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Sample records for airway dilator muscles

  1. Histochemical properties of upper airway muscles: comparison of dilator and nondilator muscles.

    PubMed

    Bracher, A; Coleman, R; Schnall, R; Oliven, A

    1997-05-01

    The upper airway dilator muscles (UADMs) represent a subgroup of muscles in the pharyngeal area which, in addition to their roles in mastication, vocalization, etc., also have an important respiratory function. Failure of these muscles to maintain upper airway patency during sleep is important in the development of the obstructive sleep apnoea syndrome. In the present study, we evaluated the histochemical properties of the UADMs and compared them to those of neighbouring muscles without respiratory functions, and to the diaphragm, to determine whether the UADMs are specifically adapted to their respiratory role. Our results, both in dogs and rats, indicate that the dilator and nondilator upper airway muscles are similar and differ from the diaphragm. In rats, there were significantly less type I fibres (<12% as compared to 42% for the diaphragm) and more type IIb fibres (39-67% as compared to 27% for the diaphragm). A similar pattern was seen in dogs: type I fibres <38% as compared to 46% for the diaphragm, and type IIb fibres, 29-35% as compared to 10% for the diaphragm. These findings suggest that the upper airway dilator muscles are not specifically designed for their respiratory role. They may fail in the presence of increased loads, often encountered in patients with obstructive sleep apnoea, unless appropriate adaptive structural changes take place. PMID:9163636

  2. Bitter tasting compounds dilate airways by inhibiting airway smooth muscle calcium oscillations and calcium sensitivity

    PubMed Central

    Tan, Xiahui; Sanderson, Michael J

    2014-01-01

    Background and Purpose While selective, bitter tasting, TAS2R agonists can relax agonist-contracted airway smooth muscle (ASM), their mechanism of action is unclear. However, ASM contraction is regulated by Ca2+ signalling and Ca2+ sensitivity. We have therefore investigated how the TAS2R10 agonists chloroquine, quinine and denotonium regulate contractile agonist-induced Ca2+ signalling and sensitivity. Experimental Approach Airways in mouse lung slices were contracted with either methacholine (MCh) or 5HT and bronchodilation assessed using phase-contrast microscopy. Ca2+ signalling was measured with 2-photon fluorescence microscopy of ASM cells loaded with Oregon Green, a Ca2+-sensitive indicator (with or without caged-IP3). Effects on Ca2+ sensitivity were assessed on lung slices treated with caffeine and ryanodine to permeabilize ASM cells to Ca2+. Key Results The TAS2R10 agonists dilated airways constricted by either MCh or 5HT, accompanied by inhibition of agonist-induced Ca2+ oscillations. However, in non-contracted airways, TAS2R10 agonists, at concentrations that maximally dilated constricted airways, did not evoke Ca2+ signals in ASM cells. Ca2+ increases mediated by the photolysis of caged-IP3 were also attenuated by chloroquine, quinine and denotonium. In Ca2+-permeabilized ASM cells, the TAS2R10 agonists dilated MCh- and 5HT-constricted airways. Conclusions and Implications TAS2R10 agonists reversed bronchoconstriction by inhibiting agonist-induced Ca2+ oscillations while simultaneously reducing the Ca2+ sensitivity of ASM cells. Reduction of Ca2+ oscillations may be due to inhibition of Ca2+ release through IP3 receptors. Further characterization of bronchodilatory TAS2R agonists may lead to the development of novel therapies for the treatment of bronchoconstrictive conditions. PMID:24117140

  3. Neostigmine but not sugammadex impairs upper airway dilator muscle activity and breathing

    PubMed Central

    Eikermann, M.; Zaremba, S.; Malhotra, A.; Jordan, A. S.; Rosow, C.; Chamberlin, N. L.

