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Sample records for airway diseases including

  1. Global airway disease beyond allergy.

    PubMed

    Hellings, Peter W; Prokopakis, Emmanuel P

    2010-03-01

    Besides the anatomic continuity of the upper and lower airways, inflammation in one part of the airway influences the homeostasis of the other. The mechanisms underlying this interaction have been studied primarily in allergic disease, showing systemic immune activation, induction of inflammation at a distance, and a negative impact of nasal inflammation on bronchial homeostasis. In addition to allergy, other inflammatory conditions of the upper airways are associated with lower airway disease. Rhinosinusitis is frequently associated with asthma and chronic obstructive pulmonary disease. The impairment of purification, humidification, and warming up of the inspired air by the nose in rhinosinusitis may be responsible in part for bronchial pathology. The resolution of sinonasal inflammation via medical and/or surgical treatment is responsible for the beneficial effect of the treatment on bronchial disease. This article provides a comprehensive overview of the current knowledge of upper and lower airway communication beyond allergic disease.

  2. The airway microbiome and disease.

    PubMed

    Marsland, Benjamin J; Yadava, Koshika; Nicod, Laurent P

    2013-08-01

    Although traditionally thought to be sterile, accumulating evidence now supports the concept that our airways harbor a microbiome. Thus far, studies have focused upon characterizing the bacterial constituents of the airway microbiome in both healthy and diseased lungs, but what perhaps provides the greatest impetus for the exploration of the airway microbiome is that different bacterial phyla appear to dominate diseased as compared with healthy lungs. As yet, there is very limited evidence supporting a functional role for the airway microbiome, but continued research in this direction is likely to provide such evidence, particularly considering the progress that has been made in understanding host-microbe mutualism in the intestinal tract. In this review, we highlight the major advances that have been made discovering and describing the airway microbiome, discuss the experimental evidence that supports a functional role for the microbiome in health and disease, and propose how this emerging field is going to impact clinical practice.

  3. United airway disease: current perspectives

    PubMed Central

    Giavina-Bianchi, Pedro; Aun, Marcelo Vivolo; Takejima, Priscila; Kalil, Jorge; Agondi, Rosana Câmara

    2016-01-01

    Upper and lower airways are considered a unified morphological and functional unit, and the connection existing between them has been observed for many years, both in health and in disease. There is strong epidemiologic, pathophysiologic, and clinical evidence supporting an integrated view of rhinitis and asthma: united airway disease in the present review. The term “united airway disease” is opportune, because rhinitis and asthma are chronic inflammatory diseases of the upper and lower airways, which can be induced by allergic or nonallergic reproducible mechanisms, and present several phenotypes. Management of rhinitis and asthma must be jointly carried out, leading to better control of both diseases, and the lessons of the Allergic Rhinitis and Its Impact on Asthma initiative cannot be forgotten. PMID:27257389

  4. The Lung Microbiome and Airway Disease.

    PubMed

    Lynch, Susan V

    2016-12-01

    A growing body of literature has demonstrated relationships between the composition of the airway microbiota (mixed-species communities of microbes that exist in the respiratory tract) and critical features of immune response and pulmonary function. These studies provide evidence that airway inflammatory status and capacity for repair are coassociated with specific taxonomic features of the airway microbiome. Although directionality has yet to be established, the fact that microbes are known drivers of inflammation and tissue damage suggests that in the context of chronic inflammatory airway disease, the composition and, more importantly, the function, of the pulmonary microbiome represent critical factors in defining airway disease outcomes.

  5. Host-microbe interactions in distal airways: relevance to chronic airway diseases.

    PubMed

    Martin, Clémence; Burgel, Pierre-Régis; Lepage, Patricia; Andréjak, Claire; de Blic, Jacques; Bourdin, Arnaud; Brouard, Jacques; Chanez, Pascal; Dalphin, Jean-Charles; Deslée, Gaetan; Deschildre, Antoine; Gosset, Philippe; Touqui, Lhousseine; Dusser, Daniel

    2015-03-01

    This article is the summary of a workshop, which took place in November 2013, on the roles of microorganisms in chronic respiratory diseases. Until recently, it was assumed that lower airways were sterile in healthy individuals. However, it has long been acknowledged that microorganisms could be identified in distal airway secretions from patients with various respiratory diseases, including cystic fibrosis (CF) and non-CF bronchiectasis, chronic obstructive pulmonary disease, asthma and other chronic airway diseases (e.g. post-transplantation bronchiolitis obliterans). These microorganisms were sometimes considered as infectious agents that triggered host immune responses and contributed to disease onset and/or progression; alternatively, microorganisms were often considered as colonisers, which were considered unlikely to play roles in disease pathophysiology. These concepts were developed at a time when the identification of microorganisms relied on culture-based methods. Importantly, the majority of microorganisms cannot be cultured using conventional methods, and the use of novel culture-independent methods that rely on the identification of microorganism genomes has revealed that healthy distal airways display a complex flora called the airway microbiota. The present article reviews some aspects of current literature on host-microbe (mostly bacteria and viruses) interactions in healthy and diseased airways, with a special focus on distal airways.

  6. Long-Acting Beta Agonists Enhance Allergic Airway Disease

    PubMed Central

    Knight, John M.; Mak, Garbo; Shaw, Joanne; Porter, Paul; McDermott, Catherine; Roberts, Luz; You, Ran; Yuan, Xiaoyi; Millien, Valentine O.; Qian, Yuping; Song, Li-Zhen; Frazier, Vincent; Kim, Choel; Kim, Jeong Joo; Bond, Richard A.; Milner, Joshua D.; Zhang, Yuan; Mandal, Pijus K.; Luong, Amber; Kheradmand, Farrah

    2015-01-01

    Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (β2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related β2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease-related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related β2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6. PMID:26605551

  7. Long-Acting Beta Agonists Enhance Allergic Airway Disease.

    PubMed

    Knight, John M; Mak, Garbo; Shaw, Joanne; Porter, Paul; McDermott, Catherine; Roberts, Luz; You, Ran; Yuan, Xiaoyi; Millien, Valentine O; Qian, Yuping; Song, Li-Zhen; Frazier, Vincent; Kim, Choel; Kim, Jeong Joo; Bond, Richard A; Milner, Joshua D; Zhang, Yuan; Mandal, Pijus K; Luong, Amber; Kheradmand, Farrah; McMurray, John S; Corry, David B

    2015-01-01

    Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (β2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related β2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease-related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related β2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6.

  8. Integrated care pathways for airway diseases (AIRWAYS-ICPs).

    PubMed

    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

    2014-08-01

    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) proposing a common simulation tool to assist physicians; and 6) ultimately reducing the healthcare burden (emergency visits, avoidable hospitalisations, disability and costs) while improving quality of life. In the longer term, the incidence of disease may be reduced by innovative prevention strategies. AIRWAYSICPs was initiated by Area 5 of the Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing. All stakeholders are involved (health and social care, patients, and policy makers).

  9. Classification of pulmonary airway disease based on mucosal color analysis

    NASA Astrophysics Data System (ADS)

    Suter, Melissa; Reinhardt, Joseph M.; Riker, David; Ferguson, John Scott; McLennan, Geoffrey

    2005-04-01

    Airway mucosal color changes occur in response to the development of bronchial diseases including lung cancer, cystic fibrosis, chronic bronchitis, emphysema and asthma. These associated changes are often visualized using standard macro-optical bronchoscopy techniques. A limitation to this form of assessment is that the subtle changes that indicate early stages in disease development may often be missed as a result of this highly subjective assessment, especially in inexperienced bronchoscopists. Tri-chromatic CCD chip bronchoscopes allow for digital color analysis of the pulmonary airway mucosa. This form of analysis may facilitate a greater understanding of airway disease response. A 2-step image classification approach is employed: the first step is to distinguish between healthy and diseased bronchoscope images and the second is to classify the detected abnormal images into 1 of 4 possible disease categories. A database of airway mucosal color constructed from healthy human volunteers is used as a standard against which statistical comparisons are made from mucosa with known apparent airway abnormalities. This approach demonstrates great promise as an effective detection and diagnosis tool to highlight potentially abnormal airway mucosa identifying a region possibly suited to further analysis via airway forceps biopsy, or newly developed micro-optical biopsy strategies. Following the identification of abnormal airway images a neural network is used to distinguish between the different disease classes. We have shown that classification of potentially diseased airway mucosa is possible through comparative color analysis of digital bronchoscope images. The combination of the two strategies appears to increase the classification accuracy in addition to greatly decreasing the computational time.

  10. Mucoactive agents for airway mucus hypersecretory diseases.

    PubMed

    Rogers, Duncan F

    2007-09-01

    Airway mucus hypersecretion is a feature of a number of severe respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF). However, each disease has a different airway inflammatory response, with consequent, and presumably linked, mucus hypersecretory phenotype. Thus, it is possible that optimal treatment of the mucus hypersecretory element of each disease should be disease-specific. Nevertheless, mucoactive drugs are a longstanding and popular therapeutic option, and numerous compounds (eg, N-acetylcysteine, erdosteine, and ambroxol) are available for clinical use worldwide. However, rational recommendation of these drugs in guidelines for management of asthma, COPD, or CF has been hampered by lack of information from well-designed clinical trials. In addition, the mechanism of action of most of these drugs is unknown. Consequently, although it is possible to categorize them according to putative mechanisms of action, as expectorants (aid and/or induce cough), mucolytics (thin mucus), mucokinetics (facilitate cough transportability), and mucoregulators (suppress mechanisms underlying chronic mucus hypersecretion, such as glucocorticosteroids), it is likely that any beneficial effects are due to activities other than, or in addition to, effects on mucus. It is also noteworthy that the mucus factors that favor mucociliary transport (eg, thin mucus gel layer, "ideal" sol depth, and elasticity greater than viscosity) are opposite to those that favor cough effectiveness (thick mucus layer, excessive sol height, and viscosity greater than elasticity), which indicates that different mucoactive drugs would be required for treatment of mucus obstruction in proximal versus distal airways, or in patients with an impaired cough reflex. With the exception of mucoregulatory agents, whose primary action is unlikely to be directed against mucus, well-designed clinical trials are required to unequivocally determine the

  11. The role of bronchoscopy in the diagnosis of airway disease

    PubMed Central

    Dixon, Jennifer; Tieu, Brandon H.

    2016-01-01

    Endoscopy of the airway is a valuable tool for the evaluation and management of airway disease. It can be used to evaluate many different bronchopulmonary diseases including airway foreign bodies, tumors, infectious and inflammatory conditions, airway stenosis, and bronchopulmonary hemorrhage. Traditionally, options for evaluation were limited to flexible and rigid bronchoscopy. Recently, more sophisticated technology has led to the development of endobronchial ultrasound (EBUS) and electromagnetic navigational bronchoscopy (ENB). These technological advances, combined with increasing provider experience have resulted in a higher diagnostic yield with endoscopic biopsies. This review will focus on the role of bronchoscopy, including EBUS, ENB, and rigid bronchoscopy in the diagnosis of bronchopulmonary diseases. In addition, it will cover the anesthetic considerations, equipment, diagnostic yield, and potential complications. PMID:28149583

  12. Inflammatory mechanisms and treatment of obstructive airway diseases with neutrophilic bronchitis.

    PubMed

    Simpson, Jodie L; Phipps, Simon; Gibson, Peter G

    2009-10-01

    Obstructive airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) are major global health issues. Although considered as distinct diseases, airway inflammation is a key underlying pathophysiological process in asthma, COPD and bronchiectasis. Persistent neutrophilic airway inflammation (neutrophilic bronchitis) occurs with innate immune activation and is a feature of each of these airway diseases. Little is known about the mechanisms leading to neutrophilic bronchitis and few treatments are effective in reducing neutrophil accumulation in the airways. There is a similar pattern of inflammatory mediator release and toll like receptor 2 expression in asthma, COPD and bronchiectasis. We propose the existence of an active amplification mechanism, an effector arm of the innate immune system, involving toll like receptor 2, operating in persistent neutrophilic bronchitis. Neutrophil persistence in the airways can occur through a number of mechanisms such as impaired apoptosis, efferocytosis and mucus hypersecretion, all of which are impaired in airways disease. Impairment of neutrophil clearance results in a reduced ability to respond to bacterial infection. Persistent activation of airway neutrophils may result in the persistent activation of the innate immune system resulting in further airway insult. Current therapies are limited for the treatment of neutrophilic bronchitis; possible treatments being investigated include theophylline, statins, antagonists of pro-inflammatory cytokines and macrolide antibiotics. Macrolides have shown great promise in their ability to reduce airway inflammation, and can reduce airway neutrophils, levels of CXCL8 and neutrophil proteases in the airways. Studies also show improvements in quality of life and exacerbation rates in airways diseases.

  13. MicroRNA in United Airway Diseases

    PubMed Central

    Liu, Zheng; Zhang, Xin-Hao; Callejas-Díaz, Borja; Mullol, Joaquim

    2016-01-01

    The concept of united airway diseases (UAD) has received increasing attention in recent years. Sustained and increased inflammation is a common feature of UAD, which is inevitably accompanied with marked gene modification and tight gene regulation. However, gene regulation in the common inflammatory processes in UAD remains unclear. MicroRNA (miRNA), a novel regulator of gene expression, has been considered to be involved in many inflammatory diseases. Although there are an increasing number of studies of miRNAs in inflammatory upper and lower airway diseases, few miRNAs have been identified that directly link the upper and lower airways. In this article, therefore, we reviewed the relevant studies available in order to improve the understanding of the roles of miRNAs in the interaction and pathogenesis of UAD. PMID:27187364

  14. Synthesis and evaluation of airway targeted PLGA nanoparticles for drug delivery in obstructive lung diseases.

    PubMed

    Vij, Neeraj

    2012-01-01

    Chronic airway inflammation is a hallmark of chronic obstructive airway diseases, including asthma, COPD (chronic obstructive pulmonary disease), and CF (cystic fibrosis). It is also a major challenge in delivery and therapeutic efficacy of nano-based delivery systems in these chronic airway conditions as nanoparticle (NP) need to bypass airways defense mechanisms as we recently discussed. NPs which are capable of overcoming airways defense mechanisms should allow targeted drug delivery to disease cells. Over the last decade there has been increasing interest in development of targeted NPs for cancer but relatively little effort on designing novel systems for treating chronic inflammatory and obstructive airway conditions. Here we describe methods for preparing drug loaded multifunctional nanoparticles for targeted delivery to specific cell types in airways. The formulations and methods for selective drug delivery, discussed here are currently under preclinical development in our laboratory for treating chronic airway conditions such as COPD, CF, and asthma.

  15. Distinct clinical phenotypes of airways disease defined by cluster analysis.

    PubMed

    Weatherall, M; Travers, J; Shirtcliffe, P M; Marsh, S E; Williams, M V; Nowitz, M R; Aldington, S; Beasley, R

    2009-10-01

    Airways disease is currently classified using diagnostic labels such as asthma, chronic bronchitis and emphysema. The current definitions of these classifications may not reflect the phenotypes of airways disease in the community, which may have differing disease processes, clinical features or responses to treatment. The aim of the present study was to use cluster analysis to explore clinical phenotypes in a community population with airways disease. A random population sample of 25-75-yr-old adults underwent detailed investigation, including a clinical questionnaire, pulmonary function tests, nitric oxide measurements, blood tests and chest computed tomography. Cluster analysis was performed on the subgroup with current respiratory symptoms or obstructive spirometric results. Subjects with a complete dataset (n = 175) were included in the cluster analysis. Five clusters were identified with the following characteristics: cluster 1: severe and markedly variable airflow obstruction with features of atopic asthma, chronic bronchitis and emphysema; cluster 2: features of emphysema alone; cluster 3: atopic asthma with eosinophilic airways inflammation; cluster 4: mild airflow obstruction without other dominant phenotypic features; and cluster 5: chronic bronchitis in nonsmokers. Five distinct clinical phenotypes of airflow obstruction were identified. If confirmed in other populations, these findings may form the basis of a modified taxonomy for the disorders of airways obstruction.

  16. Self-expandable metallic stents in nonmalignant large airway disease.

    PubMed

    Fortin, Marc; MacEachern, Paul; Hergott, Christopher A; Chee, Alex; Dumoulin, Elaine; Tremblay, Alain

    2015-01-01

    Airway self-expandable metallic stents (SEMS) were initially studied in malignant airway obstruction; however, their use in benign airway diseases has become progressively more frequent. This may be explained by their ease of insertion compared with silicone stents, which require rigid bronchoscopy for insertion. While initial experience with SEMS in benign disease suggested efficacy and promising short-term safety profile, long-term follow-up revealed significant complication rates. In addition to a high complication rate, the management of these complications is made more difficult by the semipermanent nature of these devices. Reported complications include infection, granulation tissue formation, stent migration, stent fracture, airway perforation and fistula formation, as well as extension of the initial injury, potentially eliminating other therapeutic options such as surgical resection. Therefore, SEMS should only be used in nonmalignant large airway disease as a last resort for patients in whom other endoscopic methods, including silicone stents and dilations, as well as surgical options have failed or are technically not feasible.

  17. The Diacetyl-exposed Human Airway Epithelial Secretome: New Insights Into Flavoring Induced Airways Disease.

    PubMed

    Brass, David M; Gwinn, William M; Valente, Ashlee M; Kelly, Francine L; Brinkley, Christie D; Nagler, Andrew E; Moseley, M Arthur; Morgan, Daniel L; Palmer, Scott M; Foster, Matthew W

    2017-03-01

    Bronchiolitis obliterans (BO) is an increasingly important lung disease characterized by fibroproliferative airway lesions and decrements in lung function. Occupational exposure to the artificial food flavoring ingredient diacetyl, commonly used to impart a buttery flavor to microwave popcorn, has been associated with BO development. In the occupational setting, diacetyl vapor is first encountered by the airway epithelium. To better understand the effects of diacetyl vapor on the airway epithelium we used an unbiased proteomic approach to characterize both the apical and basolateral secretomes of air liquid interface cultures of primary human airway epithelial cells from four unique donors after exposure to an occupationally relevant ~1100 ppm of diacetyl vapor or PBS as a control on alternating days. Basolateral and apical supernatants collected 48 hours after the third exposure were analyzed using one-dimensional liquid chromatography tandem mass spectrometry. Paired t-tests adjusted for multiple comparisons were used to assess differential expression between diacetyl and PBS exposure. Of the significantly differentially expressed proteins identified, 61 were unique to the apical secretome, 81 were unique to the basolateral secretome and there were an additional 11 present in both. Pathway enrichment analysis using publicly available databases reveals that proteins associated with matrix remodeling including degradation, assembly and new matrix organization were over-represented in the data sets. Similarly, protein modifiers of epidermal growth factor receptor signaling were significantly altered. The ordered changes in protein expression suggest that the airway epithelial response to diacetyl may contribute to BO pathogenesis.

  18. Neurophenotypes in Airway Diseases. Insights from Translational Cough Studies

    PubMed Central

    Birrell, Mark A.; Khalid, Saifudin; Wortley, Michael A.; Dockry, Rachel; Coote, Julie; Holt, Kimberley; Dubuis, Eric; Kelsall, Angela; Maher, Sarah A.; Bonvini, Sara; Woodcock, Ashley

    2016-01-01

    Rationale: Most airway diseases, including chronic obstructive pulmonary disease (COPD), are associated with excessive coughing. The extent to which this may be a consequence of increased activation of vagal afferents by pathology in the airways (e.g., inflammatory mediators, excessive mucus) or an altered neuronal phenotype is unknown. Understanding whether respiratory diseases are associated with dysfunction of airway sensory nerves has the potential to identify novel therapeutic targets. Objectives: To assess the changes in cough responses to a range of inhaled irritants in COPD and model these in animals to investigate the underlying mechanisms. Methods: Cough responses to inhaled stimuli in patients with COPD, healthy smokers, refractory chronic cough, asthma, and healthy volunteers were assessed and compared with vagus/airway nerve and cough responses in a cigarette smoke (CS) exposure guinea pig model. Measurements and Main Results: Patients with COPD had heightened cough responses to capsaicin but reduced responses to prostaglandin E2 compared with healthy volunteers. Furthermore, the different patient groups all exhibited different patterns of modulation of cough responses. Consistent with these findings, capsaicin caused a greater number of coughs in CS-exposed guinea pigs than in control animals; similar increased responses were observed in ex vivo vagus nerve and neuron cell bodies in the vagal ganglia. However, responses to prostaglandin E2 were decreased by CS exposure. Conclusions: CS exposure is capable of inducing responses consistent with phenotypic switching in airway sensory nerves comparable with the cough responses observed in patients with COPD. Moreover, the differing profiles of cough responses support the concept of disease-specific neurophenotypes in airway disease. Clinical trial registered with www.clinicaltrials.gov (NCT 01297790). PMID:26741046

  19. NF-kappaB Signaling in Chronic Inflammatory Airway Disease

    PubMed Central

    Schuliga, Michael

    2015-01-01

    Asthma and chronic obstructive pulmonary disease (COPD) are obstructive airway disorders which differ in their underlying causes and phenotypes but overlap in patterns of pharmacological treatments. In both asthma and COPD, oxidative stress contributes to airway inflammation by inducing inflammatory gene expression. The redox-sensitive transcription factor, nuclear factor (NF)-kappaB (NF-κB), is an important participant in a broad spectrum of inflammatory networks that regulate cytokine activity in airway pathology. The anti-inflammatory actions of glucocorticoids (GCs), a mainstay treatment for asthma, involve inhibition of NF-κB induced gene transcription. Ligand bound GC receptors (GRs) bind NF-κB to suppress the transcription of NF-κB responsive genes (i.e., transrepression). However, in severe asthma and COPD, the transrepression of NF-κB by GCs is negated as a consequence of post-translational changes to GR and histones involved in chromatin remodeling. Therapeutics which target NF-κB activation, including inhibitors of IκB kinases (IKKs) are potential treatments for asthma and COPD. Furthermore, reversing GR/histone acetylation shows promise as a strategy to treat steroid refractory airway disease by augmenting NF-κB transrepression. This review examines NF-κB signaling in airway inflammation and its potential as target for treatment of asthma and COPD. PMID:26131974

  20. Microbiota abnormalities in inflammatory airway diseases - Potential for therapy.

    PubMed

    Gollwitzer, Eva S; Marsland, Benjamin J

    2014-01-01

    Increasingly the development of novel therapeutic strategies is taking into consideration the contribution of the intestinal microbiota to health and disease. Dysbiosis of the microbial communities colonizing the human intestinal tract has been described for a variety of chronic diseases, such as inflammatory bowel disease, obesity and asthma. In particular, reduction of several so-called probiotic species including Lactobacilli and Bifidobacteria that are generally considered to be beneficial, as well as an outgrowth of potentially pathogenic bacteria is often reported. Thus a tempting therapeutic approach is to shape the constituents of the microbiota in an attempt to restore the microbial balance towards the growth of 'health-promoting' bacterial species. A twist to this scenario is the recent discovery that the respiratory tract also harbors a microbiota under steady-state conditions. Investigators have shown that the microbial composition of the airway flora is different between healthy lungs and those with chronic lung diseases, such as asthma, chronic obstructive pulmonary disease as well as cystic fibrosis. This is an emerging field, and thus far there is very limited data showing a direct contribution of the airway microbiota to the onset and progression of disease. However, should future studies provide such evidence, the airway microbiota might soon join the intestinal microbiota as a target for therapeutic intervention. In this review, we highlight the major advances that have been made describing the microbiota in chronic lung disease and discuss current and future approaches concerning manipulation of the microbiota for the treatment and prevention of disease.

  1. Hyperresponsiveness in the human nasal airway: new targets for the treatment of allergic airway disease.

    PubMed Central

    Turner, P J; Foreman, J C

    1999-01-01

    Allergic rhinitis is a condition which affects over 15% of the population in the United Kingdom. The pathological process involves two stages: nasal inflammation, and the development of nasal airway hyperresponsiveness (AHR) to allergen and a number of other stimuli. This results in the amplification of any subsequent allergic reaction, contributing to the chronic allergic state. A number of different hypotheses have been proposed to explain the underlying mechanism of AHR, including a role for eosinophil-derived proteins, free radicals and neuropeptides. While there may be a number of independent pathways which can result in AHR, evidence obtained from both animal models and in vivo experiments in humans indicate that some mediators may interact with one another, resulting in AHR. Further research into these interactions may open new avenues for the pharmacological treatment of chronic allergic rhinitis, and possibly other allergic airway diseases. PMID:10704051

  2. Systems physiology of the airways in health and obstructive pulmonary disease.

    PubMed

    Bates, Jason H T

    2016-09-01

    Fresh air entering the mouth and nose is brought to the blood-gas barrier in the lungs by a repetitively branching network of airways. Provided the individual airway branches remain patent, this airway tree achieves an enormous amplification in cross-sectional area from the trachea to the terminal bronchioles. Obstructive lung diseases such as asthma occur when airway patency becomes compromised. Understanding the pathophysiology of these obstructive diseases thus begins with a consideration of the factors that determine the caliber of an individual airway, which include the force balance between the inward elastic recoil of the airway wall, the outward tethering forces of its parenchymal attachments, and any additional forces due to contraction of airway smooth muscle. Other factors may also contribute significantly to airway narrowing, such as thickening of the airway wall and accumulation of secretions in the lumen. Airway obstruction becomes particularly severe when these various factors occur in concert. However, the effect of airway abnormalities on lung function cannot be fully understood only in terms of what happens to a single airway because narrowing throughout the airway tree is invariably heterogeneous and interdependent. Obstructive lung pathologies thus manifest as emergent phenomena arising from the way in which the airway tree behaves a system. These emergent phenomena are studied with clinical measurements of lung function made by spirometry and by mechanical impedance measured with the forced oscillation technique. Anatomically based computational models are linking these measurements to underlying anatomic structure in systems physiology terms. WIREs Syst Biol Med 2016, 8:423-437. doi: 10.1002/wsbm.1347 For further resources related to this article, please visit the WIREs website.

  3. Inflammatory Signalings Involved in Airway and Pulmonary Diseases

    PubMed Central

    Lee, I-Ta; Yang, Chuen-Mao

    2013-01-01

    In respiratory diseases, there is an increased expression of multiple inflammatory proteins in the respiratory tract, including cytokines, chemokines, and adhesion molecules. Chemokines have been shown to regulate inflammation and immune cell differentiation. Moreover, many of the known inflammatory target proteins, such as matrix metalloproteinase-9 (MMP-9), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), cyclooxygenase-2 (COX-2), and cytosolic phospholipase A2 (cPLA2), are associated with airway and lung inflammation in response to various stimuli. Injuriously environmental stimuli can access the lung through either the airways or the pulmonary and systemic circulations. The time course and intensity of responses by resident and circulating cells may be regulated by various inflammatory signalings, including Src family kinases (SFKs), protein kinase C (PKC), growth factor tyrosine kinase receptors, nicotinamide adenine dinucleotide phosphate (NADPH)/reactive oxygen species (ROS), PI3K/Akt, MAPKs, nuclear factor-kappa B (NF-κB), activator protein-1 (AP-1), and other signaling molecules. These signaling molecules regulate both key inflammatory signaling transduction pathways and target proteins involved in airway and lung inflammation. Here, we discuss the mechanisms involved in the expression of inflammatory target proteins associated with the respiratory diseases. Knowledge of the mechanisms of inflammation regulation could lead to the pharmacological manipulation of anti-inflammatory drugs in the respiratory diseases. PMID:23690670

  4. Clinical application of expectorant therapy in chronic inflammatory airway diseases (Review)

    PubMed Central

    ZHANG, TING; ZHOU, XIANGDONG

    2014-01-01

    Airway mucus hypersecretion is a significant clinical and pathological feature of chronic inflammatory airway diseases. Its clinical presentations include recurrent coughing and phlegm. Airway mucus is closely associated with the occurrence, development and prognosis of chronic inflammatory airway diseases and critically affects the lung function, quality of life, hospitalization rate and mortality of patients with chronic inflammatory airway diseases. Therefore, expectorant therapies targeting the potential mechanisms of mucus hypersecretion have been the focus of numerous studies. Conventional expectorants are mainly mucoactive medicines, including nausea-stimulating expectorants, mucolytics, mucokinetics, and proteases and nucleases. In addition, certain traditional Chinese herbal medicines and non-mucoactive agents, including muscarinic acetylcholine receptor antagonists, corticosteroids, leukotriene receptor antagonists and macrolide antibiotics, have also shown expectorant effects. Several novel medicines for expectorant therapy have emerged, including cholesterol-lowering statins, epidermal growth factor receptor tyrosine kinase inhibitors, phosphodiesterase-4 inhibitors, stanozolol, surfactants, flavonoids, tachykinin receptor antagonists, protease inhibitors, cytokine antagonists and purinergic agonists. With the increasing number of multidisciplinary studies, the effectiveness of expectorant therapy for the treatment of chronic inflammatory airway diseases has been confirmed. Therefore, the development of novel expectorants and the standardization of expectorant therapy are the direction and focus of future studies, thus benefiting patients who have a chronic inflammatory airway disease. PMID:24660026

  5. Mast cells in airway diseases and interstitial lung disease.

    PubMed

    Cruse, Glenn; Bradding, Peter

    2016-05-05

    Mast cells are major effector cells of inflammation and there is strong evidence that mast cells play a significant role in asthma pathophysiology. There is also a growing body of evidence that mast cells contribute to other inflammatory and fibrotic lung diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. This review discusses the role that mast cells play in airway diseases and highlights how mast cell microlocalisation within specific lung compartments and their cellular interactions are likely to be critical for their effector function in disease.

  6. Has the airway microbiome been overlooked in respiratory disease?

    PubMed

    Salami, Olawale; Marsland, Benjamin J

    2015-01-01

    The respiratory disease field is changing because of recent advances in our understanding of the airway microbiome. Central to this is dysbiosis, an imbalance of microbial communities that can lead to and flag inflammation in the airways. The increasing momentum of research in this area holds promise for novel treatment strategies.

  7. Prevention of house dust mite induced allergic airways disease in mice through immune tolerance.

    PubMed

    Agua-Doce, Ana; Graca, Luis

    2011-01-01

    Allergic airways disease is a consequence of a Th2 response to an allergen leading to a series of manifestations such as production of allergen-specific IgE, inflammatory infiltrates in the airways, and airway hyper-reactivity (AHR). Several strategies have been reported for tolerance induction to allergens leading to protection from allergic airways disease. We now show that CD4 blockade at the time of house dust mite sensitization induces antigen-specific tolerance in mice. Tolerance induction is robust enough to be effective in pre-sensitized animals, even in those where AHR was pre-established. Tolerant mice are protected from airways eosinophilia, Th2 lung infiltration, and AHR. Furthermore, anti-CD4 treated mice remain immune competent to mount immune responses, including Th2, to unrelated antigens. Our findings, therefore, describe a strategy for tolerance induction potentially applicable to other immunogenic proteins besides allergens.

  8. SUBCHRONIC ENDOTOXIN INHALATION CAUSES PERSISTENT AIRWAY DISEASE

    EPA Science Inventory

    ABSTRACT

    The endotoxin component of organic dusts causes acute reversible airflow obstruction and airway inflammation. To test the hypothesis that endotoxin alone causes airway remodeling, we have compared the response of two inbred mouse strains to subchronic endotoxin ...

  9. Microbiology of airway disease in patients with cystic fibrosis.

    PubMed Central

    Gilligan, P H

    1991-01-01

    Individuals with cystic fibrosis have abbreviated life spans primarily due to chronic airway infection. A limited number of types of organisms are responsible for these infections, with Staphylococcus aureus and Pseudomonas aeruginosa being of primary importance. In the pre-antibiotic era, greater than 90% of deaths due to infection were caused by S. aureus and death usually occurred in the first 2 years of life. With the advent of effective antistaphylococcal therapy, life spans increased and P. aeruginosa became the pathogen of primary importance. P. aeruginosa isolates recovered from patients with cystic fibrosis have a unique phenotypic characteristic referred to as "mucoid." The mucoid phenotype is due to the production of a mucoid exopolysaccharide. A mucoid exopolysaccharide is believed to play a central role in the establishment of chronic pseudomonal lung infection in these patients. A third organism, Pseudomonas cepacia, has recently been detected in the airways of older patients with cystic fibrosis and is associated with increased mortality. The virulence of P. cepacia is not understood, but the organism is extremely refractory to antimicrobial therapy. Other bacteria, including Haemophilus influenzae and members of the family Enterobacteriaceae, appear to play a secondary role in airway infection. Aspergillus fumigatus is the most important fungal agent causing allergic bronchopulmonary disease. The role of viruses has only recently been examined. At least in some patients with cystic fibrosis, respiratory syncytial virus may be important in predisposing to subsequent bacterial infections. PMID:1900735

  10. Airway epithelial repair, regeneration, and remodeling after injury in chronic obstructive pulmonary disease.

    PubMed

    Puchelle, Edith; Zahm, Jean-Marie; Tournier, Jean-Marie; Coraux, Christelle

    2006-11-01

    In chronic obstructive pulmonary disease (COPD), exacerbations are generally associated with several causes, including pollutants, viruses, bacteria that are responsible for an excess of inflammatory mediators, and proinflammatory cytokines released by activated epithelial and inflammatory cells. The normal response of the airway surface epithelium to injury includes a succession of cellular events, varying from the loss of the surface epithelium integrity to partial shedding of the epithelium or even complete denudation of the basement membrane. The epithelium then has to repair and regenerate to restore its functions, through several mechanisms, including basal cell spreading and migration, followed by proliferation and differentiation of epithelial cells. In COPD, the remodeling of the airway epithelium, such as squamous metaplasia and mucous hyperplasia that occur during injury, may considerably disturb the innate immune functions of the airway epithelium. In vitro and in vivo models of airway epithelial wound repair and regeneration allow the study of the spatiotemporal modulation of cellular and molecular interaction factors-namely, the proinflammatory cytokines, the matrix metalloproteinases and their inhibitors, and the intercellular adhesion molecules. These factors may be markedly altered during exacerbation periods of COPD and their dysregulation may induce remodeling of the airway mucosa and a leakiness of the airway surface epithelium. More knowledge of the mechanisms involved in airway epithelium regeneration may pave the way to cytoprotective and regenerative therapeutics, allowing the reconstitution of a functional, well-differentiated airway epithelium in COPD.

  11. Clinical significance of airway mucus hypersecretion in chronic obstructive pulmonary disease

    PubMed Central

    Tian, Pan-wen; Wen, Fu-qiang

    2015-01-01

    Airway mucus hypersecretion is one of the most important features of chronic obstructive pulmonary disease (COPD). Airway mucus hypersecretion in COPD patients results in outcomes such as rapid decline of lung function, poor quality of life, and high rate of acute exacerbation, hospitalization and mortality. Nonpharmacologic treatments for airway mucus hypersecretion in COPD include smoking cessation and physical rehabilitation. Pharmacologic therapies include expectorants, mucolytics, methylxanthines, beta-adrenergic receptor agonists, anticholinergics, glucocorticoids, phosphodiesterase-4 inhibitors, antioxidants, and antibiotics. Novel drugs with promising prospects are currently under clinical trials. PMID:27847895

  12. CT Metrics of Airway Disease and Emphysema in Severe COPD

    PubMed Central

    Kim, Woo Jin; Silverman, Edwin K.; Hoffman, Eric; Criner, Gerard J.; Mosenifar, Zab; Sciurba, Frank C.; Make, Barry J.; Carey, Vincent; Estépar, Raúl San José; Diaz, Alejandro; Reilly, John J.; Martinez, Fernando J.; Washko, George R.

    2009-01-01

    Background: CT scan measures of emphysema and airway disease have been correlated with lung function in cohorts of subjects with a range of COPD severity. The contribution of CT scan-assessed airway disease to objective measures of lung function and respiratory symptoms such as dyspnea in severe emphysema is less clear. Methods: Using data from 338 subjects in the National Emphysema Treatment Trial (NETT) Genetics Ancillary Study, densitometric measures of emphysema using a threshold of −950 Hounsfield units (%LAA-950) and airway wall phenotypes of the wall thickness (WT) and the square root of wall area (SRWA) of a 10-mm luminal perimeter airway were calculated for each subject. Linear regression analysis was performed for outcome variables FEV1 and percent predicted value of FEV1 with CT scan measures of emphysema and airway disease. Results: In univariate analysis, there were significant negative correlations between %LAA-950 and both the WT (r = −0.28, p = 0.0001) and SRWA (r = −0.19, p = 0.0008). Airway wall thickness was weakly but significantly correlated with postbronchodilator FEV1% predicted (R = −0.12, p = 0.02). Multivariate analysis showed significant associations between either WT or SRWA (β = −5.2, p = 0.009; β = −2.6, p = 0.008, respectively) and %LAA-950 (β = −10.6, p = 0.03) with the postbronchodilator FEV1% predicted. Male subjects exhibited significantly thicker airway wall phenotypes (p = 0.007 for WT and p = 0.0006 for SRWA). Conclusions: Airway disease and emphysema detected by CT scanning are inversely related in patients with severe COPD. Airway wall phenotypes were influenced by gender and associated with lung function in subjects with severe emphysema. PMID:19411295

  13. A Persistent and Diverse Airway Microbiota Present during Chronic Obstructive Pulmonary Disease Exacerbations

    PubMed Central

    Huang, Yvonne J.; Kim, Eugenia; Cox, Michael J.; Brodie, Eoin L.; Brown, Ron; Wiener-Kronish, Jeanine P.

    2010-01-01

    Abstract Acute exacerbations of chronic obstructive pulmonary disease (COPD) are a major source of morbidity and contribute significantly to healthcare costs. Although bacterial infections are implicated in nearly 50% of exacerbations, only a handful of pathogens have been consistently identified in COPD airways, primarily by culture-based methods, and the bacterial microbiota in acute exacerbations remains largely uncharacterized. The aim of this study was to comprehensively profile airway bacterial communities using a culture-independent microarray, the 16S rRNA PhyloChip, of a cohort of COPD patients requiring ventilatory support and antibiotic therapy for exacerbation-related respiratory failure. PhyloChip analysis revealed the presence of over 1,200 bacterial taxa representing 140 distinct families, many previously undetected in airway diseases; bacterial community composition was strongly influenced by the duration of intubation. A core community of 75 taxa was detected in all patients, many of which are known pathogens. Bacterial community diversity in COPD airways is substantially greater than previously recognized and includes a number of potential pathogens detected in the setting of antibiotic exposure. Comprehensive assessment of the COPD airway microbiota using high-throughput, culture-independent methods may prove key to understanding the relationships between airway bacterial colonization, acute exacerbation, and clinical outcomes in this and other chronic inflammatory airway diseases. PMID:20141328

  14. A persistent and diverse airway microbiota present during chronic obstructive pulmonary disease exacerbations.

    PubMed

    Huang, Yvonne J; Kim, Eugenia; Cox, Michael J; Brodie, Eoin L; Brown, Ron; Wiener-Kronish, Jeanine P; Lynch, Susan V

    2010-02-01

    Acute exacerbations of chronic obstructive pulmonary disease (COPD) are a major source of morbidity and contribute significantly to healthcare costs. Although bacterial infections are implicated in nearly 50% of exacerbations, only a handful of pathogens have been consistently identified in COPD airways, primarily by culture-based methods, and the bacterial microbiota in acute exacerbations remains largely uncharacterized. The aim of this study was to comprehensively profile airway bacterial communities using a culture-independent microarray, the 16S rRNA PhyloChip, of a cohort of COPD patients requiring ventilatory support and antibiotic therapy for exacerbation-related respiratory failure. PhyloChip analysis revealed the presence of over 1,200 bacterial taxa representing 140 distinct families, many previously undetected in airway diseases; bacterial community composition was strongly influenced by the duration of intubation. A core community of 75 taxa was detected in all patients, many of which are known pathogens. Bacterial community diversity in COPD airways is substantially greater than previously recognized and includes a number of potential pathogens detected in the setting of antibiotic exposure. Comprehensive assessment of the COPD airway microbiota using high-throughput, culture-independent methods may prove key to understanding the relationships between airway bacterial colonization, acute exacerbation, and clinical outcomes in this and other chronic inflammatory airway diseases.

  15. Small airways involvement in coal mine dust lung disease.

    PubMed

    Long, Joshua; Stansbury, Robert C; Petsonk, Edward L

    2015-06-01

    Inhalation of coal mine dust results in a spectrum of symptoms, dysfunction, and pathological changes in the respiratory tract that collectively have been labeled coal mine dust lung disease. Recent reports from periodic health surveillance among underground and surface coal miners in the United States have demonstrated an increasing prevalence and severity of dust diseases, and have also documented that some miners experience rapid disease progression. The coal macule is an inflammatory lesion associated with deposited dust, and occurs in the region of the most distal conducting airways and proximal respiratory bronchioles. Inflammatory changes in the small airways have long been recognized as the signature lung pathology among coal miners. Human and laboratory studies have suggested oxidant injury, and increased recruitment and activity of macrophages play important roles in dust-induced lung injury. However, the functional importance of the small airway changes was debated for many years. We reviewed published literature that documents a pervasive occurrence of both physiologic and structural abnormalities in small airways among coal miners and other workers exposed to airborne particulates. There is increasing evidence supporting an important association of abnormalities in the small peripheral airways with the development of respiratory symptoms, deficits in spirometry values, and accelerated declines in ventilatory lung function. Pathologic changes associated with mineral dust deposition in the small airways may be of particular importance in contemporary miners with rapidly progressive respiratory impairment.

  16. Airway microbiome dynamics in exacerbations of chronic obstructive pulmonary disease.

    PubMed

    Huang, Yvonne J; Sethi, Sanjay; Murphy, Timothy; Nariya, Snehal; Boushey, Homer A; Lynch, Susan V

    2014-08-01

    Specific bacterial species are implicated in the pathogenesis of exacerbations of chronic obstructive pulmonary disease (COPD). However, recent studies of clinically stable COPD patients have demonstrated a greater diversity of airway microbiota, whose role in acute exacerbations is unclear. In this study, temporal changes in the airway microbiome before, at the onset of, and after an acute exacerbation were examined in 60 sputum samples collected from subjects enrolled in a longitudinal study of bacterial infection in COPD. Microbiome composition and predicted functions were examined using 16S rRNA-based culture-independent profiling methods. Shifts in the abundance (≥ 2-fold, P < 0.05) of many taxa at exacerbation and after treatment were observed. Microbiota members that were increased at exacerbation were primarily of the Proteobacteria phylum, including nontypical COPD pathogens. Changes in the bacterial composition after treatment for an exacerbation differed significantly among the therapy regimens clinically prescribed (antibiotics only, oral corticosteroids only, or both). Treatment with antibiotics alone primarily decreased the abundance of Proteobacteria, with the prolonged suppression of some microbiota members being observed. In contrast, treatment with corticosteroids alone led to enrichment for Proteobacteria and members of other phyla. Predicted metagenomes of particular microbiota members involved in these compositional shifts indicated exacerbation-associated loss of functions involved in the synthesis of antimicrobial and anti-inflammatory products, alongside enrichment in functions related to pathogen-elicited inflammation. These trends reversed upon clinical recovery. Further larger studies will be necessary to determine whether specific compositional or functional changes detected in the airway microbiome could be useful indicators of exacerbation development or outcome.

  17. Restoring airway epithelial barrier dysfunction: a new therapeutic challenge in allergic airway disease.

    PubMed

    Steelant, B; Seys, S F; Boeckxstaens, G; Akdis, C A; Ceuppens, J L; Hellings, P W

    2016-09-01

    An intact functional mucosal barrier is considered to be crucial for the maintenance of airway homeostasis as it protects the host immune system from exposure to allergens and noxious environmental triggers. Recent data provided evidence for the contribution of barrier dysfunction to the development of inflammatory diseases in the airways, skin and gut. A defective barrier has been documented in chronic rhinosinusitis, allergic rhinitis, asthma, atopic dermatitis and inflammatory bowel diseases. However, it remains to be elucidated to what extent primary (genetic) versus secondary (inflammatory) mechanisms drive barrier dysfunction. The precise pathogenesis of barrier dysfunction in patients with chronic mucosal inflammation and its implications on tissue inflammation and systemic absorption of exogenous particles are only partly understood. Since epithelial barrier defects are linked with chronicity and severity of airway inflammation, restoring the barrier integrity may become a useful approach in the treatment of allergic diseases. We here provide a state-of-the-art review on epithelial barrier dysfunction in upper and lower airways as well as in the intestine and the skin and on how barrier dysfunction can be restored from a therapeutic perspective.

  18. Lysophosphatidylcholine plays critical role in allergic airway disease manifestation

    PubMed Central

    Bansal, Preeti; Gaur, Shailendera Nath; Arora, Naveen

    2016-01-01

    Phospholipase A2 (sPLA2), pivotal for allergic and inflammatory response, hydrolyses phosphatidylcholine (PC) to lysophosphatidylcholine (LPC). In present study, the role of LPC in allergic airway disease manifestation was studied using mouse model. Balb/c mice were immunized using cockroach extract (CE) and LPC release was blocked by sPLA2 inhibitor. Airway hyperresponse (AHR), lung-histology, total and differential leukocyte count (TLC&DLC), Th2 type cytokines, sPLA2 activity and LPC levels in bronchoalveolar lavage fluid (BALF) were measured. Exogenous LPC was given to the mice with or without CE sensitization, to demonstrate its role in allergic airway disease manifestation. Anti-CD1d antibody was given to study the involvement of natural killer T (NKT) cells in LPC induced response. AHR, lung-inflammation, TLC, DLC, Th2 type cytokines, sPLA2 activity and LPC levels were increased on CE challenge. sPLA2 activity and LPC release was blocked by sPLA2-inhibitor, which decreased AHR, and inflammatory parameters. Exogenous LPC with or without CE sensitization increased above parameters. CE challenge or LPC exposure increased LY49C+TCRβ+ NKT cells in BALF and spleen, which was reduced by anti-CD1d antibody, accompanied with reduction in AHR and allergic airway inflammation parameters. Conclusively, LPC induces allergic airway disease manifestation and it does so probably via CD1d-restricted LY49C+TCRβ+ NKT cells. PMID:27282246

  19. In Utero Cigarette Smoke Affects Allergic Airway Disease But Does Not Alter the Lung Methylome

    PubMed Central

    Eyring, Kenneth R.; Pedersen, Brent S.; Yang, Ivana V.; Schwartz, David A.

    2015-01-01

    Prenatal and postnatal cigarette smoke exposure enhances the risk of developing asthma. Despite this as well as other smoking related risks, 11% of women still smoke during pregnancy. We hypothesized that cigarette smoke exposure during prenatal development generates long lasting differential methylation altering transcriptional activity that correlates with disease. In a house dust mite (HDM) model of allergic airway disease, we measured airway hyperresponsiveness (AHR) and airway inflammation between mice exposed prenatally to cigarette smoke (CS) or filtered air (FA). DNA methylation and gene expression were then measured in lung tissue. We demonstrate that HDM-treated CS mice develop a more severe allergic airway disease compared to HDM-treated FA mice including increased AHR and airway inflammation. While DNA methylation changes between the two HDM-treated groups failed to reach genome-wide significance, 99 DMRs had an uncorrected p-value < 0.001. 6 of these 99 DMRs were selected for validation, based on the immune function of adjacent genes, and only 2 of the 6 DMRs confirmed the bisulfite sequencing data. Additionally, genes near these 6 DMRs (Lif, Il27ra, Tle4, Ptk7, Nfatc2, and Runx3) are differentially expressed between HDM-treated CS mice and HDM-treated FA mice. Our findings confirm that prenatal exposure to cigarette smoke is sufficient to modify allergic airway disease; however, it is unlikely that specific methylation changes account for the exposure-response relationship. These findings highlight the important role in utero cigarette smoke exposure plays in the development of allergic airway disease. PMID:26642056

  20. The Nose and the Lung: United Airway Disease?

    PubMed Central

    Licari, Amelia; Castagnoli, Riccardo; Denicolò, Chiara Francesca; Rossini, Linda; Marseglia, Alessia; Marseglia, Gian Luigi

    2017-01-01

    Epidemiologic, pathophysiologic, and clinical evidences recently revealed the link between upper and lower airways, changing the global pathogenic view of respiratory allergy. The aim of this review is to highlight the strong interaction between the upper and lower respiratory tract diseases, in particular allergic rhinitis and asthma. PMID:28316969

  1. Multidetector computed tomography of pediatric large airway diseases: state-of-the-art.

    PubMed

    Lee, Edward Y; Greenberg, S Bruce; Boiselle, Phillip M

    2011-09-01

    Advances in multidetector computed tomography (MDCT) technology have given rise to improvements in the noninvasive and comprehensive assessment of the large airways in pediatric patients. Superb two-dimensional and three-dimensional reconstruction MDCT images have revolutionized the display of large airways and enhanced the ability to diagnose large airway diseases in children. The 320-MDCT scanner, which provides combined detailed anatomic and dynamic functional information assessment of the large airways, is promising for the assessment of dynamic large airway disease such as tracheobronchomalacia. This article discusses imaging techniques and clinical applications of MDCT for assessing large airway diseases in pediatric patients.

  2. Airway Reflux, Cough and Respiratory Disease

    PubMed Central

    Molyneux, Ian D.; Morice, Alyn H.

    2011-01-01

    It is increasingly accepted that the effects of gastro-oesophageal reflux are not limited to the gastrointestinal tract. The adjacent respiratory structures are also at risk from material ejected from the proximal oesophagus as a result of the failure of anatomical and physiological barriers. There is evidence of the influence of reflux on several respiratory and otorhinological conditions and although in many cases the precise mechanism has yet to be elucidated, the association alone opens potential novel avenues of therapy to clinicians struggling to treat patients with apparently intractable respiratory complaints. This review provides a description of the airway reflux syndrome, its effects on the lung and current and future therapeutic options. PMID:23251752

  3. Insights into Group 2 Innate Lymphoid Cells in Human Airway Disease.

    PubMed

    Karta, Maya R; Broide, David H; Doherty, Taylor A

    2016-01-01

    Recent discoveries have led to the identification of a novel group of immune cells, the innate lymphoid cells (ILCs). The members of this group are divided into three subpopulations: ILC1s, ILC2s, and ILC3s. ILC2s produce Th2 cytokines, IL-4, IL-5, and IL-13, upon activation by epithelial cell-derived cytokines, lipid mediators (cysteinyl leukotrienes and prostaglandin D2), and TNF family member TL1A and promote structural and immune cell responses in the airways after antigen exposure. In addition, ILC2 function is also influenced by inducible T cell costimulator (ICOS)/ICOS-ligand (ICOS-L) interactions via direct contact between immune cells. The most common airway antigens are allergens and viruses which are highly linked to the induction of airway diseases with underlying type 2 inflammation including asthma and allergic rhinitis. Based on recent findings linking ILC2s and airway Th2 responses, there is intensive investigation into the role of ILC2s in human disease with the hope of a better understanding of the pathophysiology and the discovery of novel potential therapeutic targets. This review summarizes the recent advances made in elucidating ILC2 involvement in human Th2 airway disease.

  4. FACTORS THAT INFLUENCE THE RELATIVE POTENCY OF DIESEL EXHAUST PARTICLES AS ADJUVANTS IN ALLERGIC AIRWAY DISEASE

    EPA Science Inventory

    Description: Studies have shown that diesel exhaust particles (DEP) worsen respiratory diseases including allergic asthma. The adjuvant effects of DEP in the airways have been widely reported; however, the precise determinants and mechanisms of these effects are ill-defined. S...

  5. Oxidant-mediated ciliary dysfunction. Possible role in airway disease

    SciTech Connect

    Burman, W.J.; Martin, W.J. 2d.

    1986-03-01

    The effects of reactive species of oxygen on the airway are not well known. This study examined the effects of hydrogen peroxide (H2O2) on the structure and function of the airway epithelium. Tracheal rings were prepared from 200 g male rats. Damage to the airway epithelium was assayed by monitoring the ciliary beat frequency, the release of 51Cr, and histology. H2O2 at concentrations of 1.0 mM and above caused a very rapid decrease in ciliary beat frequency. After ten minutes' exposure to 1.0 mM, the ciliary beat frequency was 72 +/- 20 percent of control. Release of 51Cr was a less sensitive measure with significant release occurring after four hours of exposure to ciliotoxic concentrations of H2O2. Histologic changes were not evident within the experimental time period. All toxic effects of H2O2 were completely blocked by catalase. This study shows that H2O2 causes a rapid decline in ciliary activity and suggests that oxidant-mediated ciliary dysfunction could play a role in the pathogenesis of airway disease. The ciliary beat frequency provides a sensitive, physiologically relevant parameter for the in vitro study of these diseases.

  6. Divers' lung function: small airways disease?

    PubMed Central

    Thorsen, E; Segadal, K; Kambestad, B; Gulsvik, A

    1990-01-01

    Pulmonary function was measured in 152 professional saturation divers and in a matched control group of 106 subjects. Static lung volumes, dynamic lung volumes and flows, transfer factor for carbon monoxide (T1CO), transfer volume per unit alveolar volume (KCO), delta-N2, and closing volume (CV) were measured and compared with reference values from recent Scandinavian studies, British submariners, and the European Community for Coal and Steel (ECCS) recommended reference values. Diving exposure was assessed as years of diving experience, total number of days in saturation and depth, and as the product of days in saturation and mean depth. Divers had significantly lower values for forced expired volume in one second (FEV1), FEV1/forced vital capacity (FVC) ratio, FEF25-75%, FEF75-85%, FEF50%, FEF75%, T1CO, and KCO compared with the controls and a significantly higher CV. There was a positive correlation between diving exposure and CV, whereas the other variables had negative correlations with diving exposure. Values for the control group were not different from the predictive values of Scandinavian reference studies or British submariners, although the ECCS standard predicted significantly lower values for the lung function variables both in divers and the control group. The pattern of the differences in lung function variables between the divers and controls is consistent with small airways dysfunction and with the transient changes in lung function found immediately after a single saturation dive. The association between reduced pulmonary function and previous diving exposure further indicates the presence of cumulative long term effects of diving on pulmonary function. PMID:2393630

  7. [Environmental causes of the distal airways disease. Hypersensitivity pneumonitis and rare causes].

    PubMed

    Dalphin, J-C; Didier, A

    2013-10-01

    Hypersensitivity pneumonitis is one of the most frequent causes of distal airways disease. It is associated with inflammation of the bronchioles, predominantly by lymphocytic infiltrates, and with granuloma formation causing bronchial obstruction. This inflammation explains the clinical manifestations and the airways obstruction seen on pulmonary function tests, most often in the distal airways but proximal in almost 20%. CT scan abnormalities reflect the lymphocytic infiltrates and air trapping and, in some cases, the presence of emphysema. Bronchiolitis induced by chronic inhalation of mineral particles or acute inhalation of toxic gases (such as NO2) are other examples of small airways damage due to environmental exposure. The pathophysiological mechanisms are different and bronchiolar damage is either exclusive or predominant. Bronchiolitis induced by tobacco smoke exposure, usually classified as interstitial pneumonitis, is easily diagnosed thanks to broncho-alveolar lavage. Its prognosis is linked to the other consequences of tobacco smoke exposure including respiratory insufficiency. Finally, the complex lung exposure observed in some rare cases (such as the World Trade Center fire or during wars) may lead to a less characteristic pattern of small airways disease.

  8. Repurposing tromethamine as inhaled therapy to treat CF airway disease

    PubMed Central

    Alaiwa, Mahmoud H. Abou; Launspach, Janice L.; Sheets, Kelsey A.; Rivera, Jade A.; Gansemer, Nicholas D.; Taft, Peter J.; Thorne, Peter S.; Welsh, Michael J.; Stoltz, David A.

    2016-01-01

    In cystic fibrosis (CF), loss of CF transmembrane conductance regulator (CFTR) anion channel activity causes airway surface liquid (ASL) pH to become acidic, which impairs airway host defenses. One potential therapeutic approach is to correct the acidic pH in CF airways by aerosolizing HCO3– and/or nonbicarbonate pH buffers. Here, we show that raising ASL pH with inhaled HCO3– increased pH. However, the effect was transient, and pH returned to baseline values within 30 minutes. Tromethamine (Tham) is a buffer with a long serum half-life used as an i.v. formulation to treat metabolic acidosis. We found that Tham aerosols increased ASL pH in vivo for at least 2 hours and enhanced bacterial killing. Inhaled hypertonic saline (7% NaCl) is delivered to people with CF in an attempt to promote mucus clearance. Because an increased ionic strength inhibits ASL antimicrobial factors, we added Tham to hypertonic saline and applied it to CF sputum. We found that Tham alone and in combination with hypertonic saline increased pH and enhanced bacterial killing. These findings suggest that aerosolizing the HCO3–-independent buffer Tham, either alone or in combination with hypertonic saline, might be of therapeutic benefit in CF airway disease. PMID:27390778

  9. Relationship between gastro-oesophageal reflux and airway diseases: the airway reflux paradigm.

    PubMed

    Pacheco-Galván, Adalberto; Hart, Simon P; Morice, Alyn H

    2011-04-01

    Our understanding of the relationship between gastro-oesophageal reflux and respiratory disease has recently undergone important changes. The previous paradigm of airway reflux as synonymous with the classic gastro-oesophageal reflux disease (GORD) causing heartburn has been overturned. Numerous epidemiological studies have shown a highly significant association of the acid, liquid, and gaseous reflux of GORD with conditions such as laryngeal diseases, chronic rhinosinusitis, treatment resistant asthma, COPD and even idiopathic pulmonary fibrosis. However, it has become clear from studies on cough hypersensitivity syndrome that much reflux of importance in the airways has been missed, since it is either non- or weakly acid and gaseous in composition. The evidence for such a relationship relies on the clinical history pointing to symptom associations with known precipitants of reflux. The tools for the diagnosis of extra-oesophageal reflux, in contrast to the oesophageal reflux of GORD, lack sensitivity and reproducibility. Unfortunately, methodology for detecting such reflux is only just becoming available and much additional work is required to properly delineate its role.

  10. The role bronchoscopy in the diagnosis of airway disease in children

    PubMed Central

    Soyer, Tutku

    2016-01-01

    Bronchoscopy is endoscopic examination of airways that allows both diagnostic and interventional procedures in the evaluation of airway disease in children. It can be performed with either rigid or flexible instruments, depending on the particular needs of patients and skills of bronchoscopist. In addition to visualization of airways, bronchoscopy enables to obtain specimens from lungs and distal airways. Bronchoalveolar lavage (BAL) yields samples from surfaces of the alveoli and aids differential diagnosis of various pulmonary disease. Foreign body removal and examination of anatomy and dynamics of airways are also common indications of bronchoscopy in children. Improvement in the technology, endoscopic instrumentation allows detailed evaluation and interventional manipulation of airway lesions in small children. Although bronchoscopy is considered as a safe procedure, obstruction of airway may challenge and require special endoscopic skills with appropriate instrumentation. This review is aimed to outline the role of bronchoscopy in diagnosis airway disease in children. PMID:28066622

  11. Airway gene expression of IL-1 pathway mediators predicts exacerbation risk in obstructive airway disease

    PubMed Central

    Baines, Katherine J; Fu, Juan-juan; McDonald, Vanessa M; Gibson, Peter G

    2017-01-01

    Background Exacerbations of asthma and COPD are a major cause of morbidity and mortality and are responsible for significant health care costs. This study further investigates interleukin (IL)-1 pathway activation and its relationship with exacerbations of asthma and COPD. Methods In this prospective cohort study, 95 participants with stable asthma (n=35) or COPD (n=60) were recruited and exacerbations recorded over the following 12 months. Gene expressions of IL-1 pathway biomarkers, including the IL-1 receptors (IL1R1, IL1R2, and IL1RN), and signaling molecules (IRAK2, IRAK3, and PELI1), were measured in sputum using real-time quantitative polymerase chain reaction. Mediators were compared between the frequent (≥2 exacerbations in the 12 months) and infrequent exacerbators, and the predictive relationships investigated using receiver operating characteristic curves and area under the curve (AUC) values. Results Of the 95 participants, 89 completed the exacerbation follow-up, where 30 participants (n=22 COPD, n=8 asthma) had two or more exacerbations. At the baseline visit, expressions of IRAK2, IRAK3, PELI1, and IL1R1 were elevated in participants with frequent exacerbations of both asthma and COPD combined and separately. In the combined population, sputum gene expression of IRAK3 (AUC=75.4%; P<0.001) was the best predictor of future frequent exacerbations, followed by IL1R1 (AUC=72.8%; P<0.001), PELI1 (AUC=71.2%; P<0.001), and IRAK2 (AUC=68.6; P=0.004). High IL-1 pathway gene expression was associated with frequent prior year exacerbations and correlated with the number and severity of exacerbations. Conclusion The upregulation of IL-1 pathway mediators is associated with frequent exacerbations of obstructive airway disease. Further studies should investigate these mediators as both potential diagnostic biomarkers predicting at-risk patients and novel treatment targets. PMID:28223794

  12. Reduced levels of maternal progesterone during pregnancy increase the risk for allergic airway diseases in females only.

    PubMed

    Hartwig, Isabel R V; Bruenahl, Christian A; Ramisch, Katherina; Keil, Thomas; Inman, Mark; Arck, Petra C; Pincus, Maike

    2014-10-01

    Observational as well as experimental studies support that prenatal challenges seemed to be associated with an increased risk for allergic airway diseases in the offspring. However, insights into biomarkers involved in mediating this risk are largely elusive. We here aimed to test the association between endogenous and exogenous factors documented in pregnant women, including psychosocial, endocrine, and life style parameters, and the risk for allergic airway diseases in the children later in life. We further pursued to functionally test identified factors in a mouse model of an allergic airway response. In a prospectively designed pregnancy cohort (n = 409 families), women were recruited between the 4th and 12th week of pregnancy. To investigate an association between exposures during pregnancy and the incidence of allergic airway disease in children between 3 and 5 years of age, multiple logistic regression analyses were applied. Further, in prenatally stressed adult offspring of BALB/c-mated BALB/c female mice, asthma was experimentally induced by ovalbumin (OVA) sensitization. In addition to the prenatal stress challenge, some pregnant females were treated with the progesterone derivative dihydrodydrogesterone (DHD). In humans, we observed that high levels of maternal progesterone in early human pregnancies were associated with a decreased risk for an allergic airway disease (asthma or allergic rhinitis) in daughters (adjusted OR 0.92; 95% confidence interval [CI] 0.84 to 1.00) but not sons (aOR 1.02, 95% CI 0.94-1.10). In mice, prenatal DHD supplementation of stress-challenged dams attenuated prenatal stress-induced airway hyperresponsiveness exclusively in female offspring. Reduced levels of maternal progesterone during pregnancy-which can result from high stress perception-increase the risk for allergic airway diseases in females but not in males. Key messages: Lower maternal progesterone during pregnancy increases the risk for allergic airway disease

  13. Exhaled NO: Determinants and Clinical Application in Children With Allergic Airway Disease

    PubMed Central

    Kim, Hyo-Bin; Eckel, Sandrah P.

    2016-01-01

    Nitric oxide (NO) is endogenously released in the airways, and the fractional concentration of NO in exhaled breath (FeNO) is now recognized as a surrogate marker of eosinophilic airway inflammation that can be measured using a noninvasive technique suitable for young children. Although FeNO levels are affected by several factors, the most important clinical determinants of increased FeNO levels are atopy, asthma, and allergic rhinitis. In addition, air pollution is an environmental determinant of FeNO that may contribute to the high prevalence of allergic disease. In this review, we discuss the mechanism for airway NO production, methods for measuring FeNO, and determinants of FeNO in children, including host and environmental factors such as air pollution. We also discuss the clinical utility of FeNO in children with asthma and allergic rhinitis and further useful directions using FeNO measurement. PMID:26540497

  14. Within-breath respiratory impedance and airway obstruction in patients with chronic obstructive pulmonary disease

    PubMed Central

    da Silva, Karla Kristine Dames; Faria, Alvaro Camilo Dias; Lopes, Agnaldo José; de Melo, Pedro Lopes

    2015-01-01

    OBJECTIVE: Recent work has suggested that within-breath respiratory impedance measurements performed using the forced oscillation technique may help to noninvasively evaluate respiratory mechanics. We investigated the influence of airway obstruction on the within-breath forced oscillation technique in smokers and chronic obstructive pulmonary disease patients and evaluated the contribution of this analysis to the diagnosis of chronic obstructive pulmonary disease. METHODS: Twenty healthy individuals and 20 smokers were assessed. The study also included 74 patients with stable chronic obstructive pulmonary disease. We evaluated the mean respiratory impedance (Zm) as well as values for the inspiration (Zi) and expiration cycles (Ze) at the beginning of inspiration (Zbi) and expiration (Zbe), respectively. The peak-to-peak impedance (Zpp=Zbe-Zbi) and the respiratory cycle dependence (ΔZrs=Ze-Zi) were also analyzed. The diagnostic utility was evaluated by investigating the sensitivity, the specificity and the area under the receiver operating characteristic curve. ClinicalTrials.gov: NCT01888705. RESULTS: Airway obstruction increased the within-breath respiratory impedance parameters that were significantly correlated with the spirometric indices of airway obstruction (R=−0.65, p<0.0001). In contrast to the control subjects and the smokers, the chronic obstructive pulmonary disease patients presented significant expiratory-inspiratory differences (p<0.002). The adverse effects of moderate airway obstruction were detected based on the Zpp with an accuracy of 83%. Additionally, abnormal effects in severe and very severe patients were detected based on the Zm, Zi, Ze, Zbe, Zpp and ΔZrs with a high degree of accuracy (>90%). CONCLUSIONS: We conclude the following: (1) chronic obstructive pulmonary disease introduces higher respiratory cycle dependence, (2) this increase is proportional to airway obstruction, and (3) the within-breath forced oscillation technique may

  15. Crosscultural communication in those with airway diseases.

    PubMed

    Car, J; Partridge, M R

    2004-01-01

    Transcultural consultations are becoming commonplace. Such consultations arise because patients from ethnic groups consult doctors, but also because patients consult doctors from other ethnic backgrounds. Such consultations require a cultural awareness and sensitivity which may be particularly necessary when concerning those with respiratory illnesses which are often long-term and about which there may be considerable stigma. The prevalence of respiratory disease can vary between ethnic groups, most noticeably in tuberculosis and smoking; and in diseases such as asthma, health service usage and treatment can vary significantly with ethnicity. Some of this may represent cultural, rather than disease specific differences. Good communication is essential throughout medical practice, but in transcultural consultations it is especially important that the doctor pays appropriate attention to likely patient beliefs and approaches to shared decision making. Usual negotiation regarding goals and outcomes first requires the clinician to understand how a patient's understanding of illness may vary from a traditional western scientific approach. Special attention needs to be paid to the optimal way of using interpreters and more time is often needed for crosscultural consultations. Specific training is necessary for health practitioners to enable them to acquire the skills for crosscultural care and this involves learning about other cultures and an appreciation of how a change in attitude often needs to be incorporated into the clinical approach. Acquiring these skills and understandings to facilitate optimal transcultural consultation enables transfer of these skills to other similar clinical scenarios such as the approach to those with disability. The global burden of long-term respiratory disease, both infectious and noncommunicable, coupled with increased migration and geographical mobility means that a successful crosscultural approach is now a priority area for

  16. Airway Epithelial Cell Cilia and Obstructive Lung Disease

    PubMed Central

    Yaghi, Asma; Dolovich, Myrna B.

    2016-01-01

    Airway epithelium is the first line of defense against exposure of the airway and lung to various inflammatory stimuli. Ciliary beating of airway epithelial cells constitutes an important part of the mucociliary transport apparatus. To be effective in transporting secretions out of the lung, the mucociliary transport apparatus must exhibit a cohesive beating of all ciliated epithelial cells that line the upper and lower respiratory tract. Cilia function can be modulated by exposures to endogenous and exogenous factors and by the viscosity of the mucus lining the epithelium. Cilia function is impaired in lung diseases such as COPD and asthma, and pharmacologic agents can modulate cilia function and mucus viscosity. Cilia beating is reduced in COPD, however, more research is needed to determine the structural-functional regulation of ciliary beating via all signaling pathways and how this might relate to the initiation or progression of obstructive lung diseases. Additionally, genotypes and how these can influence phenotypes and epithelial cell cilia function and structure should be taken into consideration in future investigations. PMID:27845721

  17. Automatic construction of subject-specific human airway geometry including trifurcations based on a CT-segmented airway skeleton and surface.

    PubMed

    Miyawaki, Shinjiro; Tawhai, Merryn H; Hoffman, Eric A; Wenzel, Sally E; Lin, Ching-Long

    2017-04-01

    We propose a method to construct three-dimensional airway geometric models based on airway skeletons, or centerlines (CLs). Given a CT-segmented airway skeleton and surface, the proposed CL-based method automatically constructs subject-specific models that contain anatomical information regarding branches, include bifurcations and trifurcations, and extend from the trachea to terminal bronchioles. The resulting model can be anatomically realistic with the assistance of an image-based surface; alternatively a model with an idealized skeleton and/or branch diameters is also possible. This method systematically identifies and classifies trifurcations to successfully construct the models, which also provides the number and type of trifurcations for the analysis of the airways from an anatomical point of view. We applied this method to 16 normal and 16 severe asthmatic subjects using their computed tomography images. The average distance between the surface of the model and the image-based surface was 11 % of the average voxel size of the image. The four most frequent locations of trifurcations were the left upper division bronchus, left lower lobar bronchus, right upper lobar bronchus, and right intermediate bronchus. The proposed method automatically constructed accurate subject-specific three-dimensional airway geometric models that contain anatomical information regarding branches using airway skeleton, diameters, and image-based surface geometry. The proposed method can construct (i) geometry automatically for population-based studies, (ii) trifurcations to retain the original airway topology, (iii) geometry that can be used for automatic generation of computational fluid dynamics meshes, and (iv) geometry based only on a skeleton and diameters for idealized branches.

  18. A Novel Nonhuman Primate Model of Cigarette Smoke–Induced Airway Disease

    PubMed Central

    Polverino, Francesca; Doyle-Eisele, Melanie; McDonald, Jacob; Wilder, Julie A.; Royer, Christopher; Laucho-Contreras, Maria; Kelly, Emer M.; Divo, Miguel; Pinto-Plata, Victor; Mauderly, Joe; Celli, Bartolome R.; Tesfaigzi, Yohannes; Owen, Caroline A.

    2016-01-01

    Small animal models of chronic obstructive pulmonary disease (COPD) have several limitations for identifying new therapeutic targets and biomarkers for human COPD. These include a pulmonary anatomy that differs from humans, the limited airway pathologies and lymphoid aggregates that develop in smoke-exposed mice, and the challenges associated with serial biological sampling. Thus, we assessed the utility of cigarette smoke (CS)–exposed cynomolgus macaque as a nonhuman primate (NHP) large animal model of COPD. Twenty-eight NHPs were exposed to air or CS 5 days per week for up to 12 weeks. Bronchoalveolar lavage and pulmonary function tests were performed at intervals. After 12 weeks, we measured airway pathologies, pulmonary inflammation, and airspace enlargement. CS-exposed NHPs developed robust mucus metaplasia, submucosal gland hypertrophy and hyperplasia, airway inflammation, peribronchial fibrosis, and increases in bronchial lymphoid aggregates. Although CS-exposed NHPs did not develop emphysema over the study time, they exhibited pathologies that precede emphysema development, including increases in the following: i) matrix metalloproteinase-9 and proinflammatory mediator levels in bronchoalveolar lavage fluid, ii) lung parenchymal leukocyte counts and lymphoid aggregates, iii) lung oxidative stress levels, and iv) alveolar septal cell apoptosis. CS-exposed NHPs can be used as a model of airway disease occurring in COPD patients. Unlike rodents, NHPs can safely undergo longitudinal sampling, which could be useful for assessing novel biomarkers or therapeutics for COPD. PMID:25542772

  19. Targeted therapy of bronchitis in obstructive airway diseases.

    PubMed

    Dasgupta, Angira; Neighbour, Helen; Nair, Parameswaran

    2013-12-01

    Guidelines for the management of obstructive airway diseases do not emphasize the measurement of bronchitis to indicate appropriate treatments or monitor response to treatment. Bronchitis is the central component of airway diseases and contributes to symptoms, physiological and structural abnormalities. It can be measured directly and reliably by quantitative assay of spontaneous or induced sputum. The measurement is reproducible, valid, and responsive to treatment and to changes in disease status. Bronchitis may be eosinophilic, neutrophilic, mixed, or paucigranulocytic (eosinophils and neutrophils not elevated). Eosinophilic bronchitis is usually a Th2 driven process and therefore a sputum eosinophilia of greater than 3% usually indicates a response to treatment with corticosteroids or novel therapies directed against Th2 cytokines such as IL-4, IL-5 and IL-13. Neutrophilic bronchitis which is a non-Th2 driven disease is generally a predictor of response to antibiotics and may be a predictor to therapies targeted at pathways that lead to neutrophil recruitment such as IL-8 (eg anti-CXCR2), IL-17 (eg anti-IL17) etc. Paucigranulocytic disease may not warrant anti-inflammatory therapy. Several novel monoclonals and small molecule antagonists have been evaluated in clinical trials with variable results and several more are likely to be discovered in the near future. The success of these agents will depend on appropriate patient selection by accurate phenotyping or characterization of bronchitis.

