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Sample records for airway hyper-responsiveness ahr

  1. Multiple exposures to swine barn air induce lung inflammation and airway hyper-responsiveness

    PubMed Central

    Charavaryamath, Chandrashekhar; Janardhan, Kyathanahalli S; Townsend, Hugh G; Willson, Philip; Singh, Baljit

    2005-01-01

    Background Swine farmers repeatedly exposed to the barn air suffer from respiratory diseases. However the mechanisms of lung dysfunction following repeated exposures to the barn air are still largely unknown. Therefore, we tested a hypothesis in a rat model that multiple interrupted exposures to the barn air will cause chronic lung inflammation and decline in lung function. Methods Rats were exposed either to swine barn (8 hours/day for either one or five or 20 days) or ambient air. After the exposure periods, airway hyper-responsiveness (AHR) to methacholine (Mch) was measured and rats were euthanized to collect bronchoalveolar lavage fluid (BALF), blood and lung tissues. Barn air was sampled to determine endotoxin levels and microbial load. Results The air in the barn used in this study had a very high concentration of endotoxin (15361.75 ± 7712.16 EU/m3). Rats exposed to barn air for one and five days showed increase in AHR compared to the 20-day exposed and controls. Lungs from the exposed groups were inflamed as indicated by recruitment of neutrophils in all three exposed groups and eosinophils and an increase in numbers of airway epithelial goblet cells in 5- and 20-day exposure groups. Rats exposed to the barn air for one day or 20 days had more total leukocytes in the BALF and 20-day exposed rats had more airway epithelial goblet cells compared to the controls and those subjected to 1 and 5 exposures (P < 0.05). Bronchus-associated lymphoid tissue (BALT) in the lungs of rats exposed for 20 days contained germinal centers and mitotic cells suggesting activation. There were no differences in the airway smooth muscle cell volume or septal macrophage recruitment among the groups. Conclusion We conclude that multiple exposures to endotoxin-containing swine barn air induce AHR, increase in mucus-containing airway epithelial cells and lung inflammation. The data also show that prolonged multiple exposures may also induce adaptation in AHR response in the exposed

  2. Alterations of the Lung Methylome in Allergic Airway Hyper-Responsiveness

    PubMed Central

    Cheng, Robert YS; Shang, Yan; Limjunyawong, Nathachit; Dao, Tyna; Das, Sandhya; Rabold, Richard; Sham, James SK; Mitzner, Wayne; Tang, Wan-Yee

    2014-01-01

    Asthma is a chronic airway disorder characterized by recurrent attacks of breathlessness and wheezing, affecting 300 million people around the world (available at: www.who.int). To date, genetic factors associated with asthma susceptibility have been unable to explain the full etiology of asthma. Recent studies have demonstrated that the epigenetic disruption of gene expression plays an equally important role in the development of asthma through interaction with our environment. We sensitized 6-week-old C57BL/6J mice with house-dust-mite (HDM) extracts intraperitoneally followed by 5 weeks of exposure to HDM challenges (three times a week) intratracheally. HDM-exposed mice showed an increase in airway hyper-responsiveness (AHR) and inflammation together with structural remodeling of the airways. We applied methylated DNA immunoprecipitation-next generation sequencing (MeDIP-seq) for profiling of DNA methylation changes in the lungs in response to HDM. We observed about 20 million reads by a single-run of massive parallel sequencing. We performed bioinformatics and pathway analysis on the raw sequencing data to identify differentially methylated candidate genes in HDM-exposed mice. Specifically, we have revealed that the transforming growth factor beta signaling pathway is epigenetically modulated by chronic exposure to HDM. Here, we demonstrated that a specific allergen may play a role in AHR through an epigenetic mechanism by disrupting the expression of genes in lungs that might be involved in airway inflammation and remodeling. Our findings provide new insights into the potential mechanisms by which environmental allergens induce allergic asthma and such insights may assist in the development of novel preventive and therapeutic options for this debilitative disease. PMID:24446183

  3. Proximity to major roadways is a risk factor for airway hyper-responsiveness in adults

    PubMed Central

    Riley, Shannon; Wallace, Julie; Nair, Parameswaran

    2012-01-01

    BACKGROUND: Proximity to major roads is reported to be associated with asthma and airway hyper-responsiveness in children. Similar studies using objective measurements in adults are not available in Canada. OBJECTIVE: To test the hypothesis that adult asthmatic patients who live close to major roads and highways in an urban environment are at a risk of moderate to severe airway hyper-responsiveness. METHODS: Airway responsiveness was determined using methacholine bronchial provocation (PC20) tests in a cohort of 2625 patients who attended an outpatient clinic in Hamilton, Ontario. Patient addresses were geocoded in a geographic information system to determine proximity to major roads and highways. Multivariate linear and multinomial regression analyses were used to assess whether proximity to roads was a risk factor for airway hyper-responsiveness as measured by PC20 methacholine. RESULTS: Patients who lived within 200 m of a major road had increased odds (OR 1.38 [95% CI 1.04 to 1.85]) of having moderate airway hyper-responsiveness (0.25 mg/mL 16 mg/mL). Spatial analysis also revealed that the majority of patients with severe airway hyper-responsiveness lived within the urban core of the city while those with moderate to mild hyper-responsiveness were also dispersed in rural areas. CONCLUSIONS: In an adult population of patients attending an outpatient respiratory clinic in Hamilton, living close to major roadways was associated with an increased risk of moderate airway hyper-responsiveness. This correlation suggests that exposure to traffic emissions may provoke the pathology of airway hyper-responsiveness leading to variable airflow obstruction. PMID:22536577

  4. Curine inhibits eosinophil activation and airway hyper-responsiveness in a mouse model of allergic asthma

    SciTech Connect

    Ribeiro-Filho, Jaime; Calheiros, Andrea Surrage; Vieira-de-Abreu, Adriana; Moraes de Carvalho, Katharinne Ingrid; Silva Mendes, Diego da; Melo, Christianne Bandeira; Martins, Marco Aurélio; Silva Dias, Celidarque da; Piuvezam, Márcia Regina; and others

    2013-11-15

    Allergic asthma is a chronic inflammatory airway disease with increasing prevalence around the world. Current asthma therapy includes drugs that usually cause significant side effects, justifying the search for new anti-asthmatic drugs. Curine is a bisbenzylisoquinoline alkaloid that modulates calcium influx in many cell types; however, its anti-allergic and putative toxic effects remain to be elucidated. Our aim was to investigate the effects of curine on eosinophil activation and airway hyper-responsiveness (AHR) and to characterize its potential toxic effects. We used a mouse model of allergic asthma induced by sensitization and challenge with ovalbumin (OVA) to evaluate the anti-allergic effects of oral treatment with curine. The oral administration of curine significantly inhibited eosinophilic inflammation, eosinophil lipid body formation and AHR in animals challenged with OVA compared with animals in the untreated group. The curine treatment also reduced eotaxin and IL-13 production triggered by OVA. Verapamil, a calcium channel antagonist, had similar anti-allergic properties, and curine pre-treatment inhibited the calcium-induced tracheal contractile response ex-vivo, suggesting that the mechanism by which curine exerts its effects is through the inhibition of a calcium-dependent response. A toxicological evaluation showed that orally administered curine did not significantly alter the biochemical, hematological, behavioral and physical parameters measured in the experimental animals compared with saline-treated animals. In conclusion, curine showed anti-allergic activity through mechanisms that involve inhibition of IL-13 and eotaxin and of Ca{sup ++} influx, without inducing evident toxicity and as such, has the potential for the development of anti-asthmatic drugs. - Highlights: • Curine is a bisbenzylisoquinoline alkaloid from Chondrodendron platyphyllum. • Curine inhibits eosinophil influx and activation and airway hyper-responsiveness. • Curine

  5. Influenza A infection enhances antigen-induced airway inflammation and hyper-responsiveness in young but not aged mice

    PubMed Central

    Birmingham, Janette M.; Gillespie, Virginia L.; Srivastava, Kamal; Li, Xiu-Min; Busse, Paula J.

    2015-01-01

    Background Although morbidity and mortality rates from asthma are highest in patients > 65 years of age, the effect of older age on airway inflammation in asthma is not well established. Objective To investigate age-related differences in the promotion of allergic inflammation after influenza A viral respiratory infection on antigen specific IgE production, antigen-induced airway inflammation and airway hyper-responsiveness in mice. Methods To accomplish this objective, the following model system was used. Young (six-week) and aged (18-month) BALB/c mice were first infected with a non-lethal dose of influenza virus A (H/HK×31). Mice were then ovalbumin (OVA) sensitized during the acute-infection (3-days post inoculation) and then chronically underwent challenge to the airways with OVA. Forty-eight hours after the final OVA-challenge, airway hyperresponsiveness (AHR), bronchoalveolar fluid (BALF) cellular and cytokine profile, antigen-specific IgE and IgG1, and lung tissue inflammation were measured. Results Age-specific differences were noted on the effect of a viral infection, allergic sensitization, airway inflammation and airway hyperresponsiveness. Serum OVA-specific IgE was significantly increased in only the aged mice infected with influenza virus. Despite greater morbidity (e.g. weight loss and sickness scores) during the acute infection in the 18-month old mice that were OVA-sensitized there was little effect on the AHR and BALF cellular differential. In contrast, BALF neutrophils and AHR increased, but eosinophils decreased in 6-week mice that were OVA-sensitized during an acute influenza infection. Conclusion With increased age in a mouse model, viral infection prior to antigen sensitization affects the airway and systemic allergic response differently. These differences may reflect distinct phenotypic features of allergic inflammation in older patients with asthma PMID:25039815

  6. Parental and neonatal risk factors for atopy, airway hyper-responsiveness, and asthma.

    PubMed Central

    Sears, M R; Holdaway, M D; Flannery, E M; Herbison, G P; Silva, P A

    1996-01-01

    BACKGROUND: Previous studies have not resolved the importance of several potential risk factors for the development of childhood atopy, airway hyperresponsiveness, and wheezing, which would allow the rational selection of interventions to reduce morbidity from asthma. Risk factors for these disorders were examined in a birth cohort of 1037 New Zealand children. METHODS: Responses to questions on respiratory symptoms and measurements of lung function and airway responsiveness were obtained every two to three years throughout childhood and adolescence, with over 85% cohort retention at age 18 years. Atopy was determined by skin prick tests at age 13 years. Relations between parental and neonatal factors, the development of atopy, and features of asthma were determined by comparison of proportions and logistic regression. RESULTS: Male sex was a significant independent predictor for atopy, airway hyper-responsiveness, hay fever, and asthma. A positive family history, especially maternal, of asthma strongly predicted childhood atopy, airway hyperresponsiveness, asthma, and hay fever. Maternal smoking in the last trimester was correlated with the onset of childhood asthma by the age of 1 year. Birth in the winter season increased the risk of sensitisation to cats. Among those with a parental history of asthma or hay fever, birth in autumn and winter also increased the risk of sensitisation to house dust mites. The number of siblings, position in the family, socioeconomic status, and birth weight were not consistently predictive of any characteristic of asthma. CONCLUSIONS: Male sex, parental atopy, and maternal smoking during pregnancy are risk factors for asthma in young children. Children born in winter exhibit a greater prevalence of sensitisation to cats and house dust mites. These data suggest possible areas for intervention in children at risk because of parental atopy. PMID:8957951

  7. Inhallation of e-Cigarette Cartridge Solution Aggravates Allergen-induced Airway Inflammation and Hyper-responsiveness in Mice

    PubMed Central

    Kim, Seung Hyung

    2014-01-01

    Electronic cigarettes (e-cigarettes) are becoming increasingly popular worldwide and their cellular effects warrant further evaluation. In this study, we investigated the effects of an e-cigarette cartridge solution on allergen related asthmatic airway inflammation (AI) and airway hyperresponsiveness (AHR), when it is delivered by intratracheal route in mice. Asthmatic AI and AHR were induced by systemic sensitization to ovalbumin (OVA) followed by intratracheal, intraperitoneal, and aerosol allergen challenges in BALB/c mice. The cartridge solution of e-cigarette (containing 16 mg/ml nicotine) was diluted 50 times and 100 μl of the diluted solution was intratracheally instilled to OVA-sensitized (OVA-S) mice two times a week for 10 weeks. Long-term e-cigarette inhalation elicited no remarkable changes in the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase enzymes in serum, however, increased infiltration of inflammatory cells including eosinophils, into airways from blood, aggravated the asthmatic AI and AHR, and stimulated the production of cytokines such as interleukin (IL)-4, IL-5 and IL-13, and OVA-specific IgE production. Our data suggest that the inhalation of e-cigarette solutions can function as an important factor to exacerbate the allergy-induced asthma symptoms. Further studies are needed to address the effects of e-cigarette solutions on human health. PMID:24795794

  8. Bromodomain and Extra Terminal (BET) Inhibitor Suppresses Macrophage-Driven Steroid-Resistant Exacerbations of Airway Hyper-Responsiveness and Inflammation

    PubMed Central

    Nguyen, Thi Hiep; Maltby, Steven; Eyers, Fiona; Foster, Paul S.; Yang, Ming

    2016-01-01

    Background Exacerbations of asthma are linked to significant decline in lung function and are often poorly controlled by corticosteroid treatment. Clinical investigations indicate that viral and bacterial infections play crucial roles in the onset of steroid-resistant inflammation and airways hyperresponsiveness (AHR) that are hallmark features of exacerbations. We have previously shown that interferon γ (IFNγ) and lipopolysaccharide (LPS) cooperatively activate pulmonary macrophages and induce steroid-resistant airway inflammation and AHR in mouse models. Furthermore, we have established a mouse model of respiratory syncytial virus (RSV)-induced exacerbation of asthma, which exhibits macrophage-dependent, steroid-resistant lung disease. Emerging evidence has demonstrated a key role for bromo- and extra-terminal (BET) proteins in the regulation of inflammatory gene expression in macrophages. We hypothesised that BET proteins may be involved in the regulation of AHR and airway inflammation in our steroid-resistant exacerbation models. Methodology/Principal Findings We investigated the effects of a BET inhibitor (I-BET-762) on the development of steroid-resistant AHR and airway inflammation in two mouse models. I-BET-762 administration decreased macrophage and neutrophil infiltration into the airways, and suppressed key inflammatory cytokines in both models. I-BET treatment also suppressed key inflammatory cytokines linked to the development of steroid-resistant inflammation such as monocyte chemoattractant protein 1 (MCP-1), keratinocyte-derived protein chemokine (KC), IFNγ, and interleukin 27 (IL-27). Attenuation of inflammation was associated with suppression of AHR. Conclusions/Significance Our results suggest that BET proteins play an important role in the regulation of steroid-resistant exacerbations of airway inflammation and AHR. BET proteins may be potential targets for the development of future therapies to treat steroid-resistant inflammatory components

  9. Arylhydrocarbon receptor (AhR) activation in airway epithelial cells induces MUC5AC via reactive oxygen species (ROS) production.

    PubMed

    Chiba, Takahito; Uchi, Hiroshi; Tsuji, Gaku; Gondo, Hisaki; Moroi, Yoichi; Furue, Masutaka

    2011-02-01

    The dioxins and dioxin-like compounds in cigarette smoke regulate various immunological responses via the arylhydrocarbon receptor (AhR). These environmental toxicants are known to cause bronchitis, asthma, chronic obstructive pulmonary disease (COPD), and lung cancer. Recent studies have demonstrated that AhR activation upregulates the expression of mucin 5AC, oligomeric mucus/gel-forming (MUC5AC) in the airway epithelial cell line. However, the mechanism for the production of mucin has not been clarified. In this study, we investigated the role and pathway of AhR in airway epithelial cells by using selective agonists and antagonists. After stimulation with or without benzopyrene (B[a]P), an AhR agonist, MUC5AC expression was measured by real-time RT-PCR. The mechanism of AhR-induced MUC5AC expression in airway epithelial cells was studied in terms of the production of cytokine and reactive oxygen species (ROS). Treatment with B[a]P increased ROS generation in NCI-H₂₉₂ cells. Furthermore, B[a]P-induced MUC5AC upregulation and mucin production were inhibited by AhR siRNA or the use of an antioxidative agent. These results suggest that the AhR-induced increase of mucin production is partially mediated by ROS generation. An antioxidant therapy approach may help to cure AhR-induced mucus hypersecretory diseases. PMID:20709182

  10. Cyclic nitroxide radicals attenuate inflammation and Hyper-responsiveness in a mouse model of allergic asthma.

    PubMed

    Assayag, Miri; Goldstein, Sara; Samuni, Amram; Berkman, Neville

    2015-10-01

    The effects of stable cyclic nitroxide radicals have been extensively investigated both in vivo and in vitro demonstrating anti-inflammatory, radioprotective, anti-mutagenic, age-retardant, hypotensive, anti-cancer and anti-teratogenic activities. Yet, these stable radicals have not been evaluated in asthma and other airway inflammatory disorders. The present study investigated the effect of 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (TPL) and 3-carbamoyl-proxyl (3-CP) in a mouse model of ovalbumin (OVA)-induced allergic asthma. Both 3-CP and TPL were non-toxic when administered either orally (1% w/w nitroxide-containing chow) or via intraperitoneal (IP) injection (∼300 mg/kg). Feeding the mice orally demonstrated that 3-CP was more effective than TPL in reducing inflammatory cell recruitment into the airway and in suppressing airway hyper-responsiveness (AHR) in OVA-challenged mice. To characterize the optimal time-window of intervention and mode of drug administration, 3-CP was given orally during allergen sensitization, during allergen challenge or during both sensitization and challenge stages, and via IP injection or intranasal instillation for 3 days during the challenge period. 3-CP given via all modes of delivery markedly inhibited OVA-induced airway inflammation, expression of cytokines, AHR and protein nitration of the lung tissue. Oral administration during the entire experiment was the most efficient delivery of 3-CP and was more effective than dexamethasone a potent corticosteroid used for asthma treatment. Under a similar administration regimen (IP injection before the OVA challenge), the effect of 3-CP was similar to that of dexamethasone and even greater on AHR and protein nitration. The protective effect of the nitroxides, which preferentially react with free radicals, in suppressing the increase of main asthmatic inflammatory markers substantiate the key role played by reactive oxygen and nitrogen species in the molecular mechanism of

  11. Combination therapy with relaxin and methylprednisolone augments the effects of either treatment alone in inhibiting subepithelial fibrosis in an experimental model of allergic airways disease.

    PubMed

    Royce, Simon G; Sedjahtera, Amelia; Samuel, Chrishan S; Tang, Mimi L K

    2013-01-01

    Although CSs (corticosteroids) demonstrate potent effects in the control of airway inflammation in asthma, many patients continue to experience symptoms and AHR (airway hyper-responsiveness) despite optimal treatment with these agents, probably due to progressive airway remodelling. Identifying novel therapies that can target airway remodelling and/or airway reactivity may improve symptom control in these patients. We have demonstrated previously that the anti-fibrotic hormone RLN (relaxin) can reverse airway remodelling (epithelial thickening and subepithelial fibrosis) and AHR in a murine model of AAD (allergic airways disease). In the present study, we compared the effects of RLN with a CS (methylprednisolone) on airway remodelling and AHR when administered independently or in combination in the mouse AAD model. Female mice at 6-8 weeks of age were sensitized and challenged to OVA (ovalbumin) over a 9-week period and treated with methylprednisolone, RLN, a combination of both treatments or vehicle controls. Methylprednisolone was administered intraperitoneally on the same day as nebulization for 6 weeks, whereas recombinant human RLN-2 was administered via subcutaneously implanted osmotic mini-pumps from weeks 9-11. RLN or methylprednisolone alone were both able to significantly decrease subepithelial thickness and total lung collagen deposition; whereas RLN but not methylprednisolone significantly decreased epithelial thickness and AHR. Additionally, combination therapy with CS and RLN more effectively reduced subepithelial collagen thickness than either therapy alone. These findings demonstrate that RLN can modulate a broader range of airway remodelling changes and AHR than methylprednisolone and the combination of both treatments offers enhanced control of subepithelial fibrosis. PMID:22817662

  12. Adam8 Limits the Development of Allergic Airway Inflammation in Mice

    PubMed Central

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

    2013-01-01

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

  13. Targeting TSLP With shRNA Alleviates Airway Inflammation and Decreases Epithelial CCL17 in a Murine Model of Asthma

    PubMed Central

    Chen, Yi-Lien; Chiang, Bor-Luen

    2016-01-01

    Airway epithelium defends the invasion from microorganisms and regulates immune responses in allergic asthma. Thymic stromal lymphopoietin (TSLP) from inflamed epithelium promotes maturation of dendritic cells (DCs) to prime Th2 responses via CCL17, which induces chemotaxis of CD4+ T cells to mediate inflammation. However, few studies have investigated the regulation of epithelial CCL17. In this study, we used shRNA against TSLP to clarify the role of TSLP in the airway inflammation and whether TSLP affects the airway inflammation via epithelial CCL17. Specific shTSLP was delivered by lentivirus and selected by the knockdown efficiency. Allergic mice were intratracheally pretreated with the lentivirus and followed by intranasal ovalbumin (OVA) challenges. The sera antibody levels, airway inflammation, airway hyper-responsiveness (AHR), cytokine levels in bronchoalveolar lavage fluids, and CCL17 expressions in lungs were determined. In vivo, TSLP attenuation reduced the AHR, decreased the airway inflammation, inhibited the maturations of DCs, and suppressed the migration of T cells. Furthermore, the expression of CCL17 was particularly decreased in bronchial epithelium. In vitro, CCL17 induction was regulated by TSLP. In conclusion, TSLP might coordinate airway inflammation partially via CCL17-mediated responses and this study provides the vital utility of TSLP to develop the therapeutic approach in allergic airway inflammation. PMID:27138176

  14. Anti-CD69 monoclonal antibody treatment inhibits airway inflammation in a mouse model of asthma*

    PubMed Central

    Wang, Hui-ying; Dai, Yu; Wang, Jiao-li; Yang, Xu-yan; Jiang, Xin-guo

    2015-01-01

    Objective: Airway inflammation and airway hyper-responsiveness (AHR) are principle pathological manifestations of asthma. Cluster of differentiation 69 (CD69) is a well-known co-stimulatory factor associated with the activation, proliferation as well as apoptosis of immune cells. This study aims to examine the effect of anti-CD69 monoclonal antibody (mAb) on the pathophysiology of a mouse model of asthma. Methods: A murine model of ovalbumin (OVA)-induced allergic airway inflammation was used in this study. Briefly, mice were injected with 20 μg chicken OVA intraperitoneally on Days 0 and 14, followed by aerosol provocation with 1% (0.01 g/ml) OVA on Days 24, 25, and 26. Anti-CD69 mAb or isotype IgG was injected intraperitoneally after OVA challenge; dexamethasone (DXM) was administrated either before or after OVA challenge. AHR, mucus production, and eosinophil infiltration in the peribronchial area were examined. The levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-5 (IL-5) in bronchoalveolar lavage fluid (BALF) were also assayed as indices of airway inflammation on Day 28 following OVA injection. Results: Pretreatment with DXM together with anti-CD69 mAb treatment after OVA provocation completely inhibited AHR, eosinophil infiltration and mucus overproduction, and significantly reduced BALF IL-5. However, treatment with DXM alone after OVA challenge only partially inhibited AHR, eosinophil infiltration and mucus overproduction, and did not diminish BALF IL-5. Treatment with either DXM or anti-CD69 mAb did not alter the concentration of BALF GM-CSF. Conclusions: Anti-CD69 mAb treatment inhibits established airway inflammation as effectively as DXM pretreatment. This study provides a potential alternative therapeutic opportunity for the clinical management of asthma and its exacerbation. PMID:26160720

  15. 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...

  16. Development and maintenance of force and stiffness in airway smooth muscle.

    PubMed

    Lan, Bo; Norris, Brandon A; Liu, Jeffrey C-Y; Paré, Peter D; Seow, Chun Y; Deng, Linhong

    2015-03-01

    Airway smooth muscle (ASM) plays a central role in the excessive narrowing of the airway that characterizes the primary functional impairment in asthma. This phenomenon is known as airway hyper-responsiveness (AHR). Emerging evidence suggests that the development and maintenance of ASM force involves dynamic reorganization of the subcellular filament network in both the cytoskeleton and the contractile apparatus. In this review, evidence is presented to support the view that regulation of ASM contraction extends beyond the classical actomyosin interaction and involves processes within the cytoskeleton and at the interfaces between the cytoskeleton, the contractile apparatus, and the extracellular matrix. These processes are initiated when the muscle is activated, and collectively they cause the cytoskeleton and the contractile apparatus to undergo structural transformation, resulting in a more connected and solid state that allows force generated by the contractile apparatus to be transmitted to the extracellular domain. Solidification of the cytoskeleton also serves to stiffen the muscle and hence the airway. Oscillatory strain from tidal breathing and deep inspiration is believed to be the counter balance that prevents hypercontraction and stiffening of ASM in vivo. Dysregulation of this balance could lead to AHR seen in asthma.

  17. Genetic Deletion of β-Arrestin-2 and the Mitigation of Established Airway Hyperresponsiveness in a Murine Asthma Model.

    PubMed

    Chen, Minyong; Hegde, Akhil; Choi, Yeon Ho; Theriot, Barbara S; Premont, Richard T; Chen, Wei; Walker, Julia K L

    2015-09-01

    β-Arrestin-2 (βarr2) is a ubiquitously expressed cytosolic protein that terminates G protein-coupled receptor signaling and transduces G protein-independent signaling. We previously showed that mice lacking βarr2 do not develop an asthma phenotype when sensitized to, and challenged with, allergens. The current study evaluates if an established asthma phenotype can be mitigated by deletion of βarr2 using an inducible Cre recombinase. We sensitized and challenged mice to ovalbumin (OVA) and demonstrated that on Day (d) 24 the allergic asthma phenotype was apparent in uninduced βarr2 and wild-type (WT) mice. In a second group of OVA-treated mice, tamoxifen was injected on d24 to d28 to activate Cre recombinase, and OVA aerosol challenge was continued through d44. The asthma phenotype was assessed using lung mechanics measurements, bronchoalveolar lavage cell analysis, and histological assessment of mucin and airway inflammation. Compared with their respective saline-treated controls, OVA-treated WT mice and mice expressing the inducible Cre recombinase displayed a significant asthma phenotype at d45. Whereas tamoxifen treatment had no significant effect on the asthma phenotype in WT mice, it inhibited βarr2 expression and caused a significant reduction in airway hyper-responsiveness (AHR) in Cre-inducible mice. These findings suggest that βarr2 is actively required for perpetuation of the AHR component of the allergic asthma phenotype. Our finding that βarr2 participates in the perpetuation of AHR in an asthma model means that targeting βarr2 may provide immediate and potentially long-term relief from daily asthma symptoms due to AHR irrespective of inflammation.

  18. Polygonum multiflorum Decreases Airway Allergic Symptoms in a Murine Model of Asthma.

    PubMed

    Lee, Chen-Chen; Lee, Yueh-Lun; Wang, Chien-N; Tsai, Hsing-Chuan; Chiu, Chun-Lung; Liu, Leroy F; Lin, Hung-Yun; Wu, Reen

    2016-01-01

    The root of Polygonum multiflorum (also called He-Shou-Wu in Chinese) is a common herb and medicinal food in Asia used for its anti-aging properties. Our study investigated the therapeutic potential of an extract of the root of Polygonum multiflorum (PME) in allergic asthma by using a mouse model. Feeding of 0.5 and 1 mg/mouse PME inhibited ovalbumin (OVA)-induced allergic asthma symptoms, including airway inflammation, mucus production, and airway hyper-responsiveness (AHR), in a dose-dependent manner. To discern PME's mechanism of action, we examined the profile and cytokine production of inflammatory cells in bronchial alveolar lavage fluid (BALF). We found that eosinophils, the main inflammatory cell infiltrate in the lung of OVA-immunized mice, significantly decreased after PME treatment. Th2 cytokine levels, including interleukin (IL)-4, IL-5, IL-13, eotaxin, and the proinflammatory cytokine tumor necrosis factor (TNF)-[Formula: see text], decreased in PME-treated mice. Elevated mRNA expression of Th2 transcription factor GATA-3 in the lung tissue was also inhibited after oral feeding of PME in OVA-immunized mice. Thus, we conclude that PME produces anti-asthma activity through the inhibition of Th2 cell activation. PMID:26916919

  19. Ethanol withdrawal hyper-responsiveness mediated by NMDA receptors in spinal cord motor neurons

    PubMed Central

    Li, Hui-Fang; Kendig, Joan J

    2003-01-01

    Following ethanol (EtOH) exposure, population excitatory postsynaptic potentials (pEPSPs) in isolated spinal cord increase to a level above control (withdrawal hyper-responsiveness). The present studies were designed to characterize this phenomenon and in particular to test the hypothesis that protein kinases mediate withdrawal. Patch-clamp studies were carried out in motor neurons in rat spinal cord slices. Currents were evoked by brief pulses of glutamate, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or N-methyl-D-aspartic acid (NMDA). Of 15 EtOH-sensitive neurons in which currents were evoked by glutamate, four (27%) displayed withdrawal hyper-responsiveness in the washout period. Mean current area after washout was 129.6±5% of control. When currents were evoked by AMPA, two of 10 neurons (20%) displayed withdrawal hyper-responsiveness, with a mean current area 122±8% of control on washout. Of a group of 11 neurons in which currents were evoked by NMDA, nine (82%) displayed withdrawal hyper-responsiveness. Mean increase in current area at the end of the washout period was to 133±6% of control (n=9, P<0.001). When NMDA applications were stopped durithe period of EtOH exposure, mean area of NMDA-evoked responses on washout was only 98.0±5% of control (n=6, P>0.05). The tyrosine kinase inhibitor genistein (10–20 μM) blocked withdrawal hyper-responsiveness. Of six EtOH-sensitive neurons, the mean NMDA-evoked current area after washout was 89±6% of control, P>0.05. The protein kinase A (PKA) inhibitor Rp-cAMP (20–500 μM) did not block withdrawal hyper-responsiveness. On washout, the mean NMDA-evoked current area was 124±6% of control (n=5, P<0.05). Two broad-spectrum specific protein kinase C (PKC) inhibitors, GF-109203X (0.3 μM) and chelerythrine chloride (0.5–2 nM), blocked withdrawal hyper-responsiveness. Responses on washout were 108±7%, n=5 and 88±4%, n=4 of control, respectively, P>0.05. NMDA activation during EtOH exposure

  20. Non-specific bronchial hyper-responsiveness in children with allergic rhinitis: relationship with the atopic status.

    PubMed

    Cuttitta, Giuseppina; Cibella, Fabio; La Grutta, Stefania; Hopps, Maria R; Bucchieri, Salvatore; Passalacqua, Giovanni; Bonsignore, Giovanni

    2003-12-01

    An increased prevalence of bronchial hyper-responsiveness (BHR) has been demonstrated in children from a general population, and in non-asthmatic adults with allergic rhinitis. Thus, also children with allergic rhinitis are expected to be at higher risk of BHR. We evaluated the prevalence of BHR in a sample of non-asthmatic children with allergic rhinitis by means of the methacholine (Mch) bronchial challenge, and by monitorizing the airway patency using the daily peak expiratory flow variability (PEFv). Fifty-one children (ranged 6-15 years of age) with allergic rhinitis, ascertained by skin prick test to inhalant allergens, underwent a 14-day peak expiratory flow monitoring, and a Mch bronchial provocation challenge. Thirty healthy children matched for age, and sex served as control group. Thirty-one children in the rhinitis group (61%), and six (20%) in the control group were Mch+ (Mch provocative dose causing a 20% fall of forced expiratory volume in 1 s respect to baseline <2250 microg, equivalent to 11.50 micromol). In rhinitic children the PEFv did not significantly differ between Mch+ and Mch- subjects, but the total serum immunoglobulin E (IgE) were higher among Mch+. The persistent form of rhinitis was significantly associated to Mch positivity. Non-asthmatic children with allergic rhinitis displayed a high prevalence of BHR. The BHR was significantly associated with persistent rhinitis and with higher total IgE levels. Nevertheless, the spontaneous changes in airway patency, as expressed by PEFv, were within normal limits both in Mch+ and Mch- children.

  1. Ozone-induced airway hyperresponsiveness: roles of ROCK isoforms.

    PubMed

    Lambert, James A; Song, Weifeng

    2015-12-15

    Acute ozone (O3) inhalation has been shown to cause airway and pulmonary epithelial injury with accompanying inflammation responses. Robust evidence exists that O3 induces airway hyperresponsiveness (AHR) in humans and in animal models. Several pathways exist that culminate in airway smooth muscle contraction, but the mechanism(s) by which O3 elicits AHR are unclear. Here, we review the recent report by Kasahara et al. (Kasahara DI, Mathews JA, Park CY, Cho Y, Hunt G, Wurmbrand AP, Liao JK, Shore SA. Am J Physiol Lung Cell Mol Physiol 309: L736-L746, 2015.) describing the role of two Rho kinase (ROCK) isoforms in O3-induced AHR utilizing a murine haploinsufficiency model. Compared with wild-type (WT) mice, the authors report that ROCK1(+/-) and ROCK2(+/-) mice exhibited significantly reduced AHR following acute exposure to O3. Additionally, WT mice treated with fasudil, an FDA-approved ROCK1/2 inhibitor, recapitulated reduction in AHR as seen in ROCK haplotypes. It was suggested that, although the two ROCK isoforms are both induced by Rho, they have different mechanisms by which they mediate O3-induced AHR: ROCK1 via hyaluronan signaling vs. ROCK2 acting downstream of inflammation at the level of airway smooth muscle contraction. These observations provide an important framework to develop novel ROCK-targeting therapies for acute O3-induced AHR.

  2. Methods in assessment of airway reactivity in mice.

    PubMed

    Gold, Matthew; Blanchet, Marie-Renee

    2015-01-01

    Due to the wealth of reagents and transgenic strains available, mice have become one of the most commonly used model organisms for the study of allergic airway inflammation. One of the major hallmarks of the asthma phenotype in humans is reversible airflow obstruction, or airway hyper-responsiveness. However, the ability to confidently obtain useful physiological responses from such a small animal has presented a large technological challenge in murine studies. Recent advances have provided the technology to obtain lung mechanics through either the forced oscillation technique or plethysmography. Here we describe the utility of these measurements in mouse models of allergic airway inflammation and anaphylaxis. PMID:25388272

  3. AHR-11797: a novel benzodiazepine antagonist

    SciTech Connect

    Johnson, D.N.; Kilpatrick, B.F.; Hannaman, P.K.

    1986-03-01

    AHR-11797(5,6-dihydro-6-methyl-1-phenyl-/sup 3/H-pyrrolo(3,2,1-ij)quinazolin-3-one) displaced /sup 3/H-flunitrazepam (IC/sub 50/ = 82 nM) and /sup 3/H-Ro 15-1877 (IC/sub 50/ = 104 nM) from rat brain synaptosomes. AHR-11797 did not protect mice from seizures induced by maximal electroshock or subcutaneous Metrazol (scMET), nor did it induce seizures in doses up to the lethal dose. However, at 31.6 mg/kg, IP, it significantly increased the anticonvulsant ED/sub 50/ of chlordiazepoxide (CDPX) from 1.9 to 31.6 mg/kg, IP. With 56.7 mg/kg, IP, of AHR-11797, CDPX was inactive in doses up to 100 mg/kg, IP. AHR-11797 did not significantly increase punished responding in the Geller and Seifter conflict procedure, but it did attenuate the effects of diazepam. Although the compound is without anticonvulsant or anxiolytic activity, it did have muscle relaxant properties. AHR-11797 blocked morphine-induced Straub tail in mice (ED/sub 50/ = 31 mg/kg, IP) and it selectively suppressed the polysnaptic linguomandibular reflex in barbiturate-anesthetized cats. The apparent muscle relaxant activity of AHR-11797 suggests that different receptor sites are involved for muscle relaxant vs. anxiolytic/anticonvulsant activities of the benzodiazepines.

  4. AhR signalling and dioxin toxicity.

    PubMed

    Sorg, Olivier

    2014-10-15

    Dioxins are a family of molecules associated to several industrial accidents such as Ludwigshafen in 1953 or Seveso in 1976, to the Agent Orange used during the war of Vietnam, and more recently to the poisoning of the former president of Ukraine, Victor Yushchenko. These persistent organic pollutants are by-products of industrial activity and bind to an intracellular receptor, AhR, with a high potency. In humans, exposure to dioxins, in particular 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces a cutaneous syndrome known as chloracne, consisting in the development of many small skin lesions (hamartoma), lasting for 2-5 years. Although TCDD has been classified by the WHO as a human carcinogen, its carcinogenic potential to humans is not clearly demonstrated. It was first believed that AhR activation accounted for most, if not all, biological properties of dioxins. However, certain AhR agonists found in vegetables do not induce chloracne, and other chemicals, in particular certain therapeutic agents, may induce a chloracne-like syndrome without activating AhR. It is time to rethink the mechanism of dioxin toxicity and analyse in more details the biological events following exposure to these compounds and other AhR agonists, some of which have a very different chemical structure than TCDD. In particular various food-containing AhR agonists are non-toxic and may on the contrary have beneficial properties to human health. PMID:24239782

  5. Rapamycin decreases airway remodeling and hyperreactivity in a transgenic model of noninflammatory lung disease.

    PubMed

    Kramer, Elizabeth L; Hardie, William D; Mushaben, Elizabeth M; Acciani, Thomas H; Pastura, Patricia A; Korfhagen, Thomas R; Hershey, Gurjit Khurana; Whitsett, Jeffrey A; Le Cras, Timothy D

    2011-12-01

    Airway hyperreactivity (AHR) and remodeling are cardinal features of asthma and chronic obstructive pulmonary disease. New therapeutic targets are needed as some patients are refractory to current therapies and develop progressive airway remodeling and worsening AHR. The mammalian target of rapamycin (mTOR) is a key regulator of cellular proliferation and survival. Treatment with the mTOR inhibitor rapamycin inhibits inflammation and AHR in allergic asthma models, but it is unclear if rapamycin can directly inhibit airway remodeling and AHR, or whether its therapeutic effects are entirely mediated through immunosuppression. To address this question, we utilized transforming growth factor-α (TGF-α) transgenic mice null for the transcription factor early growth response-1 (Egr-1) (TGF-α Tg/Egr-1(ko/ko) mice). These mice develop airway smooth muscle thickening and AHR in the absence of altered lung inflammation, as previously reported. In this study, TGF-α Tg/Egr-1(ko/ko) mice lost body weight and developed severe AHR after 3 wk of lung-specific TGF-α induction. Rapamycin treatment prevented body weight loss, airway wall thickening, abnormal lung mechanics, and increases in airway resistance to methacholine after 3 wk of TGF-α induction. Increases in tissue damping and airway elastance were also attenuated in transgenic mice treated with rapamycin. TGF-α/Egr-1(ko/ko) mice on doxycycline for 8 wk developed severe airway remodeling. Immunostaining for α-smooth muscle actin and morphometric analysis showed that rapamycin treatment prevented airway smooth muscle thickening around small airways. Pentachrome staining, assessments of lung collagen and fibronectin mRNA levels, indicated that rapamycin also attenuated fibrotic pathways induced by TGF-α expression for 8 wk. Thus rapamycin reduced airway remodeling and AHR, demonstrating an important role for mTOR signaling in TGF-α-induced/EGF receptor-mediated reactive airway disease. PMID:21903885

  6. Rapamycin decreases airway remodeling and hyperreactivity in a transgenic model of noninflammatory lung disease.

    PubMed

    Kramer, Elizabeth L; Hardie, William D; Mushaben, Elizabeth M; Acciani, Thomas H; Pastura, Patricia A; Korfhagen, Thomas R; Hershey, Gurjit Khurana; Whitsett, Jeffrey A; Le Cras, Timothy D

    2011-12-01

    Airway hyperreactivity (AHR) and remodeling are cardinal features of asthma and chronic obstructive pulmonary disease. New therapeutic targets are needed as some patients are refractory to current therapies and develop progressive airway remodeling and worsening AHR. The mammalian target of rapamycin (mTOR) is a key regulator of cellular proliferation and survival. Treatment with the mTOR inhibitor rapamycin inhibits inflammation and AHR in allergic asthma models, but it is unclear if rapamycin can directly inhibit airway remodeling and AHR, or whether its therapeutic effects are entirely mediated through immunosuppression. To address this question, we utilized transforming growth factor-α (TGF-α) transgenic mice null for the transcription factor early growth response-1 (Egr-1) (TGF-α Tg/Egr-1(ko/ko) mice). These mice develop airway smooth muscle thickening and AHR in the absence of altered lung inflammation, as previously reported. In this study, TGF-α Tg/Egr-1(ko/ko) mice lost body weight and developed severe AHR after 3 wk of lung-specific TGF-α induction. Rapamycin treatment prevented body weight loss, airway wall thickening, abnormal lung mechanics, and increases in airway resistance to methacholine after 3 wk of TGF-α induction. Increases in tissue damping and airway elastance were also attenuated in transgenic mice treated with rapamycin. TGF-α/Egr-1(ko/ko) mice on doxycycline for 8 wk developed severe airway remodeling. Immunostaining for α-smooth muscle actin and morphometric analysis showed that rapamycin treatment prevented airway smooth muscle thickening around small airways. Pentachrome staining, assessments of lung collagen and fibronectin mRNA levels, indicated that rapamycin also attenuated fibrotic pathways induced by TGF-α expression for 8 wk. Thus rapamycin reduced airway remodeling and AHR, demonstrating an important role for mTOR signaling in TGF-α-induced/EGF receptor-mediated reactive airway disease.

  7. Effects of hydrofluoroalkane formulations of ciclesonide 400 µg once daily vs fluticasone 250 µg twice daily on methacholine hyper-responsiveness in mild-to-moderate persistent asthma

    PubMed Central

    Lee, Daniel K C; Haggart, Kay; Currie, Graeme P; Bates, Caroline E; Lipworth, Brian J

    2004-01-01

    Aims There are no data comparing the relative efficacy of hydrofluoroalkane (HFA) formulations of ciclesonide (CIC) and fluticasone propionate (FP) on airway hyper-responsiveness, in mild-to-moderate persistent asthma. We therefore elected to evaluate the comparative efficacy of HFA pressurized metered-dose inhaler formulations of CIC and FP, assessing methacholine challenge, in addition to exhaled nitric oxide, lung function, diary cards and quality of life. Methods Nineteen mild-to-moderate asthmatic patients completed the study per protocol in randomized, double-blind, double-dummy, crossover fashion. Patients were required to stop their usual inhaled corticosteroid therapy for the duration of the study. Pa-tients were commenced instead on salmeterol (SM) 50 µg one puff twice daily + montelukast (ML) 10 mg once daily for 2-week washout periods prior to each randomized treatment, in order to prevent dropouts. Patients received 4 weeks of either CIC 200 µg two puffs once daily (08.00 h) + CIC-placebo (PL) two puffs once daily (20.00 h) + FP-PL two puffs twice daily (08.00 h and 20.00 h), or FP 125 µg two puffs twice daily (08.00 h and 20.00 h) + CIC-PL two puffs twice daily (08.00 h and 20.00 h). SM + ML were withheld for 72 h prior to post-washout visits and CIC or FP was withheld for 24 h prior to study visits. Results There was no significant difference between CIC vs. FP for the primary outcome of methacholine PC20 as doubling dilution (dd) shift from respective baseline; mean difference: 0.4 dd (95% CI −0.4, 1.2). Moreover, there was no difference between treatments for the sequence of CIC first vs FP second; mean difference: 0.2 dd (95% CI −1.3, 1.7) or FP first vs CIC second; mean difference: 0.9 dd (95% CI −0.1, 1.8). There were also no differences for other secondary outcomes between treatments, either respective or irrespective of sequence, as change from baseline. Conclusions There were no differences between 4 weeks of CIC 400 µg once daily

  8. In vitro and in silico evaluation of transactivation potencies of avian AHR1 and AHR2 by endogenous ligands: Implications for the physiological role of avian AHR2.

    PubMed

    Kim, In-Sung; Hwang, Ji-Hee; Hirano, Masashi; Iwata, Hisato; Kim, Eun-Young

    2016-09-01

    Aryl hydrocarbon receptor (AHR) is well conserved from invertebrates to vertebrates, and it mediates the toxic effects of exogenous ligands, including dioxins. Recent studies reported that AHRs activated by endogenous ligands play critical roles in mammalian physiological homeostasis. Avian species possess at least two AHR isoforms (AHR1 and AHR2), which exhibit species- and isoform-specific transactivation potencies to exogenous ligands, whereas mammals possess a single AHR. To delineate the profiles and roles of endogenous ligands for avian AHR isoforms, we investigated in vitro transactivation potencies of avian AHRs (AHR1 and AHR2 from the jungle crow, Corvus macrorhynchos; common cormorant, Phalacrocorax carbo; and black-footed albatross, Phoebastria nigripes) treated with the endogenous tryptophan metabolites 6-formylindolo [3,2-b] carbazole (FICZ), l-kynurenine (l-Kyn), kynurenic acid (KYNA), and indoxyl sulfate (IS). Furthermore, we analyzed the binding mode of these ligands to each avian AHR isoform by in silico docking simulations. The EC50 of FICZ (0.009-0.032nM) was similar regardless of the species or isoform of AHR. The estimated in silico binding mode of FICZ to AHRs was well conserved in both isoforms. The transactivation potencies of avian AHRs to other tryptophan metabolites were 10(5)-10(7) fold lower than those for FICZ, and EC50 values varied in a species- and isoform-specific manner. This was consistent with poor conservation of the binding mode of l-Kyn, KYNA, and IS predicted in in silico docking simulations. Our results suggest that in avian species, FICZ is the most potent endogenous AHR ligand, and that AHR1 and AHR2 are physiologically functional. PMID:27060260

  9. Airways Hyperresponsiveness Following a Single Inhalation Exposure to Doxorubicin-Induced Heart Failure Prevents Airways Transition Metal-Rich Particulate Matter in Hypertensive Rats

    EPA Science Inventory

    Exposure to particulate matter (PM) air pollution results in airways hyperresponsiveness (AHR), however it also results in adverse cardiovascular effects, particularly in individuals with underlying cardiovascular disease. The impact of pre-existing cardiac deficit on PM-induced ...

  10. Airway hyperresponsiveness in elite athletes.

    PubMed

    Langdeau, J B; Turcotte, H; Bowie, D M; Jobin, J; Desgagné, P; Boulet, L P

    2000-05-01

    It has been suggested that high-level training could contribute to the development of airway hyperresponsiveness (AHR), but the comparative effects of different sports on airway function remains to be determined. We evaluated 150 nonsmoking volunteers 18 to 55 yr of age; 100 athletes divided into four subgroups of 25 subjects each according to the predominant estimated hydrocaloric characteristic of ambient air inhaled during training: dry air (DA), cold air (CA), humid air (HA) and a mixture of dry and humid air (MA), and 50 sedentary subjects. Each subject had a respiratory questionnaire, a methacholine challenge, allergy skin-prick tests, and heart rate variability recording for evaluation of parasympathetic tone. The athletes had a 49% prevalence of AHR (PC(20) < 16 mg/ml), with a mean PC(20) of 16.9 mg/ml, compared with 28% (PC(20): 35.4) in sedentary subjects (p = 0.009). The prevalence (%) of AHR and mean PC(20) (mg/ml) varied as followed in the four subgroups of athletes: DA: 32% and 30.9; CA: 52% and 15.8; HA: 76% and 7.3; and MA: 32% and 21.5 (p = 0.002). The estimated parasympathetic tone was higher in athletes (p < 0.001), but this parameter showed only a weak correlation with PC(20) (r = -0.17, p = 0.04). This study has shown a significantly higher prevalence of AHR in athletes than in the control group because of the higher prevalence in the CA and HA groups. Parasympathetic activity may act as modulator of airway responsiveness, but the increased prevalence of AHR in our athlete population may be related to the type and possibly the content of inhaled air during training.

  11. ROCK insufficiency attenuates ozone-induced airway hyperresponsiveness in mice.

    PubMed

    Kasahara, David I; Mathews, Joel A; Park, Chan Y; Cho, Youngji; Hunt, Gabrielle; Wurmbrand, Allison P; Liao, James K; Shore, Stephanie A

    2015-10-01

    Ozone causes airway hyperresponsiveness (AHR) and pulmonary inflammation. Rho kinase (ROCK) is a key regulator of smooth muscle cell contraction and inflammatory cell migration. To determine the contribution of the two ROCK isoforms ROCK1 and ROCK2 to ozone-induced AHR, we exposed wild-type, ROCK1(+/-), and ROCK2(+/-) mice to air or ozone (2 ppm for 3 h) and evaluated mice 24 h later. ROCK1 or ROCK2 haploinsufficiency did not affect airway responsiveness in air-exposed mice but significantly reduced ozone-induced AHR, with a greater reduction in ROCK2(+/-) mice despite increased bronchoalveolar lavage (BAL) inflammatory cells in ROCK2(+/-) mice. Compared with wild-type mice, ozone-induced increases in BAL hyaluronan, a matrix protein implicated in ozone-induced AHR, were lower in ROCK1(+/-) but not ROCK2(+/-) mice. Ozone-induced increases in other inflammatory moieties reported to contribute to ozone-induced AHR (IL-17A, osteopontin, TNFα) were not different in wild-type vs. ROCK1(+/-) or ROCK2(+/-) mice. We also observed a dose-dependent reduction in ozone-induced AHR after treatment with the ROCK1/ROCK2 inhibitor fasudil, even though fasudil was administered after induction of inflammation. Ozone increased pulmonary expression of ROCK2 but not ROCK1 or RhoA. A ROCK2 inhibitor, SR3677, reduced contractile forces in primary human airway smooth muscle cells, confirming a role for ROCK2 in airway smooth muscle contraction. Our results demonstrate that ozone-induced AHR requires ROCK. Whereas ROCK1-dependent changes in hyaluronan may contribute to ROCK1's role in O3-induced AHR, the role of ROCK2 is downstream of inflammation, likely at the level of airway smooth muscle contraction.

  12. The dopaminergic hyper-responsiveness of the shell of the nucleus accumbens is hormone-dependent.

    PubMed

    Barrot, M; Marinelli, M; Abrous, D N; Rougé-Pont, F; Le Moal, M; Piazza, P V

    2000-03-01

    The dopaminergic projection to the shell of the nucleus accumbens is the most reactive to stress, reward and drugs of abuse and this subregion of the nucleus accumbens is also considered a target of therapeutic effects of atypical antipsychotic drugs (APD). In this report we show, by means of in vivo microdialysis and Fos immunohistochemistry, that the hyper-responsiveness which characterizes the dopaminergic transmission to the shell is dependent on glucocorticoid hormones. In Sprague-Dawley rats, after suppression of endogenous glucocorticoids by adrenalectomy, extracellular dopamine levels selectively decreased in the shell, whilst they remained unchanged in the core. This effect was observed in basal conditions, after a mild stress (vehicle injection), as well as after subcutaneous administration of morphine (2 mg/kg, s.c. ) or intraperitoneal injection of cocaine (15 mg/kg, i.p.). The decrease in dopamine observed in the shell had a postsynaptic impact, as shown by less induction of Fos-like proteins selectively in the shell in response to cocaine. However, the induction of Fos-like proteins by the full D1 agonist SKF82958 (1.5 mg/kg, i.p.) remained unchanged after adrenalectomy, suggesting that the changes in Fos expression after cocaine injection were likely to depend on changes in extracellular dopamine levels rather than on changes in postsynaptic sensitivity to dopamine. The effects of adrenalectomy were glucocorticoid-specific given that they were prevented by corticosterone treatment. This anatomical specificity in the control of neuronal activity by a hormonal input highlights the role of steroid hormones in shaping the functional activity of the brain. PMID:10762327

  13. Kinetics of airway hyperresponsiveness and airway eosinophilia in BALB/c mice and their modulation by different dexamethasone treatment regimens.

    PubMed

    El-Hashim, A Z; Wyss, D; Zuany-Amorim, C

    2002-01-01

    The mechanisms of airway hyperresponsiveness (AHR) are still poorly understood. In this study we have established a model of persistent AHR and eosinophilia and evaluated the prophylactic vs. therapeutic effects of dexamethasone on these parameters. Mice were immunised with ovalbumin (OVA) on day 0 and challenged intranasally on days 10, 11, 12 and 13 with OVA or phosphate buffer saline (PBS). Airway responsiveness to methacholine, measured 24-h post multiple intranasal OVA challenges, was significantly increased compared to time matched PBS-controls (P<0.05). AHR could be detected for up to 14 days after the last OVA challenge although the magnitude of the AHR had diminished by day 14 compared to day 1. OVA challenge of mice induced a significant airway eosinophilia at 24h (P<0.05); this persisted for 2 weeks after the challenge. Prophylactic treatment with dexamethasone (1mg x kg (-1)) reduced the OVA induced AHR, eosinophilia and mucus cell hyperplasia/metaplasia measured 24h post challenge. Therapeutic treatment, with dexamethasone (2 mg x kg(-1)), significantly inhibited established airway eosinophilia, measured at 72 h post OVA challenge, only when treatment was initiated at 24h but not 48 h after challenge. In contrast, AHR measured at 72 h post OVA challenge was significantly reduced when treatment was started at either 24 or 48 h post challenge. Our data shows that the immunization and challenge procedures employed resulted in a persistent type of AHR. Prophylactic intervention with steroids almost completely inhibited its development; however therapeutic intervention only partially resolved AHR.

  14. Respiratory syncytial virus infection increases chlorine-induced airway hyperresponsiveness.

    PubMed

    Song, Weifeng; Yu, Zhihong; Doran, Stephen F; Ambalavanan, Namasivayam; Steele, Chad; Garantziotis, Stavros; Matalon, Sadis

    2015-08-01

    Exposure to chlorine (Cl2) damages airway and alveolar epithelia resulting in acute lung injury and reactive airway hyperresponsiveness (AHR) to methacholine. However, little is known about the effect of preexisting respiratory disease on Cl2-induced lung injury. By using a murine respiratory syncytial virus (RSV) infection model, we found that preexisting RSV infection increases Cl2 (187 ppm for 30 min)-induced lung inflammation and airway AHR at 24 h after exposure (5 days after infection). RSV infection and Cl2 exposure synergistically induced oxygen desaturation and neutrophil infiltration and increased MCP-1, MIP-1β, IL-10, IFN-γ, and RANTES concentrations in the bronchoalveolar lavage fluid (BALF). In contrast, levels of type 2 cytokines (i.e., IL-4, IL-5, IL-9, and IL-13) were not significantly affected by either RSV infection or Cl2 exposure. Cl2 exposure, but not RSV infection, induced AHR to methacholine challenge as measured by flexiVent. Moreover, preexisting RSV infection amplified BALF levels of hyaluronan (HA) and AHR. The Cl2-induced AHR was mitigated by treatment with inter-α-trypsin inhibitor antibody, which inhibits HA signaling, suggesting a mechanism of HA-mediated AHR from exacerbated oxidative injury. Our results show for the first time that preexisting RSV infection predisposes the lung to Cl2-induced injury. These data emphasize the necessity for further research on the effects of Cl2 in vulnerable populations and the development of appropriate treatments.

  15. The aryl hydrocarbon receptor (AHR) transcription factor regulates megakaryocytic polyploidization

    PubMed Central

    Lindsey, Stephan; T. Papoutsakis, Eleftherios

    2012-01-01

    Summary We propose that the aryl hydrocarbon receptor (AHR) is a novel transcriptional regulator of megakaryopoietic polyploidization. Functional evidence was obtained that AHR impacts in vivo megakaryocytic differentiation and maturation; compared to wild-type mice, AHR-null mice had lower platelet counts, fewer numbers of newly synthesized platelets, increased bleeding times and lower-ploidy megakaryocytes (Mks). AHR mRNA increased 3·6-fold during ex vivo megakaryocytic differentiation, but reduced or remained constant during parallel isogenic granulocytic or erythroid differentiation. We interrogated the role of AHR in megakaryopoiesis using a validated Mk model of megakaryopoiesis, the human megakaryoblastic leukaemia CHRF cell line. Upon CHRF Mk differentiation, AHR mRNA and protein levels increased, AHR protein shifted from the cytoplasm to the nucleus and AHR binding to its consensus DNA binding sequence increased. Protein and mRNA levels of the AHR transcriptional target HES1 also increased. Mk differentiation of CHRF cells where AHR or HES1 was knocked-down using RNAi resulted in lower ploidy distributions and cells that were incapable of reaching ploidy classes ≥16n. AHR knockdown also resulted in increased DNA synthesis of lower ploidy cells, without impacting apoptosis. Together, these data support a role for AHR in Mk polyploidization and in vivo platelet function, and warrant further detailed investigations. PMID:21226706

  16. Prevention of House Dust Mite Induced Allergic Airways Disease in Mice through Immune Tolerance

    PubMed Central

    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. PMID:21818308

  17. Outcome in adulthood of asymptomatic airway hyperresponsiveness in childhood: a longitudinal population study.

    PubMed

    Rasmussen, Finn; Taylor, D Robin; Flannery, Erin M; Cowan, Jan O; Greene, Justina M; Herbison, G Peter; Sears, Malcolm R

    2002-09-01

    The clinical outcome of asymptomatic airway hyperresponsiveness (AHR) first detected in childhood is sparsely reported, with conflicting results. We used a birth cohort of 1,037 children followed to age 26 years to assess the clinical outcome of asymptomatic AHR to methacholine first documented in study members at age 9 years. Of 547 study members who denied wheezing symptoms ever at age 9 years, 41 (7.5%) showed AHR. Forty showed methacholine responsiveness, with a provocation concentration of methacholine that elicited a 20% drop in forced expired volume in 1 sec (PC(20)) < or = 8 mg/mL, and one had baseline airway obstruction with a bronchodilator response exceeding 10%. Of these 41 study members, 18 (44%), 11 (27%), and 4 (10%) maintained AHR in 1, 2, and 3 later assessments, respectively, while 23 (56%) manifested AHR only at age 9. Compared with asymptomatic study members without AHR, those with asymptomatic AHR at age 9 years were more likely to report asthma and wheeze at any subsequent assessment, were more likely to have high IgE levels and eosinophils at ages 11 and 21, and more often demonstrated positive responses to skin allergen testing at ages 13 and 21 years. Persistent AHR at later assessments increased these likelihoods further.In conclusion, asymptomatic children with AHR are more likely to develop asthma and atopy later in life compared with asymptomatic children without AHR. Persistent AHR, even though initially asymptomatic, was associated with an even greater increased risk of development of asthma. We suggest that rather than considering AHR as a marker of asthma, it should be regarded as a parallel pathological process that may lead to subsequent symptoms and clinical evidence of asthma.

  18. Selective Hyper-responsiveness of the Interferon System in Major Depressive Disorders and Depression Induced by Interferon Therapy

    PubMed Central

    Hoyo-Becerra, Carolina; Erim, Yesim; Kis, Bernhard; Wang, Bo; Scherbaum, Norbert; Gerken, Guido

    2012-01-01

    Background Though an important percentage of patients with chronic hepatitis C virus (HCV) undergoing interferon (IFN) therapy develop depressive symptoms, the role of the IFN system in the pathogenesis of depressive disorders is not well understood. Methods 50 patients with HCV infection were treated with standard combination therapy (pegylated IFN-α2a/ribavirin). IFN-induced gene expression was analyzed to identify genes which are differentially regulated in patients with or without IFN-induced depression. For validation, PBMC from 22 psychiatric patients with a severe depressive episode (SDE) and 11 controls were cultivated in vitro with pegylated IFN-α2a and gene expression was analyzed. Results IFN-induced depression in HCV patients was associated with selective upregulation of 15 genes, including 6 genes that were previously described to be relevant for major depressive disorders or neuronal development. In addition, increased endogenous IFN-production and selective hyper-responsiveness of these genes to IFN stimulation were observed in SDE patients. Conclusions Our data suggest that selective hyper-responsiveness to exogenous (IFN therapy) or endogenous (depressive disorders) type I IFNs may lead to the development of depressive symptoms. These data could lead to the discovery of novel therapeutic approaches to treat IFN-induced and major depressive disorders. PMID:22701688

  19. Epithelium-generated neuropeptide Y induces smooth muscle contraction to promote airway hyperresponsiveness

    PubMed Central

    Li, Shanru; Koziol-White, Cynthia; Jude, Joseph; Jiang, Meiqi; Zhao, Hengjiang; Cao, Gaoyuan; Yoo, Edwin; Jester, William; Morley, Michael P.; Zhou, Su; Wang, Yi; Lu, Min Min; Panettieri, Reynold A.

    2016-01-01

    Asthma is one of the most common chronic diseases globally and can be divided into presenting with or without an immune response. Current therapies have little effect on nonimmune disease, and the mechanisms that drive this type of asthma are poorly understood. Here, we have shown that loss of the transcription factors forkhead box P1 (Foxp1) and Foxp4, which are critical for lung epithelial development, in the adult airway epithelium evokes a non-Th2 asthma phenotype that is characterized by airway hyperresponsiveness (AHR) without eosinophilic inflammation. Transcriptome analysis revealed that loss of Foxp1 and Foxp4 expression induces ectopic expression of neuropeptide Y (Npy), which has been reported to be present in the airways of asthma patients, but whose importance in disease pathogenesis remains unclear. Treatment of human lung airway explants with recombinant NPY increased airway contractility. Conversely, loss of Npy in Foxp1- and Foxp4-mutant airway epithelium rescued the AHR phenotype. We determined that NPY promotes AHR through the induction of Rho kinase activity and phosphorylation of myosin light chain, which induces airway smooth muscle contraction. Together, these studies highlight the importance of paracrine signals from the airway epithelium to the underlying smooth muscle to induce AHR and suggest that therapies targeting epithelial induction of this phenotype may prove useful in treatment of noneosinophilic asthma. PMID:27088802

  20. The effects of nociceptin peptide (N/OFQ)-receptor (NOP) system activation in the airways.

    PubMed

    Singh, Shailendra R; Sullo, Nikol; D'Agostino, Bruno; Brightling, Christopher E; Lambert, David G

    2013-01-01

    The heptadecapeptide nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the N/OFQ peptide (NOP) receptor. It is cleaved from a larger precursor identified as prepronociceptin (ppN/OFQ). NOP is a member of the seven transmembrane-spanning G-protein coupled receptor (GPCR) family. ppN/OFQ and NOP receptors are widely distributed in different human tissues. Asthma is a complex heterogeneous disease characterized by variable airflow obstruction, bronchial hyper-responsiveness and chronic airway inflammation. Limited therapeutic effectiveness of currently available asthma therapies warrants identification of new drug compounds. Evidence from animal studies suggests that N/OFQ modulates airway contraction and inflammation. Interestingly up regulation of the N/OFQ-NOP system reduces airway hyper-responsiveness. In contrast, inflammatory cells central to the inflammatory response in asthma may be both sources of N/OFQ and respond to NOP activation. Hence paradoxical dysregulation of the N/OFQ-NOP system may potentially play an important role in regulating airway inflammation and airway tone. To date there is no data on N/OFQ-NOP expression in the human airways. Therefore, the potential role of N/OFQ-NOP system in asthma is unknown. This review focuses on its physiological effects within airways and potential value as a novel asthma therapy. PMID:23123316

  1. Central Role of Cellular Senescence in TSLP-Induced Airway Remodeling in Asthma

    PubMed Central

    Wu, Jinxiang; Dong, Fangzheng; Wang, Rui-An; Wang, Junfei; Zhao, Jiping; Yang, Mengmeng; Gong, Wenbin; Cui, Rutao; Dong, Liang

    2013-01-01

    Background Airway remodeling is a repair process that occurs after injury resulting in increased airway hyper-responsiveness in asthma. Thymic stromal lymphopoietin (TSLP), a vital cytokine, plays a critical role in orchestrating, perpetuating and amplifying the inflammatory response in asthma. TSLP is also a critical factor in airway remodeling in asthma. Objectives To examine the role of TSLP-induced cellular senescence in airway remodeling of asthma in vitro and in vivo. Methods Cellular senescence and airway remodeling were examined in lung specimens from patients with asthma using immunohischemical analysis. Both small molecule and shRNA approaches that target the senescent signaling pathways were used to explore the role of cellular senescence in TSLP-induced airway remodeling in vitro. Senescence-Associated β-galactosidase (SA-β-Gal) staining, and BrdU assays were used to detect cellular senescence. In addition, the Stat3-targeted inhibitor, WP1066, was evaluated in an asthma mouse model to determine if inhibiting cellular senescence influences airway remodeling in asthma. Results Activation of cellular senescence as evidenced by checkpoint activation and cell cycle arrest was detected in airway epithelia samples from patients with asthma. Furthermore, TSLP-induced cellular senescence was required for airway remodeling in vitro. In addition, a mouse asthma model indicates that inhibiting cellular senescence blocks airway remodeling and relieves airway resistance. Conclusion TSLP stimulation can induce cellular senescence during airway remodeling in asthma. Inhibiting the signaling pathways of cellular senescence overcomes TSLP-induced airway remodeling. PMID:24167583

  2. Immunomodulatory Effects of Ambroxol on Airway Hyperresponsiveness and Inflammation

    PubMed Central

    Miyahara, Nobuaki; Matsubara, Shigeki; Taube, Christian; Kitamura, Kenichi; Hirano, Astushi; Tanimoto, Mitsune; Gelfand, Erwin W.

    2016-01-01

    Ambroxol is used in COPD and asthma to increase mucociliary clearance and regulate surfactant levels, perhaps through anti-oxidant and anti-inflammatory activities. To determine the role and effect of ambroxol in an experimental model of asthma, BALB/c mice were sensitized to ovalbumin (OVA) followed by 3 days of challenge. Airway hyperresponsiveness (AHR), lung cell composition and histology, and cytokine and protein carbonyl levels in bronchoalveolar lavage (BAL) fluid were determined. Ambroxol was administered either before the first OVA challenge or was begun after the last allergen challenge. Cytokine production levels from lung mononuclear cells (Lung MNCs) or alveolar macrophages (AM) were also determined. Administration of ambroxol prior to challenge suppressed AHR, airway eosinophilia, goblet cell metaplasia, and reduced inflammation in subepithelial regions. When given after challenge, AHR was suppressed but without effects on eosinophil numbers. Levels of IL-5 and IL-13 in BAL fluid were decreased when the drug was given prior to challenge; when given after challenge, increased levels of IL-10 and IL-12 were detected. Decreased levels of protein carbonyls were detected in BAL fluid following ambroxol treatment after challenge. In vitro, ambroxol increased levels of IL-10, IFN-γ, and IL-12 from Lung MNCs and AM, whereas IL-4, IL-5, and IL-13 production was not altered. Taken together, ambroxol was effective in preventing AHR and airway inflammation through upregulation of Th1 cytokines and protection from oxidative stress in the airways. PMID:27340385

  3. Acid aspiration-induced airways hyperresponsiveness in mice.

    PubMed

    Allen, Gilman B; Leclair, Timothy R; von Reyn, Jessica; Larrabee, Yuna C; Cloutier, Mary E; Irvin, Charles G; Bates, Jason H T

    2009-12-01

    The role of gastroesophageal reflux and micro-aspiration as a trigger of airways hyperresponsiveness (AHR) in patients with asthma is controversial. The role of acid reflux and aspiration as a direct cause of AHR in normal subjects is also unclear. We speculated that aspiration of a weak acid with a pH (1.8) equivalent to the upper range of typical gastric contents would lead to AHR in naive mice. We further speculated that modest reductions in aspirate acidity to a level expected during gastric acid suppression therapy (pH 4.0) would impede aspiration-induced AHR. BALB/c female mice were briefly anesthetized with isoflurane and allowed to aspirate 75 microl of saline with HCl (pH 1.8, 4.0, or 7.4) or underwent sham aspiration. Mice were re-anesthetized 2 or 24 h later, underwent tracheostomy, and were coupled to a mechanical ventilator. Forced oscillations were used to periodically measure respiratory impedance (Zrs) following aerosol delivery of saline and increasing doses of methacholine to measure for AHR. Values for elastance (H), airways resistance (R(N)), and tissue damping (G) were derived from Zrs. Aspirate pH of 1.8 led to a significant overall increase in peak R(N), G, and H compared with pH 4.0 and 7.4 at 2 and 24 h. Differences between pH 7.4 and 4.0 were not significant. In mice aspirating pH 1.8 compared with controls, airway lavage fluid contained more neutrophils, higher protein, and demonstrated higher permeability. We conclude that acid aspiration triggers an acute AHR, driven principally by breakdown of epithelial barrier integrity within the airways. PMID:19797689

  4. Teratogenic impact of dioxin-activated AHR in laboratory animals

    EPA Science Inventory

    AHR and ARNT are expressed in mouse and human palatal shelves and in the urinary tract of the mouse fetus. AHR expression, translocation to the nucleus, binding to DRE, and activation are required for mediation of TCDD-induction of CP and HN. Although the human palate requires a ...

  5. AHR signaling in prostate growth, morphogenesis, and disease

    PubMed Central

    Vezina, Chad M.; Lin, Tien-Min; Peterson, Richard E.

    2010-01-01

    Most evidence of aryl hydrocarbon receptor (AHR) signaling in prostate growth, morphogenesis, and disease stems from research using 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to pharmacologically activate the AHR at various stages of development. This review discusses effects of TCDD on prostate morphogenesis and highlights interactions between AHR and other signaling pathways during normal and aberrant prostate growth. Although AHR signaling modulates estrogen and androgen signaling in other tissues, crosstalk between these steroid hormone receptors and AHR signaling cannot account for actions of TCDD on prostate morphogenesis. Instead, the AHR appears to act within a cooperative framework of developmental signals to regulate timing and patterning of prostate growth. Inappropriate activation of AHR signaling as a result of early life TCDD exposure disrupts the balance of these signals, impairs prostate morphogenesis, and has an imprinting effect on the developing prostate that predisposes to prostate disease in adulthood. Mechanisms of AHR signaling in prostate growth and disease are only beginning to be unraveled and recent studies have revealed its interactions with WNT5A, retinoic acid, fibroblast growth factor 10, and vascular endothelial growth factor signaling pathways. PMID:18977204

  6. TOXICITY OF AHR AGONISTS TO FISH EARLY LIFE STAGES

    EPA Science Inventory

    Fish early life stages are exceptionally sensitive to the lethal toxicity of chemicals that act as arylhydrocarbon receptor (AhR) agonists. Toxicity characterizations based on 2,3,7,8-tetrachlorodibenzo-p-dioxin, generally the most potent AhR agonist, support the toxicity equiva...

  7. Surgical Airway

    PubMed Central

    Patel, Sapna A; Meyer, Tanya K

    2014-01-01

    Close to 3% of all intubation attempts are considered difficult airways, for which a plan for a surgical airway should be considered. Our article provides an overview of the different types of surgical airways. This article provides a comprehensive review of the main types of surgical airways, relevant anatomy, necessary equipment, indications and contraindications, preparation and positioning, technique, complications, and tips for management. It is important to remember that the placement of a surgical airway is a lifesaving procedure and should be considered in any setting when one “cannot intubate, cannot ventilate”. PMID:24741501

  8. Simulator for SUPO, a Benchmark Aqueous Homogeneous Reactor (AHR)

    SciTech Connect

    Klein, Steven Karl; Determan, John C.

    2015-10-14

    A simulator has been developed for SUPO (Super Power) an aqueous homogeneous reactor (AHR) that operated at Los Alamos National Laboratory (LANL) from 1951 to 1974. During that period SUPO accumulated approximately 600,000 kWh of operation. It is considered the benchmark for steady-state operation of an AHR. The SUPO simulator was developed using the process that resulted in a simulator for an accelerator-driven subcritical system, which has been previously reported.

  9. Hyaluronan mediates airway hyperresponsiveness in oxidative lung injury

    PubMed Central

    Lazrak, Ahmed; Creighton, Judy; Yu, Zhihong; Komarova, Svetlana; Doran, Stephen F.; Aggarwal, Saurabh; Emala, Charles W.; Stober, Vandy P.; Trempus, Carol S.; Garantziotis, Stavros

    2015-01-01

    Chlorine (Cl2) inhalation induces severe oxidative lung injury and airway hyperresponsiveness (AHR) that lead to asthmalike symptoms. When inhaled, Cl2 reacts with epithelial lining fluid, forming by-products that damage hyaluronan, a constituent of the extracellular matrix, causing the release of low-molecular-weight fragments (L-HA, <300 kDa), which initiate a series of proinflammatory events. Cl2 (400 ppm, 30 min) exposure to mice caused an increase of L-HA and its binding partner, inter-α-trypsin-inhibitor (IαI), in the bronchoalveolar lavage fluid. Airway resistance following methacholine challenge was increased 24 h post-Cl2 exposure. Intratracheal administration of high-molecular-weight hyaluronan (H-HA) or an antibody against IαI post-Cl2 exposure decreased AHR. Exposure of human airway smooth muscle (HASM) cells to Cl2 (100 ppm, 10 min) or incubation with Cl2-exposed H-HA (which fragments it to L-HA) increased membrane potential depolarization, intracellular Ca2+, and RhoA activation. Inhibition of RhoA, chelation of intracellular Ca2+, blockade of cation channels, as well as postexposure addition of H-HA, reversed membrane depolarization in HASM cells. We propose a paradigm in which oxidative lung injury generates reactive species and L-HA that activates RhoA and Ca2+ channels of airway smooth muscle cells, increasing their contractility and thus causing AHR. PMID:25747964

  10. Mono-Substituted Isopropylated Triaryl Phosphate, a Major Component of Firemaster 550, is an AHR Agonist that Exhibits AHR-Independent Cardiotoxicity in Zebrafish

    PubMed Central

    Gerlach, Cory V.; Das, Siba R.; Volz, David C.; Bisson, William H.; Kolluri, Siva K.; Tanguay, Robert L.