    2008-01-01

    Background Cholinesterase inhibitor-based reversal agents, given in the absence of neuromuscular block, evoke a partial upper airway obstruction by decreasing skeletal upper airway muscle function. Sugammadex reverses neuromuscular block by encapsulating rocuronium. However, its effects on upper airway integrity and breathing are unknown. Methods Fifty-one adult male rats were anaesthetized with isoflurane, tracheostomized, and a femoral artery and vein were cannulated. First, we compared the efficacy of sugammadex 15 mg kg−1 and neostigmine 0.06 mg kg−1 to reverse respiratory effects of rocuronium-induced partial paralysis [train-of-four ratio (T4/T1)=0.5]. Subsequently, we compared the safety of sugammadex and neostigmine given after recovery of the T4/T1 to 1, by measuring phasic genioglossus activity and breathing. Results During partial paralysis (T4/T1=0.5), time to recovery of minute volume to baseline values was 10.9 (2), 75.8 (18), and 153 (54) s with sugammadex, neostigmine, and placebo, respectively (sugammadex was significantly faster than neostigmine and placebo, P<0.05). Recovery of T4/T1 was also faster for sugammadex than neostigmine and placebo. Neostigmine administration after complete recovery of T4/T1 decreased upper airway dilator muscle activity to 64 (30)% of baseline and decreased tidal volume (P<0.05 for both variables), whereas sugammadex had no effect on either variable. Conclusions In contrast to neostigmine, which significantly impairs upper airway dilator muscle activity when given after recovery from neuromuscular block, a reversal dose of sugammadex given under the same conditions does not affect genioglossus muscle activity and normal breathing. Human studies will be required to evaluate the clinical relevance of our findings. PMID:18559352

  4. Motor unit regulation of mammalian pharyngeal dilator muscle activity.

    PubMed Central

    van Lunteren, E; Dick, T E

    1989-01-01

    The present study examined the cellular regulation of one of the pharyngeal dilator muscles, the geniohyoid, by assessing its motor unit (MU) behavior in anesthetized cats. During spontaneous breathing, MU that (a) were active during inspiration only (I-MU) and (b) were active during both inspiration and expiration (I/E-MU) were identified. I-MU had a later inspiratory onset time and a shorter duration of inspiratory firing than did I/E-MU (P less than 0.002 and P less than 0.0001, respectively). I-MU were usually quiescent whereas I/E-MU were usually active during the last 20% of inspiration. I/E-MU fired more rapidly (P less than 0.00001) and for relatively longer periods of time (P less than 0.00001) during inspiration than during expiration. End-expiratory airway occlusion (preventing lung expansion during inspiration) augmented the inspiratory activity of both I-MU and I/E-MU. Conversely, end-expiratory airway occlusion reduced the absolute and relative firing durations (P less than 0.002 and P less than 0.00002, respectively) and the firing frequency (P less than 0.001) of I/E-MU activity during expiration. These results indicate that (a) the complex pattern of pharyngeal dilator muscle activity is due to the integrated activity of a heterogeneous group of MU, (b) changes in the degree to which pharyngeal dilator muscles are active result from combinations of MU recruitment/decruitment and modulations of the frequency and duration of MU firing, and (c) gating of lung-volume afferent information occurs during the respiratory cycle. PMID:2760202

  5. Muscles involved in naris dilation and nose motion in rat

    PubMed Central

    Deschênes, Martin; Haidarliu, Sebastian; Demers, Maxime; Moore, Jeffrey; Kleinfeld, David; Ahissar, Ehud

    2016-01-01

    In a number of mammals muscle dilator nasi (naris) is known as a muscle that reduces nasal airflow resistance by dilating the nostrils. Here we show that in rats the tendon of this muscle inserts into the aponeurosis above the nasal cartilage. Electrical stimulation of this muscle lifts the nose and deflects it sideway towards the side of stimulation, but does not change the size of the nares. In the head-fixed alert rat, electromyographic activity of muscle dilator nasi is tightly coupled to nose motion, not to opening of the nares. Yet, contraction of muscle dilator nasi occurs during the pre-inspiratory phase of the respiratory cycle, suggesting a role in sniffing and sampling odorants. We also show that opening of the nares results from contraction of pars maxillaris profunda of the muscle nasolabialis profundus. This muscle attaches to the outer wall of the nasal cartilage and to the plate of the mystacial pad. Contraction of this muscle exerts a dual action: it pulls the lateral nasal cartilage outwardly, thus dilating the naris, and it drags the plate of the mystacial pad rostralward, provoking a slight retraction of the whiskers. On the basis of these results, we propose that muscle dilator nasi of the rat be renamed muscle deflector nasi, and that pars maxillaris profunda of the muscle nasolabialis profundus be named muscle dilator nasi. PMID:25257748

  6. Kinematic MRI study of upper-airway biomechanics using electrical muscle stimulation

    NASA Astrophysics Data System (ADS)

    Brennick, Michael J.; Margulies, Susan S.; Ford, John C.; Gefter, Warren B.; Pack, Allan I.

