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Sample records for airway contractile responses

  1. Airway smooth muscle cell tone amplifies contractile function in the presence of chronic cyclic strain.

    Science.gov (United States)

    Fairbank, Nigel J; Connolly, Sarah C; Mackinnon, James D; Wehry, Kathrin; Deng, Linhong; Maksym, Geoffrey N

    2008-09-01

    Chronic contractile activation, or tone, in asthma coupled with continuous stretching due to breathing may be involved in altering the contractile function of airway smooth muscle (ASM). Previously, we (11) showed that cytoskeletal remodeling and stiffening responses to acute (2 h) localized stresses were modulated by the level of contractile activation of ASM. Here, we investigated if altered contractility in response to chronic mechanical strain was dependent on repeated modulation of contractile tone. Cultured human ASM cells received 5% cyclic (0.3 Hz), predominantly uniaxial strain for 5 days, with once-daily dosing of either sham, forskolin, carbachol, or histamine to alter tone. Stiffness, contractility (KCl), and "relaxability" (forskolin) were then measured as was cell alignment, myosin light-chain phosphorylation (pMLC), and myosin light-chain kinase (MLCK) content. Cells became aligned and baseline stiffness increased with strain, but repeated lowering of tone inhibited both effects (P negative tone-modulation dependence of MLCK, observed in static conditions in agreement with previous reports, with strain and tone together increasing both MLCK and pMLC. Furthermore, contractility increased 176% (SE 59) with repeated tone elevation. These findings indicate that with strain, and not without, repeated tone elevation promoted contractile function through changes in cytoskeletal organization and increased contractile protein. The ability of repeated contractile activation to increase contractility, but only with mechanical stretching, suggests a novel mechanism for increased ASM contractility in asthma and for the role of continuous bronchodilator and corticosteroid therapy in reversing airway hyperresponsiveness.

  2. Protective effects of anisodamine on cigarette smoke extract-induced airway smooth muscle cell proliferation and tracheal contractility

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Guang-Ni; Yang, Kai; Xu, Zu-Peng; Zhu, Liang; Hou, Li-Na; Qi, Hong; Chen, Hong-Zhuan, E-mail: hongzhuan_chen@hotmail.com; Cui, Yong-Yao, E-mail: yongyaocui@yahoo.com.cn

    2012-07-01

    Anisodamine, an antagonist of muscarinic acetylcholine receptors (mAChRs), has been used therapeutically to improve smooth muscle function, including microvascular, intestinal and airway spasms. Our previous studies have revealed that airway hyper-reactivity could be prevented by anisodamine. However, whether anisodamine prevents smoking-induced airway smooth muscle (ASM) cell proliferation remained unclear. In this study, a primary culture of rat ASM cells was used to evaluate an ASM phenotype through the ability of the cells to proliferate and express contractile proteins in response to cigarette smoke extract (CSE) and intervention of anisodamine. Our results showed that CSE resulted in an increase in cyclin D1 expression concomitant with the G0/G1-to-S phase transition, and high expression of M2 and M3. Functional studies showed that tracheal hyper-contractility accompanied contractile marker α-SMA high-expression. These changes, which occur only after CSE stimulation, were prevented and reversed by anisodamine, and CSE-induced cyclin D1 expression was significantly inhibited by anisodamine and the specific inhibitor U0126, BAY11-7082 and LY294002. Thus, we concluded that the protective and reversal effects and mechanism of anisodamine on CSE-induced events might involve, at least partially, the ERK, Akt and NF-κB signaling pathways associated with cyclin D1 via mAChRs. Our study validated that anisodamine intervention on ASM cells may contribute to anti-remodeling properties other than bronchodilation. -- Highlights: ► CSE induces tracheal cell proliferation, hyper-contractility and α-SMA expression. ► Anisodamine reverses CSE-induced tracheal hyper-contractility and cell proliferation. ► ERK, PI3K, and NF-κB pathways and cyclin D1 contribute to the reversal effect.

  3. Steroids and antihistamines synergize to inhibit rat's airway smooth muscle contractility.

    Science.gov (United States)

    Liu, Shao-Cheng; Chu, Yueng-Hsiang; Kao, Chuan-Hsiang; Wu, Chi-Chung; Wang, Hsing-Won

    2015-06-01

    Both glucocorticoids and H1-antihistamines were widely used on patients with allergic rhinitis (AR) and obstructive airway diseases. However, their direct effects on airway smooth muscle were not fully explored. In this study, we tested the effectiveness of prednisolone (Kidsolone) and levocetirizine (Xyzal) on isolated rat trachea submersed in Kreb's solution in a muscle bath. Changes in tracheal contractility in response to the application of parasympathetic mimetic agents were measured. The following assessments of the drug were performed: (1) effect on tracheal smooth muscle resting tension; (2) effect on contraction caused by 10(-6) M methacholine; (3) effect of the drug on electrical field stimulation (EFS) induced tracheal smooth muscle contractions. The result revealed sole use of Kidsolone or Xyzal elicited no significant effect or only a little relaxation response on tracheal tension after methacholine treatment. The tension was 90.5 ± 7.5 and 99.5 ± 0.8 % at 10(-4) M for Xyzal and 10(-5) M for Kidsolone, respectively. However, a dramatically spasmolytic effect was observed after co-administration of Kidsolone and Xyzal and the tension dropped to 67.5 ± 13.6 %, with statistical significance (p antihistamines to dramatically relax the trachea smooth muscle within minutes. Therefore, for AR patients with acute asthma attack, combined use of those two drugs is recommended.

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

    Science.gov (United States)

    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.

  5. Stress and strain in the contractile and cytoskeletal filaments of airway smooth muscle.

    Science.gov (United States)

    Deng, Linhong; Bosse, Ynuk; Brown, Nathan; Chin, Leslie Y M; Connolly, Sarah C; Fairbank, Nigel J; King, Greg G; Maksym, Geoffrey N; Paré, Peter D; Seow, Chun Y; Stephen, Newman L

    2009-10-01

    Stress and strain are omnipresent in the lung due to constant lung volume fluctuation associated with respiration, and they modulate the phenotype and function of all cells residing in the airways including the airway smooth muscle (ASM) cell. There is ample evidence that the ASM cell is very sensitive to its physical environment, and can alter its structure and/or function accordingly, resulting in either desired or undesired consequences. The forces that are either conferred to the ASM cell due to external stretching or generated inside the cell must be borne and transmitted inside the cytoskeleton (CSK). Thus, maintaining appropriate levels of stress and strain within the CSK is essential for maintaining normal function. Despite the importance, the mechanisms regulating/dysregulating ASM cytoskeletal filaments in response to stress and strain remained poorly understood until only recently. For example, it is now understood that ASM length and force are dynamically regulated, and both can adapt over a wide range of length, rendering ASM one of the most malleable living tissues. The malleability reflects the CSK's dynamic mechanical properties and plasticity, both of which strongly interact with the loading on the CSK, and all together ultimately determines airway narrowing in pathology. Here we review the latest advances in our understanding of stress and strain in ASM cells, including the organization of contractile and cytoskeletal filaments, range and adaptation of functional length, structural and functional changes of the cell in response to mechanical perturbation, ASM tone as a mediator of strain-induced responses, and the novel glassy dynamic behaviors of the CSK in relation to asthma pathophysiology.

  6. Effects of Hindlimb Unweighting on Arterial Contractile Responses in Mice

    Science.gov (United States)

    Ma, Jia; Ren, Xin-Ling; Purdy, Ralph E.

    2003-01-01

    The aim of this work was to determine if hindlimb unweighting in mice alters arterial contractile responses. Sixteen male C57B/6 mice and 16 male Chinese Kunming mice were divided into control and 3 weeks hindlimb unweighting groups, respectively. Using isolated arterial rings from different arteries of mouse, effects of 3 weeks hindlimb unweighting on arterial contractile responsiveness were examined in vitro. The results showed that, in arterial rings from both C57B/6 and Chinese Kunming mice, maximum isometric contractile tensions evoked by either KCl or phenylephrine were significantly lower in abdominal aortic, mesenteric arterial and femoral arterial rings from hindlimb unweighting, compared to control mice. However, the maximal contractile responses of common carotid rings to KCl and PE were not significantly different between control and hindlimb unweighting groups. The sensitivity (EC(sub 50)) of all arteries to KCl or PE showed no significant differences between control and hindlimb unweighting mice. These data indicated that 3 weeks hindlimb unweighting results in a reduced capacity of the arterial smooth muscle of the hindquarter to develop tension. In addition, the alterations in arterial contractile responses caused by hindlimb unweighting in mice are similar as those in rats. Our work suggested that hindlimb unweighting mouse model may be used as a model for the study of postflight cardiovascular deconditioning.

  7. Mechanisms of impaired gallbladder contractile response in chronic acalculous cholecystitis.

    Science.gov (United States)

    Merg, Anders R; Kalinowski, Scott E; Hinkhouse, Marilyn M; Mitros, Frank A; Ephgrave, Kimberly S; Cullen, Joseph J

    2002-01-01

    The mechanisms involved in the impaired gallbladder contractile response in chronic acalculous cholecystitis are unknown. To determine the mechanisms that may lead to impaired gallbladder emptying in chronic acalculous cholecystitis, gallbladder specimens removed during hepatic resection (controls) and after cholecystectomy for chronic acalculous cholecystitis were attached to force transducers and placed in tissue baths with oxygenated Krebs solution. Electrical field stimulation (EFS) (1 to 10 Hz, 0.1 msec, 70 V) or the contractile agonists, CCK-8 (10(-9) to 10(-5)) or K(+) (80 mmol/L), were placed separately in the tissue baths and changes in tension were determined. Patients with chronic acalculous cholecystitis had a mean gallbladder ejection fraction of 12% +/- 4%. Pathologic examination of all gallbladders removed for chronic acalculous cholecystitis revealed chronic cholecystitis. Spontaneous contractile activity was present in gallbladder strips in 83% of control specimens but only 29% of gallbladder strips from patients with chronic acalculous cholecystitis (P < 0.05 vs. controls). CCK-8 contractions were decreased by 54% and EFS-stimulated contractions were decreased by 50% in the presence of chronic acalculous cholecystitis (P < 0.05 vs. controls). K(+)-induced contractions were similar between control and chronic acalculous cholecystitis gallbladder strips. The impaired gallbladder emptying in chronic acalculous cholecystitis appears to be due to diminished spontaneous contractile activity and decreased contractile responsiveness to both CCK and EFS.

  8. Mechanisms determining cholinergic neural responses in airways of young and mature rabbits.

    Science.gov (United States)

    Larsen, Gary L; Loader, Joan; Nguyen, Dee Dee; Fratelli, Cori; Dakhama, Azzeddine; Colasurdo, Giuseppe N

    2004-08-01

    Neural pathways help control airway caliber and responsiveness. Yet little is known of how neural control changes as a function of development. In rabbits, we found electrical field stimulation (EFS) of airway nerves led to more marked contractile responses in 2- vs. 13-week-old animals. This enhanced response to EFS may be due to prejunctional, junctional, and/or postjunctional neural mechanisms. We assessed these mechanisms in airways of 2- and 13-week-old rabbits. The contractile responses to methacholine did not differ in the groups, suggesting postjunctional neural events are not primarily responsible for differing responses to EFS. To address junctional events, acetylcholinesterase (AChE) was measured (spectrophotometry). AChE was elevated in 2-week-olds. However, this should lead to less and not greater responses. Prejunctionally, EFS-induced acetylcholine (ACh) release was assessed by HPLC. Airways of 2-week-old rabbits released significantly more ACh than airways from mature rabbits. Choline acetyltransferase, a marker of cholinergic nerves, was not different between groups, suggesting that more ACh release in young rabbits was not due to increased nerve density. ACh release in the presence of polyarginine increased significantly in both groups, supporting the presence of functional muscarinic autoreceptors (M2) at both ages. Because substance P (SP) increases release of ACh, SP was measured by ELISA. This neuropeptide was significantly elevated in airways of younger rabbits. Nerve growth factor (NGF) increased SP and was also significantly increased in airways from younger rabbits. This work suggests that increases in EFS-induced responsiveness in young rabbits are likely due to prejunctional events with enhanced release of ACh. Increases in NGF and SP early in life may contribute to this increased responsiveness.

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

    Directory of Open Access Journals (Sweden)

    Park Chang-Soo

    2006-02-01

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

  10. Altered diaphragmatic contractile properties after high airway pressure controlled mechanical ventilation

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    @@ Acute respiratory failure is the most frequent indication for the application of mechanical ventilation. 1 As commonly used in clinical settings, lung protective strategies and recruitment manoeuvres are applications of higher than normal airway pressure to open the collapsed alveoli and prevent lung atelectasis caused by minimal vital ventilation. Under those conditions, we pay more attention to the lung injury and circulatory failure, and less attention to the diaphragmatic structure and function.

  11. Alteration of airway responsiveness mediated by receptors in ovalbumin-induced asthmatic E3 rats

    Institute of Scientific and Technical Information of China (English)

    Jing-wen LONG; Xu-dong YANG; Lei CAO; She-min LU; Yong-xiao CAO

    2009-01-01

    Aim:Airway hyperresponsiveness is a constant feature of asthma.The aim of the present study was to investigate airway hyperreactivity mediated by contractile and dilative receptors in an ovalbumin (OVA)-induced model of rat asthma.Methods:Asthmatic E3 rats were prepared by intraperitoneal injection with OVA/aluminum hydroxide and then challenged with intranasal instillation of OVA-PBS two weeks later.The myograph method was used to measure the responses of constriction and dilatation in the trachea,main bronchi and lobar bronchi.Results:In asthmatic E3 rata,β2 adrenoceptor-mediated relaxation of airway smooth muscle pre-contracted with 5-HT was inhibited,and there were no obvious difference in relaxation compared with normal E3 rats.Contraction of lobar bronchi mediated by 5-HT and sarafotoxin 6c was more potent than in the trachea or main bronchi.Airway contractions mediated by the endothelin (ET)A receptor,ETB receptor and M3 muscarinic receptor were augmented,and the augmented contraction was most obvious in lobar bronchi.The order of efficacy of contraction for lobar bronchi induced by agonists was ET-1,sarafotoxin 6c>ACh>5-HT.OX8 (an antibody against CD8+ T cells) strongly shifted and 0X35 (an antibody against CD4+ T cells) modestly shifted isoprenaline-induced concentration-relaxation curves in a nonparallel fashion to the left with an increased Rmax in asthmatic rats and sarafotoxin 6c-induced concentration-contractile curves to the right with a decreased Emax.Conclusion:The inhibition of airway relaxation and the augmentation of contraction mediated by receptors contribute to airway hyperresponsiveness and involve CD8+ and CD4+ T cells.

  12. Allergen-induced changes in airway responsiveness are related to baseline airway responsiveness

    NARCIS (Netherlands)

    deBruinWeller, MS; Weller, FR; RijssenbeekNouwens, LHM; Jansen, HM; deMonchy, JGR

    1996-01-01

    In the literature, bronchial allergen challenge is usually reported to result in an increase in histamine-induced airway responsiveness (AR). The present study investigated the relation between baseline AR and allergen-induced changes in AR. The effect of allergen challenge on AR was investigated in

  13. Contractile responses to ergotamine and dihydroergotamine in the perfused middle cerebral artery of rat

    DEFF Research Database (Denmark)

    Tfelt-Hansen, Peer; Nilsson, Elisabeth; Edvinsson, Lars

    2007-01-01

    mmHg and luminally perfused. All vessels used attained spontaneous contractile tone (34.9+/-1.8% of resting tone) and responded to luminal adenosine triphosphate (ATP) with dilatation (24.1+/-4.0%), which showed functioning endothelium. Luminally added ergotamine or DHE induced maximal contractions...... no significant effect. Using a myograph technique, isolated ring segments of the MCA with intact endothelium were mounted on two metal wires. Neither agonist caused relaxation of resting vessels, however, they both responded by weak contractile responses (26+/-3% of submaximal contractile capacity relative to 60...

  14. Nitrogen Dioxide Exposure and Airway Responsiveness in Individuals with Asthma

    Science.gov (United States)

    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...

  15. Serum cytokine levels, cigarette smoking and airway responsiveness among pregnant women

    NARCIS (Netherlands)

    Tsunoda, M; Litonjua, AA; Kuniak, MP; Weiss, ST; Satoh, T; Guevarra, L; Tollerud, DJ

    2003-01-01

    Background. Five to twenty percent of healthy, nonasthmatic individuals exhibit airway hyperreactivity. Because cytokines are important intermediates in airway responses, we investigated the relationship between serum cytokines and airway responsiveness in a well-characterized population of pregnant

  16. Airway Responsiveness to Psychological Processes in Asthma and Health

    Directory of Open Access Journals (Sweden)

    Thomas eRitz

    2012-09-01

    Full Text Available Psychosocial factors have been found to impact airway pathophysiology in respiratory disease with considerable consistency. Influences on airway mechanics have been studied particularly well. The goal of this article is to review the literature on airway responses to psychological stimulation, discuss potential pathways of influence, and present a well-established emotion-induction paradigm to study airway obstruction elicited by unpleasant stimuli. Observational studies have found systematic associations between lung function and daily mood changes. The laboratory –based paradigm of bronchoconstrictive suggestion has been used successfully to elicit airway obstruction in a substantial proportion of asthmatic individuals. Other studies have demonstrated an enhancement of airway responses to standard airway challenges with exercise, allergens, or methacholine. Standardized emotion-induction techniques have consistently shown airway constriction during unpleasant stimulation, with surgery, blood and injury stimuli being particularly powerful. Findings with various forms of stress induction have been more mixed. A number of methodological factors may account for variability across studies, such as choice of measurement technique, temporal association between stimulation and measurement, and the specific quality and intensity of the stimulus material, in particular the extent of implied action-orientation. Research has also begun to elucidate physiological processes associated with psychologically induced airway responses, with vagal excitation and ventilatory influences being the most likely candidate pathways, whereas the role of specific central nervous system pathways and inflammatory processes has been less studied. The technique of emotion-induction using films has the potential to become a standardized challenge paradigm for the further exploration of airway hyperresponsiveness mediated by central nervous system processes.

  17. Cell stiffness, contractile stress and the role of extracellular matrix

    Science.gov (United States)

    An, Steven S.; Kim, Jina; Ahn, Kwangmi; Trepat, Xavier; Drake, Kenneth J.; Kumar, Sarvesh; Ling, Guoyu; Purington, Carolyn; Rangasamy, Tirumalai; Kensler, Thomas W.; Mitzner, Wayne; Fredberg, Jeffrey J.; Biswal, Shyam

    2010-01-01

    Here we have assessed the effects of extracellular matrix (ECM) composition and rigidity on mechanical properties of the human airway smooth muscle (ASM) cell. Cell stiffness and contractile stress showed appreciable changes from the most relaxed state to the most contracted state: we refer to the maximal range of these changes as the cell contractile scope. The contractile scope was least when the cell was adherent upon collagen V, followed by collagen IV, laminin, and collagen I, and greatest for fibronectin. Regardless of ECM composition, upon adherence to increasingly rigid substrates, the ASM cell positively regulated expression of antioxidant genes in the glutathione pathway and heme oxygenase, and disruption of a redox-sensitive transcription factor, nuclear erythroid 2 p45-related factor (Nrf2), culminated in greater contractile scope. These findings provide biophysical evidence that ECM differentially modulates muscle contractility and, for the first time, demonstrate a link between muscle contractility and Nrf2-directed responses. PMID:19327344

  18. Cell stiffness, contractile stress and the role of extracellular matrix

    Energy Technology Data Exchange (ETDEWEB)

    An, Steven S., E-mail: san@jhsph.edu [Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Room E-7616, Baltimore, MD 21205 (United States); Kim, Jina [Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Room E-7616, Baltimore, MD 21205 (United States); Ahn, Kwangmi [Division of Biostatistics, Penn State College of Medicine, Hershey, PA 17033 (United States); Trepat, Xavier [CIBER, Enfermedades Respiratorias, 07110 Bunyola (Spain); Drake, Kenneth J. [Division of Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, MA 02115 (United States); Kumar, Sarvesh; Ling, Guoyu; Purington, Carolyn; Rangasamy, Tirumalai; Kensler, Thomas W.; Mitzner, Wayne [Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Room E-7616, Baltimore, MD 21205 (United States); Fredberg, Jeffrey J. [Division of Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, MA 02115 (United States); Biswal, Shyam [Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Room E-7616, Baltimore, MD 21205 (United States); Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205 (United States)

    2009-05-15

    Here we have assessed the effects of extracellular matrix (ECM) composition and rigidity on mechanical properties of the human airway smooth muscle (ASM) cell. Cell stiffness and contractile stress showed appreciable changes from the most relaxed state to the most contracted state: we refer to the maximal range of these changes as the cell contractile scope. The contractile scope was least when the cell was adherent upon collagen V, followed by collagen IV, laminin, and collagen I, and greatest for fibronectin. Regardless of ECM composition, upon adherence to increasingly rigid substrates, the ASM cell positively regulated expression of antioxidant genes in the glutathione pathway and heme oxygenase, and disruption of a redox-sensitive transcription factor, nuclear erythroid 2 p45-related factor (Nrf2), culminated in greater contractile scope. These findings provide biophysical evidence that ECM differentially modulates muscle contractility and, for the first time, demonstrate a link between muscle contractility and Nrf2-directed responses.

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

    Science.gov (United States)

    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...

  20. The Effects of Histamine H3 Receptors on Contractile Responses on Rat Gastric Fundus

    Directory of Open Access Journals (Sweden)

    Aşkın Hekimoğlu

    2006-01-01

    Full Text Available The aim of this study is to determine the effects of histamine receptors on the gastrointestinal system smooth muscle contractions and the role of histamine H3 receptors on these effects. İsolated rat gastric fundus preparations were hanged on isolated organ bath and histamine receptor agonist and anthagonists were added to the bath solution and the electrical field stimulation-induced contractile responses were evaluated. In our study groups after blocking one of the histamine receptors H1, H2,H3; contractile responses were observed. Then, other two receptors were blocked one by one or combination of them to observe the changes on the contractile responses given to the electrical stimulation .To blocke histamine receptors pyrilamine (10-6м as H1 receptor blocker, famotidine (10-6м as H2 receptor blocker and thioperamide (10-5м as H3 receptor blocker and various combination of them were used. All groups were treated with H3 receptor anthagonist thioperamide (10-5м and agonist (R-α-methylhistamine (RMHA on 10-8, 10-7, 10-6 ve 10-5 molar concentrations cumulatively to observe its mediator effects on contractile responses. We suggested that (R-α-methylhistamine mediates the inhibition on the contractile effects of rat gastric fundus. This conclusion was supported by these findings: a the selective agonists (RMHA caused a dumping of the contractile effect of acetylcholine; b the effect of (RMHA was prevented by the selective H3 receptor antagonist thioperamide.

  1. Actions of genistein on contractile response of smooth muscle isolated from guinea pig gallbladder

    Institute of Scientific and Technical Information of China (English)

    Ya-Li Luo; Ya-Li Wang; Neng-Lian Li; Tian-Zhen Zheng; Li Zhang; Ya-Li She; Shu-Ming Hu

    2009-01-01

    BACKGROUND: Defective contractile motility of the gallbladder is an important factor for gallstone formation. Estrogen might increase the risk of gallstones and cholecystitis, and estradiol inhibits the contractile activity of isolated strips of guinea pig gallbladder. The potential risks associated with hormone replacement therapy (HRT) include symptomatic gallstones. Phytoestrogen have been used to treat menopause syndromes by replacing traditional estrogen. This experiment aimed to determine the effects of the phytoestrogen genistein on the contractile response of smooth muscle strips isolated from guinea pig gallbladder and its possible mechanism of action. METHODS: Guinea pigs were sacriifced to remove the whole gallbladder. Two or three smooth muscle strips were cut longitudinally. Each strip was suspended in a tissue chamber containing Krebs solution. After 2 hours of equilibration, contractile response indexes were recorded. Different concentrations of genistein were added to the chamber and the contractile responses were measured. Each antagonist was added 2 minutes before genistein to study possible mechanisms. The effect of genistein on calcium-dependent contraction curves and biphasic contraction in calcium-free Krebs solution were measured. RESULTS: Genistein decreased the resting tension dose-dependently, and reduced the mean contractile amplitude and frequency in gallbladder strips. Ranitidine partly inhibited the effect of genistein, but methylene blue, Nω-nitro-L-arginine, and propranolol hydrochloride did not inlfuence this action. Genistein had no signiifcant effects on calcium-dependent contraction. Genistein reduced the ifrst contraction induced by acetylcholine chloride, but did not affect the second contraction caused by CaCl2. CONCLUSIONS: Genistein relaxed smooth muscle isolated from the gallbladder of guinea pigs and this might contribute to the formation of gallstones. The inhibitory action might be related to H2 receptors and

  2. The importance of myocardial contractile reserve in predicting response to cardiac resynchronization therapy

    NARCIS (Netherlands)

    Kloosterman, Mariëlle; Damman, Kevin; Van Veldhuisen, Dirk J; Rienstra, Michiel; Maass, Alexander H

    2017-01-01

    AIM: To perform a meta-analysis and systematic review of published data to assess the relationship between contractile reserve and response to cardiac resynchronization therapy (CRT) in patients with heart failure. METHODS AND RESULTS: We searched MEDLINE/PubMed and Cochrane for all papers published

  3. Airway epithelial cell responses to ozone injury

    Energy Technology Data Exchange (ETDEWEB)

    Leikauf, G.D.; Simpson, L.G.; Zhao, Qiyu [Univ. of Cincinnati Medical Center, OH (United States)] [and others

    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.

  4. Deficiency of nitric oxide in allergen-induced airway hyperreactivity to contractile agonists after the early asthmatic reaction : An ex vivo study

    NARCIS (Netherlands)

    deBoer, J; Meurs, H; Coers, W; Koopal, M; Bottone, AE; Visser, AC; Timens, W; Zaagsma, J

    1996-01-01

    1 Using a guinea-pig model of allergic asthma, we investigated the role of nitric oxide (NO) in allergen-induced airway hyperreactivity after the early asthmatic reaction, by examining the effects of the NO-synthase inhibitor N-omega-nitro-L-arginine methyl ester (L-NAME) on the responsiveness to me

  5. Genioglossus muscle responses to upper airway pressure changes: afferent pathways.

    Science.gov (United States)

    Mathew, O P; Abu-Osba, Y K; Thach, B T

    1982-02-01

    The afferent pathway of an upper airway reflex in which genioglossus muscle electromyographic (GG EMG) activity is influenced by pharyngeal pressure changes was investigated in 20 anesthetized rabbits. We took advantage of the fact that the upper airway was separated into two compartments by pharyngeal closure occurring when the animals breathe through a tracheostomy. This allowed pressure to be delivered selectively either to the nose and nasopharynx or to the larynx and hypopharynx. Midcervical vagotomy did not eliminate the GG EMG response to pressure stimuli. On the other hand high cervical vagotomy or superior laryngeal nerve section eliminated the response in the laryngeal compartment, but not in the nasopharyngeal compartment. Topical anesthesia of the mucosa of the nose, pharynx, and larynx abolished the response in both compartments. Therefore we conclude that more than one afferent pathway exists for this upper airway pressure reflex; the primary afferent pathway from the laryngeal compartment is the superior laryngeal branch of the vagus nerve, whereas the primary afferent pathway for the nasopharynx is nonvagal. Trigeminal nerve, glossopharyngeal nerve, and/or nervus intermedius carry nonvagal afferents from the nasopharynx and nose. The topical anesthetic and nerve section studies suggest that superficial receptors mediate this response. The occurrence of swallowing in response to upper airway pressure changes and its elimination by topical anesthesia or superior mechanoreceptors may mediate both genioglossus respiratory responses and swallowing responses.

  6. Measuring the Contractile Response of Isolated Tissue Using an Image Sensor

    Directory of Open Access Journals (Sweden)

    David Díaz-Martín

    2015-04-01

    Full Text Available Isometric or isotonic transducers have traditionally been used to study the contractile/relaxation effects of drugs on isolated tissues. However, these mechanical sensors are expensive and delicate, and they are associated with certain disadvantages when performing experiments in the laboratory. In this paper, a method that uses an image sensor to measure the contractile effect of drugs on blood vessel rings and other luminal organs is presented. The new method is based on an image-processing algorithm, and it provides a fast, easy and non-expensive way to analyze the effects of such drugs. In our tests, we have obtained dose-response curves from rat aorta rings that are equivalent to those achieved with classical mechanic sensors.

  7. Bacterial flagellin triggers cardiac innate immune responses and acute contractile dysfunction.

    Directory of Open Access Journals (Sweden)

    Joelle Rolli

    Full Text Available BACKGROUND: Myocardial contractile failure in septic shock may develop following direct interactions, within the heart itself, between molecular motifs released by pathogens and their specific receptors, notably those belonging to the toll-like receptor (TLR family. Here, we determined the ability of bacterial flagellin, the ligand of mammalian TLR5, to trigger myocardial inflammation and contractile dysfunction. METHODOLOGY/PRINCIPAL FINDINGS: TLR5 expression was determined in H9c2 cardiac myoblasts, in primary rat cardiomyocytes, and in whole heart extracts from rodents and humans. The ability of flagellin to activate pro-inflammatory signaling pathways (NF-kappaB and MAP kinases and the expression of inflammatory cytokines was investigated in H9c2 cells, and, in part, in primary cardiomyocytes, as well as in the mouse myocardium in vivo. The influence of flagellin on left ventricular function was evaluated in mice by a conductance pressure-volume catheter. Cardiomyocytes and intact myocardium disclosed significant TLR5 expression. In vitro, flagellin activated NF-kappaB, MAP kinases, and the transcription of inflammatory genes. In vivo, flagellin induced cardiac activation of NF-kappaB, expression of inflammatory cytokines (TNF alpha, IL-1 beta, IL-6, MIP-2 and MCP-1, and provoked a state of reversible myocardial dysfunction, characterized by cardiac dilation, reduced ejection fraction, and decreased end-systolic elastance. CONCLUSION/SIGNIFICANCE: These results are the first to indicate that flagellin has the ability to trigger cardiac innate immune responses and to acutely depress myocardial contractility.

  8. Histamine airway hyper-responsiveness and mortality from chronic obstructive pulmonary disease : a cohort study

    NARCIS (Netherlands)

    Hospers, JJ; Postma, DS; Rijcken, B; Weiss, ST; Schouten, JP

    2000-01-01

    Background Smoking and airway lability, which is expressed by histamine airway hyper-responsiveness, are known risk factors for development of respiratory symptoms. Smoking is also associated with increased mortality risks. We studied whether airway hyper-responsiveness is associated with increased

  9. Effect of rhubarb on contractile response of gallbladder smooth muscle strips isolated from guinea pigs

    Institute of Scientific and Technical Information of China (English)

    Ya-Li Luo; Jun-Wei Zeng; Mei Yu; Yu-Ling Wei; Song-Yi Qu; Wei Li; Tian Zhen Zheng

    2005-01-01

    AIM: To investigate the effect of rhubarb on contractile response of isolated gallbladder muscle strips from guinea pigs and its mechanism.METHODS: Guinea pigs were killed to remove the whole gallbladder. Two or three smooth muscle strips (8 mm×3mm) were cut along the longitudinal direction. The mucosa on each strip was carefully removed. Each longitudinal muscle strip was suspended in a tissue chamber containing 5 mL Krebs solution (37 ℃), bubbled continuously with 950 mL/L O2 and 50 mL/L CO2. The resting tension (g), mean contractile amplitude (mm),and contractile frequency (waves/min) were simultaneously recorded on recorders. After 2-h equilibration, rhubarb (10, 20, 70, 200, 700, 1 000 g/L) was added cumulatively to the tissue chamber in turns every 2 min to observe their effects on gallbladder.Antagonists were given 3 min before administration of rhubarb to investigate the possible mechanism.RESULTS: Rhubarb increased the resting tension (from 0 to 0.40±0.02, P<0.001), and decreased the mean contractile amplitude (from 5.22±0.71 to 2.73±0.41,P<0.001). It also increased the contractile frequency of the gallbladder muscle strips in guinea pigs (from 4.09±0.46to 6.08±0.35, P<0.001). The stimulation of rhubarb on the resting tension decreased from 3.98±0.22 to 1.58±0.12by atropine (P<0.001), from3.98±0.22 to 2.09±0.19 by verapamil (P<0.001) and from 3.98±0.22 to 2.67±0.43by phentolamine (P<0.005). But the effect was not inhibited by hexamethonium (P>0.05). In addition, the action of mean amplitude and frequency was not inhibited by the above antagonists.CONCLUSION: Rhubarb can stimulate the motility of isolated gallbladder muscle strips from guinea pigs. The stimulation of rhubarb might be relevant with M receptor,Ca2+ channel and α receptor partly.

  10. Airway responsiveness in two inbred strains of mouse disparate in IgE and IL-4 production.

    Science.gov (United States)

    Fan, T; Yang, M; Halayko, A; Mohapatra, S S; Stephens, N L

    1997-08-01

    The mouse provides an excellent model for genetic studies of asthma, which is characterized by airway hyperexcitability and hyperreactivity. The former is a function of the properties of the membrane of the airway smooth muscle (ASM), whereas the latter is a function, albeit indirectly, of the mechanical properties of the muscle contractile apparatus. The very small size of the muscle has in the past hampered its study. We report herein that contractile properties of tracheal smooth muscle (TSM) can be measured in mice. We examined TSM strips from two inbred strains of mouse, ASW and SJL, which are high and low IgE responders, respectively. Force-velocity relationships were measured in four groups of mice, two ASW (control and sensitized)/and two SJL (control and sensitized). Muscle strips from sensitized SJL mice exhibited shortening velocities (V0) and maximum shortening capacities (deltaLmax), that were significantly greater than those of the other groups. However, no difference was found between the two strains in maximal isometric force (P0). The two strains also showed differences in their potential to express cytokines such as interleukin-4 (IL-4) and IL-5 in ex vivo splenocyte cultures, as measured by the cytokines' messenger RNA (mRNA) and protein expression. The SJL strain, which exhibited TSM hyperreactivity, was found to produce significantly greater amounts of IL-4 than the ASW strain. We conclude that the altered contractile properties of TSM in sensitized SJL mice are independent of IgE response, but linked to increased amounts of IL-4.

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

    Energy Technology Data Exchange (ETDEWEB)

    Ribeiro-Filho, Jaime [Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro (Brazil); Laboratório de Imunofarmacologia, Departamento de Fisiologia e Patologia, UFPB, João Pessoa, Paraíba (Brazil); Calheiros, Andrea Surrage; Vieira-de-Abreu, Adriana [Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro (Brazil); Moraes de Carvalho, Katharinne Ingrid [Laboratório de Inflamação, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro (Brazil); Silva Mendes, Diego da [Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro (Brazil); Melo, Christianne Bandeira [Laboratório de Inflamação, Instituto Biofisica Carlos Chagas Filho, UFRJ, Rio de Janeiro (Brazil); Martins, Marco Aurélio [Laboratório de Inflamação, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro (Brazil); Silva Dias, Celidarque da [Laboratório de Fitoquímica, Departamento de Ciências Farmacêuticas, UFPB, João Pessoa, Paraíba (Brazil); Piuvezam, Márcia Regina, E-mail: mrpiuvezam@ltf.ufpb.br [Laboratório de Imunofarmacologia, Departamento de Fisiologia e Patologia, UFPB, João Pessoa, Paraíba (Brazil); 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

  12. Airway responses towards allergens - from the airway epithelium to T cells.

    Science.gov (United States)

    Papazian, D; Hansen, S; Würtzen, P A

    2015-08-01

    The prevalence of allergic diseases such as allergic rhinitis is increasing, affecting up to 30% of the human population worldwide. Allergic sensitization arises from complex interactions between environmental exposures and genetic susceptibility, resulting in inflammatory T helper 2 (Th2) cell-derived immune responses towards environmental allergens. Emerging evidence now suggests that an epithelial dysfunction, coupled with inherent properties of environmental allergens, can be responsible for the inflammatory responses towards allergens. Several epithelial-derived cytokines, such as thymic stromal lymphopoietin (TSLP), IL-25 and IL-33, influence tissue-resident dendritic cells (DCs) as well as Th2 effector cells. Exposure to environmental allergens does not elicit Th2 inflammatory responses or any clinical symptoms in nonatopic individuals, and recent findings suggest that a nondamaged, healthy epithelium lowers the DCs' ability to induce inflammatory T-cell responses towards allergens. The purpose of this review was to summarize the current knowledge on which signals from the airway epithelium, from first contact with inhaled allergens all the way to the ensuing Th2-cell responses, influence the pathology of allergic diseases.

  13. Colon-specific contractile responses to tetrodotoxin in the isolated mouse gastrointestinal tract.

    Science.gov (United States)

    Okuno, Y; Kondo, T; Saeki, A; Uchida, E; Teraoka, H; Kitazawa, T

    2011-01-01

    1 Tetrodotoxin (TTX) is a useful pharmacological tool for distinguishing neural and myogenic responses of isolated visceral organs to drugs. Although TTX does not generally affect smooth muscle tonus, in this study, we have found that TTX causes contraction of the mouse colon. The aim of this study was to characterize this TTX-induced contraction in the mouse gastrointestinal tract. 2 Longitudinal and circular muscle strips from the stomach and small intestine were less sensitive to TTX. However, TTX contracted both smooth muscle strips from the proximal colon and distal colon. 3 Pretreatment with TTX, Nω -nitro-L-arginine methyl ester (L-NAME), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and apamin inhibited the TTX-induced contraction. L-NAME, ODQ or apamin itself caused contraction in the colon but not in the gastric and small intestinal strips. Region dependency of L-NAME, ODQ and apamin-induced contraction correlated with that of TTX-induced contraction. 4 L-arginine but not D-arginine inhibited contractility of the colonic strips without affecting the contractility of muscle strips from other regions. Sodium nitroprusside caused strong relaxation of the colonic strips. 5 1,1-dimethyl-4-phenylpiperazinium (DMPP) caused relaxation of proximal and distal colons, which was significantly decreased by L-NAME or apamin. 6 In conclusion, among mouse gastrointestinal preparations, TTX induces contraction of colonic strips preferentially through blockade of potent tonic inhibitory neural outflow, which involves nitrergic and apamin-sensitive pathways. Colon-specific responses to L-arginine, L-NAME, ODQ and apamin support the hypothesis that there is a continuous suppression of colonic motility by enteric inhibitory neurons.

  14. MORPHOLOGICAL FEATURES OF LUNG STRUCTURE AND FUNCTIONAL ACTIVITY OF THE AIRWAYS OF GUINEA PIGS AFTER LONG-TERM EXPOSURE WITH NANOSIZED MAGNETITE A

    Directory of Open Access Journals (Sweden)

    Ye. Ye. Abramenko

    2013-01-01

    Full Text Available The results of study, in which we examined the influence of nanosized magnetite on breath organs histological structure and contractility activity of the airways of guinea pigs by method of mechanography has been presented. In the lungs of experimental animals an inflammatory response developed as a result of long-term inhalation intake of nanosized magnetite. Also the functional status of the airways changed and appeared as changing of amplitude of contractility response under the action of histamine.

  15. Effect of subarachnoid hemorrhage on contractile responses and noradrenaline release evoked in cat cerebral arteries by histamine

    Energy Technology Data Exchange (ETDEWEB)

    Lobato, R.D.; Marin, J.; Salaices, M.; Rico, M.L.; Sanchez, C.F.

    1981-10-01

    This study analyzes the changes induced by subarachnoid hemorrhage (SAH) on the contractile responses and the noradrenaline release evoked in cat cerebral arteries by histamine. The dose-dependent vasoconstriction induced by histamine on the cerebral arteries of normal cats was significantly reduced by diphenhydramine and phentolamine. When SAH was produced 3 and 7 days before the experiment, the histamine-induced vasoconstriction also decreased. Thereafter, a tendency to normalization in the contractile vascular responses was observed such that in 15 days after the hemorrhage it was not significantly different from that found in controls animals. The decrease in the contractile responses to histamine provoked by SAH was similar to that seen after pretreatment with intracisternal injections of 6-hydroxydopamine. The amount of radioactivity released by histamine following preincubation with /sup 3/H-noradrenaline from the cerebral arteries of cats exposed to SAH 3, 7, and 15 days before the experiment was significantly reduced when compared with controls. Moreover, the basal level of tritium release and the radioactivity retained at the end of the experiment were also decreased after SAH. Results indicate histamine releases noradrenaline from cat cerebral arteries, and SAH produce a transient denervation of the perivascular adrenergic nerve endings, which explained by the impairment of the indirect adrenergic mechanism involved in the overall contractile response elicited by this amine in cerebral arteries. Histamine does not seem to play a significant role in the production of the cerebral vasospasm occurring after SAH.

  16. Simulation of the contractile response of cells on an array of micro-posts.

    LENUS (Irish Health Repository)

    McGarry, J P

    2009-09-13

    A bio-chemo-mechanical model has been used to predict the contractile responses of smooth cells on a bed of micro-posts. Predictions obtained for smooth muscle cells reveal that, by converging onto a single set of parameters, the model captures all of the following responses in a self-consistent manner: (i) the scaling of the force exerted by the cells with the number of posts; (ii) actin distributions within the cells, including the rings of actin around the micro-posts; (iii) the curvature of the cell boundaries between the posts; and (iv) the higher post forces towards the cell periphery. Similar correspondences between predictions and measurements have been demonstrated for fibroblasts and mesenchymal stem cells once the maximum stress exerted by the stress fibre bundles has been recalibrated. Consistent with measurements, the model predicts that the forces exerted by the cells will increase with both increasing post stiffness and cell area (or equivalently, post spacing). In conjunction with previous assessments, these findings suggest that this framework represents an important step towards a complete model for the coupled bio-chemo-mechanical responses of cells.

  17. The utility of methacholine airway responsiveness measurements in evaluating anti-asthma drugs

    NARCIS (Netherlands)

    Inman, MD; Hamilton, AL; Kerstjens, HAM; Watson, RM; O'Byrne, PM

    1998-01-01

    Background: Measurements of airway responsiveness are frequently used to evaluate anti-asthma drugs. Objective: This study investigated the utility of methacholine airway responsiveness measurements in evaluating anti-asthma medications, both in terms of a bronchoprotective effect and the ability to

  18. Diminished contractile responses of isolated conduit arteries in two rat models of hypertension.

    Science.gov (United States)

    Zemancíková, Anna; Török, Jozef

    2013-08-31

    Hypertension is accompanied by thickening of arteries, resulting in marked changes in their passive and active mechanical properties. The aim of this study was to demonstrate that the large conduit arteries from hypertensive individuals may not exhibit enhanced contractions in vitro, as is often claimed. Mechanical responses to vasoconstrictor stimuli were measured under isometric conditions using ring arterial segments isolated from spontaneously hypertensive rats, N(omega)-nitro-L-arginine methyl ester (L-NAME)-treated Wistar rats, and untreated Wistar rats serving as normotensive control. We found that thoracic aortas from both types of hypertensive rats had a greater sensitivity but diminished maximal developed tension in response to noradrenaline, when compared with that from normotensive rats. In superior mesenteric arteries, the sensitivity to noradrenaline was similar in all examined rat groups but in L-NAME-treated rats, these arteries exhibited decreased active force when stimulated with high noradrenaline concentrations, or with 100 mM KCl. These results indicate that hypertension leads to specific biomechanical alterations in diverse arterial types which are reflected in different modifications in their contractile properties.

  19. Molecular modulation of airway epithelial ciliary response to sneezing.

    Science.gov (United States)

    Zhao, Ke-Qing; Cowan, Andrew T; Lee, Robert J; Goldstein, Natalia; Droguett, Karla; Chen, Bei; Zheng, Chunquan; Villalon, Manuel; Palmer, James N; Kreindler, James L; Cohen, Noam A

    2012-08-01

    Our purpose was to evaluate the effect of the mechanical force of a sneeze on sinonasal cilia function and determine the molecular mechanism responsible for eliciting the ciliary response to a sneeze. A novel model was developed to deliver a stimulation simulating a sneeze (55 mmHg for 50 ms) at 26°C to the apical surface of mouse and human nasal epithelial cells. Ciliary beating was visualized, and changes in ciliary beat frequency (CBF) were determined. To interrogate the molecular cascades driving sneeze-induced changes of CBF, pharmacologic manipulation of intra- and extracellular calcium, purinergic, PKA, and nitric oxide (NO) signaling were performed. CBF rapidly increases by ≥150% in response to a sneeze, which is dependent on the release of adenosine triphosphate (ATP), calcium influx, and PKA activation. Furthermore, apical release of ATP is independent of calcium influx, but calcium influx and subsequent increase in CBF are dependent on the ATP release. Lastly, we observed a blunted ciliary response in surgical specimens derived from patients with chronic rhinosinusitis compared to control patients. Apical ATP release with subsequent calcium mobilization and PKA activation are involved in sinonasal ciliary response to sneezing, which is blunted in patients with upper-airway disease.

  20. Airway, responsiveness and inflammation in adolescent elite swimmers

    DEFF Research Database (Denmark)

    Pedersen, Lise; Lund, T.K.; Barnes, P.J.

    2008-01-01

    . There was no difference in FeNO, cellular composition of sputum, airway reactivity, or prevalence of having AHR to methacholine and/or EVH between swimmers with and without respiratory symptoms. Conclusion: Adolescent elite swimmers do not have significant signs of airway damage after only a few years of intense training...... and competition. This leads us to believe that elite swimmers do not have particularly susceptible airways when they take up competitive swimming when young, but that they develop respiratory symptoms, airway inflammation, and AHR during their swimming careers Udgivelsesdato: 2008/8...

  1. Serum response factor regulates smooth muscle contractility via myotonic dystrophy protein kinases and L-type calcium channels

    Science.gov (United States)

    Lee, Moon Young; Park, Chanjae; Ha, Se Eun; Park, Paul J.; Berent, Robyn M.; Jorgensen, Brian G.; Corrigan, Robert D.; Grainger, Nathan; Blair, Peter J.; Slivano, Orazio J.; Miano, Joseph M.; Ward, Sean M.; Smith, Terence K.; Sanders, Kenton M.

    2017-01-01

    Serum response factor (SRF) transcriptionally regulates expression of contractile genes in smooth muscle cells (SMC). Lack or decrease of SRF is directly linked to a phenotypic change of SMC, leading to hypomotility of smooth muscle in the gastrointestinal (GI) tract. However, the molecular mechanism behind SRF-induced hypomotility in GI smooth muscle is largely unknown. We describe here how SRF plays a functional role in the regulation of the SMC contractility via myotonic dystrophy protein kinase (DMPK) and L-type calcium channel CACNA1C. GI SMC expressed Dmpk and Cacna1c genes into multiple alternative transcriptional isoforms. Deficiency of SRF in SMC of Srf knockout (KO) mice led to reduction of SRF-dependent DMPK, which down-regulated the expression of CACNA1C. Reduction of CACNA1C in KO SMC not only decreased intracellular Ca2+ spikes but also disrupted their coupling between cells resulting in decreased contractility. The role of SRF in the regulation of SMC phenotype and function provides new insight into how SMC lose their contractility leading to hypomotility in pathophysiological conditions within the GI tract. PMID:28152551

  2. Comparison of the contractile responses to irregular and regular trains of stimuli during microstimulation of single human motor axons.

    Science.gov (United States)

    Leitch, Michael; Macefield, Vaughan G

    2014-04-01

    During voluntary contractions, human motoneurons discharge with a physiological variability of ∼20%. However, studies that have measured the contractile responses to microstimulation of single motor axons have used regular trains of stimuli with no variability. We tested the hypothesis that irregular (physiological) trains of stimuli produce greater contractile responses than regular (nonphysiological) trains of identical mean frequency but zero variability. High-impedance tungsten microelectrodes were inserted into the common peroneal nerve and guided into fascicles supplying a toe extensor muscle. Selective microstimulation was achieved for 14 single motor axons. Contractile responses were measured via an angular displacement transducer over the relevant toe. After the responses to regular trains of 10 stimuli extending from 2 to 100 Hz were recorded, irregular trains of 10 stimuli, based on the interspike intervals recorded from single motor units during voluntary contractions, were delivered. Finally, the stimulation sequences were repeated following a 2-min period of continuous stimulation at 10 Hz to induce muscle fatigue. Regular trains of stimuli generated a sigmoidal increase in displacement with frequency, whereas irregular trains, emulating the firing of volitionally driven motoneurons, displayed significantly greater responses over the same frequency range (8-24 Hz). This was maintained even in the presence of fatigue. We conclude that physiological discharge variability, which incorporates short and long interspike intervals, offers an advantage to the neuromuscular system by allowing motor units to operate on a higher level of the contraction-frequency curve and taking advantage of catch-like properties in skeletal muscle.

  3. Innate Immune Responses to Engineered Nanomaterials During Allergic Airway Inflammation

    Science.gov (United States)

    Shipkowski, Kelly Anne

    The field of nanotechnology is continually advancing, and increasing amounts of consumer goods are being produced using engineered nanomaterials (ENMs). The health risks of occupational and/or consumer exposure to ENMs are not completely understood, although significant research indicates that pulmonary exposure to nanomaterials induces toxic effects in the lungs of exposed animals. Multi-walled carbon nanotubes (MWCNTs) are a specific category of ENMs and consist of sheets of graphene rolled into cylinders that are multiple layers thick in order to strengthen their rigidity. MWCNTs have a fiber-like shape, similar to that of asbestos, which allows for a high aspect ratio and makes them difficult to clear from the lung. Studies with rodent models have demonstrated that pulmonary exposure to ENMs, in particular MWCNTs, results in acute lung inflammation and the subsequent development of chronic fibrosis, suggesting a potential human health risk to individuals involved in the manufacturing of products utilizing these nanomaterials. Induction of IL-1beta secretion via activation of the inflammasome is a prime mechanism of MWCNT-induced inflammation. The inflammasome is a multi-protein scaffold found in a variety of cell types that forms in response to a variety of immune signals, including particulates. Sensitization with allergens, such as house dust mite (HDM), increases levels of the T helper 2 (Th2) cytokines IL-4 and IL-13 in mice and in humans, and there is particular cause for concern in cases of MWCNT exposure in individuals with pre-existing allergic airway disease, such as asthma. MWCNT exposure exacerbates airway inflammation and fibrosis in animal models of pre-existing allergic asthma, suggesting that individuals suffering from asthma are more susceptible to the toxic pulmonary effects of MWCNT exposure. Asthma is an exceptionally prominent human disease, and therefore the goal of this research was to better understand how pre-existing allergic airway

  4. Endothelin-1 and endothelin-2 initiate and maintain contractile responses by different mechanisms in rat mesenteric and cerebral arteries

    DEFF Research Database (Denmark)

    Compeer, M. G.; Janssen, G. M. J.; De Mey, J. G. R.

    2013-01-01

    Background and PurposeEndothelin (ET)-1 and ET-2 cause potent long-lasting vasoconstrictions by tight binding to smooth muscle ETA receptors. We tested the hypotheses that different mechanisms mediate initiation and maintenance of arterial contractile responses to ET-1 and ET-2 and that this diff...... and BA. Selective functional antagonism may be considered for agonist- and vascular bed selective pharmacotherapy of ET-related diseases....

  5. Phenotype modulation of airway smooth muscle in asthma

    NARCIS (Netherlands)

    Wright, David B.; Trian, Thomas; Siddiqui, Sana; Pascoe, Chris D.; Johnson, Jill R.; Dekkers, Bart G. J.; Dakshinamurti, Shyamala; Bagchi, Rushita; Burgess, Janette K.; Kanabar, Varsha; Ojo, Oluwaseun O.

    2013-01-01

    The biological responses of airway smooth muscle (ASM) are diverse, in part due to ASM phenotype plasticity. ASM phenotype plasticity refers to the ability of ASM cells to change the degree of a variety of functions, including contractility, proliferation, migration and secretion of inflammatory med

  6. Phytoestrogen genistein decreases contractile response of aortic artery in vitro and arterial blood pressure in vivo

    Institute of Scientific and Technical Information of China (English)

    Hong-fang LI; Long-de WANG; Song-yi QU

    2004-01-01

    AIM: To determine the mechanisms of effects of phytoestrogen genistein on the contracted rabbit aortic arteries in vitro, and observe the effect of genistein and 17-β estradiol on mean arterial pressure (MAP) in ovariectomized (OVX) rats. METHODS: (1) Strips of rabbit aortic smooth muscle were suspended in organ baths containing Kreb's solution, and then isometric tension was measured. (2) Female mature Wistar rats underwent a bilateral ovariectomy (OVX). Sham-operated rats (SHAM) were used as controls. After administration of genistein (0.4(1) Similar to 17-β estradiol, genistein could dose-dependently relax 40 mmol/L KCl-precontracted arterial strips.Incubation with Nω-L-nitro-arginine (L-NNA), methylene blue (MB), indomethacin, propranolol or endothelium removal did not affect relaxation induced by genistein. In calcium-free solution containing 0.01mmol/L egtazic acid (EGTA), genistein inhibited not only the first phase contraction induced by noradrenaline (NA), but also the second contraction induced by CaCl2. In addition, genistein could reduce the contractile responses of NA, KCl and CaCl2,and shift their cumulative concentration-response curves rightward. (2) MAP in OVX rats was significantly higher compared with that of SHAM rats. However, after chronically treatment with genistein or 17-β estradiol for 21 d the baseline MAP in OVX rats was reduced significantly. CONCLUSIONS: (1) The vasodilator effect of genistein in vitro is endothelium independent and not related to the nitric oxide, its mechanisms being probably due to inhibition of Ca2+ influx through calcium channels in a noncompetitive manner and Ca2+ release from intracellular store induced by NA. (2) Administration of genistein or 17-β estradiol can chronically decrease MAP in OVX rats.

  7. Repeated allergen exposure reduce early phase airway response and leukotriene release despite upregulation of 5-lipoxygenase pathways

    Directory of Open Access Journals (Sweden)

    Cui Zhi-Hua

    2012-03-01

    Full Text Available Abstract Background Allergen induced early phase airway response and airway plasma exudation are predominantly mediated by inflammatory mast cell mediators including histamine, cysteinyl leukotrienes (cysLTs and thromboxane A2 (TXA2. The aim of the present study was to evaluate whether repeated allergen exposure affects early phase airway response to allergen challenge. Methods A trimellitic anhydride (TMA sensitized guinea pig model was used to investigate the effects of low dose repeated allergen exposure on cholinergic airway responsiveness, early phase airway response and plasma exudation, as well as local airway production of mast cell derived cysteinyl leukotrienes and thromboxane B2 (TXB2 after allergen challenge. Results Repeated low dose allergen exposure increased cholinergic airway responsiveness. In contrast, early phase airway response and plasma exudation in response to a high-dose allergen challenge were strongly attenuated after repeated low dose allergen exposure. Inhibition of the airway response was unspecific to exposed allergen and independent of histamine receptor blocking. Furthermore, a significant reduction of cysteinyl leukotrienes and TXB2 was found in the airways of animals repeatedly exposed to a low dose allergen. However, in vitro stimulation of airway tissue from animals repeatedly exposed to a low dose allergen with arachidonic acid and calcium ionophore (A23187 induced production of cysteinyl leukotrienes and TXB2, suggesting enhanced activity of 5-lipoxygenase and cyclooxygenase pathways. Conclusions The inhibition of the early phase airway response, cysteinyl leukotriene and TXB2 production after repeated allergen exposure may result from unresponsive effector cells.

  8. Length adaptation of smooth muscle contractile filaments in response to sustained activation.

    Science.gov (United States)

    Stålhand, Jonas; Holzapfel, Gerhard A

    2016-05-21

    Airway and bladder smooth muscles are known to undergo length adaptation under sustained contraction. This adaptation process entails a remodelling of the intracellular actin and myosin filaments which shifts the peak of the active force-length curve towards the current length. Smooth muscles are therefore able to generate the maximum force over a wide range of lengths. In contrast, length adaptation of vascular smooth muscle has attracted very little attention and only a handful of studies have been reported. Although their results are conflicting on the existence of a length adaptation process in vascular smooth muscle, it seems that, at least, peripheral arteries and arterioles undergo such adaptation. This is of interest since peripheral vessels are responsible for pressure regulation, and a length adaptation will affect the function of the cardiovascular system. It has, e.g., been suggested that the inward remodelling of resistance vessels associated with hypertension disorders may be related to smooth muscle adaptation. In this study we develop a continuum mechanical model for vascular smooth muscle length adaptation by assuming that the muscle cells remodel the actomyosin network such that the peak of the active stress-stretch curve is shifted towards the operating point. The model is specialised to hamster cheek pouch arterioles and the simulated response to stepwise length changes under contraction. The results show that the model is able to recover the salient features of length adaptation reported in the literature.

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

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    Verena A Lambermont

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

  10. Active contractility in actomyosin networks

    CERN Document Server

    Wang, Shenshen

    2012-01-01

    Contractile forces are essential for many developmental processes involving cell shape change and tissue deformation. Recent experiments on reconstituted actomyosin networks, the major component of the contractile machinery, have shown that active contractility occurs above a threshold motor concentration and within a window of crosslink concentration. We present a microscopic dynamic model that incorporates two essential aspects of actomyosin self-organization: the asymmetric load response of individual actin filaments and the correlated motor-driven events mimicking myosin-induced filament sliding. Using computer simulations we examine how the concentration and susceptibility of motors contribute to their collective behavior and interplay with the network connectivity to regulate macroscopic contractility. Our model is shown to capture the formation and dynamics of contractile structures and agree with the observed dependence of active contractility on microscopic parameters including the contractility onse...

  11. Sinoatrial tissue of crucian carp heart has only negative contractile responses to autonomic agonists

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    Hälinen Mervi

    2010-06-01

    Full Text Available Abstract Background In the anoxia-tolerant crucian carp (Carassius carassius cardiac activity varies according to the seasons. To clarify the role of autonomic nervous control in modulation of cardiac activity, responses of atrial contraction and heart rate (HR to carbacholine (CCh and isoprenaline (Iso were determined in fish acclimatized to winter (4°C, cold-acclimated, CA and summer (18°C, warm-acclimated, WA temperatures. Results Inhibitory action of CCh was much stronger on atrial contractility than HR. CCh reduced force of atrial contraction at an order of magnitude lower concentrations (EC50 2.75-3.5·10-8 M in comparison to its depressive effect on HR (EC50 1.23-2.02·10-7 M (P -8 M and 10-7 M CCh, respectively (P + current, IK,CCh, with an EC50 value of 3-4.5·10-7 M and inhibited Ca2+ current (ICa by 28 ± 8% and 51 ± 6% at 10-7 M and 10-6 M, respectively. These currents can explain the shortening of AP. Iso did not elicit any responses in crucian carp sinoatrial preparations nor did it have any effect on atrial ICa, probably due to the saturation of the β-adrenergic cascade in the basal state. Conclusion In the crucian carp, HR and force of atrial contraction show cardio-depressive responses to the cholinergic agonist, but do not have any responses to the β-adrenergic agonist. The scope of inhibitory regulation by CCh is increased by the high basal tone of the adenylate cyclase-cAMP cascade. Higher concentrations of CCh were required to induce IK,CCh and inhibit ICa than was needed for CCh's negative inotropic effect on atrial muscle suggesting that neither IK,CCh nor ICa alone can mediate CCh's actions but they might synergistically reduce AP duration and atrial force production. Autonomic responses were similar in CA winter fish and WA summer fish indicating that cardiac sensitivity to external modulation by the autonomic nervous system is not involved in seasonal acclimatization of the crucian carp heart to cold and anoxic

  12. Relation of Airway Responsiveness to Methacholine to Parent and Child Reporting of Symptoms Suggecting Asthma

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    JM FitzGerald

    1996-01-01

    Full Text Available BACKGROUND: The lack of a relationship between airway responsiveness and respiratory symptoms in epidemiological studies of children may, in part, reflect inaccuracies in symptom reporting or inadequate knowledge by the parent of the child's symptoms.

  13. A PAF receptor antagonist inhibits acute airway inflammation and late-phase responses but not chronic airway inflammation and hyperresponsiveness in a primate model of asthma

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    R. H. Gundel

    1992-01-01

    Full Text Available We have examined the effects of a PAF receptor antagonist, WEB 2170, on several indices of acute and chronic airway inflammation and associated changes in lung function in a primate model of allergic asthma. A single oral administration WEB 2170 provided dose related inhibition of the release of leukotriene C4 (LTC4 and prostaglandin D2 (PGD2 recovered and quantified in bronchoalveolar lavage (BAL fluid obtained during the acute phase response to inhaled antigen. In addition, oral WEB 2170 treatment in dual responder primates blocked the acute influx of neutrophils into the airways as well as the associated late-phase airway obstruction occurring 6 h after antigen inhalation. In contrast, a multiple dosing regime with WEB 2170 (once a day for 7 consecutive days failed to reduce the chronic airway inflammation (eosinophilic and associated airway hyperresponsiveness to inhaled methacholine that is characteristic of dual responder monkeys. Thus, we conclude that the generation of PAF following antigen inhalation contributes to the development of lipid mediators, acute airway inflammation and associated late-phase airway obstruction in dual responder primates; however, PAF does not play a significant role in the maintenance of chronic airway inflammation and associated airway hyperresponsiveness in this primate model.

  14. TRPM8 mechanism of autonomic nerve response to cold in respiratory airway

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    Wang Cong-Yi

    2008-06-01

    Full Text Available Abstract Breathing cold air without proper temperature exchange can induce strong respiratory autonomic responses including cough, airway constriction and mucosal secretion, and can exacerbate existing asthma conditions and even directly trigger an asthma attack. Vagal afferent fiber is thought to be involved in the cold-induced respiratory responses through autonomic nerve reflex. However, molecular mechanisms by which vagal afferent fibers are excited by cold remain unknown. Using retrograde labeling, immunostaining, calcium imaging, and electrophysiological recordings, here we show that a subpopulation of airway vagal afferent nerves express TRPM8 receptors and that activation of TRPM8 receptors by cold excites these airway autonomic nerves. Thus activation of TRPM8 receptors may provoke autonomic nerve reflex to increase airway resistance. This putative autonomic response may be associated with cold-induced exacerbation of asthma and other pulmonary disorders, making TRPM8 receptors a possible target for prevention of cold-associated respiratory disorders.

  15. Siblings Promote a Type 1/Type 17-oriented immune response in the airways of asymptomatic neonates

    DEFF Research Database (Denmark)

    Wolsk, Helene Mygind; Chawes, Bo L.; Følsgaard, Nilofar V.;

    2016-01-01

    BACKGROUND: Siblings have been shown to reduce the risk of later asthma and allergy, but the mechanism driving this association is unknown. The objective was to study whether siblings affect the airway immune response in healthy neonates. We hypothesized that siblings exert immune modulatory......-cohort (COPSAC2010). The association between airway mediator levels and presence of siblings was investigated using conventional statistics and principle component analyses (PCA). RESULTS: Neonates with siblings had an up-regulated level of airway immune-mediators, with predominance of Type 1- and Type 17......-related mediators. This was supported by the PCA showing a highly significant difference between children with vs. without siblings: p

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

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    King Nicholas JC

    2006-05-01

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

  17. Sensitivity of bronchoprovocation and tracheal mucous velocity in detecting airway responses to O3. [Sheep

    Energy Technology Data Exchange (ETDEWEB)

    Abraham, W.M.; Januszkiewicz, A.J.; Mingle, M.; Welker, M.; Wanner, A.; Sackner, M.A.

    1980-05-01

    This study was undertaken to determine whether measurements of tracheal mucous velocity or airway reactivity to inhaled carbachol more sensitively detect airway effects of inhaled ozone (O3) in conscious sheep. Dose-response curves of mean pulmonary flow resistance (RL) to carbachol were obtained by measuring RL after five breaths of carbachol aerosol with stepwise increases in drug concentration. The animals then breathed 0.5 ppM O3 through an endotracheal tube for 2 h. The dose-response curves were repeated immediately after the 0.5 ppM O3 exposure and 24 h later. In conscious sheep, airway hyperreactivity appears to be a more sensitive indicator of airway effects produced by short-term exposure to 0.5 ppM O3 than depression of tracheal mucous velocity.

  18. Cough sensitivity and extrathoracic airway responsiveness to inhaled capsaicin in chronic cough patients.

    OpenAIRE

    Cho, You Sook; Lee, Chang-Keun; Yoo, Bin; Moon, Hee-Bom

    2002-01-01

    Enhanced cough response has been frequently observed in chronic cough. Recently, extrathoracic airway constriction to inhaled histamine was demonstrated in some chronic cough patients. However, relation between extrathoracic airway hyperresponsiveness (EAHR) and cough sensitivity determined by capsaicin inhalation is unclear in each etiological entity of chronic cough. Seventy-seven patients, with dry cough persisting for 3 or more weeks, normal spirometry and chest radiography, and 15 contro...

  19. Differential inflammatory response to inhaled lipopolysaccharide targeted either to the airways or the alveoli in man.

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    Winfried Möller

    Full Text Available Endotoxin (Lipopolysaccharide, LPS is a potent inducer of inflammation and there is various LPS contamination in the environment, being a trigger of lung diseases and exacerbation. The objective of this study was to assess the time course of inflammation and the sensitivities of the airways and alveoli to targeted LPS inhalation in order to understand the role of LPS challenge in airway disease.In healthy volunteers without any bronchial hyperresponsiveness we targeted sequentially 1, 5 and 20 µg LPS to the airways and 5 µg LPS to the alveoli using controlled aerosol bolus inhalation. Inflammatory parameters were assessed during a 72 h time period. LPS deposited in the airways induced dose dependent systemic responses with increases of blood neutrophils (peaking at 6 h, Interleukin-6 (peaking at 6 h, body temperature (peaking at 12 h, and CRP (peaking at 24 h. 5 µg LPS targeted to the alveoli caused significantly stronger effects compared to 5 µg airway LPS deposition. Local responses were studied by measuring lung function (FEV(1 and reactive oxygen production, assessed by hydrogen peroxide (H(2O(2 in fractionated exhaled breath condensate (EBC. FEV(1 showed a dose dependent decline, with lowest values at 12 h post LPS challenge. There was a significant 2-fold H(2O(2 induction in airway-EBC at 2 h post LPS inhalation. Alveolar LPS targeting resulted in the induction of very low levels of EBC-H(2O(2.Targeting LPS to the alveoli leads to stronger systemic responses compared to airway LPS targeting. Targeted LPS inhalation may provide a novel model of airway inflammation for studying the role of LPS contamination of air pollution in lung diseases, exacerbation and anti-inflammatory drugs.

  20. Airway responses to sulfate and sulfuric acid aerosols in asthmatics. An exposure-response relationship.

    Science.gov (United States)

    Utell, M J; Morrow, P E; Speers, D M; Darling, J; Hyde, R W

    1983-09-01

    Epidemiologic studies support an association between elevated levels of sulfates and increased symptoms in asthmatics. To determine if these pollutants produce airway responses, 17 asthmatics inhaled the following sulfates: sodium bisulfate, ammonium sulfate, ammonium bisulfate (NH4HSO4), or sulfuric acid (H2SO4) aerosols with an aerodynamic diameter of 0.80 micron at concentrations of 100 micrograms/m3, 450 micrograms/m3, and 1,000 micrograms/m3. A sodium chloride (NaCl) aerosol of similar characteristics, administered by double-blind randomization, served as a control. Subjects breathed these aerosols for a 16-minute period via a mouthpiece. Deposition studies showed 54 to 65% retention of the inhaled aerosols. At the 1,000 micrograms/m3 concentration, the Threshold Limit Value for occupational exposure, H2SO4 and NH4HSO4 inhalation produced significant reductions in specific airway conductance (SGaw) (p less than 0.05) and forced expiratory volume in one second (p less than 0.01) compared with NaCl or pre-exposure values. At the 450 micrograms/m3 concentration, only H2SO4 inhalation produced a significant reduction in SGaw (p less than 0.01). At 100 micrograms/m3, a level 3 to 5 times greater than peak urban levels, no significant change in airway function occurred after any sulfate exposure. These data indicate that asthmatics demonstrate bronchoconstriction after brief exposure to common acidic sulfate pollutants.

