic fibrosis bronchial epithelial cells.

Science.gov (United States)

Hussain, Rashida; Shahror, Rami; Karpati, Ferenc; Roomans, Godfried M

2015-01-01

Glucocorticoids (GCs) are anti-inflammatory agents, but their use in cystic fibrosis (CF) is controversial. In CF, the early colonization with Pseudomonas aeruginosa is mainly due to nonmucoid strains that can internalize, and induce apoptosis in the epithelial cells. Uptake of P. aeruginosa by the epithelial cells and subsequent apoptosis may prevent colonization of P. aeruginosa in CF airways. In the airway epithelia, several other biological effects, including an anti-secretory role by decreasing intracellular Ca(2+) concentration have been described for this anti-inflammatory drug. However, the effects of GCs on the nonmucoid P. aeruginosa internalization and intracellular Ca(2+) in CF bronchial epithelial cells have not been evaluated. We used cultured human CF bronchial airway epithelial cell (CFBE) monolayers to determine P. aeruginosa internalization, apoptosis, and intracellular Ca(2+)concentration in CF bronchial epithelial cells. Cells were treated with IL-6, IL-8, dexamethasone, betamethasone, or budesonide. GCs in co-treatments with IL-6 reversed the effect of IL-6 by decreasing the internalization of P. aeruginosa in the CFBE cells. GCs decreased the extent of apoptosis in CFBE cells infected with internalized P. aeruginosa, and increased the intracellular Ca(2+) concentration. These findings suggest that if internalization of P. aeruginosa reduces infection, GC therapy would increase the risk of pulmonary infection by decreasing the internalization of P. aeruginosa in CF cells, but GCs may improve airway hydration by increasing the intracellular Ca(2+) concentration. Whether the benefits of GC treatment outweigh the negative effects is questionable, and further clinical studies need to be carried out.

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 ...

Idiopathic pulmonary fibrosis and sleep disorders: no longer strangers in the night

Directory of Open Access Journals (Sweden)

Sophia Schiza

2015-06-01

Full Text Available The prevalence of obstructive sleep apnoea (OSA is continuously increasing in patients with idiopathic pulmonary fibrosis (IPF and, for the first time, the recent IPF guidelines recognise OSA as an important associated comorbidity that can affect patient's survival. Thus, it becomes conceivable that clinicians should refer patients with newly diagnosed IPF to sleep centres for the diagnosis and treatment of OSA as well as for addressing issues regarding the reduced compliance of patients with continuous positive airway pressure therapy. The discovery of biomarkers common to both disorders may help early diagnosis, institution of the most appropriate treatment and follow-up of patients. Better understanding of epigenetic changes may provide useful information about pathogenesis and, possibly, development of new drugs for a dismal disease like IPF.

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...

Cystic fibrosis: case report

International Nuclear Information System (INIS)

Park, Si Hyun; Lee, Hyun Ju; Kim, Ji Hye; Park, Chol Heui

2002-01-01

Cystic fibrosis is an autosomal recessive genetic disease. Among Caucasians, it is the most common cause of pulmonary insufficiency during the first three decades of life. The prevalence of cystic fibrosis varies according to ethnic origin: it is common among Caucasians but rare among Asians. We report a case in which cystic fibrosis with bronchiectasis and hyperaeration was revealed by high-resolution CT, and mutation of the cystic fibrosis conductance transmembrane regulator gene (CFTR) by DNA analysis

Cystic fibrosis: case report

International Nuclear Information System (INIS)

Park, Si Hyun; Lee, Hyun Ju; Kim, Ji Hye; Park, Chol Heui

2002-01-01

Cystic fibrosis is a autosomal recessive genetic disease. Among caucasians, it is the most common cause of pulmonary insufficiency during the first three decades of life. The prevalence of cystic fibrosis varies according to ethnic origin: it is common among caucasians but rare among Asians. We report a case in which cystic fibrosis with bronchiectasis and hyperaeration was revealed by high-resolution CT, and mutation of the cystic fibrosis conductance transmembrane regulator gene (CFTR) by DNA analysis

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 ...

Lung disease phenotypes caused by overexpression of combinations of α-, β-, and γ-subunits of the epithelial sodium channel in mouse airways.

Science.gov (United States)

Livraghi-Butrico, Alessandra; Wilkinson, Kristen J; Volmer, Allison S; Gilmore, Rodney C; Rogers, Troy D; Caldwell, Ray A; Burns, Kimberlie A; Esther, Charles R; Mall, Marcus A; Boucher, Richard C; O'Neal, Wanda K; Grubb, Barbara R

2018-02-01

The epithelial Na + channel (ENaC) regulates airway surface hydration. In mouse airways, ENaC is composed of three subunits, α, β, and γ, which are differentially expressed (α > β > γ). Airway-targeted overexpression of the β subunit results in Na + hyperabsorption, causing airway surface dehydration, hyperconcentrated mucus with delayed clearance, lung inflammation, and perinatal mortality. Notably, mice overexpressing the α- or γ-subunit do not exhibit airway Na + hyperabsorption or lung pathology. To test whether overexpression of multiple ENaC subunits produced Na + transport and disease severity exceeding that of βENaC-Tg mice, we generated double (αβ, αγ, βγ) and triple (αβγ) transgenic mice and characterized their lung phenotypes. Double αγENaC-Tg mice were indistinguishable from WT littermates. In contrast, double βγENaC-Tg mice exhibited airway Na + absorption greater than that of βENaC-Tg mice, which was paralleled by worse survival, decreased mucociliary clearance, and more severe lung pathology. Double αβENaC-Tg mice exhibited Na + transport rates comparable to those of βENaC-Tg littermates. However, αβENaC-Tg mice had poorer survival and developed severe parenchymal consolidation. In situ hybridization (RNAscope) analysis revealed both alveolar and airway αENaC-Tg overexpression. Triple αβγENaC-Tg mice were born in Mendelian proportions but died within the first day of life, and the small sample size prevented analyses of cause(s) of death. Cumulatively, these results indicate that overexpression of βENaC is rate limiting for generation of pathological airway surface dehydration. Notably, airway co-overexpression of β- and γENaC had additive effects on Na + transport and disease severity, suggesting dose dependency of these two variables.

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.

Vitamin D as an anti-microbial and anti-inflammatory therapy for Cystic Fibrosis.

Science.gov (United States)

Herscovitch, K; Dauletbaev, N; Lands, Larry C

2014-06-01

Cystic fibrosis (CF) is characterized by chronic infection and inflammation in the airways that lead to progressive lung damage and early death. Current anti-inflammatory therapies are limited by extensive adverse effects or insufficient efficacy. There is a large body of studies indicating beneficial anti-microbial and anti-inflammatory properties of vitamin D. Since most patients with CF present with vitamin D deficiency, and serum vitamin D levels demonstrate a positive correlation with lung function and negative correlation with airway inflammation and infection, correcting vitamin D deficiency may be an attractive therapeutic strategy in CF. The function of vitamin D is intricately tied to its metabolism, which may be impaired at multiple steps in patients with CF, with a potential to limit the efficacy of vitamin D supplementation. It is likely that the aforementioned beneficial properties of vitamin D require supplementation with doses of vitamin D markedly higher than those recommended to maintain proper bone function. This review will illustrate the potential for supplementation with vitamin D or its metabolites to modulate inflammation and improve defence against chronic infection in CF lung, as well as appropriate vitamin D supplementation strategies for improving lung function in CF. Copyright © 2013 Elsevier Ltd. All rights reserved.

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.

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...

Computationally efficient analysis of particle transport and deposition in a human whole-lung-airway model. Part II: Dry powder inhaler application.

Science.gov (United States)

Kolanjiyil, Arun V; Kleinstreuer, Clement; Sadikot, Ruxana T

2017-05-01

Pulmonary drug delivery is becoming a favored route for administering drugs to treat both lung and systemic diseases. Examples of lung diseases include asthma, cystic fibrosis and chronic obstructive pulmonary disease (COPD) as well as respiratory distress syndrome (ARDS) and pulmonary fibrosis. Special respiratory drugs are administered to the lungs, using an appropriate inhaler device. Next to the pressurized metered-dose inhaler (pMDI), the dry powder inhaler (DPI) is a frequently used device because of the good drug stability and a minimal need for patient coordination. Specific DPI-designs and operations greatly affect drug-aerosol formation and hence local lung deposition. Simulating the fluid-particle dynamics after use of a DPI allows for the assessment of drug-aerosol deposition and can also assist in improving the device configuration and operation. In Part I of this study a first-generation whole lung-airway model (WLAM) was introduced and discussed to analyze particle transport and deposition in a human respiratory tract model. In the present Part II the drug-aerosols are assumed to be injected into the lung airways from a DPI mouth-piece, forming the mouth-inlet. The total as well as regional particle depositions in the WLAM, as inhaled from a DPI, were successfully compared with experimental data sets reported in the open literature. The validated modeling methodology was then employed to study the delivery of curcumin aerosols into lung airways using a commercial DPI. Curcumin has been implicated to possess high therapeutic potential as an antioxidant, anti-inflammatory and anti-cancer agent. However, efficacy of curcumin treatment is limited because of the low bioavailability of curcumin when ingested. Hence, alternative drug administration techniques, e.g., using inhalable curcumin-aerosols, are under investigation. Based on the present results, it can be concluded that use of a DPI leads to low lung deposition efficiencies because large amounts of

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.

Airway structure and function in Eisenmenger's syndrome.

Science.gov (United States)

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.

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.

Effect of Corbrin Capsule combined with routine western medicine on the airway remodeling process in patients with stable COPD

Directory of Open Access Journals (Sweden)

Su-Li Song

2017-08-01

Full Text Available Objective: To explore the effect of Corbrin Capsule combined with routine western medicine on the airway remodeling process in patients with stable COPD. Methods: A total of 120 patients with stable COPD who were treated in the hospital between May 2014 and December 2016 were collected and divided into control group and observation group according to the random number table method, 60 cases in each group. The control group received routine western medicine treatment, and the observation group received Corbrin Capsule combined with routine western medicine treatment. The differences in serum levels of inflammatory factors, growth factors and fibrosis indexes were compared between the two groups before and after treatment. Results: Before treatment, difference in serum levels of inflammatory factors, growth factors and fibrosis indexes were not statistically significant between the two groups of patients. After 8 weeks of treatment, serum IL-2, IL-4, IL-8, IL-18, VEGF, b-FGF, NGF, LN, HA, PⅢNP and C-Ⅳ levels of both groups of patients were significantly lower than those before treatment, and serum IL-2, IL-4, IL-8, IL-18, VEGF, b-FGF, NGF, LN, HA, PⅢNP and C-Ⅳ levels of observation group were lower than those of control group. Conclusion: Corbrin Capsule combined with routine western medicine treatment can effectively inhibit the fibrosis process in patients with stable COPD.

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...

Airway Clearance Techniques (ACTs)

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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...

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 .

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.