    1997-05-01

    We have developed a new and powerful method to study the movement and function of upper airway muscles. Our method is to use direct electrical stimulation of individual upper airway muscles, while performing state of the art high resolution magnetic resonance imaging (MRI). We have adapted a paralyzed isolated UA cat model so that positive or negative static pressure in the UA can be controlled at specific levels while electrical muscle stimulation is applied during MRI. With these techniques we can assess the effect of muscle stimulation on airway cross-sectional area compliance and soft tissue motion. We are reporting the preliminary results and MRI techniques which have enabled us to examine changes in airway dimensions which result form electrical stimulation of specific upper airway dilator muscles. The results of this study will be relevant to the development of new clinical treatments for obstructive sleep apnea by providing new information as to exactly how upper airway muscles function to dilate the upper airway and the strength of stimulation required to prevent the airway obstruction when overall muscle tone may not be sufficient to maintain regular breathing.

  7. Genetic differences in airway smooth muscle function.

    PubMed

    Martin, James G; Jo, Taisuke

    2008-01-01

    The genetic basis for airway smooth muscle properties is poorly explored. Contraction and relaxation are altered in asthmatic airway smooth muscle, but the basis for the alterations and the role that muscle-specific susceptibility genes may play is largely unexplored. Alterations in the beta-adrenergic receptor, signaling pathways affecting inositol phosphate metabolism, adenylyl and guanylyl cyclase activity, and contractile proteins such as the myosin heavy chain are all suggested by experimental model systems. Significant changes in proliferative and secretory capacities of asthmatic smooth muscle are also demonstrated, but their genetic basis also requires elucidation. Certain asthma-related genes such as ADAM33, although potentially important for smooth muscle function, have been incompletely explored. PMID:18094088

  8. Effects of theophylline on pharyngeal dilator and diaphragm muscle contractile properties.

    PubMed

    van Lunteren, E; Vafaie, H; Miller, M J

    1996-01-01

    Theophylline alleviates central and obstructive apneas of prematurity, and may improve adult obstructive sleep apnea. One mechanism of action appears to be a stimulatory effect on the motor output to upper airway dilator muscles. The purpose of the present study was to determine whether theophylline might have a second mechanism of action, namely that of improving the force and/or endurance of the pharyngeal dilator musculature. Rat sternohyoid muscle strips were studied in vitro and compared to diaphragm strips. The isometric twitch force and twitch kinetics of neither muscle were altered by theophylline (100 mg/l). Theophylline significantly slowed the rate at which the diaphragm fatigued during intermittent 40-Hz stimulation (p < 0.001). In contrast, theophylline produced no improvement in the fatigue resistance of the sternohyoid muscle. The degree of force potentiation during the early portion of the fatigue protocol was not altered by theophylline for either muscle. These results suggest that the mechanism by which theophylline improves obstructive apnea is unlikely to be due to a beneficial effect on pharyngeal dilator muscle force or endurance. PMID:8966372

  9. Origins of increased airway smooth muscle mass in asthma.

    PubMed

    Berair, Rachid; Saunders, Ruth; Brightling, Christopher E

    2013-01-01

    Asthma is characterized by both chronic inflammation and airway remodeling. Remodeling--the structural changes seen in asthmatic airways--is pivotal in the pathogenesis of the disease. Although significant advances have been made recently in understanding the different aspects of airway remodeling, the exact biology governing these changes remains poorly understood. There is broad agreement that, in asthma, increased airway smooth muscle mass, in part due to smooth muscle hyperplasia, is a very significant component of airway remodeling. However, significant debate persists on the origins of these airway smooth muscle cells. In this review article we will explore the natural history of airway remodeling in asthma and we will discuss the possible contribution of progenitors, stem cells and epithelial cells in mesenchymal cell changes, namely airway smooth muscle hyperplasia seen in the asthmatic airways. PMID:23742314