  1. Effects of pincainide on contractile responses and /sup 45/Ca movements in rat isolated vascular smooth muscle

    Energy Technology Data Exchange (ETDEWEB)

    Barrigon, S.; Diez, J.J.; Tamargo, J.; Tejerina, M.T.

    1985-05-08

    The effects of pincainide, a new ..beta..-amino anilide, on contractile responses and /sup 45/Ca fluxes were studied in rat aorta and on spontaneous mechanical activity in rat portal veins. Pincainide (10/sup 5/ to 10/sup 2/ M) produced a dose-dependent inhibition of noradrenaline (NA) and high K/sup +/-induced contractions. These inhibitory effects were observed with pincainide added either before or after the induced contractions. The Ca/sup 2 +/-induced contractions of K/sup +/-depolarized aorta as well as the spontaneous mechanical activity of portal veins were also inhibited by pincainide. Pincainide (5 x 10/sup 3/ M) inhibited the /sup 45/Ca influx stimulated by 10/sup 6/ M NA and increased /sup 45/Ca efflux. It was concluded that in isolated rat aorta, pincainide not only inhibited the influx of Ca/sup 2 +/ reducing the contractile responses to NA and high K/sup +/ but it also inhibited other effects related to NA-induced release of intracellular Ca/sup 2 +/ stores.

  2. Fractalkine depresses cardiomyocyte contractility.

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    David Taube

    Full Text Available BACKGROUND: Our laboratory reported that male mice with cardiomyocyte-selective knockout of the prostaglandin E2 EP4 receptor sub-type (EP4 KO exhibit reduced cardiac function. Gene array on left ventricles (LV showed increased fractalkine, a chemokine implicated in heart failure. We therefore hypothesized that fractalkine is regulated by PGE2 and contributes to depressed contractility via alterations in intracellular calcium. METHODS: Fractalkine was measured in LV of 28-32 week old male EP4 KO and wild type controls (WT by ELISA and the effect of PGE2 on fractalkine secretion was measured in cultured neonatal cardiomyocytes and fibroblasts. The effect of fractalkine on contractility and intracellular calcium was determined in Fura-2 AM-loaded, electrical field-paced cardiomyocytes. Cardiomyocytes (AVM from male C57Bl/6 mice were treated with fractalkine and responses measured under basal conditions and after isoproterenol (Iso stimulation. RESULTS: LV fractalkine was increased in EP4 KO mice but surprisingly, PGE2 regulated fractalkine secretion only in fibroblasts. Fractalkine treatment of AVM decreased both the speed of contraction and relaxation under basal conditions and after Iso stimulation. Despite reducing contractility after Iso stimulation, fractalkine increased the Ca(2+ transient amplitude but decreased phosphorylation of cardiac troponin I, suggesting direct effects on the contractile machinery. CONCLUSIONS: Fractalkine depresses myocyte contractility by mechanisms downstream of intracellular calcium.

  3. Airway blood flow response to dry air hyperventilation in sheep

    Energy Technology Data Exchange (ETDEWEB)

    Parsons, G.H.; Baile, E.M.; Pare, P.D.

    1986-03-01

    Airway blood flow (Qaw) may be important in conditioning inspired air. To determine the effect of eucapneic dry air hyperventilation (hv) on Qaw in sheep the authors studied 7 anesthetized open-chest sheep after 25 min. of warm dry air hv. During each period of hv the authors have recorded vascular pressures, cardiac output (CO), and tracheal mucosal and inspired air temperature. Using a modification of the reference flow technique radiolabelled microspheres were injected into the left atrium to make separate measurements after humid air and dry air hv. In 4 animals a snare around the left main pulmonary artery was used following microsphere injection to prevent recirculation (entry into L lung of microspheres from the pulmonary artery). Qaw to the trachea and L lung as measured and Qaw for the R lung was estimated. After the final injection the sheep were killed and bronchi (Br) and lungs removed. Qaw (trachea plus L lung plus R lung) in 4 sheep increased from a mean of 30.8 to 67.0 ml/min. Airway mucosal temp. decreased from 39/sup 0/ to 33/sup 0/C. The authors conclude that dry air hv cools airway mucosa and increases Qaw in sheep.

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

    Science.gov (United States)

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

    2016-03-01

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

  5. Nebulized lidocaine blunts airway hyper-responsiveness in experimental feline asthma.

    Science.gov (United States)

    Nafe, Laura A; Guntur, Vamsi P; Dodam, John R; Lee-Fowler, Tekla M; Cohn, Leah A; Reinero, Carol R

    2013-08-01

    Nebulized lidocaine may be a corticosteroid-sparing drug in human asthmatics, reducing airway resistance and peripheral blood eosinophilia. We hypothesized that inhaled lidocaine would be safe in healthy and experimentally asthmatic cats, diminishing airflow limitation and eosinophilic airway inflammation in the latter population. Healthy (n = 5) and experimentally asthmatic (n = 9) research cats were administered 2 weeks of nebulized lidocaine (2 mg/kg q8h) or placebo (saline) followed by a 2-week washout and crossover to the alternate treatment. Cats were anesthetized to measure the response to inhaled methacholine (MCh) after each treatment. Placebo and doubling doses of methacholine (0.0625-32.0000 mg/ml) were delivered and results were expressed as the concentration of MCh increasing baseline airway resistance by 200% (EC200Raw). Bronchoalveolar lavage was performed after each treatment and eosinophil numbers quantified. Bronchoalveolar lavage fluid (BALF) % eosinophils and EC200Raw within groups after each treatment were compared using a paired t-test (P eosinophils in asthmatic cats treated with lidocaine (36±10%) or placebo (33 ± 6%). However, lidocaine increased the EC200Raw compared with placebo 10 ± 2 versus 5 ± 1 mg/ml; P = 0.043). Chronic nebulized lidocaine was well-tolerated in all cats, and lidocaine did not induce airway inflammation or airway hyper-responsiveness in healthy cats. Lidocaine decreased airway response to MCh in asthmatic cats without reducing airway eosinophilia, making it unsuitable for monotherapy. However, lidocaine may serve as a novel adjunctive therapy in feline asthmatics with beneficial effects on airflow obstruction.

  6. Hemodynamic responses and upper airway morbidity following tracheal intubation in patients with hypertension: conventional laryngoscopy versus an intubating laryngeal mask airway

    Directory of Open Access Journals (Sweden)

    Elif Bengi Sener

    2012-01-01

    Full Text Available OBJECTIVES: We compared hemodynamic responses and upper airway morbidity following tracheal intubation via conventional laryngoscopy or intubating laryngeal mask airway in hypertensive patients. METHODS: Forty-two hypertensive patients received a conventional laryngoscopy or were intubated with a intubating laryngeal mask airway. Anesthesia was induced with propofol, fentanyl, and cis-atracurium. Measurements of systolic and diastolic blood pressures, heart rate, rate pressure product, and ST segment changes were made at baseline, preintubation, and every minute for the first 5 min following intubation. The number of intubation attempts, the duration of intubation, and airway complications were recorded. RESULTS: The intubation time was shorter in the conventional laryngoscopy group than in the intubating laryngeal mask airway group (16.33 ± 10.8 vs. 43.04±19.8 s, respectively (p<0.001. The systolic and diastolic blood pressures in the intubating laryngeal mask airway group were higher than those in the conventional laryngoscopy group at 1 and 2 min following intubation (p<0.05. The rate pressure product values (heart rate x systolic blood pressure at 1 and 2 min following intubation in the intubating laryngeal mask airway group (15970.90 ± 3750 and 13936.76 ± 2729, respectively were higher than those in the conventional laryngoscopy group (13237.61 ± 3413 and 11937.52 ± 3160, respectively (p<0.05. There were no differences in ST depression or elevation between the groups. The maximum ST changes compared with baseline values were not significant between the groups (conventional laryngoscopy group: 0.328 mm versus intubating laryngeal mask airway group: 0.357 mm; p = 0.754. The number and type of airway complications were similar between the groups. CONCLUSION: The intense and repeated oropharyngeal and tracheal stimulation resulting from intubating laryngeal mask airway induces greater pressor responses than does stimulation resulting from

  7. Respiratory symptoms and airway responsiveness in apparently healthy workers exposed to flour dust.

    Science.gov (United States)

    Bohadana, A B; Massin, N; Wild, P; Kolopp, M N; Toamain, J P

    1994-06-01

    Our aim was to measure the levels of exposure to wheat flour dust in a modern industrial bakery, and to assess the relationship between respiratory symptoms, sensitization to wheat flour antigens and airway responsiveness in the workforce. Forty four flour-exposed male workers and 164 unexposed controls were examined. Inspirable dust concentrations were measured using personal samplers. Respiratory symptoms were assessed by questionnaire, sensitization to wheat flour antigens by skin-prick tests, and methacholine airway challenge (MAC) test using an abbreviated method. Subjects were labelled MAC+ if forced expiratory volume in one second (FEV1) fell by 20% or more. The linear dose-response slope (DRS) was calculated as the percentage fall in FEV1 at last dose divided by the total dose administered. Inspirable dust concentrations were within acceptable limits in all working areas but one. The proportion of subjects with one or more symptoms and with airway hyperresponsiveness was significantly greater among flour-exposed workers than among controls. Using logistic or linear regression analysis, airway responsiveness was found to be strongly related to working at the bakery and to the baseline level of lung function. A positive skin-prick test was found in only 11% of flour-exposed workers and 6% of controls. In conclusion, our data show that despite exposure to relatively low concentration levels of inspirable flour dust, subjects working in the baking industry are at risk of developing both respiratory symptoms and airway hyperresponsiveness.

  8. Increased Contractile Response to Noradrenaline Induced By Factors Associated with the Metabolic Syndrome in Cultured Small Mesenteric Arteries

    DEFF Research Database (Denmark)

    Blædel, Martin; Sams, Anette; Boonen, Harrie C M

    2016-01-01

    UNLABELLED: This study investigated the effect of the metabolic syndrome associated risk factors hyperglycemia (glucose [Glc]), hyperinsulinemia (insulin [Ins]) and low-grade inflammation (tumor necrosis factor α [TNFα]) on the vasomotor responses of resistance arteries. Isolated small mesenteric...... arteries from 3-month-old Sprague-Dawley rats, were suspended for 21-23 h in tissue cultures containing either elevated Glc (30 mmol/l), Ins (100 nmol/l), TNFα (100 ng/ml) or combinations thereof. After incubation, the vascular response to noradrenaline (NA), phenylephrine, isoprenaline and NA...... in the presence of propranolol (10 µmol/l) was measured by wire myography. RESULTS: Arteries exposed only to combinations of the risk factors showed a significant 1.6-fold increase in the contractile NA sensitivity, which suggests that complex combinations of metabolic risk factors might lead to changes...

  9. Inhibition of neutrophil elastase attenuates airway hyperresponsiveness and inflammation in a mouse model of secondary allergen challenge: neutrophil elastase inhibition attenuates allergic airway responses

    Directory of Open Access Journals (Sweden)

    Koga Hikari

    2013-01-01

    Full Text Available Abstract Background Chronic asthma is often associated with neutrophilic infiltration in the airways. Neutrophils contain elastase, a potent secretagogue in the airways, nonetheless the role for neutrophil elastase as well as neutrophilic inflammation in allergen-induced airway responses is not well defined. In this study, we have investigated the impact of neutrophil elastase inhibition on the development of allergic airway inflammation and airway hyperresponsiveness (AHR in previously sensitized and challenged mice. Methods BALB/c mice were sensitized and challenged (primary with ovalbumin (OVA. Six weeks later, a single OVA aerosol (secondary challenge was delivered and airway inflammation and airway responses were monitored 6 and 48 hrs later. An inhibitor of neutrophil elastase was administered prior to secondary challenge. Results Mice developed a two-phase airway inflammatory response after secondary allergen challenge, one neutrophilic at 6 hr and the other eosinophilic, at 48 hr. PAR-2 expression in the lung tissues was enhanced following secondary challenge, and that PAR-2 intracellular expression on peribronchial lymph node (PBLN T cells was also increased following allergen challenge of sensitized mice. Inhibition of neutrophil elastase significantly attenuated AHR, goblet cell metaplasia, and inflammatory cell accumulation in the airways following secondary OVA challenge. Levels of IL-4, IL-5 and IL-13, and eotaxin in BAL fluid 6 hr after secondary allergen challenge were significantly suppressed by the treatment. At 48 hr, treatment with the neutrophil elastase inhibitor significantly reduced the levels of IL-13 and TGF-β1 in the BAL fluid. In parallel, in vitro IL-13 production was significantly inhibited in spleen cells from sensitized mice. Conclusion These data indicate that neutrophil elastase plays an important role in the development of allergic airway inflammation and hyperresponsiveness, and would suggest that the

  10. Comparison of gel contraction mediated by airway smooth muscle cells from patients with and without asthma

    NARCIS (Netherlands)

    Matsumoto, Hisako; Moir, Lyn M; Oliver, Brian G G; Burgess, Janette K; Roth, Michael; Black, Judith L; McParland, Brent E

    2007-01-01

    BACKGROUND: Exaggerated bronchial constriction is the most significant and life threatening response of patients with asthma to inhaled stimuli. However, few studies have investigated the contractility of airway smooth muscle (ASM) from these patients. The purpose of this study was to establish a me

  11. Antioxidant airway responses following experimental exposure to wood smoke in man

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    Sehlstedt Maria

    2010-08-01

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

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

    NARCIS (Netherlands)

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

    2015-01-01

    Increased airway responsiveness is linked to lung function decline and mortality in subjects with chronic obstructive pulmonary disease (COPD); however, the genetic contribution to airway responsiveness remains largely unknown. A genome-wide association study (GWAS) was performed using the Illumina

  13. Phenotypic responses of differentiated asthmatic human airway epithelial cultures to rhinovirus.

    Directory of Open Access Journals (Sweden)

    Jianwu Bai

    Full Text Available Human airway epithelial cells are the principal target of human rhinovirus (HRV, a common cold pathogen that triggers the majority of asthma exacerbations. The objectives of this study were 1 to evaluate an in vitro air liquid interface cultured human airway epithelial cell model for HRV infection, and 2 to identify gene expression patterns associated with asthma intrinsically and/or after HRV infection using this model.Air-liquid interface (ALI human airway epithelial cell cultures were prepared from 6 asthmatic and 6 non-asthmatic donors. The effects of rhinovirus RV-A16 on ALI cultures were compared. Genome-wide gene expression changes in ALI cultures following HRV infection at 24 hours post exposure were further analyzed using RNA-seq technology. Cellular gene expression and cytokine/chemokine secretion were further evaluated by qPCR and a Luminex-based protein assay, respectively.ALI cultures were readily infected by HRV. RNA-seq analysis of HRV infected ALI cultures identified sets of genes associated with asthma specific viral responses. These genes are related to inflammatory pathways, epithelial structure and remodeling and cilium assembly and function, including those described previously (e.g. CCL5, CXCL10 and CX3CL1, MUC5AC, CDHR3, and novel ones that were identified for the first time in this study (e.g. CCRL1.ALI-cultured human airway epithelial cells challenged with HRV are a useful translational model for the study of HRV-induced responses in airway epithelial cells, given that gene expression profile using this model largely recapitulates some important patterns of gene responses in patients during clinical HRV infection. Furthermore, our data emphasize that both abnormal airway epithelial structure and inflammatory signaling are two important asthma signatures, which can be further exacerbated by HRV infection.

  14. IL-17A modulates oxidant stress-induced airway hyperresponsiveness but not emphysema.

    Science.gov (United States)

    Pinart, Mariona; Zhang, Min; Li, Feng; Hussain, Farhana; Zhu, Jie; Wiegman, Coen; Ryffel, Bernard; Chung, Kian Fan

    2013-01-01

    IL-17A induces the release of pro-inflammatory cytokines and of reactive oxygen species which could lead to neutrophilic inflammation. We determined the role of IL-17 receptor (IL-17R) signalling in oxidant-induced lung emphysema and airway hyperresponsiveness. IL-17R(-/-) and wild-type C57/BL6 mice were exposed to ozone (3 ppm; 3 hours) for 12 times over 6 weeks. Bronchial responsiveness to acetylcholine was measured, and lungs were retrieved. Mean linear intercept (Lm) and isometric contractile responses of intrapulmonary airways to acetylcholine were determined. In wild-type mice but not in IL-17R(-/-), chronic ozone exposure caused airway hyperresponsiveness. The increase in Lm after chronic ozone exposure of wild-type mice was also observed in IL-17R(-/-) mice. The increased maximal contractile response to acetylcholine seen in airways of wild-type mice exposed to ozone was abolished in IL-17R(-/-) mice. p38-mitogen-activated protein kinase (MAPK) and dexamethasone-dependent increase in contractile response was reduced in airways from IL-17R(-/-) ozone-exposed mice. Lung inflammation scores were not altered in IL-17R(-/-) mice exposed to ozone compared to wild-type mice. The increased release of IL-17 and IL-1β, and the activation of p38 MAPK in the lungs of ozone-exposed mice was reduced in IL-17R(-/-) mice. IL-17R signalling underlies the increase in airway hyperresponsiveness seen after ozone exposure, mediated by the increased contractility of airway smooth muscle. The emphysema and lung inflammation induced by ozone is not dependent on IL-17.

  15. IL-17A modulates oxidant stress-induced airway hyperresponsiveness but not emphysema.

    Directory of Open Access Journals (Sweden)

    Mariona Pinart

    Full Text Available IL-17A induces the release of pro-inflammatory cytokines and of reactive oxygen species which could lead to neutrophilic inflammation. We determined the role of IL-17 receptor (IL-17R signalling in oxidant-induced lung emphysema and airway hyperresponsiveness. IL-17R(-/- and wild-type C57/BL6 mice were exposed to ozone (3 ppm; 3 hours for 12 times over 6 weeks. Bronchial responsiveness to acetylcholine was measured, and lungs were retrieved. Mean linear intercept (Lm and isometric contractile responses of intrapulmonary airways to acetylcholine were determined. In wild-type mice but not in IL-17R(-/-, chronic ozone exposure caused airway hyperresponsiveness. The increase in Lm after chronic ozone exposure of wild-type mice was also observed in IL-17R(-/- mice. The increased maximal contractile response to acetylcholine seen in airways of wild-type mice exposed to ozone was abolished in IL-17R(-/- mice. p38-mitogen-activated protein kinase (MAPK and dexamethasone-dependent increase in contractile response was reduced in airways from IL-17R(-/- ozone-exposed mice. Lung inflammation scores were not altered in IL-17R(-/- mice exposed to ozone compared to wild-type mice. The increased release of IL-17 and IL-1β, and the activation of p38 MAPK in the lungs of ozone-exposed mice was reduced in IL-17R(-/- mice. IL-17R signalling underlies the increase in airway hyperresponsiveness seen after ozone exposure, mediated by the increased contractility of airway smooth muscle. The emphysema and lung inflammation induced by ozone is not dependent on IL-17.

  16. Arsenic alters ATP-dependent Ca²+ signaling in human airway epithelial cell wound response.

    Science.gov (United States)

    Sherwood, Cara L; Lantz, R Clark; Burgess, Jefferey L; Boitano, Scott

    2011-05-01

    Arsenic is a natural metalloid toxicant that is associated with occupational inhalation injury and contaminates drinking water worldwide. Both inhalation of arsenic and consumption of arsenic-tainted water are correlated with malignant and nonmalignant lung diseases. Despite strong links between arsenic and respiratory illness, underlying cell responses to arsenic remain unclear. We hypothesized that arsenic may elicit some of its detrimental effects on the airway through limitation of innate immune function and, specifically, through alteration of paracrine ATP (purinergic) Ca²+ signaling in the airway epithelium. We examined the effects of acute (24 h) exposure with environmentally relevant levels of arsenic (i.e., salt and water transport, bactericide production, and wound repair). Arsenic-induced compromise of such airway defense mechanisms may be an underlying contributor to chronic lung disease.

  17. Specific immune responses against airway epithelial cells in a transgenic mouse-trachea transplantation model for obliterative airway disease

    NARCIS (Netherlands)

    Qu, N; de Haan, A; Harmsen, MC; Kroese, FGM; de Leij, LFMH; Prop, J

    2003-01-01

    Background. Immune injury to airway epithelium is suggested to play a central role in the pathogenesis of obliterative bronchiolitis (OB) after clinical lung transplantation. In several studies, a rejection model of murine trachea transplants is used, resulting in obliterative airway disease (OAD) w

  18. Effects of single or repeated administration of a carbamate, propoxur, and an organophosphate, DDVP, on jejunal cholinergic activities and contractile responses in rats.

    Science.gov (United States)

    Kobayashi, H; Sato, I; Akatsu, Y; Fujii, S; Suzuki, T; Matsusaka, N; Yuyama, A

    1994-01-01

    Wistar rats were injected once or repeatedly for 10 days with dichlorvos (DDVP, 5 mg kg-1), propoxur (10 mg kg-1), oxotremorine (0.1 mg kg-1) or atropine (5 mg kg-1). Animals were killed 20 min or 24 h after single or consecutive injections, respectively, for determinations of cholinergic activities and contractile responses to acetylcholine (ACh) of the jejunum. Single treatments: while DDVP and propoxur decreased acetylcholinesterase (AChE) activity, oxotremorine and atropine did not. Although DDVP, propoxur and oxotremorine increased levels of ACh, atropine decreased them. Contractile responses to ACh were enhanced by DDVP and reduced by oxotremorine and atropine. The Bmax value of binding of [3H]quinuclidinyl benzylate (QNB) to muscarinic ACh receptors was decreased by atropine. Consecutive treatments: DDVP and oxotremorine decreased AChE activity markedly and slightly, respectively. Although DDVP and oxotremorine increased levels of ACh, propoxur decreased them. Without affecting the contractile responses, DDVP caused a reduction and propoxur and atropine caused an increase in the Bmax value for binding of [3H]QNB. Both the contractile responses and the value of Bmax for binding of [3H]-QNB were decreased by oxotremorine. In summary, propoxur and DDVP showed similar effects mainly through their anticholinesterase properties in the case of single injection, but DDVP had similar effects to those of oxotremorine and propoxur had similar effects to those of atropine in the case of repeated injection.

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

    DEFF Research Database (Denmark)

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

    2016-01-01

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

  20. Defective excitation-contraction coupling is partially responsible for impaired contractility in hindlimb muscles of Stac3 knockout mice

    Science.gov (United States)

    Cong, Xiaofei; Doering, Jonathan; Grange, Robert W.; Jiang, Honglin

    2016-01-01

    The Stac3 gene is exclusively expressed in skeletal muscle, and Stac3 knockout is perinatal lethal in mice. Previous data from Stac3-deleted diaphragms indicated that Stac3-deleted skeletal muscle could not contract because of defective excitation-contraction (EC) coupling. In this study, we determined the contractility of Stac3-deleted hindlimb muscle. In response to frequent electrostimulation, Stac3-deleted hindlimb muscle contracted but the maximal tension generated was only 20% of that in control (wild type or heterozygous) muscle (P < 0.05). In response to high [K+], caffeine, and 4-chloro-m-cresol (4-CMC), the maximal tensions generated in Stac3-deleted muscle were 29% (P < 0.05), 58% (P = 0.08), and 55% (P < 0.05) of those in control muscle, respectively. In response to 4-CMC or caffeine, over 90% of myotubes formed from control myoblasts contracted, but only 60% of myotubes formed from Stac3-deleted myoblasts contracted (P = 0.05). However, in response to 4-CMC or caffeine, similar increases in intracellular calcium concentration were observed in Stac3-deleted and control myotubes. Gene expression and histological analyses revealed that Stac3-deleted hindlimb muscle contained more slow type-like fibers than control muscle. These data together confirm a critical role of STAC3 in EC coupling but also suggest that STAC3 may have additional functions in skeletal muscle, at least in the hindlimb muscle. PMID:27184118

  1. Impact of Adiponectin Overexpression on Allergic Airways Responses in Mice

    Directory of Open Access Journals (Sweden)

    Norah G. Verbout

    2013-01-01

    Full Text Available Obesity is an important risk factor for asthma. Obese individuals have decreased circulating adiponectin, an adipose-derived hormone with anti-inflammatory properties. We hypothesized that transgenic overexpression of adiponectin would attenuate allergic airways inflammation and mucous hyperplasia in mice. To test this hypothesis, we used mice overexpressing adiponectin (Adipo Tg. Adipo Tg mice had marked increases in both serum adiponectin and bronchoalveolar lavage (BAL fluid adiponectin. Both acute and chronic ovalbumin (OVA sensitization and challenge protocols were used. In both protocols, OVA-induced increases in total BAL cells were attenuated in Adipo Tg versus WT mice. In the acute protocol, OVA-induced increases in several IL-13 dependent genes were attenuated in Adipo Tg versus WT mice, even though IL-13 per se was not affected. With chronic exposure, though OVA-induced increases in goblet cells numbers per millimeter of basement membrane were greater in Adipo Tg versus WT mice, mRNA abundance of mucous genes in lungs was not different. Also, adiponectin overexpression did not induce M2 polarization in alveolar macrophages. Our results indicate that adiponectin protects against allergen-induced inflammatory cell recruitment to the airspaces, but not development of goblet cell hyperplasia.

  2. Airway Responsiveness: Role of Inflammation, Epithelium Damage and Smooth Muscle Tension

    Directory of Open Access Journals (Sweden)

    K. I. Gourgoulianis

    1999-01-01

    Full Text Available The purpose of this study was the effect of epithelium damage on mechanical responses of airway smooth muscles under different resting tension. We performed acetylcholine (ACh (10-5M-induced contraction on tracheal strips from 30 rabbits in five groups (0.5, 1, 1.5, 2 and 2.5 g before and after epithelium removal. At low resting tension (0.5-1.5g, the epithelium removal decreased the ACh-induced contractions. At 2g resting tension, the epithelium removal increased the ACh-induced contractions of airways with intact epithelium about 20%. At 2.5 g resting tension, the elevation of contraction is about 25% (p<0.01. Consequently, after epithelium loss, the resting tension determines the airway smooth muscles responsiveness. In asthma, mediators such as ACh act on already contracted inflammatory airways, which results in additional increase of contraction. In contrast, low resting tension, a condition that simulates normal tidal breathing, protects from bronchoconstriction even when the epithelium is damaged.

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

    Directory of Open Access Journals (Sweden)

    Daly Melissa

    2006-08-01

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

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

    Directory of Open Access Journals (Sweden)

    Eastwood Peter R

    2010-01-01

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

  5. 20-HETE mediates ozone-induced, neutrophil-independent airway hyper-responsiveness in mice.

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    Philip R Cooper

    Full Text Available BACKGROUND: Ozone, a pollutant known to induce airway hyper-responsiveness (AHR, increases morbidity and mortality in patients with obstructive airway diseases and asthma. We postulate oxidized lipids mediate in vivo ozone-induced AHR in murine airways. METHODOLOGY/PRINCIPAL FINDINGS: Male BALB/c mice were exposed to ozone (3 or 6 ppm or filtered air (controls for 2 h. Precision cut lung slices (PCLS; 250 microm thickness containing an intrapulmonary airway ( approximately 0.01 mm(2 lumen area were prepared immediately after exposure or 16 h later. After 24 h, airways were contracted to carbachol (CCh. Log EC(50 and E(max values were then calculated by measuring the airway lumen area with respect to baseline. In parallel studies, dexamethasone (2.5 mg/kg, or 1-aminobenzotriazol (ABT (50 mg/kg were given intraperitoneal injection to naïve mice 18 h prior to ozone exposure. Indomethacin (10 mg/kg was administered 2 h prior. Cell counts, cytokine levels and liquid chromatography-mass spectrometry (LC-MS for lipid analysis were assessed in bronchoalveolar lavage (BAL fluid from ozone exposed and control mice. Ozone acutely induced AHR to CCh. Dexamethasone or indomethacin had little effect on the ozone-induced AHR; while, ABT, a cytochrome P450 inhibitor, markedly attenuated airway sensitivity. BAL fluid from ozone exposed animals, which did not contain an increase in neutrophils or interleukin (IL-6 levels, increased airway sensitivity following in vitro incubation with a naïve PCLS. In parallel, significant increases in oxidized lipids were also identified using LC-MS with increases of 20-HETE that were decreased following ABT treatment. CONCLUSIONS/SIGNIFICANCE: These data show that ozone acutely induces AHR to CCh independent of inflammation and is insensitive to steroid treatment or cyclooxygenase (COX inhibition. BAL fluid from ozone exposed mice mimicked the effects of in vivo ozone exposure that were associated with marked increases in

  6. Endothelin-1-induced modulation of contractile responses elicited by an alpha 1-adrenergic agonist on human corpus cavernosum smooth muscle.

    Science.gov (United States)

    Kim, D C; Gondré, C M; Christ, G J

    1996-03-01

    The goal of these studies was to examine endothelin-1 (ET-1)-induced modulation of contractile responses elicited by the selective alpha 1-adrenergic agonist, phenylephrine (PE), on isolated human corporal tissue strips. Pharmacological studies were conducted on human corporal tissue strips obtained from 22 patients undergoing implantation of penile prostheses for erectile dysfunction. For the purposes of statistical analysis, the patients were stratified into two age groups: A, age or = 60 y (n = 12). The patients were further sub-divided into two diagnostic categories, diabetics (DM, n = 9) and nondiabetics (ND, n = 13). Cumulative concentration-response curves (CRCs) were constructed to the alpha 1-adrenergic agonist, PE, prior to constructing a CRC to a single mixture of PE and ET-1 on the same tissue. A previously described fixed molar ratio (FMR) protocol was used to generate CRCs to mixtures of PE and ET-1. In all cases, for the PE:ET-1 FMRs of 90:10, 80:20 and 70:30, the partial substitution of PE with ET-1 resulted in an approx 3-fold leftward shift in the EC50 of the PE alone CRC with an approx 4% concomitant increase in Emax and a decrease in the slope factor value. There were no significant age- or disease-related differences in any of the logistic parameter estimates that describe the FMR CRC, indicating that there are no detectable age- or disease-related alterations in ET-1-induced amplification of alpha 1-adrenergic-mediated contractions in these studies. In addition, the location of the FMR CRC was precisely predicted by the theoretical CRC for simple additivity of agonist effects. In conclusion, since relatively small increases in ET-1 concentrations were associated with significant increases in alpha 1-adrenergic-mediated contractile responses, these data provide further testimony to the importance of ET-1 in modulating corporal smooth muscle tone, and moreover, establish a conceptual framework for understanding the mechanism of its action(s).

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

    NARCIS (Netherlands)

    Oliver, Brian G G; Johnston, Sebastian L; Baraket, Melissa; Burgess, Janette K; King, Nicholas J C; Roth, Michael; Lim, Sam; Black, Judith L

    2006-01-01

    BACKGROUND: Exacerbations of asthma are associated with viral respiratory tract infections, of which rhinoviruses (RV) are the predominant virus type. Airway smooth muscle is important in asthma pathogenesis, however little is known about the potential interaction of RV and human airway smooth muscl

  8. Establishment of Allergic Airway Inflammation Model in Late- phase Response of Sprague- Dawley Rats

    Institute of Scientific and Technical Information of China (English)

    朱敏敏; 傅诚章; 周钦海

    2002-01-01

    Objective To establish allergic airway inflammation model in late-phase airwayreaction of Sprague-Dawley (SD) rats. Methods Thirty-six SD rats were randomly divided intothree groups: control group (Group Ⅰ),single challenge group (Group Ⅱ),consecutive challenge group(Group Ⅲ). The rats in Group Ⅱ and Group Ⅲ were sensitized twice by injection of ovalbumin (OA) to-gether with aluminum hydroxide and Bordetella pertussis as adjuvants, followed by challenge withaerosolized OA for 20 min once in Group Ⅱ or one time on each day for one week in Group Ⅲ . Therats in Group Ⅰ received 0.9 % saline by injection and inhalation. Results Conpared uith groupⅠ , there were positive symptoms observed in the group Ⅱ and group Ⅲ; the amount of total leucocytesand eosinophil percentage in brochoalveolar lauage fluid (BALF) significantly increased (P<0.05 orP <0.01 respectively) in Group Ⅱ or Ⅲ; histopathologic changes of lung showed acute allergic inflam-mation changes in Group Ⅱ : Disrupted epithelium damaged subepithelial structure and eosinophil infiltra-tion the in the airway wall. As for the Group Ⅲ , there were allergen-induced characteristic features ofchronic allergic airways inflammation: hypertrophy and hyperplasia of bronchial smooth muscle, gobletcell hyperplasia , basement membrane thickening, eosinophil infiltration, edema. Conclusion The mod-el of allergic airway inflammation in late-phase response of SD rats was successfully established by OAsensitization (twice) and consecutive challenge.

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

    Science.gov (United States)

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

  10. Contractile abnormalities and altered drug response in engineered heart tissue from Mybpc3-targeted knock-in mice.

    Science.gov (United States)

    Stöhr, Andrea; Friedrich, Felix W; Flenner, Frederik; Geertz, Birgit; Eder, Alexandra; Schaaf, Sebastian; Hirt, Marc N; Uebeler, June; Schlossarek, Saskia; Carrier, Lucie; Hansen, Arne; Eschenhagen, Thomas

    2013-10-01

    Myosin-binding protein C (Mybpc3)-targeted knock-in mice (KI) recapitulate typical aspects of human hypertrophic cardiomyopathy. We evaluated whether these functional alterations can be reproduced in engineered heart tissue (EHT) and yield novel mechanistic information on the function of cMyBP-C. EHTs were generated from cardiac cells of neonatal KI, heterozygous (HET) or wild-type controls (WT) and developed without apparent morphological differences. KI had 70% and HET 20% lower total cMyBP-C levels than WT, accompanied by elevated fetal gene expression. Under standard culture conditions and spontaneous beating, KI EHTs showed more frequent burst beating than WT and occasional tetanic contractions (14/96). Under electrical stimulation (6Hz, 37°C) KI EHTs exhibited shorter contraction and relaxation times and a twofold higher sensitivity to external [Ca(2+)]. Accordingly, the sensitivity to verapamil was 4-fold lower and the response to isoprenaline or the Ca(2+) sensitizer EMD 57033 2- to 4-fold smaller. The loss of EMD effect was verified in 6-week-old KI mice in vivo. HET EHTs were apparently normal under basal conditions, but showed similarly altered contractile responses to [Ca(2+)], verapamil, isoprenaline and EMD. In contrast, drug-induced changes in intracellular Ca(2+) transients (Fura-2) were essentially normal. In conclusion, the present findings in auxotonically contracting EHTs support the idea that cMyBP-C's normal role is to suppress force generation at low intracellular Ca(2+) and stabilize the power-stroke step of the cross bridge cycle. Pharmacological testing in EHT unmasked a disease phenotype in HET. The altered drug response may be clinically relevant.

  11. Humoral immune response against contractile proteins (actin and myosin) during cardiovascular disease.

    Science.gov (United States)

    De Scheerder, I K; De Buyzere, M; Delanghe, J; Maas, A; Clement, D L; Wieme, R

    1991-08-01

    Sensitive and highly specific ELISA assays were developed to determine humoral immune response against actin and myosin in 122 patients suffering from various cardiovascular diseases: acute viral myocarditis (n = 10, MYO), acute myocardial infarction (n = 28, AMI), valve surgery (n = 35, VALVE), coronary bypass surgery (n = 35, CABG), and peripheral vascular surgery (n = 14, VASC). Anti-actin and anti-myosin antibodies were determined on admission and serially during a period of 90 days. Anti-actin and anti-myosin immune response (IgG, IgM) was expressed comparing absorbance of the patients' serum with a reference serum. In the different patient groups significantly (P less than 0.01) higher anti-actin and anti-myosin antibody concentrations were found on admission compared with age-matched control groups. During follow-up, all patient groups except the vascular surgery group showed a significant immune response against actin and myosin, with an immune response ratio (peak/admission) for AMA IgG and IgM respectively of 2.12 and 2.40 in the VALVE group, 1.30 and 1.99 in the CABG group, 1.42 and 1.48 in the AMI group and 1.66 and 1.25 in the MYO group; and for AAA IgG and IgM respectively of 1.57 and 3.00 in the VALVE group, 1.54 and 1.64 in the CABG group, 1.25 and 1.07 in the AMI group, and 1.42 and 1.42 in the MYO group. A significant correlation between pre-cardiac injury and peak post-cardiac injury anti-myosin and anti-actin autoantibody levels could be demonstrated suggesting that pre-injury sensitization to these antigens plays an important role in evoking post-cardiac injury immune response.(ABSTRACT TRUNCATED AT 250 WORDS)

  12. In vivo role of platelet-derived growth factor-BB in airway smooth muscle proliferation in mouse lung.

    Science.gov (United States)

    Hirota, Jeremy A; Ask, Kjetil; Farkas, Laszlo; Smith, Jane Ann; Ellis, Russ; Rodriguez-Lecompte, Juan Carlos; Kolb, Martin; Inman, Mark D

    2011-09-01

    Airway smooth muscle (ASM) hyperplasia in asthma likely contributes considerably to functional changes. Investigating the mechanisms behind proliferation of these cells may lead to therapeutic benefit. Platelet-derived growth factor (PDGF)-BB is a well known ASM mitogen in vitro but has yet to be directly explored using in vivo mouse models in the context of ASM proliferation and airway responsiveness. To determine the in vivo influence of PDGF-BB on gene transcripts encoding contractile proteins, ASM proliferation, and airway physiology, we used an adenovirus overexpression system and a model of chronic allergen exposure. We used adenovirus technology to selectively overexpress PDGF-BB in the airway epithelium of mice. Outcome measurements, including airway physiology, real time RT-PCR measurements, proliferating cell nuclear antigen staining, and airway smooth muscle quantification, were performed 7 days after exposure. The same outcome measurements were performed 24 hours and 4 weeks after a chronic allergen exposure model. PDGF-BB overexpression resulted in airway hyperresponsiveness, decreased lung compliance, increased airway smooth muscle cell numbers, positive proliferating cell nuclear antigen-stained airway smooth muscle cells, and a reduction in genes encoding contractile proteins. Chronic allergen exposure resulted in elevations in lung lavage PDGF-BB, which were observed in conjunction with changes in gene transcript expression encoding contractile proteins and ASM proliferation. We demonstrate for the first time in vivo that PDGF-BB induces ASM hyperplasia and changes in lung mechanics in mice and that, during periods of allergen exposure changes in lung, PDGF-BB are associated with changes in airway structure and function.

  13. Consecutive bouts of diverse contractile activity alter acute responses in human skeletal muscle

    DEFF Research Database (Denmark)

    Coffey, Vernon G; Pilegaard, Henriette; Garnham, Andrew P

    2009-01-01

    assigned to complete trials consisting of either resistance exercise (8 x 5 leg extension, 80% 1 repetition maximum) followed by a bout of endurance exercise (30 min cycling, 70% Vo(2peak)) or vice versa. Muscle biopsies were obtained from the vastus lateralis at rest, 15 min after each exercise bout......, and after 3 h of passive recovery to determine early signaling and mRNA responses. Phosphorylation of Akt and Akt1(Ser473) were elevated 15 min after resistance exercise compared with cycling, with the greatest increase observed when resistance exercise followed cycling ( approximately 55%; P ...-mTOR-S6 kinase phosphorylation 15 min after each bout of exercise was similar regardless of the exercise mode. The cumulative effect of combined exercise resulted in disparate mRNA responses. IGF-I mRNA content was reduced when cycling preceded resistance exercise (-42%), whereas muscle ring finger...

  14. Cessation of dexamethasone exacerbates airway responses to methacholine in asthmatic mice.

    Science.gov (United States)

    Stengel, Peter W; Nickell, Laura E; Wolos, Jeffrey A; Snyder, David W

    2007-06-01

    In asthmatic mice, dexamethasone (30.0 mg/kg) was administered orally once daily on Days 24-27. One hour after dexamethasone on Day 25-27, the mice were exposed to ovalbumin aerosols. Twenty-eight days after the initial ovalbumin immunization, we found that dexamethasone reduced methacholine-induced pulmonary gas trapping and inhibited bronchoalveolar lavage eosinophils and neutrophils. However, five days after the last dose of dexamethasone and last ovalbumin aerosol exposure in other asthmatic mice, the airway obstructive response to methacholine was exacerbated in dexamethasone-treated mice compared to vehicle-treated mice on Day 32. Further, eosinophils, but not neutrophils, were still inhibited after cessation of dexamethasone. Thus, discontinuing dexamethasone worsened methacholine-induced pulmonary gas trapping of asthmatic mice in the absence of eosinophilic airway inflammation.

  15. Cystic fibrosis gene modifier SLC26A9 modulates airway response to CFTR-directed therapeutics.

    Science.gov (United States)

    Strug, Lisa J; Gonska, Tanja; He, Gengming; Keenan, Katherine; Ip, Wan; Boëlle, Pierre-Yves; Lin, Fan; Panjwani, Naim; Gong, Jiafen; Li, Weili; Soave, David; Xiao, Bowei; Tullis, Elizabeth; Rabin, Harvey; Parkins, Michael D; Price, April; Zuberbuhler, Peter C; Corvol, Harriet; Ratjen, Felix; Sun, Lei; Bear, Christine E; Rommens, Johanna M

    2016-08-29

    Cystic fibrosis is realizing the promise of personalized medicine. Recent advances in drug development that target the causal CFTR directly result in lung function improvement, but variability in response is demanding better prediction of outcomes to improve management decisions. The genetic modifier SLC26A9 contributes to disease severity in the CF pancreas and intestine at birth and here we assess its relationship with disease severity and therapeutic response in the airways. SLC26A9 association with lung disease was assessed in individuals from the Canadian and French CF Gene Modifier consortia with CFTR-gating mutations and in those homozygous for the common Phe508del mutation. Variability in response to a CFTR-directed therapy attributed to SLC26A9 genotype was assessed in Canadian patients with gating mutations. A primary airway model system determined if SLC26A9 shows modification of Phe508del CFTR function upon treatment with a CFTR corrector.In those with gating mutations that retain cell surface-localized CFTR we show that SLC26A9 modifies lung function while this is not the case in individuals homozygous for Phe508del where cell surface expression is lacking. Treatment response to ivacaftor, which aims to improve CFTR-channel opening probability in patients with gating mutations, shows substantial variability in response, 28% of which can be explained by rs7512462 in SLC26A9 (P = 0.0006). When homozygous Phe508del primary bronchial cells are treated to restore surface CFTR, SLC26A9 likewise modifies treatment response (P = 0.02). Our findings indicate that SLC26A9 airway modification requires CFTR at the cell surface, and that a common variant in SLC26A9 may predict response to CFTR-directed therapeutics.

  16. Contractile responses to rat urotensin II in resting and depolarized basilar arteries.

    Science.gov (United States)

    Porras-González, Cristina; Ureña, Juan; Egea-Guerrero, Juan José; Gordillo-Escobar, Elena; Murillo-Cabezas, Francisco; González-Montelongo, María del Carmen; Muñoz-Sánchez, María Angeles

    2014-03-01

    The effects of human urotensin II (hUII) on the vascular tone of different animal species has been studied extensively. However, little has been reported on the vasoactive effects of rat urotensin (rUII) in murine models. The aim of the present study was to investigate the effects of rUII on vasoreactivity in rat basilar arteries. Basilar arteries from adult male Wistar rats (300-350 g) were isolated, cut in rings, and mounted on a small vessel myograph to measure isometric tension. rUII concentrations were studied in both resting and depolarized state. To remove endothelial nitric oxide effects from the rUII response, we treated selected arterial rings with Nω-nitro-L-arginine methyl ester (L-NAME). 10 μM rUII produced a potent vasoconstrictor response in rat basilar arteries with intact endothelium, while isometric forces remained unaffected in arterial rings treated with lower rUII concentrations. Although L-NAME did not have a significant effect on 10 μM rUII-evoked contraction, it slightly increased arterial ring contraction elicited by 1 μM rUII. In depolarized arteries, dose-dependent rUII increased depolarization-induced contractions. This effect was suppressed by L-NAME. Our results show that the rat basilar artery has a vasoconstrictor response to rUII. The most potent vasoconstrictor effect was produced by lower doses of rUII (0.1 and 1 μM) in depolarized arteries with intact endothelium. This effect could facilitate arterial vasospasm in vascular pathophysiological processes such as subarachnoid hemorrhage and hypertension, when sustained depolarization and L-type Ca(2+) channel activation are present.

  17. Augmentation of sarcolemmal Ca by anionic amphiphile: contractile response of three ventricular tissues.

    Science.gov (United States)

    Langer, G A; Rich, T L

    1986-02-01

    The anionic amphiphile dodecyl sulfate was used at the concentration of 100 microM, below the concentration at which membrane permeability is compromised. In rat myocardial tissue culture dodecyl sulfate induced a large increase in Ca uptake in the intact cells, of which 84% was distributed in a rapidly exchangeable (t1/2 less than 18 s) and 16% in a slowly exchangeable (t1/2 = 17 min) compartment. Dodecyl sulfate induced a large increase in Ca bound to isolated sarcolemmal membrane of these cells. This increase in membrane binding and the distribution in whole cells is consistent with insertion of dodecyl sulfate in the sarcolemma (SL) with subsequent Ca binding to its anionic head group. With perfusate extracellular calcium concentration ([Ca]o) equal to 1 mM, dodecyl sulfate produced greater than 60% increase in active force in ventricular tissue from adult rabbit and neonatal rat but virtually no increase in adult rat ventricle. Preperfusion with 0.1 mM [Ca]o or 10(-6) M ryanodine markedly increased the relative response of adult rat ventricle to dodecyl sulfate. After a quiescent period in rabbit ventricle, dodecyl sulfate caused a progressive increase of force of each beat compared with control; i.e., the treppe response was increased at each successive beat. This did not occur in adult rat ventricle. These results further clarify the different quantitative role of SL-bound versus sarcotubular Ca in the hearts of different species.

  18. Effect of aqueous fraction of Rosa damascena on ileum contractile response of guinea pigs

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    Karim Dolati

    2013-05-01

    Full Text Available Objective: The use of drugs with herbal origin is increasing for treatment of gastrointestinal (GI disorders. Rosa damascena (R. damascena is a well-known plant suggested to have beneficial effect on GI system. In this study, the effect of aqueous fraction of R. damascena on the contractionsofisolated guinea pig ileum was investigated. Materials and Methods: Aqueous fraction of plant was obtained from ethanolic extract after ethyl acetate and n-butanol fractions were discarded. To evaluate effect of this fraction on ileum contraction, guinea pig ileum was removed and mounted on organ bath and its contraction was recorded. Effect of various concentrations (0.66, 0.83, and 1.3 mg/ml of aqueous fraction on ileum contraction in comparison with Ach in presence and absense of atropine, a muscarinic antagonist of cholinergic, was evaluated. The response of ileum to 1 µg/ml of acetylcholine was considered as 100% response. Results:Our results showed that aqueous fractions of R. damascena dose-dependently increased basal guinea pigs ileum contractions (pConclusion: It is concluded that aqueous fraction of R. damascena has mild excitatory effect on ileum contraction and this fraction may be beneficial as a mild laxative agent.

  19. Comparison of contractile responses of single human motor units in the toe extensors during unloaded and loaded isotonic and isometric conditions.

    Science.gov (United States)

    Leitch, Michael; Macefield, Vaughan G

    2015-08-01

    Much of the repertoire of muscle function performed in everyday life involves isotonic dynamic movements, either with or without an additional load, yet most studies of single motor units measure isometric forces. To assess the effects of muscle load on the contractile response, we measured the contractile properties of single motor units supplying the toe extensors, assessed by intraneural microstimulation of single human motor axons, in isotonic, loaded isotonic, and isometric conditions. Tungsten microelectrodes were inserted into the common peroneal nerve, and single motor axons (n = 10) supplying the long toe extensors were electrically stimulated through the microelectrode. Displacement was measured from the distal phalanx of the toe with either an angular displacement transducer for the unloaded (i.e., no additional load) and loaded (addition of a 4-g mass) isotonic conditions or a force transducer for the isometric conditions. Mean twitch profiles were measured at 1 Hz for all conditions: rise time, fall time, and duration were shortest for the unloaded isotonic conditions and longest for the isometric conditions. Peak displacements were lower in the loaded than unloaded isotonic conditions, and the half-maximal response in the loaded condition was achieved at lower frequencies than in the unloaded isotonic condition. We have shown that the contractile responses of single motor units supplying the human toe extensors are influenced by how they are measured: twitches are much slower when measured in loaded than unloaded isotonic conditions and slowest when measured in isometric conditions.

  20. Chitin-Induced Airway Epithelial Cell Innate Immune Responses Are Inhibited by Carvacrol/Thymol.

    Science.gov (United States)

    Khosravi, Ali Reza; Erle, David J

    2016-01-01

    Chitin is produced in large amounts by fungi, insects, and other organisms and has been implicated in the pathogenesis of asthma. Airway epithelial cells are in direct contact with environmental particles and serve as the first line of defense against inhaled allergens and pathogens. The potential contributions of airway epithelial cells to chitin-induced asthma remain poorly understood. We hypothesized that chitin directly stimulates airway epithelial cells to release cytokines that promote type 2 immune responses and to induce expression of molecules which are important in innate immune responses. We found that chitin exposure rapidly induced the expression of three key type 2-promoting cytokines, IL-25, IL-33 and TSLP, in BEAS-2B transformed human bronchial epithelial cells and in A549 and H292 lung carcinoma cells. Chitin also induced the expression of the key pattern recognition receptors TLR2 and TLR4. Chitin induced the expression of miR-155, miR-146a and miR-21, each of which is known to up-regulate the expression of pro-inflammatory cytokines. Also the expression of SOCS1 and SHIP1 which are known targets of miR-155 was repressed by chitin treatment. The monoterpene phenol carvacrol (Car) and its isomer thymol (Thy) are found in herbal essential oils and have been shown to inhibit allergic inflammation in asthma models. We found that Car/Thy inhibited the effects of chitin on type 2-promoting cytokine release and on the expression of TLRs, SOCS1, SHIP1, and miRNAs. Car/Thy could also efficiently reduce the protein levels of TLR4, inhibit the increase in TLR2 protein levels in chitin plus Car/Thy-treated cells and increase the protein levels of SHIP1 and SOCS1, which are negative regulators of TLR-mediated inflammatory responses. We conclude that direct effects of chitin on airway epithelial cells are likely to contribute to allergic airway diseases like asthma, and that Car/Thy directly inhibits epithelial cell pro-inflammatory responses to chitin.

  1. Chitin-Induced Airway Epithelial Cell Innate Immune Responses Are Inhibited by Carvacrol/Thymol.

    Directory of Open Access Journals (Sweden)

    Ali Reza Khosravi

    Full Text Available Chitin is produced in large amounts by fungi, insects, and other organisms and has been implicated in the pathogenesis of asthma. Airway epithelial cells are in direct contact with environmental particles and serve as the first line of defense against inhaled allergens and pathogens. The potential contributions of airway epithelial cells to chitin-induced asthma remain poorly understood. We hypothesized that chitin directly stimulates airway epithelial cells to release cytokines that promote type 2 immune responses and to induce expression of molecules which are important in innate immune responses. We found that chitin exposure rapidly induced the expression of three key type 2-promoting cytokines, IL-25, IL-33 and TSLP, in BEAS-2B transformed human bronchial epithelial cells and in A549 and H292 lung carcinoma cells. Chitin also induced the expression of the key pattern recognition receptors TLR2 and TLR4. Chitin induced the expression of miR-155, miR-146a and miR-21, each of which is known to up-regulate the expression of pro-inflammatory cytokines. Also the expression of SOCS1 and SHIP1 which are known targets of miR-155 was repressed by chitin treatment. The monoterpene phenol carvacrol (Car and its isomer thymol (Thy are found in herbal essential oils and have been shown to inhibit allergic inflammation in asthma models. We found that Car/Thy inhibited the effects of chitin on type 2-promoting cytokine release and on the expression of TLRs, SOCS1, SHIP1, and miRNAs. Car/Thy could also efficiently reduce the protein levels of TLR4, inhibit the increase in TLR2 protein levels in chitin plus Car/Thy-treated cells and increase the protein levels of SHIP1 and SOCS1, which are negative regulators of TLR-mediated inflammatory responses. We conclude that direct effects of chitin on airway epithelial cells are likely to contribute to allergic airway diseases like asthma, and that Car/Thy directly inhibits epithelial cell pro-inflammatory responses

  2. Actin-myosin contractility is responsible for the reduced viability of dissociated human embryonic stem cells.

    Science.gov (United States)

    Chen, Guokai; Hou, Zhonggang; Gulbranson, Daniel R; Thomson, James A

    2010-08-06

    Human ESCs are the pluripotent precursor of the three embryonic germ layers. Human ESCs exhibit basal-apical polarity, junctional complexes, integrin-dependent matrix adhesion, and E-cadherin-dependent cell-cell adhesion, all characteristics shared by the epiblast epithelium of the intact mammalian embryo. After disruption of epithelial structures, programmed cell death is commonly observed. If individualized human ESCs are prevented from reattaching and forming colonies, their viability is significantly reduced. Here, we show that actin-myosin contraction is a critical effector of the cell death response to human ESC dissociation. Inhibition of myosin heavy chain ATPase, downregulation of myosin heavy chain, and downregulation of myosin light chain all increase survival and cloning efficiency of individualized human ESCs. ROCK inhibition decreases phosphorylation of myosin light chain, suggesting that inhibition of actin-myosin contraction is also the mechanism through which ROCK inhibitors increase cloning efficiency of human ESCs.

  3. Airway hyperresponsiveness; smooth muscle as the principal actor [version 1; referees: 2 approved

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    Anne-Marie Lauzon

    2016-03-01

    Full Text Available Airway hyperresponsiveness (AHR is a defining characteristic of asthma that refers to the capacity of the airways to undergo exaggerated narrowing in response to stimuli that do not result in comparable degrees of airway narrowing in healthy subjects. Airway smooth muscle (ASM contraction mediates airway narrowing, but it remains uncertain as to whether the smooth muscle is intrinsically altered in asthmatic subjects or is responding abnormally as a result of the milieu in which it sits. ASM in the trachea or major bronchi does not differ in its contractile characteristics in asthmatics, but the more pertinent peripheral airways await complete exploration. The mass of ASM is increased in many but not all asthmatics and therefore cannot be a unifying hypothesis for AHR, although when increased in mass it may contribute to AHR. The inability of a deep breath to reverse or prevent bronchial narrowing in asthma may reflect an intrinsic difference in the mechanisms that lead to softening of contracted ASM when subjected to stretch. Cytokines such as interleukin-13 and tumor necrosis factor-α promote a more contractile ASM phenotype. The composition and increased stiffness of the matrix in which ASM is embedded promotes a more proliferative and pro-inflammatory ASM phenotype, but the expected dedifferentiation and loss of contractility have not been shown. Airway epithelium may drive ASM proliferation and/or molecular remodeling in ways that may lead to AHR. In conclusion, AHR is likely multifactorial in origin, reflecting the plasticity of ASM properties in the inflammatory environment of the asthmatic airway.

  4. Accumulating evidence for increased velocity of airway smooth muscle shortening in asthmatic airway hyperresponsiveness.

    Science.gov (United States)

    Ijpma, Gijs; Matusovsky, Oleg; Lauzon, Anne-Marie

    2012-01-01

    It remains unclear whether airway smooth muscle (ASM) mechanics is altered in asthma. While efforts have originally focussed on contractile force, some evidence points to an increased velocity of shortening. A greater rate of airway renarrowing after a deep inspiration has been reported in asthmatics compared to controls, which could result from a shortening velocity increase. In addition, we have recently shown in rats that increased shortening velocity correlates with increased muscle shortening, without increasing muscle force. Nonetheless, establishing whether or not asthmatic ASM shortens faster than that of normal subjects remains problematic. Endobronchial biopsies provide excellent tissue samples because the patients are well characterized, but the size of the samples allows only cell level experiments. Whole human lungs from transplant programs suffer primarily from poor patient characterization, leading to high variability. ASM from several animal models of asthma has shown increased shortening velocity, but it is unclear whether this is representative of human asthma. Several candidates have been suggested as responsible for increased shortening velocity in asthma, such as alterations in contractile protein expression or changes in the contractile apparatus structure. There is no doubt that more remains to be learned about the role of shortening velocity in asthma.

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

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    Yuan Ma

    2016-01-01

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

  6. Inhibition of allergic airway responses by heparin derived oligosaccharides: identification of a tetrasaccharide sequence

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    Ahmed Tahir

    2012-01-01

    Full Text Available Abstract Background Previous studies showed that heparin's anti-allergic activity is molecular weight dependent and resides in oligosaccharide fractions of Objective To investigate the structural sequence of heparin's anti-allergic domain, we used nitrous acid depolymerization of porcine heparin to prepare an oligosaccharide, and then fractionated it into disaccharide, tetrasaccharide, hexasaccharide, and octasaccharide fractions. The anti-allergic activity of each oligosaccharide fraction was tested in allergic sheep. Methods Allergic sheep without (acute responder and with late airway responses (LAR; dual responder were challenged with Ascaris suum antigen with and without inhaled oligosaccharide pretreatment and the effects on specific lung resistance and airway hyperresponsiveness (AHR to carbachol determined. Additional inflammatory cell recruitment studies were performed in immunized ovalbumin-challenged BALB/C mice with and without treatment. Results The inhaled tetrasaccharide fraction was the minimal effective chain length to show anti-allergic activity. This fraction showed activity in both groups of sheep; it was also effective in inhibiting LAR and AHR, when administered after the antigen challenge. Tetrasaccharide failed to modify the bronchoconstrictor responses to airway smooth muscle agonists (histamine, carbachol and LTD4, and had no effect on antigen-induced histamine release in bronchoalveolar lavage fluid in sheep. In mice, inhaled tetrasaccharide also attenuated the ovalbumin-induced peribronchial inflammatory response and eosinophil influx in the bronchoalveolar lavage fluid. Chemical analysis identified the active structure to be a pentasulfated tetrasaccharide ([IdoU2S (1→4GlcNS6S (1→4 IdoU2S (1→4 AMan-6S] which lacked anti-coagulant activity. Conclusions These results demonstrate that heparin tetrasaccharide possesses potent anti-allergic and anti-inflammatory properties, and that the domains responsible for anti

  7. Comparison of dexmedetomidine and lignocaine on attenuation of airway and pressor responses during tracheal extubation

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    Vivek Bharti Sharma

    2014-01-01

    Full Text Available Background: Haemodynamic stability and rapid emergence after general anaesthesia used in spinal surgery is a common practice, the goal of which is to permit early neurological motor and sensory examination. Extubation is almost always associated with hypertension, increased airway response and arrhythmias. We have compared the effects of the α-2 agonist Dexmedetomidine and Lignocaine given at the end of the procedure on attenuation of airway and pressor responses following tracheal extubation. This study is a randomised, placebo-controlled, double-blinded study. Materials and Methods: Sixty ASA I-III patients, aged 18-70 years, scheduled to undergo spinal surgery at the level of thoracic, lumbar or sacral region were randomly divided into three groups. Balanced general anaesthesia comprising standard procedures and drugs were used for monitoring, induction and maintenance. At the last skin suture, inhalation anaesthetic was discontinued. After turning the patient supine and return of spontaneous efforts, in Group D Dexmedetomidine 0.5 μg/kg, in Group L Lignocaine 1.5 mg/kg and in Group P normal saline (10 ml were administered as bolus intravenously over 60 seconds. Systolic, diastolic and mean arterial pressures and heart rate were recorded before intravenous administration and also every minute for 3 minutes, at 5, 10 and 15 minutes post-extubation. Duration of emergence and extubation were noted and attenuation of airway response and quality of extubation was evaluated on cough grading. Results: Mean arterial pressures and heart rate were higher in Group L and Group P than in Group D but not statistically significant. The duration of emergence, extubation and recovery were comparable in all the groups (P > 0.05. Extubation Quality Scores was 1 in 80%, 2 in 20% in Group D; in Group L, the quality scores were 1 for 55%, 2 for 45% and I Group P 1 for 35%, 2 for 45% and 3 for 20% of the patients. The requirement of rescue analgesia was also less

  8. Relationship among bacterial colonization, airway inflam- mation, and bronchodilator response in patients with stable chronic obstructive pulmonary disease

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    @@ Bronchodilator reversibility, a response of airway to bronchodilator, occurred in 64% of stable patients with chronic obstructive pulmonary disease (COPD).1 In patients with COPD who have a significant response to bronchodilators, a clinical and functional response to inhaled corticosteroids is similar to that in asthmatics.2

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

    Science.gov (United States)

    Blankman, Elizabeth; Jensen, Christopher C.; Krishnan, Ramaswamy; James, Alan L.; Elliot, John G.; Green, Francis H.; Liu, Jeffrey C.; Seow, Chun Y.; Park, Jin-Ah; Beckerle, Mary C.; Paré, Peter D.; Fredberg, Jeffrey J.; Smith, Mark A.

    2017-01-01

    Bronchospasm induced in non-asthmatic human subjects can be easily reversed by a deep inspiration (DI) whereas bronchospasm that occurs spontaneously in asthmatic subjects cannot. This physiological effect of a DI has been attributed to the manner in which a DI causes airway smooth muscle (ASM) cells to stretch, but underlying molecular mechanisms–and their failure in asthma–remain obscure. Using cells and tissues from wild type and zyxin-/- mice we report responses to a transient stretch of physiologic magnitude and duration. At the level of the cytoskeleton, zyxin facilitated repair at sites of stress fiber fragmentation. At the level of the isolated ASM cell, zyxin facilitated recovery of contractile force. Finally, at the level of the small airway embedded with a precision cut lung slice, zyxin slowed airway dilation. Thus, at each level zyxin stabilized ASM structure and contractile properties at current muscle length. Furthermore, when we examined tissue samples from humans who died as the result of an asthma attack, we found increased accumulation of zyxin compared with non-asthmatics and asthmatics who died of other causes. Together, these data suggest a biophysical role for zyxin in fatal asthma. PMID:28278518

  10. Gene expression in asthmatic airway smooth muscle: a mixed bag.

    Science.gov (United States)

    Pascoe, Christopher D; Swyngedouw, Nicholas E; Seow, Chun Y; Paré, Peter D

    2015-02-01

    It has long been known that airway smooth muscle (ASM) contraction contributes significantly to the reversible airflow obstruction that defines asthma. It has also been postulated that phenotypic changes in ASM contribute to the airway hyper-responsiveness (AHR) that is a characteristic feature of asthma. Although there is agreement that the mass of ASM surrounding the airways is significantly increased in asthmatic compared with non-asthmatic airways, it is still uncertain whether there are quantitative or qualitative changes in the level of expression of the genes and proteins involved in the canonical contractile pathway in ASM that could account for AHR. This review will summarize past attempts at quantifying gene expression changes in the ASM of asthmatic lungs as well as non-asthmatic ASM cells stimulated with various inflammatory cytokines. The lack of consistent findings in asthmatic samples coupled with the relative concordance of results from stimulated ASM cells suggests that changes to the contractility of ASM tissues in asthma may be dependent on the presence of an inflammatory environment surrounding the ASM layer. Removal of the ASM from this environment could explain why hypercontractility is rarely seen ex vivo.

  11. The effects of cannabidiol on the antigen-induced contraction of airways smooth muscle in the guinea-pig.

    Science.gov (United States)

    Dudášová, A; Keir, S D; Parsons, M E; Molleman, A; Page, C P

    2013-06-01

    (-)-Δ(9)-Tetrahydrocannabinol has been demonstrated to have beneficial effects in the airways, but its psychoactive effects preclude its therapeutic use for the treatment of airways diseases. In the present study we have investigated the effects of (-)-cannabidiol, a non-psychoactive component of cannabis for its actions on bronchial smooth muscle in vitro and in vivo. Guinea-pig bronchial smooth muscle contractions induced by exogenously applied spasmogens were measured isometrically. In addition, contractile responses of bronchial smooth muscle from ovalbumin-sensitized guinea-pigs were investigated in the absence or presence of (-)-cannabidiol. Furthermore, the effect of (-)-cannabidiol against ovalbumin-induced airway obstruction was investigated in vivo in ovalbumin-sensitized guinea-pigs. (-)-Cannabidiol did not influence the bronchial smooth muscle contraction induced by carbachol, histamine or neurokinin A. In contrast, (-)-cannabidiol inhibited anandamide- and virodhamine-induced responses of isolated bronchi. A fatty acid amide hydrolase inhibitor, phenylmethanesulfonyl fluoride reversed the inhibitory effect of (-)-cannabidiol on anandamide-induced contractions. In addition, (-)-cannabidiol inhibited the contractile response of bronchi obtained from allergic guinea-pigs induced by ovalbumin. In vivo, (-)-cannabidiol reduced ovalbumin-induced airway obstruction. In conclusion, our results suggest that cannabidiol can influence antigen-induced airway smooth muscle tone suggesting that this molecule may have beneficial effects in the treatment of obstructive airway disorders.

  12. Small airway dysfunction and flow and volume bronchodilator responsiveness in patients with chronic obstructive pulmonary disease

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    Pisi R

    2015-06-01

    Full Text Available Roberta Pisi,1 Marina Aiello,1 Andrea Zanini,2 Panagiota Tzani,1 Davide Paleari,3 Emilio Marangio,1 Antonio Spanevello,2,4 Gabriele Nicolini,5 Alfredo Chetta1 1Department of Clinical and Experimental Medicine, University of Parma, Parma, 2Division of Pneumology, IRCCS Rehabilitation Institute of Tradate, Salvatore Maugeri Foundation, Tradate, 3Medical Department, Chiesi Farmaceutici SpA, Parma, 4Department of Clinical and Experimental Medicine, University of Insubria, Varese, 5Corporate Clinical Development, Chiesi Farmaceutici SpA, Parma, Italy Background: We investigated whether a relationship between small airways dysfunction and bronchodilator responsiveness exists in patients with chronic obstructive pulmonary disease (COPD.Methods: We studied 100 (20 female; mean age: 68±10 years patients with COPD (forced expiratory volume in 1 second [FEV1]: 55% pred ±21%; FEV1/forced vital capacity [FVC]: 53%±10% by impulse oscillometry system. Resistance at 5 Hz and 20 Hz (R5 and R20, in kPa·s·L-1 and the fall in resistance from 5 Hz to 20 Hz (R5 – R20 were used as indices of total, proximal, and peripheral airway resistance; reactance at 5 Hz (X5, in kPa·s·L-1 was also measured. Significant response to bronchodilator (salbutamol 400 µg was expressed as absolute (≥0.2 L and percentage (≥12% change relative to the prebronchodilator value of FEV1 (flow responders, FRs and FVC (volume responders, VRs.Results: Eighty out of 100 participants had R5 – R20 >0.03 kPa·s·L-1 (> upper normal limit and, compared to patients with R5 – R20 ≤0.030 kPa·s·L-1, showed a poorer health status, lower values of FEV1, FVC, FEV1/FVC, and X5, along with higher values of residual volume/total lung capacity and R5 (P<0.05 for all comparisons. Compared to the 69 nonresponders and the 8 FRs, the 16 VRs had significantly higher R5 and R5 – R20 values (P<0.05, lower X5 values (P<0.05, and greater airflow obstruction and lung

  13. B cells play key roles in th2-type airway immune responses in mice exposed to natural airborne allergens.

    Science.gov (United States)

    Drake, Li Yin; Iijima, Koji; Hara, Kenichiro; Kobayashi, Takao; Kephart, Gail M; Kita, Hirohito

    2015-01-01

    Humans are frequently exposed to various airborne allergens. In addition to producing antibodies, B cells participate in immune responses via various mechanisms. The roles of B cells in allergic airway inflammation and asthma have been controversial. We examined the functional importance of B cells in a mouse model of asthma, in which mice were exposed repeatedly to common airborne allergens. Naïve wild-type BALB/c mice or B cell-deficient JH-/- mice were exposed intranasally to a cocktail of allergen extracts, including Alternaria, Aspergillus, and house dust mite, every other day for two weeks. Ovalbumin was included in the cocktail to monitor the T cell immune response. Airway inflammation, lung pathology, and airway reactivity were analyzed. The airway exposure of naïve wild type mice to airborne allergens induced robust eosinophilic airway inflammation, increased the levels of Th2 cytokines and chemokines in the lung, and increased the reactivity to inhaled methacholine. These pathological changes and immune responses were attenuated in B cell-deficient JH-/- mice. The allergen-induced expansion of CD4+ T cells was impaired in the lungs and draining lymph nodes of JH-/- mice. Furthermore, lymphocytes from JH-/- mice failed to produce Th2 cytokines in response to ovalbumin re-stimulation in vitro. Our results suggest that B cells are required for the optimal development of Th2-type immune responses and airway inflammation when exposed to common airborne allergens. The therapeutic targeting of B cells may be beneficial to treat asthma in certain patients.