  20. Cystic fibrosis lung disease starts in the small airways: can we treat it more effectively?

    PubMed

    Tiddens, Harm A W M; Donaldson, Scott H; Rosenfeld, Margaret; Paré, Peter D

    2010-02-01

    The aims of this article are to summarize existing knowledge regarding the pathophysiology of small airways disease in cystic fibrosis (CF), to speculate about additional mechanisms that might play a role, and to consider the available or potential options to treat it. In the first section, we review the evidence provided by pathologic, physiologic, and imaging studies suggesting that obstruction of small airways begins early in life and is progressive. In the second section we discuss how the relationships between CF transmembrane conductance regulator (CFTR), ion transport, the volume of the periciliary liquid layer and airway mucus might lead to defective mucociliary clearance in small airways. In addition, we discuss how chronic endobronchial bacterial infection and a chronic neutrophilic inflammatory response increase the viscosity of CF secretions and exacerbate the clearance problem. Next, we discuss how the mechanical properties of small airways could be altered early in the disease process and how remodeling can contribute to small airways disease. In the final section, we discuss how established therapies impact small airways disease and new directions that may lead to improvement in the treatment of small airways disease. We conclude that there are many reasons to believe that small airways play an important role in the pathophysiology of (early) CF lung disease. Therapy should be aimed to target the small airways more efficiently, especially with drugs that can correct the basic defect at an early stage of disease.

  1. Serum periostin in obstructive airways disease

    PubMed Central

    Braithwaite, Irene; Travers, Justin; Bowles, Darren; Strik, Rianne; Siebers, Rob; Holweg, Cecile; Matthews, John; Weatherall, Mark; Beasley, Richard

    2016-01-01

    Serum periostin is a potential biomarker of response to therapies that target type 2 inflammation in asthma. The objectives of this study were to describe: 1) the distribution of serum periostin levels in adults with symptomatic airflow obstruction; 2) its relationship with other variables, including type 2 biomarkers; and 3) the effect of inhaled corticosteroids on periostin levels. Serum periostin levels were measured in a cross-sectional study exploring phenotypes and biomarkers in 386 patients aged 18–75 years who reported wheeze and breathlessness in the past 12 months. In 49 ICS-naïve patients, periostin levels were measured again after 12 weeks of budesonide (800 μg·day−1). The distribution of serum periostin levels was right skewed (mean±sd 57.3±18.6 ng·mL−1, median (interquartile range) 54.0 (45.1–65.6) ng·mL−1, range 15.0–164.7 ng·mL−1). Periostin was positively associated with exhaled nitric oxide (Spearman's rho=0.22, p<0.001), blood eosinophil count (Spearman's rho=0.21, p<0.001), and total IgE (Spearman's rho=0.14, p=0.007). The Hodges–Lehmann estimator (95% CI) of change in periostin level after ICS therapy was −4.8 (−6.7– −3.2) ng·mL−1 (p<0.001). These findings provide data on the distribution of serum periostin in adults with symptomatic airflow obstruction, the weak associations between periostin and other type 2 markers, and the reduction in periostin with inhaled corticosteroid therapy. PMID:26917610

  2. Pathway Reconstruction of Airway Remodeling in Chronic Lung Diseases: A Systems Biology Approach

    PubMed Central

    Najafi, Ali; Masoudi-Nejad, Ali; Ghanei, Mostafa; Nourani, Mohamad-Reza; Moeini, Ali

    2014-01-01

    Airway remodeling is a pathophysiologic process at the clinical, cellular, and molecular level relating to chronic obstructive airway diseases such as chronic obstructive pulmonary disease (COPD), asthma and mustard lung. These diseases are associated with the dysregulation of multiple molecular pathways in the airway cells. Little progress has so far been made in discovering the molecular causes of complex disease in a holistic systems manner. Therefore, pathway and network reconstruction is an essential part of a systems biology approach to solve this challenging problem. In this paper, multiple data sources were used to construct the molecular process of airway remodeling pathway in mustard lung as a model of airway disease. We first compiled a master list of genes that change with airway remodeling in the mustard lung disease and then reconstructed the pathway by generating and merging the protein-protein interaction and the gene regulatory networks. Experimental observations and literature mining were used to identify and validate the master list. The outcome of this paper can provide valuable information about closely related chronic obstructive airway diseases which are of great importance for biologists and their future research. Reconstructing the airway remodeling interactome provides a starting point and reference for the future experimental study of mustard lung, and further analysis and development of these maps will be critical to understanding airway diseases in patients. PMID:24978043

  3. Smokers with emphysema and small airway disease on computed tomography have lower bone density.

    PubMed

    Pompe, Esther; de Jong, Pim A; van Rikxoort, Eva M; Gallardo Estrella, Leticia; de Jong, Werner U; Vliegenthart, Rozemarijn; Oudkerk, Matthijs; van der Aalst, Carlijn M; van Ginneken, Bram; Lammers, Jan-Willem J; Mohamed Hoesein, Firdaus Aa

    2016-01-01

    Osteoporosis is more common in patients with COPD and in smokers. The aim of this study was to assess whether measures of emphysema and airway disease on computed tomography (CT) were associated with lower bone density or vertebral fractures in smokers with and without COPD. For this purpose, we included participants from the NELSON lung cancer screening trial. Bone density was measured as Hounsfield Units in the first lumbar vertebra, and vertebral fractures were assessed semiquantitatively. The 15th percentile method (Perc15) was used to assess emphysema, and the airway lumen perimeter (Pi10) was used for airway wall thickness. Expiratory/inspiratory-ratiomean lung density (E/I-ratioMLD) was used as a measure for air trapping and tracheal index to assess tracheal deformity. Linear regression models and logistic regression models were used to assess associations between CT biomarkers, bone density, and presence of fractures. Exactly 1,093 male participants were eligible for analysis. Lower Perc15 and higher E/I-ratioMLD were significantly associated with lower bone density (b=-1.27, P=0.02 and b=-0.37, P=0.02, respectively). Pi10 and tracheal index were not associated with bone density changes. CT-derived biomarkers were not associated with fracture prevalence. Bone density is lower with increasing extent of emphysema and small airway disease but is not associated with large airway disease and tracheal deformity. This may indicate the necessity to measure bone density early in smokers with emphysema and air trapping to prevent vertebral fractures.

  4. Haemophilus influenzae Disease (Including Hib) Symptoms

    MedlinePlus

    ... Search The CDC Cancel Submit Search The CDC Haemophilus influenzae Disease (Including Hib) Note: Javascript is disabled or ... and Symptoms Recommend on Facebook Tweet Share Compartir Haemophilus influenzae , including Hib, disease causes different symptoms depending on ...

  5. Using biomarkers in the assessment of airways disease.

    PubMed

    Taylor, D Robin

    2011-11-01

    A biomarker provides a window on underlying disease activity. This is helpful when the pathology, treatment response, or both are heterogeneous or when trying to interpret nonspecific respiratory symptoms in patients with comorbidities. The successful application of a biomarker result is critically dependent on the specific question being addressed and the performance characteristics of the biomarker in relation to that question in the context of pretest probabilities. Negative prediction might be the best way to use a biomarker, such as a D-dimer, pro-brain natriuretic peptide, and exhaled nitric oxide. In this review the role of biomarkers in airways disease (notably induced sputum eosinophils and exhaled nitric oxide) is considered in relation to risk stratification, identification of treatment responders, identification of a clinical phenotype, monitoring of disease, and new drug development.

  6. The emerging relationship between the airway microbiota and chronic respiratory disease: clinical implications

    PubMed Central

    Huang, Yvonne J; Lynch, Susan V

    2012-01-01

    Until recently, relationships between evidence of colonization or infection by specific microbial species and the development, persistence or exacerbation of pulmonary disease have informed our opinions of airway microbiology. However, recent applications of culture-independent tools for microbiome profiling have revealed a more diverse microbiota than previously recognized in the airways of patients with chronic pulmonary disease. New evidence indicates that the composition of airway microbiota differs in states of health and disease and with severity of symptoms and that the microbiota, as a collective entity, may contribute to pathophysiologic processes associated with chronic airway disease. Here, we review the evolution of airway microbiology studies of chronic pulmonary disease, focusing on asthma, chronic obstructive pulmonary disease and cystic fibrosis. Building on evidence derived from traditional microbiological approaches and more recent culture-independent microbiome studies, we discuss the implications of recent findings on potential microbial determinants of respiratory health or disease. PMID:22082166

  7. The emerging relationship between the airway microbiota and chronic respiratory disease: clinical implications.

    PubMed

    Huang, Yvonne J; Lynch, Susan V

    2011-12-01

    Until recently, relationships between evidence of colonization or infection by specific microbial species and the development, persistence or exacerbation of pulmonary disease have informed our opinions of airway microbiology. However, recent applications of culture-independent tools for microbiome profiling have revealed a more diverse microbiota than previously recognized in the airways of patients with chronic pulmonary disease. New evidence indicates that the composition of airway microbiota differs in states of health and disease and with severity of symptoms and that the microbiota, as a collective entity, may contribute to pathophysiologic processes associated with chronic airway disease. Here, we review the evolution of airway microbiology studies of chronic pulmonary disease, focusing on asthma, chronic obstructive pulmonary disease and cystic fibrosis. Building on evidence derived from traditional microbiological approaches and more recent culture-independent microbiome studies, we discuss the implications of recent findings on potential microbial determinants of respiratory health or disease.

  8. Tracheobronchomalacia/excessive dynamic airway collapse in patients with chronic obstructive pulmonary disease with persistent expiratory wheeze: A pilot study

    PubMed Central

    Sindhwani, Girish; Sodhi, Rakhee; Saini, Manju; Jethani, Varuna; Khanduri, Sushant; Singh, Baltej

    2016-01-01

    Background: Tracheobronchomalacia (TBM) refers to a condition in which structural integrity of cartilaginous wall of trachea is lost. Excessive dynamic airway collapse (EDAC) is characterized by excessive invagination of posterior wall of trachea. In both these conditions, airway lumen gets compromised, especially during expiration, which can lead to symptoms such as breathlessness, cough, and wheezing. Both these conditions can be present in obstructive lung diseases; TBM due to chronic airway inflammation and EDAC due to dynamic compressive forces during expiration. The present study was planned with the hypothesis that TBM/EDAC could also produce expiratory wheeze in patients with obstructive airway disorders. Hence, prevalence and factors affecting presence of this entity in patients with obstructive airway diseases were the aims and objectives of this study. Materials and Methods: Twenty-five patients with obstructive airway disorders (chronic obstructive pulmonary disease [COPD] or bronchial asthma), who were stable on medical management, but having persistent expiratory wheezing, were included in the study. They were evaluated for TBM/EDAC by bronchoscopy and computed tomographic scan of chest. The presence of TBM/EDAC was correlated with variables including age, sex, body mass index (BMI), smoking index, level of dyspnea, and severity of disease. Results: Mean age of the patients was 62.7 ± 7.81 years. Out of 25 patients, 14 were males. TBM/EDAC was found in 40% of study subjects. Age, sex, BMI, severity of disease, frequency of exacerbations and radiological findings etc., were not found to have any association with presence of TBM/EDAC. Conclusion: TBM/EDAC is common in patients with obstructive airway disorders and should be evaluated in these patients, especially with persistent expiratory wheezing as diagnosis of this entity could provide another treatment option in these patients with persistent symptoms despite medical management. PMID:27578929

  9. [Anticholinergic drugs in the therapy of obstructive airway diseases].

    PubMed

    Windt, Roland

    2011-04-01

    The anticholinergic effects from botanical preparations of the deadly nightshade family have been used for hundreds of years for the treatment of obstructive airway diseases. Nowadays, derivatives of the plant alkaloids with quaternary ammonium structure, ipratropium bromide and tiotropium bromide, are used, which retain the bronchodilator properties of the parent compounds but are much safer since they are poorly absorbed across biologic membranes. They are the bronchodilators of choice in the management of chronic obstructive pulmonary disease (COPD). However, ipratropium is considered a second-line agent in the treatment of asthma as the bronchodilatory effects seen with ipratropium are less than those seen with beta-adrenergic drugs. Tiotropium is only approved for use in COPD. Though, a recent study provides some evidence that this agent may be an alternative to long-acting beta agonists as an add-on therapy to inhaled glucocorticoids for asthma.

  10. Lung Disease Including Asthma and Adult Vaccination

    MedlinePlus

    ... Healthcare Professionals Lung Disease including Asthma and Adult Vaccination Language: English Español (Spanish) Recommend on Facebook Tweet ... more about health insurance options. Learn about adult vaccination and other health conditions Asplenia Diabetes Heart Disease, ...

  11. Airway-Clearance Techniques in Children and Adolescents with Chronic Suppurative Lung Disease and Bronchiectasis

    PubMed Central

    Lee, Annemarie L.; Button, Brenda M.; Tannenbaum, Esta-Lee

    2017-01-01

    Common symptoms of chronic suppurative lung disease or bronchiectasis in children and adolescents are chronic cough with sputum production, retention of excess secretions in dilated airways, and a history of recurrent infections. Clinical management includes the prescription of airway-clearance techniques (ACTs) to facilitate mucociliary clearance, optimize sputum expectoration, relieve symptoms, and improve well-being. A wide range of ACTs are available for selection, and these strategies may be applied in isolation or in combination. The choice of technique will depend in part on the age of the child, their clinical state, and factors which may influence treatment adherence. While the evidence base for ACTs in children and adolescent with these conditions is not robust, the current available evidence in addition to clinical expertise provides guidance for technique prescription and clinical effect. An overview of the most commonly applied ACTs, including their physiological rationale and discussion of factors influencing prescription in children and adolescents is outlined in this review. PMID:28168184

  12. NEUROTROPHIN MEDIATION OF ALLERGIC AIRWAYS RESPONSES TO INHALED DIESEL PARTICLES IN MICE

    EPA Science Inventory

    Neurotrophins, including nerve growth factor (NGF) partially mediate many features of allergic airways disease including airway hyper-responsiveness. Diesel exhaust particulates (DEP) associated with the combustion of diesel fuel exacerbate many of these allergic airways respons...

  13. Acute and Chronic Airway Disease After Human Respiratory Syncytial Virus Infection in Cotton Rats (Sigmodon hispidus).

    PubMed

    Grieves, Jessica L; Yin, Zhiwei; Durbin, Russell K; Durbin, Joan E

    2015-08-01

    Infection with respiratory syncytial virus (RSV) generally presents as a mild, upper airway disease in human patients but may cause severe lower airway disease in the very young and very old. Progress toward understanding the mechanisms of RSV pathogenesis has been hampered by a lack of relevant rodent models. Mice, the species most commonly used in RSV research, are resistant to upper respiratory infection and do not recapitulate the pattern of virus spread in the human host. To address the need for better rodent models of RSV infection, we have characterized the acute and chronic pathology of RSV infection of a relatively permissive host, cotton rats (Sigmodon hispidus). We demonstrate that virus delivered to the upper airway results in widespread RSV replication in the ciliated respiratory epithelial cells of the nasal cavity and, to a lesser extent, of the lung. Although acute inflammation is relatively mild and rapidly eliminated after viral clearance, chronic, eosinophilic lung pathology persists. These data support the use of cotton rats as a robust rodent model of human RSV disease, including the association between RSV pneumonia and subsequent development of allergic asthma.

  14. Acute and Chronic Airway Disease After Human Respiratory Syncytial Virus Infection in Cotton Rats (Sigmodon hispidus)

    PubMed Central

    Grieves, Jessica L; Yin, Zhiwei; Durbin, Russell K; Durbin, Joan E

    2015-01-01

    Infection with respiratory syncytial virus (RSV) generally presents as a mild, upper airway disease in human patients but may cause severe lower airway disease in the very young and very old. Progress toward understanding the mechanisms of RSV pathogenesis has been hampered by a lack of relevant rodent models. Mice, the species most commonly used in RSV research, are resistant to upper respiratory infection and do not recapitulate the pattern of virus spread in the human host. To address the need for better rodent models of RSV infection, we have characterized the acute and chronic pathology of RSV infection of a relatively permissive host, cotton rats (Sigmodon hispidus). We demonstrate that virus delivered to the upper airway results in widespread RSV replication in the ciliated respiratory epithelial cells of the nasal cavity and, to a lesser extent, of the lung. Although acute inflammation is relatively mild and rapidly eliminated after viral clearance, chronic, eosinophilic lung pathology persists. These data support the use of cotton rats as a robust rodent model of human RSV disease, including the association between RSV pneumonia and subsequent development of allergic asthma. PMID:26310461

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

    PubMed Central

    da Silva, Aline Correa; Brass, Karin Erica; da Silva Loreto, Elgion; Vinocur, Myriam Elizabeth; Pozzobon, Ricardo; da Silva Azevedo, Marcos

    2011-01-01

    The aim was to detect the presence of polymorphisms at exons 1, 2, 3 and 4 of the Spi2 gene, and evaluate a possible association between them and recurrent airway obstruction (RAO) or inflammatory airway disease (IAD) in thoroughbred horses, through single-strand conformational-polymorphism (SSCP) screening. Although polymorphism was not detected in exons 1, 2 and 3, three alleles and six genotypes were identified in exon 4. The frequencies of allele A (0.6388) and genotype AA (0.3888) were higher in horses affected by RAO, although no association was found between polymorphism and horses with either RAO or IAD. PMID:21931519

  16. THE SPONTANEOUSLY HYPERTENSIVE RAT: AN EXPERIMENTAL MODEL OF SULFUR DIOXIDE-INDUCED AIRWAYS DISEASE

    EPA Science Inventory

    Chronic obstructive pulmonary disease (COPD) is characterized by airway obstruction, inflammation and mucus hypersecretion; features that capture bronchitis, emphysema and often asthma. However, current rodent models do not reflect this human disease. Because genetically predisp...

  17. A novel microbe-based treatment that attenuates the inflammatory profile in a mouse model of allergic airway disease

    PubMed Central

    Bazett, Mark; Biala, Agnieszka; Huff, Ryan D.; Bosiljcic, Momir; Gunn, Hal; Kalyan, Shirin; Hirota, Jeremy A.

    2016-01-01

    There is an unmet need for effective new and innovative treatments for asthma. It is becoming increasingly evident that bacterial stimulation can have beneficial effects at attenuating allergic airway disease through immune modulation. Our aim was to test the ability of a novel inactivated microbe-derived therapeutic based on Klebsiella (KB) in a model of allergic airway disease in mice. BALB/c mice were exposed intranasally to house dust mite (HDM) for two weeks. Mice were treated prophylactically via subcutaneous route with either KB or placebo for one week prior to HDM exposure and throughout the two week exposure period. 24 hours after the last exposure, lungs were analysed for inflammatory cell infiltrate, gene expression, cytokine levels, goblet cell metaplasia, and serum was analysed for allergen-specific serum IgE levels. HDM exposed mice developed goblet cell hyperplasia, elevated allergen-specific serum IgE, airway eosinophilia, and a concomitant increase in TH2 cytokines including IL-4, IL-13 and IL-5. Treatment with KB attenuated HDM-mediated airway eosinophilia, total bronchoalveolar lavage (BAL) cell numbers, BAL TH2 cytokine production, and goblet cell metaplasia. Our prophylactic intervention study illustrates the potential of subcutaneous treatment with bacterial derived biologics as a promising approach for allergic airway disease treatment. PMID:27734946

  18. Airway Epithelial Expression Quantitative Trait Loci Reveal Genes Underlying Asthma and Other Airway Diseases

    PubMed Central

    Luo, Wei; Obeidat, Ma’en; Di Narzo, Antonio Fabio; Chen, Rong; Sin, Don D.; Paré, Peter D.

    2016-01-01

    Genome-wide association studies (GWASs) have identified loci that are robustly associated with asthma and related phenotypes; however, the molecular mechanisms underlying these associations need to be explored. The most relevant tissues to study the functional consequences of asthma are the airways. We used publically available data to derive expression quantitative trait loci (eQTLs) for human epithelial cells from small and large airways and applied the eQTLs in the interpretation of GWAS results of asthma and related phenotypes. For the small airways (n = 105), we discovered 660 eQTLs at a 10% false discovery rate (FDR), among which 315 eQTLs were not previously reported in a large-scale eQTL study of whole lung tissue. A large fraction of the identified eQTLs is supported by data from Encyclopedia of DNA Elements (ENCODE) showing that the eQTLs reside in regulatory elements (57.5 and 67.6% of cis- and trans-eQTLs, respectively). Published pulmonary GWAS hits were enriched as airway epithelial eQTLs (9.2-fold). Further, genes regulated by asthma GWAS loci in epithelium are significantly enriched in immune response pathways, such as IL-4 signaling (FDR, 5.2 × 10−4). The airway epithelial eQTLs described in this study are complementary to previously reported lung eQTLs and represent a powerful resource to link GWAS-associated variants to their regulatory function and thus elucidate the molecular mechanisms underlying asthma and airway-related conditions. PMID:26102239

  19. [Research progress on role of chemokine receptor CCR3 signaling in allergic airway diseases].

    PubMed

    Xu, Yi; Liu, Yuehui

    2012-12-01

    Allergic airway diseases have been identified as chronic inflammatory diseases of respiratory membranes, characterized by infiltration of many inflammatory cells, especially eosinophils. The expression of CCR3 is abundant on the cell surface of eosinophils. Increased accumulation of CCR3-driven inflammatory cells is thought to favor the development of allergy. In this review, we survey the properties of CCR3 and its ligands and highlight the roles of CCR3 signaling in allergic airway diseases.

  20. Occupational rhinitis and occupational asthma; one airway two diseases?

    NASA Astrophysics Data System (ADS)

    Seed, M. J.; Gittins, M.; DeVocht, F.; Agius, R. M.

    2009-02-01

    The concept of 'one airway, one disease' refers to the frequent comorbidity of asthma and rhinitis. However, only limited research has been done on this association for the diverse range of occupational respiratory sensitisers. The relative frequency of rhinitis was determined for the 15 respiratory sensitisers reported to cause at least 10 cases of rhinitis or asthma to The Health and Occupation Reporting (THOR) network between 1997 and 2006. Of 1408 cases, 1190 were sole diagnoses of asthma, 138 sole diagnoses of rhinitis and in 80 cases asthma coexisted with rhinitis. The six sensitisers for which rhinitis featured in over 15% of cases were all particulates and known to cause release of mast cell mediators, either directly or through IgE antibodies. Four of the other nine sensitisers often exist as vapours and only two have been consistently associated with IgE-mediated disease mechanisms. Particle size did not appear to correlate with the relative frequency of rhinitis. Despite its limitations this study would support the hypothesis that there are at least two mechanistic categories of respiratory sensitisation with rhinitis being relatively more common where the mechanism is IgE-mediated. Particulate nature may be another important factor to consider in future studies.

  1. Barrier function of the nasal mucosa in health and type-2 biased airway diseases.

    PubMed

    Zhang, N; Van Crombruggen, K; Gevaert, E; Bachert, C

    2016-03-01

    The mucosal lining of the upper airways represents the outer surface of the body to the ambient air and its contents and is prepared for it as the first line of defense. Apart from the well-described physical barrier and the mucociliary clearance, a variety of systems, including the airway microbiome, antimicrobial proteins, damage-associated molecular patterns, innate lymphoid cells, epithelial-derived cytokines and chemokines, and finally the adaptive immune system, as well as eosinophils as newly appreciated defense cells form different levels of protection against and response to any possible intruder. Of interest especially for allergic airway disease, mucosal germs might not just elicit a classical Th1/Th17-biased inflammatory response, but may directly induce a type-2 mucosal inflammation. Innovative therapeutic interventions may be possible at different levels also; however, whether modulations of the innate or adaptive immune responses will finally be more successful, and how the correction of the adaptive immune response might impact on the innate side, will be determined in the near future.

  2. European symposium on precision medicine in allergy and airways diseases: report of the European Union parliament symposium (October 14, 2015).

    PubMed

    Muraro, A; Fokkens, W J; Pietikainen, S; Borrelli, D; Agache, I; Bousquet, J; Costigliola, V; Joos, G; Lund, V J; Poulsen, L K; Price, D; Rolland, C; Zuberbier, T; Hellings, P W

    2015-12-01

    On 14 October 2015, the European Academy of Allergy and Clinical Immunology (EAACI), the European Rhinologic Society (ERS) and the European Medical Association (EMA) organized a symposium in the European Parliament in Brussels on Precision Medicine in Allergy and Airways Diseases, hosted by MEP David Borrelli and with active participation of the European Respiratory Society (ERS), the European Federations of Allergy and Airways Diseases Patients Associations (EFA), the Global Allergy and Asthma European Network (Ga2len), Allergic Rhinitis and Its Impact on Asthma (ARIA) and the Respiratory Effectiveness Group (REG). MEP Sirpa Pietikainen, Chair of the European Parliament Interest Group on Allergy and Asthma, underlined the importance of the need for a better diagnostic and therapeutic approach for patients with Allergies and Chronic Airways Diseases, and encouraged a joint initiative to control the epidemic of Allergy and Asthma in Europe. The socio-economic impact of allergies and chronic airways diseases cannot be underestimated, as they represent the most frequently diagnosed chronic non-communicable diseases in the EU. Despite the fact that 30% of the total European population is nowadays suffering from allergies and asthma, more than half of these patients are deprived from adequate diagnosis and treatment. Precision Medicine represents a novel approach in medicine, embracing 4 key features: personalized care based on molecular, immunologic and functional endotyping of the disease, with participation of the patient in the decision making process of therapeutic actions, and taking into account predictive and preventive aspects of the treatment. Implementation of Precision Medicine into clinical practice may help to achieve the arrest of the Epidemic of Allergies and Chronic Airways Diseases. This report summarizes the key messages delivered during the symposium by the speakers, including the EU Commissioner for Health and Food Safety Vitenys Andriukaitis. The

  3. The Contribution of Small Airway Obstruction to the Pathogenesis of Chronic Obstructive Pulmonary Disease.

    PubMed

    Hogg, James C; Paré, Peter D; Hackett, Tillie-Louise

    2017-04-01

    The hypothesis that the small conducting airways were the major site of obstruction to airflow in normal lungs was introduced by Rohrer in 1915 and prevailed until Weibel introduced a quantitative method of studying lung anatomy in 1963. Green repeated Rohrer's calculations using Weibels new data in 1965 and found that the smaller conducting airways offered very little resistance to airflow. This conflict was resolved by seminal experiments conducted by Macklem and Mead in 1967, which confirmed that a small proportion of the total lower airways resistance is attributable to small airways <2 mm in diameter. Shortly thereafter, Hogg, Macklem, and Thurlbeck used this technique to show that small airways become the major site of obstruction in lungs affected by emphysema. These and other observations led Mead to write a seminal editorial in 1970 that postulated the small airways are a silent zone within normal lungs where disease can accumulate over many years without being noticed. This review provides a progress report since the 1970s on methods for detecting chronic obstructive pulmonary disease, the structural nature of small airways' disease, and the cellular and molecular mechanisms that are thought to underlie its pathogenesis.

  4. A pathogenic role for the integrin CD103 in experimental allergic airways disease.

    PubMed

    Fear, Vanessa S; Lai, Siew Ping; Zosky, Graeme R; Perks, Kara L; Gorman, Shelley; Blank, Fabian; von Garnier, Christophe; Stumbles, Philip A; Strickland, Deborah H

    2016-11-01

    The integrin CD103 is the αE chain of integrin αEβ7 that is important in the maintenance of intraepithelial lymphocytes and recruitment of T cells and dendritic cells (DC) to mucosal surfaces. The role of CD103 in intestinal immune homeostasis has been well described, however, its role in allergic airway inflammation is less well understood. In this study, we used an ovalbumin (OVA)-induced, CD103-knockout (KO) BALB/c mouse model of experimental allergic airways disease (EAAD) to investigate the role of CD103 in disease expression, CD4(+) T-cell activation and DC activation and function in airways and lymph nodes. We found reduced airways hyper-responsiveness and eosinophil recruitment to airways after aerosol challenge of CD103 KO compared to wild-type (WT) mice, although CD103 KO mice showed enhanced serum OVA-specific IgE levels. Following aerosol challenge, total numbers of effector and regulatory CD4(+) T-cell subsets were significantly increased in the airways of WT but not CD103 KO mice, as well as a lack of DC recruitment into the airways in the absence of CD103. While total airway DC numbers, and their in vivo allergen capture activity, were essentially normal in steady-state CD103 KO mice, migration of allergen-laden airway DC to draining lymph nodes was disrupted in the absence of CD103 at 24 h after aerosol challenge. These data support a role for CD103 in the pathogenesis of EAAD in BALB/c mice through local control of CD4(+) T cell and DC subset recruitment to, and migration from, the airway mucosa during induction of allergic inflammation.

  5. Antioxidant trace elements in serum of draft horses with acute and chronic lower airway disease.

    PubMed

    Youssef, Mohamed Ahmed; El-Khodery, Sabry Ahmed; Ibrahim, Hussam Mohamed Mohamed

    2012-12-01

    The aim of the present study was to evaluate the oxidative stress level and antioxidant trace elements status associated with lower airway disease in draft horses. For this purpose, venous blood samples were obtained from draft horses exhibiting signs of lower respiratory tract disorders (n = 83) and from control group (n = 20). Serum trace elements including selenium (Se), copper (Cu), zinc (Zn), manganese (Mn), and iron (Fe) were assayed. Serum malondialdehyde (MDA) and low-density lipoprotein (LDL) levels as well as plasma hydrogen peroxides (H₂O₂) concentration and activity of plasma glutathione reductase (GR), glutathione-S-transferase (GST) and catalase (CAT) were measured. There was a significant (p < 0.05) decrease of Se, Cu, Zn, and Fe in diseased horses compared with healthy ones, but the Cu/Zn ratio and Mn were increased (p < 0.05). Se was significantly (p < 0.05) decreased in chronically affected horses compared with acute cases, but Mn was increased (p < 0.05). There was an increase of MDA, LDL, and H₂O₂ levels and GR activity in diseased cases compared with healthy horses. However, there was a significant (p < 0.05) decrease of GST and CAT activity. MDA and LDL levels were increased (p < 0.05) in horses with chronic respiratory disease compared to acute cases, but CAT activity was decreased (p < 0.05). In horses with acute lower airway disease, there was a negative correlation between GR and H₂O₂ (r = -0.458), and LDL and CAT (r = -0.816). However, in chronic disease, a negative correlation was recorded between Se and MDA (r = -0.590). The results of the present study indicate that oxidative stress, with alteration of antioxidant trace element levels, is a feature of respiratory disease in draft horses.

  6. Automated detection of presence of mucus foci in airway diseases: preliminary results

    NASA Astrophysics Data System (ADS)

    Odry, Benjamin L.; Kiraly, Atilla P.; Novak, Carol L.; Naidich, David P.; Ko, Jane; Godoy, Myrna C. B.

    2009-02-01

    Chronic Obstructive Pulmonary Disease (COPD) is often characterized by partial or complete obstruction of airflow in the lungs. This can be due to airway wall thickening and retained secretions, resulting in foci of mucoid impactions. Although radiologists have proposed scoring systems to assess extent and severity of airway diseases from CT images, these scores are seldom used clinically due to impracticality. The high level of subjectivity from visual inspection and the sheer number of airways in the lungs mean that automation is critical in order to realize accurate scoring. In this work we assess the feasibility of including an automated mucus detection method in a clinical scoring system. Twenty high-resolution datasets of patients with mild to severe bronchiectasis were randomly selected, and used to test the ability of the computer to detect the presence or absence of mucus in each lobe (100 lobes in all). Two experienced radiologists independently scored the presence or absence of mucus in each lobe based on the visual assessment method recommended by Sheehan et al [1]. These results were compared with an automated method developed for mucus plug detection [2]. Results showed agreement between the two readers on 44% of the lobes for presence of mucus, 39% of lobes for absence of mucus, and discordant opinions on 17 lobes. For 61 lobes where 1 or both readers detected mucus, the computer sensitivity was 75.4%, the specificity was 69.2%, and the positive predictive value (PPV) was 79.3%. Six computer false positives were a-posteriori reviewed by the experts and reassessed as true positives, yielding results of 77.6% sensitivity, 81.8% for specificity, and 89.6% PPV.

  7. Assessment of Risk in Chronic Airways Disease Evaluation (ARCADE): Protocol and preliminary data.

    PubMed

    Gale, Nichola S; Albarrati, Ali M; Munnery, Margaret M; Munnery, Iain C; Irfan, Mujammil; Bolton, Charlotte E; Rambaran, Curtis N; Singer, Ruth M Tal; Cockcroft, John R; Shale, Dennis J

    2014-11-01

    Chronic obstructive pulmonary disease (COPD) is a multisystem disease. Established comorbidities include cardiovascular disease, osteoporosis, loss of muscle mass and function, depression, and impaired quality of life. The natural history is not well understood. The Assessment of Risk in Chronic Airways Disease Evaluation (ARCADE) is a longitudinal study of comorbidities in COPD. The primary aims are to delineate the progression and interrelationships of cardiovascular disease and associated comorbidities. Each year ARCADE aims to recruit 250 patients diagnosed with COPD and 50 comparators (free from respiratory disease). Assessments include spirometry, body composition, blood pressure, aortic stiffness (pulse wave velocity (PWV)), noninvasive measures of cardiac output, systemic inflammatory mediators, blood and urine biochemistry, and physical and health outcomes. These will be repeated at 2 and 5 years. In the first year of recruitment, 350 patients and 100 comparators were recruited. The reproducibility of aortic PWV, cardiac output, stroke volume, and cardiac index was evaluated and accepted in 30 patients free from overt cardiovascular disease. The preliminary data from ARCADE have demonstrated acceptable reproducibility of hemodynamic outcome measures. Further longitudinal data collection will increase knowledge of the progression and interactions between cardiovascular risk factors and other comorbidities in COPD.

  8. Recurrent airway obstruction: a review.

    PubMed

    Pirie, R S

    2014-05-01

    Recurrent airway obstruction is a widely recognised airway disorder, characterised by hypersensitivity-mediated neutrophilic airway inflammation and lower airway obstruction in a subpopulation of horses when exposed to suboptimal environments high in airborne organic dust. Over the past decade, numerous studies have further advanced our understanding of different aspects of the disease. These include clarification of the important inhaled airborne agents responsible for disease induction, improving our understanding of the underlying genetic basis of disease susceptibility and unveiling the fundamental immunological mechanisms leading to establishment of the classic disease phenotype. This review, as well as giving a clinical overview of recurrent airway obstruction, summarises much of the work in these areas that have culminated in a more thorough understanding of this debilitating disease.

  9. Frequency and time domain analysis of airflow breath patterns in patients with chronic obstructive airway disease.

    PubMed

    Abboud, S; Bruderman, I; Sadeh, D

    1986-06-01

    Airflow patterns from patients with chronic obstructive airway diseases (COAD) and normal subjects were analyzed using time and frequency domain analysis. Data were recorded during tidal breathing with a pause between the breaths, digitized at 320 samples per second (10-bit resolution), and processed with a CDC 6600 computer. The appearance of high-frequency components (10-20 Hz) in the time domain waveform and the spectral curve in the power spectrum were studied. One complete waveform was taken as a reference signal and all subsequent waves were analyzed using the cross-correlation function which was employed via the cross spectrum and the fast Fourier transform algorithm. The energy content from the averaged spectrum and the root mean square (RMS) value from the filtered waveforms were calculated. Our study indicated that the RMS and the power content estimated from a part of the filtered wave (10-20 Hz) which included the time interval from the peak of the expiratory flow (tE) to the end of the flow curve (tN) were significantly greater in normal subjects (n = 13; 0.86 +/- 0.30 X 10(-2) I/s; P less than 0.00005 for RMS value, and 0.76 +/- 0.32 I/s; P less than 0.00005 for the power content) than in patients with chronic airways obstruction (n = 19; 0.40 +/- 0.13 X 10(-2) I/s; for RMS value and 0.35 +/- 0.16 I/s; for the power content). It is concluded that the RMS and the power values of the filtered flow curve during tidal breathing over the time interval tE-tN can detect chronic airway obstruction.

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

    PubMed

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

    2017-01-01

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

  11. Novel cAMP signalling paradigms: therapeutic implications for airway disease.

    PubMed

    Billington, Charlotte K; Hall, Ian P

    2012-05-01

    Since its discovery over 50 years ago, cAMP has been the archetypal second messenger introducing students to the concept of cell signalling at the simplest level. As explored in this review, however, there are many more facets to cAMP signalling than the path from Gs-coupled receptor to adenylyl cyclase (AC) to cAMP to PKA to biological effect. After a brief description of this canonical cAMP signalling pathway, a snapshot is provided of the novel paradigms of cAMP signalling. As in the airway the cAMP pathway relays the major bronchorelaxant signal and as such is the target for frontline therapy for asthma and COPD, particular emphasis is given to airway disease and therapy. Areas discussed include biased agonism, continued signalling following internalization, modulation of cAMP by AC, control of cAMP degradation, cAMP and calcium crosstalk, Epac-mediated signalling and finally the implications of altered genotypes will be considered. LINKED ARTICLES This article is part of a themed section on Novel cAMP Signalling Paradigms. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.166.issue-2.

  12. Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease

    PubMed Central

    Paré, Peter D.; Rafaels, Nicholas; Sin, Don D.; Sandford, Andrew; Daley, Denise; Vergara, Candelaria; Huang, Lili; Elliott, W. Mark; Pascoe, Chris D.; Arsenault, Bryna A.; Postma, Dirkje S.; Boezen, H. Marike; Bossé, Yohan; van den Berge, Maarten; Hiemstra, Pieter S.; Cho, Michael H.; Litonjua, Augusto A.; Sparrow, David; Ober, Carole; Wise, Robert A.; Connett, John; Neptune, Enid R.; Beaty, Terri H.; Ruczinski, Ingo; Mathias, Rasika A.; Barnes, Kathleen C.

    2015-01-01

    Increased airway responsiveness is linked to lung function decline and mortality in subjects with chronic obstructive pulmonary disease (COPD); however, the genetic contribution to airway responsiveness remains largely unknown. A genome-wide association study (GWAS) was performed using the Illumina (San Diego, CA) Human660W-Quad BeadChip on European Americans with COPD from the Lung Health Study. Linear regression models with correlated meta-analyses, including data from baseline (n = 2,814) and Year 5 (n = 2,657), were used to test for common genetic variants associated with airway responsiveness. Genotypic imputation was performed using reference 1000 Genomes Project data. Expression quantitative trait loci (eQTL) analyses in lung tissues were assessed for the top 10 markers identified, and immunohistochemistry assays assessed protein staining for SGCD and MYH15. Four genes were identified within the top 10 associations with airway responsiveness. Markers on chromosome 9p21.2 flanked by LINGO2 met a predetermined threshold of genome-wide significance (P < 9.57 × 10−8). Markers on chromosomes 3q13.1 (flanked by MYH15), 5q33 (SGCD), and 6q21 (PDSS2) yielded suggestive evidence of association (9.57 × 10−8 < P ≤ 4.6 × 10−6). Gene expression studies in lung tissue showed single nucleotide polymorphisms on chromosomes 5 and 3 to act as eQTL for SGCD (P = 2.57 × 10−9) and MYH15 (P = 1.62 × 10−6), respectively. Immunohistochemistry confirmed localization of SGCD protein to airway smooth muscle and vessels and MYH15 to airway epithelium, vascular endothelium, and inflammatory cells. We identified novel loci associated with airway responsiveness in a GWAS among smokers with COPD. Risk alleles on chromosomes 5 and 3 acted as eQTLs for SGCD and MYH15 messenger RNA, and these proteins were expressed in lung cells relevant to the development of airway responsiveness. PMID:25514360

  13. Effects of Educational Interventions for Chronic Airway Disease on Primary Care.

    PubMed

    Lee, Jung Yeon; Yoo, Kwang Ha; Kim, Deog Kyeom; Kim, Sang-Ha; Kim, Tae-Eun; Kim, Tae-Hyung; Rhee, Chin Kook; Park, Yong Bum; Yoon, Hyoung Kyu; Yum, Ho-Kee

    2016-07-01

    Education has been known to essential for management of chronic airway diseases. However the real benefits remain unclear. We evaluated the effectiveness of an organized educational intervention for chronic airway diseases directed at primary care physicians and patients. The intervention was a 1-month education program of three visits, during which subjects were taught about their disease, an action plan in acute exacerbation and inhaler technique. Asthma control tests (ACT) for asthma and, chronic obstructive pulmonary disease (COPD) assessment tests (CAT) for COPD subjects were compared before and after education as an index of quality of life. Educational effectiveness was also measured associated with improvement of their knowledge for chronic airway disease itself, proper use of inhaler technique, and satisfaction of the subjects and clinicians before and after education. Among the 285 participants, 60.7% (n = 173) were men and the mean age was 62.2 ± 14.7. ACT for asthma and CAT in COPD patients were significantly improved by 49.7% (n = 79) and 51.2% (n = 65) more than MCID respectively after education (P < 0.05). In all individual items, knowledge about their disease, inhaler use and satisfaction of the patients and clinicians were also improved after education (P < 0.05). This study demonstrates the well-organized education program for primary care physicians and patients is a crucial process for management of chronic airway diseases.

  14. The effect of increased lung volume in chronic obstructive pulmonary disease on upper airway obstruction during sleep

    PubMed Central

    Biselli, Paolo; Grossman, Peter R.; Kirkness, Jason P.; Patil, Susheel P.; Smith, Philip L.; Schwartz, Alan R.

    2015-01-01

    Patients with chronic obstructive pulmonary disease (COPD) exhibit increases in lung volume due to expiratory airflow limitation. Increases in lung volumes may affect upper airway patency and compensatory responses to inspiratory flow limitation (IFL) during sleep. We hypothesized that COPD patients have less collapsible airways inversely proportional to their lung volumes, and that the presence of expiratory airflow limitation limits duty cycle responses to defend ventilation in the presence of IFL. We enrolled 18 COPD patients and 18 controls, matched by age, body mass index, sex, and obstructive sleep apnea disease severity. Sleep studies, including quantitative assessment of airflow at various nasal pressure levels, were conducted to determine upper airway mechanical properties [passive critical closing pressure (Pcrit)] and for quantifying respiratory timing responses to experimentally induced IFL. COPD patients had lower passive Pcrit than their matched controls (COPD: −2.8 ± 0.9 cmH2O; controls: −0.5 ± 0.5 cmH2O, P = 0.03), and there was an inverse relationship of subject's functional residual capacity and passive Pcrit (−1.7 cmH2O/l increase in functional residual capacity, r2 = 0.27, P = 0.002). In response to IFL, inspiratory duty cycle increased more (P = 0.03) in COPD patients (0.40 to 0.54) than in controls (0.41 to 0.51) and led to a marked reduction in expiratory time from 2.5 to 1.5 s (P < 0.01). COPD patients have a less collapsible airway and a greater, not reduced, compensatory timing response during upper airway obstruction. While these timing responses may reduce hypoventilation, it may also increase the risk for developing dynamic hyperinflation due to a marked reduction in expiratory time. PMID:26048975

  15. TGF-β-dependent dendritic cell chemokinesis in murine models of airway disease

    PubMed Central

    Hashimoto, Mitsuo; Yanagisawa, Haruhiko; Minagawa, Shunsuke; Sen, Debasish; Ma, Royce; Murray, Lynne A.; Tsui, Ping; Lou, Jianlong; Marks, James D.; Baron, Jody L.; Krummel, Matthew F.; Nishimura, Stephen L.

    2015-01-01

    Small airway chronic inflammation is a major pathologic feature of chronic obstructive pulmonary disease (COPD) and is refractory to current treatments. Dendritic cells (DCs) accumulate around small airways in COPD. DCs are critical mediators of antigen surveillance and antigen presentation and amplify adaptive immune responses. How DCs accumulate around airways remains largely unknown. We use 2-photon DC imaging of living murine lung sections to directly visualize the dynamic movement of living DCs around airways in response to either soluble mediators (IL-1β) or environmental stimuli (cigarette smoke or TLR3 ligands) implicated in COPD pathogenesis. We find that DCs accumulate around murine airways primarily by increasing velocity (chemokinesis) rather than directional migration (chemotaxis) in response to all three stimuli. DC accumulation maximally occurs in a specific zone located 26-50 μm from small airways, which overlaps with zones of maximal DC velocity. Our data suggest that increased accumulation of DCs around airways results from increased numbers of highly chemokinetic DCs entering the lung from the circulation with balanced rates of immigration and emigration. Increases in DC accumulation and chemokinesis are partially dependent on ccr6, a crucial DC chemokine receptor, and fibroblast expression of the integrin αvβ8, a critical activator of TGF-β αvβ8-mediated TGF-β activation is known to enhance IL-1β-dependent fibroblast expression of the only known endogenous ccr6 chemokine ligand, ccl20. Taken together, these data suggest a mechanism by which αvβ8, ccl20 and ccr6 interact to lead to DC accumulation around airways in response to COPD-relevant stimuli. PMID:26109638

  16. Bromodomain and Extra-Terminal Protein Inhibition Attenuates Neutrophil-dominant Allergic Airway Disease.

    PubMed

    Manni, Michelle L; Mandalapu, Sivanarayana; Salmeron, Andres; Lora, Jose M; Kolls, Jay K; Alcorn, John F

    2017-02-24

    Atopic asthma is a prevalent respiratory disease that is characterized by inflammation, mucus hypersecretion, and airway hyperresponsiveness. The complexity of this heterogeneous disorder has commanded the need to better define asthma phenotypes based on underlying molecular mechanisms of disease. Although classically viewed as a type 2-regulated disease, type 17 helper T (Th17) cells are known to be influential in asthma pathogenesis, predominantly in asthmatics with neutrophilia and severe refractory disease. Bromodomain and extra-terminal domain (BET) chromatin adaptors serve as immunomodulators by directly regulating Th17 responses and Th17-mediated pathology in murine models of autoimmunity and infection. Based on this, we hypothesized that BET proteins may also play an essential role in neutrophil-dominant allergic airway disease. Using a murine model of neutrophil-dominant allergic airway disease, we demonstrate that BET inhibition limits pulmonary inflammation and alters the Th17-related inflammatory milieu in the lungs. In addition, inhibition of BET proteins improved lung function (specifically quasi-static lung compliance and tissue elastance) and reduced mucus production in airways. Overall, these studies show that BET proteins may have a critical role in asthma pathogenesis by altering type 17 inflammation, and thus interfering with BET-dependent chromatin signaling may provide clinical benefits to patients suffering from asthma.

  17. Bromodomain and Extra-Terminal Protein Inhibition Attenuates Neutrophil-dominant Allergic Airway Disease

    PubMed Central

    Manni, Michelle L.; Mandalapu, Sivanarayana; Salmeron, Andres; Lora, Jose M.; Kolls, Jay K.; Alcorn, John F.

    2017-01-01

    Atopic asthma is a prevalent respiratory disease that is characterized by inflammation, mucus hypersecretion, and airway hyperresponsiveness. The complexity of this heterogeneous disorder has commanded the need to better define asthma phenotypes based on underlying molecular mechanisms of disease. Although classically viewed as a type 2-regulated disease, type 17 helper T (Th17) cells are known to be influential in asthma pathogenesis, predominantly in asthmatics with neutrophilia and severe refractory disease. Bromodomain and extra-terminal domain (BET) chromatin adaptors serve as immunomodulators by directly regulating Th17 responses and Th17-mediated pathology in murine models of autoimmunity and infection. Based on this, we hypothesized that BET proteins may also play an essential role in neutrophil-dominant allergic airway disease. Using a murine model of neutrophil-dominant allergic airway disease, we demonstrate that BET inhibition limits pulmonary inflammation and alters the Th17-related inflammatory milieu in the lungs. In addition, inhibition of BET proteins improved lung function (specifically quasi-static lung compliance and tissue elastance) and reduced mucus production in airways. Overall, these studies show that BET proteins may have a critical role in asthma pathogenesis by altering type 17 inflammation, and thus interfering with BET-dependent chromatin signaling may provide clinical benefits to patients suffering from asthma. PMID:28233801

  18. Long-term macrolide treatment of chronic inflammatory airway diseases: risks, benefits and future developments.

    PubMed

    Cameron, E J; McSharry, C; Chaudhuri, R; Farrow, S; Thomson, N C

    2012-09-01

    Macrolide antibiotics were discovered over 50 years ago and following their use as antimicrobials it became apparent that this group of antibiotics also possessed anti-inflammatory properties. Subsequent clinical trials showed benefits of macrolides as long-term adjuncts in the treatment of a spectrum of chronic inflammatory respiratory diseases, particularly diffuse panbronchiolitis, cystic fibrosis, post-transplant bronchiolitis obliterans and more recently chronic obstructive pulmonary disease (COPD). The evidence for efficacy of macrolides in the long-term treatment of chronic asthma and bronchiectasis is less well established. The mechanism(s) of action of macrolides in the treatment of these diseases remains unexplained, but may be due to their antibacterial and/or anti-inflammatory actions, which include reductions in interleukin-8 production, neutrophil migration and/or function. Macrolides have additional potentially beneficial properties including anti-viral actions and an ability to restore corticosteroid sensitivity. The increased prescribing of macrolides for long-term treatment could result in the development of microbial resistance and adverse drug effects. New macrolides have been developed which do not possess any antimicrobial activity and hence lack the ability to produce microbial resistance, but which still retain immunomodulatory effects. Potentially novel macrolides may overcome a significant barrier to the use of this type of drug for the long-term treatment of chronic inflammatory airway diseases.

  19. Advances in upper airway diseases and allergen immunotherapy.

    PubMed

    Nelson, Harold S

    2004-04-01

    Evidence for one airway continues to accumulate. Nasal allergen challenges increase lower airway inflammation, and nasal corticosteroid treatment reduces lower airway inflammation. Allergic respiratory inflammation might even spread systemically to involve nonrespiratory organs. Eosinophilic enteritis and eosinophilic esophagitis are reported during pollen seasons in patients with seasonal allergic rhinitis. Chronic hypertrophic sinusitis (CHS) is found in the majority of patients with asthma. Like asthma, the histology of CHS is characterized by epithelial damage, basement membrane thickening, and eosinophilic inflammation. The damaged epithelium might explain the acute bacterial exacerbations seen in patients with CHS. Studies have extended evidence of the safety and efficacy of the second- and third-generation antihistamines to younger children and to patients with perennial rhinitis but continue to show improvement of symptom scores over that seen with placebo of less than 20%. Studies on antihistamine use in the first trimester in nearly 500 women (65% taking loratadine) revealed no increase in the complications of pregnancy or congenital anomalies. Positive skin prick test responses to birch in asymptomatic young adults predicted later development of clinical allergic rhinitis. A dose response was demonstrated for immunotherapy with cat dander extract. The best results were in subjects receiving a dose containing 15 microg of the major cat allergen Fel d 1 (equivalent to approximately 2500 bioequivalent allergen units). Both topical intranasal immunotherapy and high-dose sublingual immunotherapy have been repeatedly proved to be safe and effective in double-blind, placebo-controlled studies. CD4+CD25+ regulatory T cells secreting IL-10, TGF-beta, or both appear important in normal individuals and in patients treated with allergen immunotherapy in maintaining or restoring normal T(H)1/T(H)2 balance and overall suppression of both phenotypes.

  20. A critical role for dendritic cells in the evolution of IL-1β-mediated murine airway disease

    PubMed Central

    Hashimoto, Mitsuo; Yanagisawa, Haruhiko; Minagawa, Shunsuke; Sen, Debasish; Goodsell, Amanda; Ma, Royce; Moermans, Catherine; McKnelly, Kate J.; Baron, Jody L.; Krummel, Matthew F.; Nishimura, Stephen L.

    2015-01-01

    Chronic airway inflammation and fibrosis, known as airway remodeling, are defining features of chronic obstructive pulmonary disease (COPD) and are refractory to current treatments. How and if chronic inflammation contributes to airway fibrosis remains controversial. Here, we use a model of COPD airway disease utilizing adenoviral (Ad) delivery of IL-1β to determine that adaptive T-cell immunity is required for airway remodeling since mice deficient in α/β T-cells (tcra −/−) are protected. Dendritic cells (DCs) accumulate around COPD airways and are critical to prime adaptive immunity, but have not been shown to directly influence airway remodeling. We show that DC depletion or deficiency in the crucial DC chemokine receptor, ccr6, both protect from Ad-IL-1β-induced airway adaptive T-cell immune responses, and fibrosis in mice. These results provide evidence that chronic airway inflammation, mediated by accumulation of α/β T-cells and driven by DCs, is critical to airway fibrosis. PMID:25786688

  1. Approaches to prevent the patients with chronic airway diseases from exacerbation in the haze weather

    PubMed Central

    Ren, Jin; Li, Bo; Yu, Dan; Liu, Jing

    2016-01-01

    Haze weather is becoming one of the biggest problems in many big cities in China. It triggers both public anxiety and official concerns. Particulate matter (PM) plays the most important role in causing the adverse health effects. Chemical composition of PM2.5 includes primary particles and secondary particles. The toxicological mechanisms of PM2.5 to the human body include the oxidative stress, inflammation and carcinogenesis. Short or long-term exposure to PM (especially PM2.5) can cause a series of symptoms including respiratory symptoms such as cough, wheezing and dyspnea as well as other symptoms. There are positive associations between PM2.5 and mortality due to a number of causes. PM2.5 is considered to contribute to the onset of asthma, the exacerbation of chronic obstructive pulmonary disease (COPD) in haze weather. Some approaches including outdoor health care, indoor health care and preventive medications can prevent the patients with chronic airway diseases from exacerbations. PMID:26904232

  2. NEUTROPHILS PLAY A CRITICAL ROLE IN THE DEVELOPMENT OF LPS-INDUCED AIRWAY DISEASE

    EPA Science Inventory

    ETD-02-045 (GAVETT) GPRA # 10108

    Neutrophils Play a Critical Role in the Development of LPS-Induced Airway Disease.
    Jordan D. Savov, Stephen H. Gavett*, David M. Brass, Daniel L. Costa*, and David A. Schwartz

    ABSTRACT
    We investigated the role of neutrophils...

  3. EFFECTS OF SYSTEMIC NEUTROPHIL DEPLETION ON LPS-INDUCED AIRWAY DISEASE

    EPA Science Inventory

    Effects of Systemic Neutrophil Depletion on LPS-induced Airway Disease
    Jordan D. Savov, Stephen H. Gavett*, David M. Brass, Daniel L. Costa*, David A. Schwartz
    Pulmonary and Critical Care Division, Dept of Medicine ? Duke University Medical Center
    * National Health and E...

  4. Newly Recognized Occupational and Environmental Causes of Chronic Terminal Airways and Parenchymal Lung Disease

    PubMed Central

    Sauler, Maor; Gulati, Mridu

    2012-01-01

    Synopsis With the introduction of new materials and changes in manufacturing practices, occupational health investigators continue to uncover associations between novel exposures and chronic forms of diffuse parenchymal lung disease and terminal airways disease. In order to discern exposure disease relationships, clinicians must maintain a high index of suspicion for the potential toxicity of occupational and environmental exposures. This article details several newly recognized chronic parenchymal and terminal airways. Diseases related to exposure to Indium, Nylon Flock, Diacetyl used in the flavorings industry, nanoparticles, and the World Trade Center disaster are reviewed. Additionally, this article will review methods in worker surveillance as well as the potential use of biomarkers in the evaluation of exposure disease relationships. PMID:23153608

  5. Pluripotent allospecific CD8+ effector T cells traffic to lung in murine obliterative airway disease.

    PubMed

    West, Erin E; Lavoie, Tera L; Orens, Jonathan B; Chen, Edward S; Ye, Shui Q; Finkelman, Fred D; Garcia, Joe G N; McDyer, John F

    2006-01-01

    Long-term success in lung transplantation is limited by obliterative bronchiolitis, whereas T cell effector mechanisms in this process remain incompletely understood. Using the mouse heterotopic allogeneic airway transplant model, we studied T cell effector responses during obliterative airways disease (OAD). Allospecific CD8+ IFN-gamma+ T cells were detected in airway allografts, with significant coexpression of TNF-alpha and granzyme B. Therefore, using IFN-gamma as a surrogate marker, we assessed the distribution and kinetics of extragraft allo-specific T cells during OAD. Robust allospecific IFN-gamma was produced by draining the lymph nodes, spleen, and lung mononuclear cells from allograft, but not isograft recipients by Day 14, and significantly decreased by Day 28. Although the majority of allospecific T cells were CD8+, allospecific CD4+ T cells were also detected in these compartments, with each employing distinct allorecognition pathways. An influx of pluripotent CD8+ effector cells with a memory phenotype were detected in the lung during OAD similar to those seen in the allografts and secondary lymphoid tissue. Antibody depletion of CD8+ T cells markedly reduced airway lumen obliteration and fibrosis at Day 28. Together, these data demonstrate that allospecific CD8+ effector T cells play an important role in OAD and traffic to the lung after heterotopic airway transplant, suggesting that the lung is an important immunologic site, and perhaps a reservoir, for effector cells during the rejection process.

  6. The nervous system of airways and its remodeling in inflammatory lung diseases.

    PubMed

    Audrit, Katrin Julia; Delventhal, Lucas; Aydin, Öznur; Nassenstein, Christina

    2017-03-01

    Inflammatory lung diseases are associated with bronchospasm, cough, dyspnea and airway hyperreactivity. The majority of these symptoms cannot be primarily explained by immune cell infiltration. Evidence has been provided that vagal efferent and afferent neurons play a pivotal role in this regard. Their functions can be altered by inflammatory mediators that induce long-lasting changes in vagal nerve activity and gene expression in both peripheral and central neurons, providing new targets for treatment of pulmonary inflammatory diseases.

  7. Continuous Positive Airway Pressure Improves Sleep and Daytime Sleepiness in Patients with Parkinson Disease and Sleep Apnea

    PubMed Central

    Neikrug, Ariel B.; Liu, Lianqi; Avanzino, Julie A.; Maglione, Jeanne E.; Natarajan, Loki; Bradley, Lenette; Maugeri, Alex; Corey-Bloom, Jody; Palmer, Barton W.; Loredo, Jose S.; Ancoli-Israel, Sonia

    2014-01-01

    Study Objectives: Obstructive sleep apnea (OSA), common in Parkinson disease (PD), contributes to sleep disturbances and daytime sleepiness. We assessed the effect of continuous positive airway pressure (CPAP) on OSA, sleep, and daytime sleepiness in patients with PD. Design: This was a randomized placebo-controlled, crossover design. Patients with PD and OSA were randomized into 6 w of therapeutic treatment or 3 w of placebo followed by 3 w of therapeutic treatment. Patients were evaluated by polysomnography (PSG) and multiple sleep latency test (MSLT) pretreatment (baseline), after 3 w, and after 6 w of CPAP treatment. Analyses included mixed models, paired analysis, and within-group analyses comparing 3 w to 6 w of treatment. Setting: Sleep laboratory. Participants: Thirty-eight patients with PD (mean age = 67.2 ± 9.2 y; 12 females). Intervention: Continuous positive airway pressure. Measurements: PSG outcome measures: sleep efficiency, %sleep stages (N1, N2, N3, R), arousal index, apnea-hypopnea index (AHI), and % time oxygen saturation < 90% (%time SaO2 < 90%). MSLT outcome measures: mean sleep-onset latency (MSL). Results: There were significant group-by-time interactions for AHI (P < 0.001), % time SaO2 < 90% (P = 0.02), %N2 (P = 0.015) and %N3 (P = 0.014). Subjects receiving therapeutic CPAP showed significant decrease in AHI, %time SaO2 < 90%, %N2, and significant increase in %N3 indicating effectiveness of CPAP in the treatment of OSA, improvement in nighttime oxygenation, and in deepening sleep. The paired sample analyses revealed that 3 w of therapeutic treatment resulted in significant decreases in arousal index (t = 3.4, P = 0.002). All improvements after 3 w were maintained at 6 w. Finally, 3 w of therapeutic CPAP also resulted in overall decreases in daytime sleepiness (P = 0.011). Conclusions: Therapeutic continuous positive airway pressure versus placebo was effective in reducing apnea events, improving oxygen saturation, and deepening sleep in

  8. IgE sensitization to inhalant allergens and the risk of airway infection and disease: A population-based study

    PubMed Central

    Husemoen, Lise Lotte Nystrup; Thuesen, Betina Heinsbæk; Fenger, Runa Vavia; Linneberg, Allan

    2017-01-01

    Background Immunoglobulin E (IgE) sensitization, which is the propensity to develop IgE antibodies against common environmental allergens, is associated with a lymphocyte T-helper type 2 (Th2) skewed immune response and a high risk of allergic respiratory disease. Little is known about whether IgE sensitization confers an increased risk of respiratory infections in adults. We investigated the association between IgE sensitization and the incidence of acute airway infections, other infections and chronic lower airway disease events as recorded in nation-wide registries. Methods We included 14,849 persons from five population-based studies with measurements of serum specific IgE positivity against inhalant allergens. Participants were followed by linkage to Danish national registries (median follow-up time 11.3 years). The study-specific relative risks were estimated by Cox regression analysis, meta-analysed, and expressed as hazard ratios, HRs (95% confidence intervals, CIs). Results The relative risks for IgE sensitized vs. non-sensitized were: for pneumonia (HR = 1.20, 95% CI: 1.01, 1.41), other acute airway infection (HR = 0.86, 95% CI: 0.60, 1.22), infection (HR = 1.06, 95% CI: 0.90, 1.24), asthma (HR = 2.26, 95% CI: 1.79, 2.86), and other chronic lower airway disease (HR = 1.31, 95% CI: 1.08, 1.58). In never smokers, the higher risk of pneumonia (HR = 1.73, 95% CI: 1.23, 2.44) and asthma (HR = 3.17, 95% CI: 2.10, 4.76) among IgE sensitized was more pronounced. Conclusions IgE sensitization was associated with a higher risk of asthma, other chronic lower airway diseases, and pneumonia. However, the association between IgE sensitization and pneumonia may be explained by undiagnosed asthma causing the pneumonia. Further studies are needed for confirmation. PMID:28182643

  9. Animal models of allergic airways disease: where are we and where to next?

    PubMed

    Chapman, David G; Tully, Jane E; Nolin, James D; Janssen-Heininger, Yvonne M; Irvin, Charles G

    2014-12-01

    In a complex inflammatory airways disease such as asthma, abnormalities in a plethora of molecular and cellular pathways ultimately culminate in characteristic impairments in respiratory function. The ability to study disease pathophysiology in the setting of a functioning immune and respiratory system therefore makes mouse models an invaluable tool in translational research. Despite the vast understanding of inflammatory airways diseases gained from mouse models to date, concern over the validity of mouse models continues to grow. Therefore the aim of this review is twofold; firstly, to evaluate mouse models of asthma in light of current clinical definitions, and secondly, to provide a framework by which mouse models can be continually refined so that they continue to stand at the forefront of translational science. Indeed, it is in viewing mouse models as a continual work in progress that we will be able to target our research to those patient populations in whom current therapies are insufficient.

  10. Exogenous surfactant therapy and mucus rheology in chronic obstructive airway diseases.

    PubMed

    Banerjee, R; Puniyani, R R

    2000-01-01

    Exogenous surfactant is a specialized biomaterial used for substitution of the lipoprotein mixture normally present in the lungs-pulmonary surfactant. Respiratory Distress Syndrome is a disease of preterm infants mainly caused by pulmonary immaturity as evidenced by a deficiency of mature lung surfactant. Pulmonary surfactant is known to stabilize small alveoli and prevent them from collapsing during expiration. However, apart from alveoli, surfactant also lines the narrow conducting airways of the tracheobronchial tree. This paper reviews the role of this surfactant in the airways and its effect on mucus rheology and mucociliary clearance. Its potential role as a therapeutic biomaterial in chronic obstructive airway diseases, namely asthma, chronic bronchitis, and respiratory manifestations of cystic fibrosis, are discussed. This paper also attempts to elucidate the exact steps in the pathogenic pathway of these diseases which could be reversed by supplementation of exogenous surfactant formulations. It is shown that there is great potential for the use of present day surfactants (which are actually formulated for use in Respiratory Disease Syndrome) as therapy in the aforementioned diseases of altered mucus viscoelasticity and mucociliary clearance. However, for improved effectiveness, specific surfactant formulations satisfying certain specific criteria should be tailor-made for the clinical condition for which they are intended. The properties required to be fulfilled by the optimal exogenous surfactant in each of the above clinical conditions are enumerated in this paper.

  11. Bactericidal/Permeability-Increasing Protein Fold–Containing Family Member A1 in Airway Host Protection and Respiratory Disease

    PubMed Central

    Britto, Clemente J.

    2015-01-01

    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. PMID:25265466

  12. Increased Epicardial Adipose Tissue Is Associated with the Airway Dominant Phenotype of Chronic Obstructive Pulmonary Disease

    PubMed Central

    Higami, Yuichi; Ogawa, Emiko; Ryujin, Yasushi; Goto, Kenichi; Seto, Ruriko; Wada, Hiroshi; Tho, Nguyen Van; Lan, Le Thi Tuyet; Paré, Peter D.; Nakano, Yasutaka

    2016-01-01

    Background Epicardial adipose tissue (EAT) has been shown to be a non-invasive marker that predicts the progression of cardiovascular disease (CVD). It has been reported that the EAT volume is increased in patients with chronic obstructive pulmonary disease (COPD). However, little is known about which phenotypes of COPD are associated with increased EAT. Methods One hundred and eighty smokers who were referred to the clinic were consecutively enrolled. A chest CT was used for the quantification of the emphysematous lesions, airway lesions, and EAT. These lesions were assessed as the percentage of low attenuation volume (LAV%), the square root of airway wall area of a hypothetical airway with an internal perimeter of 10 mm (√Aaw at Pi10) and the EAT area, respectively. The same measurements were made on 225 Vietnamese COPD patients to replicate the results. Results Twenty-six of the referred patients did not have COPD, while 105 were diagnosed as having COPD based on a FEV1/FVC<0.70. The EAT area was significantly associated with age, BMI, FEV1 (%predicted), FEV1/FVC, self-reported hypertension, self-reported CVD, statin use, LAV%, and √Aaw at Pi10 in COPD patients. The multiple regression analyses showed that only BMI, self-reported CVD and √Aaw at Pi10 were independently associated with the EAT area (R2 = 0.51, p<0.0001). These results were replicated in the Vietnamese population. Conclusions The EAT area is independently associated with airway wall thickness. Because EAT is also an independent predictor of CVD risk, these data suggest a mechanistic link between the airway predominant form of COPD and CVD. PMID:26866482

  13. The nitrated fatty acid 10-nitro-oleate attenuates allergic airway disease.

    PubMed

    Reddy, Aravind T; Lakshmi, Sowmya P; Dornadula, Sireesh; Pinni, Sudheer; Rampa, Dileep R; Reddy, Raju C

    2013-09-01

    Asthma is a serious, growing problem worldwide. Inhaled steroids, the current standard therapy, are not always effective in this chronic inflammatory disease and can cause adverse effects. We tested the hypothesis that nitrated fatty acids (NFAs) may provide an effective alternative treatment. NFAs are endogenously produced by nonenzymatic reaction of NO with unsaturated fatty acids and exert anti-inflammatory actions both by activating the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR)γ and via PPAR-independent mechanisms, but whether they might ameliorate allergic airway disease was previously untested. We found that pulmonary delivery of the NFA 10-nitro-oleic acid (OA-NO2) reduced the severity of murine allergic airway disease, as assessed by various pathological and molecular markers. Fluticasone, an inhaled steroid commonly used to treat asthma, produced similar effects on most end points, but only OA-NO2 induced robust apoptosis of neutrophils and their phagocytosis by alveolar macrophages. This suggests that OA-NO2 may be particularly effective in neutrophil-rich, steroid-resistant severe asthma. In primary human bronchial epithelial cells, OA-NO2 blocked phosphorylation and degradation of IκB and enhanced inhibitory binding of PPARγ to NF-κB. Our results indicate that the NFA OA-NO2 is efficacious in preclinical models of allergic airway disease and may have potential for treating asthma patients.

  14. Airway shape assessment with visual feed-back in asthma and obstructive diseases

    NASA Astrophysics Data System (ADS)

    Fetita, Catalin; Ortner, Margarete; Brillet, Pierre-Yves; Ould Hmeidi, Yahya; Pr"teux, Françoise

    2010-02-01

    Airway remodeling in asthma patients has been studied in vivo by means of endobronchial biopsies allowing to assess structural and inflammatory changes. However, this technique remains relatively invasive and difficult to use in longitudinal trials. The development of alternative non-invasive tests, namely exploiting high-resolution imaging modalities such as MSCT, is gaining interest in the medical community. This paper develops a fullyautomated airway shape assessment approach based on the 3D segmentation of the airway lumen from MSCT data. The objective is to easily notify the radiologist on bronchus shape variations (stenoses, bronchiectasis) along the airway tree during a simple visual investigation. The visual feed-back is provided by means of a volumerendered color coding of the airway calibers which are robustly defined and computed, based on a specific 3D discrete distance function able to deal with small size structures. The color volume rendering (CVR) information is further on reinforced by the definition and computation of a shape variation index along the airway medial axis enabling to detect specific configurations of stenoses. Such cases often occur near bifurcations (bronchial spurs) and they are either missed in the CVR or difficult to spot due to occlusions by other segments. Consequently, all detected shape variations (stenoses, dilations and thickened spurs) can be additionally displayed on the medial axis and investigated together with the CVR information. The proposed approach was evaluated on a MSCT database including twelve patients with severe or moderate persistent asthma, or severe COPD, by analyzing segmental and subsegmental bronchi of the right lung. The only CVR information provided for a limited number of views allowed to detect 78% of stenoses and bronchial spurs in these patients, whereas the inclusion of the shape variation index enabled to complement the missing information.

  15. Multi-dimensional phenotyping: towards a new taxonomy for airway disease.

    PubMed

    Wardlaw, A J; Silverman, M; Siva, R; Pavord, I D; Green, R

    2005-10-01

    All the real knowledge which we possess, depends on methods by which we distinguish the similar from the dissimilar. The greater the number of natural distinctions this method comprehends the clearer becomes our idea of things. The more numerous the objects which employ our attention the more difficult it becomes to form such a method and the more necessary. Classification is a fundamental part of medicine. Diseases are often categorized according to pre-20th century descriptions and concepts of disease based on symptoms, signs and functional abnormalities rather than on underlying pathogenesis. Where the aetiology of disease has been revealed (for example in the infectious diseases) a more precise classification has become possible, but in the chronic inflammatory diseases, and in the inflammatory airway diseases in particular, where pathogenesis has been stubbornly difficult to elucidate, we still use broad descriptive terms such as asthma and chronic obstructive pulmonary disease, which defy precise definition because they encompass a wide spectrum of presentations and physiological and cellular abnormalities. It is our contention that these broad-brush terms have outlived their usefulness and that we should be looking to create a new taxonomy of airway disease-a taxonomy that more closely reflects the spectrum of phenotypes that are encompassed within the term airway inflammatory diseases, and that gives full recognition to late 20th and 21st century insights into the disordered physiology and cell biology that characterizes these conditions in the expectation that these will map more closely to both aetiology and response to treatment. Development of this taxonomy will require a much more complete and sophisticated correlation of the many variables that make up a condition than has been usual to employ in an approach that encompasses multi-dimensional phenotyping and uses complex statistical tools such as cluster analysis.