  10. Motor unit number in a small facial muscle, dilator naris.

    PubMed

    Patel-Khurana, Nilam; Fregosi, Ralph F

    2015-10-01

    A loss of functioning motor units underlies many neuromuscular disorders. The facial nerve innervates the muscles of facial expression, including nasal muscles, which also play an important role in the regulation of airflow resistance. It is difficult to accurately assess motor unit number in the facial muscles, because the muscles are difficult to activate in isolation. Here, we apply the manual McComas method to estimate the number of motor units in a nasal dilator muscle. EMG of the dilator naris was recorded during graded stimulation of the zygomatic branch of the facial nerve in 26 subjects (12 males and 14 females), aged 20-41 years. Each subject was studied twice, on separate days, to estimate method reproducibility. As a check on our use of the McComas method, we also estimated motor unit number in the first dorsal interosseus muscle (FDI) of six subjects, as the muscle is also small and has been studied with the McComas method. Reproducibility was evaluated with a rigorous statistical approach, the Bland-Altman procedure. We estimate that dilator naris is composed of 75 ± 15.6 (SD) motor units, compared to 144 ± 35.5 in FDI. The coefficient of variation for test-retest reproducibility of dilator naris motor unit estimates was 29.6 %, similar to separate-day reproducibility reported for other muscles. Recording and stimulation were done with surface electrodes, and the recordings were of high quality and reproducible. This simple technique could be applied clinically to track motor neuron loss and to monitor facial nerve integrity. PMID:26169101

  11. Effects of tracheal airway occlusion on hyoid muscle length and upper airway volume.

    PubMed

    van Lunteren, E; Haxhiu, M A; Cherniack, N S

    1989-12-01

    Complex relationships exist among electromyograms (EMGs) of the upper airway muscles, respective changes in muscle length, and upper airway volume. To test the effects of preventing lung inflation on these relationships, recordings were made of EMGs and length changes of the geniohyoid (GH) and sternohyoid (SH) muscles as well as of tidal changes in upper airway volume in eight anesthetized cats. During resting breathing, tracheal airway occlusion tended to increase the inspiratory lengthening of GH and SH. In response to progressive hypercapnia, the GH eventually shortened during inspiration in all animals; the extent of muscle shortening was minimally augmented by airway occlusion despite substantial increases in EMGs. SH lengthened during inspiration in six of eight animals under hypercapnic conditions, and in these cats lengthening was greater during airway occlusion even though EMGs increased. Despite the above effects on SH and GH length, upper airway tidal volume was increased significantly by tracheal occlusion under hypercapnic conditions. These data suggest that the thoracic and upper airway muscle reflex effects of preventing lung inflation during inspiration act antagonistically on hyoid muscle length, but, because of the mechanical arrangement of the hyoid muscles relative to the airway and thorax, they act agonistically to augment tidal changes in upper airway volume. The augmentation of upper airway tidal volume may occur in part as a result of the effects of thoracic movements being passively transmitted through the hyoid muscles. PMID:2606835

  12. Effect of hypothyroidism on myosin heavy chain expression in rat pharyngeal dilator muscles.

    PubMed

    Petrof, B J; Kelly, A M; Rubinstein, N A; Pack, A I

    1992-07-01

    Although the association between hypothyroidism and obstructive sleep apnea is well established, the effect of thyroid hormone deficiency on contractile proteins in pharyngeal dilator muscles responsible for maintaining upper airway patency is unknown. In the present study, the effects of hypothyroidism on myosin heavy chain (MHC) expression were examined in the sternohyoid, geniohyoid, and genioglossus muscles of adult rats (n = 20). The relative proportions of MHC isoforms present were determined using MHC-specific monoclonal antibodies and oligonucleotide probes. All control muscles showed a paucity of type I MHC fibers, with greater than 90% of fibers containing fast-twitch type II MHCs. In the genioglossus muscle, a population of non-IIa non-IIb fast-twitch type II fibers (putatively identified as type IIx MHC fibers) were detected. Hypothyroidism induced significant changes in MHC expression in all muscles studied. In the sternohyoid, type I fibers increased from 6.2 to 16.9%, whereas type IIa fibers increased from 25.9 to 30.7%. Type I fibers in the geniohyoid increased from 1.2 to 12.8%, whereas type IIa fibers increased from 34.1 to 42.7%. The genioglossus showed the smallest relative increase in type I expression but the greatest induction of type IIa MHC. None of the muscles examined demonstrated reinduction of embryonic or neonatal MHC in response to thyroid hormone deficiency. In summary, hypothyroidism alters the MHC profile of pharyngeal dilators in a muscle-specific manner. These changes may play a role in the pathogenesis of obstructive apnea in hypothyroid patients. PMID:1506366