  14. B cells play key roles in th2-type airway immune responses in mice exposed to natural airborne allergens.

    Directory of Open Access Journals (Sweden)

    Li Yin Drake

    Full Text Available Humans are frequently exposed to various airborne allergens. In addition to producing antibodies, B cells participate in immune responses via various mechanisms. The roles of B cells in allergic airway inflammation and asthma have been controversial. We examined the functional importance of B cells in a mouse model of asthma, in which mice were exposed repeatedly to common airborne allergens. Naïve wild-type BALB/c mice or B cell-deficient JH-/- mice were exposed intranasally to a cocktail of allergen extracts, including Alternaria, Aspergillus, and house dust mite, every other day for two weeks. Ovalbumin was included in the cocktail to monitor the T cell immune response. Airway inflammation, lung pathology, and airway reactivity were analyzed. The airway exposure of naïve wild type mice to airborne allergens induced robust eosinophilic airway inflammation, increased the levels of Th2 cytokines and chemokines in the lung, and increased the reactivity to inhaled methacholine. These pathological changes and immune responses were attenuated in B cell-deficient JH-/- mice. The allergen-induced expansion of CD4+ T cells was impaired in the lungs and draining lymph nodes of JH-/- mice. Furthermore, lymphocytes from JH-/- mice failed to produce Th2 cytokines in response to ovalbumin re-stimulation in vitro. Our results suggest that B cells are required for the optimal development of Th2-type immune responses and airway inflammation when exposed to common airborne allergens. The therapeutic targeting of B cells may be beneficial to treat asthma in certain patients.

  15. A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma.

    Science.gov (United States)

    Caceres, Ana I; Brackmann, Marian; Elia, Maxwell D; Bessac, Bret F; del Camino, Donato; D'Amours, Marc; Witek, JoAnn S; Fanger, Chistopher M; Chong, Jayhong A; Hayward, Neil J; Homer, Robert J; Cohn, Lauren; Huang, Xiaozhu; Moran, Magdalene M; Jordt, Sven-Eric

    2009-06-02

    Asthma is an inflammatory disorder caused by airway exposures to allergens and chemical irritants. Studies focusing on immune, smooth muscle, and airway epithelial function revealed many aspects of the disease mechanism of asthma. However, the limited efficacies of immune-directed therapies suggest the involvement of additional mechanisms in asthmatic airway inflammation. TRPA1 is an irritant-sensing ion channel expressed in airway chemosensory nerves. TRPA1-activating stimuli such as cigarette smoke, chlorine, aldehydes, and scents are among the most prevalent triggers of asthma. Endogenous TRPA1 agonists, including reactive oxygen species and lipid peroxidation products, are potent drivers of allergen-induced airway inflammation in asthma. Here, we examined the role of TRPA1 in allergic asthma in the murine ovalbumin model. Strikingly, genetic ablation of TRPA1 inhibited allergen-induced leukocyte infiltration in the airways, reduced cytokine and mucus production, and almost completely abolished airway hyperreactivity to contractile stimuli. This phenotype is recapitulated by treatment of wild-type mice with HC-030031, a TRPA1 antagonist. HC-030031, when administered during airway allergen challenge, inhibited eosinophil infiltration and prevented the development of airway hyperreactivity. Trpa1(-/-) mice displayed deficiencies in chemically and allergen-induced neuropeptide release in the airways, providing a potential explanation for the impaired inflammatory response. Our data suggest that TRPA1 is a key integrator of interactions between the immune and nervous systems in the airways, driving asthmatic airway inflammation following inhaled allergen challenge. TRPA1 may represent a promising pharmacological target for the treatment of asthma and other allergic inflammatory conditions.

  16. Device for Investigation of Mechanical Tension of Isolated Smooth Muscle Vessels and Airway Segments of Animals

    Science.gov (United States)

    Aleinik, A.; Karpovich, N.; Turgunova, N.; Nosarev, A.

    2016-11-01

    For the purpose of testing and the search for new drug compounds, designed to heal many human diseases, it is necessary to investigate the deformation of experimental tissue samples under influence of these drugs. For this task a precision force sensor for measuring the mechanical tension, produced by isolated ring segments of blood vessels and airways was created. The hardware and software systems for the study of changes in contractile responses of the airway smooth muscles and blood vessels of experimental animals was developed.

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

    Science.gov (United States)

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

    2015-01-01

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

  18. Quantitation of the Contractile Response Mediated by Two Receptors: M2 and M3 Muscarinic Receptor-Mediated Contractions of Human Gastroesophageal Smooth MuscleS⃞

    Science.gov (United States)

    Braverman, Alan S.; Miller, Larry S.; Vegesna, Anil K.; Tiwana, Mansoor I.; Tallarida, Ronald J.; Ruggieri, Michael R.

    2009-01-01

    Although muscarinic receptors are known to mediate tonic contraction of human gastrointestinal tract smooth muscle, the receptor subtypes that mediate the tonic contractions are not entirely clear. Whole human stomachs with attached esophagus were procured from organ transplant donors. Cholinergic contractile responses of clasp, sling, lower esophageal circular (LEC), midesophageal circular (MEC), and midesophageal longitudinal (MEL) muscle strips were determined. Sling fibers contracted greater than the other fibers. Total, M2 and M3 muscarinic receptor density was determined for each of these dissections by immunoprecipitation. M2 receptor density is greatest in the sling fibers, followed by clasp, LEC, MEC, and then MEL, whereas M3 density is greatest in LEC, followed by MEL, MEC, sling, and then clasp. The potency of subtype-selective antagonists to inhibit bethanechol-induced contraction was calculated by Schild analysis to determine which muscarinic receptor subtypes contribute to contraction. The results suggest both M2 and M3 receptors mediate contraction in clasp and sling fibers. Thus, this type of analysis in which multiple receptors mediate the contractile response is inappropriate, and an analysis method relating dual occupation of M2 and M3 receptors to contraction is presented. Using this new method of analysis, it was found that the M2 muscarinic receptor plays a greater role in mediating contraction of clasp and sling fibers than in LEC, MEC, and MEL muscles in which the M3 receptor predominantly mediates contraction. PMID:19126780

  19. Quantitation of the contractile response mediated by two receptors: M2 and M3 muscarinic receptor-mediated contractions of human gastroesophageal smooth muscle.

    Science.gov (United States)

    Braverman, Alan S; Miller, Larry S; Vegesna, Anil K; Tiwana, Mansoor I; Tallarida, Ronald J; Ruggieri, Michael R

    2009-04-01

    Although muscarinic receptors are known to mediate tonic contraction of human gastrointestinal tract smooth muscle, the receptor subtypes that mediate the tonic contractions are not entirely clear. Whole human stomachs with attached esophagus were procured from organ transplant donors. Cholinergic contractile responses of clasp, sling, lower esophageal circular (LEC), midesophageal circular (MEC), and midesophageal longitudinal (MEL) muscle strips were determined. Sling fibers contracted greater than the other fibers. Total, M(2) and M(3) muscarinic receptor density was determined for each of these dissections by immunoprecipitation. M(2) receptor density is greatest in the sling fibers, followed by clasp, LEC, MEC, and then MEL, whereas M(3) density is greatest in LEC, followed by MEL, MEC, sling, and then clasp. The potency of subtype-selective antagonists to inhibit bethanechol-induced contraction was calculated by Schild analysis to determine which muscarinic receptor subtypes contribute to contraction. The results suggest both M(2) and M(3) receptors mediate contraction in clasp and sling fibers. Thus, this type of analysis in which multiple receptors mediate the contractile response is inappropriate, and an analysis method relating dual occupation of M(2) and M(3) receptors to contraction is presented. Using this new method of analysis, it was found that the M(2) muscarinic receptor plays a greater role in mediating contraction of clasp and sling fibers than in LEC, MEC, and MEL muscles in which the M(3) receptor predominantly mediates contraction.

  20. Airway Epithelial Orchestration of Innate Immune Function in Response to Virus Infection. A Focus on Asthma.

    Science.gov (United States)

    Ritchie, Andrew I; Jackson, David J; Edwards, Michael R; Johnston, Sebastian L

    2016-03-01

    Asthma is a very common respiratory condition with a worldwide prevalence predicted to increase. There are significant differences in airway epithelial responses in asthma that are of particular interest during exacerbations. Preventing exacerbations is a primary aim when treating asthma because they often necessitate unscheduled healthcare visits and hospitalizations and are a significant cause of morbidity and mortality. The most common cause of asthma exacerbations is a respiratory virus infection, of which the most likely type is rhinovirus infection. This article focuses on the role played by the epithelium in orchestrating the innate immune responses to respiratory virus infection. Recent studies show impaired bronchial epithelial cell innate antiviral immune responses, as well as augmentation of a pro-Th2 response characterized by the epithelial-derived cytokines IL-25 and IL-33, crucial in maintaining the Th2 cytokine response to virus infection in asthma. A better understanding of the mechanisms of these abnormal immune responses has the potential to lead to the development of novel therapeutic targets for virus-induced exacerbations. The aim of this article is to highlight current knowledge regarding the role of viruses and immune modulation in the asthmatic epithelium and to discuss exciting areas for future research and novel treatments.

  1. Airway responses to eucapnic hyperpnea, exercise, and methacholine in elite swimmers

    DEFF Research Database (Denmark)

    Pedersen, Lise; Winther, S.; Backer, V.;

    2008-01-01

    Purpose: The International Olympic Committee Medical Commission (IOC-MC) requires athletes to provide the result of an objective test to support a diagnosis of asthma or exercise-induced bronchoconstriction (EIB) if they want to inhale a beta-2-agonist. The purpose of the study was to evaluate...... the airway response to a methacholine challenge and to hyperpnea induced by exercise in the field and in the laboratory or that induced voluntarily by eucapnic hyperpnea in a group of female elite swimmers. Methods: Sixteen female nonasthmatic elite swimmers performed a eucapnic voluntary hyperpnea (EVH...... of diagnosing EIB. We recommend performing the EVH test when diagnosing and evaluating EIB in elite swimmers and if EVH test negative then proceeding to a strenuous LBT Udgivelsesdato: 2008/9...

  2. Role of M2 Muscarinic Receptor in the Airway Response to Methacholine of Mice Selected for Minimal or Maximal Acute Inflammatory Response

    Directory of Open Access Journals (Sweden)

    Juciane Maria de Andrade Castro

    2013-01-01

    Full Text Available Airway smooth muscle constriction induced by cholinergic agonists such as methacholine (MCh, which is typically increased in asthmatic patients, is regulated mainly by muscle muscarinic M3 receptors and negatively by vagal muscarinic M2 receptors. Here we evaluated basal (intrinsic and allergen-induced (extrinsic airway responses to MCh. We used two mouse lines selected to respond maximally (AIRmax or minimally (AIRmin to innate inflammatory stimuli. We found that in basal condition AIRmin mice responded more vigorously to MCh than AIRmax. Treatment with a specific M2 antagonist increased airway response of AIRmax but not of AIRmin mice. The expression of M2 receptors in the lung was significantly lower in AIRmin compared to AIRmax animals. AIRmax mice developed a more intense allergic inflammation than AIRmin, and both allergic mouse lines increased airway responses to MCh. However, gallamine treatment of allergic groups did not affect the responses to MCh. Our results confirm that low or dysfunctional M2 receptor activity is associated with increased airway responsiveness to MCh and that this trait was inherited during the selective breeding of AIRmin mice and was acquired by AIRmax mice during allergic lung inflammation.

  3. The compatible solute ectoine reduces the exacerbating effect of environmental model particles on the immune response of the airways.

    Science.gov (United States)

    Unfried, Klaus; Kroker, Matthias; Autengruber, Andrea; Gotić, Marijan; Sydlik, Ulrich

    2014-01-01

    Exposure of humans to particulate air pollution has been correlated with the incidence and aggravation of allergic airway diseases. In predisposed individuals, inhalation of environmental particles can lead to an exacerbation of immune responses. Previous studies demonstrated a beneficial effect of the compatible solute ectoine on lung inflammation in rats exposed to carbon nanoparticles (CNP) as a model of environmental particle exposure. In the current study we investigated the effect of such a treatment on airway inflammation in a mouse allergy model. Ectoine in nonsensitized animals significantly reduced the neutrophilic lung inflammation after CNP exposure. This effect was accompanied by a reduction of inflammatory factors in the bronchoalveolar lavage. Reduced IL-6 levels in the serum also indicate the effects of ectoine on systemic inflammation. In sensitized animals, an aggravation of the immune response was observed when animals were exposed to CNP prior to antigen provocation. The coadministration of ectoine together with the particles significantly reduced this exacerbation. The data indicate the role of neutrophilic lung inflammation in the exacerbation of allergic airway responses. Moreover, the data suggest to use ectoine as a preventive treatment to avoid the exacerbation of allergic airway responses induced by environmental air pollution.

  4. The Compatible Solute Ectoine Reduces the Exacerbating Effect of Environmental Model Particles on the Immune Response of the Airways

    Directory of Open Access Journals (Sweden)

    Klaus Unfried

    2014-01-01

    Full Text Available Exposure of humans to particulate air pollution has been correlated with the incidence and aggravation of allergic airway diseases. In predisposed individuals, inhalation of environmental particles can lead to an exacerbation of immune responses. Previous studies demonstrated a beneficial effect of the compatible solute ectoine on lung inflammation in rats exposed to carbon nanoparticles (CNP as a model of environmental particle exposure. In the current study we investigated the effect of such a treatment on airway inflammation in a mouse allergy model. Ectoine in nonsensitized animals significantly reduced the neutrophilic lung inflammation after CNP exposure. This effect was accompanied by a reduction of inflammatory factors in the bronchoalveolar lavage. Reduced IL-6 levels in the serum also indicate the effects of ectoine on systemic inflammation. In sensitized animals, an aggravation of the immune response was observed when animals were exposed to CNP prior to antigen provocation. The coadministration of ectoine together with the particles significantly reduced this exacerbation. The data indicate the role of neutrophilic lung inflammation in the exacerbation of allergic airway responses. Moreover, the data suggest to use ectoine as a preventive treatment to avoid the exacerbation of allergic airway responses induced by environmental air pollution.

  5. REAL-TIME MEASUREMENT OF AIRWAY RESPONSES TO SULOFUR DIOXIDE (SO2) IN AN INTACT, AWAKE GUINEA PIG MODEL

    Science.gov (United States)

    Real-time measurment of airway responses to Sulfur Dioxide (SO2) in an intact, awake guinea pig model. J Stanek1,2, Q Krantz2, J Nolan2, D Winsett2, W Watkinson2, and D Costa2. 1College of Veterinary Medicine, NCSU, Raleigh, NC, USA; 2Pulmonary Toxicology Branch, ETD, NHEERL, US...

  6. Chitin-Induced Airway Epithelial Cell Innate Immune Responses Are Inhibited by Carvacrol/Thymol

    OpenAIRE

    Ali Reza Khosravi; David J Erle

    2016-01-01

    Chitin is produced in large amounts by fungi, insects, and other organisms and has been implicated in the pathogenesis of asthma. Airway epithelial cells are in direct contact with environmental particles and serve as the first line of defense against inhaled allergens and pathogens. The potential contributions of airway epithelial cells to chitin-induced asthma remain poorly understood. We hypothesized that chitin directly stimulates airway epithelial cells to release cytokines that promote ...

  7. Pharmacology of airway smooth muscle proliferation

    NARCIS (Netherlands)

    Gosens, Reinoud; Roscioni, Sara S.; Dekkers, Bart G. J.; Pera, Tonio; Schmidt, Martina; Schaafsma, Dedmer; Zaagsma, Johan; Meurs, Herman

    2008-01-01

    Airway smooth muscle thickening is a pathological feature that contributes significantly to airflow limitation and airway hyperresponsiveness in asthma. Ongoing research efforts aimed at identifying the mechanisms responsible for the increased airway smooth muscle mass have indicated that hyperplasi

  8. Alterations in Muscle Mass and Contractile Phenotype in Response to Unloading Models: Role of Transcriptional/Pretranslational Mechanisms

    Directory of Open Access Journals (Sweden)

    Kenneth M Baldwin

    2013-10-01

    Full Text Available Skeletal muscle is the largest organ system in mammalian organisms providing postural control and movement patterns of varying intensity. Through evolution, skeletal muscle fibers have evolved into three phenotype clusters defined as a muscle unit which consists of all muscle fibers innervated by a single motoneuron linking varying numbers of fibers of similar phenotype. This fundamental organization of the motor unit reflects the fact that there is a remarkable interdependence of gene regulation between the motoneurons and the muscle mainly via activity-dependent mechanisms. These fiber types can be classified via the primary type of myosin heavy chain (MHC gene expressed in the motor unit. Four MHC gene encoded proteins have been identified in striated muscle: slow type I MHC and three fast MHC types, IIa, IIx, and IIb. These MHCs dictate the intrinsic contraction speed of the myofiber with the type I generating the slowest and IIb the fastest contractile speed. Over the last ~35 years, a large body of knowledge suggests that altered loading state cause both fiber atrophy/wasting and a slow to fast shift in the contractile phenotype in the target muscle(s. Hence, this review will examine findings from three different animal models of unloading: 1 space flight (SF, i.e., microgravity; 2 hindlimb suspension (HS, a procedure that chronically eliminates weight bearing of the lower limbs; and 3 spinal cord isolation (SI, a surgical procedure that eliminates neural activation of the motoneurons and associated muscles while maintaining neurotrophic motoneuron-muscle connectivity. The collective findings demonstrate: 1 all three models show a similar pattern of fiber atrophy with differences mainly in the magnitude and kinetics of alteration; 2 transcriptional/pretranslational processes play a major role in both the atrophy process and phenotype shifts; and 3 signaling pathways impacting these alterations appear to be similar in each of the models

  9. Effects of superoxide generating systems on muscle tone, cholinergic and NANC responses in cat airway.

    Science.gov (United States)

    Bauer, V; Nakajima, T; Pucovsky, V; Onoue, H; Ito, Y

    2000-02-14

    To study the possible role of reactive oxygen species in airway hyperreactivity, we examined the effects of the superoxide anion radical (O(2)(-)) generating systems, pyrogallol and xanthine with xanthine oxidase, on muscle tone, excitatory and inhibitory neurotransmission in the cat airway. Smooth muscle contraction or non-adrenergic non-cholinergic (NANC) relaxation evoked by electrical field stimulation (EFS) were measured before or after O(2)(-) generating systems with or without diethydithiocarbamic acid (DEDTCA), an inhibitor of endogenous superoxide dismutase (SOD). Resting membrane potential or excitatory junction potential (EJP) were also measured in vitro. Both pyrogallol and xanthine/xanthine oxidase produced biphasic changes in basal and elevated (by 5-HT) muscle tone. After SOD pretreatment, both systems consistently produced a prolonged contraction, thereby indicating that O(2)(-) was converted to H(2)O(2) by the action of SOD and as a result the actions of O(2)(-) were lost but those of H(2)O(2) introduced. The O(2)(-) showed no significant effect on smooth muscle contraction or EJP evoked by EFS, however after DEDTCA pretreatment, it evoked initial enhancement followed by suppression of the contraction and EJP. DEDTCA pretreatment ameliorated the inhibitory action of pyrogallol and xanthine/xanthine oxidase on the NANC relaxation, probably because O(2)(-) could combine with endogenous NO to form peroxynitrite. These results indicate that the O(2)(-) generating systems have multiple actions, presumably due to the presence and simultaneous action of at least two different reactive oxygen species (O(2)(-) and H(2)O(2)). While H(2)O(2) seems to be responsible for elevation of muscle tone and augmentation of smooth muscle contraction by EFS, O(2)(-) inhibits muscle tone, cholinergic and NANC neurotransmission.

  10. MicroRNA Mediated Chemokine Responses in Human Airway Smooth Muscle Cells.

    Directory of Open Access Journals (Sweden)

    Mythili Dileepan

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

  11. The laminin beta 1-competing peptide YIGSR induces a hypercontractile, hypoproliferative airway smooth muscle phenotype in an animal model of allergic asthma

    NARCIS (Netherlands)

    Dekkers, Bart G. J.; Bos, I. Sophie T.; Halayko, Andrew J.; Zaagsma, Johan; Meurs, Herman

    2010-01-01

    Background: Fibroproliferative airway remodelling, including increased airway smooth muscle (ASM) mass and contractility, contributes to airway hyperresponsiveness in asthma. In vitro studies have shown that maturation of ASM cells to a (hyper)contractile phenotype is dependent on laminin, which can

  12. Cellular contractility requires ubiquitin mediated proteolysis.

    Directory of Open Access Journals (Sweden)

    Yuval Cinnamon

    Full Text Available BACKGROUND: Cellular contractility, essential for cell movement and proliferation, is regulated by microtubules, RhoA and actomyosin. The RhoA dependent kinase ROCK ensures the phosphorylation of the regulatory Myosin II Light Chain (MLC Ser19, thereby activating actomyosin contractions. Microtubules are upstream inhibitors of contractility and their depolymerization or depletion cause cells to contract by activating RhoA. How microtubule dynamics regulates RhoA remains, a major missing link in understanding contractility. PRINCIPAL FINDINGS: We observed that contractility is inhibited by microtubules not only, as previously reported, in adherent cells, but also in non-adhering interphase and mitotic cells. Strikingly we observed that contractility requires ubiquitin mediated proteolysis by a Cullin-RING ubiquitin ligase. Inhibition of proteolysis, ubiquitination and neddylation all led to complete cessation of contractility and considerably reduced MLC Ser19 phosphorylation. CONCLUSIONS: Our results imply that cells express a contractility inhibitor that is degraded by ubiquitin mediated proteolysis, either constitutively or in response to microtubule depolymerization. This degradation seems to depend on a Cullin-RING ubiquitin ligase and is required for cellular contractions.

  13. Carbon Nanofibers Have IgE Adjuvant Capacity but Are Less Potent Than Nanotubes in Promoting Allergic Airway Responses

    Directory of Open Access Journals (Sweden)

    Unni Cecilie Nygaard

    2013-01-01

    Full Text Available There is a growing concern for the possible health impact of nanoparticles. The main objective of this study was to investigate the allergy-promoting capacity of four different carbon nanofiber (CNF samples in an injection and an airway mouse model of allergy. Secondly, the potency of the CNF was compared to the previously reported allergy-promoting capacity of carbon nanotubes (CNT in the airway model. Ultrafine carbon black particles (ufCBP were used as a positive control. Particles were given together with the allergen ovalbumin (OVA either by subcutaneous injection into the footpad or intranasally to BALB/cA mice. After allergen booster, OVA-specific IgE, IgG1, and IgG2a in serum were measured. In the airway model, inflammation was determined as influx of inflammatory cells (eosinophils, neutrophils, lymphocytes, and macrophages and by mediators (MCP-1 and TNF-α present in bronchoalveolar fluid (BALF. CNF and CNT both increased OVA-specific IgE levels in the two models, but in the airway model, the CNT gave a significantly stronger IgE response than the CNF. Furthermore, the CNT and not the CNF promoted eosinophil lung inflammation. Our data therefore suggest that nanotube-associated properties are particularly potent in promoting allergic responses.

  14. Does Moderate Intensity Exercise Attenuate the Postprandial Lipemic and Airway Inflammatory Response to a High-Fat Meal?

    Directory of Open Access Journals (Sweden)

    Stephanie P. Kurti

    2015-01-01

    Full Text Available We investigated whether an acute bout of moderate intensity exercise in the postprandial period attenuates the triglyceride and airway inflammatory response to a high-fat meal (HFM compared to remaining inactive in the postprandial period. Seventeen (11 M/6 F physically active (≥150 min/week of moderate-vigorous physical activity (MVPA subjects were randomly assigned to an exercise (EX; 60% VO2peak or sedentary (CON condition after a HFM (10 kcal/kg, 63% fat. Blood analytes and airway inflammation via exhaled nitric oxide (eNO were measured at baseline, and 2 and 4 hours after HFM. Airway inflammation was assessed with induced sputum and cell differentials at baseline and 4 hours after HFM. Triglycerides doubled in the postprandial period (~113 ± 18%, P<0.05, but the increase did not differ between EX and CON. Percentage of neutrophils was increased 4 hours after HFM (~17%, but the increase did not differ between EX and CON. Exhaled nitric oxide changed nonlinearly from baseline to 2 and 4 hours after HFM (P<0.05, η2=0.36. Our findings suggest that, in active individuals, an acute bout of moderate intensity exercise does not attenuate the triglyceride or airway inflammatory response to a high-fat meal.

  15. Cigarette Smoke and Estrogen Signaling in Human Airway Smooth Muscle

    Directory of Open Access Journals (Sweden)

    Venkatachalem Sathish

    2015-06-01

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

  16. Role of cholinergic neural transmission on airway resistance in the dog.

    Science.gov (United States)

    Kondo, T; Kobayashi, I; Hayama, N; Tazaki, G; Ohta, Y

    2000-04-12

    The unique contractile profiles of bronchial smooth muscle (Kondo et al., 1995) and its neural control were investigated by comparing responses of the bronchus and trachea to acute hypercapnia, stimulation of vagus efferent fibers before and after intravenous atropine, and intravenous acetylcholine in decerebrated and paralyzed dogs. During acute hypercapnia, airway resistance represented by peak airway pressure (Pedley et al., 1970) significantly increased as well as tracheal tension (Ttr). During electric stimulation of the vagal efferent fibers, Ttr increased and was sustained throughout the simulation period while the peak airway pressure was not maintained at the peak level. The peak Ttr and the airway resistance (Raw) calculated from ventilatory flow and airway pressure increased with increases in intensity of electric stimulation. Ttr reached its maximal level at an intensity 16 times of the threshold (T), while Raw became maximal at 4T. Although both the Ttr-stimulus intensity and Raw-intensity curves were shifted to the right by administration of intravenous atropine, the Raw curve shifted more to the right than the Ttr curve with the same dose of atropine. When muscular muscarinic receptors were directly stimulated by intravenous acetylcholine, Ttr once increased and then decreased promptly while peak airway pressure remained at a high level for a few minutes. These findings suggested that the bronchus is more sensitive to vagal efferent stimulation and susceptible to competitive antagonist of actylcholine than the trachea. In conclusion, the contractile profiles of the fifth-order bronchus we have reported (Kondo et al., 1995) were reflected in airway resistance, and the neuromuscular junction may be the site of adaptation of bronchoconstrictor response to motor nerve adaptation.

  17. Pulmonary surfactant in the airway physiology: a direct relaxing effect on the smooth muscle.

    Science.gov (United States)

    Calkovska, A; Uhliarova, B; Joskova, M; Franova, S; Kolomaznik, M; Calkovsky, V; Smolarova, S

    2015-04-01

    Beside alveoli, surface active material plays an important role in the airway physiology. In the upper airways it primarily serves in local defense. Lower airway surfactant stabilizes peripheral airways, provides the transport and defense, has barrier and anti-edematous functions, and possesses direct relaxant effect on the smooth muscle. We tested in vitro the effect of two surfactant preparations Curosurf® and Alveofact® on the precontracted smooth muscle of intra- and extra-pulmonary airways. Relaxation was more pronounced for lung tissue strip containing bronchial smooth muscle as the primary site of surfactant effect. The study does not confirm the participation of ATP-dependent potassium channels and cAMP-regulated epithelial chloride channels known as CFTR chloride channels, or nitric oxide involvement in contractile response of smooth muscle to surfactant.By controlling wall thickness and airway diameter, pulmonary surfactant is an important component of airway physiology. Thus, surfactant dysfunction may be included in pathophysiology of asthma, COPD, or other diseases with bronchial obstruction.

  18. Involvement of α-adrenoceptors to the implementation of the contractile effects in the capsule of mesenteric lymph nodes in response to electrostimulation.

    Science.gov (United States)

    Lobov, G I; Pan'kova, M N

    2013-03-01

    We studied changes in the contractile function of smooth muscle cells in bovine mesenteric lymph node capsule caused by electrical stimulation of nerve fibers in vitro. It was found that electrostimulation increased tonic tension and frequency of smooth muscle contractions in the node capsule. Tetrodotoxin prevented the stimulatory effect of electrical stimulation on the smooth muscle cells. Phentolamine, prazosin, and yohimbine significantly reduced the capsule response to electrical stimulation and norepinephrine application. It was concluded that excitation of nerve fibers in the capsule of bovine mesenteric lymph nodes upon electrical stimulation is realized, at least in part, via activation of α1-adrenoceptors and, to a lesser extent, via α2-adrenoceptors located on the membrane of smooth muscle cells.

  19. Detrimental effects of albuterol on airway responsiveness requires airway inflammation and is independent of β-receptor affinity in murine models of asthma

    Directory of Open Access Journals (Sweden)

    Aimi Steven

    2011-03-01

    Full Text Available Abstract Background Inhaled short acting β2-agonists (SABA, e.g. albuterol, are used for quick reversal of bronchoconstriction in asthmatics. While SABA are not recommended for maintenance therapy, it is not uncommon to find patients who frequently use SABA over a long period of time and there is a suspicion that long term exposure to SABA could be detrimental to lung function. To test this hypothesis we studied the effect of long-term inhaled albuterol stereoisomers on immediate allergic response (IAR and airway hyperresponsiveness (AHR in mouse models of asthma. Methods Balb/C mice were sensitized and challenged with ovalbumin (OVA and then we studied the IAR to inhaled allergen and the AHR to inhaled methacholine. The mice were pretreated with nebulizations of either racemic (RS-albuterol or the single isomers (S- and (R-albuterol twice daily over 7 days prior to harvest. Results We found that all forms of albuterol produced a significant increase of IAR measured as respiratory elastance. Similarly, we found that AHR was elevated by albuterol. At the same time a mouse strain that is intrinsically hyperresponsive (A/J mouse was not affected by the albuterol isomers nor was AHR induced by epithelial disruption with Poly-L-lysine affected by albuterol. Conclusions We conclude that long term inhalation treatment with either isomer of albuterol is capable of precipitating IAR and AHR in allergically inflamed airways but not in intrinsically hyperresponsive mice or immunologically naïve mice. Because (S-albuterol, which lacks affinity for the β2-receptor, did not differ from (R-albuterol, we speculate that isomer-independent properties of the albuterol molecule, other than β2-agonism, are responsible for the effect on AHR.

  20. Response of Differentiated Human Airway Epithelia to Alcohol Exposure and Klebsiella pneumoniae Challenge

    Directory of Open Access Journals (Sweden)

    Sammeta V. Raju

    2013-07-01

    Full Text Available Alcohol abuse has been associated with increased susceptibility to pulmonary infection. It is not fully defined how alcohol contributes to the host defense compromise. Here primary human airway epithelial cells were cultured at an air-liquid interface to form a differentiated and polarized epithelium. This unique culture model allowed us to closely mimic lung infection in the context of alcohol abuse by basolateral alcohol exposure and apical live bacterial challenge. Application of clinically relevant concentrations of alcohol for 24 h did not significantly alter epithelial integrity or barrier function. When apically challenged with viable Klebsiella pneumoniae, the cultured epithelia had an enhanced tightness which was unaffected by alcohol. Further, alcohol enhanced apical bacterial growth, but not bacterial binding to the cells. The cultured epithelium in the absence of any treatment or stimulation had a base-level IL-6 and IL-8 secretion. Apical bacterial challenge significantly elevated the basolateral secretion of inflammatory cytokines including IL-2, IL-4, IL-6, IL-8, IFN-γ, GM-CSF, and TNF-α. However, alcohol suppressed the observed cytokine burst in response to infection. Addition of adenosine receptor agonists negated the suppression of IL-6 and TNF-α. Thus, acute alcohol alters the epithelial cytokine response to infection, which can be partially mitigated by adenosine receptor agonists.

  1. The influence of experimental hyperlipidemia on the time course of contractility during simulated ischaemia and reperfusion and responsiveness to phenylephrine of rat heart papillary muscle.

    Science.gov (United States)

    Kocić, I; Dworakowska, D; Konstański, Z; Dworakowski, R

    1998-09-01

    The aim of this study was to examine the influence of simulated ischaemia on the contractility and responsiveness to phenylephrine of rat isolated papillary muscle in standard diet fed (SD) and hyperlipidemic diet fed (HLD) rats. The following parameters were measured: force of contraction (Fc), rate of rise (+dF/dt) and rate of fall (-dF/dt) of force of contraction, time to peak contraction (ttp) and relaxation time at 10% of total amplitude of contraction (tt10). The baseline values of Fc and +dF/dt, but, not -dF/dt, were significantly lower in HLD group than in SD group. Tissues from HLD rats were more sensitive to ischaemia regarding Fc, +dF/dt and -dF/dt. Moreover, reprefusion completely reversed the effects of ischaemia only in SD rats, but not in HLD rats, regarding Fc and +dF/dt. In contrast, a recovery of -dF/dt during reperfusion occurred only in the HLD group. In SD rats, phenylephrine (10 and 30 microM) had no effect on the contractility or induced megative inotropic effects (100 and 300 microM). Propranolol (1 microM), a non-selective blocker of beta-adrenoceptors, had no effects on this action. Chloroethylclonidine (CEC) (1 microM), a selectivw blocker of alpha 1b-adrenoceptor subtype, but not WB-4101(2-((2,6-dimethoxyphenoxyethyl)amino-methyl-1,4-benzodioxane), a selective blocker of alpha 1a adrenoceptor subtype, abolishes the negative inotropic action of phenylephrine. In HLD rats, phenylephrine had positive inotropic action (10 and 30 microM). The results indicate that hyperlipidemic diet in rats leads to the suppression of force of contraction and velocity of contraction, but not velocity of relaxation of isolated heart muscle. Under such a condition, heart muscle is more sensitive to ischaemia, but has better responsiveness to phenylephrine after ischeamia-reperfusion period.

  2. A GM-CSF/IL-33 pathway facilitates allergic airway responses to sub-threshold house dust mite exposure.

    Directory of Open Access Journals (Sweden)

    Alba Llop-Guevara

    Full Text Available Allergic asthma is a chronic immune-inflammatory disease of the airways. Despite aeroallergen exposure being universal, allergic asthma affects only a fraction of individuals. This is likely related, at least in part, to the extent of allergen exposure. Regarding house dust mite (HDM, we previously identified the threshold required to elicit allergic responses in BALB/c mice. Here, we investigated the impact of an initial immune perturbation on the response to sub-threshold HDM exposure. We show that transient GM-CSF expression in the lung facilitated robust eosinophilic inflammation, long-lasting antigen-specific Th2 responses, mucus production and airway hyperresponsiveness. This was associated with increased IL-33 levels and activated CD11b(+ DCs expressing OX40L. GM-CSF-driven allergic responses were significantly blunted in IL-33-deficient mice. IL-33 was localized on alveolar type II cells and in vitro stimulation of human epithelial cells with GM-CSF enhanced intracellular IL-33 independently of IL-1α. Likewise, GM-CSF administration in vivo resulted in increased levels of IL-33 but not IL-1α. These findings suggest that exposures to environmental agents associated with GM-CSF production, including airway infections and pollutants, may decrease the threshold of allergen responsiveness and, hence, increase the susceptibility to develop allergic asthma through a GM-CSF/IL-33/OX40L pathway.

  3. Distending Pressure Did Not Activate Acute Phase or Inflammatory Responses in the Airways and Lungs of Fetal, Preterm Lambs.

    Directory of Open Access Journals (Sweden)

    Rebecca Y Petersen

    Full Text Available Mechanical ventilation at birth causes airway injury and lung inflammation in preterm sheep. Continuous positive airway pressure (CPAP is being increasingly used clinically to transition preterm infants at birth.To test if distending pressures will activate acute phase reactants and inflammatory changes in the airways of fetal, preterm lambs.The head and chest of fetal lambs at 128±1 day GA were surgically exteriorized. With placental circulation intact, fetal lambs were then randomized to one of five 15 minute interventions: PEEP of 0, 4, 8, 12, or 16 cmH2O. Recruitment volumes were recorded. Fetal lambs remained on placental support for 30 min after the intervention. The twins of each 0 cmH2O animal served as controls. Fetal lung fluid (FLF, bronchoalveolar lavage fluid (BAL, right mainstem bronchi and peripheral lung tissue were evaluated for inflammation.Recruitment volume increased from 0.4±0.04 mL/kg at 4 cmH2O to 2.4±0.3 mL/kg at 16 cmH2O. The lambs were surfactant deficient, and all pressures were below the opening inflection pressure on pressure-volume curve. mRNA expression of early response genes and pro-inflammatory cytokines did not increase in airway tissue or lung tissue at any pressure compared to controls. FLF and BAL also did not have increases in early response proteins. No histologic changes or Egr-1 activation was present at the pressures used.Distending pressures as high as 16 cmH2O did not recruit lung volume at birth and did not increase markers of injury in the lung or airways in non-breathing preterm fetal sheep.

  4. Airway inflammatory response to ozone in subjects with different asthma severity

    Energy Technology Data Exchange (ETDEWEB)

    Vagaggini, B.; Carnevali, S.; Macchioni, P. [Univ. of Pisa, Cardio-Thoracic Dept., Respiratory patho-physiology (IT)] (and others)

    1999-07-01

    The aim of this study was to evaluate whether ozone exposure induces a similar airway inflammatory response in subjects with different degrees of asthma severity. Two groups of asthmatic subjects were studied: seven with intermittent mild asthma not requiring regular treatment (group A); and seven with persistent mild asthma requiring regular treatment with inhaled corticosteroids and long-acting {beta}{sub 2}-agonists (group B). All subjects were exposed, in a randomized cross-over design, to air or O{sub 3} (0.26 parts per million (ppm) for 2 h with intermittent exercise); subjects in group B withdrew from regular treatment 72 h before each exposure. Before the exposure, and 1 and 2 h after the beginning of the exposure they performed a pulmonary function test, and a questionnaire was completed to obtain a total symptom score (TSS). Six hours after the end of the exposure, hypertonic saline (HS) sputum induction was conducted. Sputum cell percentages, eosinophil cationic protein (ECP) and interleukin (IL)-8 concentrations in the sputum supernatant were measured. TSS significantly increased and forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) significantly decreased after O{sub 3} exposure in comparison with air exposure in group A, whereas no changes were observed in group B except for a significant decrement of FEV1 2 h after the beginning of O{sub 3} exposure. Sputum neutrophil percentage was significantly higher after O{sub 3} exposure than after air exposure in both groups (Group A: 70.2% (28-87) versus 26.6% (8.6-73.2); Group B: 62.1% (25-82.4) versus 27.9% (14.4-54)). IL-8 was higher in sputum supernatant collected 6 h after O{sub 3} exposure than after air, only in group A. No change due to O{sub 3} has been found in sputum eosinophil percentage and ECP concentration in both groups. In conclusion, the degree of airway response to a short-term exposure to ozone is different in subjects with asthma of different severity. The

  5. Airway epithelium is a predominant source of endogenous airway GABA and contributes to relaxation of airway smooth muscle tone

    OpenAIRE

    Gallos, George; Townsend, Elizabeth; Yim, Peter; Virag, Laszlo; Zhang, Yi; Xu, Dingbang; Bacchetta, Matthew; Emala, Charles W.

    2012-01-01

    Chronic obstructive pulmonary disease and asthma are characterized by hyperreactive airway responses that predispose patients to episodes of acute airway constriction. Recent studies suggest a complex paradigm of GABAergic signaling in airways that involves GABA-mediated relaxation of airway smooth muscle. However, the cellular source of airway GABA and mechanisms regulating its release remain unknown. We questioned whether epithelium is a major source of GABA in the airway and whether the ab...

  6. Comparative study of hemodynamic responses to orotracheal intubation with intubating laryngeal mask airway and direct laryngoscope

    Institute of Scientific and Technical Information of China (English)

    ZHANG Guo-hua; XUE Fu-shan; SUN Hai-yan; LI Cheng-wen; SUN Hai-tao; LI Ping; LIU Kun-peng

    2006-01-01

    Background Intubating laryngeal mask airway (ILMA) offers a new approach for orotracheal intubation and is expected to produce less cardiovascular stress responses. However, the available studies provide inconsistent results. The purpose of this study was to identify whether there is a clinically relevant difference in hemodynamic responses to orotracheal intubation by using ILMA and direct laryngoscope (DLS).Methods A total of 53 adult patients, ASA physical status Ⅰ-Ⅱ, scheduled for elective plastic surgery under general anesthesia requiring the orotracheal intubation, were randomly allocated to either DLS or ILMA groups.After a standard intravenous anesthesia induction, orotracheal intubation was performed. Noninvasive blood pressure and heart rate were recorded before (baseline values) and after anesthesia induction (post-induction values), at intubation and every minute for the first 5 minutes after intubation. The data were analyzed using Chisquare test, paired and unpaired Student's t test, and repeated-measures analysis of variance as appropriate.Results The mean intubation time in the ILMA group was longer than that in the DLS group (P<0.05). The blood pressure and heart rate increased significantly after intubation in the two groups compared to the postinduction values (P<0.05), but the maximum value of blood pressure during the observation did not exceed the baseline value, while the maximum value of heart rate was higher than the baseline (P<0.05). During the observation, there were no significant differences in blood pressure and heart rate among each time point and in the maximum values between the two groups.Conclusions Orotracheal intubations by using ILMA and DLS produce similar hemodynamic response. ILMA has no advantage in attenuating the hemodynamic responses to orotracheal intubation compared with DLS.

  7. Myocardial response to incremental exercise in endurance-trained athletes: influence of heart rate, contractility and the Frank-Starling effect.

    Science.gov (United States)

    Warburton, Darren E R; Haykowsky, Mark J; Quinney, H Arthur; Blackmore, Derrick; Teo, Koon K; Humen, Dennis P

    2002-09-01

    Recent evidence indicates that endurance-trained athletes are able to increase their stroke volume (SV) throughout incremental upright exercise, probably due to a progressively greater effect of the Frank-Starling mechanism. This is contrary to the widely held belief that SV reaches a plateau at a submaximal heart rate (irrespective of fitness level), owing to a limitation in the time for diastolic filling. The purpose of this investigation was to evaluate whether endurance-trained athletes rely on a progressively greater effect of the Frank-Starling mechanism throughout incremental exercise. A secondary purpose was to evaluate the effects of postural position on the cardiovascular responses to incremental exercise. Ten male cyclists participated in this investigation. Left ventricular function was assessed throughout incremental exercise in the supine and upright positions (counterbalanced) using radionuclide ventriculography. Stroke volume increased in a linear fashion during incremental exercise in both the upright and supine positions. The increases in cardiac output (Q) throughout incremental to maximal exercise (in both the supine and upright positions) were significantly related to changes in heart rate, myocardial contractility and the Frank-Starling mechanism. Percentage changes in end-diastolic volume and SV were significantly greater in the upright position versus the supine position, reflecting an increased reliance on the Frank-Starling effect to increase Q. We conclude from this investigation that highly trained endurance athletes are able to make progressively increasing usage of the Frank-Starling effect throughout incremental exercise. Postural position has a significant effect on the relative contribution of heart rate, myocardial contractility and the Frank-Starling mechanism to the increase in Q during exercise conditions.

  8. Relation of airway responsiveness to duration of work in a dusty environment.

    OpenAIRE

    Ernst, P.; Dales, R E; Nunes, F.; Becklake, M. R.

    1989-01-01

    Health selection within a workforce has been found in several industries and appears to be more pronounced in dustier occupations. In this study of airway disease among workers exposed to asbestos and man made mineral fibres, 215 of 246 construction insulators 50 years old or less and currently working in the Montreal area were examined. Spirometry was completed successfully in 214 workers without known asbestosis and 207 underwent methacholine bronchoprovocation testing. Airway responsivenes...

  9. Improved throughput traction microscopy reveals pivotal role for matrix stiffness in fibroblast contractility and TGF-β responsiveness

    Science.gov (United States)

    Marinković, Aleksandar; Mih, Justin D.; Park, Jin-Ah; Liu, Fei

    2012-01-01

    Lung fibroblast functions such as matrix remodeling and activation of latent transforming growth factor-β1 (TGF-β1) are associated with expression of the myofibroblast phenotype and are directly linked to fibroblast capacity to generate force and deform the extracellular matrix. However, the study of fibroblast force-generating capacities through methods such as traction force microscopy is hindered by low throughput and time-consuming procedures. In this study, we improved at the detail level methods for higher-throughput traction measurements on polyacrylamide hydrogels using gel-surface-bound fluorescent beads to permit autofocusing and automated displacement mapping, and transduction of fibroblasts with a fluorescent label to streamline cell boundary identification. Together these advances substantially improve the throughput of traction microscopy and allow us to efficiently compute the forces exerted by lung fibroblasts on substrates spanning the stiffness range present in normal and fibrotic lung tissue. Our results reveal that lung fibroblasts dramatically alter the forces they transmit to the extracellular matrix as its stiffness changes, with very low forces generated on matrices as compliant as normal lung tissue. Moreover, exogenous TGF-β1 selectively accentuates tractions on stiff matrices, mimicking fibrotic lung, but not on physiological stiffness matrices, despite equivalent changes in Smad2/3 activation. Taken together, these results demonstrate a pivotal role for matrix mechanical properties in regulating baseline and TGF-β1-stimulated contraction of lung fibroblasts and suggest that stiff fibrotic lung tissue may promote myofibroblast activation through contractility-driven events, whereas normal lung tissue compliance may protect against such feedback amplification of fibroblast activation. PMID:22659883

  10. Invasive versus noninvasive measurement of allergic and cholinergic airway responsiveness in mice

    Directory of Open Access Journals (Sweden)

    Hohlfeld Jens M

    2005-11-01

    Full Text Available Abstract Background This study seeks to compare the ability of repeatable invasive and noninvasive lung function methods to assess allergen-specific and cholinergic airway responsiveness (AR in intact, spontaneously breathing BALB/c mice. Methods Using noninvasive head-out body plethysmography and the decrease in tidal midexpiratory flow (EF50, we determined early AR (EAR to inhaled Aspergillus fumigatus antigens in conscious mice. These measurements were paralleled by invasive determination of pulmonary conductance (GL, dynamic compliance (Cdyn and EF50 in another group of anesthetized, orotracheally intubated mice. Results With both methods, allergic mice, sensitized and boosted with A. fumigatus, elicited allergen-specific EAR to A. fumigatus (p Conclusion We conclude that invasive and noninvasive pulmonary function tests are capable of detecting both allergen-specific and cholinergic AR in intact, allergic mice. The invasive determination of GL and Cdyn is superior in sensitivity, whereas the noninvasive EF50 method is particularly appropriate for quick and repeatable screening of respiratory function in large numbers of conscious mice.

  11. Role of CO2 responsiveness and breathing efficiency in determining exercise capacity of patients with chronic airway obstruction.

    Science.gov (United States)

    Chonan, T; Hida, W; Kikuchi, Y; Shindoh, C; Takishima, T

    1988-12-01

    We examined the role of CO2 responsiveness and breathing efficiency in limiting exercise capacity in 15 patients with chronic airway obstruction (FEV1 = 0.88 +/- 0.25 L, mean +/- SD). Responses of minute ventilation and P0.1 (mouth pressure 0.1 s after the onset of occluded inspiration) to hypercapnia (delta VE/delta PCO2, delta P0.1/delta PCO2) were measured by rebreathing, and the ratio of the two (delta VE/delta P0.1) was defined as an index of breathing efficiency during hyperventilation. Exercise capacity was measured as symptom-limited, maximal oxygen consumption (VO2max/BW) in an incremental treadmill test and also as the 12-min walking distance (TMD). All patients discontinued the treadmill test because of dyspnea, and the exercise capacity correlated with the degree of airway obstruction, although there was a wide variability among patients with comparable FEV1. There were no significant correlations between the responses to CO2 and exercise capacity. However, there was a significant correlation between delta VE/delta P0.1 and VO2max/BW (r = 0.87, p less than 0.001) or TMD (r = 0.78, p less than 0.001), and these correlations remained significant even when the relational effects of FEV1 were taken out. These results support the hypothesis that airway obstruction and breathing efficiency are important, but that CO2 responsiveness is not a major factor in determining the exercise capacity of patients with chronic airway obstruction.

  12. The Compatible Solute Ectoine Reduces the Exacerbating Effect of Environmental Model Particles on the Immune Response of the Airways

    OpenAIRE

    Klaus Unfried; Matthias Kroker; Andrea Autengruber; Marijan Gotić; Ulrich Sydlik

    2014-01-01

    Exposure of humans to particulate air pollution has been correlated with the incidence and aggravation of allergic airway diseases. In predisposed individuals, inhalation of environmental particles can lead to an exacerbation of immune responses. Previous studies demonstrated a beneficial effect of the compatible solute ectoine on lung inflammation in rats exposed to carbon nanoparticles (CNP) as a model of environmental particle exposure. In the current study we investigated the effect of su...

  13. Intranasal organic dust exposure-induced airway adaptation response marked by persistent lung inflammation and pathology in mice

    OpenAIRE

    Poole, Jill A.; Wyatt, Todd A; Oldenburg, Peter J.; Elliott, Margaret K.; West, William W.; Sisson, Joseph H.; Von Essen, Susanna G.; Romberger, Debra J.

    2009-01-01

    Organic dust exposure in agricultural environments results in an inflammatory response that attenuates over time, but repetitive exposures can result in chronic respiratory disease. Animal models to study these mechanisms are limited. This study investigated the effects of single vs. repetitive dust-induced airway inflammation in mice by intranasal exposure method. Mice were exposed to swine facility dust extract (DE) or saline once and once daily for 1 and 2 wk. Dust exposure resulted in inc...

  14. Regulation of cyclooxygenase-2 expression by cAMP response element and mRNA stability in a human airway epithelial cell line exposed to zinc

    Science.gov (United States)

    Exposure to zinc-laden particulate matter in ambient and occupational settings has been associated with proinflammatory responses in the lung. Cyclooxygenase 2-derived eicosanoids are important modulators of airway inflammation. In this study, we characterized the transcriptional...

  15. Effect of montelukast combined with procaterol treatment on airway remodeling and inflammatory response in children with mycoplasma pneumonia

    Institute of Scientific and Technical Information of China (English)

    Jian-Mei Zhang; Fen-Xia Zhang; Yan Jia; Min Wang; Jue Bai

    2016-01-01

    Objective:To study the effect of montelukast combined with procaterol treatment on airway remodeling and inflammatory response in children with mycoplasma pneumonia.Methods:A total of 60 mycoplasma pneumonia children with acute asthma attack treated in our hospital were selected and randomly divided into two groups, observation group received conventional anti-infection, cough-relieving and sputum-reducing combined with montelukast and procaterol spasmolysis and asthma-relieving treatment, control group received conventional anti-infection, cough-relieving and sputum-reducing combined with procaterol spasmolysis and asthma-relieving treatment, and then the degree of airway remodeling and inflammatory response was compared between two groups.Results:Serum MCP-4, MDC and CysLTs levels of both groups 1 week after treatment were significantly lower than those before treatment and serum MCP-4, MDC and CysLTs levels of observation group after treatment were lower than those of control group; 1 week after treatment, LD and the proportion of Treg in induced sputum of observation group were significantly higher than those of control group, WT, WA%, PEF25, PEF50 and PEF75 as well as FN1 and Col-1 levels and the proportion of Th17 in induced sputum were significantly lower than those of control group, and FVC, PEF and FEV1 were not different from those of control group.Conclusions:Montelukast combined with procaterol treatment can significantly improve the airway remodeling and inflammatory response in mycoplasma pneumonia children with acute asthma attack.

  16. High degree of overlap between responses to a virus and to the house dust mite allergen in airway epithelial cells.

    Directory of Open Access Journals (Sweden)

    Korneliusz Golebski

    Full Text Available BACKGROUND: Airway epithelium is widely considered to play an active role in immune responses through its ability to detect changes in the environment and to generate a microenvironment for immune competent cells. Therefore, besides its role as a physical barrier, epithelium affects the outcome of the immune response by the production of various pro-inflammatory mediators. METHODS: We stimulated airway epithelial cells with viral double stranded RNA analogue poly(I:C or with house dust mite in a time course of 24 hours. In order to determine cytokines production by stimulated cells, we performed multiplex enzyme linked immunosorbant assay (ELISA. RESULTS: We demonstrate that the temporal pattern of the genes that respond to virus exposure in airway epithelium resembles to a significant degree their pattern of response to HDM. The gene expression pattern of EGR1, DUSP1, FOSL1, JUN, MYC, and IL6 is rather similar after viral (poly(I:C and HDM exposure. However, both triggers also induce a specific response (e.g. ATF3, FOS, and NFKB1. We confirmed these data by showing that epithelial cells produce a variety of similar mediators in response to both poly(I:C and HDM challenge (IL1-RA, IL-17, IFN-α and MIP1-α, sometimes with a quantitative difference in response (IL2-R, IL-6, IL-8, MCP-1, MIG, and HGF. Interestingly, only four mediators (IL-12, IP-10, RANTES and VEGF where up-regulated specifically by poly(I:C and not by HDM. Additionally, we report that pre-exposure to HDM deregulates production of cytokines and mediators in response to poly(I:C. CONCLUSIONS: Epithelial cells responses to the HDM-allergen and a virus strongly resemble both in gene expression and in protein level explaining why these two responses may affect each other.

  17. Behavioral inhibition in rhesus monkeys (Macaca mulatta is related to the airways response, but not immune measures, commonly associated with asthma.

    Directory of Open Access Journals (Sweden)

    Katie Chun

    Full Text Available Behavioral inhibition reflects a disposition to react warily to novel situations, and has been associated with atopic diseases such as asthma. Retrospective work established the relationship between behavioral inhibition in rhesus monkeys (Macaca mulatta and airway hyperresponsiveness, but not atopy, and the suggestion was made that behavioral inhibition might index components of asthma that are not immune-related. In the present study, we prospectively examined the relationship between behavioral inhibition and airway hyperresponsiveness, and whether hormonal and immune measures often associated with asthma were associated with behavioral inhibition and/or airway hyperresponsiveness. In a sample of 49 yearling rhesus monkeys (mean=1.25 years, n=24 behaviorally inhibited animals, we measured in vitro cytokine levels (IL-4, IL-10, IL-12, IFN-γ in response to stimulation, as well as peripheral blood cell percentages, cortisol levels, and percentage of regulatory T-cells (CD3+CD4+CD25+FOXP3+. Airway reactivity was assessed using an inhaled methacholine challenge. Bronchoalveolar lavage was performed and the proportion of immune cells was determined. Behaviorally inhibited monkeys had airway hyperresponsiveness as indicated by the methacholine challenge (p=0.031, confirming our earlier retrospective result. Airway hyperresponsiveness was also associated with lower lymphocyte percentages in lavage fluid and marginally lower plasma cortisol concentrations. However, none of the tested measures was significantly related to both behavioral inhibition and airway hyperresponsiveness, and so could not mediate their relationship. Airway hyperresponsiveness is common to atopic and non-atopic asthma and behavioral inhibition has been related to altered autonomic activity in other studies. Our results suggest that behavioral inhibition might index an autonomically mediated reactive airway phenotype, and that a variety of stimuli (including inflammation within

  18. Effect of adjuvant nasal continuous positive airway pressure therapy on immune response and organ injury in children with severe pneumonia

    Institute of Scientific and Technical Information of China (English)

    Ni-Na Huang; Yu-Dan Zhang

    2016-01-01

    Objective:To analyze the effect of adjuvant nasal continuous positive airway pressure therapy on immune response and organ injury in children with severe pneumonia.Methods:A total of 90 children with severe pneumonia were randomly divided into observation group and control group (n=45), control group received conventional therapy, observation group accepted regular + adjuvant nasal continuous positive airway pressure therapy, and then differences in immune globulin, Th1/Th2 indexes, blood coagulation indexes, echocardiography parameters and so on were compared between two groups of children.Results:IgG2, IgG3, IgA and IgM content in peripheral blood of observation group were higher than those of control group; Th1/Th2 indexes IL-4 and IFN-γ content in serum as well as IL-4/IFN-γ level were lower than those of control group; blood coagulation indexes PT, TT, APTT and D-D levels were lower than those of control group while FIB and PLT levels were higher than those of control group; echocardiography parameters PVAT and AVAT levels were higher than those of control group while PFVMA level was lower than that of control group.Conclusions: Adjuvant nasal continuous positive airway pressure therapy helps to enhance the immune response and optimize blood coagulation function and cardiac function in children with severe pneumonia.

  19. Glucocorticosteroids and beta(2)-Adrenoceptor Agonists Synergize to Inhibit Airway Smooth Muscle Remodeling

    NARCIS (Netherlands)

    Dekkers, Bart G. J.; Pehlic, Adnan; Mariani, Raissa; Bos, I. Sophie T.; Meurs, Herman; Zaagsma, Johan

    2012-01-01

    Airway remodeling, including increased airway smooth muscle (ASM) mass and contractility, contributes to increased airway narrowing in asthma. Increased ASM mass may be caused by exposure to mitogens, including platelet-derived growth factor (PDGF) and collagen type I, which induce a proliferative,

  20. Ginsenoside Rb1 Attenuates Agonist-Induced Contractile Response via Inhibition of Store-Operated Calcium Entry in Pulmonary Arteries of Normal and Pulmonary Hypertensive Rats

    Directory of Open Access Journals (Sweden)

    Rui-Xing Wang

    2015-03-01

    Full Text Available Background: Pulmonary hypertension (PH is characterized by sustained vasoconstriction, enhanced vasoreactivity and vascular remodeling, which leads to right heart failure and death. Despite several treatments are available, many forms of PH are still incurable. Ginsenoside Rb1, a principle active ingredient of Panax ginseng, exhibits multiple pharmacological effects on cardiovascular system, and suppresses monocrotaline (MCT-induced right heart hypertrophy. However, its effect on the pulmonary vascular functions related to PH is unknown. Methods: We examined the vasorelaxing effects of ginsenoside Rb1 on endothelin-1 (ET-1 induced contraction of pulmonary arteries (PAs and store-operated Ca2+ entry (SOCE in pulmonary arterial smooth muscle cells (PASMCs from chronic hypoxia (CH and MCT-induced PH. Results: Ginsenoside Rb1 elicited concentration-dependent relaxation of ET-1-induced PA contraction. The vasorelaxing effect was unaffected by nifedipine, but abolished by the SOCE blocker Gd3+. Ginsenoside Rb1 suppressed cyclopiazonic acid (CPA-induced PA contraction, and CPA-activated cation entry and Ca2+ transient in PASMCs. ET-1 and CPA-induced contraction, and CPA-activated cation entry and Ca2+ transients were enhanced in PA and PASMCs of CH and MCT-treated rats; the enhanced responses were abolished by ginsenoside Rb1. Conclusion: Ginsenoside Rb1 attenuates ET-1-induced contractile response via inhibition of SOCE, and it can effectively antagonize the enhanced pulmonary vasoreactivity in PH.

  1. Airway Management in Disaster Response: A Manikin Study Comparing Direct and Video Laryngoscopy for Endotracheal Intubation by Prehospital Providers in Level C Personal Protective Equipment.

    Science.gov (United States)

    Yousif, Sami; Machan, Jason T; Alaska, Yasser; Suner, Selim

    2017-03-20

    Introduction Airway management is one of many challenges that medical providers face in disaster response operations. The use of personal protective equipment (PPE), in particular, was found to be associated with higher failure rates and a prolonged time to achieve airway control. Hypothesis/Problem The objective of this study was to determine whether video laryngoscopy could facilitate the performance of endotracheal intubation by disaster responders wearing Level C PPE.

  2. Isoquercitrin from Argemone platyceras inhibits carbachol and leukotriene D4-induced contraction in guinea-pig airways.

    Science.gov (United States)

    Fernandez, Jacquelina; Reyes, Ricardo; Ponce, Hector; Oropeza, Martha; Vancalsteren, Marie-Rose; Jankowski, Christopher; Campos, Maria G

    2005-10-17

    Argemone platyceras is used in Mexico as a remedy for cough, bronchitis and pneumonia. The present study was performed to investigate the pharmacological anti-asthmatic properties of Argemone platyceras on airways and to identify its active principles. Methanol extracts of leaves and flowers, subsequent organic and aqueous extraction phases, and silica gel chromatography fractions were assayed on the carbachol-induced response, and/or on ovalbumin antigenic challenge, and on leukotriene D(4)-induced response of tracheae from sensitized and non-sensitized guinea-pigs. Methanol extracts, ethyl-acetate phase, and its fractions 6 and 7 inhibited the carbachol-induced contractile response. Isoquercitrin and rutin were the main compounds found in fractions 6 and 7 respectively. Isoquercitrin (fraction 6) abolished the response to ovalbumin, and decreased the contractile response to leukotriene D(4). Because of its effect on carbachol-induced contractile response, on the late-phase response to ovalbumin, and on leukotriene D(4)-induced contractile response, isoquercitrin might be highly useful in treatment of asthma.

  3. Flow cytometry of sputum: assessing inflammation and immune response elements in the bronchial airways**

    Science.gov (United States)

    Rationale: The evaluation of sputum leukocytes by flow cytometry is an opportunity to assess characteristics of cells residing in the central airways, yet it is hampered by certain inherent properties of sputum including mucus and large amounts of contaminating cells and debris. ...

  4. The Antimuscarinic Effects of Anticholinesterase Drugs on Electrical Field Stimulation-Induced Contractile Responses in Rat Gastric Fundus and Ileum Smooth Muscle

    Directory of Open Access Journals (Sweden)

    Ilker Kelle

    2007-01-01

    Full Text Available Parasympathetic component of autonomic nervous system is known as involving in majority of intestinal smooth muscle contractions and motility. Acetylcholine can be released from parasympathetic nerve terminals by an excitation which is formed by a physiological or an electrical stimulation in order to elicit smooth muscle contractions. Anticholinesterase drugs are expected to increase the levels of acetylcholine in cholinergic synapses via inhibiting the enzyme acetylcholinesterase. In recent studies, it has been shown that anticholinesterase drugs may cause an antimuscarinic effect on the contrary of their usual effects such as amplifying of cholinergic transmission. In this study, we investigated the antimuscarinic effects of neostigmine, edrophonium and piridostigmine on gastric fundus and ileum smooth muscle preparations isolated from Wistar albino rats. The contactions were induced by using electrical field stimulation (EFS which is a direct stimulation technique. Both neostigmine and piridostigmine increased the E max values of contractile responses for EFS at their first three concentrations; but only the changes in gastric fundus strips has found significant as statistically. At their highest concentration such as 1000 M, both neostigmine and piridostigmine attenuated the EFS induced smooth muscle contractions and caused an antimuscarinic effect (p  0,05; paired samples Student’s t test. In contrast, edrophonium had no effect on EFS induced smooth muscle contractions, at none of its four concentrations as statistically. Our results suggest that larger doses of neostigmine and piridostigmine, but not edrophonium, may evoke antimuscarinic effects on intestinal smooth muscle contractions.

  5. Experimental hyperlipidemia prevents the protective effect of ischemic preconditioning on the contractility and responsiveness to phenylephrine of rat-isolated stunned papillary muscle.

    Science.gov (United States)

    Kocić, I; Konstański, Z; Kaminski, M; Dworakowska, D; Dworakowski, R

    1999-09-01

    This study was designed to establish a hyperlipidemic diet (significant increase in the cholesterol and triglycerides blood levels, but without atherogenic changes in heart muscle and coronary vessels) and to investigate the influence of experimental hyperlipidemia on the effects of ischemic preconditioning (PC) of rat-isolated papillary muscle on the time course of contractility during simulated ischemia and reperfusion and responsiveness to phenylephrine under such a condition. The animals were divided in four experimental groups: standard diet-fed control group (SD), SD underwent ischemic preconditioning (SD-PC), hyperlipidemic diet-fed group (HLD) and HLD underOFFt PC (HLD-PC). Force of contraction (Fc), velocity of contraction (+dF/dt), and velocity of relaxation (-dF/dt) were measured. HLD preparations were more sensitive to ischemia then SD ones. PC, performed by 5-min perfusion with no-substrate solution gassing with 95% N2/5% CO2 in the presence of fast electrical stimulation, and 10 min of reperfusion with normal solution and rate of stimulation, significantly increased the resistance of isolated cardiac tissues to simulated ischemia in SD-PC group, but not in HLD-PC group. Negative inotropic action of phenylephrine occured in SD group of preparations after simulated-ischemia/reperfusion period was also prevented by PC. Therefore, we conclude that experimental hyperlipidemia significantly influenced the function of rat heart muscle including the higher sensitivity to ischemia and different reaction to the same PC procedure.

  6. Effect of montelukast on excessive airway narrowing response to methacholine in adult asthmatic patients not on controller therapy

    DEFF Research Database (Denmark)

    Ulrik, Charlotte Suppli; Diamant, Zuzana

    2009-01-01

    2-agonists p.r.n. only with a twice-documented absence of dose-response plateau, participated in a double-blind, parallel study with Mont (10 mg) or placebo once daily for 12 weeks. Mtc dose-response curves (0.03-256 mumol or >40% FEV(1) decline) were repeated every 4 weeks. The primary objective......Excessive airway narrowing is an important determinant of fatal asthma. This pathophysiological feature is characterized by the absence of a dose-response plateau to methacholine (Mtc). We investigated if the leukotriene receptor antagonist (LTRA) montelukast (Mont) can induce a dose-response.......9%, respectively, with no differences between the groups. After 12 weeks, a dose-response plateau was observed in two patients (Mont) and one patient (placebo) (NS), and comparison of changes from baseline in maximal decline in FEV(1) or PD(20) revealed no significant differences between groups. Twelve weeks...

  7. SIGIRR inhibits toll-like receptor 4, 5, 9-mediated immune responses in human airway epithelial cells.

    Science.gov (United States)

    Zhang, Chun; Wu, Xueling; Zhao, Yunfeng; Deng, Zhaoxia; Qian, Guisheng

    2011-01-01

    Human airway epithelial cells (HAEC) may contribute to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) through toll-like receptors (TLRs)-mediated molecular mechanisms. TLRs exist on the surface of HAEC where binding to their cognate ligands initiates airway inflammation. Single immunoglobulin interleukin-1 receptor-related protein (SIGIRR) is a member of the toll-interleukin-1 receptor (TIR) family that can negatively modulate the immune response. We carried out studies to characterize SIGIRR modulation of TLR-mediated immune response in HAEC and to define its mechanisms of action. Following treatment with various concentrations of LPS, flagellin and CpG DNA, the levels of cognate TLRs 4, 5, and 9 were measured in the supernatants of HAEC over-expressing the SIGIRR molecule. Moreover, the interaction of the TLR adaptor myeloid differentiation factor 88 (MyD88) with SIGIRR in response to LPS-, flagellin- and CpG DNA-stimulation was examined by co-immunoprecipitation. The findings from this study revealed that overexpression of SIGIRR in HAEC stimulated by LPS, flagellin or CpG DNA resulted in attenuated production of the inflammatory mediators IL-6 and TNF-α. This attenuation was not the result of decreased expression of TLR4, 5 or 9, but rather a sequestration of MyD88 to the TLRs. In conclusion, SIGIRR can inhibit TLR4, 5, and 9-mediated immune responses in HAEC and may be a valuable therapeutic target for the prevention of ALI/ARDS.

  8. Dual effects of respiratory syncytial virus infections on airway inflammation by regulation of Th17/Treg responses in ovalbumin-challenged mice.