Exhaled Breath Condensate Detects Baseline Reductions in Chloride and Increases in Response to Albuterol in Cystic Fibrosis Patients

Directory of Open Access Journals (Sweden)

Courtney M. Wheatley

2013-01-01

Full Text Available Impaired ion regulation and dehydration is the primary pathophysiology in cystic fibrosis (CF lung disease. A potential application of exhaled breath condensate (EBC collection is to assess airway surface liquid ionic composition at baseline and in response to pharmacological therapy in CF. Our aims were to determine if EBC could detect differences in ion regulation between CF and healthy and measure the effect of the albuterol on EBC ions in these populations. Baseline EBC Cl − , DLCO and SpO 2 were lower in CF (n = 16 compared to healthy participants (n = 16. EBC Cl − increased in CF subjects, while there was no change in DLCO or membrane conductance, but a decrease in pulmonary-capillary blood volume in both groups following albuterol. This resulted in an improvement in diffusion at the alveolar-capillary unit, and removal of the baseline difference in SpO 2 by 90-minutes in CF subjects. These results demonstrate that EBC detects differences in ion regulation between healthy and CF individuals, and that albuterol mediates increases in Cl − in CF, suggesting that the benefits of albuterol extend beyond simple bronchodilation.

Fitness of isogenic colony morphology variants of Pseudomonas aeruginosa in murine airway infection.

Directory of Open Access Journals (Sweden)

Elza Rakhimova

Full Text Available Chronic lung infections with Pseudomonas aeruginosa are associated with the diversification of the persisting clone into niche specialists and morphotypes, a phenomenon called 'dissociative behaviour'. To explore the potential of P. aeruginosa to change its morphotype by single step loss-of-function mutagenesis, a signature-tagged mini-Tn5 plasposon library of the cystic fibrosis airway isolate TBCF10839 was screened for colony morphology variants under nine different conditions in vitro. Transposon insertion into 1% of the genome changed colony morphology into eight discernable morphotypes. Half of the 55 targets encode features of primary or secondary metabolism whereby quinolone production was frequently affected. In the other half the transposon had inserted into genes of the functional categories transport, regulation or motility/chemotaxis. To mimic dissociative behaviour of isogenic strains in lungs, pools of 25 colony morphology variants were tested for competitive fitness in an acute murine airway infection model. Six of the 55 mutants either grew better or worse in vivo than in vitro, respectively. Metabolic proficiency of the colony morphology variant was a key determinant for survival in murine airways. The most common morphotype of self-destructive autolysis did unexpectedly not impair fitness. Transposon insertions into homologous genes of strain PAO1 did not reproduce the TBCF10839 mutant morphotypes for 16 of 19 examined loci pointing to an important role of the genetic background on colony morphology. Depending on the chosen P. aeruginosa strain, functional genome scans will explore other areas of the evolutionary landscape. Based on our discordant findings of mutant phenotypes in P. aeruginosa strains PAO1, PA14 and TBCF10839, we conclude that the current focus on few reference strains may miss modes of niche adaptation and dissociative behaviour that are relevant for the microevolution of complex traits in the wild.

High-resolution CT of airway reactivity

International Nuclear Information System (INIS)

Herold, C.J.; Brown, R.H.; Hirshman, C.A.; Mitzner, W.; Zerhouni, E.A.

1990-01-01

Assessment of airway reactivity has generally been limited to experimental nonimaging models. This authors of this paper used high-resolution CT (HRCT) to evaluate airway reactivity and to calculate airway resistance (Raw) compared with lung resistance (RL). Ten anesthetized and ventilated dogs were investigated with HRCT (10 contiguous 2-mm sections through the lower lung lobes) during control state, following aerosol histamine challenge, and following posthistamine hyperinflation. The HRCT scans were digitized, and areas of 10 airways per dog (diameter, 1-10 mm) were measured with a computer edging process. Changes in airway area and Raw (calculated by 1/[area] 2 ) were measured. RL was assessed separately, following the same protocol. Data were analyzed by use of a paired t-test with significance at p < .05

RAGE: a new frontier in chronic airways disease.

Science.gov (United States)

Sukkar, Maria B; Ullah, Md Ashik; Gan, Wan Jun; Wark, Peter A B; Chung, Kian Fan; Hughes, J Margaret; Armour, Carol L; Phipps, Simon

2012-11-01

Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous inflammatory disorders of the respiratory tract characterized by airflow obstruction. It is now clear that the environmental factors that drive airway pathology in asthma and COPD, including allergens, viruses, ozone and cigarette smoke, activate innate immune receptors known as pattern-recognition receptors, either directly or indirectly by causing the release of endogenous ligands. Thus, there is now intense research activity focused around understanding the mechanisms by which pattern-recognition receptors sustain the airway inflammatory response, and how these mechanisms might be targeted therapeutically. One pattern-recognition receptor that has recently come to attention in chronic airways disease is the receptor for advanced glycation end products (RAGE). RAGE is a member of the immunoglobulin superfamily of cell surface receptors that recognizes pathogen- and host-derived endogenous ligands to initiate the immune response to tissue injury, infection and inflammation. Although the role of RAGE in lung physiology and pathophysiology is not well understood, recent genome-wide association studies have linked RAGE gene polymorphisms with airflow obstruction. In addition, accumulating data from animal and clinical investigations reveal increased expression of RAGE and its ligands, together with reduced expression of soluble RAGE, an endogenous inhibitor of RAGE signalling, in chronic airways disease. In this review, we discuss recent studies of the ligand-RAGE axis in asthma and COPD, highlight important areas for future research and discuss how this axis might potentially be harnessed for therapeutic benefit in these conditions. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

SPDEF regulates goblet cell hyperplasia in the airway epithelium

Science.gov (United States)

Park, Kwon-Sik; Korfhagen, Thomas R.; Bruno, Michael D.; Kitzmiller, Joseph A.; Wan, Huajing; Wert, Susan E.; Khurana Hershey, Gurjit K.; Chen, Gang; Whitsett, Jeffrey A.

2007-01-01

Goblet cell hyperplasia and mucous hypersecretion contribute to the pathogenesis of chronic pulmonary diseases including cystic fibrosis, asthma, and chronic obstructive pulmonary disease. In the present work, mouse SAM pointed domain-containing ETS transcription factor (SPDEF) mRNA and protein were detected in subsets of epithelial cells lining the trachea, bronchi, and tracheal glands. SPDEF interacted with the C-terminal domain of thyroid transcription factor 1, activating transcription of genes expressed selectively in airway epithelial cells, including Sftpa, Scgb1a1, Foxj1, and Sox17. Expression of Spdef in the respiratory epithelium of adult transgenic mice caused goblet cell hyperplasia, inducing both acidic and neutral mucins in vivo, and stainined for both acidic and neutral mucins in vivo. SPDEF expression was increased at sites of goblet cell hyperplasia caused by IL-13 and dust mite allergen in a process that was dependent upon STAT-6. SPDEF was induced following intratracheal allergen exposure and after Th2 cytokine stimulation and was sufficient to cause goblet cell differentiation of Clara cells in vivo. PMID:17347682

Airway Clearance Techniques (ACTs)

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Airway Clearance Techniques (ACTs)

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Deep learning for staging liver fibrosis on CT: a pilot study.

Science.gov (United States)

Yasaka, Koichiro; Akai, Hiroyuki; Kunimatsu, Akira; Abe, Osamu; Kiryu, Shigeru

2018-05-14

To investigate whether liver fibrosis can be staged by deep learning techniques based on CT images. This clinical retrospective study, approved by our institutional review board, included 496 CT examinations of 286 patients who underwent dynamic contrast-enhanced CT for evaluations of the liver and for whom histopathological information regarding liver fibrosis stage was available. The 396 portal phase images with age and sex data of patients (F0/F1/F2/F3/F4 = 113/36/56/66/125) were used for training a deep convolutional neural network (DCNN); the data for the other 100 (F0/F1/F2/F3/F4 = 29/9/14/16/32) were utilised for testing the trained network, with the histopathological fibrosis stage used as reference. To improve robustness, additional images for training data were generated by rotating or parallel shifting the images, or adding Gaussian noise. Supervised training was used to minimise the difference between the liver fibrosis stage and the fibrosis score obtained from deep learning based on CT images (F DLCT score) output by the model. Testing data were input into the trained DCNNs to evaluate their performance. The F DLCT scores showed a significant correlation with liver fibrosis stage (Spearman's correlation coefficient = 0.48, p deep learning model based on CT images, with moderate performance. • Liver fibrosis can be staged by a deep learning model based on magnified CT images including the liver surface, with moderate performance. • Scores from a trained deep learning model showed moderate correlation with histopathological liver fibrosis staging. • Further improvement are necessary before utilisation in clinical settings.

Chemotaxis and Binding of Pseudomonas aeruginosa to Scratch-Wounded Human Cystic Fibrosis Airway Epithelial Cells.

Directory of Open Access Journals (Sweden)

Christian Schwarzer

Full Text Available Confocal imaging was used to characterize interactions of Pseudomonas aeruginosa (PA, expressing GFP or labeled with Syto 11 with CF airway epithelial cells (CFBE41o-, grown as confluent monolayers with unknown polarity on coverglasses in control conditions and following scratch wounding. Epithelia and PAO1-GFP or PAK-GFP (2 MOI were incubated with Ringer containing typical extracellular salts, pH and glucose and propidium iodide (PI, to identify dead cells. PAO1 and PAK swam randomly over and did not bind to nonwounded CFBE41o- cells. PA migrated rapidly (began within 20 sec, maximum by 5 mins and massively (10-80 fold increase, termed "swarming", but transiently (random swimming after 15 mins, to wounds, particularly near cells that took up PI. Some PA remained immobilized on cells near the wound. PA swam randomly over intact CFBE41o- monolayers and wounded monolayers that had been incubated with medium for 1 hr. Expression of CFTR and altered pH of the media did not affect PA interactions with CFBE41o- wounds. In contrast, PAO1 swarming and immobilization along wounds was abolished in PAO1 (PAO1ΔcheYZABW, no expression of chemotaxis regulatory components cheY, cheZ, cheA, cheB and cheW and greatly reduced in PAO1 that did not express amino acid receptors pctA, B and C (PAO1ΔpctABC and in PAO1 incubated in Ringer containing a high concentration of mixed amino acids. Non-piliated PAKΔpilA swarmed normally towards wounded areas but bound infrequently to CFBE41o- cells. In contrast, both swarming and binding of PA to CFBE41o- cells near wounds were prevented in non-flagellated PAKΔfliC. Data are consistent with the idea that (i PA use amino acid sensor-driven chemotaxis and flagella-driven swimming to swarm to CF airway epithelial cells near wounds and (ii PA use pili to bind to epithelial cells near wounds.

Mechanisms of humoral immune response against Pseudomonas aeruginosa biofilm infection in cystic fibrosis

DEFF Research Database (Denmark)

Mauch, Renan Marrichi; Jensen, Peter Østrup; Moser, Claus

2018-01-01

P. aeruginosa chronic lung infection is the major cause of morbidity and mortality in patients with cystic fibrosis (CF), and is characterized by a biofilm mode of growth, increased levels of specific IgG antibodies and immune complex formation. However, despite being designed to combat...... this infection, such elevated humoral response is not associated with clinical improvement, pointing to a lack of anti-pseudomonas effectiveness. The mode of action of specific antibodies, as well as their structural features, and even the background involving B-cell production, stimulation and differentiation...... into antibody-producing cells in the CF airways are poorly understood. Thus, the aim of this review is to discuss studies that have addressed the intrinsic features of the humoral immune response and provide new insights regarding its insufficiency in the CF context....

Airway injury during emergency transcutaneous airway access: a comparison at cricothyroid and tracheal sites.