  13. Cortex phellodendri Extract Relaxes Airway Smooth Muscle

    PubMed Central

    Jiang, Qiu-Ju; Chen, Weiwei; Dan, Hong; Tan, Li; Zhu, He; Yang, Guangzhong; Shen, Jinhua; Peng, Yong-Bo; Zhao, Ping; Xue, Lu; Yu, Meng-Fei; Ma, Liqun; Si, Xiao-Tang; Wang, Zhuo; Dai, Jiapei; Qin, Gangjian; Zou, Chunbin; Liu, Qing-Hua

    2016-01-01

    Cortex phellodendri is used to reduce fever and remove dampness and toxin. Berberine is an active ingredient of C. phellodendri. Berberine from Argemone ochroleuca can relax airway smooth muscle (ASM); however, whether the nonberberine component of C. phellodendri has similar relaxant action was unclear. An n-butyl alcohol extract of C. phellodendri (NBAECP, nonberberine component) was prepared, which completely inhibits high K+- and acetylcholine- (ACH-) induced precontraction of airway smooth muscle in tracheal rings and lung slices from control and asthmatic mice, respectively. The contraction induced by high K+ was also blocked by nifedipine, a selective blocker of L-type Ca2+ channels. The ACH-induced contraction was partially inhibited by nifedipine and pyrazole 3, an inhibitor of TRPC3 and STIM/Orai channels. Taken together, our data demonstrate that NBAECP can relax ASM by inhibiting L-type Ca2+ channels and TRPC3 and/or STIM/Orai channels, suggesting that NBAECP could be developed to a new drug for relieving bronchospasm. PMID:27239213

  14. Non-Surgical Management of Critically Compromised Airway Due to Dilatation of Interposed Colon

    PubMed Central

    Min, Jinsoo

    2016-01-01

    We present a rare case of critically compromised airway secondary to a massively dilated sequestered colon conduit after several revision surgeries. A 71-year-old male patient had several operations after the diagnosis of gastric cancer. After initial treatment of pneumonia in the pulmonology department, he was transferred to the surgery department for feeding jejunostomy because of recurrent aspiration. However, he had respiratory failure requiring mechanical ventilation. The chest computed tomography (CT) scan showed pneumonic consolidation at both lower lungs and massive dilatation of the substernal interposed colon compressing the trachea. The dilated interposed colon was originated from the right colon, which was sequestered after the recent esophageal reconstruction with left colon interposition resulting blind pouch at both ends. It was treated with CT-guided pigtail catheter drainage via right supraclavicular route, which was left in place for 2 weeks, and then removed. The patient remained well clinically, and was discharged home. PMID:27066087

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

    PubMed Central

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

    2008-01-01

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

  16. Airway smooth muscle in the pathophysiology and treatment of asthma

    PubMed Central

    Solway, Julian

    2013-01-01

    Airway smooth muscle (ASM) plays an integral part in the pathophysiology of asthma. It is responsible for acute bronchoconstriction, which is potentiated by constrictor hyperresponsiveness, impaired relaxation and length adaptation. ASM also contributes to airway remodeling and inflammation in asthma. In light of this, ASM is an important target in the treatment of asthma. PMID:23305987

  17. Bronchospasm and its biophysical basis in airway smooth muscle

    PubMed Central

    Fredberg, Jeffrey J

    2004-01-01

    Airways hyperresponsiveness is a cardinal feature of asthma but remains unexplained. In asthma, the airway smooth muscle cell is the key end-effector of bronchospasm and acute airway narrowing, but in just the past five years our understanding of the relationship of responsiveness to muscle biophysics has dramatically changed. It has become well established, for example, that muscle length is equilibrated dynamically rather than statically, and that non-classical features of muscle biophysics come to the forefront, including unanticipated interactions between the muscle and its time-varying load, as well as the ability of the muscle cell to adapt rapidly to changes in its dynamic microenvironment. These newly discovered phenomena have been described empirically, but a mechanistic basis to explain them is only beginning to emerge. PMID:15084229