    Science.gov (United States)

    Wang, Jia; Kong, Lingwen; Luo, Qingli; Li, Bei; Wu, Jinfeng; Liu, Baojun; Wu, Xiao; Dong, Jingcheng

    2014-12-01

    We investigated the effects of respiratory syncytial virus (RSV) infections on ovalbumin (OVA)-challenged mice via regulation of Th17/Treg cell responses. BALB/c mice were challenged with OVA, followed by RSV infections twice. In OVA-challenged mice, the secretion of Th2/Th17-type cytokines, airway hyperresponsiveness and inflammation were significantly inhibited by initial RSV infection. Moreover, the in vivo findings demonstrated that initial RSV infection reversed the imbalance of Th17/Treg responses. In contrast, RSV re-infection strengthened Th2/Th17-type cytokine secretion, airway hyperresponsiveness, and inflammation, especially for lymphocyte infiltration in OVA-challenged mice. Meanwhile, RSV re-infection enhanced the imbalanced Th17/Treg responses. Upon all results reveal that RSV-induced respiratory infections may lead to dual effects pertaining to allergic airway inflammation by regulation of Th17/Treg responses.

  9. Mycoplasma ovipneumoniae induces inflammatory response in sheep airway epithelial cells via a MyD88-dependent TLR signaling pathway.

    Science.gov (United States)

    Xue, Di; Ma, Yan; Li, Min; Li, Yanan; Luo, Haixia; Liu, Xiaoming; Wang, Yujiong

    2015-01-15

    Mycoplasma ovipneumoniae (M. ovipneumoniae) is a bacterium that specifically infects sheep and goat and causes ovine infectious pleuropneumonia. In an effort to understand the pathogen-host interaction between the M. ovipneumoniae and airway epithelial cells, we investigated the host inflammatory response using a primary air-liquid interface (ALI) epithelial culture model generated from bronchial epithelial cells of Ningxia Tan sheep (Ovis aries). The ALI culture of sheep bronchial epithelial cells showed a fully differentiated epithelium comprising distinct epithelial types, including the basal, ciliated and goblet cells. Exposure of ALI cultures to M. ovipneumoniae led to increased expression of Toll-like receptors (TLRs), and components of the myeloid differentiation factor 88 (MyD88)-dependent TLR signaling pathway, including the MyD88, TNF receptor-associated factor 6 (TRAF6), IL-1 receptor-associated kinases (IRAKs) and nuclear factor-kappa B (NF-κB), as well as subsequent pro-inflammatory cytokines in the epithelial cells. Of interest, infection with M. ovipneumoniae failed to induce the expression of TANK-binding kinase 1 (TBK1), TRAF3 and interferon regulatory factor 3 (IRF3), key components of the MyD88-independent signaling pathway. These results suggest that the MyD88-dependent TLR pathway may play a crucial role in sheep airway epithelial cells in response to M. ovipneumoniae infection, which also indicate that the ALI culture system may be a reliable model for investigating pathogen-host interactions between M. ovipneumoniae and airway epithelial cells.

  10. Susceptibility to Lower Respiratory Infections in Childhood is Associated with Perturbation of the Cytokine Response to Pathogenic Airway Bacteria

    DEFF Research Database (Denmark)

    Vissing, Nadja Hawwa; Larsen, Jeppe Madura; Rasmussen, Morten Arendt

    2016-01-01

    BACKGROUND: Neonatal colonization of the airways with respiratory pathogens is associated with increased risk of lower respiratory infections (LRI) in early childhood. Therefore, we hypothesized that children developing LRI have an aberrant immune response to pathogenic bacteria in infancy....... OBJECTIVE: To characterize in vitro the early life systemic immune response to pathogenic bacteria and study the possible association with incidence of LRI during the first 3 years of life. METHODS: The Copenhagen Prospective Study on Asthma in Childhood2000 (COPSAC2000) is a clinical birth cohort study......, IL-5, IL-10, IL-13, and IL-17 in peripheral blood mononuclear cells isolated at age 6 months from 291 infants. Data were analyzed by Poisson regression against incidence of LRI in infancy. RESULTS:: A multivariable model including all cytokine responses from the three different bacterial stimulations...

  11. Inhibition of pan neurotrophin receptor p75 attenuates diesel particulate-induced enhancement of allergic airway responses in C57/B16J mice.

    Science.gov (United States)

    Farraj, Aimen K; Haykal-Coates, Najwa; Ledbetter, Allen D; Evansky, Paul A; Gavett, Stephen H

    2006-06-01

    Recent investigations have linked neurotrophins, including nerve growth factor (NGF), neurotrophin-3 (NT-3), and brain-derived neurotrophic factor (BDNF), to allergic airways diseases. Antibody blockade of NGF attenuates airway resistance in allergic mice. Diesel exhaust particle (DEP) exposure has been linked to asthma exacerbation in many cities with vehicular traffic congestion. We tested the hypothesis that DEP-induced enhancement of the hallmark features of allergic airway disease in a murine model is dependent on the function of the pan neurotrophin receptor p75. Ovalbumin (OVA)-sensitized C57B1/6J mice were intranasally instilled with an antibody against the p75 receptor or saline alone 1 h before OVA challenge. The mice were then exposed nose-only to the PM2.5 fraction of SRM2975 DEP or air alone for 5 h beginning 1 h after OVA challenge. Two days later, air-exposed OVA-allergic mice developed a small but insignificant increase in methacholine-induced airflow obstruction relative to air-exposed, vehicle-sensitized mice. DEP-exposed OVA-allergic mice had a significantly greater degree of airway obstruction than all other groups. Instillation of anti-p75 significantly attenuated the DEP-induced increase in airway obstruction in OVA-allergic mice to levels similar to non-sensitized mice. The DEP-induced exacerbation of allergic airway responses may, in part, be mediated by neurotrophins.

  12. IL-25 promotes Th2 immunity responses in airway inflammation of asthmatic mice via activation of dendritic cells.

    Science.gov (United States)

    Hongjia, Li; Caiqing, Zhang; Degan, Lu; Fen, Liu; Chao, Wang; Jinxiang, Wu; Liang, Dong

    2014-08-01

    Allergic asthma occurs as a consequence of inappropriate immunologic inflammation to allergens and characterized by Th2 adaptive immune response. Recent studies indicated that interleukin (IL)-25, a member of the IL-17 cytokine family, had been implicated in inducing Th2 cell-dependent inflammation in airway epithelium and IL-25-deficient mice exhibit impaired Th2 immunity responses; however, how these cytokines influence innate immune responses remains poorly understood. In this study, we used ovalbumin (OVA) sensitization and challenge to induce the murine asthmatic model and confirmed by histological analysis of lung tissues and serum levels of total and OVA-specific immunoglobulin (Ig)-E. The expression of IL-25 was detected by quantitative real-time PCR and immunohistochemistry, respectively, and the dendritic cells (DCs) activation was detected by levels of CD80 and CD86 in bronchoalveolar lavage fluid (BALF) by flow cytometry. The mice sensitized and challenged with OVA showed high expression of IL-25 in both mRNA and protein levels in lungs. We detected the expression of CD80 and CD86 in BALF was also increased. A tight correlation between IL-25 mRNA and other Th2 cells producing cytokines such as IL-4, IL-5, and IL-13 in BALF was identified. Furthermore, when the asthmatic mice were treated with inhaled corticosteroids, the inflammatory cells infiltration and the inflammatory cytokines secretion were significantly decreased. In this study, we show that IL-25 promoted the accumulation of co-stimulatory molecules of CD80 and CD86 on DCs and then induced the differentiation of prime naive CD4(+) T cells to become proinflammatory Th2 cells and promoted Th2 cytokine responses in OVA-induced airway inflammation. The ability of IL-25 to promote the activation and differentiation of DCs population was identified as a link between the IL-17 cytokine family and the innate immune response and suggested a previously unrecognized innate immune pathway that promotes Th2

  13. Protective effects of the polyphenol sesamin on allergen-induced T(H2 responses and airway inflammation in mice.

    Directory of Open Access Journals (Sweden)

    Ching-Huei Lin

    Full Text Available Allergic asthma is a lifelong airway condition that affects people of all ages. In recent decades, asthma prevalence continues to increase globally, with an estimated number of 250,000 annual deaths attributed to the disease. Although inhaled corticosteroids and β-adrenergic receptor agonists are the primary therapeutic avenues that effectively reduce asthma symptoms, profound side effects may occur in patients with long-term treatments. Therefore, development of new therapeutic strategies is needed as alternative or supplement to current asthma treatments. Sesamin is a natural polyphenolic compound with strong anti-oxidative effects. Several studies have reported that sesamin is effective in preventing hypertension, thrombotic tendency, and neuroinflammation. However, it is still unknown whether sesamin can reduce asthma-induced allergic inflammation and airway hyperresponsiveness (AHR. Our study has revealed that sesamin exhibited significant anti-inflammatory effects in ovalbumin (OVA-induced murine asthma model. We found that treatments with sesamin after OVA sensitization and challenge significantly decreased expression levels of interleukin-4 (IL-4, IL-5, IL-13, and serum IgE. The numbers of total inflammatory cells and eosinophils in BALF were also reduced in the sesamin-treated animals. Histological results demonstrated that sesamin attenuated OVA-induced eosinophil infiltration, airway goblet cell hyperplasia, mucus occlusion, and MUC5AC expression in the lung tissue. Mice administered with sesamin showed limited increases in AHR compared with mice receiving vehicle after OVA challenge. OVA increased phosphorylation levels of IκB-α and nuclear expression levels of NF-κB, both of which were reversed by sesamin treatments. These data indicate that sesamin is effective in treating allergic asthma responses induced by OVA in mice.

  14. Protective effects of the polyphenol sesamin on allergen-induced T(H)2 responses and airway inflammation in mice.

    Science.gov (United States)

    Lin, Ching-Huei; Shen, Mei-Lin; Zhou, Ning; Lee, Chen-Chen; Kao, Shung-Te; Wu, Dong Chuan

    2014-01-01

    Allergic asthma is a lifelong airway condition that affects people of all ages. In recent decades, asthma prevalence continues to increase globally, with an estimated number of 250,000 annual deaths attributed to the disease. Although inhaled corticosteroids and β-adrenergic receptor agonists are the primary therapeutic avenues that effectively reduce asthma symptoms, profound side effects may occur in patients with long-term treatments. Therefore, development of new therapeutic strategies is needed as alternative or supplement to current asthma treatments. Sesamin is a natural polyphenolic compound with strong anti-oxidative effects. Several studies have reported that sesamin is effective in preventing hypertension, thrombotic tendency, and neuroinflammation. However, it is still unknown whether sesamin can reduce asthma-induced allergic inflammation and airway hyperresponsiveness (AHR). Our study has revealed that sesamin exhibited significant anti-inflammatory effects in ovalbumin (OVA)-induced murine asthma model. We found that treatments with sesamin after OVA sensitization and challenge significantly decreased expression levels of interleukin-4 (IL-4), IL-5, IL-13, and serum IgE. The numbers of total inflammatory cells and eosinophils in BALF were also reduced in the sesamin-treated animals. Histological results demonstrated that sesamin attenuated OVA-induced eosinophil infiltration, airway goblet cell hyperplasia, mucus occlusion, and MUC5AC expression in the lung tissue. Mice administered with sesamin showed limited increases in AHR compared with mice receiving vehicle after OVA challenge. OVA increased phosphorylation levels of IκB-α and nuclear expression levels of NF-κB, both of which were reversed by sesamin treatments. These data indicate that sesamin is effective in treating allergic asthma responses induced by OVA in mice.

  15. Comparison of hemodynamic and metabolic stress responses caused by endotracheal tube and Proseal laryngeal mask airway in laparoscopic cholecystectomy

    Directory of Open Access Journals (Sweden)

    Handan Güleç

    2012-01-01

    Full Text Available Background: We aimed to compare hemodynamic and endocrine alterations caused by stress response due to Proseal laryngeal mask airway and endotracheal tube usage in laparoscopic cholecystectomy. Materials and Methods: Sixty-three ASA I-II patients scheduled for elective laparoscopic cholecystectomy were included in the study. Patients were randomly allocated into two groups of endotracheal tube and Proseal laryngeal mask airway. Standard general anaesthesia was performed in both groups with the same drugs in induction and maintenance of anaesthesia. After anaesthesia induction and 20 minutes after CO 2 insufflations, venous blood samples were obtained for measuring adrenalin, noradrenalin, dopamine and cortisol levels. Hemodynamic and respiratory parameters were recorded at the 1 st , 5 th , 15 th , 30 th and 45 th minutes after the insertion of airway devices. Results: No statistically significant differences in age, body mass index, gender, ASA physical status, and operation time were found between the groups (p > 0.05. Changes in hemodynamic and respiratory parameters were not statistically significant when compared between and within groups (p > 0.05. Although no statistically significant differences were observed between and within groups when adrenalin, noradrenalin and dopamine values were compared, serum cortisol levels after CO 2 insufflation in PLMA group were significantly lower than the ETT group (p = 0.024. When serum cortisol levels were compared within groups, cortisol levels 20 minutes after CO 2 insufflation were significantly higher (46.1 (9.5-175.7 and 27.0 (8.3-119.4 in the ETT and PLMA groups, respectively than cortisol levels after anaesthesia induction (11.3 (2.8-92.5 and 16.6 (4.4-45.4 in the ETT and PLMA groups, respectively in both groups (p = 0.001. Conclusion: PLMA usage is a suitable, effective and safe alternative to ETT in laparoscopic cholecystectomy patients with lower metabolic stress.

  16. Time-course changes in nasal airway resistance after house dust antigen challenge: With special reference to late phase response

    Directory of Open Access Journals (Sweden)

    Kimihiro Okubo

    1998-01-01

    Full Text Available The definition of late-phase response (LPR associated with nasal allergy is not as clear as that associated with asthma. Furthermore, LPR and immediate-phase response often act in concert to produce confounding symptoms due to repeated attacks over a short period of time. We examined the nasal airway resistance (NAR, allergic symptoms, eosinophil cationic protein and histamine concentration in nasal surface tissue 30 min before, and 10 min, 1, 3, 5, 7 and 9 h after a house dust (HD nasal challenge test was performed twice on 10 patients with HD perennial nasal allergy. Nasal airway resistance readings after the HD nasal challenge test were classified into three types based on changes in NAR: type I (short-lasting, five cases; type II (prolonged, eight cases; and type III (biphasic, six cases. Delayed increases in NAR were not observed in type I patients with weak responses to nasal challenge. In type II patients, baseline NAR was elevated and numerous basophilic metachromatic cells (BC were present in the epithelial layer. In type III patients, baseline NAR was not as elevated as it was in type II patients, but marked responses to challenge were noted. In all three types of changes in NAR, eosinophil leukocyte increased at late phase. Moreover, there was no correlation of change in NAR with an increase in the number of eosinophil leukocyte and BC at the epithelial layer in all three types, which suggests that further study is required to confirm the exact role of eosinophils and basophilic cells in LPR.

  17. Prospective Comparison of Pressor and Airway Responses to IV Esmolol and IV Dexmedetomidine during Emergence from General Anaesthesia and Extubation

    Directory of Open Access Journals (Sweden)

    Malvika Prasad Tendulkar

    2017-01-01

    Full Text Available Background: Tracheal extubation causes significant hemodynamic stimulation resulting in transient increase in blood pressure and heart rate. Aim and Objectives: To compare the efficacy of Esmolol and Dexmedetomidine given intravenously to attenuate the pressor and airway response to emergence from general anaesthesia and tracheal extubation. Materials and Methods: After obtaining institutional ethical committee approval and written informed consent, 90 ASA grade I and II patients, in the age group of 20-70 years, of either sex, undergoing elective surgery under general anaesthesia were included. At the end of surgery, patients received IV Esmolol 1.5 mg/kg (Group E two minutes prior to extubation or IV Dexmedetomidine 0.5 mcg/kg (Group D over ten minutes prior to extubation or no drug in the control group (Group C. Hemodynamic parameters were assessed before giving study drugs, before extubation and after extubation upto 15 minutes. Extubation quality was rated using 5 point cough grading. Sedation scoring was done using Modified Ramsay Sedation scale. Results: All hemodynamic parameters showed attenuation upto 15 minutes post extubation, in both Group E and Group D as compared to Group C. However, even though Injection Esmolol successfully controlled the hemodynamic response to extubation, the attenuation was more evident with Injection Dexmedetomidine, as the parameters were below the baseline values at all times after extubation, without excessive bradycardia or hypotension. None of the patients showed incidence of desaturation. The cough grading, and hence the quality of extubation, was better with Group D as compared to Group C and E. Patients in the Dexmedetomidine group, were significantly sedated as compared to Esmolol and Control group, but this aided a smooth extubation without any agitation. Conclusion: We conclude that IV Esmolol 1.5 mg/kg attenuates the pressor response, but IV Dexmedetomidine attenuates both pressor as well as the

  18. Lower airway colonization and inflammatory response in COPD: a focus on Haemophilus influenzae.

    Science.gov (United States)

    Finney, Lydia J; Ritchie, Andrew; Pollard, Elizabeth; Johnston, Sebastian L; Mallia, Patrick

    2014-01-01

    Bacterial infection of the lower respiratory tract in chronic obstructive pulmonary disease (COPD) patients is common both in stable patients and during acute exacerbations. The most frequent bacteria detected in COPD patients is Haemophilus influenzae, and it appears this organism is uniquely adapted to exploit immune deficiencies associated with COPD and to establish persistent infection in the lower respiratory tract. The presence of bacteria in the lower respiratory tract in stable COPD is termed colonization; however, there is increasing evidence that this is not an innocuous phenomenon but is associated with airway inflammation, increased symptoms, and increased risk for exacerbations. In this review, we discuss host immunity that offers protection against H. influenzae and how disturbance of these mechanisms, combined with pathogen mechanisms of immune evasion, promote persistence of H. influenzae in the lower airways in COPD. In addition, we examine the role of H. influenzae in COPD exacerbations, as well as interactions between H. influenzae and respiratory virus infections, and review the role of treatments and their effect on COPD outcomes. This review focuses predominantly on data derived from human studies but will refer to animal studies where they contribute to understanding the disease in humans.

  19. Genetic fuzzy system predicting contractile reactivity patterns of small arteries

    DEFF Research Database (Denmark)

    Tang, J; Sheykhzade, Majid; Clausen, B F;

    2014-01-01

    strategies. Results show that optimized fuzzy systems (OFSs) predict contractile reactivity of arteries accurately. In addition, OFSs identified significant differences that were undetectable using conventional analysis in the responses of arteries between groups. We concluded that OFSs may be used...

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

    Directory of Open Access Journals (Sweden)

    Gustavo Nino

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

  1. Vessel-guided airway tree segmentation

    DEFF Research Database (Denmark)

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

    2010-01-01

    This paper presents a method for airway tree segmentation that uses a combination of a trained airway appearance model, vessel and airway orientation information, and region growing. We propose a voxel classification approach for the appearance model, which uses a classifier that is trained...... to differentiate between airway and non-airway voxels. This is in contrast to previous works that use either intensity alone or hand crafted models of airway appearance. We show that the appearance model can be trained with a set of easily acquired, incomplete, airway tree segmentations. A vessel orientation...... similarity measure is introduced, which indicates how similar the orientation of an airway candidate is to the orientation of the neighboring vessel. We use this vessel orientation similarity measure to overcome regions in the airway tree that have a low response from the appearance model. The proposed...

  2. EFFECTS OF PROPRANOLOL INHALATION ON THE DIURNAL INCREASE IN FEV(1) AND ON PROPRANOLOL AIRWAYS RESPONSIVENESS IN ATOPIC SUBJECTS WITH ASTHMA

    NARCIS (Netherlands)

    OOSTERHOFF, Y; KOETER, GH; POSTMA, DS

    1995-01-01

    Background - Propranolol inhalation provocation tests are used to measure indirect airways responsiveness in the investigation of asthma. In this study the effects of repeated propranolol inhalation provocation tests within the same day on normal diurnal variation in the forced expiratory volume in

  3. Growth of airway epithelial cells at an air-liquid interface changes both the response to particle exposure and iron homeostasis

    Science.gov (United States)

    We tested the hypothesis that 1) relative to submerged cells, airway epithelial cells grown at an air-liquid interface and allowed to differentiate would have an altered response to particle exposure and 2) that these differences would be associated with indices of iron homeostas...

  4. Contractile dysfunction of the shoulder (rotator cuff tendinopathy): an overview.

    Science.gov (United States)

    Littlewood, Chris

    2012-11-01

    It is now over a decade since the features defining a contractile dysfunction of the shoulder were first reported. Since this time, some progress has been made to better understand this mechanical syndrome. In response to these developments, this narrative review will explore current understanding in relation to pathology, diagnosis, treatment, and prognosis of this syndrome with reference to literature specifically relating to contractile dysfunction but also literature relating to rotator cuff tendinopathy where necessary. The review not only identifies the strengths of the mechanical diagnosis and therapy approach with reference to a contractile dysfunction of the shoulder but also identifies where further progress needs to be made.

  5. Contractile Changes in the Vasculature After Subchronic Smoking

    DEFF Research Database (Denmark)

    Haanes, Kristian Agmund; Kruse, Lars Schack; Johansson, Helle Wulf;

    2016-01-01

    : Wild type (WT) and SP-D KO mice were exposed to cigarette smoke (CS) or room air for 12 weeks. The pulmonary artery, left anterior descending coronary artery, and basilar artery (BA) were isolated and mounted in wire myographs. Contractile concentration response curves to endothelin-1 and UDP were...... displayed no smoke induced changes, but were surprisingly similar to the CSE WT. CONCLUSION: The contractility to UDP was altered in the brain and heart vasculature of CSE mice. SP-D KO (both control and CSE) and CSE WT had similar changes in contractility compared to control WT. IMPLICATIONS: These results...

  6. Proton-sensing ovarian cancer G protein-coupled receptor 1 on dendritic cells is required for airway responses in a murine asthma model.

    Science.gov (United States)

    Aoki, Haruka; Mogi, Chihiro; Hisada, Takeshi; Nakakura, Takashi; Kamide, Yosuke; Ichimonji, Isao; Tomura, Hideaki; Tobo, Masayuki; Sato, Koichi; Tsurumaki, Hiroaki; Dobashi, Kunio; Mori, Tetsuya; Harada, Akihiro; Yamada, Masanobu; Mori, Masatomo; Ishizuka, Tamotsu; Okajima, Fumikazu

    2013-01-01

    Ovarian cancer G protein-coupled receptor 1 (OGR1) stimulation by extracellular protons causes the activation of G proteins and subsequent cellular functions. However, the physiological and pathophysiological roles of OGR1 in airway responses remain largely unknown. In the present study, we show that OGR1-deficient mice are resistant to the cardinal features of asthma, including airway eosinophilia, airway hyperresponsiveness (AHR), and goblet cell metaplasia, in association with a remarkable inhibition of Th2 cytokine and IgE production, in an ovalbumin (OVA)-induced asthma model. Intratracheal transfer to wild-type mice of OVA-primed bone marrow-derived dendritic cells (DCs) from OGR1-deficient mice developed lower AHR and eosinophilia after OVA inhalation compared with the transfer of those from wild-type mice. Migration of OVA-pulsed DCs to peribronchial lymph nodes was also inhibited by OGR1 deficiency in the adoption experiments. The presence of functional OGR1 in DCs was confirmed by the expression of OGR1 mRNA and the OGR1-sensitive Ca(2+) response. OVA-induced expression of CCR7, a mature DC chemokine receptor, and migration response to CCR7 ligands in an in vitro Transwell assay were attenuated by OGR1 deficiency. We conclude that OGR1 on DCs is critical for migration to draining lymph nodes, which, in turn, stimulates Th2 phenotype change and subsequent induction of airway inflammation and AHR.

  7. [Response mechanisms of the airway smooth muscle tissue in experimental bronchial spasm].

    Science.gov (United States)

    Zashikhin, A L; Agafonov, Iu V; Barmina, A O

    2009-01-01

    This investigation was aimed at the complex evaluation of the reactivity mechanisms of bronchial smooth muscle tissue (SMT) in experimental bronchial spasm. Morphometric, cytospectrophotometric and electron microscopical analysis demonstrated the presence of three types of smooth muscle cells (SMC) within the bronchial SMT (small, medium, large), that differed in their linear and metabolic parameters. The findings of this study indicate that under the conditions of experimental bronchial spasm development, the ratios of SMC in bronchial SMT are changed with the increase in proportion of small SMC and the elimination of large SMC. In the dynamics of experimental bronchial spasm development, the activation of cytoplasmic synthesis as well as of DNA synthesis was detected mainly in group of small SMC. The reactive-dystrophic changes were marked at the subcellular level, that were most often identified in large SMC resulting in their elimination from population in the dynamics of an experiment. The data obtained suggest that one of the important mechanisms of airway SMT adaptation to the bronchial spasm development is a dynamic reorganization of SMC population.

  8. I-gel Laryngeal Mask Airway Combined with Tracheal Intubation Attenuate Systemic Stress Response in Patients Undergoing Posterior Fossa Surgery

    Directory of Open Access Journals (Sweden)

    Chaoliang Tang

    2015-01-01

    patients. In this study, we proposed that I-gel combined with tracheal intubation could reduce the stress response of posterior fossa surgery patients. Methods. Sixty-six posterior fossa surgery patients were randomly allocated to receive either tracheal tube intubation (Group TT or I-gel facilitated endotracheal tube intubation (Group TI. Hemodynamic and respiratory variables, stress and inflammatory response, oxidative stress, anesthesia recovery parameters, and adverse events during emergence were compared. Results. Mean arterial pressure and heart rate were lower in Group TI during intubation and extubation (P<0.05 versus Group TT. Respiratory variables including peak airway pressure and end-tidal carbon dioxide tension were similar intraoperative, while plasma β-endorphin, cortisol, interleukin-6, tumor necrosis factor-alpha, malondialdehyde concentrations, and blood glucose were significantly lower in Group TI during emergence relative to Group TT. Postoperative bucking and serious hypertensions were seen in Group TT but not in Group TI. Conclusion. Utilization of I-gel combined with endotracheal tube in posterior fossa surgery patients is safe which can yield more stable hemodynamic profile during intubation and emergence and lower inflammatory and oxidative response, leading to uneventful recovery.

  9. Relationship between airway responsiveness to mannitol and to methacholine and markers of airway inflammation, peak flow variability and quality of life in asthma patients

    DEFF Research Database (Denmark)

    Porsbjerg, C.; Brannan, J.D.; Anderson, S.D.;

    2008-01-01

    Initiative for Asthma guidelines were measured in addition to the health-related quality-of-life score using the Juniper asthma quality-of-life questionnaire. Findings Both ABR to mannitol as well as to methacholine was associated with elevated markers of airway inflammation: in 83% of asthma patients...... with AHR to mannitol, and in 88% of asthma patients with AHR to methacholine, the eNO level was > 20 p.p.b. Sputum% eosinophils >1% was measured in 70% of asthma patients with AHR to mannitol and in 77% of asthma patients with AHR to methacholine. In asthma patients without AHR, 15% had an eNO level >20p......, there was a stronger correlation between AHR to mannitol and the level of eNO [PD15 to mannitol vs. eNO (p.p.b.): r: -0.63, P patients not being treated with steroids, AHR to mannitol...

  10. Exploiting the relationship between birefringence and force to measure airway smooth muscle contraction with PS-OCT (Conference Presentation)

    Science.gov (United States)

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

    2016-03-01

    The ability to observe airway dynamics is fundamental to forming a complete understanding of pulmonary diseases such as asthma. We have previously demonstrated that Optical Coherence Tomography (OCT) can be used to observe structural changes in the airway during bronchoconstriction, but standard OCT lacks the contrast to discriminate airway smooth muscle (ASM) bands- ASM being responsible for generating the force that drives airway constriction- from the surrounding tissue. Since ASM in general exhibits a greater degree of birefringence than the surrounding tissue, a potential solution to this problem lies in the implementation of polarization sensitivity (PS) to the OCT system. By modifying the OCT system so that it is sensitive to the birefringence of tissue under inspection, we can visualize the ASM with much greater clarity and definition. In this presentation we show that the force of contraction can be indirectly measured by an associated increase in the birefringence signal of the ASM. We validate this approach by attaching segments of swine trachea to an isometric force transducer and stimulating contraction, while simultaneously measuring the exerted force and imaging the segment with PS-OCT. We then show how our results may be used to extrapolate the force of contraction of closed airways in absence of additional measurement devices. We apply this technique to assess ASM contractility volumetrically and in vivo, in both asthmatic and non-asthmatic human volunteers.

  11. A comparison of intraocular pressure and hemodynamic responses to insertion of laryngeal mask airway or endotracheal tube using anesthesia with propofol and remifentanil in cataract surgery

    Directory of Open Access Journals (Sweden)

    Mohsen Ziyaeifard

    2012-01-01

    Full Text Available Background: The aim of this study was to evaluate intraocular pressure (IOP and hemodynamic responses following insertion of laryngeal mask airway (LMA or endotracheal tube (ETT after anesthesia induction with propofol and remifentanil in cataract surgery. Materials and Methods: In a randomized controlled study, 50 adults scheduled for elective cataract extraction procedure under general anesthesia were allocated to LMA insertion (n = 25 or ETT (n = 25 groups. IOP, systolic blood pressure (SBP, diastolic blood pressure (DBP, and heart rate (HR were measured after insertion of the airway device every minute up to 5 min. Results: There were no significant differences between LMA and ETT groups in SBP, DBP, HR, and IOP immediately after airway instrumentation up to 5 min, except in 4th min in DBP, 2nd min in HR, and 5th min in IOP (7.9 ± 2.3 mmHg in LMA and 9.4 ± 2.5 mmHg in ETT group; P = 0.030. There was good surgeon satisfaction for providing acceptable surgical field in both groups (88% in LMA and 80% in ETT group; P = 0.702. Conclusion: Propofol combined with remifentanil provides good and excellent conditions for insertion of LMA or ETT with minimal hemodynamic disturbances in cataract surgery. Considering LMA insertion is less traumatic than ETT, using LMA may be better than ETT for airway securing in these patients.

  12. Virulence Factors of Pseudomonas aeruginosa Induce Both the Unfolded Protein and Integrated Stress Responses in Airway Epithelial Cells.

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    Emily F A van 't Wout

    2015-06-01

    Full Text Available Pseudomonas aeruginosa infection can be disastrous in chronic lung diseases such as cystic fibrosis and chronic obstructive pulmonary disease. Its toxic effects are largely mediated by secreted virulence factors including pyocyanin, elastase and alkaline protease (AprA. Efficient functioning of the endoplasmic reticulum (ER is crucial for cell survival and appropriate immune responses, while an excess of unfolded proteins within the ER leads to "ER stress" and activation of the "unfolded protein response" (UPR. Bacterial infection and Toll-like receptor activation trigger the UPR most likely due to the increased demand for protein folding of inflammatory mediators. In this study, we show that cell-free conditioned medium of the PAO1 strain of P. aeruginosa, containing secreted virulence factors, induces ER stress in primary bronchial epithelial cells as evidenced by splicing of XBP1 mRNA and induction of CHOP, GRP78 and GADD34 expression. Most aspects of the ER stress response were dependent on TAK1 and p38 MAPK, except for the induction of GADD34 mRNA. Using various mutant strains and purified virulence factors, we identified pyocyanin and AprA as inducers of ER stress. However, the induction of GADD34 was mediated by an ER stress-independent integrated stress response (ISR which was at least partly dependent on the iron-sensing eIF2α kinase HRI. Our data strongly suggest that this increased GADD34 expression served to protect against Pseudomonas-induced, iron-sensitive cell cytotoxicity. In summary, virulence factors from P. aeruginosa induce ER stress in airway epithelial cells and also trigger the ISR to improve cell survival of the host.

  13. Protective Effects of Fluticasone on Allergen-Induced Airway Responses and Sputum Inflammatory Markers

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    Krishnan Parameswaran

    2000-01-01

    Full Text Available BACKGROUND: A direct comparison of the protective effects of single and regular doses of inhaled glucocorticoid on allergen-induced asthmatic responses and inflammation has not been made.

  14. The Lung Microbiome and Airway Disease.

    Science.gov (United States)

    Lynch, Susan V

    2016-12-01

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

  15. Anti-angiogenic Nanotherapy Inhibits Airway Remodeling and Hyper-responsiveness of Dust Mite Triggered Asthma in the Brown Norway Rat

    Science.gov (United States)

    Lanza, Gregory M.; Jenkins, John; Schmieder, Anne H.; Moldobaeva, Aigul; Cui, Grace; Zhang, Huiying; Yang, Xiaoxia; Zhong, Qiong; Keupp, Jochen; Sergin, Ismail; Paranandi, Krishna S.; Eldridge, Lindsey; Allen, John S.; Williams, Todd; Scott, Michael J.; Razani, Babak; Wagner, Elizabeth M.

    2017-01-01

    Although angiogenesis is a hallmark feature of asthmatic inflammatory responses, therapeutic anti-angiogenesis interventions have received little attention. Objective: Assess the effectiveness of anti-angiogenic Sn2 lipase-labile prodrugs delivered via αvβ3-micellar nanotherapy to suppress microvascular expansion, bronchial remodeling, and airway hyper-responsiveness in Brown Norway rats exposed to serial house dust mite (HDM) inhalation challenges. Results: Anti-neovascular effectiveness of αvβ3-mixed micelles incorporating docetaxel-prodrug (Dxtl-PD) or fumagillin-prodrug (Fum-PD) were shown to robustly suppress neovascular expansion (p<0.01) in the upper airways/bronchi of HDM rats using simultaneous 19F/1H MR neovascular imaging, which was corroborated by adjunctive fluorescent microscopy. Micelles without a drug payload (αvβ3-No-Drug) served as a carrier-only control. Morphometric measurements of HDM rat airway size (perimeter) and vessel number at 21d revealed classic vascular expansion in control rats but less vascularity (p<0.001) after the anti-angiogenic nanotherapies. CD31 RNA expression independently corroborated the decrease in airway microvasculature. Methacholine (MCh) induced respiratory system resistance (Rrs) was high in the HDM rats receiving αvβ3-No-Drug micelles while αvβ3-Dxtl-PD or αvβ3-Fum-PD micelles markedly and equivalently attenuated airway hyper-responsiveness and improved airway compliance. Total inflammatory BAL cells among HDM challenged rats did not differ with treatment, but αvβ3+ macrophages/monocytes were significantly reduced by both nanotherapies (p<0.001), most notably by the αvβ3-Dxtl-PD micelles. Additionally, αvβ3-Dxtl-PD decreased BAL eosinophil and αvβ3+ CD45+ leukocytes relative to αvβ3-No-Drug micelles, whereas αvβ3-Fum-PD micelles did not. Conclusion: These results demonstrate the potential of targeted anti-angiogenesis nanotherapy to ameliorate the inflammatory hallmarks of asthma in a

  16. Pim1 kinase protects airway epithelial cells from cigarette smoke-induced damage and airway inflammation

    NARCIS (Netherlands)

    de Vries, M.; Heijink, Hilde; Gras, R.; den Boef, L. E.; Reinders-Luinge, M.; Pouwels, S. D.; Hylkema, Machteld; van der Toorn, Marco; Brouwer, U.; van Oosterhout, A. J. M.; Nawijn, M. C.

    2014-01-01

    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

  17. Structural comparison of contractile nanomachines

    Directory of Open Access Journals (Sweden)

    Sebastian Kube

    2015-05-01

    Full Text Available Contractile molecular machines are a common feature among bacteriophages and prokaryotes. Due to their stability and the large size, contractile-tailed bacteriophages are traditionally investigated by electron microscopic methods. Complemented by crystallographic studies, a molecular model of contraction for the T4 phage was developed. Lately, also related contractile structures like the Photorhabdus virulence cassette-like particles, the R-Type pyocins and the contractile tubule of the bacterial Type VI secretion system have been analyzed by cryo electron microscopy. Photorhabdus virulence cassette particles and R-Type pyocins are toxin complexes reminiscent of bacteriophage tails that are secreted by bacteria to kill their insect host or competing bacteria. In contrast, the Type VI secretion system is an intracellular apparatus for injection of effector proteins into bacterial and eukaryotic cells. Although it shares homology with other contractile systems, the Type VI secretion system is additionally equipped with a recycling function, which makes it suitable for multiple rounds of action. Starting from the 3D reconstructions, we compare these molecular machines structurally and functionally to their viral counterparts and summarize the current knowledge on their respective mode of action.

  18. Deep Inspiration Avoidance and Airway Response to Methacholine: Influence of Body Mass Index

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    Louis-Philippe Boulet

    2005-01-01

    Full Text Available OBJECTIVE: To evaluate the effects of deep inspiration avoidance response to methacholine inhalation in 23 nonobese (body mass index between 18 kg/m2 and 30 kg/m2 and 27 obese (body mass index 30 kg/m2 or greater, nonatopic, nonasthmatic normal subjects.

  19. Children with asthma by school age display aberrant immune responses to pathogenic airway bacteria as infants

    DEFF Research Database (Denmark)

    Larsen, Jeppe Madura; Pedersen, Susanne Brix; Thysen, Anna Hammerich

    2014-01-01

    was assessed based on the pattern of cytokines produced and T-cell activation. ResultsThe immune response to pathogenic bacteria was different in infants with asthma by 7 years of age (P = .0007). In particular, prospective asthmatic subjects had aberrant production of IL-5 (P = .008), IL-13 (P = .057), IL-17...

  20. Human rhinovirus induced cytokine/chemokine responses in human airway epithelial and immune cells.

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    Devi Rajan

    Full Text Available Infections with human rhinovirus (HRV are commonly associated with acute upper and lower respiratory tract disease and asthma exacerbations. The role that HRVs play in these diseases suggests it is important to understand host-specific or virus-specific factors that contribute to pathogenesis. Since species A HRVs are often associated with more serious HRV disease than species B HRVs, differences in immune responses they induce should inform disease pathogenesis. To identify species differences in induced responses, we evaluated 3 species A viruses, HRV 25, 31 and 36 and 3 species B viruses, HRV 4, 35 and 48 by exposing human PBMCs to HRV infected Calu-3 cells. To evaluate the potential effect of memory induced by previous HRV infection on study responses, we tested cord blood mononuclear cells that should be HRV naïve. There were HRV-associated increases (significant increase compared to mock-infected cells for one or more HRVs for IP-10 and IL-15 that was unaffected by addition of PBMCs, for MIP-1α, MIP-1β, IFN-α, and HGF only with addition of PBMCs, and for ENA-78 only without addition of PBMCs. All three species B HRVs induced higher levels, compared to A HRVs, of MIP-1α and MIP-1β with PBMCs and ENA-78 without PBMCs. In contrast, addition of CBMCs had less effect and did not induce MIP-1α, MIP-1β, or IFN-α nor block ENA-78 production. Addition of CBMCs did, however, increase IP-10 levels for HRV 35 and HRV 36 infection. The presence of an effect with PBMCs and no effect with CBMCs for some responses suggest differences between the two types of cells possibly because of the presence of HRV memory responses in PBMCs and not CBMCs or limited response capacity for the immature CBMCs relative to PBMCs. Thus, our results indicate that different HRV strains can induce different patterns of cytokines and chemokines; some of these differences may be due to differences in memory responses induced by past HRV infections, and other differences

  1. The severity of airways obstruction as a determinant of treatment response in COPD

    DEFF Research Database (Denmark)

    Calverley, Peter Ma; Pauwels, Romain A; Jones, Paul W;

    2006-01-01

    improved with Sal/FP irrespective of baseline FEV1; adverse events were similar across subgroups. The spirometric response to Sal/FP varied with baseline FEV1, and clinical benefits were not restricted to patients with severe disease. These data have implications for COPD management decisions, suggesting...... that arbitrary stratifications of baseline severity are not necessarily indicative of treatment efficacy and that the benefits of assessing baseline severity as a continuous variable should be assessed in future trials....

  2. A comparison of the contractile properties of myometrium from singleton and twin pregnancies.

    Directory of Open Access Journals (Sweden)

    Peter Turton

    Full Text Available OBJECTIVE: Over half of twin pregnancies in US and UK deliver prematurely but the reasons for this are unclear. The contractility of myometrium from twin pregnancies has not been directly investigated. The objective of this research was to determine if there are differences in the contractile activity and response to oxytocin, between myometrium from singleton and twin pregnancies, across a range of gestational ages. Furthermore, we wished to determine if contractile activity correlates with increasing level of stretch, using neonatal birth weights as a marker of uterine stretch. METHODS: This was an in vitro, laboratory based study of myometrial contractility in women pregnant with one or two babies, using biopsies obtained from non-labouring women undergoing Caesarean section. Spontaneous, oxytocin-stimulated and depolarization induced contractile activity was compared. RESULTS: Direct measurements of myometrial contractility under controlled conditions show that the frequency of contractions and responses to oxytocin are significantly increased in twins compared to singletons. The duration of contraction however was significantly reduced. We find that contractile activity correlates with increasing levels of stretch, using neonatal birth weights as a surrogate for uterine stretch, with response to oxytocin being significantly positively correlated with birth weight. CONCLUSIONS: We have found significant differences in contractile properties between myometrium from singleton and twin pregnancies and that increasing uterine stretch can alter the contractile properties of myometrium. We discuss the implication of these findings to preterm delivery and future studies.

  3. The use of oscillometry as a measure of airway responsiveness in asthmatic children after histamine and methacholine bronchoprovocation with dosimeter-MedicAid and DeVilbiss nebulizers.

    Science.gov (United States)

    Kopriva, F; Szotkowská, J; Plocová, A; Závodská, J; Zápalka, M; Smatanová, D; Látalová, M; Slezáková, L; Radová, L

    2007-05-01

    To explore the use of oscillometry as a measure of airway responsiveness, 69 asthmatic children underwent histamine and methacholine bronchoprovocation using dosimeter-MedicAid (Jaeger Co.; Germany) and DeVilbiss nebulizers (DeVilbiss, Bornemouth; England). The mean increase in R5 resistance in challenge testing measured after methacholine with the dosimeter-MedicAid nebulizer was 77.14% compared with 65.05% using histamine. Using the dosimeter-DeVilbiss nebulizer, the mean increases in R5 resistance following methacholine and histamine testing were 57.50% and 59.36%, respectively. The resistance R5 over R20 significantly correlated with forced expiratory volume in 1 second (FEV1). The MedicAid produced a more aggressive challenge than the DeVilbliss nebulizer. Oscillometry can be used to monitor the level of airway hyperresponsiveness following bronchoprovocation tests.

  4. Induction of tachykinin production in airway epithelia in response to viral infection.

    Directory of Open Access Journals (Sweden)

    James P Stewart

    Full Text Available BACKGROUND: The tachykinins are implicated in neurogenic inflammation and the neuropeptide substance P in particular has been shown to be a proinflammatory mediator. A role for the tachykinins in host response to lung challenge has been previously demonstrated but has been focused predominantly on the release of the tachykinins from nerves innervating the lung. We have previously demonstrated the most dramatic phenotype described for the substance P encoding gene preprotachykinin-A (PPT-A to date in controlling the host immune response to the murine gammaherpesvirus 68, in the lung. METHODOLOGY/PRINCIPAL FINDINGS: In this study we have utilised transgenic mice engineered to co-ordinately express the beta-galactosidase marker gene along with PPT-A to facilitate the tracking of PPT-A expression. Using a combination of these mice and conventional immunohistology we now demonstrate that PPT-A gene expression and substance P peptide are induced in cells of the respiratory tract including tracheal, bronchiolar and alveolar epithelial cells and macrophages after viral infection. This induction was observed 24h post infection, prior to observable inflammation and the expression of pro-inflammatory chemokines in this model. Induced expression of the PPT-A gene and peptide persisted in the lower respiratory tract through day 7 post infection. CONCLUSIONS/SIGNIFICANCE: Non-neuronal PPT-A expression early after infection may have important clinical implications for the progression or management of lung disease or infection aside from the well characterised later involvement of the tachykinins during the inflammatory response.

  5. Induction of Tachykinin Production in Airway Epithelia in Response to Viral Infection

    Science.gov (United States)

    Stewart, James P.; Kipar, Anja; Cox, Helen; Payne, Catherine; Vasiliou, Sylvia; Quinn, John P.

    2008-01-01

    Background The tachykinins are implicated in neurogenic inflammation and the neuropeptide substance P in particular has been shown to be a proinflammatory mediator. A role for the tachykinins in host response to lung challenge has been previously demonstrated but has been focused predominantly on the release of the tachykinins from nerves innervating the lung. We have previously demonstrated the most dramatic phenotype described for the substance P encoding gene preprotachykinin-A (PPT-A) to date in controlling the host immune response to the murine gammaherpesvirus 68, in the lung. Methodology/Principal Findings In this study we have utilised transgenic mice engineered to co-ordinately express the beta-galactosidase marker gene along with PPT-A to facilitate the tracking of PPT-A expression. Using a combination of these mice and conventional immunohistology we now demonstrate that PPT-A gene expression and substance P peptide are induced in cells of the respiratory tract including tracheal, bronchiolar and alveolar epithelial cells and macrophages after viral infection. This induction was observed 24h post infection, prior to observable inflammation and the expression of pro-inflammatory chemokines in this model. Induced expression of the PPT-A gene and peptide persisted in the lower respiratory tract through day 7 post infection. Conclusions/Significance Non-neuronal PPT-A expression early after infection may have important clinical implications for the progression or management of lung disease or infection aside from the well characterised later involvement of the tachykinins during the inflammatory response. PMID:18320026

  6. The human airway epithelial basal cell transcriptome.

    Directory of Open Access Journals (Sweden)

    Neil R Hackett

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

  7. Bronchoconstriction Induces TGF-β Release and Airway Remodelling in Guinea Pig Lung Slices.

    Directory of Open Access Journals (Sweden)

    Tjitske A Oenema

    Full Text Available Airway remodelling, including smooth muscle remodelling, is a primary cause of airflow limitation in asthma. Recent evidence links bronchoconstriction to airway remodelling in asthma. The mechanisms involved are poorly understood. A possible player is the multifunctional cytokine TGF-β, which plays an important role in airway remodelling. Guinea pig lung slices were used as an in vitro model to investigate mechanisms involved in bronchoconstriction-induced airway remodelling. To address this aim, mechanical effects of bronchoconstricting stimuli on contractile protein expression and TGF-β release were investigated. Lung slices were viable for at least 48 h. Both methacholine and TGF-β1 augmented the expression of contractile proteins (sm-α-actin, sm-myosin, calponin after 48 h. Confocal fluorescence microscopy showed that increased sm-myosin expression was enhanced in the peripheral airways and the central airways. Mechanistic studies demonstrated that methacholine-induced bronchoconstriction mediated the release of biologically active TGF-β, which caused the increased contractile protein expression, as inhibition of actin polymerization (latrunculin A or TGF-β receptor kinase (SB431542 prevented the methacholine effects, whereas other bronchoconstricting agents (histamine and KCl mimicked the effects of methacholine. Collectively, bronchoconstriction promotes the release of TGF-β, which induces airway smooth muscle remodelling. This study shows that lung slices are a useful in vitro model to study mechanisms involved in airway remodelling.

  8. Chronic treatment with indacaterol and airway response to salbutamol in stable COPD.

    Science.gov (United States)

    Cazzola, Mario; Rogliani, Paola; Ruggeri, Paolo; Segreti, Andrea; Proietto, Alfio; Picciolo, Stefano; Matera, Maria Gabriella

    2013-06-01

    Tolerance to both the bronchoprotective effect, and, to a lesser extent, the bronchodilator activity, occurs with all inhaled β2-agonists. Assumed the importance of this topic and the lack of a clinical evaluation specifically designed to assess the impact of chronic administration of indacaterol on the response to salbutamol, we sought to compare the effect of 4-week treatment with indacaterol 150 μg once-daily versus formoterol 12 μg twice-daily on the dose-response curve to inhaled salbutamol (total cumulative dose of 800 μg) in a non-double-blinded, crossover, randomised, and controlled pilot trial that enrolled 20 outpatients with moderate to severe COPD. At the end of 4-week treatments, there was not a statistically significant difference between the two trough FEV1 (p = 0.16), and both indacaterol and formoterol were able to produce a significant (p Salbutamol elicited an evident dose-dependent increase in FEV1 and this occurred also after regular treatment with indacaterol and formoterol with a further mean maximum increase of 0.10L (95% CI 0.05-0.14) and 0.05L (95% CI 0.02-0.08), respectively. The differences between indacaterol and formoterol in FEV1 increases after salbutamol were never statistically significant. The results of this study support the use of salbutamol as rescue medication for rapid relief of bronchospasm in patients suffering from COPD, even when they are under regular treatment with indacaterol.

  9. Airway remodeling in asthma: what really matters.

    Science.gov (United States)

    Fehrenbach, Heinz; Wagner, Christina; Wegmann, Michael

    2017-03-01

    Airway remodeling is generally quite broadly defined as any change in composition, distribution, thickness, mass or volume and/or number of structural components observed in the airway wall of patients relative to healthy individuals. However, two types of airway remodeling should be distinguished more clearly: (1) physiological airway remodeling, which encompasses structural changes that occur regularly during normal lung development and growth leading to a normal mature airway wall or as an acute and transient response to injury and/or inflammation, which ultimately results in restoration of a normal airway structures; and (2) pathological airway remodeling, which comprises those structural alterations that occur as a result of either disturbed lung development or as a response to chronic injury and/or inflammation leading to persistently altered airway wall structures and function. This review will address a few major aspects: (1) what are reliable quantitative approaches to assess airway remodeling? (2) Are there any indications supporting the notion that airway remodeling can occur as a primary event, i.e., before any inflammatory process was initiated? (3) What is known about airway remodeling being a secondary event to inflammation? And (4), what can we learn from the different animal models ranging from invertebrate to primate models in the study of airway remodeling? Future studies are required addressing particularly pheno-/endotype-specific aspects of airway remodeling using both endotype-specific animal models and "endotyped" human asthmatics. Hopefully, novel in vivo imaging techniques will be further advanced to allow monitoring development, growth and inflammation of the airways already at a very early stage in life.

  10. Biomarkers in Airway Diseases

    Directory of Open Access Journals (Sweden)

    Janice M Leung

    2013-01-01

    Full Text Available The inherent limitations of spirometry and clinical history have prompted clinicians and scientists to search for surrogate markers of airway diseases. Although few biomarkers have been widely accepted into the clinical armamentarium, the authors explore three sources of biomarkers that have shown promise as indicators of disease severity and treatment response. In asthma, exhaled nitric oxide measurements can predict steroid responsiveness and sputum eosinophil counts have been used to titrate anti-inflammatory therapies. In chronic obstructive pulmonary disease, inflammatory plasma biomarkers, such as fibrinogen, club cell secretory protein-16 and surfactant protein D, can denote greater severity and predict the risk of exacerbations. While the multitude of disease phenotypes in respiratory medicine make biomarker development especially challenging, these three may soon play key roles in the diagnosis and management of airway diseases.

  11. Time- and concentration-dependent genomic responses of the rat airway to inhaled nickel subsulfide

    Energy Technology Data Exchange (ETDEWEB)

    Efremenko, A.Y., E-mail: aefremenko@thehamner.org [The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709 (United States); Campbell, J.L.; Dodd, D.E. [The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709 (United States); Oller, A.R. [NiPERA, Inc., 2525 Meridian Parkway, Suite 240, Durham, NC 27713 (United States); Clewell, H.J. [The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709 (United States)

    2014-09-15

    Objective: To provide insights into the mode of action for Ni{sub 3}S{sub 2} lung carcinogenicity by examining gene expression changes in target cells after inhalation exposure. Methods: Gene expression changes were determined in micro-dissected lung broncho-alveolar cells from Fischer 344 rats following inhalation of Ni{sub 3}S{sub 2} at 0.0, 0.04, 0.08, 0.15, and 0.60 mg/m{sup 3} (0.03, 0.06, 0.11, and 0.44 mg Ni/m{sup 3}) for one and four weeks (6 h/day, 5 days/week). Results: Broncho-alveolar lavage fluid evaluation and lung histopathology provided evidence of inflammation only at the two highest concentrations, which were similar to those tested in the 2-year bioassay. The number of statistically significant up- and down-regulated genes decreased markedly from one to four weeks of exposure, suggesting adaptation. Cell signal pathway enrichment at both time-points primarily reflected responses to toxicity, including inflammatory and proliferative signaling. While proliferative signaling was up-regulated at both time points, some inflammatory signaling reversed from down-regulation at 1 week to up-regulation at 4 weeks. Conclusions: These results support a mode of action for Ni{sub 3}S{sub 2} carcinogenicity driven by chronic toxicity, inflammation and proliferation, leading to mis-replication, rather than by direct genotoxicity. Benchmark dose (BMD) analysis identified the lowest pathway transcriptional BMD exposure concentration as 0.026 mg Ni/m{sup 3}, for apoptosis/survival signaling. When conducted on the basis of lung Ni concentration the lowest pathway BMD was 0.64 μg Ni/g lung, for immune/inflammatory signaling. Implications: These highly conservative BMDs could be used to derive a point of departure in a nonlinear risk assessment for Ni{sub 3}S{sub 2} toxicity and carcinogenicity. - Highlights: • The mode of action for lung carcinogenicity of inhaled Ni{sub 3}S{sub 2} was investigated in rats. • Gene expression changes were determined in micro

  12. Different aspects of the effects of thapsigargin on automatism, contractility and responsiveness to phenylephrine in cardiac preparations from rats and guinea pigs.

    Science.gov (United States)

    Kocic, I; Dworakowska, D; Dworakowski, R

    1998-04-01

    Sarcoplasmic reticulum (SR) Ca(2+)-ATPase play a very important role in excitation-contraction coupling in the heart. The effects of thapsigargin (TG), a selective inhibitor of SR Ca(2+)-ATPase in the heart muscle, on automatism and contractility of the rat and guinea pig heart were examined. Experiments were performed on isolated right auricula and right ventricle papillary muscle. The following parameters were registered: force of contraction (Fc); rate of rise of force (+dF/dt); rate of fall of force (-dF/dt); time to peak contraction (ttp); duration of relaxation phase of contraction at the level of 10% of total amplitude (tt10); and automatism (b.p.m.). Additionally, the influence of thapsigargin on the effects of phenylephrine on the above mentioned parameters were studied. It was found that TG (1 microM) decreased only the automatism in rat heart, but increased automatism and ttp duration and decreased Fc in guinea pig heart. The positive force-frequency relation in the guinea pig heart was attenuated. The effects of phenylephrine in the rat heart were not significantly different before and after pretreatment with TG. Alternatively, pretreatment with TG exerted a profound influence on the effects of phenylephrine in the guinea pig heart. The results indicate that TG has different effects on the guinea pig and rat hearts. The reason for this could be due to species differences, i.e. the weaker crossing of TG through the membrane of rat myocytes or a different mechanism of Ca2+ homeostasis in rat and guinea pig hearts.

  13. Children developing asthma by school-age display aberrant immune responses to pathogenic airway bacteria as infants

    DEFF Research Database (Denmark)

    Larsen, Jeppe Madura; Pedersen, Susanne Brix; Thysen, Anna Hammerich;

    2014-01-01

    Asthma is a highly prevalent chronic lung disease that commonly originates in early childhood. Colonisation of neonatal airways with the pathogenic bacterial strains H. influenzae, M. catarrhalis and S. pneumoniae is associated with increased risk of later childhood asthma. We hypothesized...

  14. Notch ligand delta-like 4-pretreated dendritic cells alleviate allergic airway responses by enhancing IL-10 production.

    Directory of Open Access Journals (Sweden)

    Huei-Mei Huang

    Full Text Available The Notch pathway plays a role in the processes of cell proliferation, differentiation, and apoptosis, which affect the development and function of various organs. Dendritic cells (DCs, as professional antigen-presenting cells (APCs, induce T cell activation and promote T cell differentiation by antigen stimulation. Research has shown that Notch ligand delta-like 4 (Dll4 in APCs is associated with stimulation of a Th1-type response. However, the regulatory roles of Dll4 in the activation and function of DCs have yet to be clearly elucidated. In this study, we demonstrated that activation of Dll4-pretreated bone marrow-derived DCs by performing ovalbumin (OVA stimulation expressed a high level of interleukin (IL-10 without diminishing IL-12 production. By contrast, the proinflammatory cytokines, IL-1β, IL-6, and tumor necrosis factor (TNF-α, decreased in Dll4-pretreated DCs by performing either lipopolysaccharide (LPS or OVA stimulation. Compared to fully mature DCs, lower levels of MHC class II CD40 and higher levels of CD80 and CD86 molecules were expressed in these semi-mature like DCs. Dll4 Notch signaling also enhanced Notch ligand mRNA expression of Dll1, Dll4, and Jagged1 in DCs. Dll4-modified DCs exhibited a reduced capacity to stimulate the proliferation of OVA-specific CD4(+ T cells, but actively promoted large amounts of IL-10 production in these activated T cells. Furthermore, immunomodulatory effects of Dll4-modified DCs were examined in an established asthmatic animal model. After adoptive transfer of OVA-pulsed plus Dll4-pretreated DCs in OVA-immunized mice, OVA challenge induced lower OVA-specific immunoglobulin E (IgE and higher IgG2a antibody production, lower eotaxin, keratinocyte-derived chemokine (KC, IL-5, and IL-13 release in bronchial alveolar lavage fluid, attenuated airway hyper-responsiveness, and promoted higher IL-10 and interferon (IFN-γ production in the spleen. In summary, our findings elucidate the new role of

  15. A multi-scale approach to airway hyperresponsiveness: from molecule to organ

    Directory of Open Access Journals (Sweden)

    Anne-Marie eLauzon

    2012-06-01

    Full Text Available Airway hyperresponsiveness (AHR, a characteristic of asthma that involves an excessive reduction in airway caliber, is a complex mechanism reflecting multiple processes that manifest over a large range of length and time scales. At one extreme, molecular interactions determine the force generated by airway smooth muscle (ASM. At the other, the spatially distributed constriction of the branching airways leads to breathing difficulties. Similarly, asthma therapies act at the molecular scale while clinical outcomes are determined by lung function. These extremes are linked by events operating over intermediate scales of length and time. Thus, AHR is an emergent phenomenon that limits our understanding of asthma and confounds the interpretation of studies that address physiological mechanisms over a limited range of scales. A solution is a modular computational model that integrates experimental and mathematical data from multiple scales. This includes, at the molecular scale, kinetics and force production of actin-myosin contractile proteins during cross-bridge and latch-state cycling; at the cellular scale, Ca2+ signaling mechanisms that regulate ASM force production; at the tissue scale, forces acting between contracting ASM and opposing viscoelastic tissue that determine airway narrowing; at the organ scale, the topographic distribution of ASM contraction dynamics that determine mechanical impedance of the lung. At each scale, models are constructed with iterations between theory and experimentation to identify the parameters that link adjacent scales. This modular model establishes algorithms for modeling over a wide range of scales and provides a frame-work for the inclusion of other responses such as inflammation or therapeutic regimes. The goal is to develop this lung model so that it can make predictions about bronchoconstriction and identify the pathophysiologic mechanisms having the greatest impact on AHR and its therapy.

  16. cAMP-mediated secretion of brain-derived neurotrophic factor in developing airway smooth muscle.

    Science.gov (United States)

    Thompson, Michael A; Britt, Rodney D; Kuipers, Ine; Stewart, Alecia; Thu, James; Pandya, Hitesh C; MacFarlane, Peter; Pabelick, Christina M; Martin, Richard J; Prakash, Y S

    2015-10-01

    Moderate hyperoxic exposure in preterm infants contributes to subsequent airway dysfunction and to risk of developing recurrent wheeze and asthma. The regulatory mechanisms that can contribute to hyperoxia-induced airway dysfunction are still under investigation. Recent studies in mice show that hyperoxia increases brain-derived neurotrophic factor (BDNF), a growth factor that increases airway smooth muscle (ASM) proliferation and contractility. We assessed the mechanisms underlying effects of moderate hyperoxia (50% O2) on BDNF expression and secretion in developing human ASM. Hyperoxia increased BDNF secretion, but did not alter endogenous BDNF mRNA or intracellular protein levels. Exposure to hyperoxia significantly increased [Ca2+]i responses to histamine, an effect blunted by the BDNF chelator TrkB-Fc. Hyperoxia also increased ASM cAMP levels, associated with reduced PDE4 activity, but did not alter protein kinase A (PKA) activity or adenylyl cyclase mRNA levels. However, 50% O2 increased expression of Epac2, which is activated by cAMP and can regulate protein secretion. Silencing RNA studies indicated that Epac2, but not Epac1, is important for hyperoxia-induced BDNF secretion, while PKA inhibition did not influence BDNF secretion. In turn, BDNF had autocrine effects of enhancing ASM cAMP levels, an effect inhibited by TrkB and BDNF siRNAs. Together, these novel studies suggest that hyperoxia can modulate BDNF secretion, via cAMP-mediated Epac2 activation in ASM, resulting in a positive feedback effect of BDNF-mediated elevation in cAMP levels. The potential functional role of this pathway is to sustain BDNF secretion following hyperoxic stimulus, leading to enhanced ASM contractility and proliferation.

  17. Long-term exposure to IL-1beta enhances Toll-IL-1 receptor-mediated inflammatory signaling in murine airway hyperresponsiveness

    DEFF Research Database (Denmark)

    Zhang, Yaping; Xu, Cang-Bao; Cardell, Lars-Olaf

    2009-01-01

    Toll-interleukin-1 (Toll-IL-1) receptor signaling may play a key role in the development of airway hyperreactivity (AHR) and chronic airway inflammatory diseases such as asthma. Previously, we have demonstrated that pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin......-time PCR-based cDNA array. The key gene expressions that were altered were verified by immunohistochemistry using confocal microscopy. Tracheal ring segment contractile responsiveness to the inflammatory mediator bradykinin was monitored using a sensitive myograph system. The results showed that after......-1beta (IL-1beta), induce AHR. However, the underlying intracellular signaling mechanisms that lead to AHR remain elusive. In order to see if the Toll-IL-1 receptor-mediated inflammatory signal pathways are involved in the development of AHR, the present study was designed to use a real-time PCR...

  18. Airway management in trauma

    Directory of Open Access Journals (Sweden)

    Rashid M Khan

    2011-01-01

    Full Text Available Trauma has assumed epidemic proportion. 10% of global road accident deaths occur in India. Hypoxia and airway mismanagement are known to contribute up to 34% of pre-hospital deaths in these patients. A high degree of suspicion for actual or impending airway obstruction should be assumed in all trauma patients. Objective signs of airway compromise include agitation, obtundation, cyanosis, abnormal breath sound and deviated trachea. If time permits, one should carry out a brief airway assessment prior to undertaking definitive airway management in these patients. Simple techniques for establishing and maintaining airway patency include jaw thrust maneuver and/or use of oro- and nas-opharyngeal airways. All attempts must be made to perform definitive airway management whenever airway is compromised that is not amenable to simple strategies. The selection of airway device and route- oral or -nasal, for tracheal intubation should be based on nature of patient injury, experience and skill level.

  19. Naturally occurring lung CD4(+)CD25(+) T cell regulation of airway allergic responses depends on IL-10 induction of TGF-beta.

    Science.gov (United States)

    Joetham, Anthony; Takeda, Katsuyuki; Takada, Katsuyuki; Taube, Christian; Miyahara, Nobuaki; Matsubara, Shigeki; Matsubara, Satoko; Koya, Toshiyuki; Rha, Yeong-Ho; Dakhama, Azzeddine; Gelfand, Erwin W

    2007-02-01

    Peripheral tolerance to allergens is mediated in large part by the naturally occurring lung CD4(+)CD25(+) T cells, but their effects on allergen-induced airway responsiveness have not been well defined. Intratracheal, but not i.v., administration of naive lung CD4(+)CD25(+) T cells before allergen challenge of sensitized mice, similar to the administration of the combination of rIL-10 and rTGF-beta, resulted in reduced airway hyperresponsiveness (AHR) and inflammation, lower levels of Th2 cytokines, higher levels of IL-10 and TGF-beta, and less severe lung histopathology. Significantly, CD4(+)CD25(+) T cells isolated from IL-10(-/-) mice had no effect on AHR and inflammation, but when incubated with rIL-10 before transfer, suppressed AHR, and inflammation, and was associated with elevated levels of bronchoalveolar lavage TGF-beta levels. By analogy, anti-TGF-beta treatment reduced regulatory T cell activity. These data identify naturally occurring lung CD4(+)CD25(+) T cells as capable of regulating lung allergic responses in an IL-10- and TGF-beta-dependent manner.

  20. Differential Gene Expression Profiles and Selected Cytokine Protein Analysis of Mediastinal Lymph Nodes of Horses with Chronic Recurrent Airway Obstruction (RAO Support an Interleukin-17 Immune Response.

    Directory of Open Access Journals (Sweden)

    Alexandra Korn

    Full Text Available Recurrent airway obstruction (RAO is a pulmonary inflammatory condition that afflicts certain mature horses exposed to organic dust particulates in hay. Its clinical and pathological features, manifested by reversible bronchoconstriction, excessive mucus production and airway neutrophilia, resemble the pulmonary alterations that occur in agricultural workers with occupational asthma. The immunological basis of RAO remains uncertain although its chronicity, its localization to a mucosal surface and its domination by a neutrophilic, non-septic inflammatory response, suggest involvement of Interleukin-17 (IL-17. We examined global gene expression profiles in mediastinal (pulmonary-draining lymph nodes isolated from RAO-affected and control horses. Differential expression of > 200 genes, coupled with network analysis, supports an IL-17 response centered about NF-κB. Immunohistochemical analysis of mediastinal lymph node sections demonstrated increased IL-17 staining intensity in diseased horses. This result, along with the finding of increased IL-17 concentrations in lymph node homogenates from RAO-affected horses (P = 0.1 and a down-regulation of IL-4 gene and protein expression, provides additional evidence of the involvement of IL-17 in the chronic stages of RAO. Additional investigations are needed to ascertain the cellular source of IL-17 in this equine model of occupational asthma. Understanding the immunopathogenesis of this disorder likely will enhance the development of therapeutic interventions beneficial to human and animal pulmonary health.

  1. Effects of PARP-1 deficiency on airway inflammatory cell recruitment in response to LPS or TNF: differential effects on CXCR2 ligands and Duffy Antigen Receptor for Chemokines.

    Science.gov (United States)

    Zerfaoui, Mourad; Naura, Amarjit S; Errami, Youssef; Hans, Chetan P; Rezk, Bashir M; Park, Jiwon; Elsegeiny, Waleed; Kim, Hogyoung; Lord, Kevin; Kim, Jong G; Boulares, A Hamid

    2009-12-01

    We reported that PARP-1 exhibits differential roles in expression of inflammatory factors. Here, we show that PARP-1 deletion was associated with a significant reduction in inflammatory cell recruitment to mouse airways upon intratracheal administration of LPS. However, PARP-1 deletion exerted little effect in response to TNF exposure. LPS induced massive neutrophilia and moderate recruitment of macrophages, and TNF induced recruitment of primarily macrophages with smaller numbers of neutrophils in the lungs. Following either exposure, macrophage recruitment was blocked severely in PARP-1(-/-) mice, and this was associated with a marked reduction in MCP-1 and MIP-1alpha. This association was corroborated partly by macrophage recruitment in response to intratracheal administration of MCP-1 in PARP-1(-/-) mice. Surprisingly, although neutrophil recruitment was reduced significantly in LPS-treated PARP-1(-/-) mice, neutrophil numbers increased in TNF-treated mice, suggesting that PARP-1 deletion may promote a macrophagic-to-neutrophilic shift in the inflammatory response upon TNF exposure. Neutrophil-specific chemokines mKC and MIP-2 were reduced significantly in lungs of LPS-treated but only partially reduced in TNF-treated PARP-1(-/-) mice. Furthermore, the MIP-2 antagonist abrogated the shift to a neutrophilic response in TNF-exposed PARP-1(-/-) mice. Although CXCR2 expression increased in response to either stimulus in PARP-1(+/+) mice, the DARC increased only in lungs of TNF-treated PARP-1(+/+) mice; both receptors were reduced to basal levels in treated PARP-1(-/-) mice. Our results show that the balance of pro-neutrophilic or pro-macrophagic stimulatory factors and the differential influence of PARP-1 on these factors are critical determinants for the nature of the airway inflammatory response.