LENUS (Irish Health Repository)

Salah, Nazar

2009-12-01

Oxygenation via the cricothyroid membrane (CTM) may be required in emergencies, but inadvertent tracheal cannulation may occur. In this study, we compared airway injury between the tracheal and CTM sites using different techniques for airway access.

Post-extubation airway obstruction. Literature review

Directory of Open Access Journals (Sweden)

Álvaro SÁNCHEZ-TABERNERO

2017-03-01

Full Text Available Introduction and objective: airway obstruction after extubation in any surgery is a critical event with low incidence, which may require reintubation or tracheostomy, which often otolaryngologist is required. Objective: To determine the prevalence of BVA and its causes through systematic literature review. Method: Literature review in PubMed, Scopus and Cochrane clinical trials, meta-analysis, reviews and case series and control over airway obstruction after extubation that requires reintubation in adults. Results: 6 studies and one clinical practice guidelines were selected. The most common cause of extubation failure is blocking the airway for various reasons (pharyngeal muscle weakness residual effect -often farmacologycal-, laryngospasm, vocal cord paralysis, edema of upper respiratory tract, cervical postoperative hematoma, foreign bodies or secretions. Most cases of re-intubation occurred within 2 hours after extubation. Conclusions: The most common cause of failure after general anesthesia extubation is blocking the airway generally caused by residual neuromuscular blocking effect. Airway obstruction risk increases in airway and head and neck surgery. Difficult intubation guidlines have improved performance and reduced adverse events and similar strategies must be implemented in extubation. The procedure extubation and reintubation should be documented. Working groups airway must be multidisciplinary and include specialists in otolaryngology.

Alcohol and airways function in health and disease.

Science.gov (United States)

Sisson, Joseph H

2007-08-01

The volatility of alcohol promotes the movement of alcohol from the bronchial circulation across the airway epithelium and into the conducting airways of the lung. The exposure of the airways through this route likely accounts for many of the biologic effects of alcohol on lung airway functions. The effect of alcohol on lung airway functions is dependent on the concentration, duration, and route of exposure. Brief exposure to mild concentrations of alcohol may enhance mucociliary clearance, stimulates bronchodilation, and probably attenuates the airway inflammation and injury observed in asthma and chronic obstructive pulmonary disease (COPD). Prolonged and heavy exposure to alcohol impairs mucociliary clearance, may complicate asthma management, and likely worsens outcomes including lung function and mortality in COPD patients. Nonalcohol congeners and alcohol metabolites act as triggers for airway disease exacerbations especially in atopic asthmatics and in Asian populations who have a reduced capacity to metabolize alcohol. Research focused on the mechanisms of alcohol-mediated changes in airway functions has identified specific mechanisms that mediate alcohol effects within the lung airways. These include prominent roles for the second messengers calcium and nitric oxide, regulatory kinases including PKG and PKA, alcohol- and acetaldehyde-metabolizing enzymes such as aldehyde dehydrogenase 2. The role alcohol may play in the pathobiology of airway mucus, bronchial blood flow, airway smooth muscle regulation, and the interaction with other airway exposure agents, such as cigarette smoke, represents opportunities for future investigation.

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Full Text Available ... in CF Clinical Care Guidelines Cystic Fibrosis-Related Diabetes Clinical Care Guidelines Liver Disease Clinical Care Guidelines ... improve the treatment of cystic fibrosis. CFTR Modulator Types Clinical Trials Clinical Trials 101 What to Consider ...

Airway Clearance Techniques (ACTs)

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Full Text Available ... of CFTR Mutations DIAGNOSIS If you or your child has just been diagnosed with cystic fibrosis, or ... Life With CF X close Caring for a Child With CF Raising a child with cystic fibrosis ...

Airway Clearance Techniques (ACTs)

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Airway Clearance Techniques (ACTs)

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Airway Clearance Techniques (ACTs)

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Airway Clearance Techniques (ACTs)

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Airway Clearance Techniques (ACTs)

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Airway Clearance Techniques (ACTs)

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Exercise Training in Children and Adolescents with Cystic Fibrosis: Theory into Practice

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Craig A. Williams

2010-01-01

Full Text Available Physical activity and exercise training play an important role in the clinical management of patients with cystic fibrosis (CF. Exercise training is more common and recognized as an essential part of rehabilitation programmes and overall CF care. Regular exercise training is associated with improved aerobic and anaerobic capacity, higher pulmonary function, and enhanced airway mucus clearance. Furthermore, patients with higher aerobic fitness have an improved survival. Aerobic and anaerobic training may have different effects, while the combination of both have been reported to be beneficial in CF. However, exercise training remains underutilised and not always incorporated into routine CF management. We provide an update on aerobic and anaerobic responses to exercise and general training recommendations in children and adolescents with CF. We propose that an active lifestyle and exercise training are an efficacious part of regular CF patient management.

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

Airway Clearance Techniques (ACTs)

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Regulation of ion transport via apical purinergic receptors in intact rabbit airway epithelium

DEFF Research Database (Denmark)

Poulsen, Asser Nyander; Klausen, Thomas Levin; Pedersen, Peter Steen

2005-01-01

and unidirectional Cl- fluxes decreased significantly. The results suggest that nucleotides released to the airway surface liquid exert an autocrine regulation of epithelial NaCl absorption mainly by inhibiting the amiloride-sensitive epithelial Na+ channel (ENaC) and paracellular anion conductance via a P2Y......We investigated purinergic receptors involved in ion transport regulation in the intact rabbit nasal airway epithelium. Stimulation of apical membrane P2Y receptors with ATP or UTP (200 microM) induced transient increases in short-circuit current (Isc) of 13 and 6% followed by sustained inhibitions...

Volúmenes pulmonares normales en pacientes con fibrosis pulmonar idiopática y enfisema Normal lung volumes in patients with idiopathic pulmonary fibrosis and emphysema

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Juan Pablo Casas

2008-08-01

pattern with hyperinflation results in emphysema by loss of elastic recoil, expiratory collapse of the peripheral airways and air trapping. Previous reports suggest that when both diseases coexist, pulmonary volumes are compensated and a smaller than expected reduction or even normal lung volumes can be found. We report 4 male patients of 64, 60, 73 and 70 years, all with heavy cigarette smoking history and progressive breathlessness. Three of them had severe limitation in their quality of life. All four showed advanced lung interstitial involvement, at high resolution CT scan, fibrotic changes predominantly in the subpleural areas of lower lung fields and concomitant emphysema in the upper lobes. Emphysema and pulmonary fibrosis was confirmed by open lung biopsy in one patient. The four patients showed normal spirometry and lung volumes with severe compromise of gas exchange and poor exercise tolerance evaluated by 6 minute walk test. Severe pulmonary arterial hypertension was also confirmed in three patients. Normal lung volumes does not exclude diagnosis of idiopathic pulmonary fibrosis in patients with concomitant emphysema. The relatively preserved lung volumes may underestimate the severity of idiopathic pulmonary fibrosis and attenuate its effects on lung function parameters.

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.

Fibrosis pulmonar asociada a vasculitis con anticuerpos anticitoplasmáticos positivos Pulmonary fibrosis associated with anti-neutrophil cytoplasmic antibody-positive vasculitis

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Marcelo Fernández Casares

2012-08-01

Full Text Available Las complicaciones pulmonares más conocidas de las vasculitis con anticuerpos anticitoplasmáticos de los neutrófilos (ANCA positivos (VAA, son la hemorragia alveolar, los granulomas y la estenosis de la vía aérea. En los últimos años han aparecido algunos informes aislados que muestran la asociación con fibrosis pulmonar (FP, sugiriendo que ésta sería otra complicación de las VAA. En este trabajo informamos dos casos con dicha asociación describiendo sus características clínicas, tomográficas e inmunológicas. Dado que en la asociación de FP y VAA notificada en los últimos años, la FP puede ser su primera manifestación, podría ser necesaria la búsqueda de ANCA en pacientes con FP, como causa de la misma y por el posible desarrollo posterior de vasculitis.The most frequently observed pulmonary complications of vasculitis (AAV with anti-neutrophil cytoplasmic positive antibodies (ANCA are alveolar hemorrhage, granulomas and airway stenosis. In recent years, some reports have been published that show the association of vasculitis with pulmonary fibrosis (PF, suggesting that it may be another complication of AAV. We report and describe here two cases with such association, and their clinical, tomographic and immunological characteristics. Given that in the association between PF and AAV, as reported in the last years, PF could be the first manifestation of AAV, the search for ANCA in patients with PF may be necessary, as a cause of it and for the possible subsequent development of vasculitis.

Non-invasive measurement of liver and pancreas fibrosis in patients with cystic fibrosis.

Science.gov (United States)

Friedrich-Rust, Mireen; Schlueter, Nina; Smaczny, Christina; Eickmeier, Olaf; Rosewich, Martin; Feifel, Kirstin; Herrmann, Eva; Poynard, Thierry; Gleiber, Wolfgang; Lais, Christoph; Zielen, Stefan; Wagner, Thomas O F; Zeuzem, Stefan; Bojunga, Joerg

2013-09-01

Patients with cystic fibrosis (CF) have a relevant morbidity and mortality caused by CF-related liver-disease. While transient elastography (TE) is an established elastography method in hepatology centers, Acoustic-Radiation-Force-Impulse (ARFI)-Imaging is a novel ultrasound-based elastography method which is integrated in a conventional ultrasound-system. The aim of the present study was to evaluate the prevalence of liver-fibrosis in patients with CF using TE, ARFI-imaging and fibrosis blood tests. 106 patients with CF were prospectively included in the present study and received ARFI-imaging of the left and right liver-lobe, ARFI of the pancreas TE of the liver and laboratory evaluation. The prevalence of liver-fibrosis according to recently published best practice guidelines for CFLD was 22.6%. Prevalence of significant liver-fibrosis assessed by TE, ARFI-right-liver-lobe, ARFI-left-liver-lobe, Fibrotest, Fibrotest-corrected-by-haptoglobin was 17%, 24%, 40%, 7%, and 16%, respectively. The best agreement was found for TE, ARFI-right-liver-lobe and Fibrotest-corrected-by-haptoglobin. Patients with pancreatic-insufficiency had significantly lower pancreas-ARFI-values as compared to patients without. ARFI-imaging and TE seem to be promising non-invasive methods for detection of liver-fibrosis in patients with CF. Copyright © 2013 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Pathological assessment of liver fibrosis regression

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WANG Bingqiong

2017-03-01

Full Text Available Hepatic fibrosis is the common pathological outcome of chronic hepatic diseases. An accurate assessment of fibrosis degree provides an important reference for a definite diagnosis of diseases, treatment decision-making, treatment outcome monitoring, and prognostic evaluation. At present, many clinical studies have proven that regression of hepatic fibrosis and early-stage liver cirrhosis can be achieved by effective treatment, and a correct evaluation of fibrosis regression has become a hot topic in clinical research. Liver biopsy has long been regarded as the gold standard for the assessment of hepatic fibrosis, and thus it plays an important role in the evaluation of fibrosis regression. This article reviews the clinical application of current pathological staging systems in the evaluation of fibrosis regression from the perspectives of semi-quantitative scoring system, quantitative approach, and qualitative approach, in order to propose a better pathological evaluation system for the assessment of fibrosis regression.

Experimental models of liver fibrosis.