    2014-01-01

    Firemaster 550 (FM550) is an additive flame retardant mixture used within polyurethane foam and is increasingly found in house dust and the environment due to leaching. Despite the widespread use of FM550, very few studies have investigated the potential toxicity of its ingredients during early vertebrate development. In the current study, we sought to specifically investigate mono-substituted isopropylated triaryl phosphate (mITP), a component comprising approximately 32% of FM550, which has been shown to cause cardiotoxicity during zebrafish embryogenesis. Previous research showed that developmental defects are rescued using an aryl hydrocarbon receptor (AHR) antagonist (CH223191), suggesting that mITP-induced toxicity was AHR-dependent. As zebrafish have three known AHR isoforms, we used a functional AHR2 knockout line along with AHR1A-and AHR1B-specific morpholinos to determine which AHR isoform, if any, mediates mITP-induced cardiotoxicity. As in silico structural homology modeling predicted that mITP may bind favorably to both AHR2 and AHR1B isoforms, we evaluated AHR involvement in vivo by measuring CYP1A mRNA and protein expression following exposure to mITP in the presence or absence of CH223191 or AHR-specific morpholinos. Based on these studies, we found that mITP interacts with both AHR2 and AHR1B isoforms to induce CYP1A expression. However, while CH223191 blocked mITP-induced CYP1A induction and cardiotoxicity, knockdown of all three AHR isoforms failed to block mITP-induced cardiotoxicity in the absence of detectable CYP1A induction. Overall, these results suggest that, while mITP is an AHR agonist, mITP causes AHR-independent cardiotoxicity through a pathway that is also antagonized by CH223191. PMID:24865613

  11. Phenotyping airways disease: an A to E approach.

    PubMed

    Gonem, S; Raj, V; Wardlaw, A J; Pavord, I D; Green, R; Siddiqui, S

    2012-12-01

    The airway diseases asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous conditions with overlapping pathophysiological and clinical features. It has previously been proposed that this heterogeneity may be characterized in terms of five relatively independent domains labelled from A to E, namely airway hyperresponsiveness (AHR), bronchitis, cough reflex hypersensitivity, damage to the airways and surrounding lung parenchyma, and extrapulmonary factors. Airway hyperresponsiveness occurs in both asthma and COPD, accounting for variable day to day symptoms, although the mechanisms most likely differ between the two conditions. Bronchitis, or airway inflammation, may be predominantly eosinophilic or neutrophilic, with different treatments required for each. Cough reflex hypersensitivity is thought to underlie the chronic dry cough out of proportion to other symptoms that can occur in association with airways disease. Structural changes associated with airway disease (damage) include bronchial wall thickening, airway smooth muscle hypertrophy, bronchiectasis and emphysema. Finally, a variety of extrapulmonary factors may impact upon airway disease, including rhinosinusitis, gastroesophageal reflux disease, obesity and dysfunctional breathing. This article discusses the A to E concept in detail and describes how this framework may be used to assess and treat patients with airway diseases in the clinic. PMID:23181785

  12. Aryl hydrocarbon receptor (AHR)-active pharmaceuticals are selective AHR modulators in MDA-MB-468 and BT474 breast cancer cells.

    PubMed

    Jin, Un-Ho; Lee, Syng-ook; Safe, Stephen

    2012-11-01

    Leflunomide, flutamide, nimodipine, mexiletine, sulindac, tranilast, 4-hydroxytamoxifen, and omeprazole are pharmaceuticals previously characterized as aryl hydrocarbon receptor (AHR) agonists in various cell lines and animal models. In this study, the eight AHR-active pharmaceuticals were investigated in highly aggressive aryl hydrocarbon (Ah)-responsive BT474 and MDA-MB-468 breast cancer cell lines, and their effects on AHR protein, CYP1A1 (protein and mRNA), CYP1B1 (mRNA), and cell migration were determined. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was used as a positive control. The AHR agonist activities of the pharmaceuticals depended on structure, response, and cell context. Most compounds induced one or more AHR-mediated responses in BT474 cells, whereas in Ah-responsive MDA-MB-468 cells effects of the AHR-active pharmaceuticals were highly variable. 4-Hydroxytamoxifen, mexiletine, and tranilast did not induce CYP1A1 in MDA-MB-468 cells; moreover, in combination with TCDD, mexiletine was a potent AHR antagonist, tranilast was a partial antagonist, and 4-hydroxytamoxifen also exhibited some AHR antagonist activity. Omeprazole and, to a lesser extent, sulindac and leflunomide were full and partial AHR agonists, respectively, in both breast cancer cell lines. These data indicate that the AHR-active pharmaceuticals are selective AHR modulators, and applications of these drugs for targeting the AHR must be confirmed by studies using the most relevant cell context. PMID:22879383

  13. AHR-5850: a potent anti-inflammatory compound.

    PubMed

    Sancilio, L F; Reese, D L; Cheung, S; Alphin, R S

    1977-03-01

    AHR-5850 is a non-steroidal anti-inflammatory compound possessing antipyretic and analgesic properties. AHR-5850 was 16.4 and 22.8 times more potent than phenylbutazone in suppressing acute (Evans blue-carrageenan pleural effusion) and chronic (adjuvant-induced arthritis) inflammation, respectively. The analgesic activity of AHR 5850 was 43 times that of acetylsalicylic acid in the Randall-Selitto assay, and 156 and 56.3 times more potent than phenylbutazone in the acetylcholine-induced abdominal constriction in mice and in the bradykinin-induced nociceptive response in dogs, respectively. Single-dose studies showed that AHR-5850 produced less gastric irritation than acetylsalicylic acid when applied topically to the exposed gastric mucosa of cats or when administered orally to rats and dogs. Upon subchronic oral administration to rats, the therapeutic ratio of AHR-5850 was twice that of phenylbutazone. This was based on the ratio of its potency relative to phenylbutazone in producing intestinal lesions to its anti-inflammatory potency relative to phenylbutazone in the adjuvant-induced arthritis.

  14. Genetic and pharmacological analysis identifies a physiological role for the AHR in epidermal differentiation

    PubMed Central

    van den Bogaard, Ellen; Podolsky, Michael; Smits, Jos; Cui, Xiao; John, Christian; Gowda, Krishne; Desai, Dhimant; Amin, Shantu; Schalkwijk, Joost; Perdew, Gary H.

    2015-01-01

    Stimulation of the aryl hydrocarbon receptor (AHR) by xenobiotics is known to affect epidermal differentiation and skin barrier formation. The physiological role of endogenous AHR signaling in keratinocyte differentiation is not known. We used murine and human skin models to address the hypothesis that AHR activation is required for normal keratinocyte differentiation. Using transcriptome analysis of Ahr-/- and Ahr+/+ murine keratinocytes, we found significant enrichment of differentially expressed genes linked to epidermal differentiation. Primary Ahr-/- keratinocytes showed a significant reduction in terminal differentiation gene and protein expression, similar to Ahr+/+ keratinocytes treated with AHR antagonists GNF351 and CH223191, or the selective AHR modulator (SAhRM), SGA360. In vitro keratinocyte differentiation led to increased AHR levels and subsequent nuclear translocation, followed by induced CYP1A1 gene expression. Monolayer cultured primary human keratinocytes treated with AHR antagonists also showed an impaired terminal differentiation program. Inactivation of AHR activity during human skin equivalent development severely impaired epidermal stratification, terminal differentiation protein expression and stratum corneum formation. As disturbed epidermal differentiation is a main feature of many skin diseases, pharmacological agents targeting AHR signaling or future identification of endogenous keratinocyte-derived AHR ligands should be considered as potential new drugs in dermatology. PMID:25602157

  15. Atopy, airway reactivity and compressed air diving in males.

    PubMed

    Tetzlaff, K; Neubauer, B; Reuter, M; Friege, L

    1998-01-01

    A decline in expiratory flow rates in divers has recently been attributed to chronic exposure to hyberbaric air. Airway hyperresponsiveness (AHR) to stimuli due to a hyperbaric environment may play a certain role in this context. The aim of this study was to determine the prevalence of AHR in compressed air divers and to assess the value of bronchial challenges for prediction of fitness to dive. A cross-sectional sample of 59 healthy male volunteers--28 divers and 31 diving candidates (controls)--who had been found fit to dive in a diving medical examination underwent additional allergy screening (skin prick and serum IgE) and a histamine bronchial challenge. Pre- and postchallenge body plethysmography was completed to assess AHR. AHR to histamine was significantly increased among divers and positively related to diving experience whereas divers and controls did not differ significantly with respect to age, anthropometric data, current smoking habits, skin prick reaction, and elevated serum IgE. Our results indicate an increased prevalence of AHR to nonspecific inhalation stimuli in experienced divers. Bronchial challenge tests may be helpful to detect asthmatics in the medical assessment of fitness to dive and for follow-up examinations during a diver's career. PMID:9730792

  16. Placenta growth factor augments airway hyperresponsiveness via leukotrienes and IL-13.

    PubMed

    Eiymo Mwa Mpollo, Marthe-Sandrine; Brandt, Eric B; Shanmukhappa, Shiva Kumar; Arumugam, Paritha I; Tiwari, Swati; Loberg, Anastacia; Pillis, Devin; Rizvi, Tilat; Lindsey, Mark; Jonck, Bart; Carmeliet, Peter; Kalra, Vijay K; Le Cras, Timothy D; Ratner, Nancy; Wills-Karp, Marsha; Hershey, Gurjit K Khurana; Malik, Punam

    2016-02-01

    Airway hyperresponsiveness (AHR) affects 55%-77% of children with sickle cell disease (SCD) and occurs even in the absence of asthma. While asthma increases SCD morbidity and mortality, the mechanisms underlying the high AHR prevalence in a hemoglobinopathy remain unknown. We hypothesized that placenta growth factor (PlGF), an erythroblast-secreted factor that is elevated in SCD, mediates AHR. In allergen-exposed mice, loss of Plgf dampened AHR, reduced inflammation and eosinophilia, and decreased expression of the Th2 cytokine IL-13 and the leukotriene-synthesizing enzymes 5-lipoxygenase and leukotriene-C4-synthase. Plgf-/- mice treated with leukotrienes phenocopied the WT response to allergen exposure; conversely, anti-PlGF Ab administration in WT animals blunted the AHR. Notably, Th2-mediated STAT6 activation further increased PlGF expression from lung epithelium, eosinophils, and macrophages, creating a PlGF/leukotriene/Th2-response positive feedback loop. Similarly, we found that the Th2 response in asthma patients is associated with increased expression of PlGF and its downstream genes in respiratory epithelial cells. In an SCD mouse model, we observed increased AHR and higher leukotriene levels that were abrogated by anti-PlGF Ab or the 5-lipoxygenase inhibitor zileuton. Overall, our findings indicate that PlGF exacerbates AHR and uniquely links the leukotriene and Th2 pathways in asthma. These data also suggest that zileuton and anti-PlGF Ab could be promising therapies to reduce pulmonary morbidity in SCD.

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

    PubMed

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

    2004-06-01

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

  18. AHR promoter variant modulates its transcription and downstream effectors by allele-specific AHR-SP1 interaction functioning as a genetic marker for vitiligo.

    PubMed

    Wang, Xiaowen; Li, Kai; Liu, Ling; Shi, Qiong; Song, Pu; Jian, Zhe; Guo, Sen; Wang, Gang; Li, Chunying; Gao, Tianwen

    2015-09-15

    Vitiligo is an acquired depigmentation disorder largely caused by defective melanocyte- or autoimmunity-induced melanocyte destruction. The aryl hydrocarbon receptor (AHR) is essential for melanocyte homeostasis and immune process, and abnormal AHR was observed in vitiligo. We previously identified the T allele of AHR -129C > T variant as a protective factor against vitiligo. However, biological characterization underlying such effects is not fully certain, further validation by mechanistic research is warranted and was conducted in the present study. We showed that -129T allele promoted AHR transcriptional activity through facilitating its interaction with SP1 transcription factor (SP1) compared with -129C allele. We subsequently found reduced peripheral AHR and SP1 transcript expressions in vitiligo and a negative correlation of AHR level with disease duration. We also investigated AHR-related cytokines and observed increased serum TNF-α concentration and diminished serum levels of IL-10 and TGF-β1 in vitiligo. Further genetic analysis showed that -129T carriers possessed higher levels of AHR and IL-10 than -129C carriers. Therefore, our study indicates that the modulation of AHR transcription by a promoter variant has a profound influence on vitiligo, not only advancing our understanding on AHR function but also providing novel insight into the pathogenesis of degenerative or autoimmune diseases including vitiligo.

  19. AHR promoter variant modulates its transcription and downstream effectors by allele-specific AHR-SP1 interaction functioning as a genetic marker for vitiligo

    PubMed Central

    Wang, Xiaowen; Li, Kai; Liu, Ling; Shi, Qiong; Song, Pu; Jian, Zhe; Guo, Sen; Wang, Gang; Li, Chunying; Gao, Tianwen

    2015-01-01

    Vitiligo is an acquired depigmentation disorder largely caused by defective melanocyte- or autoimmunity-induced melanocyte destruction. The aryl hydrocarbon receptor (AHR) is essential for melanocyte homeostasis and immune process, and abnormal AHR was observed in vitiligo. We previously identified the T allele of AHR −129C > T variant as a protective factor against vitiligo. However, biological characterization underlying such effects is not fully certain, further validation by mechanistic research is warranted and was conducted in the present study. We showed that −129T allele promoted AHR transcriptional activity through facilitating its interaction with SP1 transcription factor (SP1) compared with −129C allele. We subsequently found reduced peripheral AHR and SP1 transcript expressions in vitiligo and a negative correlation of AHR level with disease duration. We also investigated AHR-related cytokines and observed increased serum TNF-α concentration and diminished serum levels of IL-10 and TGF-β1 in vitiligo. Further genetic analysis showed that -129T carriers possessed higher levels of AHR and IL-10 than −129C carriers. Therefore, our study indicates that the modulation of AHR transcription by a promoter variant has a profound influence on vitiligo, not only advancing our understanding on AHR function but also providing novel insight into the pathogenesis of degenerative or autoimmune diseases including vitiligo. PMID:26370050

  20. Respiratory health of elite athletes – preventing airway injury: a critical review

    PubMed Central

    Kippelen, Pascale; Fitch, Kenneth D; Anderson, Sandra Doreen; Bougault, Valerie; Boulet, Louis-Philippe; Rundell, Kenneth William; Sue-Chu, Malcolm; McKenzie, Donald C

    2012-01-01

    Elite athletes, particularly those engaged in endurance sports and those exposed chronically to airborne pollutants/irritants or allergens, are at increased risk for upper and lower airway dysfunction. Airway epithelial injury may be caused by dehydration and physical stress applied to the airways during severe exercise hyperpnoea and/or by inhalation of noxious agents. This is thought to initiate an inflammatory cascade/repair process that, ultimately, could lead to airway hyperresponsiveness (AHR) and asthma in susceptible athletes. The authors review the evidence relating to prevention or reduction of the risk of AHR/asthma development. Appropriate measures should be implemented when athletes exercise strenuously in an attempt to attenuate the dehydration stress and reduce the exposure to noxious airborne agents. Environmental interventions are the most important. Non-pharmacological strategies can assist, but currently, pharmacological measures have not been demonstrated to be effective. Whether early prevention of airway injury in elite athletes can prevent or reduce progression to AHR/asthma remains to be established. PMID:22522585

  1. In vitro re-expression of the aryl hydrocarbon receptor (Ahr) in cultured Ahr-deficient mouse antral follicles partially restores the phenotype to that of cultured wild-type mouse follicles

    PubMed Central

    Ziv-Gal, A; Gao, L.; Karman, B.N.; Flaws, J.A.

    2014-01-01

    Background The aryl hydrocarbon receptor (AHR) mediates the toxic effects of various endocrine disrupting chemicals. In female mice, global deletion of the Ahr (AhrKO) results in slow growth of ovarian antral follicles. No studies, however, have examined whether injection of the Ahr restores the phenotypes of cultured AhrKO ovarian antral follicles to wild-type levels. Methods We developed a system to construct a recombinant adenovirus containing the Ahr to re-express the Ahr in AhrKO granulosa cells and whole antral follicles. We then compared follicle growth and levels of factors in the AHR signaling pathway (Ahr, Ahrr, Cyp1a1, and Cyp1b1) in wild-type, AhrKO, and Ahr re-expressed follicles. Further, we compared the response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in wild-type, AhrKO, and Ahr re-expressed follicles. Results AdAhr injection into AhrKO follicles partially restored their growth pattern to wild-type levels. Further, Ahr re-expressed follicles had significantly higher levels of Ahr, Ahrr, Cyp1a1, and Cyp1b1 compared to wild-type follicles. Upon TCDD treatment, only Cyp1a1 levels were significantly higher in Ahr re-expressed follicles compared to the levels in wild-type follicles. Conclusion Our system of re-expression of the Ahr partially restores follicle growth and transcript levels of factors in the AHR signaling pathway to wild-type levels. PMID:25500125

  2. Nicotinic acetylcholine receptor agonist attenuates ILC2-dependent airway hyperreactivity

    PubMed Central

    Galle-Treger, Lauriane; Suzuki, Yuzo; Patel, Nisheel; Sankaranarayanan, Ishwarya; Aron, Jennifer L.; Maazi, Hadi; Chen, Lin; Akbari, Omid

    2016-01-01

    Allergic asthma is a complex and chronic inflammatory disorder that is associated with airway hyperreactivity (AHR) and driven by Th2 cytokine secretion. Type 2 innate lymphoid cells (ILC2s) produce large amounts of Th2 cytokines and contribute to the development of AHR. Here, we show that ILC2s express the α7-nicotinic acetylcholine receptor (α7nAChR), which is thought to have an anti-inflammatory role in several inflammatory diseases. We show that engagement of a specific agonist with α7nAChR on ILC2s reduces ILC2 effector function and represses ILC2-dependent AHR, while decreasing expression of ILC2 key transcription factor GATA-3 and critical inflammatory modulator NF-κB, and reducing phosphorylation of upstream kinase IKKα/β. Additionally, the specific α7nAChR agonist reduces cytokine production and AHR in a humanized ILC2 mouse model. Collectively, our data suggest that α7nAChR expressed by ILC2s is a potential therapeutic target for the treatment of ILC2-mediated asthma. PMID:27752043

  3. Suhuang antitussive capsule at lower doses attenuates airway hyperresponsiveness, inflammation, and remodeling in a murine model of chronic asthma

    PubMed Central

    Zhang, Chao; Zhang, Lan-Hong; Wu, Yin-Fang; Lai, Tian-Wen; Wang, Hai-Sheng; Xiao, Hui; Che, Luan-Qing; Ying, Song-Min; Li, Wen; Chen, Zhi-Hua; Shen, Hua-Hao

    2016-01-01

    Suhuang antitussive capsule (Suhuang), a traditional Chinese medication, is found effective in treating chronic cough and cough variant asthma (CVA). This study aimed to determine the possible effects and underlying mechanisms of Suhuang on chronic ovalbumin (OVA)-induced airway hyperresponsiveness (AHR), inflammation, and remodeling in mice. Mice were randomly assigned to six experimental groups: control, OVA model with or without Suhuang (low dose: 3.5 g/kg, middle dose: 7.0 g/kg, high dose: 14.0 g/kg), or dexamethasone (2.5 mg/kg). AHR, inflammatory cells, cytokines in bronchoalveolar lavage fluid (BALF), lung pathology, mucus production, and airway remodeling were examined. We found Suhuang treated at lower doses effectively inhibited OVA-induced AHR, airway inflammation, mucus production and collagen deposition around the airway. High dose of Suhuang reduced most of the inflammatory hallmarks while exerted inconsiderable effects on the number of macrophages in BALF and AHR. At all doses, Suhuang significantly reduced the levels of interlukin (IL) -13 and transforming growth factor (TGF)-β1, but had little effects on IL-4, IL-5, IL-17A and interferon (IFN)-γ. Thus, Suhuang administration alleviates the pathological changes of chronic asthma likely through inhibition of IL-13 and TGF-β1. Suhuang might be a promising therapy for patients with allergic asthma in the future. PMID:26861679

  4. Increased airway reactivity and hyperinsulinemia in obese mice are linked by ERK signaling in brain stem cholinergic neurons.

    PubMed

    Leiria, Luiz O S; Arantes-Costa, Fernanda M; Calixto, Marina C; Alexandre, Eduardo C; Moura, Rodrigo F; Folli, Franco; Prado, Carla M; Prado, Marco Antonio; Prado, Vania F; Velloso, Licio A; Donato, José; Antunes, Edson; Martins, Milton A; Saad, Mario J A

    2015-05-12

    Obesity is a major risk factor for asthma, which is characterized by airway hyperreactivity (AHR). In obesity-associated asthma, AHR may be regulated by non-TH2 mechanisms. We hypothesized that airway reactivity is regulated by insulin in the CNS, and that the high levels of insulin associated with obesity contribute to AHR. We found that intracerebroventricular (ICV)-injected insulin increases airway reactivity in wild-type, but not in vesicle acetylcholine transporter knockdown (VAChT KD(HOM-/-)), mice. Either neutralization of central insulin or inhibition of extracellular signal-regulated kinases (ERK) normalized airway reactivity in hyperinsulinemic obese mice. These effects were mediated by insulin in cholinergic nerves located at the dorsal motor nucleus of the vagus (DMV) and nucleus ambiguus (NA), which convey parasympathetic outflow to the lungs. We propose that increased insulin-induced activation of ERK in parasympathetic pre-ganglionic nerves contributes to AHR in obese mice, suggesting a drug-treatable link between obesity and asthma.

  5. Suhuang antitussive capsule at lower doses attenuates airway hyperresponsiveness, inflammation, and remodeling in a murine model of chronic asthma.

    PubMed

    Zhang, Chao; Zhang, Lan-Hong; Wu, Yin-Fang; Lai, Tian-Wen; Wang, Hai-Sheng; Xiao, Hui; Che, Luan-Qing; Ying, Song-Min; Li, Wen; Chen, Zhi-Hua; Shen, Hua-Hao

    2016-01-01

    Suhuang antitussive capsule (Suhuang), a traditional Chinese medication, is found effective in treating chronic cough and cough variant asthma (CVA). This study aimed to determine the possible effects and underlying mechanisms of Suhuang on chronic ovalbumin (OVA)-induced airway hyperresponsiveness (AHR), inflammation, and remodeling in mice. Mice were randomly assigned to six experimental groups: control, OVA model with or without Suhuang (low dose: 3.5 g/kg, middle dose: 7.0 g/kg, high dose: 14.0 g/kg), or dexamethasone (2.5 mg/kg). AHR, inflammatory cells, cytokines in bronchoalveolar lavage fluid (BALF), lung pathology, mucus production, and airway remodeling were examined. We found Suhuang treated at lower doses effectively inhibited OVA-induced AHR, airway inflammation, mucus production and collagen deposition around the airway. High dose of Suhuang reduced most of the inflammatory hallmarks while exerted inconsiderable effects on the number of macrophages in BALF and AHR. At all doses, Suhuang significantly reduced the levels of interlukin (IL) -13 and transforming growth factor (TGF)-β1, but had little effects on IL-4, IL-5, IL-17A and interferon (IFN)-γ. Thus, Suhuang administration alleviates the pathological changes of chronic asthma likely through inhibition of IL-13 and TGF-β1. Suhuang might be a promising therapy for patients with allergic asthma in the future. PMID:26861679

  6. Lung morphometry changes in prevention of airway remodeling by protocatechuic aldehyde in asthmatic mice

    PubMed Central

    Zhang, Jiankai; Ma, Mulan; Qin, Dongyun; Huang, Jianping; Cui, Xiaojun; Wu, Yongfu; Yang, Huiling; Fu, Hui; Liao, Cui

    2015-01-01

    Airway remodeling can lead to irreversible airflow obstruction and persistent airway hyper-responsiveness, which is the pathological basis of refractory asthma. To investigate the preventive effect of protocatechuic aldehyde on airway remodeling in asthmatic mice by lung morphometry methods. BALB/c mice were used to establish model of airway remodeling by ovalbumin (OVA) inhalation. Bronchoalveolar lavage fluid (BALF) were collected for eosinophils (EOS) count and detection of interleukin 4 (IL-4), interleukin-13 (IL-13) and interferon (IFN-γ) content. The left lung pathological sections were performed HE, AB-PAS and Masson staining. The epithelial lamina thickness of the left main bronchus (Re), the smooth muscle layer thickness (Rm), the number of goblet cells and goblet cell area percentage (%Ac) and gas side of the road and vascular collagen deposition (%Aco, %Avc) situation were measured. Protocatechuic aldehyde gavage made the reduction of BALF EOS count. IL-4 and IL-13 levels also decreased, while the IFN-γ level increased. The left main bronchus Re, Rm, goblet cell count, Ac% and Aco% and Avc% reduced. Protocatechuic aldehyde can significantly control airway inflammation and prevent airway remodeling. PMID:26221226

  7. [Allergens-induced sensitization alters airway epithelial adhesion molecules expression in mice].

    PubMed

    Zeng, Dan; Tan, Mei-Ling; Xiang, Yang; Qin, Xiao-Qun; Zhu, Li-Ming; Dai, Ai-Guo

    2015-12-25

    To explore the relationship between the epithelial adhesion molecules and immune responses of airway epithelium, we observed the expression of integrin β4 and intercellular adhesion molecule-1 (ICAM-1) in the mice airway epithelium after sensitization with allergens. BALB/c mice were sensitized with intraperitoneal injection of ovalbumin (OVA) or house dust mite (HDM) and then developed airway hyper-responsiveness as determined by barometric whole-body plethysmography. Both OVA and HDM sensitization led to increases of the number of peripheral leukocytes as well as inflammatory cells infiltration in lungs. OVA sensitized mice showed more severe inflammatory cells infiltration than HDM sensitized mice. Immunohistochemistry analysis of mice lung tissues revealed that sensitization with both allergens also led to a decrease of integrin β4 expression and an increase of ICAM-1 expression in airway epithelia. OVA sensitized mice showed a more significant increase of ICAM-1 expression compared with HDM sensitized mice. siRNA mediated silencing of integrin β4 gene in 16HBE cells resulted in an up-regulation of ICAM-1 expression. Our results indicate a possible role of airway epithelial adhesion molecules in allergen-induced airway immune responses. PMID:26701635

  8. Immunomodulation of airway epithelium cell activation by mesenchymal stromal cells ameliorates house dust mite-induced airway inflammation in mice.

    PubMed

    Duong, Khang M; Arikkatt, Jaisy; Ullah, M Ashik; Lynch, Jason P; Zhang, Vivian; Atkinson, Kerry; Sly, Peter D; Phipps, Simon

    2015-11-01

    Allergic asthma is underpinned by T helper 2 (Th2) inflammation. Redundancy in Th2 cytokine function and production by innate and adaptive immune cells suggests that strategies aimed at immunomodulation may prove more beneficial. Hence, we sought to determine whether administration of mesenchymal stromal cells (MSCs) to house dust mite (HDM) (Dermatophagoides pteronyssinus)-sensitized mice would suppress the development of Th2 inflammation and airway hyperresponsiveness (AHR) after HDM challenge. We report that the intravenous administration of allogeneic donor MSCs 1 hour before allergen challenge significantly attenuated the features of allergic asthma, including tissue eosinophilia, Th2 cytokine (IL-5 and IL-13) levels in bronchoalveolar lavage fluid, and AHR. The number of infiltrating type 2 innate lymphoid cells was not affected by MSC transfer, suggesting that MSCs may modulate the adaptive arm of Th2 immunity. The effect of MSC administration was long lasting; all features of allergic airway disease were significantly suppressed in response to a second round of HDM challenge 4 weeks after MSC administration. Further, we observed that MSCs decreased the release of epithelial cell-derived alarmins IL-1α and high mobility group box-1 in an IL-1 receptor antagonist-dependent manner. This significantly decreased the expression of the pro-Th2 cytokine IL-25 and reduced the number of activated and antigen-acquiring CD11c(+)CD11b(+) dendritic cells in the lung and mediastinal lymph nodes. Our findings suggest that MSC administration can ameliorate allergic airway inflammation by blunting the amplification of epithelial-derived inflammatory cytokines induced by HDM exposure and may offer long-term protection against Th2-mediated allergic airway inflammation and AHR.

  9. Airway smooth muscle and bronchospasm: fluctuating, fluidizing, freezing

    PubMed Central

    Krishnan, Ramaswamy; Trepat, Xavier; Nguyen, Trang T. B.; Lenormand, Guillaume; Oliver, Madavi; Fredberg, Jeffrey J.

    2008-01-01

    We review here four recent findings that have altered in a fundamental way our understanding of airways smooth muscle (ASM), its dynamic responses to physiological loading, and their dominant mechanical role in bronchospasm. These findings highlight ASM remodeling processes that are innately out-of-equilibrium and dynamic, and bring to the forefront a striking intersection between topics in condensed matter physics and ASM cytoskeletal biology. By doing so, they place in a new light the role of enhanced ASM mass in airway hyper-responsiveness as well as in the failure of a deep inspiration to relax the asthmatic airway. These findings have established that (i) ASM length is equilibrated dynamically, not statically; (ii) ASM dynamics closely resemble physical features exhibited by so-called soft glassy materials; (iii) static force-length relationships fail to describe dynamically contracted ASM states; (iv) stretch fluidizes the ASM cytoskeleton. Taken together, these observations suggest that at the origin of the bronchodilatory effect of a deep inspiration, and its failure in asthma, may lie glassy dynamics of the ASM cell. PMID:18514592

  10. Inhaled extended-release microparticles of heparin elicit improved pulmonary pharmacodynamics against antigen-mediated airway hyper-reactivity and inflammation.

    PubMed

    Yildiz, Ayca; John, Elinor; Özsoy, Yildiz; Araman, Ahmet; Birchall, James C; Broadley, Kenneth J; Gumbleton, Mark

    2012-09-10

    Inhaled heparin appears to provide benefit in the management of airway hyper-reactivity and inflammation. The pharmacodynamics of inhaled heparin are however transient. Providing sustained heparin concentrations in the respiratory tract should provide for an extended duration of action. We examined the in-vivo efficacy of a nebulised controlled-release microparticle formulation of heparin in modifying antigen-induced airway hyper-reactivity (AHR) and lung inflammation. Heparin-loaded biodegradable poly (D,L-lactide-co-glycolide) microparticles were prepared by spray-drying. Aerosol properties for both nebulised heparin solution and heparin microparticles displayed characteristics consistent with heparin delivery to the respiratory tract. In vitro release assays showed heparin to be released from the microparticles over 8-12 h and for the heparin to remain functional. Temporal pharmacodynamic responses were studied in an ovalbumin-sensitised in vivo model exhibiting AHR and airway inflammation. Despite a reduced total dose of heparin deposited in the airways following nebulisation with heparin microparticles, this treatment led to a more sustained inhibitory effect upon AHR and airway inflammation than equivalent doses of nebulised heparin solution. The work supports extended-release heparin as an inhalation dosing strategy in experimental therapeutic applications aimed at improving the pharmacodynamics of heparin in the treatment of AHR and lung inflammation.

  11. Intratracheal myriocin enhances allergen‐induced Th2 inflammation and airway hyper‐responsiveness

    PubMed Central

    Edukulla, Ramakrishna; Rehn, Kira Lee; Liu, Bo; McAlees, Jaclyn W.; Hershey, Gurjit K.; Wang, Yui Hsi; Lewkowich, Ian

    2016-01-01

    Introduction Ceramide is the central substrate of sphingolipid metabolism and plays a key role in cellular signal transduction pathways, regulating apoptosis, differentiation, and chemotaxis. Alterations in airway ceramide levels are observed in multiple pulmonary diseases and recent human genetic association studies have linked dysregulation of sphingolipid regulatory genes with asthma pathogenesis. Methods Utilizing myriocin, a potent inhibitor of sphingolipid synthesis, we evaluated the immune regulatory role of de novo ceramide generation in vitro and in vivo. Intratracheal myriocin was administered alone or during house dust mite sensitization (HDM) of BALB/C mice and airway hyper‐responsiveness (AHR) was evaluated by invasive plethysmography followed by bronchial lavage (BAL) cytology and cytokine quantification. Results Myriocin inhibits and HDM exposure activates de novo ceramide synthesis in bone marrow‐derived dendritic cells. Mice receiving intratracheal myriocin developed a mild airway neutrophilic infiltrate without inducing a significant increase in AHR. CXCL1 was elevated in the BAL fluid of myriocin‐treated mice while the neutrophilic chemotactic factors anaphylatoxin C5a, leukotriene B4, and IL‐17 were unaffected. HDM treatment combined with myriocin led to a dramatic enhancement of AHR (63% increase over HDM alone, p < 0.001) and increased granulocyte pulmonary infiltrates versus HDM or myriocin alone. Elevated Th2 T cell counts and Th2 cytokines/chemokines (IL5, IL13, CCL17) were observed in mice treated with combined HDM/myriocin compared to HDM alone. Myriocin‐treated pulmonary CD11c+ cells stimulated with HDM secreted significantly more CXCL1 than cells stimulated with HDM alone while HDM stimulated airway epithelial cells showed no change in CXCL1 secretion following myriocin treatment. Conclusions Intratracheal myriocin, likely acting via ceramide synthesis inhibition, enhances allergen‐induced airway inflammation

  12. Inhaled birch pollen extract induces airway hyperresponsiveness via oxidative stress but independently of pollen-intrinsic NADPH oxidase activity, or the TLR4-TRIF pathway.

    PubMed

    Shalaby, Karim H; Allard-Coutu, Alexandra; O'Sullivan, Michael J; Nakada, Emily; Qureshi, Salman T; Day, Brian J; Martin, James G

    2013-07-15

    Oxidative stress in allergic asthma may result from oxidase activity or proinflammatory molecules in pollens. Signaling via TLR4 and its adaptor Toll-IL-1R domain-containing adapter inducing IFN-β (TRIF) has been implicated in reactive oxygen species-mediated acute lung injury and in Th2 immune responses. We investigated the contributions of oxidative stress and TLR4/TRIF signaling to experimental asthma induced by birch pollen exposure exclusively via the airways. Mice were exposed to native or heat-inactivated white birch pollen extract (BPEx) intratracheally and injected with the antioxidants, N-acetyl-L-cysteine or dimethylthiourea, prior to sensitization, challenge, or all allergen exposures, to assess the role of oxidative stress and pollen-intrinsic NADPH oxidase activity in allergic sensitization, inflammation, and airway hyperresponsiveness (AHR). Additionally, TLR4 signaling was antagonized concomitantly with allergen exposure, or the development of allergic airway disease was evaluated in TLR4 or TRIF knockout mice. N-acetyl-L-cysteine inhibited BPEx-induced eosinophilic airway inflammation and AHR except when given exclusively during sensitization, whereas dimethylthiourea was inhibitory even when administered with the sensitization alone. Heat inactivation of BPEx had no effect on the development of allergic airway disease. Oxidative stress-mediated AHR was also TLR4 and TRIF independent; however, TLR4 deficiency decreased, whereas TRIF deficiency increased BPEx-induced airway inflammation. In conclusion, oxidative stress plays a significant role in allergic sensitization to pollen via the airway mucosa, but the pollen-intrinsic NADPH oxidase activity and TLR4 or TRIF signaling are unnecessary for the induction of allergic airway disease and AHR. Pollen extract does, however, activate TLR4, thereby enhancing airway inflammation, which is restrained by the TRIF-dependent pathway.

  13. Reactive airways dysfunction syndrome from acute inhalation of a dishwasher detergent powder.

    PubMed

    Hannu, Timo J; Riihimäki, Vesa E; Piirilä, Päivi L

    2012-01-01

    Reactive airway dysfunction syndrome, a type of occupational asthma without a latency period, is induced by irritating vapour, fumes or smoke. The present report is the first to describe a case of reactive airway dysfunction syndrome caused by acute exposure to dishwater detergent containing sodium metasilicate and sodium dichloroisocyanurate. The diagnosis was based on exposure data, clinical symptoms and signs, as well as respiratory function tests. A 43-year-old nonatopic male apprentice cook developed respiratory symptoms immediately after exposure to a cloud of detergent powder that was made airborne by vigorous shaking of the package. In spirometry, combined obstructive and restrictive ventilatory impairment developed, and the histamine challenge test revealed bronchial hyper-responsiveness. Even routine handling of a strongly caustic detergent, such as filling a dishwasher container, is not entirely risk free and should be performed with caution. PMID:22679618

  14. Reactive airways dysfunction syndrome from acute inhalation of dishwasher detergent powder

    PubMed Central

    Hannu, Timo J; Riihimäki, Vesa E; Piirilä, Päivi L

    2012-01-01

    Reactive airway dysfunction syndrome, a type of occupational asthma without a latency period, is induced by irritating vapour, fumes or smoke. The present report is the first to describe a case of reactive airway dysfunction syndrome caused by acute exposure to dishwater detergent containing sodium metasilicate and sodium dichloroisocyanurate. The diagnosis was based on exposure data, clinical symptoms and signs, as well as respiratory function tests. A 43-year-old nonatopic male apprentice cook developed respiratory symptoms immediately after exposure to a cloud of detergent powder that was made airborne by vigorous shaking of the package. In spirometry, combined obstructive and restrictive ventilatory impairment developed, and the histamine challenge test revealed bronchial hyper-responsiveness. Even routine handling of a strongly caustic detergent, such as filling a dishwasher container, is not entirely risk free and should be performed with caution. PMID:22679618

  15. Cardiac Myocyte-Specific AHR Activation Phenocopies TCDD-Induced Toxicity in Zebrafish

    PubMed Central

    Lanham, Kevin A.; Plavicki, Jessica; Peterson, Richard E.; Heideman, Warren

    2014-01-01

    Exposure of zebrafish embryos to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activates the zebrafish aryl hydrocarbon receptor 2 (AHR) to produce developmental and cardiovascular toxicity. AHR is found in the heart; however, AHR activation by TCDD is not confined to the heart and occurs throughout the organism. In order to understand the cause of cardiotoxicity, we constructed a constitutively active AHR (caAHR) based on the zebrafish AHR2 and expressed it specifically in cardiomyocytes. We show that AHR activation within the cardiomyocytes can account for the heart failure induced by TCDD. Expression of the caAHR within the heart produced cardiac malformations, loss of circulation, and pericardial edema. The heart-specific activation of AHR reproduced several other well-characterized endpoints of TCDD toxicity outside of the cardiovascular system, including defects in swim bladder and craniofacial development. This work identifies a single cellular site of TCDD action, the myocardial cell, that can account for the severe cardiovascular collapse observed following early life stage exposure to TCDD, and contributes to other forms of toxicity. PMID:25037585

  16. Combination effects of AHR agonists and Wnt/β-catenin modulators in zebrafish embryos: Implications for physiological and toxicological AHR functions

    SciTech Connect

    Wincent, Emma; Stegeman, John J.; Jönsson, Maria E.

    2015-04-15

    Wnt/β-catenin signaling regulates essential biological functions and acts in developmental toxicity of some chemicals. The aryl hydrocarbon receptor (AHR) is well-known to mediate developmental toxicity of persistent dioxin-like compounds (DLCs). Recent studies indicate a crosstalk between β-catenin and the AHR in some tissues. However the nature of this crosstalk in embryos is poorly known. We observed that zebrafish embryos exposed to the β-catenin inhibitor XAV939 display effects phenocopying those of the dioxin-like 3,3′,4,4′,5-pentachlorobiphenyl (PCB126). This led us to investigate the AHR interaction with β-catenin during development and ask whether developmental toxicity of DLCs involves antagonism of β-catenin signaling. We examined phenotypes and transcriptional responses in zebrafish embryos exposed to XAV939 or to a β-catenin activator, 1-azakenpaullone, alone or with AHR agonists, either PCB126 or 6-formylindolo[3,2-b]carbazole (FICZ). Alone 1-azakenpaullone and XAV939 both were embryo-toxic, and we found that in the presence of FICZ, the toxicity of 1-azakenpaullone decreased while the toxicity of XAV939 increased. This rescue of 1-azakenpaullone effects occurred in the time window of Ahr2-mediated toxicity and was reversed by morpholino-oligonucleotide knockdown of Ahr2. Regarding PCB126, addition of either 1-azakenpaullone or XAV939 led to lower mortality than with PCB126 alone but surviving embryos showed severe edemas. 1-Azakenpaullone induced transcription of β-catenin-associated genes, while PCB126 and FICZ blocked this induction. The data indicate a stage-dependent antagonism of β-catenin by Ahr2 in zebrafish embryos. We propose that the AHR has a physiological role in regulating β-catenin during development, and that this is one point of intersection linking toxicological and physiological AHR-governed processes.

  17. Combination effects of AHR agonists and Wnt/β-catenin modulators in zebrafish embryos: implications for physiological and toxicological AHR functions

    PubMed Central

    Wincent, Emma; Stegeman, John J.; Jönsson, Maria E.

    2016-01-01

    Wnt/β-catenin signaling regulates essential biological functions and acts in developmental toxicity of some chemicals. The aryl hydrocarbon receptor (AHR) is well-known to mediate developmental toxicity of persistent dioxin-like compounds (DLCs). Recent studies indicate a crosstalk between β-catenin and the AHR in some tissues. However the nature of this crosstalk in embryos is poorly known. We observed that zebrafish embryos exposed to the β-catenin inhibitor XAV939 display effects phenocopying those of the dioxin-like 3,3′,4,4′,5-pentachlorobiphenyl (PCB126). This led us to investigate AHR interaction with β-catenin during development and ask whether developmental toxicity of DLCs involves antagonism of β-catenin signaling. We examined phenotypes and transcriptional responses in zebrafish embryos exposed to XAV939 or to a β-catenin activator, 1-azakenpaullone, alone or with AHR agonists, either PCB126 or 6-formylindolo[3,2-b]carbazole (FICZ). Alone 1-azakenpaullone and XAV939 both were embryo-toxic, and we found that in presence of FICZ, the toxicity of 1-azakenpaullone decreased while the toxicity of XAV939 increased. This rescue of 1-azakenpaullone effects occurred in the time window of Ahr2-mediated toxicity and was reversed by morpholine-oligonucleotide knockdown of Ahr2. Regarding PCB126, addition of either 1-azakenpaullone or XAV939 led to lower mortality than with PCB126 alone but surviving embryos showed severe edemas. 1-Azakenpaullone induced transcription of β-catenin-associated genes, while PCB126 and FICZ blocked this induction. The data indicate a stage-dependent antagonism of β-catenin by Ahr2 in zebrafish embryos. We propose that the AHR has a physiological role in regulating β-catenin during development, and that this is one point of intersection linking toxicological and physiological AHR-governed processes. PMID:25711857

  18. Placenta growth factor augments airway hyperresponsiveness via leukotrienes and IL-13

    PubMed Central

    Eiymo Mwa Mpollo, Marthe-Sandrine; Brandt, Eric B.; Shanmukhappa, Shiva Kumar; Arumugam, Paritha I.; Tiwari, Swati; Loberg, Anastacia; Pillis, Devin; Rizvi, Tilat; Lindsey, Mark; Jonck, Bart; Carmeliet, Peter; Kalra, Vijay K.; Le Cras, Timothy D.; Ratner, Nancy; Wills-Karp, Marsha; Hershey, Gurjit K. Khurana; Malik, Punam

    2015-01-01

    Airway hyperresponsiveness (AHR) affects 55%–77% of children with sickle cell disease (SCD) and occurs even in the absence of asthma. While asthma increases SCD morbidity and mortality, the mechanisms underlying the high AHR prevalence in a hemoglobinopathy remain unknown. We hypothesized that placenta growth factor (PlGF), an erythroblast-secreted factor that is elevated in SCD, mediates AHR. In allergen-exposed mice, loss of Plgf dampened AHR, reduced inflammation and eosinophilia, and decreased expression of the Th2 cytokine IL-13 and the leukotriene-synthesizing enzymes 5-lipoxygenase and leukotriene-C4-synthase. Plgf–/– mice treated with leukotrienes phenocopied the WT response to allergen exposure; conversely, anti-PlGF Ab administration in WT animals blunted the AHR. Notably, Th2-mediated STAT6 activation further increased PlGF expression from lung epithelium, eosinophils, and macrophages, creating a PlGF/leukotriene/Th2-response positive feedback loop. Similarly, we found that the Th2 response in asthma patients is associated with increased expression of PlGF and its downstream genes in respiratory epithelial cells. In an SCD mouse model, we observed increased AHR and higher leukotriene levels that were abrogated by anti-PlGF Ab or the 5-lipoxygenase inhibitor zileuton. Overall, our findings indicate that PlGF exacerbates AHR and uniquely links the leukotriene and Th2 pathways in asthma. These data also suggest that zileuton and anti-PlGF Ab could be promising therapies to reduce pulmonary morbidity in SCD. PMID:26690703

  19. Relationship between sputum inflammatory markers and osmotic airway hyperresponsiveness during induction of sputum in asthmatic patients.

    PubMed Central

    Jang, A. S.; Choi, I. S.

    2001-01-01

    Hypertonic saline aerosols are being used increasingly for bronchial provocation testing and induction of sputum. The aims of this study were to assess the response to challenge with 3% hypertonic saline administered via a ultrasonic nebulizer in patients with asthma, and to evaluate relationship between % fall of FEV1 during induction of sputum (osmotic airway hyperresponsiveness; osmotic AHR) and biochemical markers of induced sputum. We investigated changes in FEV1 in response to inhaling ultrasonically nebulized 3% saline in 25 patients with asthma and 10 control subjects. FEV1 was measured before, during, and after induction of sputum. We used fluoroimmunoassay to detect eosinophil cationic protein (ECP), immunohistochemical staining to detect EG2+ (secretory form of ECP) eosinophils, and a sandwich ELISA to detect interleukin (IL)-5. Protein concentration was determined by using bicinchoninic acid protein assay reagent. Asthmatics, compared with controls, had significantly higher osmotic AHR. Moderate to severe asthmatics had significantly higher osmotic AHR compared to mild asthmatics. Osmotic AHR was significantly correlated with the proportion of eosinophils, the levels of ECP, EG2+ eosinophils, IL-5, and proteins. These data suggest that osmotic AHR is closely related to the clinical status and biochemical markers of sputum supernatant in asthmatic patients. PMID:11511785

  20. TCDD and omeprazole prime platelets through the aryl hydrocarbon receptor (AhR) non-genomic pathway.

    PubMed

    Pombo, Mónica; Lamé, Michael W; Walker, Naomi J; Huynh, Danh H; Tablin, Fern

    2015-05-19

    The role of the aryl hydrocarbon receptor (AhR) in hemostasis has recently gained increased attention. Here, we demonstrate, by qRT-PCR and western blot, that human platelets express both AhR mRNA and AhR protein. AhR protein levels increase in a dose dependent manner when incubated with either 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or omeprazole. Treatment of platelets with puromycin blocks increased AhR protein synthesis in the presence of AhR activators. Additionally, treatment of platelets with either activator results in phosphorylation of p38MAPK and cPLA2, two key signaling molecules in platelet activation pathways. Using the AhR competitive inhibitors alpha naphthoflavone and CH-223191, we show that phosphorylation of p38MAPK is AhR dependent. Further, inhibition of p38MAPK blocks downstream cPLA2 phosphorylation induced by TCDD or omeprazole. Treatment with AhR activators results in platelet priming, as demonstrated by increased platelet aggregation, which is inhibited by AhR antagonists. Our data support a model of the platelet AhR non-genomic pathway in which treatment with AhR activators results in increased expression of the AhR, phosphorylation of p38MAPK and cPLA2, leading to platelet priming in response to agonist. PMID:25797602

  1. Use of natural AhR ligands as potential therapeutic modalities against inflammatory disorders

    PubMed Central

    Busbee, Philip B; Rouse, Michael; Nagarkatti, Mitzi; Nagarkatti, Prakash S

    2014-01-01

    The aim of this review is to discuss research involving ligands for the aryl hydrocarbon receptor (AhR) and their role in immunomodulation. While activation of the AhR is well known for its ability to regulate the biochemical and toxic effects of environmental chemicals, more recently an exciting discovery has been made indicating that AhR ligation can also regulate T-cell differentiation, specifically through activation of Foxp3+ regulatory T cells (Tregs) and downregulation of the proinflammatory Th17 cells. Such findings have opened new avenues of research on the possibility of targeting the AhR to treat inflammatory and autoimmune diseases. Specifically, this review will discuss the current research involving natural and dietary AhR ligands. In addition, evidence indicating the potential use of these ligands in regulating inflammation in various diseases will be highlighted. The importance of the AhR in immunological processes can be illustrated by expression of this receptor on a majority of immune cell types. In addition, AhR signaling pathways have been reported to influence a number of genes responsible for mediating inflammation and other immune responses. As interest in the AhR and its ligands increases, it seems prudent to consolidate current research on the contributions of these ligands to immune regulation during the course of inflammatory diseases. PMID:23731446

  2. 75 FR 49550 - Fifth Meeting: RTCA Special Committee 219: Attitude and Heading Reference System (AHRS)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-13

    ... Federal Aviation Administration Fifth Meeting: RTCA Special Committee 219: Attitude and Heading Reference...: Notice of RTCA Special Committee 219: Attitude and Heading Reference System (AHRS). SUMMARY: The FAA is... Heading Reference System (AHRS). DATES: The meeting will be held September 14-16, 2010 from 9 a.m. to 5...

  3. Microarray analysis of the AHR system: Tissue-specific flexibility in signal and target genes

    SciTech Connect

    Frericks, Markus; Meissner, Marc; Esser, Charlotte . E-mail: chesser@uni-duesseldorf.de

    2007-05-01

    Data mining published microarray experiments require that expression profiles are directly comparable. We performed linear global normalization on the data of 1967 Affymetrix U74av2 microarrays, i.e. the transcriptomes of > 100 murine tissues or cell types. The mathematical transformation effectively nullifies inter-experimental or inter-laboratory differences between microarrays. The correctness of expression values was validated by quantitative RT-PCR. Using the database we analyze components of the aryl hydrocarbon receptor (AHR) signaling pathway in various tissues. We identified lineage and differentiation specific variant expression of AHR, ARNT, and HIF1{alpha} in the T-cell lineage and high expression of CYP1A1 in immature B cells and dendritic cells. Performing co-expression analysis we found unorthodox expression of the AHR in the absence of ARNT, particularly in stem cell populations, and can reject the hypothesis that ARNT2 takes over and is highly expressed when ARNT expression is low or absent. Furthermore the AHR shows no co-expression with any other transcript present on the chip. Analysis of differential gene expression under 308 conditions revealed 53 conditions under which the AHR is regulated, numerous conditions under which an intrinsic AHR action is modified as well as conditions activating the AHR even in the absence of known AHR ligands. Thus meta-analysis of published expression profiles is a powerful tool to gain novel insights into known and unknown systems.

  4. Nrf2 reduces allergic asthma in mice through enhanced airway epithelial cytoprotective function.

    PubMed

    Sussan, Thomas E; Gajghate, Sachin; Chatterjee, Samit; Mandke, Pooja; McCormick, Sarah; Sudini, Kuladeep; Kumar, Sarvesh; Breysse, Patrick N; Diette, Gregory B; Sidhaye, Venkataramana K; Biswal, Shyam

    2015-07-01

    Asthma development and pathogenesis are influenced by the interactions of airway epithelial cells and innate and adaptive immune cells in response to allergens. Oxidative stress is an important mediator of asthmatic phenotypes in these cell types. Nuclear erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that is the key regulator of the response to oxidative and environmental stress. We previously demonstrated that Nrf2-deficient mice have heightened susceptibility to asthma, including elevated oxidative stress, inflammation, mucus, and airway hyperresponsiveness (AHR) (Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, Yamamoto M, Kensler TW, Tuder RM, Georas SN, Biswal S. J Exp Med 202: 47-59, 2005). Here we dissected the role of Nrf2 in lung epithelial cells and tested whether genetic or pharmacological activation of Nrf2 reduces allergic asthma in mice. Cell-specific activation of Nrf2 in club cells of the airway epithelium significantly reduced allergen-induced AHR, inflammation, mucus, Th2 cytokine secretion, oxidative stress, and airway leakiness and increased airway levels of tight junction proteins zonula occludens-1 and E-cadherin. In isolated airway epithelial cells, Nrf2 enhanced epithelial barrier function and increased localization of zonula occludens-1 to the cell surface. Pharmacological activation of Nrf2 by 2-trifluoromethyl-2'-methoxychalone during the allergen challenge was sufficient to reduce allergic inflammation and AHR. New therapeutic options are needed for asthma, and this study demonstrates that activation of Nrf2 in lung epithelial cells is a novel potential therapeutic target to reduce asthma susceptibility.

  5. Persistence of Serotonergic Enhancement of Airway Response in a Model of Childhood Asthma

    PubMed Central

    Moore, Brian D.; Hyde, Dallas M.; Miller, Lisa A.; Wong, Emily M.

    2014-01-01

    The persistence of airway hyperresponsiveness (AHR) and serotonergic enhancement of airway smooth muscle (ASM) contraction induced by ozone (O3) plus allergen has not been evaluated. If this mechanism persists after a prolonged recovery, it would indicate that early-life exposure to O3 plus allergen induces functional changes predisposing allergic individuals to asthma-related symptoms throughout life, even in the absence of environmental insult. A persistent serotonergic mechanism in asthma exacerbations may offer a novel therapeutic target, widening treatment options for patients with asthma. The objective of this study was to determine if previously documented AHR and serotonin-enhanced ASM contraction in allergic monkeys exposed to O3 plus house dust mite allergen (HDMA) persist after prolonged recovery. Infant rhesus monkeys sensitized to HDMA were exposed to filtered air (FA) (n = 6) or HDMA plus O3 (n = 6) for 5 months. Monkeys were then housed in a FA environment for 30 months. At 3 years, airway responsiveness was assessed. Airway rings were then harvested, and ASM contraction was evaluated using electrical field stimulation with and without exogenous serotonin and serotonin-subtype receptor antagonists. Animals exposed to O3 plus HDMA exhibited persistent AHR. Serotonin exacerbated the ASM contraction in the exposure group but not in the FA group. Serotonin subtype receptors 2, 3, and 4 appear to drive the response. Our study shows that AHR and serotonin-dependent exacerbation of cholinergic-mediated ASM contraction induced by early-life exposure to O3 plus allergen persist for at least 2.5 years and may contribute to a persistent asthma phenotype. PMID:24484440

  6. Persistence of serotonergic enhancement of airway response in a model of childhood asthma.

    PubMed

    Moore, Brian D; Hyde, Dallas M; Miller, Lisa A; Wong, Emily M; Schelegle, Edward S

    2014-07-01

    The persistence of airway hyperresponsiveness (AHR) and serotonergic enhancement of airway smooth muscle (ASM) contraction induced by ozone (O3) plus allergen has not been evaluated. If this mechanism persists after a prolonged recovery, it would indicate that early-life exposure to O3 plus allergen induces functional changes predisposing allergic individuals to asthma-related symptoms throughout life, even in the absence of environmental insult. A persistent serotonergic mechanism in asthma exacerbations may offer a novel therapeutic target, widening treatment options for patients with asthma. The objective of this study was to determine if previously documented AHR and serotonin-enhanced ASM contraction in allergic monkeys exposed to O3 plus house dust mite allergen (HDMA) persist after prolonged recovery. Infant rhesus monkeys sensitized to HDMA were exposed to filtered air (FA) (n = 6) or HDMA plus O3 (n = 6) for 5 months. Monkeys were then housed in a FA environment for 30 months. At 3 years, airway responsiveness was assessed. Airway rings were then harvested, and ASM contraction was evaluated using electrical field stimulation with and without exogenous serotonin and serotonin-subtype receptor antagonists. Animals exposed to O3 plus HDMA exhibited persistent AHR. Serotonin exacerbated the ASM contraction in the exposure group but not in the FA group. Serotonin subtype receptors 2, 3, and 4 appear to drive the response. Our study shows that AHR and serotonin-dependent exacerbation of cholinergic-mediated ASM contraction induced by early-life exposure to O3 plus allergen persist for at least 2.5 years and may contribute to a persistent asthma phenotype. PMID:24484440

  7. Vitamin D deficiency causes airway hyperresponsiveness, increases airway smooth muscle mass, and reduces TGF‐β expression in the lungs of female BALB/c mice

    PubMed Central

    Foong, Rachel E.; Shaw, Nicole C.; Berry, Luke J.; Hart, Prue H.; Gorman, Shelley; Zosky, Graeme R.

    2014-01-01

    Abstract Vitamin D deficiency is associated with disease severity in asthma. We tested whether there is a causal association between vitamin D deficiency, airway smooth muscle (ASM) mass, and the development of airway hyperresponsiveness (AHR). A physiologically relevant mouse model of vitamin D deficiency was developed by raising BALB/c mice on vitamin D‐deficient or ‐replete diets. AHR was assessed by measuring lung function responses to increasing doses of inhaled methacholine. Five‐micron sections from formalin‐fixed lungs were used for ASM measurement and assessment of lung structure using stereological methods. Transforming growth factor (TGF)‐β levels were measured in bronchoalveolar lavage fluid (BALF). Lungs were dissected from embryonic day (E) 17.5 vitamin D‐deficient and ‐replete fetal mice for quantification of ASM density and relative gene expression of TGF‐β signaling pathway molecules. Eight‐week‐old adult vitamin D‐deficient female mice had significantly increased airway resistance and ASM in the large airways compared with controls. Vitamin D‐deficient female mice had a smaller lung volume, volume of parenchyma, and alveolar septa. Both vitamin D‐deficient male and female mice had reduced TGF‐β levels in BALF. Vitamin D deficiency did not have an effect on ASM density in E17.5 mice, however, expression of TGF‐β1 and TGF‐β receptor I was downregulated in vitamin D‐deficient female fetal mice. Decreased expression of TGF‐β1 and TGF‐β receptor I during early lung development in vitamin D‐deficient mice may contribute to airway remodeling and AHR in vitamin D‐deficient adult female mice. This study provides a link between vitamin D deficiency and respiratory symptoms in chronic lung disease. PMID:24760528

  8. 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. PMID:3533597

  9. Accurate Orientation Estimation Using AHRS under Conditions of Magnetic Distortion

    PubMed Central

    Yadav, Nagesh; Bleakley, Chris

    2014-01-01

    Low cost, compact attitude heading reference systems (AHRS) are now being used to track human body movements in indoor environments by estimation of the 3D orientation of body segments. In many of these systems, heading estimation is achieved by monitoring the strength of the Earth's magnetic field. However, the Earth's magnetic field can be locally distorted due to the proximity of ferrous and/or magnetic objects. Herein, we propose a novel method for accurate 3D orientation estimation using an AHRS, comprised of an accelerometer, gyroscope and magnetometer, under conditions of magnetic field distortion. The system performs online detection and compensation for magnetic disturbances, due to, for example, the presence of ferrous objects. The magnetic distortions are detected by exploiting variations in magnetic dip angle, relative to the gravity vector, and in magnetic strength. We investigate and show the advantages of using both magnetic strength and magnetic dip angle for detecting the presence of magnetic distortions. The correction method is based on a particle filter, which performs the correction using an adaptive cost function and by adapting the variance during particle resampling, so as to place more emphasis on the results of dead reckoning of the gyroscope measurements and less on the magnetometer readings. The proposed method was tested in an indoor environment in the presence of various magnetic distortions and under various accelerations (up to 3 g). In the experiments, the proposed algorithm achieves <2° static peak-to-peak error and <5° dynamic peak-to-peak error, significantly outperforming previous methods. PMID:25347584

  10. The antidiabetic agent glibenclamide protects airway hyperresponsiveness and inflammation in mice.

    PubMed

    Cui, Wei; Zhang, Shufang; Cai, Zhijian; Hu, Xinlei; Zhang, Ruifeng; Wang, Yong; Li, Na; Chen, Zhihua; Zhang, Gensheng

    2015-04-01

    Glibenclamide has a newly discovered role in inflammation regulation besides its antidiabetic effect. As an inhibitor of ATP-sensitive potassium (KATP) channel, glibenclamide antagonizes the relaxation of the tracheal smooth muscle. This indicates that glibenclamide might attenuate airway inflammation while aggravate airway hyperresponsiveness (AHR) in asthmatics. Clinically, many diabetics with asthma are prescribed with glibenclamide to control blood glucose. However, whether glibenclamide could exert any effects on asthmatic inflammation remains unknown. Using an ovalbumin (OVA)-induced mouse model of asthma, we evaluated the effects of glibenclamide on the AHR and inflammation. Interestingly, glibenclamide reduced all the cardinal features of asthma in OVA-challenged mice, including AHR, airway inflammation, and T-helper type 2 (Th2) cytokines. Glibenclamide also downregulated OVA-induced expressions of vascular cell adhesion molecule 1 (VCAM-1) and phosphorylated signal transducer and activator of transcription 6 (p-STAT6) in the lung. In addition, increased sulfonylurea receptor 1 (SUR1) expression in the lung was observed after the OVA challenge. These findings suggest that the classic sulfonylurea glibenclamide plays an important protective role in the development of asthma, which not only provides the evidence for the safety of prescribed glibenclamide in diabetics combined with asthma but also indicates a possible new therapeutic for asthma via targeting glibenclamide-related pathways.

  11. Regulation of actin dynamics by WNT-5A: implications for human airway smooth muscle contraction

    PubMed Central

    Koopmans, Tim; Kumawat, Kuldeep; Halayko, Andrew J; Gosens, Reinoud

    2016-01-01

    A defining feature of asthma is airway hyperresponsiveness (AHR), which underlies the exaggerated bronchoconstriction response of asthmatics. The role of the airway smooth muscle (ASM) in AHR has garnered increasing interest over the years, but how asthmatic ASM differs from healthy ASM is still an active topic of debate. WNT-5A is increasingly expressed in asthmatic ASM and has been linked with Th2-high asthma. Due to its link with calcium and cytoskeletal remodelling, we propose that WNT-5A may modulate ASM contractility. We demonstrated that WNT-5A can increase maximum isometric tension in bovine tracheal smooth muscle strips. In addition, we show that WNT-5A is preferentially expressed in contractile human airway myocytes compared to proliferative cells, suggesting an active role in maintaining contractility. Furthermore, WNT-5A treatment drives actin polymerisation, but has no effect on intracellular calcium flux. Next, we demonstrated that WNT-5A directly regulates TGF-β1-induced expression of α-SMA via ROCK-mediated actin polymerization. These findings suggest that WNT-5A modulates fundamental mechanisms that affect ASM contraction and thus may be of relevance for AHR in asthma. PMID:27468699

  12. Construction of a Der p2-transgenic plant for the alleviation of airway inflammation.

    PubMed

    Lee, C C; Ho, H; Lee, K T; Jeng, S T; Chiang, B L

    2011-09-01

    In clinical therapy, the amount of antigen administered to achieve oral tolerance for allergic diseases is large, and the cost is a major consideration. In this study, we used tobacco plants to develop a large-scale protein production system for allergen-specific immunotherapy, and we investigated the mechanisms of oral tolerance induced by a transgenic plant-derived antigen. We used plants (tobacco leaves) transgenic for the Dermatophagoides pteronyssinus 2 (Der p2) antigen to produce Der p2. Mice received total protein extract from Der p2 orally once per day over 6 days (days 0-2 and days 6-8). Mice were also sensitized and challenged with yeast-derived recombinant Der p2 (rDer p2), after which the mice were examined for airway hyper-responsiveness and airway inflammation. After sensitization and challenge with rDer p2, mice that were fed with total protein extracted from transgenic plants showed decreases in serum Der p2-specific IgE and IgG1 titers, decreased IL-5 and eotaxin levels in bronchial alveolar lavage fluid, and eosinophil infiltration in the airway. In addition, hyper-responsiveness was also decreased in mice that were fed with total protein extracted from transgenic plants, and CD4(+)CD25(+)Foxp3(+) regulatory T cells were significantly increased in mediastinal and mesenteric lymph nodes. Furthermore, splenocytes isolated from transgenic plant protein-fed mice exhibited decreased proliferation and increased IL-10 secretion after stimulation with rDer p2. The data here suggest that allergen-expressing transgenic plants could be used for therapeutic purposes for allergic diseases.

  13. Acebrophylline: an airway mucoregulator and anti-inflammatory agent.

    PubMed

    Pozzi, E

    2007-06-01

    Acebrophylline is an airway mucus regulator with antiinflammatory action. The drug's approach involves several points of attack in obstructive airway disease. The molecule contains ambroxol, which facilitates various steps in the biosynthesis of pulmonary surfactant, theophylline-7 acetic acid whose carrier function raises blood levels of ambroxol, thus rapidly and intensely stimulating surfactant production. The resulting reduction in the viscosity and adhesivity of the mucus greatly improves ciliary clearance. By deviating phosphatidylcholine towards surfactant synthesis, making it no longer available for the synthesis of inflammatory mediators such as the leukotrienes, acebrophylline also exerts an inflammatory effect. This is confirmed in vivo by the reduction in aspecific bronchial hyper-responsiveness in patients with stable bronchial asthma. On a clinical level, acebrophylline is therapeutically effective in patients with acute or chronic bronchitis, chronic obstructive or asthma-like bronchitis and recurrence of chronic bronchitis; it reduces the frequency of episodes of bronchial obstruction and reduces the need for beta2-agonists, and improves indexes of ventilatory function.

  14. INSIGHTS FROM AHR AND ARNT GENE KNOCKOUT STUDIES REGARDING RESPONSES TO TCDD AND REGULATION OF NORMAL EMBRYONIC DEVELOPMENT

    EPA Science Inventory

    The aryl hydrocarbon receptor (AhR) and the AhR nuclear translocator (ARNT) are members of the Per-ARNT-Sim (PAS) family of proteins. The AhR binds members of the chemical family that includes dioxins, furans and coplanar polychlorinated biphenyls (PCBs). A ligand-AhR-ARNT comp...

  15. The novel compound Sul-121 inhibits airway inflammation and hyperresponsiveness in experimental models of chronic obstructive pulmonary disease

    PubMed Central

    Han, Bing; Poppinga, Wilfred J.; Zuo, Haoxiao; Zuidhof, Annet B.; Bos, I. Sophie T.; Smit, Marieke; Vogelaar, Pieter; Krenning, Guido; Henning, Robert H.; Maarsingh, Harm; Halayko, Andrew J.; van Vliet, Bernard; Stienstra, Stef; Graaf, Adrianus Cornelis van der; Meurs, Herman; Schmidt, Martina

    2016-01-01

    COPD is characterized by persistent airflow limitation, neutrophilia and oxidative stress from endogenous and exogenous insults. Current COPD therapy involving anticholinergics, β2-adrenoceptor agonists and/or corticosteroids, do not specifically target oxidative stress, nor do they reduce chronic pulmonary inflammation and disease progression in all patients. Here, we explore the effects of Sul-121, a novel compound with anti-oxidative capacity, on hyperresponsiveness (AHR) and inflammation in experimental models of COPD. Using a guinea pig model of lipopolysaccharide (LPS)-induced neutrophilia, we demonstrated that Sul-121 inhalation dose-dependently prevented LPS-induced airway neutrophilia (up to ~60%) and AHR (up to ~90%). Non-cartilaginous airways neutrophilia was inversely correlated with blood H2S, and LPS-induced attenuation of blood H2S (~60%) was prevented by Sul-121. Concomitantly, Sul-121 prevented LPS-induced production of the oxidative stress marker, malondialdehyde by ~80%. In immortalized human airway smooth muscle (ASM) cells, Sul-121 dose-dependently prevented cigarette smoke extract-induced IL-8 release parallel with inhibition of nuclear translocation of the NF-κB subunit, p65 (each ~90%). Sul-121 also diminished cellular reactive oxygen species production in ASM cells, and inhibited nuclear translocation of the anti-oxidative response regulator, Nrf2. Our data show that Sul-121 effectively inhibits airway inflammation and AHR in experimental COPD models, prospectively through inhibition of oxidative stress. PMID:27229886

  16. Emergency airway puncture

    MedlinePlus

    Emergency airway puncture is the placement of a hollow needle through the throat into the airway. It ... efforts to assist with breathing have failed. A hollow needle or tube can be inserted into the ...

  17. 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…

  18. Models to study airway smooth muscle contraction in vivo, ex vivo and in vitro: implications in understanding asthma.

    PubMed

    Wright, David; Sharma, Pawan; Ryu, Min-Hyung; Rissé, Paul-Andre; Ngo, Melanie; Maarsingh, Harm; Koziol-White, Cynthia; Jha, Aruni; Halayko, Andrew J; West, Adrian R

    2013-02-01

    Asthma is a chronic obstructive airway disease characterised by airway hyperresponsiveness (AHR) and airway wall remodelling. The effector of airway narrowing is the contraction of airway smooth muscle (ASM), yet the question of whether an inherent or acquired dysfunction in ASM contractile function plays a significant role in the disease pathophysiology remains contentious. The difficulty in determining the role of ASM lies in limitations with the models used to assess contraction. In vivo models provide a fully integrated physiological response but ASM contraction cannot be directly measured. Ex vivo and in vitro models can provide more direct assessment of ASM contraction but the loss of factors that may modulate ASM responsiveness and AHR, including interaction between multiple cell types and disruption of the mechanical environment, precludes a complete understanding of the disease process. In this review we detail key advantages of common in vivo, ex vivo and in vitro models of ASM contraction, as well as emerging tissue engineered models of ASM and whole airways. We also highlight important findings from each model with respect to the pathophysiology of asthma.

  19. Identification and expression of aryl hydrocarbon receptors (AhR1 and AhR2) provide insight in an evolutionary context regarding sensitivity of white sturgeon (Acipenser transmontanus) to dioxin-like compounds.

    PubMed

    Doering, Jon A; Wiseman, Steve; Beitel, Shawn C; Giesy, John P; Hecker, Markus

    2014-05-01

    Sturgeons are ancient fishes, which are endangered in many parts of the world. Due to their benthic nature and longevity, sturgeon are at great risk of exposure to bioaccumulative contaminants such as dioxin-like compounds (DLCs). Despite their endangered status, little research has been conducted to characterize the relative sensitivity of sturgeons to DLCs. Proper assessment of risk of DLCs posed to these fishes therefore, requires a better understanding of this sensitivity and the factors that are driving it. Adverse effects associated with exposure to DLCs are mediated by the aryl hydrocarbon receptor (AhR). This study identified and characterized two distinct AhRs, AhR1 and AhR2, in white sturgeon (Acipenser transmontanus) for the first time as a first step in studying the relative sensitivities of sturgeons to DLCs. Furthermore, tissue-specific expression of both AhRs under basal conditions and in response to exposure to the model DLC, β-naphthoflavone (βNF), was determined. The sequence of amino acids of AhR1 of white sturgeon had greater similarity to AhRs of tetrapods, including amphibians, birds, and mammals, than to AhR1s of other fishes. The sequence of amino acids in the ligand binding domain of the AhR1 had greater than 80% similarity to AhRs known to bind DLCs and was less similar to AhRs not known to bind DLCs. AhR2 of white sturgeon had greatest similarity to AhR2 of other fishes. Profiles of expression of AhR1 and AhR2 in white sturgeon were distinct from those known in other fishes and appear more similar to profiles observed in birds. Expressions of both AhR1 and AhR2 of white sturgeon were greatest in liver and heart, which are target organs for DLCs. Furthermore, abundances of transcripts of AhR1 and AhR2 in all tissues from white sturgeon were greater than controls (up to 35-fold) following exposure to βNF. Based upon both AhRs having similar abundances of transcript in target organs of DLC toxicity, both AhRs being up-regulated following

  20. Identification and expression of aryl hydrocarbon receptors (AhR1 and AhR2) provide insight in an evolutionary context regarding sensitivity of white sturgeon (Acipenser transmontanus) to dioxin-like compounds.