  2. IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH Oxidase-mediated airway antiviral response

    Institute of Scientific and Technical Information of China (English)

    Karin Fink; Lydie Martin; Esperance Mukawera; Stéfany Chartier; Xavier De Deken; Emmanuelle Brochiero; Fran(c)oise Miot

    2013-01-01

    Airway epithelial cells are key initial innate immune responders in the fight against respiratory viruses,primarily via the secretion of antiviral and proinflammatory cytokines that act in an autocrine/paracrine fashion to trigger the establishment of an antiviral state.It is currently thought that the early antiviral state in airway epithelial cells primarily relies on IFNβ secretion and the subsequent activation of the interferon-stimulated gene factor 3 (ISGF3) transcription factor complex,composed of STAT1,STAT2 and IRF9,which regulates the expression of a panoply of interferon-stimulated genes encoding proteins with antiviral activities.However,the specific pathways engaged by the synergistic action of different cytokines during viral infections,and the resulting physiological outcomes are still ill-defined.Here,we unveil a novel delayed antiviral response in the airways,which is initiated by the synergistic autocrine/paracrine action of IFNβ and TNFα,and signals through a non-canonical STAT2-and IRF9-dependent,but STAT1-independent cascade.This pathway ultimately leads to the late induction of the DUOX2 NADPH oxidase expression.Importantly,our study uncovers that the development of the antiviral state relies on DUOX2-dependent H2O2 production.Key antiviral pathways are often targeted by evasion strategies evolved by various pathogenic viruses.In this regard,the importance of the novel DUOX2-dependent antiviral pathway is further underlined by the observation that the human respiratory syncytial virus is able to subvert DUOX2 induction.

  3. High-throughput screening for modulators of cellular contractile force

    CERN Document Server

    Park, Chan Young; Tambe, Dhananjay; Chen, Bohao; Lavoie, Tera; Dowell, Maria; Simeonov, Anton; Maloney, David J; Marinkovic, Aleksandar; Tschumperlin, Daniel J; Burger, Stephanie; Frykenberg, Matthew; Butler, James P; Stamer, W Daniel; Johnson, Mark; Solway, Julian; Fredberg, Jeffrey J; Krishnan, Ramaswamy

    2014-01-01

    When cellular contractile forces are central to pathophysiology, these forces comprise a logical target of therapy. Nevertheless, existing high-throughput screens are limited to upstream signaling intermediates with poorly defined relationship to such a physiological endpoint. Using cellular force as the target, here we screened libraries to identify novel drug candidates in the case of human airway smooth muscle cells in the context of asthma, and also in the case of Schlemm's canal endothelial cells in the context of glaucoma. This approach identified several drug candidates for both asthma and glaucoma. We attained rates of 1000 compounds per screening day, thus establishing a force-based cellular platform for high-throughput drug discovery.

  4. Research on airway inflammation: present status in Mainland China

    Institute of Scientific and Technical Information of China (English)

    WANG Zeng-li

    2005-01-01

    @@ Airway inflammation involving activated eosinophils, mast cells and T lymphocytes is an established feature of asthma and has been the key target to treatment. Airway structural changes that occur in patients with asthma in response to persistent inflammation are termed airway remodeling.

  5. Picornavirus-Induced Airway Mucosa Immune Profile in Asymptomatic Neonates

    DEFF Research Database (Denmark)

    Wolsk, Helene M.; Følsgaard, Nilofar V.; Birch, Sune;

    2016-01-01

    Bacterial airway colonization is known to alter the airway mucosa immune response in neonates whereas the impact of viruses is unknown. The objective was therefore to examine the effect of respiratory viruses on the immune signature in the airways of asymptomatic neonates. Nasal aspirates from 571...

  6. Anatomic Optical Coherence Tomography of Upper Airways

    Science.gov (United States)

    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.

  7. (Airway response to short-term inhalation of NO2, O3 and their mixture in healthy men (author's transl))

    Energy Technology Data Exchange (ETDEWEB)

    Toyama, T.; Tsunoda, T.; Nakaza, M.; Higashi, T.; Nakadate, T.

    1981-05-01

    One hour inhalation of 0.7 ppm (1.32 mg/m3) of nitrogen dioxide (NO2), 0.7 ppm (1.4 mg/m3) of ozone (O3), and their mixture, 0.5 ppm (0.9 mg/m3) of NO2 and 0.5 ppm (1.0 mg/m3) of O3, and sham inhalation were conducted in five healthy male volunteers through mouth breathing using a multipurpose inhalation apparatus. Airway response was measured by specific airway conductance (Gaw/Vtg) and maximum expiratory flow rate at 50 and 25 percent forced vital capacity (Vmax50, Vmax25). Evaluations by analysis of variance revealed: no significant effect of inhalation of NO2 alone, slight significant transient decrease of Vmax50 in inhalation of O3 along (0.1 greater than p greater than 0.05), and slight reversible decrease of Gaw/Vtg and Vmax50 in inhalation of NO2 and O3 in combination (0.1 greater than p greater than 0.05). As their variations were within the range of normal diurnal change, these results were considered to be non-adverse effects.

  8. Increase in markers of airway inflammation after ozone exposure can be observed also in stable treated asthmatics with minimal functional response to ozone

    Directory of Open Access Journals (Sweden)

    Dente Federico L

    2010-01-01

    Full Text Available Abstract Background The discrepancy between functional and inflammatory airway response to ozone has been reported in normal subjects, but few data are available for stable asthmatics regularly treated with inhaled corticosteroids. Methods Twenty-three well controlled, regularly treated, mild-to-moderate asthmatic patients underwent two sequential randomised exposures to either filtered air or ozone (0.3 ppm for 2 hours in a challenge chamber. Pulmonary function (PF was monitored, and patients with FEV1 decrease greater than 10% from pre-challenge value were considered as responders. Immediately after each exposure, exhaled breath condensate (EBC was collected to measure malondialdehyde (MDA. Six hours after each exposure, PF and EBC collection were repeated, and sputum was induced to measure inflammatory cell counts and soluble mediators (IL-8 and neutrophil elastase. The response to ozone was also evaluated according to the presence of polymorphism in oxidative stress related NQO1 and GSTM1 genes. Results After ozone exposure, sputum neutrophils significantly increased in responders (n = 8, but not in nonresponders (n = 15. Other markers of neutrophil activation in sputum supernatant and MDA in EBC significantly increased in all patients, but only in nonresponders the increase was significant. In nonresponders, sputum eosinophils also significantly increased after ozone. There was a positive correlation between ozone-induced FEV1 fall and increase in sputum neutrophils. No difference in functional or inflammatory response to ozone was observed between subjects with or without the combination of NQO1wt- GSTM1null genotypes. Conclusions Markers of neutrophilic inflammation and oxidative stress increase also in asthmatic subjects not responding to ozone. A greater functional response to ozone is associated with greater neutrophil airway recruitment in asthmatic subjects.

  9. LPS from Porphyromonas gingivalis increases the sensitivity of contractile response mediated by endothelin-B (ET(B)) receptors in cultured endothelium-intact rat coronary arteries

    DEFF Research Database (Denmark)

    Ghorbani, Bahareh; Holmstrup, Palle; Edvinsson, Lars;

    2010-01-01

    The purpose of our study was to examine if lipopolysaccharide (LPS) from Porphyromonas gingivalis (P.g.) modifies the vasomotor responses to Endothelin-1 (ET-1) and Sarafotoxin 6c (S6c) in rat coronary arteries. The arteries were studied directly or following organ culture for 24h in absence and ...

  10. Functional phenotype of airway myocytes from asthmatic airways

    NARCIS (Netherlands)

    Wright, David B.; Trian, Thomas; Siddiqui, Sana; Pascoe, Chris D.; Ojo, Oluwaseun O.; Johnson, Jill R.; Dekkers, Bart G. J.; Dakshinamurti, Shyamala; Bagchi, Rushita; Burgess, Janette K.; Kanabar, Varsha

    2013-01-01

    In asthma, the airway smooth muscle (ASM) cell plays a central role in disease pathogenesis through cellular changes which may impact on its microenvironment and alter ASM response and function. The answer to the long debated question of what makes a 'healthy' ASM cell become 'asthmatic' still remai

  11. Airway distensibility in Chronic Obstructive Airway Disease

    DEFF Research Database (Denmark)

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

    2013-01-01

    -20% (mild), 20%-30% (moderate) or >30% (severe). Spirometry was performed annually and participants were divided into severity groups according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Data were analysed in a mixed effects regression model with log(airway lumen diameter......Rationale – Chronic Obstructive Pulmonary Disease (COPD) is a combination of chronic bronchitis and emphysema, which both may lead to airway obstruction. Under normal circumstances, airway dimensions vary as a function of inspiration level. We aim to study the influence of COPD and emphysema...... in causing airway narrowing, the latter most likely due to loss of elastic recoil of surrounding tissue....

  12. Modulatory effects of taurine on jejunal contractility

    Directory of Open Access Journals (Sweden)

    Q.Y. Yao

    2014-12-01

    Full Text Available Taurine (2-aminoethanesulfonic acid is widely distributed in animal tissues and has diverse pharmacological effects. However, the role of taurine in modulating smooth muscle contractility is still controversial. We propose that taurine (5-80 mM can exert bidirectional modulation on the contractility of isolated rat jejunal segments. Different low and high contractile states were induced in isolated jejunal segments of rats to observe the effects of taurine and the associated mechanisms. Taurine induced stimulatory effects on the contractility of isolated rat jejunal segments at 3 different low contractile states, and inhibitory effects at 3 different high contractile states. Bidirectional modulation was not observed in the presence of verapamil or tetrodotoxin, suggesting that taurine-induced bidirectional modulation is Ca2+ dependent and requires the presence of the enteric nervous system. The stimulatory effects of taurine on the contractility of isolated jejunal segments was blocked by atropine but not by diphenhydramine or by cimetidine, suggesting that muscarinic-linked activation was involved in the stimulatory effects when isolated jejunal segments were in a low contractile state. The inhibitory effects of taurine on the contractility of isolated jejunal segments were blocked by propranolol and L-NG-nitroarginine but not by phentolamine, suggesting that adrenergic β receptors and a nitric oxide relaxing mechanism were involved when isolated jejunal segments were in high contractile states. No bidirectional effects of taurine on myosin phosphorylation were observed. The contractile states of jejunal segments determine taurine-induced stimulatory or inhibitory effects, which are associated with muscarinic receptors and adrenergic β receptors, and a nitric oxide associated relaxing mechanism.

  13. Modulatory effects of taurine on jejunal contractility

    Energy Technology Data Exchange (ETDEWEB)

    Yao, Q.Y.; Chen, D.P.; Ye, D.M.; Diao, Y.P.; Lin, Y. [Dalian Medical University, Dalian, Liaoning (China)

    2014-10-14

    Taurine (2-aminoethanesulfonic acid) is widely distributed in animal tissues and has diverse pharmacological effects. However, the role of taurine in modulating smooth muscle contractility is still controversial. We propose that taurine (5-80 mM) can exert bidirectional modulation on the contractility of isolated rat jejunal segments. Different low and high contractile states were induced in isolated jejunal segments of rats to observe the effects of taurine and the associated mechanisms. Taurine induced stimulatory effects on the contractility of isolated rat jejunal segments at 3 different low contractile states, and inhibitory effects at 3 different high contractile states. Bidirectional modulation was not observed in the presence of verapamil or tetrodotoxin, suggesting that taurine-induced bidirectional modulation is Ca{sup 2+} dependent and requires the presence of the enteric nervous system. The stimulatory effects of taurine on the contractility of isolated jejunal segments was blocked by atropine but not by diphenhydramine or by cimetidine, suggesting that muscarinic-linked activation was involved in the stimulatory effects when isolated jejunal segments were in a low contractile state. The inhibitory effects of taurine on the contractility of isolated jejunal segments were blocked by propranolol and L-NG-nitroarginine but not by phentolamine, suggesting that adrenergic β receptors and a nitric oxide relaxing mechanism were involved when isolated jejunal segments were in high contractile states. No bidirectional effects of taurine on myosin phosphorylation were observed. The contractile states of jejunal segments determine taurine-induced stimulatory or inhibitory effects, which are associated with muscarinic receptors and adrenergic β receptors, and a nitric oxide associated relaxing mechanism.

  14. ALTERATION IN CONTRACTILE RESPONSE TO NORADRENALINE,5-HYDROXYTRYPTAMINE,SARAFOTOXIN 6c,AND ANGIOTENSINⅡIN RAT MESENTERIC ARTERY DURING ORGAN CULTURE

    Institute of Scientific and Technical Information of China (English)

    Cao Yongxiao(曹永孝); He Langchong(贺浪冲); Xu Cangbao(徐仓宝); EDVINSSON Lars

    2004-01-01

    Objective To compare the vasoconstrictive effects of 9 mediators on fresh and incubated mesenteric arteries of rats. Methods The superior mesenteric artery of rat was removed and the endothelium was denuded. The vessels were cut into 1 mm long cylindrical segments and subjected to organ culture for 24 hours. Fresh or incubated segments were immersed into tissue baths and the concentration-response curves were obtained by cumulative administration of the vasoconstrictors. Results In fresh mesenteric artery, endothelin-1 (ET-1), 5-hydroxytryptamine (5-HT), noradrenaline (NA), 5-carboxamidotryptamine (5-CT), and angiotensinⅡ (AngⅡ) induced potent and sustained constrictions in a concentration-dependent manner. The contraction induced by sarafotoxin 6c (S6c) was weak, while bradykinin (BK), des-Arg-bradykinin (DA-BK), and human urotensinⅡ (hUT-II) showed no detectable contraction. The concentraion-response curves in order of slopes was ET-1, NA, 5-HT, 5-CT, and AngⅡ. The order of the maximum contractions was ET-1>NA=5-HT=5-CT>AngⅡ>S6c. After organ culture, the concentration-response curves induced by S6c, NA, and 5-HT were significantly increased, while that induced by AngⅡ was decreased as comparing to fresh arteries. BK contracted the artery only weakly. Conclusion Organ culture changed the phenotypes towards an increased efficacy of NA, 5-HT, S6c, and a reduced efficacy of AngⅡ, which is in accordance with the results of pharmacological characterization in some human vascular disease.

  15. Pharmacogenetics, pharmacogenomics and airway disease

    Directory of Open Access Journals (Sweden)

    Hall Ian P

    2001-11-01

    Full Text Available Abstract The availability of a draft sequence for the human genome will revolutionise research into airway disease. This review deals with two of the most important areas impinging on the treatment of patients: pharmacogenetics and pharmacogenomics. Considerable inter-individual variation exists at the DNA level in targets for medication, and variability in response to treatment may, in part, be determined by this genetic variation. Increased knowledge about the human genome might also permit the identification of novel therapeutic targets by expression profiling at the RNA (genomics or protein (proteomics level. This review describes recent advances in pharmacogenetics and pharmacogenomics with regard to airway disease.

  16. Vascular smooth muscle cell glycocalyx mediates shear stress-induced contractile responses via a Rho kinase (ROCK)-myosin light chain phosphatase (MLCP) pathway.

    Science.gov (United States)

    Kang, Hongyan; Liu, Jiajia; Sun, Anqiang; Liu, Xiao; Fan, Yubo; Deng, Xiaoyan

    2017-02-13

    The vascular smooth muscle cells (VSMCs) are exposed to interstitial flow induced shear stress that may be sensed by the surface glycocalyx, a surface layer composed primarily of proteoglycans and glycoproteins, to mediate cell contraction during the myogenic response. We, therefore, attempted to elucidate the signal pathway of the glycocalyx mechanotransduction in shear stress regulated SMC contraction. Human umbilical vein SMCs (HUVSMCs) deprived of serum for 3-4 days were exposed to a step increase (0 to 20 dyn/cm(2)) in shear stress in a parallel plate flow chamber, and reduction in the cell area was quantified as contraction. The expressions of Rho kinase (ROCK) and its downstream signal molecules, the myosin-binding subunit of myosin phosphatase (MYPT) and the myosin light chain 2 (MLC2), were evaluated. Results showed that the exposure of HUVSMCs to shear stress for 30 min induced cell contraction significantly, which was accompanied by ROCK1 up-regulation, re-distribution, as well as MYPT1 and MLC activation. However, these shear induced phenomenon could be completely abolished by heparinase III or Y-27632 pre-treatment. These results indicate shear stress induced VSMC contraction was mediated by cell surface glycocalyx via a ROCK-MLC phosphatase (MLCP) pathway, providing evidence of the glycocalyx mechanotransduction in myogenic response.

  17. Compensatory Hypertrophy of Skeletal Muscle: Contractile Characteristics

    Science.gov (United States)

    Ianuzzo, C. D.; Chen, V.

    1977-01-01

    Describes an experiment using rats that demonstrates contractile characteristics of normal and hypertrophied muscle. Compensatory hypertrophy of the plantaris muscle is induced by surgical removal of the synergistic gastrocnemium muscle. Includes methods for determination of contractile properties of normal and hypertrophied muscle and…

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

    Directory of Open Access Journals (Sweden)

    O'Connor George T

    2011-07-01

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

  19. Obesity Appears to Be Associated With Altered Muscle Protein Synthetic and Breakdown Responses to Increased Nutrient Delivery in Older Men, but Not Reduced Muscle Mass or Contractile Function.

    Science.gov (United States)

    Murton, Andrew J; Marimuthu, Kanagaraj; Mallinson, Joanne E; Selby, Anna L; Smith, Kenneth; Rennie, Michael J; Greenhaff, Paul L

    2015-09-01

    Obesity is increasing, yet despite the necessity of maintaining muscle mass and function with age, the effect of obesity on muscle protein turnover in older adults remains unknown. Eleven obese (BMI 31.9 ± 1.1 kg · m(-2)) and 15 healthy-weight (BMI 23.4 ± 0.3 kg · m(-2)) older men (55-75 years old) participated in a study that determined muscle protein synthesis (MPS) and leg protein breakdown (LPB) under postabsorptive (hypoinsulinemic-euglycemic clamp) and postprandial (hyperinsulinemic hyperaminoacidemic-euglycemic clamp) conditions. Obesity was associated with systemic inflammation, greater leg fat mass, and patterns of mRNA expression consistent with muscle deconditioning, whereas leg lean mass, strength, and work done during maximal exercise were no different. Under postabsorptive conditions, MPS and LPB were equivalent between groups, whereas insulin and amino acid administration increased MPS in only healthy-weight subjects and was associated with lower leg glucose disposal (LGD) (63%) in obese men. Blunting of MPS in the obese men was offset by an apparent decline in LPB, which was absent in healthy-weight subjects. Lower postprandial LGD in obese subjects and blunting of MPS responses to amino acids suggest that obesity in older adults is associated with diminished muscle metabolic quality. This does not, however, appear to be associated with lower leg lean mass or strength.

  20. Western-style diet modulates contractile responses to phenylephrine differently in mesenteric arteries from senescence-accelerated prone (SAMP8) and resistant (SAMR1) mice.

    Science.gov (United States)

    Jiménez-Altayó, Francesc; Onetti, Yara; Heras, Magda; Dantas, Ana P; Vila, Elisabet

    2013-08-01

    The influence of two known cardiovascular risk factors, aging and consumption of a high-fat diet, on vascular mesenteric artery reactivity was examined in a mouse model of accelerated senescence (SAM). Five-month-old SAM prone (SAMP8) and resistant (SAMR1) female mice were fed a Western-type high-fat diet (WD; 8 weeks). Mesenteric arteries were dissected, and vascular reactivity, protein and messenger RNA expression, superoxide anion (O 2 (·-) ) and hydrogen peroxide formation were evaluated by wire myography, immunofluorescence, RT-qPCR, ethidium fluorescence and ferric-xylenol orange, respectively. Contraction to KCl and relaxation to acetylcholine remained unchanged irrespective of senescence and diet. Although similar contractions to phenylephrine were observed in SAMR1 and SAMP8, accelerated senescence was associated with decreased eNOS and nNOS and increased O 2 (·-) synthesis. Senescence-related alterations were compensated, at least partly, by the contribution of NO derived from iNOS and the enhanced endogenous antioxidant capacity of superoxide dismutase 1 to maintain vasoconstriction. Administration of a WD induced qualitatively different alterations in phenylephrine contractions of mesenteric arteries from SAMR1 and SAMP8. SAMR1 showed increased contractions partly as a result of decreased NO availability generated by decreased eNOS and nNOS and enhanced O 2 (·-) formation. In contrast, WD feeding in SAMP8 resulted in reduced contractions due to, at least in part, the increased functional participation of iNOS-derived NO. In conclusion, senescence-dependent intrinsic alterations during early stages of vascular senescence may promote vascular adaptation and predispose to further changes in response to high-fat intake, which may lead to the progression of aging-related cardiovascular disease, whereas young subjects lack the capacity for this adaptation.

  1. Role of dystrophin in airway smooth muscle phenotype, contraction and lung function.

    Directory of Open Access Journals (Sweden)

    Pawan Sharma

    Full Text Available Dystrophin links the transmembrane dystrophin-glycoprotein complex to the actin cytoskeleton. We have shown that dystrophin-glycoprotein complex subunits are markers for airway smooth muscle phenotype maturation and together with caveolin-1, play an important role in calcium homeostasis. We tested if dystrophin affects phenotype maturation, tracheal contraction and lung physiology. We used dystrophin deficient Golden Retriever dogs (GRMD and mdx mice vs healthy control animals in our approach. We found significant reduction of contractile protein markers: smooth muscle myosin heavy chain (smMHC and calponin and reduced Ca2+ response to contractile agonist in dystrophin deficient cells. Immunocytochemistry revealed reduced stress fibers and number of smMHC positive cells in dystrophin-deficient cells, when compared to control. Immunoblot analysis of Akt1, GSK3β and mTOR phosphorylation further revealed that downstream PI3K signaling, which is essential for phenotype maturation, was suppressed in dystrophin deficient cell cultures. Tracheal rings from mdx mice showed significant reduction in the isometric contraction to methacholine (MCh when compared to genetic control BL10ScSnJ mice (wild-type. In vivo lung function studies using a small animal ventilator revealed a significant reduction in peak airway resistance induced by maximum concentrations of inhaled MCh in mdx mice, while there was no change in other lung function parameters. These data show that the lack of dystrophin is associated with a concomitant suppression of ASM cell phenotype maturation in vitro, ASM contraction ex vivo and lung function in vivo, indicating that a linkage between the DGC and the actin cytoskeleton via dystrophin is a determinant of the phenotype and functional properties of ASM.

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

    DEFF Research Database (Denmark)

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

    2012-01-01

    Recent studies using culture-independent methods have characterized the human airway microbiota and report microbial communities distinct from other body sites. Changes in these airway bacterial communities appear to be associated with inflammatory lung disease, yet the pro-inflammatory properties...... differences in DC stimulating properties of bacteria associated with the airway microbiota....... of individual bacterial species are unknown. In this study, we compared the immune stimulatory capacity on human monocyte-derived dendritic cells (DCs) of selected airway commensal and pathogenic bacteria predominantly associated with lungs of asthma or COPD patients (pathogenic Haemophillus spp. and Moraxella...

  3. In vivo adenosine A(2B) receptor desensitization in guinea-pig airway smooth muscle: implications for asthma.

    Science.gov (United States)

    Breschi, Maria Cristina; Blandizzi, Corrado; Fogli, Stefano; Martinelli, Cinzia; Adinolfi, Barbara; Calderone, Vincenzo; Camici, Marcella; Martinotti, Enrica; Nieri, Paola

    2007-12-01

    This study was aimed at characterizing the role of adenosine receptor subtypes in the contractility modulation of guinea-pig airway smooth muscle in normal and pathological settings. In vitro and in vivo experiments were performed by testing selective agonists and antagonists on isolated tracheal smooth muscle preparations and pulmonary inflation pressure, respectively, under normal conditions or following ovalbumin-induced allergic sensitization. In normal and sensitized animals, the adenosine A(2A)/A(2B) receptor agonist, NECA, evoked relaxing responses of isolated tracheal preparations precontracted with histamine, and such an effect was reversed by the adenosine A(2B) antagonist, MRS 1706, in the presence or in the absence of epithelium. The expression of mRNA coding for adenosine A(2B) receptors was demonstrated in tracheal specimens. In vitro desensitization with 100 microM NECA markedly reduced the relaxing effect of the agonist. In vivo NECA or adenosine administration to normal animals inhibited histamine-mediated bronchoconstriction, while these inhibitory effects no longer occurred in sensitized guinea-pigs. Adenosine plasma levels were significantly higher in sensitized than normal animals. In conclusion, our data demonstrate that: (i) adenosine A(2B) receptors are responsible for the relaxing effects of adenosine on guinea-pig airways; (ii) these receptors can undergo rapid adaptive changes that may affect airway smooth muscle responsiveness to adenosine; (iii) ovalbumin-induced sensitization promotes a reversible inactivation of adenosine A(2B) receptors which can be ascribed to homologous desensitization. These findings can be relevant to better understand adenosine functions in airways as well as mechanisms of action of asthma therapies targeting the adenosine system.

  4. A key role for STIM1 in store operated calcium channel activation in airway smooth muscle

    Directory of Open Access Journals (Sweden)

    Peel Samantha E

    2006-09-01

    Full Text Available Abstract Background Control of cytosolic calcium plays a key role in airway myocyte function. Changes in intracellular Ca2+ stores can modulate contractile responses, modulate proliferation and regulate synthetic activity. Influx of Ca2+ in non excitable smooth muscle is believed to be predominantly through store operated channels (SOC or receptor operated channels (ROC. Whereas agonists can activate both SOC and ROC in a range of smooth muscle types, the specific trigger for SOC activation is depletion of the sarcoplasmic reticulum Ca2+ stores. The mechanism underlying SOC activation following depletion of intracellular Ca2+ stores in smooth muscle has not been identified. Methods To investigate the roles of the STIM homologues in SOC activation in airway myocytes, specific siRNA sequences were utilised to target and selectively suppress both STIM1 and STIM2. Quantitative real time PCR was employed to assess the efficiency and the specificity of the siRNA mediated knockdown of mRNA. Activation of SOC was investigated by both whole cell patch clamp electrophysiology and a fluorescence based calcium assay. Results Transfection of 20 nM siRNA specific for STIM1 or 2 resulted in robust decreases (>70% of the relevant mRNA. siRNA targeted at STIM1 resulted in a reduction of SOC associated Ca2+ influx in response to store depletion by cyclopiazonic acid (60% or histamine but not bradykinin. siRNA to STIM2 had no effect on these responses. In addition STIM1 suppression resulted in a more or less complete abrogation of SOC associated inward currents assessed by whole cell patch clamp. Conclusion Here we show that STIM1 acts as a key signal for SOC activation following intracellular Ca2+ store depletion or following agonist stimulation with histamine in human airway myocytes. These are the first data demonstrating a role for STIM1 in a physiologically relevant, non-transformed endogenous expression cell model.

  5. [Modern airway management--current concepts for more patient safety].

    Science.gov (United States)

    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.

  6. Response to rhinovirus infection by human airway epithelial cells and peripheral blood mononuclear cells in an in vitro two-chamber tissue culture system.

    Directory of Open Access Journals (Sweden)

    Devi Rajan

    Full Text Available Human rhinovirus (HRV infections are associated with the common cold, occasionally with more serious lower respiratory tract illnesses, and frequently with asthma exacerbations. The clinical features of HRV infection and its association with asthma exacerbation suggest that some HRV disease results from virus-induced host immune responses to infection. To study the HRV-infection-induced host responses and the contribution of these responses to disease, we have developed an in vitro model of HRV infection of human airway epithelial cells (Calu-3 cells and subsequent exposure of human peripheral blood mononuclear cells (PBMCs to these infected cells in a two-chamber trans-well tissue culture system. Using this model, we studied HRV 14 (species B and HRV 16 (species A induced cytokine and chemokine responses with PBMCs from four healthy adults. Infection of Calu-3 cells with either virus induced HRV-associated increases in FGF-Basic, IL-15, IL-6, IL-28A, ENA-78 and IP-10. The addition of PBMCs to HRV 14-infected cells gave significant increases in MIP-1β, IL-28A, MCP-2, and IFN-α as compared with mock-infected cells. Interestingly, ENA-78 levels were reduced in HRV 14 infected cells that were exposed to PBMCs. Addition of PBMCs to HRV 16-infected cells did not induce MIP-1β, IL-28A and IFN-α efficiently nor did it decrease ENA-78 levels. Our results demonstrate a clear difference between HRV 14 and HRV 16 and the source of PBMCs, in up or down regulation of several cytokines including those that are linked to airway inflammation. Such differences might be one of the reasons for variation in disease associated with different HRV species including variation in their link to asthma exacerbations as suggested by other studies. Further study of immune responses associated with different HRVs and PBMCs from different patient groups, and the mechanisms leading to these differences, should help characterize pathogenesis of HRV disease and generate

  7. Supreme 喉罩与普通型喉罩对侧卧位老年手术患者气道管理和血流动力学的影响%Effects of Laryngeal Mask Airway Supreme and Laryngeal Mask Airway Classic on Airway Management and Hemodynamic Response in Elderly Patients Undergoing Surgery in Lateral Decubitus Position

    Institute of Scientific and Technical Information of China (English)

    张芳; 戴寒英; 戴祺; 雷恩骏

    2016-01-01

    ABSTRACT:Objective To study the effects of laryngeal mask airway(LMA)Supreme and LMA Classic on airway management and hemodynamic response in elderly patients undergoing surgery in lateral decubitus position.Methods Sixty patients scheduled for elective surgery were divided into two groups,with 30 patients in each group.After anesthesia induction,LMA Supreme and LMA Classic insertion were performed in group S and group C,respectively.Intravenous propofol infusion and sevoflurane inhalation were used to maintain the bispectral index(BIS)between 50 and 60.The catheterization time,success rate of LMA insertion,peak airway pressure(Ppeak), end-tidal carbon dioxide partial pressure(PET CO2 ),oropharyngeal leak pressure(OLP),mean arte-rial blood pressure(MAP),heart rate(HR),and incidence of postoperative adverse events(nause-a,vomiting,sore throat,hoarseness)were recorded in both groups.Results Compared with LMA Classic,LMA Supreme shortened catheterization time((23.29±6.52)s vs (32.81±7.36)s),re-duced intraoperative Ppeak in lateral decubitus position,and increased OLP in both lateral decubi-tus and supine position(P < 0.05).Conclusion LMA Supreme can shorten the catheterization time,improve the success rate of LMA insertion and achieve a high airway sealing pressure. Therefore,LMA Supreme is a safer and more effective airway management device than LMA Classic in elderly patients undergoing surgery in lateral decubitus position.%目的:探讨一次性双管喉罩(Supreme 喉罩)与普通型喉罩对侧卧位老年手术患者气道管理和血流动力学的影响。方法将60例择期手术患者按使用不同的喉罩分为 Supreme 喉罩(S)组和普通型喉罩(C)组,每组30例。2组均行麻醉诱导。麻醉诱导后,S 组置入 Supreme 喉罩,C 组置入普通型喉罩,2组均经静脉泵泵注丙泊酚注射液及吸入七氟醚维持麻醉,维持脑电双频指数值50~60。观察2组置管时间、置入喉罩成功率,术中

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

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    Carla M. P. Ribeiro

    2017-01-01

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

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

    NARCIS (Netherlands)

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

    2012-01-01

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

  10. Dissociation of FK506-binding protein 12.6 kD from ryanodine receptor in bronchial smooth muscle cells in airway hyperresponsiveness in asthma.

    Science.gov (United States)

    Du, Ying; Zhao, Jianhong; Li, Xi; Jin, Si; Ma, Wan-Li; Mu, Qing; Xu, Shuxiang; Yang, Jie; Rao, Shanshan; Zhu, Liping; Xin, Jianbao; Cai, Peng-Cheng; Su, Yunchao; Ye, Hong

    2014-02-01

    Airway hyperresponsiveness (AHR) in asthma is predominantly caused by increased sensitivity of bronchial smooth muscle cells (BSMCs) to stimuli. The sarcoplasmic reticulum (SR)-Ca(2+) release channel, known as ryanodine receptor (RyR), mediates the contractive response of BSMCs to stimuli. FK506-binding protein 12.6 kD (FKBP12.6) stabilizes the RyR2 channel in a closed state. However, the interaction of FKBP12.6 with RyR2 in AHR remains unknown. This study examined the interaction of FKBP12.6 with RyR2 in BSMCs in AHR of asthma. The interaction of FKBP12.6 with RyR2 and FKBP12.6 expression was determined in a rat asthma model and in BSMCs treated with inflammatory cytokines. The calcium responses to contractile agonists were determined in BSMCs with overexpression and knockdown of FKBP12.6. Asthmatic serum, IL-5, IL-13, and TNF-α enhance the calcium response of BSMCs to contractile agonists and cause dissociation of FKBP12.6 from RyR2 and a decrease in FKBP12.6 gene expression in BSMCs in culture and in ovalbumin (OVA)-sensitized and -challenged rats. Knockdown of FKBP12.6 in BSMCs causes a decrease in the association of RyR2 with FKBP12.6 and an increase in the calcium response of BSMCs. Overexpression of FKBP12.6 increases the association of FKBP12.6 with RyR2, decreases the calcium response of BSMCs, and normalizes airway responsiveness in OVA-sensitized and -challenged rats. Dissociation of FKBP12.6 from RyR2 in BSMCs is responsible for the increased calcium response contributing to AHR in asthma. Manipulating the interaction of FKBP12.6 with RyR2 might be a novel and useful treatment for asthma.

  11. Requirements for disordered actomyosin bundle contractility

    CERN Document Server

    Lenz, Martin

    2011-01-01

    Actomyosin contractility is essential for biological force generation, and is well understood in highly ordered structures such as striated muscle. In vitro experiments have shown that non-sarcomeric bundles comprised only of F-actin and myosin thick filaments can also display contractile behavior, which cannot be described by standard muscle models. Here we investigate the microscopic symmetries underlying this process in large non-sarcomeric bundles with long actin filaments. We prove that contractile behavior requires non-identical motors that generate large enough forces to probe the nonlinear elastic behavior of F-actin. A simple disordered bundle model demonstrates a contraction mechanism based on these assumptions and predicts realistic bundle deformations. Recent experimental observations of F-actin buckling in in vitro contractile bundles support our model.

  12. Myocardial contractile function and intradialytic hypotension.

    Science.gov (United States)

    Owen, Paul J; Priestman, William S; Sigrist, Mhairi K; Lambie, Stewart H; John, Stephen G; Chesterton, Lindsay J; McIntyre, Christopher W

    2009-07-01

    Dialysis-induced hypotension remains a significant problem in hemodialysis (HD) patients. Numerous factors result in dysregulation of blood pressure control and impaired myocardial reserve in response to HD-induced cardiovascular stress. Episodic intradialytic hypotension may be involved in the pathogenesis of evolving myocardial injury. We performed an initial pilot investigation of cardiovascular functional response to pharmacological cardiovascular stress in hypotension-resistant (HR) and hypotension-prone (HP) HD patients. We studied 10 matched chronic HD patients (5 HP, 5 HR). Dobutamine-atropine stress (DAS) was performed on a nondialysis short interval day, with noninvasive pulse-wave analysis using the Finometer to continuously measure hemodynamic variables. Baroreflex sensitivity was assessed at rest and during DAS. Baseline hemodynamic variables were not significantly different. The groups had differing hemodynamic responses to DAS. The Mean arterial pressure was unchanged in the HR group but decreased in HP patients (-13.6 +/- 3.5 mmHg; P<0.001). This was associated with failure to significantly increase cardiac output in the HP group (cf. increase in cardiac output in the HR group of +33.4 +/- 6%; P<0.05), and a reduced response in total peripheral resistance (HP -10.3 +/- 6.8%, HR -22.7 +/- 2.9%, P=NS). Baroreflex sensitivity was not significantly different between groups at baseline or within groups with increasing levels of DAS; however, the mean baroreflex sensitivity was higher in HR cf. HP subjects throughout pharmacological stress (P<0.05). Hypotension-prone patients appear to have an impaired cardiovascular response to DAS. The most significant abnormality is an impaired myocardial contractile reserve. Early identification of these patients would allow utilization of therapeutic strategies to improve intradialytic tolerability, potentially abrogating aggravation of myocardial injury.

  13. Reproducibility of the airway response to an exercise protocol standardized for intensity, duration, and inspired air conditions, in subjects with symptoms suggestive of asthma

    Directory of Open Access Journals (Sweden)

    Anderson Sandra D

    2010-09-01

    Full Text Available Abstract Background Exercise testing to aid diagnosis of exercise-induced bronchoconstriction (EIB is commonly performed. Reproducibility of the airway response to a standardized exercise protocol has not been reported in subjects being evaluated with mild symptoms suggestive of asthma but without a definite diagnosis. This study examined reproducibility of % fall in FEV1 and area under the FEV1 time curve for 30 minutes in response to two exercise tests performed with the same intensity and duration of exercise, and inspired air conditions. Methods Subjects with mild symptoms of asthma exercised twice within approximately 4 days by running for 8 minutes on a motorized treadmill breathing dry air at an intensity to induce a heart rate between 80-90% predicted maximum; reproducibility of the airway response was expressed as the 95% probability interval. Results Of 373 subjects challenged twice 161 were positive (≥10% fall FEV1 on at least one challenge. The EIB was mild and 77% of subjects had 1 and 19.3% (72 positive on both challenges. The remaining 23.9% of subjects had only one positive test. The 95% probability interval for reproducibility of the % fall in FEV1 and AUC0-30 min was ± 9.7% and ± 251% for all 278 adults and ± 13.4% and ± 279% for all 95 children. The 95% probability interval for reproducibility of % fall in FEV1 and AUC0-30 min for the 72 subjects with two tests ≥10% fall FEV1 was ± 14.6% and ± 373% and for the 34 subjects with two tests ≥15% fall FEV1 it was ± 12.2% and ± 411%. Heart rate and estimated ventilation achieved were not significantly different either on the two test days or when one test result was positive and one was negative. Conclusions Under standardized, well controlled conditions for exercise challenge, the majority of subjects with mild symptoms of asthma demonstrated agreement in test results. Performing two tests may need to be considered when using exercise to exclude or diagnose EIB, when

  14. Phospholipase cε, an effector of ras and rap small GTPases, is required for airway inflammatory response in a mouse model of bronchial asthma.

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    Tatsuya Nagano

    Full Text Available BACKGROUND: Phospholipase Cε (PLCε is an effector of Ras and Rap small GTPases and expressed in non-immune cells. It is well established that PLCε plays an important role in skin inflammation, such as that elicited by phorbol ester painting or ultraviolet irradiation and contact dermatitis that is mediated by T helper (Th 1 cells, through upregulating inflammatory cytokine production by keratinocytes and dermal fibroblasts. However, little is known about whether PLCε is involved in regulation of inflammation in the respiratory system, such as Th2-cells-mediated allergic asthma. METHODS: We prepared a mouse model of allergic asthma using PLCε+/+ mice and PLCεΔX/ΔX mutant mice in which PLCε was catalytically-inactive. Mice with different PLCε genotypes were immunized with ovalbumin (OVA followed by the challenge with an OVA-containing aerosol to induce asthmatic response, which was assessed by analyzing airway hyper-responsiveness, bronchoalveolar lavage fluids, inflammatory cytokine levels, and OVA-specific immunoglobulin (Ig levels. Effects of PLCε genotype on cytokine production were also examined with primary-cultured bronchial epithelial cells. RESULTS: After OVA challenge, the OVA-immunized PLCεΔX/ΔX mice exhibited substantially attenuated airway hyper-responsiveness and broncial inflammation, which were accompanied by reduced Th2 cytokine content in the bronchoalveolar lavage fluids. In contrast, the serum levels of OVA-specific IgGs and IgE were not affected by the PLCε genotype, suggesting that sensitization was PLCε-independent. In the challenged mice, PLCε deficiency reduced proinflammatory cytokine production in the bronchial epithelial cells. Primary-cultured bronchial epithelial cells prepared from PLCεΔX/ΔX mice showed attenuated pro-inflammatory cytokine production when stimulated with tumor necrosis factor-α, suggesting that reduced cytokine production in PLCεΔX/ΔX mice was due to cell-autonomous effect of

  15. Engineering Airway Epithelium

    Directory of Open Access Journals (Sweden)

    John P. Soleas

    2012-01-01

    Full Text Available 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.

  16. Expression and activation of the oxytocin receptor in airway smooth muscle cells: Regulation by TNFα and IL-13

    Directory of Open Access Journals (Sweden)

    Siddiqui Salman

    2010-07-01

    Full Text Available Abstract Background During pregnancy asthma may remain stable, improve or worsen. The factors underlying the deleterious effect of pregnancy on asthma remain unknown. Oxytocin is a neurohypophyseal protein that regulates a number of central and peripheral responses such as uterine contractions and milk ejection. Additional evidence suggests that oxytocin regulates inflammatory processes in other tissues given the ubiquitous expression of the oxytocin receptor. The purpose of this study was to define the role of oxytocin in modulating human airway smooth muscle (HASMCs function in the presence and absence of IL-13 and TNFα, cytokines known to be important in asthma. Method Expression of oxytocin receptor in cultured HASMCs was performed by real time PCR and flow cytomery assays. Responses to oxytocin was assessed by fluorimetry to detect calcium signals while isolated tracheal rings and precision cut lung slices (PCLS were used to measure contractile responses. Finally, ELISA was used to compare oxytocin levels in the bronchoalveloar lavage (BAL samples from healthy subjects and those with asthma. Results PCR analysis demonstrates that OXTR is expressed in HASMCs under basal conditions and that both interleukin (IL-13 and tumor necrosis factor (TNFα stimulate a time-dependent increase in OXTR expression at 6 and 18 hr. Additionally, oxytocin increases cytosolic calcium levels in fura-2-loaded HASMCs that were enhanced in cells treated for 24 hr with IL-13. Interestingly, TNFα had little effect on oxytocin-induced calcium response despite increasing receptor expression. Using isolated murine tracheal rings and PCLS, oxytocin also promoted force generation and airway narrowing. Further, oxytocin levels are detectable in bronchoalveolar lavage (BAL fluid derived from healthy subjects as well as from those with asthma. Conclusion Taken together, we show that cytokines modulate the expression of functional oxytocin receptors in HASMCs suggesting a

  17. Airway management in trauma

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    Rao B

    2004-01-01

    Full Text Available Airway Management for the victims of major trauma is the first priority in the care of the trauma victim and is a core skill in emergency medicine and critical care. Endotracheal intubation remains the gold standard for trauma airway management. Airway management in trauma patients is not just the capability to insert an oral/nasal airway or endotracheal tube beyond the vocal cords. The five components integral to modern, sophisticated airway management in trauma patients include equipment, pharmacologic adjuncts, manual techniques, physical circumstances, and patient profile. A trauma patient may require airway management in a variety of physical circumstances. Whereas, the commonly used airway management algorithms may not suffice in all these situations, the construction of a truly complete decision tree is also virtually impossible. There is consensus that it is not the intervention per se but rather the conditions, skills, and performance that might be the possible variables that affect outcome. Paramedics have only limited experience and on-the-job skills for invasive airway management. Difficult airway management is best left for the experienced physicians to handle.

  18. IP3 receptors regulate vascular smooth muscle contractility and hypertension

    Science.gov (United States)

    Lin, Qingsong; Zhao, Guiling; Fang, Xi; Peng, Xiaohong; Tang, Huayuan; Wang, Hong; Jing, Ran; Liu, Jie; Ouyang, Kunfu

    2016-01-01

    Inositol 1, 4, 5-trisphosphate receptor–mediated (IP3R-mediated) calcium (Ca2+) release has been proposed to play an important role in regulating vascular smooth muscle cell (VSMC) contraction for decades. However, whether and how IP3R regulates blood pressure in vivo remains unclear. To address these questions, we have generated a smooth muscle–specific IP3R triple-knockout (smTKO) mouse model using a tamoxifen-inducible system. In this study, the role of IP3R-mediated Ca2+ release in adult VSMCs on aortic vascular contractility and blood pressure was assessed following tamoxifen induction. We demonstrated that deletion of IP3Rs significantly reduced aortic contractile responses to vasoconstrictors, including phenylephrine, U46619, serotonin, and endothelin 1. Deletion of IP3Rs also dramatically reduced the phosphorylation of MLC20 and MYPT1 induced by U46619. Furthermore, although the basal blood pressure of smTKO mice remained similar to that of wild-type controls, the increase in systolic blood pressure upon chronic infusion of angiotensin II was significantly attenuated in smTKO mice. Taken together, our results demonstrate an important role for IP3R-mediated Ca2+ release in VSMCs in regulating vascular contractility and hypertension.

  19. Modulation of human uterine smooth muscle cell collagen contractility by thrombin, Y-27632, TNF alpha and indomethacin

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    Smith Terry J

    2009-01-01

    Full Text Available Abstract Background Preterm labour occurs in approximately 10% of pregnancies and is a major cause of infant morbidity and mortality. However, the pathways involved in regulating contractility in normal and preterm labour are not fully elucidated. Our aim was to utilise a human myometrial contractility model to investigate the effect of a number of uterine specific contractility agents in this system. Therefore, we investigated the contractile response of human primary uterine smooth muscle cells or immortalised myometrial smooth muscle cells cultured within collagen lattices, to known mediators of uterine contractility, which included thrombin, the ROCK-1 inhibitor Y-27632, tumour necrosis factor alpha (TNF alpha and the non-steroidal anti-inflammatory indomethacin. Methods Cell contractility was calculated over time, with the collagen gel contraction assay, utilising human primary uterine smooth muscle cells (hUtSMCs and immortalised myometrial smooth muscle cells (hTERT-HM: a decrease in collagen gel area equated to an increase in contractility. RNA was isolated from collagen embedded cells and gene expression changes were analysed by real time fluorescence reverse transcription polymerase chain reaction. Scanning electron and fluorescence microscopy were employed to observe cell morphology and cell collagen gel interactions. Statistical analysis was performed using ANOVA followed by Tukey's post hoc tests. Results TNF alpha increased collagen contractility in comparison to the un-stimulated collagen embedded hUtSMC cells, which was inhibited by indomethacin, while indomethacin alone significantly inhibited contraction. Thrombin augmented the contractility of uterine smooth muscle cell and hTERT-HM collagen gels, this effect was inhibited by the thrombin specific inhibitor, hirudin. Y-27632 decreased both basal and thrombin-induced collagen contractility in the hTERT-HM embedded gels. mRNA expression of the thrombin receptor, F2R was up

  20. Effect of montelukast on excessive airway narrowing response to methacholine in adult asthmatic patients not on controller therapy

    DEFF Research Database (Denmark)

    Ulrik, Charlotte Suppli; Diamant, Zuzana

    2009-01-01

    2-agonists p.r.n. only with a twice-documented absence of dose-response plateau, participated in a double-blind, parallel study with Mont (10 mg) or placebo once daily for 12 weeks. Mtc dose-response curves (0.03-256 mumol or >40% FEV(1) decline) were repeated every 4 weeks. The primary objective...

  1. Innate immune response in airway epithelium fight against respiratory bacterial pathongens%气道上皮细胞对细菌病原的天然免疫应答

    Institute of Scientific and Technical Information of China (English)

    林立; 李昌崇

    2012-01-01

    气道上皮细胞是肺天然免疫系统的重要组成部分,通过模式识别受体识别病原相关分子模式,启动天然免疫反应,随后通过抗原呈递和共刺激信号,活化获得性免疫反应.气道上皮细胞的天然免疫反应与抵御病原菌高度相关.本文就气道上皮细胞对细菌病原的天然免疫应答研究进展作一综述.%Airway epithelial cells are an important part of the lung innate immune system,they recognize conserved structures in microorganisms,called pathogen-associated molecular patterns through apically exposed and intracellular receptors,called pattern-recognition receptors and initiate innate immune response.Subsequently,they activate adaptive immnue response through antigen presentation and co-stimulatory signals.Innate immune responses of the airway epithelium play a critical role in resisting pathongens.The research progress of innate immune response in the airway epithelium fight against respiratory bacterial pathongens is reviewed here.

  2. Airway hyperresponsiveness induced by repeated esophageal infusion of HCl in guinea pigs.

    Science.gov (United States)

    Cheng, Yan-Mei; Cao, Ai-Li; Zheng, Jian-Pu; Wang, Hong-Wei; Sun, Yong-Shun; Liu, Chun-Fang; Zhang, Bei-Bei; Wang, Yi; Zhu, Sheng-Liang; Wu, Da-Zheng

    2014-11-01

    Gastroesophageal reflux is a common disorder closely related to chronic airway diseases, such as chronic cough, asthma, chronic bronchitis, and chronic obstructive disease. Indeed, gastroesophageal acid reflux into the respiratory tract causes bronchoconstriction, but the underlying mechanisms have still not been clarified. This study aimed to elucidate functional changes of bronchial smooth muscles (BSMs) isolated from guinea pigs in an animal model of gastroesophageal reflux. The marked airway inflammation, hyperresponsiveness and remodeling were observed after guinea pigs were exposed to intraesophageal HCl infusion for 14 days. In addition, contractile responses to acetylcholine (ACh), KCl, electrical field stimulation, and extracellular Ca(2+) were greater in guinea pigs infused with HCl compared with control groups. The L-type voltage-dependent Ca(2+) channels (L-VDCC) blocker, nicardipine, significantly inhibited ACh- and Ca(2+)-enhanced BSM contractions in guinea pigs infused with HCl. The Rho-kinase inhibitor, Y27632, attenuated ACh-enhanced BSM contractions in guinea pigs infused with HCl. Moreover, mRNA and protein expressions for muscarinic M2 and M3 receptors, RhoA, and L-VDCC in BSM were detected by real-time PCR and Western blot. Expressions of mRNA and protein for muscarinic M3 receptors, RhoA, and L-VDCC were greater than in BSM of HCl-infused guinea pigs, whereas levels of muscarinic M2 receptors were unchanged. We demonstrate that acid infusion to the lower esophagus and, subsequently, microaspiration into the respiratory tract in guinea pigs leads to airway hyperresponsiveness and overactive BSM. Functional and molecular results indicate that overactive BSM is the reason for enhancement of extracellular Ca(2+) influx via L-VDCC and Ca(2+) sensitization through Rho-kinase signaling.

  3. Comparative assessment of ProSeal™ laryngeal mask airway intervention versus standard technique of endotracheal extubation for attenuation of pressor response in controlled hypertensive patients

    Directory of Open Access Journals (Sweden)

    Raj Pal Singh

    2016-01-01

    Full Text Available Background and Aims: Swapping of the endotracheal tube with laryngeal mask airway (LMA before emergence from anaesthesia is one of the methods employed for attenuation of pressor response at extubation. We decided to compare the placement of ProSeal ™ LMA (PLMA before endotracheal extubation versus conventional endotracheal extubation in controlled hypertensive patients scheduled for elective surgeries under general anaesthesia. Methods: Sixty consenting adult patients were randomly allocated to two groups of thirty each; Group E in whom extubation was performed using standard technique and Group P in whom PLMA was inserted before endotracheal extubation (Bailey manoeuvre. The primary outcome parameter was heart rate (HR. The secondary outcomes were systolic, diastolic and mean blood pressure (MBP, electrocardiogram, oxygen saturation and end-tidal carbon dioxide. Two-tailed paired Student's t-test was used for comparison between the two study groups. The value of P< 0.05 was considered as statistically significant. Results: The patient characteristics, demographic data and surgical procedures were comparable in the two groups. A statistically significant decrease was observed in HR in Group P as compared to Group E. Secondary outcomes such as systolic, diastolic and MBP depicted a statistically insignificant difference. Conclusion: Bailey manoeuvre was not effective method to be completely relied upon during extubation when compared to standard extubation.

  4. Reliability of contractile properties of the knee extensor muscles in individuals with post-polio syndrome.

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    Eric L Voorn

    Full Text Available To assess the reliability of contractile properties of the knee extensor muscles in 23 individuals with post-polio syndrome (PPS and 18 age-matched healthy individuals.Contractile properties of the knee extensors were assessed from repeated electrically evoked contractions on 2 separate days, with the use of a fixed dynamometer. Reliability was determined for fatigue resistance, rate of torque development (MRTD, and early and late relaxation time (RT50 and RT25, using the intraclass correlation coefficient (ICC and standard error of measurement (SEM, expressed as % of the mean.In both groups, reliability for fatigue resistance was good, with high ICCs (>0.90 and small SEM values (PPS: 7.1%, healthy individuals: 7.0%. Reliability for contractile speed indices varied, with the best values found for RT50 (ICCs>0.82, SEM values <2.8%. We found no systematic differences between test and retest occasions, except for RT50 in healthy subjects (p = 0.016.In PPS and healthy individuals, the reliability of fatigue resistance, as obtained from electrically evoked contractions is high. The reliability of contractile speed is only moderate, except for RT50 in PPS, demonstrating high reliability.This was the first study to examine the reliability of electrically evoked contractile properties in individuals with PPS. Our results demonstrate its potential to study mechanisms underlying muscle fatigue in PPS and to evaluate changes in contractile properties over time in response to interventions or from natural course.

  5. Indirect airway challenges

    NARCIS (Netherlands)

    Joos, GF; O'Connor, B; Anderson, SD; Chung, F; Cockcroft, DW; Dahlen, B; DiMaria, G; Foresi, A; Hargreave, FE; Holgate, ST; Inman, M; Lotvall, J; Magnussen, H; Polosa, R; Postma, DS; Riedler, J

    2003-01-01

    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. Di

  6. Pediatric airway nightmares.

    Science.gov (United States)

    D'Agostino, James

    2010-02-01

    Pediatric disorders that involve actual or potential airway compromise are among the most challenging cases that emergency department providers face. This article discusses the diagnosis and management of common and uncommon conditions in infants and children who may present with airway obstruction.

  7. A Brief History of Airway Smooth Muscle’s Role in Airway Hyperresponsiveness

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    C. D. Pascoe

    2012-01-01

    Full Text Available A link between airway smooth muscle (ASM and airway hyperresponsiveness (AHR in asthma was first postulated in the midnineteenth century, and the suspected link has garnered ever increasing interest over the years. AHR is characterized by excessive narrowing of airways in response to nonspecific stimuli, and it is the ASM that drives this narrowing. The stimuli that can be used to demonstrate AHR vary widely, as do the potential mechanisms by which phenotypic changes in ASM or nonmuscle factors can contribute to AHR. In this paper, we review the history of research on airway smooth muscle’s role in airway hyperresponsiveness. This research has ranged from analyzing the quantity of ASM in the airways to testing for alterations in the plastic behavior of smooth muscle, which distinguishes it from skeletal and cardiac muscles. This long history of research and the continued interest in this topic mean that the precise role of ASM in airway responsiveness remains elusive, which makes it a pertinent topic for this collection of articles.

  8. Matrix metalloprotease 9 mediates neutrophil migration into the airways in response to influenza virus-induced toll-like receptor signaling.

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    Linda M Bradley

    Full Text Available The early inflammatory response to influenza virus infection contributes to severe lung disease and continues to pose a serious threat to human health. The mechanisms by which neutrophils gain entry to the respiratory tract and their role during pathogenesis remain unclear. Here, we report that neutrophils significantly contributed to morbidity in a pathological mouse model of influenza virus infection. Using extensive immunohistochemistry, bone marrow transfers, and depletion studies, we identified neutrophils as the predominant pulmonary cellular source of the gelatinase matrix metalloprotease (MMP 9, which is capable of digesting the extracellular matrix. Furthermore, infection of MMP9-deficient mice showed that MMP9 was functionally required for neutrophil migration and control of viral replication in the respiratory tract. Although MMP9 release was toll-like receptor (TLR signaling-dependent, MyD88-mediated signals in non-hematopoietic cells, rather than neutrophil TLRs themselves, were important for neutrophil migration. These results were extended using multiplex analyses of inflammatory mediators to show that neutrophil chemotactic factor, CCL3, and TNFα were reduced in the Myd88⁻/⁻ airways. Furthermore, TNFα induced MMP9 secretion by neutrophils and blocking TNFα in vivo reduced neutrophil recruitment after infection. Innate recognition of influenza virus therefore provides the mechanisms to induce recruitment of neutrophils through chemokines and to enable their motility within the tissue via MMP9-mediated cleavage of the basement membrane. Our results demonstrate a previously unknown contribution of MMP9 to influenza virus pathogenesis by mediating excessive neutrophil migration into the respiratory tract in response to viral replication that could be exploited for therapeutic purposes.

  9. Polarized secretion of interleukin (IL-6 and IL-8 by human airway epithelia 16HBE14o- cells in response to cationic polypeptide challenge.

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    Alison Wai-ming Chow

    Full Text Available BACKGROUND: The airway epithelium participates in asthmatic inflammation in many ways. Target cells of the epithelium can respond to a variety of inflammatory mediators and cytokines. Damage to the surface epithelium occurs following the secretion of eosinophil-derived, highly toxic cationic proteins. Moreover, the surface epithelium itself is responsible for the synthesis and release of cytokines that cause the selective recruitment, retention, and accumulation of various inflammatory cells. To mimic the damage seen during asthmatic inflammation, the bronchial epithelium can be challenged with highly charged cationic polypeptides such as poly-L-arginine. METHODOLOGY/PRINCIPAL FINDINGS: In this study, human bronchial epithelial cells, 16HBE14o- cells, were "chemically injured" by exposing them to poly-l-arginine as a surrogate of the eosinophil cationic protein. Cytokine antibody array data showed that seven inflammatory mediators were elevated out of the 40 tested, including marked elevation in interleukin (IL-6 and IL-8 secretion. IL-6 and IL-8 mRNA expression levels were elevated as measured with real-time PCR. Cell culture supernatants from apical and basolateral compartments were collected, and the IL-6 and IL-8 production was quantified with ELISA. IL-6 and IL-8 secretion by 16HBE14o- epithelia into the apical compartment was significantly higher than that from the basolateral compartment. Using specific inhibitors, the production of IL-6 and IL-8 was found to be dependent on p38 MAPK, ERK1/2 MAPK, and NF-kappaB pathways. CONCLUSIONS/SIGNIFICANCE: The results clearly demonstrate that damage to the bronchial epithelia by poly-L-arginine stimulates polarized IL-6 and IL-8 secretion. This apically directed secretion of cytokines may play an important role in orchestrating epithelial cell responses to inflammation.

  10. Elastase-Induced Parenchymal Disruption and Airway Hyper Responsiveness in Mouse Precision Cut Lung Slices: Toward an Ex vivo COPD Model

    Science.gov (United States)

    Van Dijk, Eline M.; Culha, Sule; Menzen, Mark H.; Bidan, Cécile M.; Gosens, Reinoud

    2017-01-01

    Background: COPD is a progressive lung disease characterized by emphysema and enhanced bronchoconstriction. Current treatments focused on bronchodilation can delay disease progression to some extent, but recovery or normalization of loss of lung function is impossible. Therefore, novel therapeutic targets are needed. The importance of the parenchyma in airway narrowing is increasingly recognized. In COPD, the parenchyma and extracellular matrix are altered, possibly affecting airway mechanics and enhancing bronchoconstriction. Our aim was to set up a comprehensive ex vivo Precision Cut Lung Slice (PCLS) model with a pathophysiology resembling that of COPD and integrate multiple readouts in order to study the relationship between parenchyma, airway functionality, and lung repair processes. Methods: Lungs of C57Bl/6J mice were sliced and treated ex vivo with elastase (2.5 μg/ml) or H2O2 (200 μM) for 16 h. Following treatment, parenchymal structure, airway narrowing, and gene expression levels of alveolar Type I and II cell repair were assessed. Results: Following elastase, but not H2O2 treatment, slices showed a significant increase in mean linear intercept (Lmi), reflective of emphysema. Only elastase-treated slices showed disorganization of elastin and collagen fibers. In addition, elastase treatment lowered both alveolar Type I and II marker expression, whereas H2O2 stimulation lowered alveolar Type I marker expression only. Furthermore, elastase-treated slices showed enhanced methacholine-induced airway narrowing as reflected by increased pEC50 (5.87 at basal vs. 6.50 after elastase treatment) and Emax values (47.96 vs. 67.30%), and impaired chloroquine-induced airway opening. The increase in pEC50 correlated with an increase in mean Lmi. Conclusion: Using this model, we show that structural disruption of elastin fibers leads to impaired alveolar repair, disruption of the parenchymal compartment, and altered airway biomechanics, enhancing airway contraction

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

    Science.gov (United States)

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

    2012-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Jeppe Madura Larsen

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

  13. Genetic fuzzy system predicting contractile reactivity patterns of small arteries

    DEFF Research Database (Denmark)

    Tang, J; Sheykhzade, Majid; Clausen, B F;

    2014-01-01

    information. We developed a genetic fuzzy system (GFS) algorithm that is capable of learning all information in time-domain physiological data. Data on isometric force development of isolated small arteries were used as a framework for developing and optimizing a GFS. GFS performance was improved by several...... strategies. Results show that optimized fuzzy systems (OFSs) predict contractile reactivity of arteries accurately. In addition, OFSs identified significant differences that were undetectable using conventional analysis in the responses of arteries between groups. We concluded that OFSs may be used...

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

    Science.gov (United States)

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

    2015-03-01

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

  15. Host–microbe interactions in distal airways: relevance to chronic airway diseases

    Directory of Open Access Journals (Sweden)

    Clémence Martin

    2015-03-01

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

  16. Uterine contractility and blood flow are reflexively regulated by cutaneous afferent stimulation in anesthetized rats.

    Science.gov (United States)

    Hotta, H; Uchida, S; Shimura, M; Suzuki, H

    1999-01-15

    The effects of cutaneous mechanical afferent stimulation of various skin areas on uterine contractility and blood flow were examined in anesthetized non-pregnant rats. The contractility of the uterus was measured by the balloon method in the uterus. The uterine blood flow was measured by laser Doppler flowmetry. Noxious pinching stimulation of the perineum for 1 min induced an abrupt contraction of the uterus during stimulation. Pinching of a hindpaw or perineum and innocuous brushing of the perineum for 1 min increased uterine blood flow. Stimulation of other skin areas produced no changes in uterine contractility or blood flow. Most uterine responses were abolished by severance of the pelvic nerves, which innervated the uterus. The activity of pelvic parasympathetic efferent nerves to the uterus increased following perineal pinching. All these cutaneous stimulation-induced responses of uterine contractility, blood flow and pelvic efferent nerve activity still existed, and were even augmented, after acute spinalization. These results indicate that cutaneous mechanical sensory stimulation can regulate uterine contractility and blood flow by a segmental spinal reflex mechanism via uterine parasympathetic efferent nerves.

  17. Study of myogenic spontaneous contractile activities in the detrusor instability rats

    Institute of Scientific and Technical Information of China (English)

    JIANG Hai-hong; WEN Qian-jun; SONG Bo

    2006-01-01

    Objective: To explore a myogenic basis of the spontaneous contractions on the rat bladder smooth muscle strip in a detrusor instability (DI) model in vitro, and to study a nerve blocker's cocktail affecting the spontaneous contractions as well as electrical stimulated contractile response. Methods: DI model rats were made by partial bladder outlet obstruction (BOO) and confirmed by the filling cystometry. Detrusor strip was dissected from fresh bladder, fixed for an isometric tension trial. The contractions were recorded during electrical stimulation or exposure to some agents. Results: The cocktail diminished the nerve-mediated contractile response effectively in DI preparation. DI's spontaneous contractions remained during the presence of the cocktail with a significant change in its contractile amplitude. Conclusion: With the local nerve-concerned factors abolishment by the cocktail, the DI bladder preparations still have the spontaneous contractions, indicating a myogenic basis from themselves.

  18. Contractile Properties of Esophageal Striated Muscle: Comparison with Cardiac and Skeletal Muscles in Rats

    Directory of Open Access Journals (Sweden)

    Takahiko Shiina

    2010-01-01

    Full Text Available The external muscle layer of the mammalian esophagus consists of striated muscles. We investigated the contractile properties of esophageal striated muscle by comparison with those of skeletal and cardiac muscles. Electrical field stimulation with single pulses evoked twitch-like contractile responses in esophageal muscle, similar to those in skeletal muscle in duration and similar to those in cardiac muscle in amplitude. The contractions of esophageal muscle were not affected by an inhibitor of gap junctions. Contractile responses induced by high potassium or caffeine in esophageal muscle were analogous to those in skeletal muscle. High-frequency stimulation induced a transient summation of contractions followed by sustained contractions with amplitudes similar to those of twitch-like contractions, although a large summation was observed in skeletal muscle. The results demonstrate that esophageal muscle has properties similar but not identical to those of skeletal muscle and that some specific properties may be beneficial for esophageal peristalsis.

  19. Emergency airway puncture - slideshow

    Science.gov (United States)

    ... presentations/100113.htm Emergency airway puncture - series—Normal anatomy To ... larynx is a tubular structure in the neck, through which air passes to the lungs. The thryoid and cricoid cartilage form the narrowest ...

  20. Emergency airway puncture

    Science.gov (United States)

    ... inserted into the throat, just below the Adam's apple (cricoid cartilage), into the airway. In a hospital, ... Choking Browse the Encyclopedia A.D.A.M., Inc. is accredited by URAC, also known as the ...

  1. Airway management in trauma.

    Science.gov (United States)

    Langeron, O; Birenbaum, A; Amour, J

    2009-05-01

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

  2. Airway smooth muscle relaxation results from a reduction in the frequency of Ca2+ oscillations induced by a cAMP-mediated inhibition of the IP3 receptor

    Directory of Open Access Journals (Sweden)

    Sanderson Michael J

    2006-02-01

    Full Text Available Abstract Background It has been shown that the contractile state of airway smooth muscle cells (SMCs in response to agonists is determined by the frequency of Ca2+ oscillations occurring within the SMCs. Therefore, we hypothesized that the relaxation of airway SMCs induced by agents that increase cAMP results from the down-regulation or slowing of the frequency of the Ca2+ oscillations. Methods The effects of isoproterenol (ISO, forskolin (FSK and 8-bromo-cAMP on the relaxation and Ca2+ signaling of airway SMCs contracted with methacholine (MCh was investigated in murine lung slices with phase-contrast and laser scanning microscopy. Results All three cAMP-elevating agents simultaneously induced a reduction in the frequency of Ca2+ oscillations within the SMCs and the relaxation of contracted airways. The decrease in the Ca2+ oscillation frequency correlated with the extent of airway relaxation and was concentration-dependent. The mechanism by which cAMP reduced the frequency of the Ca2+ oscillations was investigated. Elevated cAMP did not affect the re-filling rate of the internal Ca2+ stores after emptying by repetitive exposure to 20 mM caffeine. Neither did elevated cAMP limit the Ca2+ available to stimulate contraction because an elevation of intracellular Ca2+ concentration induced by exposure to a Ca2+ ionophore (ionomycin or by photolysis of caged-Ca2+ did not reverse the effect of cAMP. Similar results were obtained with iberiotoxin, a blocker of Ca2+-activated K+ channels, which would be expected to increase Ca2+ influx and contraction. By contrast, the photolysis of caged-IP3 in the presence of agonist, to further elevate the intracellular IP3 concentration, reversed the slowing of the frequency of the Ca2+ oscillations and relaxation of the airway induced by FSK. This result implied that the sensitivity of the IP3R to IP3 was reduced by FSK and this was supported by the reduced ability of IP3 to release Ca2+ in SMCs in the presence of

  3. Synthesis and contractile activity of the C-terminal heptapeptide of substance P with N5-dimethyl glutamine in the 6-position. Active site studies.

    Science.gov (United States)

    Poulos, C P; Pinas, N; Theodoropoulos, D

    1980-09-15

    The synthesis and testing of [N5-dimethyl-Gln6]-SP5-11 showed 37 +/- 12% contractile activity relative to SP, and intrinsic efficacy 98 +/- 4%. This finding indicates that the carboxamide groups of the dual Gln5-Cln6 moiety are not equally related with the contractile response of the C-terminal heptapeptide of SP.

  4. Macrophage adaptation in airway inflammatory resolution

    Directory of Open Access Journals (Sweden)

    Manminder Kaur

    2015-09-01

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

  5. Interaction between endoplasmic/sarcoplasmic reticulum stress (ER/SR stress), mitochondrial signaling and Ca(2+) regulation in airway smooth muscle (ASM).