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Yanguas, Sara Crespo; Cogliati, Bruno; Willebrords, Joost; Maes, Michaël; Colle, Isabelle; van den Bossche, Bert; de Oliveira, Claudia Pinto Marques Souza; Andraus, Wellington; Alves, Venâncio Avancini Ferreira; Leclercq, Isabelle; Vinken, Mathieu

2016-05-01

Hepatic fibrosis is a wound healing response to insults and as such affects the entire world population. In industrialized countries, the main causes of liver fibrosis include alcohol abuse, chronic hepatitis virus infection and non-alcoholic steatohepatitis. A central event in liver fibrosis is the activation of hepatic stellate cells, which is triggered by a plethora of signaling pathways. Liver fibrosis can progress into more severe stages, known as cirrhosis, when liver acini are substituted by nodules, and further to hepatocellular carcinoma. Considerable efforts are currently devoted to liver fibrosis research, not only with the goal of further elucidating the molecular mechanisms that drive this disease, but equally in view of establishing effective diagnostic and therapeutic strategies. The present paper provides a state-of-the-art overview of in vivo and in vitro models used in the field of experimental liver fibrosis research.

Continuous Positive Airway Pressure (CPAP)

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... ENT Doctor Near You Continuous Positive Airway Pressure (CPAP) Continuous Positive Airway Pressure (CPAP) Patient Health Information ... relations staff at newsroom@entnet.org . What Is CPAP? The most common and effective nonsurgical treatment for ...

The Difficult Airway Society 'ADEPT' guidance on selecting airway devices: the basis of a strategy for equipment evaluation.

Science.gov (United States)

Pandit, J J; Popat, M T; Cook, T M; Wilkes, A R; Groom, P; Cooke, H; Kapila, A; O'Sullivan, E

2011-08-01

Faced with the concern that an increasing number of airway management devices were being introduced into clinical practice with little or no prior evidence of their clinical efficacy or safety, the Difficult Airway Society formed a working party (Airway Device Evaluation Project Team) to establish a process by which the airway management community within the profession could itself lead a process of formal device/equipment evaluation. Although there are several national and international regulations governing which products can come on to the market and be legitimately sold, there has hitherto been no formal professional guidance relating to how products should be selected (i.e. purchased). The Airway Device Evaluation Project Team's first task was to formulate such advice, emphasising evidence-based principles. Team discussions led to a definition of the minimum level of evidence needed to make a pragmatic decision about the purchase or selection of an airway device. The Team concluded that this definition should form the basis of a professional standard, guiding those with responsibility for selecting airway devices. We describe how widespread adoption of this professional standard can act as a driver to create an infrastructure in which the required evidence can be obtained. Essential elements are that: (i) the Difficult Airway Society facilitates a coherent national network of research-active units; and (ii) individual anaesthetists in hospital trusts play a more active role in local purchasing decisions, applying the relevant evidence and communicating their purchasing decisions to the Difficult Airway Society. © 2011 The Authors. Anaesthesia © 2011 The Association of Anaesthetists of Great Britain and Ireland.

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

Thoracic periaortal fibrosis and Ormond's disease

International Nuclear Information System (INIS)

Kacl, G.M.; Bino, M.; Salomon, F.; Risti, B.; Marincek, B.

1995-01-01

Two cases of thoracic periaortal fibrosis as a manifestation of retroperitoneal fibrosis (Ormond's disease) are shown on CT and MRI. Thoracic periaortal fibrosis can result in an inflammatory aneurysmo with chronic dissection. Manifestation of thoracic periaortal fibrosis may typically occur intermittently over decades. (orig.) [de

Individualized unsupervised exercise programs and chest physiotherapy in children with cystic fibrosis

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Bogdan ALMĂJAN-GUȚĂ

2013-12-01

Full Text Available Traditionally, physiotherapy for cystic fibrosis focused mainly on airway clearance (clearing mucus from the lungs. This still makes up a large part of daily treatment, but the role of the physiotherapist in cystic fibrosis has expanded to include daily exercise, inhalation therapy, posture awareness and, for some, the management of urinary incontinence. The purpose of this study is to demonstrate the necessity and the efficiency of various methods of chest physiotherapy and individualized unsupervised exercise program, in the improvement of body composition and physical performance. This study included 12 children with cystic fibrosis, with ages between 8-13 years. Each subject was evaluated in terms of body composition, effort capacity and lower body muscular performance, at the beginning of the study and after 12 months.The intervention consisted in classic respiratory clearance and physiotherapy techniques (5 times a week and an individualized unsupervised exercise program (3 times a week. After 12 months we noticed a significant improvement of the measured parameters: body weight increased from 32.25±5.5 to 33.53±5.4 kg (p <0.001, skeletal muscle mass increased from a mean of 16.04±4.1 to 17.01±4.2 (p<0.001, the fitness score, increased from a mean of 71±3.8 points to73±3.8, (p<0.001 and power and force also registered positive evolutions (from 19.3±2.68 to 21.65±2.4 W/kg and respectively 19.68±2.689 to 20.81±2.98 N/kg.The association between physiotherapy procedures and an individualized (after a proper clinical assessment unsupervised exercise program, proved to be an effective, relatively simple and accessible (regardless of social class intervention.

SERS detection of the biomarker hydrogen cyanide from Pseudomonas aeruginosa cultures isolated from cystic fibrosis patients

Science.gov (United States)

Lauridsen, Rikke Kragh; Sommer, Lea M.; Johansen, Helle Krogh; Rindzevicius, Tomas; Molin, Søren; Jelsbak, Lars; Engelsen, Søren Balling; Boisen, Anja

2017-03-01

Pseudomonas aeruginosa is the primary cause of chronic airway infections in cystic fibrosis (CF) patients. Persistent infections are seen from the first P. aeruginosa culture in about 75% of young CF patients, and it is important to discover new ways to detect P. aeruginosa at an earlier stage. The P. aeruginosa biomarker hydrogen cyanide (HCN) contains a triple bond, which is utilized in this study because of the resulting characteristic C≡N peak at 2135 cm-1 in a Raman spectrum. The Raman signal was enhanced by surface-enhanced Raman spectroscopy (SERS) on a Au-coated SERS substrate. After long-term infection, a mutation in the patho-adaptive lasR gene can alter the expression of HCN, which is why it is sometimes not possible to detect HCN in the breath of chronically infected patients. Four P. aeruginosa reference strains and 12 clinical P. aeruginosa strains isolated from CF children were evaluated, and HCN was clearly detected from overnight cultures of all wild type-like isolates and half of the later isolates from the same patients. The clinical impact could be that P. aeruginosa infections could be detected at an earlier stage, because daily breath sampling with an immediate output could be possible with a point-of-care SERS device.

Tissue factor pathway inhibitor prevents airway obstruction, respiratory failure and death due to sulfur mustard analog inhalation

International Nuclear Information System (INIS)

Rancourt, Raymond C.; Veress, Livia A.; Ahmad, Aftab; Hendry-Hofer, Tara B.; Rioux, Jacqueline S.; Garlick, Rhonda B.; White, Carl W.

2013-01-01

Sulfur mustard (SM) inhalation causes airway injury, with enhanced vascular permeability, coagulation, and airway obstruction. The objective of this study was to determine whether recombinant tissue factor pathway inhibitor (TFPI) could inhibit this pathogenic sequence. Methods: Rats were exposed to the SM analog 2-chloroethyl ethyl sulfide (CEES) via nose-only aerosol inhalation. One hour later, TFPI (1.5 mg/kg) in vehicle, or vehicle alone, was instilled into the trachea. Arterial O 2 saturation was monitored using pulse oximetry. Twelve hours after exposure, animals were euthanized and bronchoalveolar lavage fluid (BALF) and plasma were analyzed for prothrombin, thrombin–antithrombin complex (TAT), active plasminogen activator inhibitor-1 (PAI-1) levels, and fluid fibrinolytic capacity. Lung steady-state PAI-1 mRNA was measured by RT-PCR analysis. Airway-capillary leak was estimated by BALF protein and IgM, and by pleural fluid measurement. In additional animals, airway cast formation was assessed by microdissection and immunohistochemical detection of airway fibrin. Results: Airway obstruction in the form of fibrin-containing casts was evident in central conducting airways of rats receiving CEES. TFPI decreased cast formation, and limited severe hypoxemia. Findings of reduced prothrombin consumption, and lower TAT complexes in BALF, demonstrated that TFPI acted to limit thrombin activation in airways. TFPI, however, did not appreciably affect CEES-induced airway protein leak, PAI-1 mRNA induction, or inhibition of the fibrinolytic activity present in airway surface liquid. Conclusions: Intratracheal administration of TFPI limits airway obstruction, improves gas exchange, and prevents mortality in rats with sulfur mustard-analog-induced acute lung injury. - Highlights: • TFPI administration to rats after mustard inhalation reduces airway cast formation. • Inhibition of thrombin activation is the likely mechanism for limiting casts. • Rats given TFPI had

Tissue factor pathway inhibitor prevents airway obstruction, respiratory failure and death due to sulfur mustard analog inhalation

Energy Technology Data Exchange (ETDEWEB)

Rancourt, Raymond C., E-mail: raymond.rancourt@ucdenver.edu; Veress, Livia A., E-mail: livia.veress@ucdenver.edu; Ahmad, Aftab, E-mail: aftab.ahmad@ucdenver.edu; Hendry-Hofer, Tara B., E-mail: tara.hendry-hofer@ucdenver.edu; Rioux, Jacqueline S., E-mail: jacqueline.rioux@ucdenver.edu; Garlick, Rhonda B., E-mail: rhonda.garlick@ucdenver.edu; White, Carl W., E-mail: carl.w.white@ucdenver.edu

2013-10-01

Sulfur mustard (SM) inhalation causes airway injury, with enhanced vascular permeability, coagulation, and airway obstruction. The objective of this study was to determine whether recombinant tissue factor pathway inhibitor (TFPI) could inhibit this pathogenic sequence. Methods: Rats were exposed to the SM analog 2-chloroethyl ethyl sulfide (CEES) via nose-only aerosol inhalation. One hour later, TFPI (1.5 mg/kg) in vehicle, or vehicle alone, was instilled into the trachea. Arterial O{sub 2} saturation was monitored using pulse oximetry. Twelve hours after exposure, animals were euthanized and bronchoalveolar lavage fluid (BALF) and plasma were analyzed for prothrombin, thrombin–antithrombin complex (TAT), active plasminogen activator inhibitor-1 (PAI-1) levels, and fluid fibrinolytic capacity. Lung steady-state PAI-1 mRNA was measured by RT-PCR analysis. Airway-capillary leak was estimated by BALF protein and IgM, and by pleural fluid measurement. In additional animals, airway cast formation was assessed by microdissection and immunohistochemical detection of airway fibrin. Results: Airway obstruction in the form of fibrin-containing casts was evident in central conducting airways of rats receiving CEES. TFPI decreased cast formation, and limited severe hypoxemia. Findings of reduced prothrombin consumption, and lower TAT complexes in BALF, demonstrated that TFPI acted to limit thrombin activation in airways. TFPI, however, did not appreciably affect CEES-induced airway protein leak, PAI-1 mRNA induction, or inhibition of the fibrinolytic activity present in airway surface liquid. Conclusions: Intratracheal administration of TFPI limits airway obstruction, improves gas exchange, and prevents mortality in rats with sulfur mustard-analog-induced acute lung injury. - Highlights: • TFPI administration to rats after mustard inhalation reduces airway cast formation. • Inhibition of thrombin activation is the likely mechanism for limiting casts. • Rats given TFPI

Airway Clearance Techniques (ACTs)

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Full Text Available ... for Cystic Fibrosis CFTR-Related Metabolic Syndrome (CRMS) How Babies Are Screened in IRT-Only vs. ... Raising a child with cystic fibrosis can bring up many questions because CF affects many aspects of your child’s life. Here you’ ...