    PubMed

    Doering, Jon A; Wiseman, Steve; Beitel, Shawn C; Giesy, John P; Hecker, Markus

    2014-05-01

    Sturgeons are ancient fishes, which are endangered in many parts of the world. Due to their benthic nature and longevity, sturgeon are at great risk of exposure to bioaccumulative contaminants such as dioxin-like compounds (DLCs). Despite their endangered status, little research has been conducted to characterize the relative sensitivity of sturgeons to DLCs. Proper assessment of risk of DLCs posed to these fishes therefore, requires a better understanding of this sensitivity and the factors that are driving it. Adverse effects associated with exposure to DLCs are mediated by the aryl hydrocarbon receptor (AhR). This study identified and characterized two distinct AhRs, AhR1 and AhR2, in white sturgeon (Acipenser transmontanus) for the first time as a first step in studying the relative sensitivities of sturgeons to DLCs. Furthermore, tissue-specific expression of both AhRs under basal conditions and in response to exposure to the model DLC, β-naphthoflavone (βNF), was determined. The sequence of amino acids of AhR1 of white sturgeon had greater similarity to AhRs of tetrapods, including amphibians, birds, and mammals, than to AhR1s of other fishes. The sequence of amino acids in the ligand binding domain of the AhR1 had greater than 80% similarity to AhRs known to bind DLCs and was less similar to AhRs not known to bind DLCs. AhR2 of white sturgeon had greatest similarity to AhR2 of other fishes. Profiles of expression of AhR1 and AhR2 in white sturgeon were distinct from those known in other fishes and appear more similar to profiles observed in birds. Expressions of both AhR1 and AhR2 of white sturgeon were greatest in liver and heart, which are target organs for DLCs. Furthermore, abundances of transcripts of AhR1 and AhR2 in all tissues from white sturgeon were greater than controls (up to 35-fold) following exposure to βNF. Based upon both AhRs having similar abundances of transcript in target organs of DLC toxicity, both AhRs being up-regulated following

  1. Non-dioxin-like AhR ligands in a mouse peanut allergy model.

    PubMed

    Schulz, Veronica J; Smit, Joost J; Huijgen, Veerle; Bol-Schoenmakers, Marianne; van Roest, Manon; Kruijssen, Laura J W; Fiechter, Daniëlle; Hassing, Ine; Bleumink, Rob; Safe, Stephen; van Duursen, Majorie B M; van den Berg, Martin; Pieters, Raymond H H

    2012-07-01

    Recently, we have shown that AhR activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppresses sensitization to peanut at least in part by inducing a functional shift toward CD4(+)CD25(+)Foxp3(+) T cells. Next to TCDD, numerous other AhR ligands have been described. In this study, we investigated the effect of three structurally different non-dioxin-like AhR ligands, e.g., 6-formylindolo[3,2-b]carbazole (FICZ), β-naphthoflavone (β-NF), and 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF), on peanut sensitization. Female C57BL/6 mice were sensitized by administering peanut extract (PE) by gavage in the presence of cholera toxin. Before and during peanut sensitization, mice were treated with FICZ, β-NF, or 6-MCDF. AhR gene transcription in duodenum and liver was investigated on day 5, even as the effect of these AhR ligands on CD4(+)CD25(+)Foxp3(+) T(reg) cells in spleen and mesenteric lymph nodes (MLNs). Mice treated with TCDD were included as a positive control. Furthermore, the murine reporter cell line H1G1.1c3 (CAFLUX) was used to investigate the possible role of metabolism of TCDD, FICZ, β-NF, and 6-MCDF on AhR activation in vitro. TCDD, but not FICZ, β-NF, and 6-MCDF, suppressed sensitization to peanut (measured by PE-specific IgE, IgG1, IgG2a and PE-induced interleukin (IL)-5, IL-10, IL-13, IL-17a, IL-22, and interferon-γ). In addition, FICZ, β-NF, and 6-MCDF treatments less effectively induced AhR gene transcription (measured by gene expression of AhR, AhRR, CYP1A1, CYP1A2, CYP1B1) compared with TCDD-treated mice. Furthermore, FICZ, β-NF and 6-MCDF did not increase the percentage of CD4(+)CD25(+)Foxp3(+) T(reg) cells in spleen and mesenteric lymph nodes compared with PE-sensitized mice, in contrast to TCDD. Inhibition of metabolism in vitro increased AhR activation. Together, these data shows that TCDD, but not FICZ, β-NF, and 6-MCDF suppresses sensitization to peanut. Differences in metabolism, AhR binding and subsequent gene transcription might

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

    PubMed

    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

  3. Potential of Inducible Nitric Oxide Synthase as a Therapeutic Target for Allergen-Induced Airway Hyperresponsiveness: A Critical Connection to Nitric Oxide Levels and PARP Activity

    PubMed Central

    Ghonim, Mohamed A.; Pyakurel, Kusma; Mishra, Anil

    2016-01-01

    Although expression of inducible NO synthase (iNOS) in the lungs of asthmatics and associated nitrosative damage are established, iNOS failed as a therapeutic target for blocking airway hyperresponsiveness (AHR) and inflammation in asthmatics. This dichotomy calls for better strategies with which the enzyme is adequately targeted. Here, we confirm iNOS expression in the asthmatic lung with concomitant protein nitration and poly(ADP-ribose) polymerase (PARP) activation. We show, for the first time, that iNOS is highly expressed in peripheral blood mononuclear cells (PBMCs) of asthmatics with uncontrolled disease, which did not correspond to protein nitration. Selective iNOS inhibition with L-NIL protected against AHR upon acute, but not chronic, exposure to ovalbumin or house dust mite (HDM) in mice. Supplementation of NO by nitrite administration significantly blocked AHR in chronically HDM-exposed mice that were treated with L-NIL. Protection against chronic HDM exposure-induced AHR by olaparib-mediated PARP inhibition may be associated with the partial but not the complete blockade of iNOS expression. Indeed, L-NIL administration prevented olaparib-mediated protection against AHR in chronically HDM-exposed mice. Our study suggests that the amount of iNOS and NO are critical determinants in the modulation of AHR by selective iNOS inhibitors and renews the potential of iNOS as a therapeutic target for asthma. PMID:27524861

  4. Potential of Inducible Nitric Oxide Synthase as a Therapeutic Target for Allergen-Induced Airway Hyperresponsiveness: A Critical Connection to Nitric Oxide Levels and PARP Activity.

    PubMed

    Ibba, Salome' V; Ghonim, Mohamed A; Pyakurel, Kusma; Lammi, Matthew R; Mishra, Anil; Boulares, A Hamid

    2016-01-01

    Although expression of inducible NO synthase (iNOS) in the lungs of asthmatics and associated nitrosative damage are established, iNOS failed as a therapeutic target for blocking airway hyperresponsiveness (AHR) and inflammation in asthmatics. This dichotomy calls for better strategies with which the enzyme is adequately targeted. Here, we confirm iNOS expression in the asthmatic lung with concomitant protein nitration and poly(ADP-ribose) polymerase (PARP) activation. We show, for the first time, that iNOS is highly expressed in peripheral blood mononuclear cells (PBMCs) of asthmatics with uncontrolled disease, which did not correspond to protein nitration. Selective iNOS inhibition with L-NIL protected against AHR upon acute, but not chronic, exposure to ovalbumin or house dust mite (HDM) in mice. Supplementation of NO by nitrite administration significantly blocked AHR in chronically HDM-exposed mice that were treated with L-NIL. Protection against chronic HDM exposure-induced AHR by olaparib-mediated PARP inhibition may be associated with the partial but not the complete blockade of iNOS expression. Indeed, L-NIL administration prevented olaparib-mediated protection against AHR in chronically HDM-exposed mice. Our study suggests that the amount of iNOS and NO are critical determinants in the modulation of AHR by selective iNOS inhibitors and renews the potential of iNOS as a therapeutic target for asthma. PMID:27524861

  5. Prenatal and Postnatal Polycyclic Aromatic Hydrocarbon Exposure, Airway Hyperreactivity, and Beta-2 Adrenergic Receptor Function in Sensitized Mouse Offspring

    PubMed Central

    Zhang, Hanjie; Maher, Christina; McDonald, Jacob D.; Zhang, Xiang; Ho, Shuk-Mei; Yan, Beizhan; Chillrud, Steven; Perera, Frederica; Factor, Phillip; Miller, Rachel L.

    2013-01-01

    Despite data associating exposure to traffic-related polycyclic aromatic hydrocarbons (PAH) in asthma, mechanistic support has been limited. We hypothesized that both prenatal and early postnatal exposure to PAH would increase airway hyperreactivity (AHR) and that the resulting AHR may be insensitive to treatment with a β2AR agonist drug, procaterol. Further, we hypothesized that these exposures would be associated with altered β2AR gene expression and DNA methylation in mouse lungs. Mice were exposed prenatally or postnatally to a nebulized PAH mixture versus negative control aerosol 5 days a week. Double knockout β2AR mice were exposed postnatally only. Prenatal exposure to PAH was associated with reduced β2AR gene expression among nonsensitized mice offspring, but not increases in DNA methylation or AHR. Postnatal exposure to PAH was borderline associated with increased AHR among sensitized wildtype, but not knockout mice. In the first study that delivers PAH aerosols to mice in a relatively physiological manner, small effects on AHR and β2AR gene expression, but not β2AR agonist drug activity, were observed. If confirmed, the results may suggest that exposure to PAH, common ambient urban pollutants, affects β2AR function, although the impact on the efficacy of β2AR agonist drugs used in treating asthma remains uncertain. PMID:24454363

  6. Pityriazepin and other potent AhR ligands isolated from Malassezia furfur yeast

    PubMed Central

    Mexia, Nikitia; Gaitanis, George; Velegraki, Aristea; Soshilov, Anatoly; Denison, Michael S.; Magiatis, Prokopios

    2015-01-01

    Malassezia furfur yeast strains isolated from diseased human skin preferentially biosynthesize indole alkaloids which can be detected in human skin and are highly potent activators of the aryl hydrocarbon receptor (AhR) and AhR-dependent gene expression. Chemical analysis of an EtOAc extract of a M. furfur strain obtained from diseased human skin and grown on L-tryptophan agar revealed several known AhR active tryptophan metabolites along with a previously unidentified compound, pityriazepin. While its structure resembled that of the known alkaloid pityriacitrin, the comprised pyridine ring had been transformed into an azepinone. The indoloazepinone scaffold of pityriazepin is extremely rare in nature and has only been reported once previously. Pityriazepin, like the other isolated compounds, was found to be a potent activator of the AhR-dependent reporter gene assays in recombinant cell lines derived from four different species, although significant species differences in relative potency was observed. The ability of pityriazepin to competitively bind to the AhR and directly stimulate AhR DNA binding classified it as a new naturally-occurring potent AhR agonist. Malassezia furfur produces an expanded collection of extremely potent naturally occurring AhR agonists, which produce their biological effects in a species-specific manner.1 PMID:25721496

  7. Mast cell-derived neurotrophin 4 mediates allergen-induced airway hyperinnervation in early life

    PubMed Central

    Patel, Kruti R.; Aven, Linh; Shao, Fengzhi; Krishnamoorthy, Nandini; Duvall, Melody G.; Levy, Bruce D.; Ai, Xingbin

    2016-01-01

    Asthma often progresses from early episodes of insults. How early life events connect to long-term airway dysfunction remains poorly understood. We demonstrated previously that increased neurotrophin 4 (NT4) levels following early life allergen exposure cause persistent changes in airway smooth muscle (ASM) innervation and airway hyper-reactivity (AHR) in mice. Herein, we identify pulmonary mast cells as a key source of aberrant NT4 expression following early insults. NT4 is selectively expressed by ASM and mast cells in mice, nonhuman primates and humans. We show in mice that mast cell-derived NT4 is dispensable for ASM innervation during development. However, upon insults, mast cells expand in number and degranulate to release NT4 and thus become the major source of NT4 under pathological condition. Adoptive transfer of wild type mast cells, but not NT4−/− mast cells restores ASM hyperinnervation and AHR in KitW-sh/W-sh mice following early life insults. Notably, an infant nonhuman primate model of asthma also exhibits ASM hyperinnervation associated with the expansion and degranulation of mast cells. Together, these findings identify an essential role of mast cells in mediating ASM hyperinnervation following early life insults by producing NT4. This role may be evolutionarily conserved in linking early insults to long-term airway dysfunction. PMID:26860818

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

    SciTech Connect

    Jonasson, Sofia; Wigenstam, Elisabeth; Koch, Bo; Bucht, Anders

    2013-09-01

    Chlorine (Cl{sub 2}) is an industrial gas that is highly toxic and irritating when inhaled causing tissue damage and an acute inflammatory response in the airways followed by a long-term airway dysfunction. The aim of this study was to evaluate whether early anti-inflammatory treatment can protect against the delayed symptoms in Cl{sub 2}-exposed mice. BALB/c mice were exposed by nose-only inhalation using 200 ppm Cl{sub 2} during 15 min. Assessment of airway hyperresponsiveness (AHR), inflammatory cell counts in bronchoalveolar lavage, occurrence of lung edema and lung fibrosis were analyzed 24 h or 14 days post-exposure. A single dose of the corticosteroid dexamethasone (10 or 100 mg/kg) was administered intraperitoneally 1, 3, 6, or 12 h following Cl{sub 2} exposure. High-dose of dexamethasone reduced the acute inflammation if administered within 6 h after exposure but treated animals still displayed a significant lung injury. The effect of dexamethasone administered within 1 h was dose-dependent; high-dose significantly reduced acute airway inflammation (100 mg/kg) but not treatment with the relatively low-dose (10 mg/kg). Both doses reduced AHR 14 days later, while lung fibrosis measured as collagen deposition was not significantly reduced. The results point out that the acute inflammation in the lungs due to Cl{sub 2} exposure only partly is associated with the long-term AHR. We hypothesize that additional pathogenic mechanisms apart from the inflammatory reactions contribute to the development of long-term airway dysfunction. By using this mouse model, we have validated early administration of corticosteroids in terms of efficacy to prevent acute lung injury and delayed symptoms induced by Cl{sub 2} exposure. - Highlights: • Inhalation of Cl{sub 2} may lead to a long-standing airway hyperresponsiveness. • The symptoms in Cl{sub 2}-exposed mice are similar to those described for RADS in humans. • Corticosteroids prevent delayed symptoms such as AHR in

  9. Phosphodiesterase 4B is essential for TH2-cell function and development of airway hyperresponsiveness in allergic asthma

    PubMed Central

    Catherine Jin, S.-L.; Goya, Sho; Nakae, Susumu; Wang, Dan; Bruss, Matthew; Hou, Chiaoyin; Umetsu, Dale; Conti, Marco

    2010-01-01

    Background Cyclic AMP (cAMP) signaling modulates functions of inflammatory cells involved in the pathogenesis of asthma, and type 4 cAMP-specific phosphodiesterases (PDE4s) are essential components of this pathway. Induction of the PDE4 isoform PDE4B is necessary for Toll-like receptor signaling in monocytes and macrophages and is associated with T cell receptor/CD3 in T cells; however, its exact physiological function in the development of allergic asthma remains undefined. Objectives We investigated the role of PDE4B in the development of allergen-induced airway hyperresponsiveness (AHR) and TH2-driven inflammatory responses. Methods Wild-type and PDE4B−/− mice were sensitized and challenged with ovalbumin and AHR measured in response to inhaled methacholine. Airway inflammation was characterized by analyzing leukocyte infiltration and cytokine accumulation in the airways. Ovalbumin-stimulated cell proliferation and TH2 cytokine production were determined in cultured bronchial lymph node cells. Results Mice deficient in PDE4B do not develop AHR. This protective effect was associated with a significant decrease in eosinophils recruitment to the lungs and decreased TH2 cytokine levels in the bronchoalveolar lavage fluid. Defects in T-cell replication, TH2 cytokine production, and dendritic cell migration were evident in cells from the airway-draining lymph nodes. Conversely, accumulation of the TH1 cytokine IFN-γ was not affected in PDE4B−/− mice. Ablation of the orthologous PDE4 gene PDE4A has no impact on airway inflammation. Conclusion By relieving a cAMP-negative constraint, PDE4B plays an essential role in TH2-cell activation and dendritic cell recruitment during airway inflammation. These findings provide proof of concept that PDE4 inhibitors with PDE4B selectivity may have efficacy in asthma treatment. PMID:21047676

  10. The emergency airway.

    PubMed

    Goon, Serena S H; Stephens, Robert C M; Smith, Helen

    2009-12-01

    The 'can't intubate, can't ventilate' scenario is a nightmare for all clinicians who manage airways. Cricothyroidotomy is one of several emergency airway management techniques. Cricothyroidotomy is a short-term solution which provides oxygenation, not ventilation, and is not a definitive airway. Although there are tests which can help predict whether an intubation will be difficult, they are not always good predictors. As the can't intubate, can't ventilate scenario is rare, cricothyroidotomy is an unfamiliar procedure to many. In this situation, expert help must be called for early on. In the meantime, it is vital that all other simple airway manoeuvres have been attempted, such as good positioning of the patient with head tilt and chin lift, and use of airway adjuncts like the oral (Guedel) airway or nasopharyngeal airway, and the laryngeal mask airway. However, if attempts to secure the airway are unsuccessful, there may be no other option than to perform a cricothyroidotomy. It is a difficult decision to make, but with increasing hypoxia, it is essential that one oxygenates the patient. Cricothyroidotomy provides an opening in the pace between the anterior inferior border of the thyroid cartilage and the anterior superior border of the cricoid cartilage, allowing access to the airway below the glottis. The anatomical considerations are important when performing this procedure (Ellis, 2009), and there are other scenarios when it is used. It is not without consequence, as with any procedure.

  11. Elevated levels of NO are localized to distal airways in asthma

    PubMed Central

    Anderson, John T.; Zeng, Meiqin; Li, Qian; Stapley, Ryan; Moore, Doyle Ray; Chenna, Balachandra; Fineberg, Naomi; Zmijewski, Jaroslaw; Eltoum, Isam-Eldin; Siegal, Gene P.; Gaggar, Amit; Barnes, Stephen; Velu, Sadanandan E.; Thannickal, Victor J.; Abraham, Edward; Patel, Rakesh P.; Lancaster, Jack R.; Chaplin, David D.; Dransfield, Mark T.; Deshane, Jessy S.

    2011-01-01

    The contribution of nitric oxide (NO) to the pathophysiology of asthma remains incompletely defined despite its established pro- and anti-inflammatory effects. Induction of the inducible nitric oxide synthase (iNOS), arginase and superoxide pathways is correlated with increased airway hyperresponsiveness (AHR) in asthmatic subjects. To determine the contributions of these pathways in proximal and distal airways, we compared bronchial wash (BW) to traditional bronchoalveolar lavage (BAL) for measurements of reactive nitrogen/oxygen species, arginase activation, and cytokine/chemokine levels in asthmatic and normal subjects. Levels of NO were preferentially elevated in the BAL, demonstrating higher-level NOS activation in the distal airway compartment of asthmatic subjects. In contrast, DHE+ cells which have the potential to generate reactive oxygen species were found to be increased in both proximal and distal airway compartments of asthmatics compared to controls. Different patterns of cytokines and chemokines were observed, with a predominance of epithelial cell-associated mediators in the BW as compared to macrophage/monocyte-derived mediators in the BAL of asthmatic subjects. Our study demonstrates differential production of reactive species and soluble mediators within the distal airways as compared to the proximal airways in asthma. These results indicate that cellular mechanisms are activated in the distal airways of asthmatics and must be considered in the development of therapeutic strategies for this chronic inflammatory disorder. PMID:21419218

  12. Characterization testing of a 40 Ahr bipolar nickel hydrogen battery

    NASA Technical Reports Server (NTRS)

    Brewer, Jeffrey C.; Manzo, Michelle A.; Gahn, Randall F.

    1989-01-01

    In a continuing effort to develop NiH2 bipolar technology to a point where it can be used efficiently in space flight, testing of a second 40 Ahr, 10-cell bipolar battery has begun. This battery has undergone extensive characterization testing to determine the effects of such operating parameters as charge and discharge rates, temperature, and pressure. The fundamental design of this actively cooled bipolar battery is the same as the first battery. Most of the individual components, however, are from different manufacturers. Different testing procedures as well as certain unique battery characteristics make it difficult to directly compare the two sets of results. In general, the performance of this battery throughout characterization produced expected results. The main differences seen between the first and second batteries occurred during the high-rate discharge portion of the test matrix. The first battery also had poor high-rate discharge results, although better than those of the second battery. Minor changes were made to the battery frame design used for the first battery in an attempt to allow better gas access to the reaction sites for the second build and hopefully improve performance. The changes, however, did not improve the performance of the second battery and could have possibly contributed to the poorer performance that was observed. There are other component differences that could have contributed to the poorer performance of the second battery. The H2 electrode in the second battery was constructed with a Goretex backing which could have limited the high-rate current flow. The gas screen in the second battery had a larger mesh which again could have limited the high-rate current flow. Small scale 2 x 2 batteries are being tested to evaluate the effects of the component variations.

  13. Programmed Death Ligand 1 Promotes Early-Life Chlamydia Respiratory Infection-Induced Severe Allergic Airway Disease.

    PubMed

    Starkey, Malcolm R; Nguyen, Duc H; Brown, Alexandra C; Essilfie, Ama-Tawiah; Kim, Richard Y; Yagita, Hideo; Horvat, Jay C; Hansbro, Philip M

    2016-04-01

    Chlamydia infections are frequent causes of respiratory illness, particularly pneumonia in infants, and are linked to permanent reductions in lung function and the induction of asthma. However, the immune responses that protect against early-life infection and the mechanisms that lead to chronic lung disease are incompletely understood. In the current study, we investigated the role of programmed death (PD)-1 and its ligands PD-L1 and PD-L2 in promoting early-life Chlamydia respiratory infection, and infection-induced airway hyperresponsiveness (AHR) and severe allergic airway disease in later life. Infection increased PD-1 and PD-L1, but not PD-L2, mRNA expression in the lung. Flow cytometric analysis of whole lung homogenates identified monocytes, dendritic cells, CD4(+), and CD8(+) T cells as major sources of PD-1 and PD-L1. Inhibition of PD-1 and PD-L1, but not PD-L2, during infection ablated infection-induced AHR in later life. Given that PD-L1 was the most highly up-regulated and its targeting prevented infection-induced AHR, subsequent analyses focused on this ligand. Inhibition of PD-L1 had no effect on Chlamydia load but suppressed infection-induced pulmonary inflammation. Infection decreased the levels of the IL-13 decoy receptor in the lung, which were restored to baseline levels by inhibition of PD-L1. Finally, inhibition of PD-L1 during infection prevented subsequent infection-induced severe allergic airways disease in later life by decreasing IL-13 levels, Gob-5 expression, mucus production, and AHR. Thus, early-life Chlamydia respiratory infection-induced PD-L1 promotes severe inflammation during infection, permanent reductions in lung function, and the development of more severe allergic airway disease in later life.

  14. A constitutive active MAPK/ERK pathway due to BRAFV600E positively regulates AHR pathway in PTC

    PubMed Central

    Regazzo, Daniela; Bertazza, Loris; Galuppini, Francesca; Guzzardo, Vincenza; Jaffrain-Rea, Marie Lise; Vianello, Federica; Ciato, Denis; Ceccato, Filippo; Watutantrige-Fernando, Sara; Bisognin, Andrea; Bortoluzzi, Stefania; Pennelli, Gianmaria; Boscaro, Marco; Scaroni, Carla; Mian, Caterina

    2015-01-01

    The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor mediating the toxicity and tumor-promoting properties of dioxin. AHR has been reported to be overexpressed and constitutively active in a variety of solid tumors, but few data are currently available concerning its role in thyroid cancer. In this study we quantitatively explored a series of 51 paired-normal and papillary thyroid carcinoma (PTC) tissues for AHR-related genes. We identified an increased AHR expression/activity in PTC, independently from its nuclear dimerization partner and repressor but strictly related to a constitutive active MAPK/ERK pathway. The AHR up-regulation followed by an increased expression of AHR target genes was confirmed by a meta-analysis of published microarray data, suggesting a ligand-independent active AHR pathway in PTC. In-vitro studies using a PTC-derived cell line (BCPAP) and HEK293 cells showed that BRAFV600E may directly modulate AHR localization, induce AHR expression and activity in an exogenous ligand-independent manner. The AHR pathway might represent a potential novel therapeutic target for PTC in the clinical practice. PMID:26392334

  15. Engineering Airway Epithelium

    PubMed Central

    Soleas, John P.; Paz, Ana; Marcus, Paula; McGuigan, Alison; Waddell, Thomas K.

    2012-01-01

    Airway epithelium is constantly presented with injurious signals, yet under healthy circumstances, the epithelium maintains its innate immune barrier and mucociliary elevator function. This suggests that airway epithelium has regenerative potential (I. R. Telford and C. F. Bridgman, 1990). In practice, however, airway regeneration is problematic because of slow turnover and dedifferentiation of epithelium thereby hindering regeneration and increasing time necessary for full maturation and function. Based on the anatomy and biology of the airway epithelium, a variety of tissue engineering tools available could be utilized to overcome the barriers currently seen in airway epithelial generation. This paper describes the structure, function, and repair mechanisms in native epithelium and highlights specific and manipulatable tissue engineering signals that could be of great use in the creation of artificial airway epithelium. PMID:22523471

  16. Epithelial EGF receptor signaling mediates airway hyperreactivity and remodeling in a mouse model of chronic asthma.

    PubMed

    Le Cras, Timothy D; Acciani, Thomas H; Mushaben, Elizabeth M; Kramer, Elizabeth L; Pastura, Patricia A; Hardie, William D; Korfhagen, Thomas R; Sivaprasad, Umasundari; Ericksen, Mark; Gibson, Aaron M; Holtzman, Michael J; Whitsett, Jeffrey A; Hershey, Gurjit K Khurana

    2011-03-01

    Increases in the epidermal growth factor receptor (EGFR) have been associated with the severity of airway thickening in chronic asthmatic subjects, and EGFR signaling is induced by asthma-related cytokines and inflammation. The goal of this study was to determine the role of EGFR signaling in a chronic allergic model of asthma and specifically in epithelial cells, which are increasingly recognized as playing an important role in asthma. EGFR activation was assessed in mice treated with intranasal house dust mite (HDM) for 3 wk. EGFR signaling was inhibited in mice treated with HDM for 6 wk, by using either the drug erlotinib or a genetic approach that utilizes transgenic mice expressing a mutant dominant negative epidermal growth factor receptor in the lung epithelium (EGFR-M mice). Airway hyperreactivity (AHR) was assessed by use of a flexiVent system after increasing doses of nebulized methacholine. Airway smooth muscle (ASM) thickening was measured by morphometric analysis. Sensitization to HDM (IgG and IgE), inflammatory cells, and goblet cell changes were also assessed. Increased EGFR activation was detected in HDM-treated mice, including in bronchiolar epithelial cells. In mice exposed to HDM for 6 wk, AHR and ASM thickening were reduced after erlotinib treatment and in EGFR-M mice. Sensitization to HDM and inflammatory cell counts were similar in all groups, except neutrophil counts, which were lower in the EGFR-M mice. Goblet cell metaplasia with HDM treatment was reduced by erlotinib, but not in EGFR-M transgenic mice. This study demonstrates that EGFR signaling, especially in the airway epithelium, plays an important role in mediating AHR and remodeling in a chronic allergic asthma model.

  17. An altered hydrotropic response (ahr1) mutant of Arabidopsis recovers root hydrotropism with cytokinin

    PubMed Central

    Saucedo, Manuel; Ponce, Georgina; Campos, María Eugenia; Eapen, Delfeena; García, Edith; Luján, Rosario; Sánchez, Yoloxóchitl; Cassab, Gladys I.

    2012-01-01

    Roots are highly plastic and can acclimate to heterogeneous and stressful conditions. However, there is little knowledge of the effect of moisture gradients on the mechanisms controlling root growth orientation and branching, and how this mechanism may help plants to avoid drought responses. The aim of this study was to isolate mutants of Arabidopsis thaliana with altered hydrotropic responses. Here, altered hydrotropic response 1 (ahr1), a semi-dominant allele segregating as a single gene mutation, was characterized. ahr1 directed the growth of its primary root towards the source of higher water availability and developed an extensive root system over time. This phenotype was intensified in the presence of abscisic acid and was not observed if ahr1 seedlings were grown in a water stress medium without a water potential gradient. In normal growth conditions, primary root growth and root branching of ahr1 were indistinguishable from those of the wild type (wt). The altered hydrotropic growth of ahr1 roots was confirmed when the water-rich source was placed at an angle of 45° from the gravity vector. In this system, roots of ahr1 seedlings grew downward and did not display hydrotropism; however, in the presence of cytokinins, they exhibited hydrotropism like those of the wt, indicating that cytokinins play a critical role in root hydrotropism. The ahr1 mutant represents a valuable genetic resource for the study of the effects of cytokinins in the differential growth of hydrotropism and control of lateral root formation during the hydrotropic response. PMID:22442413

  18. AHR2-Mediated Transcriptomic Responses Underlying the Synergistic Cardiac Developmental Toxicity of PAHs

    PubMed Central

    Jayasundara, Nishad; Van Tiem Garner, Lindsey; Meyer, Joel N.; Erwin, Kyle N.; Di Giulio, Richard T.

    2015-01-01

    Polycyclic aromatic hydrocarbons (PAHs) induce developmental defects including cardiac deformities in fish. The aryl hydrocarbon receptor (AHR) mediates the toxicity of some PAHs. Exposure to a simple PAH mixture during embryo development consisting of an AHR agonist (benzo(a)pyrene-BaP) with fluoranthene (FL), an inhibitor of cytochrome p450 1(CYP1)—a gene induced by AHR activation—results in cardiac deformities. Exposure to BaP or FL alone at similar concentrations alters heart rates, but does not induce morphological deformities. Furthermore, AHR2 knockdown prevents the toxicity of BaP + FL mixture. Here, we used a zebrafish microarray analysis to identify heart-specific transcriptomic changes during early development that might underlie cardiotoxicity of BaP + FL. We used AHR2 morphant embryos to determine the role of this receptor in mediating toxicity. Control and knockdown embryos at 36 h post-fertilization were exposed to DMSO, 100 μg/l BaP, 500 μg/l FL, or 100 μg/l BaP + 500 μg/l FL, and heart tissues for RNA were extracted at 2, 6, 12, and 18 h-post-exposure (hpe), prior to the appearance of cardiac deformities. Data show AHR2-dependent BaP + FL effects on expression of genes involved in protein biosynthesis and neuronal development in addition to signaling molecules and their associated molecular pathways. Ca2+-cycling and muscle contraction genes were the most significantly differentially expressed category of transcripts when comparing BaP + FL-treated AHR2 morphant and control embryos. These differences were most prominent at 2 and 6 hpe. Therefore, we postulate that BaP + FL may affect cellular Ca2+ levels and subsequently cardiac muscle function, potentially underlying BaP + FL cardiotoxicity. PMID:25412620

  19. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) reduces vascular endothelial growth factor expression in allergen-induced airway inflammation.

    PubMed

    Lee, Kyung Sun; Kim, So Ri; Park, Seoung Ju; Lee, Ho Kyung; Park, Hee Sun; Min, Kyung Hoon; Jin, Sun Mi; Lee, Yong Chul

    2006-06-01

    Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of bronchial asthma. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has been implicated in regulating cell survival signaling through the phosphoinositide 3-kinase (PI3K)/Akt pathway. The key role of PI3K in VEGF-mediated signal transduction is established. However, the effects of PTEN on VEGF-mediated signaling in asthma are unknown. This study aimed to determine the effect of PI3K inhibitors and PTEN on VEGF expression in allergen-induced airway inflammation. We have used a female C57BL/6 mouse model for asthma to determine the role of PTEN in allergen-induced airway inflammation, specifically in the expression of VEGF. Allergen-induced airway inflammation leads to increased activity of PI3K in lung tissue. These mice develop the following typical pathophysiological features of asthma in the lungs: increased numbers of inflammatory cells of the airways; airway hyper-responsiveness; increased expression of interleukin (IL)-4, IL-5, IL-13, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, regulated on activation normal T cell expressed and secreted (RANTES), and eotaxin; increased vascular permeability; and increased levels of VEGF. Administration of PI3K inhibitors or adenoviruses carrying PTEN cDNA reduced the symptoms of asthma and decreased the increased levels of plasma extravasation and VEGF in allergen-induced asthmatic lungs. These results indicate that PTEN reduces VEGF expression in allergen-induced airway inflammation.

  20. Targeted inhibition of KCa3.1 channel attenuates airway inflammation and remodeling in allergic asthma.

    PubMed

    Yu, Zhi-Hua; Xu, Jian-Rong; Wang, Yan-Xia; Xu, Guang-Ni; Xu, Zu-Peng; Yang, Kai; Wu, Da-Zheng; Cui, Yong-Yao; Chen, Hong-Zhuan

    2013-06-01

    KCa3.1 has been suggested to be involved in regulating cell activation, proliferation, and migration in multiple cell types, including airway inflammatory and structural cells. However, the contributions of KCa3.1 to airway inflammation and remodeling and subsequent airway hyperresponsiveness (AHR) in allergic asthma remain to be explored. The main purpose of this study was to elucidate the roles of KCa3.1 and the potential therapeutic value of KCa3.1 blockers in chronic allergic asthma. Using real-time PCR, Western blotting, or immunohistochemical analyses, we explored the precise role of KCa3.1 in the bronchi of allergic mice and asthmatic human bronchial smooth muscle cells (BSMCs). We found that KCa3.1 mRNA and protein expression were elevated in the bronchi of allergic mice, and double labeling revealed that up-regulation occurred primarily in airway smooth muscle cells. Triarylmethane (TRAM)-34, a KCa3.1 blocker, dose-dependently inhibited the generation and maintenance of the ovalbumin-induced airway inflammation associated with increased Th2-type cytokines and decreased Th1-type cytokine, as well as subepithelial extracellular matrix deposition, goblet-cell hyperplasia, and AHR in a murine model of asthma. Moreover, the pharmacological blockade and gene silencing of KCa3.1, which was evidently elevated after mitogen stimulation, suppressed asthmatic human BSMC proliferation and migration, and arrested the cell cycle at the G0/G1 phase. In addition, the KCa3.1 activator 1-ethylbenzimidazolinone-induced membrane hyperpolarization and intracellular calcium increase in asthmatic human BSMCs were attenuated by TRAM-34. We demonstrate for the first time an important role for KCa3.1 in the pathogenesis of airway inflammation and remodeling in allergic asthma, and we suggest that KCa3.1 blockers may represent a promising therapeutic strategy for asthma.

  1. Dioxin-Dependent and Dioxin-Independent Gene Batteries: Comparison of Liver and Kidney in AHR-Null Mice

    PubMed Central

    Boutros, Paul C.; Bielefeld, Kirsten A.; Pohjanvirta, Raimo; Harper, Patricia A.

    2009-01-01

    The aryl hydrocarbon receptor (AHR) is a widely expressed ligand-dependent transcription factor that mediates cellular responses to dioxins and other planar aromatic hydrocarbons. Ahr-null mice are refractory to the toxic effects of dioxin exposure. Although some mechanistic aspects of AHR activity are well understood, the tissue specificity of AHR effects remains unclear, both during development and following administration of exogenous ligands. To address the latter issue, we defined and compared transcriptional responses to dioxin exposure in the liver and kidney of wild-type and Ahr-null adult C57BL/6J mice treated with either 2,3,7,8-tetrachlorodibenzo-p-dioxin or corn-oil vehicle. In both tissues, essentially all effects of dioxin on hepatic mRNA levels were mediated by the AHR. Although 297 genes were altered by dioxin exposure in the liver, only 17 were changed in the kidney, including a number of well-established AHR target genes. Ahr genotype had a large effect in both tissues, profoundly remodeling both the renal and hepatic transcriptomes. Surprisingly, a large number of genes were affected by Ahr genotype in both tissues, suggesting the presence of a basal AHR gene battery. Alterations of the renal transcriptome in Ahr-null animals were associated with perturbation of specific functional pathways and enrichment of specific DNA motifs. Our results demonstrate the importance of intertissue comparisons, highlight the basal role of the AHR in liver and kidney, and support a role in development or normal physiology. PMID:19759094

  2. Regulation of zebrafish CYP3A65 transcription by AHR2

    SciTech Connect

    Chang, Chin-Teng; Chung, Hsin-Yu; Su, Hsiao-Ting; Tseng, Hua-Pin; Tzou, Wen-Shyong; Hu, Chin-Hwa

    2013-07-15

    CYP3A proteins are the most abundant CYPs in the liver and intestines, and they play a pivotal role in drug metabolism. In mammals, CYP3A genes are induced by various xenobiotics through processes mediated by PXR. We previously identified zebrafish CYP3A65 as a CYP3A ortholog that is constitutively expressed in gastrointestinal tissues, and is upregulated by treatment with dexamethasone, rifampicin or tetrachlorodibenzo-p-dioxin (TCDD). However, the underlying mechanism of TCDD-mediated CYP3A65 transcription is unclear. Here we generated two transgenic zebrafish, Tg(CYP3A65S:EGFP) and Tg(CYP3A65L:EGFP), which contain 2.1 and 5.4 kb 5′ flanking sequences, respectively, of the CYP3A65 gene upstream of EGFP. Both transgenic lines express EGFP in larval gastrointestinal tissues in a pattern similar to that of the endogenous CYP3A65 gene. Moreover, EGFP expression can be significantly induced by TCDD exposure during the larval stage. In addition, EGFP expression can be stimulated by kynurenine, a putative AHR ligand produced during tryptophan metabolism. AHRE elements in the upstream regulatory region of the CYP3A65 gene are indispensible for basal and TCDD-induced transcription. Furthermore, the AHR2 DNA and ligand-binding domains are required to mediate effective CYP3A65 transcription. AHRE sequences are present in the promoters of many teleost CYP3 genes, but not of mammalian CYP3 genes, suggesting that AHR/AHR2-mediated transcription is likely a common regulatory mechanism for teleost CYP3 genes. It may also reflect the different environments that terrestrial and aquatic organisms encounter. - Highlights: • Tg(CYP3A65:EGFP) and CYP3A65 exhibits identical expression pattern. • CYP3A65 can be significantly induced by TCDD or kynurenine. • The AHRE elements are required to mediate CYP3A65 transcription. • The AHR2 DNA and ligand-binding domains are required for CYP3A65 transcription. • AHRE elements are present in many teleost CYP3 genes, but not in

  3. The circadian clock circuitry and the AHR signaling pathway in physiology and pathology.

    PubMed

    Anderson, George; Beischlag, Timothy V; Vinciguerra, Manlio; Mazzoccoli, Gianluigi

    2013-05-15

    Life forms populating the Earth must face environmental challenges to assure individual and species survival. The strategies predisposed to maintain organismal homeostasis and grant selective advantage rely on anticipatory phenomena facing periodic modifications, and compensatory phenomena facing unpredictable changes. Biological processes bringing about these responses are respectively driven by the circadian timing system, a complex of biological oscillators entrained to the environmental light/dark cycle, and by regulatory and metabolic networks that precisely direct the body's adjustments to variations of external conditions and internal milieu. A critical role in organismal homeostatic functions is played by the aryl hydrocarbon receptor (AHR) complex, which senses environmental and endogenous compounds, influences metabolic responses controlling phase I/II gene expression, and modulates vital phenomena such as development, inflammation and adaptive immunity. A physiological cross-talk between circadian and AHR signaling pathways has been evidenced. The alteration of AHR signaling pathway deriving from genetic damage with polymorphisms or mutations, or produced by exogenous or endogenous AHR activation, and chronodisruption caused by mismatch between the body's internal clock and geophysical time/social schedules, are capable of triggering pathological mechanisms involved in metabolic, immune-related and neoplastic diseases. On the other hand, the molecular components of the circadian clock circuitry and AHR signaling pathway may represent useful tools for preventive interventions and valuable targets of therapeutic approaches.

  4. AhR expression and polymorphisms are associated with risk of coronary arterial disease in Chinese population

    PubMed Central

    Huang, Shian; Shui, Xiaorong; He, Yuan; Xue, Yiqiang; Li, Jianwen; Li, Guoming; Lei, Wei; Chen, Can

    2015-01-01

    The aryl hydrocarbon receptor (AhR) mediates the control of environmental toxicity, and modulates the development and pathogenesis of the cardiovascular system. However, little is known about the role of AhR in coronary arterial disease (CAD) susceptibility. We therefore conducted a case-control study in a Chinese population, and assessed the potential association between AhR variants and CAD susceptibility. Compared with the controls, circulating AhR expression was found to be significantly increased in patients with CAD and its subtypes including ST-segment and non-ST-segment elevation myocardial infarction, and stable and unstable angina pectoris. Receiver operating characteristic (ROC) analysis to evaluate the effect of AhR on CAD progression showed it to be a potent biomarker for CAD. Genotype frequencies of AhR rs2066853 differed significantly between CAD and control subjects, while smoking and hyperlipidemia markedly promoted CAD risk relative to the AhR polymorphism. Moreover, a significant difference in AhR variant distribution was observed between the four CAD subtypes with different severities. The expression level and functional polymorphisms of circulating AhR may affect the susceptibility and progression of CAD in Chinese populations. This provides a novel view of the etiology and epidemiology of CAD, and will contribute to the diagnosis and therapy of this severe disease. PMID:25620626

  5. Genetic variation at aryl hydrocarbon receptor (AHR) loci in populations of Atlantic killifish (Fundulus heteroclitus) inhabiting polluted and reference habitats

    PubMed Central

    2014-01-01

    Background The non-migratory killifish Fundulus heteroclitus inhabits clean and polluted environments interspersed throughout its range along the Atlantic coast of North America. Several populations of this species have successfully adapted to environments contaminated with toxic aromatic hydrocarbon pollutants such as polychlorinated biphenyls (PCBs). Previous studies suggest that the mechanism of resistance to these and other “dioxin-like compounds” (DLCs) may involve reduced signaling through the aryl hydrocarbon receptor (AHR) pathway. Here we investigated gene diversity and evidence for positive selection at three AHR-related loci (AHR1, AHR2, AHRR) in F. heteroclitus by comparing alleles from seven locations ranging over 600 km along the northeastern US, including extremely polluted and reference estuaries, with a focus on New Bedford Harbor (MA, USA), a PCB Superfund site, and nearby reference sites. Results We identified 98 single nucleotide polymorphisms within three AHR-related loci among all populations, including synonymous and nonsynonymous substitutions. Haplotype distributions were spatially segregated and F-statistics suggested strong population genetic structure at these loci, consistent with previous studies showing strong population genetic structure at other F. heteroclitus loci. Genetic diversity at these three loci was not significantly different in contaminated sites as compared to reference sites. However, for AHR2 the New Bedford Harbor population had significant FST values in comparison to the nearest reference populations. Tests for positive selection revealed ten nonsynonymous polymorphisms in AHR1 and four in AHR2. Four nonsynonymous SNPs in AHR1 and three in AHR2 showed large differences in base frequency between New Bedford Harbor and its reference site. Tests for isolation-by-distance revealed evidence for non-neutral change at the AHR2 locus. Conclusion Together, these data suggest that F. heteroclitus populations in reference

  6. Rapamycin attenuates airway hyperreactivity, goblet cells, and IgE in experimental allergic asthma.

    PubMed

    Mushaben, Elizabeth M; Kramer, Elizabeth L; Brandt, Eric B; Khurana Hershey, Gurjit K; Le Cras, Timothy D

    2011-12-01

    The mammalian target of rapamycin (mTOR) signaling pathway integrates environmental cues, promotes cell growth/differentiation, and regulates immune responses. Although inhibition of mTOR with rapamycin has potent immunosuppressive activity, mixed effects have been reported in OVA-induced models of allergic asthma. We investigated the impact of two rapamycin treatment protocols on the major characteristics of allergic asthma induced by the clinically relevant allergen, house dust mite (HDM). In protocol 1, BALB/c mice were exposed to 10 intranasal HDM doses over a period of 24 d and treated with rapamycin simultaneously during the sensitization/exposure period. In protocol 2, rapamycin was administered after the mice had been sensitized to HDM (i.p. injection) and prior to initiation of two intranasal HDM challenges over 4 d. Airway hyperreactivity (AHR), IgE, inflammatory cells, cytokines, leukotrienes, goblet cells, and activated T cells were assessed. In protocol 1, rapamycin blocked HDM-induced increases in AHR, inflammatory cell counts, and IgE, as well as attenuated goblet cell metaplasia. In protocol 2, rapamycin blocked increases in AHR, IgE, and T cell activation and reduced goblet cell metaplasia, but it had no effect on inflammatory cell counts. Increases in IL-13 and leukotrienes were also blocked by rapamycin, although increases in IL-4 were unaffected. These data demonstrated that rapamycin can inhibit cardinal features of allergic asthma, including increases in AHR, IgE, and goblet cells, most likely as a result of its ability to reduce the production of two key mediators of asthma: IL-13 and leukotrienes. These findings highlight the importance of the mTOR pathway in allergic airway disease. PMID:22021618

  7. Rapamycin attenuates airway hyperreactivity, goblet cells, and IgE in experimental allergic asthma.

    PubMed

    Mushaben, Elizabeth M; Kramer, Elizabeth L; Brandt, Eric B; Khurana Hershey, Gurjit K; Le Cras, Timothy D

    2011-12-01

    The mammalian target of rapamycin (mTOR) signaling pathway integrates environmental cues, promotes cell growth/differentiation, and regulates immune responses. Although inhibition of mTOR with rapamycin has potent immunosuppressive activity, mixed effects have been reported in OVA-induced models of allergic asthma. We investigated the impact of two rapamycin treatment protocols on the major characteristics of allergic asthma induced by the clinically relevant allergen, house dust mite (HDM). In protocol 1, BALB/c mice were exposed to 10 intranasal HDM doses over a period of 24 d and treated with rapamycin simultaneously during the sensitization/exposure period. In protocol 2, rapamycin was administered after the mice had been sensitized to HDM (i.p. injection) and prior to initiation of two intranasal HDM challenges over 4 d. Airway hyperreactivity (AHR), IgE, inflammatory cells, cytokines, leukotrienes, goblet cells, and activated T cells were assessed. In protocol 1, rapamycin blocked HDM-induced increases in AHR, inflammatory cell counts, and IgE, as well as attenuated goblet cell metaplasia. In protocol 2, rapamycin blocked increases in AHR, IgE, and T cell activation and reduced goblet cell metaplasia, but it had no effect on inflammatory cell counts. Increases in IL-13 and leukotrienes were also blocked by rapamycin, although increases in IL-4 were unaffected. These data demonstrated that rapamycin can inhibit cardinal features of allergic asthma, including increases in AHR, IgE, and goblet cells, most likely as a result of its ability to reduce the production of two key mediators of asthma: IL-13 and leukotrienes. These findings highlight the importance of the mTOR pathway in allergic airway disease.

  8. 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

  9. Association of Specific Immunoglobulin E to Staphylococcal Enterotoxin with Airway Hyperresponsiveness in Asthma Patients

    PubMed Central

    Kim, Seong Han; Yang, Seo Yeon; You, Jihong; Lee, Sang Bae; You, Jin; Chang, Yoon Soo; Kim, Hyung Jung; Ahn, Chul Min; Byun, Min Kwang; Park, Jung-Won

    2016-01-01

    Background Specific immunoglobulin E (IgE) sensitization to staphylococcal enterotoxin (SE) has been recently considered to be related to allergic disease, including asthma. Despite studies on specific IgE (sIgE) to SE and its relationship to asthma diagnosis and severity, the association of sIgE to SE with airway hyperresponsiveness (AHR) remains unclear. Methods We enrolled 81 asthma patients admitted to the Severance Hospital in Korea from March 1, 2013, to February 28, 2015 and retrospectively reviewed the electronic medical records of the enrolled subjects. The serum levels of sIgE to SE (A/B) of all subjects was measured using the ImmunoCAP 250 (Phadia) system with SE-sIgE positive defined as >0.10 kU/mL. Results The SE-sIgE level was not significantly correlated with asthma severity (forced expiratory volume in 1 second [FEV1], FEV1/forced vital capacity, sputum eosinophils, and serum eosinophils), whereas the SE-sIgE level in patients with positive AHR (mean±standard error of the mean, 0.606±0.273 kU/mL) was significantly higher than that in patients with negative AHR (0.062±0.015 kU/mL, p=0.034). In regression analysis, SE sensitization (sIgE to SE ≥0.010 kU/mL) was a significant risk factor for AHR, after adjustment for age, sex, FEV1, and sputum eosinophils (odds ratio, 7.090; 95% confidence interval, 1.180–42.600; p=0.032). Prevalence of SE sensitization was higher in patients with allergic rhinitis and non-atopic asthma patients, as compared to patients without allergic rhinitis and atopic asthma patients, respectively, but without statistical significance. Conclusion SE sensitization is significantly associated with AHR. PMID:27790282

  10. Rhinitis Patients With Sputum Eosinophilia Show Decreased Lung Function in the Absence of Airway Hyperresponsiveness

    PubMed Central

    Yang, Min-Suk; Lee, Hyun-Seung; Kim, Min-Hye; Song, Woo-Jung; Kim, Tae-Wan; Kwon, Jae-Woo; Kim, Sae-Hoon; Park, Heung-Woo; Chang, Yoon-Seok; Min, Kyung-Up

    2013-01-01

    Purpose Sputum eosinophilia is observed frequently in patients with rhinitis. Sputum eosinophilia in patients with non-asthmatic allergic rhinitis has been suggested to be related to nonspecific airway hyperresponsiveness (AHR). However, the clinical significance of sputum eosinophilia in patients with non-asthmatic rhinitis without AHR has not been determined. We conducted a retrospective study examining the influence of sputum eosinophilia in patients with non-asthmatic rhinitis without AHR on pulmonary function and expression of fibrosis-related mediators. Methods Eighty-nine patients with moderate-to-severe perennial rhinitis without AHR were included. All underwent lung function tests (forced expiratory volume in 1 second [FEV1] and forced vital capacity [FVC]), skin tests to inhalant allergens, methacholine bronchial challenge tests, and hypertonic saline-induced sputum to determine eosinophil counts. Sputum mRNA levels for transforming growth factor-β (TGF-β), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were also examined. Patients were divided into two groups according to the presence of sputum eosinophilia (≥3%, eosinophilia-positive [EP] and <3%, eosinophilia-negative [EN] groups). Results FEV1 was significantly lower (P=0.04) and FEV1/FVC tended to be lower (P=0.1) in the EP group than in the EN group. In sputum analyses, the MMP-9 mRNA level (P=0.005) and the ratio of MMP-9 to TIMP-1 expression (P=0.01) were significantly higher in the EP group than in the EN group. There was no significant difference in TGF-β mRNA expression between the two groups. Conclusions Sputum eosinophilia in patients with moderate-to-severe perennial rhinitis without AHR influenced FEV1 and the expression pattern of fibrosis-related mediators. PMID:23814677

  11. In silico predictive studies of mAHR congener binding using homology modelling and molecular docking.

    PubMed

    Panda, Roshni; Cleave, A Suneetha Susan; Suresh, P K

    2014-09-01

    The aryl hydrocarbon receptor (AHR) is one of the principal xenobiotic, nuclear receptor that is responsible for the early events involved in the transcription of a complex set of genes comprising the CYP450 gene family. In the present computational study, homology modelling and molecular docking were carried out with the objective of predicting the relationship between the binding efficiency and the lipophilicity of different polychlorinated biphenyl (PCB) congeners and the AHR in silico. Homology model of the murine AHR was constructed by several automated servers and assessed by PROCHECK, ERRAT, VERIFY3D and WHAT IF. The resulting model of the AHR by MODWEB was used to carry out molecular docking of 36 PCB congeners using PatchDock server. The lipophilicity of the congeners was predicted using the XLOGP3 tool. The results suggest that the lipophilicity influences binding energy scores and is positively correlated with the same. Score and Log P were correlated with r = +0.506 at p = 0.01 level. In addition, the number of chlorine (Cl) atoms and Log P were highly correlated with r = +0.900 at p = 0.01 level. The number of Cl atoms and scores also showed a moderate positive correlation of r = +0.481 at p = 0.01 level. To the best of our knowledge, this is the first study employing PatchDock in the docking of AHR to the environmentally deleterious congeners and attempting to correlate structural features of the AHR with its biochemical properties with regards to PCBs. The result of this study are consistent with those of other computational studies reported in the previous literature that suggests that a combination of docking, scoring and ranking organic pollutants could be a possible predictive tool for investigating ligand-mediated toxicity, for their subsequent validation using wet lab-based studies.

  12. Management of the difficult airway.

    PubMed

    Strauss, Robert A; Noordhoek, Roseanna

    2010-03-01

    The oral and maxillofacial surgeon frequently encounters and manages difficult airways. Knowledge of and calm progression by practitioner and staff through different means to ventilate and manage a difficult airway are crucial. Practitioners should become comfortable with different types of alternative or rescue airways in order to intervene quickly in case of emergent or unanticipated airway compromise.

  13. Toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in developing red seabream (Pagrus major) embryo: an association of morphological deformities with AHR1, AHR2 and CYP1A expressions.

    PubMed

    Yamauchi, Masanobu; Kim, Eun-Young; Iwata, Hisato; Shima, Yasuhiro; Tanabe, Shinsuke

    2006-11-16

    The toxicity of dioxins such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is mainly mediated by the aryl hydrocarbon receptor (AHR), which regulates the multiple target genes including cytochrome P4501A (CYP1A). In general, bony fishes, which possess at least two distinct AHRs are one of the most sensitive vertebrates to TCDD in early life stage. However, the physiological and toxicological roles of piscine multiple AHRs are not fully understood, especially in marine fish. To understand which AHR is responsible for TCDD toxicity in a marine fish species, we characterized the early life stage toxicity related to the expression of AHRs and CYP1A in red seabream (Pagrus major). The embryos at 10h post-fertilization (hpf) were treated with 0-100 microg/L TCDD for 80 min waterborne exposure. TCDD dose-dependently elicited developmental toxicities including mortality, yolk sac edema, retarded body growth, spinal deformity, reduced heart rate, shortened snout, underdeveloped fin, heart, and lower jaw. Intriguingly, hemorrhage and pericardium edema, typical TCDD developmental defects noticed in other fish species, were not found in red seabream until test termination. The EC(egg)50s for yolk sac edema, underdeveloped fin, and spinal deformity were 170, 240, and 340 pg/g, respectively. The LC(egg)50 was 360 pg/g embryo, indicating that this species is one of the most sensitive fishes to TCDD toxicity. The expression levels of rsAHR1, rsAHR2 and CYP1A mRNAs were also determined in different developmental stages. The rsAHR2 mRNA expression dose-dependently increased following TCDD exposure, while rsAHR1 mRNA level was not altered. Level of rsAHR2 mRNA measured by two-step real-time PCR was 30 times higher than rsAHR1 in embryos treated with the highest dose. Temporal patterns of rsAHR2 and CYP1A mRNAs were similar in TCDD-treated embryos, representing a significant positive correlation between rsAHR2 and CYP1A mRNA levels, but not between rsAHR1 and CYP1A. In comparison of

  14. Progesterone, as well as 17β-estradiol, is important for regulating AHR battery homoeostasis in the rat uterus.

    PubMed

    Rataj, Felicitas; Möller, Frank Josef; Jähne, Maria; Hönscheid, Pia; Zierau, Oliver; Vollmer, Günter; Kretzschmar, Georg

    2015-03-01

    Several studies indicate that the aryl hydrocarbon receptor (AHR), which plays an important role in mediating the toxicity of many industrial chemicals, plays an important role in the physiology of female reproductive tract organs. This makes it likely that the AHR and additional components of the AHR signalling pathway are under the control of female sex steroids. In a previous study, we could already demonstrate the regulation of many members of the AHR battery by 17β-estradiol (E2) in the uterus of rats. In this study, we addressed the potential role of progesterone (P4) in this context. In a comparative approach using ovariectomized rats which were treated for 3 days with either vehicle control, E2, progesterone (P4) or the combination of both hormones in addition to sham-operated animals, we could demonstrate that in addition to E2, P4 is also an important factor in regulating AHR signalling in the rat uterus. P4 has effects similar to E2 on uterine Ahr, Arnt and Arnt2 mRNA levels, resulting in a downregulation of these genes, while the E2-mediated downregulation of key AHR response genes Cyp1a1, Gsta2 and Ugt1 is completely antagonized by P4. As with E2, P4 leads to an increase in uterine AHR levels, especially in the endometrial epithelium despite the decrease in corresponding mRNA levels. This indicates a complex gene-specific regulatory network involving E2, P4 and possibly AHR itself to maintain all components of the AHR signalling cascade at the required levels during all stages of the oestrous cycle and pregnancy.

  15. Metabolic control of type 1 regulatory (Tr1) cell differentiation by AHR and HIF1-α

    PubMed Central

    Mascanfroni, Ivan D.; Takenaka, Maisa C.; Yeste, Ada; Patel, Bonny; Wu, Yan; Kenison, Jessica E.; Siddiqui, Shafiuddin; Basso, Alexandre S.; Otterbein, Leo E.; Pardoll, Drew M.; Pan, Fan; Priel, Avner; Clish, Clary B.; Robson, Simon C.; Quintana, Francisco J.

    2015-01-01

    Our understanding of the pathways that regulate lymphocyte metabolism, as well as the effects of metabolism and its products on the immune response, is still limited. We report that a metabolic program controlled by the transcription factors hypoxia inducible factor-1α (HIF1-α) and aryl hydrocarbon receptor (AHR) supports the differentiation of type 1 regulatory (Tr1) cells. HIF1-α controls the early metabolic reprograming of Tr1 cells. At later time points, AHR promotes HIF1-α degradation and takes control of Tr1 cell metabolism. Extracellular adenosine triphosphate (eATP) and hypoxia, linked to inflammation, trigger AHR inactivation by HIF1-α and inhibit Tr1 cell differentiation. Conversely, CD39 promotes Tr1 cell differentiation by depleting eATP. CD39 also contributes to Tr1 suppressive activity by generating adenosine in cooperation with CD73 expressed by responder T cells and antigen presenting cells. These results suggest that HIF1-α and AHR integrate immunological, metabolic and environmental signals to regulate the immune response. PMID:26005855

  16. 76 FR 80447 - Eighth Meeting: RTCA Special Committee 219: Attitude and Heading Reference Systems (AHRS)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-23

    ... Federal Aviation Administration Eighth Meeting: RTCA Special Committee 219: Attitude and Heading Reference...). ACTION: Notice of RTCA Special Committee 219: Attitude and Heading Reference Systems (AHRS). SUMMARY: The FAA is issuing this notice to advise the public of the eighth meeting of RTCA Special Committee...

  17. EXPRESSION OF AHR AND ARNT MRNA IN CULTURED HUMAN ENDOMETRIAL EXPLANTS EXPOSED TO TCDD

    EPA Science Inventory

    Expression of AhR and ARNT mRNA in cultured human endometrial explants exposed to TCDD.

    Pitt JA, Feng L, Abbott BD, Schmid J, Batt RE, Costich TG, Koury ST, Bofinger DP.

    Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC 27599, USA.

    Endom...

  18. Autoradiographic localization of aromatic hydrocarbon receptor (AHR) in rhesus monkey ovary.

    PubMed

    Baldridge, Monika G; Hutz, Reinhold J

    2007-06-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic congener of a large class of manmade pollutants that persist in the environment. TCDD exerts its toxic effects, in part, by binding to its receptor known as the aromatic hydrocarbon receptor (AHR). TCDD is estrogen modulatory and in some systems its receptor associates directly with estrogen receptors via co-activator molecules. TCDD inhibits steroid synthesis in human ovarian granulosa cells and AHR is found in these cells. We have previously shown that AHR is found in whole rhesus monkey ovary, but have yet to establish its location. In the present study, we set out to show that radiolabeled TCDD binds to monkey ovarian follicles and that this binding is receptor mediated. Ovaries from Macaca mulatta were sectioned on a cryostat at 10 micro m; and sections were incubated with either control vehicle, (3)H-TCDD, or (3)H-TCDD plus alpha-naphthoflavone (ANF), a known receptor-blocking agent. Here, we show for the first time specific binding of TCDD to the granulosa cells of antral follicles and other regions of the rhesus monkey ovary. Our data indicate a 60-fold increase in binding with (3)H-TCDD over that of control, and that this binding is reduced to the levels seen in controls with the addition of the competitive antagonist ANF. These findings support the hypothesis that TCDD directly affects primate ovarian function via the AHR.

  19. Intersection of AHR and Wnt Signaling in Development, Health, and Disease

    PubMed Central

    Schneider, Andrew J.; Branam, Amanda M.; Peterson, Richard E.

    2014-01-01

    The AHR (aryl hydrocarbon receptor) and Wnt (wingless-related MMTV integration site) signaling pathways have been conserved throughout evolution. Appropriately regulated signaling through each pathway is necessary for normal development and health, while dysregulation can lead to developmental defects and disease. Though both pathways have been vigorously studied, there is relatively little research exploring the possibility of crosstalk between these pathways. In this review, we provide a brief background on (1) the roles of both AHR and Wnt signaling in development and disease, and (2) the molecular mechanisms that characterize activation of each pathway. We also discuss the need for careful and complete experimental evaluation of each pathway and describe existing research that explores the intersection of AHR and Wnt signaling. Lastly, to illustrate in detail the intersection of AHR and Wnt signaling, we summarize our recent findings which show that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced disruption of Wnt signaling impairs fetal prostate development. PMID:25286307

  20. Functional and phenotypic effects of AhR activation in inflammatory dendritic cells

    SciTech Connect

    Bankoti, Jaishree; Rase, Ben; Simones, Tom; Shepherd, David M.

    2010-07-15

    Aryl hydrocarbon receptor (AhR) activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces immune suppression. Dendritic cells (DCs) are key antigen presenting cells governing T cell activation and differentiation. However, the consequences of AhR activation in DCs are not fully defined. We hypothesized that AhR activation alters DC differentiation and generates dysfunctional DCs. To test this hypothesis, inflammatory bone marrow-derived DCs (BMDCs) from C57Bl/6 mice were generated in the presence of vehicle or TCDD. TCDD decreased CD11c expression but increased MHC class II, CD86 and CD25 expression on the BMDCs. The effects of TCDD were strictly AhR-dependent but not exclusively DRE-mediated. Similar effects were observed with two natural AhR ligands, 6-formylindolo[3,2-b]carbazole (FICZ) and 2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid (ITE). TCDD increased LPS- and CpG-induced IL-6 and TNF-{alpha} production by BMDCs but decreased their NO production. TCDD decreased CpG-induced IL-12p70 production by BMDCs but did not affect their secretion of IL-10. TCDD downregulated LPS- and CpG-induced NF-kB p65 levels and induced a trend towards upregulation of RelB levels in the BMDCs. AhR activation by TCDD modulated BMDC uptake of both soluble and particulate antigens. Induction of indoleamine-2,3-dioxygenase (IDO) and TGF-{beta}3 has been implicated in the generation of regulatory T cells following AhR activation. TCDD increased IDO1, IDO2 and TGF-{beta}3 mRNA levels in BMDCs as compared to vehicle. Despite the induction of regulatory mediators, TCDD-treated BMDCs failed to suppress antigen-specific T cell activation. Thus, AhR activation can directly alter the differentiation and innate functions of inflammatory DCs without affecting their ability to successfully interact with T cells.

  1. Airway management in trauma.

    PubMed

    Langeron, O; Birenbaum, A; Amour, J

    2009-05-01

    Maintenance of a patent and prevention of aspiration are essential for the management of the trauma patient, that requires experienced physicians in airway control techniques. Difficulties of the airway control in the trauma setting are increased by the vital failures, the risk of aspiration, the potential cervical spine injury, the combative patient, and the obvious risk of difficult tracheal intubation related to specific injury related to the trauma. Endotracheal intubation remains the gold standard in trauma patient airway management and should be performed via the oral route with a rapid sequence induction and a manual in-line stabilization maneuver, to decrease the risks previously mentioned. Different techniques to control the airway in trauma patients are presented: improvement of the laryngoscopic vision, lighted stylet tracheal intubation, retrograde technique for orotracheal intubation, the laryngeal mask and the intubating laryngeal mask airways, the combitube and cricothyroidotomy. Management of the airway in trauma patients requires regular training in these techniques and the knowledge of complementary techniques allowing tracheal intubation or oxygenation to overcome difficult intubation and to prevent major complications as hypoxemia and aspiration. PMID:19412149

  2. AHR2 morpholino knockdown reduces the toxicity of total particulate matter to zebrafish embryos.

    PubMed

    Massarsky, Andrey; Bone, Audrey J; Dong, Wu; Hinton, David E; Prasad, G L; Di Giulio, Richard T

    2016-10-15

    The zebrafish embryo has been proposed as a 'bridge model' to study the effects of cigarette smoke on early development. Previous studies showed that exposure to total particulate matter (TPM) led to adverse effects in developing zebrafish, and suggested that the antioxidant and aryl hydrocarbon receptor (AHR) pathways play important roles. This study investigated the roles of these two pathways in mediating TPM toxicity. The study consisted of four experiments. In experiment I, zebrafish embryos were exposed from 6h post fertilization (hpf) until 96hpf to TPM0.5 and TPM1.0 (corresponding to 0.5 and 1.0μg/mL equi-nicotine units) in the presence or absence of an antioxidant (N-acetyl cysteine/NAC) or a pro-oxidant (buthionine sulfoximine/BSO). In experiment II, TPM exposures were performed in embryos that were microinjected with nuclear factor erythroid 2-related factor 2 (Nrf2), AHR2, cytochrome P450 1A (CYP1A), or CYP1B1 morpholinos, and deformities were assessed. In experiment III, embryos were exposed to TPM, and embryos/larvae were collected at 24, 48, 72, and 96hpf to assess several genes associated with the antioxidant and AHR pathways. Lastly, experiment IV assessed the activity and protein levels of CYP1A and CYP1B1 after exposure to TPM. We demonstrate that the incidence of TPM-induced deformities was generally not affected by NAC/BSO treatments or Nrf2 knockdown. In contrast, AHR2 knockdown reduced, while CYP1A or CYP1B1 knockdowns elevated the incidence of some deformities. Moreover, as shown by gene expression the AHR pathway, but not the antioxidant pathway, was induced in response to TPM exposure, providing further evidence for its importance in mediating TPM toxicity.

  3. AHR2 morpholino knockdown reduces the toxicity of total particulate matter to zebrafish embryos.

    PubMed

    Massarsky, Andrey; Bone, Audrey J; Dong, Wu; Hinton, David E; Prasad, G L; Di Giulio, Richard T

    2016-10-15

    The zebrafish embryo has been proposed as a 'bridge model' to study the effects of cigarette smoke on early development. Previous studies showed that exposure to total particulate matter (TPM) led to adverse effects in developing zebrafish, and suggested that the antioxidant and aryl hydrocarbon receptor (AHR) pathways play important roles. This study investigated the roles of these two pathways in mediating TPM toxicity. The study consisted of four experiments. In experiment I, zebrafish embryos were exposed from 6h post fertilization (hpf) until 96hpf to TPM0.5 and TPM1.0 (corresponding to 0.5 and 1.0μg/mL equi-nicotine units) in the presence or absence of an antioxidant (N-acetyl cysteine/NAC) or a pro-oxidant (buthionine sulfoximine/BSO). In experiment II, TPM exposures were performed in embryos that were microinjected with nuclear factor erythroid 2-related factor 2 (Nrf2), AHR2, cytochrome P450 1A (CYP1A), or CYP1B1 morpholinos, and deformities were assessed. In experiment III, embryos were exposed to TPM, and embryos/larvae were collected at 24, 48, 72, and 96hpf to assess several genes associated with the antioxidant and AHR pathways. Lastly, experiment IV assessed the activity and protein levels of CYP1A and CYP1B1 after exposure to TPM. We demonstrate that the incidence of TPM-induced deformities was generally not affected by NAC/BSO treatments or Nrf2 knockdown. In contrast, AHR2 knockdown reduced, while CYP1A or CYP1B1 knockdowns elevated the incidence of some deformities. Moreover, as shown by gene expression the AHR pathway, but not the antioxidant pathway, was induced in response to TPM exposure, providing further evidence for its importance in mediating TPM toxicity. PMID:27576004

  4. Induction of human UGT1A1 by bilirubin through AhR dependent pathway.

    PubMed

    Togawa, Hiroshi; Shinkai, Shigeko; Mizutani, Takaharu

    2008-12-01

    UDP-glucuronosyltransferase1A1 (UGT1A1) plays a key role to conjugate bilirubin and preventing jaundice, but there is no report showing the induction of human UGT1A1 (UGT1A1) by bilirubin. In this report, we show findings of the induction of the reporter gene (-3475/+14) of UGT1A1 in HepG2 cells by bilirubin at 50 microM, 100 microM, with human aryl hydrocarbon receptor (hAhR). We confirmed that induction of the reporter gene by bilirubin is dependent on the position of the xenobiotic responsive element (XRE) (-3328/-3319) of UGT1A1, because the XRE deletion UGT1A1 gene did not respond to stimulation by a complex of bilirubin and hAhR. alpha-Naphthoflavone (alpha-NF) of a typical AhR antagonist at 50 microM inhibited induction by bilirubin, suggesting that bilirubin stimulates through binding with hAhR. Meanwhile, bilirubin itself did not stimulate the induction of AhR, because we detected no-elevation of the mRNA level of AhR by RT-PCR. These results indicate that the induction of UGT1A1 by bilirubin-AhR did not depend on the elevation of AhR but on ligand binding. From this result, we considered that high bilirubin in neonates must induce the elevation of UGT1A1 after birth to prevent jaundice, and bilirubin in adults also regulates the level of UGT1A1. This is the first report showing direct induction of UGT1A1 by a bilirubin through AhR pathway. PMID:19356098

  5. Alternative in vitro approach for assessing AHR-mediated CYP1A induction by dioxins in wild cormorant (Phalacrocorax carbo) population.

    PubMed

    Thuruthippallil, Leena Mol; Kubota, Akira; Kim, Eun-Young; Iwata, Hisato

    2013-06-18

    Our line of papers revealed that the common (great) cormorant (Phalacrocorax carbo) possesses two isoforms of the aryl hydrocarbon receptor (ccAHR1 and ccAHR2). This paper addresses in vitro tests of the ccAHR signaling pathways to solve two questions: (1) whether there are functional differences in the two ccAHR isoforms, and (2) whether a molecular perturbation, cytochrome P450 1A (ccCYP1A) induction, in the population-level can be predicted from the in vitro tests. The transactivation potencies mediated by ccAHR1 and ccAHR2 were measured in COS-7 cells treated with 15 selected dioxins and related compounds (DRCs), where ccAHR1 or ccAHR2 expression plasmid and ccCYP1A5 promoter/enhancer-linked luciferase reporter plasmid were transfected. For congeners that exhibited dose-dependent luciferase activities, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) relative potencies (REPs) and induction equivalency factors (IEFs) were estimated. ccAHR1-IEF profile was similar to WHO avian TCDD toxic equivalency factor (TEF) profile except for dioxin-like polychlorinated biphenyls that showed lower IEFs in ccAHR1-driven reporter assay. ccAHR2-IEF profile was different from WHO TEFs and ccAHR1-IEFs. Notably, 2,3,4,7,8-PeCDF was more potent than TCDD for ccAHR2-mediated response. Using ccAHR1- and ccAHR2-IEFs and hepatic DRC concentrations in the Lake Biwa cormorant population, total TCDD induction equivalents (IEQs) were calculated for each ccAHR-mediated response. Nonlinear regression analyses provided significant sigmoidal relationships of ccAHR1- and ccAHR2-derived IEQs with hepatic ccCYP1A5 mRNA levels, supporting the results of in vitro ccAHR-mediated TCDD dose-response curves. Collectively, our in vitro AHR reporter assay potentially could be an alternative to molecular epidemiology of the species of concern regarding CYP1A induction by AHR ligands. PMID:23676118

  6. The immune phenotype of AhR null mouse mutants: not a simple mirror of xenobiotic receptor over-activation.

    PubMed

    Esser, Charlotte

    2009-02-15

    Intrinsic and induced cell differentiation and the cellular response to endogenous and exogenous signals are hallmarks of the immune system. Specific and common signalling cascades ensure a highly flexible and adapted response. Increasing evidence suggests that gene modulation by the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is an important part of these processes. For decades the AhR has been studied mainly for its toxic effects after artificial activation by man-made chemical pollutants such as dioxins. These studies gave important, albeit to some extent skewed, evidence for a mechanistic link between the AhR and the immune system. AhR null mutants and other mutants of the AhR signalling pathway have been generated and used to analyse the physiological function of the AhR, including for the developing and antigen-responding immune system. In this review I look at the natural immunological function(s) of the AhR.

  7. Role of upper airway ultrasound in airway management.

    PubMed

    Osman, Adi; Sum, Kok Meng

    2016-01-01

    Upper airway ultrasound is a valuable, non-invasive, simple, and portable point of care ultrasound (POCUS) for evaluation of airway management even in anatomy distorted by pathology or trauma. Ultrasound enables us to identify important sonoanatomy of the upper airway such as thyroid cartilage, epiglottis, cricoid cartilage, cricothyroid membrane, tracheal cartilages, and esophagus. Understanding this applied sonoanatomy facilitates clinician to use ultrasound in assessment of airway anatomy for difficult intubation, ETT and LMA placement and depth, assessment of airway size, ultrasound-guided invasive procedures such as percutaneous needle cricothyroidotomy and tracheostomy, prediction of postextubation stridor and left double-lumen bronchial tube size, and detecting upper airway pathologies. Widespread POCUS awareness, better technological advancements, portability, and availability of ultrasound in most critical areas facilitate upper airway ultrasound to become the potential first-line non-invasive airway assessment tool in the future. PMID:27529028

  8. Role of upper airway ultrasound in airway management.

    PubMed

    Osman, Adi; Sum, Kok Meng

    2016-01-01

    Upper airway ultrasound is a valuable, non-invasive, simple, and portable point of care ultrasound (POCUS) for evaluation of airway management even in anatomy distorted by pathology or trauma. Ultrasound enables us to identify important sonoanatomy of the upper airway such as thyroid cartilage, epiglottis, cricoid cartilage, cricothyroid membrane, tracheal cartilages, and esophagus. Understanding this applied sonoanatomy facilitates clinician to use ultrasound in assessment of airway anatomy for difficult intubation, ETT and LMA placement and depth, assessment of airway size, ultrasound-guided invasive procedures such as percutaneous needle cricothyroidotomy and tracheostomy, prediction of postextubation stridor and left double-lumen bronchial tube size, and detecting upper airway pathologies. Widespread POCUS awareness, better technological advancements, portability, and availability of ultrasound in most critical areas facilitate upper airway ultrasound to become the potential first-line non-invasive airway assessment tool in the future.

  9. DDE and PCB 153 independently induce aryl hydrocarbon receptor (AhR) expression in peripheral blood mononuclear cells.