    Science.gov (United States)

    Delmotte, Philippe; Sieck, Gary C

    2015-02-01

    Airway inflammation is a key aspect of diseases such as asthma. Several inflammatory cytokines (e.g., TNFα and IL-13) increase cytosolic Ca(2+) ([Ca(2+)]cyt) responses to agonist stimulation and Ca(2+) sensitivity of force generation, thereby enhancing airway smooth muscle (ASM) contractility (hyper-reactive state). Inflammation also induces ASM proliferation and remodeling (synthetic state). In normal ASM, the transient elevation of [Ca(2+)]cyt induced by agonists leads to a transient increase in mitochondrial Ca(2+) ([Ca(2+)]mito) that may be important in matching ATP production with ATP consumption. In human ASM (hASM) exposed to TNFα and IL-13, the transient increase in [Ca(2+)]mito is blunted despite enhanced [Ca(2+)]cyt responses. We also found that TNFα and IL-13 induce reactive oxidant species (ROS) formation and endoplasmic/sarcoplasmic reticulum (ER/SR) stress (unfolded protein response) in hASM. ER/SR stress in hASM is associated with disruption of mitochondrial coupling with the ER/SR membrane, which relates to reduced mitofusin 2 (Mfn2) expression. Thus, in hASM it appears that TNFα and IL-13 result in ROS formation leading to ER/SR stress, reduced Mfn2 expression, disruption of mitochondrion-ER/SR coupling, decreased mitochondrial Ca(2+) buffering, mitochondrial fragmentation, and increased cell proliferation.

  6. Myocardial ischemia-reperfusion induces upregulation of contractile endothelin ETB receptor in rat coronary arteries

    DEFF Research Database (Denmark)

    Skovsted, Gry Freja; Sheykhzade, Majid; Trautner, Simon;

    2011-01-01

    ETB receptor upregulation. Methods and Results Thirteen Sprague-Dawley male rats (body weight 260-410 g) were anaesthetized with Hypnorm-Midazolam and subjected to 15 min occlusion of left anterior descending coronary artery (LAD) followed by 22 h of reperfusion. The contractile response...

  7. Stimulation of the cardiopulmonary baroreflex enhances ventricular contractility in awake dogs: a mathematical analysis study.

    Science.gov (United States)

    Sala-Mercado, Javier A; Moslehpour, Mohsen; Hammond, Robert L; Ichinose, Masashi; Chen, Xiaoxiao; Evan, Sell; O'Leary, Donal S; Mukkamala, Ramakrishna

    2014-08-15

    The cardiopulmonary baroreflex responds to an increase in central venous pressure (CVP) by decreasing total peripheral resistance and increasing heart rate (HR) in dogs. However, the direction of ventricular contractility change is not well understood. The aim was to elucidate the cardiopulmonary baroreflex control of ventricular contractility during normal physiological conditions via a mathematical analysis. Spontaneous beat-to-beat fluctuations in maximal ventricular elastance (Emax), which is perhaps the best available index of ventricular contractility, CVP, arterial blood pressure (ABP), and HR were measured from awake dogs at rest before and after β-adrenergic receptor blockade. An autoregressive exogenous input model was employed to jointly identify the three causal transfer functions relating beat-to-beat fluctuations in CVP to Emax (CVP → Emax), which characterizes the cardiopulmonary baroreflex control of ventricular contractility, ABP to Emax, which characterizes the arterial baroreflex control of ventricular contractility, and HR to Emax, which characterizes the force-frequency relation. The CVP → Emax transfer function showed a static gain of 0.037 ± 0.010 ml(-1) (different from zero; P < 0.05) and an overall time constant of 3.2 ± 1.2 s. Hence, Emax would increase and reach steady state in ∼16 s in response to a step increase in CVP, without any change to ABP or HR, due to the cardiopulmonary baroreflex. Following β-adrenergic receptor blockade, the CVP → Emax transfer function showed a static gain of 0.0007 ± 0.0113 ml(-1) (different from control; P < 0.10). Hence, Emax would change little in steady state in response to a step increase in CVP. Stimulation of the cardiopulmonary baroreflex increases ventricular contractility through β-adrenergic receptor system mediation.

  8. Silibinin attenuates allergic airway inflammation in mice

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Yun Ho [Department of Anatomy, Medical School, Institute for Medical Sciences, Chonbuk National University, Jeonju, Jeonbuk 561-756 (Korea, Republic of); Jin, Guang Yu [Department of Radiology, Yanbian University Hospital, YanJi 133002 (China); Guo, Hui Shu [Centralab, The First Affiliated Hospital of Dalian Medical University, Dalian 116011 (China); Piao, Hong Mei [Department of Respiratory Medicine, Yanbian University Hospital, YanJi 133000 (China); Li, Liang chang; Li, Guang Zhao [Department of Anatomy and Histology and Embryology, Yanbian University School of Basic Medical Sciences, 977 Gongyuan Road, YanJi 133002, Jilin (China); Lin, Zhen Hua [Department of Pathology, Yanbian University School of Basic Medical Sciences, YanJi 133000 (China); Yan, Guang Hai, E-mail: ghyan@ybu.edu.cn [Department of Anatomy and Histology and Embryology, Yanbian University School of Basic Medical Sciences, 977 Gongyuan Road, YanJi 133002, Jilin (China)

    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.

  9. Elastomeric contractile actuators for hand rehabilitation splints

    Science.gov (United States)

    Carpi, Federico; Mannini, Andrea; De Rossi, Danilo

    2008-03-01

    The significant electromechanical performances typically shown by dielectric elastomer actuators make this polymer technology particularly attractive for possible active orthoses for rehabilitation. Folded contractile actuators made of dielectric elastomers were recently described as a simple configuration, suitable to easily implement linear contractile devices. This paper describes an application of folded actuators for so-called hand splints: they consist of orthotic systems for hand rehabilitation. The dynamic versions of the state-of-the-art splints typically include elastic bands, which exert a passive elastic resistance to voluntary elongations of one or more fingers. In order to provide such splints with the possibility of electrically modulating the compliance of the resistive elements, the substitution of the passive elastic bands with the contractile actuators is here described. The electrical activation of the actuators is used to vary the compliance of the system; this enables modulations of the force that acts as an antagonist to voluntary finger movements, according to programmable rehabilitation exercises. The paper reports results obtained from the first prototype implementations of such a type of system.

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

    NARCIS (Netherlands)

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

    2014-01-01

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

  11. Airway reconstruction in children

    Directory of Open Access Journals (Sweden)

    Rao Sanjay

    2009-01-01

    Full Text Available Aim/Background : Airway anomalies are infrequent but potentially life threatening in children. A program to care for these difficult children was set up at our institution, and this paper summarizes our experience. Methods: A total of 34 children were enrolled in the program over a period of three years. These children were evaluated as per the standard protocols. Treatment was individualized. Results: Of these 34 children, 28 had their airways restored and are doing well. Four children continue to remain on tracheostomy and two will require long term tracheostomy. There were two deaths. All children are under surveillance as there is a risk of recurrence. Conclusions: Airway anomalies are complex problems with significant morbidity and mortality. Current therapeutic modalities allow for good results. Most children were successfully decannulated and did well.

  12. Deposition of graphene nanomaterial aerosols in human upper airways.

    Science.gov (United States)

    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.

  13. Paediatric airway management: basic aspects

    DEFF Research Database (Denmark)

    Holm-Knudsen, R J; Rasmussen, L S

    2009-01-01

    . Airway obstruction can be avoided by paying close attention to the positioning of the head of the child and by keeping the mouth of the child open during mask ventilation. The use of oral and nasopharyngeal airways, laryngeal mask airways, and cuffed endotracheal tubes is discussed with special reference...... to the circumstances in infants. A slightly different technique during laryngoscopy is suggested. The treatment of airway oedema and laryngospasm is described....

  14. Induction, duration, and resolution of airway goblet cell hyperplasia in a murine model of atopic asthma: effect of concurrent infection with respiratory syncytial virus and response to dexamethasone.

    Science.gov (United States)

    Blyth, D I; Pedrick, M S; Savage, T J; Bright, H; Beesley, J E; Sanjar, S

    1998-07-01

    We recently described a murine model of atopic asthma in which a marked, extensive hyperplasia of airway goblet cells is induced by repeated challenge of ovalbumin (OA)-sensitized mice with intratracheally administered allergen (Am. J. Respir. Cell Mol. Biol. 1996;14:425-438). We report here the time course of the duration of this feature and of its spontaneous resolution in the absence of further allergen exposure. Induction of severe neutrophilic inflammation in the airways by repeated intratracheal administration of lipopolysaccharide failed to induce goblet cell hyperplasia (GCH) to as great a degree as that induced by allergen, suggesting that nonallergic inflammation is a relatively poor inducer of this phenotype change in mice. When a "subclinical" infection of the lungs with the human A2 strain of respiratory syncytial virus was superimposed on the model of atopic asthma, recruitment of monocytes and lymphocytes to the airways was enhanced and a discharge of goblet cell mucin contents was observed. This may partly explain the respiratory difficulty that typifies virally induced exacerbations of asthma in humans. Daily systemic treatment of sensitized mice with dexamethasone during the period of allergen challenge produced a dose-related suppression of developing GCH, while similar treatment during the period following the establishment of extensive hyperplasia induced an accelerated resolution toward a normal epithelial phenotype. These results confirm and extend the relevance of this model as a representation of the human disease.

  15. JunB mediates basal- and TGFβ1-induced smooth muscle cell contractility.

    Directory of Open Access Journals (Sweden)

    Aruna Ramachandran

    Full Text Available Smooth muscle contraction is a dynamic process driven by acto-myosin interactions that are controlled by multiple regulatory proteins. Our studies have shown that members of the AP-1 transcription factor family control discrete behaviors of smooth muscle cells (SMC such as growth, migration and fibrosis. However, the role of AP-1 in regulation of smooth muscle contractility is incompletely understood. In this study we show that the AP-1 family member JunB regulates contractility in visceral SMC by altering actin polymerization and myosin light chain phosphorylation. JunB levels are robustly upregulated downstream of transforming growth factor beta-1 (TGFβ1, a known inducer of SMC contractility. RNAi-mediated silencing of JunB in primary human bladder SMC (pBSMC inhibited cell contractility under both basal and TGFβ1-stimulated conditions, as determined using gel contraction and traction force microscopy assays. JunB knockdown did not alter expression of the contractile proteins α-SMA, calponin or SM22α. However, JunB silencing decreased levels of Rho kinase (ROCK and myosin light chain (MLC20. Moreover, JunB silencing attenuated phosphorylation of the MLC20 regulatory phosphatase subunit MYPT1 and the actin severing protein cofilin. Consistent with these changes, cells in which JunB was knocked down showed a reduction in the F:G actin ratio in response to TGFβ1. Together these findings demonstrate a novel function for JunB in regulating visceral smooth muscle cell contractility through effects on both myosin and the actin cytoskeleton.

  16. Distinct PKA and Epac compartmentalization in airway function and plasticity

    NARCIS (Netherlands)

    Dekkers, Bart G. J.; Racke, Kurt; Schmidt, Martina

    2013-01-01

    Asthma and chronic obstructive pulmonary disease (COPD) are obstructive lung diseases characterized by airway obstruction, airway inflammation and airway remodelling. Next to inflammatory cells and airway epithelial cells, airway mesenchymal cells, including airway smooth muscle cells and (myo)fibro

  17. In vivo models of human airway epithelium repair and regeneration

    Directory of Open Access Journals (Sweden)

    C. Coraux

    2005-12-01

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

  18. Airway management and morbid obesity

    DEFF Research Database (Denmark)

    Kristensen, Michael S

    2010-01-01

    airway and the function of the lungs (decreased residual capacity and aggravated ventilation perfusion mismatch) worse than in lean patients. Proper planning and preparation of airway management is essential, including elevation of the patient's upper body, head and neck. Preoxygenation is mandatory...... solely on whether morbid obesity is present or not. It is important to ensure sufficient depth of anaesthesia before initiating manipulation of the airway because inadequate anaesthesia depth predisposes to aspiration if airway management becomes difficult. The intubating laryngeal mask airway is more...... pressure, noninvasive ventilation and physiotherapy....

  19. Potential of Helper-Dependent Adenoviral Vectors in Modulating Airway Innate Immunity

    Institute of Scientific and Technical Information of China (English)

    Rahul Kushwah; Huibi Cao; Jim Hu

    2007-01-01

    Innate immune responses form the first line of defense against foreign insults and recently significant advances have been made in our understanding of the initiation of innate immune response along with its ability to modulate inflammation. In airway diseases such as asthma, COPD and cystic fibrosis, over reacting of the airway innate immune responses leads to cytokine imbalance and airway remodeling or damage. Helper-dependent adenoviral vectors have the potential to deliver genes to modulate airway innate immune responses and have many advantages over its predecessors. However, there still are a few limitations that need to be addressed prior to their use in clinical applications.

  20. Modeling the dynamics of airway constriction: effects of agonist transport and binding.

    Science.gov (United States)

    Amin, Samir D; Majumdar, Arnab; Frey, Urs; Suki, Béla

    2010-08-01

    Recent advances have revealed that during exogenous airway challenge, airway diameters cannot be adequately predicted by their initial diameters. Furthermore, airway diameters can also vary greatly in time on scales shorter than a breath. To better understand these phenomena, we developed a multiscale model that allowed us to simulate aerosol challenge in the airways during ventilation. The model incorporates agonist-receptor binding kinetics to govern the temporal response of airway smooth muscle contraction on individual airway segments, which, together with airway wall mechanics, determines local airway caliber. Global agonist transport and deposition are coupled with pressure-driven flow, linking local airway constrictions with global flow dynamics. During the course of challenge, airway constriction alters the flow pattern, redistributing the agonist to less constricted regions. This results in a negative feedback that may be a protective property of the normal lung. As a consequence, repetitive challenge can cause spatial constriction patterns to evolve in time, resulting in a loss of predictability of airway diameters. Additionally, the model offers new insights into several phenomena including the intra- and interbreath dynamics of airway constriction throughout the tree structure.

  1. MRTF-A signaling regulates the acquisition of the contractile phenotype in dedifferentiated chondrocytes.

    Science.gov (United States)

    Parreno, Justin; Raju, Sneha; Wu, Po-Han; Kandel, Rita A

    2016-10-14

    Chondrocyte culture as a monolayer for cell number expansion results in dedifferentiation whereby expanded cells acquire contractile features and increased actin polymerization status. This study determined whether the actin polymerization based signaling pathway, myocardin-related transcription factor-a (MRTF-A) is involved in regulating this contractile phenotype. Serial passaging of chondrocytes in monolayer culture to passage 2 resulted in increased gene and protein expression of the contractile molecules alpha-smooth muscle actin, transgelin and vinculin compared to non-passaged, primary cells. This resulted in a functional change as passaged 2, but not primary, chondrocytes were capable of contracting type I collagen gels in a stress-relaxed contraction assay. These changes were associated with increased actin polymerization and MRTF-A nuclear localization. The involvement of actin was demonstrated by latrunculin B depolymerization of actin which reversed these changes. Alternatively cytochalasin D which activates MRTF-A increased gene and protein expression of α-smooth muscle actin, transgelin and vinculin, whereas CCG1423 which deactivates MRTF-A decreased these molecules. The involvement of MRTF-A signaling was confirmed by gene silencing of MRTF or its co-factor serum response factor. Knockdown experiments revealed downregulation of α-smooth muscle actin and transgelin gene and protein expression, and inhibition of gel contraction. These findings demonstrate that passaged chondrocytes acquire a contractile phenotype and that this change is modulated by the actin-MRTF-A-serum response factor signaling pathway.

  2. Studies of membrane fluidity and heart contractile force in Trypanosoma cruzi infected mice

    Directory of Open Access Journals (Sweden)

    Julio E Enders

    2004-11-01

    Full Text Available In Chagas disease serious cardiac dysfunction can appear. We specifically studied the cardiac function by evaluating: ventricle contractile force and norepinephrine response, affinity and density of beta-adrenergic receptors, dynamic properties of myocardial membranes, and electrocardiography. Albino swiss mice (n = 250 were infected with 55 trypomastigotes, Tulahuen strain and studied at 35, 75, and 180 days post-infection, that correspond to the acute, indeterminate, and chronic phase respectively. Cardiac beta-adrenergic receptors' affinity, myocardial contractility, and norepinephrine response progressively decreased from the acute to the chronic phase of the disease (p < 0.01. The density (expressed as fmol/mg.prot of the receptors was similar to non-infected mice (71.96 ± 0.36 in both the acute (78.24 ± 1.67 and indeterminate phases (77.28 ± 0.91, but lower in the chronic disease (53.32 ± 0.71. Electrocardiographic abnormalities began in the acute phase and were found in 65% of the infected-mice during the indeterminate and chronic phases. Membrane contents of triglycerides, cholesterol, and anisotropy were similar in all groups. A quadratic correlation between the affinity to beta-adrenergic receptors and cardiac contractile force was obtained. In conclusion the changes in cardiac beta-adrenergic receptors suggests a correlation between the modified beta-adrenergic receptors affinity and the cardiac contractile force.

  3. Cellular contractility and extracellular matrix stiffness regulate matrix metalloproteinase activity in pancreatic cancer cells.

    Science.gov (United States)

    Haage, Amanda; Schneider, Ian C

    2014-08-01

    The pathogenesis of cancer is often driven by local invasion and metastasis. Recently, mechanical properties of the tumor microenvironment have been identified as potent regulators of invasion and metastasis, while matrix metalloproteinases (MMPs) are classically known as significant enhancers of cancer cell migration and invasion. Here we have been able to sensitively measure MMP activity changes in response to specific extracellular matrix (ECM) environments and cell contractility states. Cells of a pancreatic cancer cell line, Panc-1, up-regulate MMP activities between 3- and 10-fold with increased cell contractility. Conversely, they down-regulate MMP activities when contractility is blocked to levels seen with pan-MMP activity inhibitors. Similar, albeit attenuated, responses are seen in other pancreatic cancer cell lines, BxPC-3 and AsPC-1. In addition, MMP activity was modulated by substrate stiffness, collagen gel concentration, and the degree of collagen cross-linking, when cells were plated on collagen gels ranging from 0.5 to 5 mg/ml that span the physiological range of substrate stiffness (50-2000 Pa). Panc-1 cells showed enhanced MMP activity on stiffer substrates, whereas BxPC-3 and AsPC-1 cells showed diminished MMP activity. In addition, eliminating heparan sulfate proteoglycans using heparinase completely abrogated the mechanical induction of MMP activity. These results demonstrate the first functional link between MMP activity, contractility, and ECM stiffness and provide an explanation as to why stiffer environments result in enhanced cell migration and invasion.

  4. Advances in prehospital airway management.

    Science.gov (United States)

    Jacobs, Pe; Grabinsky, A

    2014-01-01

    Prehospital airway management is a key component of emergency responders and remains an important task of Emergency Medical Service (EMS) systems worldwide. The most advanced airway management techniques involving placement of oropharyngeal airways such as the Laryngeal Mask Airway or endotracheal tube. Endotracheal tube placement success is a common measure of out-of-hospital airway management quality. Regional variation in regard to training, education, and procedural exposure may be the major contributor to the findings in success and patient outcome. In studies demonstrating poor outcomes related to prehospital-attempted endotracheal intubation (ETI), both training and skill level of the provider are usually often low. Research supports a relationship between the number of intubation experiences and ETI success. National standards for certification of emergency medicine provider are in general too low to guarantee good success rate in emergency airway management by paramedics and physicians. Some paramedic training programs require more intense airway training above the national standard and some EMS systems in Europe staff their system with anesthesia providers instead. ETI remains the cornerstone of definitive prehospital airway management, However, ETI is not without risk and outcomes data remains controversial. Many systems may benefit from more input and guidance by the anesthesia department, which have higher volumes of airway management procedures and extensive training and experience not just with training of airway management but also with different airway management techniques and adjuncts.

  5. Regulation of tissue morphodynamics: an important role for actomyosin contractility

    Science.gov (United States)

    Siedlik, Michael J.; Nelson, Celeste M.

    2015-01-01

    Forces arising from contractile actomyosin filaments help shape tissue form during morphogenesis. Developmental events that result from actomyosin contractility include tissue elongation, bending, budding, and collective migration. Here, we highlight recent insights into these morphogenetic processes from the perspective of actomyosin contractility as a key regulator. Emphasis is placed on a range of results obtained through live imaging, culture, and computational methods. Combining these approaches in the future has the potential to generate a robust, quantitative understanding of tissue morphodynamics. PMID:25748251

  6. Permanent Distal Occlusion of Middle Cerebral Artery in Rat Causes Local Increased ETB, 5-HT1B and AT1 Receptor-Mediated Contractility Downstream of Occlusion

    DEFF Research Database (Denmark)

    Rasmussen, Marianne N P; Hornbak, Malene; Larsen, Stine S;

    2013-01-01

    a model of permanent distal occlusion of rat middle cerebral arteries, we investigated whether there was a regional difference in receptor-mediated contractility of segments located upstream and downstream of the occlusion site. The contractile response to endothelin, angiotensin and 5-hydroxytryptamine...... occlusion without significant visible infarct resulted in locally increased ETB, angiotensin type 1 and 5-hydroxytryptamine 1B receptor-mediated contractile responses only in segments located downstream of the occlusion site. This suggests lack of wall stress as an initiating trigger leading to regulation...

  7. Molecular Model of the Contractile Ring

    CERN Document Server

    Biron, D; Tlusty, Tsvi; Moses, Elisha; 10.1103/PhysRevLett.95.098102

    2010-01-01

    We present a model for the actin contractile ring of adherent animal cells. The model suggests that the actin concentration within the ring and consequently the power that the ring exerts both increase during contraction. We demonstrate the crucial role of actin polymerization and depolymerization throughout cytokinesis, and the dominance of viscous dissipation in the dynamics. The physical origin of two phases in cytokinesis dynamics ("biphasic cytokinesis") follows from a limitation on the actin density. The model is consistent with a wide range of measurements of the midzone of dividing animal cells.

  8. Contractile reaction of isolated frog aorta after X-irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Michailov, M.C.; Prechter, I.; Greimel, H.; Welscher, U.E.

    1983-07-01

    The action of X-rays (50 kV, filtered by 0.3 mm Al) on helical strip of frog aorta (rana esculenta) has been investigated. The isolated preparations have a stable basal tone and are radio-sensitive to X-rays which induce reversible, dose-dependent, contractile responses. After repeated irradiational tachyphylaxis appears. The threshold doses are about 250 R at 3 to 6 kR/min, antiadrenergic (phentolamine, propranolol), anticholinergic (atropin), antihistaminic (Neo-Bridal) and serotoninergic (Deseril) drugs have no visible influence on the X-ray induced reaction, i.e. these action mechanisms of the irradiation-induced contraction do not seem probable. Theophylline and cAMP inhibit the X-ray contraction probably non-specifically. Indometacin also inhibits the X-ray contraction: this suggests participation of prostaglandin-mechanism on the contraction of frog aorta after irradiation.

  9. Endogenous laminin is required for human airway smooth muscle cell maturation

    Directory of Open Access Journals (Sweden)

    Tran Thai

    2006-09-01

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

  10. Effect of the Velvet Antler of Formosan Sambar Deer (Cervus unicolor swinhoei on the Prevention of an Allergic Airway Response in Mice

    Directory of Open Access Journals (Sweden)

    Ching-Yun Kuo

    2012-01-01

    Full Text Available Two mouse models were used to assay the antiallergic effects of the velvet antler (VA of Formosan sambar deer (Cervus unicolor swinhoei in this study. The results using the ovalbumin- (OVA- sensitized mouse model showed that the levels of total IgE and OVA-specific IgE were reduced after VA powder was administrated for 4 weeks. In addition, the ex vivo results indicated that the secretion of T helper cell 1 (Th1, regulatory T (Treg, and Th17 cytokines by splenocytes was significantly increased (P<0.05 when VA powder was administered to the mice. Furthermore, OVA-allergic asthma mice that have been orally administrated with VA powder showed a strong inhibition of Th2 cytokine and proinflammatory cytokine production in bronchoalveolar fluid compared to control mice. An increase in the regulatory T-cell population of splenocytes in the allergic asthma mice after oral administration of VA was also observed. All the features of the asthmatic phenotype, including airway inflammation and the development of airway hyperresponsiveness, were reduced by treatment with VA. These findings support the hypothesis that oral feeding of VA may be an effective way of alleviating asthmatic symptoms in humans.

  11. Contractile Dysfunction in Sarcomeric Hypertrophic Cardiomyopathy.

    Science.gov (United States)

    MacIver, David H; Clark, Andrew L

    2016-09-01

    The pathophysiological mechanisms underlying the clinical phenotype of sarcomeric hypertrophic cardiomyopathy are controversial. The development of cardiac hypertrophy in hypertension and aortic stenosis is usually described as a compensatory mechanism that normalizes wall stress. We suggest that an important abnormality in hypertrophic cardiomyopathy is reduced contractile stress (the force per unit area) generated by myocardial tissue secondary to abnormalities such as cardiomyocyte disarray. In turn, a progressive deterioration in contractile stress provokes worsening hypertrophy and disarray. A maintained or even exaggerated ejection fraction is explained by the increased end-diastolic wall thickness producing augmented thickening. We propose that the nature of the hemodynamic load in an individual with hypertrophic cardiomyopathy could determine its phenotype. Hypertensive patients with hypertrophic cardiomyopathy are more likely to develop exaggerated concentric hypertrophy; athletic individuals an asymmetric pattern; and inactive individuals a more apical hypertrophy. The development of a left ventricular outflow tract gradient and mitral regurgitation may be explained by differential regional strain resulting in mitral annular rotation.

  12. Upper airway imaging and its role in preoperative airway evaluation

    Directory of Open Access Journals (Sweden)

    Jagadish G Sutagatti

    2016-01-01

    Full Text Available Ultrasonography (USG is well-known as a fast, safe, and noninvasive technique. Its application for imaging of the airway is now gaining momentum. The upper airway has a complex anatomy, and its assessment forms a vital part of every preanesthetic evaluation. Ultrasound (US imaging can help in upper airway assessment in the preoperative period. There are various approaches to upper airway USG. The technique has its own advantages, disadvantages, and limitations. This simple yet challenging imaging technique is all set to become an important part of routine preoperative airway evaluation. This article reviews the various approaches to upper airway US imaging, interpretation of the images, limitations, and disadvantages of the technique and its varied clinical applications in the preoperative period. The scientific material presented here was hand searched from textbooks and journals, electronically from PubMed, and Google scholar using text words.

  13. Relationship between airway pathophysiology and airway inflammation in older asthmatics

    DEFF Research Database (Denmark)

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

    2013-01-01

    BACKGROUND AND OBJECTIVE: Asthma-related morbidity is greater in older compared with younger asthmatics. Airway closure is also greater in older asthmatics, an observation that may be explained by differences in airway inflammation. We hypothesized that in older adult patients with asthma......: Mean patient age was 67 years (confidence interval: 63-71) with a mean FEV1 of 78 % predicted (confidence interval: 70-85%). AHR correlated with sputum eosinophils (r = 0.68, P = 0.005) and eNO (r = 0.71, P ... or eNO. CONCLUSIONS: In older patients with asthma, airway inflammatory cells are linked to abnormal airway physiology. Eosinophilic airway inflammation is associated with AHR while neutrophilic inflammation may be an important determinant of airflow limitation at rest and airway closure during...

  14. A device for rapid and quantitative measurement of cardiac myocyte contractility

    Science.gov (United States)

    Gaitas, Angelo; Malhotra, Ricky; Li, Tao; Herron, Todd; Jalife, José

    2015-03-01

    Cardiac contractility is the hallmark of cardiac function and is a predictor of healthy or diseased cardiac muscle. Despite advancements over the last two decades, the techniques and tools available to cardiovascular scientists are limited in their utility to accurately and reliably measure the amplitude and frequency of cardiomyocyte contractions. Isometric force measurements in the past have entailed cumbersome attachment of isolated and permeabilized cardiomyocytes to a force transducer followed by measurements of sarcomere lengths under conditions of submaximal and maximal Ca2+ activation. These techniques have the inherent disadvantages of being labor intensive and costly. We have engineered a micro-machined cantilever sensor with an embedded deflection-sensing element that, in preliminary experiments, has demonstrated to reliably measure cardiac cell contractions in real-time. Here, we describe this new bioengineering tool with applicability in the cardiovascular research field to effectively and reliably measure cardiac cell contractility in a quantitative manner. We measured contractility in both primary neonatal rat heart cardiomyocyte monolayers that demonstrated a beat frequency of 3 Hz as well as human embryonic stem cell-derived cardiomyocytes with a contractile frequency of about 1 Hz. We also employed the β-adrenergic agonist isoproterenol (100 nmol l-1) and observed that our cantilever demonstrated high sensitivity in detecting subtle changes in both chronotropic and inotropic responses of monolayers. This report describes the utility of our micro-device in both basic cardiovascular research as well as in small molecule drug discovery to monitor cardiac cell contractions.

  15. In vivo visualization and quantification of collecting lymphatic vessel contractility using near-infrared imaging

    Science.gov (United States)

    Chong, Chloé; Scholkmann, Felix; Bachmann, Samia B.; Luciani, Paola; Leroux, Jean-Christophe; Detmar, Michael; Proulx, Steven T.

    2016-01-01

    Techniques to image lymphatic vessel function in either animal models or in the clinic are limited. In particular, imaging methods that can provide robust outcome measures for collecting lymphatic vessel function are sorely needed. In this study, we aimed to develop a method to visualize and quantify collecting lymphatic vessel function in mice, and to establish an in vivo system for evaluation of contractile agonists and antagonists using near-infrared fluorescence imaging. The flank collecting lymphatic vessel in mice was exposed using a surgical technique and a near-infrared tracer was infused into the inguinal lymph node. Collecting lymphatic vessel contractility and valve function could be easily visualized after the infusion. A diameter tracking method was established and the diameter of the vessel was found to closely correlate to near-infrared fluorescence signal. Phasic contractility measures of frequency and amplitude were established using an automated algorithm. The methods were validated by tracking the vessel response to topical application of a contractile agonist, prostaglandin F2α, and by demonstrating the potential of the technique for non-invasive evaluation of modifiers of lymphatic function. These new methods will enable high-resolution imaging and quantification of collecting lymphatic vessel function in animal models and may have future clinical applications. PMID:26960708

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

    DEFF Research Database (Denmark)

    Bousquet, J; Addis, A; Adcock, I

    2014-01-01

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

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

    Science.gov (United States)

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

    2005-04-01

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

  18. Ultrasound of the airway

    Directory of Open Access Journals (Sweden)

    Pankaj Kundra

    2011-01-01

    Full Text Available Currently, the role of ultrasound (US in anaesthesia-related airway assessment and procedural interventions is encouraging, though it is still ill defined. US can visualise anatomical structures in the supraglottic, glottic and subglottic regions. The floor of the mouth can be visualised by both transcutaneous view of the neck and also by transoral or sublinguial views. However, imaging the epiglottis can be challenging as it is suspended in air. US may detect signs suggestive of difficult intubation, but the data are limited. Other possible applications in airway management include confirmation of correct endotracheal tube placement, prediction of post-extubation stridor, evaluation of soft tissue masses in the neck prior to intubation, assessment of subglottic diameter for determination of paediatric endotracheal tube size and percutaneous dilatational tracheostomy. With development of better probes, high-resolution imaging, real-time picture and clinical experience, US has become the potential first-line noninvasive airway assessment tool in anaesthesia and intensive care practice.

  19. Contractility is the main determinant of coronary systolic flow impediment.

    Science.gov (United States)

    Krams, R; Sipkema, P; Zegers, J; Westerhof, N

    1989-12-01

    We measured the relation between coronary flow amplitude (delta F = Fd-Fs; where d is diastolic and s is systolic) and developed left ventricular pressure (delta PLV = Ps-Pd) at a constant perfusion pressure of 75 mmHg (10 kPa) in the maximally vasodilated blood-perfused isolated cat heart for different steady-state levels of contractility (protocol A) and during transients in contractility (protocol B). Contractility was defined as the slope of the end-systolic pressure-volume relation (Emax). From protocol A it appeared that the coronary flow amplitude was only weakly related to left ventricular pressure at each steady-state level of contractility studied. However, the coronary flow amplitude was strongly related to the different levels of contractility. In protocol B, contractility was changed over a wide range of values (0-100%) but developed pressure and contractility changed simultaneously. Using multiple linear regression analysis, we found that contractility has approximately 10 times (range: 2.8-57.3) stronger effect than left ventricular pressure on coronary flow amplitude (n = 10 experiments). These data and our earlier observations suggest that it is the difference in stiffness of cardiac muscle between systole and diastole that determines coronary flow amplitude.

  20. The airway epithelium is central to the pathogenesis of asthma.

    Science.gov (United States)

    Holgate, Stephen T

    2008-03-01

    Asthma is an inflammatory disorder principally involving the conducting airways and characterised by infiltration of the airway wall with a range of inflammatory cells driven in large part by activation of Th2-type lymphocytes, mast cells and eosinophils. However a key component of asthma is the structural change that involves all of the elements of the airway wall. Here evidence is presented to suggest that the airway epithelium in asthma is fundamentally abnormal with increased susceptibility to environmental injury and impaired repair associated with activation of the epithelial-mesenchymal trophic unit (EMTU). In addition to adopting an activated phenotype, the barrier function of the epithelium is impaired through defective tight junction formation thereby facilitating penetration of potentially toxic or damaging environmental insults. Activated and repairing epithelial cells generate a range of growth factors that are involved in the early life origins of this disease as well as its progression in the form of mucous metaplasia and airway wall remodeling. By placing the epithelium at the forefront of asthma pathogenesis, different approaches to treatment can be devised focused more on protecting vulnerable airways against environmental injury rather than focusing on suppressing airway inflammation or manipulating the immune response.

  1. Non-muscle contractile proteins in the organ of corti

    Energy Technology Data Exchange (ETDEWEB)

    Thalmann, I.; Giometti, C.S.; Thalmann, R. (Washington Univ., St. Louis, MO (USA))

    1985-01-01

    Evidence indicates that an active contractile process exists in the outer hair cells of the mammalian cochlea. Proteins ordinarily associated with muscle contraction have been identified in the outer hair cells by immunohistologic techniques. On this basis a muscle-like mechanism of contraction/relaxation has been postulated by several investigators. The possibility must be considered, however, that the contractile proteins identified thus far in inner ear structures may be nonmuscle rather than muscle forms. In skeletal muscle, actin and myosin are responsible for the physical movement of the muscle fibers, and tropomyosin and troponin are involved in regulating this movement; these four proteins, as well as a variety of proteins involved with the normal cell maintenance functions are all of a muscle-specific type. Non-muscle-like motion also depends upon the interaction of actin with myosin; however, not only are these proteins structurally different from those specific to skeletal muscle but their proportions are also different. We have used two-dimensional polyacrylamide gel electrophoresis to study the proteins in freeze dried preparations of whole organ of Corti from the guinea pig. The identified proteins include non-muscle actin, three forms of non-muscle tropomyosin, alpha- and beta-tubulin, alpha-actinin, and lactate dehydrogenase (LDH B). Myosin heavy and light chains were not detected in the organ of Corti preparation, but the levels of those proteins might be too low to be detected with the protein load used of those proteins might be too low to be detected with the protein load used for this analysis. Although troponin could not be detected, calmodulin was present. All of these findings tend to indicate that the contraction/relaxation processes that have been associated with the organ of Corti by others are of the non-muscle variety.

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

    Science.gov (United States)

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

    2004-06-01

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

  3. Characteristics of deslanoside-induced modulation on jejunal contractility

    Institute of Scientific and Technical Information of China (English)

    Da-Peng Chen; Yong-Jian Xiong; Ze-Yao Tang; Qi-Ying Yao; Dong-Mei Ye; Sha-Sha Liu; Yuan Lin

    2012-01-01

    AIM:TO characterize the dual effects of deslanoside on the contractility of jejunal smooth muscle.METHODS:Eight pairs of different low and high contractile states of isolated jejunal smooth muscle fragment (JSMF) were established.Contractile amplitude of JSMF in different low and high contractile states was selected to determine the effects of deslanoside,and Western blotting analysis was performed to measure the effects of deslanoside on myosin phosphorylation of jejunal smooth muscle.RESULTS:Stimulatory effects on the contractility of JSMF were induced (45.3% ± 4.0% vs 87.0% ± 7.8%,P < 0.01) by deslanoside in 8 low contractile states,and inhibitory effects were induced (180.6% ± 17.8%vs 109.9% ± 10.8%,P < 0.01) on the contractility of JSMF in 8 high contractile states.The effect of deslanoside on the phosphorylation of myosin light chain ofJSMF in low (78.1% ± 4.1% vs 96.0% ± 8.1%,P <0.01) and high contractile state (139.2% ± 8.5% vs 105.5 ± 7.34,P < 0.01) was also bidirectional.Bidirectional regulation (BR) was abolished in the presence of tetrodotoxin.Deslanoside did not affect jejunal contractility pretreated with the Ca2+ channel blocker verapamil or in a Ca2+-free assay condition.The stimulatory effect of deslanoside on JSMF in a low contractile state (low Ca2+ induced) was abolished by atropine.The inhibitory effect of deslanoside on jejunal contractility in a high contractile state (high Ca2+ induced) was blocked by phentolamine,propranolol and L-NG-nitroarginine,respectively.CONCLUSION:Deslanoside-induced BR is Ca2+ dependent and is related to cholinergic and adrenergic systems when JSMF is in low or high contractile states.

  4. Anticholinergic treatment in airways diseases.

    LENUS (Irish Health Repository)

    Flynn, Robert A

    2009-10-01

    The prevalence of chronic airways diseases such as chronic obstructive pulmonary disease and asthma is increasing. They lead to symptoms such as a cough and shortness of breath, partially through bronchoconstriction. Inhaled anticholinergics are one of a number of treatments designed to treat bronchoconstriction in airways disease. Both short-acting and long-acting agents are now available and this review highlights their efficacy and adverse event profile in chronic airways diseases.

  5. Research Upregulation of CD23 (FcεRII Expression in Human Airway Smooth Muscle Cells (huASMC in Response to IL-4, GM-CSF, and IL-4/GM-CSF

    Directory of Open Access Journals (Sweden)

    Lew D Betty

    2005-05-01

    Full Text Available Abstract Background Airway smooth muscle cells play a key role in remodeling that contributes to airway hyperreactivity. Airway smooth muscle remodeling includes hypertrophy and hyperplasia. It has been previously shown that the expression of CD23 on ASMC in rabbits can be induced by the IgE component of the atopic serum. We examined if other components of atopic serum are capable of inducing CD23 expression independent of IgE. Methods Serum starved huASMC were stimulated with either IL-4, GM-CSF, IL-13, IL-5, PGD2, LTD4, tryptase or a combination of IL-4, IL-5, IL-13 each with GM-CSF for a period of 24 h. CD23 expression was analyzed by flow cytometry, western blot, and indirect immunofluorescence. Results The CD23 protein expression was upregulated in huASMC in response to IL-4, GM-CSF, and IL-4/GM-CSF. The percentage of cells with increased fluorescence intensity above the control was 25.1 ± 4.2% (IL-4, 15.6 ± 2.7% (GM-CSF and 32.9 ± 13.9% (IL-4/GMCSF combination(n = 3. The protein content of IL-4/GMCSF stimulated cells was significantly elevated. Expression of CD23 in response to IL-4, GM-CSF, IL-4/GM-CSF was accompanied by changes in cell morphology including depolymerization of isoactin fibers, cell spreading, and membrane ruffling. Western blot revealed abundant expression of the IL-4Rα and a low level expression of IL-2Rγc in huASMC. Stimulation with IL-4 resulted in the phosphorylation of STAT-6 and an increase in the expression of the IL-2Rγc. Conclusion CD23 on huASMC is upregulated by IL-4, GM-CSF, and IL-4/GM-CSF. The expression of CD23 is accompanied by an increase in cell volume and an increase in protein content per cell, suggesting hypertrophy. Upregulation of CD23 by IL-4/GM-CSF results in phenotypic changes in huASMC that could play a role in cell migration or a change in the synthetic function of the cells. Upregulation of CD23 in huASMC by IL-4 and GM-CSF can contribute to changes in huASMC and may provide an avenue

  6. Genome sequence of Haloplasma contractile, an unusual contractile bacterium from a deep-sea anoxic brine lake.

    KAUST Repository

    Antunes, Andre

    2011-09-01

    We present the draft genome of Haloplasma contractile, isolated from a deep-sea brine and representing a new order between Firmicutes and Mollicutes. Its complex morphology with contractile protrusions might be strongly influenced by the presence of seven MreB/Mbl homologs, which appears to be the highest copy number ever reported.

  7. Considerations for Contractile Electroactive Materials and Actuators

    Energy Technology Data Exchange (ETDEWEB)

    Lenore Rasmussen, David Schramm, Paul Rasmussen, Kevin Mullaly, Ras Labs, LLC, Intelligent Materials for Prosthetics & Automation, Lewis D. Meixler, Daniel Pearlman and Alice Kirk

    2011-05-23

    Ras Labs produces contractile electroactive polymer (EAP) based materials and actuators that bend, swell, ripple, and contract (new development) with low electric input. In addition, Ras Labs produces EAP materials that quickly contract and expand, repeatedly, by reversing the polarity of the electric input, which can be cycled. This phenomenon was explored using molecular modeling, followed by experimentation. Applied voltage step functions were also investigated. High voltage steps followed by low voltage steps produced a larger contraction followed by a smaller contraction. Actuator control by simply adjusting the electric input is extremely useful for biomimetic applications. Muscles are able to partially contract. If muscles could only completely contract, nobody could hold an egg, for example, without breaking it. A combination of high and low voltage step functions could produce gross motor function and fine manipulation within the same actuator unit. Plasma treated electrodes with various geometries were investigated as a means of providing for more durable actuation.

  8. Considerations for contractile electroactive materials and actuators

    Science.gov (United States)

    Rasmussen, Lenore; Schramm, David; Rasmussen, Paul; Mullally, Kevin; Meixler, Lewis D.; Pearlman, Daniel; Kirk, Alice

    2011-04-01

    Ras Labs produces contractile electroactive polymer (EAP) based materials and actuators that bend, swell, ripple, and contract (new development) with low electric input. In addition, Ras Labs produces EAP materials that quickly contract and expand, repeatedly, by reversing the polarity of the electric input, which can be cycled. This phenomenon was explored using molecular modeling, followed by experimentation. Applied voltage step functions were also investigated. High voltage steps followed by low voltage steps produced a larger contraction followed by a smaller contraction. Actuator control by simply adjusting the electric input is extremely useful for biomimetic applications. Muscles are able to partially contract. If muscles could only completely contract, nobody could hold an egg, for example, without breaking it. A combination of high and low voltage step functions could produce gross motor function and fine manipulation within the same actuator unit. Plasma treated electrodes with various geometries were investigated as a means of providing for more durable actuation.

  9. Considerations For Contractile Electroactive Materials and Actuators

    Energy Technology Data Exchange (ETDEWEB)

    Lenore Rasmussen, Lewis D. Meixler and Charles A. Gentile

    2012-02-29

    Electroactive polymers (EAPs) that bend, swell, ripple (first generation materials), and now contract with low electric input (new development) have been produced. The mechanism of contraction is not well understood. Radionuclide-labeled experiments, molecular modeling, electrolyte experiments, pH experiments, and an ionic concentration experiment were used to determine the chain of events that occur during contraction and, reciprocally, expansion when the polarity is reversed, in these ionic EAPs. Plasma treatment of the electrodes, along with other strategies, allows for the embedded electrodes and the EAP material of the actuator to work and move as a unit, with no detachment, by significantly improving the metal-polymer interface, analogous to nerves and tendons moving with muscles during movement. Challenges involved with prototyping actuation using contractile EAPs are also discussed.

  10. Cholinergic regulation of airway inflammation and remodelling

    NARCIS (Netherlands)

    Kolahian, Saeed; Gosens, Reinoud

    2012-01-01

    Acetylcholine is the predominant parasympathetic neurotransmitter in the airways that regulates bronchoconstriction and mucus secretion. Recent findings suggest that acetylcholine regulates additional functions in the airways, including inflammation and remodelling during inflammatory airway disease

  11. [Effects of once-daily low-dose administration of sustained-release theophylline on airway inflammation and airway hyperresponsiveness in patients with asthma].

    Science.gov (United States)

    Terao, Ichiro

    2002-04-01

    Bronchial asthma is eosinophilic airway inflammation with enhanced airway responsiveness induced by eosinophilic granule proteins such as eosinophilic cationic protein (ECP) that are released from eosinophils. In the present study using 30 outpatients with mild to moderate asthma who had no history of treatment with steroid inhalation, we examined the effects of 4-week low-dose (200 mg/day) treatment with Uniphyl Tablets, a sustained-release theophylline formulated for once-daily dosing, on airway inflammation and airway hyperresponsiveness, as well as on respiratory function. Uniphyl Tablets significantly (p statistically significant (p V50 also showed statistically significant (p < 0.05) improvement. Mean blood theophylline concentration at the time the improvements were seen was 3.95 mg/mL. These results suggest that low-dose administration of Uniphyl Tablets has anti-airway inflammatory and anti-airway hyperresponsiveness effects in mild to moderate asthmatic patients.

  12. 哮喘豚鼠气道重塑与气道反应性 的图像分析%Image analysis of airway remodeling and responsiveness in asthmatic guinea pig

    Institute of Scientific and Technical Information of China (English)

    章晓初; 姚婉贞; 赵鸣武; 何其华; 陈月

    2001-01-01

    目的研究哮喘豚鼠气道重塑的机制及气道反应性的变化。方法实验分二组:对照组(20只)和哮喘组(20只),取双肺与不同刺激因素作用后作组织切片、HE染色,通过图像分析仪测定支气管内周长、管壁厚度、外周长,并计算平滑肌收缩百分比(PMS)。结果(1)哮喘组支气管壁厚度(WA/Pi)为(10.0±2.0)μm2/μm,支气管壁平滑肌厚度(平滑肌的面积/Pi)为(4.8±1.5)μm2/μm,对照组WA/Pi为(7.9±2.1)μm2/μm,平滑肌的面积/Pi为(3.1±2.0)μm2/μm,两组比较差异均有显著性(P<0.01),支气管壁平滑肌细胞核数量(N/Pi)哮喘组为(0.012 3±0.002 7)个/μm,对照组为(0.010±0.003)个/μm,两组比较差异有显著性(P<0.05)。(2)哮喘组气道平滑肌对腺苷的反应性(以PMS表示)为0.34±0.07,对照组为0.29±0.08,两组比较差异有显著性(P<0.05),联用氨茶碱和腺苷后,哮喘组PMS为0.26±0.07,与单用腺苷组(0.34±0.07)比较差异有显著性(P<0.01)。(3)在Ach作用下哮喘组的PMS为0.24±0.04,对照组为0.19±0.06,两组比较差异有显著性(P<0.05),联用肝素和Ach后,哮喘组PMS为0.20±0.04,与单用Ach组(0.24±0.04)比较差异有显著性(P<0.05)。结论哮喘气道平滑肌增生是气道重塑的主要原因,氨茶碱和肝素可以抑制气道对腺苷和乙酰胆碱的反应性。%Objective To observe the mechanism of airway remodeling and changes of airway responsiveness in guinea pig model of asthma. Methods 40 guinea pigs were randomly divided into two groups: control (20)and asthmatic group (20). After incubating with different stimulus, bilateral lung tissue section were stained with HE. Using image analysis system to measure the airway internal perimeter, wall area, external perimeter, etc. and calculate percentage of muscle shortening (PMS) according to formula

  13. Zinc supplementation alters airway inflammation and airway hyperresponsiveness to a common allergen

    Directory of Open Access Journals (Sweden)

    Morgan Carrie I

    2011-12-01

    Full Text Available Abstract Background Zinc supplementation can modulate immunity through inhibition of NF-κB, a transcription factor that controls many immune response genes. Thus, we sought to examine the mechanism by which zinc supplementation tempers the response to a common allergen and determine its effect on allergic airway inflammation. Methods Mice were injected with zinc gluconate prior to German cockroach (GC feces (frass exposure and airway inflammation was assessed. Primary bone marrow-derived neutrophils and DMSO-differentiated HL-60 cells were used to assess the role of zinc gluconate on tumor necrosis factor (TNFα expression. NF-κB:DNA binding and IKK activity were assessed by EMSA and in vitro kinase assay. Protein levels of A20, RIP1 and TRAF6 were assessed by Western blot analysis. Establishment of allergic airway inflammation with GC frass was followed by administration of zinc gluconate. Airway hyperresponsiveness, serum IgE levels, eosinophilia and Th2 cytokine production were assessed. Results Administration of zinc gluconate prior to allergen exposure resulted in significantly decreased neutrophil infiltration and TNFα cytokine release into the airways. This correlated with decreased NF-κB activity in the whole lung. Treatment with zinc gluconate significantly decreased GC frass-mediated TNFα production from bone-marrow derived neutrophils and HL-60 cells. We confirmed zinc-mediated decreases in NF-κB:DNA binding and IKK activity in HL-60 cells. A20, a natural inhibitor of NF-κB and a zinc-fingered protein, is a potential target of zinc. Zinc treatment did not alter A20 levels in the short term, but resulted in the degradation of RIP1, an important upstream activator of IKK. TRAF6 protein levels were unaffected. To determine the application for zinc as a therapeutic for asthma, we administered zinc following the establishment of allergic airway inflammation in a murine model. Zinc supplementation decreased airway hyperresponsiveness

  14. Inhibitory effects of genistein and resveratrol on guinea pig gallbladder contractility in vitro

    Institute of Scientific and Technical Information of China (English)

    Long-De Wang; Xiao-Qing Qiu; Zhi-Feng Tian; Ying-Fu Zhang; Hong-Fang Li

    2008-01-01

    AIM:To observe and compare the effects of phytoestrogen genistein,resveratrol and 17β-estradiol on the tonic contraction and the phasic contraction of isolated gallbladder muscle strips and to study the underlying mechanisms.METHODS:Isolated strips of gallbladder muscle from guinea pigs were suspended in organ baths containing Kreb's solution,and the contractilities of strips were measured before and after incubation with genistein,resveratrol and 17β-estradiol respectively.RESULTS:Similar to 17β-estradiol,genistein and resveratrol could dose-dependently inhibit the phasic contractile activities,they decreased the mean contractlie amplitude and the contractlie frequencies of gallbladder muscle strips,and also produced a marked reduction in resting tone.The blocker of estrogen receptor ICI 182780 failed to alter the inhibitory effects induced by genistein and resveratrol,but potassium bisperoxo(1,10 phenanthroline)oxovanadate bpV(phen),a potent protein tyrosine phosphatase inhibitor,markedly attenuated the inhibitory effects induced by genistein and resveratrol.In calcium-free Kreb's solution containing 0.01 mmol/L egtazic acid(EGTA),genistein and resveratrol inhibited the first phasic contraction induced by acetylcholine(Ach),but did not affect the second contraction induced by CaCl2.In addition,genistein,resveratrol and 17β-estradiol also could reduce the contractile responses of Ach and KCI,and shift their cumulative concentration-response curves rightward.CONCLUSION:Phytoestrogen genistein and resveratrol can directly inhibit the contractile activity of isolated gallbladder muscle both at rest and in response to stimulation.The mechanisms responsible for the inhibitory effects probably due mainly to inhibition of tyrosine kinase,Ca2+ influx through potential-dependent calcium channels(PDCs)and Ca2+ release from sarcoplasmic reticulum(SR),but were not related to the estrogen receptors.

  15. Altered Epithelial Gene Expression in Peripheral Airways of Severe Asthma

    Science.gov (United States)

    Singhania, Akul; Rupani, Hitasha; Jayasekera, Nivenka; Lumb, Simon; Hales, Paul; Gozzard, Neil; Davies, Donna E.

    2017-01-01

    Management of severe asthma remains a challenge despite treatment with glucocorticosteroid therapy. The majority of studies investigating disease mechanisms in treatment-resistant severe asthma have previously focused on the large central airways, with very few utilizing transcriptomic approaches. The small peripheral airways, which comprise the majority of the airway surface area, remain an unexplored area in severe asthma and were targeted for global epithelial gene expression profiling in this study. Differences between central and peripheral airways were evaluated using transcriptomic analysis (Affymetrix HG U133 plus 2.0 GeneChips) of epithelial brushings obtained from severe asthma patients (N = 17) and healthy volunteers (N = 23). Results were validated in an independent cohort (N = 10) by real-time quantitative PCR. The IL-13 disease signature that is associated with an asthmatic phenotype was upregulated in severe asthmatics compared to healthy controls but was predominantly evident within the peripheral airways, as were genes related to mast cell presence. The gene expression response associated with glucocorticosteroid therapy (i.e. FKBP5) was also upregulated in severe asthmatics compared to healthy controls but, in contrast, was more pronounced in central airways. Moreover, an altered epithelial repair response (e.g. FGFBP1) was evident across both airway sites reflecting a significant aspect of disease in severe asthma unadressed by current therapies. A transcriptomic approach to understand epithelial activation in severe asthma has thus highlighted the need for better-targeted therapy to the peripheral airways in severe asthma, where the IL-13 disease signature persists despite treatment with currently available therapy. PMID:28045928

  16. In vitro drug testing based on contractile activity of C2C12 cells in an epigenetic drug model

    Science.gov (United States)

    Ikeda, Kazushi; Ito, Akira; Imada, Ryusuke; Sato, Masanori; Kawabe, Yoshinori; Kamihira, Masamichi

    2017-01-01

    Skeletal muscle tissue engineering holds great promise for pharmacological studies. Herein, we demonstrated an in vitro drug testing system using tissue-engineered skeletal muscle constructs. In response to epigenetic drugs, myotube differentiation of C2C12 myoblast cells was promoted in two-dimensional cell cultures, but the levels of contractile force generation of tissue-engineered skeletal muscle constructs prepared by three-dimensional cell cultures were not correlated with the levels of myotube differentiation in two-dimensional cell cultures. In contrast, sarcomere formation and contractile activity in two-dimensional cell cultures were highly correlated with contractile force generation of tissue-engineered skeletal muscle constructs. Among the epigenetic drugs tested, trichostatin A significantly improved contractile force generation of tissue-engineered skeletal muscle constructs. Follistatin expression was also enhanced by trichostatin A treatment, suggesting the importance of follistatin in sarcomere formation of muscular tissues. These observations indicate that contractility data are indispensable for in vitro drug screening. PMID:28300163

  17. Fungal colonization with Pneumocystis correlates to increasing chloride channel accessory 1 (hCLCA1 suggesting a pathway for up-regulation of airway mucus responses, in infant lungs

    Directory of Open Access Journals (Sweden)

    Francisco J. Pérez

    2014-01-01

    Full Text Available Fungal colonization with Pneumocystis is associated with increased airway mucus in infants during their primary Pneumocystis infection, and to severity of COPD in adults. The pathogenic mechanisms are under investigation. Interestingly, increased levels of hCLCA1 – a member of the calcium-sensitive chloride conductance family of proteins that drives mucus hypersecretion – have been associated with increased mucus production in patients diagnosed with COPD and in immunocompetent rodents with Pneumocystis infection. Pneumocystis is highly prevalent in infants; therefore, the contribution of Pneumocystis to hCLCA1 expression was examined in autopsied infant lungs. Respiratory viruses that may potentially increase mucus, were also examined. hCLCA1 expression was measured using actin-normalized Western-blot, and the burden of Pneumocystis organisms was quantified by qPCR in 55 autopsied lungs from apparently healthy infants who died in the community. Respiratory viruses were diagnosed using RT-PCR for RSV, metapneumovirus, influenza, and parainfluenza viruses; and by PCR for adenovirus. hCLCA1 levels in virus positive samples were comparable to those in virus-negative samples. An association between Pneumocystis and increased hCLCA1 expression was documented (P=0.028. Additionally, increasing Pneumocystis burden correlated with increasing hCLCA1 protein expression levels (P=0.017. Results strengthen the evidence of Pneumocystis-associated up-regulation of mucus-related airway responses in infant lungs. Further characterization of this immunocompetent host-Pneumocystis-interaction, including assessment of potential clinical significance, is warranted.

  18. Innate immune receptors in human airway smooth muscle cells: activation by TLR1/2, TLR3, TLR4, TLR7 and NOD1 agonists.

    Directory of Open Access Journals (Sweden)

    Anne Månsson Kvarnhammar

    Full Text Available BACKGROUND: Pattern-recognition receptors (PRRs, including Toll-like receptors (TLRs, NOD-like receptors (NLRs and RIG-I-like receptors (RLRs, recognize microbial components and trigger a host defense response. Respiratory tract infections are common causes of asthma exacerbations, suggesting a role for PRRs in this process. The present study aimed to examine the expression and function of PRRs on human airway smooth muscle cells (HASMCs. METHODS: Expression of TLR, NLR and RLR mRNA and proteins was determined using real-time RT-PCR, flow cytometry and immunocytochemistry. The functional responses to ligand stimulation were investigated in terms of cytokine and chemokine release, cell surface marker expression, proliferation and proteins regulating the contractile state. RESULTS: HASMCs expressed functional TLR2, TLR3, TLR4, TLR7 and NOD1. Stimulation with the corresponding agonists Pam3CSK4, poly(I:C, LPS, R-837 and iE-DAP, respectively, induced IL-6, IL-8 and GM-CSF release and up-regulation of ICAM-1 and HLA-DR, while poly(I:C also affected the release of eotaxin and RANTES. The proliferative response was slightly increased by LPS. Stimulation, most prominently with poly(I:C, down-regulated myosin light chain kinase and cysteinyl leukotriene 1 receptor expression and up-regulated β2-adrenoceptor expression. No effects were seen for agonist to TLR2/6, TLR5, TLR8, TLR9, NOD2 or RIG-I/MDA-5. CONCLUSION: Activation of TLR2, TLR3, TLR4, TLR7 and NOD1 favors a synthetic phenotype, characterized by an increased ability to release inflammatory mediators, acquire immunomodulatory properties by recruiting and interacting with other cells, and reduce the contractile state. The PRRs might therefore be of therapeutic use in the management of asthma and infection-induced disease exacerbations.

  19. Airway smooth muscle hyperplasia and hypertrophy correlate with glycogen synthase kinase-3(beta) phosphorylation in a mouse model of asthma.

    Science.gov (United States)

    Bentley, J Kelley; Deng, Huan; Linn, Marisa J; Lei, Jing; Dokshin, Gregoriy A; Fingar, Diane C; Bitar, Khalil N; Henderson, William R; Hershenson, Marc B

    2009-02-01

    Increased airway smooth muscle (ASM) mass, a characteristic finding in asthma, may be caused by hyperplasia or hypertrophy. Cell growth requires increased translation of contractile apparatus mRNA, which is controlled, in part, by glycogen synthase kinase (GSK)-3beta, a constitutively active kinase that inhibits eukaryotic initiation factor-2 activity and binding of methionyl tRNA to the ribosome. Phosphorylation of GSK-3beta inactivates it, enhancing translation. We sought to quantify the contributions of hyperplasia and hypertrophy to increased ASM mass in ovalbumin (OVA)-sensitized and -challenged BALB/c mice and the role of GSK-3beta in this process. Immunofluorescent probes, confocal microscopy, and stereological methods were used to analyze the number and volume of cells expressing alpha-smooth muscle actin and phospho-Ser(9) GSK-3beta (pGSK). OVA treatment caused a 3-fold increase in ASM fractional unit volume or volume density (Vv) (PBS, 0.006 +/- 0.0003; OVA, 0.014 +/- 0.001), a 1.5-fold increase in ASM number per unit volume (Nv), and a 59% increase in volume per cell (Vv/Nv) (PBS, 824 +/- 76 microm(3); OVA, 1,310 +/- 183 mum(3)). In OVA-treated mice, there was a 12-fold increase in the Vv of pGSK (+) ASM, a 5-fold increase in the Nv of pGSK (+) ASM, and a 1.6-fold increase in Vv/Nv. Lung homogenates from OVA-treated mice showed increased GSK-3beta phosphorylation and lower GSK-3beta activity. Both hyperplasia and hypertrophy are responsible for increased ASM mass in OVA-treated mice. Phosphorylation and inactivation of GSK-3beta are associated with ASM hypertrophy, suggesting that this kinase may play a role in asthmatic airway remodeling.

  20. Ferulic Acid Induces Th1 Responses by Modulating the Function of Dendritic Cells and Ameliorates Th2-Mediated Allergic Airway Inflammation in Mice

    Directory of Open Access Journals (Sweden)

    Chen-Chen Lee

    2015-01-01

    Full Text Available This study investigated the immunomodulatory effects of ferulic acid (FA on antigen-presenting dendritic cells (DCs in vitro and its antiallergic effects against ovalbumin- (OVA- induced Th2-mediated allergic asthma in mice. The activation of FA-treated bone marrow-derived DCs by lipopolysaccharide (LPS stimulation induced a high level of interleukin- (IL- 12 but reduced the expression levels of the proinflammatory cytokines IL-1β, IL-6, and tumor necrosis factor- (TNF- α. Compared to control-treated DCs, FA significantly enhanced the expressions of Notch ligand Delta-like 4 (Dll4, MHC class II, and CD40 molecules by these DCs. Furthermore, these FA-treated DCs enhanced T-cell proliferation and Th1 cell polarization. In animal experiments, oral administration of FA reduced the levels of OVA-specific immunoglobulin E (IgE and IgG1 and enhanced IgG2a antibody production in serum. It also ameliorated airway hyperresponsiveness and attenuated eosinophilic pulmonary infiltration in dose-dependent manners. In addition, FA treatment inhibited the production of eotaxin, Th2 cytokines (IL-4, IL-5, and IL-13, and proinflammatory cytokines but promoted the Th1 cytokine interferon- (IFN- γ production in bronchoalveolar lavage fluid (BALF and the culture supernatant of spleen cells. These findings suggest that FA exhibits an antiallergic effect via restoring Th1/Th2 imbalance by modulating DCs function in an asthmatic mouse model.

  1. Compliance Measurements of the Upper Airway in Pediatric Down Syndrome Sleep Apnea Patients.

    Science.gov (United States)

    Subramaniam, Dhananjay Radhakrishnan; Mylavarapu, Goutham; McConnell, Keith; Fleck, Robert J; Shott, Sally R; Amin, Raouf S; Gutmark, Ephraim J

    2016-04-01

    Compliance of soft tissue and muscle supporting the upper airway are two of several factors contributing to pharyngeal airway collapse. We present a novel, minimally invasive method of estimating regional variations in pharyngeal elasticity. Magnetic resonance images for pediatric sleep apnea patients with Down syndrome [9.5 ± 4.3 years (mean age ± standard deviation)] were analyzed to segment airways corresponding to baseline (no mask pressure) and two positive pressures. A three dimensional map was created to evaluate axial and circumferential variation in radial displacements of the airway, dilated by the positive pressures. The displacements were then normalized with respect to the appropriate transmural pressure and radius of an equivalent circle to obtain a measure of airway compliance. The resulting elasticity maps indicated the least and most compliant regions of the pharynx. Airway stiffness of the most compliant region [403 ± 204 (mean ± standard deviation) Pa] decreased with severity of obstructive sleep apnea. The non-linear response of the airway wall to continuous positive airway pressure was patient specific and varied between anatomical locations. We identified two distinct elasticity phenotypes. Patient phenotyping based on airway elasticity can potentially assist clinical practitioners in decision making on the treatments needed to improve airway patency.

  2. The Effect of Cleft Palate Repair on Contractile Properties of Single Permeabilized Muscle Fibers From Congenitally Cleft Goats Palates

    Science.gov (United States)

    A cleft palate goat model was used to study the contractile properties of the levator veli palatini (LVP) muscle which is responsible for the movement of the soft palate. In 15-25% of patients that undergo palatoplasty, residual velopharyngeal insufficiency (VPI) remains a problem and often require...

  3. Alteration in contractile G-protein coupled receptor expression by moist snuff and nicotine in rat cerebral arteries

    DEFF Research Database (Denmark)

    Sandhu, Hardip; Xu, Cang-Bao; Edvinsson, Lars

    2011-01-01

    was kept at plasma level of snus users (25ng nicotine/ml). A high dose (250ng nicotine/ml) was also included due to the previous results showing alteration in the GPCR expression by nicotine at this concentration. Contractile responses to the ET(B) receptor agonist sarafotoxin 6c, 5-HT(1B) receptor agonist...

  4. Pharmacology of Casimiroa edulis; III. Relaxant and contractile effects in rat aortic rings.

    Science.gov (United States)

    Magos, G A; Vidrio, H; Enríquez, R

    1995-06-23

    The relaxant and contractile effects of an aqueous extract of the seeds of the hypotensive plant Casimiroa edulis were investigated in rat aortic rings. The extract inhibited contractions elicited by noradrenaline, serotonin and prostaglandin F2 alpha, but did not affect responses to KCl. Inhibition did not require the presence of intact vascular endothelium and was not affected by histamine antagonists. In this preparation, the extract also elicited concentration-related contractions which were more marked in the absence of endothelium, were not blocked by histamine antagonists, and were completely suppressed by alpha-adrenergic blockade. It was concluded that the relaxant effect of the extract is not exerted through release of an endothelial relaxing factor nor through blockade of calcium channels or of specific smooth muscle receptors, and does not involve histaminergic mechanisms. The contractile effect is modulated by vascular endothelium and is alpha-adrenergic in nature.

  5. Arginine vasopressin, via activation of post-junctional V1 receptors, induces contractile effects in mouse distal colon.

    Science.gov (United States)

    Mastropaolo, Mariangela; Zizzo, Maria Grazia; Auteri, Michelangelo; Mulè, Flavia; Serio, Rosa

    2013-11-10

    The aim of this study was to analyze whether arginine vasopressin (AVP) may be considered a modulator of intestinal motility. In this view, we evaluated, in vitro, the effects induced by exogenous administration of AVP on the contractility of mouse distal colon, the subtype(s) of receptor(s) activated and the action mechanism. Isometric recordings were performed on longitudinal and circular muscle strips of mouse distal colon. AVP (0.001 nM-100 nM) caused concentration-dependent contractile effects only on the longitudinal muscle, antagonized by the V1 receptor antagonist, V-1880. AVP-induced effect was not modified by tetrodotoxin, atropine and indomethacin. Contractile response to AVP was reduced in Ca(2+)-free solution or in the presence of nifedipine, and it was abolished by depletion of calcium intracellular stores after repetitive addition of carbachol in calcium-free medium with addition of cyclopiazonic acid. U-73122, an inhibitor of the phospholipase C, effectively antagonized AVP effects, whilst it was not affected by an adenylyl cyclase inhibitor. Oxytocin induced an excitatory effect in the longitudinal muscle of distal colon at very high concentrations, effect antagonized by V-1880. The results of this study shown that AVP, via activation of V1 receptors, is able to modulate positively contractile activity of longitudinal muscle of mouse distal colon, independently by enteric nerve activation and prostaglandin synthesis. Contractile response is achieved by increase in cytoplasmatic Ca(2+) concentration via extracellular Ca(2+) influx from L-type Ca(2+) channels and via Ca(2+) release from intracellular stores through phospholipase C pathway. No modulation has been observed on the contractility of the circular muscle.

  6. Considerations for Contractile Electroactive Materials and Actuators

    Energy Technology Data Exchange (ETDEWEB)

    Rasmussen, Lenore; Erickson, Carl J.; Meixler, Lewis D.; Ascione, George; Gentile, Charles A.; Tilson, Carl; Bernasek, Stephen L.; Abelev, Esta

    2010-02-19

    Ras Labs produces electroactive polymer (EAP) based materials and actuators that bend, swell, ripple and now contract (new development) with low electric input. This is an important attribute because of the ability of contraction to produce life-like motion. The mechanism of contraction is not well understood. Radionuclide-labeled experiments were conducted to follow the movement of electrolytes and water in these EAPs when activated. Extreme temperature experiments were performed on the contractile EAPs with very favorable results. One of the biggest challenges in developing these actuators, however, is the electrode-EAP interface because of the pronounced movement of the EAP. Plasma treatments of metallic electrodes were investigated in order to improve the attachment of the embedded electrodes to the EAP material. Surface analysis, adhesive testing, and mechanical testing were conducted to test metal surfaces and metal-polymer interfaces. The nitrogen plasma treatment of titanium produced a strong metal-polymer interface; however, oxygen plasma treatment of both stainless steel and titanium produced even stronger metal-polymer interfaces. Plasma treatment of the electrodes allows for the embedded electrodes and the EAP material of the actuator to work and move as a unit, with no detachment, by significantly improving the metal-polymer interface.