  16. Pulmonary iron overload in thalassemia major presenting as small airway disease.

    PubMed

    Ooi, G C; Khong, P L; Lam, W K; Trendell-Smith, N J; Tsang, K W T

    2002-01-01

    Lung function abnormalities that are associated with thalassemia major are variable with etiology that is yet undetermined. Some studies have suggested that pulmonary iron deposition is a probable cause for these lung defects although there has been no antemortem histopathological and radiological evidence for this. We report a case of thalassemia major with biopsy-proven pulmonary iron overload, in which thoracic high-resolution computed tomography revealed a morphological-functional correlation consistent with small airway disease.

  17. EFFECTS OF ALLERGIC AIRWAYS DISEASE ON INFLUENZA VIRUS INFECTION IN BROWN NORWAY RATS

    EPA Science Inventory

    EFFECTS OF ALLERGIC AIRWAYS DISEASE ON INFLUENZA VIRUS INFECTION IN BROWN NORWAY RATS (P. Singhl, D.W. Winsett2, M.J. Daniels2,
    C.A.J. Dick', K.B. Adlerl and M.I. Gilmour2, INCSU, Raleigh, N.C., 2NHEERL/ORD/ USEPA, RTP, N.C. and 3UNC, Chapel Hill, N.C.)The interaction between ...

  18. Eosinophilic airway inflammation: role in asthma and chronic obstructive pulmonary disease

    PubMed Central

    George, Leena; Brightling, Christopher E.

    2016-01-01

    The chronic lung diseases, asthma and chronic obstructive pulmonary disease (COPD), are common affecting over 500 million people worldwide and causing substantial morbidity and mortality. Asthma is typically associated with Th2-mediated eosinophilic airway inflammation, in contrast to neutrophilic inflammation observed commonly in COPD. However, there is increasing evidence that the eosinophil might play an important role in 10–40% of patients with COPD. Consistently in both asthma and COPD a sputum eosinophilia is associated with a good response to corticosteroid therapy and tailored strategies aimed to normalize sputum eosinophils reduce exacerbation frequency and severity. Advances in our understanding of the multistep paradigm of eosinophil recruitment to the airway, and the consequence of eosinophilic inflammation, has led to the development of new therapies to target these molecular pathways. In this article we discuss the mechanisms of eosinophilic trafficking, the tools to assess eosinophilic airway inflammation in asthma and COPD during stable disease and exacerbations and review current and novel anti-eosinophilic treatments. PMID:26770668

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

    PubMed Central

    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

  20. Haemophilus influenzae Disease (Including Hib) Diagnosis and Treatment

    MedlinePlus

    ... Search The CDC Cancel Submit Search The CDC Haemophilus influenzae Disease (Including Hib) Note: Javascript is disabled or ... Compartir On this Page Diagnosis Treatment Complications Diagnosis Haemophilus influenzae , including Hib, disease is usually diagnosed with one ...

  1. Immunological basis of reversible and fixed airways disease.

    PubMed

    Tubby, Carolyn; Harrison, Tim; Todd, Ian; Fairclough, Lucy

    2011-10-01

    Asthma is characterized by airflow obstruction that is usually completely reversible either spontaneously or in response to treatment. However, a small subset of patients with asthma display FAO (fixed airflow obstruction) despite optimal treatment, a feature more commonly associated with smoking-induced COPD (chronic obstructive pulmonary disease). Why some asthma patients develop FAO is not understood, and it is not clear whether (i) they represent a subset of patients with more severe disease, (ii) they share some characteristics of patients who develop COPD, or (iii) they represent a different disease entity altogether. The present review compares the pulmonary inflammatory profile of asthma patients with FAO with those without FAO, as well as COPD sufferers. The inflammation in asthma patients with FAO can vary from neutrophilic with CD8 T-cell involvement, similar to that of COPD, to eosinophilic with CD4 Th2 cell involvement, akin to that of asthma patients without FAO. Although studies of FAO in asthma sufferers would benefit hugely from consistent inclusion criteria, further research work is also required to shed more light on the immunological processes involved.

  2. Breaking barriers. New insights into airway epithelial barrier function in health and disease.

    PubMed

    Rezaee, Fariba; Georas, Steve N

    2014-05-01

    Epithelial permeability is a hallmark of mucosal inflammation, but the molecular mechanisms involved remain poorly understood. A key component of the epithelial barrier is the apical junctional complex that forms between neighboring cells. Apical junctional complexes are made of tight junctions and adherens junctions and link to the cellular cytoskeleton via numerous adaptor proteins. Although the existence of tight and adherens junctions between epithelial cells has long been recognized, in recent years there have been significant advances in our understanding of the molecular regulation of junctional complex assembly and disassembly. Here we review the current thinking about the structure and function of the apical junctional complex in airway epithelial cells, emphasizing the translational aspects of relevance to cystic fibrosis and asthma. Most work to date has been conducted using cell culture models, but technical advancements in imaging techniques suggest that we are on the verge of important new breakthroughs in this area in physiological models of airway diseases.

  3. The innate immune function of airway epithelial cells in inflammatory lung disease

    PubMed Central

    Hiemstra, Pieter S.; McCray, Paul B.; Bals, Robert

    2016-01-01

    The airway epithelium is now considered central to the orchestration of pulmonary inflammatory and immune responses, and is also key to tissue remodelling. It acts as a first barrier in the defence against a wide range of inhaled challenges, and is critically involved in the regulation of both innate and adaptive immune responses to these challenges. Recent progress in our understanding of the developmental regulation of this tissue, the differentiation pathways, recognition of pathogens and antimicrobial responses is now exploited to help understand how epithelial cell function and dysfunction contributes to the pathogenesis of a variety of inflammatory lung diseases. In the review, advances in our knowledge of the biology of airway epithelium, as well as its role and (dys)function in asthma, COPD and cystic fibrosis, are discussed. PMID:25700381

  4. Smoking-induced CXCL14 expression in the human airway epithelium links chronic obstructive pulmonary disease to lung cancer.

    PubMed

    Shaykhiev, Renat; Sackrowitz, Rachel; Fukui, Tomoya; Zuo, Wu-Lin; Chao, Ion Wa; Strulovici-Barel, Yael; Downey, Robert J; Crystal, Ronald G

    2013-09-01

    CXCL14, a recently described epithelial cytokine, plays putative multiple roles in inflammation and carcinogenesis. In the context that chronic obstructive pulmonary disease (COPD) and lung cancer are both smoking-related disorders associated with airway epithelial disorder and inflammation, we hypothesized that the airway epithelium responds to cigarette smoking with altered CXCL14 gene expression, contributing to the disease-relevant phenotype. Using genome-wide microarrays with subsequent immunohistochemical analysis, the data demonstrate that the expression of CXCL14 is up-regulated in the airway epithelium of healthy smokers and further increased in COPD smokers, especially within hyperplastic/metaplastic lesions, in association with multiple genes relevant to epithelial structural integrity and cancer. In vitro experiments revealed that the expression of CXCL14 is induced in the differentiated airway epithelium by cigarette smoke extract, and that epidermal growth factor mediates CXCL14 up-regulation in the airway epithelium through its effects on the basal stem/progenitor cell population. Analyses of two independent lung cancer cohorts revealed a dramatic up-regulation of CXCL14 expression in adenocarcinoma and squamous-cell carcinoma. High expression of the COPD-associated CXCL14-correlating cluster of genes was linked in lung adenocarcinoma with poor survival. These data suggest that the smoking-induced expression of CXCL14 in the airway epithelium represents a novel potential molecular link between smoking-associated airway epithelial injury, COPD, and lung cancer.

  5. Noninvasive ventilation in patients with chronic obstructive airway disease.

    PubMed

    Khilnani, Gopi C; Banga, Amit

    2008-01-01

    Recent years have seen the emergence of noninvasive ventilation (NIV) as an important tool for management of patients with acute exacerbation of chronic obstructive pulmonary disease (COPD). Several well conducted studies in the recent years have established its role in the initial, as well as later management of these patients. However, some grey areas remain. Moreover, data is emerging on the role of long term nocturnal NIV use in patients with very severe stable COPD. This review summarizes the evidence supporting the use of NIV in various stages of COPD, discuss the merits as well as demerits of this novel ventilatory strategy and highlight the grey areas in the current body of knowledge.

  6. Noninvasive ventilation in patients with chronic obstructive airway disease

    PubMed Central

    Khilnani, Gopi C; Banga, Amit

    2008-01-01

    Recent years have seen the emergence of noninvasive ventilation (NIV) as an important tool for management of patients with acute exacerbation of chronic obstructive pulmonary disease (COPD). Several well conducted studies in the recent years have established its role in the initial, as well as later management of these patients. However, some grey areas remain. Moreover, data is emerging on the role of long term nocturnal NIV use in patients with very severe stable COPD. This review summarizes the evidence supporting the use of NIV in various stages of COPD, discuss the merits as well as demerits of this novel ventilatory strategy and highlight the grey areas in the current body of knowledge. PMID:18990962

  7. Mouse models of rhinovirus infection and airways disease.

    PubMed

    Bartlett, Nathan W; Singanayagam, Aran; Johnston, Sebastian L

    2015-01-01

    Mouse models are invaluable tools for gaining insight into host immunity during virus infection. Until recently, no practical mouse model for rhinovirus infection was available. Development of infection models was complicated by the existence of distinct groups of viruses that utilize different host cell surface proteins for binding and entry. Here, we describe mouse infection models, including virus purification and measurement of host immune responses, for representative viruses from two of these groups: (1) infection of unmodified Balb/c mice with minor group rhinovirus serotype 1B (RV-1B) and (2) infection of transgenic Balb/c mice with major group rhinovirus serotype 16 (RV-16).

  8. Paired inspiratory-expiratory chest CT scans to assess for small airways disease in COPD

    PubMed Central

    2013-01-01

    Background Gas trapping quantified on chest CT scans has been proposed as a surrogate for small airway disease in COPD. We sought to determine if measurements using paired inspiratory and expiratory CT scans may be better able to separate gas trapping due to emphysema from gas trapping due to small airway disease. Methods Smokers with and without COPD from the COPDGene Study underwent inspiratory and expiratory chest CT scans. Emphysema was quantified by the percent of lung with attenuation < −950HU on inspiratory CT. Four gas trapping measures were defined: (1) Exp−856, the percent of lung < −856HU on expiratory imaging; (2) E/I MLA, the ratio of expiratory to inspiratory mean lung attenuation; (3) RVC856-950, the difference between expiratory and inspiratory lung volumes with attenuation between −856 and −950 HU; and (4) Residuals from the regression of Exp−856 on percent emphysema. Results In 8517 subjects with complete data, Exp−856 was highly correlated with emphysema. The measures based on paired inspiratory and expiratory CT scans were less strongly correlated with emphysema. Exp−856, E/I MLA and RVC856-950 were predictive of spirometry, exercise capacity and quality of life in all subjects and in subjects without emphysema. In subjects with severe emphysema, E/I MLA and RVC856-950 showed the highest correlations with clinical variables. Conclusions Quantitative measures based on paired inspiratory and expiratory chest CT scans can be used as markers of small airway disease in smokers with and without COPD, but this will require that future studies acquire both inspiratory and expiratory CT scans. PMID:23566024

  9. Early cystic fibrosis lung disease: Role of airway surface dehydration and lessons from preventive rehydration therapies in mice.

    PubMed

    Mall, Marcus A; Graeber, Simon Y; Stahl, Mirjam; Zhou-Suckow, Zhe

    2014-07-01

    Cystic fibrosis (CF) lung disease starts in the first months of life and remains one of the most common fatal hereditary diseases. Early therapeutic interventions may provide an opportunity to prevent irreversible lung damage and improve outcome. Airway surface dehydration is a key disease mechanism in CF, however, its role in the in vivo pathogenesis and as therapeutic target in early lung disease remains poorly understood. Mice with airway-specific overexpression of the epithelial Na(+) channel (βENaC-Tg) recapitulate airway surface dehydration and phenocopy CF lung disease. Recent studies in neonatal βENaC-Tg mice demonstrated that airway surface dehydration produces early mucus plugging in the absence of mucus hypersecretion, which triggers airway inflammation, promotes bacterial infection and causes early mortality. Preventive rehydration therapy with hypertonic saline or amiloride effectively reduced mucus plugging and mortality in neonatal βENaC-Tg mice. These results support clinical testing of preventive/early rehydration strategies in infants and young children with CF.

  10. Hyperpolarized 3He functional magnetic resonance imaging of bronchoscopic airway bypass in chronic obstructive pulmonary disease

    PubMed Central

    Mathew, Lindsay; Kirby, Miranda; Farquhar, Donald; Licskai, Christopher; Santyr, Giles; Etemad-Rezai, Roya; Parraga, Grace; McCormack, David G

    2012-01-01

    A 73-year-old exsmoker with Global initiative for chronic Obstructive Lung Disease stage III chronic obstructive pulmonary disease underwent airway bypass (AB) as part of the Exhale Airway Stents for Emphysema (EASE) trial, and was the only EASE subject to undergo hyperpolarized 3He magnetic resonance imaging for evaluation of lung function pre- and post-AB. 3He magnetic resonance imaging was acquired twice previously (32 and eight months pre-AB) and twice post-AB (six and 12 months post-AB). Six months post-AB, his increase in forced vital capacity was <12% predicted, and he was classified as an AB nonresponder. However, post-AB, he also demonstrated improvements in quality of life scores, 6 min walk distance and improvements in 3He gas distribution in the regions of stent placement. Given the complex relationship between well-established pulmonary function and quality of life measurements, the present case provides evidence of the value-added information functional imaging may provide in chronic obstructive pulmonary disease interventional studies. PMID:22332133

  11. Hyperpolarized 3He functional magnetic resonance imaging of bronchoscopic airway bypass in chronic obstructive pulmonary disease.

    PubMed

    Mathew, Lindsay; Kirby, Miranda; Farquhar, Donald; Licskai, Christopher; Santyr, Giles; Etemad-Rezai, Roya; Parraga, Grace; McCormack, David G

    2012-01-01

    A 73-year-old exsmoker with Global initiative for chronic Obstructive Lung Disease stage III chronic obstructive pulmonary disease underwent airway bypass (AB) as part of the Exhale Airway Stents for Emphysema (EASE) trial, and was the only EASE subject to undergo hyperpolarized 3He magnetic resonance imaging for evaluation of lung function pre- and post-AB. 3He magnetic resonance imaging was acquired twice previously (32 and eight months pre-AB) and twice post-AB (six and 12 months post-AB). Six months post-AB, his increase in forced vital capacity was <12% predicted, and he was classified as an AB nonresponder. However, post-AB, he also demonstrated improvements in quality of life scores, 6 min walk distance and improvements in 3He gas distribution in the regions of stent placement. Given the complex relationship between well-established pulmonary function and quality of life measurements, the present case provides evidence of the value-added information functional imaging may provide in chronic obstructive pulmonary disease interventional studies.

  12. Vitronectin Expression in the Airways of Subjects with Asthma and Chronic Obstructive Pulmonary Disease

    PubMed Central

    Salazar-Peláez, Lina M.; Abraham, Thomas; Herrera, Ana M.; Correa, Mario A.; Ortega, Jorge E.; Paré, Peter D.; Seow, Chun Y.

    2015-01-01

    Vitronectin, a multifunctional glycoprotein, is involved in coagulation, inhibition of the formation of the membrane attack complex (MAC), cell adhesion and migration, wound healing, and tissue remodeling. The primary cellular source of vitronectin is hepatocytes; it is not known whether resident cells of airways produce vitronectin, even though the glycoprotein has been found in exhaled breath condensate and bronchoalveolar lavage from healthy subjects and patients with interstitial lung disease. It is also not known whether vitronectin expression is altered in subjects with asthma and COPD. In this study, bronchial tissue from 7 asthmatic, 10 COPD and 14 control subjects was obtained at autopsy and analyzed by immunohistochemistry to determine the percent area of submucosal glands occupied by vitronectin. In a separate set of experiments, quantitative colocalization analysis was performed on tracheobronchial tissue sections obtained from donor lungs (6 asthmatics, 4 COPD and 7 controls). Vitronectin RNA and protein expressions in bronchial surface epithelium were examined in 12 subjects who undertook diagnostic bronchoscopy. Vitronectin was found in the tracheobronchial epithelium from asthmatic, COPD, and control subjects, although its expression was significantly lower in the asthmatic group. Colocalization analysis of 3D confocal images indicates that vitronectin is expressed in the glandular serous epithelial cells and in respiratory surface epithelial cells other than goblet cells. Expression of the 65-kDa vitronectin isoform was lower in bronchial surface epithelium from the diseased subjects. The cause for the decreased vitronectin expression in asthma is not clear, however, the reduced concentration of vitronectin in the epithelial/submucosal layer of airways may be linked to airway remodeling. PMID:25768308

  13. Controlled trial of continuous positive airway pressure given by face mask for hyaline membrane disease.

    PubMed Central

    Allen, L P; Reynolds, E R; Rivers, R P; Le Souëf, P M; Wimberley, P D

    1977-01-01

    A controlled trial of elective intervention with continuous positive airway pressure (CPAP) was performed on 24 infants with hyaline membrane disease whose arterial oxygen tension (Pao2) fell below 8kPa (60 mmHg) while they were breathing a fractional inspired oxygen concentration (F1O2) greater than 0.60. A face mask was used to apply the CPAP. The progress of the 12 infants who were treated on entry to the trial was compared with that of 12 infants who were treated later. All 12 infants in the early-intervention group and 8 infants in the late-intervention group survived. When CPAP was started, Pao2 increased and the early-treated infants breathed high concentrations of oxygen for a shorter period than the late-treated infants. The 4 infants in the early-intervention group who required mechanical ventilation needed lower mean airway pressures to achieve satisfactory gas exchange than the 7 ventilated infants in the late-intervention group. We conclude that a Pao2 less than 8 kPa while breathing an F1o2 greater than 0.60 is an adequate indication for giving CPAP in hyaline membrane disease, and that early intervention with CPAP allows infants who go on to require mechanical ventilation to be ventilated at lower pressures. PMID:326199

  14. Green tea epigallo-catechin-galleate ameliorates the development of obliterative airway disease.

    PubMed

    Liang, Olin D; Kleibrink, Bjoern E; Schuette-Nuetgen, Katharina; Khatwa, Umakanth U; Mfarrej, Bechara; Subramaniam, Meera

    2011-09-01

    Lung transplantation has the worst outcome compared to all solid organ transplants due to chronic rejection known as obliterative bronchiolitis (OB). Pathogenesis of OB is a complex interplay of alloimmune-dependent and -independent factors, which leads to the development of inflammation, fibrosis, and airway obliteration that have been resistant to therapy. The alloimmune-independent inflammatory pathway has been the recent focus in the pathogenesis of rejection, suggesting that targeting this may offer therapeutic benefits. As a potent anti-inflammatory agent, epigallo-catechin-galleate (EGCG), a green tea catechin, has been very effective in ameliorating inflammation in a variety of diseases, providing the rationale for its use in this study in a murine heterotopic tracheal allograft model of OB. Mice treated with EGCG had reduced inflammation, with significantly less neutrophil and macrophage infiltration and significantly reduced fibrosis. On further investigation into the mechanisms, inflammatory cytokines keratinocyte (KC), interleukin-17 (IL-17), and tumor necrosis factor-α (TNF-α), involved in neutrophil recruitment, were reduced in the EGCG-treated mice. In addition, monocyte chemokine monocyte chemoattractant protein-1 (MCP-1) was significantly reduced by EGCG treatment. Antifibrotic cytokine interferon-γ-inducible protein-10 (IP-10) was increased and profibrotic cytokine transforming growth factor-β (TGF-β) was reduced, further characterizing the antifibrotic effects of EGCG. These findings suggest that EGCG has great potential in ameliorating the development of obliterative airway disease.

  15. Sleep and neuromuscular disease: bilevel positive airway pressure by nasal mask as a treatment for sleep disordered breathing in patients with neuromuscular disease

    PubMed Central

    Guilleminault, C.; Philip, P.; Robinson, A.

    1998-01-01

    OBJECTIVE—Investigation of the therapeutic effects of bilevel positive airway pressure delivered by nasal mask in patients with neuromuscular disease.
METHODS—20 patients with neuromuscular disease were evaluated for symptoms of nocturnal sleep disruption. These symptoms included daytime tiredness, fatigue, sleepiness, and complaints of insomnia. The patients were studied with nocturnal polysomnograms and daytime multiple sleep latency tests (MSLT). Their immediate and long term responses to bilevel positive airway pressure were also investigated. The study took place at the Stanford University Sleep Disorders Clinic. Some of the polygraphic evaluations were performed with portable equipment in the patients' homes. The reported population comprised 20 patients, all of whom had progressive neuromuscular disease. Five of the patients were women. Four patients had muscular dystrophy, six had myotonic dystrophy, and two patients each had mitochondrial myopathy and glycogen storage disease. Two patients had post-traumatic lesions, one bulbar and the other phrenic. The remaining patients had vascular myopathy, unclassified myopathy, syringomyelia, and slow evolving spinocerebellar degeneration.
RESULTS—19 of the 20 patients accepted some form of non-invasive ventilation. All but one of these were initially maintained on bilevel positive airway pressure spontaneous (S) mode, although one patient required a switch to the timed (T) mode within a year. The mean expiratory positive airway pressure (EPAP) used was 4.5 with a range of 4 to 5 cm H2O. The mean inspiratory positive airway pressure (IPAP) was 11.5, range 9 to 14 cm H2O. Before treatment the MSLTs were ⩽ 8 minutes in 11 of the patients. The overall mean score was 8.2 (SD) 1.3 minutes. After long term treatment the mean MSLT was 12.5 (SD 2) minutes and the mean ESS score was 7 (SD 3). During the mean 3.5 years of follow up, three patients needed supplemental oxygen at a flow of 0.5 to 1.0 l/min bled into

  16. Sleep · 9: An approach to treatment of obstructive sleep apnoea/hypopnoea syndrome including upper airway surgery

    PubMed Central

    Ryan, C

    2005-01-01

    This article provides an overview of the management of the obstructive sleep apnoea/hypopnoea syndrome (OSAHS). Where possible, recommendations are based on a review of the relevant literature. With the exception of nasal continuous positive airway pressure, which is considered in greater detail elsewhere in the series, and certain oral appliances, the efficacy of many proposed treatments for OSAHS is not supported by data from randomised controlled clinical trials. To a considerable extent, treatment recommendations are based on data from uncontrolled studies, case series, consensus guidelines, practice parameters, and other less rigorous forms of evidence. PMID:15994269

  17. Morbidly obese parturient: Challenges for the anaesthesiologist, including managing the difficult airway in obstetrics. What is new?

    PubMed

    Rao, Durga Prasada; Rao, Venkateswara A

    2010-11-01

    The purpose of this article is to review the fundamental aspects of obesity, pregnancy and a combination of both. The scientific aim is to understand the physiological changes, pathological clinical presentations and application of technical skills and pharmacological knowledge on this unique clinical condition. The goal of this presentation is to define the difficult airway, highlight the main reasons for difficult or failed intubation and propose a practical approach to management Throughout the review, an important component is the necessity for team work between the anaesthesiologist and the obstetrician. Certain protocols are recommended to meet the anaesthetic challenges and finally concluding with "what is new?" in obstetric anaesthesia.

  18. European Symposium on Precision Medicine in Allergy and Airways Diseases: Report of the European Union Parliament Symposium (October 14, 2015).

    PubMed

    Muraro, A; Fokkens, W J; Pietikainen, S; Borrelli, D; Agache, I; Bousquet, J; Costigliola, V; Joos, G; Lund, V J; Poulsen, L K; Price, D; Rolland, C; Zuberbier, T; Hellings, P W

    2016-05-01

    The European Academy of Allergy and Clinical Immunology (EAACI), the European Rhinologic Society (ERS), and the European Medical Association (EMA) organized, on October 14, 2015, a symposium in the European Parliament in Brussels on Precision Medicine in Allergy and Airways Diseases, hosted by MEP David Borrelli, and with active participation of the EU Commissioner for Health and Food Safety Vytenis Andriukaitis, MEP Sirpa Pietikainen, Chair of the European Parliament Interest Group on Allergy and Asthma, the European Respiratory Society (ERS), the European Federations of Allergy and Airways Diseases Patients Associations (EFA), the Global Allergy and Asthma European Network (Ga2len), Allergic Rhinitis and Its Impact on Asthma (ARIA), and the Respiratory Effectiveness Group (REG). The socioeconomic impact of allergies and chronic airways diseases cannot be underestimated, as they represent the most frequently diagnosed chronic noncommunicable diseases in the EU; 30% of the total European population is suffering from allergies and asthma, and more than half are deprived from adequate diagnosis and treatment. Precision medicine represents a novel approach, embracing four key features: personalized care based on molecular, immunologic, and functional endotyping of the disease, with participation of the patient in the decision-making process of therapeutic actions, and considering predictive and preventive aspects of the treatment. Implementation of precision medicine into clinical practice may help to achieve the arrest of the epidemic of allergies and chronic airways diseases. Participants underscored the need for optimal patient care in Europe, supporting joint action plans for disease prevention, patient empowerment, and cost-effective treatment strategies.

  19. Occupational obstructive airway diseases in Germany: Frequency and causes in an international comparison

    SciTech Connect

    Latza, U.; Baur, X.

    2005-08-01

    Occupational inhalative exposures contribute to a significant proportion of obstructive airway diseases (OAD), namely chronic obstructive pulmonary disease (COPD) and asthma. The number of occupational OAD in the German industrial sector for the year 2003 are presented. Other analyses of surveillance data were retrieved from Medline. Most confirmed reports of OAD are cases of sensitizer induced occupational asthma (625 confirmed cases) followed by COPD in coal miners (414 cases), irritant induced occupational asthma (156 cases), and isocyanate asthma (54 cases). Main causes of occupational asthma in Germany comprise flour/flour constituents (35.9%), food/feed dust (9.0%), and isocyanates (6.5%). Flour and grain dust is a frequent cause of occupational asthma in most European countries and South Africa. Isocyanates are still a problem worldwide. Although wide differences in the estimated incidences between countries exist due to deficits in the coverage of occupational OAD, the high numbers necessitate improvement of preventive measures.

  20. Mycoplasma species in cats with lower airway disease: improved detection and species identification using a polymerase chain reaction assay.

    PubMed

    Reed, Nicki; Simpson, Kerry; Ayling, Roger; Nicholas, Robin; Gunn-Moore, Danielle

    2012-12-01

    There is some evidence that Mycoplasma species may be associated with lower airway disease in cats. Retrospective and prospective studies were carried out on a total population of 76 cats but failed to identify any cases of Mycoplasma species infection by bacterial culture alone. The overall prevalence of bacterial infection (15.8%) was also lower than that identified in previous studies. When a molecular detection technique, the PCR-DGGE, was employed the prevalence of Mycoplasma species detected was 15.4%, with M felis, M gateae and M feliminutum species identified, although the significance of these Mycoplasma species in feline lower airway disease remains in question. However, the PCR-DGGE technique allowed species identification and indicated the presence of M feliminutum, a species not previously isolated from the lower airways of cats.

  1. Wood combustion particles induce adverse effects to normal and diseased airway epithelia.

    PubMed

    Krapf, Manuel; Künzi, Lisa; Allenbach, Sandrine; Bruns, Emily A; Gavarini, Ilaria; El-Haddad, Imad; Slowik, Jay G; Prévôt, André S H; Drinovec, Luka; Močnik, Griša; Dümbgen, Lutz; Salathe, Matthias; Baumlin, Nathalie; Sioutas, Constantinos; Baltensperger, Urs; Dommen, Josef; Geiser, Marianne

    2017-02-27

    Residential wood burning is a major source of poorly characterized, deleterious particulate matter, whose composition and toxicity may vary with wood type, burning condition and photochemical age. The causative link between ambient wood particle constituents and observed adverse health effects is currently lacking. Here we investigate the relationship between chemical properties of primary and atmospherically aged wood combustion particles and acute toxicity in human airway epithelial cells. Emissions from a log wood burner were diluted and injected into a smog chamber for photochemical aging. After concentration-enrichment and removal of oxidizing gases, directly emitted and atmospherically aged particles were deposited on cell cultures at the air-liquid interface for 2 hours in an aerosol deposition chamber mimicking physiological conditions in lungs. Cell models were fully differentiated normal and diseased (cystic fibrosis and asthma) human bronchial epithelia (HBE) and the bronchial epithelial cell line BEAS-2B. Cell responses were assessed at 24 hours after aerosol exposure. Atmospherically relevant doses of wood combustion particles significantly increased cell death in all but the asthma cell model. Expression of oxidative stress markers increased in HBE from all donors. Increased cell death and inflammatory responses could not be assigned to a single chemical fraction of the particles. Exposure to primary and aged wood combustion particles caused adverse effects to airway epithelia, apparently induced by several interacting components.

  2. Alterations of the Murine Gut Microbiome with Age and Allergic Airway Disease.

    PubMed

    Vital, Marius; Harkema, Jack R; Rizzo, Mike; Tiedje, James; Brandenberger, Christina

    2015-01-01

    The gut microbiota plays an important role in the development of asthma. With advanced age the microbiome and the immune system are changing and, currently, little is known about how these two factors contribute to the development of allergic asthma in the elderly. In this study we investigated the associations between the intestinal microbiome and allergic airway disease in young and old mice that were sensitized and challenged with house dust mite (HDM). After challenge, the animals were sacrificed, blood serum was collected for cytokine analysis, and the lungs were processed for histopathology. Fecal pellets were excised from the colon and subjected to 16S rRNA analysis. The microbial community structure changed with age and allergy development, where alterations in fecal communities from young to old mice resembled those after HDM challenge. Allergic mice had induced serum levels of IL-17A and old mice developed a greater allergic airway response compared to young mice. This study demonstrates that the intestinal bacterial community structure differs with age, possibly contributing to the exaggerated pulmonary inflammatory response in old mice. Furthermore, our results show that the composition of the gut microbiota changes with pulmonary allergy, indicating bidirectional gut-lung communications.

  3. The Expression of NOX4 in Smooth Muscles of Small Airway Correlates with the Disease Severity of COPD

    PubMed Central

    2016-01-01

    Airway smooth muscle (ASM) remodeling is a hallmark in chronic obstructive pulmonary disease (COPD), and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases (NOXs) produced reactive oxygen species (ROS) play a crucial role in COPD pathogenesis. In the present study, the expression of NOX4 and its correlation with the ASM hypertrophy/hyperplasia, clinical pulmonary functions, and the expression of transforming growth factor β (TGF-β) in the ASM of COPD small airways were investigated by semiquantitative morphological and/or immunohistochemistry staining methods. The results showed that an elevated expression of NOX4 and TGF-β, along with an increased volume of ASM mass, was found in the ASM of small airways in COPD patients. The abundance of NOX4 protein in the ASM was increased with disease severity and inversely correlated with the pulmonary functions in COPD patients. In addition, the expression of NOX4 and ASM marker α-SMA was colocalized, and the increased NOX4 expression was found to accompany an upregulated expression of TGF-β in the ASM of small airways of COPD lung. These results indicate that NOX4 may be a key regulator in ASM remodeling of small airway, in part through a mechanism interacting with TGF-β signaling in the pathogenesis of COPD, which warrants further investigation. PMID:27656649

  4. Heterogeneity of bronchitis in airway diseases in tertiary care clinical practice

    PubMed Central

    D’silva, Liesel; Hassan, Nesreen; Wang, Hong-Yu; Kjarsgaard, Melanie; Efthimiadis, Ann; Hargreave, Frederick E; Nair, Parameswaran

    2011-01-01

    BACKGROUND: Sputum cell counts have identified inflammatory subtypes of bronchitis in relatively small numbers of subjects with asthma, chronic obstructive pulmonary disease (COPD) and chronic cough in research studies. The prevalence of different subtypes of bronchitis in routine clinical practice, however, has not been reported. OBJECTIVE: To examine the heterogeneity of bronchitis and its relationship to the severity of airflow obstruction. METHODS: A retrospective cross-sectional survey based on a computerized database of spontaneous or induced sputum cell counts examined in a large university tertiary respiratory outpatient clinic. RESULTS: The database contained 4232 consecutive sputum records from 2443 patients with chronic cough (39%), asthma (37%), asthma with COPD (9%), COPD (13%) and bronchiectasis (3%). Total and differential cell counts were obtained from 86% of successful sputum samples. Induced sputum provided more viable samples than spontaneous expectorate. Approximately one-third of patients with asthma and one-fifth of patients with COPD experience eosinophilic bronchitis. Asthmatic patients with moderate to severe airflow obstruction had a greater number of sputum eosinophils. There was a significantly higher number of total cell counts and percentage of neutrophils in the sputum of COPD patients with moderate and severe airflow obstruction than in those with mild airflow obstruction. CONCLUSION: There is heterogeneity in the cellularity of sputum in various airway diseases. Patients with clinically stable airway diseases may have high sputum cell counts. During exacerbations, more patients may experience neutrophilic bronchitis. Severity of airflow obstruction is associated with eosinophilic bronchitis in patients with asthma, and neutrophilic bronchitis in patients with nonasthmatic COPD. PMID:21766077

  5. Effects of concentrated ambient particles and diesel engine exhaust on allergic airway disease in Brown Norway rats.

    PubMed

    Harkema, Jack R; Wagner, James G; Kaminski, Norbert E; Morishita, Masako; Keeler, Gerald J; McDonald, Jacob D; Barrett, Edward G

    2009-11-01

    Increased concentrations of airborne fine particulate matter (PM2.5; particulate matter with an aerodynamic diameter < or = 2.5 microm) are associated with increases in emergency room visits and hospitalizations of asthmatic patients. Emissions from local stationary combustion sources (e.g., coal-burning power plants) or mobile motor vehicles (e.g., diesel-powered trucks) have been identified as potential contributors to the development or exacerbation of allergic airway disease. In the present study, a rodent model of allergic airway disease was used to study the effects of concentrated ambient particles (CAPs) or diesel engine exhaust (DEE) on the development of allergic airway disease in rats sensitized to the allergen ovalbumin (OVA). The overall objective of our project was to understand the effects of PM2.5 on the development of OVA-induced allergic airway disease. Our specific aims were to test the following hypotheses: (1) exposure to CAPs during OVA challenge enhances epithelial remodeling of the airway and inflammation in rats previously sensitized to the allergen; and (2) exposure to DEE during OVA sensitization, or during OVA challenge, exacerbates epithelial remodeling of the airway and inflammation in rats. In the DEE studies, Brown Norway (BN) rats were sensitized with three daily intranasal (IN) instillations of 0.5% OVA, and then two weeks later were challenged with IN OVA or saline for 3 consecutive days. Rats were exposed to DEE diluted to mass concentrations of 30 or 300 microg/m3 diesel exhaust particles (DEPs) or to filtered air during either the sensitization or challenge periods. For the CAPs studies, the same OVA sensitization and challenge rat model was used but exposures to Detroit, Michigan, CAPs were limited to the OVA challenge period. Two separate 3-day CAPs exposures were conducted (week 1, high mean mass concentration = 595 microg/m3; week 2, low mean mass concentration = 356 microg/m3) during OVA challenge. In both the DEE and CAPs

  6. Periostin in Exhaled Breath Condensate and in Serum of Asthmatic Patients: Relationship to Upper and Lower Airway Disease

    PubMed Central

    Wardzyńska, Aleksandra; Makowska, Joanna S.; Pawełczyk, Małgorzata; Piechota-Polańczyk, Aleksandra; Kurowski, Marcin

    2017-01-01

    Purpose Periostin is considered a biomarker for eosinophilic airway inflammation and have been associated with NSAID-Exacerbated Respiratory Disease (NERD) and chronic rhinosinusitis (CRS). In this study, we aimed to evaluate periostin in exhaled breath condensate (EBC) and in serum of patients with various asthma phenotypes. Methods The study included 40 asthmatic patients (22 with NERD) and 17 healthy controls. All the procedures (questionnaire, spirometry, FeNO, nasal swabs, EBC collecting, and blood sampling) were performed on the same day. Periostin concentrations were measured using an ELISA kit. Results Periostin was detected in EBC from 37 of 40 asthmatics and in 16 from 17 of controls. The concentration of periostin in EBC did not differ between the study groups and was not associated with NERD or asthma severity. However, the EBC periostin was significantly higher in asthmatics with CRS as compared to those without (3.1 vs 2 ng/mL, P=0.046). Patients with positive bacterial culture from nasal swabs had higher EBC periostin concentrations than those without (3.2 vs 2.1 ng/mL; P=0.046). The mean serum periostin level was higher in asthmatics with a 1-year history of exacerbation than in those without (3.2 vs 2.3 ng/mL, P=0.045). Asthmatics with skin manifestation of NSAIDs hypersensitivity had higher serum periostin levels as compared to those without (3.5 vs 2.3 ng/mL; P=0.03). Conclusions EBC periostin levels seem to reflect intensity of upper airway disease in asthmatics, while serum levels of periostin are associated with asthma activity (exacerbations or FeNO) or NERD subphenotypes. PMID:28102057

  7. A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-kappaB and hypoxia-inducible factor-1alpha.

    PubMed

    Lee, Kyung Sun; Kim, So Ri; Park, Hee Sun; Park, Seoung Ju; Min, Kyung Hoon; Lee, Ka Young; Choe, Yeong Hun; Hong, Sang Hyun; Han, Hyo Jin; Lee, Young Rae; Kim, Jong Suk; Atlas, Daphne; Lee, Yong Chul

    2007-12-31

    Reactive oxygen species (ROS) play an important role in the pathogenesis of airway inflammation and hyperresponsiveness. Recent studies have demonstrated that antioxidants are able to reduce airway inflammation and hyperreactivity in animal models of allergic airway disease. A newly developed antioxidant, small molecular weight thiol compound, N-acetylcysteine amide (AD4) has been shown to increase cellular levels of glutathione and to attenuate oxidative stress related disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. However, the effects of AD4 on allergic airway disease such as asthma are unknown. We used ovalbumin (OVA)-inhaled mice to evaluate the role of AD4 in allergic airway disease. In this study with OVA-inhaled mice, the increased ROS generation, the increased levels of Th2 cytokines and VEGF, the increased vascular permeability, the increased mucus production, and the increased airway resistance in the lungs were significantly reduced by the administration of AD4. We also found that the administration of AD4 decreased the increases of the NF-kappaB and hypoxia-inducible factor-1alpha (HIF-1alpha) levels in nuclear protein extracts of lung tissues after OVA inhalation. These results suggest that AD4 attenuates airway inflammation and hyperresponsiveness by regulating activation of NF-kappaB and HIF-1alpha as well as reducing ROS generation in allergic airway disease.

  8. Identification of genes differentially regulated by vitamin D deficiency that alter lung pathophysiology and inflammation in allergic airways disease.

    PubMed

    Foong, Rachel E; Bosco, Anthony; Troy, Niamh M; Gorman, Shelley; Hart, Prue H; Kicic, Anthony; Zosky, Graeme R

    2016-09-01

    Vitamin D deficiency is associated with asthma risk. Vitamin D deficiency may enhance the inflammatory response, and we have previously shown that airway remodeling and airway hyperresponsiveness is increased in vitamin D-deficient mice. In this study, we hypothesize that vitamin D deficiency would exacerbate house dust mite (HDM)-induced inflammation and alterations in lung structure and function. A BALB/c mouse model of vitamin D deficiency was established by dietary manipulation. Responsiveness to methacholine, airway smooth muscle (ASM) mass, mucus cell metaplasia, lung and airway inflammation, and cytokines in bronchoalveolar lavage (BAL) fluid were assessed. Gene expression patterns in mouse lung samples were profiled by RNA-Seq. HDM exposure increased inflammation and inflammatory cytokines in BAL, baseline airway resistance, tissue elastance, and ASM mass. Vitamin D deficiency enhanced the HDM-induced influx of lymphocytes into BAL, ameliorated the HDM-induced increase in ASM mass, and protected against the HDM-induced increase in baseline airway resistance. RNA-Seq identified nine genes that were differentially regulated by vitamin D deficiency in the lungs of HDM-treated mice. Immunohistochemical staining confirmed that protein expression of midline 1 (MID1) and adrenomedullin was differentially regulated such that they promoted inflammation, while hypoxia-inducible lipid droplet-associated, which is associated with ASM remodeling, was downregulated. Protein expression studies in human bronchial epithelial cells also showed that addition of vitamin D decreased MID1 expression. Differential regulation of these genes by vitamin D deficiency could determine lung inflammation and pathophysiology and suggest that the effect of vitamin D deficiency on HDM-induced allergic airways disease is complex.

  9. SUBCHRONIC ENDOTOXIN INHALATION CAUSES CHRONIC AIRWAY DISEASE IN ENDOTOXIN-SENSITIVE BUT NOT ENDOTOXIN-RESISTANT MICE

    EPA Science Inventory

    SUBCHRONIC ENDOTOXIN INHALATION CAUSES CHRONIC AIRWAY DISEASE IN ENDOTOXIN-SENSITIVE BUT NOT ENDOTOXIN-RESISTANT MICE. D. M. Brass, J. D. Savov, *S. H. Gavett, ?C. George, D. A. Schwartz. Duke Univ Medical Center Durham, NC, *U.S. E.P.A. Research Triangle Park, NC, ?Univ of Iowa,...

  10. Effects of lung disease on the three-dimensional structure and air flow pattern in the human airway tree

    NASA Astrophysics Data System (ADS)

    van de Moortele, Tristan; Nemes, Andras; Wendt, Christine; Coletti, Filippo

    2016-11-01

    The morphological features of the airway tree directly affect the air flow features during breathing, which determines the gas exchange and inhaled particle transport. Lung disease, Chronic Obstructive Pulmonary Disease (COPD) in this study, affects the structural features of the lungs, which in turn negatively affects the air flow through the airways. Here bronchial tree air volume geometries are segmented from Computed Tomography (CT) scans of healthy and diseased subjects. Geometrical analysis of the airway centerlines and corresponding cross-sectional areas provide insight into the specific effects of COPD on the airway structure. These geometries are also used to 3D print anatomically accurate, patient specific flow models. Three-component, three-dimensional velocity fields within these models are acquired using Magnetic Resonance Imaging (MRI). The three-dimensional flow fields provide insight into the change in flow patterns and features. Additionally, particle trajectories are determined using the velocity fields, to identify the fate of therapeutic and harmful inhaled aerosols. Correlation between disease-specific and patient-specific anatomical features with dysfunctional airflow patterns can be achieved by combining geometrical and flow analysis.

  11. Allergic airway disease in mice alters T and B cell responses during an acute respiratory poxvirus infection.

    PubMed

    Walline, Crystal C; Sehra, Sarita; Fisher, Amanda J; Guindon, Lynette M; Kratzke, Ian M; Montgomery, Jessica B; Lipking, Kelsey P; Glosson, Nicole L; Benson, Heather L; Sandusky, George E; Wilkes, David S; Brutkiewicz, Randy R; Kaplan, Mark H; Blum, Janice S

    2013-01-01

    Pulmonary viral infections can exacerbate or trigger the development of allergic airway diseases via multiple mechanisms depending upon the infectious agent. Respiratory vaccinia virus transmission is well established, yet the effects of allergic airway disease on the host response to intra-pulmonary vaccinia virus infection remain poorly defined. As shown here BALB/c mice with preexisting airway disease infected with vaccinia virus developed more severe pulmonary inflammation, higher lung virus titers and greater weight loss compared with mice inoculated with virus alone. This enhanced viremia was observed despite increased pulmonary recruitment of CD8(+) T effectors, greater IFNγ production in the lung, and high serum levels of anti-viral antibodies. Notably, flow cytometric analyses of lung CD8(+) T cells revealed a shift in the hierarchy of immunodominant viral epitopes in virus inoculated mice with allergic airway disease compared to mice treated with virus only. Pulmonary IL-10 production by T cells and antigen presenting cells was detected following virus inoculation of animals and increased dramatically in allergic mice exposed to virus. IL-10 modulation of host responses to this respiratory virus infection was greatly influenced by the localized pulmonary microenvironment. Thus, blocking IL-10 signaling in virus-infected mice with allergic airway disease enhanced pulmonary CD4(+) T cell production of IFNγ and increased serum anti-viral IgG1 levels. In contrast, pulmonary IFNγ and virus-specific IgG1 levels were reduced in vaccinia virus-treated mice with IL-10 receptor blockade. These observations demonstrate that pre-existing allergic lung disease alters the quality and magnitude of immune responses to respiratory poxviruses through an IL-10-dependent mechanism.

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

    PubMed

    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.

  13. Predictors of Long-Term Adherence to Continuous Positive Airway Pressure Therapy in Patients with Obstructive Sleep Apnea and Cardiovascular Disease in the SAVE Study

    PubMed Central

    Chai-Coetzer, Ching Li; Luo, Yuan-Ming; Antic, Nick A.; Zhang, Xi-Long; Chen, Bao-Yuan; He, Quan-Ying; Heeley, Emma; Huang, Shao-Guang; Anderson, Craig; Zhong, Nan-Shan; McEvoy, R. Doug

    2013-01-01

    Study Objectives: To determine the clinical variables that best predict long- term continuous positive airway pressure (CPAP) adherence among patients with cardiovascular disease who have obstructive sleep apnea (OSA). Design: 12-mo prospective within-trial observational study. Setting: Centers in China, Australia, and New Zealand participating in the Sleep Apnea cardioVascular Endpoints (SAVE) study. Patients: There were 275 patients age 45-70 y with cardiovascular disease (i.e., previously documented transient ischemic attack, stroke, or coronary artery disease) and OSA (4% oxygen desaturation index (ODI) > 12) who were randomized into the CPAP arm of the SAVE trial prior to July 1, 2010. Methods: Age, sex, country of residence, type of cardiovascular disease, baseline ODI, severity of sleepiness, and Hospital Anxiety and Depression Scale (HADS) scores plus CPAP side effects and adherence at 1 mo were entered in univariate analyses in an attempt to identify factors predictive of CPAP adherence at 12 mo. Variables with P < 0.2 were then included in a multivariate analysis using a linear mixed model with sites as a random effect and 12-mo CPAP use as the dependent outcome variable. Measurements and Results: CPAP adherence at 1, 6, and 12 mo was (mean ± standard deviation) 4.4 ± 2.0, 3.8 ± 2.3, and 3.3 ± 2.4 h/night, respectively. CPAP use at 1 mo (effect estimate ± standard error, 0.65 ± 0.07 per h increase, P < 0.001) and side effects at 1 mo (-0.24 ± 0.092 per additional side effect, P = 0.009) were the only independent predictors of 12- mo CPAP adherence. Conclusion: Continuous positive airway pressure use in patients with coexisting cardiovascular disease and moderate to severe obstructive sleep apnea decreases significantly over 12 months. This decline can be predicted by early patient experiences with continuous positive airway pressure (i.e., adherence and side effects at 1 month), raising the possibility that intensive early interventions could

  14. Spray cryotherapy (SCT): institutional evolution of techniques and clinical practice from early experience in the treatment of malignant airway disease

    PubMed Central

    Turner, J. Francis; Parrish, Scott

    2015-01-01

    Background Spray cryotherapy (SCT) was initially developed for gastroenterology (GI) endoscopic use in the esophagus. In some institutions where a device has been utilized by GI, transition to use in the airways by pulmonologists and thoracic surgeons occurred. Significant differences exist, however, in the techniques for safely using SCT in the airways. Methods We describe the early experience at Walter Reed National Military Medical Center from 2011 to 2013 using SCT in patients with malignant airway disease and the evolution of our current techniques and clinical practice patterns for SCT use in patients. In November 2013 enrollment began in a multi-institutional prospective SCT registry in which we are still enrolling and will be reported on separately. Results Twenty-seven patients that underwent 80 procedures (2.96 procedures/patient). The average age was 63 years with a range of 20 to 87 years old. The average Eastern Cooperative Oncology Group (ECOG) status was 1.26. All malignancies were advanced stage disease. All procedures were performed in the central airways. Other modalities were used in combination with SCT in 31 (39%) of procedures. Additionally 45 of the 80 (56%) procedures were performed in proximity to a silicone, hybrid, or metal stent. Three complications occurred out of the 80 procedures. All three were transient hypoxia that limited continued SCT treatments. These patients were all discharged from the bronchoscopy recovery room to their pre-surgical state. Conclusions SCT can be safely used for treatment of malignant airway tumor (MAT) in the airways. Understanding passive venting of the nitrogen gas produced as the liquid nitrogen changes to gas is important for safe use of the device. Complications can be minimized by adopting strict protocols to maximize passive venting and to allow for adequate oxygenation in between sprays. PMID:26807288

  15. Temperature effects on outpatient visits of respiratory diseases, asthma, and chronic airway obstruction in Taiwan

    NASA Astrophysics Data System (ADS)

    Wang, Yu-Chun; Lin, Yu-Kai

    2015-07-01

    This study evaluated the risk of outpatient visits for respiratory diseases, asthma, and chronic airway obstruction not elsewhere classified (CAO) associated with ambient temperatures and extreme temperature events from 2000 to 2008 in Taiwan. Based on geographical and socioeconomics characteristics, this study divided the whole island into seven areas. A distributed lag non-linear model was used to estimate the area-disease-specific cumulative relative risk (RR), and random-effect meta-analysis was used to estimate the pooled RR of outpatient visits, from lag 0 to lag 7 days, associated with daily temperature, and added effects of prolonged extreme heat and cold for population of all ages, the elderly and younger than 65 years. Pooled analyses showed that younger population had higher outpatient visits for exposing to low temperature of 18 °C, with cumulative 8-day RRs of 1.36 (95 % confidence interval (CI) 1.31-1.42) for respiratory diseases, 1.10 (95 % CI 1.03-1.18) for asthma, and 1.12 (95 % CI 1.02-1.22) for CAO. The elderly was more vulnerable to high temperature of 30 °C with the cumulative 8-day RR of 1.08 (95 % CI 1.03-1.13) for CAO. Elevated outpatient visits for all respiratory diseases and asthma were associated with extreme heat lasting for 6 to 8 days. On the contrary, the extreme cold lasting more than 8 days had significant negative association with outpatient visits of all respiratory diseases. In summary, elderly patients of respiratory diseases and CAO are vulnerable to high temperature. Cold temperature is associated with all types of respiratory diseases for younger patients.

  16. Temperature effects on outpatient visits of respiratory diseases, asthma, and chronic airway obstruction in Taiwan

    NASA Astrophysics Data System (ADS)

    Wang, Yu-Chun; Lin, Yu-Kai

    2014-09-01

    This study evaluated the risk of outpatient visits for respiratory diseases, asthma, and chronic airway obstruction not elsewhere classified (CAO) associated with ambient temperatures and extreme temperature events from 2000 to 2008 in Taiwan. Based on geographical and socioeconomics characteristics, this study divided the whole island into seven areas. A distributed lag non-linear model was used to estimate the area-disease-specific cumulative relative risk (RR), and random-effect meta-analysis was used to estimate the pooled RR of outpatient visits, from lag 0 to lag 7 days, associated with daily temperature, and added effects of prolonged extreme heat and cold for population of all ages, the elderly and younger than 65 years. Pooled analyses showed that younger population had higher outpatient visits for exposing to low temperature of 18 °C, with cumulative 8-day RRs of 1.36 (95 % confidence interval (CI) 1.31-1.42) for respiratory diseases, 1.10 (95 % CI 1.03-1.18) for asthma, and 1.12 (95 % CI 1.02-1.22) for CAO. The elderly was more vulnerable to high temperature of 30 °C with the cumulative 8-day RR of 1.08 (95 % CI 1.03-1.13) for CAO. Elevated outpatient visits for all respiratory diseases and asthma were associated with extreme heat lasting for 6 to 8 days. On the contrary, the extreme cold lasting more than 8 days had significant negative association with outpatient visits of all respiratory diseases. In summary, elderly patients of respiratory diseases and CAO are vulnerable to high temperature. Cold temperature is associated with all types of respiratory diseases for younger patients.

  17. Role of interleukin-8 (IL-8) and an inhibitory effect of erythromycin on IL-8 release in the airways of patients with chronic airway diseases.

    PubMed Central

    Oishi, K; Sonoda, F; Kobayashi, S; Iwagaki, A; Nagatake, T; Matsushima, K; Matsumoto, K

    1994-01-01

    To evaluate of the role of interleukin-8 (IL-8), a chemotactic cytokine, in the continuous neutrophil accumulation in the airways of patients with chronic airway disease (CAD) and persistent Pseudomonas aeruginosa infection, we investigated the cell population, IL-8 levels, IL-1 beta levels, tumor necrosis factor (TNF) activities, and neutrophil elastase (NE) activities of bronchoalveolar lavage (BAL) fluids in 17 CAD patients (with P. aeruginosa infections [CAD+PA], n = 9; without any bacterial infections [CAD-PA], n = 8) and 8 normal volunteers. We found significant elevations of neutrophil numbers, IL-8/albumin ratios, and NE/albumin ratios in BAL fluids from CAD patients, in the following rank order: CAD+PA > CAD-PA > normal volunteers. IL-1 beta/albumin ratios were elevated only in CAD+PA, while no TNF bioactivity was detected in BAL fluids. The neutrophil numbers correlated significantly with the IL-8/albumin ratios and NE/albumin ratios in the BAL fluids of CAD patients. When anti-human IL-8 immunoglobulin G was used for neutralizing neutrophil chemotactic factor (NCF) activities in BAL fluids, the mean reduction rate of NCF activities in CAD+PA patients was significantly higher than that in CAD-PA patients. We also evaluated the effects of low-dose, long-term erythromycin therapy in BAL fluids from three CAD+PA and two CAD-PA patients. Treatment with erythromycin caused significant reductions of neutrophil numbers, IL-8/albumin ratios, and NE/albumin ratios in BAL fluids from these patients. To elucidate the mechanism of erythromycin therapy, we also examined whether erythromycin suppressed IL-8 production by human alveolar macrophages and neutrophils in vitro. We demonstrated a moderate inhibitory effect of erythromycin on IL-8 production in Pseudomonas-stimulated neutrophils but not in alveolar macrophages. Our data support the view that persistent P. aeruginosa infection enhances IL-8 production and IL-8-derived NCF activity, causing neutrophil

  18. Airway smooth muscle in airway reactivity and remodeling: what have we learned?

    PubMed Central

    2013-01-01

    It is now established that airway smooth muscle (ASM) has roles in determining airway structure and function, well beyond that as the major contractile element. Indeed, changes in ASM function are central to the manifestation of allergic, inflammatory, and fibrotic airway diseases in both children and adults, as well as to airway responses to local and environmental exposures. Emerging evidence points to novel signaling mechanisms within ASM cells of different species that serve to control diverse features, including 1) [Ca2+]i contractility and relaxation, 2) cell proliferation and apoptosis, 3) production and modulation of extracellular components, and 4) release of pro- vs. anti-inflammatory mediators and factors that regulate immunity as well as the function of other airway cell types, such as epithelium, fibroblasts, and nerves. These diverse effects of ASM “activity” result in modulation of bronchoconstriction vs. bronchodilation relevant to airway hyperresponsiveness, airway thickening, and fibrosis that influence compliance. This perspective highlights recent discoveries that reveal the central role of ASM in this regard and helps set the stage for future research toward understanding the pathways regulating ASM and, in turn, the influence of ASM on airway structure and function. Such exploration is key to development of novel therapeutic strategies that influence the pathophysiology of diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. PMID:24142517

  19. Is airway inflammation in chronic obstructive pulmonary disease (COPD) a risk factor for cardiovascular events?

    PubMed

    Calverley, Peter M A; Scott, Stephen

    2006-12-01

    Cardiovascular disease (CVD) is a very common cause of death in patients with chronic obstructive pulmonary disease (COPD). Smoking is a well-described risk factor for both COPD and CVD, but CVD in patients with COPD is likely to be due to other factors in addition to smoking. Inflammation may be an important common etiological link between COPD and CVD, being well described in both diseases. It is hypothesized that in COPD a "spill-over" of local airway inflammation into the systemic circulation could contribute to increased CVD in these patients. Inhaled corticosteroids (ICS) have well-documented anti-inflammatory effects and are commonly used for the treatment of COPD, but their effects on cardiovascular endpoints and all-cause mortality have only just started to be examined. A recent meta-analysis has suggested that ICS may reduce all-cause mortality in COPD by around 25%. A case-controlled study specifically examined the effects of ICS on myocardial infarction and suggested that ICS may decrease the incidence of MI by as much as 32%. A large multicenter prospective randomized trial (Towards a Revolution in COPD Health [TORCH]) is now ongoing and will examine the effect of fluticasone propionate in combination with salmeterol on all-cause mortality.

  20. Airway segmentation and analysis for the study of mouse models of lung disease using micro-CT

    NASA Astrophysics Data System (ADS)

    Artaechevarria, X.; Pérez-Martín, D.; Ceresa, M.; de Biurrun, G.; Blanco, D.; Montuenga, L. M.; van Ginneken, B.; Ortiz-de-Solorzano, C.; Muñoz-Barrutia, A.

    2009-11-01

    Animal models of lung disease are gaining importance in understanding the underlying mechanisms of diseases such as emphysema and lung cancer. Micro-CT allows in vivo imaging of these models, thus permitting the study of the progression of the disease or the effect of therapeutic drugs in longitudinal studies. Automated analysis of micro-CT images can be helpful to understand the physiology of diseased lungs, especially when combined with measurements of respiratory system input impedance. In this work, we present a fast and robust murine airway segmentation and reconstruction algorithm. The algorithm is based on a propagating fast marching wavefront that, as it grows, divides the tree into segments. We devised a number of specific rules to guarantee that the front propagates only inside the airways and to avoid leaking into the parenchyma. The algorithm was tested on normal mice, a mouse model of chronic inflammation and a mouse model of emphysema. A comparison with manual segmentations of two independent observers shows that the specificity and sensitivity values of our method are comparable to the inter-observer variability, and radius measurements of the mainstem bronchi reveal significant differences between healthy and diseased mice. Combining measurements of the automatically segmented airways with the parameters of the constant phase model provides extra information on how disease affects lung function.

  1. INHIBITION OF PAN NEUROTROPHIN RECEPTOR P75 ATTENUATES DIESEL PARTICULATE-INDUCED ENHANCEMENT OF ALLERGIC AIRWAY RESPONSES IN C57/BL6J MICE

    EPA Science Inventory

    Recent investigations have linked neurotrophins including nerve growth factor (NGF), neurotrophin-3 (NT-3), and brain-derived neurotrophic factor (BDNF) to allergic airways diseases. Antibody blockade of NGF attenuates airway resistance in allergic mice. Diesel exhaust particle...

  2. DNA methylation is globally disrupted and associated with expression changes in chronic obstructive pulmonary disease small airways.

    PubMed

    Vucic, Emily A; Chari, Raj; Thu, Kelsie L; Wilson, Ian M; Cotton, Allison M; Kennett, Jennifer Y; Zhang, May; Lonergan, Kim M; Steiling, Katrina; Brown, Carolyn J; McWilliams, Annette; Ohtani, Keishi; Lenburg, Marc E; Sin, Don D; Spira, Avrum; Macaulay, Calum E; Lam, Stephen; Lam, Wan L

    2014-05-01

    DNA methylation is an epigenetic modification that is highly disrupted in response to cigarette smoke and involved in a wide spectrum of malignant and nonmalignant diseases, but surprisingly not previously assessed in small airways of patients with chronic obstructive pulmonary disease (COPD). Small airways are the primary sites of airflow obstruction in COPD. We sought to determine whether DNA methylation patterns are disrupted in small airway epithelia of patients with COPD, and evaluate whether changes in gene expression are associated with these disruptions. Genome-wide methylation and gene expression analysis were performed on small airway epithelial DNA and RNA obtained from the same patient during bronchoscopy, using Illumina's Infinium HM27 and Affymetrix's Genechip Human Gene 1.0 ST arrays. To control for known effects of cigarette smoking on DNA methylation, methylation and gene expression profiles were compared between former smokers with and without COPD matched for age, pack-years, and years of smoking cessation. Our results indicate that aberrant DNA methylation is (1) a genome-wide phenomenon in small airways of patients with COPD, and (2) associated with altered expression of genes and pathways important to COPD, such as the NF-E2-related factor 2 oxidative response pathway. DNA methylation is likely an important mechanism contributing to modulation of genes important to COPD pathology. Because these methylation events may underlie disease-specific gene expression changes, their characterization is a critical first step toward the development of epigenetic markers and an opportunity for developing novel epigenetic therapeutic interventions for COPD.

  3. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis.

    PubMed

    Trompette, Aurélien; Gollwitzer, Eva S; Yadava, Koshika; Sichelstiel, Anke K; Sprenger, Norbert; Ngom-Bru, Catherine; Blanchard, Carine; Junt, Tobias; Nicod, Laurent P; Harris, Nicola L; Marsland, Benjamin J

    2014-02-01

    Metabolites from intestinal microbiota are key determinants of host-microbe mutualism and, consequently, the health or disease of the intestinal tract. However, whether such host-microbe crosstalk influences inflammation in peripheral tissues, such as the lung, is poorly understood. We found that dietary fermentable fiber content changed the composition of the gut and lung microbiota, in particular by altering the ratio of Firmicutes to Bacteroidetes. The gut microbiota metabolized the fiber, consequently increasing the concentration of circulating short-chain fatty acids (SCFAs). Mice fed a high-fiber diet had increased circulating levels of SCFAs and were protected against allergic inflammation in the lung, whereas a low-fiber diet decreased levels of SCFAs and increased allergic airway disease. Treatment of mice with the SCFA propionate led to alterations in bone marrow hematopoiesis that were characterized by enhanced generation of macrophage and dendritic cell (DC) precursors and subsequent seeding of the lungs by DCs with high phagocytic capacity but an impaired ability to promote T helper type 2 (TH2) cell effector function. The effects of propionate on allergic inflammation were dependent on G protein-coupled receptor 41 (GPR41, also called free fatty acid receptor 3 or FFAR3), but not GPR43 (also called free fatty acid receptor 2 or FFAR2). Our results show that dietary fermentable fiber and SCFAs can shape the immunological environment in the lung and influence the severity of allergic inflammation.

  4. Dual PDE3/4 and PDE4 inhibitors: novel treatments for COPD and other inflammatory airway diseases.

    PubMed

    Abbott-Banner, Katharine H; Page, Clive P

    2014-05-01

    Selective phosphodiesterase (PDE) 4 and dual PDE3/4 inhibitors have attracted considerable interest as potential therapeutic agents for the treatment of respiratory diseases, largely by virtue of their anti-inflammatory (PDE4) and bifunctional bronchodilator/anti-inflammatory (PDE3/4) effects. Many of these agents have, however, failed in early development for various reasons, including dose-limiting side effects when administered orally and lack of sufficient activity when inhaled. Indeed, only one selective PDE4 inhibitor, the orally active roflumilast-n-oxide, has to date received marketing authorization. The majority of the compounds that have failed were, however, orally administered and non-selective for either PDE3 (A,B) or PDE4 (A,B,C,D) subtypes. Developing an inhaled dual PDE3/4 inhibitor that is rapidly cleared from the systemic circulation, potentially with subtype specificity, may represent one strategy to improve the therapeutic index and also exhibit enhanced efficacy versus inhibition of either PDE3 or PDE4 alone, given the potential positive interactions with regard to anti-inflammatory and bronchodilator effects that have been observed pre-clinically with dual inhibition of PDE3 and PDE4 compared with inhibition of either isozyme alone. This MiniReview will summarize recent clinical data obtained with PDE inhibitors and the potential for these drugs to treat COPD and other inflammatory airways diseases such as asthma and cystic fibrosis.

  5. Effects of bile acids on human airway epithelial cells: implications for aerodigestive diseases

    PubMed Central

    Aldhahrani, Adil; Verdon, Bernard; Pearson, Jeffery

    2017-01-01

    Gastro-oesophageal reflux and aspiration have been associated with chronic and end-stage lung disease and with allograft injury following lung transplantation. This raises the possibility that bile acids may cause lung injury by damaging airway epithelium. The aim of this study was to investigate the effect of bile acid challenge using the immortalised human bronchial epithelial cell line (BEAS-2B). The immortalised human bronchial epithelial cell line (BEAS-2B) was cultured. A 48-h challenge evaluated the effect of individual primary and secondary bile acids. Post-challenge concentrations of interleukin (IL)-8, IL-6 and granulocyte−macrophage colony-stimulating factor were measured using commercial ELISA kits. The viability of the BEAS-2B cells was measured using CellTiter-Blue and MTT assays. Lithocholic acid, deoxycholic acid, chenodeoxycholic acid and cholic acid were successfully used to stimulate cultured BEAS-2B cells at different concentrations. A concentration of lithocholic acid above 10 μmol·L−1 causes cell death, whereas deoxycholic acid, chenodeoxycholic acid and cholic acid above 30 μmol·L−1 was required for cell death. Challenge with bile acids at physiological levels also led to a significant increase in the release of IL-8 and IL6 from BEAS-2B. Aspiration of bile acids could potentially cause cell damage, cell death and inflammation in vivo. This is relevant to an integrated gastrointestinal and lung physiological paradigm of chronic lung disease, where reflux and aspiration are described in both chronic lung diseases and allograft injury. PMID:28344983

  6. Upcoming treatments in Parkinson's disease, including gene therapy.

    PubMed

    Rodnitzky, Robert L

    2012-01-01

    Progress is being made in the development of three categories of therapy for Parkinson's disease: (1) Symptomatic, (2) Neuroprotective, (3) Neurorestorative. Evolving approaches to symptomatic therapy, already in clinical trials, include the use of adenosine 2(A) antagonists, novel glutamate antagonists, and serotonin receptor antagonists, the latter for the therapy of Parkinson's psychosis and/or levodopa-induced dyskinesias. Examples of promising neuroprotective therapies under evaluation include the administration of creatine, urate-inducing compounds, calcium channel blockers, and pioglitazone, a peroxisome proliferator-activated receptor agonist. Cell-based restorative therapies are not the subject of this presentation, but various forms of gene therapy have shown promise in human Parkinson's disease trials. These protocols typically involve gene transfer into the CNS through the use of viral vectors. Currently, the most advanced studies of this technique involve delivery of an adeno-associated viral vector encoding glutamic acid decarboxylase into the subthalamic nucleus. This treatment has shown modest benefit in early clinical trials. Other gene therapies, in various stages of human clinical trials, include gene transfer for the production of trophic factors, for aromatic amino acid decarboxylase alone, and most recently, a lentiviral vector transfer of an enzymatic dopamine "factory" consisting of three essential enzymes required for production for this neurotransmitter.

  7. Intrathoracic airway measurement: ex-vivo validation

    NASA Astrophysics Data System (ADS)

    Reinhardt, Joseph M.; Raab, Stephen A.; D'Souza, Neil D.; Hoffman, Eric A.

    1997-05-01

    High-resolution x-ray CT (HRCT) provides detailed images of the lungs and bronchial tree. HRCT-based imaging and quantitation of peripheral bronchial airway geometry provides a valuable tool for assessing regional airway physiology. Such measurements have been sued to address physiological questions related to the mechanics of airway collapse in sleep apnea, the measurement of airway response to broncho-constriction agents, and to evaluate and track the progression of disease affecting the airways, such as asthma and cystic fibrosis. Significant attention has been paid to the measurements of extra- and intra-thoracic airways in 2D sections from volumetric x-ray CT. A variety of manual and semi-automatic techniques have been proposed for airway geometry measurement, including the use of standardized display window and level settings for caliper measurements, methods based on manual or semi-automatic border tracing, and more objective, quantitative approaches such as the use of the 'half-max' criteria. A recently proposed measurements technique uses a model-based deconvolution to estimate the location of the inner and outer airway walls. Validation using a plexiglass phantom indicates that the model-based method is more accurate than the half-max approach for thin-walled structures. In vivo validation of these airway measurement techniques is difficult because of the problems in identifying a reliable measurement 'gold standard.' In this paper we report on ex vivo validation of the half-max and model-based methods using an excised pig lung. The lung is sliced into thin sections of tissue and scanned using an electron beam CT scanner. Airways of interest are measured from the CT images, and also measured with using a microscope and micrometer to obtain a measurement gold standard. The result show no significant difference between the model-based measurements and the gold standard; while the half-max estimates exhibited a measurement bias and were significantly

  8. Airway Microbiota and the Implications of Dysbiosis in Asthma.

    PubMed

    Durack, Juliana; Boushey, Homer A; Lynch, Susan V

    2016-07-01

    The mucosal surfaces of the human body are typically colonized by polymicrobial communities seeded in infancy and are continuously shaped by environmental exposures. These communities interact with the mucosal immune system to maintain homeostasis in health, but perturbations in their composition and function are associated with lower airway diseases, including asthma, a developmental and heterogeneous chronic disease with various degrees and types of airway inflammation. This review will summarize recent studies examining airway microbiota dysbioses associated with asthma and their relationship with the pathophysiology of this disease.

  9. Mechanical Properties of the Upper Airway

    PubMed Central

    Strohl, Kingman P.; Butler, James P.; Malhotra, Atul

    2013-01-01

    The importance of the upper airway (nose, pharynx, and larynx) in health and in the pathogenesis of sleep apnea, asthma, and other airway diseases, discussed elsewhere in the Comprehensive Physiology series, prompts this review of the biomechanical properties and functional aspects of the upper airway. There is a literature based on anatomic or structural descriptions in static circumstances, albeit studied in limited numbers of individuals in both health and disease. As for dynamic features, the literature is limited to studies of pressure and flow through all or parts of the upper airway and to the effects of muscle activation on such features; however, the links between structure and function through airway size, shape, and compliance remain a topic that is completely open for investigation, particularly through analyses using concepts of fluid and structural mechanics. Throughout are included both historically seminal references, as well as those serving as signposts or updated reviews. This article should be considered a resource for concepts needed for the application of biomechanical models of upper airway physiology, applicable to understanding the pathophysiology of disease and anticipated results of treatment interventions. PMID:23723026

  10. Advances in pleural disease management including updated procedural coding.

    PubMed

    Haas, Andrew R; Sterman, Daniel H

    2014-08-01

    Over 1.5 million pleural effusions occur in the United States every year as a consequence of a variety of inflammatory, infectious, and malignant conditions. Although rarely fatal in isolation, pleural effusions are often a marker of a serious underlying medical condition and contribute to significant patient morbidity, quality-of-life reduction, and mortality. Pleural effusion management centers on pleural fluid drainage to relieve symptoms and to investigate pleural fluid accumulation etiology. Many recent studies have demonstrated important advances in pleural disease management approaches for a variety of pleural fluid etiologies, including malignant pleural effusion, complicated parapneumonic effusion and empyema, and chest tube size. The last decade has seen greater implementation of real-time imaging assistance for pleural effusion management and increasing use of smaller bore percutaneous chest tubes. This article will briefly review recent pleural effusion management literature and update the latest changes in common procedural terminology billing codes as reflected in the changing landscape of imaging use and percutaneous approaches to pleural disease management.