    PubMed

    Gaspar-Ramírez, Octavio; Pérez-Vázquez, Francisco J; Salgado-Bustamante, Mariana; González-Amaro, Roberto; Hernandez-Castro, Berenice; Pérez-Maldonado, Ivan N

    2015-01-01

    Recent studies have demonstrated that compounds inducing pro-inflammatory cytokines enhance AhR expression. The aim of this study was 2-fold: (1) to determine if two pro-inflammatory compounds, dichlorodiphenyldichloroethylene (DDE) and 2,2',4,4',5,5'-hexa-chlorobiphenyl (PCB 153), independently affect AhR gene expression in peripheral blood mononuclear cells (PBMC); and (2) if affected, to determine whether the mechanism involved was due to AhR activation or to a pro-inflammatory effect of the chemicals. PBMC isolated from healthy individuals were incubated in the presence of DDE (10 µg/ml) and PCB 153 (20 ng/ml) over time and AhR and CYP1A1 expression was assessed with a real-time PCR technique. The results indicated there was over-expression of the AhR mRNA in PBMC when the cells were treated with DDE and PCB 153. No changes in expression levels of CYP1A1 mRNA were found. Importantly, when the cells were exposed to DDE and PCB 153 in the presence of an antagonist of tumor necrosis factor (TNF)-α, the over-expression of AhR was abolished; as expected, the expression of CYP1A1 was unaffected. In conclusion, these studies demonstrated for the first time an increment of AhR expression "in vitro" in PBMC treated with two pro-inflammatory environmental pollutants, DDE and PCB153. Moreover, the over-expression of AhR was dependent of TNFα induced by DDE and PCB 153 and was independent of AhR activation.

  10. Perinatal paracetamol exposure in mice does not affect the development of allergic airways disease in early life

    PubMed Central

    Lee, Debbie C P; Walker, Simone A; Byrne, Adam J; Gregory, Lisa G; Buckley, James; Bush, Andrew; Shaheen, Seif O; Saglani, Sejal; Lloyd, Clare M

    2015-01-01

    Background Current data concerning maternal paracetamol intake during pregnancy, or intake during infancy and risk of wheezing or asthma in childhood is inconclusive based on epidemiological studies. We have investigated whether there is a causal link between maternal paracetamol intake during pregnancy and lactation and the development of house dust mite (HDM) induced allergic airways disease (AAD) in offspring using a neonatal mouse model. Methods Pregnant mice were administered paracetamol or saline by oral gavage from the day of mating throughout pregnancy and/or lactation. Subsequently, their pups were exposed to intranasal HDM or saline from day 3 of life for up to 6 weeks. Assessments of airway hyper-responsiveness, inflammation and remodelling were made at weaning (3 weeks) and 6 weeks of age. Results Maternal paracetamol exposure either during pregnancy and/or lactation did not affect development of AAD in offspring at weaning or at 6 weeks. There were no effects of maternal paracetamol at any time point on airway remodelling or IgE levels. Conclusions Maternal paracetamol did not enhance HDM induced AAD in offspring. Our mechanistic data do not support the hypothesis that prenatal paracetamol exposure increases the risk of childhood asthma. PMID:25841236

  11. Indirect airway challenges.

    PubMed

    Joos, G F; O'Connor, B; Anderson, S D; Chung, F; Cockcroft, D W; Dahlén, B; DiMaria, G; Foresi, A; Hargreave, F E; Holgate, S T; Inman, M; Lötvall, J; Magnussen, H; Polosa, R; Postma, D S; Riedler, J

    2003-06-01

    Indirect challenges act by causing the release of endogenous mediators that cause the airway smooth muscle to contract. This is in contrast to the direct challenges where agonists such as methacholine or histamine cause airflow limitation predominantly via a direct effect on airway smooth muscle. Direct airway challenges have been used widely and are well standardised. They are highly sensitive, but not specific to asthma and can be used to exclude current asthma in a clinic population. Indirect bronchial stimuli, in particular exercise, hyperventilation, hypertonic aerosols, as well as adenosine, may reflect more directly the ongoing airway inflammation and are therefore more specific to identify active asthma. They are increasingly used to evaluate the prevalence of bronchial hyperresponsiveness and to assess specific problems in patients with known asthma, e.g. exercise-induced bronchoconstriction, evaluation before scuba diving. Direct bronchial responsiveness is only slowly and to a modest extent, influenced by repeated administration of inhaled steroids. Indirect challenges may reflect more closely acute changes in airway inflammation and a change in responsiveness to an indirect stimulus may be a clinically relevant marker to assess the clinical course of asthma. Moreover, some of the indirect challenges, e.g. hypertonic saline and mannitol, can be combined with the assessment of inflammatory cells by induction of sputum.

  12. Augmentation of arginase 1 expression by exposure to air pollution exacerbates the airways hyperresponsiveness in murine models of asthma

    PubMed Central

    2011-01-01

    Background Arginase overexpression contributes to airways hyperresponsiveness (AHR) in asthma. Arginase expression is further augmented in cigarette smoking asthmatics, suggesting that it may be upregulated by environmental pollution. Thus, we hypothesize that arginase contributes to the exacerbation of respiratory symptoms following exposure to air pollution, and that pharmacologic inhibition of arginase would abrogate the pollution-induced AHR. Methods To investigate the role of arginase in the air pollution-induced exacerbation of airways responsiveness, we employed two murine models of allergic airways inflammation. Mice were sensitized to ovalbumin (OVA) and challenged with nebulized PBS (OVA/PBS) or OVA (OVA/OVA) for three consecutive days (sub-acute model) or 12 weeks (chronic model), which exhibit inflammatory cell influx and remodeling/AHR, respectively. Twenty-four hours after the final challenge, mice were exposed to concentrated ambient fine particles plus ozone (CAP+O3), or HEPA-filtered air (FA), for 4 hours. After the CAP+O3 exposures, mice underwent tracheal cannulation and were treated with an aerosolized arginase inhibitor (S-boronoethyl-L-cysteine; BEC) or vehicle, immediately before determination of respiratory function and methacholine-responsiveness using the flexiVent®. Lungs were then collected for comparison of arginase activity, protein expression, and immunohistochemical localization. Results Compared to FA, arginase activity was significantly augmented in the lungs of CAP+O3-exposed OVA/OVA mice in both the sub-acute and chronic models. Western blotting and immunohistochemical staining revealed that the increased activity was due to arginase 1 expression in the area surrounding the airways in both models. Arginase inhibition significantly reduced the CAP+O3-induced increase in AHR in both models. Conclusions This study demonstrates that arginase is upregulated following environmental exposures in murine models of asthma, and contributes

  13. Airway statuses and nasopharyngeal airway use for airway obstruction in syndromic craniosynostosis.

    PubMed

    Kouga, Takeshi; Tanoue, Koji; Matsui, Kiyoshi

    2014-05-01

    Syndromic craniosynostosis is associated with a high rate of respiratory difficulty, due mainly to midfacial hypoplasia. Nasopharyngeal airway establishment has been reported as the first-line approach to airway obstruction and may obviate the need for a highly invasive tracheotomy. No previous studies have compared airway obstruction status in syndromic craniosynostosis between cases requiring and not requiring airway managements. We focus on nasopharyngeal airway use and airway status outcomes to assess respiratory difficulty in patients with syndromic craniosynostosis. A retrospective data analysis of 51 cases with syndromic craniosynostosis was carried out. We divided 30 of the 51 cases with lateral pharyngeal x-rays taken before operations affecting airway diameters into 2 groups, one with neither nasopharyngeal airway insertion nor tracheotomy and the other with one or both of these interventions, and the mean diameters for 8 indices related to the pharyngeal space were compared. Cases with respiratory difficulty due to nasopharyngeal stenosis and requiring airway managements comprised a significantly higher proportion of those with Pfeiffer syndrome than patients with Crouzon or Apert syndrome. Comparative examination of lateral x-ray cephalometry between cases with neither nasopharyngeal airway insertion nor tracheotomy and cases with one or both revealed oropharyngeal diameters tended to be smaller in those with interventions. Cases requiring nasopharyngeal airway insertion were able to continue nasopharyngeal airway use for more than 1 year and a considerable number avoided tracheotomy. It may be worth considering an oropharyngeal-bypass nasopharyngeal airway before performing a tracheotomy. PMID:24820706

  14. Endogenous osteopontin promotes ozone-induced neutrophil recruitment to the lungs and airway hyperresponsiveness to methacholine

    PubMed Central

    Barreno, Ramon X.; Richards, Jeremy B.; Schneider, Daniel J.; Cromar, Kevin R.; Nadas, Arthur J.; Hernandez, Christopher B.; Hallberg, Lance M.; Price, Roger E.; Hashmi, Syed S.; Blackburn, Michael R.; Haque, Ikram U.

    2013-01-01

    Inhalation of ozone (O3), a common environmental pollutant, causes pulmonary injury, pulmonary inflammation, and airway hyperresponsiveness (AHR) in healthy individuals and exacerbates many of these same sequelae in individuals with preexisting lung disease. However, the mechanisms underlying these phenomena are poorly understood. Consequently, we sought to determine the contribution of osteopontin (OPN), a hormone and a pleiotropic cytokine, to the development of O3-induced pulmonary injury, pulmonary inflammation, and AHR. To that end, we examined indices of these aforementioned sequelae in mice genetically deficient in OPN and in wild-type, C57BL/6 mice 24 h following the cessation of an acute (3 h) exposure to filtered room air (air) or O3 (2 parts/million). In wild-type mice, O3 exposure increased bronchoalveolar lavage fluid (BALF) OPN, whereas immunohistochemical analysis demonstrated that there were no differences in the number of OPN-positive alveolar macrophages between air- and O3-exposed wild-type mice. O3 exposure also increased BALF epithelial cells, protein, and neutrophils in wild-type and OPN-deficient mice compared with genotype-matched, air-exposed controls. However, following O3 exposure, BALF neutrophils were significantly reduced in OPN-deficient compared with wild-type mice. When airway responsiveness to inhaled acetyl-β-methylcholine chloride (methacholine) was assessed using the forced oscillation technique, O3 exposure caused hyperresponsiveness to methacholine in the airways and lung parenchyma of wild-type mice, but not OPN-deficient mice. These results demonstrate that OPN is increased in the air spaces following acute exposure to O3 and functionally contributes to the development of O3-induced pulmonary inflammation and airway and lung parenchymal hyperresponsiveness to methacholine. PMID:23666750

  15. Wood Smoke Enhances Cigarette Smoke–Induced Inflammation by Inducing the Aryl Hydrocarbon Receptor Repressor in Airway Epithelial Cells

    PubMed Central

    Awji, Elias G.; Chand, Hitendra; Bruse, Shannon; Smith, Kevin R.; Colby, Jennifer K.; Mebratu, Yohannes; Levy, Bruce D.

    2015-01-01

    Our previous studies showed that cigarette smokers who are exposed to wood smoke (WS) are at an increased risk for chronic bronchitis and reduced lung function. The present study was undertaken to determine the mechanisms for WS-induced adverse effects. We studied the effect of WS exposure using four cohorts of mice. C57Bl/6 mice were exposed for 4 or 12 weeks to filtered air, to 10 mg/m3 WS for 2 h/d, to 250 mg/m3 cigarette smoke (CS) for 6 h/d, or to CS followed by WS (CW). Inflammation was absent in the filtered air and WS groups, but enhanced by twofold in the bronchoalveolar lavage of the CW compared with CS group as measured by neutrophil numbers and levels of the neutrophil chemoattractant, keratinocyte-derived chemokine. The levels of the anti-inflammatory lipoxin, lipoxin A4, were reduced by threefold along with cyclo-oxygenase (COX)-2 and microsomal prostaglandin E synthase (mPGES)-1 in airway epithelial cells and PGE2 levels in the bronchoalveolar lavage of CW compared with CS mice. We replicated, in primary human airway epithelial cells, the changes observed in mice. Immunoprecipitations showed that WS blocked the interaction of aryl hydrocarbon receptor (AHR) with AHR nuclear transporter to reduce expression of COX-2 and mPGES-1 by increasing expression of AHR repressor (AHRR). Collectively, these studies show that exposure to low concentrations of WS enhanced CS-induced inflammation by inducing AHRR expression to suppress AHR, COX-2, and mPGES-1 expression, and levels of PGE2 and lipoxin A4. Therefore, AHRR is a potential therapeutic target for WS-associated exacerbations of CS-induced inflammation. PMID:25137396

  16. Vascular Anomalies and Airway Concerns

    PubMed Central

    Clarke, Caroline; Lee, Edward I.; Edmonds, Joseph

    2014-01-01

    Vascular anomalies, both tumors and malformations, can occur anywhere in the body, including the airway, often without any external manifestations. However, vascular anomalies involving the airway deserve special consideration as proper recognition and management can be lifesaving. In this article, the authors discuss vascular anomalies as they pertains to the airway, focusing on proper diagnosis, diagnostic modalities, and therapeutic options. PMID:25045336

  17. Characterization testing of a 40 AHR bipolar nickel-hydrogen battery

    NASA Astrophysics Data System (ADS)

    Brewer, Jeffrey C.; Manzo, Michelle A.; Gemeiner, Russel P.

    1989-12-01

    Extensive characterization testing has been done on a second 40 amp-hour (Ahr), 10-cell bipolar nickel-hydrogen (Ni-H2) battery to study the effects of such operating parameters as charge and discharge rates, temperature, and pressure, on capacity, Ahr and watt-hour (Whr) efficiencies, end-of-charge (EOC) and mid-point discharge voltages. Testing to date has produced many interesting results, with the battery performing well throughout all of the test matrix except during the high-rate (5C and 10C) discharges, where poorer than expected results were observed. The exact cause of this poor performance is, as yet, unknown. Small scale 2 x 2 inch battery tests are to be used in studying this problem. Low earth orbit (LEO) cycle life testing at a 40 percent depth of discharge (DOD) and 10 C is scheduled to follow the characterization testing.

  18. Characterization testing of a 40 AHR bipolar nickel-hydrogen battery

    NASA Technical Reports Server (NTRS)

    Brewer, Jeffrey C.; Manzo, Michelle A.; Gemeiner, Russel P.

    1989-01-01

    Extensive characterization testing has been done on a second 40 amp-hour (Ahr), 10-cell bipolar nickel-hydrogen (Ni-H2) battery to study the effects of such operating parameters as charge and discharge rates, temperature, and pressure, on capacity, Ahr and watt-hour (Whr) efficiencies, end-of-charge (EOC) and mid-point discharge voltages. Testing to date has produced many interesting results, with the battery performing well throughout all of the test matrix except during the high-rate (5C and 10C) discharges, where poorer than expected results were observed. The exact cause of this poor performance is, as yet, unknown. Small scale 2 x 2 inch battery tests are to be used in studying this problem. Low earth orbit (LEO) cycle life testing at a 40 percent depth of discharge (DOD) and 10 C is scheduled to follow the characterization testing.

  19. Comparative Study of Protective Effects of Salbutamol and Beclomethasone against Insulin Induced Airway Hyper-reactivity on Isolated Tracheal Smooth Muscle of Guinea Pig

    PubMed Central

    Sharif, Mahjabeen; Tayyaba Khan, Bushra; Bakhtiar, Salman; Anwar, Mohammad Asim

    2015-01-01

    Inhalational insulin was withdrawn from the market due to its potential to produce airway hyper-reactivity and bronchoconstriction. So the present study was designed to explore the acute effects of insulin on airway reactivity of guinea pigs and protective effects of salbutamol and beclomethasone against insulin induced airway hyper-responsiveness on isolated tracheal smooth muscle of guinea pig. Effects of varying concentrations of insulin (10-7 to 10-3 M), insulin pretreated with fixed concentration of salbutamol (10-7 M) and beclomethasone (10-6 M) were studied on isolated tracheal tissue of guinea pig by constructing cumulative concentration response curves. Changes in tracheal smooth muscle contractions were recorded on four channel oscillograph. The mean ± SEM of maximum amplitudes of contraction with increasing concentrations of insulin, insulin pretreated with fixed concentration of salbutamol and beclomethasone were 35 ± 1.13 mm, 14.55 ± 0.62 mm and 22 ± 1.154 mm respectively. Although salbutamol and beclomethasone both had a profound inhibitory effect on insulin induced airway hyper-reactivity, yet salbutamol is more efficacious than beclomethasone. So we suggest that pretreatment of inhaled insulin with salbutamol may be preferred over beclomethasone in amelioration of its potential respiratory adverse effects such as bronchoconstriction. PMID:25901165

  20. Pneumocystis Elicits a STAT6-Dependent, Strain-Specific Innate Immune Response and Airway Hyperresponsiveness

    PubMed Central

    Meissner, Nicole N.; Siemsen, Dan W.; McInnerney, Kate; Harmsen, Allen G.

    2012-01-01

    It is widely held that exposure to pathogens such as fungi can be an agent of comorbidity, such as exacerbation of asthma or chronic obstructive pulmonary disease. Although many studies have examined allergic responses to fungi and their effects on pulmonary function, the possible pathologic implications of the early innate responses to fungal pathogens have not been explored. We examined early responses to the atypical fungus Pneumocystis in two common strains of mice in terms of overall immunological response and related pathology, such as cell damage and airway hyperresponsiveness (AHR). We found a strong strain-specific response in BALB/c mice that included recruitment of neutrophils, NK, NKT, and CD4 T cells. This response was accompanied by elevated indicators of lung damage (bronchoalveolar lavage fluid albumin and LDH) and profound AHR. This early response was absent in C57BL/6 mice, although both strains exhibited a later response associated with the clearance of Pneumocystis. We found that this AHR could not be attributed exclusively to the presence of recruited neutrophils, NKT, NK, or CD4 cells or to the actions of IFN-γ or IL-4. However, in the absence of STAT6 signaling, AHR and inflammatory cell recruitment were virtually absent. Gene expression analysis indicated that this early response included activation of several transcription factors that could be involved in pulmonary remodeling. These results show that exposure to a fungus such as Pneumocystis can elicit pulmonary responses that may contribute to morbidity, even without prior sensitization, in the context of certain genetic backgrounds. PMID:21960549

  1. A novel AhR ligand, 2AI, protects the retina from environmental stress

    PubMed Central

    Gutierrez, Mark A.; Davis, Sonnet S.; Rosko, Andrew; Nguyen, Steven M.; Mitchell, Kylie P.; Mateen, Samiha; Neves, Joana; Garcia, Thelma Y.; Mooney, Shaun; Perdew, Gary H.; Hubbard, Troy D.; Lamba, Deepak A.; Ramanathan, Arvind

    2016-01-01

    Various retinal degenerative diseases including dry and neovascular age-related macular degeneration (AMD), retinitis pigmentosa, and diabetic retinopathy are associated with the degeneration of the retinal pigmented epithelial (RPE) layer of the retina. This consequently results in the death of rod and cone photoreceptors that they support, structurally and functionally leading to legal or complete blindness. Therefore, developing therapeutic strategies to preserve cellular homeostasis in the RPE would be a favorable asset in the clinic. The aryl hydrocarbon receptor (AhR) is a conserved, environmental ligand-dependent, per ARNT-sim (PAS) domain containing bHLH transcription factor that mediates adaptive response to stress via its downstream transcriptional targets. Using in silico, in vitro and in vivo assays, we identified 2,2′-aminophenyl indole (2AI) as a potent synthetic ligand of AhR that protects RPE cells in vitro from lipid peroxidation cytotoxicity mediated by 4-hydroxynonenal (4HNE) as well as the retina in vivo from light-damage. Additionally, metabolic characterization of this molecule by LC-MS suggests that 2AI alters the lipid metabolism of RPE cells, enhancing the intracellular levels of palmitoleic acid. Finally, we show that, as a downstream effector of 2AI-mediated AhR activation, palmitoleic acid protects RPE cells from 4HNE-mediated stress, and light mediated retinal degeneration in mice. PMID:27364765

  2. Alveolar macrophages from allergic lungs are not committed to a pro-allergic response and can reduce airway hyperresponsiveness following ex vivo culture

    PubMed Central

    Pouliot, P.; Spahr, A.; Careau, É.; Turmel, V.; Bissonnette, E. Y.

    2016-01-01

    Summary Background We already demonstrated that adoptive transfer of alveolar macrophages (AMs) from non-allergic rats into AM-depleted allergic rats prevents airway hyperresponsiveness (AHR). We also showed that AMs from non-sensitized, but not from sensitized, allergy-prone rats can prevent AHR following allergen challenge in sensitized allergic animals, establishing the importance of rat immunological status on the modulation of AM functions and suggesting that an allergic lung environment alters AM functions. Objective We investigated how the activation of allergic AMs can be modulated to reinstitute them with their capacity to reduce AHR. Methods AMs from sensitized Brown Norway rats were cultured ex vivo for up to 18 h in culture media to deprogram them from the influence of the allergic lung before being reintroduced into the lung of AM-depleted sensitized recipient. AHR and cytokines in bronchoalveolar lavage (BAL) were measured following allergen challenge. AMs stimulated ex vivo with Bacillus Calmette-Guerin(BCG) were used as positive controls as BCG induces a T-helper type 1 activation in AMs. Results AMs ex vivo cultured for 4–18 h reduced AHR to normal level. Interestingly, pro-allergic functions of AMs were dampened by 18 h culture and they reduced AHR even after spending 48 h in an allergic lung microenvironment. Furthermore, transfer of cultured AMs caused an increase in the levels of IFN-γ and IL-12 in BAL when compared with their ovalbumin control. After 18 h of ex vivo culture, AMs expressed reduced levels of TNF, IL-1α, IL-6, and Arginase-2 mRNAs compared with freshly isolated AMs, suggesting that ex vivo culture exempted AMs from lung stimuli that affected their functions. Conclusions There is a significant crosstalk between lung microenvironment and AMs, affecting their functions. It is also the first report showing that sensitized AMs can be modulated ex vivo to reduce lung pro-allergic environment, opening the way to therapies targetting

  3. Total airway reconstruction.

    PubMed

    Connor, Matthew P; Barrera, Jose E; Eller, Robert; McCusker, Scott; O'Connor, Peter

    2013-02-01

    We present a case of obstructive sleep apnea (OSA) that required multilevel surgical correction of the airway and literature review and discuss the role supraglottic laryngeal collapse can have in OSA. A 34-year-old man presented to a tertiary otolaryngology clinic for treatment of OSA. He previously had nasal and palate surgeries and a Repose tongue suspension. His residual apnea hypopnea index (AHI) was 67. He had a dysphonia associated with a true vocal cord paralysis following resection of a benign neck mass in childhood. He also complained of inspiratory stridor with exercise and intolerance to continuous positive airway pressure. Physical examination revealed craniofacial hypoplasia, full base of tongue, and residual nasal airway obstruction. On laryngoscopy, the paretic aryepiglottic fold arytenoid complex prolapsed into the laryngeal inlet with each breath. This was more pronounced with greater respiratory effort. Surgical correction required a series of operations including awake tracheostomy, supraglottoplasty, midline glossectomy, genial tubercle advancement, maxillomandibular advancement, and reconstructive rhinoplasty. His final AHI was 1.9. Our patient's supraglottic laryngeal collapse constituted an area of obstruction not typically evaluated in OSA surgery. In conjunction with treating nasal, palatal, and hypopharyngeal subsites, our patient's supraglottoplasty represented a key component of his success. This case illustrates the need to evaluate the entire upper airway in a complicated case of OSA. PMID:22965285

  4. An Assessment of Technical and Production Risks of Candidate Low-Cost Attitude/Heading Reference Systems(AHRS)

    NASA Technical Reports Server (NTRS)

    Yuchnovicz, Daniel; Burgess, Malcolm; Hammers, William

    1999-01-01

    This report provides an assessment of technical and production risks of candidate low-cost attitude/heading reference systems (AHRS) for use in the Advanced General Aviation Transport Experiments (AGATE) airplanes. A low-cost AHRS is a key component of modem "glass cockpit" flight displays for General Aviation (GA) aircraft. The technical capabilities of several candidate low-cost AHRS were examined and described along with the technical issues involved with using all solid-state components for attitude measurement. An economic model was developed which describes the expected profit, rate of return, and volume requirements for the manufacture of low-cost AHRS for GA aircraft in the 2000 to 2020 time frame. The model is the result of interviews with GA airframe manufacturers, avionics manufacturers and historical analysis of avionics of similar complexity. The model shows that a manufacturer will break even after three years of AHRS production, realizing an 18 percent rate of return (23 percent profit) on an investment of $3.5M over the 20 year period. A start-up production estimate showed costs of $6-12M for a new company to build and certify an AHRS from scratch, considered to be a high-risk proposition, versus $0.25-0.75M for an experienced avionics manufacturer to manufacture a design under license, a low-risk proposition.

  5. Methods of airway resistance assessment.

    PubMed

    Urbankowski, Tomasz; Przybyłowski, Tadeusz

    2016-01-01

    Airway resistance is the ratio of driving pressure to the rate of the airflow in the airways. The most frequent methods used to measure airway resistance are whole-body plethysmography, the interrupter technique and the forced oscillation technique. All these methods allow to measure resistance during respiration at the level close to tidal volume, they do not require forced breathing manoeuvres or deep breathing during measurement. The most popular method for measuring airway resistance is whole-body plethysmography. The results of plethysmography include among others the following parameters: airway resistance (Raw), airway conductance (Gaw), specific airway resistance (sRaw) and specific airway conductance (sGaw). The interrupter technique is based on the assumption that at the moment of airway occlusion, air pressure in the mouth is equal to the alveolar pressure . In the forced oscillation technique (FOT), airway resistance is calculated basing on the changes in pressure and flow caused by air vibration. The methods for measurement of airway resistance that are described in the present paper seem to be a useful alternative to the most common lung function test - spirometry. The target group in which these methods may be widely used are particularly the patients who are unable to perform spirometry.

  6. AhR activation underlies the CYP1A autoinduction by A-998679 in rats

    PubMed Central

    Liguori, Michael J.; Lee, Chih-Hung; Liu, Hong; Ciurlionis, Rita; Ditewig, Amy C.; Doktor, Stella; Andracki, Mark E.; Gagne, Gerard D.; Waring, Jeffrey F.; Marsh, Kennan C.; Gopalakrishnan, Murali; Blomme, Eric A. G.; Yang, Yi

    2012-01-01

    Xenobiotic-mediated induction of cytochrome P450 (CYP) drug metabolizing enzymes (DMEs) is frequently encountered in drug discovery and can influence disposition, pharmacokinetic, and toxicity profiles. The CYP1A subfamily of DMEs plays a central role in the biotransformation of several drugs and environmental chemicals. Autoinduction of drugs through CYP3A enzymes is a common mechanism for their enhanced clearance. However, autoinduction via CYP1A is encountered less frequently. In this report, an experimental compound, A-998679 [3-(5-pyridin-3-yl-1,2,4-oxadiazol-3-yl) benzonitrile], was shown to enhance its own clearance via induction of Cyp1a1 and Cyp1a2. Rats were dosed for 5 days with 30, 100, and 200 mg/kg/day A-998679. During the dosing period, the compound's plasma AUC decreased at 30 mg/kg (95%) and 100 mg/kg (80%). Gene expression analysis and immunohistochemistry of the livers showed a large increase in the mRNA and protein levels of Cyp1a, which was involved in the biotransformation of A-998679. Induction of CYP1A was confirmed in primary rat, human, and dog hepatocytes. The compound also weakly inhibited CYP1A2 in human liver microsomes. A-998679 activated the aryl hydrocarbon receptor (AhR) in a luciferase gene reporter assay in HepG2 cells, upregulated expression of genes associated with AhR activation in rat liver and enhanced nuclear migration of AhR in HepG2 cells. Collectively these results demonstrate that A-998679 is an AhR activator that induces Cyp1a1 and Cyp1a2 expression, resulting in an autoinduction phenomenon. The unique properties of A-998679, along with its novel structure distinct from classical polycyclic aromatic hydrocarbons (PAHs), may warrant its further evaluation as a tool compound for use in studies involving AhR biology and CYP1A-related mechanisms of drug metabolism and toxicity. PMID:23112805

  7. Functionality of aryl hydrocarbon receptors (AhR1 and AhR2) of white sturgeon (Acipenser transmontanus) and implications for the risk assessment of dioxin-like compounds.

    PubMed

    Doering, Jon A; Farmahin, Reza; Wiseman, Steve; Kennedy, Sean W; Giesy, John P; Hecker, Markus

    2014-07-15

    Worldwide, populations of sturgeons are endangered, and it is hypothesized that anthropogenic chemicals, including dioxin-like compounds (DLCs), might be contributing to the observed declines in populations. DLCs elicit their toxic action through activation of the aryl hydrocarbon receptor (AhR), which is believed to regulate most, if not all, adverse effects associated with exposure to these chemicals. Currently, risk assessment of DLCs in fishes uses toxic equivalency factors (TEFs) developed for the World Health Organization (WHO) that are based on studies of embryo-lethality with salmonids. However, there is a lack of knowledge of the sensitivity of sturgeons to DLCs, and it is uncertain whether TEFs developed by the WHO are protective of these fishes. Sturgeons are evolutionarily distinct from salmonids, and the AhRs of sturgeons differ from those of salmonids. Therefore, this study investigated the sensitivity of white sturgeon (Acipenser transmontanus) to DLCs in vitro via the use of luciferase reporter gene assays using COS-7 cells transfected with AhR1 or AhR2 of white sturgeon. Specifically, activation and relative potencies (RePs) of 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachloro-dibenzofuran, 2,3,7,8-tetrachloro-dibenzofuran, 3,3',4,4',5-pentachlorobiphenyl, 3,3',4,4'-tetrachlorobiphenyl, and 2,3,3',4,4'-pentachlorobiphenyl were determined for each AhR. It was demonstrated that white sturgeon expresses AhR1s and AhR2s that are both activated by DLCs with EC50 values for 2,3,7,8-TCDD that are lower than those of any other AhR of vertebrates tested to date. Both AhRs of white sturgeon had RePs for polychlorinated dibenzofurans more similar to TEFs for birds, while RePs for polychlorinated biphenyls were most similar to TEFs for fishes. Measured concentrations of select DLCs in tissues of white sturgeon from British Columbia, Canada, were used to calculate toxic equivalents (TEQs) by use of TEFs for fishes used by the WHO and TCDD

  8. 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

  9. Single-Cell Analysis of Mast Cell Degranulation Induced by Airway Smooth Muscle-Secreted Chemokines

    PubMed Central

    Manning, Benjamin M.; Meyer, Audrey F.; Gruba, Sarah M.; Haynes, Christy L.

    2015-01-01

    Background Asthma is a chronic inflammatory disease characterized by narrowed airways, bronchial hyper-responsiveness, mucus hyper-secretion, and airway remodeling. Mast cell (MC) infiltration into airway smooth muscle (ASM) is a defining feature of asthma, and ASM regulates the inflammatory response by secreting chemokines, including CXCL10 and CCL5. Single cell analysis offers a unique approach to study specific cellular signaling interactions within large and complex signaling networks such as the inflammatory microenvironment in asthma. Methods Carbon fiber microelectrode amperometry was used to study the effects of ASM–secreted chemokines on mouse peritoneal MC degranulation. Results MC degranulation in response to CXCL10 and CCL5 was monitored at the single cell level. Relative to IgE-mediated degranulation, CXCL10- and CCL5-stimulated MCs released a decreased amount of serotonin per granule with fewer release events per cell. Decreased serotonin released per granule was correlated with increased spike half-width and rise-time values. Conclusions MCs are directly activated with ASM-associated chemokines. CXCL10 and CCL5 induce less robust MC degranulation compared to IgE- and A23187-stimulation. The kinetics of MC degranulation are signaling pathway-dependent, suggesting a biophysical mechanism of regulated degranulation that incorporates control over granule trafficking, transport, and docking machinery. General Significance The biophysical mechanisms, including variations in number of exocytotic release events, serotonin released per granule, and the membrane kinetics of exocytosis that underlie MC degranulation in response to CXCL10 and CCL5 were characterized at the single cell level. These findings clarify the function of ASM-derived chemokines as instigators of MC degranulation relative to classical mechanisms of MC stimulation. PMID:25986989

  10. Synergistic induction of AHR regulated genes in developmental toxicity from co-exposure to two model PAHs in zebrafish

    PubMed Central

    Timme-Laragy, Alicia. R.; Cockman, Crystal. J.; Matson, Cole. W.; Di Giulio, Richard. T.

    2007-01-01

    Polycyclic aromatic hydrocarbons (PAHs) are pollutants created by the incomplete combustion of carbon, and are increasing in the environment largely due to the burning of fossil fuels. PAHs occur as complex mixtures, and some combinations have been shown to cause synergistic developmental toxicity in fish embryos, characterized by pericardial edema and craniofacial malformations. Previous studies have indicated that in the zebrafish model, this toxicity is mediated by the aryl hydrocarbon receptor 2 (AHR2), and enhanced by inhibition of CYP1A activity. In this study, we further examined this interaction of the model PAH and AHR agonist β-naphthoflavone (BNF) with and without the AHR partial agonist/antagonist and CYP1A inhibitor α-naphthoflavone (ANF) to determine 1) whether ANF was acting as an AHR antagonist, 2) what alterations BNF and ANF both alone and in combination had on mRNA expression of the AHR regulated genes cytochrome P450 (cyp) 1a, 1b1, and 1c1, and the AHR repressor (ahrr2) prior to vs. during deformity onset, and 3) compare CYP1A enzyme activity with mRNA induction. Zebrafish embryos were exposed from 24–48 or 24–96 hpf to BNF, 1–100 μg/L, ANF, 1–150 μg/L, a BNF+ANF co-exposure (1 μg/L + 100 μg/L), or a DMSO solvent control. RNA was extracted and examined by quantitative real time PCR. Both BNF and ANF each individually resulted in a dose dependent increase CYP1A, CYP1B1, CYP1C1, and AHRR2 mRNA, confirming their activities as AHR agonists. In the BNF+ANF co-exposures prior to deformity onset, expression of these genes was synergistic, and expression levels of the AHR regulated genes resembled the higher doses of BNF alone. Gene induction during deformities was also significantly increased in the co-exposure, but to a lesser magnitude than prior to deformity onset. EROD measurements of CYP1A activity showed ANF inhibited activity induction by BNF in the co-exposure group; this finding is not predicted by mRNA expression, which is

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

    SciTech Connect

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

    2011-10-07

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

  12. Effects of scorched food leachates with or without activated charcoal pretreatment on AhR activation in cultured cells.

    PubMed

    Takahashi, Satoshi; Morita, Koji; Kinoshita, Makoto; Fujimori, Shin; Ishikawa, Toshio

    2015-12-01

    Aryl hydrocarbon receptor (AhR) is a transcription factor activated by xenobiotics, including dioxins and polycyclic aromatic hydrocarbons (PAHs). Although AhR is also activated by some dietary constituents, it has not been completely clarified in what circumstances AhR ligands are ingested in our daily life. Because PAHs are formed by the incomplete combustion of organic materials, we hypothesized that scorched foods might contain and leach out AhR ligands sufficient to stimulate AhR in vitro. To test this hypothesis, scorched foods (bread, cheese, etc.) were mixed vigorously with water, and the supernatants were retrieved as samples. The samples were added to HepG2 cells stably expressing an AhR-responsive reporter gene. Also, expression of CYP1A1, an endogenous AhR-responsive gene, was analyzed by RT-PCR in different cell lines treated with the samples. We further tested whether pretreatment of the samples with activated charcoal would alter their AhR-stimulating activity. All the supernatant samples tested induced AhR-dependent reporter gene activity and CYP1A1 mRNA expression. In some samples, these inductions were inhibited by pretreatment with activated charcoal. Our findings indicate that scorched food leachates stimulate AhR in cultured cells and that activated charcoal adsorbs the AhR-stimulating substances in some leachates. Thus, people who habitually eat scorched foods are exposed to AhR ligands on a regular basis. Further studies are needed to elucidate whether burnt foods actually exert biological effects on our health.

  13. Effects of scorched food leachates with or without activated charcoal pretreatment on AhR activation in cultured cells.

    PubMed

    Takahashi, Satoshi; Morita, Koji; Kinoshita, Makoto; Fujimori, Shin; Ishikawa, Toshio

    2015-12-01

    Aryl hydrocarbon receptor (AhR) is a transcription factor activated by xenobiotics, including dioxins and polycyclic aromatic hydrocarbons (PAHs). Although AhR is also activated by some dietary constituents, it has not been completely clarified in what circumstances AhR ligands are ingested in our daily life. Because PAHs are formed by the incomplete combustion of organic materials, we hypothesized that scorched foods might contain and leach out AhR ligands sufficient to stimulate AhR in vitro. To test this hypothesis, scorched foods (bread, cheese, etc.) were mixed vigorously with water, and the supernatants were retrieved as samples. The samples were added to HepG2 cells stably expressing an AhR-responsive reporter gene. Also, expression of CYP1A1, an endogenous AhR-responsive gene, was analyzed by RT-PCR in different cell lines treated with the samples. We further tested whether pretreatment of the samples with activated charcoal would alter their AhR-stimulating activity. All the supernatant samples tested induced AhR-dependent reporter gene activity and CYP1A1 mRNA expression. In some samples, these inductions were inhibited by pretreatment with activated charcoal. Our findings indicate that scorched food leachates stimulate AhR in cultured cells and that activated charcoal adsorbs the AhR-stimulating substances in some leachates. Thus, people who habitually eat scorched foods are exposed to AhR ligands on a regular basis. Further studies are needed to elucidate whether burnt foods actually exert biological effects on our health. PMID:26558458

  14. Managing upper airway obstruction.

    PubMed

    Innes, M H

    A complete respiratory obstruction can lead to death in 3 minutes. The first and constant duty of the nurse aider is to check that the person is breathing by looking, listening and feeling. Partial obstruction is no less serious than complete obstruction. The nurse aider, in any situation, should assess the problem and attempt to overcome the airway obstruction using the measures described. PMID:1490067

  15. Airway gene therapy.

    PubMed

    Davies, Jane C; Alton, Eric W F W

    2005-01-01

    Given both the accessibility and the genetic basis of several pulmonary diseases, the lungs and airways initially seemed ideal candidates for gene therapy. Several routes of access are available, many of which have been refined and optimized for nongene drug delivery. Two respiratory diseases, cystic fibrosis (CF) and alpha1-antitrypsin (alpha1-AT) deficiency, are relatively common; the single gene responsible has been identified and current treatment strategies are not curative. This type of inherited disease was the obvious initial target for gene therapy, but it has become clear that nongenetic and acquired diseases, including cancer, may also be amenable to this approach. The majority of preclinical and clinical studies in the airway have involved viral vectors, although for diseases such as CF, likely to require repeated application, non-viral delivery systems have clear advantages. However, with both approaches a range of barriers to gene expression have been identified that are limiting success in the airway and alveolar region. This chapter reviews these issues, strategies aimed at overcoming them, and progress into clinical trials with non-viral vectors in a variety of pulmonary diseases.

  16. TCDD dysregulation of 13 AHR-target genes in rat liver

    SciTech Connect

    Watson, John D.; Prokopec, Stephenie D.; Smith, Ashley B.; Okey, Allan B.; Pohjanvirta, Raimo; Boutros, Paul C.

    2014-02-01

    Despite several decades of research, the complete mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other xenobiotic agonists of the aryl hydrocarbon receptor (AHR) cause toxicity remains unclear. While it has been shown that the AHR is required for all major manifestations of toxicity, the specific downstream changes involved in the development of toxic phenotypes remain unknown. Here we examine a panel of 13 genes that are AHR-regulated in many species and tissues. We profiled their hepatic mRNA abundances in two rat strains with very different sensitivities to TCDD: the TCDD-sensitive Long–Evans (Turku/AB; L–E) and the TCDD-resistant Han/Wistar (Kuopio; H/W). We evaluated doses ranging from 0 to 3000 μg/kg at 19 h after TCDD exposure and time points ranging from 1.5 to 384 h after exposure to 100 μg/kg TCDD. Twelve of 13 genes responded to TCDD in at least one strain, and seven of these showed statistically significant inter-strain differences in the time course analysis (Aldh3a1, Cyp1a2, Cyp1b1, Cyp2a1, Fmo1, Nfe2l2 and Nqo1). Cyp2s1 did not respond to TCDD in either rat strain. Five genes exhibited biphasic responses to TCDD insult (Ahrr, Aldh3a1, Cyp1b1, Nfe2l2 and Nqo1), suggesting a secondary event, such as association with additional transcriptional modulators. Of the 12 genes that responded to TCDD during the dose–response analysis, none had an ED{sub 50} equivalent to that of Cyp1a1, the most sensitive gene in this study, while nine genes responded to doses at least 10–100 fold higher, in at least one strain (Ahrr (L–E), Aldh3a1 (both), Cyp1a2 (both), Cyp1b1 (both), Cyp2a1 (L–E), Inmt (both), Nfe2l2 (L–E), Nqo1 (L–E) and Tiparp (both)). These data shed new light on the association of the AHR target genes with TCDD toxicity, and in particular the seven genes exhibiting strain-specific differences represent strong candidate mediators of Type-II toxicities. - Highlights: • NanoString measured hepatic mRNA molecules

  17. Causes of the difficult airway.

    PubMed

    Orfanos, John G; Quereshy, Faisal A

    2010-03-01

    Recognizing a potentially difficult airway is important in avoiding a life-threatening emergency. There are 2 separate scenarios for considering the difficult airway: difficult mask ventilation (DMV) and difficult tracheal intubation (DTI). DMV can be described as lacking the ability to maintain oxygen saturation or lacking the ability to reverse signs of inadequate ventilation with positive-pressure mask ventilation under general anesthesia. DTI remains constant among anesthesia-related patient injuries, and is the third most common respiratory-related episode leading to death and possible brain damage. It is important to preoperatively assess every patient by completing a full history and physical. A thorough history can provide clues in detecting a possible difficult airway. Airway impairment has been further subdivided into the anatomic regions that affect the airway, namely above the larynx, supraglottic, glottic, subglottic, and tracheobronchial. This article discusses the factors that can result in a difficult airway.

  18. A crucial role of sialidase Neu1 in hyaluronan receptor function of CD44 in T helper type 2-mediated airway inflammation of murine acute asthmatic model.

    PubMed

    Katoh, S; Maeda, S; Fukuoka, H; Wada, T; Moriya, S; Mori, A; Yamaguchi, K; Senda, S; Miyagi, T

    2010-08-01

    CD44 is a highly glycosylated cell adhesion molecule that is involved in lymphocyte infiltration of inflamed tissues. We have demonstrated previously that sialic acid residues of CD44 negatively regulates its receptor function and CD44 plays an important role in the accumulation of T helper type 2 (Th2) cells in the airway of a murine model of acute asthma. Here we evaluated the role of sialidase in the hyaluronic acid (HA) receptor function of CD44 expressed on CD4+ T cells, as well as in the development of a mite antigen-induced murine model of acute asthma. Splenic CD4+ T cell binding of HA was examined with flow cytometry. Expression of sialidases (Neu1, Neu2, Neu3 and Neu4) in spleen cells was evaluated by quantitative real-time reverse transcription-polymerase chain reaction. Airway inflammation and airway hyperresponsiveness (AHR) were evaluated in the asthmatic Neu1-deficient mouse strain SM/J model. Splenic CD4+ T cells from asthmatic model mice displayed increased HA receptor activity of CD44 after culture with the antigen, along with characteristic parallel induction of sialidase (Neu1) expression. This induction of HA binding was suppressed significantly by a sialidase inhibitor and was not observed in SM/J mice. Th2 cytokine concentration and absolute number of Th2 cells in the bronchoalveolar lavage fluid, and AHR were decreased in SM/J mice. In conclusion, HA receptor activity of CD44 and acute asthmatic reactions, including Th2-mediated airway inflammation and AHR, are dependent upon Neu1 enzymatic activity. Our observation suggests that Neu1 may be a target molecule for the treatment of asthma.

  19. CD4+ T cells enhance the unloaded shortening velocity of airway smooth muscle by altering the contractile protein expression.

    PubMed

    Matusovsky, Oleg S; Nakada, Emily M; Kachmar, Linda; Fixman, Elizabeth D; Lauzon, Anne-Marie

    2014-07-15

    Abundant data indicate that pathogenesis in allergic airways disease is orchestrated by an aberrant T-helper 2 (Th2) inflammatory response. CD4(+) T cells have been localized to airway smooth muscle (ASM) in both human asthmatics and in rodent models of allergic airways disease, where they have been implicated in proliferative responses of ASM. Whether CD4(+) T cells also alter ASM contractility has not been addressed. We established an in vitro system to assess the ability of antigen-stimulated CD4(+) T cells to modify contractile responses of the Brown Norway rat trachealis muscle. Our data demonstrated that the unloaded velocity of shortening (Vmax) of ASM was significantly increased upon 24 h co-incubation with antigen-stimulated CD4(+) T cells, while stress did not change. Enhanced Vmax was dependent upon contact between the CD4(+) T cells and the ASM and correlated with increased levels of the fast (+)insert smooth muscle myosin heavy chain isoform. The levels of myosin light chain kinase and myosin light chain phosphorylation were also increased within the muscle. The alterations in mechanics and in the levels of contractile proteins were transient, both declining to control levels after 48 h of co-incubation. More permanent alterations in muscle phenotype might be attainable when several inflammatory cells and mediators interact together or after repeated antigenic challenges. Further studies will await new tissue culture methodologies that preserve the muscle properties over longer periods of time. In conclusion, our data suggest that inflammatory cells promote ASM hypercontractility in airway hyper-responsiveness and asthma.

  20. The Q-rich/PST domain of the AHR regulates both ligand-induced nuclear transport and nucleocytoplasmic shuttling

    PubMed Central

    Tkachenko, Anna; Henkler, Frank; Brinkmann, Joep; Sowada, Juliane; Genkinger, Doris; Kern, Christian; Tralau, Tewes; Luch, Andreas

    2016-01-01

    The aryl hydrocarbon receptor (AHR) shuttles continuously between cytoplasm and nucleus, unless ligand-binding triggers association with the AHR nuclear translocator (ARNT) and subsequent binding to cognate DNA motifs. We have now identified Val 647 as mandatory residue for export from the nucleus and AHR-function. This residue prevents inactivation of the receptor as a consequence of nuclear sequestration via constitutive import. Concomitantly mutants lacking this residue are exclusively localised in the nucleus. Although ligands accelerate nuclear import transiently, stable nuclear transition depends on a motif adjacent to Val 647 that comprises residues 650–661. Together, this defined region within the Q-rich domain regulates intracellular trafficking of the AHR in context of both nucleocytoplasmic shuttling and receptor activation. Nuclear export therefore depends on the previously characterised N-terminal NES and the newly identified motif that includes V647. Nucleocytoplasmic distribution of full-length human AHR is further affected by a section of the PST domain that shows sequence similarities with nuclear export signals. In concert, these motifs maintain a predominant cytoplasmic compartmentalisation, receptive for ligand binding. PMID:27535013

  1. The Q-rich/PST domain of the AHR regulates both ligand-induced nuclear transport and nucleocytoplasmic shuttling.

    PubMed

    Tkachenko, Anna; Henkler, Frank; Brinkmann, Joep; Sowada, Juliane; Genkinger, Doris; Kern, Christian; Tralau, Tewes; Luch, Andreas

    2016-01-01

    The aryl hydrocarbon receptor (AHR) shuttles continuously between cytoplasm and nucleus, unless ligand-binding triggers association with the AHR nuclear translocator (ARNT) and subsequent binding to cognate DNA motifs. We have now identified Val 647 as mandatory residue for export from the nucleus and AHR-function. This residue prevents inactivation of the receptor as a consequence of nuclear sequestration via constitutive import. Concomitantly mutants lacking this residue are exclusively localised in the nucleus. Although ligands accelerate nuclear import transiently, stable nuclear transition depends on a motif adjacent to Val 647 that comprises residues 650-661. Together, this defined region within the Q-rich domain regulates intracellular trafficking of the AHR in context of both nucleocytoplasmic shuttling and receptor activation. Nuclear export therefore depends on the previously characterised N-terminal NES and the newly identified motif that includes V647. Nucleocytoplasmic distribution of full-length human AHR is further affected by a section of the PST domain that shows sequence similarities with nuclear export signals. In concert, these motifs maintain a predominant cytoplasmic compartmentalisation, receptive for ligand binding. PMID:27535013

  2. The association between reflux esophagitis and airway hyper-reactivity in patients with gastro-esophageal reflux

    PubMed Central

    Karbasi, Ashraf; Ardestani, Mohammad Emami; Ghanei, Mostafa; Harandi, Ali Amini

    2013-01-01

    Background: The association of gastro-esophageal reflux (GER) with a wide variety of pulmonary disorders was recognized. We aimed to evaluate the effect of GER-induced esophagitis on airway hyper-reactivity (AHR) in patients and the response to treatment. Materials and Methods: In this cohort study, 30 patients attending the gastrointestinal clinic of a university hospital with acid reflux symptoms were included. All patients were evaluated endoscopically and divided into case group with esophagitis and control group without any evidence of esophagitis. Spirometry and methacholine test were done in all patients before and after treatment of GER with pantoprazole 40 mg daily for six months. Results: There was a significant difference in the rate of positive methacholine test between the cases (40%) and the controls (6.7%) prior to anti-acid therapy (P < 0.0001). After six months of treatment, the frequency of positive methacholine test diminished from 40 to 13.3% in the case group (P < 0.05) but did not change in the controls (P = 0.15). Conclusion: The presence of esophagitis due to GER would increase the AHR and treatment with pantoperazole would decrease AHR in patients with proved esophagitis and no previous history of asthma after six months. PMID:24250694

  3. Benzo[ghi]perylene activates the AHR pathway to exert biological effects on the NL-20 human bronchial cell line.

    PubMed

    Zaragoza-Ojeda, Montserrat; Eguía-Aguilar, Pilar; Perezpeña-Díazconti, Mario; Arenas-Huertero, Francisco

    2016-08-10

    Polycyclic aromatic hydrocarbons (PAH) are produced by incomplete combustion of organic material. In the Mexico City atmosphere, the most abundant PAH is benzo[ghi]perylene (BghiP), a gasoline combustion marker. At present, there are no reports of the effects of BghiP on human bronchial cells, so the aim of the study was to evaluate the effects in vitro of BghiP on the NL-20 cell line. Results showed that BghiP induced the formation of small vesicles throughout the cytoplasm, with absence of nuclear fragmentation. At 48h exposition, damage in cell membrane increased significantly at 1.24μg/mL of BghiP (p<0.05). Immunocytochemistry revealed that BghiP provokes nuclear translocation of AhR receptor, which indicates that this compound can induce transcription of genes via receptor binding (AhR pathway activation). BghiP induced a two-fold increase (p<0.05) in the expression of AhR and CYP4B1 (a lung-specific pathway effector). In the presence of the receptor antagonist CH-223191, the loss of viability, the nuclear translocation and the overexpression of genes decreased, though this did not prevent the formation of vesicles. BghiP induced oxidative stress and in presence of the receptor antagonist this increased significantly. In conclusion, BghiP can activate the overexpression of AhR and CYP4B1, and the effects are abated by the AhR receptor antagonist. This is the first report to prove that BghiP utilizes the AhR pathway to exert its toxic effects on the NL-20 human bronchial cell line . PMID:27234499

  4. Inhibition of AHR transcription by NF1C is affected by a single-nucleotide polymorphism, and is involved in suppression of human uterine endometrial cancer.

    PubMed

    Li, D; Takao, T; Tsunematsu, R; Morokuma, S; Fukushima, K; Kobayashi, H; Saito, T; Furue, M; Wake, N; Asanoma, K

    2013-10-10

    Involvement of the aryl hydrocarbon receptor (AHR) in carcinogenesis has been suggested in many studies. Upregulation of AHR has been reported in some cancer species, and an association between single-nucleotide polymorphisms (SNPs) of AHR and cancer risk or cancer development has also been reported. This evidence suggests the involvement of some specific SNPs in AHR transcriptional regulation in the process of carcinogenesis or cancer development, but there have been no studies to elucidate the mechanism involved. In this study, we identified the transcription factor Nuclear Factor 1-C (NF1C) as a candidate to regulate AHR transcription in a polymorphism-dependent manner. SNP rs10249788 was included in a consensus binding site for NF1C. Our results suggested that NF1C preferred the C allele to the T allele at rs10249788 for binding. Forced expression of NF1C suppressed the activity of the AHR promoter with C at rs10249788 stronger than that with T. Moreover, expression analysis of human uterine endometrial cancer (HEC) specimens showed greater upregulation of AHR and downregulation of NF1C than those of normal endometrium specimens. Sequence analysis showed HEC patients at advanced stages tended to possess T/T alleles more frequently than healthy women. We also demonstrated that NF1C suppressed proliferation, motility and invasion of HEC cells. This function was at least partially mediated by AHR. This study is the first to report that a polymorphism on the AHR regulatory region affected transcriptional regulation of the AHR gene in vitro. Because NF1C is a tumor suppressor, our new insights into AHR deregulation and its polymorphisms could reveal novel mechanisms of genetic susceptibility to cancer.

  5. Inhibition of constitutive aryl hydrocarbon receptor (AhR) signaling attenuates androgen independent signaling and growth in (C4-2) prostate cancer cells

    PubMed Central

    Tran, Cindy; Richmond, Oliver; Aaron, LaTayia; Powell, Joann B.

    2013-01-01

    The aryl hydrocarbon receptor is a member of the basic-helix-loop-helix family of transcription factors. AhR mediates the biochemical and toxic effects of a number of polyaromatic hydrocarbons such as 2,3,7,8,-tetrachloro-dibenzo-p-dioxin (TCDD). AhR is widely known for regulating the transcription of drug metabolizing enzymes involved in the xenobiotic metabolism of carcinogens and therapeutic agents, such as cytochrome P450-1B1 (CYP1B1). Additionally, AhR has also been reported to interact with multiple signaling pathways during prostate development. Here we investigate the effect of sustained AhR signaling on androgen receptor function in prostate cancer cells. Immunoblot analysis shows that AhR expression is increased in androgen independent (C4-2) prostate cancer cells when compared to androgen sensitive (LNCaP) cells. RT-PCR studies revealed constitutive AhR signaling in C4-2 cells without the ligand induced activation required in LNCaP cells. A reduction of AhR activity by short RNA mediated silencing in C4-2 cells reduced expression of both AhR and androgen responsive genes. The decrease in androgen responsive genes correlates to a decrease in phosphorylated androgen receptor and androgen receptor expression in the nucleus. Furthermore, the forced decrease in AhR expression resulted in a 50% decline in the growth rate of C4-2 cells. These data indicates that AhR is required to maintain hormone independent signaling and growth by the androgen receptor in C4-2 cells. Collectively, these data provide evidence of a direct role for AhR in androgen independent signaling and provides insight into the molecular mechanisms responsible for sustained androgen receptor signaling in hormone refractory prostate cancer. PMID:23266674

  6. The MIF Antagonist ISO-1 Attenuates Corticosteroid-Insensitive Inflammation and Airways Hyperresponsiveness in an Ozone-Induced Model of COPD

    PubMed Central

    Russell, Kirsty E.; Chung, Kian Fan; Clarke, Colin J.; Durham, Andrew L.; Mallia, Patrick; Johnston, Sebastian L.; Barnes, Peter J.; Hall, Simon R.; Simpson, Karen D.; Starkey, Malcolm R.; Hansbro, Philip M.; Adcock, Ian M.; Wiegman, Coen H.

    2016-01-01

    Introduction Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine associated with acute and chronic inflammatory disorders and corticosteroid insensitivity. Its expression in the airways of patients with chronic obstructive pulmonary disease (COPD), a relatively steroid insensitive inflammatory disease is unclear, however. Methods Sputum, bronchoalveolar lavage (BAL) macrophages and serum were obtained from non-smokers, smokers and COPD patients. To mimic oxidative stress-induced COPD, mice were exposed to ozone for six-weeks and treated with ISO-1, a MIF inhibitor, and/or dexamethasone before each exposure. BAL fluid and lung tissue were collected after the final exposure. Airway hyperresponsiveness (AHR) and lung function were measured using whole body plethysmography. HIF-1α binding to the Mif promoter was determined by Chromatin Immunoprecipitation assays. Results MIF levels in sputum and BAL macrophages from COPD patients were higher than those from non-smokers, with healthy smokers having intermediate levels. MIF expression correlated with that of HIF-1α in all patients groups and in ozone-exposed mice. BAL cell counts, cytokine mRNA and protein expression in lungs and BAL, including MIF, were elevated in ozone-exposed mice and had increased AHR. Dexamethasone had no effect on these parameters in the mouse but ISO-1 attenuated cell recruitment, cytokine release and AHR. Conclusion MIF and HIF-1α levels are elevated in COPD BAL macrophages and inhibition of MIF function blocks corticosteroid-insensitive lung inflammation and AHR. Inhibition of MIF may provide a novel anti-inflammatory approach in COPD. PMID:26752192

  7. 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.

  8. The mechanics of airway closure.

    PubMed

    Heil, Matthias; Hazel, Andrew L; Smith, Jaclyn A

    2008-11-30

    We describe how surface-tension-driven instabilities of the lung's liquid lining may lead to pulmonary airway closure via the formation of liquid bridges that occlude the airway lumen. Using simple theoretical models, we demonstrate that this process may occur via a purely fluid-mechanical "film collapse" or through a coupled, fluid-elastic "compliant collapse" mechanism. Both mechanisms can lead to airway closure in times comparable with the breathing cycle, suggesting that surface tension is the primary mechanical effect responsible for the closure observed in peripheral regions of the human lungs. We conclude by discussing the influence of additional effects not included in the simple models, such as gravity, the presence of pulmonary surfactant, respiratory flow and wall motion, the airways' geometry, and the mechanical structure of the airway walls. PMID:18595784

  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. A Mutant Ahr Allele Protects the Embryonic Kidney from Hydrocarbon-Induced Deficits in Fetal Programming

    PubMed Central

    Nanez, Adrian

    2011-01-01

    Background: The use of experimental model systems has expedited the elucidation of pathogenetic mechanisms of renal developmental disease in humans and the identification of genes that orchestrate developmental programming during nephrogenesis. Objectives: We conducted studies to evaluate the role of AHR polymorphisms in the disruption of renal developmental programming by benzo(a)pyrene (BaP). Methods: We used metanephric cultures of C57BL/6J (C57) mice expressing the Ahrb-1 allele and B6.D2N-Ahrd/J (D2N) mice expressing a mutant allele deficient in ligand binding (Ahrd) to investigate molecular mechanisms of renal development. Deficits in fetal programming were evaluated in the offspring of pregnant mice treated with BaP during nephrogenesis. Results: Hydrocarbon challenge of metanephri from C57 mice altered Wilms’ tumor suppressor gene (Wt1) mRNA splice variant ratios and reduced mRNAs of the Wt1 transcriptional targets syndecan-1 (Sdc1) paired box gene 2 (Pax2), epidermal growth factor receptor (Egfr), and retinoic acid receptor, alpha (Rarα). These changes correlated with down-regulation of effectors of differentiation [secreted frizzled-related sequence protein 1 (Sfrp1), insulin-like growth factor 1 receptor (Igf1r), wingless-related MMTV-integration site 4 (Wnt4), Lim homeobox protein 1 (Lhx1), E-cadherin]. In contrast, metanephri from D2N mice were spared hydrocarbon-induced changes in Wt1 splice variant ratios and deficits of differentiation. We observed similar patterns of dysmorphogenesis and progressive loss of renal function at postnatal weeks 7 and 52 in the offspring of pregnant C57 but not D2N mice gavaged with 0.1 or 0.5 mg/kg BaP on gestation days 10–13. Conclusions: These findings support a functional link between AHR and WT1 in the regulation of renal morphogenesis and raise important questions about the contribution of human AHR polymorphisms to the fetal origins of adult-onset kidney disease. PMID:21803694

  11. Characterization of AhR agonists reveals antagonistic activity in European herring gull (Larus argentatus) eggs.

    PubMed

    Muusse, Martine; Christensen, Guttorm; Gomes, Tânia; Kočan, Anton; Langford, Katherine; Tollefsen, Knut Erik; Vaňková, Lenka; Thomas, Kevin V

    2015-05-01

    European herring gull (Larus argentatus) eggs from two Norwegian islands, Musvær in the south east and Reiaren in Northern Norway, were screened for dioxins, furans, and dioxin-like and selected non-dioxin-like polychlorinated biphenyls (PCBs), and subjected to non-target analysis to try to identify the aryl hydrocarbon receptor (AhR) agonists, responsible for elevated levels measured using the dioxin responsive chemically activated luciferase expression (DR-CALUX) assay. Eggs from Musvær contained chemically calculated toxic equivalent (WHO TEQ) levels of between 109 and 483 pg TEQ/g lw, and between 82 and 337 pg TEQ/g lw was determined in eggs from Reiaren. In particular PCB126 contributed highly to the total TEQ (69-82%). In 19 of the 23 samples the calculated WHO TEQ was higher than the TEQCALUX. Using CALUX specific relative effect potencies (REPs), the levels were lower at between 77 and 292 pg/g lw in eggs from Musvær and between 55 and 223 pg/g lw in eggs from Reiaren, which was higher than the TEQCALUX in 16 of the 23 samples. However, the means of the REP values and the TEQCALUX were not significantly different. This suggests the presence of compounds that can elicit antagonist effects, with a low binding affinity to the AhR. Non-target analysis identified the presence of hexachlorobenzene (HCB) (quantified at 9.6-185 pg/g lw) but neither this compound nor high concentrations of PCB126 and non-dioxin-like PCBs could explain the differences between the calculated TEQ or REP values and the TEQCALUX. Even though, for most AhR agonists, the sensitivity of herring gulls is not known, the reported levels can be considered to represent a risk for biological effects in the developing embryo, compared to LC50 values in chicken embryos. For human consumers of herring gull eggs, these eggs contain TEQ levels up to four times higher than the maximum tolerable weekly intake.

  12. The AhR is involved in the regulation of LoVo cell proliferation through cell cycle-associated proteins.

    PubMed

    Yin, Jiuheng; Sheng, Baifa; Han, Bin; Pu, Aimin; Yang, Kunqiu; Li, Ping; Wang, Qimeng; Xiao, Weidong; Yang, Hua

    2016-05-01

    Some ingredients in foods can activate the aryl hydrocarbon receptor (AhR) and arrest cell proliferation. In this study, we hypothesized that 6-formylindolo [3, 2-b] carbazole (FICZ) arrests the cell cycle in LoVo cells (a colon cancer line) through the AhR. The AhR agonist FICZ and the AhR antagonist CH223191 were used to treat LoVo cells. Real-time PCR and Western blot analyses were performed to detect the expression of the AhR, CYP1A1, CDK4, cyclinD1, cyclin E, CDK2, P27, and pRb. The distribution and activation of the AhR were detected with immunofluorescence. A 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and flow cytometric analysis were performed to measure cell viability, cell cycle stage, and apoptosis. Our results show that FICZ inhibited LoVo cell proliferation by inducing G1 cell cycle arrest but had no effect on epithelial apoptosis. Further analysis found that FICZ downregulated cyclinD1 and upregulated p27 expression to arrest Rb phosphorylation. The downregulation of cyclinD1 and upregulation of p27 were abolished by co-treatment with CH223191. We conclude that the AhR, when activated by FICZ (an endogenous AhR ligand), can arrest the cell cycle and block LoVo cell proliferation.

  13. Dioxin induces Ahr-dependent robust DNA demethylation of the Cyp1a1 promoter via Tdg in the mouse liver

    PubMed Central

    Amenya, Hesbon Z.; Tohyama, Chiharu; Ohsako, Seiichiroh

    2016-01-01

    The aryl hydrocarbon receptor (Ahr) is a highly conserved nuclear receptor that plays an important role in the manifestation of toxicity induced by polycyclic aromatic hydrocarbons. As a xenobiotic sensor, Ahr is involved in chemical biotransformation through activation of drug metabolizing enzymes. The activated Ahr cooperates with coactivator complexes to induce epigenetic modifications at target genes. Thus, it is conceivable that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent Ahr ligand, may elicit robust epigenetic changes in vivo at the Ahr target gene cytochrome P450 1a1 (Cyp1a1). A single dose of TCDD administered to adult mice induced Ahr-dependent CpG hypomethylation, changes in histone modifications, and thymine DNA glycosylase (Tdg) recruitment at the Cyp1a1 promoter in the liver within 24 hrs. These epigenetic changes persisted until 40 days post-TCDD treatment and there was Cyp1a1 mRNA hyperinduction upon repeat administration of TCDD at this time-point. Our demethylation assay using siRNA knockdown and an in vitro methylated plasmid showed that Ahr, Tdg, and the ten-eleven translocation methyldioxygenases Tet2 and Tet3 are required for the TCDD-induced DNA demethylation. These results provide novel evidence of Ahr-driven active DNA demethylation and epigenetic memory. The epigenetic alterations influence response to subsequent chemical exposure and imply an adaptive mechanism to xenobiotic stress. PMID:27713569

  14. Dioxin induces Ahr-dependent robust DNA demethylation of the Cyp1a1 promoter via Tdg in the mouse liver

    NASA Astrophysics Data System (ADS)

    Amenya, Hesbon Z.; Tohyama, Chiharu; Ohsako, Seiichiroh

    2016-10-01

    The aryl hydrocarbon receptor (Ahr) is a highly conserved nuclear receptor that plays an important role in the manifestation of toxicity induced by polycyclic aromatic hydrocarbons. As a xenobiotic sensor, Ahr is involved in chemical biotransformation through activation of drug metabolizing enzymes. The activated Ahr cooperates with coactivator complexes to induce epigenetic modifications at target genes. Thus, it is conceivable that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent Ahr ligand, may elicit robust epigenetic changes in vivo at the Ahr target gene cytochrome P450 1a1 (Cyp1a1). A single dose of TCDD administered to adult mice induced Ahr-dependent CpG hypomethylation, changes in histone modifications, and thymine DNA glycosylase (Tdg) recruitment at the Cyp1a1 promoter in the liver within 24 hrs. These epigenetic changes persisted until 40 days post-TCDD treatment and there was Cyp1a1 mRNA hyperinduction upon repeat administration of TCDD at this time-point. Our demethylation assay using siRNA knockdown and an in vitro methylated plasmid showed that Ahr, Tdg, and the ten-eleven translocation methyldioxygenases Tet2 and Tet3 are required for the TCDD-induced DNA demethylation. These results provide novel evidence of Ahr-driven active DNA demethylation and epigenetic memory. The epigenetic alterations influence response to subsequent chemical exposure and imply an adaptive mechanism to xenobiotic stress.

  15. Inhibitory Effect of Sihuangxiechai Decoction on Ovalbumin-Induced Airway Inflammation in Guinea Pigs

    PubMed Central

    Huang, Xue Ping; Tao, En Xue; Feng, Zhan Qin; Yang, Zhao Lu; Zhang, Wei Fen

    2014-01-01

    The aim of this study was to investigate the effect of sihuangxiechai decoction on asthmatic Guinea pig model which was sensitized by intraperitoneal (i.p.) injection of ovalbumin (OVA) and challenged by OVA inhalation to induce chronic airway inflammation. Differential cell counts of cytospins were performed after staining with Giemsa solution. The quantity of leukocytes and its classification in bronchoalveolar lavage fluid (BALF) and blood were evaluated by blood cell analyzer and microscope. Histological analysis of the lung was performed by hematoxylin and eosin (H&E) staining. The levels of interleukin-4 (IL-4) and tumor necrosis factor-alpha (TNF-α) in BALF and serum were detected by radioimmunoassay (RIA). The total number of leukocytes in BALF and blood has no significant difference between Sihuangxiechaitang decoction treated group and dexamethasone (DXM) treated group but was significantly lower than those of asthma group. The percentage of eosinophils in lung tissues of sihuangxiechai decoction treated group was significantly lower than that of asthma group. The results demonstrated that the levels of IL-4 and TNF-α in the sihuangxiechai decoction treated group were significantly reduced compared with the asthma group. In conclusion, these findings demonstrate that sihuangxiechai decoction has a protective effect on OVA-induced asthma in reducing airway inflammation and airway hyperresponsiveness (AHR) in a Guinea pig model and may be useful as an adjuvant therapy for the treatment of bronchial asthma. PMID:25101137

  16. Improved calibration of IMU biases in analytic coarse alignment for AHRS

    NASA Astrophysics Data System (ADS)

    Lu, Jiazhen; Lei, Chaohua; Li, Baoguo; Wen, Ting

    2016-07-01

    An improved method for the inertial measurement unit (IMU) calibration of coarse alignment for the low-accuracy attitude heading reference system (AHRS) is proposed in this paper. The sensitivities of the Euler angles with respect to the inertial sensor biases are studied based on the analytic coarse alignment principle, and the errors of earth rotation rate and local gravity in the body frame caused by initial attitude error are analyzed. Then, an improved analytic coarse alignment algorithm with accelerometer and gyro bias calibration in an arbitrary three-position is proposed. Simulation and experiment results show that the novel method can calibrate accelerometer and gyro biases, reduce Euler angle attitude error, and improve navigation precision in practical applications. Moreover, this method can be applied to other low-accuracy inertial navigation systems.

  17. Increased airway glucose increases airway bacterial load in hyperglycaemia.

    PubMed

    Gill, Simren K; Hui, Kailyn; Farne, Hugo; Garnett, James P; Baines, Deborah L; Moore, Luke S P; Holmes, Alison H; Filloux, Alain; Tregoning, John S

    2016-01-01

    Diabetes is associated with increased frequency of hospitalization due to bacterial lung infection. We hypothesize that increased airway glucose caused by hyperglycaemia leads to increased bacterial loads. In critical care patients, we observed that respiratory tract bacterial colonisation is significantly more likely when blood glucose is high. We engineered mutants in genes affecting glucose uptake and metabolism (oprB, gltK, gtrS and glk) in Pseudomonas aeruginosa, strain PAO1. These mutants displayed attenuated growth in minimal medium supplemented with glucose as the sole carbon source. The effect of glucose on growth in vivo was tested using streptozocin-induced, hyperglycaemic mice, which have significantly greater airway glucose. Bacterial burden in hyperglycaemic animals was greater than control animals when infected with wild type but not mutant PAO1. Metformin pre-treatment of hyperglycaemic animals reduced both airway glucose and bacterial load. These data support airway glucose as a critical determinant of increased bacterial load during diabetes. PMID:27273266

  18. Increased airway glucose increases airway bacterial load in hyperglycaemia

    PubMed Central

    Gill, Simren K.; Hui, Kailyn; Farne, Hugo; Garnett, James P.; Baines, Deborah L.; Moore, Luke S.P.; Holmes, Alison H.; Filloux, Alain; Tregoning, John S.

    2016-01-01

    Diabetes is associated with increased frequency of hospitalization due to bacterial lung infection. We hypothesize that increased airway glucose caused by hyperglycaemia leads to increased bacterial loads. In critical care patients, we observed that respiratory tract bacterial colonisation is significantly more likely when blood glucose is high. We engineered mutants in genes affecting glucose uptake and metabolism (oprB, gltK, gtrS and glk) in Pseudomonas aeruginosa, strain PAO1. These mutants displayed attenuated growth in minimal medium supplemented with glucose as the sole carbon source. The effect of glucose on growth in vivo was tested using streptozocin-induced, hyperglycaemic mice, which have significantly greater airway glucose. Bacterial burden in hyperglycaemic animals was greater than control animals when infected with wild type but not mutant PAO1. Metformin pre-treatment of hyperglycaemic animals reduced both airway glucose and bacterial load. These data support airway glucose as a critical determinant of increased bacterial load during diabetes. PMID:27273266

  19. A prebiotic galactooligosaccharide mixture reduces severity of hyperpnoea-induced bronchoconstriction and markers of airway inflammation.

    PubMed

    Williams, Neil C; Johnson, Michael A; Shaw, Dominick E; Spendlove, Ian; Vulevic, Jelena; Sharpe, Graham R; Hunter, Kirsty A

    2016-09-01

    Gut microbes have a substantial influence on systemic immune function and allergic sensitisation. Manipulation of the gut microbiome through prebiotics may provide a potential strategy to influence the immunopathology of asthma. This study investigated the effects of prebiotic Bimuno-galactooligosaccharide (B-GOS) supplementation on hyperpnoea-induced bronchoconstriction (HIB), a surrogate for exercise-induced bronchoconstriction, and airway inflammation. A total of ten adults with asthma and HIB and eight controls without asthma were randomised to receive 5·5 g/d of either B-GOS or placebo for 3 weeks separated by a 2-week washout period. The peak fall in forced expiratory volume in 1 s (FEV1) following eucapnic voluntary hyperpnoea (EVH) defined HIB severity. Markers of airway inflammation were measured at baseline and after EVH. Pulmonary function remained unchanged in the control group. In the HIB group, the peak post-EVH fall in FEV1 at day 0 (-880 (sd 480) ml) was unchanged after placebo, but was attenuated by 40 % (-940 (sd 460) v. -570 (sd 310) ml, P=0·004) after B-GOS. In the HIB group, B-GOS reduced baseline chemokine CC ligand 17 (399 (sd 140) v. 323 (sd 144) pg/ml, P=0·005) and TNF-α (2·68 (sd 0·98) v. 2·18 (sd 0·59) pg/ml, P=0·040) and abolished the EVH-induced 29 % increase in TNF-α. Baseline C-reactive protein was reduced following B-GOS in HIB (2·46 (sd 1·14) v. 1·44 (sd 0·41) mg/l, P=0·015) and control (2·16 (sd 1·02) v. 1·47 (sd 0·33) mg/l, P=0·050) groups. Chemokine CC ligand 11 and fraction of exhaled nitric oxide remained unchanged. B-GOS supplementation attenuated airway hyper-responsiveness with concomitant reductions in markers of airway inflammation associated with HIB.