  7. Geometrical Origins of Contractility in Disordered Actomyosin Networks

    Science.gov (United States)

    Lenz, Martin

    2014-10-01

    Movement within eukaryotic cells largely originates from localized forces exerted by myosin motors on scaffolds of actin filaments. Although individual motors locally exert both contractile and extensile forces, large actomyosin structures at the cellular scale are overwhelmingly contractile, suggesting that the scaffold serves to favor contraction over extension. While this mechanism is well understood in highly organized striated muscle, its origin in disordered networks such as the cell cortex is unknown. Here, we develop a mathematical model of the actin scaffold's local two- or three-dimensional mechanics and identify four competing contraction mechanisms. We predict that one mechanism dominates, whereby local deformations of the actin break the balance between contraction and extension. In this mechanism, contractile forces result mostly from motors plucking the filaments transversely rather than buckling them longitudinally. These findings shed light on recent in vitro experiments and provide a new geometrical understanding of contractility in the myriad of disordered actomyosin systems found in vivo.

  8. Influence of the cardiac myosin hinge region on contractile activity.

    OpenAIRE

    Margossian, S S; Krueger, J W; Sellers, J R; Cuda, G; Caulfield, J B; Norton, P.; Slayter, H. S.

    1991-01-01

    The participation of cardiac myosin hinge in contractility was investigated by in vitro motility and ATPase assays and by measurements of sarcomere shortening. The effect on contractile activity was analyzed using an antibody directed against a 20-amino acid peptide within the hinge region of myosin. This antibody bound specifically at the hinge at a distance of 55 nm from the S1/S2 junction, was specific to human, dog, and rat cardiac myosins, did not crossreact with gizzard or skeletal myos...

  9. Remodeling of Afferent Arterioles From Mice With Oxidative Stress Does Not Account for Increased Contractility but Does Limit Excessive Wall Stress.

    Science.gov (United States)

    Li, Lingli; Feng, Di; Luo, Zaiming; Welch, William J; Wilcox, Christopher S; Lai, En Yin

    2015-09-01

    Because superoxide dismutase (SOD) knockout enhances arteriolar remodeling and contractility, we hypothesized that remodeling enhances contractility. In the isolated and perfused renal afferent arterioles from SOD wild type (+/+) and gene-deleted mice, contractility was assessed from reductions in luminal diameter with perfusion pressure from 40 to 80 mm Hg (myogenic responses) or angiotensin II (10(-6) mol/L), remodeling from media:lumen area ratio, superoxide (O2 (·-)) and hydrogen peroxide (H2O2) from fluorescence microscopy, and wall stress from wall tension/wall thickness. Compared with +/+ strains, arterioles from SOD1-/-, SOD2+/-, and SOD3-/- mice developed significantly (Premodeling. Although remodeling does not enhance contractility, it does prevent the potentially damaging effects of increased wall stress.

  10. Exposure to a Low Lead Concentration Impairs Contractile Machinery in Rat Cardiac Muscle.

    Science.gov (United States)

    Silva, Marito A S C; de Oliveira, Thiago F; Almenara, Camila C P; Broseghini-Filho, Gilson B; Vassallo, Dalton V; Padilha, Alessandra S; Silveira, Edna A

    2015-10-01

    Lead exposure has been considered to be a risk factor for hypertension and cardiovascular disease. Our purpose was to evaluate the effects of low plasma lead concentration on cardiac contractility in isolated papillary muscles. Wistar rats were divided in control group or group treated with 100 ppm of lead acetate in the drinking water for 15 days. Blood pressure (BP) was measured weekly. At the end of the treatment period, the animals were anesthetized and euthanized, and parameters related to isolated papillary muscle contractility were recorded. The lead concentrations in the blood reached 12.3 ± 2 μg/dL. The BP was increased in the group treated with 100 ppm of lead acetate. Lead treatment did not alter force and time derivatives of the force of left ventricular papillary muscles. In addition, the inotropic response induced by an increase in the extracellular Ca(2+) concentration was reduced in the Pb(2+) group. However, the uptake of Ca(2+) by the sarcoplasmic reticulum and the protein expression of SERCA and phospholamban remained unchanged. Postrest contraction was similar in the both groups, and tetanic peak and plateau tension were reduced in lead group. These results demonstrated that the reduction in the inotropic response to calcium does not appear to be caused by changes in the trans-sarcolemmal calcium flux but suggest that an impairment of the contractile machinery might be taking place. Our results demonstrate that even at a concentration below the limit considered to be safe, lead exerts deleterious effects on the cardiac contractile machinery.

  11. Vessel-guided Airway Tree Segmentation

    DEFF Research Database (Denmark)

    Lo, P.; Sporring, J.; Ashraf, H.;

    2010-01-01

    This paper presents a method for airway tree segmentation that uses a combination of a trained airway appearance model, vessel and airway orientation information, and region growing. We propose a voxel classification approach for the appearance model, which uses a classifier that is trained...... to differentiate between airway and non-airway voxels. This is in contrast to previous works that use either intensity alone or hand crafted models of airway appearance. We show that the appearance model can be trained with a set of easily acquired, incomplete, airway tree segmentations. A vessel orientation...

  12. Caveolin-1 regulates contractility in differentiated vascular smooth muscle.

    Science.gov (United States)

    Je, Hyun-Dong; Gallant, Cynthia; Leavis, Paul C; Morgan, Kathleen G

    2004-01-01

    Caveolin is a principal component of caveolar membranes. In the present study, we utilized a decoy peptide approach to define the degree of involvement of caveolin in PKC-dependent regulation of contractility of differentiated vascular smooth muscle. The primary isoform of caveolin in ferret aorta vascular smooth muscle is caveolin-1. Chemical loading of contractile vascular smooth muscle tissue with a synthetic caveolin-1 scaffolding domain peptide inhibited PKC-dependent increases in contractility induced by a phorbol ester or an alpha agonist. Peptide loading also resulted in a significant inhibition of phorbol ester-induced adducin Ser662 phosphorylation, an intracellular monitor of PKC kinase activity, ERK1/2 activation, and Ser789 phosphorylation of the actin binding protein caldesmon. alpha-Agonist-induced ERK1-1/2 activation was also inhibited by the caveolin-1 peptide. Scrambled peptide-loaded tissues or sham-loaded tissues were unaffected with respect to both contractility and signaling. Depolarization-induced activation of contraction was not affected by caveolin peptide loading. Similar results with respect to contractility and ERK1/2 activation during exposure to the phorbol ester or the alpha-agonist were obtained with the cholesterol-depleting agent methyl-beta-cyclodextrin. These results are consistent with a role for caveolin-1 in the coordination of signaling leading to the regulation of contractility of smooth muscle.

  13. Airway complications after lung transplantation.

    Science.gov (United States)

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

    2015-01-01

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

  14. Potential role of the airway wall in the asthma of obesity.

    Science.gov (United States)

    Bates, Jason H T; Dixon, Anne E

    2015-01-01

    The pathogenesis of late-onset TH2-low asthma in obesity is thought to be related to weight-related decreases in lung volume, but why only a subset of individuals with obesity develop this condition is unknown. We tested the hypothesis that natural variations in both airway wall stiffness and airway wall thickness could lead to a subpopulation of hyperresponsive individuals exhibiting the symptoms of asthma in the setting of obesity. Increases in airway resistance (Raw) after airway smooth muscle stimulation were simulated using a computational model of an elastic airway embedded in elastic parenchyma. Using a range of randomly chosen values for both airway wall stiffness and thickness, we determined the resulting probability distributions of Raw responsiveness for a variety of different levels of transpulmonary pressure (Ptp). As Ptp decreased from 5 to 1 cmH2O, the resulting distributions of Raw moved toward progressively higher levels of responsiveness. With appropriate choices for the mean and standard deviation of the parameter that controls either airway wall stiffness or thickness, the model predicts a relationship between airway hyperresponsiveness and body mass index that is similar to that which has been reported in populations with obesity. We conclude that natural variations in airway wall mechanics and geometry between different individuals can potentially explain why an increasing percentage of the population exhibits the symptoms of asthma as the obesity of the population increases.

  15. Airway vascular reactivity and vascularisation in human chronic airway disease

    NARCIS (Netherlands)

    Bailey, Simon R; Boustany, Sarah; Burgess, Janette K; Hirst, Stuart J; Sharma, Hari S; Simcock, David E; Suravaram, Padmini R; Weckmann, Markus

    2009-01-01

    Altered bronchial vascular reactivity and remodelling including angiogenesis are documented features of asthma and other chronic inflammatory airway diseases. Expansion of the bronchial vasculature under these conditions involves both functional (vasodilation, hyperperfusion, increased microvascular

  16. Further identification of bioactive peptides in the anterior byssus retractor muscle of Mytilus: two contractile and three inhibitory peptides.

    Science.gov (United States)

    Fujisawa, Y; Takahashi, T; Ikeda, T; Muneoka, Y; Kubota, I; Minakata, H; Nomoto, K; Nose, T; Miki, W

    1993-09-01

    1. Two contractile and three inhibitory peptides were newly isolated from the anterior byssus retractor muscles (ABRMs) of the bivalve mollusc Mytilus edulis by using the muscle as the bioassay system. 2. The structures of the two contractile peptides were GPFGTHIKamide (GPFG-8) and GPFGLNKHGamide (GPFG-9). The contractile response of the ABRM to the first-time application of GPFG-8 or GPFG-9 was of considerable size. The threshold concentrations of the peptides were around 10(-9) M. However, the contractile response to the second-time application was far smaller than that to the first-time application in both cases. Namely, the muscle showed tachyphylaxis to the peptides. 3. Two of the three inhibitory peptides were members of the Mytilus-inhibitory-peptide (MIP) family. Their structures were RAPLFIamide (MIP6) and RSPMFVamide (MIP7). The peptides, as well as the other MIPs previously identified, showed a potent inhibitory effect on phasic contraction of the ABRM in response to repetitive electrical stimulation. The remaining one was an MIP-related peptide (MIP-RP) having the sequence of MRYFVamide. The MIP-RP was less potent than the two MIPs in inhibiting the contraction of the ABRM.

  17. Airway Epithelium Stimulates Smooth Muscle Proliferation

    OpenAIRE

    Malavia, Nikita K.; Raub, Christopher B.; Mahon, Sari B.; Brenner, Matthew; Reynold A Panettieri; George, Steven C.

    2009-01-01

    Communication between the airway epithelium and stroma is evident during embryogenesis, and both epithelial shedding and increased smooth muscle proliferation are features of airway remodeling. Hence, we hypothesized that after injury the airway epithelium could modulate airway smooth muscle proliferation. Fully differentiated primary normal human bronchial epithelial (NHBE) cells at an air–liquid interface were co-cultured with serum-deprived normal primary human airway smooth muscle cells (...

  18. Comparative study of heart rate responses to laryngoscopic endotracheal intubation and to endotracheal intubation using intubating laryngeal mask airway under general anaesthesia in patients with pure mitral stenosis for closed mitral commissurotomy.

    Science.gov (United States)

    Das, Soumi; Gupta, Sampa Dutta; Goswampi, Anupam; Kundu, Kanak Kanti

    2013-04-01

    The various drugs and methods studied in an attempt to curb the haemodynamic stress response associated with conventional laryngoscopic endotracheal intubation have not been found to be ompletely satisfactory. The rise in heart rate can be detrimental to patients with mitral stenosis. This study was aimed to compare the heart rate responses to endotracheal intubation using conventional laryngoscope and with the help of intubating laryngeal mask airway (ILMA) in patients with isolated mitral stenosis. Thirty-four adult patients of either sex, aged between 18 and 40 years with isolated mitral stenosis to undergo closed mitral commissurotomy were randomly allocated into two groups : Group A (n=17)- To be intubated using laryngoscopy. Group B (n=17)- To be intubated with the help of ILMA. The heart rate was recorded immediately preinduction, just prior to introducing the intubating device and postintubation every minute up to first 5 minutes. On applying statistical tests, it was found that the median heart rate values in group A at 2, 3, 4 and 5 minutes postintubation were significantly higher than in group B (pendotracheal intubation was associated with rise in heart rate, the rise was less with ILMA compared to laryngoscope. Hence, it can be concluded that use of ILMA may be a preferable device for endotracheal intubation laryngoscopy in patients with isolated mitral stenosis.

  19. Contractile force measured in unskinned isolated adult rat heart fibres.

    Science.gov (United States)

    Brady, A J; Tan, S T; Ricchiuti, N V

    1979-12-13

    A number of investigators have succeeded in preparing isolated cardiac cells by enzymatic digestion which tolerate external [Ca2+] in the millimolar range. However, a persistent problem with these preparations is that, unlike in situ adult ventricular fibres, the isolated fibres usually beat spontaneously. This spontaneity suggests persistent ionic leakage not present in situ. A preferable preparation for mechanical and electrical studies would be one which is quiescent but excitable in response to electrical stimulation and which does not undergo contracture with repeated stimulation. We report here a modified method of cardiac fibre isolation and perfusion which leaves the fibre membrane electrically excitable and moderately resistant to mechanical stress so that the attachment of suction micropipettes to the fibre is possible for force measurement and length control. Force generation in single isolated adult rat heart fibres is consistent with in situ contractile force. The negative staircase effect (treppe) characteristic of adult not heart tissue is present with increased frequency of stimulation. Isometric developed tension increases with fibre length as in in situ ventricular tissue.

  20. Effects of Gestational and Postnatal Exposure to Chronic Intermittent Hypoxia on Diaphragm Muscle Contractile Function in the Rat

    Science.gov (United States)

    McDonald, Fiona B.; Dempsey, Eugene M.; O'Halloran, Ken D.

    2016-01-01

    Alterations to the supply of oxygen during early life presents a profound stressor to physiological systems with aberrant remodeling that is often long-lasting. Chronic intermittent hypoxia (CIH) is a feature of apnea of prematurity, chronic lung disease, and sleep apnea. CIH affects respiratory control but there is a dearth of information concerning the effects of CIH on respiratory muscles, including the diaphragm—the major pump muscle of breathing. We investigated the effects of exposure to gestational CIH (gCIH) and postnatal CIH (pCIH) on diaphragm muscle function in male and female rats. CIH consisted of exposure in environmental chambers to 90 s of hypoxia reaching 5% O2 at nadir, once every 5 min, 8 h a day. Exposure to gCIH started within 24 h of identification of a copulation plug and continued until day 20 of gestation; animals were studied on postnatal day 22 or 42. For pCIH, pups were born in normoxia and within 24 h of delivery were exposed with dams to CIH for 3 weeks; animals were studied on postnatal day 22 or 42. Sham groups were exposed to normoxia in parallel. Following gas exposures, diaphragm muscle contractile, and endurance properties were examined ex vivo. Neither gCIH nor pCIH exposure had effects on diaphragm muscle force-generating capacity or endurance in either sex. Similarly, early life exposure to CIH did not affect muscle tolerance of severe hypoxic stress determined ex vivo. The findings contrast with our recent observation of upper airway dilator muscle weakness following exposure to pCIH. Thus, the present study suggests a relative resilience to hypoxic stress in diaphragm muscle. Co-ordinated activity of thoracic pump and upper airway dilator muscles is required for optimal control of upper airway caliber. A mismatch in the force-generating capacity of the complementary muscle groups could have adverse consequences for the control of airway patency and respiratory homeostasis. PMID:27462274

  1. CORRELATES BETWEEN HUMAN LUNG INJURY AFTER PARTICLE EXPOSURE AND RECURRENT AIRWAY OBSTRUCTION IN THE HORSE

    Science.gov (United States)

    Characteristics of the clinical presentation, physiologic changes, and pathology of the human response to particulate matter (PM) are comparable to inflammatory airway disease (lAD) and recurrent airway obstruction (RAO)lheaves in the horse. Both present with symptoms of cough,...

  2. Effects of a mandibular advancement device on the upper airway morphology : a cephalometric analysis

    NARCIS (Netherlands)

    Doff, M. H. J.; Hoekema, A.; Pruim, G. J.; van der Hoeven, J. H.; de Bont, L. G. M.; Stegenga, B.

    2009-01-01

    The aims of this study were to assess changes in the upper airway morphology associated with an oral appliance in situ in patients suffering from the obstructive sleep apnoea-hypopnoea syndrome and to relate these changes to treatment response. Changes in upper airway morphology as a result of an or

  3. Airway management and morbid obesity

    DEFF Research Database (Denmark)

    Kristensen, Michael S

    2010-01-01

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

  4. New insights into the relationship between airway inflammation and asthma.

    Science.gov (United States)

    Wardlaw, A J; Brightling, C E; Green, R; Woltmann, G; Bradding, P; Pavord, I D

    2002-08-01

    Asthma is a condition characterized by variable airflow obstruction, airway hyper-responsiveness (AHR) and airway inflammation which is usually, but not invariably, eosinophilic. Current thoughts on the pathogenesis of asthma are focused on the idea that it is caused by an inappropriate response of the specific immune system to harmless antigens, particularly allergens such as cat dander and house dust mite, that result in Th2-mediated chronic inflammation. However, the relationship between inflammation and asthma is complex, with no good correlation between the severity of inflammation, at least as measured by the number of eosinophils, and the severity of asthma. In addition, there are a number of conditions, such as eosinophilic bronchitis and allergic rhinitis, in which there is a Th2-mediated inflammatory response, but no asthma, as measured by variable airflow obstruction or AHR. Bronchoconstriction can also occur without obvious airway inflammation, and neutrophilic inflammation can in some cases be associated with asthma. When we compared the immunopathology of eosinophilic bronchitis and asthma, the only difference we observed was that, in asthma, the airway smooth muscle (ASM) was infiltrated by mast cells, suggesting that airway obstruction and AHR are due to an ASM mast cell myositis. This observation emphasizes that the features that characterize asthma, as opposed to bronchitis, are due to abnormalities in smooth muscle responsiveness, which could be intrinsic or acquired, and that inflammation is only relevant in that it leads to these abnormalities. It also emphasizes the importance of micro-localization as an organizing principle in physiological responses to airway inflammation. Thus, if inflammation is localized to the epithelium and lamina propria, then the symptoms of bronchitis (cough and mucus hypersecretion) result, and it is only if the ASM is involved -- for reasons that remain to be established -- that asthma occurs.

  5. A new removable airway stent

    Directory of Open Access Journals (Sweden)

    Tore Amundsen

    2016-09-01

    Full Text Available 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.

  6. Microtubule depolymerization normalizes in vivo myocardial contractile function in dogs with pressure-overload left ventricular hypertrophy

    Science.gov (United States)

    Koide, M.; Hamawaki, M.; Narishige, T.; Sato, H.; Nemoto, S.; DeFreyte, G.; Zile, M. R.; Cooper G, I. V.; Carabello, B. A.

    2000-01-01

    BACKGROUND: Because initially compensatory myocardial hypertrophy in response to pressure overloading may eventually decompensate to myocardial failure, mechanisms responsible for this transition have long been sought. One such mechanism established in vitro is densification of the cellular microtubule network, which imposes a viscous load that inhibits cardiocyte contraction. METHODS AND RESULTS: In the present study, we extended this in vitro finding to the in vivo level and tested the hypothesis that this cytoskeletal abnormality is important in the in vivo contractile dysfunction that occurs in experimental aortic stenosis in the adult dog. In 8 dogs in which gradual stenosis of the ascending aorta had caused severe left ventricular (LV) pressure overloading (gradient, 152+/-16 mm Hg) with contractile dysfunction, LV function was measured at baseline and 1 hour after the intravenous administration of colchicine. Cardiocytes obtained by biopsy before and after in vivo colchicine administration were examined in tandem. Microtubule depolymerization restored LV contractile function both in vivo and in vitro. CONCLUSIONS: These and additional corroborative data show that increased cardiocyte microtubule network density is an important mechanism for the ventricular contractile dysfunction that develops in large mammals with adult-onset pressure-overload-induced cardiac hypertrophy.

  7. Viral bronchiolitis in young rats causes small airway lesions that correlate with reduced lung function.

    Science.gov (United States)

    Sorkness, Ronald L; Szakaly, Renee J; Rosenthal, Louis A; Sullivan, Ruth; Gern, James E; Lemanske, Robert F; Sun, Xin

    2013-11-01

    Viral illness with wheezing during infancy is associated with the inception of childhood asthma. Small airway dysfunction is a component of childhood asthma, but little is known about how viral illness at an early age may affect the structure and function of small airways. We used a well-characterized rat model of postbronchiolitis chronic airway dysfunction to address how postinfectious small airway lesions affect airway physiological function and if the structure/function correlates persist into maturity. Brown Norway rats were sham- or virus inoculated at 3 to 4 weeks of age and allowed to recover from the acute illness. At 3 to 14 months of age, physiology (respiratory system resistance, Newtonian resistance, tissue damping, and static lung volumes) was assessed in anesthetized, intubated rats. Serial lung sections revealed lesions in the terminal bronchioles that reduced luminal area and interrupted further branching, affecting 26% (range, 13-39%) of the small airways at 3 months of age and 22% (range, 6-40%) at 12 to 14 months of age. At 3 months of age (n = 29 virus; n = 7 sham), small airway lesions correlated with tissue damping (rs = 0.69) but not with Newtonian resistance (rs = 0.23), and Newtonian resistance was not elevated compared with control rats, indicating that distal airways were primarily responsible for the airflow obstruction. Older rats (n = 7 virus; n = 6 sham) had persistent small airway dysfunction and significantly increased Newtonian resistance in the postbronchiolitis group. We conclude that viral airway injury at an early age may induce small airway lesions that are associated quantitatively with small airway physiological dysfunction early on and that these defects persist into maturity.

  8. Using optical coherence tomography (OCT) imaging in the evaluation of airway dynamics (Conference Presentation)

    Science.gov (United States)

    Szabari, Margit V.; Kelly, Vanessa J.; Applegate, Matthew B.; Chee, Chunmin; Tan, Khay M.; Hariri, Lida P.; Harris, R. Scott; Winkler, Tilo; Suter, Melissa J.

    2016-03-01

    Asthma is a chronic disease resulting in periodic attacks of coughing and wheezing due to temporarily constricted and clogged airways. The pathophysiology of asthma and the process of airway narrowing are not completely understood. Appropriate in vivo imaging modality with sufficient spatial and temporal resolution to dynamically assess the behavior of airways is missing. Optical coherence tomography (OCT) enables real-time evaluation of the airways during dynamic and static breathing maneuvers. Our aim was to visualize the structure and function of airways in healthy and Methacholine (MCh) challenged lung. Sheep (n=3) were anesthetized, mechanically ventilated and imaged with OCT in 4 dependent and 4 independent airways both pre- and post-MCh administration. The OCT system employed a 2.4 Fr (0.8 mm diameter) catheter and acquired circumferential cross-sectional images in excess of 100 frames per second during dynamic tidal breathing, 20 second static breath-holds at end-inspiration and expiration pressure, and in a response to a single deep inhalation. Markedly different airway behavior was found in dependent versus non-dependent airway segments before and after MCh injection. OCT is a non-ionizing light-based imaging modality, which may provide valuable insight into the complex dynamic behavior of airway structure and function in the normal and asthmatic lung.

  9. The importance of synergy between deep inspirations and fluidization in reversing airway closure.

    Science.gov (United States)

    Donovan, Graham M; Sneyd, James; Tawhai, Merryn H

    2012-01-01

    Deep inspirations (DIs) and airway smooth muscle fluidization are two widely studied phenomena in asthma research, particularly for their ability (or inability) to counteract severe airway constriction. For example, DIs have been shown effectively to reverse airway constriction in normal subjects, but this is impaired in asthmatics. Fluidization is a connected phenomenon, wherein the ability of airway smooth muscle (ASM, which surrounds and constricts the airways) to exert force is decreased by applied strain. A maneuver which sufficiently strains the ASM, then, such as a DI, is thought to reduce the force generating capacity of the muscle via fluidization and hence reverse or prevent airway constriction. Understanding these two phenomena is considered key to understanding the pathophysiology of asthma and airway hyper-responsiveness, and while both have been extensively studied, the mechanism by which DIs fail in asthmatics remains elusive. Here we show for the first time the synergistic interaction between DIs and fluidization which allows the combination to provide near complete reversal of airway closure where neither is effective alone. This relies not just on the traditional model of airway bistability between open and closed states, but also the critical addition of previously-unknown oscillatory and chaotic dynamics. It also allows us to explore the types of subtle change which can cause this interaction to fail, and thus could provide the missing link to explain DI failure in asthmatics.

  10. The importance of synergy between deep inspirations and fluidization in reversing airway closure.

    Directory of Open Access Journals (Sweden)

    Graham M Donovan

    Full Text Available Deep inspirations (DIs and airway smooth muscle fluidization are two widely studied phenomena in asthma research, particularly for their ability (or inability to counteract severe airway constriction. For example, DIs have been shown effectively to reverse airway constriction in normal subjects, but this is impaired in asthmatics. Fluidization is a connected phenomenon, wherein the ability of airway smooth muscle (ASM, which surrounds and constricts the airways to exert force is decreased by applied strain. A maneuver which sufficiently strains the ASM, then, such as a DI, is thought to reduce the force generating capacity of the muscle via fluidization and hence reverse or prevent airway constriction. Understanding these two phenomena is considered key to understanding the pathophysiology of asthma and airway hyper-responsiveness, and while both have been extensively studied, the mechanism by which DIs fail in asthmatics remains elusive. Here we show for the first time the synergistic interaction between DIs and fluidization which allows the combination to provide near complete reversal of airway closure where neither is effective alone. This relies not just on the traditional model of airway bistability between open and closed states, but also the critical addition of previously-unknown oscillatory and chaotic dynamics. It also allows us to explore the types of subtle change which can cause this interaction to fail, and thus could provide the missing link to explain DI failure in asthmatics.

  11. Analysis of airways in computed tomography

    DEFF Research Database (Denmark)

    Petersen, Jens

    Chronic Obstructive Pulmonary Disease (COPD) is major cause of death and disability world-wide. It affects lung function through destruction of lung tissue known as emphysema and inflammation of airways, leading to thickened airway walls and narrowed airway lumen. Computed Tomography (CT) imaging...... have become the standard with which to assess emphysema extent but airway abnormalities have so far been more challenging to quantify. Automated methods for analysis are indispensable as the visible airway tree in a CT scan can include several hundreds of individual branches. However, automation...... of scan on airway dimensions in subjects with and without COPD. The results show measured airway dimensions to be affected by differences in the level of inspiration and this dependency is again influenced by COPD. Inspiration level should therefore be accounted for when measuring airways, and airway...

  12. 不同剂量致敏原对小鼠哮喘模型气道反应性的影响%Different doeses of ovalbumin sensitization in airway responsiveness in a murine model of asthma

    Institute of Scientific and Technical Information of China (English)

    唐晓媛; 于化鹏; 邓火金; 陈新; 樊慧珍; 龚雨新; 刘俊芳

    2011-01-01

    目的:探讨不同剂量致敏原鸡卵蛋白(OVA)制备哮喘模型时对哮喘小鼠气道反应性的影响.方法:将30只BALB/c小鼠随机分为哮喘组和正常对照组(C组),哮喘组又分为小剂量OVA致敏组(A组)和大剂量OVA致敏组(B组),每组各10只.A、B组在开始和第14天时给予含OVA的致敏液200 μl(A组含10 μg OVA,B组含2 mg OVA,两者含同样的氢氧化铝及生理盐水),21 d开始雾化吸入OVA,连续雾化6 d,操作时观察小鼠活动及呼吸情况;各组分别于末次雾化激发24 h后测定小鼠的无创肺功能中的增强呼气间歇(Penh)值以评价气道反应性;对支气管肺泡灌洗液(BALF)行细胞总数、嗜酸粒细胞计数;取肺组织作HE染色病理切片;ELISA方法测外周血、BALF上清液中的IgE、IFN-γ含量.结果:哮喘B组在第二次致敏后可见喘息、呼吸困难、口唇和尾巴黏膜发紫表现,并在雾化时出现扭体、燥动、呼吸加快等症状.哮喘A、B组的Penh值明显高于C组(P0.05).结论:哮喘小鼠组模型制备成功.在观察气道高反应方面,较高剂量OVA致敏哮喘模型较低剂量OVA致敏的气道高反应性更敏感.%Objective: To explore the different does of ovalbumin(OVA) sensitization whether have influences on airway hyper responsiveness of mice model of asthma.Methods: The mice were randomly divided into 3 groups,with 10 mice in each group: control group and asthmatic groups( including asthma A group, the does of OVA sensitization was 10 μg every time; and asthma B group,which was 2 rog).The asthmatic A and B group were sensitized on the 0th, 14th day with different does of OVA, then inhaled OVA beginning on the 21st day for 6 days.Meanwhile the breathing and the color of oral and tail mucosa were monitered.The last time OVA stimulated and 24 hours later, Penh were measured to evaluate the airway responsiveness by noninvasive lung functional instrument,bronchoalveolar lavage cytology was performed and lung tissue

  13. Upper airway resistance syndrome.

    Science.gov (United States)

    Montserrat, J M; Badia, J R

    1999-03-01

    This article reviews the clinical picture, diagnosis and management of the upper airway resistance syndrome (UARS). Presently, there is not enough data on key points like the frequency of UARS and the morbidity associated with this condition. Furthermore, the existence of LIARS as an independent sleep disorder and its relation with snoring and obstructive events is in debate. The diagnosis of UARS is still a controversial issue. The technical limitations of the classic approach to monitor airflow with thermistors and inductance plethysmography, as well as the lack of a precise definition of hypopnea, may have led to a misinterpretation of UARS as an independent diagnosis from the sleep apnea/hypopnea syndrome. The diagnosis of this syndrome can be missed using a conventional polysomnographic setting unless appropriate techniques are applied. The use of an esophageal balloon to monitor inspiratory effort is currently the gold standard. However, other sensitive methods such as the use of a pneumotachograph and, more recently, nasal cannula/pressure transducer systems or on-line monitoring of respiratory impedance with the forced oscillation technique may provide other interesting possibilities. Recognition and characterization of this subgroup of patients within sleep breathing disorders is important because they are symptomatic and may benefit from treatment. Management options to treat UARS comprise all those currently available for sleep apnea/hypopnea syndrome (SAHS). However, the subset of patients classically identified as LIARS that exhibit skeletal craneo-facial abnormalities might possibly obtain further benefit from maxillofacial surgery.

  14. Changes of smooth muscle contractile filaments in small bowel atresia

    Institute of Scientific and Technical Information of China (English)

    Stefan Gfroerer; Henning Fiegel; Priya Ramachandran; Udo Rolle; Roman Metzger

    2012-01-01

    AIM:To investigate morphological changes of intestinal smooth muscle contractile fibres in small bowel atresia patients.METHODS:Resected small bowel specimens from small bowel atresia patients (n =12) were divided into three sections (proximal,atretic and distal).Standard histology hematoxylin-eosin staining and enzyme immunohistochemistry was performed to visualize smooth muscle contractile markers α-smooth muscle actin (SMA) and desmin using conventional paraffin sections of the proximal and distal bowel.Small bowel from agematched patients (n =2) undergoing Meckel's diverticulum resection served as controls.RESULTS:The smooth muscle coat in the proximal bowel of small bowel atresia patients was thickened compared with control tissue,but the distal bowel was unchanged.Expression of smooth muscle contractile fibres SMA and desmin within the proximal bowel was slightly reduced compared with the distal bowel and control tissue.There were no major differences in the architecture of the smooth muscle within the proximal bowel and the distal bowel.The proximal and distal bowel in small bowel atresia patients revealed only minimal differences regarding smooth muscle morphology and the presence of smooth muscle contractile filament markers.CONCLUSION:Changes in smooth muscle contractile filaments do not appear to play a major role in postoperative motility disorders in small bowel atresia.

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

    Science.gov (United States)

    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.

  16. Cromoglycate and Nedocromil: Influence on Airway Reactivity

    Science.gov (United States)

    Valletta, E. A.

    1994-01-01

    Although basic mechanisms of bronchial hyper-responsiveness (BHR) are still incompletely understood, inflammation of airways is likely to play a fundamental role in modulating BHR in patients with asthma. The involvement of several inflammatory cells (eosinophils, mast cells, lymphocytes, neutrophils, macrophages and platelets) and of bioactive mediators secreted by these cells in the pathogenesis of asthma is well documented. Sodium cromoglycate and nedocromil sodium are two pharmacological agents which have anti-allergic and anti-inflammatory properties. Their clinical effectiveness in mild to moderate asthma, and the capacity to reduce BHR under different natural and experimental conditions, make them valuable drugs for maintenance therapy in patients with asthma. PMID:18475597

  17. Menthol inhibits detrusor contractility independently of TRPM8 activation.

    Directory of Open Access Journals (Sweden)

    Antonio Celso Saragossa Ramos-Filho

    Full Text Available Agonists such as icilin and menthol can activate the cool temperature-sensitive ion channel TRPM8. However, biological responses to menthol may occur independently of TRPM8 activation. In the rodent urinary bladder, menthol facilitates the micturition reflex but inhibits muscarinic contractions of the detrusor smooth muscle. The site(s of TRPM8 expression in the bladder are controversial. In this study we investigated the regulation of bladder contractility in vitro by menthol. Bladder strips from wild type and TRPM8 knockout male mice (25-30 g were dissected free and mounted in organ baths. Isometric contractions to carbachol (1 nM-30 µM, CaCl2 (1 µM to 100 mM and electrical field stimulation (EFS; 8, 16, 32 Hz were measured. Strips from both groups contracted similarly in response to both carbachol and EFS. Menthol (300 µM or nifedipine (1 µM inhibited carbachol and EFS-induced contractions in both wild type and TRPM8 knockout bladder strips. Incubation with the sodium channel blocker tetrodotoxin (1 µM, replacement of extracellular sodium with the impermeant cation N-Methyl-D-Glucamine, incubation with a cocktail of potassium channel inhibitors (100 nM charybdotoxin, 1 µM apamin, 10 µM glibenclamide and 1 µM tetraethylammonium or removal of the urothelium did not affect the inhibitory actions of menthol. Contraction to CaCl2 was markedly inhibited by either menthol or nifedipine. In cultured bladder smooth muscle cells, menthol or nifedipine abrogated the carbachol or KCl-induced increases in [Ca2+]i. Intravesical administration of menthol increased voiding frequency while decreasing peak voiding pressure. We conclude that menthol inhibits muscarinic bladder contractions through blockade of L-type calcium channels, independently of TRPM8 activation.

  18. Menthol inhibits detrusor contractility independently of TRPM8 activation.

    Science.gov (United States)

    Ramos-Filho, Antonio Celso Saragossa; Shah, Ajay; Augusto, Taize Machado; Barbosa, Guilherme Oliveira; Leiria, Luiz Osorio; de Carvalho, Hernandes Faustino; Antunes, Edson; Grant, Andrew Douglas

    2014-01-01

    Agonists such as icilin and menthol can activate the cool temperature-sensitive ion channel TRPM8. However, biological responses to menthol may occur independently of TRPM8 activation. In the rodent urinary bladder, menthol facilitates the micturition reflex but inhibits muscarinic contractions of the detrusor smooth muscle. The site(s) of TRPM8 expression in the bladder are controversial. In this study we investigated the regulation of bladder contractility in vitro by menthol. Bladder strips from wild type and TRPM8 knockout male mice (25-30 g) were dissected free and mounted in organ baths. Isometric contractions to carbachol (1 nM-30 µM), CaCl2 (1 µM to 100 mM) and electrical field stimulation (EFS; 8, 16, 32 Hz) were measured. Strips from both groups contracted similarly in response to both carbachol and EFS. Menthol (300 µM) or nifedipine (1 µM) inhibited carbachol and EFS-induced contractions in both wild type and TRPM8 knockout bladder strips. Incubation with the sodium channel blocker tetrodotoxin (1 µM), replacement of extracellular sodium with the impermeant cation N-Methyl-D-Glucamine, incubation with a cocktail of potassium channel inhibitors (100 nM charybdotoxin, 1 µM apamin, 10 µM glibenclamide and 1 µM tetraethylammonium) or removal of the urothelium did not affect the inhibitory actions of menthol. Contraction to CaCl2 was markedly inhibited by either menthol or nifedipine. In cultured bladder smooth muscle cells, menthol or nifedipine abrogated the carbachol or KCl-induced increases in [Ca2+]i. Intravesical administration of menthol increased voiding frequency while decreasing peak voiding pressure. We conclude that menthol inhibits muscarinic bladder contractions through blockade of L-type calcium channels, independently of TRPM8 activation.

  19. Routes of allergic sensitization and myeloid cell IKKβ differentially regulate antibody responses and allergic airway inflammation in male and female mice.

    Science.gov (United States)

    Bonnegarde-Bernard, Astrid; Jee, Junbae; Fial, Michael J; Steiner, Haley; DiBartola, Stephanie; Davis, Ian C; Cormet-Boyaka, Estelle; Tomé, Daniel; Boyaka, Prosper N

    2014-01-01

    Gender influences the incidence and/or the severity of several diseases and evidence suggests a higher rate of allergy and asthma among women. Most experimental models of allergy use mice sensitized via the parenteral route despite the fact that the mucosal tissues of the gastrointestinal and respiratory tracts are major sites of allergic sensitization and/or allergic responses. We analyzed allergen-specific Ab responses in mice sensitized either by gavage or intraperitoneal injection of ovalbumin together with cholera toxin as adjuvant, as well as allergic inflammation and lung functions following subsequent nasal challenge with the allergen. Female mice sensitized intraperitoneally exhibited higher levels of serum IgE than their male counterparts. After nasal allergen challenge, these female mice expressed higher Th2 responses and associated inflammation in the lung than males. On the other hand, male and female mice sensitized orally developed the same levels of allergen-specific Ab responses and similar levels of lung inflammation after allergen challenge. Interestingly, the difference in allergen-specific Ab responses between male and female mice sensitized by the intraperitoneal route was abolished in IKKβΔMye mice, which lack IKKβ in myeloid cells. In summary, the oral or systemic route of allergic sensitization and IKKβ signaling in myeloid cells regulate how the gender influences allergen-specific responses and lung allergic inflammation.

  20. Distinct contractile and cytoskeletal protein patterns in the Antarctic midge are elicited by desiccation and rehydration.

    Science.gov (United States)

    Li, Aiqing; Benoit, Joshua B; Lopez-Martinez, Giancarlo; Elnitsky, Michael A; Lee, Richard E; Denlinger, David L

    2009-05-01

    Desiccation presents a major challenge for the Antarctic midge, Belgica antarctica. In this study, we use proteomic profiling to evaluate protein changes in the larvae elicited by dehydration and rehydration. Larvae were desiccated at 75% relative humidity (RH) for 12 h to achieve a body water loss of 35%, approximately half of the water that can be lost before the larvae succumb to dehydration. To evaluate the rehydration response, larvae were first desiccated, then rehydrated for 6 h at 100% RH and then in water for 6 h. Controls were held continuously at 100% RH. Protein analysis was performed using 2-DE and nanoscale capillary LC/MS/MS. Twenty-four identified proteins changed in abundance in response to desiccation: 16 were more abundant and 8 were less abundant; 84% of these proteins were contractile or cytoskeletal proteins. Thirteen rehydration-regulated proteins were identified: 8 were more abundant and 5 were less abundant, and 69% of these proteins were also contractile or cytoskeletal proteins. Additional proteins responsive to desiccation and rehydration were involved in functions including stress responses, energy metabolism, protein synthesis, glucogenesis and membrane transport. We conclude that the major protein responses elicited by both desiccation and rehydration are linked to body contraction and cytoskeleton rearrangements.

  1. Mechanisms of Cigarette Smoke Effects on Human Airway Smooth Muscle.

    Directory of Open Access Journals (Sweden)

    Mark E Wylam

    Full Text Available Cigarette smoke contributes to or exacerbates airway diseases such as asthma and COPD, where airway hyperresponsiveness and airway smooth muscle (ASM proliferation are key features. While factors such as inflammation contribute to asthma in part by enhancing agonist-induced intracellular Ca(2+ ([Ca(2+]i responses of ASM, the mechanisms by which cigarette smoke affect ASM are still under investigation. In the present study, we tested the hypothesis that cigarette smoke enhances the expression and function of Ca(2+ regulatory proteins leading to increased store operated Ca(2+ entry (SOCE and cell proliferation. Using isolated human ASM (hASM cells, incubated in the presence and absence cigarette smoke extract (CSE we determined ([Ca(2+]i responses and expression of relevant proteins as well as ASM proliferation, reactive oxidant species (ROS and cytokine generation. CSE enhanced [Ca(2+]i responses to agonist and SOCE: effects mediated by increased expression of TRPC3, CD38, STIM1, and/or Orai1, evident by attenuation of CSE effects when siRNAs against these proteins were used, particularly Orai1. CSE also increased hASM ROS generation and cytokine secretion. In addition, we found in the airways of patients with long-term smoking history, TRPC3 and CD38 expression were significantly increased compared to life-long never-smokers, supporting the role of these proteins in smoking effects. Finally, CSE enhanced hASM proliferation, an effect confirmed by upregulation of PCNA and Cyclin E. These results support a critical role for Ca(2+ regulatory proteins and enhanced SOCE to alter airway structure and function in smoking-related airway disease.

  2. Geometrical origins of contractility in disordered actomyosin networks

    CERN Document Server

    Lenz, Martin

    2014-01-01

    Movement within eukaryotic cells largely originates from localized forces exerted by myosin motors on scaffolds of actin filaments. Although individual motors locally exert both contractile and extensile forces, large actomyosin structures at the cellular scale are overwhelmingly contractile, suggesting that the scaffold serves to favor contraction over extension. While this mechanism is well understood in highly organized striated muscle, its origin in disordered networks such as the cell cortex is unknown. Here we develop a mathematical model of the actin scaffold's local two- or three-dimensional mechanics and identify four competing contraction mechanisms. We predict that one mechanism dominates, whereby local deformations of the actin break the balance between contraction and extension. In this mechanism, contractile forces result mostly from motors plucking the filaments transversely rather than buckling them longitudinally. These findings sheds light on recent $\\textit{in vitro}$ experiments, and provi...

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

    Science.gov (United States)

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

    2006-11-01

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

  4. Effects of Flavin7 on allergen induced hyperreactivity of airways

    Directory of Open Access Journals (Sweden)

    Franova S

    2009-12-01

    Full Text Available Abstract Some studies have suggested that the polyphenolic compounds might reduce the occurrence of asthma symptoms. The aim of our experiments was to evaluate the effects of 21 days of the flavonoid Flavin7 administration on experimentally induced airway inflammation in ovalbumin-sensitized guinea pigs. We assessed tracheal smooth muscle reactivity by an in vitro muscle-strip method; changes in airway resistance by an in vivo plethysmographic method; histological picture of tracheal tissue; and the levels of interleukin 4 (IL-4, and interleukin 5 (IL-5 in bronchoalveolar lavage fluid (BALF. Histological investigation of tracheal tissue and the concentrations of the inflammatory cytokines IL-4 and IL-5 in BALF were used as indices of airway inflammation. Administration of Flavin7 caused a significant decrease of specific airway resistance after histamine nebulization and a decline in tracheal smooth muscle contraction amplitude in response to bronchoconstricting mediators. Flavin7 minimized the degree of inflammation estimated on the basis of eosinophil calculation and IL-4 and IL-5 concentrations. In conclusion, administration of Flavin7 showed bronchodilating and anti-inflammatory effects on allergen-induced airway inflammation.

  5. NF-kappaB Signaling in Chronic Inflammatory Airway Disease

    Directory of Open Access Journals (Sweden)

    Michael Schuliga

    2015-06-01

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

  6. Inhibition of MMP-2 Expression with siRNA Increases Baseline Cardiomyocyte Contractility and Protects against Simulated Ischemic Reperfusion Injury

    Directory of Open Access Journals (Sweden)

    Han-Bin Lin

    2014-01-01

    Full Text Available Matrix metalloproteinases (MMPs significantly contribute to ischemia reperfusion (I/R injury, namely, by the degradation of contractile proteins. However, due to the experimental models adopted and lack of isoform specificity of MMP inhibitors, the cellular source and identity of the MMP(s involved in I/R injury remain to be elucidated. Using isolated adult rat cardiomyocytes, subjected to chemically induced I/R-like injury, we show that specific inhibition of MMP-2 expression and activity using MMP-2 siRNA significantly protected cardiomyocyte contractility from I/R-like injury. This was also associated with increased expression of myosin light chains 1 and 2 (MLC1/2 in comparison to scramble siRNA transfection. Moreover, the positive effect of MMP-2 siRNA transfection on cardiomyocyte contractility and MLC1/2 expression levels was also observed under control conditions, suggesting an important additional role for MMP-2 in physiological sarcomeric protein turnover. This study clearly demonstrates that intracellular expression of MMP-2 plays a significant role in sarcomeric protein turnover, such as MLC1 and MLC2, under aerobic (physiological conditions. In addition, this study identifies intracellular/autocrine, cardiomyocyte-produced MMP-2, rather than paracrine/extracellular, as responsible for the degradation of MLC1/2 and consequent contractile dysfunction in cardiomyocytes subjected to I/R injury.

  7. A review on airway biomarkers: exposure, effect and susceptibility.

    Science.gov (United States)

    Corradi, Massimo; Goldoni, Matteo; Mutti, Antonio

    2015-04-01

    Current research in pulmonology requires the use of biomarkers to investigate airway exposure and diseases, for both diagnostic and prognostic purposes. The traditional approach based on invasive approaches (lung lavages and biopsies) can now be replaced, at least in part, through the use of non invasively collected specimens (sputum and breath), in which biomarkers of exposure, effect and susceptibility can be searched. The discovery of specific lung-related proteins, which can spill over in blood or excreted in urine, further enhanced the spectrum of airway specific biomarkers to be studied. The recent introduction of high-performance 'omic' technologies - genomics, proteomics and metabolomics, and the rate at which biomarker candidates are being discovered, will permit the use of a combination of biomarkers for a more precise selection of patient with different outcomes and responses to therapies. The aim of this review is to critically evaluate the use of airway biomarkers in the context of research and clinical practice.

  8. Airway microbiota and acute respiratory infection in children.

    Science.gov (United States)

    Hasegawa, Kohei; Camargo, Carlos A

    2015-01-01

    Acute respiratory infections (ARIs), such as bronchiolitis and pneumonia, are the leading cause of hospitalization of infants in the US. While the incidence and severity of ARI can vary widely among children, the reasons for these differences are not fully explained by traditional risk factors (e.g., prematurity, viral pathogens). The recent advent of molecular diagnostic techniques has revealed the presence of highly functional communities of microbes inhabiting the human body (i.e., microbiota) that appear to influence development of local and systemic immune response. We propose a 'risk and resilience' model in which airway microbiota are associated with an increased (risk microbiota) or decreased (resilience microbiota) incidence and severity of ARI in children. We also propose that modulating airway microbiota (e.g., from risk to resilience microbiota) during early childhood will optimize airway immunity and, thereby, decrease ARI incidence and severity in children.

  9. Olfactory receptors modulate physiological processes in human airway smooth muscle cells

    Directory of Open Access Journals (Sweden)

    Benjamin Kalbe

    2016-08-01

    Full Text Available Pathophysiological mechanisms in human airway smooth muscle cells (HASMCs significantly contribute to the progression of chronic inflammatory airway diseases with limited therapeutic options, such as severe asthma and COPD. These abnormalities include the contractility and hyperproduction of inflammatory proteins. To develop therapeutic strategies, key pathological mechanisms and putative clinical targets need to be identified. In the present study, we demonstrated that the human olfactory receptors (ORs OR1D2 and OR2AG1 are expressed at the RNA and protein levels in HASMCs. Using fluorometric calcium imaging, specific agonists for OR2AG1 and OR1D2 were identified to trigger transient Ca2+ increases in HASMCs via a cAMP-dependent signal transduction cascade. Furthermore, the activation of OR2AG1 via amyl butyrate inhibited the histamine-induced contraction of HASMCs, whereas the stimulation of OR1D2 with bourgeonal led to an increase in cell contractility. In addition, OR1D2 activation induced the secretion of IL-8 and GM-CSF. Both effects were inhibited by the specific OR1D2 antagonist undecanal. We herein provide the first evidence to show that ORs are functionally expressed in HASMCs and regulate pathophysiological processes. Therefore, ORs might be new therapeutic targets for these diseases, and blocking ORs could be an auspicious strategy for the treatment of early-stage chronic inflammatory lung diseases.

  10. Contractility and protein phosphorylation in cardiomyocytes: effects of isoproterenol and AR-L57.

    Science.gov (United States)

    Hayes, J S; Bowling, N; Boder, G B

    1984-08-01

    The cardiotonic drugs AR-L57 [2-(2,4-dimethoxyphenyl)-1H-imidazo(4,5b)-pyridine] and isoproterenol stimulated contractility in cultured heart cells in concentration-dependent manners; only the effects of isoproterenol were blocked by propranolol. Isoproterenol, but not AR-L57, enhanced the phosphorylation state of seven protein bands [relative molecular weights (MrS) 155,000, 96,000, 27,000, 24,000, 20,000, 16,000, 12,000] and resulted in the dephosphorylation of one protein band (Mr 21,000). Also, only isoproterenol increased the activation states of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase and glycogen phosphorylase. The eight protein bands resolved by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis and detected by autoradiography were altered by isoproterenol in time- and concentration-dependent manners. The 24,000-Mr protein substrate phosphorylated in response to isoproterenol was converted to a 12,000-Mr species by heating in the presence of SDS prior to electrophoresis, suggesting that the two substrates were in fact identical proteins. A comparison of the 2-min responses to varying concentrations of isoproterenol resulted in excellent correlations between the phosphorylation states of individual protein bands and contractility. This was true even for the 21,000-Mr species that was dephosphorylated. However, only the 27,000-, 24-12,000-, and 16,000-Mr substrates were phosphorylated rapidly enough to be associated with the onset of the inotropic response. Cultured myocytes are an important feature of these studies as they are 84% pure ventricular cells that remain 100% viable throughout an experiment. Because this system is suitable for biochemical measurements and the effects of agents on heart cell contractility can be determined, it is possible to correlate changes in biochemical parameters with alterations in physiological state.

  11. Treating asthma means treating airway smooth muscle cells

    NARCIS (Netherlands)

    Zuyderduyn, S; Sukkar, M B; Fust, A; Dhaliwal, S; Burgess, J K

    2008-01-01

    Asthma is characterised by airway hyperresponsiveness, airway inflammation and airway remodelling. Airway smooth muscle cells are known to be the main effector cells of airway narrowing. In the present paper, studies will be discussed that have led to a novel view of the role of airway smooth muscle

  12. The laminin β1-competing peptide YIGSR induces a hypercontractile, hypoproliferative airway smooth muscle phenotype in an animal model of allergic asthma

    Directory of Open Access Journals (Sweden)

    Zaagsma Johan

    2010-12-01

    Full Text Available Abstract Background Fibroproliferative airway remodelling, including increased airway smooth muscle (ASM mass and contractility, contributes to airway hyperresponsiveness in asthma. In vitro studies have shown that maturation of ASM cells to a (hypercontractile phenotype is dependent on laminin, which can be inhibited by the laminin-competing peptide Tyr-Ile-Gly-Ser-Arg (YIGSR. The role of laminins in ASM remodelling in chronic asthma in vivo, however, has not yet been established. Methods Using an established guinea pig model of allergic asthma, we investigated the effects of topical treatment of the airways with YIGSR on features of airway remodelling induced by repeated allergen challenge, including ASM hyperplasia and hypercontractility, inflammation and fibrosis. Human ASM cells were used to investigate the direct effects of YIGSR on ASM proliferation in vitro. Results Topical administration of YIGSR attenuated allergen-induced ASM hyperplasia and pulmonary expression of the proliferative marker proliferating cell nuclear antigen (PCNA. Treatment with YIGSR also increased both the expression of sm-MHC and ASM contractility in saline- and allergen-challenged animals; this suggests that treatment with the laminin-competing peptide YIGSR mimics rather than inhibits laminin function in vivo. In addition, treatment with YIGSR increased allergen-induced fibrosis and submucosal eosinophilia. Immobilized YIGSR concentration-dependently reduced PDGF-induced proliferation of cultured ASM to a similar extent as laminin-coated culture plates. Notably, the effects of both immobilized YIGSR and laminin were antagonized by soluble YIGSR. Conclusion These results indicate that the laminin-competing peptide YIGSR promotes a contractile, hypoproliferative ASM phenotype in vivo, an effect that appears to be linked to the microenvironment in which the cells are exposed to the peptide.

  13. Effects of histamine on atrial and ventricular contractility in the canine isovolumic heart.

    Science.gov (United States)

    Vidrio, H; Priola, D V

    1990-03-01

    The effects of intracoronary administration of histamine on atrial and ventricular contractility were determined in a paced canine isovolumic heart preparation. Contractility was assessed by recording the pressure developed in saline-filled balloons placed in each of the four cardiac chambers. At doses above 0.1 mg and up to 100 mg histamine produced dose-related positive inotropic responses in all chambers. These were preceded by transient negative effects. The positive responses were not affected by a combination of H1 and H2 receptor antagonists antazoline and cimetidine but were almost completely abolished by the beta adrenoceptor blocker timolol. The negative responses were uninfluenced by either treatment. It was concluded that, in the canine isovolumic heart not subjected to complicating chronotropic and extracardiac factors, moderate doses of histamine are devoid of inotropic effects. Higher doses do produce myocardial stimulation, not mediated by histamine receptors, but probably due to norepinephrine release. These responses are preceded by transient non-specific depressant effects.

  14. Activation of Proinflammatory Responses in Cells of the Airway Mucosa by Particulate Matter: Oxidant- and Non-Oxidant-Mediated Triggering Mechanisms

    Directory of Open Access Journals (Sweden)

    Johan Øvrevik

    2015-07-01

    Full Text Available Inflammation is considered to play a central role in a diverse range of disease outcomes associated with exposure to various types of inhalable particulates. The initial mechanisms through which particles trigger cellular responses leading to activation of inflammatory responses are crucial to clarify in order to understand what physico-chemical characteristics govern the inflammogenic activity of particulate matter and why some particles are more harmful than others. Recent research suggests that molecular triggering mechanisms involved in activation of proinflammatory genes and onset of inflammatory reactions by particles or soluble particle components can be categorized into direct formation of reactive oxygen species (ROS with subsequent oxidative stress, interaction with the lipid layer of cellular membranes, activation of cell surface receptors, and direct interactions with intracellular molecular targets. The present review focuses on the immediate effects and responses in cells exposed to particles and central down-stream signaling mechanisms involved in regulation of proinflammatory genes, with special emphasis on the role of oxidant and non-oxidant triggering mechanisms. Importantly, ROS act as a central second-messenger in a variety of signaling pathways. Even non-oxidant mediated triggering mechanisms are therefore also likely to activate downstream redox-regulated events.

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

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    Romina Nassini

    Full Text Available BACKGROUND: The transient receptor potential ankyrin 1 (TRPA1 channel, localized to airway sensory nerves, has been proposed to mediate airway inflammation evoked by allergen and cigarette smoke (CS in rodents, via a neurogenic mechanism. However the limited clinical evidence for the role of neurogenic inflammation in asthma or chronic obstructive pulmonary disease raises an alternative possibility that airway inflammation is promoted by non-neuronal TRPA1. METHODOLOGY/PRINCIPAL FINDINGS: By using Real-Time PCR and calcium imaging, we found that cultured human airway cells, including fibroblasts, epithelial and smooth muscle cells express functional TRPA1 channels. By using immunohistochemistry, TRPA1 staining was observed in airway epithelial and smooth muscle cells in sections taken from human airways and lung, and from airways and lung of wild-type, but not TRPA1-deficient mice. In cultured human airway epithelial and smooth muscle cells and fibroblasts, acrolein and CS extract evoked IL-8 release, a response selectively reduced by TRPA1 antagonists. Capsaicin, agonist of the transient receptor potential vanilloid 1 (TRPV1, a channel co-expressed with TRPA1 by airway sensory nerves, and acrolein or CS (TRPA1 agonists, or the neuropeptide substance P (SP, which is released from sensory nerve terminals by capsaicin, acrolein or CS, produced neurogenic inflammation in mouse airways. However, only acrolein and CS, but not capsaicin or SP, released the keratinocyte chemoattractant (CXCL-1/KC, IL-8 analogue in bronchoalveolar lavage (BAL fluid of wild-type mice. This effect of TRPA1 agonists was attenuated by TRPA1 antagonism or in TRPA1-deficient mice, but not by pharmacological ablation of sensory nerves. CONCLUSIONS: Our results demonstrate that, although either TRPV1 or TRPA1 activation causes airway neurogenic inflammation, solely TRPA1 activation orchestrates an additional inflammatory response which is not neurogenic. This finding suggests

  16. Multiscale Vessel-guided Airway Tree Segmentation

    DEFF Research Database (Denmark)

    Lo, Pechin Chien Pau; Sporring, Jon; de Bruijne, Marleen

    2009-01-01

    that is trained to differentiate between airway and non-airway voxels. Vessel and airway orientation information are used in the form of a vessel orientation similarity measure, which indicates how similar the orientation of the an airway candidate is to the orientation of the neighboring vessel. The method...... is evaluated within EXACT’09 on a diverse set of CT scans. Results show a favorable combination of a relatively large portion of the tree detected correctly with very few false positives....

  17. Bone marrow cell derived arginase I is the major source of allergen-induced lung arginase but is not required for airway hyperresponsiveness, remodeling and lung inflammatory responses in mice

    Directory of Open Access Journals (Sweden)

    Rothenberg Marc E

    2009-06-01

    Full Text Available Abstract Background Arginase is significantly upregulated in the lungs in murine models of asthma, as well as in human asthma, but its role in allergic airway inflammation has not been fully elucidated in mice. Results In order to test the hypothesis that arginase has a role in allergic airway inflammation we generated arginase I-deficient bone marrow (BM chimeric mice. Following transfer of arginase I-deficient BM into irradiated recipient mice, arginase I expression was not required for hematopoietic reconstitution and baseline immunity. Arginase I deficiency in bone marrow-derived cells decreased allergen-induced lung arginase by 85.8 ± 5.6%. In contrast, arginase II-deficient mice had increased lung arginase activity following allergen challenge to a similar level to wild type mice. BM-derived arginase I was not required for allergen-elicited sensitization, recruitment of inflammatory cells in the lung, and proliferation of cells. Furthermore, allergen-induced airway hyperresponsiveness and collagen deposition were similar in arginase-deficient and wild type mice. Additionally, arginase II-deficient mice respond similarly to their control wild type mice with allergen-induced inflammation, airway hyperresponsiveness, proliferation and collagen deposition. Conclusion Bone marrow cell derived arginase I is the predominant source of allergen-induced lung arginase but is not required for allergen-induced inflammation, airway hyperresponsiveness or collagen deposition.

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

    Science.gov (United States)

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

  19. Clinical Relationship between Steatocholecystitis and Gallbladder Contractility Measured by Cholescintigraphy

    Directory of Open Access Journals (Sweden)

    Chang Seok Bang

    2015-01-01

    Full Text Available Objective. Contractility of gallbladder is known to be decreased in fatty gallbladder diseases. However, clinical estimation data about this relationship is still lacking. The aim of this study was to investigate the association between steatocholecystitis and contractility of gallbladder. Methods. Patients with cholecystitis (steatocholecystitis versus nonsteatocholecystitis who underwent cholescintigraphy before cholecystectomy were retrospectively evaluated in a single teaching hospital of Korea. The association of steatocholecystitis with contractility of gallbladder, measured by preoperative cholescintigraphy, was assessed by univariable and multivariable analysis. Results. A total of 432 patients were finally enrolled (steatocholecystitis versus nonsteatocholecystitis; 75 versus 357, calculous versus acalculous cholecystitis; 316 versus 116. In the multivariable analysis, age (OR: 0.94, 95% CI: 0.90–0.99, P=0.01 and total serum cholesterol (OR: 1.02, 95% CI: 1.01–1.04, P=0.04 were related to steatocholecystitis in patients with acalculous cholecystitis. Only age (OR: 0.97, 95% CI: 0.94–0.99, P=0.004 was significantly related to steatocholecystitis in patients with calculous cholecystitis. However, ejection fraction of gallbladder reflecting contractility measured by cholescintigraphy was not related to steatocholecystitis irrespective of presence of gallbladder stone in patients with cholecystitis. Conclusion. Ejection fraction of gallbladder measured by cholescintigraphy cannot be used for the detection or confirmation of steatocholecystitis.

  20. Myocardial contractile function in survived neonatal piglets after cardiopulmonary bypass

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    Popov Aron-Frederik

    2010-11-01

    Full Text Available Abstract Background Hemodynamic function may be depressed in the early postoperative stages after cardiac surgery. The aim of this study was the analysis of the myocardial contractility in neonates after cardiopulmonary bypass (CPB and mild hypothermia. Methods Three indices of left ventricular myocardial contractile function (dP/dt, (dP/dt/P, and wall thickening were studied up to 6 hours after CPB in neonatal piglets (CPB group; n = 4. The contractility data were analysed and then compared to the data of newborn piglets who also underwent median thoracotomy and instrumentation for the same time intervals but without CPB (non-CPB group; n = 3. Results Left ventricular dP/dtmax and (dP/dtmax/P remained stable in CPB group, while dP/dtmax decreased in non-CPB group 5 hours postoperatively (1761 ± 205 mmHg/s at baseline vs. 1170 ± 205 mmHg/s after 5 h; p max and (dP/dtmax/P there were no statistically significant differences between the two groups. Comparably, although myocardial thickening decreased in the non-CPB group the differences between the two groups were not statistically significant. Conclusions The myocardial contractile function in survived neonatal piglets remained stable 6 hours after cardiopulmonary bypass and mild hypothermia probably due to regional hypercontractility.

  1. Inhalation of Budesonide/Formoterol Increases Diaphragm Muscle Contractility

    Directory of Open Access Journals (Sweden)

    Chiyohiko Shindoh

    2012-01-01

    Conclusions: BUD/FORM inhalation has an inotropic effect on diaphragm muscle, protects diaphragm muscle deterioration after endotoxin injection, and inhibits NO production. Increments in muscle contractility with BUD/FORM inhalation are induced through a synergistic effect of an anti-inflammatory agent and 02-agonist.

  2. Effect of pinaverium bromide on stress-induced colonic smooth muscle contractility disorder in rats

    Institute of Scientific and Technical Information of China (English)

    Yun Dai; Jian-Xiang Liu; Jun-Xia Li; Yun-Feng Xu

    2003-01-01

    AIM: To investigate the effect of pinaverium bromide, a Ltype calcium channel blocker with selectivity for the gastrointestinal tract on contractile activity of colonic circular smooth muscle in normal or cold-restraint stressed rats and its possible mechanism.METHODS: Cold-restraint stress was conducted on rats to increase fecal pellets output. Each isolated colonic circular muscle strip was suspended in a tissue chamber containing warm oxygenated Tyrode-Ringer solution. The contractile response to ACh or KCl was measured isometrically on inkwriting recorder. Incubated muscle in different concentrations of pinaverium and the effects of pinaverium were investigated on ACh or KCl-induced contraction. Colon smooth muscle cells were cultured from rats and [Ca2+]i was measured in cell suspension using the Ca2+ fluorescent dye fura-2/AlMl.RESULTS: During stress, rats fecal pellet output increased 61% (P<0.01). Stimulated with ACh or KCl, the muscle contractility was higher in stress than that in control. Pinaverium inhibited the increment of [Ca2+]i and the muscle contraction in response to ACh or KCl in a dose dependent manner. A significant inhibition of pinaverium to ACh or KCl induced [Ca2+]i increment was observed at 10-6 mol/L. The IC50 values for inhibition of ACh induced contraction for the stress and control group were 1.66×10-6 mol/L and 0.91×10-6mol/L, respectively. The ICs0 values for inhibition of KCl induced contraction for the stress and control group were 8.13×10-7 mol/L and 3.80×10-7 mol/L, respectively.CONCLUSION: Increase in [Ca2+]i of smooth muscle cells is directly related to the generation of contraction force in colon. L-type Ca2+ channels represent the main route of Ca2+ entry.Pinaverium inhibits the calcium influx through L-type channels;decreases the contractile response to many kinds of agonists and regulates the stress-induced colon hypermotility.

  3. A Small Molecule Inhibitor of Sarcomere Contractility Acutely Relieves Left Ventricular Outflow Tract Obstruction in Feline Hypertrophic Cardiomyopathy

    Science.gov (United States)

    Stern, Joshua A.; Markova, Svetlana; Ueda, Yu; Kim, Jae B.; Pascoe, Peter J.; Evanchik, Marc J.; Green, Eric M.; Harris, Samantha P.

    2016-01-01

    Hypertrophic cardiomyopathy (HCM) is an inherited disease of the heart muscle characterized by otherwise unexplained thickening of the left ventricle. Left ventricular outflow tract (LVOT) obstruction is present in approximately two-thirds of patients and substantially increases the risk of disease complications. Invasive treatment with septal myectomy or alcohol septal ablation can improve symptoms and functional status, but currently available drugs for reducing obstruction have pleiotropic effects and variable therapeutic responses. New medical treatments with more targeted pharmacology are needed, but the lack of preclinical animal models for HCM with LVOT obstruction has limited their development. HCM is a common cause of heart failure in cats, and a subset exhibit systolic anterior motion of the mitral valve leading to LVOT obstruction. MYK-461 is a recently-described, mechanistically novel small molecule that acts at the sarcomere to specifically inhibit contractility that has been proposed as a treatment for HCM. Here, we use MYK-461 to test whether direct reduction in contractility is sufficient to relieve LVOT obstruction in feline HCM. We evaluated mixed-breed cats in a research colony derived from a Maine Coon/mixed-breed founder with naturally-occurring HCM. By echocardiography, we identified five cats that developed systolic anterior motion of the mitral valve and LVOT obstruction both at rest and under anesthesia when provoked with an adrenergic agonist. An IV MYK-461 infusion and echocardiography protocol was developed to serially assess contractility and LVOT gradient at multiple MYK-461 concentrations. Treatment with MYK-461 reduced contractility, eliminated systolic anterior motion of the mitral valve and relieved LVOT pressure gradients in an exposure-dependent manner. Our findings provide proof of principle that acute reduction in contractility with MYK-461 is sufficient to relieve LVOT obstruction. Further, these studies suggest that feline

  4. Parasympathetic neurons in the cranial medial ventricular fat pad on the dog heart selectively decrease ventricular contractility.

    Science.gov (United States)

    Dickerson, L W; Rodak, D J; Fleming, T J; Gatti, P J; Massari, V J; McKenzie, J C; Gillis, R A

    1998-05-28

    We hypothesized that selective control of ventricular contractility might be mediated by postganglionic parasympathetic neurons in the cranial medial ventricular (CMV) ganglion plexus located in a fat pad at the base of the aorta. Sinus rate, atrioventricular (AV) conduction (ventricular rate during atrial pacing), and left ventricular contractile force (LV dP/dt during right ventricular pacing) were measured in eight chloralose-anesthetized dogs both before and during bilateral cervical vagus stimulation (20-30 V, 0.5 ms pulses, 15-20 Hz). Seven of these dogs were tested under beta-adrenergic blockade (propranolol, 0.8 mg kg(-1) i.v.). Control responses included sinus node bradycardia or arrest during spontaneous rhythm, high grade AV block or complete heart block, and a 30% decrease in contractility from 2118 +/- 186 to 1526 +/- 187 mm Hg s(-1) (P 0.05) decrease in contractility but still elicited the same degree of sinus bradycardia and AV block (N = 8, P < 0.05). Five dogs were re-tested 3 h after trimethaphan fat pad injection, at which time blockade of vagally-induced negative inotropy was partially reversed, as vagal stimulation decreased LV dP/dt by 19%. The same dose of trimethaphan given either locally into other fat pads (PVFP or IVC-ILA) or systemically (i.v.) had no effect on vagally-induced negative inotropy. Thus, parasympathetic ganglia located in the CMV fat pad mediated a decrease in ventricular contractility during vagal stimulation. Blockade of the CMV fat pad had no effect on vagally-mediated slowing of sinus rate or AV conduction.