  18. Evidence of hypoxic tolerance in weak upper airway muscle from young mdx mice.

    PubMed

    Burns, David P; O'Halloran, Ken D

    2016-06-01

    Duchenne muscular dystrophy (DMD) is a genetic disease characterised by deficiency in the protein dystrophin. The respiratory system is weakened and patients suffer from sleep disordered breathing and hypoventilation culminating in periods of hypoxaemia. We examined the effects of an acute (6h) hypoxic stress on sternohyoid muscle function (representative pharyngeal dilator). 8 week old male, wild-type (WT; C57BL/10ScSnJ; n=18) and mdx (C57BL/10ScSn-Dmd(mdx)/J; n=16) mice were exposed to sustained hypoxia (FIO2=0.10) or normoxia. Muscle functional properties were examined ex vivo. Additional WT (n=5) and mdx (n=5) sternohyoid muscle was exposed to an anoxic challenge. Sternohyoid dysfunction was observed in mdx mice with significant reductions in force and power. Following exposure to the acute in vivo hypoxic stress, WT sternohyoid muscle showed evidence of functional impairment (reduced force, work and power). Conversely, mdx sternohyoid showed an apparent tolerance to the acute hypoxic stress. This tolerance was not maintained for mdx following a severe hypoxic stress. A dysfunctional upper airway muscle phenotype is present at 8 weeks of age in the mdx mouse, which may have implications for the control of airway patency in DMD. Hypoxic tolerance in mdx respiratory muscle is suggestive of adaptation to chronic hypoxia, which could be present due to respiratory morbidity. We speculate a role for hypoxia in mdx respiratory muscle morbidity. PMID:26691169

  19. Airway smooth muscle responsiveness from dogs with airway hyperresponsiveness after O/sub 3/ inhalation

    SciTech Connect

    Jones, G.L.; O'Byrne, P.M.; Pashley, M.; Serio, R.; Jury, J.; Lane, C.G.; Daniel, E.E.

    1988-07-01

    Airway hyperresponsiveness occurs after inhalation of O3 in dogs. The purpose of this study was to examine the responsiveness of trachealis smooth muscle in vitro to electrical field stimulation, exogenous acetylcholine, and potassium chloride from dogs with airway hyperresponsiveness after inhaled O3 in vivo and to compare this with the responsiveness of trachealis muscle from control dogs. In addition, excitatory junction potentials were measured with the use of single and double sucrose gap techniques in both groups of dogs to determine whether inhaled O3 affects the release of acetylcholine from parasympathetic nerves in trachealis muscle. Airway hyperresponsiveness developed in all dogs after inhaled O3 (3 ppm for 30 min). The acetylcholine provocative concentration decreased from 4.11 mg/ml before O3 inhalation to 0.66 mg/ml after O3 (P less than 0.0001). The acetylcholine provocative concentration increased slightly after control inhalation of dry room air. Airway smooth muscle showed increased responses to both electrical field stimulation and exogenous acetylcholine but not to potassium chloride in preparations from dogs with airway hyperresponsiveness in vivo. The increased response to electrical field stimulation was not associated with a change in excitatory junctional potentials. These results suggest that a postjunctional alteration in trachealis muscle function occurs after inhaled O3 in dogs, which may account for airway hyperresponsiveness after O3 in vivo.

  20. Smooth muscle in human bronchi is disposed to resist airway distension.

    PubMed

    Gazzola, Morgan; Henry, Cyndi; Couture, Christian; Marsolais, David; King, Gregory G; Fredberg, Jeffrey J; Bossé, Ynuk

    2016-07-15

    Studying airway smooth muscle (ASM) in conditions that emulate the in vivo environment within which the bronchi normally operate may provide important clues regarding its elusive physiological function. The present study examines the effect of lengthening and shortening of ASM on tension development in human bronchial segments. ASM from each bronchial segment was set at a length approximating in situ length (Linsitu). Bronchial tension was then measured during a slow cyclical strain (0.004Hz, from 0.7Linsitu to 1.3Linsitu) in the relaxed state and at graded levels of activation by methacholine. In all cases, tension was greater at longer ASM lengths, and greater during lengthening than shortening. The threshold of methacholine concentration that was required for ASM to account for bronchial tension across the entire range of ASM lengths tested was on average smaller by 2.8 logs during lengthening than during shortening. The length-dependency of ASM tension, together with this lower threshold of methacholine concentration during lengthening versus shortening, suggest that ASM has a greater ability to resist airway dilation during lung inflation than to narrow the airways during lung deflation. More than serving to narrow the airway, as has long been thought, these data suggest that the main function of ASM contraction is to limit airway wall distension during lung inflation. PMID:27095271

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

    PubMed Central

    2013-01-01

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

  2. Critical role of actin-associated proteins in smooth muscle contraction, cell proliferation, airway hyperresponsiveness and airway remodeling.