  20. A prebiotic galactooligosaccharide mixture reduces severity of hyperpnoea-induced bronchoconstriction and markers of airway inflammation.

    PubMed

    Williams, Neil C; Johnson, Michael A; Shaw, Dominick E; Spendlove, Ian; Vulevic, Jelena; Sharpe, Graham R; Hunter, Kirsty A

    2016-09-01

    Gut microbes have a substantial influence on systemic immune function and allergic sensitisation. Manipulation of the gut microbiome through prebiotics may provide a potential strategy to influence the immunopathology of asthma. This study investigated the effects of prebiotic Bimuno-galactooligosaccharide (B-GOS) supplementation on hyperpnoea-induced bronchoconstriction (HIB), a surrogate for exercise-induced bronchoconstriction, and airway inflammation. A total of ten adults with asthma and HIB and eight controls without asthma were randomised to receive 5·5 g/d of either B-GOS or placebo for 3 weeks separated by a 2-week washout period. The peak fall in forced expiratory volume in 1 s (FEV1) following eucapnic voluntary hyperpnoea (EVH) defined HIB severity. Markers of airway inflammation were measured at baseline and after EVH. Pulmonary function remained unchanged in the control group. In the HIB group, the peak post-EVH fall in FEV1 at day 0 (-880 (sd 480) ml) was unchanged after placebo, but was attenuated by 40 % (-940 (sd 460) v. -570 (sd 310) ml, P=0·004) after B-GOS. In the HIB group, B-GOS reduced baseline chemokine CC ligand 17 (399 (sd 140) v. 323 (sd 144) pg/ml, P=0·005) and TNF-α (2·68 (sd 0·98) v. 2·18 (sd 0·59) pg/ml, P=0·040) and abolished the EVH-induced 29 % increase in TNF-α. Baseline C-reactive protein was reduced following B-GOS in HIB (2·46 (sd 1·14) v. 1·44 (sd 0·41) mg/l, P=0·015) and control (2·16 (sd 1·02) v. 1·47 (sd 0·33) mg/l, P=0·050) groups. Chemokine CC ligand 11 and fraction of exhaled nitric oxide remained unchanged. B-GOS supplementation attenuated airway hyper-responsiveness with concomitant reductions in markers of airway inflammation associated with HIB. PMID:27523186

  1. Access Path to the Ligand Binding Pocket May Play a Role in Xenobiotics Selection by AhR

    PubMed Central

    Szöllősi, Dániel; Erdei, Áron; Gyimesi, Gergely; Magyar, Csaba; Hegedűs, Tamás

    2016-01-01

    Understanding of multidrug binding at the atomic level would facilitate drug design and strategies to modulate drug metabolism, including drug transport, oxidation, and conjugation. Therefore we explored the mechanism of promiscuous binding of small molecules by studying the ligand binding domain, the PAS-B domain of the aryl hydrocarbon receptor (AhR). Because of the low sequence identities of PAS domains to be used for homology modeling, structural features of the widely employed HIF-2α and a more recent suitable template, CLOCK were compared. These structures were used to build AhR PAS-B homology models. We performed molecular dynamics simulations to characterize dynamic properties of the PAS-B domain and the generated conformational ensembles were employed in in silico docking. In order to understand structural and ligand binding features we compared the stability and dynamics of the promiscuous AhR PAS-B to other PAS domains exhibiting specific interactions or no ligand binding function. Our exhaustive in silico binding studies, in which we dock a wide spectrum of ligand molecules to the conformational ensembles, suggest that ligand specificity and selection may be determined not only by the PAS-B domain itself, but also by other parts of AhR and its protein interacting partners. We propose that ligand binding pocket and access channels leading to the pocket play equally important roles in discrimination of endogenous molecules and xenobiotics. PMID:26727491

  2. Nonspecific airway reactivity in a mouse model of asthma

    SciTech Connect

    Collie, D.D.; Wilder, J.A.; Bice, D.E.

    1995-12-01

    Animal models are indispensable for studies requiring an intact immune system, especially for studying the pathogenic mechanisms in atopic diseases, regulation of IgE production, and related biologic effects. Mice are particularly suitable and have been used extensively for such studies because their immune system is well characterized. Further, large numbers of mutants or inbred strains of mice are available that express deficiencies of individual immunologic processes, inflammatory cells, or mediator systems. By comparing reactions in such mice with appropriate control animals, the unique roles of individual cells or mediators may be characterized more precisely in the pathogenesis of atopic respiratory diseases including asthma. However, given that asthma in humans is characterized by the presence of airway hyperresponsiveness to specific and nonspecific stimuli, it is important that animal models of this disease exhibit similar physiologic abnormalities. In the past, the size of the mouse has limited its versatility in this regard. However, recent studies indicate the feasibility of measuring pulmonary responses in living mice, thus facilitating the physiologic evaluation of putative mouse models of human asthma that have been well charcterized at the immunologic and patholigic level. Future work will provide details of the morphometry of the methacholine-induced bronchoconstriction and will further seek to determine the relationship between cigarette smoke exposure and the development of NS-AHR in the transgenic mouse model.

  3. Analysis of the AHR gene proximal promoter GGGGC-repeat polymorphism in lung, breast, and colon cancer

    SciTech Connect

    Spink, Barbara C.; Bloom, Michael S.; Wu, Susan; Sell, Stewart; Schneider, Erasmus; Ding, Xinxin; Spink, David C.

    2015-01-01

    The aryl hydrocarbon receptor (AhR) regulates expression of numerous genes, including those of the CYP1 gene family. With the goal of determining factors that control AHR gene expression, our studies are focused on the role of the short tandem repeat polymorphism, (GGGGC){sub n}, located in the proximal promoter of the human AHR gene. When luciferase constructs containing varying GGGGC repeats were transfected into cancer cell lines derived from the lung, colon, and breast, the number of GGGGC repeats affected AHR promoter activity. The number of GGGGC repeats was determined in DNA from 327 humans and from 38 samples representing 5 species of non-human primates. In chimpanzees and 3 species of macaques, only (GGGGC){sub 2} alleles were observed; however, in western gorilla, (GGGGC){sub n} alleles with n = 2, 4, 5, 6, 7, and 8 were identified. In all human populations examined, the frequency of (GGGGC){sub n} was n = 4 > 5 ≫ 2, 6. When frequencies of the (GGGGC){sub n} alleles in DNA from patients with lung, colon, or breast cancer were evaluated, the occurrence of (GGGGC){sub 2} was found to be 8-fold more frequent among lung cancer patients in comparison with its incidence in the general population, as represented by New York State neonates. Analysis of matched tumor and non-tumor DNA samples from the same individuals provided no evidence of microsatellite instability. These studies indicate that the (GGGGC){sub n} short tandem repeats are inherited, and that the (GGGGC){sub 2} allele in the AHR proximal promoter region should be further investigated with regard to its potential association with lung cancer susceptibility. - Highlights: • The AHR proximal promoter contains a polymorphism, (GGGGC){sub n}, where n = 4 > 5 ≫ 2, 6 • Matched tumor and non-tumor DNA did not show (GGGGC){sub n} microsatellite instability • AHR promoter activity of a construct with (GGGGC){sub 2} was lower than that of (GGGGC){sub 4} • The frequency of (GGGGC){sub 2} in lung

  4. Clonorchis sinensis-derived total protein attenuates airway inflammation in murine asthma model by inducing regulatory T cells and modulating dendritic cell functions

    SciTech Connect

    Jeong, Young-Il; Kim, Seung Hyun; Ju, Jung Won; Cho, Shin Hyeong; Lee, Won Ja; Park, Jin Wook; Park, Yeong-Min; Lee, Sang Eun

    2011-04-22

    Highlights: {yields} Treatment with Clonorchis sinensis-derived total protein attenuates OVA-induced airway inflammation and AHR to methacholine. {yields} Induction of CD4{sup +}CD25{sup +}Foxp3{sup +} T cells and IL-10 along with suppression of splenocyte proliferation by C. sinensis-derived total protein. {yields} C. sinensis-derived total protein interferes with the expression of co-stimulatory molecules in DCs. -- Abstract: Asthma is characterized by Th2-mediated inflammation, resulting in airway hyperresponsiveness (AHR) through airway remodeling. Recent epidemiological and experimental reports have suggested an inverse relationship between the development of allergy and helminth infections. Infection by Clonorchis sinensis, a liver fluke that resides in the bile duct of humans, is endemic predominantly in Asia including Korea and China. Using a murine model for asthma, we investigated the effects of C. sinensis-derived total protein (Cs-TP) on allergen-induced airway inflammation and the mechanism underlying the protective effects of Cs-TP administration on asthma. Treatment with Cs-TP attenuated OVA-induced airway inflammation and methacholine-induced AHR, as well as eosinophilia development, lymphocyte infiltration into the lung, and goblet cell metaplasia. This protective effect of Cs-TP is associated with markedly reduced OVA-specific IgE and Th1/Th2 cytokine production. Moreover, Cs-TP increased the number of CD4{sup +}CD25{sup +}Foxp3{sup +} regulatory T (Treg) cells as well as their suppressive activity. In fact, proliferation of OVA-restimulated splenocytes was suppressed significantly. Cs-TP also inhibited the expression of such co-stimulatory molecules as CD80, CD86, and CD40 in LPS- or OVA-stimulated dendritic cells (DCs), suggesting that Cs-TP could interfere with the capacity of airway DCs to prime naive T cells. These data demonstrate the capacity of C. sinensis to ameliorate allergic asthma and broaden our understanding of the paradoxical

  5. The Effects of Chronic Lifelong Activation of the AHR Pathway by Industrial Chemical Pollutants on Female Human Reproduction

    PubMed Central

    Vacca, Margherita; Nardelli, Claudia; Castegna, Alessandra; Arnesano, Fabio; Carella, Nicola; Depalo, Raffaella

    2016-01-01

    Environmental chemicals, such as heavy metals, affect female reproductive function. A biological sensor of the signals of many toxic chemical compounds seems to be the aryl hydrocarbon receptor (AHR). Previous studies demonstrated the environmental of heavy metals in Taranto city (Italy), an area that has been influenced by anthropogenic factors such as industrial activities and waste treatments since 1986. However, the impact of these elements on female fertility in this geographic area has never been analyzed. Thus, in the present study, we evaluated the AHR pathway, sex steroid receptor pattern and apoptotic process in granulosa cells (GCs) retrieved from 30 women, born and living in Taranto, and 30 women who are living in non-contaminated areas (control group), who were undergoing in vitro fertilization (IVF) protocol. In follicular fluids (FFs) of both groups the toxic and essential heavy metals, such as chromiun (Cr), Manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), cadmium (Cd) and lead (Pb), were also analyzed. Higher levels of Cr, Fe, Zn and Pb were found in the FFs of the women from Taranto as compared to the control group, as were the levels of AHR and AHR-dependent cytochrome P450 1A1 and 1B1; while CYP19A1 expression was decreased. The anti-apoptotic process found in the GCs of women fromTaranto was associated with the highest levels of progesterone receptor membrane component 1 (PGRMC1), a novel progesterone receptor, the expression of which is subjected to AHR activated by its highest affinity ligands (e.g., dioxins) or indirectly by other environmental pollutants, such as heavy metals. In conclusion, decreased production of estradiol and decreased number of retrieved mature oocytes found in women from Taranto could be due to chronic exposure to heavy metals, in particular to Cr and Pb. PMID:27008165

  6. Analysis of the AHR gene proximal promoter GGGGC-repeat polymorphism in lung, breast, and colon cancer.

    PubMed

    Spink, Barbara C; Bloom, Michael S; Wu, Susan; Sell, Stewart; Schneider, Erasmus; Ding, Xinxin; Spink, David C

    2015-01-01

    The aryl hydrocarbon receptor (AhR) regulates expression of numerous genes, including those of the CYP1 gene family. With the goal of determining factors that control AHR gene expression, our studies are focused on the role of the short tandem repeat polymorphism, (GGGGC)n, located in the proximal promoter of the human AHR gene. When luciferase constructs containing varying GGGGC repeats were transfected into cancer cell lines derived from the lung, colon, and breast, the number of GGGGC repeats affected AHR promoter activity. The number of GGGGC repeats was determined in DNA from 327 humans and from 38 samples representing 5 species of non-human primates. In chimpanzees and 3 species of macaques, only (GGGGC)2 alleles were observed; however, in western gorilla, (GGGGC)n alleles with n=2, 4, 5, 6, 7, and 8 were identified. In all human populations examined, the frequency of (GGGGC)n was n=4>5≫2, 6. When frequencies of the (GGGGC)n alleles in DNA from patients with lung, colon, or breast cancer were evaluated, the occurrence of (GGGGC)2 was found to be 8-fold more frequent among lung cancer patients in comparison with its incidence in the general population, as represented by New York State neonates. Analysis of matched tumor and non-tumor DNA samples from the same individuals provided no evidence of microsatellite instability. These studies indicate that the (GGGGC)n short tandem repeats are inherited, and that the (GGGGC)2 allele in the AHR proximal promoter region should be further investigated with regard to its potential association with lung cancer susceptibility.

  7. 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

  8. Extraglottic airway devices: A review

    PubMed Central

    Ramaiah, Ramesh; Das, Debasmita; Bhananker, Sanjay M; Joffe, Aaron M

    2014-01-01

    Extraglottic airway devices (EAD) have become an integral part of anesthetic care since their introduction into clinical practice 25 years ago and have been used safely hundreds of millions of times, worldwide. They are an important first option for difficult ventilation during both in-hospital and out-of-hospital difficult airway management and can be utilized as a conduit for tracheal intubation either blindly or assisted by another technology (fiberoptic endoscopy, lightwand). Thus, the EAD may be the most versatile single airway technique in the airway management toolbox. However, despite their utility, knowledge regarding specific devices and the supporting data for their use is of paramount importance to patient's safety. In this review, number of commercially available EADs are discussed and the reported benefits and potential pitfalls are highlighted. PMID:24741502

  9. 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

  10. Airway Surface Mycosis in Chronic Th2-Associated Airway Disease

    PubMed Central

    Porter, Paul; Lim, Dae Jun; Maskatia, Zahida Khan; Mak, Garbo; Tsai, Chu-Lin; Citardi, Martin J; Fakhri, Samer; Shaw, Joanne L.; Fothergil, Annette; Kheradmand, Farrah; Corry, David B; Luong, Amber

    2014-01-01

    Background Environmental fungi have been linked to T helper type 2 (Th2) cell-related airway inflammation and the Th2-associated chronic airway diseases asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and allergic fungal rhinosinusitis (AFRS), but whether these organisms participate directly or indirectly in disease pathology remains unknown. Objective To determine the frequency of fungus isolation and fungus-specific immunity in Th2-associated and non-associated airway disease patients. Methods Sinus lavage fluid and blood were collected from sinus surgery patients (n=118) including CRS patients with and without nasal polyps and AFRS and non-CRS/non-asthmatic control patients. Asthma status was deteremined from medical history. Sinus lavage fluids were cultured and directly examined for evidence of viable fungi. Peripheral blood mononuclear cells were restimulated with fungal antigens in an enzyme linked immunocell spot (ELISpot) assay to determine total memory fungus-specific IL-4-secreting cells. These data were compared to fungus-specific IgE levels measured from plasma by ELISA. Results Filamentous fungi were significantly more commonly cultured from Th2-associated airway disease subjects (asthma, CRSwNP, or AFRS: n=68) compared to non-Th2-associated control patients (n=31); 74% vs 16% respectively, p<0.001. Both fungus-specific IL-4 ELISpot (n=48) and specific IgE (n=70) data correlated with Th2-associated diseases (sensitivity 73% and specificity 100% vs. 50% and 77%, respectively). Conclusions The frequent isolation of fungi growing directly within the airways accompanied by specific immunity to these organisms only in patients with Th2-associated chronic airway diseases suggests that fungi participate directly in the pathogenesis of these conditions. Efforts to eradicate airway fungi from the airways should be considered in selected patients. Clinical Implications Airway fungi may contribute to the expression of sinusitis with nasal polyps and

  11. Airway obstruction with cricoid pressure.

    PubMed

    Hartsilver, E L; Vanner, R G

    2000-03-01

    Cricoid pressure may cause airway obstruction. We investigated whether this is related to the force applied and to the technique of application. We recorded expired tidal volumes and inflation pressures during ventilation via a face-mask and oral airway in 52 female patients who were anaesthetised and about to undergo elective surgery. An inspired tidal volume of 900 ml was delivered using a ventilator. Ventilation was assessed under five different conditions: no cricoid pressure, backwards cricoid pressure applied with a force of 30 N, cricoid pressure applied in an upward and backward direction with a force of 30 N, backwards cricoid pressure with a force of 44 N and through a tracheal tube. An expired tidal volume of < 200 ml was taken to indicate airway obstruction. Airway obstruction did not occur without cricoid pressure, but did occur in one patient (2%) with cricoid pressure at 30 N, in 29 patients (56%) with 30 N applied in an upward and backward direction and in 18 (35%) patients with cricoid pressure at 44 N. Cricoid pressure applied with a force of 44 N can cause airway obstruction but if cricoid pressure is applied with a force of 30 N, airway obstruction occurs less frequently (p = 0.0001) unless the force is applied in an upward and backward direction.

  12. A new removable airway stent

    PubMed Central

    Amundsen, Tore; Sørhaug, Sveinung; Leira, Håkon Olav; Tyvold, Stig Sverre; Langø, Thomas; Hammer, Tommy; Manstad-Hulaas, Frode; Mattsson, Erney

    2016-01-01

    Background Malignant airway obstruction is a feared complication and will most probably occur more frequently in the future because of increasing cancer incidence and increased life expectancy in cancer patients. Minimal invasive treatment using airway stents represents a meaningful and life-saving palliation. We present a new removable airway stent for improved individualised treatment. Methods To our knowledge, the new airway stent is the world's first knitted and uncovered self-expanding metal stent, which can unravel and be completely removed. In an in vivo model using two anaesthetised and spontaneously breathing pigs, we deployed and subsequently removed the stents by unravelling the device. The procedures were executed by flexible bronchoscopy in an acute and a chronic setting – a ‘proof-of-principle’ study. Results The new stent was easily and accurately deployed in the central airways, and it remained fixed in its original position. It was easy to unravel and completely remove from the airways without clinically significant complications. During the presence of the stent in the chronic study, granulation tissue was induced. This tissue disappeared spontaneously with the removal. Conclusions The new removable stent functioned according to its purpose and unravelled easily, and it was completely removed without significant technical or medical complications. Induced granulation tissue disappeared spontaneously. Further studies on animals and humans are needed to define its optimal indications and future use. PMID:27608269

  13. Airway obstruction with cricoid pressure.

    PubMed

    Hartsilver, E L; Vanner, R G

    2000-03-01

    Cricoid pressure may cause airway obstruction. We investigated whether this is related to the force applied and to the technique of application. We recorded expired tidal volumes and inflation pressures during ventilation via a face-mask and oral airway in 52 female patients who were anaesthetised and about to undergo elective surgery. An inspired tidal volume of 900 ml was delivered using a ventilator. Ventilation was assessed under five different conditions: no cricoid pressure, backwards cricoid pressure applied with a force of 30 N, cricoid pressure applied in an upward and backward direction with a force of 30 N, backwards cricoid pressure with a force of 44 N and through a tracheal tube. An expired tidal volume of < 200 ml was taken to indicate airway obstruction. Airway obstruction did not occur without cricoid pressure, but did occur in one patient (2%) with cricoid pressure at 30 N, in 29 patients (56%) with 30 N applied in an upward and backward direction and in 18 (35%) patients with cricoid pressure at 44 N. Cricoid pressure applied with a force of 44 N can cause airway obstruction but if cricoid pressure is applied with a force of 30 N, airway obstruction occurs less frequently (p = 0.0001) unless the force is applied in an upward and backward direction. PMID:10671836

  14. Genome Editing of the CYP1A1 Locus in iPSCs as a Platform to Map AHR Expression throughout Human Development

    PubMed Central

    Smith, Brenden W.; Stanford, Elizabeth A.; Sherr, David H.; Murphy, George J.

    2016-01-01

    The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that increases the expression of detoxifying enzymes upon ligand stimulation. Recent studies now suggest that novel endogenous roles of the AHR exist throughout development. In an effort to create an optimized model system for the study of AHR signaling in several cellular lineages, we have employed a CRISPR/CAS9 genome editing strategy in induced pluripotent stem cells (iPSCs) to incorporate a reporter cassette at the transcription start site of one of its canonical targets, cytochrome P450 1A1 (CYP1A1). This cell line faithfully reports on CYP1A1 expression, with luciferase levels as its functional readout, when treated with an endogenous AHR ligand (FICZ) at escalating doses. iPSC-derived fibroblast-like cells respond to acute exposure to environmental and endogenous AHR ligands, and iPSC-derived hepatocytes increase CYP1A1 in a similar manner to primary hepatocytes. This cell line is an important innovation that can be used to map AHR activity in discrete cellular subsets throughout developmental ontogeny. As further endogenous ligands are proposed, this line can be used to screen for safety and efficacy and can report on the ability of small molecules to regulate critical cellular processes by modulating the activity of the AHR. PMID:27148368

  15. Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR.

    PubMed

    Litzenburger, Ulrike M; Opitz, Christiane A; Sahm, Felix; Rauschenbach, Katharina J; Trump, Saskia; Winter, Marcus; Ott, Martina; Ochs, Katharina; Lutz, Christian; Liu, Xiangdong; Anastasov, Natasa; Lehmann, Irina; Höfer, Thomas; von Deimling, Andreas; Wick, Wolfgang; Platten, Michael

    2014-02-28

    Indoleamine-2,3-dioxygenase (IDO) inhibitors have entered clinical trials based on their ability to restore anti-tumor immunity in preclinical studies. However, the mechanisms leading to constitutive expression of IDO in human tumors are largely unknown. Here we analyzed the pathways mediating constitutive IDO expression in human cancer. IDO-positive tumor cells and tissues showed basal phosphorylation and acetylation of STAT3 as evidenced by western blotting and immunoprecipitation. Inhibition of IL-6 or STAT3 using siRNA and/or pharmacological inhibitors reduced IDO mRNA and protein expression as well as kynurenine formation. In turn, IDO enzymatic activity activated the AHR as shown by the induction of AHR target genes. IDO-mediated AHR activation induced IL-6 expression, while inhibition or knockdown of the AHR reduced IL-6 expression. IDO activity thus sustains its own expression via an autocrine AHR-IL-6-STAT3 signaling loop. Inhibition of the AHR-IL-6-STAT3 signaling loop restored T-cell proliferation in mixed leukocyte reactions performed in the presence of IDO-expressing human cancer cells. Identification of the IDO-AHR-IL-6-STAT3 signaling loop maintaining IDO expression in human cancers reveals novel therapeutic targets for the inhibition of this core pathway promoting immunosuppression of human cancers. The relevance of the IDO-AHR-IL-6-STAT3 transcriptional circuit is underscored by the finding that high expression of its members IDO, STAT3 and the AHR target gene CYP1B1 is associated with reduced relapse-free survival in lung cancer patients.

  16. Molecular characterization of the aryl hydrocarbon receptor (AhR) pathway in goldfish (Carassius auratus) exposure to TCDD: the mRNA and protein levels.

    PubMed

    Lu, Ming; Chang, Ziwei; Bae, Min-Ji; Oh, Seung Min; Chung, Kyu-Hyuck; Park, Jang-Su

    2013-08-01

    In bony fish or other aquatic vertebrates, the aryl hydrocarbon receptor (AhR) signaling pathway is initiated by exposure to polycyclic (or/and halogenated) aromatic hydrocarbons (PAHs, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD), which subsequently induces the up-regulated expression of a series of related genes (such as cytochrome P4501A (CYP1A)). However, a lack of applicable protein reagents hinders our further understanding of the AhR signaling pathway, which focuses only on gene-based investigations. The goldfish (Carassius auratus) is an ideal model for a study of environmental pollution in whole-Asian fresh water. Here, three sensitive and specific polyclonal antisera against goldfish AhR1, AhR2, and CYP1A proteins were developed. These antisera not only bound the in-vitro synthesized target proteins, but recognized the real proteins expressed in goldfish tissues, with minimal cross-reactivity to non-specific proteins. Together with the analysis of semi-quantitative RT-PCR and polyclonal-antibody-based sandwich ELISA, we confirmed that goldfish AhRs differed in the expression (mRNA and protein levels) patterns among test tissues. Importantly, the relative abundance of each AhR mRNA levels from the different tissues showed no obvious consistency with their protein levels. After exposure to TCDD, goldfish AhR2 showed a more sensitivity than AhR1, and stimulated CYP1A expression directly, similar with the other reported fish models. Overall, development of these antibodies in this study will allow valuable and versatile investigations to further understand the AhR signaling pathway, and different expression (mRNA and protein) patterns represent the first step in determining the regulatory mechanisms underlying the TCDD-exposed aquatic environment.

  17. Human airway ciliary dynamics

    PubMed Central

    Thompson, Kristin; Knowles, Michael R.; Davis, C. William

    2013-01-01

    Airway cilia depend on precise changes in shape to transport the mucus gel overlying mucosal surfaces. The ciliary motion can be recorded in several planes using video microscopy. However, cilia are densely packed, and automated computerized systems are not available to convert these ciliary shape changes into forms that are useful for testing theoretical models of ciliary function. We developed a system for converting planar ciliary motions recorded by video microscopy into an empirical quantitative model, which is easy to use in validating mathematical models, or in examining ciliary function, e.g., in primary ciliary dyskinesia (PCD). The system we developed allows the manipulation of a model cilium superimposed over a video of beating cilia. Data were analyzed to determine shear angles and velocity vectors of points along the cilium. Extracted waveforms were used to construct a composite waveform, which could be used as a standard. Variability was measured as the mean difference in position of points on individual waveforms and the standard. The shapes analyzed were the end-recovery, end-effective, and fastest moving effective and recovery with mean (± SE) differences of 0.31(0.04), 0.25(0.06), 0.50(0.12), 0.50(0.10), μm, respectively. In contrast, the same measures for three different PCD waveforms had values far outside this range. PMID:23144323

  18. 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

  19. Efficacy of Surgical Airway Plasty for Benign Airway Stenosis

    PubMed Central

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

    2015-01-01

    Background: Long-term patency is required during treatment for benign airway stenosis. This study investigated the effectiveness of surgical airway plasty for benign airway stenosis. Methods: Clinical courses of 20 patients, who were treated with surgical plasty for their benign airway stenosis, were retrospectively investigated. Results: Causes of stenosis were tracheobronchial tuberculosis in 12 patients, post-intubation stenosis in five patients, malacia in two patients, and others in one patient. 28 interventional pulmonology procedures and 20 surgical plasty were performed. Five patients with post-intubation stenosis and four patients with tuberculous stenosis were treated with tracheoplasty. Eight patients with tuberculous stenosis were treated with bronchoplasty, and two patients with malacia were treated with stabilization of the membranous portion. Anastomotic stenosis was observed in four patients, and one to four additional treatments were required. Performance status, Hugh–Jones classification, and ventilatory functions were improved after surgical plasty. Outcomes were fair in patients with tuberculous stenosis and malacia. However, efficacy of surgical plasty for post-intubation stenosis was not observed. Conclusion: Surgical airway plasty may be an acceptable treatment for tuberculous stenosis. Patients with malacia recover well after surgical plasty. There may be untreated patients with malacia who have the potential to benefit from surgical plasty. PMID:26567879

  20. Hesperidin-3'-o-methylether is more potent than hesperidin in phosphodiesterase inhibition and suppression of ovalbumin-induced airway hyperresponsiveness.

    PubMed

    Yang, You-Lan; Hsu, Hsin-Te; Wang, Kuo-Hsien; Wang, Chao-Sian; Chen, Chien-Ming; Ko, Wun-Chang

    2012-01-01

    Hesperidin is present in the traditional Chinese medicine, "Chen Pi," and recently was reported to have anti-inflammatory effects. Therefore, we were interested in comparing the effects of hesperidin and hesperidin-3'-O-methylether on phosphodiesterase inhibition and airway hyperresponsiveness (AHR) in a murine model of asthma. In the present results, hesperidin-3'-O-methylether, but not hesperidin, at 30 μmol/kg (p.o.) significantly attenuated the enhanced pause (P(enh)) value, suppressed the increases in numbers of total inflammatory cells, macrophages, lymphocytes, neutrophils, and eosinophils, suppressed total and OVA-specific immunoglobulin (Ig)E levels in the serum and BALF, and enhanced the level of total IgG(2a) in the serum of sensitized and challenged mice, suggesting that hesperidin-3'-O-methylether is more potent than hesperidin in suppression of AHR and immunoregulation. The different potency between them may be due to their aglycons, because these two flavanone glycosides should be hydrolyzed by β-glucosidase after oral administration. Neither influenced xylazine/ketamine-induced anesthesia, suggesting that they may have few or no adverse effects, such as nausea, vomiting, and gastric hypersecretion. In conclusion, hesperidin-3'-O-methylether is more potent in phosphodiesterase inhibition and suppression of AHR and has higher therapeutic (PDE4(H)/PDE4(L)) ratio than hesperidin. Thus, hesperidin-3'-O-methylether may have more potential for use in treating allergic asthma and chronic obstructive pulmonary disease. PMID:23082087

  1. Long-Term Effects of Diesel Exhaust Particles on Airway Inflammation and Remodeling in a Mouse Model

    PubMed Central

    Kim, Byeong-Gon; Lee, Pureun-Haneul; Lee, Shin-Hwa; Kim, Young-En; Shin, Mee-Yong; Kang, Yena; Bae, Seong-Hwan; Kim, Min-Jung; Rhim, TaiYoun; Park, Choon-Sik

    2016-01-01

    Purpose Diesel exhaust particles (DEPs) can induce and trigger airway hyperresponsiveness (AHR) and inflammation. The aim of this study was to investigate the effect of long-term DEP exposure on AHR, inflammation, lung fibrosis, and goblet cell hyperplasia in a mouse model. Methods BALB/c mice were exposed to DEPs 1 hour a day for 5 days a week for 3 months in a closed-system chamber attached to a ultrasonic nebulizer (low dose: 100 µg/m3 DEPs, high dose: 3 mg/m3 DEPs). The control group was exposed to saline. Enhanced pause was measured as an indicator of AHR. Animals were subjected to whole-body plethysmography and then sacrificed to determine the performance of bronchoalveolar lavage and histology. Results AHR was higher in the DEP group than in the control group, and higher in the high-dose DEP than in the low-dose DEP groups at 4, 8, and 12 weeks. The numbers of neutrophils and lymphocytes were higher in the high-dose DEP group than in the low-dose DEP group and control group at 4, 8, and 12 weeks. The levels of interleukin (IL)-5, IL-13, and interferon-γ were higher in the low-dose DEP group than in the control group at 12 weeks. The level of IL-10 was higher in the high-dose DEP group than in the control group at 12 weeks. The level of vascular endothelial growth factor was higher in the low-dose and high-dose DEP groups than in the control group at 12 weeks. The level of IL-6 was higher in the low-dose DEP group than in the control group at 12 weeks. The level of transforming growth factor-β was higher in the high-dose DEP group than in the control group at 4, 8, and 12 weeks. The collagen content and lung fibrosis in lung tissue was higher in the high-dose DEP group at 8 and 12 weeks. Conclusions These results suggest that long-term DEP exposure may increase AHR, inflammation, lung fibrosis, and goblet cell hyperplasia in a mouse model. PMID:26922935

  2. Allergen-induced airway responses.

    PubMed

    Gauvreau, Gail M; El-Gammal, Amani I; O'Byrne, Paul M

    2015-09-01

    Environmental allergens are an important cause of asthma and can contribute to loss of asthma control and exacerbations. Allergen inhalation challenge has been a useful clinical model to examine the mechanisms of allergen-induced airway responses and inflammation. Allergen bronchoconstrictor responses are the early response, which reaches a maximum within 30 min and resolves by 1-3 h, and late responses, when bronchoconstriction recurs after 3-4 h and reaches a maximum over 6-12 h. Late responses are followed by an increase in airway hyperresponsiveness. These responses occur when IgE on mast cells is cross-linked by an allergen, causing degranulation and the release of histamine, neutral proteases and chemotactic factors, and the production of newly formed mediators, such as cysteinyl leukotrienes and prostaglandin D2. Allergen-induced airway inflammation consists of an increase in airway eosinophils, basophils and, less consistently, neutrophils. These responses are mediated by the trafficking and activation of myeloid dendritic cells into the airways, probably as a result of the release of epithelial cell-derived thymic stromal lymphopoietin, and the release of pro-inflammatory cytokines from type 2 helper T-cells. Allergen inhalation challenge has also been a widely used model to study potential new therapies for asthma and has an excellent negative predictive value for this purpose. PMID:26206871

  3. 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

  4. CD11b+ and Sca-1+ Cells Exert the Main Beneficial Effects of Systemically Administered Bone Marrow-Derived Mononuclear Cells in a Murine Model of Mixed Th2/Th17 Allergic Airway Inflammation

    PubMed Central

    Cruz, Fernanda F.; Borg, Zachary D.; Goodwin, Meagan; Coffey, Amy L.; Wagner, Darcy E.; Rocco, Patricia R.M.

    2016-01-01

    Systemic administration of bone marrow-derived mononuclear cells (BMDMCs) or bone marrow-derived mesenchymal stromal cells (MSCs) reduces inflammation and airway hyperresponsiveness (AHR) in a murine model of Th2-mediated eosinophilic allergic airway inflammation. However, since BMDMCs are a heterogeneous population that includes MSCs, it is unclear whether the MSCs alone are responsible for the BMDMC effects. To determine which BMDMC population(s) is responsible for ameliorating AHR and lung inflammation in a model of mixed Th2-eosinophilic and Th17-neutrophilic allergic airway inflammation, reminiscent of severe clinical asthma, BMDMCs obtained from normal C57Bl/6 mice were serially depleted of CD45, CD34, CD11b, CD3, CD19, CD31, or Sca-1 positive cells. The different resulting cell populations were then assessed for ability to reduce lung inflammation and AHR in mixed Th2/Th17 allergic airway inflammation induced by mucosal sensitization to and challenge with Aspergillus hyphal extract (AHE) in syngeneic C56Bl/6 mice. BMDMCs depleted of either CD11b-positive (CD11b+) or Sca-1-positive (Sca-1+) cells were unable to ameliorate AHR or lung inflammation in this model. Depletion of the other cell types did not diminish the ameliorating effects of BMDMC administration. In conclusion, in the current model of allergic inflammation, CD11b+ cells (monocytes, macrophages, dendritic cells) and Sca-1+ cells (MSCs) are responsible for the beneficial effects of BMDMCs. Significance This study shows that bone marrow-derived mononuclear cells (BMDMCs) are as effective as bone marrow-derived mesenchymal stromal cells (MSCs) in ameliorating experimental asthma. It also demonstrates that not only MSCs present in the pool of BMDMCs are responsible for BMDMCs’ beneficial effects but also monocytes, which are the most important cell population to trigger these effects. All of this is in the setting of a clinically relevant model of severe allergic airways inflammation and thus

  5. TCDD promoted EMT of hFPECs via AhR, which involved the activation of EGFR/ERK signaling.

    PubMed

    Gao, Zhan; Bu, Yongjun; Liu, Xiaozhuan; Wang, Xugang; Zhang, Guofu; Wang, Erhui; Ding, Shibin; Liu, Yongfeng; Shi, Ruling; Li, Qiaoyun; Fu, Jianhong; Yu, Zengli

    2016-05-01

    One critical step of second palatal fusion is the newly formed medial epithelia seam (MES) disintegration, which involves apoptosis, epithelial to mesenchymal transition (EMT), and cell migration. Although the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) produces cleft palate at high rates, little is known about the effects of TCDD exposure on the fate of palatal epithelial cells. By using primary epithelial cells isolated from human fetal palatal shelves (hFPECs), we show that TCDD increased cell proliferation and EMT, as demonstrated by increased the epithelial markers (E-cadherin and cytokeratin14) and enhanced the mesenchymal markers (vimentin and fibronectin), but had no effect on cell migration and apoptosis. TCDD exposure led to a dose-dependent increase in Slug protein expression. Coimmunoprecipitation revealed that TCDD promoted AhR to form a protein complex with Slug. ChIP assay confirmed that TCDD exposure recruited AhR to the xenobiotic responsive element of Slug promoter. Knockdown of AhR by siRNA remarkably weakened TCDD-induced binding of AhR to the XRE promoter of slug, thereby suppressed TCDD-induced vimentin. Further experiment showed that TCDD stimulated EGFR phosphorylation did not influence the TGFβ3/Smad signaling; whereas TCDD increased phosphorylation of ERK1/2 and p38 with no effect on activation of JNK. By using varieties of inhibitors, we confirmed that TCDD promoted proliferation and EMT of hFPECs via activation of EGFR/ERK pathway. These data make a novel contribution to the molecular mechanism of cleft palate by TCDD. PMID:26971374

  6. Zebrafish Cardiotoxicity: The Effects of CYP1A Inhibition and AHR2 Knockdown Following Exposure to Weak Aryl Hydrocarbon Receptor Agonists

    PubMed Central

    Clark, Bryan William; Van Tiem Garner, Lindsey; Di Giulio, Richard Thomas

    2014-01-01

    The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates many of the toxic effects of dioxin-like compounds (DLCs) and some polycyclic aromatic hydrocarbons (PAHs). Strong AHR agonists, such as certain polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), cause severe cardiac teratogenesis in fish embryos. Moderately strong AHR agonists, such as benzo[a]pyrene and β-naphthoflavone, have been shown to cause similar cardiotoxic effects when coupled with a cytochrome P450 1A (CYP1A) inhibitor, such as fluoranthene (FL). We sought to determine if weak AHR agonists, when combined with a CYP1A inhibitor (FL) or CYP1A morpholino gene knockdown, are capable of causing cardiac deformities similar to moderately strong AHR agonists (Wassenberg and Di Giulio 2004; Wassenberg and Di Giulio 2004; Billiard, Timme-Laragy et al. 2006; Van Tiem and Di Giulio 2011). The weak AHR agonists included the following: carbaryl, phenanthrene, 2-methylindole, 3-methylindole, indigo, and indirubin. The results showed a complex pattern of cardiotoxic response to weak agonist inhibitor exposure and morpholino-knockdown. Danio rerio (zebrafish) embryos were first exposed to weak AHR agonists at equimolar concentrations. The agonists were assessed for their relative potency as inducers of CYP1 enzyme activity, measured by the ethoxyresorufin-o-deethylase (EROD) assay, and cardiac deformities. Carbaryl, 2-methylindole, and 3-methylindole induced the highest CYP1A activity in zebrafish. Experiments were then conducted to determine the individual cardiotoxicity of each compound. Next, zebrafish were co-exposed to each agonist (at concentrations below those determined to be cardiotoxic) and FL in combination to assess if CYP1A inhibition could induce cardiac deformities. Carbaryl, 2-methylindole, 3-methylindole, and phenanthrene significantly increased pericardial edema relative to controls when combined with FL. To further evaluate the

  7. Gene cloning and expression analysis of AhR and CYP4 from Pinctada martensii after exposed to pyrene.

    PubMed

    Du, Junqiao; Liao, Chenghong; Zhou, Hailong; Diao, Xiaoping; Li, Yuhu; Zheng, Pengfei; Wang, Fuqiang

    2015-10-01

    Pyrene, a typical polycyclic aromatic hydrocarbon, is a common pollutant in the marine environment. Polycyclic aromatic hydrocarbons initiate cellular detoxification in an exposed organism via the activation of the aryl hydrocarbon receptor (AhR). Subsequent metabolism of these xenobiotics is mainly by the cytochrome P450 enzymes of the phase I detoxification system. Full-length complementary DNA sequences from the pearl oyster Pinctada martensii (pm) encoding AhR and cytochrome P4 were cloned. The P. martensii AhR complementary DNA sequence constitutes an open reading frame that encodes for 848 amino acids. Sequence analysis indicated PmAhR showed high similarity with its homologues of other bivalve species. The cytochrome P(CYP)4 complementary DNA sequence of P. martensii constitutes an open reading frame that encodes for 489 amino acids. Quantitative real-time analysis detected both PmAhR and PmCYP4 messenger RNA expressions in the mantle, gill, hepatapancreas and adductor muscle of P. martensii exposed to pyrene. The highest transcript-band intensities of PmAhR and PmCYP4 were observed in the gill. Temporal expression of PmAhR and PmCYP4 messenger RNAs induction was observed in gills and increased between 3 and 5 days post exposure; then returned to control level. These results suggest that messenger RNAs of PmAhR and PmCYP4 in pearl oysters might be useful parameters for monitoring marine environment pyrene pollution.

  8. AhR signaling activation disrupts migration and dendritic growth of olfactory interneurons in the developing mouse

    PubMed Central

    Kimura, Eiki; Ding, Yunjie; Tohyama, Chiharu

    2016-01-01

    Perinatal exposure to a low level of dioxin, a ubiquitous environmental pollutant, has been shown to induce abnormalities in learning and memory, emotion, and sociality in laboratory animals later in adulthood. However, how aryl hydrocarbon receptor (AhR) signaling activation disrupts the higher brain function remains unclear. Therefore, we studied the possible effects of excessive activation of AhR signaling on neurodevelopmental processes, such as cellular migration and neurite growth, in mice. To this end, we transfected a constitutively active-AhR plasmid into stem cells in the lateral ventricle by in vivo electroporation on postnatal day 1. Transfection was found to induce tangential migration delay and morphological abnormalities in neuronal precursors in the rostral migratory stream at 6 days post-electroporation (dpe) as well as disrupt radial migration in the olfactory bulb and apical and basal dendritic growth of the olfactory interneurons in the granule cell layer at 13 and 20 dpe. These results suggest that the retarded development of interneurons by the excessive AhR signaling may at least in part explain the dioxin-induced abnormal behavioral alterations previously reported in laboratory animals. PMID:27197834

  9. Clarithromycin might attenuate the airway inflammation of smoke-exposed asthmatic mice via affecting HDAC2

    PubMed Central

    Hao, Min; Shu, Jun; Zhang, Xiaoyan; Luo, Qiongzhen; Pan, Lin; Guo, Jing

    2015-01-01

    Background Smoke has been proved to be one of the most dangerous ingredients leading to the unsatisfying treatment response of asthmatics to inhaled corticosteroids (ICS) therapy. Macrolides, a class of antibiotics, possess the traits of immunomodulation and anti-inflammation besides antimicrobial activity. Given that studies on the efficacy of macrolides on the refractory asthma patient have diverting conclusions, this article was carried on to investigate the effects of macrolide on the airway inflammation of smoke-exposed asthmatic mice. Methods BALB/c mice were chosen to be the subjects of this study. They were raised to establish asthma model (OVA group); and one asthma group were exposed to the smoke (SEA group), one asthma group were treat with clarithromycin (CAM group) after smoke exposure. Control group mice were used as parallel comparison. Total inspiratory resistance (RL), expiratory resistance of the lung (Re) and lung compliance (Cdyn) were the main index to evaluate airway hyperresponsiveness (AHR). The histopathological change was studied to assess lung tissue inflammation. Cell counts in bronchoalveolar lavage fluid (BALF) were also tested to represent airway inflammation. IL-4 and CXCL1 in BALF and serum were also used to evaluate the airway inflammation. Histone deacelytase2 (HDAC2) activity of lung tissues was measure by assay kit. HDAC2 expression in the lung tissue had been detected by western blot. Results Re, RL and Cdyn were monitored to represent airway responsiveness. All of the three indicators in SEA group were significantly different from control group, while clarithromycin improved airway responsiveness and the three indicator were statistically significant (P<0.01). Histopathology observation had showed massive infiltration of inflammatory cells in both OVA group and SEA group, while inflammation infiltration attenuated in CAM group. Total cell counts in SEA group was much higher than that in CAM group (P=0.019), so were neutrophils

  10. Postnatal Exposure History and Airways

    PubMed Central

    Murphy, Shannon R.; Schelegle, Edward S.; Edwards, Patricia C.; Miller, Lisa A.; Hyde, Dallas M.

    2012-01-01

    Postnatally, the lung continues to grow and differentiate while interacting with the environment. Exposure to ozone (O3) and allergens during postnatal lung development alters structural elements of conducting airways, including innervation and neurokinin abundance. These changes have been linked with development of asthma in a rhesus monkey model. We hypothesized that O3 exposure resets the ability of the airways to respond to oxidant stress and that this is mediated by changes in the neurokinin-1 receptor (NK-1R). Infant rhesus monkeys received episodic exposure to O3 biweekly with or without house dust mite antigen (HDMA) from 6 to 12 months of age. Age-matched monkeys were exposed to filtered air (FA). Microdissected airway explants from midlevel airways (intrapulmonary generations 5–8) for four to six animals in each of four groups (FA, O3, HDMA, and HDMA+O3) were tested for NK-1R gene responses to acute oxidant stress using exposure to hydrogen peroxide (1.2 mM), a lipid ozonide (10 μM), or sham treatment for 4 hours in vitro. Airway responses were measured using real-time quantitative RT-PCR of NK-1R and IL-8 gene expression. Basal NK-1R gene expression levels were not different between the exposure groups. Treatment with ozonide or hydrogen peroxide did not change NK-1R gene expression in animals exposed to FA, HDMA, or HDMA+O3. However, treatment in vitro with lipid ozonide significantly increased NK-1R gene expression in explants from O3–exposed animals. We conclude that a history of prior O3 exposure resets the steady state of the airways to increase the NK-1R response to subsequent acute oxidant stresses. PMID:22962062

  11. Integration of Genome-Wide Computation DRE Search, AhR ChIP-chip and Gene Expression Analyses of TCDD-Elicited Responses in the Mouse Liver

    PubMed Central

    2011-01-01

    Background The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor (TF) that mediates responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Integration of TCDD-induced genome-wide AhR enrichment, differential gene expression and computational dioxin response element (DRE) analyses further elucidate the hepatic AhR regulatory network. Results Global ChIP-chip and gene expression analyses were performed on hepatic tissue from immature ovariectomized mice orally gavaged with 30 μg/kg TCDD. ChIP-chip analysis identified 14,446 and 974 AhR enriched regions (1% false discovery rate) at 2 and 24 hrs, respectively. Enrichment density was greatest in the proximal promoter, and more specifically, within ± 1.5 kb of a transcriptional start site (TSS). AhR enrichment also occurred distal to a TSS (e.g. intergenic DNA and 3' UTR), extending the potential gene expression regulatory roles of the AhR. Although TF binding site analyses identified over-represented DRE sequences within enriched regions, approximately 50% of all AhR enriched regions lacked a DRE core (5'-GCGTG-3'). Microarray analysis identified 1,896 number of TCDD-responsive genes (|fold change| ≥ 1.5, P1(t) > 0.999). Integrating this gene expression data with our ChIP-chip and DRE analyses only identified 625 differentially expressed genes that involved an AhR interaction at a DRE. Functional annotation analysis of differentially regulated genes associated with AhR enrichment identified overrepresented processes related to fatty acid and lipid metabolism and transport, and xenobiotic metabolism, which are consistent with TCDD-elicited steatosis in the mouse liver. Conclusions Details of the AhR regulatory network have been expanded to include AhR-DNA interactions within intragenic and intergenic genomic regions. Moreover, the AhR can interact with DNA independent of a DRE core suggesting there are alternative mechanisms of AhR-mediated gene regulation. PMID:21762485

  12. Characterizing the role of endothelin-1 in the progression of cardiac hypertrophy in aryl hydrocarbon receptor (AhR) null mice

    SciTech Connect

    Lund, Amie K.; Goens, M. Beth; Nunez, Bethany A.; Walker, Mary K. . E-mail: mkwalker@unm.edu

    2006-04-15

    The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor characterized to play a role in detection and adaptation to environmental stimuli. Genetic deletion of AhR results in hypertension, and cardiac hypertrophy and fibrosis, associated with elevated plasma angiotensin II (Ang II) and endothelin-1 (ET-1), thus AhR appears to contribute to cardiovascular homeostasis. In these studies, we tested the hypothesis that ET-1 mediates cardiovascular pathology in AhR null mice via ET{sub A} receptor activation. First, we determine the time courses of cardiac hypertrophy, and of plasma and tissue ET-1 expression in AhR wildtype and null mice. AhR null mice exhibited increases in heart-to-body weight ratio and age-related expression of cardiac hypertrophy markers, {beta}-myosin heavy chain ({beta}-MHC), and atrial natriuretic factor (ANF), which were significant at 2 months. Similarly, plasma and tissue ET-1 expression was significantly elevated at 2 months and increased further with age. Second, AhR null mice were treated with ET{sub A} receptor antagonist, BQ-123 (100 nmol/kg/day), for 7, 28, or 58 days and blood pressure, cardiac fibrosis, and cardiac hypertrophy assessed, respectively. BQ-123 for 7 days significantly reduced mean arterial pressure in conscious, catheterized mice. BQ-123 for 28 days significantly reduced the histological appearance of cardiac fibrosis. Treatment for 58 days significantly reduced cardiac mass, assessed by heart weight, echocardiography, and {beta}-MHC and ANF expression; and reduced cardiac fibrosis as determined by osteopontin and collagen I mRNA expression. These findings establish ET-1 and the ET{sub A} receptor as primary determinants of hypertension and cardiac pathology in AhR null mice.

  13. Airway Assessment for Office Sedation/Anesthesia.

    PubMed

    Rosenberg, Morton B; Phero, James C

    2015-01-01

    Whenever a patient is about to receive sedation or general anesthesia, no matter what the technique, the preoperative assessment of the airway is one of the most important steps in ensuring patient safety and positive outcomes. This article, Part III in the series on airway management, is directed at the ambulatory office practice and focuses on predicting the success of advanced airway rescue techniques.

  14. Ultraviolet light converts propranolol, a nonselective β-blocker and potential lupus-inducing drug, into a proinflammatory AhR ligand.

    PubMed

    Dorgham, Karim; Amoura, Zahir; Parizot, Christophe; Arnaud, Laurent; Frances, Camille; Pionneau, Cédric; Devilliers, Hervé; Pinto, Sandra; Zoorob, Rima; Miyara, Makoto; Larsen, Martin; Yssel, Hans; Gorochov, Guy; Mathian, Alexis

    2015-11-01

    UV light and some medications are known to trigger lupus erythematosus (LE). A common mechanism underlying the immunopathologic effect, resulting from exposure to these two seemingly unrelated factors, remains unknown. The aryl hydrocarbon receptor (AhR) plays a key role in the regulation of IL-22 production in humans and can be activated by both xenobiotics and naturally occurring photoproducts. A significant expansion of Th17 and Th22 cells was observed in the peripheral blood of active systemic LE (SLE) patients, compared to inactive patients and controls. We also show that propranolol, a potential lupus-inducing drug, induced stronger AhR activation in PBMCs of SLE patients than in those of controls. AhR agonist activity of propranolol was enhanced by UV light exposure. MS analysis of irradiated propranolol revealed the generation of a proinflammatory photoproduct. This compound behaves like the prototypic AhR ligand 6-formylindolo[3,2-b]carbazole, a cutaneous UV light-induced tryptophan metabolite, both promoting IL-22, IL-8, and CCL2 secretion by T-cells and macrophages. Finally, LE patients exhibit signs of cutaneous AhR activation that correlate with lesional expression of the same proinflammatory cytokines, suggesting a role for photometabolites in the induction of skin inflammation. The AhR might therefore represent a target for therapeutic intervention in LE. PMID:26354876

  15. Ultraviolet light converts propranolol, a nonselective β-blocker and potential lupus-inducing drug, into a proinflammatory AhR ligand.

    PubMed

    Dorgham, Karim; Amoura, Zahir; Parizot, Christophe; Arnaud, Laurent; Frances, Camille; Pionneau, Cédric; Devilliers, Hervé; Pinto, Sandra; Zoorob, Rima; Miyara, Makoto; Larsen, Martin; Yssel, Hans; Gorochov, Guy; Mathian, Alexis

    2015-11-01

    UV light and some medications are known to trigger lupus erythematosus (LE). A common mechanism underlying the immunopathologic effect, resulting from exposure to these two seemingly unrelated factors, remains unknown. The aryl hydrocarbon receptor (AhR) plays a key role in the regulation of IL-22 production in humans and can be activated by both xenobiotics and naturally occurring photoproducts. A significant expansion of Th17 and Th22 cells was observed in the peripheral blood of active systemic LE (SLE) patients, compared to inactive patients and controls. We also show that propranolol, a potential lupus-inducing drug, induced stronger AhR activation in PBMCs of SLE patients than in those of controls. AhR agonist activity of propranolol was enhanced by UV light exposure. MS analysis of irradiated propranolol revealed the generation of a proinflammatory photoproduct. This compound behaves like the prototypic AhR ligand 6-formylindolo[3,2-b]carbazole, a cutaneous UV light-induced tryptophan metabolite, both promoting IL-22, IL-8, and CCL2 secretion by T-cells and macrophages. Finally, LE patients exhibit signs of cutaneous AhR activation that correlate with lesional expression of the same proinflammatory cytokines, suggesting a role for photometabolites in the induction of skin inflammation. The AhR might therefore represent a target for therapeutic intervention in LE.

  16. RNA interference against interleukin-5 attenuates airway inflammation and hyperresponsiveness in an asthma model.

    PubMed

    Chen, Shao-xing; Huang, Feng-ying; Tan, Guang-hong; Wang, Cai-chun; Huang, Yong-hao; Wang, Hua; Zhou, Song-lin; Chen, Fan; Lin, Ying-ying; Liu, Jun-bao

    2009-01-01

    Interleukin-5 (IL-5) accompanies the development of airway inflammation and hyperresponsiveness through the activation of eosinophils. Therefore, interference of IL-5 expression in lung tissue seems to be an accepted approach in asthma therapy. In this study, we designed a small interfering RNA (siRNA) to inhibit the expression of IL-5. The siRNAs against IL-5 were constructed in a lentivirus expressing system, and 1.5x10(6) IFU (inclusion-forming unit) lentiviruses were administered intratracheally to ovalbumin (OVA)-sensitized murine asthmatic models. Our results show that lentivirus-delivered siRNA against IL-5 efficiently inhibited the IL-5 messenger ribonucleic acid (mRNA) expression and significantly attenuated the inflammation in lung tissue. Significant decrease of eosinophils and inflammatory cells were found in peripheral blood, bronchoalveolar lavage fluid (BALF), and lung tissue. In addition, significant inhibition of airway hyperresponsiveness (AHR) was found in the mice treated with siRNA against IL-5. These observations demonstrate that siRNA delivered by means of the lentivirus system is possibly an efficacious therapeutic approach for asthma.

  17. Airway hyperresponsiveness to methacholine, adenosine 5-monophosphate, mannitol, eucapnic voluntary hyperpnoea and field exercise challenge in elite cross-country skiers

    PubMed Central

    Sue-Chu, Malcolm; Brannan, John D; Anderson, Sandra D; Chew, Nora; Bjermer, Leif

    2010-01-01

    Background Methacholine hyperresponsiveness is prevalent in elite athletes. Comparative studies have hitherto been limited to methacholine, eucapnic voluntary hyperpnoea and exercise. This study investigated airway responsiveness to these stimuli as well as to adenosine 5′-monophosphate (AMP) and mannitol, in 58 cross-country ski athletes. Methods Exhaled nitric oxide concentration (FENO), spirometry and bronchial challenge in random order with methacholine, AMP and mannitol were consecutively performed on three study days in the autumn. Specific IgE to eight aeroallergens and a self-completed questionnaire about respiratory symptoms, allergy and asthmatic medication were also performed on day 1. Eucapnic voluntary hyperventilation (EVH) and field exercise tests were randomly performed in 33 of the skiers on two study days in the following winter. Results Of 25 (43%) skiers with airway hyperresponsiveness (AHR), 23, five and three skiers were hyperresponsive to methacholine, AMP and mannitol, respectively. Methacholine hyperresponsiveness was more prevalent in subjects without asthma-like symptoms. The FENO was not significantly different in skiers with and without methacholine hyperresponsiveness. Four of 14 skiers with and four of 19 skiers without methacholine hyperresponsiveness were hyperresponsive to EVH or exercise challenge. AHR to any stimulus was present in 16 asymptomatic and nine symptomatic skiers. Asthma-like symptoms were not correlated with AHR to any stimulus. Conclusions Methacholine hyperresponsiveness is more common in asymptomatic skiers and is a poor predictor of hyperresponsiveness to mannitol and hyperpnoea. The low prevalence of hyperresponsiveness to indirect stimuli may suggest differences in the pathogenesis of methacholine hyperresponsiveness in elite skiers and non-athletes. PMID:20460257

  18. [Airway equipment and its maintenance for a non difficult adult airway management (endotracheal intubation and its alternative: face mask, laryngeal mask airway, laryngeal tube)].

    PubMed

    Francon, D; Estèbe, J P; Ecoffey, C

    2003-08-01

    The airway equipment for a non difficult adult airway management are described: endotracheal tubes with a specific discussion on how to inflate the balloon, laryngoscopes and blades, stylets and intubation guides, oral airways, face masks, laryngeal mask airways and laryngeal tubes. Cleaning and disinfections with the maintenance are also discussed for each type of airway management.

  19. Human mesenchymal stem cells resolve airway inflammation, hyperreactivity, and histopathology in a mouse model of occupational asthma.

    PubMed

    Martínez-González, Itziar; Cruz, Maria-Jesús; Moreno, Rafael; Morell, Ferran; Muñoz, Xavier; Aran, Josep M

    2014-10-01

    Occupational asthma (OA) is characterized by allergic airway inflammation and hyperresponsiveness, leading to progressive airway remodeling and a concomitant decline in lung function. The management of OA remains suboptimal in clinical practice. Thus, establishing effective therapies might overcome the natural history of the disease. We evaluated the ability of human adipose-tissue-derived mesenchymal stem cells (hASCs), either unmodified or engineered to secrete the IL-33 decoy receptor sST2, to attenuate the inflammatory and respiratory symptoms in a previously validated mouse model of OA to ammonium persulfate (AP). Twenty-four hours after a dermal AP sensitization and intranasal challenge regimen, the animals received intravenously 1 × 10(6) cells (either hASCs or hASCs overexpressing sST2) or saline and were analyzed at 1, 3, and 6 days after treatment. The infused hASCs induced an anti-inflammatory and restorative program upon reaching the AP-injured, asthmatic lungs, leading to early reduction of neutrophilic inflammation and total IgE production, preserved alveolar architecture with nearly absent lymphoplasmacytic infiltrates, negligible smooth muscle hyperplasia/hypertrophy in the peribronchiolar areas, and baseline airway hyperreactivity (AHR) to methacholine. Local sST2 overexpression barely increased the substantial efficacy displayed by unmodified hASCs. Thus, hASCs may represent a viable multiaction therapeutic capable to adequately respond to the AP-injured lung environment by resolving inflammation, tissue remodeling, and bronchial hyperresponsiveness typical of OA. PMID:24798370

  20. Emergence of airway smooth muscle mechanical behavior through dynamic reorganization of contractile units and force transmission pathways.

    PubMed

    Brook, Bindi S

    2014-04-15

    Airway hyperresponsiveness (AHR) in asthma remains poorly understood despite significant research effort to elucidate relevant underlying mechanisms. In particular, a significant body of experimental work has focused on the effect of tidal fluctuations on airway smooth muscle (ASM) cells, tissues, lung slices, and whole airways to understand the bronchodilating effect of tidal breathing and deep inspirations. These studies have motivated conceptual models that involve dynamic reorganization of both cytoskeletal components as well as contractile machinery. In this article, a biophysical model of the whole ASM cell is presented that combines 1) crossbridge cycling between actin and myosin; 2) actin-myosin disconnectivity, under imposed length changes, to allow dynamic reconfiguration of "force transmission pathways"; and 3) dynamic parallel-to-serial transitions of contractile units within these pathways that occur through a length fluctuation. Results of this theoretical model suggest that behavior characteristic of experimentally observed force-length loops of maximally activated ASM strips can be explained by interactions among the three mechanisms. Crucially, both sustained disconnectivity and parallel-to-serial transitions are necessary to explain the nature of hysteresis and strain stiffening observed experimentally. The results provide strong evidence that dynamic rearrangement of contractile machinery is a likely mechanism underlying many of the phenomena observed at timescales associated with tidal breathing. This theoretical cell-level model captures many of the salient features of mechanical behavior observed experimentally and should provide a useful starting block for a bottom-up approach to understanding tissue-level mechanical behavior.

  1. Human Mesenchymal Stem Cells Resolve Airway Inflammation, Hyperreactivity, and Histopathology in a Mouse Model of Occupational Asthma

    PubMed Central

    Martínez-González, Itziar; Moreno, Rafael; Morell, Ferran; Muñoz, Xavier

    2014-01-01

    Occupational asthma (OA) is characterized by allergic airway inflammation and hyperresponsiveness, leading to progressive airway remodeling and a concomitant decline in lung function. The management of OA remains suboptimal in clinical practice. Thus, establishing effective therapies might overcome the natural history of the disease. We evaluated the ability of human adipose-tissue-derived mesenchymal stem cells (hASCs), either unmodified or engineered to secrete the IL-33 decoy receptor sST2, to attenuate the inflammatory and respiratory symptoms in a previously validated mouse model of OA to ammonium persulfate (AP). Twenty-four hours after a dermal AP sensitization and intranasal challenge regimen, the animals received intravenously 1×106 cells (either hASCs or hASCs overexpressing sST2) or saline and were analyzed at 1, 3, and 6 days after treatment. The infused hASCs induced an anti-inflammatory and restorative program upon reaching the AP-injured, asthmatic lungs, leading to early reduction of neutrophilic inflammation and total IgE production, preserved alveolar architecture with nearly absent lymphoplasmacytic infiltrates, negligible smooth muscle hyperplasia/hypertrophy in the peribronchiolar areas, and baseline airway hyperreactivity (AHR) to methacholine. Local sST2 overexpression barely increased the substantial efficacy displayed by unmodified hASCs. Thus, hASCs may represent a viable multiaction therapeutic capable to adequately respond to the AP-injured lung environment by resolving inflammation, tissue remodeling, and bronchial hyperresponsiveness typical of OA. PMID:24798370

  2. Bisulfite and sulfite as derivatives of sulfur dioxide alters biomechanical behaviors of airway smooth muscle cells in culture.

    PubMed

    Song, Aijing; Lin, Feng; Li, Jianming; Liao, Qingfeng; Liu, Enmei; Jiang, Xuemei; Deng, Linhong

    2014-02-01

    Sulfur dioxide (SO2) is a common air pollutant that triggers asthmatic symptoms, but its toxicological mechanisms are not fully understood. Specifically, it is unclear how SO2 in vivo affects airway smooth muscle (ASM) cells of which the mechanics is known to ultimately mediate airway hyperresponsiveness (AHR) - a hallmark feature of asthma. To this end, we investigated the effects of bisulfite/sulfite (1:3 M/M in neutral fluid to simulate the in vivo derivatives of inhaled SO2 in the airways), on the viability, migration, stiffness and contractility of ASM cells cultured in vitro. The results showed that bisulfite/sulfite consistently increased viability, migration, F-actin intensity and stiffness of ASM cells in similar fashion as concentration increasing from 10(-4) to 10(-1) mmol/L. However, bisulfite/sulfite increased the ASM cell contractility induced by KCl only at the concentration between 10(-4) and 10(-3) mmol/L (p < 0.05), while having no consistent effect on that induced by histamine. At the concentration of 10(0) mmol/L, bisulfite/sulfite became acutely toxic to the ASM cells. Taken together, the data suggest that SO2 derivatives at low levels in vivo may directly increase the mass, stiffness and contractility of ASM cells, which may help understand the mechanism in which specific air pollutants contribute in vivo to the pathogenesis of asthma.

  3. Inflammatory bowel disease and airway diseases

    PubMed Central

    Vutcovici, Maria; Brassard, Paul; Bitton, Alain

    2016-01-01

    Airway diseases are the most commonly described lung manifestations of inflammatory bowel disease (IBD). However, the similarities in disease pathogenesis and the sharing of important environmental risk factors and genetic susceptibility suggest that there is a complex interplay between IBD and airway diseases. Recent evidence of IBD occurrence among patients with airway diseases and the higher than estimated prevalence of subclinical airway injuries among IBD patients support the hypothesis of a two-way association. Future research efforts should be directed toward further exploration of this association, as airway diseases are highly prevalent conditions with a substantial public health impact. PMID:27678355

  4. Inflammatory bowel disease and airway diseases

    PubMed Central

    Vutcovici, Maria; Brassard, Paul; Bitton, Alain

    2016-01-01

    Airway diseases are the most commonly described lung manifestations of inflammatory bowel disease (IBD). However, the similarities in disease pathogenesis and the sharing of important environmental risk factors and genetic susceptibility suggest that there is a complex interplay between IBD and airway diseases. Recent evidence of IBD occurrence among patients with airway diseases and the higher than estimated prevalence of subclinical airway injuries among IBD patients support the hypothesis of a two-way association. Future research efforts should be directed toward further exploration of this association, as airway diseases are highly prevalent conditions with a substantial public health impact.

  5. Lung function and airway diseases.

    PubMed

    Weiss, Scott T

    2010-01-01

    Two studies report genome-wide association studies for lung function, using cross-sectional spirometric measurements in healthy individuals. They identify six genetic loci newly associated to natural variation in lung function, which may have implications for the related airway diseases of asthma and chronic obstructive pulmonary disease. PMID:20037613

  6. Phenotype refinement strengthens the association of AHR and CYP1A1 genotype with caffeine consumption.

    PubMed

    McMahon, George; Taylor, Amy E; Davey Smith, George; Munafò, Marcus R

    2014-01-01

    Two genetic loci, one in the cytochrome P450 1A1 (CYP1A1) and 1A2 (CYP1A2) gene region (rs2472297) and one near the aryl-hydrocarbon receptor (AHR) gene (rs6968865), have been associated with habitual caffeine consumption. We sought to establish whether a more refined and comprehensive assessment of caffeine consumption would provide stronger evidence of association, and whether a combined allelic score comprising these two variants would further strengthen the association. We used data from between 4,460 and 7,520 women in the Avon Longitudinal Study of Parents and Children, a longitudinal birth cohort based in the United Kingdom. Self-report data on coffee, tea and cola consumption (including consumption of decaffeinated drinks) were available at multiple time points. Both genotypes were individually associated with total caffeine consumption, and with coffee and tea consumption. There was no association with cola consumption, possibly due to low levels of consumption in this sample. There was also no association with measures of decaffeinated drink consumption, indicating that the observed association is most likely mediated via caffeine. The association was strengthened when a combined allelic score was used, accounting for up to 1.28% of phenotypic variance. This was not associated with potential confounders of observational association. A combined allelic score accounts for sufficient phenotypic variance in caffeine consumption that this may be useful in Mendelian randomization studies. Future studies may therefore be able to use this combined allelic score to explore causal effects of habitual caffeine consumption on health outcomes. PMID:25075865

  7. Phenotype Refinement Strengthens the Association of AHR and CYP1A1 Genotype with Caffeine Consumption

    PubMed Central

    McMahon, George; Taylor, Amy E.; Davey Smith, George; Munafò, Marcus R.

    2014-01-01

    Two genetic loci, one in the cytochrome P450 1A1 (CYP1A1) and 1A2 (CYP1A2) gene region (rs2472297) and one near the aryl-hydrocarbon receptor (AHR) gene (rs6968865), have been associated with habitual caffeine consumption. We sought to establish whether a more refined and comprehensive assessment of caffeine consumption would provide stronger evidence of association, and whether a combined allelic score comprising these two variants would further strengthen the association. We used data from between 4,460 and 7,520 women in the Avon Longitudinal Study of Parents and Children, a longitudinal birth cohort based in the United Kingdom. Self-report data on coffee, tea and cola consumption (including consumption of decaffeinated drinks) were available at multiple time points. Both genotypes were individually associated with total caffeine consumption, and with coffee and tea consumption. There was no association with cola consumption, possibly due to low levels of consumption in this sample. There was also no association with measures of decaffeinated drink consumption, indicating that the observed association is most likely mediated via caffeine. The association was strengthened when a combined allelic score was used, accounting for up to 1.28% of phenotypic variance. This was not associated with potential confounders of observational association. A combined allelic score accounts for sufficient phenotypic variance in caffeine consumption that this may be useful in Mendelian randomization studies. Future studies may therefore be able to use this combined allelic score to explore causal effects of habitual caffeine consumption on health outcomes. PMID:25075865

  8. Assessment of inhibitory potential of Pothos scandens L. on ovalbumin-induced airway hyperresponsiveness in balb/c mice.

    PubMed

    Gupta, Saurabh; Basavan, Duraiswamy; Muthureddy Nataraj, Satish Kumar; Raju, K Rama Satyanarayana; Babu, U V; L M, Sharath Kumar; Gupta, Renu

    2014-01-01

    Pothos scandens L. was used in Indian traditional medicine as an antiasthmatic drug. The ethanolic and aqueous extracts were prepared with aerial parts of P. scandens (PSE & PSA). ESI MS/MS of PSE ethanolic extract was carried out for the determination of chemical constituents. CP1 is isolated from the PSE, structurally confirmed with NMR and LCMS/MS. PSE, PSA and CP1 are evaluated against ovalbumin (OVA) induced airway hyperresponsiveness (AHR) in balb/c mice. The test drugs are administered p.o. prior to challenge with aerosolized 2.5% w/v OVA. Total and differential leucocyte count, nitrite (NO2), nitrate (NO3), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-13 (IL-13) are estimated in bronchoalveolar lavage fluid (BALF). Similarly, myeloperoxidase (MPO), malonaldehyde (MDA) and total lung protein (TLP) are estimated in the lungs. The results reveal a significant increase in total and differential leucocyte count, NO2, NO3, TNF-α, IL-6, and IL-13 in OVA induced AHR. However, these parameters are significantly decreased in PSE and PSA tested doses (PSE 100 & 200mg/kg). While, treatment with CP1 is less effective at 5 & 10mg/kg doses. Similar observations obtain for MPO and MDA in lungs. However, the mean value indicated that the PSE at 200mg/kg showed a significant restoration in all the parameters. Pro-inflammatory mediators are known to be responsible for AHR. Histopathology revealed justifies the effectiveness. The present investigations suggest PSE are interesting molecules for further research for asthma, with an approach through pro-inflammatory inhibitory pathway. P. scandens is a potential herbal medicine for allergy induced asthma. PMID:24287447

  9. Management of the difficult airway.

    PubMed

    Schwartz, D E; Wiener-Kronish, J P

    1991-09-01

    For clinicians involved in airway management, a plan of action for dealing with the difficult airway or a failed intubation should be developed well in advance of encountering a patient in whom intubation is not routine. When difficulty is anticipated, the equipment necessary for performing a difficult intubation should be immediately available. It also is prudent to have a surgeon skilled in performing a tracheotomy and a criothyroidotomy stand by. The intubation should be attempted in the awake state, preferably using the fiberoptic bronchoscope. The more challenging situation is when the difficult airway is confronted unexpectedly. After the first failed attempt at laryngoscopy, head position should be checked and the patient ventilated with oxygen by mask. A smaller styletted tube and possibly a different laryngoscope blade should be selected for a second attempt at intubation. The fiberoptic bronchoscope and other equipment for difficult intubation should be obtained. A second attempt should then be made. If this is unsuccessful, the patient should be reoxygenated, and assistance including a skilled anesthesiologist and surgeon should be summoned. On a third attempt, traction to the tongue can be applied by an assistant, a tube changer could be used to enter the larynx, or one of the other special techniques previously described can be used. If this third attempt fails, it may be helpful to have a physician more experienced in airway management attempt intubation after oxygen has been administered to the patient. If all attempts are unsuccessful, then invasive techniques to secure the airway will have to be performed. PMID:1934950

  10. [Supraglottic airways in infants and children].

    PubMed

    Goldmann, Kai

    2013-04-01

    The development of the LMA-Classic™ revolutionized anaesthesia practice as its wide-spread use led to the establishment of a unique form of airway management, the "supraglottic airway management", besides the existing classical airway management with the face mask or endotracheal tube. Today, 25 years later, along with the original prototype of supraglottic airways quite a few numbers of different devices exist that can be used to secure the airway "above the glottis". After initially primarily marketing adult sizes many suppliers offer paediatric sizes nowadays. However, the scientific evidence in terms of superiority or at a least equality to the original LMA-Classic( of any of these airway devices must be considered insufficient except for the LMA-ProSeal™. Consequently, the routine use of these devices outside controlled clinical studies must be considered questionable. The following article aims at providing a critical appraisal of currently available supraglottic airway devices for neonates and infants. PMID:23633256

  11. Laryngeal mask airway: uses in anesthesiology.

    PubMed

    Pinosky, M

    1996-06-01

    The laryngeal mask airway (LMA), developed in 1983, is a new device to assist in the management of the pediatric and adult airway. In 1991, the Food and Drug Administration gave its approval for use of the LMA in the United States. The LMA is reusable and appears to provide cost-effective airway management in numerous situations. The LMA is simple to use, atraumatic to insert, and helpful in overcoming an obstructed airway. Its role in management of the difficult airway and the traumatic airway is still evolving. This review will introduce the LMA to the nonanesthesiologist and review for the anesthesiologist the origins of the LMA, its physical structure, the technical aspects of insertion, problems with aspiration, its role in the difficult airway, and experience with the pediatric population.