  11. CT based computerized identification and analysis of human airways: A review

    SciTech Connect

    Pu Jiantao; Gu Suicheng; Liu Shusen; Zhu Shaocheng; Wilson, David; Siegfried, Jill M.; Gur, David

    2012-05-15

    As one of the most prevalent chronic disorders, airway disease is a major cause of morbidity and mortality worldwide. In order to understand its underlying mechanisms and to enable assessment of therapeutic efficacy of a variety of possible interventions, noninvasive investigation of the airways in a large number of subjects is of great research interest. Due to its high resolution in temporal and spatial domains, computed tomography (CT) has been widely used in clinical practices for studying the normal and abnormal manifestations of lung diseases, albeit there is a need to clearly demonstrate the benefits in light of the cost and radiation dose associated with CT examinations performed for the purpose of airway analysis. Whereas a single CT examination consists of a large number of images, manually identifying airway morphological characteristics and computing features to enable thorough investigations of airway and other lung diseases is very time-consuming and susceptible to errors. Hence, automated and semiautomated computerized analysis of human airways is becoming an important research area in medical imaging. A number of computerized techniques have been developed to date for the analysis of lung airways. In this review, we present a summary of the primary methods developed for computerized analysis of human airways, including airway segmentation, airway labeling, and airway morphometry, as well as a number of computer-aided clinical applications, such as virtual bronchoscopy. Both successes and underlying limitations of these approaches are discussed, while highlighting areas that may require additional work.

  12. CT based computerized identification and analysis of human airways: a review.

    PubMed

    Pu, Jiantao; Gu, Suicheng; Liu, Shusen; Zhu, Shaocheng; Wilson, David; Siegfried, Jill M; Gur, David

    2012-05-01

    As one of the most prevalent chronic disorders, airway disease is a major cause of morbidity and mortality worldwide. In order to understand its underlying mechanisms and to enable assessment of therapeutic efficacy of a variety of possible interventions, noninvasive investigation of the airways in a large number of subjects is of great research interest. Due to its high resolution in temporal and spatial domains, computed tomography (CT) has been widely used in clinical practices for studying the normal and abnormal manifestations of lung diseases, albeit there is a need to clearly demonstrate the benefits in light of the cost and radiation dose associated with CT examinations performed for the purpose of airway analysis. Whereas a single CT examination consists of a large number of images, manually identifying airway morphological characteristics and computing features to enable thorough investigations of airway and other lung diseases is very time-consuming and susceptible to errors. Hence, automated and semiautomated computerized analysis of human airways is becoming an important research area in medical imaging. A number of computerized techniques have been developed to date for the analysis of lung airways. In this review, we present a summary of the primary methods developed for computerized analysis of human airways, including airway segmentation, airway labeling, and airway morphometry, as well as a number of computer-aided clinical applications, such as virtual bronchoscopy. Both successes and underlying limitations of these approaches are discussed, while highlighting areas that may require additional work.

  13. Computed tomography of pulmonary changes in rheumatoid arthritis: carcinoembryonic antigen (CEA) as a marker of airway disease.

    PubMed

    Koch, Milene Caroline; Pereira, Ivânio Alves; Nobre, Luiz Felipe Souza; Neves, Fabricio Souza

    2016-04-01

    Rheumatoid arthritis (RA) classically affects the joints, but can present extra-articular manifestations, including pulmonary disease. The present study aimed to identify possible risk factors or laboratory markers for lung involvement in RA, particularly the presence of rheumatoid factor (RF), anti-citrullinated peptide antibodies (ACPA), and tumor markers, by correlating them with changes observed on chest high-resolution computerized tomography (HRCT). This cross-sectional study involved RA patients who were examined and questioned by a specialist physician and later subjected to chest HRCT and blood collection for measurement of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), ACPA (anti-vimentin and/or anti-CCP3), and the tumor markers carcinoembryonic antigen (CEA), CA 125, CA 15-3, and CA 19-9. A total of 96 patients underwent chest HRCT. The most frequent findings were bronchial thickening (27/28.1 %) and bronchiectasis (25/26 %). RF was present in 63.2 % of patients (55/87), and ACPA (anti-vimentin or anti-CCP3) was present in 72.7 % of patients (64/88). CEA levels were high in 14 non-smokers (37.8 %) and 23 smokers (62.2 %). CA-19-9 levels were high in 6 of 86 patients (7.0 %), CA 15-3 levels were high in 3 of 85 patients (3.5 %), and CA 125 levels were high in 4 of 75 patients (5.3 %). Multivariate analysis indicated a statistically significant association between high CEA levels and the presence of airway changes in patients with RA (p = 0.048). CEA can serve as a predictor of lung disease in RA and can help identify individuals who require more detailed examination for the presence of respiratory disorders.

  14. Maintaining Control of Chronic Obstructive Airway Disease: Adherence to Inhaled Therapy and Risks and Benefits of Switching Devices.

    PubMed

    Melani, Andrea S; Paleari, Davide

    2016-01-01

    Asthma and chronic obstructive pulmonary disease (COPD) are major obstructive airway diseases that involve underlying airway inflammation. The most widely used pharmacotherapies for asthma and COPD are inhaled agents that have been shown to be effective and safe in these patients. However, despite the availability of effective pharmacologic treatment and comprehensive treatment guidelines, the prevalence of inadequately controlled asthma and COPD is high. A main reason for this is poor adherence. Adherence is a big problem for all chronic diseases, but in asthma and COPD patients there are some additional difficulties because of poor inhalation technique and inhaler choice. Easier-to-use devices and educational strategies on proper inhaler use from health caregivers can improve inhaler technique. The type of device used and the concordance between patient and physician in the choice of inhaler can also improve adherence and are as important as the drug. Adherence to inhaled therapy is absolutely necessary for optimizing patient control. If disease control is not adequate despite good adherence, switching to a more appropriate inhaled therapy is recommended. By contrast, uninformed switching or switching to less user-friendly inhaler may impact disease control negatively. This critical review of the available literature is aimed to provide a guidance protocol on when a switch may be recommended in individual patients.

  15. GPCRs and arrestins in airways: implications for asthma

    PubMed Central

    Penn, Raymond B.; Bond, Richard A.; Walker, Julia K. L.

    2015-01-01

    The obstructive lung disease asthma is treated by drugs that target, either directly or indirectly, G protein-coupled receptors (GPCRs). GPCRs coupled to Gq are the primary mediators of airway smooth muscle (ASM) contraction and increased airway resistance, whereas the Gs-coupled beta-2-adrenoceptor (β2AR) promotes pro-relaxant signaling in and relaxation of ASM resulting in greater airway patency and reversal of life-threatening bronchoconstriction. In additions, GPCR-mediated functions in other cell types, including airway epithelium and hematopoietic cells, are involved in control of lung inflammation that causes most asthma. The capacity of arrestins to regulate GPCR signaling, via either control of GPCR desensitization/resensitization, or via G protein-independent signaling, renders arrestins an intriguing therapeutic target for asthma and other obstructive lung diseases. This review will focus on the potential role of arrestins in those GPCR-mediated airway cell functions that are dysregulated in asthma. PMID:24292841

  16. Allogeneic transplantation strategies including haploidentical transplantation in sickle cell disease.

    PubMed

    Gluckman, Eliane

    2013-01-01

    Sickle cell disease (SCD) is the most common inherited hemoglobinopathy. Despite antenatal counseling and neonatal screening programs implemented in higher income countries, SCD is still associated with multiple morbidities and early mortality. To date, the only curative approach to SCD is hematopoietic stem cell transplantation, but this therapy is not yet established worldwide. The registries of the European Blood and Marrow Transplant (EBMT) and the Centre for International Blood and Marrow Transplant Research (CIBMTR) account, respectively, for 611 and 627 patients receiving transplantations for SCD. Most of these patients were transplanted with grafts from an HLA-identical sibling donor. The main obstacles to increasing the number of transplantations are a lack of awareness on the part of physicians and families, the absence of reliable prognostic factors for severity, and the perceived risk that transplantation complications may outweigh the benefits of early transplantation. Results show that more than 90% of patients having undergone an HLA-identical sibling transplantation after myeloablative conditioning are cured, with very limited complications. Major improvement is expected from the use of new reduced-toxicity conditioning regimens and the use of alternative donors, including unrelated cord blood transplantations and related haploidentical bone marrow or peripheral blood stem cell transplantations.

  17. Epithelial mesenchymal transition (EMT) and non-small cell lung cancer (NSCLC): a mutual association with airway disease.

    PubMed

    Mahmood, Malik Quasir; Ward, Chris; Muller, Hans Konrad; Sohal, Sukhwinder Singh; Walters, Eugene Haydn

    2017-03-01

    NSCLC is a leading cause of morbidity and mortality worldwide. It includes adeno- and squamous cell carcinoma. In the background, COPD and smoking play a vital role in development of NSCLC. Local progression and metastasis of NSCLC has been associated with various mechanisms, but in particular by a process called epithelial mesenchymal transition (EMT), which is implicated in COPD pathogenesis. In this study, we have investigated whether expression of EGFR (activation marker) and S100A4, vimentin and N-cadherin (as EMT) is different both in central and leading edge of NSCLC and to what extent related to EMT activity of both small and large airways, stage and differentiation of NSCLC. We have investigated EMT biomarkers (S100A4, vimentin, and N-cadherin), an epithelial activation marker (EGFR) and a vascularity marker (Type-IV collagen) in surgically resected tissue from patients with NSCLC (adeno- and squamous cell carcinoma), and compared them with expression in the corresponding non-tumorous airways. EGFR, S100A4, vimentin, N-cadherin expression was higher in tumor cells located at the peripheral leading edge of NSCLC when compared with centrally located tumor cells of same subjects (P < 0.01). Type-IV collagen-expressing blood vessels were also more at the leading edge in comparison with central parts of NSCLC. EGFR and S100A4 expression was related to differentiation status (P < 0.05) and TNM stage (P < 0.05) of NSCLC. Moreover, EMT markers in the leading edge were significantly related to airway EMT activity, while peripheral edge vascularity of squamous cell carcinoma only was significantly related to large airway Rbm vascularity (P < 0.05). EGFR- and EMT-related protein expression was markedly high in the peripheral leading edge of NSCLCs and related to tumor characteristics associated with poor prognosis. The relationships between EMT-related tumor biomarker expression and those in the airway epithelium and Rbm provide a background for utility of

  18. Citrus diseases with global ramifications including citrus canker and huanglongbing

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Although there are a number of diseases that plague citrus production worldwide, two bacterial diseases are particularly problematic. Both are of Asian origin and currently cause severe economic damage: Asiatic citrus canker (ACC) and citrus huanglongbing (HLB). Although ACC has been found in the ...

  19. Role of Autonomic Nervous System and the Cough Reflex in the Increased Responsiveness of Airways in Patients with Obstructive Airway Disease*

    PubMed Central

    Simonsson, B. G.; Jacobs, F. M.; Nadel, J. A.

    1967-01-01

    Inhalation of aerosols of citric acid, histamine phosphate, or carbon dust, or air cooled to - 20°C or rapid respiratory maneuvers (inspiration or expiration) results in an increase in airway resistance in some patients with asthma or bronchitis. It has been shown previously in animals that stimulation of cough receptors results in bronchoconstriction through efferent cholinergic pathways. In the patients studied, the administration of atropine sulfate, which would block such pathways, abolished the bronchoconstrictor effects of all the stimuli except large doses of histamine, which may exert a direct effect on airway smooth muscle. These data suggest that sensitized cough receptors may be involved in triggering reflex airway constriction in such patients. PMID:6070326

  20. Contribution of SRF, Elk-1, and myocardin to airway smooth muscle remodeling in heaves, an asthma-like disease of horses.

    PubMed

    Chevigny, Mylène; Guérin-Montpetit, Karine; Vargas, Amandine; Lefebvre-Lavoie, Josiane; Lavoie, Jean-Pierre

    2015-07-01

    Myocyte hyperplasia and hypertrophy contribute to the increased mass of airway smooth muscle (ASM) in asthma. Serum-response factor (SRF) is a transcription factor that regulates myocyte differentiation in vitro in vascular and intestinal smooth muscles. When SRF is associated with phosphorylated (p)Elk-1, it promotes ASM proliferation while binding to myocardin (MYOCD) leading to the expression of contractile elements in these tissues. The objective of this study was therefore to characterize the expression of SRF, pElk-1, and MYOCD in ASM cells from central and peripheral airways in heaves, a spontaneously occurring asthma-like disease of horses, and in controls. Six horses with heaves and five aged-matched controls kept in the same environment were studied. Nuclear protein expression of SRF, pElk-1, and MYOCD was evaluated in peripheral airways and endobronchial biopsies obtained during disease remission and after 1 and 30 days of naturally occurring antigenic exposure using immunohistochemistry and immunofluorescence techniques. Nuclear expression of SRF (P = 0.03, remission vs. 30 days) and MYOCD (P = 0.05, controls vs. heaves at 30 days) increased in the peripheral airways of horses with heaves during disease exacerbation, while MYOCD (P = 0.04, remission vs. 30 days) decreased in the central airways of control horses. No changes were observed in the expression of pElk-1 protein in either tissue. In conclusion, SRF and its cofactor MYOCD likely contribute to the hypertrophy of peripheral ASM observed in equine asthmatic airways, while the remodeling of the central airways is more static or involves different transcription factors.

  1. Macrophage adaptation in airway inflammatory resolution.

    PubMed

    Kaur, Manminder; Bell, Thomas; Salek-Ardakani, Samira; Hussell, Tracy

    2015-09-01

    Bacterial and viral infections (exacerbations) are particularly problematic in those with underlying respiratory disease, including post-viral infection, asthma, chronic obstructive pulmonary disease and pulmonary fibrosis. Patients experiencing exacerbations tend to be at the more severe end of the disease spectrum and are often difficult to treat. Most of the unmet medical need remains in this patient group. Airway macrophages are one of the first cell populations to encounter airborne pathogens and, in health, exist in a state of reduced responsiveness due to interactions with the respiratory epithelium and specific factors found in the airway lumen. Granulocyte-macrophage colony-stimulating factor, interleukin-10, transforming growth factor-β, surfactant proteins and signalling via the CD200 receptor, for example, all raise the threshold above which airway macrophages can be activated. We highlight that following severe respiratory inflammation, the airspace microenvironment does not automatically re-set to baseline and may leave airway macrophages more restrained than they were at the outset. This excessive restraint is mediated in part by the clearance of apoptotic cells and components of extracellular matrix. This implies that one strategy to combat respiratory exacerbations would be to retune airway macrophage responsiveness to allow earlier bacterial recognition.

  2. Oxidative stress–induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease

    PubMed Central

    Wiegman, Coen H.; Michaeloudes, Charalambos; Haji, Gulammehdi; Narang, Priyanka; Clarke, Colin J.; Russell, Kirsty E.; Bao, Wuping; Pavlidis, Stelios; Barnes, Peter J.; Kanerva, Justin; Bittner, Anton; Rao, Navin; Murphy, Michael P.; Kirkham, Paul A.; Chung, Kian Fan; Adcock, Ian M.; Brightling, Christopher E.; Davies, Donna E.; Finch, Donna K.; Fisher, Andrew J.; Gaw, Alasdair; Knox, Alan J.; Mayer, Ruth J.; Polkey, Michael; Salmon, Michael; Singh, David

    2015-01-01

    Background Inflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD). Mitochondrial oxidative stress might be involved in driving the oxidative stress–induced pathology. Objective We sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells. Methods Mice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined. Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD. Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ. Results Mice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression. Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR. ASM cells from patients with COPD have reduced ΔΨm, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased. Healthy smokers were intermediate between healthy nonsmokers and patients with COPD. Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects. MitoQ and Tiron inhibited TGF-β–induced ASM cell proliferation and CXCL8 release. Conclusions Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell

  3. Ultrasound in obstructive lung diseases: the effect of airway obstruction on diaphragm kinetics. A short pictorial essay.

    PubMed

    Zanforlin, Alessandro; Smargiassi, Andrea; Inchingolo, Riccardo; Valente, Salvatore; Ramazzina, Emilio

    2015-12-01

    The ultrasound study of the chest is showing a continuous development. This technique could be helpful in managing several chest diseases, but it is limited to the acoustic windows provided by intercostal spaces and by the inability to study healthy lung parenchyma and all intra-parenchymal diseases such as chronic obstructive lung disease (COPD), because the interaction between ventilated lung and ultrasound generates only artifacts. Currently, there are few applications of ultrasound that are useful in COPD, with recent studies providing some innovation potentially useful in clinical practice. The similarity of the trend between the time/volume curve of spirometry and the M-mode representation of diaphragm during forced breath allowed to identify the M-mode Index of Obstruction (MIO), an index obtained from the ratio between forced diaphragmatic excursion in the first second (FEDE1, cm) and the maximal expiratory diaphragmatic excursion (EDEMax, cm). MIO has shown a linear correlation with the ratio between forced expiratory volume in the first second (FEV1) and vital capacity (VC), used in spirometry to identify airways obstruction. The value of MIO seems to be lower in patients affected by airways obstruction as showed by a recent study. The technique is easy to learn and fast to perform and the analysis could be provided with any ultrasound machine equipped with M-mode. In conclusion, these findings, if confirmed by other studies, could suggest a new add-on screening tool for obstructive lung diseases, in particular COPD, that could be performed during a routine abdominal ultrasound exam.

  4. Bromelain exerts anti-inflammatory effects in an ovalbumin-induced murine model of allergic airway disease

    PubMed Central

    Secor, Eric R.; Carson, William F.; Cloutier, Michelle M.; Guernsey, Linda A.; Schramm, Craig M.; Wu, Carol A.; Thrall, Roger S.

    2008-01-01

    Objective Bromelain, a clinically used pineapple extract and natural product, has reported anti-inflammatory and immunomodulatory activities. The purpose of this study was to determine the effect of bromelain treatment in an ovalbumin (OVA)-induced murine model of allergic airway disease (AAD). Methods To establish AAD, mice were sensitized with intraperitoneal (i.p.) OVA/alum and challenged with daily OVA aerosols. Mice were treated i.p. with either saline, 2 or 6 mg/kg bromelain, twice daily for four consecutive days. Bronchoalveolar lavage leukocytes and cytokines, lung histology, airway hyperresponsiveness, and lymphocyte populations via flow cytometry were compared between groups. Results Bromelain treatment of AAD mice resulted in reduced total BAL leukocytes, eosinophils, CD4+ and CD8+ T lymphocytes, CD4+/CD8+ T cell ratio, and IL-13. Conclusion Bromelain attenuated development of AAD while altering CD4+ to CD8+ T lymphocyte populations. The reduction in AAD outcomes suggests that bromelain may have similar effects in the treatment of human asthma and hypersensitivity disorders. PMID:16337164

  5. Sarcoidosis of the upper and lower airways.

    PubMed

    Morgenthau, Adam S; Teirstein, Alvin S

    2011-12-01

    Sarcoidosis is a systemic granulomatous disease of undetermined etiology characterized by a variable clinical presentation and disease course. Although clinical granulomatous inflammation may occur within any organ system, more than 90% of sarcoidosis patients have lung disease. Sarcoidosis is considered an interstitial lung disease that is frequently characterized by restrictive physiologic dysfunction on pulmonary function tests. However, sarcoidosis also involves the airways (large and small), causing obstructive airways disease. It is one of a few interstitial lung diseases that affects the entire length of the respiratory tract - from the nose to the terminal bronchioles - and causes a broad spectrum of airways dysfunction. This article examines airway dysfunction in sarcoidosis. The anatomical structure of the airways is the organizational framework for our discussion. We discuss sarcoidosis involving the nose, sinuses, nasal passages, larynx, trachea, bronchi and small airways. Common complications of airways disease, such as, atelectasis, fibrosis, bullous leions, bronchiectasis, cavitary lesions and mycetomas, are also reviewed.

  6. All India Difficult Airway Association 2016 guidelines for the management of anticipated difficult extubation

    PubMed Central

    Kundra, Pankaj; Garg, Rakesh; Patwa, Apeksh; Ahmed, Syed Moied; Ramkumar, Venkateswaran; Shah, Amit; Divatia, Jigeeshu Vasishtha; Shetty, Sumalatha Radhakrishna; Raveendra, Ubaradka S; Doctor, Jeson R; Pawar, Dilip K; Singaravelu, Ramesh; Das, Sabyasachi; Myatra, Sheila Nainan

    2016-01-01

    Extubation has an important role in optimal patient recovery in the perioperative period. The All India Difficult Airway Association (AIDAA) reiterates that extubation is as important as intubation and requires proper planning. AIDAA has formulated an algorithm based on the current evidence, member survey and expert opinion to incorporate all patients of difficult extubation for a successful extubation. The algorithm is not designed for a routine extubation in a normal airway without any associated comorbidity. Extubation remains an elective procedure, and hence, patient assessment including concerns related to airway needs to be done and an extubation strategy must be planned before extubation. Extubation planning would broadly be dependent on preventing reflex responses (haemodynamic and cardiovascular), presence of difficult airway at initial airway management, delayed recovery after the surgical intervention or airway difficulty due to pre-existing diseases. At times, maintaining a patent airway may become difficult either due to direct handling during initial airway management or due to surgical intervention. This also mandates a careful planning before extubation to avoid extubation failure. Certain long-standing diseases such as goitre or presence of obesity and obstructive sleep apnoea may have increased chances of airway collapse. These patients require planned extubation strategies for extubation. This would avoid airway collapse leading to airway obstruction and its sequelae. AIDAA suggests that the extubation plan would be based on assessment of the airway. Patients requiring suppression of haemodynamic responses would require awake extubation with pharmacological attenuation or extubation under deep anaesthesia using supraglottic devices as bridge. Patients with difficult airway (before surgery or after surgical intervention) or delayed recovery or difficulty due to pre-existing diseases would require step-wise approach. Oxygen supplementation should

  7. What does airway resistance tell us about lung function?

    PubMed

    Kaminsky, David A

    2012-01-01

    Spirometry is considered the primary method to detect the air flow limitation associated with obstructive lung disease. However, air flow limitation is the end-result of many factors that contribute to obstructive lung disease. One of these factors is increased airway resistance. Airway resistance is traditionally measured by relating air flow and driving pressure using body plethysmography, thus deriving airway resistance (R(aw)), specific airway resistance (sR(aw)), and specific airway conductance (sG(aw)). Other methods to measure airway resistance include the forced oscillation technique (FOT), which allows calculation of respiratory system resistance (R(RS)) and reactance (X(RS)), and the interrupter technique, which allows calculation of interrupter resistance (R(int)). An advantage of these other methods is that they may be easier to perform than spirometry, making them particularly suited to patients who cannot perform spirometry, such as young children, patients with neuromuscular disorders, or patients on mechanical ventilation. Since spirometry also requires a deep inhalation, which can alter airway resistance, these alternative methods may provide more sensitive measures of airway resistance. Furthermore, the FOT provides unique information about lung mechanics that is not available from analysis using spirometry, body plethysmography, or the interrupter technique. However, it is unclear whether any of these measures of airway resistance contribute clinically important information to the traditional measures derived from spirometry (FEV(1), FVC, and FEV(1)/FVC). The purpose of this paper is to review the physiology and methodology of these measures of airway resistance, and then focus on their clinical utility in relation to each other and to spirometry.

  8. Chlorinated pool attendance, airway epithelium defects and the risks of allergic diseases in adolescents: Interrelationships revealed by circulating biomarkers

    SciTech Connect

    Bernard, Alfred Nickmilder, Marc; Dumont, Xavier

    2015-07-15

    It has been suggested that allergic diseases might be epithelial disorders driven by various environmental stressors but the epidemiological evidence supporting this concept is limited. In a cross-sectional study of 835 school adolescents (365 boys; mean age, 15.5 yr), we measured the serum concentrations of Club cell protein (CC16), surfactant-associated protein D (SP-D) and of total and aeroallergen-specific IgE. We used the serum CC16/SP-D concentration ratio as an index integrating changes in the permeability (SP-D) and secretory function (CC16) of the airway epithelium. In both sexes, early swimming in chlorinated pools emerged as the most consistent and strongest predictor of low CC16 and CC16/SP-D ratio in serum. Among girls, a low CC16/SP-D ratio was associated with increased odds (lowest vs. highest tertile) for pet sensitization (OR 2.97, 95% CI 1.19–8.22) and for hay fever in subjects sensitized to pollen (OR 4.12, 95% CI 1.28–14.4). Among boys, a low CC16/SP-D ratio was associated with increased odds for house-dust mite (HDM) sensitization (OR 2.01, 95% CI 1.11–3.73), for allergic rhinitis in subjects sensitized to HDM (OR 3.52, 95% CI 1.22–11.1) and for asthma in subjects sensitized to any aeroallergen (OR 3.38, 95% CI 1.17–11.0), HDM (OR 5.20, 95% CI 1.40–24.2) or pollen (OR 5.82, 95% CI 1.51–27.4). Odds for allergic sensitization or rhinitis also increased with increasing SP-D or decreasing CC16 in serum. Our findings support the hypothesis linking the development of allergic diseases to epithelial barrier defects due to host factors or environmental stressors such as early swimming in chlorinated pools. - Highlights: • We conducted a cross-sectional study of 835 school adolescents. • The airway epithelium integrity was evaluated by measuring serum pneumoproteins. • The risk of allergic diseases was associated with a defective airway epithelium. • Childhood swimming in chlorinated pools can cause persistent epithelial

  9. Sleep Apnea and Obstructive Airway Disease in Older Men: Outcomes of Sleep Disorders in Older Men Study

    PubMed Central

    Zhao, Ying Y.; Blackwell, Terri; Ensrud, Kristine E.; Stone, Katie L.; Omachi, Theodore A.; Redline, Susan

    2016-01-01

    Study Objectives: To evaluate the association between obstructive airway disease (OAD) and sleep apnea in older men. Methods: A community-based cross-sectional study of 853 community-dwelling older men (mean age 80.7 ± 4.1 years [range 73 to 90]) across 6 centers in the United States from the Outcomes of Sleep Disorders in Older Men Study. Sleep was objectively measured using full in-home polysomnography and lung function was objectively measured using spirometry. The association of OAD (pre-bronchodilator FEV1/FVC ratio < 0.7 and FEV1 < 80% predicted) and sleep apnea (apnea-hypopnea index [AHI] ≥ 15 events/hour) was assessed using logistic regression. Results: OAD and sleep apnea were identified in 111 (13.0%) and 247 (29.0%) men, respectively. In univariate analysis, participants with OAD had a lower AHI (mean ± SD; 8.7 ± 11.7 vs. 12.7 ± 13.8, P = 0.0009) and a lower prevalence of sleep apnea (14.4 vs. 31.1%, P = 0.0003) compared to participants without OAD. OAD remained independently associated with a lower odds of sleep apnea (odds ratio 0.30, 95% CI 0.16 to 0.55, P = 0.0001) after adjustment for demographics, body composition, smoking, and potential mediators (arousal index, time spent in rapid eye movement sleep). Individuals with OAD and sleep apnea (n = 16) had an increased arousal index and lower oxygen saturation level as compared to individuals with OAD alone (P values < 0.05). Conclusions: Obstructive airway disease was associated with a lower prevalence of sleep apnea in a cohort of community-dwelling elderly men, and unexplained by differences in adiposity or sleep architecture. Although uncommon in this cohort, coexisting sleep apnea and OAD was associated with increased sleep fragmentation and nocturnal oxygen desaturation compared to OAD alone. Citation: Zhao YY, Blackwell T, Ensrud KE, Stone KL, Omachi TA, Redline S, Osteoporotic Fractures in Men (MrOS) Study Group. Sleep apnea and obstructive airway disease in older men: outcomes of sleep

  10. What we can learn from a tadpole about ciliopathies and airway diseases: Using systems biology in Xenopus to study cilia and mucociliary epithelia.

    PubMed

    Walentek, Peter; Quigley, Ian K

    2017-01-01

    Over the past years, the Xenopus embryo has emerged as an incredibly useful model organism for studying the formation and function of cilia and ciliated epithelia in vivo. This has led to a variety of findings elucidating the molecular mechanisms of ciliated cell specification, basal body biogenesis, cilia assembly, and ciliary motility. These findings also revealed the deep functional conservation of signaling, transcriptional, post-transcriptional, and protein networks employed in the formation and function of vertebrate ciliated cells. Therefore, Xenopus research can contribute crucial insights not only into developmental and cell biology, but also into the molecular mechanisms underlying cilia related diseases (ciliopathies) as well as diseases affecting the ciliated epithelium of the respiratory tract in humans (e.g., chronic lung diseases). Additionally, systems biology approaches including transcriptomics, genomics, and proteomics have been rapidly adapted for use in Xenopus, and broaden the applications for current and future translational biomedical research. This review aims to present the advantages of using Xenopus for cilia research, highlight some of the evolutionarily conserved key concepts and mechanisms of ciliated cell biology that were elucidated using the Xenopus model, and describe the potential for Xenopus research to address unresolved questions regarding the molecular mechanisms of ciliopathies and airway diseases.

  11. Risks for Infection in Patients With Asthma (or Other Atopic Conditions): Is Asthma More Than a Chronic Airway Disease?

    PubMed Central

    Juhn, Young J.

    2014-01-01

    Most of the research effort regarding asthma has been devoted to its causes, therapy, and prognosis. There is also evidence that the presence of asthma can influence patients’ susceptibility to infections, yet research in this aspect of asthma has been limited. There is additional debate in this field, with current literature tending to view the increased risk of infection among atopic patients as due to opportunistic infections secondary to airway inflammation, especially in severe atopic diseases. Other evidence, however, suggests that such risk and its underlying immune dysfunction may be a phenotypic or clinical feature of atopic conditions. This review argues that 1) improved understanding of the effects of asthma or other atopic conditions on the risk of microbial infections will bring important and new perspectives to clinical practice, research, and public health concerning atopic conditions and that 2) research efforts into the causes and effects of asthma must be juxtaposed because they are likely to guide each other. PMID:25087224

  12. RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection.

    PubMed

    Jozwik, Agnieszka; Habibi, Maximillian S; Paras, Allan; Zhu, Jie; Guvenel, Aleks; Dhariwal, Jaideep; Almond, Mark; Wong, Ernie H C; Sykes, Annemarie; Maybeno, Matthew; Del Rosario, Jerico; Trujillo-Torralbo, Maria-Belen; Mallia, Patrick; Sidney, John; Peters, Bjoern; Kon, Onn Min; Sette, Alessandro; Johnston, Sebastian L; Openshaw, Peter J; Chiu, Christopher

    2015-12-21

    In animal models, resident memory CD8+ T (Trm) cells assist in respiratory virus elimination but their importance in man has not been determined. Here, using experimental human respiratory syncytial virus (RSV) infection, we investigate systemic and local virus-specific CD8+ T-cell responses in adult volunteers. Having defined the immunodominance hierarchy, we analyse phenotype and function longitudinally in blood and by serial bronchoscopy. Despite rapid clinical recovery, we note surprisingly extensive lower airway inflammation with persistent viral antigen and cellular infiltrates. Pulmonary virus-specific CD8+ T cells display a CD69+CD103+ Trm phenotype and accumulate to strikingly high frequencies into convalescence without continued proliferation. While these have a more highly differentiated phenotype, they express fewer cytotoxicity markers than in blood. Nevertheless, their abundance before infection correlates with reduced symptoms and viral load, implying that CD8+ Trm cells in the human lung can confer protection against severe respiratory viral disease when humoral immunity is overcome.

  13. Coupled cellular therapy and magnetic targeting for airway regeneration.

    PubMed

    Ordidge, Katherine L; Gregori, Maria; Kalber, Tammy L; Lythgoe, Mark F; Janes, Sam M; Giangreco, Adam

    2014-06-01

    Airway diseases including COPD (chronic obstructive pulmonary disease), cystic fibrosis and lung cancer are leading causes of worldwide morbidity and mortality, with annual healthcare costs of billions of pounds. True regeneration of damaged airways offers the possibility of restoring lung function and protecting against airway transformation. Recently, advances in tissue engineering have allowed the development of cadaveric and biosynthetic airway grafts. Although these have produced encouraging results, the ability to achieve long-term functional airway regeneration remains a major challenge. To promote regeneration, exogenously delivered stem and progenitor cells are being trialled as cellular therapies. Unfortunately, current evidence suggests that only small numbers of exogenously delivered stem cells engraft within lungs, thereby limiting their utility for airway repair. In other organ systems, magnetic targeting has shown promise for improving long-term robust cell engraftment. This technique involves in vitro cell expansion, magnetic actuation and magnetically guided cell engraftment to sites of tissue damage. In the present paper, we discuss the utility of coupling stem cell-mediated cellular therapy with magnetic targeting for improving airway regeneration.

  14. Airflow mechanics in models of equine obstructive airway disease under conditions simulating exercise.

    PubMed

    Bayly, W M; Slocombe, R F

    1997-01-01

    Effects of respiratory tract obstructions on ventilatory mechanics in horses exercising at high speeds were tested with a fibreglass replica of the airways (nares to mainstem bronchi) of an adult horse. Segmental pressures were recorded at six sites along the model at four different unidirectional flows (1300-4100 litre min-1), and the respective resistances (R) to airflow were calculated. The external nares and the larynx made the greatest contributions to the total resistance (RTOT) when no obstruction was present. Modifying the model to simulate severe pharyngeal lymphoid hyperplasia (PLH) had no effect on R at the larynx or at any point in the trachea under these flow conditions. Two 16 litre anaesthetic rebreathing bags were attached to the bronchial end of the model, and tidal ventilation generated by a piston pump. Upper (nares to pharynx) and lower tract R (RU and RL) and RTOT, and dynamic compliance were determined for pump volumes (Vp) of six and 12 litres, at pumping frequencies (fp) of 20-100 min-1 while the airway was clear, and after modifying it to simulate either PLH or partial bronchial obstruction. Model condition had no effect on RU. However, RL and RTOT were higher in the PLH simulated condition when fp > or = 90 and Vp = 12 litres (P < 0.05). This suggested that severe PLH may significantly interfere with airflow distal to the site of the lesions during high frequency high volume ventilation of the type seen in galloping horses. With partial bronchial obstruction RL and RTOT were increased when fp > 34 with each Vp. The applicability of the model was verified by comparing results from the unobstructed state with those from normal horses exercising on a treadmill.

  15. The Impact of Vitamin D on Asthmatic Human Airway Smooth Muscle

    PubMed Central

    Hall, Sannette C.; Fischer, Kimberly D.; Agrawal, Devendra K.

    2016-01-01

    Asthma is a chronic heterogeneous disorder, which involves airway inflammation, airway hyperresponsiveness (AHR) and airway remodeling. The airway smooth muscle (ASM) bundle regulates the broncho-motor tone and plays a critical role in AHR as well as orchestrating inflammation. Vitamin D deficiency has been linked to increased severity and exacerbations of symptoms in asthmatic patients. It has been shown to modulate both immune and structural cells, including ASM cells, in inflammatory diseases. Given that current asthma therapies have not been successful in reversing airway remodeling, vitamin D supplementation as a potential therapeutic option has gained a great deal of attention. Here, we highlight the potential immunomodulatory properties of vitamin D in regulating ASM function and airway inflammation in bronchial asthma. PMID:26634624

  16. Manual therapy for chronic obstructive airways disease: a systematic review of current evidence.

    PubMed

    Heneghan, Nicola R; Adab, Peymane; Balanos, George M; Jordan, Rachel E

    2012-12-01

    Chronic obstructive pulmonary disease (COPD) is a growing global problem. Despite mounting evidence of significant co morbidity including musculoskeletal changes, evidenced based non pharmacological management approaches are limited to smoking cessation and pulmonary rehabilitation. Existing evidence suggests manual therapy may be beneficial in the management of COPD. A systematic review was conducted of key databases up until May 2010. Studies were included if they were RCTs or pre/post study designs testing an MT intervention and included a physiological measure of lung function. Descriptive results were collated. Pooling of data and meta-analysis was not possible due to heterogeneity in key characteristics. From 3086 articles 24 full text articles were evaluated, resulting in 7 included studies (5 RCTs, 2 pre-post studies) from 2 countries. Of all COPD subjects (n = 131) interventions included; osteopathic manipulative therapy (OMT) (n = 100), massage (n = 5), muscle stretching (n = 14), and passive movements (n = 12). Of the 7 included studies, 6 had high risk of bias with many design/reporting faults, with only one OMT study (n = 25) being evaluated as low risk of bias. In this study, performance based measures of pulmonary function (FEV1, FVC) changed minimally (<1.5%) following OMT techniques. Paradoxically patient reported measures for 'improved health' and 'breathing difficulty' however did improve following OMT compared to the control. Evidence for MT as an adjunctive management approach for COPD is lacking. More exploratory research is first required to better understand the nature and extent of changes in the musculoskeletal system in patients with COPD and their possible relationship with pulmonary function.

  17. Cystic Fibrosis Transmembrane Conductance Regulator in Sarcoplasmic Reticulum of Airway Smooth Muscle. Implications for Airway Contractility

    PubMed Central

    Cook, Daniel P.; Rector, Michael V.; Bouzek, Drake C.; Michalski, Andrew S.; Gansemer, Nicholas D.; Reznikov, Leah R.; Li, Xiaopeng; Stroik, Mallory R.; Ostedgaard, Lynda S.; Abou Alaiwa, Mahmoud H.; Thompson, Michael A.; Prakash, Y. S.; Krishnan, Ramaswamy; Meyerholz, David K.; Seow, Chun Y.

    2016-01-01

    Rationale: An asthma-like airway phenotype has been described in people with cystic fibrosis (CF). Whether these findings are directly caused by loss of CF transmembrane conductance regulator (CFTR) function or secondary to chronic airway infection and/or inflammation has been difficult to determine. Objectives: Airway contractility is primarily determined by airway smooth muscle. We tested the hypothesis that CFTR is expressed in airway smooth muscle and directly affects airway smooth muscle contractility. Methods: Newborn pigs, both wild type and with CF (before the onset of airway infection and inflammation), were used in this study. High-resolution immunofluorescence was used to identify the subcellular localization of CFTR in airway smooth muscle. Airway smooth muscle function was determined with tissue myography, intracellular calcium measurements, and regulatory myosin light chain phosphorylation status. Precision-cut lung slices were used to investigate the therapeutic potential of CFTR modulation on airway reactivity. Measurements and Main Results: We found that CFTR localizes to the sarcoplasmic reticulum compartment of airway smooth muscle and regulates airway smooth muscle tone. Loss of CFTR function led to delayed calcium reuptake following cholinergic stimulation and increased myosin light chain phosphorylation. CFTR potentiation with ivacaftor decreased airway reactivity in precision-cut lung slices following cholinergic stimulation. Conclusions: Loss of CFTR alters porcine airway smooth muscle function and may contribute to the airflow obstruction phenotype observed in human CF. Airway smooth muscle CFTR may represent a therapeutic target in CF and other diseases of airway narrowing. PMID:26488271

  18. Occupational asthma and occupational rhinitis: the united airways disease model revisited

    PubMed Central

    Ameille, Jacques; Hamelin, Karine; Andujar, Pascal; Bensefa-Colas, Lynda; Bonneterre, Vincent; Dupas, Dominique; Garnier, Robert; Loddé, Brice Alain; Rinaldo, Mickael; Descatha, Alexis; Lasfargues, Gérard; Pairon, Jean-Claude

    2013-01-01

    Objectives Whereas accumulating evidence indicates close associations between rhinitis and asthma, little is known about the relationships between occupational rhinitis (OR) and occupational asthma (OA). This study analyses the prevalence of OR associated with OA, globally and according to the various causal agents, and investigates the temporal relationships between these two conditions. Methods Data on incident cases of OA (2008–2010) were collected through the French national occupational disease surveillance and prevention network, using a standardized form including information on occupation, causal agents, presence of OR, and respective dates of occurrence of rhinitis and asthma. Results Among the 596 reported OA cases with latency period, 555 could be attributed to identified agents: high molecular weight (HMW) agents (n=174); low molecular weight (LMW) agents (n=381). Overall, OR was associated with OA in 324 (58.4%) cases. The frequency of association was significantly higher for HMW agents than for LMW agents (72.2% vs 51.5%, p<0.001). OR occurred before OA significantly more frequently for HMW agents than for LMW agents (p<0.01). Conclusions These results show that OR is frequently associated with OA, especially when HMW agents are involved. They are consistent with the hypothesis that OR, in conjunction with OA, is more likely to be caused by sensitizers that cause disease via IgE-mediated mechanisms and suggest that symptoms of OR should be taken into account in the medical surveillance of workers exposed to HMW agents. PMID:23390199

  19. The effects of three models of airway disease on tidal breathing flow-volume loops of thoroughbred horses.

    PubMed

    Guthrie, A J; Beadle, R E; Bateman, R D; White, C E

    1995-01-01

    The effects of histamine and methacholine aerosols and of a fixed inspiratory resistance on tidal breathing flow-volume loops (TBFVL) were investigated using 18 unsedated, standing, healthy thoroughbred horses. The data were first analysed using traditional flow-volume loop indices and then reduced using standardized factor scoring coefficients obtained in a previous study in this laboratory using similar experimental techniques. On the basis of resting TBFVL analysis, the degree of pulmonary dysfunction caused by inhalation of histamine and methacholine aerosols with concentrations of 10 and 2 mg/ml, respectively, was similar. The fixed resistance also caused significant changes in the resting spirogram and TBFVL indices, suggesting that this model may prove valuable for further studies involving upper respiratory tract (URT) conditions. Administration of histamine and methacholine aerosols resulted in significant changes in all factor scores, although most of the observed changes were due to the effects of these aerosols on the respiratory rate. These findings re-emphasize the importance of the effects of respiratory rate on pulmonary mechanics. Application of the resistance resulted in significant changes in factor score 3, the 'inspiratory' factor, which lends support to the validity of this model for URT conditions. The close agreement between the factor scores obtained under controlled conditions in this study and in a previous study in this laboratory confirms that the factor analysis used for both of these studies provides an adequate means of reducing TBFVL data obtained from thoroughbred horses. The large intra- and inter-individual variation observed both with the indices of TBFVL and with the factor scores limits the potential of these variables for detecting individual animals with obstructive airway disease. Re-evaluation of these indices under the stress of exercise may reduce the variability observed in these data and may increase the magnitude of

  20. Activation of eosinophil CCR3 signaling and eotaxin using a bioinformatics analysis of a mouse model of obliterative airway disease.

    PubMed

    Dosanjh, Amrita

    2014-07-01

    The role of eosinophils in the development and progression of chronic allograft rejection is recognized in multiple organ transplantation settings. The CCR3 signaling pathway is one of the key regulatory pathways in eosinophil migration to the engrafted tissue. Eotaxin is a ligand for CCR3 and reflects eosinophilic inflammation, which can lead to fibrosis. We hypothesized that the CCR3 pathway would be upregulated in obliterative airway disease (OAD) in an established model of chronic airway allograft rejection. The mouse gene microarray data from a heterotopic mouse model of OAD in the NIH Gene Expression Omnibus (GEO) repository were analyzed for differentially expressed eosinophil pathways, using the Partek Suite and Ingenuity Pathway Analysis. A P value of <0.005 was defined as significant for differential expression, and P value of <0.05 for pathways. Day 25 allografts were defined as chronic allograft rejection and day 4 as acute allograft rejection. The isografts and allografts at day 25 showed significant upregulation of the eosinophil CCR3 pathway (P=0.04), based on the analysis of 1,299 uniquely expressed genes. The isografts at day 4 were compared with those at day 25 based on the identification of 1,859 unique genes, and there was a trend toward the CCR3 pathway upregulation over time (P=0.06). CCR3 pathways were not upregulated during the progression of alloimmune rejection in the allografts at day 4 versus day 25 in comparison, based on the analysis of 1,603 genes. Eotaxin was upregulated in chronic allograft rejection by 2.5-fold. The eosinophil signaling pathway CCR3 and eotaxin were significantly expressed in chronic allograft rejection and our results imply a role in controlling early alloimmune damage in controls.

  1. Abdominal adiposity and obstructive airway disease: testing insulin resistance and sleep disordered breathing mechanisms

    PubMed Central

    2012-01-01

    Background This study examined associations of abdominal adiposity with lung function, asthma symptoms and current doctor-diagnosed asthma and mediation by insulin resistance (IR) and sleep disordered breathing (SDB). Methods A random sample of 2500 households was drawn from the community of Whyalla, South Australia (The Whyalla Intergenerational Study of Health, WISH February 2008 - July 2009). Seven-hundred twenty-two randomly selected adults (≥18 years) completed clinical protocols (32.2% response rate). Lung function was measured by spirometry. Post-bronchodilator FEV1/FVC was used to measure airway obstruction and reversibility of FEV1 was calculated. Current asthma was defined by self-reported doctor-diagnosis and evidence of currently active asthma. Symptom scores for asthma (CASS) and SDB were calculated. Intra-abdominal fat (IAF) was estimated using dual-energy x-ray absorptiometry (DXA). IR was calculated from fasting glucose and insulin concentrations. Results The prevalence of current doctor-diagnosed asthma was 19.9% (95% CI 16.7 – 23.5%). The ratio of observed to expected cases given the age and sex distribution of the population was 2.4 (95%CI 2.1, 2.9). IAF was not associated with current doctor-diagnosed asthma, FEV1/FVC or FEV1 reversibility in men or women but was positively associated with CASS independent of IR and SDB in women. A 1% increase in IAF was associated with decreases of 12 mL and 20 mL in FEV1 and FVC respectively in men, and 4 mL and 7 mL respectively in women. SDB mediated 12% and 26% of these associations respectively in men but had minimal effects in women. Conclusions In this population with an excess of doctor-diagnosed asthma, IAF was not a major factor in airway obstruction or doctor-diagnosed asthma, although women with higher IAF perceived more severe asthma symptoms which did not correlate with lower FEV1. Higher IAF was significantly associated with lower FEV1 and FVC and in men SDB mechanisms may

  2. Modelling resistance and reactance with heterogeneous airway narrowing in mild to severe asthma.

    PubMed

    Bhatawadekar, Swati A; Leary, Del; Maksym, Geoffrey N

    2015-03-01

    Ventilation heterogeneity is an important marker of small airway dysfunction in asthma. The frequency dependence of respiratory system resistance (Rrs) from oscillometry is used as a measure of this heterogeneity. However, this has not been quantitatively assessed or compared with other outcomes from oscillometry, including respiratory system reactance (Xrs) and the associated elastance (Ers). Here, we used a multibranch model of the human lung, including an upper airway shunt, to match previously reported respiratory mechanics in mild to severe asthma. We imposed heterogeneity by narrowing a proportion of the peripheral airways to account for patient Ers at 5 Hz, and then narrowed central airways to account for the remaining Rrs at 18 Hz. The model required >75% of the small airways to be occluded to reproduce severe asthma. While the model produced frequency dependence in Rrs, it was upward-shifted below 5 Hz compared with in-vivo results, indicating that other factors, including more distributed airway narrowing or central airway wall compliance, are required. However, Ers quantitatively reflected the imposed heterogeneity better than the frequency dependence of Rrs, independent of the frequency range for the estimation, and thus was a more robust measure of small-airway function. Thus, Ers appears to have greater potential as a clinical measure of early small-airway disease in asthma.

  3. Recent advances in the management of obstructive airways disease. Auxiliary MDI aerosol delivery systems.

    PubMed

    Sackner, M A; Kim, C S

    1985-08-01

    Aerosol delivered through metered-dose inhalers (MDI) offers a potentially convenient way to deliver bronchodilator agents and corticosteroids to the lungs of patients with asthma and COPD. Unfortunately, most patients are unable to coordinate satisfactorily their actuation with inhalation, a problem overcome by using auxiliary MDI aerosol delivery systems. Left to their own judgment, patients often inhale the aerosol with a high inspiratory flow rather than slowly to produce optimal aerosol deposition within the airways. This problem has been corrected by one of the auxiliary MDI aerosol delivery systems (InspirEase) through auditory, visual, and tactile feedback mechanisms. MDI devices release aerosol at a high jet velocity in large particle sizes, depositing most of the aerosol in the oropharynx which can lead to potential systemic absorption of adrenergic agonists with CNS and cardiovascular side effects, oral thrush, and suppression of adrenocortical activity. All the auxiliary MDI aerosol systems promote delivery of small aerosol particles and markedly diminish oropharyngeal impaction. Of all the systems, only InspirEase provides volume and flow feedback controls to ensure an optimal inhalation maneuver. Auxiliary MDI aerosol systems should always be used for aerosolized corticosteroid administration because they minimize oropharyngeal deposition and improve aerosol delivery efficiency.

  4. The usefulness of biomarkers of airway inflammation in managing asthma.

    PubMed

    Patil, Sarita U; Long, Aidan A

    2010-01-01

    The goal of managing asthma is to maintain disease control. Current approaches to assessment of control do not include measurement of airway inflammation. This study was designed to assess the usefulness of biomarkers of airway inflammation in guiding asthma management decisions. A literature review was performed. Bronchial biopsy is a direct measure of airway inflammation but not practical for routine use. Enumeration of sputum eosinophils is very useful in guiding changes in controller medication to decrease asthma exacerbations, whereas measurement of exhaled nitric oxide has not proven to be useful in this regard. Serial measurement of airway hyperreactivity as a guide to asthma management yields inconclusive results. Use of indirect stimuli for bronchial challenge offers both practical and theoretical advantages in the assessment of airway hyperreactivity. Data on the analysis of exhaled breath condensate have not yet been studied adequately in guiding management decisions. Enumeration of sputum cell counts appears to be the most useful biomarker of airway inflammation in guiding asthma management decisions. Combined approaches using simple methods of measuring airway hyperreactivity and obtaining sputum samples hold promise for the future, particularly if rapid analysis of cellular products in sputum can be developed.

  5. Mitochondrial Transplantation Attenuates Airway Hyperresponsiveness by Inhibition of Cholinergic Hyperactivity

    PubMed Central

    Su, Yuan; Zhu, Liping; Yu, Xiangyuan; Cai, Lei; Lu, Yankai; Zhang, Jiwei; Li, Tongfei; Li, Jiansha; Xia, Jingyan; Xu, Feng; Hu, Qinghua

    2016-01-01

    Increased cholinergic activity has been highlighted in the pathogenesis of airway hyperresponsiveness, and alternations of mitochondrial structure and function appear to be involved in many lung diseases including airway hyperresponsiveness. It is crucial to clarify the cause-effect association between mitochondrial dysfunction and cholinergic hyperactivity in the pathogenesis of airway hyperresponsiveness. Male SD rats and cultured airway epithelial cells were exposed to cigarette smoke plus lipopolysaccharide administration; mitochondria isolated from airway epithelium were delivered into epithelial cells in vitro and in vivo. Both the cigarette smoke plus lipopolysaccharide-induced cholinergic hyperactivity in vitro and the airway hyperresponsiveness to acetylcholine in vivo were reversed by the transplantation of exogenous mitochondria. The rescue effects of exogenous mitochondria were imitated by the elimination of excessive reactive oxygen species or blockage of muscarinic M3 receptor, but inhibited by M receptor enhancer. Mitochondrial transplantation effectively attenuates cigarette smoke plus lipopolysaccharide-stimulated airway hyperresponsiveness through the inhibition of ROS-enhanced epithelial cholinergic hyperactivity. PMID:27279915

  6. C5 Modulates Airway Hyperreactivity and Pulmonary Eosinophilia during Enhanced Respiratory Syncytial Virus Disease by Decreasing C3a Receptor Expression▿

    PubMed Central

    Melendi, Guillermina A.; Hoffman, Scott J.; Karron, Ruth A.; Irusta, Pablo M.; Laham, Federico R.; Humbles, Alison; Schofield, Brian; Pan, Chien-Hsiung; Rabold, Richard; Thumar, Bhagvanji; Thumar, Adeep; Gerard, Norma P.; Mitzner, Wayne; Barnum, Scott R.; Gerard, Craig; Kleeberger, Steven R.; Polack, Fernando P.

    2007-01-01

    Enhanced respiratory syncytial virus disease, a serious pulmonary disorder that affected recipients of an inactivated vaccine against respiratory syncytial virus in the 1960s, has delayed the development of vaccines against the virus. The enhanced disease was characterized by immune complex-mediated airway hyperreactivity and a severe pneumonia associated with pulmonary eosinophilia. In this paper, we show that complement factors contribute to enhanced-disease phenotypes. Mice with a targeted disruption of complement component C5 affected by the enhanced disease displayed enhanced airway reactivity, lung eosinophilia, and mucus production compared to wild-type mice and C5-deficient mice reconstituted with C5. C3aR expression in bronchial epithelial and smooth muscle cells in the lungs of C5-deficient mice was enhanced compared to that in wild-type and reconstituted rodents. Treatment of C5-deficient mice with a C3aR antagonist significantly attenuated airway reactivity, eosinophilia, and mucus production. These results indicate that C5 plays a crucial role in modulating the enhanced-disease phenotype, by affecting expression of C3aR in the lungs. These findings reveal a novel autoregulatory mechanism for the complement cascade that affects the innate and adaptive immune responses. PMID:17079327

  7. Nedocromil sodium is more effective than cromolyn sodium for the treatment of chronic reversible obstructive airway disease.

    PubMed

    Lal, S; Dorow, P D; Venho, K K; Chatterjee, S S

    1993-08-01

    In a multicenter, double-blind, group comparative trial, the efficacy of nedocromil sodium (nedocromil, 4 mg, four times daily [qid]), cromolyn sodium (2 mg, qid), and placebo was compared in patients receiving inhaled beta 2-agonists and inhaled corticosteroids for the treatment of chronic reversible obstructive airway disease. After a 2-week baseline period, 132 patients (8 centers) between the ages of 20 and 75 years entered a 4-week run-in period in which the dose of inhaled corticosteroid was reduced by 50 percent. During the run-in phase, deterioration of symptoms (total symptom score) by ten points qualified patients to enter the 6-week drug trial period. Patients in the nedocromil treatment group showed the most robust and consistent improvements over placebo and cromolyn sodium for all daily dairy variables. Statistically significant improvements over placebo were noted for both active treatment groups for daytime, nighttime, and total symptom score. Symptom scores for nedocromil were statistically significantly improved over both cromolyn sodium and placebo for both daytime and nighttime asthma. Patients treated with nedocromil also demonstrated a significant reduction in the use of nighttime as needed (prn) beta 2-agonists as compared with either the placebo- or cromolyn sodium-treated groups. Only nedocromil-treated patients demonstrated a statistically significant improvement in morning peak expiratory flow rate (PEFR) as compared with placebo. Both nedocromil and cromolyn sodium groups demonstrated statistically significant improvements in afternoon and evening PEFRs. Collectively, the improvements in nighttime symptoms, decreased bronchodilator use, and improved morning PEFR show that patients treated with nedocromil had improved nocturnal symptoms. Pulmonary function tests (FEV1, FVC, PEFR) demonstrated no statistically significant differences between the two active treatments, although trends favored nedocromil for both FEV1 and PEFR. Although

  8. Progenitor Cells in Proximal Airway Epithelial Development and Regeneration

    PubMed Central

    Lynch, Thomas J.; Engelhardt, John F.

    2015-01-01

    Multiple distinct epithelial domains are found throughout the airway that are distinguishable by location, structure, function, and cell-type composition. Several progenitor cell populations in the proximal airway have been identified to reside in confined microenvironmental niches including the submucosal glands (SMGs), which are embedded in the tracheal connective tissue between the surface epithelium and cartilage, and basal cells that reside within the surface airway epithelium (SAE). Current research suggests that regulatory pathways that coordinate development of the proximal airway and establishment of progenitor cell niches may overlap with pathways that control progenitor cell responses during airway regeneration following injury. SMGs have been shown to harbor epithelial progenitor cells, and this niche is dysregulated in diseases such as cystic fibrosis. However, mechanisms that regulate progenitor cell proliferation and maintenance within this glandular niche are not completely understood. Here we discuss glandular progenitor cells during development and regeneration of the proximal airway and compare properties of glandular progenitors to those of basal cell progenitors in the SAE. Further investigation into glandular progenitor cell control will provide a direction for interrogating therapeutic interventions to correct aberrant conditions affecting the SMGs in diseases such as cystic fibrosis, chronic bronchitis, and asthma. PMID:24818588

  9. Operative endoscopy of the airway

    PubMed Central

    Walters, Dustin M.

    2016-01-01

    Airway endoscopy has long been an important and useful tool in the management of thoracic diseases. As thoracic specialists have gained experience with both flexible and rigid bronchoscopic techniques, the technology has continued to evolve so that bronchoscopy is currently the foundation for diagnosis and treatment of many thoracic ailments. Airway endoscopy plays a significant role in the biopsy of tumors within the airways, mediastinum, and lung parenchyma. Endoscopic methods have been developed to treat benign and malignant airway stenoses and tracheomalacia. And more recently, techniques have been conceived to treat end-stage emphysema and prolonged air leaks in select patients. This review describes the abundant uses of airway endoscopy, as well as technical considerations and limitations of the current technologies. PMID:26981263

  10. RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection

    PubMed Central

    Jozwik, Agnieszka; Habibi, Maximillian S.; Paras, Allan; Zhu, Jie; Guvenel, Aleks; Dhariwal, Jaideep; Almond, Mark; Wong, Ernie H. C.; Sykes, Annemarie; Maybeno, Matthew; Del Rosario, Jerico; Trujillo-Torralbo, Maria-Belen; Mallia, Patrick; Sidney, John; Peters, Bjoern; Kon, Onn Min; Sette, Alessandro; Johnston, Sebastian L.; Openshaw, Peter J.; Chiu, Christopher

    2015-01-01

    In animal models, resident memory CD8+ T (Trm) cells assist in respiratory virus elimination but their importance in man has not been determined. Here, using experimental human respiratory syncytial virus (RSV) infection, we investigate systemic and local virus-specific CD8+ T-cell responses in adult volunteers. Having defined the immunodominance hierarchy, we analyse phenotype and function longitudinally in blood and by serial bronchoscopy. Despite rapid clinical recovery, we note surprisingly extensive lower airway inflammation with persistent viral antigen and cellular infiltrates. Pulmonary virus-specific CD8+ T cells display a CD69+CD103+ Trm phenotype and accumulate to strikingly high frequencies into convalescence without continued proliferation. While these have a more highly differentiated phenotype, they express fewer cytotoxicity markers than in blood. Nevertheless, their abundance before infection correlates with reduced symptoms and viral load, implying that CD8+ Trm cells in the human lung can confer protection against severe respiratory viral disease when humoral immunity is overcome. PMID:26687547

  11. Mass psychogenic illness: psychological predisposition and iatrogenic pseudo-vocal cord dysfunction and pseudo-reactive airways disease syndrome.

    PubMed

    Staudenmayer, Herman; Christopher, Kent L; Repsher, Lawrence; Hill, Ronald H

    2011-06-01

    A multidisciplinary team assessed five patients who alleged chronic medically unexplained multiorgan system symptoms described by idiopathic environmental intolerance allegedly triggered by exposure to solvents used in membrane roofing repair work on an office building. The event precipitated an incident of mass psychogenic illness (MPI). Treating physicians diagnosed irritant-associated vocal cord dysfunction (IVCD) and reactive airways disease syndrome (RADS) resulting from exposure. The authors conducted medical, psychological, and industrial hygiene evaluations. Air monitoring data for total volatile organic compounds obtained during the 2-day exposure period, measurements of emissions during membrane roofing repair at a similar site, mathematical modeling of air contaminant concentrations, and injection of tracer gas into the incident building revealed exposure levels well below those doses anticipated to cause clinical symptoms. There was no objective medical evidence validating symptoms. Review of the medical records indicated that the video laryngoscopy data, pulmonary function tests, and medical examinations relied upon by the treating physicians were inconsistent with published criteria for IVCD and RADS. Psychological evaluation identified defensiveness and self-serving misrepresentations of exaggerated health concerns associated with somatization and malingering. Each case had personality traits associated with at least one personality disorder. Social histories identified premorbid life events and stressors associated with distress. This is the first study to assess psychological predisposition, social interaction among the plaintiffs, and iatrogenic reinforcement of beliefs by diagnoses of pseudo-disorders associated with patient misrepresentation of exaggerated health concerns in an incident of MPI.

  12. Elevated circulating PAI-1 levels are related to lung function decline, systemic inflammation, and small airway obstruction in chronic obstructive pulmonary disease

    PubMed Central

    Wang, Hao; Yang, Ting; Li, Diandian; Wu, Yanqiu; Zhang, Xue; Pang, Caishuang; Zhang, Junlong; Ying, Binwu; Wang, Tao; Wen, Fuqiang

    2016-01-01

    Background Plasminogen activator inhibitor-1 (PAI-1) and soluble urokinase-type plasminogen activator receptor (suPAR) participate in inflammation and tissue remolding in various diseases, but their roles in chronic obstructive pulmonary disease (COPD) are not yet clear. This study aimed to investigate if PAI-1 and suPAR were involved in systemic inflammation and small airway obstruction (SAO) in COPD. Methods Demographic and clinical characteristics, spirometry examination, and blood samples were obtained from 84 COPD patients and 51 healthy volunteers. Serum concentrations of PAI-1, suPAR, tissue inhibitor of metalloproteinase-1 (TIMP-1), Matrix metalloproteinase-9 (MMP-9), and C-reactive protein (CRP) were detected with Magnetic Luminex Screening Assay. Differences between groups were statistically analyzed using one-way analysis of variance or chi-square test. Pearson’s partial correlation test (adjusted for age, sex, body mass index, cigarette status, and passive smoke exposure) and multivariable linear analysis were used to explore the relationships between circulating PAI-1 and indicators of COPD. Results First, we found that serum PAI-1 levels but not suPAR levels were significantly increased in COPD patients compared with healthy volunteers (125.56±51.74 ng/mL versus 102.98±36.62 ng/mL, P=0.007). Then, the correlation analysis showed that circulating PAI-1 was inversely correlated with pulmonary function parameters including the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC), FEV1/Pre (justified r=−0.308, P<0.001; justified r=−0.295, P=0.001, respectively) and SAO indicators such as FEV3/FVC, MMEF25–75/Pre (justified r=−0.289, P=0.001; justified r=−0.273, P=0.002, respectively), but positively related to the inflammatory marker CRP (justified r=0.351, P<0.001), the small airway remolding biomarker TIMP-1, and MMP-9 (justified r=0.498, P<0.001; justified r=0.267, P=0.002, respectively). Besides, multivariable

  13. Overexpression of farnesoid X receptor in small airways contributes to epithelial to mesenchymal transition and COX-2 expression in chronic obstructive pulmonary disease

    PubMed Central

    Chen, Bi; You, Wen-Jie; Xue, Shan; Qin, Hui; Zhao, Xu-Ji; Zhang, Miao; Liu, Xue-Qing; Zhu, Shu-Yang

    2016-01-01

    Background Epithelial-mesenchymal transition (EMT) and cyclooxygenase-2 (COX-2) contribute to airway remodelling and inflammation in chronic obstructive pulmonary disease (COPD). Recent data suggest that the farnesoid X receptor (FXR), a nuclear receptor traditionally considered as bile acid-activated receptor, is also expressed in non-classical bile acids target tissues with novel functions beyond regulating bile acid homeostasis. This study aimed to investigate the potential role of FXR in the development of COPD, as well as factors that affect FXR expression. Methods Expression of FXR, EMT biomarkers and COX-2 was examined by immunohistochemistry in lung tissues from non-smokers, smokers, and smokers with COPD. The role of FXR in TGF-β1-induced EMT and COX-2 expression in human bronchial epithelial (HBE) cells was evaluated in vitro. Factors regulating FXR expression were assessed in cultured HBE cells and a cigarette smoke-induced rat model of COPD. Results Expression of FXR, EMT markers and COX-2 was significantly elevated in small airway epithelium of COPD patients compared with controls. The staining scores of FXR in small airway epithelium were negatively related with FEV1% of predicted of smokers without and with COPD. FXR agonist GW4064 remarkably enhanced and FXR antagonist Z-Guggulsterone significantly inhibited EMT changes in TGF-β1-treated HBE cells. Both chenodeoxycholic acid (CDCA) and GW4064 increased COX-2 expression in HBE cells, whereas Z-Guggulsterone dramatically restrained CDCA-induced COX-2 expression. Finally, FXR expression is induced by IL-4 and IL-13 in HBE cells, as well as by cigarette smoke exposure in a rat model of COPD. Conclusions Overexpression of FXR in small airway may contribute to airway remodelling and inflammation in COPD by regulating EMT and COX-2 expression. PMID:28066584

  14. Adenosine deaminase 1 and concentrative nucleoside transporters 2 and 3 regulate adenosine on the apical surface of human airway epithelia: implications for inflammatory lung diseases.

    PubMed

    Hirsh, Andrew J; Stonebraker, Jaclyn R; van Heusden, Catja A; Lazarowski, Eduardo R; Boucher, Richard C; Picher, Maryse

    2007-09-11

    Adenosine is a multifaceted signaling molecule mediating key aspects of innate and immune lung defenses. However, abnormally high airway adenosine levels exacerbate inflammatory lung diseases. This study identifies the mechanisms regulating adenosine elimination from the apical surface of human airway epithelia. Experiments conducted on polarized primary cultures of nasal and bronchial epithelial cells showed that extracellular adenosine is eliminated by surface metabolism and cellular uptake. The conversion of adenosine to inosine was completely inhibited by the adenosine deaminase 1 (ADA1) inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA). The reaction exhibited Km and Vmax values of 24 microM and 0.14 nmol x min(-1) x cm(-2). ADA1 (not ADA2) mRNA was detected in human airway epithelia. The adenosine/mannitol permeability coefficient ratio (18/1) indicated a minor contribution of paracellular absorption. Adenosine uptake was Na+-dependent and was inhibited by the concentrative nucleoside transporter (CNT) blocker phloridzin but not by the equilibrative nucleoside transporter (ENT) blocker dipyridamole. Apparent Km and Vmax values were 17 microM and 7.2 nmol x min(-1) x cm(-2), and transport selectivity was adenosine = inosine = uridine > guanosine = cytidine > thymidine. CNT3 mRNA was detected throughout the airways, while CNT2 was restricted to nasal epithelia. Inhibition of adenosine elimination by EHNA or phloridzin raised apical adenosine levels by >3-fold and stimulated IL-13 and MCP-1 secretion by 6-fold. These responses were reproduced by the adenosine receptor agonist 5'-(N-ethylcarboxamido)adenosine (NECA) and blocked by the adenosine receptor antagonist, 8-(p-sulfophenyl) theophylline (8-SPT). This study shows that adenosine elimination on human airway epithelia is mediated by ADA1, CNT2, and CNT3, which constitute important regulators of adenosine-mediated inflammation.

  15. Multi-scale computational models of the airways to unravel the pathophysiological mechanisms in asthma and chronic obstructive pulmonary disease (AirPROM)

    PubMed Central

    Burrowes, K. S.; De Backer, J.; Smallwood, R.; Sterk, P. J.; Gut, I.; Wirix-Speetjens, R.; Siddiqui, S.; Owers-Bradley, J.; Wild, J.; Maier, D.; Brightling, C.

    2013-01-01

    The respiratory system comprises several scales of biological complexity: the genes, cells and tissues that work in concert to generate resultant function. Malfunctions of the structure or function of components at any spatial scale can result in diseases, to the detriment of gas exchange, right heart function and patient quality of life. Vast amounts of data emerge from studies across each of the biological scales; however, the question remains: how can we integrate and interpret these data in a meaningful way? Respiratory disease presents a huge health and economic burden, with the diseases asthma and chronic obstructive pulmonary disease (COPD) affecting over 500 million people worldwide. Current therapies are inadequate owing to our incomplete understanding of the disease pathophysiology and our lack of recognition of the enormous disease heterogeneity: we need to characterize this heterogeneity on a patient-specific basis to advance healthcare. In an effort to achieve this goal, the AirPROM consortium (Airway disease Predicting Outcomes through patient-specific computational Modelling) brings together a multi-disciplinary team and a wealth of clinical data. Together we are developing an integrated multi-scale model of the airways in order to unravel the complex pathophysiological mechanisms occurring in the diseases asthma and COPD. PMID:24427517

  16. Effects of inhaled budesonide on spirometric values, reversibility, airway responsiveness, and cough threshold in smokers with chronic obstructive lung disease.

    PubMed Central

    Auffarth, B; Postma, D S; de Monchy, J G; van der Mark, T W; Boorsma, M; Koëter, G H

    1991-01-01

    Inhaled corticosteroids are known to reduce respiratory symptoms and airway responsiveness in allergic patients with asthma. The aim of the present randomised, double blind study was to assess the effect of eight weeks' treatment with inhaled budesonide in non-allergic smokers with chronic obstructive lung disease. Twenty four subjects (23 male) entered the study. Their ages ranged from 40 to 70 (mean 57) years, with a mean of 35 (range 9-80) pack years of smoking; the mean FEV1 was 53% (range 32-74%) predicted and geometric mean PC20 (histamine concentration causing a 20% fall in FEV1) 0.96 (range 0.07-7.82) mg/ml. After a two week washout, single blind, placebo period, 12 patients were allocated to treatment with budesonide 1600 microgram/day and 12 to placebo for eight weeks. The only additional drug to be taken was ipratropium bromide "if needed." Twenty one patients completed the study, 10 in the budesonide group and 11 in the placebo group. The standard deviation of the difference between duplicate measurements of PC20 histamine and citric acid cough threshold made two weeks apart was below one doubling dose step. There was a significant reduction in dyspnoea in the budesonide group, but otherwise no change in symptom scores or use of ipratropium bromide over the eight weeks of treatment within or between the two groups. No significant differences in spirometric values, peak expiratory flow, PC20 histamine, or citric acid cough threshold were found between the groups. Although differences were not significant, some of the changes showed a trend in favour of budesonide. Whether a longer observation period would show a significant influence of inhaled corticosteroids in patients with chronic obstructive lung disease remains to be determined. Images PMID:2068695

  17. Estimating the time interval between exposure to the World Trade Center disaster and incident diagnoses of obstructive airway disease.

    PubMed

    Glaser, Michelle S; Webber, Mayris P; Zeig-Owens, Rachel; Weakley, Jessica; Liu, Xiaoxue; Ye, Fen; Cohen, Hillel W; Aldrich, Thomas K; Kelly, Kerry J; Nolan, Anna; Weiden, Michael D; Prezant, David J; Hall, Charles B

    2014-08-01

    Respiratory disorders are associated with occupational and environmental exposures. The latency period between exposure and disease onset remains uncertain. The World Trade Center (WTC) disaster presents a unique opportunity to describe the latency period for obstructive airway disease (OAD) diagnoses. This prospective cohort study of New York City firefighters compared the timing and incidence of physician-diagnosed OAD relative to WTC exposure. Exposure was categorized by WTC arrival time as high (on the morning of September 11, 2001), moderate (after noon on September 11, 2001, or on September 12, 2001), or low (during September 13-24, 2001). We modeled relative rates and 95% confidence intervals of OAD incidence by exposure over the first 5 years after September 11, 2001, estimating the times of change in the relative rate with change point models. We observed a change point at 15 months after September 11, 2001. Before 15 months, the relative rate for the high- versus low-exposure group was 3.96 (95% confidence interval: 2.51, 6.26) and thereafter, it was 1.76 (95% confidence interval: 1.26, 2.46). Incident OAD was associated with WTC exposure for at least 5 years after September 11, 2001. There were higher rates of new-onset OAD among the high-exposure group during the first 15 months and, to a lesser extent, throughout follow-up. This difference in relative rate by exposure occurred despite full and free access to health care for all WTC-exposed firefighters, demonstrating the persistence of WTC-associated OAD risk.

  18. Estimating the Time Interval Between Exposure to the World Trade Center Disaster and Incident Diagnoses of Obstructive Airway Disease

    PubMed Central

    Glaser, Michelle S.; Webber, Mayris P.; Zeig-Owens, Rachel; Weakley, Jessica; Liu, Xiaoxue; Ye, Fen; Cohen, Hillel W.; Aldrich, Thomas K.; Kelly, Kerry J.; Nolan, Anna; Weiden, Michael D.; Prezant, David J.; Hall, Charles B.