    PubMed

    Tang, Dale D

    2015-01-01

    Asthma is characterized by airway hyperresponsiveness and airway remodeling, which are largely attributed to increased airway smooth muscle contractility and cell proliferation. It is known that both chemical and mechanical stimulation regulates smooth muscle contraction. Recent studies suggest that contractile activation and mechanical stretch induce actin cytoskeletal remodeling in smooth muscle. However, the mechanisms that control actin cytoskeletal reorganization are not completely elucidated. This review summarizes our current understanding regarding how actin-associated proteins may regulate remodeling of the actin cytoskeleton in airway smooth muscle. In particular, there is accumulating evidence to suggest that Abelson tyrosine kinase (Abl) plays a critical role in regulating airway smooth muscle contraction and cell proliferation in vitro, and airway hyperresponsiveness and remodeling in vivo. These studies indicate that Abl may be a novel target for the development of new therapy to treat asthma. PMID:26517982

  3. Epithelial modulation of preterm airway smooth muscle contraction.

    PubMed

    Panitch, H B; Wolfson, M R; Shaffer, T H

    1993-03-01

    To determine if epithelium from immature airways can modulate the responsiveness of smooth muscle, we studied paired trachealis muscle strips from preterm sheep. The epithelium was removed from one strip and left undisturbed in the other. Concentration-effect (CE) curves to acetylcholine (ACh), KCl, and isoproterenol were obtained. To evaluate maturational effects, responses to ACh and isoproterenol were studied in trachealis strips from adult airways. Maximal stress (Po) to ACh increased after epithelium removal in preterm (P < 0.05) but not adult strips. Epithelium removal caused a leftward shift of the ACh CE curves in both preterm and adult strips (P < 0.001) and a decrease in the dose required to achieve a one-half maximal response (ED50) in both preterm (P < 0.005) and adult strips (P < 0.05). The magnitude of the change in Po as well as in the ED50 for ACh between preterms and adults was similar. Epithelium removal did not alter either the Po or the CE curves of preterm strips stimulated by KCl. Response to isoproterenol in precontracted strips was enhanced in the presence of an intact epithelium in both groups (P < 0.05). These data demonstrate that preterm airway epithelium is able to modulate the responsiveness of smooth muscle. Additionally, the magnitude of the effect is unchanged with maturation. We speculate that damage of airway epithelium from mechanical ventilation may contribute to the increased incidence of airway hyperreactivity observed in preterm infants. PMID:8482688

  4. Airway hyperresponsiveness; smooth muscle as the principal actor

    PubMed Central

    Lauzon, Anne-Marie; Martin, James G.

    2016-01-01

    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. PMID:26998246

  5. Airway hyperresponsiveness; smooth muscle as the principal actor.

    PubMed

    Lauzon, Anne-Marie; Martin, James G

    2016-01-01

    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. PMID:26998246

  6. The Three A's in Asthma - Airway Smooth Muscle, Airway Remodeling & Angiogenesis.

    PubMed

    Keglowich, L F; Borger, P

    2015-01-01

    Asthma affects more than 300 million people worldwide and its prevalence is still rising. Acute asthma attacks are characterized by severe symptoms such as breathlessness, wheezing, tightness of the chest, and coughing, which may lead to hospitalization or death. Besides the acute symptoms, asthma is characterized by persistent airway inflammation and airway wall remodeling. The term airway wall remodeling summarizes the structural changes in the airway wall: epithelial cell shedding, goblet cell hyperplasia, hyperplasia and hypertrophy of the airway smooth muscle (ASM) bundles, basement membrane thickening and increased vascular density. Airway wall remodeling starts early in the pathogenesis of asthma and today it is suggested that remodeling is a prerequisite for other asthma pathologies. The beneficial effect of bronchial thermoplasty in reducing asthma symptoms, together with the increased potential of ASM cells of asthmatics to produce inflammatory and angiogenic factors, indicate that the ASM cell is a major effector cell in the pathology of asthma. In the present review we discuss the ASM cell and its role in airway wall remodeling and angiogenesis. PMID:26106455