  12. 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. PMID:22082167

  13. Behavioral Rhythmicity of Mice Lacking AhR and Attenuation of Light-induced Phase Shift by 2,3,7,8-Tetracholordibenzo-p-dioxin

    PubMed Central

    Mukai, Motoko; Lin, Tien-Min; Peterson, Richard E.; Cooke, Paul S.; Tischkau, Shelley A.

    2008-01-01

    Transcription factors belonging to the Per/Arnt/Sim (PAS) domain family are highly conserved and many are involved in circadian rhythm regulation. One member of this family, aryl hydrocarbon receptor (AhR), is an orphan receptor whose physiological role is unknown. Recent findings have led to the hypothesis that AhR has a role in circadian rhythm, which is the focus of the present investigation. First, time-of-day dependent mRNA expression of AhR and its signaling target, cytochrome p4501A1 (Cyp1a1) was determined in C57BL/6J mice by quantitative RT-PCR. Circadian expression of AhR and Cyp1a1 was observed both in the suprachiasmatic nucleus (SCN) and liver. Next, the circadian phenotype of mice lacking AhR (AhRKO) was investigated using behavioral monitoring. Intact AhRKO mice had robust circadian rhythmicity with a similar tau under constant conditions compared to wild-type mice, but a significant difference in tau was observed between genotypes in ovariectomized female mice. Time to re-entrainment following 6-h advances or delays of the light/dark cycle was not significantly different between genotypes. However, mice exposed to the AhR agonist 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD, 1 μg/kg BW) displayed decreased phase shifts in response to light and had altered expression of Per1 and Bmal1. These results suggest that chronic activation of AhR may affect the ability of the circadian timekeeping system to adjust to alterations in environmental lighting by affecting canonical clock genes. Further studies are necessary to decipher the mechanism of how AhR agonists could disrupt light-induced phase shifts. If AhR does have a role in circadian rhythm, it may share redundant roles with other PAS domain proteins and/or the role of AhR may not be exhibited in the behavioral activity rhythm, but could be important elsewhere in the peripheral circadian system. PMID:18487412

  14. Sequence and in vitro function of chicken, ring-necked pheasant, and Japanese quail AHR1 predict in vivo sensitivity to dioxins.

    PubMed

    Farmahin, Reza; Wu, Dongmei; Crump, Doug; Hervé, Jessica C; Jones, Stephanie P; Hahn, Mark E; Karchner, Sibel I; Giesy, John P; Bursian, Steven J; Zwiernik, Matthew J; Kennedy, Sean W

    2012-03-01

    There are large differences in sensitivity to the toxic and biochemical effects of dioxins and dioxin-like compounds (DLCs) among vertebrates. Previously, we demonstrated that the difference in sensitivity between domestic chicken (Gallus gallus domesticus) and common tern (Sterna hirundo) to aryl hydrocarbon receptor 1 (AHR1)-dependent changes in gene expression following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is based upon the identities of the amino acids at two sites within the ligand binding domain of AHR1 (chicken--highly sensitive; Ile324_Ser380 vs common tern--250-fold less sensitive than chicken; Val325_Ala381). Here, we tested the hypotheses that (i) the sensitivity of other avian species to TCDD, 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), and 2,3,7,8-tetrachlorodibenzofuran (TCDF) is also determined by the amino acids at sites that are equivalent to sites 324 and 380 in chicken, and (ii) Ile324_Ala380 and Val324_Ser380 genotypes confer intermediate sensitivity to DLCs in birds. We compared ligand-induced transactivation function of full-length AHR1s from chicken, common tern, ring-necked pheasant (Phasianus colchicus; Ile324_Ala380) and Japanese quail (Coturnix japonica; Val324_Ala380), and three Japanese quail AHR1 mutants. The results support our hypothesis that avian species can be grouped into three general classes of sensitivity to DLCs. Both AHR1 genotype and in vitro transactivation assays predict in vivo sensitivity. Contrary to the assumption that TCDD is the most potent DLC, PeCDF was more potent than TCDD at activating Japanese quail (13- to 26-fold) and common tern (23- to 30-fold) AHR1. Our results support and expand previous in vitro and in vivo work that demonstrated ligand-dependent species differences in AHR1 affinity. The findings and methods will be of use for DLC risk assessments.

  15. 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). PMID:24925919

  16. UPPER AIRWAY BLOCKS FOR AWAKE DIFFICULT AIRWAY MANAGEMENT.

    PubMed

    Pintaric, Tatjana Stopar

    2016-03-01

    Airway anesthesia is pivotal for successful awake intubation provided either topically or by blocks. Airway blocks are considered technically more difficult to perform and carry a higher risk of complications. However, in experienced hands, they can be useful as they provide excellent intubating conditions. For complete upper airway anesthesia, bilateral glossopharyngeal and superior laryngeal nerve blocks with translaryngeal injection are required. Superior laryngeal nerve block and translaryngeal injection can be performed easily, safely and with a high success rate in patients with normal anatomy. In those with difficult landmarks, ultrasound can be of assistance. For the superior laryngeal nerve block, other targets than the nerve itself must be established to make the technique consistently successful, easy to teach, learn and perform. The same applies to the translaryngeal injection, where the use of ultrasound is necessary for correct midline identification. Intraoral glossopharyngeal nerve block is also safe and easy to perform, but associated with long lasting discomfort. Bilateral extraoral peristyloid approach should be discouraged since inadvertent blocks of the closely adjacent vagus nerve cannot be prevented in this location. A safe and easy method of blocking the distal portions of the glossopharyngeal nerve for awake intubation is therefore required. PMID:27276778

  17. 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).

  18. Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR).

    PubMed

    Cheng, Xingguo; Vispute, Saurabh G; Liu, Jie; Cheng, Christine; Kharitonenkov, Alexei; Klaassen, Curtis D

    2014-07-01

    The toxic effects of dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), mainly through activation of the aryl hydrocarbon receptor (AhR) are well documented. Fibroblast growth factor (Fgf) 21 plays critical roles in metabolic adaptation to fasting by increasing lipid oxidation and ketogenesis in the liver. The present study was performed to determine whether activation of the AhR induces Fgf21 expression. In mouse liver, TCDD increased Fgf21 mRNA in both dose- and time-dependent manners. In addition, TCDD markedly increased Fgf21 mRNA expression in cultured mouse and human hepatocytes. Moreover, TCDD increased mRNA (in liver) and protein levels (in both liver and serum) of Fgf21 in wild-type mice, but not in AhR-null mice. Chromatin immunoprecipitation assays showed that TCDD increased AhR protein binding to the Fgf21 promoter (-105/+1 base pair). Fgf21-null mice administered 200μg/kg of TCDD died within 20days, whereas wild-type mice receiving the same treatment were still alive at one month after administration. This indicates that TCDD-induced Fgf21 expression protects against TCDD toxicity. Diethylhexylphthalate (DEHP) pretreatment attenuated TCDD-induced Fgf21 expression in mouse liver and white adipose tissue, which may explain a previous report that DEHP pretreatment decreases TCDD-induced wasting. In conclusion, Fgf21 appears to be a target gene of AhR-signaling pathway in mouse and human liver.

  19. Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR)

    SciTech Connect

    Cheng, Xingguo; Vispute, Saurabh G.; Liu, Jie; Cheng, Christine; Kharitonenkov, Alexei; Klaassen, Curtis D.

    2014-07-01

    The toxic effects of dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), mainly through activation of the aryl hydrocarbon receptor (AhR) are well documented. Fibroblast growth factor (Fgf) 21 plays critical roles in metabolic adaptation to fasting by increasing lipid oxidation and ketogenesis in the liver. The present study was performed to determine whether activation of the AhR induces Fgf21 expression. In mouse liver, TCDD increased Fgf21 mRNA in both dose- and time-dependent manners. In addition, TCDD markedly increased Fgf21 mRNA expression in cultured mouse and human hepatocytes. Moreover, TCDD increased mRNA (in liver) and protein levels (in both liver and serum) of Fgf21 in wild-type mice, but not in AhR-null mice. Chromatin immunoprecipitation assays showed that TCDD increased AhR protein binding to the Fgf21 promoter (− 105/+ 1 base pair). Fgf21-null mice administered 200 μg/kg of TCDD died within 20 days, whereas wild-type mice receiving the same treatment were still alive at one month after administration. This indicates that TCDD-induced Fgf21 expression protects against TCDD toxicity. Diethylhexylphthalate (DEHP) pretreatment attenuated TCDD-induced Fgf21 expression in mouse liver and white adipose tissue, which may explain a previous report that DEHP pretreatment decreases TCDD-induced wasting. In conclusion, Fgf21 appears to be a target gene of AhR-signaling pathway in mouse and human liver. - Highlights: • TCDD induced Fgf21 expression at both mRNA and protein levels. • Fgf21 induction by TCDD is AhR-dependent. • DEHP attenuated TCDD-induced Fgf21 expression.

  20. Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR).

    PubMed

    Cheng, Xingguo; Vispute, Saurabh G; Liu, Jie; Cheng, Christine; Kharitonenkov, Alexei; Klaassen, Curtis D

    2014-07-01

    The toxic effects of dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), mainly through activation of the aryl hydrocarbon receptor (AhR) are well documented. Fibroblast growth factor (Fgf) 21 plays critical roles in metabolic adaptation to fasting by increasing lipid oxidation and ketogenesis in the liver. The present study was performed to determine whether activation of the AhR induces Fgf21 expression. In mouse liver, TCDD increased Fgf21 mRNA in both dose- and time-dependent manners. In addition, TCDD markedly increased Fgf21 mRNA expression in cultured mouse and human hepatocytes. Moreover, TCDD increased mRNA (in liver) and protein levels (in both liver and serum) of Fgf21 in wild-type mice, but not in AhR-null mice. Chromatin immunoprecipitation assays showed that TCDD increased AhR protein binding to the Fgf21 promoter (-105/+1 base pair). Fgf21-null mice administered 200μg/kg of TCDD died within 20days, whereas wild-type mice receiving the same treatment were still alive at one month after administration. This indicates that TCDD-induced Fgf21 expression protects against TCDD toxicity. Diethylhexylphthalate (DEHP) pretreatment attenuated TCDD-induced Fgf21 expression in mouse liver and white adipose tissue, which may explain a previous report that DEHP pretreatment decreases TCDD-induced wasting. In conclusion, Fgf21 appears to be a target gene of AhR-signaling pathway in mouse and human liver. PMID:24769090

  1. Obesity and upper airway control during sleep

    PubMed Central

    Patil, Susheel P.; Squier, Samuel; Schneider, Hartmut; Kirkness, Jason P.; Smith, Philip L.

    2010-01-01

    Mechanisms linking obesity with upper airway dysfunction in obstructive sleep apnea are reviewed. Obstructive sleep apnea is due to alterations in upper airway anatomy and neuromuscular control. Upper airway structural alterations in obesity are related to adipose deposition around the pharynx, which can increase its collapsibility or critical pressure (Pcrit). In addition, obesity and, particularly, central adiposity lead to reductions in resting lung volume, resulting in loss of caudal traction on upper airway structures and parallel increases in pharyngeal collapsibility. Metabolic and humoral factors that promote central adiposity may contribute to these alterations in upper airway mechanical function and increase sleep apnea susceptibility. In contrast, neural responses to upper airway obstruction can mitigate these mechanical loads and restore pharyngeal patency during sleep. Current evidence suggests that these responses can improve with weight loss. Improvements in these neural responses with weight loss may be related to a decline in systemic and local pharyngeal concentrations of specific inflammatory mediators with somnogenic effects. PMID:19875707

  2. Airway management in cervical spine injury

    PubMed Central

    Austin, Naola; Krishnamoorthy, Vijay; Dagal, Arman

    2014-01-01

    To minimize risk of spinal cord injury, airway management providers must understand the anatomic and functional relationship between the airway, cervical column, and spinal cord. Patients with known or suspected cervical spine injury may require emergent intubation for airway protection and ventilatory support or elective intubation for surgery with or without rigid neck stabilization (i.e., halo). To provide safe and efficient care in these patients, practitioners must identify high-risk patients, be comfortable with available methods of airway adjuncts, and know how airway maneuvers, neck stabilization, and positioning affect the cervical spine. This review discusses the risks and benefits of various airway management strategies as well as specific concerns that affect patients with known or suspected cervical spine injury. PMID:24741498

  3. Airway obstruction in congenital central hypoventilation syndrome.

    PubMed

    Reverdin, Alexandra K; Mosquera, Ricardo; Colasurdo, Giuseppe N; Jon, Cindy K; Clements, Roya M

    2014-01-01

    Congenital central hypoventilation syndrome (CCHS) is the failure of the autonomic system to control adequate ventilation while asleep with preserved ventilatory response while awake. We report a case of a patient with CCHS who presented with intrathoracic and extrathoracic airway obstruction after tracheostomy tube decannulation and phrenic nerve pacer placement. Nocturnal polysomnography (NPSG) revealed hypoxia, hypercapnia and obstructive sleep apnoea, which required bilevel positive airway pressure titration. Airway endoscopy demonstrated tracheomalacia and paretic true vocal cords in the paramedian position during diaphragmatic pacing. Laryngeal electromyography demonstrated muscular electrical impulses that correlated with diaphragmatic pacer settings. Thus, we surmise that the patient's upper and lower airway obstruction was secondary to diaphragmatic pacer activity. Thorough airway evaluation, including NPSG and endoscopy, may help identify the side effects of diaphragmatic pacing, such as airway obstruction, in patients with CCHS.

  4. Anatomic Optical Coherence Tomography of Upper Airways

    NASA Astrophysics Data System (ADS)

    Chin Loy, Anthony; Jing, Joseph; Zhang, Jun; Wang, Yong; Elghobashi, Said; Chen, Zhongping; Wong, Brian J. F.

    The upper airway is a complex and intricate system responsible for respiration, phonation, and deglutition. Obstruction of the upper airways afflicts an estimated 12-18 million Americans. Pharyngeal size and shape are important factors in the pathogenesis of airway obstructions. In addition, nocturnal loss in pharyngeal muscular tone combined with high pharyngeal resistance can lead to collapse of the airway and periodic partial or complete upper airway obstruction. Anatomical optical coherence tomography (OCT) has the potential to provide high-speed three-dimensional tomographic images of the airway lumen without the use of ionizing radiation. In this chapter we describe the methods behind endoscopic OCT imaging and processing to generate full three dimensional anatomical models of the human airway which can be used in conjunction with numerical simulation methods to assess areas of airway obstruction. Combining this structural information with flow dynamic simulations, we can better estimate the site and causes of airway obstruction and better select and design surgery for patients with obstructive sleep apnea.

  5. AIRWAY VISUALIZATION: EYES SEE WHAT MIND KNOWS.

    PubMed

    Sorbello, Massimiliano; Frova, Giulio; Zdravković, Ivana

    2016-03-01

    Airway management is basic for anesthesia practice, and sometimes it can represent a really dramatic scenario for both the patient and the physicians. Laryngoscopy has been the gold standard of airway visualization for more than 60 years, showing its limitations and failure rates with time. New technology has made available an opportunity to move the physician's eye inside patient airways thanks to video laryngoscopy and video assisted airway management technique. Undoubtedly, we have entered a new era of high resolution airway visualization and different approach in airway instrumentation. Nevertheless, each new technology needs time to be tested and considered reliable, and pitfalls and limitations may come out with careful and long lasting analysis, so it is probably not the right time yet to promote video assisted approach as a new gold standard for airway visualization, despite the fact that it certainly offers some new prospects. In any case, whatever the visualization approach, no patient dies because of missed airway visualization or failed intubation, but due to failed ventilation, which remains without doubt the gold standard of any patient safety goal and airway management technique.

  6. Method for 3D Airway Topology Extraction

    PubMed Central

    Grothausmann, Roman; Kellner, Manuela; Heidrich, Marko; Lorbeer, Raoul-Amadeus; Ripken, Tammo; Meyer, Heiko; Kuehnel, Mark P.; Ochs, Matthias; Rosenhahn, Bodo

    2015-01-01

    In lungs the number of conducting airway generations as well as bifurcation patterns varies across species and shows specific characteristics relating to illnesses or gene variations. A method to characterize the topology of the mouse airway tree using scanning laser optical tomography (SLOT) tomograms is presented in this paper. It is used to test discrimination between two types of mice based on detected differences in their conducting airway pattern. Based on segmentations of the airways in these tomograms, the main spanning tree of the volume skeleton is computed. The resulting graph structure is used to distinguish between wild type and surfactant protein (SP-D) deficient knock-out mice. PMID:25767561

  7. Sequential Stenting for Extensive Malignant Airway Stenosis

    PubMed Central

    Takahama, Makoto; Nakajima, Ryu; Kimura, Michitaka; Tei, Keiko; Yamamoto, Ryoji

    2014-01-01

    Purpose: Malignant airway stenosis extending from the bronchial bifurcation to the lower lobar orifice was treated with airway stenting. We herein examine the effectiveness of airway stenting for extensive malignant airway stenosis. Methods: Twelve patients with extensive malignant airway stenosis underwent placement of a silicone Dumon Y stent (Novatech, La Ciotat, France) at the tracheal bifurcation and a metallic Spiral Z-stent (Medico’s Hirata, Osaka, Japan) at either distal side of the Y stent. We retrospectively analyzed the therapeutic efficacy of the sequential placement of these silicone and metallic stents in these 12 patients. Results: The primary disease was lung cancer in eight patients, breast cancer in two patients, tracheal cancer in one patient, and thyroid cancer in one patient. The median survival period after airway stent placement was 46 days. The Hugh–Jones classification and performance status improved in nine patients after airway stenting. One patient had prolonged hemoptysis and died of respiratory tract hemorrhage 15 days after the treatment. Conclusion: Because the initial disease was advanced and aggressive, the prognosis after sequential airway stent placement was significantly poor. However, because respiratory distress decreased after the treatment in most patients, this treatment may be acceptable for selected patients with extensive malignant airway stenosis. PMID:25273272

  8. High-fat diet promotes lung fibrosis and attenuates airway eosinophilia after exposure to cockroach allergen in mice

    PubMed Central

    Ge, Xiao Na; Greenberg, Yana; Hosseinkhani, M. Reza; Long, Eric K.; Bahaie, Nooshin S.; Rao, Amrita; Ha, Sung Gil; Rao, Savita P.; Bernlohr, David A.; Sriramarao, P.

    2015-01-01

    Obesity is an important risk factor for asthma but the mechanistic basis for this association is not well understood. In the current study, the impact of obesity on lung inflammatory responses after allergen exposure was investigated. C57BL/6 mice maintained on a high-fat diet (HFD) or a normal diet (ND) after weaning were sensitized and challenged with cockroach allergen (CRA). Airway inflammation was assessed based on inflammatory cell recruitment, measurement of lung Th1-Th2 cytokines, chemokines, eicosanoids, and other proinflammatory mediators as well as airway hyperresponsiveness (AHR). CRA-challenged mice fed a HFD exhibited significantly decreased allergen-induced airway eosinophilia along with reduced lung IL-5, IL-13, LTC4, CCL11, and CCL2 levels as well as reduced mucus secretion and smooth muscle mass compared to ND fed mice. However, allergen-challenged HFD fed mice demonstrated significantly increased PAI-1 and reduced PGE2 levels in the lung relative to corresponding ND fed mice. Interestingly, saline-exposed HFD fed mice demonstrated elevated baseline levels of TGF-α1, arginase-1, hypoxia-inducible factor-1α, and lung collagen expression associated with decreased lung function compared to corresponding ND fed mice. These studies indicate that a HFD inhibits airway eosinophilia while altering levels of PAI-1 and PGE2 in response to CRA in mice. Further, a HFD can lead to the development of lung fibrosis even in the absence of allergen exposure which could be due to innate elevated levels of specific profibrotic factors, potentially affecting lung function during asthma. PMID:24102347

  9. Physical principle of airway design in human lungs

    NASA Astrophysics Data System (ADS)

    Park, Keunhwan; Son, Taeho; Kim, Wonjung; Kim, Ho-Young

    2014-11-01

    From an engineering perspective, lungs are natural microfluidic devices that extract oxygen from air. In the bronchial tree, airways branch by dichotomy with a systematic reduction of their diameters. It is generally accepted that in conducting airways, which air passes on the way to the acinar airways from the atmosphere, the reduction ratio of diameter is closely related to the minimization of viscous dissipation. Such a principle is formulated as the Hess-Murray law. However, in acinar airways, where oxygen transfer to alveolae occurs, the diameter reduction with progressive generations is more moderate than in conducting airways. Noting that the dominant transfer mechanism in acinar airways is diffusion rather than advection, unlike conducting airways, we construct a mathematical model for oxygen transfer through a series of acinar airways. Our model allows us to predict the optimal airway reduction ratio that maximizes the oxygen transfer in a finite airway volume, thereby rationalizing the observed airway reduction ratio in acinar airways.

  10. Measured and predicted affinities of binding and relative potencies to activate the AhR of PAHs and their alkylated analogues.

    PubMed

    Lee, Sangwoo; Shin, Woong-Hee; Hong, Seongjin; Kang, Habyeong; Jung, Dawoon; Yim, Un Hyuk; Shim, Won Joon; Khim, Jong Seong; Seok, Chaok; Giesy, John P; Choi, Kyungho

    2015-11-01

    Polycyclic aromatic hydrocarbons (PAHs) and their alkylated forms are important components of crude oil. Both groups of PAHs have been reported to cause dioxin-like responses, mediated by aryl hydrocarbon receptor (AhR). Thus, characterization of binding affinity to the AhR of unsubstituted or alkylated PAHs is important to understand the toxicological consequences of oil contamination on ecosystems. We investigated the potencies of major PAHs of crude oil, e.g., chrysene, phenanthrene and dibenzothiophene, and their alkylated forms (n=17) to upregulate expression of AhR-mediated processes by use of the H4IIE-luc transactivation bioassay. In addition, molecular descriptors of different AhR activation potencies among PAHs were investigated by use of computational molecular docking models. Based on responses of the H4IIE-luc in vitro assay, it was shown that potencies of PAHs were determined by alkylation in addition to the number and conformation of rings. Potencies of AhR-mediated processes were generally greater when a chrysene group was substituted, especially in 1-methyl-chrysene. Significant negative correlations were observed between the in vitro dioxin-like potency measured in H4IIE-luc cells and the binding distance estimated from the in silico modeling. The difference in relative potency for AhR activation observed among PAHs and their alkylated forms could be explained by differences among binding distances in the ligand binding domain of the AhR caused by alkylation. The docking model developed in the present study may have utility in predicting risks of environmental contaminants of which toxicities are mediated by AhR binding.

  11. Effects of 4-nitrophenol on expression of the ER-α and AhR signaling pathway-associated genes in the small intestine of rats.

    PubMed

    Tang, Juan; Song, Meiyan; Watanabe, Gen; Nagaoka, Kentaro; Rui, Xiaoli; Li, ChunMei

    2016-09-01

    4-Nitrophenol (PNP) is a persistent organic pollutant that was proven to be an environmental endocrine disruptor. The aim of this study was to evaluate the role of the estrogen receptor-α (ER-α) and aryl hydrocarbon receptor (AhR) signaling pathway in regulating the damage response to PNP in the small intestine of rats. Wistar-Imamichi male rats (21 d) were randomly divided into two groups: the control group and PNP group. Each group had three processes that were gavaged with PNP or vehicle daily: single dose (1 d), repeated dose (3 consecutive days) (3 d), and repeated dose with recovery (3 consecutive days and 3 recovery days) (6 d). The weight of the body, the related viscera, and small intestine were examined. Histological parameters of the small intestine and the quantity of mucus proteins secreted by small goblet cells were determined using HE staining and PAS staining. The mRNA expression of AhR, ER-α, CYP1A1, and GST was measured by real-time qPCR. In addition, we also analyzed the AhR, ER-α, and CYP1A1 expression in the small intestine by immunohistochemical staining. The small intestines histologically changed in the PNP-treated rat and the expression of AhR, CYP1A1, and GST was increased. While ER-α was significantly decreased in the small intestine, simultaneously, when rats were exposed to a longer PNP treatment, the damages disappeared. Our results demonstrate that PNP has an effect on the expression of AhR signaling pathway genes, AhR, CYP1A1, and GST, and ER-α in the rat small intestine.

  12. Combined chemical and toxicological long-term monitoring for AhR agonists with SPMD-based virtual organisms in drinking water Danjiangkou Reservoir, China.

    PubMed

    Wang, Jingxian; Song, Guoqiang; Li, Aimin; Henkelmann, Bernhard; Pfister, Gerd; Tong, Anthony Z; Schramm, Karl-Werner

    2014-08-01

    SPMD-based virtual organisms (VOs) were employed for time-integrating, long-term sampling combined biological and chemical analyses for exposure assessment of hydrophobic organic pollutants (HOPs) in a drinking water reservoir, China. The SPMDs were deployed at four and five sites in the Danjiangkou (DJK) reservoir over two periods of 26 and 31 d to sequester the hydrophobic contaminants in water. The chosen bioassay response for the extracts of the SPMDs, the induction of 7-ethoxyresorufin-o-deethylase (EROD) was assayed using a rat hepatoma cell line (H4IIE). The known aryl hydrocarbon receptor (AhR) agonists PAHs and PCBs were analyzed by HRGC/HRMS instrument. The cause-effect relationship between the observed AhR activities and chemical concentrations of detected AhR agonists was examined. The results show that the extracts from the SPMD samples could induce AhR activity significantly, whereas the chemically derived 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalent (TEQcal) was not correlated with the bioassay-derived TCDD equivalent (TEQbio). The known AhR agonists could only account for 2-10% of the observed AhR responses among which the contribution of PCBs could almost be neglected. Unidentified AhR-active compounds represented a greater proportion of the TCDD equivalent (TCDD-EQ) in SPMD samples from DJK. Based on the first assessment, the VO followed by the combination of chemical and biological analyses emerges as a resource efficient water monitoring device in ecotoxicological assessment for toxicologically relevant compounds which are readily available for uptake by resident aquatic biota in drinking water resources. PMID:24548649

  13. Disruption of period gene expression alters the inductive effects of dioxin on the AhR signaling pathway in the mouse liver

    SciTech Connect

    Qu Xiaoyu; Metz, Richard P.; Porter, Weston W.; Cassone, Vincent M.; Earnest, David J.

    2009-02-01

    The aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT) are transcription factors that express Per-Arnt-Sim (PAS) DNA-binding motifs and mediate the metabolism of drugs and environmental toxins in the liver. Because these transcription factors interact with other PAS genes in molecular feedback loops forming the mammalian circadian clockworks, we determined whether targeted disruption or siRNA inhibition of Per1 and Per2 expression alters toxin-mediated regulation of the AhR signaling pathway in the mouse liver and Hepa1c1c7 hepatoma cells in vitro. Treatment with the prototypical Ahr ligand, 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), had inductive effects on the primary targets of AhR signaling, Cyp1A1 and Cyp1B1, in the liver of all animals, but genotype-based differences were evident such that the toxin-mediated induction of Cyp1A1 expression was significantly greater (2-fold) in mice with targeted disruption of Per1 (Per1{sup ldc} and Per1{sup ldc}/Per2{sup ldc}). In vitro experiments yielded similar results demonstrating that siRNA inhibition of Per1 significantly increases the TCDD-induced expression of Cyp1A1 and Cyp1B1 in Hepa1c1c7 cells. Per2 inhibition in siRNA-infected Hepa1c1c7 cells had the opposite effect and significantly decreased both the induction of these p450 genes as well as AhR and Arnt expression in response to TCDD treatment. These findings suggest that Per1 may play a distinctive role in modulating AhR-regulated responses to TCDD in the liver.

  14. Combined chemical and toxicological long-term monitoring for AhR agonists with SPMD-based virtual organisms in drinking water Danjiangkou Reservoir, China.

    PubMed

    Wang, Jingxian; Song, Guoqiang; Li, Aimin; Henkelmann, Bernhard; Pfister, Gerd; Tong, Anthony Z; Schramm, Karl-Werner

    2014-08-01

    SPMD-based virtual organisms (VOs) were employed for time-integrating, long-term sampling combined biological and chemical analyses for exposure assessment of hydrophobic organic pollutants (HOPs) in a drinking water reservoir, China. The SPMDs were deployed at four and five sites in the Danjiangkou (DJK) reservoir over two periods of 26 and 31 d to sequester the hydrophobic contaminants in water. The chosen bioassay response for the extracts of the SPMDs, the induction of 7-ethoxyresorufin-o-deethylase (EROD) was assayed using a rat hepatoma cell line (H4IIE). The known aryl hydrocarbon receptor (AhR) agonists PAHs and PCBs were analyzed by HRGC/HRMS instrument. The cause-effect relationship between the observed AhR activities and chemical concentrations of detected AhR agonists was examined. The results show that the extracts from the SPMD samples could induce AhR activity significantly, whereas the chemically derived 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalent (TEQcal) was not correlated with the bioassay-derived TCDD equivalent (TEQbio). The known AhR agonists could only account for 2-10% of the observed AhR responses among which the contribution of PCBs could almost be neglected. Unidentified AhR-active compounds represented a greater proportion of the TCDD equivalent (TCDD-EQ) in SPMD samples from DJK. Based on the first assessment, the VO followed by the combination of chemical and biological analyses emerges as a resource efficient water monitoring device in ecotoxicological assessment for toxicologically relevant compounds which are readily available for uptake by resident aquatic biota in drinking water resources.

  15. Baicalein induces G1 arrest in oral cancer cells by enhancing the degradation of cyclin D1 and activating AhR to decrease Rb phosphorylation

    SciTech Connect

    Cheng, Ya-Hsin; Li, Lih-Ann; Lin, Pinpin; Cheng, Li-Chuan; Hung, Chein-Hui; Chang, Nai Wen; Lin, Chingju

    2012-09-15

    Baicalein is a flavonoid, known to have anti-inflammatory and anti-cancer effects. As an aryl hydrocarbon receptor (AhR) ligand, baicalein at high concentrations blocks AhR-mediated dioxin toxicity. Because AhR had been reported to play a role in regulating the cell cycle, we suspected that the anti-cancer effect of baicalein is associated with AhR. This study investigated the molecular mechanism involved in the anti-cancer effect of baicalein in oral cancer cells HSC-3, including whether such effect would be AhR-mediated. Results revealed that baicalein inhibited cell proliferation and increased AhR activity in a dose-dependent manner. Cell cycle was arrested at the G1 phase and the expression of CDK4, cyclin D1, and phosphorylated retinoblastoma (pRb) was decreased. When the AhR was suppressed by siRNA, the reduction of pRb was partially reversed, accompanied by a decrease of cell population at G1 phase and an increase at S phase, while the reduction of cyclin D1 and CDK4 did not change. This finding suggests that the baicalein activation of AhR is indeed associated with the reduction of pRb, but is independent of the reduction of cyclin D1 and CDK4. When cells were pre-treated with LiCl, the inhibitor of GSK-3β, the decrease of cyclin D1 was blocked and the reduction of pRb was recovered. The data indicates that in HSC-3 the reduction of pRb is both mediated by baicalein through activation of AhR and facilitation of cyclin D1 degradation, which causes cell cycle arrest at the G1 phase, and results in the inhibition of cell proliferation. -- Highlights: ► Baicalein causes the G1 phase arrest by decreasing Rb phosphorylation. ► Baicalein modulates AhR-mediated cell proliferation. ► Both AhR activation and cyclin D1 degradation results in hypophosphorylation of Rb. ► Baicalein facilitates cyclin D1 degradation by signalling the GSK-3β pathway.

  16. In Utero and Lactational Exposure to PCBs in Mice: Adult Offspring Show Altered Learning and Memory Depending on Cyp1a2 and Ahr Genotypes

    PubMed Central

    Curran, Christine P.; Genter, Mary Beth; Patel, Krishna V.; Schaefer, Tori L.; Skelton, Matthew R.; Williams, Michael T.; Vorhees, Charles V.

    2011-01-01

    Background: Both coplanar and noncoplanar polychlorinated biphenyls (PCBs) exhibit neurotoxic effects in animal studies, but individual congeners do not always produce the same effects as PCB mixtures. Humans genetically have > 60-fold differences in hepatic cytochrome P450 1A2 (CYP1A2)-uninduced basal levels and > 12-fold variability in aryl hydrocarbon receptor (AHR)affinity; because CYP1A2 is known to sequester coplanar PCBs and because AHR ligands include coplanar PCBs, both genotypes can affect PCB response. Objectives: We aimed to develop a mouse paradigm with extremes in Cyp1a2 and Ahr genotypes to explore genetic susceptibility to PCB-induced developmental neurotoxicity using an environmentally relevant mixture of PCBs. Methods: We developed a mixture of eight PCBs to simulate human exposures based on their reported concentrations in human tissue, breast milk, and food supply. We previously characterized specific differences in PCB congener pharmacokinetics and toxicity, comparing high-affinity–AHR Cyp1a2 wild-type [Ahrb1_Cyp1a2(+/+)], poor-affinity–AHR Cyp1a2 wild-type [Ahrd_Cyp1a2(+/+)], and high-affinity–AHR Cyp1a2 knockout [Ahrb1_Cyp1a2(–/–)] mouse lines [Curran CP, Vorhees CV, Williams MT, Genter MB, Miller ML, Nebert DW. 2011. In utero and lactational exposure to a complex mixture of polychlorinated biphenyls: toxicity in pups dependent on the Cyp1a2 and Ahr genotypes. Toxicol Sci 119:189–208]. Dams received a mixture of three coplanar and five noncoplanar PCBs on gestational day 10.5 and postnatal day (PND) 5. In the present study we conducted behavioral phenotyping of exposed offspring at PND60, examining multiple measures of learning, memory, and other behaviors. Results: We observed the most significant deficits in response to PCB treatment in Ahrb1_Cyp1a2(–/–) mice, including impaired novel object recognition and increased failure rate in the Morris water maze. However, all PCB-treated genotypes showed significant differences on

  17. Silencing of miR-124 induces neuroblastoma SK-N-SH cell differentiation, cell cycle arrest and apoptosis through promoting AHR.

    PubMed

    Huang, Tsui-Chin; Chang, Hsin-Yi; Chen, Cheng-Yu; Wu, Pei-Yi; Lee, Hsinyu; Liao, Yung-Feng; Hsu, Wen-Ming; Huang, Hsuan-Cheng; Juan, Hsueh-Fen

    2011-11-16

    Neuroblastoma is the most common extracranial solid tumor in children. We investigate whether miR-124, the abundant neuronal miRNA, plays a pivotal role in neuroblastoma. Knockdown of miR-124 promotes neuroblastoma SK-N-SH cell differentiation, cell cycle arrest and apoptosis. Further miR-124 is predicted to target aryl hydrocarbon receptor (AHR) which may promote neuroblastoma cell differentiation. We validate that miR-124 may suppress the expression of AHR by targeting its 3'-UTR. These results suggest that miR-124 could serve as a potential therapeutic target of neuroblastoma.

  18. Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma

    PubMed Central

    An, S.S.; Bai, T.R.; Bates, J.H.T.; Black, J.L.; Brown, R.H.; Brusasco, V.; Chitano, P.; Deng, L.; Dowell, M.; Eidelman, D.H.; Fabry, B.; Fairbank, N.J.; Ford, L.E.; Fredberg, J.J.; Gerthoffer, W.T.; Gilbert, S.H.; Gosens, R.; Gunst, S.J.; Halayko, A.J.; Ingram, R.H.; Irvin, C.G.; James, A.L.; Janssen, L.J.; King, G.G.; Knight, D.A.; Lauzon, A.M.; Lakser, O.J.; Ludwig, M.S.; Lutchen, K.R.; Maksym, G.N.; Martin, J.G.; Mauad, T.; McParland, B.E.; Mijailovich, S.M.; Mitchell, H.W.; Mitchell, R.W.; Mitzner, W.; Murphy, T.M.; Paré, P.D.; Pellegrino, R.; Sanderson, M.J.; Schellenberg, R.R.; Seow, C.Y.; Silveira, P.S.P.; Smith, P.G.; Solway, J.; Stephens, N.L.; Sterk, P.J.; Stewart, A.G.; Tang, D.D.; Tepper, R.S.; Tran, T.; Wang, L.

    2008-01-01

    Excessive airway obstruction is the cause of symptoms and abnormal lung function in asthma. As airway smooth muscle (ASM) is the effecter controlling airway calibre, it is suspected that dysfunction of ASM contributes to the pathophysiology of asthma. However, the precise role of ASM in the series of events leading to asthmatic symptoms is not clear. It is not certain whether, in asthma, there is a change in the intrinsic properties of ASM, a change in the structure and mechanical properties of the noncontractile components of the airway wall, or a change in the interdependence of the airway wall with the surrounding lung parenchyma. All these potential changes could result from acute or chronic airway inflammation and associated tissue repair and remodelling. Anti-inflammatory therapy, however, does not “cure” asthma, and airway hyperresponsiveness can persist in asthmatics, even in the absence of airway inflammation. This is perhaps because the therapy does not directly address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM. In the present study, a central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored. PMID:17470619

  19. 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 ...

  20. Airway and Extracellular Matrix Mechanics in COPD.

    PubMed

    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.

  1. Athletic Trainers' Knowledge Regarding Airway Adjuncts

    ERIC Educational Resources Information Center

    Edler, Jessica R.; Eberman, Lindsey E.; Kahanov, Leamor; Roman, Christopher; Mata, Heather Lynne

    2015-01-01

    Context: Research suggests that knowledge gaps regarding the appropriate use of airway adjuncts exist among various health care practitioners, and that knowledge is especially limited within athletic training. Objective: To determine the relationship between perceived knowledge (PK) and actual knowledge (AK) of airway adjunct use and the…

  2. 21 CFR 868.5110 - Oropharyngeal airway.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Oropharyngeal airway. 868.5110 Section 868.5110 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Therapeutic Devices § 868.5110 Oropharyngeal airway....

  3. 21 CFR 868.5100 - Nasopharyngeal airway.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Nasopharyngeal airway. 868.5100 Section 868.5100 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Therapeutic Devices § 868.5100 Nasopharyngeal airway....

  4. 21 CFR 868.5100 - Nasopharyngeal airway.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Nasopharyngeal airway. 868.5100 Section 868.5100 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Therapeutic Devices § 868.5100 Nasopharyngeal airway....

  5. 21 CFR 868.5110 - Oropharyngeal airway.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Oropharyngeal airway. 868.5110 Section 868.5110 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Therapeutic Devices § 868.5110 Oropharyngeal airway....

  6. 21 CFR 868.5110 - Oropharyngeal airway.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Oropharyngeal airway. 868.5110 Section 868.5110 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Therapeutic Devices § 868.5110 Oropharyngeal airway....

  7. 21 CFR 868.5110 - Oropharyngeal airway.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Oropharyngeal airway. 868.5110 Section 868.5110 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Therapeutic Devices § 868.5110 Oropharyngeal airway....

  8. 21 CFR 868.5100 - Nasopharyngeal airway.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Nasopharyngeal airway. 868.5100 Section 868.5100 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Therapeutic Devices § 868.5100 Nasopharyngeal airway....

  9. 21 CFR 868.5100 - Nasopharyngeal airway.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Nasopharyngeal airway. 868.5100 Section 868.5100 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Therapeutic Devices § 868.5100 Nasopharyngeal airway....

  10. 21 CFR 868.5110 - Oropharyngeal airway.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Oropharyngeal airway. 868.5110 Section 868.5110 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Therapeutic Devices § 868.5110 Oropharyngeal airway....

  11. 21 CFR 868.5100 - Nasopharyngeal airway.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Nasopharyngeal airway. 868.5100 Section 868.5100 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Therapeutic Devices § 868.5100 Nasopharyngeal airway....

  12. 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

  13. 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

  14. TLR2, TLR4 AND MyD88 Mediate Allergic Airway Disease (AAD) and Streptococcus pneumoniae-Induced Suppression of AAD

    PubMed Central

    Thorburn, Alison N.; Tseng, Hsin-Yi; Donovan, Chantal; Hansbro, Nicole G.; Jarnicki, Andrew G.; Foster, Paul S.; Gibson, Peter G.; Hansbro, Philip M.

    2016-01-01

    Background Exposure to non-pathogenic Streptococcus pneumoniae and vaccination are inversely associated with asthma. Studies in animal models demonstrate that airway administration of S. pneumoniae (live or killed), or its vaccines or components, suppresses the characteristic features of asthma in mouse models of allergic airway disease (AAD). These components could be developed into immunoregulatory therapies. S. pneumoniae components are recognized by Toll-like receptors (TLR) 2 and TLR4, and both induce inflammatory cell responses through the adaptor protein myeloid differentiation primary response gene 88 (MyD88). The involvement of TLR2, TLR4 and MyD88 in the pathogenesis of AAD and asthma is incompletely understood, and has not been studied in S. pneumoniae-mediated suppression of AAD. We investigated the role of TLR2, TLR4 and MyD88 in the development of AAD and S. pneumoniae-mediated suppression of AAD. Methods and Findings OVA-induced AAD and killed S. pneumoniae-mediated suppression of AAD were assessed in wild-type, TLR2-/-, TLR4-/-, TLR2/4-/- and MyD88-/- BALB/c mice. During OVA-induced AAD, TLR2, TLR4 and MyD88 were variously involved in promoting eosinophil accumulation in bronchoalveolar lavage fluid and blood, and T-helper type (Th)2 cytokine release from mediastinal lymph node T cells and splenocytes. However, all were required for the induction of airways hyperresponsiveness (AHR). In S. pneumoniae-mediated suppression of AAD, TLR2, TLR4 and MyD88 were variously involved in the suppression of eosinophilic and splenocyte Th2 responses but all were required for the reduction in AHR. Conclusions These results highlight important but complex roles for TLR2, TLR4 and MyD88 in promoting the development of OVA-induced AAD, but conversely in the S. pneumoniae-mediated suppression of AAD, with consistent and major contributions in both the induction and suppression of AHR. Thus, TLR signaling is likely required for both the development of asthma and the

  15. Airway fires during surgery: Management and prevention

    PubMed Central

    Akhtar, Navaid; Ansar, Farrukh; Baig, Mirza Shahzad; Abbas, Akbar

    2016-01-01

    Airway fires pose a serious risk to surgical patients. Fires during surgery have been reported for many years with flammable anesthetic agents being the main culprits in the past. Association of airway fires with laser surgery is well-recognized, but there are reports of endotracheal tube fires ignited by electrocautery during pharyngeal surgery or tracheostomy or both. This uncommon complication has potentially grave consequences. While airway fires are relatively uncommon occurrences, they are very serious and can often be fatal. Success in preventing such events requires a thorough understanding of the components leading to a fire (fuel, oxidizer, and ignition source), as well as good communication between all members present to appropriately manage the fire and ensure patient safety. We present a case of fire in the airway during routine adenotonsillectomy. We will review the causes, preventive measures, and brief management for airway fires. PMID:27006554

  16. Airway fires during surgery: Management and prevention.

    PubMed

    Akhtar, Navaid; Ansar, Farrukh; Baig, Mirza Shahzad; Abbas, Akbar

    2016-01-01

    Airway fires pose a serious risk to surgical patients. Fires during surgery have been reported for many years with flammable anesthetic agents being the main culprits in the past. Association of airway fires with laser surgery is well-recognized, but there are reports of endotracheal tube fires ignited by electrocautery during pharyngeal surgery or tracheostomy or both. This uncommon complication has potentially grave consequences. While airway fires are relatively uncommon occurrences, they are very serious and can often be fatal. Success in preventing such events requires a thorough understanding of the components leading to a fire (fuel, oxidizer, and ignition source), as well as good communication between all members present to appropriately manage the fire and ensure patient safety. We present a case of fire in the airway during routine adenotonsillectomy. We will review the causes, preventive measures, and brief management for airway fires. PMID:27006554

  17. Awake Craniotomy: A New Airway Approach.

    PubMed

    Sivasankar, Chitra; Schlichter, Rolf A; Baranov, Dimitry; Kofke, W Andrew

    2016-02-01

    Awake craniotomies have been performed regularly at the University of Pennsylvania since 2004. Varying approaches to airway management are described for this procedure, including intubation with an endotracheal tube and use of a laryngeal mask airway, simple facemask, or nasal cannula. In this case series, we describe the successful use (i.e., no need for endotracheal intubation related to inadequate gas exchange) of bilateral nasopharyngeal airways in 90 patients undergoing awake craniotomies. The use of nasopharyngeal airways can ease the transition between the asleep and awake phases of the craniotomy without the need to stimulate the airway. Our purpose was to describe our experience and report adverse events related to this technique. PMID:26579845

  18. Anaesthetic management of acute airway obstruction

    PubMed Central

    Wong, Patrick; Wong, Jolin; Mok, May Un Sam

    2016-01-01

    The acutely obstructed airway is a medical emergency that can potentially result in serious morbidity and mortality. Apart from the latest advancements in anaesthetic techniques, equipment and drugs, publications relevant to our topic, including the United Kingdom’s 4th National Audit Project on major airway complications in 2011 and the updated American Society of Anesthesiologists’ difficult airway algorithm of 2013, have recently been published. The former contained many reports of adverse events associated with the management of acute airway obstruction. By analysing the data and concepts from these two publications, this review article provides an update on management techniques for the acutely obstructed airway. We discuss the principles and factors relevant to the decision-making process in formulating a logical management plan. PMID:26996162

  19. Investigating the geometry of pig airways using computed tomography

    NASA Astrophysics Data System (ADS)

    Mansy, Hansen A.; Azad, Md Khurshidul; McMurray, Brandon; Henry, Brian; Royston, Thomas J.; Sandler, Richard H.

    2015-03-01

    Numerical modeling of sound propagation in the airways requires accurate knowledge of the airway geometry. These models are often validated using human and animal experiments. While many studies documented the geometric details of the human airways, information about the geometry of pig airways is scarcer. In addition, the morphology of animal airways can be significantly different from that of humans. The objective of this study is to measure the airway diameter, length and bifurcation angles in domestic pigs using computed tomography. After imaging the lungs of 3 pigs, segmentation software tools were used to extract the geometry of the airway lumen. The airway dimensions were then measured from the resulting 3 D models for the first 10 airway generations. Results showed that the size and morphology of the airways of different animals were similar. The measured airway dimensions were compared with those of the human airways. While the trachea diameter was found to be comparable to the adult human, the diameter, length and branching angles of other airways were noticeably different from that of humans. For example, pigs consistently had an early airway branching from the trachea that feeds the superior (top) right lung lobe proximal to the carina. This branch is absent in the human airways. These results suggested that the human geometry may not be a good approximation of the pig airways and may contribute to increasing the errors when the human airway geometric values are used in computational models of the pig chest.

  20. Nucleotide release by airway epithelia.

    PubMed

    Lazarowski, Eduardo R; Sesma, Juliana I; Seminario, Lucia; Esther, Charles R; Kreda, Silvia M

    2011-01-01

    The purinergic events regulating the airways' innate defenses are initiated by the release of purines from the epithelium, which occurs constitutively and is enhanced by chemical or mechanical stimulation. While the external triggers have been reviewed exhaustively, this chapter focuses on current knowledge of the receptors and signaling cascades mediating nucleotide release. The list of secreted purines now includes ATP, ADP, AMP and nucleotide sugars, and involves at least three distinct mechanisms reflecting the complexity of airway epithelia. First, the constitutive mechanism involves ATP translocation to the ER/Golgi complex as energy source for protein folding, and fusion of Golgi-derived vesicles with the plasma membrane. Second, goblet cells package ATP with mucins into granules, which are discharged in response to P2Y(2)R activation and Ca(2+)-dependent signaling pathways. Finally, non-mucous cells support a regulated mechanism of ATP release involving protease activated receptor (PAR)-elicited G(12/13) activation, leading to the RhoGEF-mediated exchange of GDP for GTP on RhoA, and cytoskeleton rearrangement. Together, these pathways provide fine tuning of epithelial responses regulated by purinergic signaling events. PMID:21560042

  1. Puberty and Upper Airway Dynamics During Sleep

    PubMed Central

    Bandla, Preetam; Huang, Jingtao; Karamessinis, Laurie; Kelly, Andrea; Pepe, Michelle; Samuel, John; Brooks, Lee; Mason, Thornton. A.; Gallagher, Paul R.; Marcus, Carole L.

    2008-01-01

    Study Objectives: The upper airway compensatory response to subatmospheric pressure loading declines with age. The epidemiology of obstructive sleep apnea suggests that sex hormones play a role in modulating upper airway function. Sex hormones increase gradually during puberty, from minimally detectable to adult levels. We hypothesized that the upper airway response to subatmospheric pressure loading decreased with increasing pubertal Tanner stage in males but remained stable during puberty in females. Design: Upper airway dynamic function during sleep was measured over the course of puberty. Participants: Normal subjects of Tanner stages 1 to 5. Measurements: During sleep, maximal inspiratory airflow was measured while varying the level of nasal pressure. The slope of the upstream pressure-flow relationship (SPF) was measured. Results: The SPF correlated with age and Tanner stage. However, the relationship with Tanner stage became nonsignificant when the correlation due to the mutual association with age was removed. Females had a lower SPF than males. Conclusions: In both sexes, the upper airway compensatory response to subatmospheric pressure loading decreased with age rather than degree of pubertal development. Thus, changes in sex hormones are unlikely to be a primary modulator of upper airway function during the transition from childhood to adulthood. Although further studies of upper airway structural changes during puberty are needed, we speculate that the changes in upper airway function with age are due to the depressant effect of age on ventilatory drive, leading to a decrease in upper airway neuromotor tone. Citation: Bandla P; Huang J; Karamessinis L; Kelly A; Pepe M; Samuel J; Brooks L; Mason TA; Gallagher PR; Marcus CL. Puberty and Upper Airway Dynamics During Sleep. SLEEP 2008;31(4):534-541. PMID:18457241

  2. Biological effects of 6-formylindolo[3,2-b]carbazole (FICZ) in vivo are enhanced by loss of CYP1A function in an Ahr2-dependent manner.

    PubMed

    Wincent, Emma; Kubota, Akira; Timme-Laragy, Alicia; Jönsson, Maria E; Hahn, Mark E; Stegeman, John J

    2016-06-15

    6-Formylindolo[3,2-b]carbazole (FICZ) is a potent aryl hydrocarbon receptor (AHR) agonist that is efficiently metabolized by AHR-regulated cytochrome P4501 enzymes. FICZ is a proposed physiological AHR ligand that induces its own degradation as part of a regulatory negative feedback loop. In vitro studies in cells show that CYP1 inhibition in the presence of FICZ results in enhanced AHR activation, suggesting that FICZ accumulates in the cell when its metabolism is blocked. We used zebrafish (Danio rerio) embryos to investigate the in vivo effects of FICZ when CYP1A is knocked down or inhibited. Embryos were injected with morpholino antisense oligonucleotides targeting CYP1A (CYP1A-MO), Ahr2, or a combination of both. FICZ exposure of non-injected embryos or embryos injected with control morpholino had little effect. In CYP1A-MO-injected embryos, however, FICZ dramatically increased mortality, incidence and severity of pericardial edema and circulation failure, reduced hatching frequency, blocked swim bladder inflation, and strongly potentiated expression of Ahr2-regulated genes. These effects were substantially reduced in embryos with a combined knockdown of Ahr2 and CYP1A, indicating that the toxicity was mediated at least partly by Ahr2. Co-exposure to the CYP1 inhibitor alpha-naphthoflavone (αNF) and FICZ had similar effects as the combination of CYP1A-MO and FICZ. HPLC analysis of FICZ-exposed embryos showed increased levels of FICZ after concomitant CYP1A-MO injection or αNF co-exposure. Together, these results show that a functioning CYP1/AHR feedback loop is crucial for regulation of AHR signaling by a potential physiological ligand in vivo and further highlights the role of CYP1 enzymes in regulating biological effects of FICZ.

  3. Aromatic hydrocarbons upregulate glyceraldehyde-3-phosphate dehydrogenase and induce changes in actin cytoskeleton. Role of the aryl hydrocarbon receptor (AhR).

    PubMed

    Reyes-Hernández, O D; Mejía-García, A; Sánchez-Ocampo, E M; Castro-Muñozledo, F; Hernández-Muñoz, R; Elizondo, G

    2009-12-21

    Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional enzyme involved in several cellular functions including glycolysis, membrane transport, microtubule assembly, DNA replication and repair, nuclear RNA export, apoptosis, and the detection of nitric oxide stress. Therefore, modifications in the regulatory ability and function of GAPDH may alter cellular homeostasis. We report here that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and beta-naphthoflavone, which are well-known ligands for the aryl hydrocarbon receptor (AhR), increase GAPDH mRNA levels in vivo and in vitro, respectively. These compounds fail to induce GAPDH transcription in an AhR-null mouse model, suggesting that the increase in GAPDH level is dependent upon AhR activation. To analyse the consequences of AhR ligands on GAPDH function, mice were treated with TCDD and the level of liver activity of GAPDH was determined. The results showed that TCDD treatment increased GAPDH activity. On the other hand, treatment of Hepa-1 cells with beta-naphthoflavone leads to an increase in microfilament density when compared to untreated cultures. Collectively, these results suggest that AhR ligands, such as polycyclic hydrocarbons, can modify GAPDH expression and, therefore, have the potential to alter the multiple functions of this enzyme.

  4. USE OF THE TEQ MODEL FOR ASSESSING AHR MEDIATED TOXICITY RISKS TO POPULATIONS OF LAKE TROUT AND OTHER SPECIES IN LAKE ONTARIO

    EPA Science Inventory

    The toxicity equivalence (TEQ) model for assessing aryl hydrocarbon receptor (AHR) mediated toxicity risks associated with polyhalogenated aromatic chemicals structurally similar to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been applied to human health risks for more than 15...

  5. Effects of artificial sweeteners on the AhR- and GR-dependent CYP1A1 expression in primary human hepatocytes and human cancer cells.

    PubMed

    Kamenickova, Alzbeta; Pecova, Michaela; Bachleda, Petr; Dvorak, Zdenek

    2013-12-01

    Food constituents may cause a phenomenon of food-drug interactions. In the current study, we examined the effects of artificial sweeteners (aspartame, acesulfame, cyclamate, saccharin) on the aryl hydrocarbon receptor (AhR) and glucocorticoid receptor (GR)-dependent expression of CYP1A1 in human hepatocytes, hepatic HepG2 and intestinal LS174T cancer cell lines. Sweeteners were tested in concentrations up to those occurring in non-alcoholic beverages. Basal and ligand-inducible AhR- and GR-dependent reporter gene activation in stably transfected HepG2 and HeLa cells, respectively, were not affected by either of the sweeteners tested after 24h of incubation. The expression of CYP1A1 mRNA and protein in primary cultures of human hepatocytes and in LS174T and HepG2 cells was not induced by any of the tested sweeteners. Overall, aspartame, acesulfame, saccharin and cyclamate had no effects on CYP1A1 expression and transcriptional activities of AhR and GR. These data imply the safety of artificial sweeteners in terms of interference with AhR, GR and CYP1A1.

  6. Deciphering Dimerization Modes of PAS Domains: Computational and Experimental Analyses of the AhR:ARNT Complex Reveal New Insights Into the Mechanisms of AhR Transformation

    PubMed Central

    Corrada, Dario; Soshilov, Anatoly A.; Denison, Michael S.

    2016-01-01

    The Aryl hydrocarbon Receptor (AhR) is a transcription factor that mediates the biochemical response to xenobiotics and the toxic effects of a number of environmental contaminants, including dioxins. Recently, endogenous regulatory roles for the AhR in normal physiology and development have also been reported, thus extending the interest in understanding its molecular mechanisms of activation. Since dimerization with the AhR Nuclear Translocator (ARNT) protein, occurring through the Helix-Loop-Helix (HLH) and PER-ARNT-SIM (PAS) domains, is needed to convert the AhR into its transcriptionally active form, deciphering the AhR:ARNT dimerization mode would provide insights into the mechanisms of AhR transformation. Here we present homology models of the murine AhR:ARNT PAS domain dimer developed using recently available X-ray structures of other bHLH-PAS protein dimers. Due to the different reciprocal orientation and interaction surfaces in the different template dimers, two alternative models were developed for both the PAS-A and PAS-B dimers and they were characterized by combining a number of computational evaluations. Both well-established hot spot prediction methods and new approaches to analyze individual residue and residue-pairwise contributions to the MM-GBSA binding free energies were adopted to predict residues critical for dimer stabilization. On this basis, a mutagenesis strategy for both the murine AhR and ARNT proteins was designed and ligand-dependent DNA binding ability of the AhR:ARNT heterodimer mutants was evaluated. While functional analysis disfavored the HIF2α:ARNT heterodimer-based PAS-B model, most mutants derived from the CLOCK:BMAL1-based AhR:ARNT dimer models of both the PAS-A and the PAS-B dramatically decreased the levels of DNA binding, suggesting this latter model as the most suitable for describing AhR:ARNT dimerization. These novel results open new research directions focused at elucidating basic molecular mechanisms underlying the

  7. AHR2 knockdown prevents PAH-mediated cardiac toxicity and XRE- and ARE-associated gene induction in zebrafish (Danio rerio)

    SciTech Connect

    Van Tiem, Lindsey A.; Di Giulio, Richard T.

    2011-08-01

    Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants often present in aquatic systems as complex mixtures. Embryonic fish are sensitive to the developmental toxicity of some PAHs, but the exact mechanisms involved in this toxicity are still unknown. This study explored the role of the aryl hydrocarbon receptor (AHR) in the oxidative stress response of zebrafish to the embryotoxicity of select PAHs. Embryos were exposed to two PAHs, benzo[k]fluoranthene (BkF; a strong AHR agonist) and fluoranthene (FL; a cytochrome P4501A (CYP1A) inhibitor), alone and in combination. CYP1A, CYP1B1, CYP1C1, and redox-responsive genes glutathione s-transferase pi 2 (GSTp2), glutathione peroxidase 1 (GPx1), the glutamate-cysteine ligase catalytic subunit (GCLc), MnSOD and CuZnSOD mRNA expression was examined. CYP1 activity was measured via an in vivo ethoxyresorufin-O-deethlyase (EROD) activity assay, and the area of the pericardium was measured as an index of cardiotoxicity. BkF or FL alone caused no deformities whereas BkF + FL resulted in extreme pericardial effusion. BkF induced CYP activity above controls and co-exposure with FL inhibited this activity. BkF induced expression of all three CYPs, GSTp2, and GCLc. BkF + FL caused greater than additive induction of the three CYPs, GSTp2, GPx1, and GCLc but had no effect on MnSOD or CuZnSOD. AHR2 knockdown protected against the cardiac deformities caused by BkF + FL and significantly inhibited the induction of the CYPs, GSTp2, GPx1, and GCLc after BkF + FL compared to non-injected controls. These results further show the protective role of AHR2 knockdown against cardiotoxic PAHs and the role of AHR2 as a mediator of redox-responsive gene induction. - Research Highlights: > Co-exposure of the PAHs BkF and FL causes cardiotoxicity in zebrafish. > BkF and FL co-exposure upregulates certain XRE- and ARE-associated genes. > AHR2 knockdown prevents the deformities caused by BkF and FL co-exposure. > AHR2

  8. Ahr2-dependence of PCB126 effects on the swim bladder in relation to expression of CYP1 and cox-2 genes in developing zebrafish

    SciTech Connect

    Jönsson, Maria E.; Kubota, Akira; Timme-Laragy, Alicia R.; Woodin, Bruce; Stegeman, John J.

    2012-12-01

    The teleost swim bladder is assumed a homolog of the tetrapod lung. Both swim bladder and lung are developmental targets of persistent aryl hydrocarbon receptor (AHR) agonists; in zebrafish (Danio rerio) the swim bladder fails to inflate with exposure to 3,3′,4,4′,5-pentachlorobiphenyl (PCB126). The mechanism for this effect is unknown, but studies have suggested roles of cytochrome P450 1 (CYP1) and cyclooxygenase 2 (Cox-2) in some Ahr-mediated developmental effects in zebrafish. We determined relationships between swim bladder inflation and CYP1 and Cox-2 mRNA expression in PCB126-exposed zebrafish embryos. We also examined effects on β-catenin dependent transcription, histological effects, and Ahr2 dependence of the effect of PCB126 on swim bladder using morpholinos targeting ahr2. One-day-old embryos were exposed to waterborne PCB126 or carrier (DMSO) for 24 h and then held in clean water until day 4, a normal time for swim bladder inflation. The effects of PCB126 were concentration-dependent with EC{sub 50} values of 1.4 to 2.0 nM for induction of the CYP1s, 3.7 and 5.1 nM (or higher) for cox-2a and cox-2b induction, and 2.5 nM for inhibition of swim bladder inflation. Histological defects included a compaction of the developing bladder. Ahr2-morpholino treatment rescued the effect of PCB126 (5 nM) on swim bladder inflation and blocked induction of CYP1A, cox-2a, and cox-2b. With 2 nM PCB126 approximately 30% of eleutheroembryos failed to inflate the swim bladder, but there was no difference in CYP1 or cox-2 mRNA expression between those embryos and embryos showing inflated swim bladder. Our results indicate that PCB126 blocks swim bladder inflation via an Ahr2-mediated mechanism. This mechanism seems independent of CYP1 or cox-2 mRNA induction but may involve abnormal development of swim bladder cells. -- Highlights: ► PCB126 caused cellular changes in the developing swim bladder. ► Swim bladder inflation was not related to expression of CYP1 or cox

  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. Small particles disrupt postnatal airway development

    PubMed Central

    Lee, DongYoub; Wallis, Chris; Schelegle, Edward S.; Van Winkle, Laura S.; Plopper, Charles G.; Fanucchi, Michelle V.; Kumfer, Ben; Kennedy, Ian M.; Chan, Jackie K. W.

    2010-01-01

    Increasing numbers of epidemiologic studies associate air pollution exposure in children with decreased lung function development. The objective of this study was to examine the effects of exposure to combustion-generated fine [230 and 212 nm number mean aerodynamic particle diameter (NMAD)] to ultrafine (73 nm NMAD) particles differing in elemental (EC) and organic (OC) carbon content on postnatal airway development in rats. Neonatal Sprague-Dawley rats were exposed from postnatal day 7 through 25, and lung function and airway architecture were evaluated 81 days of age. In a separate group of rats, cell proliferation was examined after a single particle exposure at 7 days of age. Early life exposure to 73 nm high OC/EC particles altered distal airway architecture and resulted in subtle changes in lung mechanics. Early life exposure to 212 nm high OC/EC particles did not alter lung architecture but did alter lung mechanics in a manner suggestive of central airway changes. In contrast, early life exposure to 230 nm low OC/EC particles did not alter lung architecture or mechanics. A single 6-h exposure to 73 nm high OC/EC particle decreased airway cell proliferation, whereas 212 nm high OC/EC particles increased it and 230 nm low OC/EC particles did not. The early life exposure to ultrafine, high OC/EC particles results in persistent alterations in distal airway architecture that is characterized by an initial decrease in airway cell proliferation. PMID:20634362

  11. 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.

  12. Evaluation of the Enterococcus faecalis Biofilm-Associated Virulence Factors AhrC and Eep in Rat Foreign Body Osteomyelitis and In Vitro Biofilm-Associated Antimicrobial Resistance

    PubMed Central

    Frank, Kristi L.; Vergidis, Paschalis; Brinkman, Cassandra L.; Greenwood Quaintance, Kerryl E.; Barnes, Aaron M. T.; Mandrekar, Jayawant N.; Schlievert, Patrick M.; Dunny, Gary M.; Patel, Robin

    2015-01-01

    Enterococcus faecalis can cause healthcare-associated biofilm infections, including those of orthopedic devices. Treatment of enterococcal prosthetic joint infection is difficult, in part, due to biofilm-associated antimicrobial resistance. We previously showed that the E. faecalis OG1RF genes ahrC and eep are in vitro biofilm determinants and virulence factors in animal models of endocarditis and catheter-associated urinary tract infection. In this study, we evaluated the role of these genes in a rat acute foreign body osteomyelitis model and in in vitro biofilm-associated antimicrobial resistance. Osteomyelitis was established for one week following the implantation of stainless steel orthopedic wires inoculated with E. faecalis strains OG1RF, ΩahrC, and ∆eep into the proximal tibiae of rats. The median bacterial loads recovered from bones and wires did not differ significantly between the strains at multiple inoculum concentrations. We hypothesize that factors present at the infection site that affect biofilm formation, such as the presence or absence of shear force, may account for the differences in attenuation in the various animal models we have used to study the ΩahrC and ∆eep strains. No differences among the three strains were observed in the planktonic and biofilm antimicrobial susceptibilities to ampicillin, vancomycin, daptomycin, linezolid, and tetracycline. These findings suggest that neither ahrC nor eep directly contribute to E. faecalis biofilm-associated antimicrobial resistance. Notably, the experimental evidence that the biofilm attachment mutant ΩahrC displays biofilm-associated antimicrobial resistance suggests that surface colonization alone is sufficient for E. faecalis cells to acquire the biofilm antimicrobial resistance phenotype. PMID:26076451

  13. In Utero and Lactational Exposure to a Complex Mixture of Polychlorinated Biphenyls: Toxicity in Pups Dependent on the Cyp1a2 and Ahr Genotypes

    PubMed Central

    Curran, Christine P.; Vorhees, Charles V.; Williams, Michael T.; Genter, Mary Beth; Miller, Marian L.; Nebert, Daniel W.

    2011-01-01

    Polychlorinated biphenyls (PCBs) are persistent toxic pollutants occurring as complex mixtures in the environment. Humans are known genetically to have > 60-fold differences in hepatic cytochrome P450 1A2 (CYP1A2) levels and > 12-fold differences in aryl hydrocarbon receptor (AHR) affinity, both of which could affect PCB pharmacokinetics. Thus, we compared Ahrb1_Cyp1a2(+/+) high-affinity AHR wild-type, Ahrd_Cyp1a2(+/+) poor affinity AHR wild-type, Ahrb1_Cyp1a2(−/−) knockout, and Ahrd_Cyp1a2(−/−) knockout mouse lines. We chose a mixture of three coplanar and five noncoplanar PCBs to reproduce that seen in human tissues, breast milk, and the food supply. The mixture was given by gavage to the mother on gestational day 10.5 (GD10.5) and postnatal day 5 (PND5); tissues were collected from pups and mothers at GD11.5, GD18.5, PND6, PND13, and PND28. Ahrb1_Cyp1a2(−/−) pups showed lower weight at birth and slower rate of growth postnatally. Absence of CYP1A2 resulted in significant splenic atrophy at PND13 and PND28. Presence of high-affinity AHR enhanced thymic atrophy and liver hypertrophy in the pups. Concentrations of each congener were analyzed at all time points: maximal noncoplanar congener levels in maternal tissues were observed from GD18 until PND6, whereas the highest levels in pups were found between PND6 and PND28. Coplanar PCB concentrations were generally higher in Ahrd-containing pup tissues; these findings are consistent with earlier studies demonstrating the crucial importance of AHR-mediated inducible CYP1 in the gastrointestinal tract as a means of detoxication of oral planar polycyclic aromatic hydrocarbons. PMID:20961953

  14. Evaluation of the Enterococcus faecalis Biofilm-Associated Virulence Factors AhrC and Eep in Rat Foreign Body Osteomyelitis and In Vitro Biofilm-Associated Antimicrobial Resistance.

    PubMed

    Frank, Kristi L; Vergidis, Paschalis; Brinkman, Cassandra L; Greenwood Quaintance, Kerryl E; Barnes, Aaron M T; Mandrekar, Jayawant N; Schlievert, Patrick M; Dunny, Gary M; Patel, Robin

    2015-01-01

    Enterococcus faecalis can cause healthcare-associated biofilm infections, including those of orthopedic devices. Treatment of enterococcal prosthetic joint infection is difficult, in part, due to biofilm-associated antimicrobial resistance. We previously showed that the E. faecalis OG1RF genes ahrC and eep are in vitro biofilm determinants and virulence factors in animal models of endocarditis and catheter-associated urinary tract infection. In this study, we evaluated the role of these genes in a rat acute foreign body osteomyelitis model and in in vitro biofilm-associated antimicrobial resistance. Osteomyelitis was established for one week following the implantation of stainless steel orthopedic wires inoculated with E. faecalis strains OG1RF, ΩahrC, and ∆eep into the proximal tibiae of rats. The median bacterial loads recovered from bones and wires did not differ significantly between the strains at multiple inoculum concentrations. We hypothesize that factors present at the infection site that affect biofilm formation, such as the presence or absence of shear force, may account for the differences in attenuation in the various animal models we have used to study the ΩahrC and ∆eep strains. No differences among the three strains were observed in the planktonic and biofilm antimicrobial susceptibilities to ampicillin, vancomycin, daptomycin, linezolid, and tetracycline. These findings suggest that neither ahrC nor eep directly contribute to E. faecalis biofilm-associated antimicrobial resistance. Notably, the experimental evidence that the biofilm attachment mutant ΩahrC displays biofilm-associated antimicrobial resistance suggests that surface colonization alone is sufficient for E. faecalis cells to acquire the biofilm antimicrobial resistance phenotype.

  15. Mixed-ligand copper(II) complexes activate aryl hydrocarbon receptor AhR and induce CYP1A genes expression in human hepatocytes and human cell lines.

    PubMed

    Kubešová, Kateřina; Dořičáková, Aneta; Trávníček, Zdeněk; Dvořák, Zdeněk

    2016-07-25

    The effects of four copper(II) mixed-ligand complexes [Cu(qui1)(L)]NO3·H2O (1-3) and [Cu(qui2)(phen)]NO3 (4), where qui1=2-phenyl-3-hydroxy-4(1H)-quinolinone, Hqui2=2-(4-amino-3,5-dichlorophenyl)-N-propyl-3-hydroxy-4(1H)-quinolinone-7-carboxamide, L=1,10-phenanthroline (phen) (1), 5-methyl-1,10-phenanthroline (mphen) (2), bathophenanthroline (bphen) (3), on transcriptional activities of steroid receptors, nuclear receptors and xenoreceptors have been studied. The complexes (1-4) did not influence basal or ligand-inducible activities of glucocorticoid receptor, androgen receptor, thyroid receptor, pregnane X receptor and vitamin D receptor, as revealed by gene reporter assays. The complexes 1 and 2 dose-dependently induced luciferase activity in stable gene reporter AZ-AhR cell line, and this induction was reverted by resveratrol, indicating involvement of aryl hydrocarbon receptor (AhR) in the process. The complexes 1, 2 and 3 induced CYP1A1 mRNA in LS180 cells and CYP1A1/CYP1A2 in human hepatocytes through AhR. Electrophoretic mobility shift assay EMSA showed that the complexes 1 and 2 transformed AhR in its DNA-binding form. Collectively, we demonstrate that the complexes 1 and 2 activate AhR and induce AhR-dependent genes in human hepatocytes and cancer cell lines. In conclusion, the data presented here might be of toxicological importance, regarding the multiple roles of AhR in human physiology and pathophysiology. PMID:27180721

  16. Firefighting acutely increases airway responsiveness.

    PubMed

    Sherman, C B; Barnhart, S; Miller, M F; Segal, M R; Aitken, M; Schoene, R; Daniell, W; Rosenstock, L

    1989-07-01

    The acute effects of the products of combustion and pyrolysis on airway responsiveness among firefighters are poorly documented. To study this relationship, spirometry and methacholine challenge testing (MCT) were performed on 18 active Seattle firefighters before and 5 to 24 h after firefighting. Body plethysmography was used to measure changes in specific airway conductance (SGaw), and results of MCT were analyzed using PD35-SGaw, the cumulative dose causing a 35% decrease in SGaw. Subjects who did not react by the end of the protocol were assigned a value of 640 inhalational units, the largest cumulative dose. Fire exposure was defined as the total time (hours) spent without a self-contained breathing apparatus at the firesite and was categorized as mild (less than 1 h, n = 7), moderate (1 to 2 h, n = 5), or severe (greater than 2 h, n = 6). Mean age of the 18 firefighters was 36.7 +/- 6.7 yr (range, 25 to 51), with a mean of 9.1 +/- 7.9 active years in the trade (range, zero to 22). None was known to be asthmatic. After firefighting, FEV1 % predicted (%pred) and FEF25-75 %pred significantly decreased by means of 3.4 +/- 1.1% and 5.6 +/- 2.6%, respectively. The mean decline in PD35-SGaw after firefighting was 184.5 +/- 53.2 units (p = 0.003). This observed decline in PD35-SGaw could not be explained by decrements in prechallenge SGaw, FEV1, or FVC.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. Mechanisms Linking Advanced Airway Management and Cardiac Arrest Outcomes

    PubMed Central

    Benoit, Justin L.; Prince, David K.; Wang, Henry E.