Airway Clearance Techniques (ACTs)

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Full Text Available ... ultimately help find a balance between your busy lifestyle and your CF care. Adult Guide to Cystic Fibrosis CF and School For Teachers Managing My CF in College CYSTIC FIBROSIS-RELATED DIABETES Emotional Wellness Anxiety and CF Coping While Caring ...

Airway responsiveness to mannitol in asthma is associated with chymase-positive mast cells and eosinophilic airway inflammation

DEFF Research Database (Denmark)

Sverrild, Asger; Bergqvist, Anders; Baines, Katherine J

2016-01-01

BACKGROUND: Airway hyperresponsiveness (AHR) to inhaled mannitol is associated with indirect markers of mast cell activation and eosinophilic airway inflammation. It is unknown how AHR to mannitol relates to mast cell phenotype, mast cell function and measures of eosinophilic inflammation in airway...... tissue. We compared the number and phenotype of mast cells, mRNA expression of mast cell-associated genes and number of eosinophils in airway tissue of subjects with asthma and healthy controls in relation to AHR to mannitol. METHODS: Airway hyperresponsiveness to inhaled mannitol was measured in 23 non......-smoking, corticosteroid-free asthmatic individuals and 10 healthy controls. Mast cells and eosinophils were identified in mucosal biopsies from all participants. Mast cells were divided into phenotypes based on the presence of chymase. mRNA expression of mast cell-associated genes was measured by real-time PCR. RESULTS...

Airway Clearance Techniques (ACTs)

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Full Text Available ... Managing My CF in College CYSTIC FIBROSIS-RELATED DIABETES Emotional Wellness Anxiety and CF Coping While Caring for Someone With Cystic Fibrosis Depression and CF Working With Your Care Team Fitness and Nutrition Fitness Nutrition and Your Digestive System Germs and ...

Airway exploration in children

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Fernando GÓMEZ-SÁEZ

2018-03-01

Full Text Available Introduction and objective: The management of the airways represents a constant challenge in pediatric practice. In the last years, bronchoscopy has become an essential technique in the diagnosis and treatment of various abnormalities of the child's respiratory system. The special characteristics of the pediatric airway and the differentiated pathology it presents give pediatric bronchoscopy its own entity. Pediatric bronchoscopy is a safe technique with many applications, both diagnostic and therapeutic. The use of both types of bronchoscopes (flexible and rigid allows to take advantage of each one of them. Flexible bronchoscopy in pediatrics is a relatively simple and low-risk procedure that provides anatomical and dynamic information on the airways, as well as cytological and microbiological studies. The simplicity and low risk of this technique, in addition to not requiring general anesthesia, allows it to be performed even at the head of the patient, which has led to an increasingly extensive field of indications. The purpose of this article is to provide a review on the timeliness of the pediatric bronchoscopy procedure, especially about its indications. Method: Narrative review. Conclusion: The endoscopic examination of the airway is a cost-effective technique in pediatrics, with little complications and can offer very valuable diagnostic information, as well as perform certain therapeutic procedures. It is recommended that all professionals involved in the management of patients with airway pathology should know their indications, contraindications, complications, as well as their therapeutic applications.

Airway management and morbid obesity

DEFF Research Database (Denmark)

Kristensen, Michael S

2010-01-01

Morbidly obese patients present with excess fatty tissue externally on the breast, neck, thoracic wall and abdomen and internally in the mouth, pharynx and abdomen. This excess tissue tends to make access (intubation, tracheostomy) to and patency (during sedation or mask ventilation) of the upper...... in morbidly obese patients and should be followed by actions to counteract atelectasis formation. The decision as to weather to use a rapid sequence induction, an awake intubation or a standard induction with hypnotics should depend on the thorough airway examination and comorbidity and should not be based...... solely on whether morbid obesity is present or not. It is important to ensure sufficient depth of anaesthesia before initiating manipulation of the airway because inadequate anaesthesia depth predisposes to aspiration if airway management becomes difficult. The intubating laryngeal mask airway is more...

Mutating the Conserved Q-loop Glutamine 1291 Selectively Disrupts Adenylate Kinase-dependent Channel Gating of the ATP-binding Cassette (ABC) Adenylate Kinase Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and Reduces Channel Function in Primary Human Airway Epithelia.

Science.gov (United States)

Dong, Qian; Ernst, Sarah E; Ostedgaard, Lynda S; Shah, Viral S; Ver Heul, Amanda R; Welsh, Michael J; Randak, Christoph O

2015-05-29

The ATP-binding cassette (ABC) transporter cystic fibrosis transmembrane conductance regulator (CFTR) and two other non-membrane-bound ABC proteins, Rad50 and a structural maintenance of chromosome (SMC) protein, exhibit adenylate kinase activity in the presence of physiologic concentrations of ATP and AMP or ADP (ATP + AMP ⇆ 2 ADP). The crystal structure of the nucleotide-binding domain of an SMC protein in complex with the adenylate kinase bisubstrate inhibitor P(1),P(5)-di(adenosine-5') pentaphosphate (Ap5A) suggests that AMP binds to the conserved Q-loop glutamine during the adenylate kinase reaction. Therefore, we hypothesized that mutating the corresponding residue in CFTR, Gln-1291, selectively disrupts adenylate kinase-dependent channel gating at physiologic nucleotide concentrations. We found that substituting Gln-1291 with bulky side-chain amino acids abolished the effects of Ap5A, AMP, and adenosine 5'-monophosphoramidate on CFTR channel function. 8-Azidoadenosine 5'-monophosphate photolabeling of the AMP-binding site and adenylate kinase activity were disrupted in Q1291F CFTR. The Gln-1291 mutations did not alter the potency of ATP at stimulating current or ATP-dependent gating when ATP was the only nucleotide present. However, when physiologic concentrations of ADP and AMP were added, adenylate kinase-deficient Q1291F channels opened significantly less than wild type. Consistent with this result, we found that Q1291F CFTR displayed significantly reduced Cl(-) channel function in well differentiated primary human airway epithelia. These results indicate that a highly conserved residue of an ABC transporter plays an important role in adenylate kinase-dependent CFTR gating. Furthermore, the results suggest that adenylate kinase activity is important for normal CFTR channel function in airway epithelia. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

l-2-Oxothiazolidine-4-Carboxylic Acid or α-Lipoic Acid Attenuates Airway Remodeling: Involvement of Nuclear Factor-κB (NF-κB, Nuclear Factor Erythroid 2p45-Related Factor-2 (Nrf2, and Hypoxia-Inducible Factor (HIF

Directory of Open Access Journals (Sweden)

Heung Bum Lee

2012-06-01

Full Text Available Reactive oxygen species (ROS play a crucial role in the pathogenesis of acute and chronic respiratory diseases. Antioxidants have been found to ameliorate airway inflammation and hyperresponsiveness in animal models employing short-term exposure to allergen. However, little data are available on the effect of antioxidants on airway remodeling and signaling pathways in chronic asthma. In the present study, we used a long-term exposure murine model of allergic airway disease to evaluate the effects of an antioxidant, l-2-oxothiazolidine-4-carboxylic acid (OTC or α-lipoic acid (LA on airway remodeling, focusing on the ROS-related hypoxia-inducible signaling. Long-term challenge of ovalbumin (OVA increased ROS production, airway inflammation, and airway hyperresponsiveness, and developed features of airway remodeling such as excessive mucus secretion, subepithelial fibrosis, and thickening of the peribronchial smooth muscle layer. Administration of OTC or LA reduced these features of asthma, including airway remodeling, which was accompanied by suppression of transforming growth factor-β1, vascular endothelial growth factor, and T-helper 2 cytokines. In addition, OVA-induced activation of nuclear factor-κB (NF-κB, nuclear factor erythroid 2p45-related factor-2 (Nrf2, hypoxia-inducible factor (HIF-1α, and HIF-2α was reduced by OTC or LA. Our results also showed that OTC or LA down-regulated phosphoinositide 3-kinase activity and decreased phosphorylation of p38 mitogen-activated protein kinase but not extracellular signal-regulated kinase 1/2 or c-Jun N-terminal kinase. These findings demonstrate that OTC and LA can inhibit activation of NF-κB, Nrf2, and HIF, leading to attenuate allergen-induced airway remodeling.

Rhinosinusitis and the lower airways

NARCIS (Netherlands)

Hellings, Peter W.; Hens, Greet

2009-01-01

The interaction between upper and lower airway disease has been recognized for centuries, with recent studies showing a direct link between upper and airway inflammation in allergic patients. The mechanisms underlying the interaction between nasal and bronchial inflammation have primarily been

Airway Clearance Techniques (ACTs)

Medline Plus

Full Text Available ... Carrier Testing for Cystic Fibrosis CFTR-Related Metabolic Syndrome (CRMS) How Babies Are Screened in IRT-Only vs. IRT-DNA States Newborn Screening for CF Sweat Test Life With CF X close Caring for a Child With CF Raising a child with cystic fibrosis ...

Airway Clearance Techniques (ACTs)

Medline Plus

Full Text Available ... in College CYSTIC FIBROSIS-RELATED DIABETES Emotional Wellness Anxiety and CF Coping While Caring for Someone With Cystic Fibrosis Depression and CF Working With Your Care Team Fitness and Nutrition Fitness Nutrition and Your Digestive System Germs and Staying Healthy How Can You Avoid ...

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.

Are new supraglottic airway devices, tracheal tubes and airway viewing devices cost-effective?

Science.gov (United States)

Slinn, Simon J; Froom, Stephen R; Stacey, Mark R W; Gildersleve, Christopher D

2015-01-01

Over the past two decades, a plethora of new airway devices has become available to the pediatric anesthetist. While all have the laudable intention of improving patient care and some have proven clinical benefits, these devices are often costly and at times claims of an advantage over current equipment and techniques are marginal. Supraglottic airway devices are used in the majority of pediatric anesthetics delivered in the U.K., and airway-viewing devices provide an alternative for routine intubation as well as an option in the management of the difficult airway. Yet hidden beneath the convenience of the former and the technology of the latter, the impact on basic airway skills with a facemask and the lack of opportunities to fine-tune the core skill of intubation represent an unrecognised and unquantifiable cost. A judgement on this value must be factored into the absolute purchase cost and any potential benefits to the quality of patient care, thus blurring any judgement on cost-effectiveness that we might have. An overall value on cost-effectiveness though not in strict monetary terms can then be ascribed. In this review, we evaluate the role of these devices in the care of the pediatric patient and attempt to balance the advantages they offer against the cost they incur, both financial and environmental, and in any quality improvement they might offer in clinical care. © 2014 John Wiley & Sons Ltd.

Syndecans in heart fibrosis.