    2014-01-01

    Respiratory disorders are associated with occupational and environmental exposures. The latency period between exposure and disease onset remains uncertain. The World Trade Center (WTC) disaster presents a unique opportunity to describe the latency period for obstructive airway disease (OAD) diagnoses. This prospective cohort study of New York City firefighters compared the timing and incidence of physician-diagnosed OAD relative to WTC exposure. Exposure was categorized by WTC arrival time as high (on the morning of September 11, 2001), moderate (after noon on September 11, 2001, or on September 12, 2001), or low (during September 13–24, 2001). We modeled relative rates and 95% confidence intervals of OAD incidence by exposure over the first 5 years after September 11, 2001, estimating the times of change in the relative rate with change point models. We observed a change point at 15 months after September 11, 2001. Before 15 months, the relative rate for the high- versus low-exposure group was 3.96 (95% confidence interval: 2.51, 6.26) and thereafter, it was 1.76 (95% confidence interval: 1.26, 2.46). Incident OAD was associated with WTC exposure for at least 5 years after September 11, 2001. There were higher rates of new-onset OAD among the high-exposure group during the first 15 months and, to a lesser extent, throughout follow-up. This difference in relative rate by exposure occurred despite full and free access to health care for all WTC-exposed firefighters, demonstrating the persistence of WTC-associated OAD risk. PMID:24980522

  19. The Role of Vascular Endothelial Growth Factor in Small-airway Remodelling in a Rat Model of Chronic Obstructive Pulmonary Disease

    PubMed Central

    Wang, Lu; Xu, Zhibo; Chen, Bin; He, Wei; Hu, Jingxian; Zhang, Liting; Liu, Xianzhong; Chen, Fang

    2017-01-01

    Small-airway remodelling is one of the most remarkable pathological features of chronic obstructive pulmonary disease (COPD), in which angiogenesis plays a critical role that contributes to disease progression. The endothelial cell-specific mitogen vascular endothelial growth factor (VEGF), as well as its receptors, VEGFR1, VEGFR2, are thought to be the major mediators of pathological angiogenesis, and sunitinib exhibits anti-angiogenesis property through VEGF blockage and has been widely used to treat various cancers. In our study, Sprague-Dawley rats were subjected to lipopolysaccharide (LPS) injection and cigarette smoke (CS) inhalation to induce COPD, following sunitinib administration was conducted. Haematoxylin-eosin, Masson staining and immunostaining analysis were used to evaluate the pathological changes; quantitative real-time PCR and enzyme-linked immunosorbent assay were performed to provide more compelling data on the function of VEGF, VEGFR1, VEGFR2 in angiogenesis. Sunitinib treatment was associated with less angiogenesis in small-airway remodelling with a slightly disordered lung architecture, and lower expression level of VEGF, VEGFR1, VEGFR2. Overall, our results indicate that VEGF is a vital important factor that contributes to the small-airway remodelling in a rat model of COPD through promoting angiogenesis, which mainly depend on the specific binding between VEGF and VEGFR1 and can be effectively attenuated by sunitinib. PMID:28117425

  20. Lymphocyte Gene Expression Characteristic of Immediate Airway Responses (IAR) and Methacholine (MCH) Hyperresponsiveness in Mice Sensitized and Challenged with Isocyanates

    EPA Science Inventory

    Exposure to isocyanates has been associated with occupational airway diseases, including asthma. Previously we reported on respiratory and immune responses following dermal sensitization and intranasal challenge of BALB/c mice with 6 different isocyanates. The purpose of this st...

  1. Airway complications after lung transplantation.

    PubMed

    Machuzak, Michael; Santacruz, Jose F; Gildea, Thomas; Murthy, Sudish C

    2015-01-01

    Airway complications after lung transplantation present a formidable challenge to the lung transplant team, ranging from mere unusual images to fatal events. The exact incidence of complications is wide-ranging depending on the type of event, and there is still evolution of a universal characterization of the airway findings. Management is also wide-ranging. Simple observation or simple balloon bronchoplasty is sufficient in many cases, but vigilance following more severe necrosis is required for late development of both anastomotic and nonanastomotic airway strictures. Furthermore, the impact of coexisting infection, rejection, and medical disease associated with high-level immunosuppression further complicates care.

  2. Macrophage/epithelial cell CCL2 contributes to rhinovirus-induced hyperresponsiveness and inflammation in a mouse model of allergic airways disease.

    PubMed

    Schneider, Dina; Hong, Jun Young; Bowman, Emily R; Chung, Yutein; Nagarkar, Deepti R; McHenry, Christina L; Goldsmith, Adam M; Bentley, J Kelley; Lewis, Toby C; Hershenson, Marc B

    2013-02-01

    Human rhinovirus (HRV) infections lead to exacerbations of lower airways disease in asthmatic patients but not in healthy individuals. However, underlying mechanisms remain to be completely elucidated. We hypothesized that the Th2-driven allergic environment enhances HRV-induced CC chemokine production, leading to asthma exacerbations. Ovalbumin (OVA)-sensitized and -challenged mice inoculated with HRV showed significant increases in the expression of lung CC chemokine ligand (CCL)-2/monocyte chemotactic protein (MCP)-1, CCL4/macrophage inflammatory protein (MIP)-1β, CCL7/MCP-3, CCL19/MIP-3β, and CCL20/MIP3α compared with mice treated with OVA alone. Inhibition of CCL2 with neutralizing antibody significantly attenuated HRV-induced airways inflammation and hyperresponsiveness in OVA-treated mice. Immunohistochemical stains showed colocalization of CCL2 with HRV in epithelial cells and CD68-positive macrophages, and flow cytometry showed increased CCL2(+), CD11b(+) cells in the lungs of OVA-treated, HRV-infected mice. Compared with lung macrophages from naïve mice, macrophages from OVA-exposed mice expressed significantly more CCL2 in response to HRV infection ex vivo. Pretreatment of mouse lung macrophages and BEAS-2B human bronchial epithelial cells with interleukin (IL)-4 and IL-13 increased HRV-induced CCL2 expression, and mouse lung macrophages from IL-4 receptor knockout mice showed reduced CCL2 expression in response to HRV, suggesting that exposure to these Th2 cytokines plays a role in the altered HRV response. Finally, bronchoalveolar macrophages from children with asthma elaborated more CCL2 upon ex vivo exposure to HRV than cells from nonasthmatic patients. We conclude that CCL2 production by epithelial cells and macrophages contributes to HRV-induced airway hyperresponsiveness and inflammation in a mouse model of allergic airways disease and may play a role in HRV-induced asthma exacerbations.

  3. Repeat perfusion imaging may differentiate airways obstruction from pulomonary embolic disease: report of two cases

    SciTech Connect

    Greenspon, L.W.; LaManna, M.M.; Dhand, S.

    1987-06-01

    Two cases are presented in which patients with obstructive lung disease were considered to have a pulmonary embolism (PE). Emergency lung perfusion scans supported the diagnosis of PE in both cases. However, rapid resolution of the symptoms and perfusion defects by repeat ventilation-perfusion scanning at 24 hr suggested that PE was unlikely. In selected cases of wheezing patients, repeat perfusion scans may obviate the need for pulmonary angiography. The authors report two cases in which repeat perfusion scans almost normalized by 24 hr. Review of the literature indicates that the rate of resolution of perfusion defects would have been much slower had pulmonary embolism occurred.

  4. Respiratory syncytial virus predisposes mice to augmented allergic airway responses via IL-13-mediated mechanisms.

    PubMed

    Lukacs, N W; Tekkanat, K K; Berlin, A; Hogaboam, C M; Miller, A; Evanoff, H; Lincoln, P; Maassab, H

    2001-07-15

    The development of severe childhood asthma may be influenced by several factors including environmental and infectious stimuli. The causal relationship between infectious viral responses, such as respiratory syncytial virus (RSV), and severe asthma during early childhood is unclear. In these studies, the ability for an initial RSV infection to exacerbate and promote a more severe asthmatic-type response was investigated by combining established murine models of disease. We examined the ability of RSV to induce exacerbation of allergic disease over a relatively long period, leading to development of severe airway responses including airway inflammation and hyperreactivity. The preferential production of IL-13 during a primary RSV infection appears to play a critical role for the exacerbation of cockroach allergen-induced disease. The depletion of IL-13 during RSV infections inhibited the exacerbation and acceleration of severe allergen-induced airway hyperreactivity. This was indicated by decreases in airway hyperreactivity and changes in lung chemokine production. These data suggest that the airway responses during asthma can be greatly affected by a previous RSV infection, even when infection occurs before allergen sensitization. Overall, infection of the airways with RSV can induce an IL-13-dependent change in airway function and promotes an environment that contributes to the development of severe allergic asthmatic responses.

  5. Air pollution and chronic airway diseases: what should people know and do?

    PubMed

    Jiang, Xu-Qin; Mei, Xiao-Dong; Feng, Di

    2016-01-01

    The health effects of air pollution remain a public health concern worldwide. Exposure to air pollution has many substantial adverse effects on human health. Globally, seven million deaths were attributable to the joint effects of household and ambient air pollution. Subjects with chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma are especially vulnerable to the detrimental effects of air pollutants. Air pollution can induce the acute exacerbation of COPD and onset of asthma, increase the respiratory morbidity and mortality. The health effects of air pollution depend on the components and sources of pollutants, which varied with countries, seasons, and times. Combustion of solid fuels is a major source of air pollutants in developing countries. To reduce the detrimental effects of air pollution, people especially those with COPD or asthma should be aware of the air quality and take extra measures such as reducing the time outdoor and wearing masks when necessary. For reducing the air pollutants indoor, people should use clean fuels and improve the stoves so as to burn fuel more efficiently and vent emissions to the outside. Air cleaners that can improve the air quality efficiently are recommended.

  6. Air pollution and chronic airway diseases: what should people know and do?

    PubMed Central

    Jiang, Xu-Qin; Feng, Di

    2016-01-01

    The health effects of air pollution remain a public health concern worldwide. Exposure to air pollution has many substantial adverse effects on human health. Globally, seven million deaths were attributable to the joint effects of household and ambient air pollution. Subjects with chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma are especially vulnerable to the detrimental effects of air pollutants. Air pollution can induce the acute exacerbation of COPD and onset of asthma, increase the respiratory morbidity and mortality. The health effects of air pollution depend on the components and sources of pollutants, which varied with countries, seasons, and times. Combustion of solid fuels is a major source of air pollutants in developing countries. To reduce the detrimental effects of air pollution, people especially those with COPD or asthma should be aware of the air quality and take extra measures such as reducing the time outdoor and wearing masks when necessary. For reducing the air pollutants indoor, people should use clean fuels and improve the stoves so as to burn fuel more efficiently and vent emissions to the outside. Air cleaners that can improve the air quality efficiently are recommended. PMID:26904251

  7. Airway evaluation in obstructive sleep apnea.

    PubMed

    Stuck, Boris A; Maurer, Joachim T

    2008-12-01

    As the interest in sleep-disordered breathing has increased, various attempts have been made to assess upper airway anatomy in patients with this relatively frequent disorder. The aim is not only to reveal potential differences in upper airway anatomy to better understand origin and pathophysiology of the disease but also to improve patient management and treatment success. The present review is based on a systematic literature search with regard to upper airway evaluation in sleep-disordered breathing; the articles were selected and discussed in light of our clinical experiences. Based on clinical assessment including endoscopy during wakefulness, the value of the Mueller Maneuver, static radiologic imaging techniques (X-ray cephalometry, computed tomography (CT) scanning and magnetic resonance imaging (MRI)), dynamic scanning protocols (e.g. ultrafast CT or cine MRI), upper airway endoscopy during sleep and sedated sleep, pressure measurements and the assessment of the critical closing pressure are discussed. Each technique itself and its history in the field of sleep medicine are briefly reviewed and problems of standardization and interpretation are discussed when appropriate. Insights into the pathophysiology of the disease gained with the help of the investigational techniques are presented and the impact of the techniques on patient management is reported. Although all these additional techniques for upper airway assessment have substantially improved our understanding of sleep-disordered breathing, their significance in daily practice is limited. In contrast to the widespread use of the Mueller maneuver and sedated endoscopy, convincing data supporting their use in terms of treatment outcome are lacking. So far, there is only very limited evidence that selected techniques improve treatment outcome for selected indications. In general, there is not enough evidence that these techniques are superior to the routine clinical assessment.

  8. Wogonin Induces Eosinophil Apoptosis and Attenuates Allergic Airway Inflammation

    PubMed Central

    Dorward, David A.; Sharma, Sidharth; Rennie, Jillian; Felton, Jennifer M.; Alessandri, Ana L.; Duffin, Rodger; Schwarze, Jurgen; Haslett, Christopher; Rossi, Adriano G.

    2015-01-01

    Rationale: Eosinophils are key effector cells in allergic diseases, including allergic rhinitis, eczema, and asthma. Their tissue presence is regulated by both recruitment and increased longevity at inflamed sites. Objectives: To investigate the ability of the flavone wogonin to induce eosinophil apoptosis in vitro and attenuate eosinophil-dominant allergic inflammation in vivo in mice. Methods: Human and mouse eosinophil apoptosis in response to wogonin was investigated by cellular morphology, flow cytometry, mitochondrial membrane permeability, and pharmacological caspase inhibition. Allergic lung inflammation was modeled in mice sensitized and challenged with ovalbumin. Bronchoalveolar lavage (BAL) and lung tissue were examined for inflammation, mucus production, and inflammatory mediator production. Airway hyperresponsiveness to aerosolized methacholine was measured. Measurements and Main Results: Wogonin induced time- and concentration-dependent human and mouse eosinophil apoptosis in vitro. Wogonin-induced eosinophil apoptosis occurred with activation of caspase-3 and was inhibited by pharmacological caspase inhibition. Wogonin administration attenuated allergic airway inflammation in vivo with reductions in BAL and interstitial eosinophil numbers, increased eosinophil apoptosis, reduced airway mucus production, and attenuated airway hyperresponsiveness. This wogonin-induced reduction in allergic airway inflammation was prevented by concurrent caspase inhibition in vivo. Conclusions: Wogonin induces eosinophil apoptosis and attenuates allergic airway inflammation, suggesting that it has therapeutic potential for the treatment of allergic inflammation in humans. PMID:25629436

  9. Educating the Educator: Teaching Airway Adjunct Techniques in Athletic Training

    ERIC Educational Resources Information Center

    Berry, David C.; Seitz, S. Robert

    2011-01-01

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

  10. Current use of beta blockers in patients with reactive airway disease who are hospitalized with acute coronary syndromes.

    PubMed

    Olenchock, Benjamin A; Fonarow, Gregg G; Pan, Wenqin; Hernandez, Adrian; Cannon, Christopher P

    2009-02-01

    Beta blockers have a proven benefit in the management of patients with acute coronary syndromes (ACS) and for secondary prevention of coronary events. Current guidelines list such reactive airway diseases (RADs) such as asthma and chronic obstructive pulmonary disease as relative contraindications to beta-blocker use. However, the co-morbid burden of RAD and coronary heart disease is substantial, and data suggest that the treatment benefit of beta blockers is shared by patients with RAD. The Get with the Guidelines (GWTG) database was used to evaluate use of beta blockers within 24 hours of admission and at discharge in patients with ACS with (n = 12,967) and without (n = 81,140) a history of RAD. Data were collected in 435 hospitals between January 2000 and September 2006. A multivariable logistic regression model was used to determine predictors of beta-blocker treatment. In patients with no RAD history, beta-blocker prescription rates were 78.3% at admission and 88.7% at discharge; in patients with a RAD history, rates were 65.6% at admission and 77.2% at discharge. Compared with patients with no history of RAD, patients with a history of RAD were 42% less likely (odds ratio 0.58, confidence interval 0.54 to 0.62, p <0.0001) to receive a beta blocker upon admission and 55% less likely (odds ratio 0.45, confidence interval 0.41 to 0.48, p <0.0001) to receive a beta blocker at discharge in multivariable analysis. Among all other clinical factors, RAD history was the most significant predictor of likelihood of not receiving a beta blocker at admission or discharge. Receipt of beta blockers within 24 hours after admission was associated with a lower in-hospital mortality rate for patients with RAD (odds ratio = 0.52, p <0.001) and for patients without RAD (odds ratio = 0.38, p <0.001). Careful assessment of beta-blocker safety and RAD severity by physicians is needed to improve beta-blocker prescription rates in this large group of patients with ACS.

  11. Biofilm-dependent airway infections: a role for ambroxol?

    PubMed

    Cataldi, M; Sblendorio, V; Leo, A; Piazza, O

    2014-08-01

    Biofilms are a key factor in the development of both acute and chronic airway infections. Their relevance is well established in ventilator associated pneumonia, one of the most severe complications in critically ill patients, and in cystic fibrosis, the most common lethal genetic disease in Caucasians. Accumulating evidence suggests that biofilms could have also a role in chronic obstructive pulmonary disease and their involvement in bronchiectasis has been proposed as well. When they grow in biofilms, microorganisms become multidrug-resistant. Therefore the treatment of biofilm-dependent airway infections is problematic. Indeed, it still largely based on measures aiming to prevent the formation of biofilms or remove them once that they are formed. Here we review recent evidence suggesting that the mucokinetic drug ambroxol has specific anti-biofilm properties. We also discuss how additional pharmacological properties of this drug could be beneficial in biofilm-dependent airway infections. Specifically, we review the evidence showing that: 1-ambroxol exerts anti-inflammatory effects by inhibiting at multiple levels the activity of neutrophils, and 2-it improves mucociliary clearance by interfering with the activity of airway epithelium ion channels and transporters including sodium/bicarbonate and sodium/potassium/chloride cotransporters, cystic fibrosis transmembrane conductance regulator and aquaporins. As a whole, the data that we review here suggest that ambroxol could be helpful in biofilm-dependent airway infections. However, considering the limited clinical evidence available up to date, further clinical studies are required to support the use of ambroxol in these diseases.

  12. Toxicity of aged gasoline exhaust particles to normal and diseased airway epithelia

    PubMed Central

    Künzi, Lisa; Krapf, Manuel; Daher, Nancy; Dommen, Josef; Jeannet, Natalie; Schneider, Sarah; Platt, Stephen; Slowik, Jay G.; Baumlin, Nathalie; Salathe, Matthias; Prévôt, André S. H.; Kalberer, Markus; Strähl, Christof; Dümbgen, Lutz; Sioutas, Constantinos; Baltensperger, Urs; Geiser, Marianne

    2015-01-01

    Particulate matter (PM) pollution is a leading cause of premature death, particularly in those with pre-existing lung disease. A causative link between particle properties and adverse health effects remains unestablished mainly due to complex and variable physico-chemical PM parameters. Controlled laboratory experiments are required. Generating atmospherically realistic aerosols and performing cell-exposure studies at relevant particle-doses are challenging. Here we examine gasoline-exhaust particle toxicity from a Euro-5 passenger car in a uniquely realistic exposure scenario, combining a smog chamber simulating atmospheric ageing, an aerosol enrichment system varying particle number concentration independent of particle chemistry, and an aerosol deposition chamber physiologically delivering particles on air-liquid interface (ALI) cultures reproducing normal and susceptible health status. Gasoline-exhaust is an important PM source with largely unknown health effects. We investigated acute responses of fully-differentiated normal, distressed (antibiotics-treated) normal, and cystic fibrosis human bronchial epithelia (HBE), and a proliferating, single-cell type bronchial epithelial cell-line (BEAS-2B). We show that a single, short-term exposure to realistic doses of atmospherically-aged gasoline-exhaust particles impairs epithelial key-defence mechanisms, rendering it more vulnerable to subsequent hazards. We establish dose-response curves at realistic particle-concentration levels. Significant differences between cell models suggest the use of fully-differentiated HBE is most appropriate in future toxicity studies. PMID:26119831

  13. Toxicity of aged gasoline exhaust particles to normal and diseased airway epithelia.

    PubMed

    Künzi, Lisa; Krapf, Manuel; Daher, Nancy; Dommen, Josef; Jeannet, Natalie; Schneider, Sarah; Platt, Stephen; Slowik, Jay G; Baumlin, Nathalie; Salathe, Matthias; Prévôt, André S H; Kalberer, Markus; Strähl, Christof; Dümbgen, Lutz; Sioutas, Constantinos; Baltensperger, Urs; Geiser, Marianne

    2015-06-29

    Particulate matter (PM) pollution is a leading cause of premature death, particularly in those with pre-existing lung disease. A causative link between particle properties and adverse health effects remains unestablished mainly due to complex and variable physico-chemical PM parameters. Controlled laboratory experiments are required. Generating atmospherically realistic aerosols and performing cell-exposure studies at relevant particle-doses are challenging. Here we examine gasoline-exhaust particle toxicity from a Euro-5 passenger car in a uniquely realistic exposure scenario, combining a smog chamber simulating atmospheric ageing, an aerosol enrichment system varying particle number concentration independent of particle chemistry, and an aerosol deposition chamber physiologically delivering particles on air-liquid interface (ALI) cultures reproducing normal and susceptible health status. Gasoline-exhaust is an important PM source with largely unknown health effects. We investigated acute responses of fully-differentiated normal, distressed (antibiotics-treated) normal, and cystic fibrosis human bronchial epithelia (HBE), and a proliferating, single-cell type bronchial epithelial cell-line (BEAS-2B). We show that a single, short-term exposure to realistic doses of atmospherically-aged gasoline-exhaust particles impairs epithelial key-defence mechanisms, rendering it more vulnerable to subsequent hazards. We establish dose-response curves at realistic particle-concentration levels. Significant differences between cell models suggest the use of fully-differentiated HBE is most appropriate in future toxicity studies.

  14. Toxicity of aged gasoline exhaust particles to normal and diseased airway epithelia

    NASA Astrophysics Data System (ADS)

    Künzi, Lisa; Krapf, Manuel; Daher, Nancy; Dommen, Josef; Jeannet, Natalie; Schneider, Sarah; Platt, Stephen; Slowik, Jay G.; Baumlin, Nathalie; Salathe, Matthias; Prévôt, André S. H.; Kalberer, Markus; Strähl, Christof; Dümbgen, Lutz; Sioutas, Constantinos; Baltensperger, Urs; Geiser, Marianne

    2015-06-01

    Particulate matter (PM) pollution is a leading cause of premature death, particularly in those with pre-existing lung disease. A causative link between particle properties and adverse health effects remains unestablished mainly due to complex and variable physico-chemical PM parameters. Controlled laboratory experiments are required. Generating atmospherically realistic aerosols and performing cell-exposure studies at relevant particle-doses are challenging. Here we examine gasoline-exhaust particle toxicity from a Euro-5 passenger car in a uniquely realistic exposure scenario, combining a smog chamber simulating atmospheric ageing, an aerosol enrichment system varying particle number concentration independent of particle chemistry, and an aerosol deposition chamber physiologically delivering particles on air-liquid interface (ALI) cultures reproducing normal and susceptible health status. Gasoline-exhaust is an important PM source with largely unknown health effects. We investigated acute responses of fully-differentiated normal, distressed (antibiotics-treated) normal, and cystic fibrosis human bronchial epithelia (HBE), and a proliferating, single-cell type bronchial epithelial cell-line (BEAS-2B). We show that a single, short-term exposure to realistic doses of atmospherically-aged gasoline-exhaust particles impairs epithelial key-defence mechanisms, rendering it more vulnerable to subsequent hazards. We establish dose-response curves at realistic particle-concentration levels. Significant differences between cell models suggest the use of fully-differentiated HBE is most appropriate in future toxicity studies.

  15. IL-13–induced airway mucus production is attenuated by MAPK13 inhibition

    PubMed Central

    Alevy, Yael G.; Patel, Anand C.; Romero, Arthur G.; Patel, Dhara A.; Tucker, Jennifer; Roswit, William T.; Miller, Chantel A.; Heier, Richard F.; Byers, Derek E.; Brett, Tom J.; Holtzman, Michael J.

    2012-01-01

    Increased mucus production is a common cause of morbidity and mortality in inflammatory airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the precise molecular mechanisms for pathogenic mucus production are largely undetermined. Accordingly, there are no specific and effective anti-mucus therapeutics. Here, we define a signaling pathway from chloride channel calcium-activated 1 (CLCA1) to MAPK13 that is responsible for IL-13–driven mucus production in human airway epithelial cells. The same pathway was also highly activated in the lungs of humans with excess mucus production due to COPD. We further validated the pathway by using structure-based drug design to develop a series of novel MAPK13 inhibitors with nanomolar potency that effectively reduced mucus production in human airway epithelial cells. These results uncover and validate a new pathway for regulating mucus production as well as a corresponding therapeutic approach to mucus overproduction in inflammatory airway diseases. PMID:23187130

  16. Myeloid sarcoma causing airway obstruction

    PubMed Central

    Krause, John R.

    2017-01-01

    Myeloid sarcoma is an extramedullary collection of blasts of the myeloid series that partially or totally effaces the architecture of the tissue in which it is found. These tumors have been described in many sites of the body, but the skin, lymph nodes, gastrointestinal tract, bone, soft tissue, and testes are most common. They can arise in a patient following the diagnosis of acute myeloid leukemia, but they may also be precursors of leukemia and should be considered diagnostic for acute myeloid leukemia. The differential diagnosis of this neoplasm includes malignant lymphoma, with which it is often mistaken, leading to diagnostic and therapeutic delays. We present the case of an 84-year-old African American man with a history of renal disease secondary to hypertension and coronary artery disease without any prior history of malignancies who presented with airway obstruction. He was diagnosed with a myeloid sarcoma of the mediastinum compressing his trachea.

  17. Directed differentiation of airway epithelial cells of human bone marrow mesenchymal stem cells.

    PubMed

    Li, Jian-Dong

    2016-11-01

    The ability to generate lung and airway epithelial cells from human bone marrow mesenchymal stem cells (hBMSCs) would have applications in regenerative medicine, modeling of lung disease, drug screening, and studies of human lung development. In this research, hBMSCs were cultured in specialized airway epithelial cell growth media for differentiation of airway epithelial cells, including keratinocyte growth factor transferrin, bovine pituitary extract, epinephrine, triiodothyronine and retinoic acid. The surfactant protein C, a specific marker of type II pneumocytes, and its corresponding protein were demonstrated by immunofluorescence and western blotting after differentiation of airway epithelial cells, respectively. These cells were then transferred into an induced acute lung injury model. The results showed that the hBMSCs could induce differentiation in airway epithelial cells under the special conditions of the medium, the result for surfactant protein C was positive in differentiated airway epithelial cells using immunofluorescence and western blotting, and these cells were successfully colonized in the injured lung airway. In conclusion, our research shows that a population of airway epithelial cells can be specifically generated from hBMSCs and that induced cells may be allowed to participate in tissue repair.

  18. Acquisition and adaptation of the airway microbiota in the early life of cystic fibrosis patients.

    PubMed

    Boutin, Sébastien; Dalpke, Alexander H

    2017-12-01

    Cystic fibrosis (CF) is a genetic disease in which bacterial infections of the airways play a major role in the long-term clinical outcome. In recent years, a number of next-generation sequencing (NGS)-based studies aimed at deciphering the structure and composition of the airways' microbiota. It was shown that the nasal cavity of CF patients displays dysbiosis early in life indicating a failure in the first establishment of a healthy microbiota. In contrast, within the conducting and lower airways, the establishment occurs normally first, but is sensitive to future dysbiosis including chronic infections with classical pathogens in later life. The objective of this mini-review is to give an update on the current knowledge about the development of the microbiota in the early life of CF patients. Microbial acquisition in the human airways can be described by the island model: Microbes found in the lower airways of CF patients represent "islands" that are at first populated from the upper airways reflecting the "mainland." Colonization can be modeled following the neutral theory in which the most abundant bacteria in the mainland are also frequently found in the lower airways initially. At later times, however, the colonization process of the lower airways segregates by active selection of specific microbes. Future research should focus on those processes of microbial and host interactions to understand how microbial communities are shaped on short- and long-term scales. We point out what therapeutic consequences arise from the microbiome data obtained within ecological framework models.

  19. Apoptosis and the Airway Epithelium

    PubMed Central

    White, Steven R.

    2011-01-01

    The airway epithelium functions as a barrier and front line of host defense in the lung. Apoptosis or programmed cell death can be elicited in the epithelium as a response to viral infection, exposure to allergen or to environmental toxins, or to drugs. While apoptosis can be induced via activation of death receptors on the cell surface or by disruption of mitochondrial polarity, epithelial cells compared to inflammatory cells are more resistant to apoptotic stimuli. This paper focuses on the response of airway epithelium to apoptosis in the normal state, apoptosis as a potential regulator of the number and types of epithelial cells in the airway, and the contribution of epithelial cell apoptosis in important airways diseases. PMID:22203854

  20. Airway drug pharmacokinetics via analysis of exhaled breath condensate.

    PubMed

    Esther, Charles R; Boucher, Richard C; Johnson, M Ross; Ansede, John H; Donn, Karl H; O'Riordan, Thomas G; Ghio, Andrew J; Hirsh, Andrew J

    2014-02-01

    Although the airway surface is the anatomic target for many lung disease therapies, measuring drug concentrations and activities on these surfaces poses considerable challenges. We tested whether mass spectrometric analysis of exhaled breath condensate (EBC) could be utilized to non-invasively measure airway drug pharmacokinetics and predicted pharmacological activities. Mass spectrometric methods were developed to detect a novel epithelial sodium channel blocker (GS-9411/P-680), two metabolites, a chemically related internal standard, plus naturally occurring solutes including urea as a dilution marker. These methods were then applied to EBC and serum collected from four (Floridian) sheep before, during and after inhalation of nebulized GS-9411/P-680. Electrolyte content of EBC and serum was also assessed as a potential pharmacodynamic marker of drug activity. Airway surface concentrations of drug, metabolites, and electrolytes were calculated from EBC measures using EBC:serum urea based dilution factors. GS-9411/P-680 and its metabolites were quantifiable in the sheep EBC, with peak airway concentrations between 1.9 and 3.4 μM measured 1 h after inhalation. In serum, only Metabolite #1 was quantifiable, with peak concentrations ∼60-fold lower than those in the airway (45 nM at 1 h). EBC electrolyte concentrations suggested a pharmacological effect; but this effect was not statistical significant. Analysis of EBC collected during an inhalation drug study provided a method for quantification of airway drug and metabolites via mass spectrometry. Application of this methodology could provide an important tool in development and testing of drugs for airways diseases.

  1. The Phillips airway.

    PubMed

    Haridas, R P; Wilkinson, D J

    2012-07-01

    The Phillips airway was developed by George Ramsay Phillips. There is no known original description of the airway and the earliest known reference to it is from 1919. The airway and its modifications are described.

  2. Gene Delivery to the Airway

    PubMed Central

    Keiser, Nicholas W.; Engelhardt, John F.

    2013-01-01

    This unit describes generation of and gene transfer to several commonly used airway models. Isolation and transduction of primary airway epithelial cells are first described. Next, the preparation of polarized airway epithelial monolayers is outlined. Transduction of these polarized cells is also described. Methods are presented for generation of tracheal xenografts as well as both ex vivo and in vivo gene transfer to these xenografts. Finally, a method for in vivo gene delivery to the lungs of rodents is included. Methods for evaluating transgene expression are given in the support protocols. PMID:23853081

  3. Geometric tree kernels: classification of COPD from airway tree geometry.

    PubMed

    Feragen, Aasa; Petersen, Jens; Grimm, Dominik; Dirksen, Asger; Pedersen, Jesper Holst; Borgwardt, Karsten; de Bruijne, Marleen

    2013-01-01

    Methodological contributions: This paper introduces a family of kernels for analyzing (anatomical) trees endowed with vector valued measurements made along the tree. While state-of-the-art graph and tree kernels use combinatorial tree/graph structure with discrete node and edge labels, the kernels presented in this paper can include geometric information such as branch shape, branch radius or other vector valued properties. In addition to being flexible in their ability to model different types of attributes, the presented kernels are computationally efficient and some of them can easily be computed for large datasets (N - 10.000) of trees with 30 - 600 branches. Combining the kernels with standard machine learning tools enables us to analyze the relation between disease and anatomical tree structure and geometry. Experimental results: The kernels are used to compare airway trees segmented from low-dose CT, endowed with branch shape descriptors and airway wall area percentage measurements made along the tree. Using kernelized hypothesis testing we show that the geometric airway trees are significantly differently distributed in patients with Chronic Obstructive Pulmonary Disease (COPD) than in healthy individuals. The geometric tree kernels also give a significant increase in the classification accuracy of COPD from geometric tree structure endowed with airway wall thickness measurements in comparison with state-of-the-art methods, giving further insight into the relationship between airway wall thickness and COPD. Software: Software for computing kernels and statistical tests is available at http://image.diku.dk/aasa/software.php.

  4. Cardiovascular risk and mortality in end-stage renal disease patients undergoing dialysis: sleep study, pulmonary function, respiratory mechanics, upper airway collapsibility, autonomic nervous activity, depression, anxiety, stress and quality of life: a prospective, double blind, randomized controlled clinical trial

    PubMed Central

    2013-01-01

    Background Chronic kidney disease (CKD) is one of the most serious public health problems. The increasing prevalence of CKD in developed and developing countries has led to a global epidemic. The hypothesis proposed is that patients undergoing dialysis would experience a marked negative influence on physiological variables of sleep and autonomic nervous system activity, compromising quality of life. Methods/Design A prospective, consecutive, double blind, randomized controlled clinical trial is proposed to address the effect of dialysis on sleep, pulmonary function, respiratory mechanics, upper airway collapsibility, autonomic nervous activity, depression, anxiety, stress and quality of life in patients with CKD. The measurement protocol will include body weight (kg); height (cm); body mass index calculated as weight/height2; circumferences (cm) of the neck, waist, and hip; heart and respiratory rates; blood pressures; Mallampati index; tonsil index; heart rate variability; maximum ventilatory pressures; negative expiratory pressure test, and polysomnography (sleep study), as well as the administration of specific questionnaires addressing sleep apnea, excessive daytime sleepiness, depression, anxiety, stress, and quality of life. Discussion CKD is a major public health problem worldwide, and its incidence has increased in part by the increased life expectancy and increasing number of cases of diabetes mellitus and hypertension. Sleep disorders are common in patients with renal insufficiency. Our hypothesis is that the weather weight gain due to volume overload observed during interdialytic period will influence the degree of collapsibility of the upper airway due to narrowing and predispose to upper airway occlusion during sleep, and to investigate the negative influences of haemodialysis in the physiological variables of sleep, and autonomic nervous system, and respiratory mechanics and thereby compromise the quality of life of patients. Trial registration The

  5. Blockage of upper airway

    MedlinePlus

    ... Airway obstruction - acute upper Images Throat anatomy Choking Respiratory system References Cukor J, Manno M. Pediatric respiratory emergencies: upper airway obstruction and infections. In: Marx ...

  6. Advances in upper airway cough syndrome.

    PubMed

    Yu, Li; Xu, Xianghuai; Lv, Hanjing; Qiu, Zhongmin

    2015-05-01

    Upper airway cough syndrome (UACS), previously referred to as postnasal drip syndrome, is one of the most common causes of chronic cough. However, the pathogenesis of UACS/postnasal drip syndrome remains unclear, and physicians in countries throughout the world have different definitions and ways of treating this disease. The various proposed pathogeneses of UACS include the early postnasal drip theory, subsequent chronic airway inflammation theory, and a recent sensory neural hypersensitivity theory. Additionally, some researchers suggest that UACS is a clinical phenotype of cough hypersensitivity syndrome. While the general principles involved in treating UACS are similar throughout the world, the specific details of treatment differ. This review summarizes the various definitions, pathogenic mechanisms, treatments, and other aspects of UACS, to aid clinicians in expanding their knowledge of how to diagnose and treat this syndrome.

  7. Liquid secretion properties of airway submucosal glands

    PubMed Central

    Ballard, Stephen T; Inglis, Sarah K

    2004-01-01

    The tracheobronchial submucosal glands secrete liquid that is important for hydrating airway surfaces, supporting mucociliary transport, and serving as a fluid matrix for numerous secreted macromolecules including the gel-forming mucins. This review details the essential structural elements of airway glands and summarizes what is currently known regarding the ion transport processes responsible for producing the liquid component of gland secretion. Liquid secretion most likely arises from serous cells and is principally under neural control with muscarinic agonists, substance P, and vasoactive intestinal peptide (VIP) functioning as effective secretogogues. Liquid secretion is driven by the active transepithelial secretion of both Cl− and HCO3− and at least a portion of this process is mediated by the cystic fibrosis transmembrane conductance regulator (CFTR), which is highly expressed in glands. The potential role of submucosal glands in cystic fibrosis lung disease is discussed. PMID:14660706

  8. The Airway Microbiome at Birth

    PubMed Central

    Lal, Charitharth Vivek; Travers, Colm; Aghai, Zubair H.; Eipers, Peter; Jilling, Tamas; Halloran, Brian; Carlo, Waldemar A.; Keeley, Jordan; Rezonzew, Gabriel; Kumar, Ranjit; Morrow, Casey; Bhandari, Vineet; Ambalavanan, Namasivayam

    2016-01-01

    Alterations of pulmonary microbiome have been recognized in multiple respiratory disorders. It is critically important to ascertain if an airway microbiome exists at birth and if so, whether it is associated with subsequent lung disease. We found an established diverse and similar airway microbiome at birth in both preterm and term infants, which was more diverse and different from that of older preterm infants with established chronic lung disease (bronchopulmonary dysplasia). Consistent temporal dysbiotic changes in the airway microbiome were seen from birth to the development of bronchopulmonary dysplasia in extremely preterm infants. Genus Lactobacillus was decreased at birth in infants with chorioamnionitis and in preterm infants who subsequently went on to develop lung disease. Our results, taken together with previous literature indicating a placental and amniotic fluid microbiome, suggest fetal acquisition of an airway microbiome. We speculate that the early airway microbiome may prime the developing pulmonary immune system, and dysbiosis in its development may set the stage for subsequent lung disease. PMID:27488092

  9. Intranasal administration of a combination of choline chloride, vitamin C, and selenium attenuates the allergic effect in a mouse model of airway disease.

    PubMed

    Bansal, Preeti; Saw, Sanjay; Govindaraj, Dhanapal; Arora, Naveen

    2014-08-01

    Respiratory allergic disease is an inflammatory condition accompanied by oxidative stress. Supplementation of an anti-inflammatory agent with antioxidants may have a therapeutic effect. In this study, the effects of choline chloride in combination with antioxidants were evaluated via the intranasal route in a mouse model of allergic airway disease. Balb/c mice were sensitized on days 0, 7, and 14 and challenged on days 25-30 with cockroach extract (CE) and with a booster challenge on day 38. They were treated with choline chloride (ChCl; 1mg/kg), vitamin C (Vit C; 308.33 mg/kg), and selenium (Se; 1mg/kg) alone or in combination via the intranasal route on days 31, 33, 35, 37, and 39. The mice were sacrificed on day 40 to collect blood, bronchoalveolar lavage fluid, lungs, and spleen. Mice immunized with CE showed a significant increase in airway hyperresponsiveness (AHR), lung inflammation, Th2 cytokines, and the oxidative stress markers intracellular reactive oxygen species and 8-isoprostanes compared to the phosphate-buffered saline control group. A significant decrease was observed in these parameters with all the treatments (p<0.01). The highest decrease was noticed in the ChCl+Vit C+Se-treated group, with AHR decreased to the normal level. This group also showed the highest decrease in airway inflammation (p<0.001), IL-4 and IL-5 (p<0.001), IgE and IgG1 (p<0.001), NF-κB (p<0.001), and 8-isoprostane levels (p<0.001). Glutathione peroxidase activity, which was decreased significantly in CE-immunized mice, was restored to normal levels in this group (p<0.001). IL-10 level was decreased in CE-immunized mice and was restored to normal by combination treatment. The combination treatment induced FOXP3(+) cells in splenocyte culture, responsible for the upregulation of IL-10. In conclusion, the combination of choline chloride, vitamin C, and selenium via the intranasal route reduces AHR, inflammation, and oxidative stress, probably by causing IL-10 production by FOXP

  10. Effects of second hand smoke on airway secretion and mucociliary clearance

    PubMed Central

    Liu, Yanyan; Di, Y. Peter

    2012-01-01

    The airway acts as the first defense against inhaled pathogens and particulate matter from the environment. One major way for the airway to clear inhaled foreign objects is through mucociliary clearance (MCC), an important component of the respiratory innate immune defense against lung disease. MCC is characterized by the upward movement of mucus by ciliary motion that requires a balance between the volume and composition of the mucus, adequate periciliary liquid (PCL) volume, and normal ciliary beat frequency (CBF). Airway surface fluid (ASL) is a thin layer liquid that consists of the highly viscous mucus upper “gel” layer, and the watery lubricating lower “sol” layer. Mucus production, secretion and clearance are considered to play a critical role in maintenance of airway health because it maintains hydration in the airway and traps particulates, bacteria, and viruses. Different types of epithelial cells, including secretory cells, and ciliated cells, contribute to the MCC function. Cigarette smoke (CS) contains chemicals and particulates that significantly affect airway secretion. Active and passive CS-induced chronic obstructive pulmonary disease (COPD) is frequently associated with hyperplasia of goblet cells and submucosal glands (SMGs), thus increasing the secretory capacity of the airways that impairs MCC. PMID:22973232

  11. Role of nicotinic receptors and acetylcholine in mucous cell metaplasia, hyperplasia and airway mucus formation in vitro and in vivo

    PubMed Central

    Gundavarapu, Sravanthi; Wilder, Julie A.; Mishra, Neerad C.; Rir-sima-ah, Jules; Langley, Raymond J.; Singh, Shashi P.; Saeed, Ali Imran; Jaramillo, Richard J.; Gott, Katherine M.; Peña-Philippides, Juan Carlos; Harrod, Kevin S.; McIntosh, J. Michael; Buch, Shilpa; Sopori, Mohan L.

    2012-01-01

    Background Airway mucus hypersecretion is a key pathophysiological feature in number of lung diseases. Cigarette smoke/nicotine and allergens are strong stimulators of airway mucus; however, the mechanism of mucus modulation is unclear. Objectives Characterize the pathway by which cigarette smoke/nicotine regulates airway mucus and identify agents that decrease airway mucus. Methods IL-13 and gamma-aminobutyric acid receptors (GABAARs) are implicated in airway mucus. We examined the role of IL-13 and GABAARs in nicotine-induced mucus formation in normal human bronchial epithelial (NHBE) and A549 cells, and secondhand cigarette smoke and/or ovalbumin-induced mucus formation in vivo. Results Nicotine promotes mucus formation in NHBE cells; however, the nicotine-induced mucus formation is independent of IL-13 but sensitive to the GABAAR antagonist picrotoxin (PIC). Airway epithelial cells express α7/α9/α10 nicotinic acetylcholine receptors (nAChRs) and specific inhibition or knockdown of α7- but not α9/α10-nAChRs abrogates mucus formation in response to nicotine and IL-13. Moreover, addition of acetylcholine or inhibition of its degradation increases mucus in NHBE cells. Nicotinic but not muscarinic receptor antagonists block allergen or nicotine/cigarette smoke-induced airway mucus formation in NHBE cells and/or in mouse airways. Conclusions Nicotine-induced airway mucus formation is independent of IL-13 and α7-nAChRs are critical in airway mucous cell metaplasia/hyperplasia and mucus production in response to various pro-mucoid agents, including IL-13. In the absence of nicotine, acetylcholine may be the biological ligand for α7-nAChRs to trigger airway mucus formation. α7-nAChRs are downstream of IL-13 but upstream of GABAARα2 in the MUC5AC pathway. Acetylcholine and α-7-nAChRs may serve as therapeutic targets to control airway mucus. PMID:22578901

  12. Peak inspiratory flow rate measurement by using In-Check DIAL for the different inhaler devices in elderly with obstructive airway diseases

    PubMed Central

    Kawamatawong, Theerasuk; Khiawwan, Supattra; Pornsuriyasak, Prapaporn

    2017-01-01

    Background Inhaler device technique is a common cause of treatment failure in patients with asthma and chronic obstructive pulmonary disease. Dry powder inhaler (DPI) requires optimal peak inspiratory flow rate (PIFR) for drug delivery. Low PIFR generation is common in the elderly. Patient lung function and intrinsic inhaler resistance are factors for determining generated PIFR and drug delivery from DPI. Objectives We aimed to identify the PIFR of the older (aged >60 years) and the younger (aged ≤60 years) patients with obstructive airway diseases for the different inhaler devices (Turbuhaler® and Accuhaler). Patients and methods A cross-sectional study was conducted from January to December 2014. Patients with obstructive airway diseases were recruited. Spirometry was performed. PIFR was measured by using an In-Check DIAL device. Individual PIFR values for each inhaler device were obtained for three consecutive measurements and then averaged. Results A total of 139 patients diagnosed with obstructive lung diseases (asthma, n = 109; chronic obstructive pulmonary disease, n = 30) were recruited. Of these, 71 patients (51%) were >60 years. The PIFR generated by the patients who were ≤60 years for nonresistance mode was not different from that generated by those aged >60 years (115.0 ± 15.2 L/min vs 115.4 ± 13.3 L/min, p = 0.86). Regarding the DPI, PIFR generated from the older group was significantly lower than that generated from the younger group for Turbuhaler (72.5 ± 18.8 L/min vs 82.4 ± 21.1 L/min, p = 0.01), but the PIFR generated was not significantly different between the older and the younger groups for the Accuhaler (93.8 ± 22.9 L/min vs 99.4 ± 24.2 L/min, p = 0.86). The low peak expiratory flow rate and PIFR from spirometry were associated with the suboptimal PIFR measured by using In-Check DIAL. Discussion Optimal PIFR is critical for DPI use in the elderly; appropriate DPI selection is essential for management. In-Check DIAL may be useful for

  13. Development of allergic airway disease in mice following antibiotic therapy and fungal microbiota increase: role of host genetics, antigen, and interleukin-13.

    PubMed

    Noverr, Mairi C; Falkowski, Nicole R; McDonald, Rod A; McKenzie, Andrew N; Huffnagle, Gary B

    2005-01-01

    Lending support to the hygiene hypothesis, epidemiological studies have demonstrated that allergic disease correlates with widespread use of antibiotics and alterations in fecal microbiota ("microflora"). Antibiotics also lead to overgrowth of the yeast Candida albicans, which can secrete potent prostaglandin-like immune response modulators, from the microbiota. We have recently developed a mouse model of antibiotic-induced gastrointestinal microbiota disruption that is characterized by stable increases in levels of gastrointestinal enteric bacteria and Candida. Using this model, we have previously demonstrated that microbiota disruption can drive the development of a CD4 T-cell-mediated airway allergic response to mold spore challenge in immunocompetent C57BL/6 mice without previous systemic antigen priming. The studies presented here address important questions concerning the universality of the model. To investigate the role of host genetics, we tested BALB/c mice. As with C57BL/6 mice, microbiota disruption promoted the development of an allergic response in the lungs of BALB/c mice upon subsequent challenge with mold spores. In addition, this allergic response required interleukin-13 (IL-13) (the response was absent in IL-13(-/-) mice). To investigate the role of antigen, we subjected mice with disrupted microbiota to intranasal challenge with ovalbumin (OVA). In the absence of systemic priming, only mice with altered microbiota developed airway allergic responses to OVA. The studies presented here demonstrate that the effects of microbiota disruption are largely independent of host genetics and the nature of the antigen and that IL-13 is required for the airway allergic response that follows microbiota disruption.

  14. Strain-Dependent Genomic Factors Affect Allergen-Induced Airway Hyperresponsiveness in Mice

    PubMed Central

    Kelada, Samir N. P.; Wilson, Mark S.; Tavarez, Urraca; Kubalanza, Kari; Borate, Bhavesh; Whitehead, Greg S.; Maruoka, Shuichiro; Roy, Michelle G.; Olive, Michelle; Carpenter, Danielle E.; Brass, David M.; Wynn, Thomas A.; Cook, Donald N.; Evans, Christopher M.; Schwartz, David A.

    2011-01-01

    Asthma is etiologically and clinically heterogeneous, making the genomic basis of asthma difficult to identify. We exploited the strain-dependence of a murine model of allergic airway disease to identify different genomic responses in the lung. BALB/cJ and C57BL/6J mice were sensitized with the immunodominant allergen from the Dermatophagoides pteronyssinus species of house dust mite (Der p 1), without exogenous adjuvant, and the mice then underwent a single challenge with Der p 1. Allergic inflammation, serum antibody titers, mucous metaplasia, and airway hyperresponsiveness were evaluated 72 hours after airway challenge. Whole-lung gene expression analyses were conducted to identify genomic responses to allergen challenge. Der p 1–challenged BALB/cJ mice produced all the key features of allergic airway disease. In comparison, C57BL/6J mice produced exaggerated Th2-biased responses and inflammation, but exhibited an unexpected decrease in airway hyperresponsiveness compared with control mice. Lung gene expression analysis revealed genes that were shared by both strains and a set of down-regulated genes unique to C57BL/6J mice, including several G-protein–coupled receptors involved in airway smooth muscle contraction, most notably the M2 muscarinic receptor, which we show is expressed in airway smooth muscle and was decreased at the protein level after challenge with Der p 1. Murine strain–dependent genomic responses in the lung offer insights into the different biological pathways that develop after allergen challenge. This study of two different murine strains demonstrates that inflammation and airway hyperresponsiveness can be decoupled, and suggests that the down-modulation of expression of G-protein–coupled receptors involved in regulating airway smooth muscle contraction may contribute to this dissociation. PMID:21378263

  15. Delivery of Alpha-1 Antitrypsin to Airways.

    PubMed

    Griese, Matthias; Scheuch, Gerhard

    2016-08-01

    Treatment with exogenous alpha-1 antitrypsin (AAT), a potent serine protease inhibitor, was developed originally for chronic obstructive pulmonary disease associated with AAT deficiency; however, other lung conditions involving neutrophilic inflammation and proteolytic tissue injury related to neutrophil elastase and other serine proteases may also be considered for AAT therapy. These conditions include bronchiectasis caused by primary ciliary dyskinesia, cystic fibrosis, and other diseases associated with an increased free elastase activity in the airways. Inhaled AAT may be a viable option to counteract proteolytic tissue damage. This form of treatment requires efficient drug delivery to the targeted pulmonary compartment. Aerosol technology meeting this requirement is currently available and offers an alternative therapeutic approach to systemic AAT administration. To date, early studies in humans have shown biochemical efficacy and have established the safety of inhaled AAT. However, to bring aerosol AAT therapy to patients, large phase 3 protocols in carefully selected patient populations (i.e., subgroups of patients with AAT deficiency, cystic fibrosis, or other lung diseases with bronchiectasis) will be needed with clinical end points in addition to the measurement of proteolytic activity in the airway. The outcomes likely will have to include lung function, lung structure assessed by computed tomography imaging, disease exacerbations, health status, and mortality.

  16. Development of a regional-scale pollen emission and transport modeling framework for investigating the impact of climate change on allergic airway disease

    PubMed Central

    Zhang, Rui; Duhl, Tiffany; Salam, Muhammad T.; House, James M.; Flagan, Richard C.; Avol, Edward L.; Gilliland, Frank D.; Guenther, Alex; Chung, Serena H.; Lamb, Brian K.; VanReken, Timothy M.

    2014-01-01

    Exposure to bioaerosol allergens such as pollen can cause exacerbations of allergenic airway disease (AAD) in sensitive populations, and thus cause serious public health problems. Assessing these health impacts by linking the airborne pollen levels, concentrations of respirable allergenic material, and human allergenic response under current and future climate conditions is a key step toward developing preventive and adaptive actions. To that end, a regional-scale pollen emission and transport modeling framework was developed that treats allergenic pollens as non-reactive tracers within the WRF/CMAQ air-quality modeling system. The Simulator of the Timing and Magnitude of Pollen Season (STaMPS) model was used to generate a daily pollen pool that can then be emitted into the atmosphere by wind. The STaMPS is driven by species-specific meteorological (temperature and/or precipitation) threshold conditions and is designed to be flexible with respect to its representation of vegetation species and plant functional types (PFTs). The hourly pollen emission flux was parameterized by considering the pollen pool, friction velocity, and wind threshold values. The dry deposition velocity of each species of pollen was estimated based on pollen grain size and density. An evaluation of the pollen modeling framework was conducted for southern California for the period from March to June 2010. This period coincided with observations by the University of Southern California's Children's Health Study (CHS), which included O3, PM2.5, and pollen count, as well as measurements of exhaled nitric oxide in study participants. Two nesting domains with horizontal resolutions of 12 km and 4 km were constructed, and six representative allergenic pollen genera were included: birch tree, walnut tree, mulberry tree, olive tree, oak tree, and brome grasses. Under the current parameterization scheme, the modeling framework tends to underestimate walnut and peak oak pollen concentrations, and tends

  17. Development of a regional-scale pollen emission and transport modeling framework for investigating the impact of climate change on allergic airway disease

    NASA Astrophysics Data System (ADS)

    Zhang, R.; Duhl, T.; Salam, M. T.; House, J. M.; Flagan, R. C.; Avol, E. L.; Gilliland, F. D.; Guenther, A.; Chung, S. H.; Lamb, B. K.; VanReken, T. M.

    2014-03-01

    Exposure to bioaerosol allergens such as pollen can cause exacerbations of allergenic airway disease (AAD) in sensitive populations, and thus cause serious public health problems. Assessing these health impacts by linking the airborne pollen levels, concentrations of respirable allergenic material, and human allergenic response under current and future climate conditions is a key step toward developing preventive and adaptive actions. To that end, a regional-scale pollen emission and transport modeling framework was developed that treats allergenic pollens as non-reactive tracers within the coupled Weather Research and Forecasting Community Multiscale Air Quality (WRF/CMAQ) modeling system. The Simulator of the Timing and Magnitude of Pollen Season (STaMPS) model was used to generate a daily pollen pool that can then be emitted into the atmosphere by wind. The STaMPS is driven by species-specific meteorological (temperature and/or precipitation) threshold conditions and is designed to be flexible with respect to its representation of vegetation species and plant functional types (PFTs). The hourly pollen emission flux was parameterized by considering the pollen pool, friction velocity, and wind threshold values. The dry deposition velocity of each species of pollen was estimated based on pollen grain size and density. An evaluation of the pollen modeling framework was conducted for southern California (USA) for the period from March to June 2010. This period coincided with observations by the University of Southern California's Children's Health Study (CHS), which included O3, PM2.5, and pollen count, as well as measurements of exhaled nitric oxide in study participants. Two nesting domains with horizontal resolutions of 12 and 4 km were constructed, and six representative allergenic pollen genera were included: birch tree, walnut tree, mulberry tree, olive tree, oak tree, and brome grasses. Under the current parameterization scheme, the modeling framework tends to

  18. Development of a regional-scale pollen emission and transport modeling framework for investigating the impact of climate change on allergic airway disease

    NASA Astrophysics Data System (ADS)

    Zhang, R.; Duhl, T.; Salam, M. T.; House, J. M.; Flagan, R. C.; Avol, E. L.; Gilliland, F. D.; Guenther, A.; Chung, S. H.; Lamb, B. K.; VanReken, T. M.

    2013-03-01

    Exposure to bioaerosol allergens such as pollen can cause exacerbations of allergenic airway disease (AAD) in sensitive populations, and thus cause serious public health problems. Assessing these health impacts by linking the airborne pollen levels, concentrations of respirable allergenic material, and human allergenic response under current and future climate conditions is a key step toward developing preventive and adaptive actions. To that end, a regional-scale pollen emission and transport modeling framework was developed that treats allergenic pollens as non-reactive tracers within the WRF/CMAQ air-quality modeling system. The Simulator of the Timing and Magnitude of Pollen Season (STaMPS) model was used to generate a daily pollen pool that can then be emitted into the atmosphere by wind. The STaMPS is driven by species-specific meteorological (temperature and/or precipitation) threshold conditions and is designed to be flexible with respect to its representation vegetation species and plant functional types (PFTs). The hourly pollen emission flux was parameterized by considering the pollen pool, friction velocity, and wind threshold values. The dry deposition velocity of each species of pollen was estimated based on pollen grain size and density. An evaluation of the pollen modeling framework was conducted for southern California for the period from March to June 2010. This period coincided with observations by the University of Southern California's Children's Health Study (CHS), which included O3, PM2.5, and pollen count, as well as measurements of exhaled nitric oxide in study participants. Two nesting domains with horizontal resolutions of 12 km and 4 km were constructed, and six representative allergenic pollen genera were included: birch tree, walnut tree, mulberry tree, olive tree, oak tree, and brome grasses. Under the current parameterization scheme, the modeling framework tends to underestimate walnut and peak oak pollen concentrations, and tends to

  19. Development of a regional-scale pollen emission and transport modeling framework for investigating the impact of climate change on allergic airway disease.

    PubMed

    Zhang, Rui; Duhl, Tiffany; Salam, Muhammad T; House, James M; Flagan, Richard C; Avol, Edward L; Gilliland, Frank D; Guenther, Alex; Chung, Serena H; Lamb, Brian K; VanReken, Timothy M

    2013-03-01

    Exposure to bioaerosol allergens such as pollen can cause exacerbations of allergenic airway disease (AAD) in sensitive populations, and thus cause serious public health problems. Assessing these health impacts by linking the airborne pollen levels, concentrations of respirable allergenic material, and human allergenic response under current and future climate conditions is a key step toward developing preventive and adaptive actions. To that end, a regional-scale pollen emission and transport modeling framework was developed that treats allergenic pollens as non-reactive tracers within the WRF/CMAQ air-quality modeling system. The Simulator of the Timing and Magnitude of Pollen Season (STaMPS) model was used to generate a daily pollen pool that can then be emitted into the atmosphere by wind. The STaMPS is driven by species-specific meteorological (temperature and/or precipitation) threshold conditions and is designed to be flexible with respect to its representation of vegetation species and plant functional types (PFTs). The hourly pollen emission flux was parameterized by considering the pollen pool, friction velocity, and wind threshold values. The dry deposition velocity of each species of pollen was estimated based on pollen grain size and density. An evaluation of the pollen modeling framework was conducted for southern California for the period from March to June 2010. This period coincided with observations by the University of Southern California's Children's Health Study (CHS), which included O3, PM2.5, and pollen count, as well as measurements of exhaled nitric oxide in study participants. Two nesting domains with horizontal resolutions of 12 km and 4 km were constructed, and six representative allergenic pollen genera were included: birch tree, walnut tree, mulberry tree, olive tree, oak tree, and brome grasses. Under the current parameterization scheme, the modeling framework tends to underestimate walnut and peak oak pollen concentrations, and tends

  20. Antibacterial Defense of Human Airway Epithelial Cells from Chronic Obstructive Pulmonary Disease Patients Induced by Acute Exposure to Nontypeable Haemophilus influenzae: Modulation by Cigarette Smoke.

    PubMed

    Amatngalim, Gimano D; Schrumpf, Jasmijn A; Henic, Almira; Dronkers, Esther; Verhoosel, Renate M; Ordonez, Soledad R; Haagsman, Henk P; Fuentes, Maria E; Sridhar, Sriram; Aarbiou, Jamil; Janssen, Richard A J; Lekkerkerker, Annemarie N; Hiemstra, Pieter S

    2017-02-08

    Antimicrobial proteins and peptides (AMPs) are a central component of the antibacterial activity of airway epithelial cells. It has been proposed that a decrease in antibacterial lung defense contributes to an increased susceptibility to microbial infection in smokers and patients with chronic obstructive pulmonary disease (COPD). However, whether reduced AMP expression in the epithelium contributes to this lower defense is largely unknown. We investigated the bacterial killing activity and expression of AMPs by air-liquid interface-cultured primary bronchial epithelial cells from COPD patients and non-COPD (ex-)smokers that were stimulated with nontypeable Haemophilus influenzae (NTHi). In addition, the effect of cigarette smoke on AMP expression and the activation of signaling pathways was determined. COPD cell cultures displayed reduced antibacterial activity, whereas smoke exposure suppressed the NTHi-induced expression of AMPs and further increased IL-8 expression in COPD and non-COPD cultures. Moreover, smoke exposure impaired NTHi-induced activation of NF-κB, but not MAP-kinase signaling. Our findings demonstrate that the antibacterial activity of cultured airway epithelial cells induced by acute bacterial exposure was reduced in COPD and suppressed by cigarette smoke, whereas inflammatory responses persisted. These findings help to explain the imbalance between protective antibacterial and destructive inflammatory innate immune responses in COPD.

  1. The relation of airway size to lung function

    NASA Astrophysics Data System (ADS)

    Leader, J. Ken; Zheng, Bin; Sciurba, Frank C.; Fuhrman, Carl R.; Bon, Jessica M.; Park, Sang C.; Pu, Jiantao; Gur, David

    2008-03-01

    Chronic obstructive pulmonary disease may cause airway remodeling, and small airways are the mostly likely site of associated airway flow obstruction. Detecting and quantifying airways depicted on a typical computed tomography (CT) images is limited by spatial resolution. In this study, we examined the association between lung function and airway size. CT examinations and spirometry measurement of forced expiratory volume in one second as a percent predicted (FEV I%) from 240 subjects were used in this study. Airway sections depicted in axial CT section were automatically detected and quantified. Pearson correlation coefficients (PCC) were computed to compare lung function across three size categories: (1) all detected airways, (2) the smallest 50% of detected airways, and (3) the largest 50% of detected airways using the CORANOVA test. The mean number of all airways detected per subject was 117.4 (+/- 40.1) with mean size ranging from 20.2 to 50.0 mm2. The correlation between lung function (i.e., FEV I) and airway morphometry associated with airway remodeling and airflow obstruction (i.e., lumen perimeter and wall area as a percent of total airway area) was significantly stronger for smaller compared to larger airways (p < 0.05). The PCCs between FEV I and all airways, the smallest 50%, and the largest 50% were 0.583, 0.617, 0.523, respectively, for lumen perimeter and -0.560, -0.584, and -0.514, respectively, for wall area percent. In conclusion, analyzing a set of smaller airways compared to larger airways may improve detection of an association between lung function and airway morphology change.

  2. Automated Lobe-Based Airway Labeling

    PubMed Central

    Gu, Suicheng; Wang, Zhimin; Siegfried, Jill M.; Wilson, David; Bigbee, William L.; Pu, Jiantao

    2012-01-01

    Regional quantitative analysis of airway morphological abnormalities is of great interest in lung disease investigation. Considering that pulmonary lobes are relatively independent functional unit, we develop and test a novel and efficient computerized scheme in this study to automatically and robustly classify the airways into different categories in terms of pulmonary lobe. Given an airway tree, which could be obtained using any available airway segmentation scheme, the developed approach consists of four basic steps: (1) airway skeletonization or centerline extraction, (2) individual airway branch identification, (3) initial rule-based airway classification/labeling, and (4) self-correction of labeling errors. In order to assess the performance of this approach, we applied it to a dataset consisting of 300 chest CT examinations in a batch manner and asked an image analyst to subjectively examine the labeled results. Our preliminary experiment showed that the labeling accuracy for the right upper lobe, the right middle lobe, the right lower lobe, the left upper lobe, and the left lower lobe is 100%, 99.3%, 99.3%, 100%, and 100%, respectively. Among these, only two cases are incorrectly labeled due to the failures in airway detection. It takes around 2 minutes to label an airway tree using this algorithm. PMID:23093951

  3. Mechanisms of inflammation-mediated airway smooth muscle plasticity and airways remodeling in asthma.

    PubMed

    Halayko, Andrew J; Amrani, Yassine

    2003-09-16

    Recent evidence points to progressive structural change in the airway wall, driven by chronic local inflammation, as a fundamental component for development of irreversible airway hyperresponsiveness. Acute and chronic inflammation is orchestrated by cytokines from recruited inflammatory cells, airway myofibroblasts and myocytes. Airway myocytes exhibit functional plasticity in their capacity for contraction, proliferation, and synthesis of matrix protein and cytokines. This confers a principal role in driving different components of the airway remodeling process, and mediating constrictor hyperresponsiveness. Functional plasticity of airway smooth muscle (ASM) is regulated by an array of environmental cues, including cytokines, which mediate their effects through receptors and a number of intracellular signaling pathways. Despite numerous studies of the cellular effects of cytokines on cultured airway myocytes, few have identified how intracellular signaling pathways modulate or induce these cellular responses. This review summarizes current understanding of these concepts and presents a model for the effects of inflammatory mediators on functional plasticity of ASM in asthma.

  4. Quadruple cancer including Bowen's disease after arsenic injections 40 years earlier: report of a case.

    PubMed

    Murata, K; Iwazawa, T; Takayama, T; Yamashita, K; Okagawa, K

    1994-01-01

    This report describes the successful treatment of quadruple cancer including Bowen's disease in a 71-year-old man who had been given injections of salvarsan, an arsenic compound, for syphilis more than 40 years earlier. Resection of a skin lesion on his chest subsequently confirmed a diagnosis of Bowen's disease, 3 years after which he was operated on for concurrent gastric cancer and sigmoid colon cancer. A fourth cancer was discovered on his left vocal cord 2 weeks after this operation; it was resected 2 years later. A discussion of multiple malignant neoplasms and the possible relationship between arsenic and cancer is presented following this case report.

  5. Techniques of endoscopic airway tumor treatment

    PubMed Central

    Mhanna, Laurent; Droneau, Sylvain; Plat, Gavin; Didier, Alain; Mazieres, Julien; Hermant, Christophe

    2016-01-01

    Interventional bronchoscopy has a predominant role in the management of both early and advanced-stage airway tumors. Given the very poor prognosis of lung cancer, there is a need for new tools to improve early detection and bronchoscopic treatment of endo-bronchial precancerous lesions. In more advanced stages, interventional bronchoscopy plays an important role, as nearly a third of lung cancers lead to proximal airway obstruction. This will cause great discomfort or even life-threatening symptoms related to local extension, such as dyspnea, post-obstructive pneumonia, and hemoptysis. Surgery for very locally advanced disease is only effective for a limited number of patients and the effects of conventional antitumor therapies, like radiation therapy or chemotherapy, are inconstant and are too delayed in a palliative context. In this review, we aim to provide pulmonologists with an exhaustive technical overview of (I) the bronchoscopic management of benign endobronchial lesions; (II) the bronchoscopic management of malignant tumors, including the curative treatment of localized lesions and palliative management of malignant proximal airway stenosis; and (III) descriptions of the emerging endoscopic techniques used to treat peripheral lung tumors. PMID:28066616

  6. Triggers of airway inflammation.

    PubMed

    Kerrebijn, K F

    1986-01-01

    Most asthmatics have hyperresponsive airways. This makes them more sensitive than non-asthmatics to bronchoconstricting environmental exposures which, in their turn, may enhance responsiveness. Airway inflammation is considered to be a key determinant of airway hyperresponsiveness: the fact that chronic airway inflammation in cystic fibrosis does not lead to airway hyperresponsiveness of any importance indicates, however, that the role of airway inflammation is complex and incompletely elucidated. The main inducers of airway inflammation are viral infections, antigens, occupational stimuli and pollutants. Although exercise, airway cooling and hyper- or hypotonic aerosols are potent stimuli of bronchoconstriction, it is questionable if airway inflammation is involved in their mode of action. Each of the above-mentioned stimuli is discussed, with emphasis laid on the relation of symptoms to mechanisms.

  7. Airway and Extracellular Matrix Mechanics in COPD

    PubMed Central

    Bidan, Cécile M.; Veldsink, Annemiek C.; Meurs, Herman; Gosens, Reinoud

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) is one of the most common lung diseases worldwide, and is characterized by airflow obstruction that is not fully reversible with treatment. Even though airflow obstruction is caused by airway smooth muscle contraction, the extent of airway narrowing depends on a range of other structural and functional determinants that impact on active and passive tissue mechanics. Cells and extracellular matrix in the airway and parenchymal compartments respond both passively and actively to the mechanical stimulation induced by smooth muscle contraction. In this review, we summarize the factors that regulate airway narrowing and provide insight into the relative contributions of different constituents of the extracellular matrix and their biomechanical impact on airway obstruction. We then review the changes in extracellular matrix composition in the airway and parenchymal compartments at different stages of COPD, and finally discuss how these changes impact airway narrowing and the development of airway hyperresponsiveness. Finally, we position these data in the context of therapeutic research focused on defective tissue repair. As a conclusion, we propose that future works should primarily target mild or early COPD, prior to the widespread structural changes in the alveolar compartment that are more characteristic of severe COPD. PMID:26696894

  8. Hematologic manifestations of systemic disease (including iron deficiency, anemia of inflammation and DIC).

    PubMed

    Witmer, Char M

    2013-12-01

    A complete blood cell count (CBC) is a frequent test sent to aid in the diagnostic evaluation of ill patients. Not uncommonly hematologic abnormalities may be the first sign of an underlying systemic disorder. The astute clinician needs to understand how systemic disease can affect the CBC to direct further diagnostic investigations. This article focuses on the 2 most common acquired anemias including iron deficiency and anemia of inflammation as well as disseminated intravascular coagulation.

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

    PubMed Central

    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

  10. Two-dimensional airway analysis using probabilistic neural networks

    NASA Astrophysics Data System (ADS)

    Tan, Jun; Zheng, Bin; Park, Sang Cheol; Pu, Jiantao; Sciurba, Frank C.; Leader, Joseph K.

    2010-03-01

    Although 3-D airway tree segmentation permits analysis of airway tree paths of practical lengths and facilitates visual inspection, our group developed and tested an automated computer scheme that was operated on individual 2-D CT images to detect airway sections and measure their morphometry and/or dimensions. The algorithm computes a set of airway features including airway lumen area (Ai), airway cross-sectional area (Aw), the ratio (Ra) of Ai to Aw, and the airway wall thickness (Tw) for each detected airway section depicted on the CT image slice. Thus, this 2-D based algorithm does not depend on the accuracy of 3-D airway tree segmentation and does not require that CT examination encompasses the entire lung or reconstructs contiguous images. However, one disadvantage of the 2-D image based schemes is the lack of the ability to identify the airway generation (Gb) of the detected airway section. In this study, we developed and tested a new approach that uses 2-D airway features to assign a generation number to an airway. We developed and tested two probabilistic neural networks (PNN) based on different sets of airway features computed by our 2-D based scheme. The PNNs were trained and tested on 12 lung CT examinations (8 training and 4 testing). The accuracy for the PNN that utilized Ai and Ra for identifying the generation of airway sections varies from 55.4% - 100%. The overall accuracy of the PNN for all detected airway sections that are spread over all generations is 76.7%. Interestingly, adding wall thickness feature (Tw) to PNN did not improve identification accuracy. This preliminary study demonstrates that a set of 2-D airway features may be used to identify the generation number of an airway with reasonable accuracy.

  11. Treatment of disorders characterized by reversible airway obstruction in childhood: are anti-cholinergic agents the answer?

    PubMed

    Quizon, Annabelle; Colin, Andrew A; Pelosi, Umberto; Rossi, Giovanni A

    2012-01-01

    Release of acetylcholine from parasympathetic nerves in the airways activates postjunctional muscarinic receptors present on smooth muscle, submucosal glands and blood vessels. This triggers bronchoconstriction, muscle hypertrophy, mucus secretion, and vasodilatation, respectively. The release of acetylcholine from parasympathetic nerves in lungs is induced by a variety of stimuli and downregulated by the inhibitory activity of neuronal M2 muscarinic receptors via a feedback mechanism. Increased parasympathetic nerve activity occurs in a variety of airway diseases in childhood, including viral-induced wheeze and asthma. Common to these conditions are reversible airway obstruction, mucus hypersecretion, vasodilation and enhanced vascular permeability. In animal models of airway hyperreactivity similar findings of increased acetylcholine release resulting in enhanced supply of this neurotransmitter to the postjunctional smooth muscles, submucosal glands and airway vessels, were demonstrated. While the number and function of postjunctional muscarinic receptors in the airways are unchanged in such airway disorders, inhibitory activity on the parasympathetic nerves appears to be impaired. Specifically, M2 muscarinic receptor dysfunction has been demonstrated in models of bronchial hyperreactivity induced by a variety of triggers, including viruses, atmospheric pollutants and allergens. The mechanisms leading to impairment of neuronal M2 muscarinic receptor function and their putative relevance to the pathogenesis and the treatment of airway disease in childhood are described. Finally, the available data on the activity of ipratropium bromide, a short-acting anticholinergic drug, in the most common pediatric airway disease are reported and the possible therapeutic efficacy of tiotropium bromide, a more recently introduced long-acting, selective anticholinergic compound, is discussed.