    2015-01-01

    Advanced airway management – such as endotracheal intubation (ETI) or supraglottic airway (SGA) insertion – is one of the most prominent interventions in out-of-hospital cardiac arrest (OHCA) resuscitation. While randomized controlled trials are currently in progress to identify the best advanced airway technique in OHCA, the mechanisms by which airway management may influence OHCA outcomes remain unknown. We provide a conceptual model describing potential mechanisms linking advanced airway management with OHCA outcomes. PMID:26073275

  18. Nasal airway responses to nasal continuous positive airway pressure breathing: An in-vivo pilot study.

    PubMed

    White, David E; Bartley, Jim; Shakeel, Muhammad; Nates, Roy J; Hankin, Robin K S

    2016-06-14

    The nasal cycle, through variation in nasal airflow partitioning, allows the upper airway to accommodate the contrasting demands of air conditioning and removal of entrapped air contaminants. The purpose of this study was to investigate the influence of nasal continuous positive airway pressure (nCPAP) breathing has on both nasal airflow partitioning and nasal geometry. Using a custom-made nasal mask, twenty healthy participants had the airflow in each naris measured during normal nasal breathing followed by nCPAP breathing. Eight participants also underwent magnetic resonance imaging (MRI) of the nasal region during spontaneous nasal breathing, and then nCPAP breathing over a range of air pressures. During nCPAP breathing, a simultaneous reduction in airflow through the patent airway together with a corresponding increase in airway flow within the congested nasal airway were observed in sixteen of the twenty participants. Nasal airflow resistance is inversely proportional to airway cross-sectional area. MRI data analysis during nCPAP breathing confirmed airway cross-sectional area reduced along the patent airway while the congested airway experienced an increase in this parameter. During awake breathing, nCPAP disturbs the normal inter-nasal airflow partitioning. This could partially explain the adverse nasal drying symptoms frequently reported by many users of this therapy. PMID:27173595

  19. Extravascular fibrin, plasminogen activator, plasminogen activator inhibitors, and airway hyperresponsiveness

    PubMed Central

    Wagers, Scott S.; Norton, Ryan J.; Rinaldi, Lisa M.; Bates, Jason H.T.; Sobel, Burton E.; Irvin, Charles G.

    2004-01-01

    Mechanisms underlying airway hyperresponsiveness are not yet fully elucidated. One of the manifestations of airway inflammation is leakage of diverse plasma proteins into the airway lumen. They include fibrinogen and thrombin. Thrombin cleaves fibrinogen to form fibrin, a major component of thrombi. Fibrin inactivates surfactant. Surfactant on the airway surface maintains airway patency by lowering surface tension. In this study, immunohistochemically detected fibrin was seen along the luminal surface of distal airways in a patient who died of status asthmaticus and in mice with induced allergic airway inflammation. In addition, we observed altered airway fibrinolytic system protein balance consistent with promotion of fibrin deposition in mice with allergic airway inflammation. The airways of mice were exposed to aerosolized fibrinogen, thrombin, or to fibrinogen followed by thrombin. Only fibrinogen followed by thrombin resulted in airway hyperresponsiveness compared with controls. An aerosolized fibrinolytic agent, tissue-type plasminogen activator, significantly diminished airway hyperresponsiveness in mice with allergic airway inflammation. These results are consistent with the hypothesis that leakage of fibrinogen and thrombin and their accumulation on the airway surface can contribute to the pathogenesis of airway hyperresponsiveness. PMID:15232617

  20. Therapeutic bronchoscopic interventions for malignant airway obstruction

    PubMed Central

    Dalar, Levent; Özdemir, Cengiz; Abul, Yasin; Karasulu, Levent; Sökücü, Sinem Nedime; Akbaş, Ayşegül; Altın, Sedat

    2016-01-01

    Abstract There is no definitive consensus about the factors affecting the choice of interventional bronchoscopy in the management of malignant airway obstruction. The present study defines the choice of the interventional bronchoscopic modality and analyzes the factors influencing survival in patients with malignant central airway obstruction. Totally, over 7 years, 802 interventional rigid bronchoscopic procedures were applied in 547 patients having malignant airway obstruction. There was a significant association between the type of stent and the site of the lesion in the present study. Patients with tracheal involvement and/or involvement of the main bronchi had the worst prognosis. The sites of the lesion and endobronchial treatment modality were independent predictors of survival in the present study. The selection of different types of airway stents can be considered on the base of site of the lesion. Survival can be estimated based on the site of the lesion and endobronchial brochoscopic modality used. PMID:27281104

  1. 21 CFR 868.5810 - Airway connector.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... airway connector is a device intended to connect a breathing gas source to a tracheal tube, tracheostomy tube, or mask. (b) Classification. Class I (general controls). The device is exempt from the...

  2. 21 CFR 868.5810 - Airway connector.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... airway connector is a device intended to connect a breathing gas source to a tracheal tube, tracheostomy tube, or mask. (b) Classification. Class I (general controls). The device is exempt from the...

  3. 21 CFR 868.5810 - Airway connector.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... airway connector is a device intended to connect a breathing gas source to a tracheal tube, tracheostomy tube, or mask. (b) Classification. Class I (general controls). The device is exempt from the...

  4. Virtual Airway Skills Trainer (VAST) Simulator

    PubMed Central

    DEMIREL, Doga; YU, Alexander; HALIC, Tansel; SANKARANARAYANAN, Ganesh; RYASON, Adam; SPINDLER, David; BUTLER, Kathryn L.; CAO, Caroline; PETRUSA, Emil; MOLINA, Marcos; JONES, Dan; DE, Suvranu; DEMOYA, Marc; JONES, Stephanie

    2016-01-01

    This paper presents a simulation of Virtual Airway Skill Trainer (VAST) tasks. The simulated tasks are a part of two main airway management techniques; Endotracheal Intubation (ETI) and Cricothyroidotomy (CCT). ETI is a simple nonsurgical airway management technique, while CCT is the extreme surgical alternative to secure the airway of a patient. We developed identification of Mallampati class, finding the optimal angle for positioning pharyngeal/mouth axes tasks for ETI and identification of anatomical landmarks and incision tasks for CCT. Both ETI and CCT simulators were used to get physicians’ feedback at Society for Education in Anesthesiology and Association for Surgical Education spring meetings. In this preliminary validation study, total 38 participants for ETI and 48 for CCT performed each simulation task and completed pre and post questionnaires. In this work, we present the details of the simulation for the tasks and also the analysis of the collected data from the validation study. PMID:27046559

  5. 21 CFR 868.5810 - Airway connector.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... airway connector is a device intended to connect a breathing gas source to a tracheal tube, tracheostomy tube, or mask. (b) Classification. Class I (general controls). The device is exempt from the...

  6. Diesel exhaust particles and airway inflammation

    EPA Science Inventory

    Purpose of review. Epidemiologic investigation has associated traffic-related air pollution with adverse human health outcomes. The capacity ofdiesel exhaust particles (DEP), a major emission source air pollution particle, to initiate an airway inflammation has subsequently been ...

  7. Airway clearance therapy: finding the evidence.

    PubMed

    Volsko, Teresa A

    2013-10-01

    Disease processes can impair ciliary function, alter secretion production and mucus rheology, and interfere with the cough reflex. Airway clearance therapy has been a cornerstone of therapy aimed at minimizing the devastating effects of airway obstruction, infection, and inflammation due to mucus stasis on the conducting airways and lung parenchyma. Although challenges to performing clinical studies evaluating the effectiveness of airway clearance therapeutic modalities exist, resources are available in the literature. In addition to device evaluations and original clinical research, the expert opinion, systematic reviews, and evidence-based practice guidelines can be found. These tools can be used to develop protocols and pathways to guide our practice. Monitoring and reporting patient, process, and financial outcomes are essential steps germane to the implementation of evidence-based care.

  8. Airway obstruction secondary to rhinoscleroma during pregnancy.

    PubMed

    Armstrong, W B; Peskind, S P; Bressler, K L; Crockett, D M

    1995-11-01

    Dyspnea is a fairly common complaint during pregnancy. However, if one excludes allergic nasal congestion of pregnancy, upper airway obstruction is a distinctly uncommon cause of dyspnea in the pregnant patient. Three cases of laryngeal rhinoscleroma in pregnant women requiring tracheostomy for airway management are reported. All three delivered healthy infants vaginally. Postpartum, two of the three were successfully decannulated, while the third became pregnant again before decannulation was accomplished. Treatment options and a review of the literature are presented.

  9. Small Airway Dysfunction and Abnormal Exercise Responses

    PubMed Central

    Petsonk, Edward L.; Stansbury, Robert C.; Beeckman-Wagner, Lu-Ann; Long, Joshua L.; Wang, Mei Lin

    2016-01-01

    Rationale Coal mine dust exposure can cause symptoms and loss of lung function from multiple mechanisms, but the roles of each disease process are not fully understood. Objectives We investigated the implications of small airway dysfunction for exercise physiology among a group of workers exposed to coal mine dust. Methods Twenty coal miners performed spirometry, first breathing air and then helium-oxygen, single-breath diffusing capacity, and computerized chest tomography, and then completed cardiopulmonary exercise testing. Measurements and Main Results Six participants meeting criteria for small airway dysfunction were compared with 14 coal miners who did not. At submaximal workload, miners with small airway dysfunction used a higher proportion of their maximum voluntary ventilation and had higher ventilatory equivalents for both O2 and CO2. Regression modeling indicated that inefficient ventilation was significantly related to small airway dysfunction but not to FEV1 or diffusing capacity. At the end of exercise, miners with small airway dysfunction had 27% lower O2 consumption. Conclusions Small airway abnormalities may be associated with important inefficiency of exercise ventilation. In dust-exposed individuals with only mild abnormalities on resting lung function tests or chest radiographs, cardiopulmonary exercise testing may be important in defining causes of exercise intolerance. PMID:27073987

  10. Migration of Airway Smooth Muscle Cells

    PubMed Central

    Gerthoffer, William T.

    2008-01-01

    Migration of smooth muscle cells is a process fundamental to development of hollow organs, including blood vessels and the airways. Migration is also thought to be part of the response to tissue injury. It has also been suggested to contribute to airways remodeling triggered by chronic inflammation. In both nonmuscle and smooth muscle cells numerous external signaling molecules and internal signal transduction pathways contribute to cell migration. The review includes evidence for the functional significance of airway smooth muscle migration, a summary of promigratory and antimigratory agents, and summaries of important signaling pathways mediating migration. Important signaling pathways and effector proteins described include small G proteins, phosphatidylinositol 3-kinases (PI3-K), Rho activated protein kinase (ROCK), p21-activated protein kinases (PAK), Src family tyrosine kinases, and mitogen-activated protein kinases (MAPK). These signaling modules control multiple critical effector proteins including actin nucleating, capping and severing proteins, myosin motors, and proteins that remodel microtubules. Actin filament remodeling, focal contact remodeling and propulsive force of molecular motors are all coordinated to move cells along gradients of chemical cues, matrix adhesiveness, or matrix stiffness. Airway smooth muscle cell migration can be modulated in vitro by drugs commonly used in pulmonary medicine including β-adrenergic agonists and corticosteroids. Future studies of airway smooth muscle cell migration may uncover novel targets for drugs aimed at modifying airway remodeling. PMID:18094091

  11. Trichobezoar Causing Airway Compromise during Esophagogastroduodenoscopy

    PubMed Central

    Kao, Erica Y.; Scalzitti, Nicholas J.; Dion, Gregory R.; Bowe, Sarah N.

    2015-01-01

    Objectives. (1) Report the case of a 5-year-old female with trichotillomania and trichophagia that suffered airway compromise during esophagogastroduodenoscopy for removal of a trichobezoar. (2) Provide management recommendations for an unusual foreign body causing extubation and partial airway obstruction. Methods. Case report of a rare situation of airway compromise caused by a trichobezoar. Results. A 5-year-old patient underwent endoscopic retrieval of a gastric trichobezoar (hairball) by the gastroenterology service under general endotracheal anesthesia in a sedation unit. During removal, the hairball, due to its large size, dislodged the endotracheal tube, effectively extubating the patient. The bezoar became lodged at the cricopharyngeus muscle. Attempts to remove the bezoar or reintubation were unsuccessful. The child was able to be mask ventilated while the otolaryngology service was called. Direct laryngoscopy revealed a hairball partially obstructing the view of the glottis from its position in the postcricoid area. The hairball, still entrapped in the snare from the esophagoscope, was grasped with Magill forceps and slowly extracted. The patient was then reintubated and the airway and esophagus were reevaluated. Conclusions. Trichobezoar is an uncommon cause of airway foreign body. Careful attention to airway management during these and similar foreign body extractions can prevent inadvertent extubations. PMID:26457086

  12. 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. PMID:27466851

  13. 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

  14. Ahr2-dependence of PCB126 effects on the swim bladder in relation to expression of CYP1 and cox-2 genes in developing zebrafish.

    PubMed

    Jönsson, Maria E; Kubota, Akira; Timme-Laragy, Alicia R; Woodin, Bruce; Stegeman, John J

    2012-12-01

    The teleost swim bladder is assumed a homolog of the tetrapod lung. Both swim bladder and lung are developmental targets of persistent aryl hydrocarbon receptor (AHR(2)) agonists; in zebrafish (Danio rerio) the swim bladder fails to inflate with exposure to 3,3',4,4',5-pentachlorobiphenyl (PCB126). The mechanism for this effect is unknown, but studies have suggested roles of cytochrome P450 1 (CYP1) and cyclooxygenase 2 (Cox-2) in some Ahr-mediated developmental effects in zebrafish. We determined relationships between swim bladder inflation and CYP1 and Cox-2 mRNA expression in PCB126-exposed zebrafish embryos. We also examined effects on β-catenin dependent transcription, histological effects, and Ahr2 dependence of the effect of PCB126 on swim bladder using morpholinos targeting ahr2. One-day-old embryos were exposed to waterborne PCB126 or carrier (DMSO) for 24h and then held in clean water until day 4, a normal time for swim bladder inflation. The effects of PCB126 were concentration-dependent with EC(50) values of 1.4 to 2.0 nM for induction of the CYP1s, 3.7 and 5.1 nM (or higher) for cox-2a and cox-2b induction, and 2.5 nM for inhibition of swim bladder inflation. Histological defects included a compaction of the developing bladder. Ahr2-morpholino treatment rescued the effect of PCB126 (5 nM) on swim bladder inflation and blocked induction of CYP1A, cox-2a, and cox-2b. With 2nM PCB126 approximately 30% of eleutheroembryos(3) failed to inflate the swim bladder, but there was no difference in CYP1 or cox-2 mRNA expression between those embryos and embryos showing inflated swim bladder. Our results indicate that PCB126 blocks swim bladder inflation via an Ahr2-mediated mechanism. This mechanism seems independent of CYP1 or cox-2 mRNA induction but may involve abnormal development of swim bladder cells.

  15. Effects of Developmental Activation of the AhR on CD4+ T-Cell Responses to Influenza Virus Infection in Adult Mice

    PubMed Central

    Boule, Lisbeth A.; Winans, Bethany

    2014-01-01

    Background: Epidemiological and animal studies indicate that maternal exposure to pollutants that bind the aryl hydrocarbon receptor (AhR) correlates with poorer ability to combat respiratory infection and lower antibody levels in the offspring. These observations point to an impact on CD4+ T cells. Yet, the consequence of developmental exposure to AhR ligands on the activation and differentiation of CD4+ T cells has not been directly examined. Objectives: Our goal was to determine whether maternal exposure to an AhR ligand directly alters CD4+ T cell differentiation and function later in life. Methods: C57BL/6 mice were exposed to a prototypical AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in utero and via suckling. We then measured CD4+ T-cell activation and differentiation into distinct effector populations in adult offspring that were infected with influenza A virus (IAV). Reciprocal adoptive transfers were used to define whether modifications in CD4+ T-cell responses resulted from direct effects of developmental TCDD exposure on CD4+ T cells. Results: Developmental exposure skewed CD4+ T-cell responses to IAV infection. We observed fewer virus-specific, activated CD4+ T cells and a reduced frequency of conventional CD4+ effector-cell subsets. However, there was an increase in regulatory CD4+ T cells. Direct effects of AhR activation on CD4+ T cells resulted in impaired differentiation into conventional effector subsets; this defect was transferred to mice that had not been developmentally exposed to TCDD. Conclusions: Maternal exposure to TCDD resulted in durable changes in the responsive capacity and differentiation of CD4+ T cells in adult C57BL/6 mice. Citation: Boule LA, Winans B, Lawrence BP. 2014. Effects of developmental activation of the AhR on CD4+ T-cell responses to influenza virus infection in adult mice. Environ Health Perspect 122:1201–1208; http://dx.doi.org/10.1289/ehp.1408110 PMID:25051576

  16. Systemic Administration of Human Bone Marrow-Derived Mesenchymal Stromal Cell Extracellular Vesicles Ameliorates Aspergillus Hyphal Extract-Induced Allergic Airway Inflammation in Immunocompetent Mice

    PubMed Central

    Cruz, Fernanda F.; Borg, Zachary D.; Goodwin, Meagan; Sokocevic, Dino; Wagner, Darcy E.; Coffey, Amy; Antunes, Mariana; Robinson, Kristen L.; Mitsialis, S. Alex; Kourembanas, Stella; Thane, Kristen; Hoffman, Andrew M.; McKenna, David H.; Rocco, Patricia R.M.

    2015-01-01

    An increasing number of studies demonstrate that administration of either conditioned media (CM) or extracellular vesicles (EVs) released by mesenchymal stromal cells (MSCs) derived from bone marrow and other sources are as effective as the MSCs themselves in mitigating inflammation and injury. The goal of the current study was to determine whether xenogeneic administration of CM or EVs from human bone marrow-derived MSCs would be effective in a model of mixed Th2/Th17, neutrophilic-mediated allergic airway inflammation, reflective of severe refractory asthma, induced by repeated mucosal exposure to Aspergillus hyphal extract (AHE) in immunocompetent C57Bl/6 mice. Systemic administration of both CM and EVs isolated from human and murine MSCs, but not human lung fibroblasts, at the onset of antigen challenge in previously sensitized mice significantly ameliorated the AHE-provoked increases in airway hyperreactivity (AHR), lung inflammation, and the antigen-specific CD4 T-cell Th2 and Th17 phenotype. Notably, both CM and EVs from human MSCs (hMSCs) were generally more potent than those from mouse MSCs (mMSCs) in most of the outcome measures. The weak cross-linking agent 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride was found to inhibit release of both soluble mediators and EVs, fully negating effects of systemically administered hMSCs but only partly inhibited the ameliorating effects of mMSCs. These results demonstrate potent xenogeneic effects of CM and EVs from hMSCs in an immunocompetent mouse model of allergic airway inflammation and they also show differences in mechanisms of action of hMSCs versus mMSCs to mitigate AHR and lung inflammation in this model. Significance There is a growing experience demonstrating benefit of mesenchymal stromal cell (MSC)-based cell therapies in preclinical models of asthma. In the current study, conditioned media (CM) and, in particular, the extracellular vesicle fraction obtained from the CM were as potent as the

  17. Therapeutic effects of naringin in a guinea pig model of ovalbumin-induced cough-variant asthma.

    PubMed

    Jiao, Hao-yan; Su, Wei-wei; Li, Pei-bo; Liao, Yan; Zhou, Qian; Zhu, Na; He, Li-li

    2015-08-01

    Naringin, a well known component isolated from Exocarpium Citri Grandis, has significant antitussive effects. Recently, Naringin exhibited novel anti-inflammatory effect in chronic inflammatory diseases. In this work, we firstly evaluated the effects of naringin on enhanced cough, airway hyper-responsiveness (AHR), and airway inflammation in an ovalbumin-induced experimental cough-variant asthma (CVA) model in guinea pigs. We investigated the effect of naringin (18.4 mg/kg, per os, single dose or consecutively) on cough to inhaled capsaicin after challenge with an aerosolized antigen in actively sensitized guinea pigs. The effect of naringin on AHR to inhaled methacholine was evaluated 24 h after cough determination. Airway inflammation was assessed via bronchoalveolar lavage fluid (BALF) cytology and lung histopathology. Naringin, given consecutively, significantly reduced ovalbumin-induced enhanced cough and AHR, inhibited the increases in the leukocytes, interleukin-4 (IL-4), IL-5, and IL-13 in BALF compared with the model group. Moreover, the pathologic changes in lung tissues were clearly ameliorated by naringin treatment. These results suggest that naringin may be a beneficial agent for CVA treatment.

  18. Full Airway Drainage by Fiber Bronchoscopy Through Artificial Airway in the Treatment of Occult Traumatic Atelectasis.

    PubMed

    Zhao, Xue Hong; Zhang, Yun; Liang, Zhong Yan; Zhang, Shao Yang; Yu, Wen Qiao; Huang, Fang-Fang

    2015-12-01

    The objective of this study is to investigate the effects of full airway drainage by fiber bronchoscopy through artificial airway in the treatment of traumatic atelectasis with occult manifestations. From May 2006 to May 2011, 40 cases of occult traumatic atelectasis were enrolled into our prospective study. Group A (n = 18) received drainage by nasal bronchoscope; group B underwent airway drainage by fiber bronchoscopy through artificial airway (n = 22). The effects of treatment were evaluated by the incidence of adult respiratory distress syndrome (ARDS), lung abscess, and the average length of hospital stay. Compared with nasal fiber-optic treatment, airway drainage by fiber bronchoscopy through artificial airway reduced the incidence of ARDS (p = 0.013) and lung abscess (p = 0.062) and shortened the mean length of stay (p = 0.018). Making the decision to create an artificial airway timely and carry out lung lavage by fiber bronchoscopy through artificial airway played a significant role in the treatment of occult traumatic atelectasis. PMID:27011511

  19. Full Airway Drainage by Fiber Bronchoscopy Through Artificial Airway in the Treatment of Occult Traumatic Atelectasis.

    PubMed

    Zhao, Xue Hong; Zhang, Yun; Liang, Zhong Yan; Zhang, Shao Yang; Yu, Wen Qiao; Huang, Fang-Fang

    2015-12-01

    The objective of this study is to investigate the effects of full airway drainage by fiber bronchoscopy through artificial airway in the treatment of traumatic atelectasis with occult manifestations. From May 2006 to May 2011, 40 cases of occult traumatic atelectasis were enrolled into our prospective study. Group A (n = 18) received drainage by nasal bronchoscope; group B underwent airway drainage by fiber bronchoscopy through artificial airway (n = 22). The effects of treatment were evaluated by the incidence of adult respiratory distress syndrome (ARDS), lung abscess, and the average length of hospital stay. Compared with nasal fiber-optic treatment, airway drainage by fiber bronchoscopy through artificial airway reduced the incidence of ARDS (p = 0.013) and lung abscess (p = 0.062) and shortened the mean length of stay (p = 0.018). Making the decision to create an artificial airway timely and carry out lung lavage by fiber bronchoscopy through artificial airway played a significant role in the treatment of occult traumatic atelectasis.

  20. 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.

  1. Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines

    SciTech Connect

    Dumont, Julie Josse, Rozenn Lambert, Carine Antherieu, Sebastien Laurent, Veronique Loyer, Pascal Robin, Marie-Anne Guillouzo, Andre

    2010-11-15

    2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) are two of the most common heterocyclic aromatic amines (HAA) produced during cooking of meat, fish and poultry. Both HAA produce different tumor profiles in rodents and are suspected to be carcinogenic in humans. In order to better understand the molecular basis of HAA toxicity, we have analyzed gene expression profiles in the metabolically competent human HepaRG cells using pangenomic oligonucleotide microarrays, after either a single (24-h) or a repeated (28-day) exposure to 10 {mu}M PhIP or MeIQx. The most responsive genes to both HAA were downstream targets of the arylhydrocarbon receptor (AhR): CYP1A1 and CYP1A2 after both time points and CYP1B1 and ALDH3A1 after 28 days. Accordingly, CYP1A1/1A2 induction in HAA-treated HepaRG cells was prevented by chemical inhibition or small interference RNA-mediated down-regulation of the AhR. Consistently, HAA induced activity of the CYP1A1 promoter, which contains a consensus AhR-related xenobiotic-responsive element (XRE). In addition, several other genes exhibited both time-dependent and compound-specific expression changes with, however, a smaller magnitude than previously reported for the prototypical AhR target genes. These changes concerned genes mainly related to cell growth and proliferation, apoptosis, and cancer. In conclusion, these results identify the AhR gene battery as the preferential target of PhIP and MeIQx in HepaRG cells and further support the hypothesis that intake of HAA in diet might increase human cancer risk.

  2. AHR Over-Expression in Papillary Thyroid Carcinoma: Clinical and Molecular Assessments in a Series of Italian Acromegalic Patients with a Long-Term Follow-Up

    PubMed Central

    Mian, Caterina; Ceccato, Filippo; Barollo, Susi; Watutantrige-Fernando, Sara; Albiger, Nora; Regazzo, Daniela; de Lazzari, Paola; Pennelli, Gianmaria; Rotondi, Sandra; Nacamulli, Davide; Pelizzo, Maria Rosa; Jaffrain-Rea, Marie-Lise; Grimaldi, Franco; Occhi, Gianluca; Scaroni, Carla

    2014-01-01

    Aim Acromegaly reportedly carries an increased risk of malignant and benign thyroid tumors, with a prevalence of thyroid cancer of around 3–7%. Germline mutations in the aryl-hydrocarbon receptor (AHR) interacting protein (AIP) have been identified in familial forms of acromegaly. The molecular and endocrine relationships between follicular thyroid growth and GH-secreting pituitary adenoma have yet to be fully established. Our aim was to study the prevalence of differentiated thyroid cancer (DTC) in acromegaly, focusing on the role of genetic events responsible for the onset of thyroid cancer. Methods Germline mutations in the AIP gene were assessed in all patients; BRAF and H-N-K RAS status was analyzed by direct sequencing in thyroid specimens, while immunohistochemistry was used to analyze the protein expression of AIP and AHR. A set of PTCs unrelated to acromegaly was also studied. Results 12 DTCs (10 papillary and 2 follicular carcinomas) were identified in a cohort of 113 acromegalic patients. No differences in GH/IGF-1 levels or disease activity emerged between patients with and without DTC, but the former were older and more often female. BRAF V600E was found in 70% of the papillary thyroid cancers; there were no RAS mutations. AIP protein expression was similar in neoplastic and normal cells, while AHR protein was expressed more in PTCs carrying BRAF mutations than in normal tissue, irrespective of acromegaly status. Conclusions The prevalence of DTC in acromegaly is around 11% and endocrinologists should bear this in mind, especially when examining elderly female patients with uninodular goiter. The DTC risk does not seem to correlate with GH/IGF-1 levels, while it may be associated with BRAF mutations and AHR over-expression. Genetic or epigenetic events probably play a part in promoting thyroid carcinoma. PMID:25019383

  3. Exposure to Diesel Exhaust Particle Extracts (DEPe) Impairs Some Polarization Markers and Functions of Human Macrophages through Activation of AhR and Nrf2

    PubMed Central

    Jaguin, Marie; Fardel, Olivier; Lecureur, Valérie

    2015-01-01

    Macrophages (MΦ), well-known to play an important role in immune response, also respond to environmental toxic chemicals such as diesel exhaust particles (DEP). Potential effects of DEPs towards MΦ polarization, a key hall-mark of MΦ physiology, remain however poorly documented. This study was therefore designed to evaluate the effects of a reference DEP extract (DEPe) on human MΦ polarization. Human blood monocytes-derived MΦ were incubated with IFNγ+LPS or IL-4 to obtain M1 and M2 subtypes, respectively; a 24 h exposure of polarizing MΦ to 10 μg/ml DEPe was found to impair expression of some macrophagic M1 and M2 markers, without however overall inhibition of M1 and M2 polarization processes. Notably, DEPe treatment increased the secretion of the M1 marker IL-8 and the M2 marker IL-10 in both MΦ subtypes, whereas it reduced lipopolysaccharide-induced IL-6 and IL-12p40 secretion in M1 MΦ. In M2 MΦ, DEPe exposure led to a reduction of CD200R expression and of CCL17, CCL18 and CCL22 secretion, associated with a lower chemotaxis of CCR4-positive cells. DEPe activated the Nrf2 and AhR pathways and induced expression of their reference target genes such as Hmox-1 and cytochrome P-4501B1 in M1 and M2 MΦ. Nrf2 or AhR silencing through RNA interference prevented DEPe-related down-regulation of IL-6. AhR silencing also inhibited the down-secretion of IL-12p40 and CCL18 in M1- and M2-DEPe-exposed MΦ, respectively. DEPs are therefore likely to alter expression of some M1 and M2 markers in an AhR- and Nrf2-dependent manner; such regulations may contribute to deleterious immune effects of atmospheric DEP. PMID:25710172

  4. TCDD and a putative endogenous AhR ligand, ITE, elicit the same immediate changes in gene expression in mouse lung fibroblasts.

    PubMed

    Henry, Ellen C; Welle, Stephen L; Gasiewicz, Thomas A

    2010-03-01

    The aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, mediates toxicity of several classes of xenobiotics and also has important physiological roles in differentiation, reproduction, and immunity, although the endogenous ligand(s) mediating these functions is/are as yet unidentified. One candidate endogenous ligand, 2-(1'H-indolo-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), is a potent AhR agonist in vitro, activates the murine AhR in vivo, but does not induce toxicity. We hypothesized that ITE and the toxic ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), may modify transcription of different sets of genes to account for their different toxicity. To test this hypothesis, primary mouse lung fibroblasts were exposed to 0.5muM ITE, 0.2nM TCDD, or vehicle for 4 h, and total gene expression was evaluated using microarrays. After this short-term and low-dose treatment, several hundred genes were changed significantly, and the response to ITE and TCDD was remarkably similar, both qualitatively and quantitatively. Induced gene sets included the expected battery of AhR-dependent xenobiotic-metabolizing enzymes, as well as several sets that reflect the inflammatory role of lung fibroblasts. Real time quantitative RT-qPCR assay of several selected genes confirmed these microarray data and further suggested that there may be kinetic differences in expression between ligands. These data suggest that ITE and TCDD elicit an analogous change in AhR conformation such that the initial transcription response is the same. Furthermore, if the difference in toxicity between TCDD and ITE is mediated by differences in gene expression, then it is likely that secondary changes enabled by the persistent TCDD, but not by the shorter lived ITE, are responsible.

  5. 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.

  6. 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.

  7. Measles: an epidemic of upper airway obstruction.

    PubMed

    Manning, S C; Ridenour, B; Brown, O E; Squires, J

    1991-09-01

    Between October 1989 and August 1990, Dallas County experienced an 11-month epidemic of measles. Of 995 cases of pediatric measles diagnosed in the outpatient department of Children's Medical Center, 108 patients were admitted and 34 of these demonstrated significant upper airway obstruction at the time of admission. Airway problems ranged from mild inspiratory stridor with nasal flaring to frank obstruction and arrest in the emergency room, requiring intubation. Eight of the 34 airway patients were eventually diagnosed with bacterial tracheitis on the basis of endoscopic findings and culture results. The remaining patients had pictures more consistent with viral laryngotracheitis, but all patients were treated with broad-spectrum antibiotics to prevent possible progression to bacterial tracheitis. A total of nine patients overall required intubation for airway obstruction and all were successfully extubated. Large outbreaks of measles are becoming common again in populations of urban poor--largely unvaccinated children. The disease in these populations tends to occur at a younger age and may be more aggressive with more associated complications. Physicians must keep in mind the possibility of upper airway obstruction in a significant proportion of these patients. Early diagnosis on the basis of clinical signs and symptoms, endoscopy, and radiographs is the key to timely appropriate management.

  8. 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. PMID:25567545

  9. Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFβ, and IDO1.

    PubMed

    Moyer, Benjamin J; Rojas, Itzel Y; Kerley-Hamilton, Joanna S; Hazlett, Haley F; Nemani, Krishnamurthy V; Trask, Heidi W; West, Rachel J; Lupien, Leslie E; Collins, Alan J; Ringelberg, Carol S; Gimi, Barjor; Kinlaw, William B; Tomlinson, Craig R

    2016-06-01

    Obesity is an increasingly urgent global problem, yet, little is known about its causes and less is known how obesity can be effectively treated. We showed previously that the aryl hydrocarbon receptor (AHR) plays a role in the regulation of body mass in mice fed Western diet. The AHR is a ligand-activated nuclear receptor that regulates genes involved in a number of biological pathways, including xenobiotic metabolism and T cell polarization. This study was an investigation into whether inhibition of the AHR prevents Western diet-based obesity. Male C57Bl/6J mice were fed control and Western diets with and without the AHR antagonist α-naphthoflavone or CH-223191, and a mouse hepatocyte cell line was used to delineate relevant cellular pathways. Studies are presented showing that the AHR antagonists α-naphthoflavone and CH-223191 significantly reduce obesity and adiposity and ameliorates liver steatosis in male C57Bl/6J mice fed a Western diet. Mice deficient in the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) were also resistant to obesity. Using an AHR-directed, luciferase-expressing mouse hepatocyte cell line, we show that the transforming growth factor β1 (TGFβ1) signaling pathway via PI3K and NF-κB and the toll-like receptor 2/4 (TLR2/4) signaling pathway stimulated by oxidized low-density lipoproteins via NF-κB, each induce luciferase expression; however, TLR2/4 signaling was significantly reduced by inhibition of IDO1. At physiological levels, kynurenine but not kynurenic acid (both tryptophan metabolites and known AHR agonists) activated AHR-directed luciferase expression. We propose a hepatocyte-based model, in which kynurenine production is increased by enhanced IDO1 activity stimulated by TGFβ1 and TLR2/4 signaling, via PI3K and NF-κB, to perpetuate a cycle of AHR activation to cause obesity; and inhibition of the AHR, in turn, blocks the cycle's output to prevent obesity. The AHR with its broad ligand binding specificity

  10. Kinins, airway obstruction, and anaphylaxis.

    PubMed

    Kaplan, Allen P

    2010-01-01

    Anaphylaxis is a term that implies symptoms that are present in many organs, some of which are potentially fatal. The pathogenic process can either be IgE-dependent or non-IgE-dependent; the latter circumstance may be referred to as anaphylactoid. Bradykinin is frequently responsible for the manifestations of IgE-independent reactions. Blood levels may increase because of overproduction; diseases such as the various forms of C1 inhibitor deficiency (hereditary or acquired) or hereditary angioedema with normal C1 inhibitor are examples in this category. Blood levels may also increase because of an abnormality in bradykinin metabolism; the angioedema due to ACE inhibitors is a commonly encountered example. Angioedema due to bradykinin has the potential to cause airway obstruction and asphyxia as well as severe gastrointestinal symptoms simulating an acute abdomen. Formation of bradykinin in plasma is a result of a complex interaction among proteins such as factor XII, prekallikrein, and high molecular weight kininogen (HK) resulting in HK cleavage and liberation of bradykinin. These proteins also assemble along the surface of endothelial cells via zinc-dependent interactions with gC1qR, cytokeratin 1, and u-PAR. Endothelial cell expression (or secretion) of heat-shock protein 90 or prolylcarboxypeptidase can activate the prekallikrein-HK complex to generate bradykinin in the absence of factor XII, however factor XII is then secondarily activated by the kallikrein that results. Bradykinin is destroyed by carboxypeptidase N and angiotensin-converting enzyme. The hypotension associated with IgE-dependent anaphylaxis maybe mediated, in part, by massive proteolytic digestion of HK by kallikreins (tissue or plasma-derived) or other cell-derived kininogenases. PMID:20519882

  11. Atropine-resistant effects of the muscarinic agonists McN-A-343 and AHR 602 on cardiac performance and the release of noradrenaline from sympathetic nerves of the perfused rabbit heart

    PubMed Central

    Fozard, J.R.; Muscholl, E.

    1974-01-01

    1 The effects of 4-(m-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride (McN-A-343) and N-benzyl-3-pyrrolidyl acetate methobromide (AHR 602) on cardiac performance and noradrenaline release from terminal sympathetic fibres were measured in isolated perfused hearts of rabbits. 2 In the presence of sufficient atropine to block muscarinic receptors, high concentrations of McN-A-343 and AHR 602 caused no cardiac stimulation and there was no increase in the resting output of noradrenaline into the perfusates. 3 McN-A-343 and AHR 602 increased both the mechanical responses and the transmitter overflow evoked by electrical stimulation of the sympathetic nerves (SNS) but inhibited both parameters during perfusion with 1,1-dimethyl-4-phenylpiperazinium (DMPP). The effects were atropine-resistant and qualitatively similar to those seen with cocaine. Hexamethonium inhibited DMPP, but affected neither SNS per se nor the facilitatory effects of McN-A-343 and AHR 602 on SNS. 4 McN-A-343, cocaine and desipramine (but not AHR 602 or hexamethonium) blocked the net cardiac noradrenaline uptake and increased the positive chronotropic effect of noradrenaline. 5 Prior perfusion with concentrations of cocaine and desipramine sufficient to block uptake reduced or abolished the facilitatory effects of both McN-A-343 and AHR 602 on SNS. 6 Cocaine, McN-A-343 and AHR 602 displayed local anaesthetic properties on the guinea-pig wheal and frog nerve plexus tests, and their relative potencies in this respect were similar to those for inhibition of DMPP-evoked transmitter overflow. Hexamethonium did not produce local anaesthesia. 7 The results indicate that the facilitated release of noradrenaline after SNS and the inhibition of release after DMPP produced by McN-A-343 and AHR 602 are the result of their combined local anaesthetic action and inhibition of amine uptake. PMID:4447857

  12. SPONTANEOUS AIRWAY HYPERRESPONSIVENESS IN ESTROGEN RECEPTOR-A DEFICIENT MICE

    EPA Science Inventory

    Rationale: Airway hyperresponsiveness is a critical feature of asthma. Substantial epidemiologic evidence supports a role for female sex hormones in modulating lung function and airway hyperresponsiveness in humans. Objectives: To examine the role of estrogen receptors in modulat...

  13. Laser applications in pediatric airway surgery

    NASA Astrophysics Data System (ADS)

    Karamzadeh, Amir M.; Ahuja, Gurpreet S.; Nguyen, John D.; Crumley, Roger

    2003-06-01

    The smaller anatomy and limited access to instrumentation pose a challenge to the pediatric airway surgeon. The enhanced precision and ability to photocoagulate tissue while operating with the laser enhances the surgeon"s ability to successfully treat unique pediatric conditions such subglottic hemangiomas, congenital cysts, respiratory papillomatosis, and laryngeal or tracheal stenosis. Due to its shallow tissue penetration and thermal effect, the carbon dioxide (CO2) laser is generally considered the laser of choice for pediatric airway applications. The potential for increased scarring and damage to underlying tissue caused by the greater penetration depth and thermal effect of the Nd:YAG and KTP lasers preclude their use in this population. In this review, we will describe the specific advantages of using lasers in airway surgery, the current technology and where the current technology is deficient.

  14. Airway Management in Croup and Epiglottitis

    PubMed Central

    Crumley, Roger L.

    1977-01-01

    Treatment techniques for airway obstruction in croup and epiglottitis are reviewed in the medical literature. Series totaling 295 nasotracheal intubations, and 591 tracheostomies were reviewed. There were two deaths attributable to airway complications in 126 patients in whom nasotracheal intubation was carried out. In three patients subglottic granulation tissue and subglottic stenoses developed from short-term nasotracheal intubation. There were no subglottic stenoses or tracheal stenoses reported in the 591 tracheostomies. From this review, it would seem feasible to use nasotracheal intubation for short-term airway treatment in croup and epiglottitis. The increasing occurrence of laryngeal and tracheal complications with long-term intubation suggests that tracheostomy be considered in such cases. PMID:349884

  15. 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

  16. Role of zebrafish cytochrome P450 CYP1C genes in the reduced mesencephalic vein blood flow caused by activation of AHR2

    SciTech Connect

    Kubota, Akira; Stegeman, John J.; Woodin, Bruce R.; Iwanaga, Toshihiko; Harano, Ryo; Peterson, Richard E.; Hiraga, Takeo; Teraoka, Hiroki

    2011-06-15

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes various signs of toxicity in early life stages of vertebrates through activation of the aryl hydrocarbon receptor (AHR). We previously reported a sensitive and useful endpoint of TCDD developmental toxicity in zebrafish, namely a decrease in blood flow in the dorsal midbrain, but downstream genes involved in the effect are not known. The present study addressed the role of zebrafish cytochrome P450 1C (CYP1C) genes in association with a decrease in mesencephalic vein (MsV) blood flow. The CYP1C subfamily was recently discovered in fish and includes the paralogues CYP1C1 and CYP1C2, both of which are induced via AHR2 in zebrafish embryos. We used morpholino antisense oligonucleotides (MO or morpholino) to block initiation of translation of the target genes. TCDD-induced mRNA expression of CYP1Cs and a decrease in MsV blood flow were both blocked by gene knockdown of AHR2. Gene knockdown of CYP1C1 by two different morpholinos and CYP1C2 by two different morpholinos, but not by their 5 nucleotide-mismatch controls, was effective in blocking reduced MsV blood flow caused by TCDD. The same CYP1C-MOs prevented reduction of blood flow in the MsV caused by {beta}-naphthoflavone (BNF), representing another class of AHR agonists. Whole-mount in situ hybridization revealed that mRNA expression of CYP1C1 and CYP1C2 was induced by TCDD most strongly in branchiogenic primordia and pectoral fin buds. In situ hybridization using head transverse sections showed that TCDD increased the expression of both CYP1Cs in endothelial cells of blood vessels, including the MsV. These results indicate a potential role of CYP1C1 and CYP1C2 in the local circulation failure induced by AHR2 activation in the dorsal midbrain of the zebrafish embryo. - Research Highlights: > We examine the roles of zebrafish CYP1C1 and CYP1C2 in TCDD developmental toxicity. > TCDD induces mRNA expression of both CYP1Cs in the mesencephalic vein. > Knockdown of each

  17. Regulation of Ahr signaling by Nrf2 during development: Effects of Nrf2a deficiency on PCB126 embryotoxicity in zebrafish (Danio rerio)

    PubMed Central

    Rousseau, Michelle E.; Sant, Karilyn E.; Borden, Linnea R.; Franks, Diana G.; Hahn, Mark E.; Timme-Laragy, Alicia R.

    2015-01-01

    The embryotoxicity of co-planar PCBs is regulated by the aryl hydrocarbon receptor (Ahr), and has been reported to involve oxidative stress. Ahr participates in crosstalk with another transcription factor, Nfe2l2, or Nrf2. Nrf2 binds to antioxidant response elements to regulate the adaptive response to oxidative stress. To explore aspects of the crosstalk between Nrf2 and Ahr and its impact on development, we used zebrafish (Danio rerio) with a mutated DNA binding domain in Nrf2a (nrf2afh318/fh318), rendering these embryos more sensitive to oxidative stress. Embryos were exposed to 2 nM or 5 nM PCB126 at 24 hours post fertilization (prim-5 stage of pharyngula) and examined for gene expression and morphology at 4 days post fertilization (dpf; protruding –mouth stage). Nrf2a mutant eleutheroembryos were more sensitive to PCB126 toxicity at 4 dpf, and in the absence of treatment also displayed some subtle developmental differences from wildtype embryos, including delayed inflation of the swim bladder and smaller yolk sacs. We used qPCR to measure changes in expression of the nrf gene family, keap1a, keap1b, the ahr gene family, and known target genes. cyp1a induction by PCB126 was enhanced in the Nrf2a mutants (156-fold in wildtypes vs. 228-fold in mutants exposed to 5 nM). Decreased expression of heme oxygenase (decycling) 1 (hmox1) in the Nrf2a mutants was accompanied by increased nrf2b expression. Target genes of Nrf2a and AhR2, NAD(P)H:quinone oxidoreductase 1 (nqo1) and glutathione S-transferase, alpha-like (gsta1), showed a 2-5-fold increase in expression in the Nrf2a mutants as compared to wildtype. This study elucidates the interaction between two important transcription factor pathways in the developmental toxicity of co-planar PCBs. PMID:26325326

  18. Aryl hydrocarbon receptor (AhR) inducers and estrogen receptor (ER) activities in surface sediments of Three Gorges Reservoir, China evaluated with in vitro cell bioassays.

    PubMed

    Wang, Jingxian; Bovee, Toine F H; Bi, Yonghong; Bernhöft, Silke; Schramm, Karl-Werner

    2014-02-01

    Two types of biological tests were employed for monitoring the toxicological profile of sediment cores in the Three Gorges Reservoir (TGR), China. In the present study, sediments collected in June 2010 from TGR were analyzed for estrogen receptor (ER)- and aryl hydrocarbon receptor (AhR)-mediated activities. The estrogenic activity was assessed using a rapid yeast estrogen bioassay, based on the expression of a green fluorescent reporter protein. Weak anti-estrogenic activity was detected in sediments from an area close to the dam of the reservoir, and weak estrogenic activities ranging from 0.3 to 1 ng 17β-estradiol (E2) equivalents (EQ) g(-1) dry weight sediment (dw) were detected in sediments from the Wanzhou to Guojiaba areas. In the upstream areas Wanzhou and Wushan, sediments demonstrated additive effects in co-administration of 1 nM E2 in the yeast test system, while sediments from the downstream Badong and Guojiaba areas showed estrogenic activities which seemed to be more than additive (synergistic activity). There was an increasing tendency in estrogenic activity from upstream of TGR to downstream, while this tendency terminated and converted into anti-estrogenic activity in the area close to the dam. The AhR activity was detected employing rat hepatoma cell line (H4IIE). EROD activities were found homogenously distributed in sediments in TGR ranging from 200 to 311 pg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) EQ g(-1) dw for total AhR agonists and from 45 to 76 pg TCDD EQ g(-1) dw for more persistent AhR agonists. The known AhR agonists polycyclic aromatic hydrocarbon, polychlorinated biphenyl, and PCDD/F only explained up to 8 % of the more persistent AhR agonist activity in the samples, which suggests that unidentified AhR-active compounds represented a great proportion of the TCDD EQ in sediments from TGR. These findings of estrogenic potential and dioxin-like activity in TGR sediments provide possible weight-of-evidence of potential

  19. Aryl hydrocarbon receptor (AhR) inducers and estrogen receptor (ER) activities in surface sediments of Three Gorges Reservoir, China evaluated with in vitro cell bioassays.

    PubMed

    Wang, Jingxian; Bovee, Toine F H; Bi, Yonghong; Bernhöft, Silke; Schramm, Karl-Werner

    2014-02-01

    Two types of biological tests were employed for monitoring the toxicological profile of sediment cores in the Three Gorges Reservoir (TGR), China. In the present study, sediments collected in June 2010 from TGR were analyzed for estrogen receptor (ER)- and aryl hydrocarbon receptor (AhR)-mediated activities. The estrogenic activity was assessed using a rapid yeast estrogen bioassay, based on the expression of a green fluorescent reporter protein. Weak anti-estrogenic activity was detected in sediments from an area close to the dam of the reservoir, and weak estrogenic activities ranging from 0.3 to 1 ng 17β-estradiol (E2) equivalents (EQ) g(-1) dry weight sediment (dw) were detected in sediments from the Wanzhou to Guojiaba areas. In the upstream areas Wanzhou and Wushan, sediments demonstrated additive effects in co-administration of 1 nM E2 in the yeast test system, while sediments from the downstream Badong and Guojiaba areas showed estrogenic activities which seemed to be more than additive (synergistic activity). There was an increasing tendency in estrogenic activity from upstream of TGR to downstream, while this tendency terminated and converted into anti-estrogenic activity in the area close to the dam. The AhR activity was detected employing rat hepatoma cell line (H4IIE). EROD activities were found homogenously distributed in sediments in TGR ranging from 200 to 311 pg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) EQ g(-1) dw for total AhR agonists and from 45 to 76 pg TCDD EQ g(-1) dw for more persistent AhR agonists. The known AhR agonists polycyclic aromatic hydrocarbon, polychlorinated biphenyl, and PCDD/F only explained up to 8 % of the more persistent AhR agonist activity in the samples, which suggests that unidentified AhR-active compounds represented a great proportion of the TCDD EQ in sediments from TGR. These findings of estrogenic potential and dioxin-like activity in TGR sediments provide possible weight-of-evidence of potential

  20. [Modern airway management--current concepts for more patient safety].

    PubMed

    Timmermann, Arnd

    2009-04-01

    Effective and safe airway management is one of the core skills among anaesthesiologists and all physicians involved in acute care medicine. However, failure in airway management is still the most frequent single incidence with the highest impact on patient's morbidity and mortality known from closed claims analyses. The anaesthesiologist has to manage the airway in elective patients providing a high level of safety with as little airway injury and interference with the cardio-vascular system as possible. Clinical competence also includes the management of the expected and unexpected difficult airway in different clinical environments. Therefore, it is the anaesthesiologist's responsibility not only to educate and train younger residents, but also all kinds of medical personnel involved in airway management, e.g. emergency physicians, intensive care therapists or paramedics. Modern airway devices, strategies and educational considerations must fulfill these sometimes diverse and large range requirements. Supraglottic airway devices will be used more often in the daily clinical routine. This is not only due the multiple advantages of these devices compared to the tracheal tube, but also because of the new features of some supraglottic airways, which separate the airway from the gastric track and give information of the pharyngeal position. For the event of a difficult airway, new airway devices and concepts should be trained and applied in daily practice.

  1. 21 CFR 868.2600 - Airway pressure monitor.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Airway pressure monitor. 868.2600 Section 868.2600...) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Monitoring Devices § 868.2600 Airway pressure monitor. (a) Identification. An airway pressure monitor is a device used to measure the pressure in a patient's upper...

  2. 21 CFR 868.1780 - Inspiratory airway pressure meter.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Inspiratory airway pressure meter. 868.1780... (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Diagnostic Devices § 868.1780 Inspiratory airway pressure meter. (a) Identification. An inspiratory airway pressure meter is a device used to measure the...

  3. 21 CFR 868.1780 - Inspiratory airway pressure meter.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Inspiratory airway pressure meter. 868.1780... (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Diagnostic Devices § 868.1780 Inspiratory airway pressure meter. (a) Identification. An inspiratory airway pressure meter is a device used to measure the...

  4. 21 CFR 868.2600 - Airway pressure monitor.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Airway pressure monitor. 868.2600 Section 868.2600...) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Monitoring Devices § 868.2600 Airway pressure monitor. (a) Identification. An airway pressure monitor is a device used to measure the pressure in a patient's upper...

  5. 21 CFR 868.1780 - Inspiratory airway pressure meter.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Inspiratory airway pressure meter. 868.1780... (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Diagnostic Devices § 868.1780 Inspiratory airway pressure meter. (a) Identification. An inspiratory airway pressure meter is a device used to measure the...

  6. 21 CFR 868.2600 - Airway pressure monitor.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Airway pressure monitor. 868.2600 Section 868.2600...) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Monitoring Devices § 868.2600 Airway pressure monitor. (a) Identification. An airway pressure monitor is a device used to measure the pressure in a patient's upper...

  7. 21 CFR 868.2600 - Airway pressure monitor.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Airway pressure monitor. 868.2600 Section 868.2600...) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Monitoring Devices § 868.2600 Airway pressure monitor. (a) Identification. An airway pressure monitor is a device used to measure the pressure in a patient's upper...

  8. 21 CFR 868.2600 - Airway pressure monitor.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Airway pressure monitor. 868.2600 Section 868.2600...) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Monitoring Devices § 868.2600 Airway pressure monitor. (a) Identification. An airway pressure monitor is a device used to measure the pressure in a patient's upper...

  9. 21 CFR 868.1780 - Inspiratory airway pressure meter.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Inspiratory airway pressure meter. 868.1780... (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Diagnostic Devices § 868.1780 Inspiratory airway pressure meter. (a) Identification. An inspiratory airway pressure meter is a device used to measure the...

  10. 21 CFR 868.1780 - Inspiratory airway pressure meter.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Inspiratory airway pressure meter. 868.1780... (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Diagnostic Devices § 868.1780 Inspiratory airway pressure meter. (a) Identification. An inspiratory airway pressure meter is a device used to measure the...

  11. PFOS elicits transcriptional responses of the ER, AHR and PPAR pathways in Oryzias melastigma in a stage-specific manner.

    PubMed

    Fang, Chao; Wu, Xinlong; Huang, Qiansheng; Liao, Yanyan; Liu, Liangpo; Qiu, Ling; Shen, Heqing; Dong, Sijun

    2012-01-15

    Perfluorooctane sulfonate (PFOS) is widely distributed in seawater. However, the effects of PFOS on important receptors involved in the toxicity of POPs have not been fully defined, especially for the embryonic stages of marine fish. In this study, we examined the transcriptional responses and PFOS accumulation in the marine medaka embryos at the early and late developmental stages of 4 and 10 dpf upon PFOS exposure (1, 4, and 16mg/L). PFOS accumulated in the embryos, and the embryonic burdens of PFOS at 10 dpf were markedly higher than those at 4 dpf. Moreover, thirteen genes involved in three important POPs-related receptor pathways, including ER, AHR and PPAR, were cloned and investigated. The mRNA expression levels of ERα and ERγ were not significantly altered, but the estrogenic marker genes were downregulated upon PFOS exposure at 4 dpf. Conversely, ERs and related marker genes all were significantly upregulated at 10 dpf. The expressions of ARNT and cyp1a were both upregulated at 4 dpf, while no obvious changes were detected at 10 dpf. The expressions of cyp19a and cyp19b were regulated by PFOS in a stage-specific manner. PFOS produced different effects on three isoforms of PPAR. PPARα and PPARβ were first inhibited at 4 dpf and were induced at 10 dpf. PFOS did not elicit a change in PPARγ expression at either stage. In conclusion, this study showed that PFOS has an estrogenic activity and endocrine-disruptive properties. Meanwhile, PFOS could elicit transcriptional responses on POPs-related pathways in a stage-specific manner.

  12. Complementary PLS and KNN algorithms for improved 3D-QSDAR consensus modeling of AhR binding

    PubMed Central

    2013-01-01

    Multiple validation techniques (Y-scrambling, complete training/test set randomization, determination of the dependence of R2test on the number of randomization cycles, etc.) aimed to improve the reliability of the modeling process were utilized and their effect on the statistical parameters of the models was evaluated. A consensus partial least squares (PLS)-similarity based k-nearest neighbors (KNN) model utilizing 3D-SDAR (three dimensional spectral data-activity relationship) fingerprint descriptors for prediction of the log(1/EC50) values of a dataset of 94 aryl hydrocarbon receptor binders was developed. This consensus model was constructed from a PLS model utilizing 10 ppm x 10 ppm x 0.5 Å bins and 7 latent variables (R2test of 0.617), and a KNN model using 2 ppm x 2 ppm x 0.5 Å bins and 6 neighbors (R2test of 0.622). Compared to individual models, improvement in predictive performance of approximately 10.5% (R2test of 0.685) was observed. Further experiments indicated that this improvement is likely an outcome of the complementarity of the information contained in 3D-SDAR matrices of different granularity. For similarly sized data sets of Aryl hydrocarbon (AhR) binders the consensus KNN and PLS models compare favorably to earlier reports. The ability of 3D-QSDAR (three dimensional quantitative spectral data-activity relationship) to provide structural interpretation was illustrated by a projection of the most frequently occurring bins on the standard coordinate space, thus allowing identification of structural features related to toxicity. PMID:24257141

  13. Reactive airways dysfunction syndrome. Case reports of persistent airways hyperreactivity following high-level irritant exposures.

    PubMed

    Brooks, S M; Weiss, M A; Bernstein, I L

    1985-07-01

    Two individuals developed an asthma-like illness after a single exposure to high levels of an irritating aerosol, vapor, fume, or smoke. Symptoms developed within a few hours. A consistent physiologic accompaniment was airways hyperreactivity, with the two subjects showing positive methacholine challenge tests. No documented preexisting respiratory illness was identified, nor did subjects relate past respiratory complaints. Respiratory symptoms and airways hyperreactivity persisted for at least four years after the incident. The incriminated etiologic agents all shared a common characteristic of being irritant in nature. Bronchial biopsy specimens showed an airways inflammatory response. This report suggests that acute high-level irritant exposures may produce an asthma-like syndrome in some individuals, with long-term sequelae and chronic airways disease. Nonimmunologic mechanisms seems to be operative in the pathogenesis of this syndrome.

  14. Complications of upper airway surgery in companion animals.

    PubMed

    Mercurio, Andrew

    2011-09-01

    Surgery of the upper airway is performed in dogs for the correction of brachycephalic airway syndrome and laryngeal paralysis and for temporary or permanent tracheostomy. Although technically simple to perform, upper airway surgeries can lead to the development of significant postoperative complications. This article reviews complications associated with common surgical conditions of the upper airway. It involves a discussion of brachycephalic airway syndrome and associated respiratory and gastrointestinal complications. It also covers laryngeal paralysis with a focus on unilateral arytenoid lateralization and the complication of aspiration pneumonia. The condition of acquired laryngeal webbing/stenosis and potential treatment options is also discussed. Finally, tracheostomies and associated complications in dogs and cats are reviewed.

  15. Anaesthesia and airway management in mucopolysaccharidosis.

    PubMed

    Walker, Robert; Belani, Kumar G; Braunlin, Elizabeth A; Bruce, Iain A; Hack, Henrik; Harmatz, Paul R; Jones, Simon; Rowe, Richard; Solanki, Guirish A; Valdemarsson, Barbara

    2013-03-01

    This paper provides a detailed overview and discussion of anaesthesia in patients with mucopolysaccharidosis (MPS), the evaluation of risk factors in these patients and their anaesthetic management, including emergency airway issues. MPS represents a group of rare lysosomal storage disorders associated with an array of clinical manifestations. The high prevalence of airway obstruction and restrictive pulmonary disease in combination with cardiovascular manifestations poses a high anaesthetic risk to these patients. Typical anaesthetic problems include airway obstruction after induction or extubation, intubation difficulties or failure [can't intubate, can't ventilate (CICV)], possible emergency tracheostomy and cardiovascular and cervical spine issues. Because of the high anaesthetic risk, the benefits of a procedure in patients with MPS should always be balanced against the associated risks. Therefore, careful evaluation of anaesthetic risk factors should be made before the procedure, involving evaluation of airways and cardiorespiratory and cervical spine problems. In addition, information on the specific type of MPS, prior history of anaesthesia, presence of cervical instability and range of motion of the temporomandibular joint are important and may be pivotal to prevent complications during anaesthesia. Knowledge of these risk factors allows the anaesthetist to anticipate potential problems that may arise during or after the procedure. Anaesthesia in MPS patients should be preferably done by an experienced (paediatric) anaesthetist, supported by a multidisciplinary team (ear, nose, throat surgeon and intensive care team), with access to all necessary equipment and support.

  16. Nasal Airway Resistance: Its Measurement and Regulation.

    ERIC Educational Resources Information Center

    Hamilton, Lyle H.

    1979-01-01

    Reviews studies of regulation of nasal airway resistance (Rn). Describes methods of calculating Rn by measuring pressure-flow relationship. Data are presented on improved methods for measuring Rn and effects for expiratory and inspiratory Rn after topical application of phenylephrine nasal decongestant spray. (Author/SA)

  17. 21 CFR 868.5810 - Airway connector.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... DEVICES ANESTHESIOLOGY DEVICES Therapeutic Devices § 868.5810 Airway connector. (a) Identification. An... tube, or mask. (b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 868.9....

  18. Severe upper airway obstruction during sleep.

    PubMed

    Bonekat, H William; Hardin, Kimberly A

    2003-10-01

    Few disorders may manifest with predominantly sleep-related obstructive breathing. Obstructive sleep apnea (OSA) is a common disorder, varies in severity and is associated with significant cardiovascular and neurocognitive morbidity. It is estimated that between 8 and 18 million people in the United States have at least mild OSA. Although the exact mechanism of OSA is not well-delineated, multiple factors contribute to the development of upper airway obstruction and include anatomic, mechanical, neurologic, and inflammatory changes in the pharynx. OSA may occur concomitantly with asthma. Approximately 74% of asthmatics experience nocturnal symptoms of airflow obstruction secondary to reactive airways disease. Similar cytokine, chemokine, and histologic changes are seen in both disorders. Sleep deprivation, chronic upper airway edema, and inflammation associated with OSA may further exacerbate nocturnal asthma symptoms. Allergic rhinitis may contribute to both OSA and asthma. Continuous positive airway pressure (CPAP) is the gold standard treatment for OSA. Treatment with CPAP therapy has also been shown to improve both daytime and nighttime peak expiratory flow rates in patients with concomitant OSA and asthma. It is important for allergists to be aware of how OSA may complicate diagnosis and treatment of asthma and allergic rhinitis. A thorough sleep history and high clinical suspicion for OSA is indicated, particularly in asthma patients who are refractory to standard medication treatments.

  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. 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.

  1. Airway epithelial cell responses to ozone injury

    SciTech Connect

    Leikauf, G.D.; Simpson, L.G.; Zhao, Qiyu

    1995-03-01

    The airway epithelial cell is an important target in ozone injury. Once activated, the airway epithelium responds in three phases. The initial, or immediate phase, involves activation of constitutive cells, often through direct covalent interactions including the formation of secondary ozonolysis products-hydroxyhydroperoxides, aldehydes, and hydrogen peroxide. Recently, we found hydroxyhydroperoxides to be potent agonists; of bioactive eicosanoid formation by human airway epithelial cells in culture. Other probable immediate events include activation and inactivation of enzymes present on the epithelial surface (e.g., neutral endopeptidase). During the next 2 to 24 hr, or early phase, epithelial cells respond by synthesis and release of chemotactic factors, including chemokines-macrophage inflammatory protein-2, RANTES, and interleukin-8. Infiltrating leukocytes during this period also release elastase, an important agonist of epithelial cell mucus secretion and additional chemokine formation. The third (late) phase of ozone injury is characterized by eosinophil or monocyte infiltration. Cytokine expression leads to alteration of structural protein synthesis, with increases in fibronectin evident by in situ hybridization. Synthesis of epithelial antiproteases, e.g., secretary leukocyte protease inhibitor, may also increase locally 24 to 48 hr after elastase concentrations become excessive. Thus, the epithelium is not merely a passive barrier to ozone injury but has a dynamic role in directing the migration, activating, and then counteracting inflammatory cells. Through these complex interactions, epithelial cells can be viewed as the initiators (alpha) and the receptors (omega) of ozone-induced airway disease. 51 refs., 2 figs., 3 tabs.

  2. COLCHICINE DECREASES AIRWAY HYPERACTIVITY AFTER PHOSGENE EXPOSURE

    EPA Science Inventory

    Phosgene (COCl(2)) exposure affects an influx of inflammatory cells into the lung, which can be reduced in an animal model by pretreatment with colchicine. Inflammation in the respiratory tract can be associated with an increase in airway hyperreactivity. We tested the hypotheses...

  3. Difficult airway in Mowat-Wilson syndrome.

    PubMed

    Packiasabapathy, Senthil; Chandiran, Ravindran; Batra, Ravinder K; Agarwala, Sandeep

    2016-11-01

    Mowat-Wilson syndrome is a rare congenital syndrome involving multiple system abnormalities. The most consistently present components include facial deformity, mental retardation, and Hirschsprung disease. We report the anesthetic management of a case of Mowat-Wilson syndrome, with a difficult airway, who underwent Duhamel's procedure and colostomy closure. PMID:27687363

  4. Volatile Organic Compounds Contribute to Airway Hyperresponsiveness

    PubMed Central

    Jang, An-Soo; Choi, Inseon-S; Koh, Young-Il

    2007-01-01

    Background Volatile organic compounds (VOCs) in concentrations found in both the work and home environments may influence lung function. We investigated the prevalence of airway responsiveness in workers exposed to VOCs. Methods We used allergic skin tests, nonspecific airway hyperresponsiveness testing and questionnaires to study twenty exposed workers and twenty-seven control subjects. Atopy was defined as a reactor who showed >3+ response to one or more allergens on the skin prick tests. Airway hyperresponsiveness (BRindex) was defined as log [% fall of FEV1/ log (last concentration of methacholine) +10]. Results The VOC exposed workers, in comparison with the control subjects, tended to have a higher BRindex (1.19±0.07 vs. 1.15±0.08, respectively). Workers exposed to VOCs with atopy or smoker, as compared with the workers exposed to VOCs with non-atopy and who were non-smokers and the control subjects with non-atopy and who were non-smokers, had a significantly higher BRindex (1.20±0.05 vs. 1.14±0.06 vs. 1.10±0.03, respectively p<0.05). The BRindex was not correlated with atopy, the smoking status or the duration of VOC exposure. Conclusions These findings suggest that VOCs may act as a contributing factor of airway hyperresponsiveness in workers exposed to VOCs. PMID:17427638

  5. Cell Jamming in the Airway Epithelium.

    PubMed

    Park, Jin-Ah; Fredberg, Jeffrey J

    2016-03-01

    Hallmarks of asthma include chronic airway inflammation, progressive airway remodeling, and airway hyperresponsiveness. The initiation and perpetuation of these processes are attributable at least in part to critical events within the airway epithelium, but the underlying mechanisms remain poorly understood. New evidence now suggests that epithelial cells derived from donors without asthma versus donors with asthma, even in the absence of inflammatory cells or mediators, express modes of collective migration that innately differ not only in the amount of migration but also in the kind of migration. The maturing cell layer tends to undergo a transition from a hypermobile, fluid-like, unjammed phase in which cells readily rearrange, exchange places, and flow, to a quiescent, solid-like, jammed phase in which cells become virtually frozen in place. Moreover, the unjammed phase defines a phenotype that can be perpetuated by the compressive stresses caused by bronchospasm. Importantly, in cells derived from donors with asthma versus donors without asthma, this jamming transition becomes substantially delayed, thus suggesting an immature or dysmature epithelial phenotype in asthma. PMID:27027955

  6. [Quality assurance in airway management: education and training for difficult airway management].

    PubMed

    Kaminoh, Yoshiroh

    2006-01-01

    Respiratory problem is one of the main causes of death or severe brain damage in perioperative period. Three major factors of respiratory problem are esophageal intubation, inadequate ventilation, and difficult airway. The wide spread of pulse oximeter and capnograph reduced the incidences of esophageal intubation and inadequate ventilation, but the difficult airway still occupies the large portion in the causes of adverse events during anesthesia. "Practice guideline for management of the difficult airway" was proposed by American Society of Anesthesiologists (ASA) in 1992 and 2002. Improvement of knowledge, technical skills, and cognitive skills are necessary for the education and training of the difficult airway management. "The practical seminar of difficult airway management (DAM practical seminar)" has been cosponsored by the Japanese Association of Medical Simulation (JAMS) in the 51 st and 52 nd annual meetings of Japanese Society of Anesthesiologists and the 24th annual meeting of Japanese Society for Clinical Anesthesia. The DAM practical seminar is composed of the lecture session for ASA difficult airway algorithm, the hands-on training session for technical skills, and the scenario-based training session for cognitive skills. Ninty six Japanese anesthesiologists have completed the DAM practical seminar in one year. "The DAM instructor course" should be immediately prepared to organize the seminar more frequently. PMID:16440705

  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. Cytokines (interleukin-9, IL-17, IL-22, IL-25 and IL-33) and asthma

    PubMed Central

    Farahani, Rahim; Sherkat, Roya; Hakemi, Mazdak Ganjalikhani; Eskandari, Nahid; Yazdani, Reza

    2014-01-01

    Asthma is a reversible airway obstruction that is characterized by constriction of airway smooth muscle, hyper secretion of mucus, edema and airway hyper responsiveness (AHR), mucus secretion and thickening of the basement membrane underlying the airway epithelium. During the process of airway inflammation, complex interactions of innate and adaptive immune cells as well as structural cells and their cytokines have many important roles. It was believed that airway inflammation is orchestrated by allergen specific T helper (Th) 2 cells, which recruit and accumulate in the lungs and produce a range of different effector cytokines. However, more recent studies have revealed the potential collaboration of other helper T cells and their cytokines in this process. Th17 cell may have a role in severe asthma and chronic obstructive pulmonary disease (COPD). Interleukin (IL)-9-producing subset called Th9 cell, Th22 cells which primarily secrete IL-22, IL-13 and tumor necrosis factor-α and Th25 cells via producing IL-25 are believed to be important for initiating allergic reactions and developing airway inflammation. Cytokines are important in asthma and play a critical role in orchestrating the allergic inflammatory response, although the precise role of each cytokine remains to be determined. The aim of this review is to summarize the current knowledge about the possible roles of newly identified helper T cells derived cytokines (IL-9, 17, 22, 25 and IL-33) in asthma. The potential therapeutic applications emerging from the roles of these cytokines will be discussed as well. PMID:24949298

  9. Postnatal growth of tracheobronchial airways of Sprague–Dawley rats

    PubMed Central

    Lee, DongYoub; Srirama, Praveen K; Wallis, Christopher; Wexler, Anthony S

    2011-01-01

    Rats are widely used for the studies of pulmonary toxicology in both juveniles and adults. To facilitate such studies, investigators have developed models of lung architecture based on manual or computerized airway measurements. However, postnatal growth of conducting airways of rat lungs has never been reported. In this paper, we present conducting airway architecture statistics for male Sprague–Dawley rat lungs at ages 15, 28, 40, and 81 days by analyzing CT images from airway silicon casts. Detailed branching characteristics and intersubject variance are presented. This study shows that (i) airway growth in diameter and length is not linear with age, (ii) growth of airway length is faster than that of diameter during the 15–81-day postnatal period, and (iii) asymmetry in airway diameter (ratio of major to minor daughter diameter) increases with age. PMID:21534951

  10. [Clinical basics of supraglottic airway management in paediatric anaesthesia].

    PubMed

    Goldmann, Kai

    2013-04-01

    The low invasiveness and simplicity of use of the LMA-Classic™ contributed substantially to the supraglottic airway management acquiring a special role in the anaesthesia care of neonates and children. Due to the introduction of new supraglottic airway devices and the expansion of indications, this form of airway management has a predominant role in paediatric anaesthesia in many institutions nowadays. As securing the airway "above the glottis" differs substantially in some aspects from securing the airway using the endotracheal tube it is mandatory to acknowledge special aspects in routine clinical practice in order to avoid complications. The following article describes basic aspects of supraglottic airway management in paediatric anaesthesia and illustrates, where possible, the available scientific evidence in the use of different supraglottic airway devices in this regard. PMID:23633257

  11. [Airway Management in a Patient with Forestier's Disease].

    PubMed

    Kondo, Yuriko; Echigo, Noriyuki; Akata, Mariko; Yokoyama, Kaori; Takasugi, Naoya; Goto, Takahisa

    2016-04-01

    Airway management in a patient with Forestier's disease can be challenging clinically because this disease may cause not only dysphagia but also airway obstruction due to the compression of the pharynx and esophagus caused by the ossification of anterior longitudinal ligament. We report our anesthetic management in a patient with Forestier's disease. Meanwhile, we studied the causes of difficult airway and the most suitable airway device for a patient with this disease from a standpoint of anatomy of upper airway. Our study indicated the possibility that the most suitable airway device differed depending on the actual location of the ossification of anterior longitudinal ligament in the cervical spine and that more prudent airway management would be required if its lesion location extended to upper cervical spine. PMID:27188118

  12. BLUNTING AIRWAYS EOSINOPHILIC INFLAMMATION RESULTS IN A DECREASED AIRWAY NEUTROPHIL RESPONSE TO INHALED LPS IN ATOPIC ASTHMATICS A ROLE FOR CD-14

    EPA Science Inventory

    Recent data demonstrate that atopic inflammation might enhance airway responses to inhaled LPS in individuals with atopic asthma by increasing CD14 expression on airway macrophages. We sought to determine whether blunting airway eosinophilic inflammation decreases CD14 expressio...

  13. Assessment of energetic costs of AhR activation by β-naphthoflavone in rainbow trout (Oncorhynchus mykiss) hepatocytes using metabolic flux analysis

    SciTech Connect

    Nault, Rance; Abdul-Fattah, Hiba; Mironov, Gleb G.; Berezovski, Maxim V.; Moon, Thomas W.

    2013-08-15

    Exposure to environmental contaminants such as activators of the aryl hydrocarbon receptor (AhR) leads to the induction of defense and detoxification mechanisms. While these mechanisms allow organisms to metabolize and excrete at least some of these environmental contaminants, it has been proposed that these mechanisms lead to significant energetic challenges. This study tests the hypothesis that activation of the AhR by the model agonist β-naphthoflavone (βNF) results in increased energetic costs in rainbow trout (Oncorhynchus mykiss) hepatocytes. To address this hypothesis, we employed traditional biochemical approaches to examine energy allocation and metabolism including the adenylate energy charge (AEC), protein synthesis rates, Na{sup +}/K{sup +}-ATPase activity, and enzyme activities. Moreover, we have used for the first time in a fish cell preparation, metabolic flux analysis (MFA) an in silico approach for the estimation of intracellular metabolic fluxes. Exposure of trout hepatocytes to 1 μM βNF for 48 h did not alter hepatocyte AEC, protein synthesis, or Na{sup +}/K{sup +}-ATPase activity but did lead to sparing of glycogen reserves and changes in activities of alanine aminotransferase and citrate synthase suggesting altered metabolism. Conversely, MFA did not identify altered metabolic fluxes, although we do show that the dynamic metabolism of isolated trout hepatocytes poses a significant challenge for this type of approach which should be considered in future studies. - Highlights: • Energetic costs of AhR activation by βNF was examined in rainbow trout hepatocytes. • Metabolic flux analysis was performed on a fish cell preparation for the first time. • Exposure to βNF led to sparing of glycogen reserves and altered enzyme activities. • Adenylate energy charge was maintained despite temporal changes in metabolism.

  14. Selective Aryl Hydrocarbon Receptor Modulator 3,3'-Diindolylmethane Impairs AhR and ARNT Signaling and Protects Mouse Neuronal Cells Against Hypoxia.