Science.gov (United States)

Lunde, Ida G; Herum, Kate M; Carlson, Cathrine C; Christensen, Geir

2016-09-01

Heart disease is a deadly syndrome affecting millions worldwide. It reflects an unmet clinical need, and the disease mechanisms are poorly understood. Cardiac fibrosis is central to heart disease. The four-membered family of transmembrane proteoglycans, syndecan-1 to -4, is believed to regulate fibrosis. We review the current literature concerning syndecans in cardiac fibrosis. Syndecan expression is up-regulated in response to pro-inflammatory stimuli in various forms of heart disease with fibrosis. Mice lacking syndecan-1 and -4 show reduced activation of pro-fibrotic signaling and increased cardiac rupture upon infarction indicating an important role for these molecules. Whereas the short cytoplasmic tail of syndecans regulates signaling, their extracellular part, substituted with heparan sulfate glycosaminoglycan chains, binds a plethora of extracellular matrix (ECM) molecules involved in fibrosis, e.g., collagens, growth factors, cytokines, and immune cell adhesion proteins. Full-length syndecans induce pro-fibrotic signaling, increasing the expression of collagens, myofibroblast differentiation factors, ECM enzymes, growth factors, and immune cell adhesion molecules, thereby also increasing cardiac stiffness and preventing cardiac rupture. Upon pro-inflammatory stimuli, syndecan ectodomains are enzymatically released from heart cells (syndecan shedding). Shed ectodomains affect the expression of ECM molecules, promoting ECM degradation and cardiac rupture upon myocardial infarction. Blood levels of shed syndecan-1 and -4 ectodomains are associated with hospitalization, mortality, and heart remodeling in patients with heart failure. Improved understanding of syndecans and their modifying enzymes in cardiac fibrosis might contribute to the development of compounds with therapeutic potential, and enzymatically shed syndecan ectodomains might constitute a future prognostic tool for heart diseases with fibrosis. Graphical Abstract Graphical abstract summarizing

Adaptation of Staphylococcus aureus to Airway Environments in Patients With Cystic Fibrosis by Upregulation of Superoxide Dismutase M and Iron-Scavenging Proteins.

Science.gov (United States)

Treffon, Janina; Block, Desiree; Moche, Martin; Reiss, Swantje; Fuchs, Stephan; Engelmann, Susanne; Becher, Dörte; Langhanki, Lars; Mellmann, Alexander; Peters, Georg; Kahl, Barbara C

2018-04-11

Adaptation of S. aureus to the hostile environment of CF airways resulted in changed abundance of proteins involved in energy metabolism, cellular processes, transport and binding, but most importantly in an iron-scavenging phenotype and increased activity of superoxide dismutase M.

Bacteria of the genus Dyella can chronically colonise the airways of patients with cystic fibrosis and elicit a pronounced antibody response

DEFF Research Database (Denmark)

Duus, Liv M; Høiby, Niels; Wang, Mikala

2013-01-01

A patient with cystic fibrosis became chronically colonised with an unusual non-fermenting Gram-negative rod that could be cultured on Burkholderia cepacia selective agar. Phenotypic characterisation by VITEK-2 suggested identification as Elizabethkingia meningoseptica, however 16S rRNA gene sequ...

Imaging pulmonary fibrosis

International Nuclear Information System (INIS)

Brauner, M.W.; Rety, F.; Naccache, J.M.; Girard, F.; Valeyre, D.F.

2001-01-01

Localized fibrosis of the lung is usually scar tissue while diffuse pulmonary fibrosis is more often a sign of active disease. Chronic infiltrative lung disease may be classified into four categories: idiopathic pneumonitis, collagen diseases, granulomatosis (sarcoidosis), and caused by known diseases (pneumoconiosis, hypersensitivity pneumonitis, drug-induced lung disease, radiation). (authors)

An atypical presentation of sinus mucopyocele in a pediatric cystic fibrosis patient

Directory of Open Access Journals (Sweden)

Horesh E

2015-05-01

Full Text Available Elan Horesh, Andrew A Colin, Roy Casiano, Sara T WesterBascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USAAbstract: This case report details an association of chronic allergic conjunctivitis and respiratory tract colonization in a cystic fibrosis (CF patient due to an ethmoidal mucocele infected with Escherichia coli. A 3-year-old CF patient presented for evaluation with complaints of chronic periocular erythema, conjunctival injection, and irritation for 2 years. He was treated for presumed allergic conjunctivitis with no improvement and continued to have overall worsening of symptoms on the right greater than the left eye in a waxing and waning pattern. On presentation to the Bascom Palmer Eye Institute, he was noted to have telecanthus and prominent erythema in the region of the medial canthus. Orbital imaging disclosed a mucocele in the right ethmoid sinus. The patient underwent functional endoscopic sinus surgery, with successful marsupialization of the ethmoidal mucocele, which was found on culture to be infected with E. coli. Post-operatively with continuous pulmonary care, the patient remains free of allergic conjunctivitis and E. coli colonization of the upper airway. This case highlights the importance of analyzing the adjacent sinus in patients with chronic, relapsing allergic conjunctivitis refractory to medical management, particularly in patients with underlying systemic diseases such as CF.Keywords: allergic conjuncitivitis, Escherichia Coli, cystic fibrosis, mucocele

Glutathione aerosol suppresses lung epithelial surface inflammatory cell-derived oxidants in cystic fibrosis.

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Roum, J H; Borok, Z; McElvaney, N G; Grimes, G J; Bokser, A D; Buhl, R; Crystal, R G

1999-07-01

Cystic fibrosis (CF) is characterized by accumulation of activated neutrophils and macrophages on the respiratory epithelial surface (RES); these cells release toxic oxidants, which contribute to the marked epithelial derangements seen in CF. These deleterious consequences are magnified, since reduced glutathione (GSH), an antioxidant present in high concentrations in normal respiratory epithelial lining fluid (ELF), is deficient in CF ELF. To evaluate the feasibility of increasing ELF GSH levels and enhancing RES antioxidant protection, GSH aerosol was delivered (600 mg twice daily for 3 days) to seven patients with CF. ELF total, reduced, and oxidized GSH increased (P < 0.05, all compared with before GSH therapy), suggesting adequate RES delivery and utilization of GSH. Phorbol 12-myristate 13-acetate-stimulated superoxide anion (O2-.) release by ELF inflammatory cells decreased after GSH therapy (P < 0.002). This paralleled observations that GSH added in vitro to CF ELF inflammatory cells suppressed O2-. release (P < 0.001). No adverse effects were noted during treatment. Together, these observations demonstrate the feasibility of using GSH aerosol to restore RES oxidant-antioxidant balance in CF and support the rationale for further clinical evaluation.

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

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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...

Respiratory infection rates differ between geographically distant paediatric cystic fibrosis cohorts

Directory of Open Access Journals (Sweden)

Kathryn A. Ramsey

2016-09-01

Full Text Available Respiratory infections are a major cause of pulmonary decline in children with cystic fibrosis (CF. We compared the prevalence of infection in early life at geographically distant CF treatment centres participating in the same surveillance programme in Australia. Lower airway microbiology, inflammation and structural lung disease at annual review were evaluated for 260 children 0–8 years old with CF at 1032 visits to CF treatment centres in Melbourne or Perth. Melbourne patients were more likely to be culture-positive for common respiratory pathogens at all age groups (odds ratio (OR 1.85, 95% CI 1.33–2.58. Subjects 5 years old. Patients at both centres had a similar rate of hospitalisations and prescribed antibiotics. No procedural differences were identified that could explain the disparity between pathogen prevalence. Geographical differences in early acquisition of infection may contribute to variability in outcomes between CF centres.

Routine airway surveillance in pediatric tracheostomy patients.

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Gergin, Ozgul; Adil, Eelam; Kawai, Kosuke; Watters, Karen; Moritz, Ethan; Rahbar, Reza

2017-06-01

The aim of this study is to review airway findings in children with tracheostomies who underwent surveillance direct laryngoscopy and bronchoscopy (DLB) to determine the yield of routine airway evaluation in these patients. Retrospective chart review at tertiary referral children's hospital. A retrospective chart review was conducted of all of the children with tracheostomies who underwent DLB after tracheostomy between 1984 and 2015. A total of 303 patients met inclusion criteria. The median time interval between tracheostomy and first follow-up DLB was 12.0 months (IQR 4.8-28.9 months). There was no significant difference in the incidence of airway lesions between patients who underwent endoscopy tracheostomy versus those who had a longer time interval between tracheostomy and DLB (p = 0.16). One hundred sixty seven patients (55.1%) were diagnosed with lesions, with suprastomal granulation (39.9%) being the most common. Symptomatic patients were significantly more likely to have an airway lesion identified (69.9% versus 42.0%; p tracheostomy were significantly more likely to have an airway lesion (p = 0.01). The high incidence of airway lesions noted during surveillance DLB support the utility of routine airway endoscopy in pediatric tracheostomy patients. Symptomatic patients, those with ventilator dependence, or cardiopulmonary or trauma indications for tracheostomy are more likely to have airway lesions and should be monitored closely. The ideal time interval between surveillance endoscopies needs to be examined further. Copyright © 2017. Published by Elsevier B.V.

Methylene Blue-Aided In Vivo Staining of Central Airways during Flexible Bronchoscopy

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Sabine Zirlik

2012-01-01

Full Text Available Background. The early diagnosis of malignant and premalignant changes of the bronchial mucosa remains a major challenge during bronchoscopy. Intravital staining techniques are not new. Previous small case series suggested that analysis of the bronchial mucosal surface using chromoendoscopy allows a prediction between neoplastic and nonneoplastic lesions. Objectives. The aim of the present study was to evaluate chromobronchoscopy as a method to identify malignant and premalignant lesions in the central airways in a prospective manner. Methods. In 26 patients we performed chromoendoscopy with 0.1% methylene blue during ongoing flexible white light bronchoscopy. Circumscribed lesions in central airways were further analyzed by biopsies and histopathologic examination. Results. In the majority of cases neither flat nor polypoid lesions in the central airways were stained by methylene blue. In particular, exophytic growth of lung cancer did not show any specific pattern in chromobronchoscopy. However, a specific dye staining was detected in one case where exophytic growth of metastatic colorectal cancer was present in the right upper lobe. In two other cases, a circumscribed staining was noted in unsuspicious mucosa. But histology revealed inflammation only. Conclusions. In contrast to previous studies, the present findings clearly indicate that chromobronchoscopy is not useful for early detection of malignant or premalignant lesions of the central airways.

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.

Nephrogenic systemic fibrosis

DEFF Research Database (Denmark)

Marckmann, Peter; Skov, Lone; Rossen, Kristian

2006-01-01

Nephrogenic systemic fibrosis is a new, rare disease of unknown cause that affects patients with renal failure. Single cases led to the suspicion of a causative role of gadodiamide that is used for magnetic resonance imaging. This study therefore reviewed all of the authors' confirmed cases...... of nephrogenic systemic fibrosis (n = 13) with respect to clinical characteristics, gadodiamide exposure, and subsequent clinical course. It was found that all had been exposed to gadodiamide before the development of nephrogenic systemic fibrosis. The delay from exposure to first sign of the disease was 2 to 75...... d (median 25 d). Odds ratio for acquiring the disease when gadodiamide exposed was 32.5 (95% confidence interval 1.9 to 549.2; P

Fibrosis and Cancer

DEFF Research Database (Denmark)

Cox, Thomas R.; Erler, Janine T.

2016-01-01

The relation between fibrosis and cancer has long been debated, specifically whether desmoplasia precedes, accompanies, or succeeds tumourigenesis, progression, and metastasis. Recent reports have published opposing data, adding to the perplexity. However, what is emerging is that it is likely th...... the specific properties of the extracellular matrix (ECM) that determine the paradoxical nature of cancer-associated fibrosis....