  12. 3D mapping of airway wall thickening in asthma with MSCT: a level set approach

    NASA Astrophysics Data System (ADS)

    Fetita, Catalin; Brillet, Pierre-Yves; Hartley, Ruth; Grenier, Philippe A.; Brightling, Christopher

    2014-03-01

    Assessing the airway wall thickness in multi slice computed tomography (MSCT) as image marker for airway disease phenotyping such asthma and COPD is a current trend and challenge for the scientific community working in lung imaging. This paper addresses the same problem from a different point of view: considering the expected wall thickness-to-lumen-radius ratio for a normal subject as known and constant throughout the whole airway tree, the aim is to build up a 3D map of airway wall regions of larger thickness and to define an overall score able to highlight a pathological status. In this respect, the local dimension (caliber) of the previously segmented airway lumen is obtained on each point by exploiting the granulometry morphological operator. A level set function is defined based on this caliber information and on the expected wall thickness ratio, which allows obtaining a good estimate of the airway wall throughout all segmented lumen generations. Next, the vascular (or mediastinal dense tissue) contact regions are automatically detected and excluded from analysis. For the remaining airway wall border points, the real wall thickness is estimated based on the tissue density analysis in the airway radial direction; thick wall points are highlighted on a 3D representation of the airways and several quantification scores are defined. The proposed approach is fully automatic and was evaluated (proof of concept) on a patient selection coming from different databases including mild, severe asthmatics and normal cases. This preliminary evaluation confirms the discriminative power of the proposed approach regarding different phenotypes and is currently extending to larger cohorts.

  13. Comparison of analysis methods for airway quantification

    NASA Astrophysics Data System (ADS)

    Odry, Benjamin L.; Kiraly, Atilla P.; Novak, Carol L.; Naidich, David P.

    2012-03-01

    Diseased airways have been known for several years as a possible contributing factor to airflow limitation in Chronic Obstructive Pulmonary Diseases (COPD). Quantification of disease severity through the evaluation of airway dimensions - wall thickness and lumen diameter - has gained increased attention, thanks to the availability of multi-slice computed tomography (CT). Novel approaches have focused on automated methods of measurement as a faster and more objective means that the visual assessment routinely employed in the clinic. Since the Full-Width Half-Maximum (FWHM) method of airway measurement was introduced two decades ago [1], several new techniques for quantifying airways have been detailed in the literature, but no approach has truly become a standard for such analysis. Our own research group has presented two alternative approaches for determining airway dimensions, one involving a minimum path and the other active contours [2, 3]. With an increasing number of techniques dedicated to the same goal, we decided to take a step back and analyze the differences of these methods. We consequently put to the test our two methods of analysis and the FWHM approach. We first measured a set of 5 airways from a phantom of known dimensions. Then we compared measurements from the three methods to those of two independent readers, performed on 35 airways in 5 patients. We elaborate on the differences of each approach and suggest conclusions on which could be defined as the best one.

  14. Chronic obstructive pulmonary disease: knowing what we mean, meaning what we say.

    PubMed

    Joshi, J M

    2008-01-01

    Chronic obstructive pulmonary disease (COPD) is defined in several different ways using different criteria based on symptoms, physiological impairment and pathological abnormalities. While some use COPD to mean smoking related chronic airway disease, others include all disorders causing chronic airway obstruction. When COPD is used as a broad descriptive term, specific disorders that cause chronic airway obstruction remain under-diagnosed and the prevalence estimates vary considerably. The lack of agreement over the precise terminology and classification of COPD has resulted in widespread confusion. Terminology includes definition, diagnostic criteria, and a system for staging severity. Recently, COPD is defined more clearly and diagnosed using precise criteria that include tobacco smoking greater than 10 pack years, symptoms and airway obstruction on spirometry. A multi-dimensional severity grading system, the BODE (body mass index, obstruction, dyspnoea, and exercise tolerance) index has been designed to assess the respiratory and systemic expressions of COPD. This review proposes that the broad group of chronic disorders of the airways (with or without airway obstruction) be called chronic airway disease (CAD). The term COPD should be used exclusively for tobacco smoking related chronic airway disease. Chronic airway obstruction or obstructive lung disease may be used to define those conditions with airways obstruction caused by factors other than tobacco smoking. The aetiology may be appended to the label, for example, chronic airway obstruction/obstructive lung disease associated with bronchiectasis, chronic airway obstruction/obstructive lung disease associated with obliterative bronchiolitis or chronic airway obstruction/obstructive lung disease due to biomass fuel/occupational exposure.

  15. Emergency airway puncture

    MedlinePlus

    ... support for only a very short period of time. Alternative Names Needle cricothyrotomy Images Emergency airway puncture Cricoid cartilage Emergency airway puncture - series References Hebert RB, Bose S, Mace SE. Cricothyrotomy and ...

  16. Upper airway biopsy

    MedlinePlus

    ... upper airway Images Upper airway test Bronchoscopy Throat anatomy References Yung RC, Boss EF. Tracheobronchial endoscopy. In: Flint PW, Haughey BH, Lund LJ, et al, eds. Cummings Otolaryngology: Head & Neck Surgery. 5th ed. Philadelphia, PA: Elsevier Mosby; ...

  17. Preparation of the patient and the airway for awake intubation

    PubMed Central

    Ramkumar, Venkateswaran

    2011-01-01

    Awake intubation is usually performed electively in the presence of a difficult airway. A detailed airway examination is time-consuming and often not feasible in an emergency. A simple 1-2-3 rule for airway examination allows one to identify potential airway difficulty within a minute. A more detailed airway examination can give a better idea about the exact nature of difficulty and the course of action to be taken to overcome it. When faced with an anticipated difficult airway, the anaesthesiologist needs to consider securing the airway in an awake state without the use of anaesthetic agents or muscle relaxants. As this can be highly discomforting to the patient, time and effort must be spent to prepare such patients both psychologically and pharmacologically for awake intubation. Psychological preparation is best initiated by an anaesthesiologist who explains the procedure in simple language. Sedative medications can be titrated to achieve patient comfort without compromising airway patency. Additional pharmacological preparation includes anaesthetising the airway through topical application of local anaesthetics and appropriate nerve blocks. When faced with a difficult airway, one should call for the difficult airway cart as well as for help from colleagues who have interest and expertise in airway management. Preoxygenation and monitoring during awake intubation is important. Anxious patients with a difficult airway may need to be intubated under general anaesthesia without muscle relaxants. Proper psychological and pharmacological preparation of the patient by an empathetic anaesthesiologist can go a long way in making awake intubation acceptable for all concerned. PMID:22174458

  18. Careers in Airway Science.

    ERIC Educational Resources Information Center

    Federal Aviation Administration (DOT), Washington, DC.

    The Federal Aviation Administration (FAA) has initiated the Airway Science curriculum as a method of preparing the next generation of aviation technicians and managers. This document: (1) discusses the FAA's role in the Airway Science program; (2) describes some of the career fields that FAA offers to Airway Science graduates (air traffic control…

  19. Immunofluorescence Patterns in Selected Dermatoses, Including Blistering Skin Diseases Utilizing Multiple Fluorochromes

    PubMed Central

    Abreu-Velez, Ana Maria; Calle-Isaza, Juliana; Howard, Michael S.

    2015-01-01

    Background: Autoimmune vesiculobullous disorders represent a heterogeneous group of dermatoses whose diagnosis is made based on clinical history, histologic features, and immunopathologic features. The most commonly used techniques for the diagnosis of these diseases are direct and indirect immunofluorescence (DIF and IIF), including salt-split processing. NaCl split skin is used to determine the level of blister formation, and the localization of autoantibodies relative to the split. Classically, immunofluorescence has been performed with one fluorochrome in the diagnosis of autoimmune bullous skin diseases. Aims: To compare DIF and IIF of the skin, using a single fluorochrome versus multiple fluorochromes. Materials and Methods: We studied 20 autoimmune skin disease cases using fluorescein isothiocyanate (FITC) alone, in comparison to multiple fluorochromes (with or without DNA counterstaining). Results: The use of multiple fluorochromes helped to simultaneously visualize reactivity in multiple skin areas, in contrast to using FITC alone. Conclusions: Using multiple fluorochromes allows simultaneous labeling of two or more antigens within the same cell/or tissue section, assists in colocalization of unknown antigens with known molecules, and helps in ruling out “background” staining. PMID:26605203

  20. Comprehensive functional characterization of murine infantile Batten disease including Parkinson-like behavior and dopaminergic markers

    PubMed Central

    Dearborn, Joshua T.; Harmon, Steven K.; Fowler, Stephen C.; O’Malley, Karen L.; Taylor, George T.; Sands, Mark S.; Wozniak, David F.

    2015-01-01

    Infantile neuronal ceroid lipofuscinosis (INCL, Infantile Batten disease) is a neurodegenerative lysosomal storage disease caused by a deficiency in palmitoyl protein thioesterase-1 (PPT1). The PPT1-deficient mouse (Cln1−/−) is a useful phenocopy of human INCL. Cln1−/− mice display retinal dysfunction, seizures, motor deficits, and die at ~8 months of age. However, little is known about the cognitive and behavioral functions of Cln1−/− mice during disease progression. In the present study, younger (~1–2 months of age) Cln1−/− mice showed minor deficits in motor/sensorimotor functions while older (~5–6 months of age) Cln1−/− mice exhibited more severe impairments, including decreased locomotor activity, inferior cued water maze performance, decreased running wheel ability, and altered auditory cue conditioning. Unexpectedly, certain cognitive functions such as some learning and memory capabilities seemed intact in older Cln1−/− mice. Younger and older Cln1−/− mice presented with walking initiation defects, gait abnormalities, and slowed movements, which are analogous to some symptoms reported in INCL and parkinsonism. However, there was no evidence of alterations in dopaminergic markers in Cln1−/− mice. Results from this study demonstrate quantifiable changes in behavioral functions during progression of murine INCL and suggest that Parkinson-like motor/sensorimotor deficits in Cln1−/− mice are not mediated by dopamine deficiency. PMID:26238334

  1. Mitochondrial Lon protease in human disease and aging: Including an etiologic classification of Lon-related diseases and disorders

    PubMed Central

    Bota, Daniela A.; Davies, Kelvin J.A.

    2016-01-01

    The Mitochondrial Lon protease, also called LonP1 is a product of the nuclear gene LONP1. Lon is a major regulator of mitochondrial metabolism and response to free radical damage, as well as an essential factor for the maintenance and repair of mitochondrial DNA. Lon is an ATP-stimulated protease that cycles between being bound (at the inner surface of the inner mitochondrial membrane) to the mitochondrial genome, and being released into the mitochondrial matrix where it can degrade matrix proteins. At least three different roles or functions have been ascribed to Lon: 1) Proteolytic digestion of oxidized proteins and the turnover of specific essential mitochondrial enzymes such as aconitase, TFAM, and StAR; 2) Mitochondrial (mt)DNA-binding protein, involved in mtDNA replication and mitogenesis; and 3) Protein chaperone, interacting with the Hsp60–mtHsp70 complex. LONP1 orthologs have been studied in bacteria, yeast, flies, worms, and mammals, evincing the widespread importance of the gene, as well as its remarkable evolutionary conservation. In recent years, we have witnessed a significant increase in knowledge regarding Lon's involvement in physiological functions, as well as in an expanding array of human disorders, including cancer, neurodegeneration, heart disease, and stroke. In addition, Lon appears to have a significant role in the aging process. A number of mitochondrial diseases have now been identified whose mechanisms involve various degrees of Lon dysfunction. In this paper we review current knowledge of Lon's function, under normal conditions, and we propose a new classification of human diseases characterized by a either over-expression or decline or loss of function of Lon. Lon has also been implicated in human aging, and we review the data currently available as well as speculating about possible interactions of aging and disease. Finally, we also discuss Lon as potential therapeutic target in human disease. PMID:27387767

  2. Rhinovirus infections in the upper airway.

    PubMed

    Winther, Birgit

    2011-03-01

    The majority of cold and flulike illnesses are caused by human rhinoviruses (HRVs). Improved detection of HRV has shown that HRVs are also associated with more serious illness, such as exacerbation of asthma, wheezing illnesses in children, chronic obstructive pulmonary disease, cardiopulmonary disease, and fatal pneumonia in immune-compromised patients. HRV is a major cause of acute viral respiratory tract infections in hospitalized children and is among the leading causes of childhood mortality worldwide. Detection of the HRV genome by reverse transcriptase-polymerase chain reaction and genomic sequencing has brought to light a new clade, HRV-C, to the already recognized HRV-A and HRV-B clades. The clinical complications related to all rhinovirus infections include acute otitis media, acute sinusitis, and acute bronchitis. The enormous public health implications from those diseases far overshadow those of the common cold. This article provides an overview of the pathogenesis of rhinovirus infection in the upper airways. Most research has been done in young healthy adults with self-limiting experimental and natural rhinovirus infections, and this may set the stage for understanding rhinovirus infections in the ear, sinus, and lower airways.

  3. Cephalometric norms for the upper airway in a healthy North Indian population

    PubMed Central

    Shastri, Dipti; Tandon, Pradeep; Nagar, Amit; Singh, Alka

    2015-01-01

    Objective: The aim was to obtain normative data for cephalometric measurements of the upper airway in the North Indian population. Design: Observational study. Setting: University department and teaching hospital out-patient clinic. Subjects and Methods: A total of 180 healthy patients were included out of which 90 were males (age range, 8-16 years), and 90 were females (age range, 8-16 years), with normal skeletal facial profile, no history of snoring, sleep apnea, upper airway disease, tonsillectomy or adenoidectomy, obesity, or pathology in the pharynx. Twenty cephalometric airway measurements, including size of the tongue, soft palate, nasopharynx, oropharynx, hypopharynx, and relative position of the hyoid bone and valleculae were obtained. Landmarks on cephalometric radiographs were digitized and measurements were made using a specially designed computer program. Error analysis of measurements was performed and comparison of measurements according to sex was made. Results: Significant sex dimorphism was seen for the majority of measurements, with the exception of minimal depth of the airway, oropharyngeal depth of the airway, and the soft palate angle with the hard palate. Conclusion: A minimum sagittal dimension of the upper airway was evident despite differences in measurements between sexes. Findings from this study should be a useful reference for the assessment of sleep apnea in the North Indian population. PMID:26097352

  4. [Orthodontics and the upper airway].

    PubMed

    Cobo Plana, J; de Carlos Villafranca, F; Macías Escalada, E

    2004-03-01

    One of the general aims of orthodontic treatment and of the combination of orthodontics and orthognathic surgery is to achieve good occlusion and aesthetic improvement, especially in cases of severe dentoskeletal deformities. However, on many occasions, the parameters of the upper airways are not taken into account when the aims of conventional treatment are fulfilled. Patients with obstructive alterations during sleep represent for the orthodontist a type of patient who differs from the normal; for them, treatment should include the objective of improving oxygen saturation. Here, functional considerations should outweigh purely aesthetic ones. It is important, when making an orthodontic, surgical or combined diagnosis for a patient, to bear in mind the impact that treatment may have on the upper airways. Good aesthetics should never be achieved for some of our patients at the expense of diminishing the capacity of their upper airways.

  5. Role of EP2 and EP4 receptors in airway microvascular leak induced by prostaglandin E2

    PubMed Central

    Jones, Victoria C; Birrell, Mark A; Maher, Sarah A; Griffiths, Mark; Grace, Megan; O'Donnell, Valerie B; Clark, Stephen R

    2016-01-01

    Background and Purpose Airway microvascular leak (MVL) involves the extravasation of proteins from post‐capillary venules into surrounding tissue. MVL is a cardinal sign of inflammation and an important feature of airway inflammatory diseases such as asthma. PGE2, a product of COX‐mediated metabolism of arachidonic acid, binds to four receptors, termed EP1–4. PGE2 has a wide variety of effects within the airway, including modulation of inflammation, sensory nerve activation and airway tone. However, the effect of PGE2 on airway MVL and the receptor/s that mediate this have not been described. Experimental Approach Evans Blue dye was used as a marker of airway MVL, and selective EP receptor agonists and antagonists were used alongside EP receptor‐deficient mice to define the receptor subtype involved. Key Results PGE2 induced significant airway MVL in mice and guinea pigs. A significant reduction in PGE2‐induced MVL was demonstrated in Ptger2 −/− and Ptger4 −/− mice and in wild‐type mice pretreated simultaneously with EP2 (PF‐04418948) and EP4 (ER‐819762) receptor antagonists. In a model of allergic asthma, an increase in airway levels of PGE2 was associated with a rise in MVL; this change was absent in Ptger2 −/− and Ptger4 −/− mice. Conclusions and Implications PGE2 is a key mediator produced by the lung and has widespread effects according to the EP receptor activated. Airway MVL represents a response to injury and under ‘disease’ conditions is a prominent feature of airway inflammation. The data presented highlight a key role for EP2 and EP4 receptors in MVL induced by PGE2. PMID:26639895

  6. IL13 activates autophagy to regulate secretion in airway epithelial cells.

    PubMed

    Dickinson, John D; Alevy, Yael; Malvin, Nicole P; Patel, Khushbu K; Gunsten, Sean P; Holtzman, Michael J; Stappenbeck, Thaddeus S; Brody, Steven L

    2016-01-01

    Cytokine modulation of autophagy is increasingly recognized in disease pathogenesis, and current concepts suggest that type 1 cytokines activate autophagy, whereas type 2 cytokines are inhibitory. However, this paradigm derives primarily from studies of immune cells and is poorly characterized in tissue cells, including sentinel epithelial cells that regulate the immune response. In particular, the type 2 cytokine IL13 (interleukin 13) drives the formation of airway goblet cells that secrete excess mucus as a characteristic feature of airway disease, but whether this process is influenced by autophagy was undefined. Here we use a mouse model of airway disease in which IL33 (interleukin 33) stimulation leads to IL13-dependent formation of airway goblet cells as tracked by levels of mucin MUC5AC (mucin 5AC, oligomeric mucus/gel forming), and we show that these cells manifest a block in mucus secretion in autophagy gene Atg16l1-deficient mice compared to wild-type control mice. Similarly, primary-culture human tracheal epithelial cells treated with IL13 to stimulate mucus formation also exhibit a block in MUC5AC secretion in cells depleted of autophagy gene ATG5 (autophagy-related 5) or ATG14 (autophagy-related 14) compared to nondepleted control cells. Our findings indicate that autophagy is essential for airway mucus secretion in a type 2, IL13-dependent immune disease process and thereby provide a novel therapeutic strategy for attenuating airway obstruction in hypersecretory inflammatory diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis lung disease. Taken together, these observations suggest that the regulation of autophagy by Th2 cytokines is cell-context dependent.

  7. Estimation of airway obstruction using oximeter plethysmograph waveform data

    PubMed Central

    Arnold, Donald H; Spiro, David M; Desmond, Renee' A; Hagood, James S

    2005-01-01

    Background Validated measures to assess the severity of airway obstruction in patients with obstructive airway disease are limited. Changes in the pulse oximeter plethysmograph waveform represent fluctuations in arterial flow. Analysis of these fluctuations might be useful clinically if they represent physiologic perturbations resulting from airway obstruction. We tested the hypothesis that the severity of airway obstruction could be estimated using plethysmograph waveform data. Methods Using a closed airway circuit with adjustable inspiratory and expiratory pressure relief valves, airway obstruction was induced in a prospective convenience sample of 31 healthy adult subjects. Maximal change in airway pressure at the mouthpiece was used as a surrogate measure of the degree of obstruction applied. Plethysmograph waveform data and mouthpiece airway pressure were acquired for 60 seconds at increasing levels of inspiratory and expiratory obstruction. At each level of applied obstruction, mean values for maximal change in waveform area under the curve and height as well as maximal change in mouth pressure were calculated for sequential 7.5 second intervals. Correlations of these waveform variables with mouth pressure values were then performed to determine if the magnitude of changes in these variables indicates the severity of airway obstruction. Results There were significant relationships between maximal change in area under the curve (P < .0001) or height (P < 0.0001) and mouth pressure. Conclusion The findings suggest that mathematic interpretation of plethysmograph waveform data may estimate the severity of airway obstruction and be of clinical utility in objective assessment of patients with obstructive airway diseases. PMID:15985171

  8. Automated airway evaluation system for multi-slice computed tomography using airway lumen diameter, airway wall thickness and broncho-arterial ratio

    NASA Astrophysics Data System (ADS)

    Odry, Benjamin L.; Kiraly, Atilla P.; Novak, Carol L.; Naidich, David P.; Lerallut, Jean-Francois

    2006-03-01

    Pulmonary diseases such as bronchiectasis, asthma, and emphysema are characterized by abnormalities in airway dimensions. Multi-slice computed tomography (MSCT) has become one of the primary means to depict these abnormalities, as the availability of high-resolution near-isotropic data makes it possible to evaluate airways at oblique angles to the scanner plane. However, currently, clinical evaluation of airways is typically limited to subjective visual inspection only: systematic evaluation of the airways to take advantage of high-resolution data has not proved practical without automation. We present an automated method to quantitatively evaluate airway lumen diameter, wall thickness and broncho-arterial ratios. In addition, our method provides 3D visualization of these values, graphically illustrating the location and extent of disease. Our algorithm begins by automatic airway segmentation to extract paths to the distal airways, and to create a map of airway diameters. Normally, airway diameters decrease as paths progress distally; failure to taper indicates abnormal dilatation. Our approach monitors airway lumen diameters along each airway path in order to detect abnormal profiles, allowing even subtle degrees of pathologic dilatation to be identified. Our method also systematically computes the broncho-arterial ratio at every terminal branch of the tree model, as a ratio above 1 indicates potentially abnormal bronchial dilatation. Finally, the airway wall thickness is computed at corresponding locations. These measurements are used to highlight abnormal branches for closer inspection, and can be summed to compute a quantitative global score for the entire airway tree, allowing reproducible longitudinal assessment of disease severity. Preliminary tests on patients diagnosed with bronchiectasis demonstrated rapid identification of lack of tapering, which also was confirmed by corresponding demonstration of elevated broncho-arterial ratios.

  9. New insights into upper airway innate immunity

    PubMed Central

    Hariri, Benjamin M.

    2016-01-01

    Background: Protecting the upper airway from microbial infection is an important function of the immune system. Proper detection of these pathogens is paramount for sinonasal epithelial cells to be able to prepare a defensive response. Toll-like receptors and, more recently, bitter taste receptors and sweet taste receptors have been implicated as sensors able to detect the presence of these pathogens and certain compounds that they secrete. Activation of these receptors also triggers innate immune responses to prevent or counteract infection, including mucociliary clearance and the production and secretion of antimicrobial compounds (e.g., defensins). Objective: To provide an overview of the current knowledge of the role of innate immunity in the upper airway, the mechanisms by which it is carried out, and its clinical relevance. Methods: A literature review of the existing knowledge of the role of innate immunity in the human sinonasal cavity was performed. Results: Clinical and basic science studies have shown that the physical epithelial cell barrier, mucociliary clearance, and antimicrobial compound secretion play pivotal innate immune roles in defending the sinonasal cavity from infection. Clinical findings have also linked dysfunction of these defense mechanisms with diseases, such as chronic rhinosinusitis and cystic fibrosis. Recent discoveries have elucidated the significance of bitter and sweet taste receptors in modulating immune responses in the upper airway. Conclusion: Numerous innate immune mechanisms seem to work in a concerted fashion to keep the sinonasal cavity free of infection. Understanding sinonasal innate immune function and dysfunction in health and disease has important implications for patients with respiratory ailments, such as chronic rhinosinusitis and cystic fibrosis. PMID:27657896

  10. Acupuncture Alleviated the Nonmotor Symptoms of Parkinson's Disease including Pain, Depression, and Autonomic Symptoms

    PubMed Central

    Iseki, Chifumi; Furuta, Taiga; Suzuki, Masao; Koyama, Shingo; Suzuki, Keiji; Suzuki, Tomoko; Kaneko, Akiyo

    2014-01-01

    A woman started to feel intractable pain on her lower legs when she was 76. At the age of 78, she was diagnosed as having Parkinson's disease (PD). The leg pain was suspected to be a symptom of PD after eliminating other causes. The patient also suffered from nonmotor symptoms, depression, anxiety, hot flashes, and paroxysmal sweating. Though the patient had received pharmacotherapy including levodopa for 5 years, she still suffered from the nonmotor symptoms and was referred to our department. We treated her with acupuncture based on the Chinese traditional medicine and electroacupuncture five times per week. After the 2-week treatment, the assessment for the symptoms was as follows; visual analogue scale (VAS) score of the leg pain was 16 mm (70 mm, before), Hamilton's rating scales for depression (HAM-D) score was 9 (18, before), timed 3 m Up and Go took 20 steps in 30 sec (24 steps in 38 sec, before), and the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part 1 score was 13 (21, before). Autonomic symptoms, hot flashes and paroxysmal sweating, were also alleviated. Acupuncture may be a good treatment modality for nonmotor symptoms in PD. PMID:25628905

  11. Acupuncture Alleviated the Nonmotor Symptoms of Parkinson's Disease including Pain, Depression, and Autonomic Symptoms.

    PubMed

    Iseki, Chifumi; Furuta, Taiga; Suzuki, Masao; Koyama, Shingo; Suzuki, Keiji; Suzuki, Tomoko; Kaneko, Akiyo; Mitsuma, Tadamichi

    2014-01-01

    A woman started to feel intractable pain on her lower legs when she was 76. At the age of 78, she was diagnosed as having Parkinson's disease (PD). The leg pain was suspected to be a symptom of PD after eliminating other causes. The patient also suffered from nonmotor symptoms, depression, anxiety, hot flashes, and paroxysmal sweating. Though the patient had received pharmacotherapy including levodopa for 5 years, she still suffered from the nonmotor symptoms and was referred to our department. We treated her with acupuncture based on the Chinese traditional medicine and electroacupuncture five times per week. After the 2-week treatment, the assessment for the symptoms was as follows; visual analogue scale (VAS) score of the leg pain was 16 mm (70 mm, before), Hamilton's rating scales for depression (HAM-D) score was 9 (18, before), timed 3 m Up and Go took 20 steps in 30 sec (24 steps in 38 sec, before), and the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part 1 score was 13 (21, before). Autonomic symptoms, hot flashes and paroxysmal sweating, were also alleviated. Acupuncture may be a good treatment modality for nonmotor symptoms in PD.

  12. Broader prevalence of Wolbachia in insects including potential human disease vectors.

    PubMed

    de Oliveira, C D; Gonçalves, D S; Baton, L A; Shimabukuro, P H F; Carvalho, F D; Moreira, L A

    2015-06-01

    Wolbachia are intracellular, maternally transmitted bacteria considered the most abundant endosymbionts found in arthropods. They reproductively manipulate their host in order to increase their chances of being transmitted to the offspring, and currently are being used as a tool to control vector-borne diseases. Studies on distribution of Wolbachia among its arthropod hosts are important both for better understanding why this bacterium is so common, as well as for its potential use as a biological control agent. Here, we studied the incidence of Wolbachia in a broad range of insect species, collected from different regions of Brazil, using three genetic markers (16S rRNA, wsp and ftsZ), which varied in terms of their sensitivity to detect this bacterium. The overall incidence of Wolbachia among species belonging to 58 families and 14 orders was 61.9%. The most common positive insect orders were Coleoptera, Diptera, Hemiptera and Hymenoptera, with Diptera and Hemiptera having the highest numbers of Wolbachia-positive families. They included potential human disease vectors whose infection status has never been reported before. Our study further shows the importance of using quantitative polymerase chain reaction for high-throughput and sensitive Wolbachia screening.

  13. Structured Regions of Alpha-synuclein Fibrils Include the Early Onset Parkinson's Disease Mutation Sites

    SciTech Connect

    Comellas Canal, Gemma; Lemkau, Luisel R.; Nieuwkoop, Andrew J.; Kloepper, Kathryn D.; Ladror, Daniel T.; Ebisu, Reika; Woods, Wendy S.; Lipton, Andrew S.; George, Julia M.; Rienstra, Chad M.

    2011-08-26

    Alpha-Synuclein (AS) fibrils constitute the major proteinaceous component of Lewy bodies (LBs), the pathological hallmark of Parkinson’s disease (PD) and other neurodegenerative diseases. Three single point mutations in the AS gene, as well as multiplication of the wild-type (WT) AS allele, have been previously identified in families with early-onset PD. Although AS fibrils have been the subject of intense study, critical details about their structure including the precise location of the B-strands and the extent of the core, the three-dimensional structure and the effects of the mutations—remain unknown. Here, we have used magic-angle spinning solid-state NMR spectroscopy to present a detailed characterization of the full-length WT AS fibrils. With improved sample preparations, isotopic labeling patterns and NMR experiments, we have confidently assigned more than 90% of the 13C and 15N backbone and sidechain chemical shifts of the detected residues from residue 39 to 97, and quantified the conformational dynamics throughout this region. Our results demonstrate that the core of AS fibrils extends with a repeated motif and that residues 30, 46 and 53-the early-onset PD mutant sites-are located in structured regions of AS fibrils.

  14. Neuroinflammation in Alzheimer's disease: different molecular targets and potential therapeutic agents including curcumin.

    PubMed

    Ray, Balmiki; Lahiri, Debomoy K

    2009-08-01

    Alzheimer's disease (AD) is a neurodegenerative disorder of the elderly. Deposition of amyloid beta plaque and associated neuroinflammation are the major hallmarks of AD. Whereas reactive oxygen species (ROS) and activated microglial cells contribute to neuronal loss, nuclear factor kappaB and apolipoprotein E participate in inflammatory process of AD. Current FDA approved drugs provide only symptomatic relief in AD. For broad spectrum of activity, some natural products are also being tested. Turmeric is used as an anti-inflammatory medicine in various regions of Asia. Curcumin, which is a yellow colored polyphenol compound present in turmeric, showed anti-inflammatory properties. Herein, we discuss the neurobiological and neuroinflammatory pathways of AD, evaluate different molecular targets and potential therapeutic agents, including curcumin, for the treatment of AD.

  15. Distal airway dysfunction identifies pulmonary inflammation in asymptomatic smokers

    PubMed Central

    Berger, Kenneth I.; Pradhan, Deepak R.; Goldring, Roberta M.; Oppenheimer, Beno W.; Rom, William N.

    2016-01-01

    Smoking induced inflammation leads to distal airway destruction. However, the relationship between distal airway dysfunction and inflammation remains unclear, particularly in smokers prior to the development of airway obstruction. Seven normal controls and 16 smokers without chronic obstructive pulmonary disease (COPD) were studied. Respiratory function was assessed using the forced oscillation technique (FOT). Abnormal FOT was defined as elevated resistance at 5 Hz (R5). Parameters reflecting distal lung function included frequency dependence of resistance (R5–20) and dynamic elastance (X5). Inflammation was quantified in concentrated bronchoalveolar lavage utilising cell count differential and cytokines expressed as concentration per mL epithelial lining fluid. All control subjects and seven smokers had normal R5. Nine smokers had elevated R5 with abnormal R5–20 and X5, indicating distal lung dysfunction. The presence of abnormal FOT was associated with two-fold higher lymphocyte and neutrophil counts (p<0.025) and with higher interleukin (IL)-8, eotaxin and fractalkine levels (p<0.01). Reactivity of R5–20 and X5 correlated with levels of IL-8, eotaxin, fractalkine, IL-12p70 and transforming growth factor-α (r>0.47, p<0.01). Distal airway dysfunction in smokers without COPD identifies the presence of distal lung inflammation that parallel reported observations in established COPD. These findings were not evident on routine pulmonary function testing and may allow the identification of smokers at risk of progression to COPD. PMID:27995132

  16. Distal airway dysfunction identifies pulmonary inflammation in asymptomatic smokers.

    PubMed

    Berger, Kenneth I; Pradhan, Deepak R; Goldring, Roberta M; Oppenheimer, Beno W; Rom, William N; Segal, Leopoldo N

    2016-10-01

    Smoking induced inflammation leads to distal airway destruction. However, the relationship between distal airway dysfunction and inflammation remains unclear, particularly in smokers prior to the development of airway obstruction. Seven normal controls and 16 smokers without chronic obstructive pulmonary disease (COPD) were studied. Respiratory function was assessed using the forced oscillation technique (FOT). Abnormal FOT was defined as elevated resistance at 5 Hz (R5). Parameters reflecting distal lung function included frequency dependence of resistance (R5-20) and dynamic elastance (X5). Inflammation was quantified in concentrated bronchoalveolar lavage utilising cell count differential and cytokines expressed as concentration per mL epithelial lining fluid. All control subjects and seven smokers had normal R5. Nine smokers had elevated R5 with abnormal R5-20 and X5, indicating distal lung dysfunction. The presence of abnormal FOT was associated with two-fold higher lymphocyte and neutrophil counts (p<0.025) and with higher interleukin (IL)-8, eotaxin and fractalkine levels (p<0.01). Reactivity of R5-20 and X5 correlated with levels of IL-8, eotaxin, fractalkine, IL-12p70 and transforming growth factor-α (r>0.47, p<0.01). Distal airway dysfunction in smokers without COPD identifies the presence of distal lung inflammation that parallel reported observations in established COPD. These findings were not evident on routine pulmonary function testing and may allow the identification of smokers at risk of progression to COPD.

  17. Assessing mucus and airway morphology in response to a segmental allergen challenge using OCT (Conference Presentation)

    NASA Astrophysics Data System (ADS)

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

    2016-03-01

    Asthma affects hundreds of millions of people worldwide, and the prevalence of the disease appears to be increasing. One of the most important aspects of asthma is the excessive bronchoconstriction that results in many of the symptoms experienced by asthma sufferers, but the relationship between bronchoconstriction and airway morphology is not clearly established. We present the imaging results of a study involving a segmental allergen challenge given to both allergic asthmatic (n = 12) and allergic non-asthmatic (n = 19) human volunteers. Using OCT, we have imaged and assessed baseline morphology in a right upper lobe (RUL) airway, serving as the control, and a right middle lobe (RML) airway, in which the allergen was to be administered. After a period of 24 hours had elapsed following the administration of the allergen, both airways were again imaged and the response morphology assessed. A number of airway parameters were measured and compared, including epithelial thickness, mucosal thickness and buckling, lumen area, and mucus content. We found that at baseline epithelial thickness, mucosal thickness, and mucosal buckling were greater in AAs than ANAs. We also observed statistically significant increases in these values 24 hours after the allergen had been administered for both the ANA and AA sets. In comparison, the control airway which received a diluent showed no statistically significant change.

  18. Living with asthma and chronic obstructive airways disease: Using technology to support self-management - An overview.

    PubMed

    Morrison, Deborah; Mair, Frances S; Yardley, Lucy; Kirby, Sarah; Thomas, Mike

    2016-08-10

    Long-term respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD) are common, and cause high levels of morbidity and mortality. Supporting self-management is advocated for both asthma and increasingly so for COPD, and there is growing interest in the potential role of a range of new technologies, such as smartphone apps, the web or telehealth to facilitate and promote self-management in these conditions. Treatment goals for both asthma and COPD include aiming to control symptoms, maintain activities, achieve the best possible quality of life and minimize risks of exacerbation. To do this, health professionals should be (a) helping patients to recognize deteriorating symptoms and act appropriately; (b) promoting adherence to maintenance therapy; (c) promoting a regular review where triggers can be established, and strategies for managing such triggers discussed; and (d) promoting healthy lifestyles and positive self-management of symptoms. In particular, low uptake of asthma action plans is a modifiable contributor to morbidity and possibly also to mortality in those with asthma and should be addressed as a priority. Using technology to support self-management is an evolving strategy that shows promise. This review provides an overview of self-management support and discusses how newer technologies may help patients and health professionals to meet key treatment goals.

  19. Epithelial cell-extracellular matrix interactions and stem cells in airway epithelial regeneration.

    PubMed

    Coraux, Christelle; Roux, Jacqueline; Jolly, Thomas; Birembaut, Philippe

    2008-08-15

    In healthy subjects, the respiratory epithelium forms a continuous lining to the airways and to the environment, and plays a unique role as a barrier against external deleterious agents to protect the airways from the insults. In respiratory diseases such as cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), chronic bronchitis, or asthma, the airway epithelium is frequently remodeled and injured, leading to the impairment of its defense functions. The rapid restoration of the epithelial barrier is crucial for these patients. The complete regeneration of the airway epithelium is a complex phenomenon, including not only the epithelial wound repair but also the epithelial differentiation to reconstitute a fully well differentiated and functional epithelium. The regeneration implies two partners: the epithelial stem/progenitor cells and factors able to regulate this process. Among these factors, epithelial cells-extracellular matrix (ECM) interactions play a crucial role. The secretion of a provisional ECM, the cell-ECM relationships through epithelial receptors, and the remodeling of the ECM by proteases (mainly matrix metalloproteinases) contribute not only to airway epithelial repair by modulating epithelial cell migration and proliferation, but also to the differentiation of repairing cells leading to the complete restoration of the wounded epithelium. A better characterization of resident stem cells and of effectors of the regeneration process is an essential prerequisite to propose new regenerative therapeutics to patients suffering from infectious/inflammatory respiratory diseases.

  20. The non-neuronal cholinergic system as novel drug target in the airways.

    PubMed

    Pieper, Michael Paul

    2012-11-27

    The parasympathetic nervous system is a key regulator of the human organism involved in the pathophysiology of various disorders through cholinergic mechanisms. In the lungs, acetylcholine (ACh) released by vagal nerve endings stimulates muscarinic receptors thereby increasing airway smooth muscle tone. Contraction of airway smooth muscle cells leads to increased respiratory resistance and dyspnea. An additional branch of the cholinergic system is the non-neuronal cholinergic system expressed in nearly all cell types present in the airways. Activation of this system may contribute to an increased cholinergic tone in the lungs, inducing pathophysiological processes like inflammation, remodeling, mucus hypersecretion and chronic cough. Selective muscarinic receptor antagonists specifically inhibit acetylcholine at the receptor inducing bronchodilation in patients with obstructive airway diseases. This paper reviews preclinical pharmacological research activities on anticholinergics including experimental models of asthma and chronic obstructive pulmonary disease, COPD. It discloses various options to follow up the non-neuronal cholinergic system as a novel drug target for the treatment of key aspects of obstructive airway diseases, in particular those of a chronic nature.

  1. Airway uric acid is a sensor of inhaled protease allergens and initiates type 2 immune responses in respiratory mucosa1

    PubMed Central

    Hara, Kenichiro; Iijima, Koji; Elias, Martha K.; Seno, Satoshi; Tojima, Ichiro; Kobayashi, Takao; Kephart, Gail M.; Kurabayashi, Masahiko; Kita, Hirohito

    2014-01-01

    While type 2 immune responses to environmental antigens are thought to play pivotal roles in asthma and allergic airway diseases, the immunological mechanisms that initiate the responses are largely unknown. Many allergens have biologic activities, including enzymatic activities and abilities to engage innate pattern-recognition receptors such as TLR4. Here we report that IL-33 and thymic stromal lymphopoietin (TSLP) were produced quickly in the lungs of naïve mice exposed to cysteine proteases, such as bromelain and papain, as a model for allergens. IL-33 and TSLP sensitized naïve animals to an innocuous airway antigen OVA, which resulted in production of type 2 cytokines and IgE antibody and eosinophilic airway inflammation when mice were challenged with the same antigen. Importantly, upon exposure to proteases, uric acid (UA) was rapidly released into the airway lumen, and removal of this endogenous UA by uricase prevented type 2 immune responses. UA promoted secretion of IL-33 by airway epithelial cells in vitro, and administration of UA into the airways of naïve animals induced extracellular release of IL-33, followed by both innate and adaptive type 2 immune responses in vivo. Finally, a potent UA synthesis inhibitor, febuxostat, mitigated asthma phenotypes that were caused by repeated exposure to natural airborne allergens. These findings provide mechanistic insights into the development of type 2 immunity to airborne allergens and recognize airway UA as a key player that regulates the process in respiratory mucosa. PMID:24663677

  2. Airway uric acid is a sensor of inhaled protease allergens and initiates type 2 immune responses in respiratory mucosa.

    PubMed

    Hara, Kenichiro; Iijima, Koji; Elias, Martha K; Seno, Satoshi; Tojima, Ichiro; Kobayashi, Takao; Kephart, Gail M; Kurabayashi, Masahiko; Kita, Hirohito

    2014-05-01

    Although type 2 immune responses to environmental Ags are thought to play pivotal roles in asthma and allergic airway diseases, the immunological mechanisms that initiate the responses are largely unknown. Many allergens have biologic activities, including enzymatic activities and abilities to engage innate pattern-recognition receptors such as TLR4. In this article, we report that IL-33 and thymic stromal lymphopoietin were produced quickly in the lungs of naive mice exposed to cysteine proteases, such as bromelain and papain, as a model for allergens. IL-33 and thymic stromal lymphopoietin sensitized naive animals to an innocuous airway Ag OVA, which resulted in production of type 2 cytokines and IgE Ab, and eosinophilic airway inflammation when mice were challenged with the same Ag. Importantly, upon exposure to proteases, uric acid (UA) was rapidly released into the airway lumen, and removal of this endogenous UA by uricase prevented type 2 immune responses. UA promoted secretion of IL-33 by airway epithelial cells in vitro, and administration of UA into the airways of naive animals induced extracellular release of IL-33, followed by both innate and adaptive type 2 immune responses in vivo. Finally, a potent UA synthesis inhibitor, febuxostat, mitigated asthma phenotypes that were caused by repeated exposure to natural airborne allergens. These findings provide mechanistic insights into the development of type 2 immunity to airborne allergens and recognize airway UA as a key player that regulates the process in respiratory mucosa.

  3. The impacts of open-mouth breathing on upper airway space in obstructive sleep apnea: 3-D MDCT analysis.

    PubMed

    Kim, Eun Joong; Choi, Ji Ho; Kim, Kang Woo; Kim, Tae Hoon; Lee, Sang Hag; Lee, Heung Man; Shin, Chol; Lee, Ki Yeol; Lee, Seung Hoon

    2011-04-01

    Open-mouth breathing during sleep is a risk factor for obstructive sleep apnea (OSA) and is associated with increased disease severity and upper airway collapsibility. The aim of this study was to investigate the effect of open-mouth breathing on the upper airway space in patients with OSA using three-dimensional multi-detector computed tomography (3-D MDCT). The study design included a case-control study with planned data collection. The study was performed at a tertiary medical center. 3-D MDCT analysis was conducted on 52 patients with OSA under two experimental conditions: mouth closed and mouth open. Under these conditions, we measured the minimal cross-sectional area of the retropalatal and retroglossal regions (mXSA-RP, mXSA-RG), as well as the upper airway length (UAL), defined as the vertical dimension from hard palate to hyoid. We also computed the volume of the upper airway space by 3-D reconstruction of both conditions. When the mouth was open, mXSA-RP and mXSA-RG significantly decreased and the UAL significantly increased, irrespective of the severity of OSA. However, between the closed- and open-mouth states, there was no significant change in upper airway volume at any severity of OSA. Results suggest that the more elongated and narrow upper airway during open-mouth breathing may aggravate the collapsibility of the upper airway and, thus, negatively affect OSA severity.

  4. Treatment of Exudative and Vasogenic Chorioretinal Diseases Including Variants of AMD and Other CNV Related Maculopathy

    ClinicalTrials.gov

    2012-10-24

    Coats' Disease; Idiopathic Retinal Telangiectasia; Retinal Angiomatous Proliferation; Polypoidal Choroidal Vasculopathy; Pseudoxanthoma Elasticum; Pathological Myopia; Multi-focal Choroiditis; Rubeosis Iridis; Von Hippel Lindau Disease; BEST VITELLIFORM MACULAR DYSTROPHY, MULTIFOCAL (Disorder)

  5. Continuous mucociliary transport by primary human airway epithelial cells in vitro

    PubMed Central

    Sears, Patrick R.; Yin, Wei-Ning

    2015-01-01

    Mucociliary clearance (MCC) is an important innate defense mechanism that continuously removes inhaled pathogens and particulates from the airways. Normal MCC is essential for maintaining a healthy respiratory system, and impaired MCC is a feature of many airway diseases, including both genetic (cystic fibrosis, primary ciliary dyskinesia) and acquired (chronic obstructive pulmonary disease, bronchiectasis) disorders. Research into the fundamental processes controlling MCC, therefore, has direct clinical application, but has been limited in part due to the difficulty of studying this complex multicomponent system in vitro. In this study, we have characterized a novel method that allows human airway epithelial cells to differentiate into a mucociliary epithelium that transports mucus in a continuous circular track. The mucociliary transport device allows the measurement and manipulation of all features of mucociliary transport in a controlled in vitro system. In this initial study, the effect of ciliary beat frequency and mucus concentration on the speed of mucociliary transport was investigated. PMID:25979076

  6. Cystic fibrosis lung microbiome: opportunities to reconsider management of airway infection.

    PubMed

    Caverly, Lindsay J; Zhao, Jiangchao; LiPuma, John J

    2015-10-01

    The importance of infection in the pathogenesis of cystic fibrosis (CF) lung disease has been long recognized, and the use of antibiotics targeting bacteria identified in cultures of respiratory specimens has played a critical role in improving outcomes for individuals with CF. Over the past ∼15 years, the use of culture-independent methods to assess airway microbiology in CF has revealed complex and dynamic CF airway bacterial communities. Recent areas of investigation of the CF lung microbiome have included exploring how bacterial community structures change over time, particularly with respect to disease progression or pulmonary exacerbation, and in response to antibiotic therapies. This review will discuss what has been learned from these studies as well as how these findings offer opportunities to further refine management of CF airway infection.

  7. Role of IRE1α/XBP-1 in Cystic Fibrosis Airway Inflammation

    PubMed Central

    Ribeiro, Carla M. P.; Lubamba, Bob A.

    2017-01-01

    Cystic fibrosis (CF) pulmonary disease is characterized by chronic airway infection and inflammation. The infectious and inflamed CF airway environment impacts on the innate defense of airway epithelia and airway macrophages. The CF airway milieu induces an adaptation in these cells characterized by increased basal inflammation and a robust inflammatory response to inflammatory mediators. Recent studies have indicated that these responses depend on activation of the unfolded protein response (UPR). This review discusses the contribution of airway epithelia and airway macrophages to CF airway inflammatory responses and specifically highlights the functional importance of the UPR pathway mediated by IRE1/XBP-1 in these processes. These findings suggest that targeting the IRE1/XBP-1 UPR pathway may be a therapeutic strategy for CF airway disease. PMID:28075361

  8. Deletion of airway cilia results in noninflammatory bronchiectasis and hyperreactive airways

    PubMed Central

    Gilley, Sandra K.; Stenbit, Antine E.; Pasek, Raymond C.; Sas, Kelli M.; Steele, Stacy L.; Amria, May; Bunni, Marlene A.; Estell, Kimberly P.; Schwiebert, Lisa M.; Flume, Patrick; Gooz, Monika; Haycraft, Courtney J.; Yoder, Bradley K.; Miller, Caroline; Pavlik, Jacqueline A.; Turner, Grant A.; Sisson, Joseph H.

    2013-01-01

    The mechanisms for the development of bronchiectasis and airway hyperreactivity have not been fully elucidated. Although genetic, acquired diseases and environmental influences may play a role, it is also possible that motile cilia can influence this disease process. We hypothesized that deletion of a key intraflagellar transport molecule, IFT88, in mature mice causes loss of cilia, resulting in airway remodeling. Airway cilia were deleted by knockout of IFT88, and airway remodeling and pulmonary function were evaluated. In IFT88− mice there was a substantial loss of airway cilia on respiratory epithelium. Three months after the deletion of cilia, there was clear evidence for bronchial remodeling that was not associated with inflammation or apparent defects in mucus clearance. There was evidence for airway epithelial cell hypertrophy and hyperplasia. IFT88− mice exhibited increased airway reactivity to a methacholine challenge and decreased ciliary beat frequency in the few remaining cells that possessed cilia. With deletion of respiratory cilia there was a marked increase in the number of club cells as seen by scanning electron microscopy. We suggest that airway remodeling may be exacerbated by the presence of club cells, since these cells are involved in airway repair. Club cells may be prevented from differentiating into respiratory epithelial cells because of a lack of IFT88 protein that is necessary to form a single nonmotile cilium. This monocilium is a prerequisite for these progenitor cells to transition into respiratory epithelial cells. In conclusion, motile cilia may play an important role in controlling airway structure and function. PMID:24213915

  9. Airway management for cervical spine surgery.

    PubMed

    Farag, Ehab

    2016-03-01

    Cervical spine surgery is one of the most commonly performed spine surgeries in the United States, and 90% of the cases are related to degenerative cervical spine disease (the rest to cervical spine trauma and/or instability). The airway management for cervical spine surgery represents a crucial step in the anesthetic management to avoid injury to the cervical cord. The crux for upper airway management for cervical spine surgery is maintaining the neck in a neutral position with minimal neck movement during endotracheal intubation. Therefore, the conventional direct laryngoscopy (DL) can be unsuitable for securing the upper airway in cervical spine surgery, especially in cases of cervical spine instability and myelopathy. This review discusses the most recent evidence-based facts of the main advantages and limitations of different techniques available for upper airway management for cervical spine surgery.

  10. Sensory nerves in lung and airways.

    PubMed

    Lee, Lu-Yuan; Yu, Jerry

    2014-01-01

    Sensory nerves innervating the lung and airways play an important role in regulating various cardiopulmonary functions and maintaining homeostasis under both healthy and disease conditions. Their activities conducted by both vagal and sympathetic afferents are also responsible for eliciting important defense reflexes that protect the lung and body from potential health-hazardous effects of airborne particulates and chemical irritants. This article reviews the morphology, transduction properties, reflex functions, and respiratory sensations of these receptors, focusing primarily on recent findings derived from using new technologies such as neural immunochemistry, isolated airway-nerve preparation, cultured airway neurons, patch-clamp electrophysiology, transgenic mice, and other cellular and molecular approaches. Studies of the signal transduction of mechanosensitive afferents have revealed a new concept of sensory unit and cellular mechanism of activation, and identified additional types of sensory receptors in the lung. Chemosensitive properties of these lung afferents are further characterized by the expression of specific ligand-gated ion channels on nerve terminals, ganglion origin, and responses to the action of various inflammatory cells, mediators, and cytokines during acute and chronic airway inflammation and injuries. Increasing interest and extensive investigations have been focused on uncovering the mechanisms underlying hypersensitivity of these airway afferents, and their role in the manifestation of various symptoms under pathophysiological conditions. Several important and challenging questions regarding these sensory nerves are discussed. Searching for these answers will be a critical step in developing the translational research and effective treatments of airway diseases.

  11. Regulation of Airway Mucin Gene Expression

    PubMed Central

    Thai, Philip; Loukoianov, Artem; Wachi, Shinichiro; Wu, Reen

    2015-01-01

    Mucins are important components that exert a variety of functions in cell-cell interaction, epidermal growth factor receptor signaling, and airways protection. In the conducting airways of the lungs, mucins are the major contributor to the viscoelastic property of mucous secretion, which is the major barrier to trapping inhaled microbial organism, particulates, and oxidative pollutants. The homeostasis of mucin production is an important feature in conducting airways for the maintenance of mucociliary function. Aberrant mucin secretion and accumulation in airway lumen are clinical hallmarks associated with various lung diseases, such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, emphysema, and lung cancer. Among 20 known mucin genes identified, 11 of them have been verified at either the mRNA and/or protein level in airways. The regulation of mucin genes is complicated, as are the mediators and signaling pathways. This review summarizes the current view on the mediators, the signaling pathways, and the transcriptional units that are involved in the regulation of airway mucin gene expression. In addition, we also point out essential features of epigenetic mechanisms for the regulation of these genes. PMID:17961085

  12. Gene-environment interaction from international cohorts: impact on development and evolution of occupational and environmental lung and airway disease.

    PubMed

    Gaffney, Adam; Christiani, David C

    2015-06-01

    Environmental and occupational pulmonary diseases impose a substantial burden of morbidity and mortality on the global population. However, it has been long observed that only some of those who are exposed to pulmonary toxicants go on to develop disease; increasingly, it is being recognized that genetic differences may underlie some of this person-to-person variability. Studies performed throughout the globe are demonstrating important gene-environment interactions for diseases as diverse as chronic beryllium disease, coal workers' pneumoconiosis, silicosis, asbestosis, byssinosis, occupational asthma, and pollution-associated asthma. These findings have, in many instances, elucidated the pathogenesis of these highly complex diseases. At the same time, however, translation of this research into clinical practice has, for good reasons, proceeded slowly. No genetic test has yet emerged with sufficiently robust operating characteristics to be clearly useful or practicable in an occupational or environmental setting. In addition, occupational genetic testing raises serious ethical and policy concerns. Therefore, the primary objective must remain ensuring that the workplace and the environment are safe for all.

  13. Newcastle disease: An in-depth review including epidemiology and molecular diagnostics

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Infections of birds with strains of avian paramyxovirus serotype 1 (APMV-1), (synonyms: Newcastle disease virus (NDV), pigeon PMV-1 (PPMV-1)) are associated with two clinical outcomes: 1) Newcastle disease (ND) results from infections with virulent APMV-1, and is also called Exotic ND (END) in U. S...

  14. The Diagnosis and Management of Airway Complications Following Lung Transplantation.

    PubMed

    Mahajan, Amit K; Folch, Erik; Khandhar, Sandeep J; Channick, Colleen L; Santacruz, Jose F; Mehta, Atul C; Nathan, Steven D

    2017-03-05

    Airway complications following lung transplantation result in considerable morbidity and are associated with a mortality of 2-4 percent. The incidence of lethal and non-lethal airway complications has decreased since the early experiences with double- and single-lung transplantation. The most common risk factor associated with post-lung transplant airway complications is anastomotic ischemia. Airway complications include development of exophytic granulation tissue, bronchial stenosis, bronchomalacia, airway fistula, endobronchial infection, and anastomotic dehiscence. The broadening array of bronchoscopic therapies has enhanced treatment options for lung transplant recipients with airway complications. This article reviews the risk factors, clinical manifestations, and treatments of airway complications following lung transplantation, and provides our expert opinion where evidence is lacking.

  15. Soft TCPTP Agonism—Novel Target to Rescue Airway Epithelial Integrity by Exogenous Spermidine

    PubMed Central

    Ghisalberti, Carlo A.; Borzì, Rosa M.; Cetrullo, Silvia; Flamigni, Flavio; Cairo, Gaetano

    2016-01-01

    A reparative approach of disrupted epithelium in obstructive airway diseases, namely asthma and chronic obstructive pulmonary disease (COPD), may afford protection and long-lasting results compared to conventional therapies, e.g., corticosteroids or immunosuppressant drugs. Here, we propose the polyamine spermidine as a novel therapeutic agent in airways diseases, based on a recently identified mode of action: T-cell protein tyrosine phosphatase (TCPTP) agonism. It may include and surpass single-inhibitors of stress and secondary growth factor pathway signaling, i.e., the new medicinal chemistry in lung diseases. Enhanced polyamine biosynthesis has been charged with aggravating prognosis by competing for L-arginine at detriment of nitric oxide (NO) synthesis with bronchoconstrictive effects. Although excess spermine, a higher polyamine, is harmful to airways physiology, spermidine can pivot the cell homeostasis during stress conditions by the activation of TCPTP. In fact, the dephosphorylating activity of TCPTP inhibits the signaling cascade that leads to the expression of genes involved in detachment and epithelial-to-mesenchymal transition (EMT), and increases the expression of adhesion and tight junction proteins, thereby enhancing the barrier functionality in inflammation-prone tissues. Moreover, a further beneficial effect of spermidine may derive from its ability to promote autophagy, possibly in a TCPTP-dependent way. Since doses of spermidine in the micromolar range are sufficient to activate TCPTP, low amounts of spermidine administered in sustained release modality may provide an optimal pharmacologic profile for the treatment of obstructive airway diseases. PMID:27375482

  16. Anti-inflammatory properties of the monoterpene 1.8-cineole: current evidence for co-medication in inflammatory airway diseases.

    PubMed

    Juergens, U R

    2014-12-01

    1,8-cineole is a natural monoterpene, also known as eucalyptol. It is a major compound of many plant essential oils, mainly extracted from Eucalyptus globulus oil. As an isolated compound, 1,8-cineole is known for its mucolytic and spasmolytic action on the respiratory tract, with proven clinical efficacy. 1,8-cineole has also shown therapeutic benefits in inflammatory airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD). This clinical evidence refers to its anti-inflammatory and anti-oxidant mode of action, which has been proven in numerous pre-clinical studies. In vitro studies found strong evidence that 1,8-cineole controls inflammatory processes and mediator production of infection- or inflammation-induced mucus hypersecretion by its action as anti-inflammatory modifier rather than a simple mucolytic agent. The aim of this review is to present these preclinical studies performed with the pure monoterpene, and to summarize the current knowledge on the mode of action of 1,8-cineole. The actual understanding of the pure 1,8-cineole compared to mixtures of natural volatile oils containing 1,8-cineole as a major compound and to mixtures of natural terpenes, known as essential oils, will be discussed. Based on the anti-oxidative and anti-inflammatory properties, recent clinical trials with 1,8-cineole have shown first evidence for the beneficial use of 1,8-cineole as long-term therapy in the prevention of COPD-exacerbations and to improve asthma control.

  17. Inhaled Antibiotics for Lower Airway Infections

    PubMed Central

    Quon, Bradley S.; Goss, Christopher H.

    2014-01-01

    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. PMID:24673698

  18. Muc5b is required for airway defence.

    PubMed

    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

    2014-01-16

    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.

  19. Muc5b Is Required for Airway Defense

    PubMed Central

    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.; Gabriela Bowden, M.; 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.; William Davis, C.; 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 via mucociliary clearance (MCC)1,2. However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases1. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus1,3. Genetic variants are linked to diverse lung diseases4-6, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in the lungs. 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 normally7. Apoptotic macrophages accumulated, phagocytosis was impaired, and IL-23 production was reduced inMuc5b−/− mice. By contrast, in Muc5b transgenic (Tg) mice, 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 sputum1,8. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%9-11. 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. PMID:24317696

  20. Muc5b is required for airway defence

    NASA Astrophysics Data System (ADS)

    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.

  1. The role of the OIE in information exchange and the control of animal diseases, including zoonoses.

    PubMed

    Poissonnier, C; Teissier, M

    2013-08-01

    The growing importance of animal diseases and zoonoses at a time when globalisation has increased movements of people, animals and animal products across the globe, has strengthened the role of the World Organisation for Animal Health (OIE) in animal disease control. The OIE's mandate since its establishment in 1924 has been to facilitate the exchange of public health, animal health and scientific information, and to further the control and eradication of animal diseases. The OIE is recognised by the World Trade Organization Agreement on the Application of Sanitary and Phytosanitary Measures as the international reference organisation for animal diseases and zoonoses, especially for standard setting. The standards adopted by the World Assembly of OIE Delegates on veterinary public health and animal health feature in the OlE Terrestrial Animal Health Code, the Aquatic Animal Health Code, the Manual of Diagnostic Tests and Vaccines for Terrestrial Animals and the Manual of Diagnostic Tests for Aquatic Animals. The OlE is also a reference organisation for the exchange of public and animal health information among Member Countries, through an information, reporting and warning system based on transparent communication between countries. The OIE provides scientific expertise in ascertaining countries' status with regard to notifiable diseases, enabling them to secure official recognition as being free from foot and mouth disease, African horse sickness, contagious bovine pleuropneumonia and bovine spongiform encephalopathy. The OIE also contributes its scientific expertise to stakeholder training on the surveillance and control of animal diseases and zoonoses and to the evaluation of the performance of Veterinary Services, to enhance theirwork asthe cornerstone of their countries' disease control efforts.

  2. Linkage analyses of chromosome 6 loci, including HLA, in familial aggregations of Crohn disease

    SciTech Connect

    Hugot, J.P.; Laurent-Puig, P.; Gower-Rousseau, C.; Caillat-Zueman, S.; Beaugerie, L.; Dupas, J.L.; Van Gossum, A.; Bonaiti-Pellie, C.; Cortot, A.

    1994-08-15

    Segregation analyses of familial aggregations of Crohn disease have provided consistent results pointing to the involvement of a predisposing gene with a recessive mode of inheritance. Although extensively investigated, the role played by human leucocyte antigen (HLA) genes in this inflammatory bowel disease remains elusive and the major histocompatibility complex is a candidate region for the mapping of the Crohn disease susceptibility gene. A total of 25 families with multiple cases of Crohn disease was genotyped for HLA DRB1 and for 16 highly polymorphic loci evenly distributed on chromosome 6. The data were subjected to linkage analysis using the lod score method. Neither individual nor combined lod scores for any family and for any locus tested reached values suggesting linkage or genetic heterogeneity. The Crohn disease predisposing locus was excluded from the whole chromosome 6 with lod scores less than -2. It was excluded from the major histocompatibility complex and from 91% of the chromosome 6 genetic map with lod scores less than -4. The major recessive gene involved in genetic predisposition to Crohn disease does not reside on the major histocompatibility complex nor on any locus mapping to chromosome 6. 37 refs., 2 figs., 2 tabs.

  3. Development of an integral assessment approach of health status in patients with obstructive airway diseases: the CORONA study

    PubMed Central

    van den Akker, Edmée FMM; van ‘t Hul, Alex J; Chavannes, Niels H; Braunstahl, Gert-Jan; van Bruggen, Alie; Rutten-van Mölken, Maureen PMH; in ‘t Veen, Johannes CCM

    2015-01-01

    Background Traditional assessment of patients with obstructive lung diseases (asthma and chronic obstructive pulmonary disease; COPD) relies on physiological tests. The COPD and Asthma Rotterdam Integrated Care Approach (CORONA) study aims to develop a diagnostic pathway with a more comprehensive approach to the assessment of patients with asthma and COPD in secondary care. Methods An eight-step method was used to develop and implement the pathway for patients with asthma or COPD referred to an outpatient hospital setting. Results The diagnostic pathway consists of an evidence-based set of measurements prioritized by a Delphi procedure. The pathway incorporates three innovative diagnostics: the metronome-paced hyperventilation test to measure dynamic hyperinflation, an activity monitor to objectively evaluate physical activity in daily life, and the Nijmegen Clinical Screening Instrument as a comprehensive assessment tool to acquire detailed insight into symptoms, functional limitations, and quality of life. Conclusion An innovative diagnostic pathway was developed and implemented for patients with obstructive lung diseases referred to secondary care. As this pathway aims to provide a comprehensive analysis of health status, it focuses on biomedical aspects and also reviews behavioral aspects that further elucidate the patient’s health status. The added value of the diagnostic pathway needs to be determined from both an organizational perspective and from the individual patient’s viewpoint. PMID:26609228

  4. Airway Inflammation and Hypersensitivity Induced by Chronic Smoking

    PubMed Central

    Kou, Yu Ru; Kwong, Kevin; Lee, Lu-Yuan

    2011-01-01

    Airway hypersensitivity, characterized by enhanced excitability of airway sensory nerves, is a prominent pathophysiological feature in patients with airway inflammatory diseases. Although the underlying pathogenic mechanism is not fully understood, chronic airway inflammation is believed to be primarily responsible. Cigarette smoking is known to cause chronic airway inflammation, accompanied by airway hyperresponsiveness. Experimental evidence indicates that enhanced excitability of vagal bronchopulmonary sensory nerves and increased tachykinin synthesis in these nerves resulting from chronic inflammation are important contributing factors to the airway hyperresponsiveness. Multiple inflammatory mediators released from various types of structural and inflammatory cells are involved in the smoking-induced airway inflammation, which is mainly regulated by redox-sensitive signaling pathways and transcription factors. Furthermore, recent studies have reported potent sensitizing and stimulatory effects of these inflammatory mediators such as prostanoids and reactive oxygen species on these sensory nerves. In summary, these studies using cigarette smoking as an experimental approach have identified certain potentially important cell signaling pathways and underlying mechanisms of the airway hypersensitivity induced by chronic airway inflammation. PMID:21397052

  5. Controversies in Pediatric Perioperative Airways

    PubMed Central

    Klučka, Jozef; Štourač, Petr; Štoudek, Roman; Ťoukálková, Michaela; Harazim, Hana; Kosinová, Martina

    2015-01-01

    Pediatric airway management is a challenge in routine anesthesia practice. Any airway-related complication due to improper procedure can have catastrophic consequences in pediatric patients. The authors reviewed the current relevant literature using the following data bases: Google Scholar, PubMed, Medline (OVID SP), and Dynamed, and the following keywords: Airway/s, Children, Pediatric, Difficult Airways, and Controversies. From a summary of the data, we identified several controversies: difficult airway prediction, difficult airway management, cuffed versus uncuffed endotracheal tubes for securing pediatric airways, rapid sequence induction (RSI), laryngeal mask versus endotracheal tube, and extubation timing. The data show that pediatric anesthesia practice in perioperative airway management is currently lacking the strong evidence-based medicine (EBM) data that is available for adult subpopulations. A number of procedural steps in airway management are derived only from adult populations. However, the objective is the same irrespective of patient age: proper securing of the airway and oxygenation of the patient. PMID:26759809

  6. Airway Hydration and COPD

    PubMed Central

    Ghosh, Arunava; Boucher, R.C.; Tarran, Robert

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) is one of the prevalent causes of worldwide mortality and encompasses two major clinical phenotypes, i.e., chronic bronchitis (CB) and emphysema. The most common cause of COPD is chronic tobacco inhalation. Research focused on the chronic bronchitic phenotype of COPD has identified several pathological processes that drive disease initiation and progression. For example, the lung’s mucociliary clearance (MCC) system performs the critical task of clearing inhaled pathogens and toxic materials from the lung. MCC efficiency is dependent on: (i) the ability of apical plasma membrane ion channels such as the cystic fibrosis transmembrane conductance regulator (CFTR) and the epithelial Na+ channel (ENaC) to maintain airway hydration; (ii) ciliary beating; and, (iii) appropriate rates of mucin secretion. Each of these components is impaired in CB and likely contributes to the mucus stasis/accumulation seen in CB patients. This review highlights the cellular components responsible for maintaining MCC and how this process is disrupted following tobacco exposure and with CB. We shall also discuss existing therapeutic strategies for the treatment of chronic bronchitis and how components of the MCC can be used as biomarkers for the evaluation of tobacco or tobacco-like-product exposure. PMID:26068443

  7. [Diagnosis and therapy of axial spondyloarthritis including ankylosing spondylitis (Bechterew's disease)].

    PubMed

    Poddubnyy, D; Sieper, J

    2012-07-01

    The term axial spondyloarthritis covers patients with established structural changes visible on x-ray in sacroiliac joints and/or in the spine (classical ankylosing spondylitis) but also patients with non-radiographic axial spondyloarthritis in whom early inflammatory signs of the disease can only be visualized with magnetic resonance imaging (MRI). The MRI technique plays an important role in the diagnosis of this disease and an early diagnosis is normally based on a combination of clinical, laboratory and imaging parameters. Only non-steroidal anti-inflammatory drugs and TNF-α blockers are effective in the treatment of axial spondyloarthritis. Patients with short disease duration and elevated acute phase reactant levels demonstrate best therapy response and, therefore, should be closely followed-up and consistently treated.

  8. Uveitis in spondyloarthritis including psoriatic arthritis, ankylosing spondylitis, and inflammatory bowel disease.

    PubMed

    Rosenbaum, James T

    2015-06-01

    Uveitis is a common complication of spondyloarthritis. The "phenotype" of the uveitis characteristic of ankylosing spondylitis (sudden onset, anterior, unilateral, recurrent, more often male) may differ from the phenotype often seen with either psoriatic arthritis or inflammatory bowel disease (insidious onset, anterior and intermediate, bilateral, chronic, and/or more often female). The frequency of uveitis is also much greater in association with ankylosing spondylitis than with either inflammatory bowel disease or psoriasis. Uveitis may affect the choice of therapy and can rarely be a complication of therapy. Uveitis and arthritis also co-exist in several animal models.

  9. Airway wall stiffening increases peak wall shear stress: a fluid-structure interaction study in rigid and compliant airways.

    PubMed

    Xia, Guohua; Tawhai, Merryn H; Hoffman, Eric A; Lin, Ching-Long

    2010-05-01

    The airflow characteristics in a computed tomography (CT) based human airway bifurcation model with rigid and compliant walls are investigated numerically. An in-house three-dimensional (3D) fluid-structure interaction (FSI) method is applied to simulate the flow at different Reynolds numbers and airway wall stiffness. As the Reynolds number increases, the airway wall deformation increases and the secondary flow becomes more prominent. It is found that the peak wall shear stress on the rigid airway wall can be five times stronger than that on the compliant airway wall. When adding tethering forces to the model, we find that these forces, which produce larger airway deformation than without tethering, lead to more skewed velocity profiles in the lower branches and further reduced wall shear stresses via a larger airway lumen. This implies that pathologic changes in the lung such as fibrosis or remodeling of the airway wall-both of which can serve to restrain airway wall motion-have the potential to increase wall shear stress and thus can form a positive feed-back loop for the development of altered flow profiles and airway remodeling. These observations are particularly interesting as we try to understand flow and structural changes seen in, for instance, asthma, emphysema, cystic fibrosis, and interstitial lung disease.

  10. Quantitative computed tomography imaging of airway remodeling in severe asthma

    PubMed Central

    Fetita, Catalin I.; Brillet, Pierre-Yves

    2016-01-01

    Asthma is a heterogeneous condition and approximately 5–10% of asthmatic subjects have severe disease associated with structure changes of the airways (airway remodeling) that may develop over time or shortly after onset of disease. Quantitative computed tomography (QCT) imaging of the tracheobronchial tree and lung parenchyma has improved during the last 10 years, and has enabled investigators to study the large airway architecture in detail and assess indirectly the small airway structure. In severe asthmatics, morphologic changes in large airways, quantitatively assessed using 2D-3D airway registration and recent algorithms, are characterized by airway wall thickening, luminal narrowing and bronchial stenoses. Extent of expiratory gas trapping, quantitatively assessed using lung densitometry, may be used to assess indirectly small airway remodeling. Investigators have used these quantitative imaging techniques in order to attempt severity grading of asthma, and to identify clusters of asthmatic patients that differ in morphologic and functional characteristics. Although standardization of image analysis procedures needs to be improved, the identification of remodeling pattern in various phenotypes of severe asthma and the ability to relate airway structures to important clinical outcomes should help target treatment more effectively. PMID:26981458

  11. Quantitative computed tomography imaging of airway remodeling in severe asthma.

    PubMed

    Grenier, Philippe A; Fetita, Catalin I; Brillet, Pierre-Yves

    2016-02-01

    Asthma is a heterogeneous condition and approximately 5-10% of asthmatic subjects have severe disease associated with structure changes of the airways (airway remodeling) that may develop over time or shortly after onset of disease. Quantitative computed tomography (QCT) imaging of the tracheobronchial tree and lung parenchyma has improved during the last 10 years, and has enabled investigators to study the large airway architecture in detail and assess indirectly the small airway structure. In severe asthmatics, morphologic changes in large airways, quantitatively assessed using 2D-3D airway registration and recent algorithms, are characterized by airway wall thickening, luminal narrowing and bronchial stenoses. Extent of expiratory gas trapping, quantitatively assessed using lung densitometry, may be used to assess indirectly small airway remodeling. Investigators have used these quantitative imaging techniques in order to attempt severity grading of asthma, and to identify clusters of asthmatic patients that differ in morphologic and functional characteristics. Although standardization of image analysis procedures needs to be improved, the identification of remodeling pattern in various phenotypes of severe asthma and the ability to relate airway structures to important clinical outcomes should help target treatment more effectively.