    PubMed

    Rzemieniec, J; Litwa, E; Wnuk, A; Lason, W; Krzeptowski, W; Kajta, M

    2016-10-01

    The neuroprotective potential of 3,3'-diindolylmethane (DIM), which is a selective aryl hydrocarbon receptor modulator, has recently been shown in cellular and animal models of Parkinson's disease and lipopolysaccharide-induced inflammation. However, there are no data concerning the protective capacity and mechanisms of DIM action in neuronal cells exposed to hypoxia. The aim of the present study was to investigate the neuroprotective potential of DIM against the hypoxia-induced damage in mouse hippocampal cells in primary cultures, with a particular focus on DIM interactions with the aryl hydrocarbon receptor (AhR), its nuclear translocator ARNT, and estrogen receptor β (ERβ). In the present study, 18 h of hypoxia induced apoptotic processes, in terms of the mitochondrial membrane potential, activation of caspase-3, and fragmentation of cell nuclei. These effects were accompanied by substantial lactate dehydrogenase release and neuronal cell death. The results of the present study demonstrated strong neuroprotective and anti-apoptotic actions of DIM in hippocampal cells exposed to hypoxia. In addition, DIM decreased the Ahr and Arnt mRNA expression and stimulated Erβ mRNA expression level. DIM-induced mRNA alterations were mirrored by changes in protein levels, except for ERβ, as detected by ELISA, Western blotting, and immunofluorescence labeling. We also demonstrated that DIM decreased the expression of AhR-regulated CYP1A1. Using specific siRNAs, we provided evidence that impairment of AhR and ARNT, but not ERβ plays a key role in the neuroprotective action of DIM against hypoxia-induced cell damage. This study may have implication for identifying new agents that could protect neurons against hypoxia by targeting AhR/ARNT signaling. PMID:26476840

  15. New CYP1 genes in the frog Xenopus (Silurana) tropicalis: Induction patterns and effects of AHR agonists during development

    SciTech Connect

    Joensson, Maria E.; Berg, Cecilia; Goldstone, Jared V.; Stegeman, John J.

    2011-01-15

    The Xenopus tropicalis genome shows a single gene in each of the four cytochrome P450 1 (CYP1) subfamilies that occur in vertebrates, designated as CYP1A, CYP1B1, CYP1C1, and CYP1D1. We cloned the cDNAs of these genes and examined their expression in untreated tadpoles and in tadpoles exposed to waterborne aryl hydrocarbon receptor agonists, 3,3',4,4',5-pentachlorobiphenyl (PCB126), {beta}-naphthoflavone ({beta}NF), or indigo. We also examined the effects of PCB126 on expression of genes involved in stress response, cell proliferation, thyroid homeostasis, and prostaglandin synthesis. PCB126 induced CYP1A, CYP1B1, and CYP1C1 but had little effect on CYP1D1 (77-, 1.7-, 4.6- and 1.4-fold induction versus the control, respectively). {beta}NF induced CYP1A and CYP1C1 (26- and 2.5-fold), while, under conditions used, indigo tended to induce only CYP1A (1.9-fold). The extent of CYP1 induction by PCB126 and {beta}NF was positively correlated to the number of putative dioxin response elements 0-20 kb upstream of the start codons. No morphological effect was observed in tadpoles exposed to 1 nM-10 {mu}M PCB126 at two days post-fertilization (dpf) and screened 20 days later. However, in 14-dpf tadpoles a slight up-regulation of the genes for PCNA, transthyretin, HSC70, Cu-Zn SOD, and Cox-2 was observed two days after exposure to 1 {mu}M PCB126. This study of the full suite of CYP1 genes in an amphibian species reveals gene- and AHR agonist-specific differences in response, as well as a much lower sensitivity to CYP1 induction and short-term toxicity by PCB126 compared with in fish larvae. The single genes in each CYP1 subfamily may make X. tropicalis a useful model for mechanistic studies of CYP1 functions.

  16. ITE and TCDD differentially regulate the vascular remodeling of rat placenta via the activation of AhR.

    PubMed

    Wu, Yanming; Chen, Xiao; Zhou, Qian; He, Qizhi; Kang, Jiuhong; Zheng, Jing; Wang, Kai; Duan, Tao

    2014-01-01

    Vascular remodeling in the placenta is essential for normal fetal development. The previous studies have demonstrated that in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, an environmental toxicant) induces the intrauterine fetal death in many species via the activation of aryl hydrocarbon receptor (AhR). In the current study, we compared the effects of 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) and TCDD on the vascular remodeling of rat placentas. Pregnant rats on gestational day (GD) 15 were randomly assigned into 5 groups, and were exposed to a single dose of 1.6 and 8.0 mg/kg body weight (bw) ITE, 1.6 and 8.0 µg/kg bw TCDD, or an equivalent volume of the vehicle, respectively. The dams were sacrificed on GD20 and the placental tissues were gathered. The intrauterine fetal death was observed only in 8.0 µg/kg bw TCDD-exposed group and no significant difference was seen in either the placental weight or the fetal weight among all these groups. The immunohistochemical and histological analyses revealed that as compared with the vehicle-control, TCDD, but not ITE, suppressed the placental vascular remodeling, including reduced the ratio of the placental labyrinth zone to the basal zone thickness (at least 0.71 fold of control), inhibited the maternal sinusoids dilation and thickened the trophoblastic septa. However, no marked difference was observed in the density of fetal capillaries in the labyrinth zone among these groups, although significant differences were detected in the expression of angiogenic growth factors between ITE and TCDD-exposed groups, especially Angiopoietin-2 (Ang-2), Endoglin, Interferon-γ (IFN-γ) and placenta growth factor (PIGF). These results suggest ITE and TCDD differentially regulate the vascular remodeling of rat placentas, as well as the expression of angiogenic factors and their receptors, which in turn may alter the blood flow in the late gestation and partially resulted in

  17. Pim1 kinase protects airway epithelial cells from cigarette smoke-induced damage and airway inflammation.

    PubMed

    de Vries, M; Heijink, I H; Gras, R; den Boef, L E; Reinders-Luinge, M; Pouwels, S D; Hylkema, M N; van der Toorn, M; Brouwer, U; van Oosterhout, A J M; Nawijn, M C

    2014-08-01

    Exposure to cigarette smoke (CS) is the main risk factor for developing chronic obstructive pulmonary disease and can induce airway epithelial cell damage, innate immune responses, and airway inflammation. We hypothesized that cell survival factors might decrease the sensitivity of airway epithelial cells to CS-induced damage, thereby protecting the airways against inflammation upon CS exposure. Here, we tested whether Pim survival kinases could protect from CS-induced inflammation. We determined expression of Pim kinases in lung tissue, airway inflammation, and levels of keratinocyte-derived cytokine (KC) and several damage-associated molecular patterns in bronchoalveolar lavage in mice exposed to CS or air. Human bronchial epithelial BEAS-2B cells were treated with CS extract (CSE) in the presence or absence of Pim1 inhibitor and assessed for loss of mitochondrial membrane potential, induction of cell death, and release of heat shock protein 70 (HSP70). We observed increased expression of Pim1, but not of Pim2 and Pim3, in lung tissue after exposure to CS. Pim1-deficient mice displayed a strongly enhanced neutrophilic airway inflammation upon CS exposure compared with wild-type controls. Inhibition of Pim1 activity in BEAS-2B cells increased the loss of mitochondrial membrane potential and reduced cell viability upon CSE treatment, whereas release of HSP70 was enhanced. Interestingly, we observed release of S100A8 but not of double-strand DNA or HSP70 in Pim1-deficient mice compared with wild-type controls upon CS exposure. In conclusion, we show that expression of Pim1 protects against CS-induced cell death in vitro and neutrophilic airway inflammation in vivo. Our data suggest that the underlying mechanism involves CS-induced release of S100A8 and KC. PMID:24816488

  18. Genetic association of aromatic hydrocarbon receptor (AHR) and cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) polymorphisms with dioxin blood concentrations among pregnant Japanese women.

    PubMed

    Kobayashi, Sumitaka; Sata, Fumihiro; Sasaki, Seiko; Ban, Susumu; Miyashita, Chihiro; Okada, Emiko; Limpar, Mariko; Yoshioka, Eiji; Kajiwara, Jumboku; Todaka, Takashi; Saijo, Yasuaki; Kishi, Reiko

    2013-06-01

    Dioxins are metabolized by cytochrome P450, family 1 (CYP1) via the aromatic hydrocarbon receptor (AHR). We determined whether different blood dioxin concentrations are associated with polymorphisms in AHR (dbSNP ID: rs2066853), AHR repressor (AHRR; rs2292596), CYP1 subfamily A polypeptide 1 (CYP1A1; rs4646903 and rs1048963), CYP1 subfamily A polypeptide 2 (CYP1A2; rs762551), and CYP1 subfamily B polypeptide 1 (CYP1B1; rs1056836) in pregnant Japanese women. These six polymorphisms were detected in 421 healthy pregnant Japanese women. Differences in dioxin exposure concentrations in maternal blood among the genotypes were investigated. Comparisons among the GG, GA, and AA genotypes of AHR showed a significant difference (genotype model: P=0.016 for the mono-ortho polychlorinated biphenyl concentrations and toxicity equivalence quantities [TEQs]). Second, we found a significant association with the dominant genotype model ([TT+TC] vs. CC: P=0.048 for the polychlorinated dibenzo-p-dioxin TEQs; P=0.035 for polychlorinated dibenzofuran TEQs) of CYP1A1 (rs4646903). No significant differences were found among blood dioxin concentrations and polymorphisms in AHRR, CYP1A1 (rs1048963), CYP1A2, and CYP1B1. Thus, polymorphisms in AHR and CYP1A1 (rs4646903) were associated with maternal dioxin concentrations. However, differences in blood dioxin concentrations were relatively low. PMID:23528250

  19. Airway acidification initiates host defense abnormalities in cystic fibrosis mice

    PubMed Central

    Shah, Viral S.; Meyerholz, David K.; Tang, Xiao Xiao; Reznikov, Leah; Alaiwa, Mahmoud Abou; Ernst, Sarah E.; Karp, Philip H.; Wohlford-Lenane, Christine L.; Heilmann, Kristopher P.; Leidinger, Mariah R.; Allen, Patrick D.; Zabner, Joseph; McCray, Paul B.; Ostedgaard, Lynda S.; Stoltz, David A.; Randak, Christoph O.; Welsh, Michael J.

    2016-01-01

    Cystic fibrosis (CF) is caused by mutations in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. In humans and pigs, the loss of CFTR impairs respiratory host defenses, causing airway infection. But CF mice are spared. We found that in all three species, CFTR secreted bicarbonate into airway surface liquid. In humans and pigs lacking CFTR, unchecked H+ secretion by the nongastric H+/K+ adenosine triphosphatase (ATP12A) acidified airway surface liquid, which impaired airway host defenses. In contrast, mouse airways expressed little ATP12A and secreted minimal H+; consequently, airway surface liquid in CF and non-CF mice had similar pH. Inhibiting ATP12A reversed host defense abnormalities in human and pig airways. Conversely, expressing ATP12A in CF mouse airways acidified airway surface liquid, impaired defenses, and increased airway bacteria. These findings help explain why CF mice are protected from infection and nominate ATP12A as a potential therapeutic target for CF. PMID:26823428

  20. [The detection of biphasic reactivity of the airway by astograph].

    PubMed

    Ohe, Masashi; Kishi, Fujiya; Hizawa, Nobuyuki

    2010-03-01

    Dose-related curves of the airway responses to Methacholine by Astograph are frequently biphasic. That is, respiratory resistance (Rrs) increases slowly at first and rapidly after that. We proposed (-dGrs/dt)/Grs obtained by using Astograph as an index of dynamic property of the airway, which we suggested was related to a coefficient of the contraction or dilatation of the airway. Grs represents respiratory conductance. By calculating (-dGrs/dt)/Grs, we found that biphasic dose-related curves were composed of the slow and subsequently rapid contraction of the airways. And by mathematical analysis, we found that all segments of the airway contracted simultaneously at a uniform velocity. The combination of slow and rapid contraction explains three types of the airway responses, that is, the monophasic reactivity of the airway with slow contraction, the monophasic reactivity of the airway with rapid contraction and the biphasic reactivity of the airway with slow and subsequently rapid contraction. We found that the frequency of the monophasic reactivity of the airway with slow contraction was significantly higher in patients with COPD than in healthy subjects or in patients with mild asthma. But there was no significant difference in (-dGrs/dt)/Grs values among healthy subjects, patients with mild asthma and patients with COPD.

  1. 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

  2. Dynamics of Surfactant Liquid Plugs at Bifurcating Lung Airway Models

    NASA Astrophysics Data System (ADS)

    Tavana, Hossein

    2013-11-01

    A surfactant liquid plug forms in the trachea during surfactant replacement therapy (SRT) of premature babies. Under air pressure, the plug propagates downstream and continuously divides into smaller daughter plugs at continuously branching lung airways. Propagating plugs deposit a thin film on airway walls to reduce surface tension and facilitate breathing. The effectiveness of SRT greatly depends on the final distribution of instilled surfactant within airways. To understand this process, we investigate dynamics of splitting of surfactant plugs in engineered bifurcating airway models. A liquid plug is instilled in the parent tube to propagate and split at the bifurcation. A split ratio, R, is defined as the ratio of daughter plug lengths in the top and bottom daughter airway tubes and studied as a function of the 3D orientation of airways and different flow conditions. For a given Capillary number (Ca), orienting airways farther away from a horizontal position reduced R due to the flow of a larger volume into the gravitationally favored daughter airway. At each orientation, R increased with 0.0005 < Ca < 0.05. This effect diminished by decrease in airways diameter. This approach will help elucidate surfactant distribution in airways and develop effective SRT strategies.

  3. Small airways function of silica-exposed workers.

    PubMed

    Chia, K S; Ng, T P; Jeyaratnam, J

    1992-01-01

    Small airways obstruction may be present for many years before chronic airway obstruction becomes evident. Several spirometric indices, especially flow rates at low lung volumes, may reflect the status of small airways. Time domain indices, by using moments analysis of the volume time spirogram, have also been shown to be sensitive indicators of small airways obstruction. In this study, we have applied the various spirometric indices as well as time domain indices to a group of granite quarry workers without radiographic evidence of silicosis or physiological evidence of obstruction to the larger airways. The aim was to evaluate small airways function in relation to dust exposure in subjects with normal ratio of the forced expiratory volume in one second to the forced vital capacity (FEV1/FVC) and normal FVC. The volume-time spirograms of 140 quarry workers were digitized using an electronic digitizer connected to a microcomputer where flow and time domain indices were computed. The workers were divided into three exposure groups based on their occupational history. With adjustment for age, height, and smoking status, all the time domain indices showed significant small airways obstruction with increasing dust exposure. Smokers had greater degree of airways obstruction than the non-smokers, with a similar trend of increase in small airways obstruction in relation to higher exposure. Our present study suggests that small airways obstruction is present among silica exposed workers in the absence of radiological evidence of silicosis and large airways obstruction. There was also evidence of increasing small airways obstruction in higher dust exposure group. Our study also suggests that time domain indices are more sensitive to small airways obstruction.

  4. Elimination of Aspergillus fumigatus conidia from the airways of mice with allergic airway inflammation

    PubMed Central

    2013-01-01

    Background Aspergillus fumigatus conidia can exacerbate asthma symptoms. Phagocytosis of conidia is a principal component of the host antifungal defense. We investigated whether allergic airway inflammation (AAI) affects the ability of phagocytic cells in the airways to internalize the resting fungal spores. Methods Using BALB/c mice with experimentally induced AAI, we tested the ability of neutrophils, macrophages, and dendritic cells to internalize A. fumigatus conidia at various anatomical locations. We used light microscopy and differential cell and conidium counts to determine the ingestion potential of neutrophils and macrophages present in bronchoalveolar lavage (BAL). To identify phagocyte-conidia interactions in conducting airways, conidia labeled with tetramethylrhodamine-(5-(and-6))-isothiocyanate were administered to the oropharyngeal cavity of mice. Confocal microscopy was used to quantify the ingestion potential of Ly-6G+ neutrophils and MHC II+ antigen-presenting cells located in the intraepithelial and subepithelial areas of conducting airways. Results Allergen challenge induced transient neutrophil recruitment to the airways. Application of A. fumigatus conidia at the acute phase of AAI provoked recurrent neutrophil infiltration, and consequently increased the number and the ingestion potential of the airway neutrophils. In the absence of recurrent allergen or conidia provocation, both the ingestion potential and the number of BAL neutrophils decreased. As a result, conidia were primarily internalized by alveolar macrophages in both AAI and control mice at 24 hours post-inhalation. Transient influx of neutrophils to conducting airways shortly after conidial application was observed in mice with AAI. In addition, the ingestion potential of conducting airway neutrophils in mice with induced asthma exceeded that of control mice. Although the number of neutrophils subsequently decreased, the ingestion capacity remained elevated in AAI mice, even at 24

  5. Do Airway Epithelium Air–Liquid Cultures Represent the In Vivo Airway Epithelium Transcriptome?

    PubMed Central

    Dvorak, Anna; Tilley, Ann E.; Shaykhiev, Renat; Wang, Rui; Crystal, Ronald G.

    2011-01-01

    Human airway epithelial cells cultured in vitro at the air–liquid interface (ALI) form a pseudostratified epithelium that forms tight junctions and cilia, and produces mucin. These cells are widely used in models of differentiation, injury, and repair. To assess how closely the transcriptome of ALI epithelium matches that of in vivo airway epithelial cells, we used microarrays to compare the transcriptome of human large airway epithelial cells cultured at the ALI with the transcriptome of large airway epithelium obtained via bronchoscopy and brushing. Gene expression profiling showed that global gene expression correlated well between ALI cells and brushed cells, but with some differences. Gene expression patterns mirrored differences in proportions of cell types (ALIs have higher percentages of basal cells, whereas brushed cells have higher percentages of ciliated cells), that is, ALI cells expressed higher levels of basal cell–related genes, and brushed cells expressed higher levels of cilia-related genes. Pathway analysis showed that ALI cells had increased expression of cell cycle and proliferation genes, whereas brushed cells had increased expression of cytoskeletal organization and humoral immune response genes. Overall, ALI cells provide a good representation of the in vivo airway epithelial transcriptome, but for some biologic questions, the differences between in vitro and in vivo environments need to be considered. PMID:20525805

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

    PubMed

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

    2015-01-01

    Over the past two decades, a plethora of new airway devices has become available to the pediatric anesthetist. While all have the laudable intention of improving patient care and some have proven clinical benefits, these devices are often costly and at times claims of an advantage over current equipment and techniques are marginal. Supraglottic airway devices are used in the majority of pediatric anesthetics delivered in the U.K., and airway-viewing devices provide an alternative for routine intubation as well as an option in the management of the difficult airway. Yet hidden beneath the convenience of the former and the technology of the latter, the impact on basic airway skills with a facemask and the lack of opportunities to fine-tune the core skill of intubation represent an unrecognised and unquantifiable cost. A judgement on this value must be factored into the absolute purchase cost and any potential benefits to the quality of patient care, thus blurring any judgement on cost-effectiveness that we might have. An overall value on cost-effectiveness though not in strict monetary terms can then be ascribed. In this review, we evaluate the role of these devices in the care of the pediatric patient and attempt to balance the advantages they offer against the cost they incur, both financial and environmental, and in any quality improvement they might offer in clinical care. PMID:25370686

  7. Silencing Nociceptor Neurons Reduces Allergic Airway Inflammation.

    PubMed

    Talbot, Sébastien; Abdulnour, Raja-Elie E; Burkett, Patrick R; Lee, Seungkyu; Cronin, Shane J F; Pascal, Maud A; Laedermann, Cedric; Foster, Simmie L; Tran, Johnathan V; Lai, Nicole; Chiu, Isaac M; Ghasemlou, Nader; DiBiase, Matthew; Roberson, David; Von Hehn, Christian; Agac, Busranour; Haworth, Oliver; Seki, Hiroyuki; Penninger, Josef M; Kuchroo, Vijay K; Bean, Bruce P; Levy, Bruce D; Woolf, Clifford J

    2015-07-15

    Lung nociceptors initiate cough and bronchoconstriction. To elucidate if these fibers also contribute to allergic airway inflammation, we stimulated lung nociceptors with capsaicin and observed increased neuropeptide release and immune cell infiltration. In contrast, ablating Nav1.8(+) sensory neurons or silencing them with QX-314, a charged sodium channel inhibitor that enters via large-pore ion channels to specifically block nociceptors, substantially reduced ovalbumin- or house-dust-mite-induced airway inflammation and bronchial hyperresponsiveness. We also discovered that IL-5, a cytokine produced by activated immune cells, acts directly on nociceptors to induce the release of vasoactive intestinal peptide (VIP). VIP then stimulates CD4(+) and resident innate lymphoid type 2 cells, creating an inflammatory signaling loop that promotes allergic inflammation. Our results indicate that nociceptors amplify pathological adaptive immune responses and that silencing these neurons with QX-314 interrupts this neuro-immune interplay, revealing a potential new therapeutic strategy for asthma. PMID:26119026

  8. Mechanically patterning the embryonic airway epithelium

    PubMed Central

    Varner, Victor D.; Gleghorn, Jason P.; Miller, Erin; Radisky, Derek C.; Nelson, Celeste M.

    2015-01-01

    Collections of cells must be patterned spatially during embryonic development to generate the intricate architectures of mature tissues. In several cases, including the formation of the branched airways of the lung, reciprocal signaling between an epithelium and its surrounding mesenchyme helps generate these spatial patterns. Several molecular signals are thought to interact via reaction-diffusion kinetics to create distinct biochemical patterns, which act as molecular precursors to actual, physical patterns of biological structure and function. Here, however, we show that purely physical mechanisms can drive spatial patterning within embryonic epithelia. Specifically, we find that a growth-induced physical instability defines the relative locations of branches within the developing murine airway epithelium in the absence of mesenchyme. The dominant wavelength of this instability determines the branching pattern and is controlled by epithelial growth rates. These data suggest that physical mechanisms can create the biological patterns that underlie tissue morphogenesis in the embryo. PMID:26170292

  9. Silencing nociceptor neurons reduces allergic airway inflammation

    PubMed Central

    Talbot, Sébastien; Abdulnour, Raja-Elie E.; Burkett, Patrick R.; Lee, Seungkyu; Cronin, Shane J.F.; Pascal, Maud A.; Laedermann, Cedric; Foster, Simmie L.; Tran, Johnathan V.; Lai, Nicole; Chiu, Isaac M.; Ghasemlou, Nader; DiBiase, Matthew; Roberson, David; Von Hehn, Christian; Agac, Busranour; Haworth, Oliver; Seki, Hiroyuki; Penninger, Josef M.; Kuchroo, Vijay K.; Bean, Bruce P.; Levy, Bruce D.; Woolf, Clifford J.

    2015-01-01

    Summary Lung nociceptors initiate cough and bronchoconstriction. To elucidate if these fibers also contribute to allergic airway inflammation we stimulated lung nociceptors with capsaicin and observed increased neuropeptide release and immune cell infiltration. In contrast, ablating Nav1.8+ sensory neurons or silencing them with QX-314, a charged sodium channel inhibitor that enters via large pore ion channels to specifically block nociceptors, substantially reduced ovalbumin or house dust mite-induced airway inflammation and bronchial hyperresponsiveness. We also discovered that IL-5, a cytokine produced by activated immune cells, acts directly on nociceptors to induce release of vasoactive intestinal peptide (VIP). VIP then stimulates CD4+ and resident innate lymphoid type 2 cells, creating an inflammatory signaling loop that promotes allergic inflammation. Our results indicate that nociceptors amplify pathological adaptive immune responses and that silencing these neurons with QX-314 interrupts this neuro-immune interplay, revealing a potential new therapeutic strategy for asthma. PMID:26119026

  10. Tachykinin receptors mediating airway marcomolecular secretion

    SciTech Connect

    Gentry, S.E. )

    1991-01-01

    Three tachykinin receptor types, termed NK1, NK2, and NK3, can be distinguished by the relative potency of various peptides in eliciting tissue responses. Airway macromolecular secretion is stimulated by the tachykinin substance P (SP). The purposes of this study were to determine the tachykinin receptor subtype responsible for this stimulation, and to examine the possible involvement of other neurotransmitters in mediating this effect. Ferret tracheal explants maintained in organ culture were labeled with {sup 3}H-glucosamine, a precursor of high molecular weight glycoconjugates (HMWG) which are released by airway secretory cells. Secretion of labeled HMWG then was determined in the absence and presence of the tachykinins SP, neurokinin A (NKA), neurokinin B (NKB), physalaemin (PHY), and eledoisin (ELE). To evaluate the possible contribution of other mediators, tachykinin stimulation was examined in the presence of several receptor blockers.

  11. 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.

  12. Pleomorphic adenoma causing acute airway obstruction.

    PubMed

    Moraitis, D; Papakostas, K; Karkanevatos, A; Coast, G J; Jackson, S R

    2000-08-01

    A case is reported of a pleomorphic adenoma of the minor salivary glands of the oral cavity presenting with acute airway obstruction. This is the first reported case to our knowledge of a mixed salivary tumour of the upper respiratory tract causing upper airway obstruction and acute respiratory failure. The patient had to be intubated and transferred to the intensive care unit. After an elective tracheostomy was performed, the adenoma was excised from its fibrous capsule. It was found to originate from the soft palate and occupied the parapharyngeal space. A high index of suspicion should be kept in order to diagnose tumours of the parapharyngeal space with unusual presentation. These tumours which are usually benign should be considered in the differential diagnosis from more common infectious or traumatic conditions and surgical morbidity should be minimal.

  13. Airway hyperreactivity elicited by toluene diisocyanate (TDI)-albumin conjugate is not accompanied by airway eosinophilic infiltration in guinea pigs.

    PubMed

    Huang, J; Millecchia, L L; Frazer, D G; Fedan, J S

    1998-02-01

    Nonspecific airway hyperresponsiveness is present in many patients with toluene diisocyanate (TDI)-induced asthma; however, the underlying pathophysiological mechanisms of this hyperresponsiveness remain controversial. In the present study, we used a guinea pig model to investigate the association of TDI-induced airway hyperresponsiveness with eosinophilic airway infiltration, which is widely considered to play a key role in the development of allergen-induced hyperresponsiveness. Guinea pigs were sensitized by i.d. injections of 10 microl TDI on day 1 and day 6. Control animals received saline injections. Two weeks after the second injection, airway reactivity to inhaled methacholine and specific airway resistance (sRaw) was measured before and at several times after inhalation challenge with TDI-GSA (guinea pig serum albumin) conjugates. Eosinophils in the airways were detected using enzyme histochemistry and quantified using computer-assisted image analysis. TDI-specific IgG1 antibodies were found in the blood of TDI-sensitized animals. An immediate increase in sRaw was induced in these animals by TDI-GSA challenge; airway hyperresponsiveness to methacholine was observed at 6 h and 18 h after TDI-GSA challenge. However, TDI-GSA challenge did not result in an elevation of eosinophils in the airways, compared with control animals. The results suggest that the development of TDI-induced airway hyperresponsiveness is not dependent upon eosinophil infiltration in airways. PMID:9520137

  14. Exercise and airway injury in athletes.

    PubMed

    Couto, Mariana; Silva, Diana; Delgado, Luis; Moreira, André

    2013-01-01

    Olympic level athletes present an increased risk for asthma and allergy, especially those who take part in endurance sports, such as swimming or running, and in winter sports. Classical postulated mechanisms behind EIA include the osmotic, or airway-drying, hypothesis. Hyperventilation leads to evaporation of water and the airway surface liquid becomes hyperosmolar, providing a stimulus for water to move from any cell nearby, which results in the shrinkage of cells and the consequent release of inflammatory mediators that cause airway smooth muscle contraction. But the exercise-induced asthma/bronchoconstriction explanatory model in athletes probably comprises the interaction between environmental training factors, including allergens and ambient conditions such as temperature, humidity and air quality; and athlete's personal risk factors, such as genetic and neuroimmuneendocrine determinants. After the stress of training and competitions athletes experience higher rate of upper respiratory tract infections (URTI), compared with lesser active individuals. Increasing physical activity in non-athletes is associated with a decreased risk of URTI. Heavy exercise induces marked immunodepression which is multifactorial in origin. Prolonged, high intensity exercise temporarily impairs the immune competence while moderate activity may enhance immune function. The relationship between URTI and exercise is affected by poorly known individual determinants such genetic susceptibility, neurogenic mediated immune inflammation and epithelial barrier dysfunction. Further studies should better define the aetiologic factors and mechanisms involved in the development of asthma in athletes, and propose relevant preventive and therapeutic measures.

  15. Voxel classification based airway tree segmentation

    NASA Astrophysics Data System (ADS)

    Lo, Pechin; de Bruijne, Marleen

    2008-03-01

    This paper presents a voxel classification based method for segmenting the human airway tree in volumetric computed tomography (CT) images. In contrast to standard methods that use only voxel intensities, our method uses a more complex appearance model based on a set of local image appearance features and Kth nearest neighbor (KNN) classification. The optimal set of features for classification is selected automatically from a large set of features describing the local image structure at several scales. The use of multiple features enables the appearance model to differentiate between airway tree voxels and other voxels of similar intensities in the lung, thus making the segmentation robust to pathologies such as emphysema. The classifier is trained on imperfect segmentations that can easily be obtained using region growing with a manual threshold selection. Experiments show that the proposed method results in a more robust segmentation that can grow into the smaller airway branches without leaking into emphysematous areas, and is able to segment many branches that are not present in the training set.

  16. Spontaneous intrathyroidal hematoma causing airway obstruction

    PubMed Central

    Best, Corliss A.E.; Dhaliwal, Sandeep; Tam, Samantha; Low, T. Hubert; Hughes, Brian; Fung, Kevin; MacNeil, S. Danielle

    2016-01-01

    Abstract Introduction: Spontaneous thyroid hemorrhage is a rare occurrence that results in pain, discomfort, and occasionally compressive symptoms. Infrequently, extensive thyroid hemorrhage can result in a rapidly expanding hematoma resulting in airway compromise. This is a case of an otherwise healthy young woman, 3 months postpartum, with a slowly expanding spontaneous thyroid hemorrhage that measured at 7 × 5.5 × 5 cm by computed tomography. She ultimately required intubation to manage respiratory distress and subsequently a hemithyroidectomy for definitive treatment. The case presentation is followed by a literature review where known etiologies of thyroid hematoma including traumatic and nontraumatic causes, precipitating anticoagulation, and spontaneous rupture of branches of the external carotid artery are outlined. The potential links to pregnancy are explored. The roles of bedside thyroid ultrasound in the emergency department and lateral neck roentgenogram in diagnosis are explored. The importance of airway management and indications for conservative versus surgical treatments are discussed. Conclusions: This is a case of a spontaneous intrathyroidal hemorrhage, which progressed over days to ultimately cause airway compromise. It is imperative that physicians are educated on the appropriate detection and management of the potentially life-threatening spontaneous thyroid hematoma. PMID:27583841

  17. The buffer capacity of airway epithelial secretions

    PubMed Central

    Kim, Dusik; Liao, Jie; Hanrahan, John W.

    2014-01-01

    The pH of airway epithelial secretions influences bacterial killing and mucus properties and is reduced by acidic pollutants, gastric reflux, and respiratory diseases such as cystic fibrosis (CF). The effect of acute acid loads depends on buffer capacity, however the buffering of airway secretions has not been well characterized. In this work we develop a method for titrating micro-scale (30 μl) volumes and use it to study fluid secreted by the human airway epithelial cell line Calu-3, a widely used model for submucosal gland serous cells. Microtitration curves revealed that HCO−3 is the major buffer. Peak buffer capacity (β) increased from 17 to 28 mM/pH during forskolin stimulation, and was reduced by >50% in fluid secreted by cystic fibrosis transmembrane conductance regulator (CFTR)-deficient Calu-3 monolayers, confirming an important role of CFTR in HCO−3 secretion. Back-titration with NaOH revealed non-volatile buffer capacity due to proteins synthesized and released by the epithelial cells. Lysozyme and mucin concentrations were too low to buffer Calu-3 fluid significantly, however model titrations of porcine gastric mucins at concentrations near the sol-gel transition suggest that mucins may contribute to the buffer capacity of ASL in vivo. We conclude that CFTR-dependent HCO−3 secretion and epithelially-derived proteins are the predominant buffers in Calu-3 secretions. PMID:24917822

  18. The laryngeal mask airway in obstetrical anaesthesia.

    PubMed

    Gataure, P S; Hughes, J A

    1995-02-01

    The laryngeal mask airway (LMA) has been used extensively to provide a safe airway in spontaneously breathing patients who are not at risk from aspiration of gastric contents. The role of the LMA in the event of a failed intubation in an obstetrical patient, and its place in a failed intubation drill remains unclear. Two hundred and fifty consultant obstetric anaesthetists in the United Kingdom were asked to complete an anonymous questionnaire regarding their views about using the laryngeal mask airway (LMA) in obstetrical anaesthesia. The LMA was available in 91.4% of obstetric units. Seventy-two per cent of anaesthetists were in favour of using the LMA to maintain oxygenation when tracheal intubation had failed and ventilation using a face mask was inadequate. Twenty-four respondents had had personal experience with the LMA in obstetrical anaesthesia, eight of whom stated that the LMA had proved to be a lifesaver. We believe that the LMA has a role in obstetrical anaesthesia when tracheal intubation has failed and ventilation using a face mask proves to be impossible, and it should be inserted before attempting cricothyroidectomy. PMID:7720155

  19. Development of a realistic human airway model.

    PubMed

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

    2012-03-01

    Numerous models of human lungs with various levels of idealization have been reported in the literature; consequently, results acquired using these models are difficult to compare to in vivo measurements. We have developed a set of model components based on realistic geometries, which permits the analysis of the effects of subsequent model simplification. A realistic digital upper airway geometry except for the lack of an oral cavity has been created which proved suitable both for computational fluid dynamics (CFD) simulations and for the fabrication of physical models. Subsequently, an oral cavity was added to the tracheobronchial geometry. The airway geometry including the oral cavity was adjusted to enable fabrication of a semi-realistic model. Five physical models were created based on these three digital geometries. Two optically transparent models, one with and one without the oral cavity, were constructed for flow velocity measurements, two realistic segmented models, one with and one without the oral cavity, were constructed for particle deposition measurements, and a semi-realistic model with glass cylindrical airways was developed for optical measurements of flow velocity and in situ particle size measurements. One-dimensional phase doppler anemometry measurements were made and compared to the CFD calculations for this model and good agreement was obtained. PMID:22558834

  20. Surgery of the airway: historic notes.

    PubMed

    Cooper, Joel D

    2016-03-01

    Prior to the 20(th) century, the need for surgical procedures on the airway was infrequent and consisted mainly of tracheostomy to relieve airway obstruction or repair of tracheal injuries such as lacerations. Even the ability of tracheal suture lines to heal primarily was viewed with concern due to the rigidity of the tracheal wall, its precarious blood supply and uncertainty as to whether the cartilage components could heal without complications. In the 20(th) century the evolution of tracheal procedures on major airways evolved to meet the challenges provided by the expanding fields of thoracic surgery and advent of mechanical respiratory support with its associated complications. In the first half of the century lobar and lung resections done for tuberculosis and lung cancer required methods for safe closure of the resulting bronchial stumps and end-to-end bronchial anastomosis in the case of sleeve resections of the lung. Beginning in mid-century the advent of respiratory care units for the treatment of polio and for the expanding fields of thoracic and cardiac surgery resulted in a significant number of post-intubation tracheal stenosis requiring resection and primary repair. In the last 20 years of the century the development of lung transplantation with its requirement for successful bronchial anastomoses between the donor and recipient bronchi, created unique challenges including ischemia of the donor bronchus the adverse effects of immunosuppression, donor lung preservation and diagnosis and management of post-transplant infection and rejection.

  1. Surgery of the airway: historic notes

    PubMed Central

    2016-01-01

    Prior to the 20th century, the need for surgical procedures on the airway was infrequent and consisted mainly of tracheostomy to relieve airway obstruction or repair of tracheal injuries such as lacerations. Even the ability of tracheal suture lines to heal primarily was viewed with concern due to the rigidity of the tracheal wall, its precarious blood supply and uncertainty as to whether the cartilage components could heal without complications. In the 20th century the evolution of tracheal procedures on major airways evolved to meet the challenges provided by the expanding fields of thoracic surgery and advent of mechanical respiratory support with its associated complications. In the first half of the century lobar and lung resections done for tuberculosis and lung cancer required methods for safe closure of the resulting bronchial stumps and end-to-end bronchial anastomosis in the case of sleeve resections of the lung. Beginning in mid-century the advent of respiratory care units for the treatment of polio and for the expanding fields of thoracic and cardiac surgery resulted in a significant number of post-intubation tracheal stenosis requiring resection and primary repair. In the last 20 years of the century the development of lung transplantation with its requirement for successful bronchial anastomoses between the donor and recipient bronchi, created unique challenges including ischemia of the donor bronchus the adverse effects of immunosuppression, donor lung preservation and diagnosis and management of post-transplant infection and rejection. PMID:26981261

  2. Lentiviral Vector Gene Transfer to Porcine Airways

    PubMed Central

    Sinn, Patrick L; Cooney, Ashley L; Oakland, Mayumi; Dylla, Douglas E; Wallen, Tanner J; Pezzulo, Alejandro A; Chang, Eugene H; McCray, Paul B

    2012-01-01

    In this study, we investigated lentiviral vector development and transduction efficiencies in well-differentiated primary cultures of pig airway epithelia (PAE) and wild-type pigs in vivo. We noted gene transfer efficiencies similar to that observed for human airway epithelia (HAE). Interestingly, feline immunodeficiency virus (FIV)-based vectors transduced immortalized pig cells as well as pig primary cells more efficiently than HIV-1–based vectors. PAE express TRIM5α, a well-characterized species-specific lentiviral restriction factor. We contrasted the restrictive properties of porcine TRIM5α against FIV- and HIV-based vectors using gain and loss of function approaches. We observed no effect on HIV-1 or FIV conferred transgene expression in response to porcine TRIM5α overexpression or knockdown. To evaluate the ability of GP64-FIV to transduce porcine airways in vivo, we delivered vector expressing mCherry to the tracheal lobe of the lung and the ethmoid sinus of 4-week-old pigs. One week later, epithelial cells expressing mCherry were readily detected. Our findings indicate that pseudotyped FIV vectors confer similar tropisms in porcine epithelia as observed in human HAE and provide further support for the selection of GP64 as an appropriate envelope pseudotype for future preclinical gene therapy studies in the porcine model of cystic fibrosis (CF). PMID:23187455

  3. Airway management of a difficult airway due to prolonged enlarged goiter using loco-sedative technique

    PubMed Central

    Srivastava, Divya; Dhiraaj, Sanjay

    2013-01-01

    Appropriate airway management is an essential part of anesthesiologist's role. Huge goiters can lead to distorted airway and difficulty in endotracheal intubation. In this report, we present a case of a 67-year-old woman with a huge toxic multinodular thyroid swelling, gradually increasing in size for last 20 years, where trachea was successfully intubated. She had a history of deferred surgery in June 2007 due to inability to intubate, despite 5-6 attempts using different laryngoscopes, bougie, and stylet. Patient was re-admitted in December 2011 for the surgery and was successfully intubated this time with help of fiberoptic intubation using loco-sedative technique. Patient was electively kept intubated postoperatively in view of chances of tracheomalacia due to prolonged large goiter. She was extubated successfully on post-op day 2 after demonstration of leak around trachea following tracheal tube cuff deflation. The different techniques of managing the difficult airway in these patients are discussed. PMID:23717240

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

    SciTech Connect

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

    2012-05-01

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

  5. Influence of sleep on response to negative airway pressure of tensor palatini muscle and retropalatal airway.

    PubMed

    Wheatley, J R; Tangel, D J; Mezzanotte, W S; White, D P

    1993-11-01

    Increased retropalatal airway resistance may be caused by a sleep-induced loss of palatal muscle activity and a diminished ability of these muscles to respond to the increasing intrapharyngeal negative pressure that develops during sleep. To investigate these possibilities, in six normal subjects, we determined the effect of non-rapid-eye-movement sleep on 1) the tensor palatini (TP) electromyogram (EMG) response to rapid-onset negative-pressure generations (NPG) in the upper airway and 2) the collapsibility of the retropalatal airway during these NPGs. During wakefulness, the change in TP EMG from basal to peak levels (during NPG) was 19.8 +/- 3.2 arbitrary units (P < 0.005). This was markedly reduced during sleep (3.6 +/- 1.5 arbitrary units; P < 0.001). The latency of the TP EMG response was 48.5 +/- 5.6 ms during wakefulness but was prolonged during sleep (105.0 +/- 12.2 ms; P < 0.02). The peak transpalatal pressure during NPG (a measure of airway collapse) was 2.1 +/- 0.7 cmH2O during wakefulness and increased to 5.3 +/- 0.8 cmH2O during sleep (P < 0.05). We conclude that the brisk reflex response of the TP muscle to negative pressure during wakefulness is markedly reduced during non-rapid-eye-movement sleep, in association with a more collapsible retropalatal airway. We speculate that the reduction in this TP reflex response contributes to retropalatal airway narrowing during sleep in normal subjects.

  6. Air-Q intubating laryngeal airway: A study of the second generation supraglottic airway device

    PubMed Central

    Attarde, Viren Bhaskar; Kotekar, Nalini; Shetty, Sarika M

    2016-01-01

    Background and Aims: Air-Q intubating laryngeal mask airway (ILA) is used as a supraglottic airway device and as a conduit for endotracheal intubation. This study aims to assess the efficacy of the Air-Q ILA regarding ease of insertion, adequacy of ventilation, rate of successful intubation, haemodynamic response and airway morbidity. Methods: Sixty patients presenting for elective surgery at our Medical College Hospital were selected. Following adequate premedication, baseline vital parameters, pulse rate and blood pressure were recorded. Air-Q size 3.5 for patients 50-70 kg and size 4.5 for 70-100 kg was selected. After achieving adequate intubating conditions, Air-Q ILA was introduced. Confirming adequate ventilation, appropriate sized endotracheal tube was advanced through the Air-Q blindly to intubate the trachea. Placement of the endotracheal tube in trachea was confirmed. Results: Air-Q ILA was successfully inserted in 88.3% of patients in first attempt and 11.7% patients in second attempt. Ventilation was adequate in 100% of patients. Intubation was successful in 76.7% of patients with Air-Q ILA. 23.3% of patients were intubated by direct laryngoscopy following failure with two attempts using Air-Q ILA. Post-intubation the change in heart rate was statistically significant (P < 0.0001). 10% of patients were noted to have a sore throat and 5% of patients had mild airway trauma. Conclusion: Air-Q ILA is a reliable device as a supraglottic airway ensuring adequate ventilation as well as a conduit for endotracheal intubation. It benefits the patient by avoiding the stress of direct laryngoscopy and is also superior alternative device for use in a difficult airway. PMID:27212722

  7. Difficult Airway Management in Field Conditions: Somalia Experience.

    PubMed

    Özkan, Ahmet Selim; Nasır, Serdar Nazif

    2015-10-01

    Difficult airway is defined as having the patient's mask ventilation or difficult tracheal intubation of an experienced anaesthesiologist. A number of reasons, such as congenital or acquired anatomical anomalies, can cause difficult intubation and difficult ventilation. Keeping all equipment ready for airway management of patients will reduce mortality and complications. In this case, it is intended that the submission of difficult airway management who encountered in mandibular reconstruction for mandible bone defect repairing with reconstruction plates before at the field conditions in Somalia.

  8. 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

  9. Genome-wide RNAi high-throughput screen identifies proteins necessary for the AHR-dependent induction of CYP1A1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin.

    PubMed

    Solaimani, Parrisa; Damoiseaux, Robert; Hankinson, Oliver

    2013-11-01

    The aryl hydrocarbon receptor (AHR) has a plethora of physiological roles, and upon dysregulation, carcinogenesis can occur. One target gene of AHR encodes the xenobiotic and drug-metabolizing enzyme CYP1A1, which is inducible by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) via the AHR. An siRNA library targeted against over 5600 gene candidates in the druggable genome was used to transfect mouse Hepa-1 cells, which were then treated with TCDD, and subsequently assayed for CYP1A1-dependent ethoxyresorufin-o-deethylase (EROD) activity. Following redundant siRNA activity (RSA) statistical analysis, we identified 93 hits that reduced EROD activity with a p value ≤ .005 and substantiated 39 of these as positive hits in a secondary screening using endoribonuclease-prepared siRNAs (esiRNAs). Twelve of the corresponding gene products were subsequently confirmed to be necessary for the induction of CYP1A1 messenger RNA by TCDD. None of the candidates were deficient in aryl hydrocarbon nuclear translocator expression. However 6 gene products including UBE2i, RAB40C, CRYGD, DCTN4, RBM5, and RAD50 are required for the expression of AHR as well as for induction of CYP1A1. We also found 2 gene products, ARMC8 and TCF20, to be required for the induction of CYP1A1, but our data are ambiguous as to whether they are required for the expression of AHR. In contrast, SIN3A, PDC, TMEM5, and CD9 are not required for AHR expression but are required for the induction of CYP1A1, implicating a direct role in Cyp1a1 transcription. Our methods, although applied to Cyp1a1, could be modified for identifying proteins that regulate other inducible genes. PMID:23997114

  10. Genome-Wide RNAi High-Throughput Screen Identifies Proteins Necessary for the AHR-Dependent Induction of CYP1A1 by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

    PubMed Central

    Hankinson, Oliver

    2013-01-01

    The aryl hydrocarbon receptor (AHR) has a plethora of physiological roles, and upon dysregulation, carcinogenesis can occur. One target gene of AHR encodes the xenobiotic and drug-metabolizing enzyme CYP1A1, which is inducible by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) via the AHR. An siRNA library targeted against over 5600 gene candidates in the druggable genome was used to transfect mouse Hepa-1 cells, which were then treated with TCDD, and subsequently assayed for CYP1A1-dependent ethoxyresorufin-o-deethylase (EROD) activity. Following redundant siRNA activity (RSA) statistical analysis, we identified 93 hits that reduced EROD activity with a p value ≤ .005 and substantiated 39 of these as positive hits in a secondary screening using endoribonuclease-prepared siRNAs (esiRNAs). Twelve of the corresponding gene products were subsequently confirmed to be necessary for the induction of CYP1A1 messenger RNA by TCDD. None of the candidates were deficient in aryl hydrocarbon nuclear translocator expression. However 6 gene products including UBE2i, RAB40C, CRYGD, DCTN4, RBM5, and RAD50 are required for the expression of AHR as well as for induction of CYP1A1. We also found 2 gene products, ARMC8 and TCF20, to be required for the induction of CYP1A1, but our data are ambiguous as to whether they are required for the expression of AHR. In contrast, SIN3A, PDC, TMEM5, and CD9 are not required for AHR expression but are required for the induction of CYP1A1, implicating a direct role in Cyp1a1 transcription. Our methods, although applied to Cyp1a1, could be modified for identifying proteins that regulate other inducible genes. PMID:23997114

  11. Airway-parenchymal interdependence after airway contraction in rat lung explants.

    PubMed

    Adler, A; Cowley, E A; Bates, J H; Eidelman, D H

    1998-07-01

    The constriction of pulmonary airways is limited by the tethering effect exerted by parenchymal attachments. To characterize this tethering effect at the scale of intraparenchymal airways, we studied the pattern of parenchymal distortion due to bronchoconstriction in a rat lung explant system. First, we measured the elastic modulus under tension for 2% (wt/vol) agarose alone (37.6 +/- 1.5 kPa) and for agarose-filled lung (5.7 +/- 1.3 kPa). The latter is similar to the elastic modulus of air-filled lung at total lung capacity (4.5-6 kPa) (S. J. Lai-Fook, T. A. Wilson, R. E. Hyatt, and J. R. Rodarte. J. Appl. Physiol. 40: 508-513, 1976), suggesting that explants can be used as a model of lung tissue distortion. Subsequently, confocal microscopic images of fluorescently labeled 0.5-mm-thick explants prepared from agarose-filled rat lungs inflated to total lung capacity (48 ml/kg) were acquired. Images were taken before and after airway constriction was induced by direct application of 10 mM methacholine, and the pattern of parenchymal distortion was measured from the displacement of tissue landmarks identified in each image for 14 explants. The magnitude of the radial component of tissue displacement was calculated as a function of distance from the airway wall and characterized by a parameter, b, describing the rate at which tissue movement decreased with radial distance. The parameter b was 0.994 +/- 0.19 (SE), which is close to the prediction of b = 1 of micromechanical modeling (T. A. Wilson. J. Appl. Physiol. 33: 472-478, 1972). There was significant variability in b, however, which was correlated with the fractional reduction in airway diameter (r = 0.496). Additionally, parenchymal distortion showed significant torsion with respect to the radial direction. This torsion was similar in concentric zones around the airway, suggesting that it originates from inhomogeneity in the parenchyma rather than inhomogeneous airway constriction. Our results demonstrate the

  12. Practical advance in obtaining an emergency airway via cricothyroidotomy.

    PubMed

    Huber, William G; Dahman, Marc H; Thomas, Deanna; Lipschutz, Joshua H

    2007-05-01

    By the time a cricothyroidotomy is deemed necessary, the patient is in critical need of an emergency airway before anoxic damage ensues. Two things are necessary for the delivery of the requisite oxygen. First, an airway must be rapidly established. Second, the airway must be large enough to facilitate ventilation. Present methods for emergency cricothyroidotomy include needle cricothyroidotomy, which suffers from difficulties in both establishment and ventilation. We describe here a practical and widely available method for establishing a timely effective airway that has been used successfully for five patients since 1992.

  13. Airway management in patients with burn contractures of the neck.

    PubMed

    Prakash, Smita; Mullick, Parul

    2015-12-01

    Airway management of patients with burn contracture of the neck (PBC neck) is a challenge to the anesthesiologist. Patient evaluation includes history, physical and airway examination. A safe approach in the airway management of a patient with moderate to severe PBC neck is to secure the airway with the patient awake. The anesthesiologist should have a pre-planned strategy for intubation of the difficult airway. The choices advocated for airway management of such patients include awake fiberoptic-guided intubation, use of intubating laryngeal mask airway, intubation without neuromuscular blocking agents, intubation with neuromuscular blocking agents after testing the ability to ventilate by mask, pre-induction neck scar release under local anesthesia and ketamine or sedation followed by direct laryngoscopy and intubation and video-laryngoscope guided intubation, amongst others. Preparation of the patient includes an explanation of the proposed procedure, sedation, administration of antisialogogues and regional anesthesia of the airway. The various options for intubation of patients with PBC neck, intraoperative concerns and safe extubation are described. Back-up plans, airway rescue strategies and a review of literature on this subject are presented.

  14. Mechanisms of Acid and Base Secretion by the Airway Epithelium

    PubMed Central

    Fischer, Horst; Widdicombe, Jonathan H.

    2010-01-01

    SUMMARY One of the main functions of the airway epithelium is to inactivate and remove infectious particles from inhaled air and thereby prevent infection of the distal lung. This function is achieved by mucociliary and cough clearance and by antimicrobial factors present in the airway surface liquid (ASL). There are indications that airway defenses are affected by the pH of the ASL and historically, acidification of the airway surfaces has been suggested as a measure of airway disease. However, even in health, the ASL is slightly acidic, and this acidity might be part of normal airway defense. Only recently research has focused on the mechanisms responsible for acid and base secretion into the ASL. Advances resulted from research into the airway disease associated with cystic fibrosis (CF) after it was found that the CFTR C1- channel conducts HCO3- and, therefore, may contribute to ASL pH. However, the acidity of the ASL indicated parallel mechanisms for H+ secretion. Recent investigations identified several H+ transporters in the apical membrane of the airway epithelium. These include H+ channels and ATP-driven H+ pumps, including a non-gastric isoform of the H+-K+ ATPase and a vacuolar-type H+ ATPase. Current knowledge of acid and base transporters and their potential roles in airway mucosal pH regulation is reviewed here. PMID:17091214

  15. Emergency Neurological Life Support: Airway, Ventilation, and Sedation.

    PubMed

    Seder, David B; Jagoda, Andy; Riggs, Becky

    2015-12-01

    Airway management and ventilation are central to the resuscitation of the neurologically ill. These patients often have evolving processes that threaten the airway and adequate ventilation. Furthermore, intubation, ventilation, and sedative choices directly affect brain perfusion. Therefore, airway, ventilation, and sedation was chosen as an emergency neurological life support protocol. Topics include airway management, when and how to intubate with special attention to hemodynamics and preservation of cerebral blood flow, mechanical ventilation settings, and the use of sedative agents based on the patient's neurological status. PMID:26438457

  16. Cardiovascular Causes of Pediatric Airway Compression: A Pictorial Review.

    PubMed

    Singhal, Manphool; Gupta, Pankaj; Singh, Rana Sandip; Rohit, Manoj Kumar; Sodhi, Kushaljit Singh; Khandelwal, Niranjan

    2015-01-01

    Airways compression by vascular structures is one of the important comorbidities of congenital heart disease with incidence of approximately 1%-2% in children. Airways compression is a consequence of abnormal configuration of the great vessels producing a vascular ring with enlargement of normal structures (pulmonary arteries or cardiac chambers) or because of surgery. A high index of suspicion for vascular airway compression is important in children with recurrent respiratory complaints. Early diagnosis and management are essential, as chronic airway compression causes significant morbidity. As the underlying anatomical patterns tend to be highly complex, presurgical imaging assessment is essential.

  17. Strategies and algorithms for management of the difficult airway.

    PubMed

    Heidegger, Thomas; Gerig, Hans J; Henderson, John J

    2005-12-01

    Management of the difficult airway is the most important patient safety issue in the practice of anaesthesia. Many national societies have developed algorithms and guidelines for management of the difficult airway. The key issues of this chapter are definition of terms, the advantages and disadvantages of the use of guidelines, and a comparison of different algorithms and guidelines for management of the most important clinical airway scenarios. Although there is no strong evidence of benefit for any specific strategy or algorithm for management of the difficult airway, there is strong agreement that a pre-planned strategy may lead to improved outcome.

  18. Brain-Derived Neurotrophic Factor in the Airways

    PubMed Central

    Prakash, Y.S.; Martin, Richard J.

    2014-01-01

    In addition to their well-known roles in the nervous system, there is increasing recognition that neurotrophins such as brain derived neurotrophic factor (BDNF) as well as their receptors are expressed in peripheral tissues including the lung, and can thus potentially contribute to both normal physiology and pathophysiology of several diseases. The relevance of this family of growth factors lies in emerging clinical data indicating altered neurotrophin levels and function in a range of diseases including neonatal and adult asthma, sinusitis, influenza, and lung cancer. The current review focuses on 1) the importance of BDNF expression and signaling mechanisms in early airway and lung development, critical to both normal neonatal lung function and also its disruption in prematurity and insults such as inflammation and infection; 2) how BDNF, potentially derived from airway nerves modulate neurogenic control of airway tone, a key aspect of airway reflexes as well as dysfunctional responses to allergic inflammation; 3) the emerging idea that local BDNF production by resident airway cells such as epithelium and airway smooth muscle can contribute to normal airway structure and function, and to airway hyperreactivity and remodeling in diseases such as asthma. Furthermore, given its pleiotropic effects in the airway, BDNF may be a novel and appealing therapeutic target. PMID:24560686

  19. Upper airway function during maximal exercise in horses with obstructive upper airway lesions. Effect of surgical treatment.

    PubMed

    Williams, J W; Meagher, D M; Pascoe, J R; Hornof, W J

    1990-01-01

    Upper airway pressure was measured during maximal exercise in 10 Thoroughbred racehorses with naturally occurring upper airway obstruction. Left laryngeal hemiplegia and arytenoid chondropathy resulted in substantial increases (30-40 cm H2O) in inspiratory upper airway pressure (Pl), whereas complicated aryepiglottic entrapment and subepiglottic cysts produced only modest increases (15 cm H2O) in Pl. Uncomplicated aryepiglottic entrapment and grade IV pharyngeal lymphoid hyperplasia produced only slight increases (3-5 cm H2O). In general, surgical procedures restored airway pressures to within normal limits. Subtotal arytenoidectomy improved but did not normalize airway pressures in horses with arytenoid chondropathy. Pharyngeal lymphoid hyperplasia appeared to have little effect on upper airway function.

  20. AIRWAY HYPERRESPONSIVENESS IN MICE FOLLOWING ANTIGEN AND PARTICULATE MATTER EXPOSURE IS VAGALLY MEDIATED

    EPA Science Inventory

    Sensory nerves within the airways can initiate a variety of protective reflexes. We hypothesized that insults such as exposure to antigen and particulate matter (PM) might dysregulate airway sensory nerve function, thereby contributing to enhanced airway inflammation and hyperre...

  1. Submental intubation with intubating laryngeal mask airway as conduit: An airway option for oral submucous fibrosis release

    PubMed Central

    Mohambourame, Aruloli; Sameer, Mohamed; Hemanth Kumar, V. R.; Ramamirtham, Muthukumaran

    2015-01-01

    The main anesthetic concern with oral submucous fibrosis is progressive restriction of mouth opening due to fibrosis producing difficult airway. Securing airway by nasotracheal intubation and tracheostomy are associated with potential complications. Flexible fiberoscope is not available in all the institutes. Submental intubation using intubating laryngeal mask airway is an acceptable alternative technique in such situations. It also provides an unobstructed surgical field. PMID:25886429

  2. Effect of P2X4R on airway inflammation and airway remodeling in allergic airway challenge in mice

    PubMed Central

    CHEN, HONGXIA; XIA, QINGQING; FENG, XIAOQIAN; CAO, FANGYUAN; YU, HANG; SONG, YINLI; NI, XIUQIN

    2016-01-01

    P2X4 receptor (P2X4R) is the most widely expressed subtype of the P2XRs in the purinergic receptor family. Adenosine triphosphate (ATP), a ligand for this receptor, has been implicated in the pathogenesis of asthma. ATP-P2X4R signaling is involved in pulmonary vascular remodeling, and in the proliferation and differentiation of airway and alveolar epithelial cell lines. However, the role of P2X4R in asthma remains to be elucidated. This aim of the present study was to investigate the effects of P2X4R in a murine experimental asthma model. The asthmatic model was established by the inhalation of ovalbumin (OVA) in BALB/c mice. The mice were treated with P2X4R-specific agonists and antagonists to investigate the role of this receptor in vivo. Pathological changes in the bronchi and lung tissues were examined using hematoxylin and eosin staining, Masson's trichrome staining and Alcian blue staining. The inflammatory cells in the bronchoalveolar lavage fluid were counted, and the expression levels of P2X4R, α-smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) were detected using western blotting. In the OVA-challenged mice, inflammation, infiltration, collagen deposition, mucus production, and the expression levels of P2X4R and PCNA were all increased; however, the expression of α-SMA was decreased, compared with the mice in the control group. Whereas treatment with the P2X4R agonist, ATP, enhanced the allergic reaction, treatment with the P2X4R antagonist, 5-BDBD, attenuated the allergic reaction. The results suggested that ATP-P2X4R signaling may not only contribute to airway inflammation, but it may also contribute to airway remodeling in allergic asthma in mice. PMID:26648454

  3. Airway management using laryngeal mask airway in insertion of the Montgomery tracheal tube for subglottic stenosis -A case report-.

    PubMed

    Park, Jung Sun; Kwon, Young-Suk; Lee, Sangseock; Yon, Jun Heum; Kim, Dong Won

    2010-12-01

    The Montgomery tracheal tube (T-tube) is a device used as a combined tracheal stent and airway after laryngotracheoplasty for patients with tracheal stenosis. This device can present various challenges to anesthesiologists during its placement, including the potential for acute loss of the airway, inadequate administration of inhalation agents, and inadequacy of controlled mechanical ventilation. The present case of successful airway management used a laryngeal mask airway under total intravenous anesthesia with propofol and remifentanil in the insertion of a Montgomery T-tube in a tracheal resection and thyrotracheal anastomosis because of severe subglottic stenosis.

  4. Ozone-induced modulation of airway hyperresponsiveness in guinea pigs.

    PubMed

    Schlesinger, Richard B; Cohen, Mitchell; Gordon, Terry; Nadziejko, Christine; Zelikoff, Judith T; Sisco, Maureen; Regal, Jean F; Ménache, Margaret G

    2002-06-01

    Although acute exposure to ozone (03*) has been shown to influence the severity and prevalence of airway hyperresponsiveness, information has been lacking on effects due to long-term exposure at relatively low exposure concentrations. The goals of this study were to determine whether long-term repeated ozone exposures could induce nonspecific hyperresponsiveness in normal, nonatopic (nonsensitized) animals, whether such exposure could exacerbate the preexisting hyperresponsive state in atopic (sensitized) animals, or both. The study was also designed to determine whether gender modulated airway responsiveness related to ozone exposure. Airway responsiveness was measured during and after exposure to 0.1 and 0.3 ppm ozone for 4 hours/day, 4 days/week for 24 weeks in normal, nonsensitized guinea pigs, in guinea pigs sensitized to an allergen (ovalbumin) prior to initiation of ozone exposures, and in animals sensitized concurrently with ozone exposures. Both male and female animals were studied. Ozone exposure did not produce airway hyperresponsiveness in nonsensitized animals. Ozone exposure did exacerbate airway hyperresponsiveness to specific and nonspecific bronchoprovocation in both groups of sensitized animals, and this effect persisted at least 4 weeks after the end of the exposures. Although the overall degree of airway responsiveness did differ between genders (males had more responsive airways than did females), the airway response to ozone exposure did not differ between the two groups. Ozone-induced effects upon airway responsiveness were not associated with the number of pulmonary eosinophils or with any chronic pulmonary inflammatory response. Levels of antigen-specific antibodies increased in sensitized animals, and a significant correlation was observed between airway responsiveness and antibody levels. The results of this study provide support for a role of ambient ozone exposure in exacerbation of airway dysfunction in persons with atopy.

  5. Deposition of graphene nanomaterial aerosols in human upper airways.

    PubMed

    Su, Wei-Chung; Ku, Bon Ki; Kulkarni, Pramod; Cheng, Yung Sung

    2016-01-01

    Graphene nanomaterials have attracted wide attention in recent years on their application to state-of-the-art technology due to their outstanding physical properties. On the other hand, the nanotoxicity of graphene materials also has rapidly become a serious concern especially in occupational health. Graphene naomaterials inevitably could become airborne in the workplace during manufacturing processes. The inhalation and subsequent deposition of graphene nanomaterial aerosols in the human respiratory tract could potentially result in adverse health effects to exposed workers. Therefore, investigating the deposition of graphene nanomaterial aerosols in the human airways is an indispensable component of an integral approach to graphene occupational health. For this reason, this study carried out a series of airway replica deposition experiments to obtain original experimental data for graphene aerosol airway deposition. In this study, graphene aerosols were generated, size classified, and delivered into human airway replicas (nasal and oral-to-lung airways). The deposition fraction and deposition efficiency of graphene aerosol in the airway replicas were obtained by a novel experimental approach. The experimental results acquired showed that the fractional deposition of graphene aerosols in airway sections studied were all less than 4%, and the deposition efficiency in each airway section was generally lower than 0.03. These results indicate that the majority of the graphene nanomaterial aerosols inhaled into the human respiratory tract could easily penetrate through the head airways as well as the upper part of the tracheobronchial airways and then transit down to the lower lung airways, where undesired biological responses might be induced.

  6. Cytochrome P4501A induction in avian hepatocyte cultures exposed to polychlorinated biphenyls: Comparisons with AHR1-mediated reporter gene activity and in ovo toxicity

    SciTech Connect

    Manning, Gillian E.; Mundy, Lukas J.; Crump, Doug; Jones, Stephanie P.; Chiu, Suzanne; Klein, Jeff; Konstantinov, Alex; Potter, Dave; Kennedy, Sean W.

    2013-01-01

    Avian-specific toxic equivalency factors (TEFs) were developed by the World Health Organization to simplify environmental risk assessments of dioxin-like compounds (DLCs), but TEFs do not account for differences in the toxic and biochemical potencies of DLCs among species of birds. Such variability may be due to differences in species sensitivity to individual DLCs. The sensitivity of avian species to DLCs was recently associated with the identity of amino acids 324 and 380 in the aryl hydrocarbon receptor 1 (AHR1) ligand binding domain. A luciferase reporter gene (LRG) assay, measuring AHR1-mediated induction of a cytochrome P450 1A5 (CYP1A5) reporter gene, in combination with a species' AHR1 ligand binding domain sequence, were also shown to predict avian species sensitivity to polychlorinated biphenyls (PCBs) and PCB relative potency in a given species. The goals of the present study were to (1) characterize the concentration-dependent effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and PCBs 126, 77, 105 and 118 on induction of ethoxyresorufin O-deethylase (EROD) activity and CYP1A4/5 mRNA in chicken, ring-necked pheasant and Japanese quail embryo hepatocytes and (2) compare these in vitro results to those previously generated by the LRG assay and in ovo toxicity studies. EROD activity and CYP1A4/5 mRNA expression data support and complement the findings of the LRG assay. CYP1A enzyme activity and mRNA expression were significantly correlated both with luciferase activity and in ovo toxicity induced by PCBs. Relative potency values were generally similar between the LRG and EROD assays and indicate that the relative potency of some PCBs may differ among species. -- Highlights: ► The chicken isn't the most sensitive species to CYP1A induction by PCB 105 and 118. ► The relative potency of PCBs differs between avian species. ► EROD activity was correlated with luciferase activity from the LRG assay. ► EROD activity was a better predictor of toxicity than CYP

  7. Tumorigenic effects of endocrine-disrupting chemicals are alleviated by licorice (Glycyrrhiza glabra) root extract through suppression of AhR expression in mammalian cells.

    PubMed

    Chu, Xiao Ting; de la Cruz, Joseph; Hwang, Seong Gu; Hong, Heeok

    2014-01-01

    Endocrine-disrupting chemicals (EDCs) have been reported to interfere with estrogen signaling. Exposure to these chemicals decreases the immune response and causes a wide range of diseases in animals and humans. Recently, many studies showed that licorice (Glycyrrhiza glabra) root extract (LRE) commonly called "gamcho" in Korea exhibits antioxidative, chemoprotective, and detoxifying properties. This study aimed to investigate the mechanism of action of LRE and to determine if and how LRE can alleviate the toxicity of EDCs. LRE was prepared by vacuum evaporation and freeze-drying after homogenization of licorice root powder that was soaked in 80% ethanol for 72 h. We used 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as a representative EDC, which is known to induce tumors or cancers; MCF-7 breast cancer cells, used as a tumor model, were treated with TCDD and various concentrations of LRE (0, 50, 100, 200, 400 μg/mL) for 24, 48, and 72 h. As a result, TCDD stimulated MCF-7 cell proliferation, but LRE significantly inhibited TCDD-induced MCF-7 cell proliferation in a dose- and time-dependent manner. The expression of TCDD toxicity-related genes, i.e., aryl hydrocarbon receptor (AhR), AhR nuclear translocator, and cytochrome P450 1A1, was also down-regulated by LRE in a dose-dependent manner. Analysis of cell cycle distribution after treatment of MCF-7 cells with TCDD showed that LRE inhibited the proliferation of MCF-7 cells via G2/M phase arrest. Reverse transcription-polymerase chain reaction and Western blot analysis also revealed that LRE dose-dependently increased the expression of the tumor suppressor genes p53 and p27 and down-regulated the expression of cell cycle-related genes. These data suggest that LRE can mitigate the tumorigenic effects of TCDD in breast cancer cells by suppression of AhR expression and cell cycle arrest. Thus, LRE can be used as a potential toxicity-alleviating agent against EDC-mediated diseases.

  8. 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.

  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.

  10. 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

  11. 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

  12. Positive airway pressure therapy for heart failure.

    PubMed

    Kato, Takao; Suda, Shoko; Kasai, Takatoshi

    2014-11-26

    Heart failure (HF) is a life-threatening disease and is a growing public health concern. Despite recent advances in pharmacological management for HF, the morbidity and mortality from HF remain high. Therefore, non-pharmacological approaches for HF are being developed. However, most non-pharmacological approaches are invasive, have limited indication and are considered only for advanced HF. Accordingly, the development of less invasive, non-pharmacological approaches that improve outcomes for patients with HF is important. One such approach may include positive airway pressure (PAP) therapy. In this review, the role of PAP therapy applied through mask interfaces in the wide spectrum of HF care is discussed. PMID:25429330

  13. 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

  14. MOEBIUS SYNDROME: CHALLENGES OF AIRWAY MANAGEMENT.

    PubMed

    Budić, Ivana; Šurdilović, Dušan; Slavković, Anđelka; Marjanović, Vesna; Stević, Marija; Simić, Dušica

    2016-03-01

    Moebius syndrome is a rare nonprogressive congenital neurological disorder with a wide range of severity and variability of symptoms. This diversity is a consequence of dysfunction of different cranial nerves (most often facial and abducens nerves), accompanying orofacial abnormalities, musculoskeletal malformations, congenital cardiac diseases, as well as specific associations of Moebius and other syndromes. The authors present anesthesia and airway management during the multiple tooth extraction surgery in a 10-year-old girl with Moebius syndrome associated with Poland and trigeminal trophic syndromes. PMID:27276780

  15. Contribution of airway closure to chronic postbronchiolitis airway dysfunction in rats.

    PubMed

    Sorkness, Ronald L; Tuffaha, Amjad

    2004-03-01

    Genetically susceptible Brown Norway rats develop a chronic asthmalike syndrome after recovering from viral bronchiolitis at an early age. We hypothesized that airway closure is an important mechanism of airflow obstruction in postbronchiolitis rats. Rats were studied 8-12 wk after inoculation with Sendai virus or sterile vehicle at 3-4 wk of age. Under light pentobarbital anesthesia, rats were instrumented with an orotracheal catheter and an esophageal pressure monitor and placed in a total body plethysmograph. Lung volumes and forced-expiratory maneuvers were measured using the Boyle's law method and software-controlled valving of positive and negative pressures to elicit lung inflations and rapid deflations; pulmonary resistance was measured during spontaneous tidal breathing; and quasi-static pressure-volume curves were obtained with passive inflations and deflations in fully anesthetized, paralyzed rats. Compared with controls, the postbronchiolitis rats had elevated pulmonary resistance and reduced forced-expiratory volume in 0.2 s. Most of the reduced forced-expiratory volume in 0.2 s was associated with reduced forced vital capacity, indicating premature airway closure as a prominent mechanism. The reduced airflow in postbronchiolitis rats was highly dependent on lung volume, being nearly normal at 70% lung capacity, but sevenfold less than normal at 30% lung capacity. Increased respiratory system hysteresis between functional reserve capacity and total lung capacity was evidence for increased airway closure at normal end-expiratory lung volumes in postbronchiolitis rats. We conclude that airway instability and closure is a prominent mechanism of the chronic airway dysfunction in rats that have recovered from viral bronchiolitis at an early age. PMID:14594863

  16. Nitrogen Dioxide Exposure and Airway Responsiveness in Individuals with Asthma

    EPA Science Inventory

    Controlled human exposure studies evaluating the effect of inhaled NO2 on the inherent responsiveness of the airways to challenge by bronchoconstricting agents have had mixed results. In general, existing meta-analyses show statistically significant effects of NO2 on the airway r...

  17. Inertial and interceptional deposition of fibers in a bifurcating airway.

    PubMed

    Zhang, L; Asgharian, B; Anjilvel, S

    1996-01-01

    A computer model of a three-dimensional bifurcating airway was constructed in which the parent and daughter airways had different lengths but equal diameters. A diameter of 0.6 cm was chosen for the airways based on the third generation of Weibel's symmetric lung model. Different bifurcation angles of 60 degrees, 90 degrees, and 120 degrees were studied. Airflow fields in the airway were obtained by a finite-element method (FIDAP, Fluid Dynamics International, Evanston, IL) for Reynolds numbers of 500 and 1000, assuming uniform parent inlet velocities. The equations of motion for fiber transport in the airways were obtained, and deposition by the combined mechanisms of impaction and interception was incorporated. A computer code was developed that utilized the flow field data and calculated fiber transport in the airways using the equations of motion for fibers. Deposition efficiency was obtained by simulating a large number of fibers of various sizes. Fiber entering the daughter airways tended to orient themselves parallel to the flow. A site of enhanced deposition (or hot spot) was observed at the carina. The dominant parameter for the deposition was the fiber Stokes number. Flow Reynolds number and airway bifurcation angle were also found to affect the deposition.

  18. Airway smooth muscle in the pathophysiology and treatment of asthma

    PubMed Central

    Solway, Julian

    2013-01-01

    Airway smooth muscle (ASM) plays an integral part in the pathophysiology of asthma. It is responsible for acute bronchoconstriction, which is potentiated by constrictor hyperresponsiveness, impaired relaxation and length adaptation. ASM also contributes to airway remodeling and inflammation in asthma. In light of this, ASM is an important target in the treatment of asthma. PMID:23305987

  19. 21 CFR 868.5090 - Emergency airway needle.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Emergency airway needle. 868.5090 Section 868.5090 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Therapeutic Devices § 868.5090 Emergency airway needle....

  20. 21 CFR 868.5090 - Emergency airway needle.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Emergency airway needle. 868.5090 Section 868.5090 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Therapeutic Devices § 868.5090 Emergency airway needle....

  1. 21 CFR 868.5090 - Emergency airway needle.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Emergency airway needle. 868.5090 Section 868.5090 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Therapeutic Devices § 868.5090 Emergency airway needle....

  2. 21 CFR 868.5090 - Emergency airway needle.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Emergency airway needle. 868.5090 Section 868.5090 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Therapeutic Devices § 868.5090 Emergency airway needle....

  3. 21 CFR 868.5090 - Emergency airway needle.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Emergency airway needle. 868.5090 Section 868.5090 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Therapeutic Devices § 868.5090 Emergency airway needle....

  4. Dietary sodium intake, airway responsiveness, and cellular sodium transport.

    PubMed

    Tribe, R M; Barton, J R; Poston, L; Burney, P G

    1994-06-01

    Both epidemiologic and experimental evidence suggest that a high dietary sodium intake may increase airway responsiveness, but no adequate explanation exists of how changes in sodium intake might lead to increased responsiveness. This investigation was c