Anaesthesia and subglottic airway obstruction

African Journals Online (AJOL)

2009-07-14

Jul 14, 2009 ... Introduction. Surgery on the upper airway remains challenging for both surgeon and ... from her upper airway obstruction rather than asthma.1 She had made a long ... patient was well oxygenated with oxygen saturation above. 95%. .... Difficulties relate to tidal volume measurement, CO2 detection and the.

A “loop” shape descriptor and its application to automated segmentation of airways from CT scans

Energy Technology Data Exchange (ETDEWEB)

Pu, Jiantao [Department of Radiology, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Shaanxi 710061, People’s Republic of China, and Departments of Radiology and Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 (United States); Jin, Chenwang, E-mail: jcw76@163.com; Yu, Nan; Qian, Yongqiang; Guo, Youmin [Department of Radiology, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Shaanxi 710061 (China); Wang, Xiaohua [Third Affiliated Hospital, Peking University, Beijing, People’s Republic of China, 100029 (China); Meng, Xin [Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 (United States)

2015-06-15

Purpose: A novel shape descriptor is presented to aid an automated identification of the airways depicted on computed tomography (CT) images. Methods: Instead of simplifying the tubular characteristic of the airways as an ideal mathematical cylindrical or circular shape, the proposed “loop” shape descriptor exploits the fact that the cross sections of any tubular structure (regardless of its regularity) always appear as a loop. In implementation, the authors first reconstruct the anatomical structures in volumetric CT as a three-dimensional surface model using the classical marching cubes algorithm. Then, the loop descriptor is applied to locate the airways with a concave loop cross section. To deal with the variation of the airway walls in density as depicted on CT images, a multiple threshold strategy is proposed. A publicly available chest CT database consisting of 20 CT scans, which was designed specifically for evaluating an airway segmentation algorithm, was used for quantitative performance assessment. Measures, including length, branch count, and generations, were computed under the aid of a skeletonization operation. Results: For the test dataset, the airway length ranged from 64.6 to 429.8 cm, the generation ranged from 7 to 11, and the branch number ranged from 48 to 312. These results were comparable to the performance of the state-of-the-art algorithms validated on the same dataset. Conclusions: The authors’ quantitative experiment demonstrated the feasibility and reliability of the developed shape descriptor in identifying lung airways.

75 FR 13079 - Action Affecting Export Privileges; MAHAN AIRWAYS; Mahan Airways, Mahan Tower, No. 21, Azadegan...

Science.gov (United States)

2010-03-18

... Regulations and TDO, a United Kingdom court found Mahan Airways in contempt of court on February 1, 2010, for... contempt finding against Mahan Airways in the U.K. litigation, which I understand is still ongoing. I note...

Recurrent airway obstructions in a patient with benign tracheal stenosis and a silicone airway stent: a case report

Science.gov (United States)

Sriram, KB; Robinson, PC

2008-01-01

Airway stents (silicone and metal stents) are used to treat patients with benign tracheal stenosis, who are symptomatic and in whom tracheal surgical reconstruction has failed or is not appropriate. However airway stents are often associated with complications such as migration, granuloma formation and mucous hypersecretion, which cause significant morbidity, especially in patients with benign tracheal stenosis and relatively normal life expectancy. We report a patient who had frequent critical airway obstructions over 8 years due to granuloma and mucus hypersecretion in a silicone airway stent. The problem was resolved when the silicone stent was removed and replaced with a covered self expanding metal stent. PMID:18840299

Nitric oxide airway diffusing capacity and mucosal concentration in asthmatic schoolchildren.

Science.gov (United States)

Pedroletti, Christophe; Högman, Marieann; Meriläinen, Pekka; Nordvall, Lennart S; Hedlin, Gunilla; Alving, Kjell

2003-10-01

Asthmatic patients show increased concentrations of nitric oxide (NO) in exhaled air (Feno). The diffusing capacity of NO in the airways (Dawno), the NO concentrations in the alveoli and the airway wall, and the maximal airway NO diffusion rate have previously been estimated noninvasively by measuring Feno at different exhalation flow rates in adults. We investigated these variables in 15 asthmatic schoolchildren (8-18 y) and 15 age-matched control subjects, with focus on their relation to exhaled NO at the recommended exhalation flow rate of 0.05 L/s (Feno0.05), age, and volume of the respiratory anatomic dead space. NO was measured on-line by chemiluminescence according to the European Respiratory Society's guidelines, and the NO plateau values at three different exhalation flow rates (11, 99, and 382 mL/s) were incorporated in a two-compartment model for NO diffusion. The NO concentration in the airway wall (p < 0.001), Dawno (p < 0.01), and the maximal airway NO diffusion rate (p < 0.001) were all higher in the asthmatic children than in control children. In contrast, there was no difference in the NO concentration in the alveoli (p = 0.13) between the groups. A positive correlation was seen between the volume of the respiratory anatomic dead space and Feno0.05 (r = 0.68, p < 0.01), the maximal airway NO diffusion rate (r = 0.71, p < 0.01), and Dawno (r = 0.56, p < 0.01) in control children, but not in asthmatic children. Feno0.05 correlated better with Dawno in asthmatic children (r = 0.65, p < 0.01) and with the NO concentration in the airway wall in control subjects (r < 0.77, p < 0.001) than vice versa. We conclude that Feno0.05 increases with increasing volume of the respiratory anatomic dead space in healthy children, suggesting that normal values for Feno0.05 should be related to age or body weight in this age group. Furthermore, the elevated Feno0.05 seen in asthmatic children is related to an increase in both Dawno and NO concentration in the airway

Sinonasal inhalation of tobramycin vibrating aerosol in cystic fibrosis patients with upper airway Pseudomonas aeruginosa colonization: results of a randomized, double-blind, placebo-controlled pilot study

Science.gov (United States)

Mainz, Jochen G; Schädlich, Katja; Schien, Claudia; Michl, Ruth; Schelhorn-Neise, Petra; Koitschev, Assen; Koitschev, Christiane; Keller, Peter M; Riethmüller, Joachim; Wiedemann, Baerbel; Beck, James F

2014-01-01

Rationale In cystic fibrosis (CF), the paranasal sinuses are sites of first and persistent colonization by pathogens such as Pseudomonas aeruginosa. Pathogens subsequently descend to the lower airways, with P. aeruginosa remaining the primary cause of premature death in patients with the inherited disease. Unlike conventional aerosols, vibrating aerosols applied with the PARI Sinus™ nebulizer deposit drugs into the paranasal sinuses. This trial assessed the effects of vibrating sinonasal inhalation of the antibiotic tobramycin in CF patients positive for P. aeruginosa in nasal lavage. Objectives To evaluate the effects of sinonasal inhalation of tobramycin on P. aeruginosa quantification in nasal lavage; and on patient quality of life, measured with the Sino-Nasal Outcome Test (SNOT-20), and otologic and renal safety and tolerability. Methods Patients were randomized to inhalation of tobramycin (80 mg/2 mL) or placebo (2 mL isotonic saline) once daily (4 minutes/nostril) with the PARI Sinus™ nebulizer over 28 days, with all patients eligible for a subsequent course of open-label inhalation of tobramycin for 28 days. Nasal lavage was obtained before starting and 2 days after the end of each treatment period by rinsing each nostril with 10 mL of isotonic saline. Results Nine patients participated, six initially receiving tobramycin and three placebo. Sinonasal inhalation was well tolerated, with serum tobramycin <0.5 mg/L and stable creatinine. P. aeruginosa quantity decreased in four of six (67%) patients given tobramycin, compared with zero of three given placebo (non-significant). SNOT-20 scores were significantly lower in the tobramycin than in the placebo group (P=0.033). Conclusion Sinonasal inhalation of vibrating antibiotic aerosols appears promising for reducing pathogen colonization of paranasal sinuses and for control of symptoms in patients with CF. PMID:24596456

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.)

Vitamin D deficiency as a risk factor for cystic fibrosis-related diabetes in the Scandinavian Cystic Fibrosis Nutritional Study

DEFF Research Database (Denmark)

Pincikova, T; Nilsson, Kristine Kahr; Moen, I E

2011-01-01

Many cystic fibrosis patients are vitamin D-insufficient. Cystic fibrosis-related diabetes is a major complication of cystic fibrosis. The literature suggests that vitamin D might possess certain glucose-lowering properties. We aimed to assess the relationship between vitamin D and cystic fibrosis...

Proteome analysis of Radiation-induced pulmonary fibrosis

International Nuclear Information System (INIS)

Song, Jie Young; Lim, Hee Soon; Kim, Hyung Doo; Shim, Ji Young; Han, Young Soo; Son, Hyeog Jin Son; Yun, Yeon Sook

2005-01-01

Pulmonary fibrosis is perhaps the most universal late effect of organ damage after both chemical insult and irradiation in the treatment of lung cancer. The use chemotherapy and radiation therapy, alone or combined, can be associated with clinically significant pulmonary toxicity, which leads to pneumonia and pulmonary fibrosis. It is also reported that about 100,000 people in the United States are suffered from pulmonary fibrosis. Therefore, pulmonary fibrosis will be more focused by medicinal researchers. Because current therapies, aimed at inhibiting pulmonary inflammation that often precedes fibrosis, are effective only in a minority of suffered patients, novel therapeutic methods are highly needed. Some researchers have used bleomycininduced pulmonary fibrosis as a basis for looking at the molecular mechanisms of fibrosis, and total gene expression was monitored using genomics method. However, radiation-induced pulmonary fibrosis has not been fully focused and investigated. Here, we have analyzed changes in gene expression in response to γ- irradiation by using proteomic analysis

Airway contractility and remodeling : Links to asthma symptoms

NARCIS (Netherlands)

West, Adrian R.; Syyong, Harley T.; Siddiqui, Sana; Pascoe, Chris D.; Murphy, Thomas M.; Maarsingh, Harm; Deng, Linhong; Maksym, Geoffrey N.; Bosse, Ynuk

Respiratory symptoms are largely caused by obstruction of the airways. In asthma, airway narrowing mediated by airway smooth muscle (ASM) contraction contributes significantly to obstruction. The spasmogens produced following exposure to environmental triggers, such as viruses or allergens, are

Durability of Silicone Airway Stents in the Management of Benign Central Airway Obstruction.

Science.gov (United States)

Karush, Justin M; Seder, Christopher W; Raman, Anish; Chmielewski, Gary W; Liptay, Michael J; Warren, William H; Arndt, Andrew T

2017-10-01

The literature is devoid of a comprehensive analysis of silicone airway stenting for benign central airway obstruction (BCAO). With the largest series in the literature to date, we aim to demonstrate the safety profile, pattern of re-intervention, and duration of silicone airway stents. An institutional database was used to identify patients with BCAO who underwent rigid bronchoscopy with dilation and silicone stent placement between 2002 and 2015 at Rush University Medical Center. During the study period, 243 stents were utilized in 63 patients with BCAO. Pure tracheal stenosis was encountered in 71% (45/63), pure tracheomalacia in 11% (7/63), and a hybrid of both in 17% (11/63). Median freedom from re-intervention was 104 (IQR 167) days. Most common indications for re-intervention include mucus accumulation (60%; 131/220), migration (28%; 62/220), and intubation (8%; 18/220). The most common diameters of stent placed were 12 mm (94/220) and 14 mm (96/220). The most common lengths utilized were 30 mm (60/220) and 40 mm (77/220). Duration was not effected by stent size when placed for discrete stenosis. However, 14 mm stents outperformed 12 mm when tracheomalacia was present (157 vs. 37 days; p = 0.005). Patients with a hybrid stenosis fared better when longer stents were used (60 mm stents outlasted 40 mm stents 173 vs. 56 days; p = 0.05). Rigid bronchoscopy with silicone airway stenting is a safe and effective option for the management of benign central airway obstruction. Our results highlight several strategies to improve stent duration.