  5. Effects of Crocetin Esters and Crocetin from Crocus sativus L. on Aortic Contractility in Rat Genetic Hypertension

    Directory of Open Access Journals (Sweden)

    Silvia Llorens

    2015-09-01

    Full Text Available Background: Endothelial dysfunction, characterized by an enhancement in vasoconstriction, is clearly associated with hypertension. Saffron (Crocus sativus L. bioactive compounds have been recognized to have hypotensive properties. Recently, we have reported that crocetin exhibits potent vasodilator effects on isolated aortic rings from hypertensive rats. In this work, we have aimed to analyze the anticontractile ability of crocetin or crocetin esters pool (crocins isolated from saffron. Thus, we have studied the effects of saffron carotenoids on endothelium-dependent and -independent regulation of smooth muscle contractility in genetic hypertension. Methods: We have measured the isometric responses of aortic segments with or without endothelium obtained from spontaneously hypertensive rats. The effects of carotenoids were studied by assessing the endothelial modulation of phenylephrine-induced contractions (10−9–10−5 M in the presence or absence of crocetin or crocins. The role of nitric oxide and prostanoids was analyzed by performing the experiments with L-NAME (NG-nitro-l-arginine methyl ester or indomethacin (both 10−5 M, respectively. Results: Crocetin, and to a minor extent crocins, diminished the maximum contractility of phenylephrine in intact rings, while crocins, but not crocetin, increased this contractility in de-endothelizated vessels. In the intact vessels, the effect of crocetin on contractility was unaffected by indomethacin but was abolished by L-NAME. However, crocetin but not crocins, lowered the already increased contractility caused by L-NAME. Conclusions: Saffron compounds, but especially crocetin have endothelium-dependent prorelaxing actions. Crocins have procontractile actions that take place via smooth muscle cell mechanisms. These results suggest that crocetin and crocins activate different mechanisms involved in the vasoconstriction pathway in hypertension.

  6. Acanthamoeba protease activity promotes allergic airway inflammation via protease-activated receptor 2.

    Science.gov (United States)

    Park, Mi Kyung; Cho, Min Kyoung; Kang, Shin Ae; Park, Hye-Kyung; Kim, Dong-Hee; Yu, Hak Sun

    2014-01-01

    Acanthamoeba is a free-living amoeba commonly present in the environment and often found in human airway cavities. Acanthamoeba possesses strong proteases that can elicit allergic airway inflammation. To our knowledge, the aeroallergenicity of Acanthamoeba has not been reported. We repeatedly inoculated mice with Acanthamoeba trophozoites or excretory-secretory (ES) proteins intra-nasally and evaluated symptoms and airway immune responses. Acanthamoeba trophozoites or ES proteins elicited immune responses in mice that resembled allergic airway inflammation. ES proteins had strong protease activity and activated the expression of several chemokine genes (CCL11, CCL17, CCL22, TSLP, and IL-25) in mouse lung epithelial cells. The serine protease inhibitor phenyl-methane-sulfonyl fluoride (PMSF) inhibited ES protein activity. ES proteins also stimulated dendritic cells and enhanced the differentiation of naive T cells into IL-4-secreting T cells. After repeated inoculation of the protease-activated receptor 2 knockout mouse with ES proteins, airway inflammation and Th2 immune responses were markedly reduced, but not to basal levels. Furthermore, asthma patients had higher Acanthamoeba-specific IgE titers than healthy controls and we found Acanthamoeba specific antigen from house dust in typical living room. Our findings suggest that Acanthamoeba elicits allergic airway symptoms in mice via a protease allergen. In addition, it is possible that Acanthamoeba may be one of the triggers human airway allergic disease.

  7. Acanthamoeba protease activity promotes allergic airway inflammation via protease-activated receptor 2.

    Directory of Open Access Journals (Sweden)

    Mi Kyung Park

    Full Text Available Acanthamoeba is a free-living amoeba commonly present in the environment and often found in human airway cavities. Acanthamoeba possesses strong proteases that can elicit allergic airway inflammation. To our knowledge, the aeroallergenicity of Acanthamoeba has not been reported. We repeatedly inoculated mice with Acanthamoeba trophozoites or excretory-secretory (ES proteins intra-nasally and evaluated symptoms and airway immune responses. Acanthamoeba trophozoites or ES proteins elicited immune responses in mice that resembled allergic airway inflammation. ES proteins had strong protease activity and activated the expression of several chemokine genes (CCL11, CCL17, CCL22, TSLP, and IL-25 in mouse lung epithelial cells. The serine protease inhibitor phenyl-methane-sulfonyl fluoride (PMSF inhibited ES protein activity. ES proteins also stimulated dendritic cells and enhanced the differentiation of naive T cells into IL-4-secreting T cells. After repeated inoculation of the protease-activated receptor 2 knockout mouse with ES proteins, airway inflammation and Th2 immune responses were markedly reduced, but not to basal levels. Furthermore, asthma patients had higher Acanthamoeba-specific IgE titers than healthy controls and we found Acanthamoeba specific antigen from house dust in typical living room. Our findings suggest that Acanthamoeba elicits allergic airway symptoms in mice via a protease allergen. In addition, it is possible that Acanthamoeba may be one of the triggers human airway allergic disease.

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

    DEFF Research Database (Denmark)

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

    2013-01-01

    the examination and registration of predictors for difficult mask ventilation with a non-specified clinical airway assessment on prediction of difficult mask ventilation.Method/Design: We cluster-randomized 28 Danish departments of anaesthesia to airway assessment either by the SARI or by usual non...... reduction equalling a number needed to treat of 180. Sample size estimation is adjusted for the study design and based on standards for randomization on cluster-level. With an average cluster size of 2,500 patients, 70,000 patients will be enrolled over a 1-year trial period. The database is programmed so...

  9. Vasopressin Type 1A Receptor Deletion Enhances Cardiac Contractility, β-Adrenergic Receptor Sensitivity and Acute Cardiac Injury-induced Dysfunction.

    Science.gov (United States)

    Wasilewski, Melissa A; Grisanti, Laurel A; Song, Jianliang; Carter, Rhonda L; Repas, Ashley A; Myers, Valerie D; Gao, Erhe; Koch, Walter J; Cheung, Joseph Y; Feldman, Arthur M; Tilley, Douglas

    2016-09-02

    V1AR expression is elevated in chronic human heart failure and contributes to cardiac dysfunction in animal models, in part via reduced βAR responsiveness.  While cardiac V1AR overexpression and V1AR stimulation are each sufficient to decrease βAR activity, it is unknown whether V1AR inhibition conversely augments βAR responsiveness.  Further, although V1AR has been shown to contribute to chronic progression of heart failure, its impact on cardiac function following acute ischemic injury has not been reported.  Using V1AR KO mice we assessed the impact of V1AR deletion on cardiac contractility at baseline and following ischemic injury, βAR sensitivity and cardiomyocyte responsiveness to βAR stimulation.  Strikingly, baseline cardiac contractility was enhanced in V1AR KO mice and they experienced a greater loss in contractile function than control mice following acute ischemic injury, although the absolute levels of cardiac dysfunction and survival rates did not differ.  Enhanced cardiac contractility in V1AR KO mice was associated with augmented β-blocker sensitivity, suggesting increased basal βAR activity, and indeed levels of left ventricular cAMP, as well as phospholamban and cardiac troponin I phosphorylation were elevated versus control mice.  At the cellular level, myocytes isolated from V1AR KO mice demonstrated increased responsiveness to βAR stimulation consistent with the finding that acute pharmacological V1AR inhibition enhanced βAR-mediated contractility in control myocytes.  Therefore, while V1AR deletion does not protect the heart from the rapid development of cardiac dysfunction following acute ischemic injury, its effects on βAR activity suggest that acute V1AR inhibition could be utilized to promote myocyte contractile performance.

  10. Vessel-guided Airway Tree Segmentation

    DEFF Research Database (Denmark)

    Lo, P.; Sporring, J.; Ashraf, H.;

    2010-01-01

    This paper presents a method for airway tree segmentation that uses a combination of a trained airway appearance model, vessel and airway orientation information, and region growing. We propose a voxel classification approach for the appearance model, which uses a classifier that is trained...... method is evaluated on 250 low dose computed tomography images from a lung cancer screening trial. Our experiments showed that applying the region growing algorithm on the airway appearance model produces more complete airway segmentations, leading to on average 20% longer trees, and 50% less leakage...

  11. Inflammatory bowel disease and airway diseases

    Science.gov (United States)

    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

  12. Mucus hypersecretion in the airway

    Institute of Scientific and Technical Information of China (English)

    WANG Ke; WEN Fu-qiang; XU Dan

    2008-01-01

    @@ Mucus hypersecretion is a distinguishing feature of Chronic intlammation diseases,such as asthma,1chronic bronchitis.2 bronchiectasis3 and cystic fibrosis.4Mucus hypersecretion leads to impairment of mucociliary clearance,abnormal bacterial plantation,mucus plug in the airway,and dysfunction of gas exchange.5

  13. Nasal continuous positive airway pressure

    DEFF Research Database (Denmark)

    Scholze, Alexandra; Lamwers, Stephanie; Tepel, Martin;

    2012-01-01

    Obstructive sleep apnoea (OSA) is linked to increased cardiovascular risk. This risk can be reduced by nasal continuous positive airway pressure (nCPAP) treatment. As OSA is associated with an increase of several vasoconstrictive factors, we investigated whether nCPAP influences the digital volum...

  14. Airway nerves: in vitro electrophysiology.

    Science.gov (United States)

    Fox, Alyson

    2002-06-01

    Recording the activity of single airway sensory fibres or neuronal cell bodies in vitro has allowed detailed characterisation of fibre types and membrane properties. Fibre types can be identified by their conduction velocities and further studied by the application of drugs to their receptive field. C-fibres are sensitive to mechanical stimuli and a range of irritant chemicals (bradykinin, capsaicin, low pH, platelet-activating factor), whereas Adelta-fibres are relatively insensitive to chemical stimuli and appear to correlate to the rapidly adapting receptors identified in airways in vivo. Their site of origin also differs: upper airway C-fibres arise predominantly from the jugular ganglion and Adelta-fibres from the jugular and nodose ganglia. Intracellular recording from cell bodies in the ganglia has revealed a calcium-dependent potassium current common to many putative C-fibre cell bodies. This slow after hyperpolarisation current may be inhibited by stimuli that excite and sensitise C-fibres - this could be an important mechanism underlying the sensitisation of C-fibres in airway irritability.

  15. Mucoactive agents for airway mucus hypersecretory diseases.

    Science.gov (United States)

    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

  16. Up-Regulation of Endothelin Receptors Induced by Cigarette Smoke — Involvement of MAPK in Vascular and Airway Hyper-Reactivity

    Directory of Open Access Journals (Sweden)

    Yaping Zhang

    2010-01-01

    Full Text Available Cigarette smoke exposure is well known to cause cardiovascular and airway diseases, both of which are leading causes of death and disability in the world. However, the molecular mechanisms that link cigarette smoke to cardiovascular and airway diseases are not fully understood. Vascular and airway hyper-reactivity plays an important role in the pathogenesis of cardiovascular and airway diseases. Recent studies have demonstrated that endothelin receptor up-regulation mediates vascular and airway hyper-reactivity in response to endothelin-1 (ET-1, endothelin receptor agonist in cardiovascular and airway diseases. In the vasculature and airways, the main functional consequences of up-regulated endothelin receptors by cigarette smoke exposure are enhanced contraction and proliferation of the smooth muscle cells, which subsequently result in abnormal contraction (spasm and adverse proliferation (remodeling of the vasculature and airways. The structural alteration by adverse remodeling involves changes in cell growth, cell death, cell migration, and production or degradation of the extracellular matrix. This review focuses on cigarette smoke exposure that induces activation of intracellular mitogen-activated protein kinase (MAPK and subsequently results in the up-regulation of endothelin receptors in the vasculature and airways, which mediates vascular and airway hyper-reactivity, one of the important pathogenic characteristics of cardiovascular and airway diseases. Understanding the molecular mechanisms of how cigarette smoke causes up-regulation of endothelin receptors in the vasculature and airways may provide new strategies for the treatment of cigarette smoke—associated cardiovascular and lung diseases.

  17. Sarcoidosis of the upper and lower airways.

    Science.gov (United States)

    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.

  18. RAGE: a new frontier in chronic airways disease.

    Science.gov (United States)

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

    2012-11-01

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

  19. The cystic fibrosis lower airways microbial metagenome

    Science.gov (United States)

    Moran Losada, Patricia; Chouvarine, Philippe; Dorda, Marie; Hedtfeld, Silke; Mielke, Samira; Schulz, Angela; Wiehlmann, Lutz

    2016-01-01

    Chronic airway infections determine most morbidity in people with cystic fibrosis (CF). Herein, we present unbiased quantitative data about the frequency and abundance of DNA viruses, archaea, bacteria, moulds and fungi in CF lower airways. Induced sputa were collected on several occasions from children, adolescents and adults with CF. Deep sputum metagenome sequencing identified, on average, approximately 10 DNA viruses or fungi and several hundred bacterial taxa. The metagenome of a CF patient was typically found to be made up of an individual signature of multiple, lowly abundant species superimposed by few disease-associated pathogens, such as Pseudomonas aeruginosa and Staphylococcus aureus, as major components. The host-associated signatures ranged from inconspicuous polymicrobial communities in healthy subjects to low-complexity microbiomes dominated by the typical CF pathogens in patients with advanced lung disease. The DNA virus community in CF lungs mainly consisted of phages and occasionally of human pathogens, such as adeno- and herpesviruses. The S. aureus and P. aeruginosa populations were composed of one major and numerous minor clone types. The rare clones constitute a low copy genetic resource that could rapidly expand as a response to habitat alterations, such as antimicrobial chemotherapy or invasion of novel microbes. PMID:27730195

  20. Stimulation of cannabinoid CB1 receptors prevents nerve-mediated airway hyperreactivity in NGF-induced inflammation in mouse airways.

    Science.gov (United States)

    Bozkurt, Turgut Emrah; Larsson, Olivia; Adner, Mikael

    2016-04-05

    Cannabinoids are known to inhibit neuronal activity and have significant immunomodulatory effects which suggest a role in inflammatory airway diseases. In the present study, we tested the hypothesis that cannabinoids have both acute and chronic modulatory effects on nerve-mediated contractions in NGF-induced airway inflammation. Contractions induced by electrical field stimulation (EFS) were examined in tracheal segments isolated from male BALB/c mice. Tissues were both used fresh or after four days of culture with NGF to induce airway inflammation, and further exposed to cannabinoid receptor agonists. In order to evaluate nerve density, tracheal segments were also examined by immunohistochemistry after in vitro treatments. The CB1 receptor agonists ACEA and ACPA inhibited the constant train EFS-induced contractions in both fresh and NGF-exposed tracheas, an effect that could be blocked by the CB1 receptor antagonist AM251. Culturing the tissues with NGF up-regulated the frequency-dependent EFS-contractions in isolated tracheas. This up-regulation could be inhibited by concomitant treatment with ACEA or ACPA. The treatment with NGF and/or ACEA did not affect the potency or the maximum response to carbachol. In histological sections, it was recognized that the enhanced effect induced by NGF was associated with an increase in nerve density, which, similarly, could be prevented by ACEA treatment. This study shows that stimulation of cannabinoid CB1 receptors modifies the increase of neuronal activity and density in NGF-induced airway inflammation and directly inhibits cholinergic contractions in the airways by a presynaptic mechanism. These findings indicate a protective role of CB1 receptors in airway inflammation.

  1. Effects of Substrate Mechanics on Contractility of Cardiomyocytes Generated from Human Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Laurie B. Hazeltine

    2012-01-01

    Full Text Available Human pluripotent stem cell (hPSC- derived cardiomyocytes have potential applications in drug discovery, toxicity testing, developmental studies, and regenerative medicine. Before these cells can be reliably utilized, characterization of their functionality is required to establish their similarity to native cardiomyocytes. We tracked fluorescent beads embedded in 4.4–99.7 kPa polyacrylamide hydrogels beneath contracting neonatal rat cardiomyocytes and cardiomyocytes generated from hPSCs via growth-factor-induced directed differentiation to measure contractile output in response to changes in substrate mechanics. Contraction stress was determined using traction force microscopy, and morphology was characterized by immunocytochemistry for α-actinin and subsequent image analysis. We found that contraction stress of all types of cardiomyocytes increased with substrate stiffness. This effect was not linked to beating rate or morphology. We demonstrated that hPSC-derived cardiomyocyte contractility responded appropriately to isoprenaline and remained stable in culture over a period of 2 months. This study demonstrates that hPSC-derived cardiomyocytes have appropriate functional responses to substrate stiffness and to a pharmaceutical agent, which motivates their use in further applications such as drug evaluation and cardiac therapies.

  2. Poor spontaneous and oxytocin-stimulated contractility in human myometrium from postdates pregnancies.

    Directory of Open Access Journals (Sweden)

    Sarah Arrowsmith

    Full Text Available Prolongation of pregnancy i.e. going more than 10 days over the estimated due date, complicates up to 10% of all pregnancies and is associated with increased risk to both mother and fetus. Despite the obvious need for contractions of the uterus to end pregnancy, there have been no studies directly examining the role of uterine smooth muscle, myometrium, in the aetiology of prolonged pregnancy. This study tested the hypothesis that the intrinsic contractile characteristics of myometrium taken from women with prolonged pregnancy (>41 weeks and 3 days was reduced compared to those delivering at term (39-41 weeks. We recruited women undergoing Caesarean Section (CS delivery either pre-labour (n = 27 or in labour (n = 66 at term or postdates. The contractile ability of the postdates myometrium, whether spontaneous or elicited by oxytocin or high-K solution, was significantly reduced compared to term myometrium. These differences remained when adjusted for parity and other maternal characteristics. The findings remained significant when expressed per cross sectional area. Histological examination revealed no differences between the two groups. The contractile differences were however related to intracellular Ca transients suggesting an effect of [Ca] on reduced force production in the postdates group. In summary, myometrium from prolonged pregnancies contracts poorly in vitro even when stimulated with oxytocin and in active labour. Responses to high K(+ and measurements of Ca suggest that alterations in excitation contraction coupling, rather than any histological changes of the myometrium, may underlie the differences between term and postdates myometrium. We show that postdates pregnancy is associated with poor myometrial activity and suggest that this may contribute to increased myometrial quiescence and hence, prolonged gestation.

  3. Serotonin regulates contractile activity of the uterus in non-pregnant rabbits.

    Science.gov (United States)

    Lychkova, Alla Edward; De Pasquale, Valeria; Avallone, Luigi; Puzikov, Alexander Michael; Pavone, Luigi Michele

    2014-09-01

    Serotonin (5-HT) can stimulate the cholinergic system of the uterus by indirect actions on the modulation of reflexes and a direct action on smooth muscles. We investigated the role of 5-HT in the regulation of the cholinergic activity in the uterine parts of non-pregnant rabbits. The right vagus or pelvic nerve and the left sympathetic trunk were stimulated by an electrical field, and the uterine contractile activity was evaluated by measuring the amplitude and frequency of slow wave electromyogram (EMG), with the surface of microelectrodes applied to the uterus bottom, body, and cervix, respectively. Double stimulation of the vagus or pelvic nerve and the sympathetic trunk increased the frequency and the amplitude of the slow wave EMG in all the uterine parts. Furthermore, the administration of exogenous 5-HT increased the vagus or pelvic induced EMG activity in all parts of the uterus. Overall our results demonstrate that 5-HT enhances the vagus contractile activity with a magnitude of the effect decreasing from the bottom to the cervix, whereas 5-HT enhances the pelvic nerve contractile functions with a magnitude of the response increasing from the bottom to the cervix. The administration of droperidol, a 5-HT3 and 4 receptor inhibitor, and spiperone, a 5-HT2 receptor antagonist, inhibited the effect of the serotoninergic fibers of the sympathetic trunk to increase the vagus and pelvic nerve EMG activity. These data suggest that 5-HT stimulation of the parasympathetic nerves results in the induction of uterine contraction via the activation of 5-HT2, 3, and 4 receptor subfamilies.

  4. Active self-polarization of contractile cells in asymmetrically shaped domains

    Science.gov (United States)

    Zemel, A.; Safran, S. A.

    2007-08-01

    Mechanical forces generated by contractile cells allow the cells to sense their environment and to interact with other cells. By locally pulling on their environment, cells can sense and respond to mechanical features such as the local stress (or strain), the shape of a cellular domain, and the surrounding rigidity; at the same time, they also modify the mechanical state of the system. This creates a mechanical feedback loop that can result in self-polarization of cells. In this paper, we present a quantitative mechanical model that predicts the self-polarization of cells in spheroidally shaped domains, comprising contractile cells and an elastic matrix, that are embedded in a three-dimensional, cell-free gel. The theory is based on a generalization of the known results for passive inclusions in solids to include the effects of cell activity. We use the active cellular susceptibility tensor presented by Zemel [Phys. Rev. Lett. 97, 128103 (2006)] to calculate the polarization response and hence the elastic stress field developed by the cells in the cellular domain. The cell polarization is analyzed as a function of the shape and the elastic moduli of the cellular domain compared with the cell-free surrounding material. Consistent with experiment, our theory predicts the development of a stronger contractile force for cells in a gel that is surrounded by a large, cell-free material whose elastic modulus is stiffer than that of the gel that contains the cells. This provides a quantitative explanation of the differences in the development of cellular forces as observed in free and fixed gels. In the case of an asymmetrically shaped (spheroidal) domain of cells, we show that the anisotropic elastic field within the domain leads to a spontaneous self-polarization of the cells along the long axis of the domain.

  5. Facilitated ethanol metabolism promotes cardiomyocyte contractile dysfunction through autophagy in murine hearts

    Science.gov (United States)

    Guo, Rui; Hu, Nan; Kandadi, Machender R.; Ren, Jun

    2012-01-01

    Chronic drinking leads to myocardial contractile dysfunction where ethanol metabolism plays an essential role. Acetaldehyde, the main ethanol metabolite, mediates alcohol-induced cell injury although the underlying mechanism is still elusive. This study was designed to examine the mechanism involved in accelerated ethanol metabolism-induced cardiac defect with a focus on autophagy. Wild-type FVB and cardiac-specific overexpression of alcohol dehydrogenase mice were placed on a 4% nutrition-balanced alcohol diet for 8 weeks. Myocardial histology, immunohistochemistry, autophagy markers and signal molecules were examined. Expression of micro RNA miR-30a, a potential target of Beclin 1, was evaluated by real-time PCR. Chronic alcohol intake led to cardiac acetaldehyde accumulation, hypertrophy and overt autophagosome accumulation (LC3-II and Atg7), the effect of which was accentuated by ADH. Signaling molecules governing autophagy initiation including class III PtdIns3K, phosphorylation of mTOR and p70S6K were enhanced and dampened, respectively, following alcohol intake. These alcohol-induced signaling responses were augmented by ADH. ADH accentuated or unmasked alcohol-induced downregulation of Bcl-2, Bcl-xL and MiR-30a. Interestingly, ADH aggravated alcohol-induced p62 accumulation. Autophagy inhibition using 3-MA abolished alcohol-induced cardiomyocyte contractile anomalies. Moreover, acetaldehyde led to cardiomyocyte contractile dysfunction and autophagy induction, which was ablated by 3-MA. Ethanol or acetaldehyde increased GFP-LC3 puncta in H9c2 cells, the effect of which was ablated by 3-MA but unaffected by lysosomal inhibition using bafilomycin A1, E64D and pepstatin A. In summary, these data suggested that facilitated acetaldehyde production via ADH following alcohol intake triggered cardiac autophagosome formation along with impaired lysosomal degradation, en route to myocardial defect. PMID:22441020

  6. Paradoxical effects of ginkgolide B on cardiomyocyte contractile function in normal and high-glucose environments

    Institute of Scientific and Technical Information of China (English)

    Jihye KIM; Qun LI; Cindy X FANG; Jun REN

    2006-01-01

    Aim: Ginkgo biloba extract is a natural product used widely for cerebral and cardiovascular diseases. It is mainly composed of terpene lactones (ginkgolide A and B) and flavone glycosides (eg quercetin and kaempferol).To better understand the cardiac electromechanical action of Ginkgo biloba extract in normal and diabetic states, this study was designed to examine the effect of ginkgolide B on cardiomyocyte contractile function under normal and high-glucose environments. Methods: Isolated adult rat ventricular myocytes were cultured for 6 h in a serum-free medium containing either normal (NG;5.5 mmol/L) or high (HG;25.5 mmol/L) glucose with or without ginkgolide B (0.5-2.0μg/mL). Mechanical properties were evaluated using the IonOptix MyoCam system. Contractile properties analyzed included peak shortening (PS),maximal velocity of shortening/relengthening (+dl/dt),time-to-PS (TPS) and time-to-90% relengthening (TR90). Levels of essential Ca2+ regulatory proteins sarco(endo)plasmic reticulum Ca2+ -ATPase (SERCA2a),phospholamban (PLB) and Na+-Ca2+ exchanger (NCX) were assessed by Western blotting. Results: Ginkgolide B nullified HG-induced prolongation in TR90. However, ginkgolide B depressed PS.±dl/dt and shortened TPS in NG and HG cells. Ginkgolide B also prolonged TR90 in NG cells. Western blot analysis revealed that HG upregulated SERCA2a and downregulated PLB expression without affecting that of NCX. Ginkgolide B disrupted the NG-HG response pattern in SERCA2a and NCX without affecting that of PLB. Conclusion: Ginkgolide B affects cardiomyocyte contractile function under NG or HG environments in a paradoxical manner, which may be attributed to uneven action on Ca2+ regulatory proteins under NG and HG conditions.

  7. Modulation of airway inflammation and resistance in mice by a nicotinic receptor agonist.

    Science.gov (United States)

    Blanchet, M-R; Israël-Assayag, E; Cormier, Y

    2005-07-01

    Nicotinic agonists, including 1,1-dimethyl-4-phenylpiperazinium (DMPP), have anti-inflammatory properties and in some instances smooth muscle relaxing effects. Since inflammation and airway smooth muscle contraction are two major components of asthma, the present authors investigated the effects of DMPP on airway inflammation and airway resistance in a mouse model of asthma. Mice were sensitised and challenged with ovalbumin (OVA) and treated either intraperitoneally or intranasally with DMPP. The effect of DMPP was tested on airway inflammation, airway resistance and on the increase of intracellular calcium in bronchial smooth muscle cells. DMPP given either during sensitisation, OVA challenges or throughout the protocol prevented lung inflammation and decreased the serum level of OVA specific immunoglobulin E. DMPP administration reduced the number of total cells, lymphocytes and eosinophils in the bronchoalveolar lavage (BAL) fluid. Intranasal DMPP administration was as effective as dexamethasone (DEXA) in reducing total cell count and eosinophil counts in BAL fluid. DMPP, but not DEXA, reduced tissue inflammation. Intranasal DMPP, given 10 min before the test, reduced airway responsiveness to metacholine. DMPP also reduced the increase in intracellular calcium in response to bradykinin. In conclusion, these results show that 1,1-dimethyl-4-phenylpiperazinium reduces lung inflammation and prevents airway hyperresponsiveness in the mouse model of asthma.

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

    Science.gov (United States)

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

    2016-11-01

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

  9. Effects of obesity and weight loss on airway physiology and inflammation in asthma.

    Science.gov (United States)

    Sideleva, Olga; Black, Kendall; Dixon, Anne E

    2013-08-01

    Obesity is a major risk factor for asthma, but the mechanisms for the development of asthma in the setting of obesity are not known. The purpose of this article is to review the effects of obesity on airway inflammation in patients with asthma, and to discuss the effects of obesity on airway reactivity in patients with asthma. Obesity is particularly a risk factor for non-atopic asthma. Airway eosinophilic inflammation is not increased in obesity, in fact the preponderance of the evidence suggests that airway eosinophilia is decreased in obesity. There is some preliminary data suggesting that airway neutrophilia may be increased in obesity, and that this may be particularly related to dietary fats. Obesity also alters adaptive immunity, and may suppress lymphocyte function typically associated with asthmatic airway inflammation. Population based studies are somewhat inconsistent on the relationship between airway reactivity and asthma, however, recent studies in bariatric surgery show that weight loss surgery in severely obese patients decreases airway reactivity. One study suggested that this was particularly the case for those with low IgE (a marker of a low TH2 asthma phenotype), suggesting there may be some heterogeneity in asthma in obesity. There are likely to be two phenotypes of asthma in the obese: one group with early onset disease and asthma complicated by obesity, and a 2nd group with late onset disease with asthma consequent to obesity. Obesity leads to profound changes in airway function, and adaptive and innate immune responses which alter the nature of pre-existing allergic airway disease, and also cause new onset asthmatic disease.

  10. Comparative Study of laryngeal mask airway Supreme and laryngeal mask airway Classic in paralyzed patients

    OpenAIRE

    2016-01-01

    Aim and Objectives: The present study was undertaken to compare the LMA Classic with LMA Supreme in assessing the ease of insertion, number of attempts, time for insertion, any unwanted responses, stability of device, peak airway pressure, leak volume and leak fraction and postoperative complications.Methods: A total of 274 patients of ASA grade 1 and 2 were included in the study and divided into two groups with 137 patients in each group: the LMA Classic group (group C) and LMA Supreme group...

  11. Increased responsiveness to 5-hydroxytryptamine after antigenic challenge is inhibited by nifedipine and niflumic acid in rat trachea in vitro.

    Science.gov (United States)

    Moura, Carlos Tiago Martins; Bezerra, Fernanda Carvalho; de Moraes, Isabelle Maciel; Magalhães, Pedro Jorge Caldas; Capaz, Francisco Ruy

    2005-12-01

    Antigenic challenge often induces hyperreactivity in asthmatic airway, although the precise mechanism(s) underlying this increased responsiveness is not entirely known. Tracheae obtained from ovalbumin (OVA)-sensitized saline- or OVA-challenged rats were placed in 10 mL bath chambers for isometric recording of 5-hydroxytryptamine (5-HT)-induced contractions. 5-Hydroxytryptamine induced a stronger contraction compared with control in antigen-challenged trachea under normal or Ca2+-free conditions. In tracheae pretreated with the L-type Ca2+ channel blocker nifedipine (10(-6) mol/L) or the Ca2+-activated Cl- channel blocker niflumic acid (10(-4) mol/L), this hyperresponsiveness was not developed in either normal or Ca2+-free medium. The increased contractile response to 5-HT in allergic rat isolated trachea may be related to a greater ionic (Ca2+ and Cl-) channel involvement.

  12. β2-Agonist induced cAMP is decreased in asthmatic airway smooth muscle due to increased PDE4D

    NARCIS (Netherlands)

    Trian, Thomas; Burgess, Janette K; Niimi, Kyoko; Moir, Lyn M; Ge, Qi; Berger, Patrick; Liggett, Stephen B; Black, Judith L; Oliver, Brian G

    2011-01-01

    BACKGROUND AND OBJECTIVE: Asthma is associated with airway narrowing in response to bronchoconstricting stimuli and increased airway smooth muscle (ASM) mass. In addition, some studies have suggested impaired β-agonist induced ASM relaxation in asthmatics, but the mechanism is not known. OBJECTIVE:

  13. Hypoxia Potentiates Allergen Induction of HIF-1α, Chemokines, Airway Inflammation, TGF-β1, and Airway Remodeling in a mouse model

    Science.gov (United States)

    Baek, Kwang Je; Cho, Jae Youn; Rosenthal, Peter; Alexander, Laura E. Crotty; Nizet, Victor; Broide, David H.

    2013-01-01

    Whether hypoxia contributes to airway inflammation and remodeling in asthma is unknown. In this study we used mice exposed to a hypoxic environment during allergen challenge (simulating hypoxia during an asthma exacerbation) to investigate the contribution of hypoxia to airway inflammation and remodeling. Although neither hypoxia alone, nor OVA allergen alone, induced significant neutrophil influx into the lung, the combination of OVA and hypoxia induced a synergistic 27 fold increase in peribronchial neutrophils, enhanced expression of HIF-1α and one of its target genes, the CXC-family neutrophil chemokine KC. The combination of hypoxia and OVA allergen increased eotaxin-1, peribronchial eosinophils, lung TGB-β1 expression, and indices of airway remodeling (fibrosis and smooth muscle) compared to either stimulus alone. As hypoxia is present in >90% of severe asthma exacerbations, these findings underscore the potential of hypoxia to potentiate the airway inflammatory response, remodeling, and accelerate the decline of lung function in asthma exacerbations. PMID:23499929

  14. Studying airway smooth muscle in vivo with PS-OCT (Conference Presentation)

    Science.gov (United States)

    Adams, David C.; Hariri, Lida P.; Miller, Alyssa J.; Villiger, Martin; Holz, Jasmin; Szabari, Margit V.; Bouma, Brett E.; Luster, Andrew D.; Medoff, Benjamin D.; Suter, Melissa J.

    2016-03-01

    Present understanding of the pathophysiological mechanisms of asthma has been severely limited by the lack of an imaging modality capable of assessing airway conditions of asthma patients in vivo. Of particular interest is the role that airway smooth muscle (ASM) plays in the development of asthma and asthma related symptoms. We have developed novel techniques that we applied to Polarization Sensitive OCT (PS-OCT) in order to assess ASM, and validated our results with a substantial number of histological matches. In this work we employ our system in the study of ASM distributions in both asthmatic and non-asthmatic airways with data obtained in vivo from human volunteers. By isolating the ASM and performing volumetric analysis we obtain a variety of informative metrics such as ASM thickness and band width, and compare these quantities between subject types. Furthermore, we demonstrate that the degree of birefringence of the ASM can be associated with contractility, allowing us to estimate pressure exerted by ASM during contraction. We apply this technique to in vivo datasets from human volunteers as well.

  15. EFFECTS OF NOVEL PHOSPHODIESTERASE 4 INHIBITORS,ARIFLO AND SB242126A, ON ENDOTHELIN-1-INDUCED CONTRACTILITY OF ISOLATED HUMAN MYOMETRIUM

    Institute of Scientific and Technical Information of China (English)

    QI Hong(祁红); ZHANG Yong(张勇); CHEN Hong-zhuan(陈红专); Marie Jo LEROY; Charles ADVENIER

    2005-01-01

    Objective To investigate the effects of novel selective phosphodiesterase4 ( PDE4) inhibitors,Ariflo and SB242126A, on the endothelin-1 ( ET-1 ) - induced contractility occurring in nonpregnant human myometrium specimens. Methods Contractile responses to Ariflo and SB242126A were recorded cumulatively on isolated human longitudinal myometrium specimens obtained through surgical operations. Results Ariflo and SB242126A could inhibit both the frequency and amplitude of spontaneous contractions of myometrium (pD2 =8.6and 7. 6,n =4) and ET-1-induced contractions in a concentration-dependent manner (pD2 =7. 7 and 8. 1 ,n =5),with a potency similar to that of Rolipram. Conclusion Ariflo and SB242126A have an obvious inhibitory effect on endothelin-1-induced contractility of isolated human myometrium. The finding suggested that PDE4 inhibitors might have clinical potential in treating preterm labour and dysmenorrhoea.

  16. Effect of cholecystokinin and secretin on contractile activity of isolated gastric muscle strips in guinea pigs

    Institute of Scientific and Technical Information of China (English)

    Wei Li; Tian Zhen Zheng; Song Yi Qu

    2000-01-01

    AIM To study the effect of cholecystokininoctapeptide (CCK-8) and secretin on contractile activity of isolated gastric muscle strips in guinea pigs.METHODS Each isolated gastric muscle strip was suspended in a tissue chamber containing5 mL Krebs solution constantly warmed by water jacked at 37℃ and supplied with a mixed gas of 95% O2 and 5% CO2. After incubating for 1 h under 1 g tension, varied concentrations of CCK-8 and secretin were added respectively in the tissue chamber and the contractile response was measured isometrically on ink-writing recorders.circular and longitudinal muscular tension at rest (fundus LM 19.7%±2.1%, P<0.01; fundus CM 16.7%±2.2%, P<0.01; gastric body LM 16.8% ± 2.3%, P<0.01; body CM 12.7% ± 2.6%,P<0.01; antrum LM 12.3%±1.3%, P<0.01;antrum CM 16.7%±4.5%, P<0.01; pylous CM frequencies of body LM, both LM and CM of antrum and pylorus CM (5.1/min ± 0.2/min to 5.6/min ± 0.2/min, 5.9/min ± 0.2/min to 6.6/min ±0.1/min, 5.4/min ± 0.3/min to 6.3/min ± 0.4/min, 1.3/min ± 0.2/min to 2.3/min ± 0.3/min,amplitude of antral circular muscle (58.6%±pylorus CM (145.0% ± 23.8%, P<0.01), but decrease the mean contractile amplitude of gastric body and antral LM ( - 10.3% ± 3.3%, -10.5% ±4.6%, respectively, P<0.05). All the CCK-8 effects were not blocked by atropine or indomethacin. Secretin had no effect on gastric smooth muscle activity.CONCLUSION CCK-8 possessed both excitatory and inhibitory action on contractile activity of different regions of stomach in guinea pigs. Its action was not mediated via cholinergic M receptor and endogenous prostaglandin receptor.

  17. Contractile system of muscle as an auto-oscillator.

    Science.gov (United States)

    Ishiwata, Shin'ichi; Shimamoto, Yuta; Fukuda, Norio

    2011-05-01

    It is widely known that the contractile system of muscle takes on either the state of contraction (force-generating) or the state of relaxation (non-force-generating), which is known as the "all-or-nothing" principle. However, it is important to note that under intermediate activation conditions there exists a third state, which demonstrates auto-oscillatory properties and is termed SPOC (SPontaneous Oscillatory Contraction) state. We present a phase diagram, in which the states of the contractile system of muscle are divided into three regions consisting of contraction, relaxation and SPOC states. In the present review, experimental data related to the characteristics of SPOC are summarized and the mechanism of SPOC is described. We propose that the bio-motile system itself is an auto-oscillator, even in a membrane-less supra-molecular structure composed of an assembly of molecular motors and cytoskeletons (actin filaments and microtubules). Finally, the physiological significance of SPOC is discussed.

  18. Wound-induced contractile ring: a model for cytokinesis.

    Science.gov (United States)

    Darenfed, Hassina; Mandato, Craig A

    2005-12-01

    The actomyosin-based contractile ring is required for several biological processes, such as wound healing and cytokinesis of animal cells. Despite progress in defining the roles of this structure in both wound closure and cell division, we still do not fully understand how an actomyosin ring is spatially and temporally assembled, nor do we understand the molecular mechanism of its contraction. Recent results have demonstrated that microtubule-dependent local assembly of F-actin and myosin-II is present in wound closure and is similar to that in cytokinesis in animal cells. Furthermore, signalling factors such as small Rho GTPases have been shown to be involved in the regulation of actin dynamics during both processes. In this review we address recent findings in an attempt to better understand the dynamics of actomyosin contractile rings during wound healing as compared with the final step of animal cell division.

  19. Expression of mitochondrial regulatory genes parallels respiratory capacity and contractile function in a rat model of hypoxia-induced right ventricular hypertrophy

    Science.gov (United States)

    Chronic hypobaric hypoxia (CHH) increases load on the right ventricle (RV) resulting in RV hypertrophy. We hypothesized that CHH elicits distinct responses, i.e., the hypertrophied RV, unlike the left ventricle (LV), displaying enhanced mitochondrial respiratory and contractile function. Wistar rats...

  20. Intratumoral LIGHT Restores Pericyte Contractile Properties and Vessel Integrity

    OpenAIRE

    Anna Johansson-Percival; Zhi-Jie Li; Devina D. Lakhiani; Bo He; Xiao Wang; Juliana Hamzah; Ruth Ganss

    2015-01-01

    Normalization of the tumor vasculature is an emerging concept shown to improve anti-cancer therapy. However, there are currently no clinical interventions that effect long-lasting normalization. Here, we have developed a strategy for normalization by specific intratumoral delivery of LIGHT/TNFSF14. Importantly, normalization occurs by induced expression of contractile markers in intratumoral pericytes, which in turn re-establishes tight pericyte-vessel alignment. Restoring vessel integrity im...

  1. Effects of concentrated ambient particles on normal and hypersecretory airways in rats.

    Science.gov (United States)

    Harkema, Jack R; Keeler, Gerald; Wagner, James; Morishita, Masako; Timm, Edward; Hotchkiss, Jon; Marsik, Frank; Dvonch, Timothy; Kaminski, Norbert; Barr, Edward

    2004-08-01

    Epidemiological studies have reported that elevated levels of particulate air pollution in urban communities are associated with increases in attacks of asthma based on evidence from hospital admissions and emergency department visits. Principal pathologic features of chronic airway diseases, like asthma, are airway inflammation and mucous hypersecretion with excessive amounts of luminal mucus and increased numbers of mucus-secreting cells in regions of the respiratory tract that normally have few or no mucous cells (ie, mucous cell metaplasia). The overall goal of the present project was to understand the adverse effects of urban air fine particulate matter (PM2.5; aerodynamic diameter)* on normal airways and airways compromised with airway inflammation and excess mucus. Our project was specifically designed to (1) examine the chemical and physical characteristics of PM2.5 and other airborne pollutants in the outdoor air of a local Detroit community with a high incidence of childhood asthma; (2) determine the effects of this community-based PM2.5 on the airway epithelium in normal rats and rats compromised with preexisting hypersecretory airway diseases (ie, animal models of human allergic airway disease--asthma and chronic bronchitis); and (3) identify the chemical or physical components of PM2.5 that are responsible for PM2.5 -induced airway inflammation and epithelial alterations in these animal models. Two animal models of airway disease were used to examine the effects of PM2.5 exposure on preexisting hypersecretory airways: neutrophilic airway inflammation induced by endotoxin challenge in F344 rats and eosinophilic airway inflammation induced by ovalbumin (OVA) challenge in BN rats. A mobile air monitoring and exposure laboratory equipped with inhalation exposure chambers for animal toxicology studies, air pollution monitors, and particulate collection devices was used in this investigation. The mobile laboratory was parked in a community in southwestern

  2. Collective cancer cell invasion induced by coordinated contractile stresses.

    Science.gov (United States)

    Jimenez Valencia, Angela M; Wu, Pei-Hsun; Yogurtcu, Osman N; Rao, Pranay; DiGiacomo, Josh; Godet, Inês; He, Lijuan; Lee, Meng-Horng; Gilkes, Daniele; Sun, Sean X; Wirtz, Denis

    2015-12-22

    The physical underpinnings of fibrosarcoma cell dissemination from a tumor in a surrounding collagen-rich matrix are poorly understood. Here we show that a tumor spheroid embedded in a 3D collagen matrix exerts large contractile forces on the matrix before invasion. Cell invasion is accompanied by complex spatially and temporally dependent patterns of cell migration within and at the surface of the spheroids that are fundamentally different from migratory patterns of individual fibrosarcoma cells homogeneously distributed in the same type of matrix. Cells display a continuous transition from a round morphology at the spheroid core, to highly aligned elongated morphology at the spheroid periphery, which depends on both β1-integrin-based cell-matrix adhesion and myosin II/ROCK-based cell contractility. This isotropic-to-anisotropic transition corresponds to a shift in migration, from a slow and unpolarized movement at the core, to a fast, polarized and persistent one at the periphery. Our results also show that the ensuing collective invasion of fibrosarcoma cells is induced by anisotropic contractile stresses exerted on the surrounding matrix.

  3. Recovery in skeletal muscle contractile function after prolonged hindlimb immobilization

    Science.gov (United States)

    Fitts, R. H.; Brimmer, C. J.

    1985-01-01

    The effect of three-month hindlimb immobilization (IM) in rats on contractile properties of slow-twitch soleus (SOL), fast-twitch extensor digitorum longus, and fast-twitch superficial region of the vastus lateralis were measured after 0, 14, 28, 60, and 90 days of recovery on excized, horizontally suspended muscles stimulated electrically to maximal twitch tension. IM caused decreases in muscle-to-body weight ratios for all muscles, with no complete recovery even after 90 days. The contractile properties of the fast-twitch muscles were less affected by IM than those of the slow-twitch SOL. The SOL isometric twitch duration was shortened, due to reduced contraction and half-relaxation time, both of which returned to control levels after 14 days of recovery. The peak tetanic tension, P(O), g/sq cm,, decreased with IM by 46 percent in the SOL, but recovered by the 28th day. The maximum shortening velocity was not altered by IM in any of the muscles. Thus, normal contractile function could recover after prolonged limb IM.

  4. Effect of pentoxifylline on diaphragmatic contractility in septic rats.

    Directory of Open Access Journals (Sweden)

    Ujike,Yoshihito

    2008-04-01

    Full Text Available We investigated the effects of pentoxifylline (PTX on endotoxin-induced diaphragmatic dysfunction in vitro. Seventy-two rats were divided into 3 groups: a group in which endotoxin (20 mg/kg was injected intraperitoneally (endotoxin-group, a group in which PTX (100 mg/kg was injected intraperitoneally 30 min before injection of endotoxin (endotoxin-PTX group, and a group in which only saline was given (sham group. Left hemidiaphragms were removed 4 h after injection of endotoxin. We evaluated the diaphragmatic contractility by twitch characteristics and force-frequency curves in vitro. We measured serum TNF-alpha concentrations, diaphragm malondialdehyde (MDA levels (an index of oxygen-derived free radical-mediated lipid peroxidation, and diaphragm cAMP concentrations. Diaphragmatic force generation capacity was signifi cantly reduced after injection of endotoxin. Serum TNF-alpha concentrations and diaphragmatic MDA levels were significantly elevated after injection of endotoxin. PTX administration significantly improved diaphragmatic contractility and prevented the elevation in TNF-alpha concentrations and MDA levels after injection of endotoxin. There were no significant changes in the diaphragm cAMP concentrations among the 3 groups. These results demonstrated that PTX administration prevented endotoxin-induced diaphragmatic dysfunction without changing diaphragm muscle cAMP concentrations. The protective effects of PTX against endotoxininduced diaphragmatic contractile deterioration might be caused by attenuating TNF-alpha-mediated oxygen-derived free radical production.

  5. Surgical Treatment of Concomitant Atrial Fibrillation: Focus onto Atrial Contractility

    Directory of Open Access Journals (Sweden)

    Claudia Loardi

    2015-01-01

    Full Text Available Background. Maze procedure aims at restoring sinus rhythm (SR and atrial contractility (AC. This study evaluated multiple aspects of AC recovery and their relationship with SR regain after ablation. Methods. 122 mitral and fibrillating patients underwent radiofrequency Maze. Rhythm check and echocardiographic control of biatrial contractility were performed at 3, 6, 12, and 24 months postoperatively. A multivariate Cox analysis of risk factors for absence of AC recuperation was applied. Results. At 2-years follow-up, SR was achieved in 79% of patients. SR-AC coexistence increased from 76% until 98%, while biatrial contraction detection augmented from 84 to 98% at late stage. Shorter preoperative arrhythmia duration was the only common predictor of SR-AC restoring, while pulmonary artery pressure (PAP negatively influenced AC recuperation. Early AC restoration favored future freedom from arrhythmia recurrence. Minor LA dimensions correlated with improved future A/E value and vice versa. Right atrial (RA contractility restoring favored better left ventricular (LV performance and volumes. Conclusions. SR and left AC are two interrelated Maze objectives. Factors associated with arrhythmia “chronic state” (PAP and arrhythmia duration are negative predictors of procedural success. Our results suggest an association between postoperative LA dimensions and “kick” restoring and an influence of RA contraction onto LV function.

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

    LENUS (Irish Health Repository)

    Salah, Nazar

    2009-12-01

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

  7. Late sodium current is a new therapeutic target to improve contractility and rhythm in failing heart.

    Science.gov (United States)

    Undrovinas, Albertas; Maltsev, Victor A

    2008-10-01

    Most cardiac Na+ channels open transiently within milliseconds upon membrane depolarization and are responsible for the excitation propagation. However, some channels remain active during hundreds of milliseconds, carrying the so-called persistent or late Na+ current (I(NaL)) throughout the action potential plateau. I(NaL) is produced by special gating modes of the cardiac-specific Na+ channel isoform. Experimental data accumulated over the past decade show the emerging importance of this late current component for the function of both normal and especially failing myocardium, where I(NaL) is reportedly increased. Na+ channels represent a multi-protein complex and its activity is determined not only by the pore-forming alpha subunit but also by its auxiliary beta subunits, cytoskeleton, and by Ca2+ signaling and trafficking proteins. Remodeling of this protein complex and intracellular signaling pathways may lead to alterations of I(NaL) in pathological conditions. Increased I(NaL) and the corresponding Na+ influx in failing myocardium contribute to abnormal repolarization and an increased cell Ca2+ load. Interventions designed to correct I(NaL) rescue normal repolarization and improve Ca2+ handling and contractility of the failing cardiomyocytes. New therapeutic strategies to target both arrhythmias and deficient contractility in HF may not be limited to the selective inhibition of I(NaL) but also include multiple indirect, modulatory (e.g. Ca(2+)- or cytoskeleton- dependent) mechanisms of I(NaL) function.

  8. Oxidative Stress in Hypertensive Patients Induces an Increased Contractility in Vein Grafts Independent of Endothelial Function

    Directory of Open Access Journals (Sweden)

    Claudio Joo Turoni

    2011-01-01

    Full Text Available Objective. To evaluate the impact of oxidative stress on vascular reactivity to vasoconstrictors and on nitric oxide (NO bioavailability in saphenous vein (SV graft with endothelial dysfunction from hypertensive patients (HT. Methods. Endothelial function, vascular reactivity, oxidative state, nitrites and NO release were studied in isolated SV rings from HT and normotensive patients (NT. Only rings with endothelial dysfunction were used. Results. HT rings presented a hyperreactivity to vasoconstrictors that was reverted by diphenylene iodonium (DPI. In NT, no effect of DPI was obtained, but Nω-nitro-L-arginine methyl ester (L-NAME increased the contractile response. NO was present in SV rings without endothelial function. Nitrites were higher in NT than in HT (1066.1 ± 86.3 pmol/mg; n=11 versus 487.8 ± 51.6; n=23; P<0.01 and inhibited by nNOS inhibitor. L-arginine reversed this effect. Antioxidant agents increased nitrites and NO contents only in HT. The anti-nNOS-stained area by immunohistochemistry was higher in NT than HT. HT showed an elevation of oxidative state. Conclusions. Extraendothelial NO counter-regulates contractility in SV. However, this action could be altered in hypertensive situations by an increased oxidative stress or a decreased ability of nNOS to produce NO. Further studies should be performed to evaluate the implication of these results in graft patency rates.

  9. Sealing of Airway Fistulas for Metallic Covered Z-type Stents

    Directory of Open Access Journals (Sweden)

    Hongwu WANG

    2011-08-01

    Full Text Available Background and objective Treating airway fistulas, including esophagorespiratory fistulas (ERFs, bronchopleural fistulas (BPFs, and tracheomediastinal fistulas (TMFs, is difficult. The aim of this study is to evaluate the safety and clinical efficacy of metallic covered Z-type stents (CZTS for the treatment of airway fistulas through bronchoscopy or fluroscopy. Methods Thirty-eight patients with fistulas between the esophagus, mediastina, and airways (32 ERFs, 5 BPFs, and 1 TMF were retrospectively reviewed after treatment with covered metallic esophageal and airway stents. The fistulas were caused by esophageal (n=26, bronchogenic (n=11, and thyroid (n=1 carcinomas. Results Forty-six fistulas were found in 38 patients. The fistula size ranged from 0.5 cm to 7.0 cm. Forty airway covered metal stents (24 Y-type, 8 L-type, and 8 I-type and 24 esophageal metal stents were placed. Complete responses to the sealing effects of fistulas were noted in 4.3% of all the fistulas, 60.9% showed complete clinical responses, 23.9% showed partial responses, and 10.9% showed no response. An effectivity rate of 89.1% was observed, and the median survival duration of all patients was 5 months. Conclusion The use of CZTS appears to be safe and feasible for the palliative treatment of ERFs, BPFs, and TMFs. Airway stent placement is recommended for patients with ERF. In the event that airway stents fail, esophageal stents should be given. Airway bifurcation stents were observed to be especially suitable for the sealing of fistulas near the trachea carina.

  10. Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency.

    Science.gov (United States)

    Richmond, Bradley W; Brucker, Robert M; Han, Wei; Du, Rui-Hong; Zhang, Yongqin; Cheng, Dong-Sheng; Gleaves, Linda; Abdolrasulnia, Rasul; Polosukhina, Dina; Clark, Peter E; Bordenstein, Seth R; Blackwell, Timothy S; Polosukhin, Vasiliy V

    2016-04-05

    Mechanisms driving persistent airway inflammation in chronic obstructive pulmonary disease (COPD) are incompletely understood. As secretory immunoglobulin A (SIgA) deficiency in small airways has been reported in COPD patients, we hypothesized that immunobarrier dysfunction resulting from reduced SIgA contributes to chronic airway inflammation and disease progression. Here we show that polymeric immunoglobulin receptor-deficient (pIgR(-/-)) mice, which lack SIgA, spontaneously develop COPD-like pathology as they age. Progressive airway wall remodelling and emphysema in pIgR(-/-) mice are associated with an altered lung microbiome, bacterial invasion of the airway epithelium, NF-κB activation, leukocyte infiltration and increased expression of matrix metalloproteinase-12 and neutrophil elastase. Re-derivation of pIgR(-/-) mice in germ-free conditions or treatment with the anti-inflammatory phosphodiesterase-4 inhibitor roflumilast prevents COPD-like lung inflammation and remodelling. These findings show that pIgR/SIgA deficiency in the airways leads to persistent activation of innate immune responses to resident lung microbiota, driving progressive small airway remodelling and emphysema.

  11. β-Citronellol, an alcoholic monoterpene with inhibitory properties on the contractility of rat trachea

    Directory of Open Access Journals (Sweden)

    T.B. Vasconcelos

    2016-01-01

    Full Text Available β-Citronellol is an alcoholic monoterpene found in essential oils such Cymbopogon citratus (a plant with antihypertensive properties. β-Citronellol can act against pathogenic microorganisms that affect airways and, in virtue of the popular use of β-citronellol-enriched essential oils in aromatherapy, we assessed its pharmacologic effects on the contractility of rat trachea. Contractions of isolated tracheal rings were recorded isometrically through a force transducer connected to a data-acquisition device. β-Citronellol relaxed sustained contractions induced by acetylcholine or high extracellular potassium, but half-maximal inhibitory concentrations (IC50 for K+-elicited stimuli were smaller than those for cholinergic contractions. It also inhibited contractions induced by electrical field stimulation or sodium orthovanadate with pharmacologic potency equivalent to that seen against acetylcholine-induced contractions. When contractions were evoked by selective recruitment of Ca2+ from the extracellular medium, β-citronellol preferentially inhibited contractions that involved voltage-operated (but not receptor-operated pathways. β-Citronellol (but not verapamil inhibited contractions induced by restoration of external Ca2+ levels after depleting internal Ca2+ stores with the concomitant presence of thapsigargin and recurrent challenge with acetylcholine. Treatment of tracheal rings with L-NAME, indomethacin or tetraethylammonium did not change the relaxing effects of β-citronellol. Inhibition of transient receptor potential vanilloid subtype 1 (TRPV1 or transient receptor potential ankyrin 1 (TRPA1 receptors with selective antagonists caused no change in the effects of β-citronellol. In conclusion, β-citronellol exerted inhibitory effects on rat tracheal rings, with predominant effects on contractions that recruit Ca2+ inflow towards the cytosol by voltage-gated pathways, whereas it appears less active against contractions elicited by

  12. Effect of noni (Morinda citrifolia Linn.) fruit and its bioactive principles scopoletin and rutin on rat vas deferens contractility: an ex vivo study.

    Science.gov (United States)

    Pandy, Vijayapandi; Narasingam, Megala; Kunasegaran, Thubasni; Murugan, Dharmani Devi; Mohamed, Zahurin

    2014-01-01

    This study examined the effect of methanolic extract of Morinda citrifolia Linn. (MMC) and its bioactive principles, scopoletin and rutin, on dopamine- and noradrenaline-evoked contractility in isolated rat vas deferens preparations. MMC (1-40 mg/mL), scopoletin (1-200 μg/mL), and rutin hydrate (0.6-312.6 μg/mL) dose-dependently inhibited the contractility evoked by submaximal concentrations of both dopamine and noradrenaline, respectively. Haloperidol and prazosin, reference dopamine D2, and α 1-adrenoceptors antagonists significantly reversed the dopamine- and noradrenaline-induced contractions, respectively, in a dose-dependent manner. Interestingly, MMC per se at higher doses (60-100 mg/mL) showed dose-dependent contractile response in rat vas deferens which was partially inhibited by high doses of haloperidol but not by prazosin. These results demonstrated the biphasic effects of MMC on dopaminergic system; that is, antidopaminergic effect at lower concentrations (60 mg/mL). However, similar contractile response at high doses of scopoletin (0.5-5 mg/mL) and rutin hydrate (0.5-5 mg/mL) per se was not observed. Therefore, it can be concluded that the bioactive principles of MMC, scopoletin, and rutin might be responsible for the antidopaminergic and antiadrenergic activities of MMC.

  13. Effect of Noni (Morinda citrifolia Linn. Fruit and Its Bioactive Principles Scopoletin and Rutin on Rat Vas Deferens Contractility: An Ex Vivo Study

    Directory of Open Access Journals (Sweden)

    Vijayapandi Pandy

    2014-01-01

    Full Text Available This study examined the effect of methanolic extract of Morinda citrifolia Linn. (MMC and its bioactive principles, scopoletin and rutin, on dopamine- and noradrenaline-evoked contractility in isolated rat vas deferens preparations. MMC (1–40 mg/mL, scopoletin (1–200 μg/mL, and rutin hydrate (0.6–312.6 μg/mL dose-dependently inhibited the contractility evoked by submaximal concentrations of both dopamine and noradrenaline, respectively. Haloperidol and prazosin, reference dopamine D2, and α1-adrenoceptors antagonists significantly reversed the dopamine- and noradrenaline-induced contractions, respectively, in a dose-dependent manner. Interestingly, MMC per se at higher doses (60–100 mg/mL showed dose-dependent contractile response in rat vas deferens which was partially inhibited by high doses of haloperidol but not by prazosin. These results demonstrated the biphasic effects of MMC on dopaminergic system; that is, antidopaminergic effect at lower concentrations (60 mg/mL. However, similar contractile response at high doses of scopoletin (0.5–5 mg/mL and rutin hydrate (0.5–5 mg/mL per se was not observed. Therefore, it can be concluded that the bioactive principles of MMC, scopoletin, and rutin might be responsible for the antidopaminergic and antiadrenergic activities of MMC.

  14. Method for 3D Airway Topology Extraction

    Directory of Open Access Journals (Sweden)

    Roman Grothausmann

    2015-01-01

    Full Text Available 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.

  15. Airway Tree Extraction with Locally Optimal Paths

    DEFF Research Database (Denmark)

    Lo, Pechin Chien Pau; Sporring, Jon; Pedersen, Jesper Johannes Holst

    2009-01-01

    This paper proposes a method to extract the airway tree from CT images by continually extending the tree with locally optimal paths. This is in contrast to commonly used region growing based approaches that only search the space of the immediate neighbors. The result is a much more robust method...... for tree extraction that can overcome local occlusions. The cost function for obtaining the optimal paths takes into account of an airway probability map as well as measures of airway shape and orientation derived from multi-scale Hessian eigen analysis on the airway probability. Significant improvements...

  16. AIRWAY VISUALIZATION: EYES SEE WHAT MIND KNOWS.

    Science.gov (United States)

    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.

  17. Cholinergic Regulation of Airway Inflammation and Remodelling

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    Saeed Kolahian

    2012-01-01

    Full Text Available Acetylcholine is the predominant parasympathetic neurotransmitter in the airways that regulates bronchoconstriction and mucus secretion. Recent findings suggest that acetylcholine regulates additional functions in the airways, including inflammation and remodelling during inflammatory airway diseases. Moreover, it has become apparent that acetylcholine is synthesized by nonneuronal cells and tissues, including inflammatory cells and structural cells. In this paper, we will discuss the regulatory role of acetylcholine in inflammation and remodelling in which we will focus on the role of the airway smooth muscle cell as a target cell for acetylcholine that modulates inflammation and remodelling during respiratory diseases such as asthma and COPD.

  18. Ultrasonography in the management of the airway

    DEFF Research Database (Denmark)

    Kristensen, M S

    2011-01-01

    In this study, it is described how to use ultrasonography (US) for real-time imaging of the airway from the mouth, over pharynx, larynx, and trachea to the peripheral alveoli, and how to use this in airway management. US has several advantages for imaging of the airway - it is safe, quick...... or the esophagus by placing the ultrasound probe transversely on the neck at the level of the suprasternal notch during intubation, thus confirming intubation without the need for ventilation or circulation. US can be applied before anesthesia induction and diagnose several conditions that affect airway management...

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

    NARCIS (Netherlands)

    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

    2007-01-01

    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 o

  20. Notch Ligand DLL4 Alleviates Allergic Airway Inflammation via Induction of a Homeostatic Regulatory Pathway

    Science.gov (United States)

    Huang, Miao-Tzu; Chen, Yi-Lien; Lien, Chia-I; Liu, Wei-Liang; Hsu, Li-Chung; Yagita, Hideo; Chiang, Bor-Luen

    2017-01-01

    Notch is a pleiotropic signaling family that has been implicated in pathogenesis of allergic airway diseases; however, the distinct function of individual Notch ligands remains elusive. We investigated whether Notch ligands, Jagged1 and DLL4, exert differential effects in OVA-induced allergic asthma. We found that whilst Jagged1 inhibition mitigated Th2-dominated airway inflammation, blockage of DLL4 aggravated the Th2-mediated asthma phenotypes. Additionally, Jagged1 signaling blockage enhanced IL-17 production and neutrophilic airway infiltration. In vitro, exogenous Jagged1 induced Th2-skewed responses, whereas augmented DLL4 signaling displayed a dual role by promoting expansion of both Tregs and Th17. In vivo, DLL4 blockage impaired Treg differentiation which plausibly resulted in exaggerated asthma phenotypes. On the contrary, administration of DLL4-expressing antigen-presenting cells promoted endogenous Treg expansion and ameliorated the allergic responses. Therefore, whilst Jagged1 induces Th2-skewed inflammation, DLL4 elicits an essential self-regulatory mechanism via Treg-mediated pathway that counterbalances Jagged1-induced Th2 responses and facilitates resolution of the airway inflammation to restore homeostasis. These findings uncover a disparate function of Jagged1 and DLL4 in allergic airway diseases, hinting feasibility of Notch ligand-specific targeting in therapy of allergic airway diseases. PMID:28262821

  1. Effect of fenoterol-induced constitutive beta(2)-adrenoceptor activity on contractile receptor function in airway smooth muscle

    NARCIS (Netherlands)

    de Vries, B; Roffel, AF; Zaagsma, J; Meurs, H

    2001-01-01

    In the present study, we investigated the effect of fenoterol-induced constitutive beta (2)-adrenoceptor activity on muscarinic receptor agonist- and histamine-induced bovine tracheal smooth muscle contractions. Bovine tracheal smooth muscle strips were incubated with 10 muM fenoterol or vehicle for

  2. Modelling maternal obesity: the effects of a chronic high-fat, high-cholesterol diet on uterine expression of contractile-associated proteins and ex vivo contractile activity during labour in the rat.

    Science.gov (United States)

    Muir, Ronan; Ballan, Jean; Clifford, Bethan; McMullen, Sarah; Khan, Raheela; Shmygol, Anatoly; Quenby, Siobhan; Elmes, Matthew

    2016-02-01

    Maternal obesity is associated with prolonged and dysfunctional labour and emergency caesarean section, but the mechanisms are unknown. The present study investigated the effects of an adiposity-inducing high-fat, high-cholesterol (HFHC) diet on uterine contractile-associated protein (CAP) expression and ex vivo uterine contractility in term non-labouring (TNL) and term labouring (TL) rats. Female rats were fed either control chow (CON n=20) or HFHC (n=20) diet 6 weeks before conception and during pregnancy. On gestational day 21 (TNL) or day 22 (TL) CON and HFHC (n=10) rats were killed to determine plasma cholesterol, triacylglycerol and progesterone concentrations and collection of myometrium for contractility studies and expression of CAPs caveolin-1 (Cav-1), connexin-43 (CX-43) and it's phosphorylated form (pCX-43), oxytocin receptor (OXTR) and cyclooxygenase-2 (COX-2). HFHC feeding increased visceral fat (P≤0.001), plasma cholesterol (P≤0.001) and triacylglycerol (P=0.039) concentrations. Stage of labour effected uterine expression of CAV-1 (Pobesity. Uterine dose response to oxytocin was blunted during labour in HFHC rats with a log EC50 of -8.84 compared with -10.25 M in CON for integral activity (Pobese women.

  3. Inhibition of aldose reductase prevents experimental allergic airway inflammation in mice.

    Directory of Open Access Journals (Sweden)

    Umesh C S Yadav

    Full Text Available BACKGROUND: The bronchial asthma, a clinical complication of persistent inflammation of the airway and subsequent airway hyper-responsiveness, is a leading cause of morbidity and mortality in critically ill patients. Several studies have shown that oxidative stress plays a key role in initiation as well as amplification of inflammation in airways. However, still there are no good anti-oxidant strategies available for therapeutic intervention in asthma pathogenesis. Most recent studies suggest that polyol pathway enzyme, aldose reductase (AR, contributes to the pathogenesis of oxidative stress-induced inflammation by affecting the NF-kappaB-dependent expression of cytokines and chemokines and therefore inhibitors of AR could be anti-inflammatory. Since inhibitors of AR have already gone through phase-III clinical studies for diabetic complications and found to be safe, our hypothesis is that AR inhibitors could be novel therapeutic drugs for the prevention and treatment of asthma. Hence, we investigated the efficacy of AR inhibition in the prevention of allergic responses to a common natural airborne allergen, ragweed pollen that leads to airway inflammation and hyper-responsiveness in a murine model of asthma. METHODS AND FINDINGS: Primary Human Small Airway Epithelial Cells (SAEC were used to investigate the in vitro effects of AR inhibition on ragweed pollen extract (RWE-induced cytotoxic and inflammatory signals. Our results indicate that inhibition of AR prevents RWE -induced apoptotic cell death as measured by annexin-v staining, increase in the activation of NF-kappaB and expression of inflammatory markers such as inducible nitric oxide synthase (iNOS, cycloxygenase (COX-2, Prostaglandin (PG E(2, IL-6 and IL-8. Further, BALB/c mice were sensitized with endotoxin-free RWE in the absence and presence of AR inhibitor and followed by evaluation of perivascular and peribronchial inflammation, mucin production, eosinophils infiltration and

  4. Salvinorin A Inhibits Airway Hyperreactivity Induced by Ovalbumin Sensitization

    OpenAIRE

    Rossi, Antonietta; Caiazzo, Elisabetta; Bilancia, Rossella; Riemma, Maria A.; Pagano, Ester; Cicala, Carla; Ialenti, Armando; Jordan K. Zjawiony; Izzo, Angelo A; Capasso, Raffaele; Roviezzo, Fiorentina

    2017-01-01

    Salvinorin A, a neoclerodane diterpene isolated from Salvia divinorum, exerts a number of pharmacological actions which are not solely limited to the central nervous system. Recently it has been demonstrated that Salvinorin A inhibits acute inflammatory response affecting leukotriene (LT) production. Since LTs are potent lipid mediators implicated in allergic diseases, we evaluated the effect of Salvinorin A on allergic inflammation and on airways following sensitization in the mouse. Mi