  12. Gut dysbiosis promotes M2 macrophage polarization and allergic airway inflammation via fungi-induced PGE₂.

    PubMed

    Kim, Yun-Gi; Udayanga, Kankanam Gamage Sanath; Totsuka, Naoya; Weinberg, Jason B; Núñez, Gabriel; Shibuya, Akira

    2014-01-15

    Although imbalances in gut microbiota composition, or "dysbiosis," are associated with many diseases, the effects of gut dysbiosis on host systemic physiology are less well characterized. We report that gut dysbiosis induced by antibiotic (Abx) treatment promotes allergic airway inflammation by shifting macrophage polarization in the lung toward the alternatively activated M2 phenotype. Adoptive transfer of alveolar macrophages derived from Abx-treated mice was sufficient to increase allergic airway inflammation. Abx treatment resulted in the overgrowth of a commensal fungal Candida species in the gut and increased plasma concentrations of prostaglandin E₂ (PGE₂), which induced M2 macrophage polarization in the lung. Suppression of PGE₂ synthesis by the cyclooxygenase inhibitors aspirin and celecoxib suppressed M2 macrophage polarization and decreased allergic airway inflammatory cell infiltration in Abx-treated mice. Thus, Abx treatment can cause overgrowth of particular fungal species in the gut and promote M2 macrophage activation at distant sites to influence systemic responses including allergic inflammation.

  13. Rigid bronchoscopy and silicone stents in the management of central airway obstruction

    PubMed Central

    Yarmus, Lonny

    2015-01-01

    The field of interventional pulmonology has grown significantly over the past several decades now including the diagnosis and therapeutic treatment of complex airway disease. Rigid bronchoscopy is an invaluable tool in the diagnosis and management of several malignant and non-malignant causes of central airway obstruction (CAO) and has become integral after the inception of airway stenting. The management of CAO can be a complicated endeavor with significant risks making the understanding of basic rigid bronchoscopy techniques, ablative technologies, anesthetic care and stenting of utmost importance in the care of these complex patients. This review article will focus on the history of rigid bronchoscopy, the technical aspects of performing a rigid bronchoscopy as well as the use of silicone stents their indications, complications and placement techniques. PMID:26807283

  14. B Cell Activating Transcription Factor (BATF) plays a critical role in the pathogenesis of anti-MHC induced Obliterative Airway Disease

    PubMed Central

    Xu, Z.; Ramachandran, S.; Gunasekaran, M.; Nayak, D.; Benshoff, N.; Hachem, R.; Gelman, A.; Mohanakumar, T.

    2016-01-01

    Antibodies (Abs) against MHC results in T helper-17 (Th17) mediated immunity against lung self-antigens (SAgs), K-α1 tubulin and collagen V and Obliterative Airway Disease (OAD). Since B cell activating transcription factor (BATF) controls Th17 and autoimmunity, we proposed that BATF may play a critical role in OAD. Anti-H2Kb was administered intrabronchially into Batf−/− and C57BL/6 mice. Histopathology of the lungs on days 30 and 45 following Abs administration to Batf−/− mice resulted in decreased cellular infiltration, epithelial metaplasia, fibrosis and obstruction. There was lack of Abs to SAgs, reduction of SAgs specific IL17 T cells, IL-6, IL-23, IL-17, IL-1β, FGF-6 and CXCL12 and decreased Janus kinase 2, STAT3, and Retinoid-related orphan receptor gamma-T. Further, miR-301a, a regulator of Th17, was reduced in Batf−/− mice in contrast to up regulation of miR-301a and down regulation of PIAS3 in anti-MHC induced OAD animals. We also demonstrate increase in miR-301a in the bronchoalveolar lavage cells from lung transplant (LTx) recipients with Abs to HLA. This was accompanied by reduction in PIAS3 mRNA. Therefore, we conclude that BATF plays a critical role in the immune responses to SAgs and pathogenesis of anti-MHC induced rejection. Targeting BATF should be considered for preventing chronic rejection following human LTx. PMID:26844425

  15. B Cell-Activating Transcription Factor Plays a Critical Role in the Pathogenesis of Anti-Major Histocompatibility Complex-Induced Obliterative Airway Disease.

    PubMed

    Xu, Z; Ramachandran, S; Gunasekaran, M; Nayak, D; Benshoff, N; Hachem, R; Gelman, A; Mohanakumar, T

    2016-04-01

    Antibodies (Abs) against major histocompatibility complex (MHC) results in T helper-17 (Th17)-mediated immunity against lung self-antigens (SAgs), K-α1 tubulin and collagen V and obliterative airway disease (OAD). Because B cell-activating transcription factor (BATF) controls Th17 and autoimmunity, we proposed that BATF may play a critical role in OAD. Anti-H2K(b) was administered intrabronchially into Batf (-/-) and C57BL/6 mice. Histopathology of the lungs on days 30 and 45 after Ab administration to Batf (-/-) mice resulted in decreased cellular infiltration, epithelial metaplasia, fibrosis, and obstruction. There was lack of Abs to SAgs, reduction of Sag-specific interleukin (IL)-17 T cells, IL-6, IL-23, IL-17, IL-1β, fibroblast growth factor-6, and CXCL12 and decreased Janus kinase 2, signal transducer and activator of transcription 3 (STAT3), and retinoid-related orphan receptor γT. Further, micro-RNA (miR)-301a, a regulator of Th17, was reduced in Batf (-/-) mice in contrast to upregulation of miR-301a and downregulation of protein inhibitor of activated STAT3 (PIAS3) in anti-MHC-induced OAD animals. We also demonstrate an increase in miR-301a in the bronchoalveolar lavage cells from lung transplant recipients with Abs to human leukocyte antigen. This was accompanied by reduction in PIAS3 mRNA. Therefore, we conclude that BATF plays a critical role in the immune responses to SAgs and pathogenesis of anti-MHC-induced rejection. Targeting BATF should be considered for preventing chronic rejection after human lung transplantation.

  16. Small airway impairment in moderate to severe asthmatics without significant proximal airway obstruction.

    PubMed

    Perez, Thierry; Chanez, Pascal; Dusser, Daniel; Devillier, Philippe

    2013-11-01

    Asthma is a disease characterized by inflammation which affects both proximal and distal airways. We evaluated the prevalence of small airway obstruction (SAO) in a group of clinically stable asthmatics with both normal forced expiratory volume in the first second (FEV1) and normal FEV1/forced vital capacity (FVC) and treated with an association of inhaled corticosteroids (ICSs) and long acting β2-agonists (LABAs). Clinical evaluation included the measurement of dyspnea, asthma control test and drug compliance. The prevalence of SAO was estimated by spirometry and plethysmography and defined by the presence of one or more of the following criteria: functional residual capacity (FRC) > 120% predicted (pred), residual volume (RV) > pred + 1.64 residual standard deviation (RSD), RV/total lung capacity (TLC) > pred + 1.64 RSD, forced expiratory flow (FEF)25-75% < pred - 1.64 RSD, FEF50% < pred - 1.64 RSD, slow vital capacity (SVC) - FVC > 10%. Among the 441 patients who were included, 222 had normal FEV1 and FEV1/FVC. At least one criteria of SAO was found in 115 (52%) mainly lung hyperinflation (39% based on high FRC, RV or RV/TLC) and more rarely distal airflow limitation (15% based on FEF25-75% or FEF50%) or expiratory trapping (10% based on increased SVC - FVC). In the patients with only SAO (no PAO), there was no relationship between SAO, asthma history and the scores of dyspnea, asthma control or drug compliance. These results suggest that in asthmatics with normal FEV1 and FEV1/FVC, treated with ICSs and LABAs, SAO is found in more than half of the patients indicating that the routinely used lung function tests can underestimate dysfunctions occurring in the small airways.

  17. Behavioral Inhibition in Rhesus Monkeys (Macaca mulatta) Is Related to the Airways Response, but Not Immune Measures, Commonly Associated with Asthma

    PubMed Central

    Chun, Katie; Miller, Lisa A.; Schelegle, Edward S.; Hyde, Dallas M.; Capitanio, John P.

    2013-01-01

    Behavioral inhibition reflects a disposition to react warily to novel situations, and has been associated with atopic diseases such as asthma. Retrospective work established the relationship between behavioral inhibition in rhesus monkeys (Macaca mulatta) and airway hyperresponsiveness, but not atopy, and the suggestion was made that behavioral inhibition might index components of asthma that are not immune-related. In the present study, we prospectively examined the relationship between behavioral inhibition and airway hyperresponsiveness, and whether hormonal and immune measures often associated with asthma were associated with behavioral inhibition and/or airway hyperresponsiveness. In a sample of 49 yearling rhesus monkeys (mean = 1.25 years, n = 24 behaviorally inhibited animals), we measured in vitro cytokine levels (IL-4, IL-10, IL-12, IFN-γ) in response to stimulation, as well as peripheral blood cell percentages, cortisol levels, and percentage of regulatory T-cells (CD3+CD4+CD25+FOXP3+). Airway reactivity was assessed using an inhaled methacholine challenge. Bronchoalveolar lavage was performed and the proportion of immune cells was determined. Behaviorally inhibited monkeys had airway hyperresponsiveness as indicated by the methacholine challenge (p = 0.031), confirming our earlier retrospective result. Airway hyperresponsiveness was also associated with lower lymphocyte percentages in lavage fluid and marginally lower plasma cortisol concentrations. However, none of the tested measures was significantly related to both behavioral inhibition and airway hyperresponsiveness, and so could not mediate their relationship. Airway hyperresponsiveness is common to atopic and non-atopic asthma and behavioral inhibition has been related to altered autonomic activity in other studies. Our results suggest that behavioral inhibition might index an autonomically mediated reactive airway phenotype, and that a variety of stimuli (including inflammation

  18. [Zhang Zhongjings lost formulas not included in Shanghan Lun (Treatise on Cold Pathogenic Diseases)].

    PubMed

    Mi, Li

    2006-07-01

    In addition to the medical formulas of Zhang Zhongjing mostly existed in Shanghan Lun (Treatise on Cold Pathogenic Diseases) and Jinkui Yaolve Fanglun (Synopsis of Prescriptions of the Golden Chamber ) collated by Lin Yi in the Song Dynasty, there are some other lost formulas scattered in Beiji Qianjin Yao Fang (Essential Recipes for Emergent Use Worth a Thousand Gold), Qianjin Yi Fang (A Supplement to Recipes Worth a Thousand Gold ) , Waitai Miyao (Arcane Essentials from the Imperial Library) , written in the Tang Dynasty, and Taiping Shenghui Fang (Tiping Holy Prescriptions for Universal Relief) and Isimpo (Prescriptions from the Heart of Medicine)and those written in the Song Dynasty. Based on the textual research, collation, differentiation of Zhongjings formulas in different texts and medical works, the lost formulas of Zhongjing were collected besides those in Shanghan Lun (Treatise on Cold Pathogenic Diseases) and Jinkui Yaolve Fanglun (Synopsis of Prescriptions of the Golden Chamber), and then the state of the formulas were identified.

  19. Nrf2 protects against airway disorders

    SciTech Connect

    Cho, Hye-Youn; Kleeberger, Steven R.

    2010-04-01

    Nuclear factor-erythroid 2 related factor 2 (Nrf2) is a ubiquitous master transcription factor that regulates antioxidant response elements (AREs)-mediated expression of antioxidant enzyme and cytoprotective proteins. In the unstressed condition, Kelch-like ECH-associated protein 1 (Keap1) suppresses cellular Nrf2 in cytoplasm and drives its proteasomal degradation. Nrf2 can be activated by diverse stimuli including oxidants, pro-oxidants, antioxidants, and chemopreventive agents. Nrf2 induces cellular rescue pathways against oxidative injury, abnormal inflammatory and immune responses, apoptosis, and carcinogenesis. Application of Nrf2 germ-line mutant mice has identified an extensive range of protective roles for Nrf2 in experimental models of human disorders in the liver, gastrointestinal tract, airway, kidney, brain, circulation, and immune or nerve system. In the lung, lack of Nrf2 exacerbated toxicity caused by multiple oxidative insults including supplemental respiratory therapy (e.g., hyperoxia, mechanical ventilation), cigarette smoke, allergen, virus, bacterial endotoxin and other inflammatory agents (e.g., carrageenin), environmental pollution (e.g., particles), and a fibrotic agent bleomycin. Microarray analyses and bioinformatic studies elucidated functional AREs and Nrf2-directed genes that are critical components of signaling mechanisms in pulmonary protection by Nrf2. Association of loss of function with promoter polymorphisms in NRF2 or somatic and epigenetic mutations in KEAP1 and NRF2 has been found in cohorts of patients with acute lung injury/acute respiratory distress syndrome or lung cancer, which further supports the role for NRF2 in these lung diseases. In the current review, we address the role of Nrf2 in airways based on emerging evidence from experimental oxidative disease models and human studies.

  20. Use of optical coherence tomography in delineating airways microstructure: comparison of OCT images to histopathological sections

    NASA Astrophysics Data System (ADS)

    Yang, Ying; Whiteman, Suzanne; Gey van Pittius, Daniel; He, Yonghong; Wang, Ruikang K.; Spiteri, Monica A.

    2004-04-01

    An ideal diagnostic system for the human airways should be able to detect and define early development of premalignant pathological lesions, to facilitate optimal curative treatment and prevent irreversible and/or invasive lung disease. There is great need for exploration of safe, repeatable imaging techniques which can run at real-time and with high spatial resolution. In this study, optical coherence tomography (OCT) was utilized to acquire cross-sectional images of upper and lower airways using fresh pig lung resections as a model system. Obtained OCT images were compared with parallel tissue characterization by conventional histological analysis. Our objective was to determine whether OCT differentiates the composite structural layers and inherent anatomical variations along different airway locations. The data show that OCT can clearly display the multilayered structure of the airways. The subtle architectural differences in three separate anatomical locations including trachea, main bronchus and tertiary bronchus were clearly delineated. Images of the appropriate anatomical profiles, with depth of up to 2 mm and 10 µm spatial resolution were obtained by our current OCT system, which was sufficient for recognition of the epithelium, subepithelial tissues and cartilage. In addition, the relative thickness of individual structural components was accurately reflected and comparable to histological sections. These data support OCT as a highly feasible, optical biopsy tool, which merits further exploration for early diagnosis of human airway epithelial pathology.

  1. Differential cellular responses in healthy mice and in mice with established airway inflammation when exposed to hematite nanoparticles.

    PubMed

    Gustafsson, Åsa; Bergström, Ulrika; Ågren, Lina; Österlund, Lars; Sandström, Thomas; Bucht, Anders

    2015-10-01

    The aim of this study was to investigate the inflammatory and immunological responses in airways and lung-draining lymph nodes (LDLNs), following lung exposure to iron oxide (hematite) nanoparticles (NPs). The responses to the hematite NPs were evaluated in both healthy non-sensitized mice, and in sensitized mice with an established allergic airway disease. The mice were exposed intratracheally to either hematite NPs or to vehicle (PBS) and the cellular responses were evaluated on days 1, 2, and 7, post-exposure. Exposure to hematite NPs increased the numbers of neutrophils, eosinophils, and lymphocytes in the airways of non-sensitized mice on days 1 and 2 post-exposure; at these time points the number of lymphocytes was also elevated in the LDLNs. In contrast, exposing sensitized mice to hematite NPs induced a rapid and unspecific cellular reduction in the alveolar space on day 1 post-exposure; a similar decrease of lymphocytes was also observed in the LDLN. The results indicate that cells in the airways and in the LDLN of individuals with established airway inflammation undergo cell death when exposed to hematite NPs. A possible explanation for this toxic response is the extensive generation of reactive oxygen species (ROS) in the pro-oxidative environment of inflamed airways. This study demonstrates how sensitized and non-sensitized mice respond differently to hematite NP exposure, and it highlights the importance of including individuals with respiratory disorders when evaluating health effects of inhaled nanomaterials.

  2. Manifesto on small airway involvement and management in asthma and chronic obstructive pulmonary disease: an Interasma (Global Asthma Association - GAA) and World Allergy Organization (WAO) document endorsed by Allergic Rhinitis and its Impact on Asthma (ARIA) and Global Allergy and Asthma European Network (GA(2)LEN).

    PubMed

    Braido, F; Scichilone, N; Lavorini, F; Usmani, O S; Dubuske, L; Boulet, L P; Mosges, R; Nunes, C; Sanchez-Borges, M; Ansotegui, I J; Ebisawa, M; Levi-Schaffer, F; Rosenwasser, L J; Bousquet, J; Zuberbier, T; Canonica, G Walter; Cruz, A; Yanez, A; Yorgancioglu, A; Deleanu, D; Rodrigo, G; Berstein, J; Ohta, K; Vichyanond, P; Pawankar, R; Gonzalez-Diaz, S N; Nakajima, S; Slavyanskaya, T; Fink-Wagner, A; Loyola, C Baez; Ryan, D; Passalacqua, G; Celedon, J; Ivancevich, J C; Dobashi, K; Zernotti, M; Akdis, M; Benjaponpitak, S; Bonini, S; Burks, W; Caraballo, L; El-Sayed, Z Awad; Fineman, S; Greenberger, P; Hossny, E; Ortega-Martell, J A; Saito, H; Tang, M; Zhang, L

    2016-01-01

    Evidence that enables us to identify, assess, and access the small airways in asthma and chronic obstructive pulmonary disease (COPD) has led INTERASMA (Global Asthma Association) and WAO to take a position on the role of the small airways in these diseases. Starting from an extensive literature review, both organizations developed, discussed, and approved the manifesto, which was subsequently approved and endorsed by the chairs of ARIA and GA(2)LEN. The manifesto describes the evidence gathered to date and defines and proposes issues on small airway involvement and management in asthma and COPD with the aim of challenging assumptions, fostering commitment, and bringing about change. The small airways (defined as those with an internal diameter <2 mm) are involved in the pathogenesis of asthma and COPD and are the major determinant of airflow obstruction in these diseases. Various tests are available for the assessment of the small airways, and their results must be integrated to confirm a diagnosis of small airway dysfunction. In asthma and COPD, the small airways play a key role in attempts to achieve disease control and better outcomes. Small-particle inhaled formulations (defined as those that, owing to their size [usually <2 μm], ensure more extensive deposition in the lung periphery than large molecules) have proved beneficial in patients with asthma and COPD, especially those in whom small airway involvement is predominant. Functional and biological tools capable of accurately assessing the lung periphery and more intensive use of currently available tools are necessary. In patients with suspected COPD or asthma, small airway involvement must be assessed using currently available tools. In patients with subotpimal disease control and/or functional or biological signs of disease activity, the role of small airway involvement should be assessed and treatment tailored. Therefore, the choice between large- and small-particle inhaled formulations must reflect

  3. Techniques of assessing small airways dysfunction

    PubMed Central

    McNulty, William; Usmani, Omar S.

    2014-01-01

    The small airways are defined as those less than 2 mm in diameter. They are a major site of pathology in many lung diseases, not least chronic obstructive pulmonary disease (COPD) and asthma. The small airways are frequently involved early in the course of these diseases, with significant pathology demonstrable often before the onset of symptoms or changes in spirometry and imaging. Despite their importance, they have proven relatively difficult to study. This is in part due to their relative inaccessibility to biopsy and their small size which makes their imaging difficult. Traditional lung function tests may only become abnormal once there is a significant burden of disease within them. This has led to the term ‘the quiet zone’ of the lung. In recent years, more specialised tests have been developed which may detect these changes earlier, perhaps offering the possibility of earlier diagnosis and intervention. These tests are now moving from the realms of clinical research laboratories into routine clinical practice and are increasingly useful in the diagnosis and monitoring of respiratory diseases. This article gives an overview of small airways physiology and some of the routine and more advanced tests of airway function. PMID:26557240

  4. Apolipoprotein E Sets the Stage: Response to Injury Triggers Neuropathology, Including Alzheimer's Disease

    PubMed Central

    Mahley, Robert W.; Huang, Yadong

    2013-01-01

    Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease and is associated with poor clinical outcome following traumatic brain injury and other neuropathological disorders. Protein instability and an isoform-specific apoE property called domain interaction are responsible for these neuropathological effects. ApoE4 is the most neurotoxic isoform and can induce neuropathology through various cellular pathways. Neuronal damage or stress induces apoE synthesis as part of the repair response; however, when apoE4 is expressed in neurons, its unique conformation makes it susceptible to proteolysis, resulting in the generation of neurotoxic fragments. These fragments cause pathological mitochondrial dysfunction and cytoskeletal alterations. Here, we review data supporting the hypothesis that apoE4 (> apoE3 > apoE2) has direct neurotoxic effects and highlight studies showing that blocking domain interaction reverses these detrimental effects. PMID:23217737

  5. Taste Receptors in Upper Airway Immunity.

    PubMed

    Carey, Ryan M; Lee, Robert J; Cohen, Noam A

    2016-01-01

    Taste receptors are well known for their role in communicating information from the tongue to the brain about nutritional value or potential toxicity of ingested substances. More recently, it has been shown that taste receptors are expressed in other locations throughout the body, including the airway, gastrointestinal tract, brain and pancreas. The roles of some 'extraoral' taste receptors are largely unknown, but emerging research suggests that bitter and sweet taste receptors in the airway are capable of sensing bacteria and modulating innate immunity. This chapter focuses on the role of bitter and sweet taste receptors in human airway innate immunity and their clinical relevance to rhinosinusitis. The bitter taste receptor T2R38 expressed in sinonasal cilia detects bitter bacterial quorum-sensing molecules and activates a nitric oxide-dependent innate immune response; moreover, there are polymorphisms in T2R38 that underlie susceptibility to chronic rhinosinusitis (CRS). Bitter and sweet receptors in sinonasal solitary chemosensory cells control secretion of antimicrobial peptides in the upper airway and may have a profound impact on airway infections in patients with CRS and diabetes. Future research on taste receptors in the airway has enormous potential to expand our understanding of host-pathogen immune interactions and provide novel therapeutic targets.

  6. A framework for understanding shared substrates of airway protection

    PubMed Central

    TROCHE, Michelle Shevon; BRANDIMORE, Alexandra Essman; GODOY, Juliana; HEGLAND, Karen Wheeler

    2014-01-01

    Deficits of airway protection can have deleterious effects to health and quality of life. Effective airway protection requires a continuum of behaviors including swallowing and cough. Swallowing prevents material from entering the airway and coughing ejects endogenous material from the airway. There is significant overlap between the control mechanisms for swallowing and cough. In this review we will present the existing literature to support a novel framework for understanding shared substrates of airway protection. This framework was originally adapted from Eccles' model of cough28 (2009) by Hegland, et al.42 (2012). It will serve to provide a basis from which to develop future studies and test specific hypotheses that advance our field and ultimately improve outcomes for people with airway protective deficits. PMID:25141195

  7. Cold weather exercise and airway cytokine expression.

    PubMed

    Davis, Michael S; Malayer, Jerry R; Vandeventer, Lori; Royer, Christopher M; McKenzie, Erica C; Williamson, Katherine K

    2005-06-01

    Athletes who perform repeated exercise while breathing cold air have a high prevalence of asthmalike chronic airway disease, but the mechanism linking such activity to airway inflammation is unknown. We used a novel animal model (exercising horses) to test the hypothesis that exercise-induced chronic airway disease is caused by exposure of intrapulmonary airways to unconditioned air, resulting in the upregulation of cytokine expression. Bronchoalveolar lavage fluid (BALF) was obtained from eight horses 5 h after submaximal exercise while they breathed room temperature or subfreezing air in a random crossover design. BALF total and differential nucleated cell counts were determined, and relative cytokine mRNA expression in BALF nucleated cells was quantified by real-time RT-PCR using primer and probe sequences specific for equine targets. There were no significant changes in total or differential cell concentrations between BALF recovered after warm and cold air exercise, although there was a strong trend toward increased concentrations of airway epithelial cells after cold air exercise (P = 0.0625). T(H)2 cytokines IL-4, IL-5, and IL-10 were preferentially upregulated after cold air exercise 12-, 9-, and 10-fold, respectively, compared with warm air exercise. Other cytokines (IL-2 and IL-6) were upregulated to a lesser extent (6- and 3-fold, respectively) or not at all (IL-1, IL-8, IFN-gamma, and TNF-alpha). These results suggest that cold weather exercise can lead to asthmalike airway disease through the local induction of cytokines typical of the T(H)2 phenotype.

  8. Reproducibility of airway wall thickness measurements

    NASA Astrophysics Data System (ADS)

    Schmidt, Michael; Kuhnigk, Jan-Martin; Krass, Stefan; Owsijewitsch, Michael; de Hoop, Bartjan; Peitgen, Heinz-Otto

    2010-03-01

    Airway remodeling and accompanying changes in wall thickness are known to be a major symptom of chronic obstructive pulmonary disease (COPD), associated with reduced lung function in diseased individuals. Further investigation of this disease as well as monitoring of disease progression and treatment effect demand for accurate and reproducible assessment of airway wall thickness in CT datasets. With wall thicknesses in the sub-millimeter range, this task remains challenging even with today's high resolution CT datasets. To provide accurate measurements, taking partial volume effects into account is mandatory. The Full-Width-at-Half-Maximum (FWHM) method has been shown to be inappropriate for small airways1,2 and several improved algorithms for objective quantification of airway wall thickness have been proposed.1-8 In this paper, we describe an algorithm based on a closed form solution proposed by Weinheimer et al.7 We locally estimate the lung density parameter required for the closed form solution to account for possible variations of parenchyma density between different lung regions, inspiration states and contrast agent concentrations. The general accuracy of the algorithm is evaluated using basic tubular software and hardware phantoms. Furthermore, we present results on the reproducibility of the algorithm with respect to clinical CT scans, varying reconstruction kernels, and repeated acquisitions, which is crucial for longitudinal observations.

  9. Flow characteristics in the airways of a COPD patient with a saber-sheath trachea

    NASA Astrophysics Data System (ADS)

    Jin, Dohyun; Choi, Haecheon; Lee, Changhyun; Choi, Jiwoong; Kim, Kwanggi

    2016-11-01

    The chronic obstructive pulmonary disease (COPD) is a lung disease characterized by the irreversible airflow limitation caused by the damaged small airways and air sacs. Although COPD is not a disease of the trachea, many patients with COPD have saber-sheath tracheas. The effects of this morphological change in the trachea geometry on airflow are investigated in the present study. An unstructured finite volume method is used for the simulations during tidal breathing in normal and COPD airways, respectively. During inspiration, local large pressure drop is observed in the saber-sheath region of the COPD patient. During expiration, vortical structures are observed at the right main bronchus of the COPD airway, while the flow in the normal airway remains nearly laminar. High wall shear stress exists at convex regions of both airways during inspiration and expiration. However, due to the morphological changes in the COPD airway, relatively higher wall shear stress is observed in the patient airways.

  10. Prognosis and Risk Factors for Congenital Airway Anomalies in Children with Congenital Heart Disease: A Nationwide Population-Based Study in Taiwan

    PubMed Central

    Lee, Yu-Sheng; Jeng, Mei-Jy; Tsao, Pei-Chen

    2015-01-01

    Background The mortality risk associated with congenital airway anomalies (CAA) in children with congenital heart disease (CHD) is unclear. This study aimed to investigate the factors associated with CAA, and the associated mortality risk, among children with CHD. Methods This nationwide, population-based study evaluated 39,652 children with CHD aged 0–5 years between 2000 and 2011, using the Taiwan National Health Insurance Research Database (NHIRD). We performed descriptive, logistic regression, Kaplan–Meier, and Cox regression analyses of the data. Results Among the children with CHD, 1,591 (4.0%) had concomitant CAA. Children with CHD had an increased likelihood of CAA if they were boys (odds ratio [OR], 1.48; 95% confidence interval [CI], 1.33–1.64), infants (OR, 5.42; 95%CI, 4.06–7.24), or had a congenital musculoskeletal anomaly (OR, 3.19; 95%CI, 2.67–3.81), and were typically identified 0–3 years after CHD diagnosis (OR, 1.33; 95%CI 1.17–1.51). The mortality risk was increased in children with CHD and CAA (crude hazard ratio [HR], 2.05; 95%CI, 1.77–2.37), even after adjusting for confounders (adjusted HR, 1.76; 95%CI, 1.51–2.04). Mortality risk also changed by age and sex (adjusted HR and 95%CI are quoted): neonates, infants, and toddlers and preschool children, 1.67 (1.40–2.00), 1.93 (1.47–2.55), and 4.77 (1.39–16.44), respectively; and boys and girls, 1.62 (1.32–1.98) and 2.01 (1.61–2.50), respectively. Conclusion The mortality risk is significantly increased among children with CHD and comorbid CAA. Clinicians should actively seek CAA during the follow-up of children with CHD. PMID:26334302

  11. Mechanosensitive ATP Release Maintains Proper Mucus Hydration of Airways

    PubMed Central

    Button, Brian; Okada, Seiko F.; Frederick, Charles Brandon; Thelin, William R.; Boucher, Richard C.

    2013-01-01

    The clearance of mucus from the airways protects the lungs from inhaled noxious and infectious materials. Proper hydration of the mucus layer enables efficient mucus clearance through beating of cilia on airway epithelial cells, and reduced clearance of excessively concentrated mucus occurs in patients with chronic obstructive pulmonary disease and cystic fibrosis. Key steps in the mucus transport process are airway epithelia sensing and responding to changes in mucus hydration. We reported that extracellular adenosine triphosphate (ATP) and adenosine were important luminal auto-crine and paracrine signals that regulated the hydration of the surface of human airway epithelial cultures through their action on apical membrane purinoceptors. Mucus hydration in human airway epithelial cultures was sensed by an interaction between cilia and the overlying mucus layer: Changes in mechanical strain, proportional to mucus hydration, regulated ATP release rates, adjusting fluid secretion to optimize mucus layer hydration. This system provided a feedback mechanism by which airways maintained mucus hydration in an optimum range for cilia propulsion. Understanding how airway epithelia can sense and respond to changes in mucus properties helps us to understand how the mucus clearance system protects the airways in health and how it fails in lung diseases such as cystic fibrosis. PMID:23757023

  12. Mechanosensitive ATP release maintains proper mucus hydration of airways.

    PubMed

    Button, Brian; Okada, Seiko F; Frederick, Charles Brandon; Thelin, William R; Boucher, Richard C

    2013-06-11

    The clearance of mucus from the airways protects the lungs from inhaled noxious and infectious materials. Proper hydration of the mucus layer enables efficient mucus clearance through beating of cilia on airway epithelial cells, and reduced clearance of excessively concentrated mucus occurs in patients with chronic obstructive pulmonary disease and cystic fibrosis. Key steps in the mucus transport process are airway epithelia sensing and responding to changes in mucus hydration. We reported that extracellular adenosine triphosphate (ATP) and adenosine were important luminal autocrine and paracrine signals that regulated the hydration of the surface of human airway epithelial cultures through their action on apical membrane purinoceptors. Mucus hydration in human airway epithelial cultures was sensed by an interaction between cilia and the overlying mucus layer: Changes in mechanical strain, proportional to mucus hydration, regulated ATP release rates, adjusting fluid secretion to optimize mucus layer hydration. This system provided a feedback mechanism by which airways maintained mucus hydration in an optimum range for cilia propulsion. Understanding how airway epithelia can sense and respond to changes in mucus properties helps us to understand how the mucus clearance system protects the airways in health and how it fails in lung diseases such as cystic fibrosis.

  13. Computed tomography of nonanesthetized cats with upper airway obstruction.

    PubMed

    Stadler, Krystina; O'Brien, Robert

    2013-01-01

    Upper airway obstruction is a potentially life-threatening problem in cats and for which a noninvasive, sensitive method rapid diagnosis is needed. The purposes of this prospective study were to describe a computed tomography (CT) technique for nonanesthetized cats with upper airway obstruction, CT characteristics of obstructive diseases, and comparisons between CT findings and findings from other diagnostic tests. Ten cats with clinical signs of upper airway obstruction were recruited for the study. Four cats with no clinical signs of upper airway obstruction were recruited as controls. All cats underwent computed tomography imaging without sedation or anesthesia, using a 16-slice helical CT scanner and a previously described transparent positional device. Three-dimensional (3D) internal volume rendering was performed on all CT image sets and 3D external volume rendering was also performed on cats with evidence of mass lesions. Confirmation of upper airway obstruction was based on visual laryngeal examination, endoscopy, fine-needle aspirate, biopsy, or necropsy. Seven cats were diagnosed with intramural upper airway masses, two with laryngotracheitis, and one with laryngeal paralysis. The CT and 3D volume-rendered images identified lesions consistent with upper airway disease in all cats. In cats with mass lesions, CT accurately identified the mass and location. Findings from this study supported the use of CT imaging as an effective technique for diagnosing upper airway obstruction in nonanesthetized cats.

  14. Cine CT technique for dynamic airway studies

    SciTech Connect

    Ell, S.R.; Jolles, H.; Keyes, W.D.; Galvin, J.R.

    1985-07-01

    The advent of cine CT scanning with its 50-msec data acquisition time promises a much wider range of dynamic CT studies. The authors describe a method for dynamic evaluation of the extrathoracic airway, which they believe has considerable potential application in nonfixed upper-airway disease, such as sleep apnea and stridor of unknown cause. Conventional CT is limited in such studies by long data acquisition time and can be used to study only prolonged maneuvers such as phonation. Fluoroscopy and digital subtraction studies are limited by relatively high radiation dose and inability to image all wall motions simultaneously.

  15. Changes in human ecology and behavior in relation to the emergence of diarrheal diseases, including cholera.

    PubMed Central

    Levine, M M; Levine, O S

    1994-01-01

    Human populations throughout the world can be found in diverse conditions. A proportion of the population of developing countries lives in deprived conditions characterized by ramshackle housing, lack of piped water and sanitation, and widespread fecal contamination of the environment. Enteric infections, particularly due to bacterial pathogenes, are readily transmitted under these circumstances. In contrast, the majority of inhabitants of industrialized countries live in a sanitary environment that generally discourages the transmission of enteric pathogenes, particularly bacteria. In both these ecologic niches, changes in human ecology and behavior are leading to the emergence of certain enteric infections. Relevant factors in developing areas include urbanization (leading to periurban slums), diminished breastfeeding, and political upheaval that results in population migrations. In industrialized areas, large-scale food production (e.g., enormous poultry farms), distribution, and retailing (e.g., fast-food chains) create opportunities where widespread and extensive outbreaks of food-borne enteric infection can ensue if a breakdown in food hygiene occurs. PMID:8146128

  16. Acoustic simulation of a patient's obstructed airway.

    PubMed

    van der Velden, W C P; van Zuijlen, A H; de Jong, A T; Lynch, C T; Hoeve, L J; Bijl, H

    2016-01-01

    This research focuses on the numerical simulation of stridor; a high pitched, abnormal noise, resulting from turbulent airflow and vibrating tissue through a partially obstructed airway. Characteristics of stridor noise are used by medical doctors as indication for location and size of the obstruction. The relation between type of stridor and the various diseases associated with airway obstruction is unclear; therefore, simply listening to stridor is an unreliable diagnostic tool. The overall aim of the study is to better understand the relationship between characteristics of stridor noise and localization and size of the obstruction. Acoustic analysis of stridor may then in future simplify the diagnostic process, and reduce the need for more invasive procedures such as laryngoscopy under general anesthesia. In this paper, the feasibility of a coupled flow, acoustic and structural model is investigated to predict the noise generated by the obstruction as well as the propagation of the noise through the airways, taking into account a one-way coupled fluid, structure, and acoustic interaction components. The flow and acoustic solver are validated on a diaphragm and a simplified airway model. A realistic airway model of a patient suffering from a subglottic stenosis, derived from a real computed tomography scan, is further analyzed. Near the mouth, the broadband noise levels at higher frequencies increased with approximately 15-20 dB comparing the stridorous model with the healthy model, indicating stridorous sound.

  17. Silibinin attenuates allergic airway inflammation in mice

    SciTech Connect

    Choi, Yun Ho; Jin, Guang Yu; Guo, Hui Shu; Piao, Hong Mei; Li, Liang chang; Li, Guang Zhao; Lin, Zhen Hua; Yan, Guang Hai

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer Silibinin diminishes ovalbumin-induced inflammatory reactions in the mouse lung. Black-Right-Pointing-Pointer Silibinin reduces the levels of various cytokines into the lung of allergic mice. Black-Right-Pointing-Pointer Silibinin prevents the development of airway hyperresponsiveness in allergic mice. Black-Right-Pointing-Pointer Silibinin suppresses NF-{kappa}B transcriptional activity. -- Abstract: Allergic asthma is a chronic inflammatory disease regulated by coordination of T-helper2 (Th2) type cytokines and inflammatory signal molecules. Silibinin is one of the main flavonoids produced by milk thistle, which is reported to inhibit the inflammatory response by suppressing the nuclear factor-kappa B (NF-{kappa}B) pathway. Because NF-{kappa}B activation plays a pivotal role in the pathogenesis of allergic inflammation, we have investigated the effect of silibinin on a mouse ovalbumin (OVA)-induced asthma model. Airway hyperresponsiveness, cytokines levels, and eosinophilic infiltration were analyzed in bronchoalveolar lavage fluid and lung tissue. Pretreatment of silibinin significantly inhibited airway inflammatory cell recruitment and peribronchiolar inflammation and reduced the production of various cytokines in bronchoalveolar fluid. In addition, silibinin prevented the development of airway hyperresponsiveness and attenuated the OVA challenge-induced NF-{kappa}B activation. These findings indicate that silibinin protects against OVA-induced airway inflammation, at least in part via downregulation of NF-{kappa}B activity. Our data support the utility of silibinin as a potential medicine for the treatment of asthma.

  18. [Initial antibiotic therapy in maternal-fetal infections which include ampicillin even in countries where listeriosis is an incidental disease].

    PubMed

    Boukadida, J; Taher, N Bel Hadj; Seket, B; Monastiri, K; Salem, N; Snoussi, N

    2002-06-01

    Neonatal listeriosis is an exceptional disease in Northern Africa. Hence, protocols for maternal-fetal infection treatment include only a third generation cephalosporin and an aminoside. This protocol does not take into account the possibility of Listeria monocytogenes infection. We report a fatal case of neonatal listeriosis in Tunisia. The use of first antibiotics in maternal-foetal infection must be reconsidered when lacking sufficient bacteriological data and include systematically ampicillin in presumptive antibiotic protocols.

  19. Improving the safety of remote site emergency airway management.

    PubMed

    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

  20. Elevated expression of placental growth factor is associated with airway-wall vascular remodelling and thickening in smokers with asthma

    PubMed Central

    Wu, Dong; Lai, Tianwen; Yuan, Yalian; Chen, Min; Xia, Jun; Li, Wen; Pan, Guihai; Yuan, Binfan; Lv, Quanchao; Li, Yanyu; Li, Dongmin; Wu, Bin

    2017-01-01

    The increased expression of placental growth factor (PlGF) in chronic obstructive pulmonary disease and allergy-related asthma suggests its role in the pathogenesis of these diseases. In asthmatic smokers, airway remodelling is accompanied by an accelerated decline in lung function. However, whether PlGF contributes to the persistent airflow obstruction and vascular remodelling typically seen in asthmatic smokers is unknown. In this study we measured lung function, airway-wall thickening, and PlGF levels in serum and induced sputum in 74 asthmatic and 42 healthy smokers and never-smokers. Using human lung microvascular endothelial cells (HLMECs), we evaluated the in vitro effects of PlGF on each step of vascular remodelling, including proliferation, migration, stress-fibre expression, and tubule formation. Our data showed significantly higher serum and sputum PlGF levels in asthma patients, especially asthmatic smokers, than in healthy controls. Serum and sputum PlGF levels correlated negatively with post-bronchodilator forced expiratory volume in 1 s (FEV1) and the FEV1/forced vital capacity, but positively with airway-wall thickening. Stimulation of HLMECs with rhPlGF promoted all of the steps of airway-microvascular remodelling. These findings provide insights into the influence of cigarette smoking on the structural changes in the airways of asthmatics and the important pathogenic role played by PlGF. PMID:28220848

  1. Airway surface liquid homeostasis in cystic fibrosis: pathophysiology and therapeutic targets.

    PubMed

    Haq, Iram J; Gray, Michael A; Garnett, James P; Ward, Christopher; Brodlie, Malcolm

    2016-03-01

    Cystic fibrosis (CF) is a life-limiting disease characterised by recurrent respiratory infections, inflammation and lung damage. The volume and composition of the airway surface liquid (ASL) are important in maintaining ciliary function, mucociliary clearance and antimicrobial properties of the airway. In CF, these homeostatic mechanisms are impaired, leading to a dehydrated and acidic ASL. ASL volume depletion in CF is secondary to defective anion transport by the abnormal cystic fibrosis transmembrane conductance regulator protein (CFTR). Abnormal CFTR mediated bicarbonate transport creates an unfavourable, acidic environment, which impairs antimicrobial function and alters mucus properties and clearance. These disease mechanisms create a disordered airway milieu, consisting of thick mucopurulent secretions and chronic bacterial infection. In addition to CFTR, there are additional ion channels and transporters in the apical airway epithelium that play a role in maintaining ASL homeostasis. These include the epithelial sodium channel (ENaC), the solute carrier 26A (SLC26A) family of anion exchangers, and calcium-activated chloride channels. In this review we discuss how the ASL is abnormal in CF and how targeting these alternative channels and transporters could provide an attractive therapeutic strategy to correct the underlying ASL abnormalities evident in CF.

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

    NASA Astrophysics Data System (ADS)

    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.

  3. Waterpipe smoking induces epigenetic changes in the small airway epithelium.

    PubMed

    Walters, Matthew S; Salit, Jacqueline; Ju, Jin Hyun; Staudt, Michelle R; Kaner, Robert J; Rogalski, Allison M; Sodeinde, Teniola B; Rahim, Riyaad; Strulovici-Barel, Yael; Mezey, Jason G; Almulla, Ahmad M; Sattar, Hisham; Mahmoud, Mai; Crystal, Ronald G

    2017-01-01

    Waterpipe (also called hookah, shisha, or narghile) smoking is a common form of tobacco use in the Middle East. Its use is becoming more prevalent in Western societies, especially among young adults as an alternative form of tobacco use to traditional cigarettes. While the risk to cigarette smoking is well documented, the risk to waterpipe smoking is not well defined with limited information on its health impact at the epidemiologic, clinical and biologic levels with respect to lung disease. Based on the knowledge that airway epithelial cell DNA methylation is modified in response to cigarette smoke and in cigarette smoking-related lung diseases, we assessed the impact of light-use waterpipe smoking on DNA methylation of the small airway epithelium (SAE) and whether changes in methylation were linked to the transcriptional output of the cells. Small airway epithelium was obtained from 7 nonsmokers and 7 light-use (2.6 ± 1.7 sessions/wk) waterpipe-only smokers. Genome-wide comparison of SAE DNA methylation of waterpipe smokers to nonsmokers identified 727 probesets differentially methylated (fold-change >1.5, p<0.05) representing 673 unique genes. Dominant pathways associated with these epigenetic changes include those linked to G-protein coupled receptor signaling, aryl hydrocarbon receptor signaling and xenobiotic metabolism signaling, all of which have been associated with cigarette smoking and lung disease. Of the genes differentially methylated, 11.3% exhibited a corresponding significant (p<0.05) change in gene expression with enrichment in pathways related to regulation of mRNA translation and protein synthesis (eIF2 signaling and regulation of eIF4 and p70S6K signaling). Overall, these data demonstrate that light-use waterpipe smoking is associated with epigenetic changes and related transcriptional modifications in the SAE, the cell population demonstrating the earliest pathologic abnormalities associated with chronic cigarette smoking.

  4. Waterpipe smoking induces epigenetic changes in the small airway epithelium

    PubMed Central

    Ju, Jin Hyun; Staudt, Michelle R.; Kaner, Robert J.; Rogalski, Allison M.; Sodeinde, Teniola B.; Rahim, Riyaad; Strulovici-Barel, Yael; Mezey, Jason G.; Almulla, Ahmad M.; Sattar, Hisham; Mahmoud, Mai; Crystal, Ronald G.

    2017-01-01

    Waterpipe (also called hookah, shisha, or narghile) smoking is a common form of tobacco use in the Middle East. Its use is becoming more prevalent in Western societies, especially among young adults as an alternative form of tobacco use to traditional cigarettes. While the risk to cigarette smoking is well documented, the risk to waterpipe smoking is not well defined with limited information on its health impact at the epidemiologic, clinical and biologic levels with respect to lung disease. Based on the knowledge that airway epithelial cell DNA methylation is modified in response to cigarette smoke and in cigarette smoking-related lung diseases, we assessed the impact of light-use waterpipe smoking on DNA methylation of the small airway epithelium (SAE) and whether changes in methylation were linked to the transcriptional output of the cells. Small airway epithelium was obtained from 7 nonsmokers and 7 light-use (2.6 ± 1.7 sessions/wk) waterpipe-only smokers. Genome-wide comparison of SAE DNA methylation of waterpipe smokers to nonsmokers identified 727 probesets differentially methylated (fold-change >1.5, p<0.05) representing 673 unique genes. Dominant pathways associated with these epigenetic changes include those linked to G-protein coupled receptor signaling, aryl hydrocarbon receptor signaling and xenobiotic metabolism signaling, all of which have been associated with cigarette smoking and lung disease. Of the genes differentially methylated, 11.3% exhibited a corresponding significant (p<0.05) change in gene expression with enrichment in pathways related to regulation of mRNA translation and protein synthesis (eIF2 signaling and regulation of eIF4 and p70S6K signaling). Overall, these data demonstrate that light-use waterpipe smoking is associated with epigenetic changes and related transcriptional modifications in the SAE, the cell population demonstrating the earliest pathologic abnormalities associated with chronic cigarette smoking. PMID:28273093

  5. Rapid Expansion of Human Epithelial Stem Cells Suitable for Airway Tissue Engineering

    PubMed Central

    Gowers, Kate H. C.; Lee, Dani Do Hyang; Brown, James M.; Crowley, Claire; Teixeira, Vitor H.; Smith, Claire M.; Urbani, Luca; Hamilton, Nicholas J.; Thakrar, Ricky M.; Booth, Helen L.; Birchall, Martin A.; De Coppi, Paolo; Giangreco, Adam; O’Callaghan, Christopher

    2016-01-01

    Rationale: Stem cell–based tracheal replacement represents an emerging therapeutic option for patients with otherwise untreatable airway diseases including long-segment congenital tracheal stenosis and upper airway tumors. Clinical experience demonstrates that restoration of mucociliary clearance in the lungs after transplantation of tissue-engineered grafts is critical, with preclinical studies showing that seeding scaffolds with autologous mucosa improves regeneration. High epithelial cell–seeding densities are required in regenerative medicine, and existing techniques are inadequate to achieve coverage of clinically suitable grafts. Objectives: To define a scalable cell culture system to deliver airway epithelium to clinical grafts. Methods: Human respiratory epithelial cells derived from endobronchial biopsies were cultured using a combination of mitotically inactivated fibroblasts and Rho-associated protein kinase (ROCK) inhibition using Y-27632 (3T3+Y). Cells were analyzed by immunofluorescence, quantitative polymerase chain reaction, and flow cytometry to assess airway stem cell marker expression. Karyotyping and multiplex ligation-dependent probe amplification were performed to assess cell safety. Differentiation capacity was tested in three-dimensional tracheospheres, organotypic cultures, air–liquid interface cultures, and an in vivo tracheal xenograft model. Ciliary function was assessed in air–liquid interface cultures. Measurements and Main Results: 3T3-J2 feeder cells and ROCK inhibition allowed rapid expansion of airway basal cells. These cells were capable of multipotent differentiation in vitro, generating both ciliated and goblet cell lineages. Cilia were functional with normal beat frequency and pattern. Cultured cells repopulated tracheal scaffolds in a heterotopic transplantation xenograft model. Conclusions: Our method generates large numbers of functional airway basal epithelial cells with the efficiency demanded by clinical

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

    PubMed Central

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

    2013-01-01

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

  7. Cardiorenal metabolic syndrome in the African diaspora: rationale for including chronic kidney disease in the metabolic syndrome definition.

    PubMed

    Lea, Janice P; Greene, Eddie L; Nicholas, Susanne B; Agodoa, Lawrence; Norris, Keith C

    2009-01-01

    Chronic kidney disease (CKD) is more likely to progress to end-stage renal disease (ESRD) in African Americans while the reasons for this are unclear. The metabolic syndrome is a risk factor for the development of diabetes, cardiovascular disease, and has been recently linked to incident CKD. Historically, fewer African Americans meet criteria for the definition of metabolic syndrome, despite having higher rates of cardiovascular mortality than Caucasians. The presence of microalbuminuria portends increased cardiovascular risks and has been shown to cluster with the metabolic syndrome. We recently reported that proteinuria is a predictor of CKD progression in African American hypertensives with metabolic syndrome. In this review we explore the potential value of including CKD markers--microalbuminuria/proteinuria or low glomerular filtration rate (GFR)-in refining the cluster of factors defined as metabolic syndrome, ie, "cardiorenal metabolic syndrome."

  8. The difficult airway: mechanisms for effective dissemination of critical information.

    PubMed

    Mark, L J; Beattie, C; Ferrell, C L; Trempy, G; Dorman, T; Schauble, J F

    1992-01-01

    The perioperative management and dissemination of critical information regarding a patient with an unexpected difficult intubation, including successful application of a difficult airway algorithm (Figure 1), are described. Documentation and dissemination of critical information include entry of patient data into an in-hospital computerized Difficult Airway/Intubation Registry, simultaneous application of a highly visible Difficult Airway/Intubation Patient Wrist Band (coded for access to computer registry), summary reports distributed to health care providers, and enrollment of the patient in the Medic Alert Foundation International's newly established category difficult airway/intubation for 24-hour access. We postulate that the widespread use of the procedures described in this report may reduce the contribution of unexpected difficult airway/intubation to anesthetic morbidity and mortality.

  9. Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction

    PubMed Central

    Huang, Fen; Zhang, Hongkang; Wu, Meng; Yang, Huanghe; Kudo, Makoto; Peters, Christian J.; Woodruff, Prescott G.; Solberg, Owen D.; Donne, Matthew L.; Huang, Xiaozhu; Sheppard, Dean; Fahy, John V.; Wolters, Paul J.; Hogan, Brigid L. M.; Finkbeiner, Walter E.; Li, Min; Jan, Yuh-Nung; Jan, Lily Yeh; Rock, Jason R.

    2012-01-01

    Mucous cell hyperplasia and airway smooth muscle (ASM) hyperresponsiveness are hallmark features of inflammatory airway diseases, including asthma. Here, we show that the recently identified calcium-activated chloride channel (CaCC) TMEM16A is expressed in the adult airway surface epithelium and ASM. The epithelial expression is increased in asthmatics, particularly in secretory cells. Based on this and the proposed functions of CaCC, we hypothesized that TMEM16A inhibitors would negatively regulate both epithelial mucin secretion and ASM contraction. We used a high-throughput screen to identify small-molecule blockers of TMEM16A-CaCC channels. We show that inhibition of TMEM16A-CaCC significantly impairs mucus secretion in primary human airway surface epithelial cells. Furthermore, inhibition of TMEM16A-CaCC significantly reduces mouse and human ASM contraction in response to cholinergic agonists. TMEM16A-CaCC blockers, including those identified here, may positively impact multiple causes of asthma symptoms. PMID:22988107

  10. GS-5759, a Bifunctional β2-Adrenoceptor Agonist and Phosphodiesterase 4 Inhibitor for Chronic Obstructive Pulmonary Disease with a Unique Mode of Action: Effects on Gene Expression in Human Airway Epithelial Cells.

    PubMed

    Joshi, Taruna; Yan, Dong; Hamed, Omar; Tannheimer, Stacey L; Phillips, Gary B; Wright, Clifford D; Kim, Musong; Salmon, Michael; Newton, Robert; Giembycz, Mark A

    2017-02-01

    (R)-6-[(3-{[4-(5-{[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}pent-1-yn-1-yl)phenyl] carbamoyl}phenyl)sulphonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide trifluoroacetic acid (GS-5759) is a bifunctional ligand composed of a quinolinone-containing pharmacophore [β2-adrenoceptor agonist orthostere (β2A)] found in several β2-adrenoceptor agonists, including indacaterol, linked covalently to a phosphodiesterase 4 (PDE4) inhibitor related to 6-[3-(dimethylcarbamoyl)benzenesulphonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GSK 256066) by a pent-1-yn-1-ylbenzene spacer. GS-5759 had a similar affinity for PDE4B1 and the native β2-adrenoceptor expressed on BEAS-2B human airway epithelial cells. However, compared with the monofunctional parent compound, β2A, the KA of GS-5759 for the β2-adrenoceptor was 35-fold lower. Schild analysis determined that the affinities of the β-adrenoceptor antagonists, (2R,3R)-1-[(2,3-dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl) amino]-2-butanol (ICI 118551) and propranolol, were agonist-dependent, being significantly lower for GS-5759 than β2A. Collectively, these data can be explained by "forced proximity," bivalent binding where the pharmacophore in GS-5759 responsible for PDE4 inhibition also interacts with a nonallosteric domain within the β2-adrenoceptor that enhances the affinity of β2A for the orthosteric site. Microarray analyses revealed that, after 2-hour exposure, GS-5759 increased the expression of >3500 genes in BEAS-2B cells that were highly rank-order correlated with gene expression changes produced by indacaterol and GSK 256066 in combination (Ind/GSK). Moreover, the line of regression began close to the origin with a slope of 0.88, indicating that the magnitude of most gene expression changes produced by Ind/GSK was quantitatively replicated by GS-5759. Thus, GS-5759 is a novel compound exhibiting dual β2-adrenoceptor agonism and PDE4 inhibition

  11. Emphysema- and airway-dominant COPD phenotypes defined by standardised quantitative computed tomography.

    PubMed

    Subramanian, Deepak R; Gupta, Sumit; Burggraf, Dorothe; Vom Silberberg, Suzan J; Heimbeck, Irene; Heiss-Neumann, Marion S; Haeussinger, Karl; Newby, Chris; Hargadon, Beverley; Raj, Vimal; Singh, Dave; Kolsum, Umme; Hofer, Thomas P; Al-Shair, Khaled; Luetzen, Niklas; Prasse, Antje; Müller-Quernheim, Joachim; Benea, Giorgio; Leprotti, Stefano; Boschetto, Piera; Gorecka, Dorota; Nowinski, Adam; Oniszh, Karina; Castell, Wolfgang Zu; Hagen, Michael; Barta, Imre; Döme, Balázs; Strausz, Janos; Greulich, Timm; Vogelmeier, Claus; Koczulla, Andreas R; Gut, Ivo; Hohlfeld, Jens; Welte, Tobias; Lavae-Mokhtari, Mahyar; Ziegler-Heitbrock, Loems; Brightling, Christopher; Parr, David G

    2016-07-01

    EvA (Emphysema versus Airway disease) is a multicentre project to study mechanisms and identify biomarkers of emphysema and airway disease in chronic obstructive pulmonary disease (COPD). The objective of this study was to delineate objectively imaging-based emphysema-dominant and airway disease-dominant phenotypes using quantitative computed tomography (QCT) indices, standardised with a novel phantom-based approach.441 subjects with COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 1-3) were assessed in terms of clinical and physiological measurements, laboratory testing and standardised QCT indices of emphysema and airway wall geometry.QCT indices were influenced by scanner non-conformity, but standardisation significantly reduced variability (p<0.001) and led to more robust phenotypes. Four imaging-derived phenotypes were identified, reflecting "emphysema-dominant", "airway disease-dominant", "mixed" disease and "mild" disease. The emphysema-dominant group had significantly higher lung volumes, lower gas transfer coefficient, lower oxygen (PO2 ) and carbon dioxide (PCO2 ) tensions, higher haemoglobin and higher blood leukocyte numbers than the airway disease-dominant group.The utility of QCT for phenotyping in the setting of an international multicentre study is improved by standardisation. QCT indices of emphysema and airway disease can delineate within a population of patients with COPD, phenotypic groups that have typical clinical features known to be associated with emphysema-dominant and airway-dominant disease.

  12. Intrathoracic airway wall detection using graph search and scanner PSF information

    NASA Astrophysics Data System (ADS)

    Reinhardt, Joseph M.; Park, Wonkyu; Hoffman, Eric A.; Sonka, Milan

    1997-05-01

    Measurements of the in vivo bronchial tree can be used to assess regional airway physiology. High-resolution CT (HRCT) provides detailed images of the lungs and has been used to evaluate bronchial airway geometry. Such measurements have been sued to assess diseases affecting the airways, such as asthma and cystic fibrosis, to measure airway response to external stimuli, and to evaluate the mechanics of airway collapse in sleep apnea. To routinely use CT imaging in a clinical setting to evaluate the in vivo airway tree, there is a need for an objective, automatic technique for identifying the airway tree in the CT images and measuring airway geometry parameters. Manual or semi-automatic segmentation and measurement of the airway tree from a 3D data set may require several man-hours of work, and the manual approaches suffer from inter-observer and intra- observer variabilities. This paper describes a method for automatic airway tree analysis that combines accurate airway wall location estimation with a technique for optimal airway border smoothing. A fuzzy logic, rule-based system is used to identify the branches of the 3D airway tree in thin-slice HRCT images. Raycasting is combined with a model-based parameter estimation technique to identify the approximate inner and outer airway wall borders in 2D cross-sections through the image data set. Finally, a 2D graph search is used to optimize the estimated airway wall locations and obtain accurate airway borders. We demonstrate this technique using CT images of a plexiglass tube phantom.

  13. Upper airway radiographs in infants with upper airway insufficiency.

    PubMed Central

    Tonkin, S L; Davis, S L; Gunn, T R

    1994-01-01

    Upper airway measurements in nine infants considered to be at risk of upper airway insufficiency, six of whom presented after an apnoeic episode, were compared with measurements taken in two age groups of healthy infants. Paired, inspiratory and expiratory, lateral upper airway radiographs were obtained while the infants were awake and breathing quietly. The radiographs of all nine infants demonstrated narrowing in the oropharyngeal portion of the airway during inspiration and in six infants there was ballooning of the upper airway during expiration. Seven of the nine infants subsequently experienced recurrent apnoeic episodes which required vigorous stimulation to restore breathing. Experience suggests that respiratory phase timed radiographs are a useful adjunct to the evaluation of infants who are suspected of having upper airway dysfunction. They provide information regarding both the dimensions and compliance of the upper airway as well as the site of any restriction. Images PMID:8048825

  14. Electrolyte transport properties in distal small airways from cystic fibrosis pigs with implications for host defense

    PubMed Central

    Tang, Xiao Xiao; Vargas Buonfiglio, Luis G.; Comellas, Alejandro P.; Thornell, Ian M.; Ramachandran, Shyam; Karp, Philip H.; Taft, Peter J.; Sheets, Kelsey; Abou Alaiwa, Mahmoud H.; Welsh, Michael J.; Stoltz, David A.; Zabner, Joseph

    2016-01-01

    While pathological and clinical data suggest that small airways are involved in early cystic fibrosis (CF) lung disease development, little is known about how the lack of cystic fibrosis transmembrane conductance regulator (CFTR) function contributes to disease pathogenesis in these small airways. Large and small airway epithelia are exposed to different airflow velocities, temperatures, humidity, and CO2 concentrations. The cellular composition of these two regions is different, and small airways lack submucosal glands. To better understand the ion transport properties and impacts of lack of CFTR function on host defense function in small airways, we adapted a novel protocol to isolate small airway epithelial cells from CF and non-CF pigs and established an organotypic culture model. Compared with non-CF large airways, non-CF small airway epithelia cultures had higher Cl− and bicarbonate (HCO3−) short-circuit currents and higher airway surface liquid (ASL) pH under 5% CO2 conditions. CF small airway epithelia were characterized by minimal Cl− and HCO3− transport and decreased ASL pH, and had impaired bacterial killing compared with non-CF small airways. In addition, CF small airway epithelia had a higher ASL viscosity than non-CF small airways. Thus, the activity of CFTR is higher in the small airways, where it plays a role in alkalinization of ASL, enhancement of antimicrobial activity, and lowering of mucus viscosity. These data provide insight to explain why the small airways are a susceptible site for the bacterial colonization. PMID:26801568

  15. An Aboriginal-driven program to prevent, control and manage nutrition-related "lifestyle" diseases including diabetes.

    PubMed

    Gracey, Michael; Bridge, Ernie; Martin, David; Jones, Timothy; Spargo, Randolph M; Shephard, Mark; Davis, Elizabeth A

    2006-01-01

    Type 2 diabetes and other nutrition-related so-called "lifestyle" diseases, including obesity, and cardiovascular and chronic renal disease, are very prevalent in Australian Aboriginal people and contribute to their high rates of chronic illness and premature mortality. An Aboriginal-driven, community-based health protection, health promotion and improved disease detection, management and care program was introduced in four remote, discrete communities in the far north of Western Australia (WA) in order to attempt to prevent these disorders through community-based lifestyle modification. More energetic screening for early risk factors is involved as well as early dietary and exercise interventions and medical treatment, when indicated. Distinctive features of this program include its Aboriginal initiatives and perspectives, committed partnerships between the communities, the Unity of First People of Australia of Australia (UFPA) and its carers, the communities' health care providers, external clinical specialists, other external agencies and a locally-operated point-of-care (POC) pathology testing capability that is conducted by local and UFPA personnel. The POC component is quality managed by Flinders University. These features have ensured the viability of the program in three of the communities; the other one decided not to continue with the program despite risks of serious long-term health consequences. The pre-program prevalence of diabetes in screened adults was almost 40% and in adults aged (35 years was almost 60%. After several months of the program's operation, there have been positive changes in knowledge about food, nutrition, exercise and disease and altered attitudes and behaviours related to dietary and exercise patterns. There have also been improvements in weight control and in pathology test results relevant to the risk of subsequent development of diabetes and cardiovascular disease.

  16. Severe micrognathia: indications for EXIT-to-Airway.

    PubMed

    Morris, Lee M; Lim, Foong-Yen; Elluru, Ravindhra G; Hopkin, Robert J; Jaekle, Ronald K; Polzin, William J; Crombleholme, Timothy M

    2009-01-01

    The ex utero intrapartum treatment (EXIT) procedure has become an important management option in cases of fetal airway obstruction. Select cases of severe micrognathia may be candidates for EXIT-to-Airway due to high-risk of airway obstruction at birth. Here we present three successful EXIT-to-Airway procedures for the management of congenital micrognathia in its most severe manifestations. CASE 1: A 23-year-old G3P1011 with a pregnancy complicated by severe micorgnathia, jaw index <5th percentile, as well as polyhydramnios. At 36 weeks EXIT-to-Airway was performed utilizing a bronchoscopically positioned laryngeal mask airway (LMA) during 23 min of uteroplacental support followed by tracheostomy. CASE 2: A 26-year-old G4P0120 with a pregnancy complicated by severe micrognathia, jaw index <5th percentile, and an obstructed oropharynx associated with polyhydramnios. At 37 weeks EXIT-to-Airway was performed with placement of tracheostomy. CASE 3: A 36-year-old G6P3023 with fetal magnetic resonance imaging (MRI) revealing esophageal atresia, polyhydramnios, and severe micrognathia with a jaw index <5th percentile. At 35 weeks the patient underwent EXIT-to-Airway with formal tracheostomy during 35 min of uteroplacental bypass. In the most severe cases of fetal micrognathia, EXIT-to-Airway provides time to evaluate and secure the fetal airway prior to delivery. We propose indications for EXIT-to-Airway in micrognathia to include a jaw index <5%, with indirect evidence of aerodigestive tract obstruction such as polyhydramnios, glossoptosis or an absent stomach bubble.

  17. Hydrogen sulphide inhibits Ca2+ release through InsP3 receptors and relaxes airway smooth muscle

    PubMed Central

    Castro-Piedras, Isabel; Perez-Zoghbi, Jose F

    2013-01-01

    Hydrogen sulphide (H2S) is a signalling molecule that appears to regulate diverse cell physiological process in several organs and systems including vascular and airway smooth muscle cell (SMC) contraction. Decreases in endogenous H2S synthesis have been associated with the development of cardiovascular diseases and asthma. Here we investigated the mechanism of airway SMC relaxation induced by H2S in small intrapulmonary airways using mouse lung slices and confocal and phase-contrast video microscopy. Exogenous H2S donor Na2S (100 μm) reversibly inhibited Ca2+ release and airway contraction evoked by inositol-1,4,5-trisphosphate (InsP3) uncaging in airway SMCs. Similarly, InsP3-evoked Ca2+ release and contraction was inhibited by endogenous H2S precursor l-cysteine (10 mm) but not by l-serine (10 mm) or either amino acid in the presence of dl-propargylglycine (PPG). Consistent with the inhibition of Ca2+ release through InsP3 receptors (InsP3Rs), Na2S reversibly inhibited acetylcholine (ACh)-induced Ca2+ oscillations in airway SMCs. In addition, Na2S, the H2S donor GYY-4137, and l-cysteine caused relaxation of airways pre-contracted with either ACh or 5-hydroxytryptamine (5-HT). Na2S-induced airway relaxation was resistant to a guanylyl cyclase inhibitor (ODQ) and a protein kinase G inhibitor (Rp-8-pCPT-cGMPS). The effects of H2S on InsP3-evoked Ca2+ release and contraction as well as on the relaxation of agonist-contracted airways were mimicked by the thiol-reducing agent dithiothreitol (DTT, 10 mm) and inhibited by the oxidizing agent diamide (30 μm). These studies indicate that H2S causes airway SMC relaxation by inhibiting Ca2+ release through InsP3Rs and consequent reduction of agonist-induced Ca2+ oscillations in SMCs. The results suggest a novel role for endogenously produced H2S that involves the modulation of InsP3-evoked Ca2+ release – a cell-signalling system of critical importance for many physiological and pathophysiological processes. PMID

  18. Metformin prevents the effects of Pseudomonas aeruginosa on airway epithelial tight junctions and restricts hyperglycaemia-induced bacterial growth.

    PubMed

    Patkee, Wishwanath R A; Carr, Georgina; Baker, Emma H; Baines, Deborah L; Garnett, James P

    2016-04-01

    Lung disease and elevation of blood glucose are associated with increased glucose concentration in the airway surface liquid (ASL). Raised ASL glucose is associated with increased susceptibility to infection by respiratory pathogens including Staphylococcus aureus and Pseudomonas aeruginosa. We have previously shown that the anti-diabetes drug, metformin, reduces glucose-induced S. aureus growth across in vitro airway epithelial cultures. The aim of this study was to investigate whether metformin has the potential to reduce glucose-induced P. aeruginosa infections across airway epithelial (Calu-3) cultures by limiting glucose permeability. We also explored the effect of P. aeruginosa and metformin on airway epithelial barrier function by investigating changes in tight junction protein abundance. Apical P. aeruginosa growth increased with basolateral glucose concentration, reduced transepithelial electrical resistance (TEER) and increased paracellular glucose flux. Metformin pre-treatment of the epithelium inhibited the glucose-induced growth of P. aeruginosa, increased TEER and decreased glucose flux. Similar effects on bacterial growth and TEER were observed with the AMP activated protein kinase agonist, 5-aminoimidazole-4-carboxamide ribonucleotide. Interestingly, metformin was able to prevent the P. aeruginosa-induced reduction in the abundance of tight junction proteins, claudin-1 and occludin. Our study highlights the potential of metformin to reduce hyperglycaemia-induced P. aeruginosa growth through airway epithelial tight junction modulation, and that claudin-1 and occludin could be important targets to regulate glucose permeability across airway epithelia and supress bacterial growth. Further investigation into the mechanisms regulating metformin and P. aeruginosa action on airway epithelial tight junctions could yield new therapeutic targets to prevent/suppress hyperglycaemia-induced respiratory infections, avoiding the use of antibiotics.

  19. Assessing the applicability of currently available methods for attributing foodborne disease to sources, including food and food commodities.

    PubMed

    Pires, Sara M

    2013-03-01

    A variety of approaches to attribute foodborne diseases to specific sources are available, including hazard occurrence analysis, epidemiological methods, intervention studies, and expert elicitations. The usefulness of each method to attribute disease caused by a foodborne hazard depends on the public health question being addressed, on the data requirements, on advantages and limitations of the method, and on the data availability of the country or region in question. Previous articles have described available methods for source attribution, but have focused only on foodborne microbiological hazards. These articles have described strengths and weaknesses of each method, but no guidance on how to choose the most appropriate tool to address different public health questions has thus far been provided. We reviewed available source attribution methods; assessed their applicability to attribute illness caused by enteric, parasitic, and chemical foodborne hazards to the responsible sources; and renamed some of the approaches. The main objective was to make recommendations on the most appropriate method(s) to attribute human disease caused by different foodborne hazards. We concluded that the proportion of disease that can be attributed to specific foods items or transmission routes may be estimated for the majority of the evaluated hazards by applying one or more of the source attribution methods assessed. It was also recognized that the use of source attribution methods may be limited to specific countries, reflecting the data availability.

  20. Teduglutide, a glucagon-like peptide-2 analog for the treatment of gastrointestinal diseases, including short bowel syndrome.

    PubMed

    Yazbeck, Roger

    2010-12-01

    Glucagon-like peptide-2 (GLP-2) is a potent intestinotrophic growth factor with therapeutic potential for the prevention or treatment of an expanding number of gastrointestinal diseases, including short bowel syndrome (SBS). Teduglutide, being developed by NPS Allelix and licensee Nycomed, is a protease-resistant analog of GLP-2 for the potential treatment of gastrointestinal disease. Teduglutide has prolonged biological activity compared with native GLP-2, and preclinical studies demonstrated significant intestinotrophic activity in models of SBS, experimental colitis and chemotherapy-induced intestinal mucositis. Patients with SBS rely on parenteral nutrition (PN) following bowel resection, and in a phase III clinical trial with teduglutide, > 20% reduction in PN was observed in patients with SBS receiving teduglutide. A phase II clinical trial for teduglutide in Crohn's disease observed remission rates of 55.6% in patients. At the time of publication, phase III clinical trials for SBS were ongoing, as were preclinical studies for chemotherapy-induced mucositis and pediatric indications. Teduglutide represents a novel, efficacious drug capable of increasing intestinal growth and improving intestinal function, and may change clinical management of intestinal disease and damage.

  1. Induction and Antagonism of Antiviral Responses in Respiratory Syncytial Virus-Infected Pediatric Airway Epithelium

    PubMed Central

    Villenave, Rémi; Broadbent, Lindsay; Douglas, Isobel; Lyons, Jeremy D.; Coyle, Peter V.; Teng, Michael N.; Tripp, Ralph A.; Heaney, Liam G.; Shields, Michael D.