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

Science.gov (United States)

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.

Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis.

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Locatelli, Luigi; Cadamuro, Massimiliano; Spirlì, Carlo; Fiorotto, Romina; Lecchi, Silvia; Morell, Carola Maria; Popov, Yury; Scirpo, Roberto; De Matteis, Maria; Amenduni, Mariangela; Pietrobattista, Andrea; Torre, Giuliano; Schuppan, Detlef; Fabris, Luca; Strazzabosco, Mario

2016-03-01

Congenital hepatic fibrosis (CHF) is a disease of the biliary epithelium characterized by bile duct changes resembling ductal plate malformations and by progressive peribiliary fibrosis, in the absence of overt necroinflammation. Progressive liver fibrosis leads to portal hypertension and liver failure; however, the mechanisms leading to fibrosis in CHF remain elusive. CHF is caused by mutations in PKHD1, a gene encoding for fibrocystin, a ciliary protein expressed in cholangiocytes. Using a fibrocystin-defective (Pkhd1(del4/del4)) mouse, which is orthologous of CHF, we show that Pkhd1(del4/del4) cholangiocytes are characterized by a β-catenin-dependent secretion of a range of chemokines, including chemokine (C-X-C motif) ligands 1, 10, and 12, which stimulate bone marrow-derived macrophage recruitment. We also show that Pkhd1(del4/del4) cholangiocytes, in turn, respond to proinflammatory cytokines released by macrophages by up-regulating αvβ6 integrin, an activator of latent local transforming growth factor-β1. While the macrophage infiltrate is initially dominated by the M1 phenotype, the profibrogenic M2 phenotype increases with disease progression, along with the number of portal myofibroblasts. Consistent with these findings, clodronate-induced macrophage depletion results in a significant reduction of portal fibrosis and portal hypertension as well as of liver cysts. Fibrosis can be initiated by an epithelial cell dysfunction, leading to low-grade inflammation, macrophage recruitment, and collagen deposition; these findings establish a new paradigm for biliary fibrosis and represent a model to understand the relationship between cell dysfunction, parainflammation, liver fibrosis, and macrophage polarization over time. © 2015 by the American Association for the Study of Liver Diseases.

Review: Quality of Life in Children with Non-cystic Fibrosis Bronchiectasis

Directory of Open Access Journals (Sweden)

Anna Marie Nathan

2017-04-01

Full Text Available Non-cystic fibrosis bronchiectasis (NCFB has gained renewed interest, due to its increasing health-care burden. Annual mortality statistics in England and Wales showed that under 1,000 people die from bronchiectasis each year, and this number is increasing by 3% yearly. Unfortunately, there is a severe lack of well-powered, randomized controlled trials to guide clinicians how to manage NCFB effectively. Quality-of-life (QOL measures in NCFB are an important aspect of clinical care that has not been studied well. Commonly used disease-specific questionnaires in children with NCFB are the St George’s Respiratory Questionnaire, Short Form-36, the Leicester Cough Questionnaire, and the Parent Cough-Specific Quality of Life questionnaire (PC-QOL. Of these, only the PC-QOL can be used in young children, as it is a parent-proxy questionnaire. We reviewed pediatric studies looking at QOL in children with NCFB and cystic fibrosis. All types of airway clearance techniques appear to be safe and have no significant benefit over each other. Number of exacerbations and hospitalizations correlated with QOL scores, while symptom subscales correlated with lung function, worse QOL, frequent antibiotic requirements, and duration of regular follow-up in only one study. There was a correlation between QOL and age of diagnosis in children with primary ciliary dyskinesia. Other studies have shown no relationship between QOL scores and etiology of NCFB as well as CT changes. As for treatments, oral azithromycin and yoga have demonstrated some improvement in QOL scores. In conclusion, more studies are required to accurately determine important factors contributing to QOL.

Effects of Ex Vivo y-Tocopherol on Airway Macrophage ...

Science.gov (United States)

Elevated inflammation and altered immune responses are features found in atopic asthmatic airways. Recent studies indicate y-tocopherol (GT) supplementation can suppress airway inflammation in allergic asthma. We studied the effects of in vitro GT supplementation on receptor-mediated phagocytosis and expression of cell surface molecules associated with innate and adaptive immunity on sputum-derived macrophages. Cells from nonsmoking healthy (n = 6)and mild house dust mite-sensitive allergic asthmatics (n =6) were treated ex vivo with GT (300 uM) or saline (control). Phagocytosis of opsonized zymosan A bioparticles (Saccharomyces cerevisiae) and expression of surface molecules associated with innate and adaptive immunity were assessed using flow cytometry. GT caused significantly decreased (p < 0.05) internalization of attached zymosan bioparticles and decreased (p < 0.05) macrophage expression of CD206,CD36 and CD86 in allergic asthmatics but not in corntrols. Overall, GT caused down regulation of both innate and adaptive immune response elements, and atopic status appears to be an important factor. Recent studies on the effects of the fat-soluble steriod hormone vitamins D and E suggest that dietary suplementation with these vitamins may be helpful for the prevention or in the treatment of inflammatory and immune-mediated diseases, including atopic asthma.

Airway somatosensory deficits and dysphagia in Parkinson's disease.

Science.gov (United States)

Hammer, Michael J; Murphy, Caitlin A; Abrams, Trisha M

2013-01-01

Individuals with Parkinson's disease (PD) often experience substantial impairment of swallow control, and are typically unaware of the presence or severity of their impairments suggesting that these individuals may also experience airway sensory deficits. However, the degree to which impaired swallow function in PD may relate to airway sensory deficits has yet to be formally tested. The purpose of this study was to examine whether airway sensory function is associated with swallow impairment in PD. Eighteen PD participants and 18 healthy controls participated in this study and underwent endoscopic assessment of airway somatosensory function, endoscopic assessment of swallow function, and clinical ratings of swallow and disease severity. PD participants exhibited abnormal airway somatosensory function and greater swallow impairment compared with healthy controls. Swallow and sensory deficits in PD were correlated with disease severity. Moreover, PD participants reported similar self-rated swallow function as healthy controls, and swallow deficits were correlated with sensory function suggesting an association between impaired sensory function and poor self-awareness of swallow deficits in PD. These results suggest that control of swallow is influenced by airway somatosensory function, that swallow-related deficits in PD are related to abnormal somatosensation, and that swallow and airway sensory function may degrade as a function of disease severity. Therefore, the basal ganglia and related neural networks may play an important role to integrate airway sensory input for swallow-related motor control. Furthermore, the airway deficits observed in PD suggest a disintegration of swallow-related sensory and motor control.

Improving the safety of remote site emergency airway management.

Science.gov (United States)

Wijesuriya, Julian; Brand, Jonathan

2014-01-01

Airway management, particularly in non-theatre settings, is an area of anaesthesia and critical care associated with significant risk of morbidity & mortality, as highlighted during the 4th National Audit Project of the Royal College of Anaesthetists (NAP4). A survey of junior anaesthetists at our hospital highlighted a lack of confidence and perceived lack of safety in emergency airway management, especially in non-theatre settings. We developed and implemented a multifaceted airway package designed to improve the safety of remote site airway management. A Rapid Sequence Induction (RSI) checklist was developed; this was combined with new advanced airway equipment and drugs bags. Additionally, new carbon dioxide detector filters were procured in order to comply with NAP4 monitoring recommendations. The RSI checklists were placed in key locations throughout the hospital and the drugs and advanced airway equipment bags were centralised in the Intensive Care Unit (ICU). It was agreed with the senior nursing staff that an appropriately trained ICU nurse would attend all emergency situations with new airway resources upon request. Departmental guidelines were updated to include details of the new resources and the on-call anaesthetist's responsibilities regarding checks and maintenance. Following our intervention trainees reported higher confidence levels regarding remote site emergency airway management. Nine trusts within the Northern Region were surveyed and we found large variations in the provision of remote site airway management resources. Complications in remote site airway management due lack of available appropriate drugs, equipment or trained staff are potentially life threatening and completely avoidable. Utilising the intervention package an anaesthetist would be able to safely plan and prepare for airway management in any setting. They would subsequently have the drugs, equipment, and trained assistance required to manage any difficulties or complications

Inhaled antibiotics in non-cystic fibrosis bronchiectasis: A meta-analysis.

Science.gov (United States)

Xu, Li; Zhang, Fei; Du, Shuai; Yu, Qi; Chen, Lin; Long, Li-Hui; Li, Ya-Ming; Jia, Ai-Hua

2016-09-01

To evaluate the efficacy and safety of inhaled antibiotics for the treatment of non-cystic fibrosis bronchiectasis (NCFB). Pubmed, Cochrane library, Embase, Elsevier, OVID, Springerlink, Web of knowledge and NEJM were searched for randomized controlled trials (RCTs) on inhaled antibiotics in treatment of NCFB from inception until April 2015. Meta-analysis was conducted to assess the efficacy and safety of inhaled antibiotics in the treatment of NCFB. Twelve RCTs involving 1154 participants were included. They showed that inhaled antibiotics were more effective in reduction of sputum bacterial density, eradication of P. aeruginosa, prolonged time to exacerbation and reduction of new pathogens emergence with no significant difference in adverse events compared with control groups. However, we did not find significant benefits of inhaled antibiotics in reducing the risk of acute exacerbation, improving health-related quality of life and reduction of P. aeruginosa resistance. Moreover, inhaled antibiotics exerted a statistically significant reduction in FEV1%. Inhaled antibiotics may be an alternative pathway to inhibit airway inflammation with no more adverse events in patients with NCFB.

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.

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.

Angiogenesis in liver fibrosis

NARCIS (Netherlands)

Adlia, Amirah

2017-01-01

Angiogenesis emerges in parallel with liver fibrosis, but it is still unclear whether angiogenesis is a defense mechanism of the body in response to fibrosis, or whether it aggravates the fibrotic condition. In this thesis, Amirah Adlia applied different approaches to elucidate the role of

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.

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

Energy Technology Data Exchange (ETDEWEB)

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.

Dilemmas, Confusion, and Misconceptions Related to Small Airways Directed Therapy

DEFF Research Database (Denmark)

Lavorini, Federico; Pedersen, Søren; Usmani, Omar S.

2017-01-01

During the past decade, there has been increasing evidence that the small airways (ie, airways < 2 mm in internal diameter) contribute substantially to the pathophysiologic and clinical expression of asthma and COPD. The increased interest in small airways is, at least in part, a result of innova......During the past decade, there has been increasing evidence that the small airways (ie, airways COPD. The increased interest in small airways is, at least in part, a result...... of innovation in small-particle aerosol formulations that better target the distal lung and also advanced physiologic methods of assessing small airway responses. Increasing the precision of drug deposition may improve targeting of specific diseases or receptor locations, decrease airway drug exposure...... benefit, compared with large-particle aerosol treatment. However, a number of questions remain unanswered about the pragmatic approach relevant for clinicians to consider the role of small airways directed therapy in the day-to-day management of asthma and COPD. We thus have tried to clarify the dilemmas...