    2015-01-01

    ABSTRACT Airway epithelium is the primary target of many respiratory viruses. However, virus induction and antagonism of host responses by human airway epithelium remains poorly understood. To address this, we developed a model of respiratory syncytial virus (RSV) infection based on well-differentiated pediatric primary bronchial epithelial cell cultures (WD-PBECs) that mimics hallmarks of RSV disease in infants. RSV is the most important respiratory viral pathogen in young infants worldwide. We found that RSV induces a potent antiviral state in WD-PBECs that was mediated in part by secreted factors, including interferon lambda 1 (IFN-λ1)/interleukin-29 (IL-29). In contrast, type I IFNs were not detected following RSV infection of WD-PBECs. IFN responses in RSV-infected WD-PBECs reflected those in lower airway samples from RSV-hospitalized infants. In view of the prominence of IL-29, we determined whether recombinant IL-29 treatment of WD-PBECs before or after infection abrogated RSV replication. Interestingly, IL-29 demonstrated prophylactic, but not therapeutic, potential against RSV. The absence of therapeutic potential reflected effective RSV antagonism of IFN-mediated antiviral responses in infected cells. Our data are consistent with RSV nonstructural proteins 1 and/or 2 perturbing the Jak-STAT signaling pathway, with concomitant reduced expression of antiviral effector molecules, such as MxA/B. Antagonism of Jak-STAT signaling was restricted to RSV-infected cells in WD-PBEC cultures. Importantly, our study provides the rationale to further explore IL-29 as a novel RSV prophylactic. IMPORTANCE Most respiratory viruses target airway epithelium for infection and replication, which is central to causing disease. However, for most human viruses we have a poor understanding of their interactions with human airway epithelium. Respiratory syncytial virus (RSV) is the most important viral pathogen of young infants. To help understand RSV interactions with pediatric

  2. Airway responsiveness to psychological processes in asthma and health

    PubMed Central

    Ritz, Thomas

    2012-01-01

    Psychosocial factors have been found to impact airway pathophysiology in respiratory disease with considerable consistency. Influences on airway mechanics have been studied particularly well. The goal of this article is to review the literature on airway responses to psychological stimulation, discuss potential pathways of influence, and present a well-established emotion-induction paradigm to study airway obstruction elicited by unpleasant stimuli. Observational studies have found systematic associations between lung function and daily mood changes. The laboratory-based paradigm of bronchoconstrictive suggestion has been used successfully to elicit airway obstruction in a substantial proportion of asthmatic individuals. Other studies have demonstrated modulation of airway responses to standard airway challenges with exercise, allergens, or pharmacological agents by psychological factors. Standardized emotion-induction techniques have consistently shown airway constriction during unpleasant stimulation, with surgery, blood, and injury stimuli being particularly powerful. Findings with various forms of stress induction have been more mixed. A number of methodological factors may account for variability across studies, such as choice of measurement technique, temporal association between stimulation and measurement, and the specific quality and intensity of the stimulus material, in particular the extent of implied action-orientation. Research has also begun to elucidate physiological processes associated with psychologically induced airway responses, with vagal excitation and ventilatory influences being the most likely candidate pathways, whereas the role of specific central nervous system pathways and inflammatory processes has been less studied. The technique of emotion-induction using films has the potential to become a standardized challenge paradigm for the further exploration of airway hyperresponsiveness mediated by central nervous system processes. PMID

  3. Supraglottic airway devices in children

    PubMed Central

    Ramesh, S; Jayanthi, R

    2011-01-01

    Modern anaesthesia practice in children was made possible by the invention of the endotracheal tube (ET), which made lengthy and complex surgical procedures feasible without the disastrous complications of airway obstruction, aspiration of gastric contents or asphyxia. For decades, endotracheal intubation or bag-and-mask ventilation were the mainstays of airway management. In 1983, this changed with the invention of the laryngeal mask airway (LMA), the first supraglottic airway device that blended features of the facemask with those of the ET, providing ease of placement and hands-free maintenance along with a relatively secure airway. The invention and development of the LMA by Dr. Archie Brain has had a significant impact on the practice of anaesthesia, management of the difficult airway and cardiopulmonary resuscitation in children and neonates. This review article will be a brief about the clinical applications of supraglottic airways in children. PMID:22174464

  4. Syk Regulates Neutrophilic Airway Hyper-Responsiveness in a Chronic Mouse Model of Allergic Airways Inflammation

    PubMed Central

    Juvet, Stephen; Scott, Jeremy A.; Chow, Chung-Wai

    2017-01-01

    Background Asthma is a chronic inflammatory disease characterized by airways hyper-responsiveness (AHR), reversible airway obstruction, and airway inflammation and remodeling. We previously showed that Syk modulates methacholine-induced airways contractility in naïve mice and in mice with allergic airways inflammation. We hypothesize that Syk plays a role in the pathogenesis of AHR; this was evaluated in a chronic 8-week mouse model of house dust mite (HDM)-induced allergic airways inflammation. Methods We used the Sykflox/flox//rosa26CreERT2 conditional Syk knock-out mice to assess the role of Syk prior to HDM exposure, and treated HDM-sensitized mice with the Syk inhibitor, GSK143, to evaluate its role in established allergic airways inflammation. Respiratory mechanics and methacholine (MCh)-responsiveness were assessed using the flexiVent® system. Lungs underwent bronchoalveolar lavage to isolate inflammatory cells or were frozen for determination of gene expression in tissues. Results MCh-induced AHR was observed following HDM sensitization in the Syk-intact (Sykflox/flox) and vehicle-treated BALB/c mice. MCh responsiveness was reduced to control levels in HDM-sensitized Sykdel/del mice and in BALB/c and Sykflox/flox mice treated with GSK143. Both Sykdel/del and GSK143-treated mice mounted appropriate immune responses to HDM, with HDM-specific IgE levels that were comparable to Sykflox/flox and vehicle-treated BALB/c mice. HDM-induced increases in bronchoalveolar lavage cell counts were attenuated in both Sykdel/del and GSK143-treated mice, due primarily to decreased neutrophil recruitment. Gene expression analysis of lung tissues revealed that HDM-induced expression of IL-17 and CXCL-1 was significantly attenuated in both Sykdel/del and GSK143-treated mice. Conclusion Syk inhibitors may play a role in the management of neutrophilic asthma. PMID:28107345

  5. Autoimmunity Including Intestinal Behçet Disease Bearing the KRAS Mutation in Lymphocytes: A Case Report.

    PubMed

    Moritake, Hiroshi; Takagi, Masatoshi; Kinoshita, Mariko; Ohara, Osamu; Yamamoto, Shojiro; Moriguchi, Sayaka; Nunoi, Hiroyuki

    2016-03-01

    We experienced the case of a 3-year-old male with a very rare combination of autoimmunity, including immune thrombocytopenia, recurrent Henoch-Schönlein purpura and intestinal Behçet disease. Exome sequencing of the patient's peripheral blood mononuclear cells identified a KRAS G13C mutation. Interestingly, the KRAS G13C mutation was observed in T and B lymphocytes, as well as natural killer cells, but not granulocytes. Our case was completely phenotypically different from RASopathies and did not meet the criteria for Ras-associated lymphoproliferative disease or juvenile myelomonocytic leukemia. This is the first reported case in which the KRAS mutation existed only in the lymphoid lineage. Based on the findings of our case and the current literature, it is clear that the RAS mutation in lymphoid cells is tightly linked with various autoimmune symptoms. The presence of the RAS mutation in lymphocytes should be reconsidered as a pathogenesis in cases of autoimmunity.

  6. Omega-3 Fatty acids and airway hyperresponsiveness in asthma.

    PubMed

    Mickleborough, Timothy D; Ionescu, Alina A; Rundell, Kenneth W

    2004-12-01

    Despite the progress that has been made in the treatment of asthma, the prevalence and burden of this disease has continued to increase. Exercise is a powerful trigger of asthma symptoms and reversible airflow obstruction and may result in the avoidance of physical activity by patients with asthma, resulting in detrimental consequences to their health. Approximately 90% of patients with asthma are hyperresponsive to exercise and experience exercise-induced bronchoconstriction (EIB). While pharmacologic treatment of asthma is usually highly effective, medications often have significant side-effects or exhibit tachyphylaxis. Alternative therapies for treatment (complementary medicine) that reduce the dose requirements of pharmacologic interventions would be beneficial, and could potentially reduce the public health burden of this disease. There is accumulating evidence that dietary modification has potential to influence the severity of asthma and reduce the prevalence and incidence of this condition. A possible contributing factor to the increased incidence of asthma in Western societies may be the consumption of a proinflammatory diet. In the typical Western diet, 20- to 25-fold more omega- 6 polyunsaturated fatty acids (PUFA) than omega-3 PUFA are consumed, which causes the release of proinflammatory arachidonic acid metabolites (leukotrienes and prostanoids). This review analyzes the existing literature on omega-3 PUFA supplementation as a potential modifier of airway hyperresponsiveness in asthma and includes studies concerning the efficacy of omega-3 PUFA supplementation in EIB. While clinical data evaluating the effect of omega-3 PUFA supplementation in asthma has been equivocal, it has recently been shown that pharmaceutical-grade fish oil (omega-3 PUFA) supplementation reduces airway hyperresponsiveness after exercise, medication use, and proinflammatory mediator generation in nonatopic elite athletes with EIB. These findings are provocative and suggest that

  7. Peripheral Airway Smooth Muscle, but Not the Trachealis, Is Hypercontractile in an Equine Model of Asthma.

    PubMed

    Matusovsky, Oleg S; Kachmar, Linda; Ijpma, Gijs; Bates, Genevieve; Zitouni, Nedjma; Benedetti, Andrea; Lavoie, Jean-Pierre; Lauzon, Anne-Marie

    2016-05-01

    Heaves is a naturally occurring equine disease that shares many similarities with human asthma, including reversible antigen-induced bronchoconstriction, airway inflammation, and remodeling. The purpose of this study was to determine whether the trachealis muscle is mechanically representative of the peripheral airway smooth muscle (ASM) in an equine model of asthma. Tracheal and peripheral ASM of heaves-affected horses under exacerbation, or under clinical remission of the disease, and control horses were dissected and freed of epithelium to measure unloaded shortening velocity (Vmax), stress (force/cross-sectional area), methacholine effective concentration at which 50% of the maximum response is obtained, and stiffness. Myofibrillar Mg(2+)-ATPase activity, actomyosin in vitro motility, and contractile protein expression were also measured. Horses with heaves had significantly greater Vmax and Mg(2+)-ATPase activity in peripheral airway but not in tracheal smooth muscle. In addition, a significant correlation was found between Vmax and the time elapsed since the end of the corticosteroid treatment for the peripheral airways in horses with heaves. Maximal stress and stiffness were greater in the peripheral airways of the horses under remission compared with controls and the horses under exacerbation, potentially due to remodeling. Actomyosin in vitro motility was not different between controls and horses with heaves. These data demonstrate that peripheral ASM is mechanically and biochemically altered in heaves, whereas the trachealis behaves as in control horses. It is therefore conceivable that the trachealis muscle may not be representative of the peripheral ASM in human asthma either, but this will require further investigation.

  8. Staphylococcus aureus Infection Reduces Nutrition Uptake and Nucleotide Biosynthesis in a Human Airway Epithelial Cell Line

    PubMed Central

    Gierok, Philipp; Harms, Manuela; Methling, Karen; Hochgräfe, Falko; Lalk, Michael

    2016-01-01

    The Gram positive opportunistic human pathogen Staphylococcus aureus induces a variety of diseases including pneumonia. S. aureus is the second most isolated pathogen in cystic fibrosis patients and accounts for a large proportion of nosocomial pneumonia. Inside the lung, the human airway epithelium is the first line in defence with regard to microbial recognition and clearance as well as regulation of the immune response. The metabolic host response is, however, yet unknown. To address the question of whether the infection alters the metabolome and metabolic activity of airway epithelial cells, we used a metabolomics approach. The nutrition uptake by the human airway epithelial cell line A549 was monitored over time by proton magnetic resonance spectroscopy (1H-NMR) and the intracellular metabolic fingerprints were investigated by gas chromatography and high performance liquid chromatography (GC-MS) and (HPLC-MS). To test the metabolic activity of the host cells, glutamine analogues and labelled precursors were applied after the infection. We found that A549 cells restrict uptake of essential nutrients from the medium after S. aureus infection. Moreover, the infection led to a shutdown of the purine and pyrimidine synthesis in the A549 host cell, whereas other metabolic routes such as the hexosamine biosynthesis pathway remained active. In summary, our data show that the infection with S. aureus negatively affects growth, alters the metabolic composition and specifically impacts the de novo nucleotide biosynthesis in this human airway epithelial cell model. PMID:27834866

  9. TLR4 signalling in pulmonary stromal cells is critical for inflammation and immunity in the airways.

    PubMed

    Perros, Frederic; Lambrecht, Bart N; Hammad, Hamida

    2011-09-24

    Inflammation of the airways, which is often associated with life-threatening infection by Gram-negative bacteria or presence of endotoxin in the bioaerosol, is still a major cause of severe airway diseases. Moreover, inhaled endotoxin may play an important role in the development and progression of airway inflammation in asthma. Pathologic changes induced by endotoxin inhalation include bronchospasm, airflow obstruction, recruitment of inflammatory cells, injury of the alveolar epithelium, and disruption of pulmonary capillary integrity leading to protein rich fluid leak in the alveolar space. Mammalian Toll-like receptors (TLRs) are important signalling receptors in innate host defense. Among these receptors, TLR4 plays a critical role in the response to endotoxin. Lungs are a complex compartmentalized organ with separate barriers, namely the alveolar-capillary barrier, the microvascular endothelium, and the alveolar epithelium. An emerging theme in the field of lung immunology is that structural cells (SCs) of the airways such as epithelial cells (ECs), endothelial cells, fibroblasts and other stromal cells produce activating cytokines that determine the quantity and quality of the lung immune response. This review focuses on the role of TLR4 in the innate and adaptive immune functions of the pulmonary SCs.

  10. Design and Implementation of the Resuscitation Outcomes Consortium Pragmatic Airway Resuscitation Trial (PART)

    PubMed Central

    Wang, Henry E.; Prince, David; Stephens, Shannon W.; Herren, Heather; Daya, Mohamud; Richmond, Neal; Carlson, Jestin; Warden, Craig; Colella, M. Riccardo; Brienza, Ashley; Aufderheide, Tom P.; Idris, Ahamed; Schmicker, Robert; May, Susanne; Nichol, Graham

    2016-01-01

    Airway management is an important component of resuscitation from out-of-hospital cardiac arrest (OHCA). The optimal approach to advanced airway management is unknown. The Pragmatic Airway Resuscitation Trial (PART) will compare the effectiveness of endotracheal intubation (ETI) and Laryngeal Tube (LT) insertion upon 72-hour survival in adult OHCA. Encompassing United States Emergency Medical Services agencies affiliated with the Resuscitation Outcomes Consortium (ROC), PART will use a cluster-crossover randomized design. Participating subjects will include adult, non-traumatic OHCA requiring bag-valve-mask ventilation. Trial interventions will include 1) initial airway management with ETI and 2) initial airway management with LT. The primary and secondary trial outcomes are 72-hour survival and return of spontaneous circulation. Additional clinical outcomes will include airway management process and adverse events. The trial will enroll a total of 3,000 subjects. Results of PART may guide the selection of advanced airway management strategies in OHCA. PMID:26851059

  11. Vanishing Bronchus After Lung Transplantation: The Role of Sequential Airway Dilatations

    PubMed Central

    Alraiyes, Abdul Hamid; Inaty, Hanine; Machuzak, Michael S.

    2017-01-01

    Background: Airway complications after lung transplant play an important role in patient survival. Early recognition and treatment of these complications are necessary to help ensure that patients who receive lung transplants have good outcomes. Case Report: A 61-year-old female with a history of pulmonary venous occlusive disease presented to our hospital for a double-lung transplant. Her postoperative course was complicated by severe primary graft dysfunction. Airway examination showed significant mucosal ischemia distal to the anastomosis bilaterally with diffuse narrowing of all distal bronchial segments. Repeat bronchoscopies with debridement of necrotic material and balloon dilatation of stenotic airways were performed to maintain airway patency. Conclusion: Post–lung transplant airway necrosis and stenosis mandate early identification and treatment. Repetitive bronchoscopies with sequential balloon dilatations are mandatory to prevent future airway stenosis and airway vanishing. PMID:28331451

  12. Vitamin A-retinoid signaling in pulmonary development and disease.

    PubMed

    Marquez, Hector A; Cardoso, Wellington V

    2016-12-01

    Retinoic acid (RA), the active form of vitamin A, regulates key developmental processes in multiple organs. In the developing lung, RA is crucial for normal growth and differentiation of airways. Disruption in RA signaling or vitamin A deficiency (VAD) has been linked to aberrant development of the lung including alterations in the airway smooth muscle (SM) differentiation, development, and function. These alterations have been linked to disease states including asthma in both human and animal models.

  13. Airway epithelium stimulates smooth muscle proliferation.

    PubMed

    Malavia, Nikita K; Raub, Christopher B; Mahon, Sari B; Brenner, Matthew; Panettieri, Reynold A; George, Steven C

    2009-09-01

    Communication between the airway epithelium and stroma is evident during embryogenesis, and both epithelial shedding and increased smooth muscle proliferation are features of airway remodeling. Hence, we hypothesized that after injury the airway epithelium could modulate airway smooth muscle proliferation. Fully differentiated primary normal human bronchial epithelial (NHBE) cells at an air-liquid interface were co-cultured with serum-deprived normal primary human airway smooth muscle cells (HASM) using commercially available Transwells. In some co-cultures, the NHBE were repeatedly (x4) scrape-injured. An in vivo model of tracheal injury consisted of gently denuding the tracheal epithelium (x3) of a rabbit over 5 days and then examining the trachea by histology 3 days after the last injury. Our results show that HASM cell number increases 2.5-fold in the presence of NHBE, and 4.3-fold in the presence of injured NHBE compared with HASM alone after 8 days of in vitro co-culture. In addition, IL-6, IL-8, monocyte chemotactic protein (MCP)-1 and, more markedly, matrix metalloproteinase (MMP)-9 concentration increased in co-culture correlating with enhanced HASM growth. Inhibiting MMP-9 release significantly attenuated the NHBE-dependent HASM proliferation in co-culture. In vivo, the injured rabbit trachea demonstrated proliferation in the smooth muscle (trachealis) region and significant MMP-9 staining, which was absent in the uninjured control. The airway epithelium modulates smooth muscle cell proliferation via a mechanism that involves secretion of soluble mediators including potential smooth muscle mitogens such as IL-6, IL-8, and MCP-1, but also through a novel MMP-9-dependent mechanism.

  14. Pulmonary Stress Induced by Hyperthermia: Role of Airway Sensory Nerves

    DTIC Science & Technology

    2016-01-01

    selection of more suitable animal models for studying various airway diseases in humans. A continuing growth of our knowledge about the physiological and...rats, but not in control rats. Chronic airway inflammation in sensitized animals is likely a major contributing factor in causing this response. 3) A...C-fibers. 4) In an animal model of asthma (Brown-Norway rats sensitized by ovalbumin), chronic allergic inflammation sensitization increases the

  15. Altered Epithelial Gene Expression in Peripheral Airways of Severe Asthma

    PubMed Central

    Singhania, Akul; Rupani, Hitasha; Jayasekera, Nivenka; Lumb, Simon; Hales, Paul; Gozzard, Neil; Davies, Donna E.

    2017-01-01

    Management of severe asthma remains a challenge despite treatment with glucocorticosteroid therapy. The majority of studies investigating disease mechanisms in treatment-resistant severe asthma have previously focused on the large central airways, with very few utilizing transcriptomic approaches. The small peripheral airways, which comprise the majority of the airway surface area, remain an unexplored area in severe asthma and were targeted for global epithelial gene expression profiling in this study. Differences between central and peripheral airways were evaluated using transcriptomic analysis (Affymetrix HG U133 plus 2.0 GeneChips) of epithelial brushings obtained from severe asthma patients (N = 17) and healthy volunteers (N = 23). Results were validated in an independent cohort (N = 10) by real-time quantitative PCR. The IL-13 disease signature that is associated with an asthmatic phenotype was upregulated in severe asthmatics compared to healthy controls but was predominantly evident within the peripheral airways, as were genes related to mast cell presence. The gene expression response associated with glucocorticosteroid therapy (i.e. FKBP5) was also upregulated in severe asthmatics compared to healthy controls but, in contrast, was more pronounced in central airways. Moreover, an altered epithelial repair response (e.g. FGFBP1) was evident across both airway sites reflecting a significant aspect of disease in severe asthma unadressed by current therapies. A transcriptomic approach to understand epithelial activation in severe asthma has thus highlighted the need for better-targeted therapy to the peripheral airways in severe asthma, where the IL-13 disease signature persists despite treatment with currently available therapy. PMID:28045928

  16. Altered Epithelial Gene Expression in Peripheral Airways of Severe Asthma.

    PubMed

    Singhania, Akul; Rupani, Hitasha; Jayasekera, Nivenka; Lumb, Simon; Hales, Paul; Gozzard, Neil; Davies, Donna E; Woelk, Christopher H; Howarth, Peter H

    2017-01-01

    Management of severe asthma remains a challenge despite treatment with glucocorticosteroid therapy. The majority of studies investigating disease mechanisms in treatment-resistant severe asthma have previously focused on the large central airways, with very few utilizing transcriptomic approaches. The small peripheral airways, which comprise the majority of the airway surface area, remain an unexplored area in severe asthma and were targeted for global epithelial gene expression profiling in this study. Differences between central and peripheral airways were evaluated using transcriptomic analysis (Affymetrix HG U133 plus 2.0 GeneChips) of epithelial brushings obtained from severe asthma patients (N = 17) and healthy volunteers (N = 23). Results were validated in an independent cohort (N = 10) by real-time quantitative PCR. The IL-13 disease signature that is associated with an asthmatic phenotype was upregulated in severe asthmatics compared to healthy controls but was predominantly evident within the peripheral airways, as were genes related to mast cell presence. The gene expression response associated with glucocorticosteroid therapy (i.e. FKBP5) was also upregulated in severe asthmatics compared to healthy controls but, in contrast, was more pronounced in central airways. Moreover, an altered epithelial repair response (e.g. FGFBP1) was evident across both airway sites reflecting a significant aspect of disease in severe asthma unadressed by current therapies. A transcriptomic approach to understand epithelial activation in severe asthma has thus highlighted the need for better-targeted therapy to the peripheral airways in severe asthma, where the IL-13 disease signature persists despite treatment with currently available therapy.

  17. Emergency surgical airway in life-threatening acute airway emergencies--why are we so reluctant to do it?

    PubMed

    Greenland, K B; Acott, C; Segal, R; Goulding, G; Riley, R H; Merry, A F

    2011-07-01

    'Can't intubate, can't oxygenate' scenarios are rare but are often poorly managed, with potentially disastrous consequences. In our opinion, all doctors should be able to create a surgical airway if necessary. More practically, at least all anaesthetists should have this ability. There should be a change in culture to one that encourages and facilitates the performance of a life-saving emergency surgical airway when required. In this regard, an understanding of the human factors that influence the decision to perform an emergency surgical airway is as important as technical skill. Standardisation of difficult airway equipment in areas where anaesthesia is performed is a step toward ensuring that an emergency surgical airway will be performed appropriately Information on the incidence and clinical management of 'can't intubate, can't oxygenate' scenarios should be compiled through various sources, including national coronial inquest databases and anaesthetic critical incident reporting systems. A systematic approach to teaching and maintaining human factors in airway crisis management and emergency surgical airway skills to anaesthetic trainees and specialists should be developed: in our opinion participation should be mandatory. Importantly, the view that performing an emergency surgical airway is an admission of anaesthetist failure should be strongly countered.

  18. Targeted expression of IL-11 in the murine airway causes lymphocytic inflammation, bronchial remodeling, and airways obstruction.

    PubMed Central

    Tang, W; Geba, G P; Zheng, T; Ray, P; Homer, R J; Kuhn, C; Flavell, R A; Elias, J A

    1996-01-01

    Interleukin-11 is a pleotropic cytokine produced by lung stromal cells in response to respiratory viruses, cytokines, and histamine. To further define its potential effector functions, the Clara cell 10-kD protein promoter was used to express IL-11 and the airways of the resulting transgene mice were characterized. In contrast to transgene (-) littermates, the airways of IL-11 transgene (+) animals manifest nodular peribronchiolar mononuclear cell infiltrates and impressive airways remodeling with subepithelial fibrosis. The inflammatory foci contained large numbers of B220(+) and MHC Class II(+) cells and lesser numbers of CD3(+), CD4(+), and CD8(+) cells. The fibrotic response contained increased amounts of types III and I collagen, increased numbers of alpha smooth muscle actin and desmin-containing cells and a spectrum of stromal elements including fibroblasts, myofibroblasts, and smooth muscle cells. Physiologic evaluation also demonstrated that 2-mo-old transgene (+) mice had increased airways resistance and non-specific airways hyperresponsiveness to methacholine when compared with their transgene (-) littermates. These studies demonstrate that the targeted expression of IL-11 in the mouse airway causes a B and T cell-predominant inflammatory response, airway remodeling with increased types III and I collagen, the local accumulation of fibroblasts, myofibroblasts, and myocytes, and obstructive physiologic dysregulation. IL-11 may play an important role in the inflammatory and fibrotic responses in viral and/or nonviral human airway disorders. PMID:8981933

  19. Quantitative analysis of airway abnormalities in CT

    NASA Astrophysics Data System (ADS)

    Petersen, Jens; Lo, Pechin; Nielsen, Mads; Edula, Goutham; Ashraf, Haseem; Dirksen, Asger; de Bruijne, Marleen

    2010-03-01

    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 manually segmented images extracted from 15 different subjects and shown to give accurate results, with 37% less errors than the Full Width at Half Maximum (FWHM) algorithm and 62% less than a similar graph cut method without coupled surfaces. Common measures of airway wall thickness such as the Interior Area (IA) and Wall Area percentage (WA%) was measured by the proposed method on a total of 723 CT scans from a lung cancer screening study. These measures were significantly different for participants with Chronic Obstructive Pulmonary Disease (COPD) compared to asymptomatic participants. Furthermore, reproducibility was good as confirmed by repeat scans and the measures correlated well with the outcomes of pulmonary function tests, demonstrating the use of the algorithm as a COPD diagnostic tool. Additionally, a new measure of airway wall thickness is proposed, Normalized Wall Intensity Sum (NWIS). NWIS is shown to correlate better with lung function test values and to be more reproducible than previous measures IA, WA% and airway wall thickness at a lumen perimeter of 10 mm (PI10).

  20. Modeling the dynamics of airway constriction: effects of agonist transport and binding.

    PubMed

    Amin, Samir D; Majumdar, Arnab; Frey, Urs; Suki, Béla

    2010-08-01

    Recent advances have revealed that during exogenous airway challenge, airway diameters cannot be adequately predicted by their initial diameters. Furthermore, airway diameters can also vary greatly in time on scales shorter than a breath. To better understand these phenomena, we developed a multiscale model that allowed us to simulate aerosol challenge in the airways during ventilation. The model incorporates agonist-receptor binding kinetics to govern the temporal response of airway smooth muscle contraction on individual airway segments, which, together with airway wall mechanics, determines local airway caliber. Global agonist transport and deposition are coupled with pressure-driven flow, linking local airway constrictions with global flow dynamics. During the course of challenge, airway constriction alters the flow pattern, redistributing the agonist to less constricted regions. This results in a negative feedback that may be a protective property of the normal lung. As a consequence, repetitive challenge can cause spatial constriction patterns to evolve in time, resulting in a loss of predictability of airway diameters. Additionally, the model offers new insights into several phenomena including the intra- and interbreath dynamics of airway constriction throughout the tree structure.

  1. Osteopontin That Is Elevated in the Airways during COPD Impairs the Antibacterial Activity of Common Innate Antibiotics.

    PubMed

    Gela, Anele; Bhongir, Ravi K V; Mori, Michiko; Keenan, Paul; Mörgelin, Matthias; Erjefält, Jonas S; Herwald, Heiko; Egesten, Arne; Kasetty, Gopinath

    2016-01-01

    Bacterial infections of the respiratory tract contribute to exacerbations and disease progression in chronic obstructive pulmonary disease (COPD). There is also an increased risk of invasive pneumococcal disease in COPD. The underlying mechanisms are not fully understood but include impaired mucociliary clearance and structural remodeling of the airways. In addition, antimicrobial proteins that are constitutively expressed or induced during inflammatory conditions are an important part of the airway innate host defense. In the present study, we show that osteopontin (OPN), a multifunctional glycoprotein that is highly upregulated in the airways of COPD patients co-localizes with several antimicrobial proteins expressed in the airways. In vitro, OPN bound lactoferrin, secretory leukocyte peptidase inhibitor (SLPI), midkine, human beta defensin-3 (hBD-3), and thymic stromal lymphopoietin (TSLP) but showed low or no affinity for lysozyme and LL-37. Binding of OPN impaired the antibacterial activity against the important bacterial pathogens Streptococcus pneumoniae and Pseudomonas aeruginosa. Interestingly, OPN reduced lysozyme-induced killing of S. pneumoniae, a finding that could be explained by binding of OPN to the bacterial surface, thereby shielding the bacteria. A fragment of OPN generated by elastase of P. aeruginosa retained some inhibitory effect. Some antimicrobial proteins have additional functions. However, the muramidase-activity of lysozyme and the protease inhibitory function of SLPI were not affected by OPN. Taken together, OPN can contribute to the impairment of innate host defense by interfering with the function of antimicrobial proteins, thus increasing the vulnerability to acquire infections during COPD.

  2. Osteopontin That Is Elevated in the Airways during COPD Impairs the Antibacterial Activity of Common Innate Antibiotics

    PubMed Central

    Mori, Michiko; Keenan, Paul; Mörgelin, Matthias; Erjefält, Jonas S.; Herwald, Heiko; Egesten, Arne; Kasetty, Gopinath

    2016-01-01

    Bacterial infections of the respiratory tract contribute to exacerbations and disease progression in chronic obstructive pulmonary disease (COPD). There is also an increased risk of invasive pneumococcal disease in COPD. The underlying mechanisms are not fully understood but include impaired mucociliary clearance and structural remodeling of the airways. In addition, antimicrobial proteins that are constitutively expressed or induced during inflammatory conditions are an important part of the airway innate host defense. In the present study, we show that osteopontin (OPN), a multifunctional glycoprotein that is highly upregulated in the airways of COPD patients co-localizes with several antimicrobial proteins expressed in the airways. In vitro, OPN bound lactoferrin, secretory leukocyte peptidase inhibitor (SLPI), midkine, human beta defensin-3 (hBD-3), and thymic stromal lymphopoietin (TSLP) but showed low or no affinity for lysozyme and LL-37. Binding of OPN impaired the antibacterial activity against the important bacterial pathogens Streptococcus pneumoniae and Pseudomonas aeruginosa. Interestingly, OPN reduced lysozyme-induced killing of S. pneumoniae, a finding that could be explained by binding of OPN to the bacterial surface, thereby shielding the bacteria. A fragment of OPN generated by elastase of P. aeruginosa retained some inhibitory effect. Some antimicrobial proteins have additional functions. However, the muramidase-activity of lysozyme and the protease inhibitory function of SLPI were not affected by OPN. Taken together, OPN can contribute to the impairment of innate host defense by interfering with the function of antimicrobial proteins, thus increasing the vulnerability to acquire infections during COPD. PMID:26731746

  3. A Pilot Study on the Efficacy of Continuous Positive Airway Pressure on the Manifestations of Ménière's Disease in Patients with Concomitant Obstructive Sleep Apnea Syndrome

    PubMed Central

    Nakayama, Meiho; Masuda, Ayako; Ando, Kayoko Bhardwaj; Arima, Sachie; Kabaya, Kayoko; Inagaki, Akira; Nakamura, Yoshihisa; Suzuki, Motohiko; Brodie, Hilary; Diaz, Rodney C.; Murakami, Shingo

    2015-01-01

    Objective: To evaluate the effect of continuous positive airway pressure (CPAP) therapy on Ménière's disease patients with concomitant obstructive sleep apnea syndrome (OSAS), since recent reports suggest OSAS may cause dysfunction of the vestibular system. Study Design: Prospective study using CPAP administered to patients diagnosed with “Definite Ménière's disease” according to the guidelines of the American Academy of Otolaryngology— Head and Neck Surgery and combined with OSAS. Setting: University hospital. Methods: Twenty consecutive patients, 14 male and 6 female with active, unilateral, cochleovestibular Ménière's disease refractory to medical management who also had concurrent OSAS as defined by International Classification of Sleep Disorders, Second Edition were selected to undergo solitary CPAP therapy. Audiometric testing, caloric testing, and DHI survey were conducted before and after CPAP therapy and compared to assess effectiveness of CPAP therapy as utilized for treatment of Ménière's disease. Results: Although caloric testing did not show significant difference, audiometric testing and results of dizziness handicap inventory were significantly improved (p < 0.05) after CPAP therapy only, without standard treatment for Ménière's disease. Conclusions: Recent reports have suggested that OSAS may cause dysfunction of the vestibular system. We investigated whether standard therapy for OSAS would be of benefit in the management of vertigo and hearing loss in Ménière's disease patients. Our study cohort demonstrated significant improvement in both DHI and audiometric testing following solitary CPAP therapy for OSAS. Solitary CPAP therapy may become a new effective treatment strategy for Ménière's disease patients with OSAS, not just only for control of dizziness and vertigo but also for potential benefit of hearing. Citation: Nakayama M, Masuda A, Ando KB, Arima S, Kabaya K, Inagaki A, Nakamura Y, Suzuki M, Brodie H, Diaz RC, Murakami S

  4. Thick airway surface liquid volume and weak mucin expression in pendrin-deficient human airway epithelia

    PubMed Central

    Lee, Hyun Jae; Yoo, Jee Eun; Namkung, Wan; Cho, Hyung-Ju; Kim, Kyubo; Kang, Joo Wan; Yoon, Joo-Heon; Choi, Jae Young

    2015-01-01

    Pendrin is an anion exchanger whose mutations are known to cause hearing loss. However, recent data support the linkage between pendrin expression and airway diseases, such as asthma. To evaluate the role of pendrin in the regulation of the airway surface liquid (ASL) volume and mucin expression, we investigated the function and expression of pendrin and ion channels and anion exchangers. Human nasal epithelial cells were cultured from 16 deaf patients carrying pendrin mutations (DFNB4) and 17 controls. The cells were treated with IL-13 to induce mucus hypersecretion. Airway surface liquid thickness was measured and real-time polymerase chain reaction was performed targeting various transporters and MUC5AC. Anion exchanger activity was measured using a pH-sensitive fluorescent probe. Periodic acid-Schiff staining was performed on the cultured cells and inferior turbinate tissues. The ASL layer of the nasal epithelia from DFNB4 subjects was thicker than the controls, and the difference became more prominent following IL-13 stimulation. There was no difference in anion exchange activity after IL-13 treatment in the cells from DFNB4 patients, while it increased in the controls. Goblet cell metaplasia induced by IL-13 treatment seen in the controls was not observed in the DFNB4 cells. Furthermore, the periodic acid-Schiff staining-positive area was lesser in the inferior turbinate tissues from DFNB4 patients that those from controls. Pendrin plays a critical role in ASL volume regulation and mucin expression as pendrin-deficient airway epithelial cells are refractory to stimulation with IL-13. Specific blockers targeting pendrin in the airways may therefore have therapeutic potential in the treatment of allergic airway diseases. PMID:26243215

  5. Role for suppressor T cells in the pathogenesis of autoimmune diseases (including rheumatoid arthritis). Facts and hypotheses.

    PubMed

    Berthelot, Jean-Marie; Maugars, Yves

    2004-09-01

    Although uncontrolled clones of autoreactive T cells play a central role in the pathogenesis of autoimmunity, another mechanism potentially involved in many autoimmune diseases is deficiency of suppressor T cells, most notably those belonging to the antiidiopeptide TH3/Tr1 TCD4+CD25+(high) subset. Failure of suppressor mechanisms may be in part primary, due to defective positive selection of suppressor T cells in the thymus, and in part acquired, secondary to chronic infections promoted by deficiencies in innate immunity. Renewed interest in suppressor TCD4+ cells has generated plausible explanations for many events including paradoxical induction of autoimmune disorders by immunosuppressive agents or thymectomy. Insights into the physiology of these regulatory T-cell clones might suggest new treatment options, although many currently used drugs (including anti-TNF alpha agents) enhance the activity of several suppressor T-cell clones. Investigation of these suppressor clones in rheumatoid arthritis is still in its infancy and faces obstacles such as the need for identifying key clones in each individual patient and the presence of T-cell repertoire contraction. This last phenomenon exists at disease onset and may stem from early thymus dysfunction, which may also lead to a reduction in suppressor TCD4+ cell counts. Thus, although restoring deficient suppressor clones may provide a full recovery in animals, the high prevalence of T-cell repertoire contraction in humans with rheumatoid arthritis may severely limit the beneficial effects of this therapeutic approach.

  6. Effect of changes in human ecology and behavior on patterns of sexually transmitted diseases, including human immunodeficiency virus infection.

    PubMed Central

    Wasserheit, J N

    1994-01-01

    The last 20 years have witnessed six striking changes in patterns of sexually transmitted diseases (STDs): emergence of new STD organisms and etiologies, reemergence of old STDs, shifts in the populations in which STDs are concentrated, shifts in the etiological spectra of STD syndromes, alterations in the incidence of STD complications, and increases in antimicrobial resistance. For example, human immunodeficiency virus (HIV) emerged to devastate the United States with a fatal pandemic involving at least 1 million people. The incidence of syphilis rose progressively after 1956 to reach a 40-year peak by 1990. In both cases, disease patterns shifted from homosexual men to include minority heterosexuals. Over the last decade, gonorrhea became increasingly concentrated among adolescents, and several new types of antimicrobial resistance appeared. Three interrelated types of environments affect STD patterns. The microbiologic, hormonal, and immunologic microenvironments most directly influence susceptibility, infectiousness, and development of sequelae. These microenvironments are shaped, in part, by the personal environments created by an individual's sexual, substance-use, and health-related behaviors. The personal environments are also important determinants of acquisition of infection and development of sequelae but, in addition, they mediate risk of exposure to infection. These are, therefore, the environments that most directly affect changing disease patterns. Finally, individuals' personal environments are, in turn, molded by powerful macroenvironmental forces, including socioeconomic, demographic, geographic, political, epidemiologic, and technological factors. Over the past 20 years, the profound changes that have occurred in many aspects of the personal environment and the macroenvironment have been reflected in new STD patterns. PMID:8146135

  7. The Role of Bitter and Sweet Taste Receptors in Upper Airway Immunity

    PubMed Central

    Workman, Alan D.; Palmer, James N.; Adappa, Nithin D.

    2016-01-01

    Over the past several years, taste receptors have emerged as key players in the regulation of innate immune defenses in the mammalian respiratory tract. Several cell types in the airway, including ciliated epithelial cells, solitary chemosensory cells, and bronchial smooth muscle cells, all display chemoresponsive properties that utilize taste receptors. A variety of bitter products secreted by microbes are detected with resultant downstream inflammation, increased mucous clearance, antimicrobial peptide secretion, and direct bacterial killing. Genetic variation of bitter taste receptors also appears to play a role in the susceptibility to infection in respiratory disease states, including that of chronic rhinosinusitis. Ongoing taste receptor research may yield new therapeutics that harness innate immune defenses in the respiratory tract and may offer alternatives to antibiotic treatment. The present review discusses taste receptor-protective responses and analyzes the role these receptors play in mediating airway immune function. PMID:26492878

  8. The Role of Bitter and Sweet Taste Receptors in Upper Airway Immunity.

    PubMed

    Workman, Alan D; Palmer, James N; Adappa, Nithin D; Cohen, Noam A

    2015-12-01

    Over the past several years, taste receptors have emerged as key players in the regulation of innate immune defenses in the mammalian respiratory tract. Several cell types in the airway, including ciliated epithelial cells, solitary chemosensory cells, and bronchial smooth muscle cells, all display chemoresponsive properties that utilize taste receptors. A variety of bitter products secreted by microbes are detected with resultant downstream inflammation, increased mucous clearance, antimicrobial peptide secretion, and direct bacterial killing. Genetic variation of bitter taste receptors also appears to play a role in the susceptibility to infection in respiratory disease states, including that of chronic rhinosinusitis. Ongoing taste receptor research may yield new therapeutics that harness innate immune defenses in the respiratory tract and may offer alternatives to antibiotic treatment. The present review discusses taste receptor-protective responses and analyzes the role these receptors play in mediating airway immune function.

  9. Regulation of airway surface liquid volume and mucus transport by active ion transport.

    PubMed

    Tarran, Robert

    2004-01-01

    Mucus clearance is an important component of the lung's innate defense against disease, and the ability of the airways to clear mucus is strongly dependent on the volume of liquid on airway surfaces. Whether airway surface liquid (ASL) volume is maintained by passive surface forces or by active ion transport is controversial yet crucial to the understanding of how this system operates in both health and disease. In support of active ion transport being the major determinant of ASL volume, we have demonstrated that normal airway epithelia sense and autoregulate ASL height (volume) by adjusting the rates of Na+ absorption and Cl- secretion to maintain mucus transport.

  10. Phosphodiesterase 4 inhibitors augment the ability of formoterol to enhance glucocorticoid-dependent gene transcription in human airway epithelial cells: a novel mechanism for the clinical efficacy of roflumilast in severe chronic obstructive pulmonary disease.

    PubMed

    Moodley, Thunicia; Wilson, Sylvia M; Joshi, Taruna; Rider, Christopher F; Sharma, Pawan; Yan, Dong; Newton, Robert; Giembycz, Mark A

    2013-04-01

    Post-hoc analysis of two phase III clinical studies found that the phosphodiesterase 4 (PDE4) inhibitor, roflumilast, reduced exacerbation frequency in patients with severe chronic obstructive pulmonary disease (COPD) who were taking inhaled corticosteroids (ICS) concomitantly, whereas patients not taking ICS derived no such benefit. In contrast, in two different trials also performed in patients with severe COPD, roflumilast reduced exacerbation rates in the absence of ICS, indicating that PDE4 inhibition alone is sufficient for therapeutic activity to be realized. Given that roflumilast is recommended as an "add-on" medication to patients with severe disease who will inevitably be taking a long-acting β2-adrenoceptor agonist (LABA)/ICS combination therapy, we tested the hypothesis that roflumilast augments the ability of glucocorticoids to induce genes with anti-inflammatory activity. Using a glucocorticoid response element (GRE) luciferase reporter transfected into human airway epithelial cells [both bronchial epithelium + adenovirus 12 - SV40 hybrid (BEAS-2B) cells and primary cultures], roflumilast enhanced fluticasone propionate-induced GRE-dependent transcription. Roflumilast also produced a sinistral displacement of the concentration-response curves that described the augmentation of GRE-dependent transcription by the LABA formoterol. In BEAS-2B cells and primary airway epithelia, roflumilast interacted with formoterol in a positive cooperative manner to enhance the expression of several glucocorticoid-inducible genes that have anti-inflammatory potential. We suggest that the ability of roflumilast and formoterol to interact in this way supports the concept that these drugs together may impart clinical benefit beyond that achievable by an ICS alone, a PDE4 inhibitor alone, or an ICS/LABA combination therapy. Roflumilast may, therefore, be especially effective in patients with severe COPD.

  11. CD38 and airway hyper-responsiveness: studies on human airway smooth muscle cells and mouse models.

    PubMed

    Guedes, Alonso G P; Deshpande, Deepak A; Dileepan, Mythili; Walseth, Timothy F; Panettieri, Reynold A; Subramanian, Subbaya; Kannan, Mathur S

    2015-02-01

    Asthma is an inflammatory disease in which altered calcium regulation, contractility, and airway smooth muscle (ASM) proliferation contribute to airway hyper-responsiveness and airway wall remodeling. The enzymatic activity of CD38, a cell-surface protein expressed in human ASM cells, generates calcium mobilizing second messenger molecules such as cyclic ADP-ribose. CD38 expression in human ASM cells is augmented by cytokines (e.g., TNF-α) that requires the activation of MAP kinases and the transcription factors, NF-κB and AP-1, and is post-transcriptionally regulated by miR-140-3p and miR-708 by binding to 3' Untranslated Region of CD38 as well as by modulating the activation of signaling mechanisms involved in its regulation. Mice deficient in Cd38 exhibit reduced airway responsiveness to inhaled methacholine relative to the response in wild-type mice. Intranasal challenge of Cd38-deficient mice with TNF-α or IL-13, or the environmental fungus Alternaria alternata, causes significantly attenuated methacholine responsiveness compared with wild-type mice, with comparable airway inflammation. Reciprocal bone marrow transfer studies revealed partial restoration of airway hyper-responsiveness to inhaled methacholine in the Cd38-deficient mice. These studies provide evidence for CD38 involvement in the development of airway hyper-responsiveness; a hallmark feature of asthma. Future studies aimed at drug discovery and delivery targeting CD38 expression and (or) activity are warranted.

  12. Airway mucus: From production to secretion.

    PubMed

    Williams, Olatunji W; Sharafkhaneh, Amir; Kim, Victor; Dickey, Burton F; Evans, Christopher M

    2006-05-01

    Mucus hypersecretion is a phenotype associated with multiple obstructive lung diseases. However, in spite of its nefarious reputation under pathologic conditions, there are significant benefits to having low levels of mucus present in the airways at baseline, such as the ability to trap and eliminate inhaled particles and to prevent desiccation of airway surfaces. Mucins are high-molecular-weight glycoproteins that are the chief components that render viscoelastic and gel-forming properties to mucus. Recent advances in animal models and in vitro systems have provided a wealth of information regarding the identification of the mucin genes that are expressed in the lungs, the signal transduction pathways that regulate the expression of these mucins, and the secretory pathways that mediate their release into the airways. In addition, the clinical and pathologic literature has corroborated many of the basic laboratory findings. As a result, mucin overproduction and hypersecretion are moving away from being markers of disease and toward being testable as functional components of lung disease processes.

  13. Glutathione redox regulates airway hyperresponsiveness and airway inflammation in mice.

    PubMed

    Koike, Yoko; Hisada, Takeshi; Utsugi, Mitsuyoshi; Ishizuka, Tamotsu; Shimizu, Yasuo; Ono, Akihiro; Murata, Yukie; Hamuro, Junji; Mori, Masatomo; Dobashi, Kunio

    2007-09-01

    Glutathione is the major intracellular redox buffer. We have shown that glutathione redox status, which is the balance between intracellular reduced (GSH) and oxidized (GSSG) glutathione, in antigen-presenting cells (APC) regulates the helper T cell type 1 (Th1)/Th2 balance due to the production of IL-12. Bronchial asthma is a typical Th2 disease. Th2 cells and Th2 cytokines are characteristic of asthma and trigger off an inflammation. Accordingly, we studied the effects of the intracellular glutathione redox status on airway hyperresponsiveness (AHR) and allergen-induced airway inflammation in a mouse model of asthma. We used gamma-Glutamylcysteinylethyl ester (gamma-GCE), which is a membrane-permeating GSH precursor, to elevate the intracellular GSH level and GSH/GSSG ratio of mice. In vitro, gamma-GCE pretreatment of human monocytic THP-1 cells elevated the GSH/GSSG ratio and enhanced IL-12(p70) production induced by LPS. In the mouse asthma model, intraperitoneal injection of gamma-GCE elevated the GSH/GSSG ratio of lung tissue and reduced AHR. gamma-GCE reduced levels of IL-4, IL-5, IL-10, and the chemokines eotaxin and RANTES (regulated on activation, normal T cell expressed and secreted) in bronchoalveolar lavage fluid, whereas it enhanced the production of IL-12 and IFN-gamma. Histologically, gamma-GCE suppressed eosinophils infiltration. Interestingly, we also found that gamma-GCE directly inhibited chemokine-induced eosinophil chemotaxis without affecting eotaxin receptor chemokine receptor 3 (CCR3) expressions. Taken together, these findings suggest that changing glutathione redox balance, increase in GSH level, and the GSH/GSSG ratio by gamma-GCE, ameliorate bronchial asthma by altering the Th1/Th2 imbalance through IL-12 production from APC and suppressing chemokine production and eosinophil migration itself.

  14. Surgical management of dysphagia and airway obstruction in patients with prominent ventral cervical osteophytes.

    PubMed

    Carlson, Matthew L; Archibald, David J; Graner, Darlene E; Kasperbauer, Jan L

    2011-03-01

    Large projecting ventral cervical osteophytes are associated with senile degenerative skeletal disease, post-traumatic osteophytogenesis, and diffuse idiopathic skeletal hyperostosis (DISH). The vast majority of patients with cervical osteophytes are asymptomatic. However, in a small subset this condition may lead to upper aerodigestive compromise manifesting as dysphagia and/or airway obstruction. Conservative medical therapy is usually sufficient, but patients with intractable disease may require surgical intervention, including tracheostomy, feeding tube placement, or osteophytectomy. A retrospective chart review was performed on all patients who presented to a tertiary referral center over a decade (1998-2008) with complaints of dysphagia and/or respiratory compromise and underwent osteophytectomy for treatment of recalcitrant symptoms. A total of nine patients met criteria. Six patients were diagnosed with DISH, two with trauma-associated osteophytogenesis, and one with senile degenerative vertebral disease. The mean age was 68 years and included seven males and two females. All patients had symptoms of dysphagia and two had simultaneous airway complaints. All patients underwent an anterolateral approach for osteophyte decompression, one of which required concurrent tracheostomy. Following surgery, 100% of patients had significant improvement in dysphagia and respiratory complaints. Eight of nine patients returned to an unrestricted diet and only one required postoperative abstinence from bulky foods; both patients with additional airway complaints were successfully decannulated after surgery. Degenerative conditions and DISH may lead to osteophyte-associated dysphagia and/or airway complaints. Surgical decompression through osteophytectomy is an effective alternative to tracheostomy and feeding tube in carefully selected patients and should be considered for surgically fit patients who fail conservative medical management.

  15. Role of non-coding RNAs in maintaining primary airway smooth muscle cells

    PubMed Central

    2014-01-01

    Background The airway smooth muscle (ASM) cell maintains its own proliferative rate and contributes to the inflammatory response in the airways, effects that are inhibited by corticosteroids, used in the treatment of airways diseases. Objective We determined the differential expression of mRNAs, microRNAs (miRNAs) and long noncoding RNA species (lncRNAs) in primary ASM cells following treatment with a corticosteroid, dexamethasone, and fetal calf serum (FCS). Methods mRNA, miRNA and lncRNA expression was measured by microarray and quantitative real-time PCR. Results A small number of miRNAs (including miR-150, −371-5p, −718, −940, −1181, −1207-5p, −1915, and −3663-3p) were decreased following exposure to dexamethasone and FCS. The mRNA targets of these miRNAs were increased in expression. The changes in mRNA expression were associated with regulation of ASM actin cytoskeleton. We also observed changes in expression of lncRNAs, including natural antisense, pseudogenes, intronic lncRNAs, and intergenic lncRNAs following dexamethasone and FCS. We confirmed the change in expression of three of these, LINC00882, LINC00883, PVT1, and its transcriptional activator, c-MYC. We propose that four of these lincRNAs (RP11-46A10.4, LINC00883, BCYRN1, and LINC00882) act as miRNA ‘sponges’ for 4 miRNAs (miR-150, −371-5p, −940, −1207-5p). Conclusion This in-vitro model of primary ASM cell phenotype was associated with the regulation of several ncRNAs. Their identification allows for in-vitro functional experimentation to establish causality with the primary ASM phenotype, and in airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). PMID:24886442

  16. Association between lung function and airway wall density

    NASA Astrophysics Data System (ADS)

    Leader, J. Ken; Zheng, Bin; Fuhrman, Carl R.; Tedrow, John; Park, Sang C.; Tan, Jun; Pu, Jiantao; Drescher, John M.; Gur, David; Sciurba, Frank C.

    2009-02-01

    Computed tomography (CT) examination is often used to quantify the relation between lung function and airway remodeling in chronic obstructive pulmonary disease (COPD). In this preliminary study, we examined the association between lung function and airway wall computed attenuation ("density") in 200 COPD screening subjects. Percent predicted FVC (FVC%), percent predicted FEV1 (FEV1%), and the ratio of FEV1 to FVC as a percentage (FEV1/FVC%) were measured post-bronchodilator. The apical bronchus of the right upper lobe was manually selected from CT examinations for evaluation. Total airway area, lumen area, wall area, lumen perimeter and wall area as fraction of the total airway area were computed. Mean HU (meanHU) and maximum HU (maxHU) values were computed across pixels assigned membership in the wall and with a HU value greater than -550. The Pearson correlation coefficients (PCC) between FVC%, FEV1%, and FEV1/FVC% and meanHU were -0.221 (p = 0.002), -0.175 (p = 0.014), and -0.110 (p = 0.123), respectively. The PCCs for maxHU were only significant for FVC%. The correlations between lung function and the airway morphometry parameters were slightly stronger compared to airway wall density. MeanHU was significantly correlated with wall area (PCC = 0.720), airway area (0.498) and wall area percent (0.611). This preliminary work demonstrates that airway wall density is associated with lung function. Although the correlations in our study were weaker than a recent study, airway wall density initially appears to be an important parameter in quantitative CT analysis of COPD.

  17. Model Selection and Evaluation Based on Emerging Infectious Disease Data Sets including A/H1N1 and Ebola

    PubMed Central

    Liu, Wendi; Tang, Sanyi; Xiao, Yanni

    2015-01-01

    The aim of the present study is to apply simple ODE models in the area of modeling the spread of emerging infectious diseases and show the importance of model selection in estimating parameters, the basic reproduction number, turning point, and final size. To quantify the plausibility of each model, given the data and the set of four models including Logistic, Gompertz, Rosenzweg, and Richards models, the Bayes factors are calculated and the precise estimates of the best fitted model parameters and key epidemic characteristics have been obtained. In particular, for Ebola the basic reproduction numbers are 1.3522 (95% CI (1.3506, 1.3537)), 1.2101 (95% CI (1.2084, 1.2119)), 3.0234 (95% CI (2.6063, 3.4881)), and 1.9018 (95% CI (1.8565, 1.9478)), the turning points are November 7,November 17, October 2, and November 3, 2014, and the final sizes until December 2015 are 25794 (95% CI (25630, 25958)), 3916 (95% CI (3865, 3967)), 9886 (95% CI (9740, 10031)), and 12633 (95% CI (12515, 12750)) for West Africa, Guinea, Liberia, and Sierra Leone, respectively. The main results confirm that model selection is crucial in evaluating and predicting the important quantities describing the emerging infectious diseases, and arbitrarily picking a model without any consideration of alternatives is problematic. PMID:26451161

  18. Airway Fibrinogenolysis and the Initiation of Allergic Inflammation

    PubMed Central

    Millien, Valentine Ongeri; Lu, Wen; Mak, Garbo; Yuan, Xiaoyi; Knight, J. Morgan; Porter, Paul; Kheradmand, Farrah

    2014-01-01

    The past 15 years of allergic disease research have produced extraordinary improvements in our understanding of the pathogenesis of airway allergic diseases such as asthma. Whereas it was previously viewed as largely an immunoglobulin E-mediated process, the gradual recognition that T cells, especially Type 2 T helper (Th2) cells and Th17 cells, play a major role in asthma and related afflictions has inspired clinical trials targeting cytokine-based inflammatory pathways that show great promise. What has yet to be clarified about the pathogenesis of allergic inflammatory disorders, however, are the fundamental initiating factors, both exogenous and endogenous, that drive and sustain B- and T-cell responses that underlie the expression of chronic disease. Here we review how proteinases derived from diverse sources drive allergic responses. A central discovery supporting the proteinase hypothesis of allergic disease pathophysiology is the role played by airway fibrinogen, which in part appears to serve as a sensor of unregulated proteinase activity and which, when cleaved, both participates in a novel allergic signaling pathway through Toll-like receptor 4 and forms fibrin clots that contribute to airway obstruction. Unresolved at present is the ultimate source of airway allergenic proteinases. From among many potential candidates, perhaps the most intriguing is the possibility such enzymes derive from airway fungi. Together, these new findings expand both our knowledge of allergic disease pathophysiology and options for therapeutic intervention. PMID:25525732

  19. Carinal and tubular airway particle concentrations in the large airways of non-smokers in the general population: evidence for high particle concentration at airway carinas.

    PubMed Central

    Churg, A; Vedal, S

    1996-01-01

    OBJECTIVE: To evaluate the extent to which human airway carinas accumulate ambient atmospheric particles, a newly developed technique was used to micro-dissect and analyse particle concentration in tubular segments and carinas of the large airways of 10 necropsy lungs from non-smokers from the general population of Vancouver. METHODS: Ratios of the particle concentrations on the carinas to the tubular segment immediately preceding it were measured with analytical electron microscopy for the mainstem bronchus, upper and lower lobe bronchi, and four different segmental or subsegmental bronchi--that is, Weibel generations 1 to about 5. A total of 119 carinal-tubular pairs was evaluated. RESULTS: Over all cases, both carinal and tubular particle concentrations increased with increasing airway generation; the median ratio of carinal to tubular particle concentration was 9:1 and did not show any trend with airway generation. The ratio was > 5 in 71% of carinal-tubular pairs, > 10 in 42% of pairs, > 20 in 31% of pairs, and > 100 in 9% of pairs. Some subjects showed a notable tendency to high ratios, with many ratios > 100, and other subjects had a tendency toward low ratios. The predominant mineral species in both carinas and tubular airway segments was crystalline silica and the relative proportion was similar in both sites; however, mean particle diameter was consistently less in the carinal tissues. CONCLUSIONS: These findings suggest that the ratio of carinal to tubular retained particles in the large airways in non-smokers is higher than might be supposed from data generated in airway casts, and that there is considerable variation in this ratio between subjects. This finding is of potential interest in models of carcinogen, toxin, and dose of fibrogenic agent to the large airways as it suggests high and sometimes extreme concentrations of toxic particles at carinas, and thus reinforces the notion that carinas may be sites of initiation of disease. PMID:8983467

  20. Action of N-acylated ambroxol derivatives on secretion of chloride ions in human airway epithelia.

    PubMed

    Yamada, Takahiro; Takemura, Yoshizumi; Niisato, Naomi; Mitsuyama, Etsuko; Iwasaki, Yoshinobu; Marunaka, Yoshinori

    2009-03-13

    We report the effects of new N-acylated ambroxol derivatives (TEI-588a, TEI-588b, TEI-589a, TEI-589b, TEI-602a and TEI-602b: a, aromatic amine-acylated derivative; b, aliphatic amine-acylated derivative) induced from ambroxol (a mucolytic agent to treat human lung diseases) on Cl(-) secretion in human submucosal serous Calu-3 cells under a Na(+)/K(+)/2Cl(-) cotransporter-1 (NKCC1)-mediated hyper-secreting condition. TEI-589a, TEI-589b and TEI-602a diminished hyper-secretion of Cl(-) by diminishing the activity of NKCC1 without blockade of apical Cl(-) channel (TEI-589a>TEI-602a>TEI-589b), while any other tested compounds including ambroxol had no effects on Cl(-) secretion. These indicate that the inhibitory action of an aromatic amine-acylated derivative on Cl(-) secretion is stronger that that of an aliphatic amine-acylated derivative, and that 3-(2,5-dimethyl)furoyl group has a strong action in inhibition of Cl(-) secretion than cyclopropanoyl group. We here indicate that TEI-589a, TEI-589b and TEI-602a reduce hyper-secretion to an appropriate level in the airway, providing a possibility that the compound can be an effective drug in airway obstructive diseases including COPD by reducing the airway resistance under a hyper-secreting condition.

  1. Airway reopening: Steadily propagating bubbles in buckled elastic tubes

    NASA Astrophysics Data System (ADS)

    Heil, Matthias; Hazel, Andrew L.

    2001-11-01

    Many pulmonary diseases result in the collapse and occlusion of parts of the lung by viscous fluid. The subsequent airway reopening is generally assumed to occur via the propagation of an air finger into the collapsed, fluid-filled part of the airway. The problem has some similarity to the scenario of the `first breath' when air has to enter the fluid-filled lungs of a newborn baby for the first time. We have developed the first three-dimensional computational model of airway reopening, based on a finite-element solution of the free-surface Stokes equations, fully coupled to the equations of large-displacement shell theory. Following a brief discussion of the numerical method, we will present results that illustrate the 3D flow field by which the steadily propagating air finger reopens the non-axisymmetrically collapsed airway. Finally, we will contrast the system's behaviour to predictions from earlier two-dimensional models.

  2. Control of local immunity by airway epithelial cells.

    PubMed

    Weitnauer, M; Mijošek, V; Dalpke, A H

    2016-03-01

    The lung is ventilated by thousand liters of air per day. Inevitably, the respiratory system comes into contact with airborne microbial compounds, most of them harmless contaminants. Airway epithelial cells are known to have innate sensor functions, thus being able to detect microbial danger. To avoid chronic inflammation, the pulmonary system has developed specific means to control local immune responses. Even though airway epithelial cells can act as proinflammatory promoters, we propose that under homeostatic conditions airway epithelial cells are important modulators of immune responses in the lung. In this review, we discuss epithelial cell regulatory functions that control reactivity of professional immune cells within the microenvironment of the airways and how these mechanisms are altered in pulmonary diseases. Regulation by epithelial cells can be divided into two mechanisms: (1) mediators regulate epithelial cells' innate sensitivity in cis and (2) factors are produced that limit reactivity of immune cells in trans.

  3. Functional imaging using computer methods to compare the effect of salbutamol and ipratropium bromide in patient-specific airway models of COPD

    PubMed Central

    De Backer, LA; Vos, WG; Salgado, R; De Backer, JW; Devolder, A; Verhulst, SL; Claes, R; Germonpré, PR; De Backer, WA

    2011-01-01

    Background Salbutamol and ipratropium bromide improve lung function in patients with chronic obstructive pulmonary disease (COPD). However, their bronchodilating effect has not yet been compared in the central and distal airways. Functional imaging using computational fluid dynamics offers the possibility of making such a comparison. The objective of this study was to assess the effects of salbutamol and ipratropium bromide on the geometry and computational fluid dynamics-based resistance of the central and distal airways. Methods Five patients with Global Initiative for Chronic Obstructive Lung Disease Stage III COPD were randomized to a single dose of salbutamol or ipratropium bromide in a crossover manner with a 1-week interval between treatments. Patients underwent lung function testing and a multislice computed tomography scan of the thorax that was used for functional imaging. Two hours after dosing, the patients again underwent lung function tests and repeat computed tomography. Results Lung function parameters, including forced expiratory volume in 1 second, vital capacity, overall airway resistance, and specific airway resistance, changed significantly after administration of each product. On functional imaging, the bronchodilating effect was greater in the distal airways, with a corresponding drop in airway resistance, compared with the central airways. Salbutamol and ipratropium bromide were equally effective at first glance when looking at lung function tests, but when viewed in more detail with functional imaging, hyporesponsiveness could be shown for salbutamol in one patient. Salbutamol was more effective in the other patients. Conclusion This pilot study gives an innovative insight into the modes of action of salbutamol and ipratropium bromide in patients with COPD, using the new techniques of functional imaging and computational fluid dynamics. PMID:22162649

  4. Comparison of laryngeal mask airway vs tracheal intubation: a systematic review on airway complications.

    PubMed

    van Esch, Babette F; Stegeman, Inge; Smit, Adriana L

    2017-02-01

    To determine whether the laryngeal mask airway (LMA) has advantages over the tracheal tube (TT) in terms of incidence of cough, sore throat, laryngospasm, dysphagia, dysphonia, and blood staining. This is a systematic literature review performed at the Universtity Medical Center of Utrecht. The online databases PubMed, Embase, and the Cochrane Library were searched for relevant randomized controlled trials. Two independent reviewers selected relevant articles after title, abstract, and full text screening. Articles were assessed on risk of bias in accordance with the Cochrane risk of bias tool. Study results of the LMA and the TT were related to the method of selection of the device size and the method for cuff inflation. Of the 1718 unique articles, we included 19 studies which used the LMA Classic, the LMA Proseal, the Flexible Reinforced LMA, and the LMA Supreme compared with TT. After methodological inspection, data could not be pooled due to heterogeneity among the selected studies. Overall, no clear advantage of the LMA over the TT was found but the LMA Supreme was related to the lowest incidence of airway complications. In this review, no clear difference in incidence of postoperative airway complications could be demonstrated between LMA and TT. The LMA Supreme may reduce the incidence of airway complication in comparison to the TT but high quality randomized trials are recommended to further objectify if use of the LMA decreases the risk on postoperative airway complications.

  5. Protein tyrosine phosphatase SHP2 regulates TGF-β1 production in airway epithelia and asthmatic airway remodeling in mice

    PubMed Central

    Qin, X.-J.; Zhang, G.-S.; Zhang, X.; Qiu, Z.-W.; Wang, P.-L.; Li, Y.-W.; Li, W.; Xie, Q.-M.; Ke, Y.-H.; Lee, J. J.; Shen, H.-H.

    2014-01-01

    Background Transforming growth factor (TGF)-β1 produced in airway epithelia has been suggested as a contributor to the airway remodeling observed in asthma patients. The protein tyrosine phosphatase SHP2 is a demonstrable modulator of TGF-β1 production and thus a potential regulator of airway remodeling. Objectives To define the signal event by which SHP2 regulates asthmatic responses in airway epithelial cells by using a mouse model of experimental OVA-induced airway remodeling. Methods The airways of Shp2flox/flox mice were infected with recombinant adenovirus vectors expressing a Cre recombinase–green fluorescence protein (GFP) fusion protein as part of allergen provocation studies using mice sensitized with ovalbumin (OVA) and repeatedly challenged with OVA. Several endpoint pathologies were assessed, including airway hyper-responsiveness (AHR), lung inflammatory score, peribronchial collagen deposition, and α-smooth muscle actin (SMA) hyperplasia. In vitro studies using airway epithelial cells (BEAS-2B) were used to investigate the role of SHP2 in the regulation of pulmonary remodeling events, including the expression of collagen, α-SMA, and TGF-β1. Results Chronic OVA challenges in wild-type mice resulted in airway remodeling and lung dysfunction (e.g., increased inflammatory scores, collagen deposition (fibrosis), smooth muscle hyperplasia, and a significant increase in AHR). These endpoint pathology metrics were each significantly attenuated by conditional shp2 gene knockdown in airway epithelia. In vitro studies using BEAS-2B cells also demonstrated that the level of TGF-β1 production by these cells correlated with the extent of shp2 gene expression. Conclusions SHP2 activities in airway epithelial cells appear to modulate TGF-β1 production and, in turn, regulate allergic airway remodeling following allergen provocation. Clinical Implications Our findings identify SHP2 as a previously underappreciated contributor to the airway remodeling and lung

  6. Tay-Sachs Disease

    MedlinePlus

    ... supportive treatment includes proper nutrition and hydration and techniques to keep the airway open. Children may eventually need a ... supportive treatment includes proper nutrition and hydration and techniques to keep the airway open. Children may eventually need a ...

  7. Airway Management in a Patient with Wolf-Hirschhorn Syndrome

    PubMed Central

    Udani, Andrea G.

    2016-01-01

    We present a case of a 3-month-old female with Wolf-Hirschhorn syndrome (WHS) undergoing general anesthesia for laparoscopic gastrostomy tube placement with a focus on airway management. WHS is a rare 4p microdeletion syndrome resulting in multiple congenital abnormalities, including craniofacial deformities. Microcephaly, micrognathia, and glossoptosis are common features in WHS patients and risk factors for a pediatric airway that is potentially difficult to intubate. We discuss anesthesia strategies for airway preparation and management in a WHS patient requiring general anesthesia with endotracheal intubation. PMID:27752382

  8. Relationship between lung function and quantitative computed tomographic parameters of airway remodeling, air trapping, and emphysema in patients with asthma and chronic obstructive pulmonary disease: A single-center study

    PubMed Central

    Hartley, Ruth A.; Barker, Bethan L.; Newby, Chris; Pakkal, Mini; Baldi, Simonetta; Kajekar, Radhika; Kay, Richard; Laurencin, Marie; Marshall, Richard P.; Sousa, Ana R.; Parmar, Harsukh; Siddiqui, Salman; Gupta, Sumit; Brightling, Chris E.

    2016-01-01

    Background There is a paucity of studies comparing asthma and chronic obstructive pulmonary disease (COPD) based on thoracic quantitative computed tomographic (QCT) parameters. Objectives We sought to compare QCT parameters of airway remodeling, air trapping, and emphysema between asthmatic patients and patients with COPD and explore their relationship with airflow limitation. Methods Asthmatic patients (n = 171), patients with COPD (n = 81), and healthy subjects (n = 49) recruited from a single center underwent QCT and clinical characterization. Results Proximal airway percentage wall area (%WA) was significantly increased in asthmatic patients (62.5% [SD, 2.2]) and patients with COPD (62.7% [SD, 2.3]) compared with that in healthy control subjects (60.3% [SD, 2.2], P < .001). Air trapping measured based on mean lung density expiratory/inspiratory ratio was significantly increased in patients with COPD (mean, 0.922 [SD, 0.037]) and asthmatic patients (mean, 0.852 [SD, 0.061]) compared with that in healthy subjects (mean, 0.816 [SD, 0.066], P < .001). Emphysema assessed based on lung density measured by using Hounsfield units below which 15% of the voxels lie (Perc15) was a feature of COPD only (patients with COPD: mean, −964 [SD, 19.62] vs asthmatic patients: mean, −937 [SD, 22.7] and healthy subjects: mean, −937 [SD, 17.1], P < .001). Multiple regression analyses showed that the strongest predictor of lung function impairment in asthmatic patients was %WA, whereas in the COPD and asthma subgrouped with postbronchodilator FEV1 percent predicted value of less than 80%, it was air trapping. Factor analysis of QCT parameters in asthmatic patients and patients with COPD combined determined 3 components, with %WA, air trapping, and Perc15 values being the highest loading factors. Cluster analysis identified 3 clusters with mild, moderate, or severe lung function impairment with corresponding decreased lung density (Perc15 values) and increased air

  9. Effect of a mucoactive compound (CO 1408) on airway hyperreactivity and inflammation induced by passive cigarette smoke exposure in guinea-pigs.

    PubMed

    Hernandez, A; Daffonchio, L; Brandolini, L; Zuccari, G

    1994-04-01

    Environmental exposure to tobacco smoke contributes to the onset of several lung diseases, e.g. chronic bronchitis and asthma, including an increase in airway reactivity. We have investigated the effect of a new mucoactive compound, CO 1408, on airway hyperreactivity and lung inflammation induced in guinea-pigs by passive cigarette smoke exposure. Animals were exposed to cigarette smoke in a Plexi-glass box, three times a day for four days. Airway reactivity to histamine was assessed ex-vivo in lung parenchymal strips. As a measure of lung inflammation, the number of leucocytes was evaluated in bronchoalveolar lavage (BAL) fluids and histological sections. Passive smoke exposure potentiated histamine-induced contraction in lung parenchymal strips, a phenomenon associated with an increase in proinflammatory cells in the BAL fluids and enhanced eosinophil infiltration into parenchymal tissues. Pretreatment with oral CO 1408 at 400 mg.kg-1 but not 100 mg.kg-1, completely prevented the cigarette smoke-induced airway hyperreactivity. 400 mg.kg-1 CO 1408 also inhibited the increase in cell numbers in the BAL fluids, but not eosinophil recruitment in parenchymal tissues. The present data indicate the ability of CO 1408 to modulate smoke-induced airway hyperreactivity and, to some extent, lung inflammation, an effect which might be of value in the therapy of obstructive pulmonary diseases.

  10. Upper airway segmentation and measurement in MRI using fuzzy connectedness

    NASA Astrophysics Data System (ADS)

    Liu, Jianguo; Udupa, Jayaram K.; Odhner, Dewey; McDonough, Joe M.; Arens, Raanan

    2002-04-01

    The purpose of this work is to build a computerized system for the delineation of upper airway structures via MRI and to evaluate its effectiveness for routine clinical use in aiding diagnosis of upper airway disorders in children. We use two MRI protocols, axial T1 and T2, to gather information about different aspects of the airway and its surrounding soft tissue structures including adenoid, tonsils, tongue and soft palate. These images are processed and segmented to compute the architectural parameters of the airway such as its surface description, volume, central (medial) line, and cross-sectional areas at planes orthogonal to the central line. We have built a software package based on 3DVIEWNIX and running on a 450 MHz Pentium PC under Linux system (and on a Sun workstation under Unix) for the various operations of visualization, segmentation, registration, prefiltering, interpolation, standardization, and quantitative analysis of the airway. The system has been tested utilizing 40 patient studies. For every study, the system segmented and displayed a smooth 3D rendition of the airway, its central line and a plot of the cross-sectional area of the airway orthogonal to the central line as a function of the distance from one end of the central line. The tests indicate 97% precision and accuracy for segmentation. The mean time taken per study is about 4 minutes for the airway. This includes operator interaction time and processing time. This method provides a robust and fast means of assessing the airway size, shape, and places of restriction, as well as providing a structural data set suitable for use in modeling studies of airflow and mechanics.

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

    EPA Pesticide Factsheets

    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