  7. The Three A’s in Asthma – Airway Smooth Muscle, Airway Remodeling & Angiogenesis

    PubMed Central

    Keglowich, L.F; Borger, P

    2015-01-01

    Asthma affects more than 300 million people worldwide and its prevalence is still rising. Acute asthma attacks are characterized by severe symptoms such as breathlessness, wheezing, tightness of the chest, and coughing, which may lead to hospitalization or death. Besides the acute symptoms, asthma is characterized by persistent airway inflammation and airway wall remodeling. The term airway wall remodeling summarizes the structural changes in the airway wall: epithelial cell shedding, goblet cell hyperplasia, hyperplasia and hypertrophy of the airway smooth muscle (ASM) bundles, basement membrane thickening and increased vascular density. Airway wall remodeling starts early in the pathogenesis of asthma and today it is suggested that remodeling is a prerequisite for other asthma pathologies. The beneficial effect of bronchial thermoplasty in reducing asthma symptoms, together with the increased potential of ASM cells of asthmatics to produce inflammatory and angiogenic factors, indicate that the ASM cell is a major effector cell in the pathology of asthma. In the present review we discuss the ASM cell and its role in airway wall remodeling and angiogenesis. PMID:26106455

  8. CD38 and Airway hyperresponsiveness: Studies on human airway smooth muscle cells and mouse models

    PubMed Central

    Guedes, Alonso GP; Deshpande, Deepak A; Dileepan, Mythili; Walseth, Timothy F; Panettieri, Reynold A; Subramanian, Subbaya; Kannan, Mathur S

    2015-01-01

    Asthma is an inflammatory disease in which altered calcium regulation, contractility and airway smooth muscle (ASM) proliferation contribute to airway hyperresponsiveness and airway wall remodeling. The enzymatic activity of CD38, a cell-surface protein expressed in human ASM cells, generates calcium mobilizing second messenger molecules such as cyclic ADP-ribose. CD38 expression in human ASM cells is augmented by cytokines (e.g. TNF-α) that requires activation of MAP kinases and the transcription factors, NF-ƙB and AP-1 and post-transcriptionally regulated by miR-140-3p and miR-708 by binding to 3’ Untranslated Region of CD38 as well as by modulating the activation of signaling mechanisms involved in its regulation. Mice deficient in CD38 exhibit reduced airway responsiveness to inhaled methacholine relative to response in wild-type mice. Intranasal challenge of CD38 deficient mice with TNF-α or IL-13, or the environmental fungus Alternaria alternata, causes significantly attenuated methacholine responsiveness compared to wild-type mice, with comparable airway inflammation. Reciprocal bone marrow transfer studies revealed partial restoration of airway hyperresponsiveness to inhaled methacholine in the Cd38 deficient mice. These studies provide evidence for CD38 involvement in the development of airway hyperresponsiveness, a hallmark feature of asthma. Future studies aimed at drug discovery and delivery targeting CD38 expression and/or activity are warranted. PMID:25594684

  9. Emergence of airway smooth muscle functions related to structural malleability

    PubMed Central

    Fredberg, Jeffrey J.

    2011-01-01

    The function of a complex system such as a smooth muscle cell is the result of the active interaction among molecules and molecular aggregates. Emergent macroscopic manifestations of these molecular interactions, such as the length-force relationship and its associated length adaptation, are well documented, but the molecular constituents and organization that give rise to these emergent muscle behaviors remain largely unknown. In this minireview, we describe emergent properties of airway smooth muscle that seem to have originated from inherent fragility of the cellular structures, which has been increasingly recognized as a unique and important smooth muscle attribute. We also describe molecular interactions (based on direct and indirect evidence) that may confer malleability on fragile structural elements that in turn may allow the muscle to adapt to large and frequent changes in cell dimensions. Understanding how smooth muscle works may hinge on how well we can relate molecular events to its emergent macroscopic functions. PMID:21127211

  10. MicroRNA regulation of airway smooth muscle function.

    PubMed

    Sun, Maoyun; Lu, Quan

    2016-06-01

    Airway smooth muscle (ASM) controls airway narrowing and plays a pivotal role in the pathogenesis of asthma. MicroRNAs are small yet powerful gene tuners that regulate diverse cellular processes. Recent studies have demonstrated the versatile role of microRNAs in regulating multiple ASM phenotypes that are critically involved in asthma pathogenesis. These ASM phenotypes include proliferation, cell size, chemokine secretion, and contractility. Here we review microRNA-mediated regulation of ASM functions and discuss the potential of microRNAs as a novel class of therapeutic targets to improve ASM function for asthma therapy. PMID:26812790

  11. Angiogenesis is induced by airway smooth muscle strain.

    PubMed

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

    2007-10-01

    Angiogenesis is an important feature of airway remodeling in both chronic asthma and chronic obstructive pulmonary disease (COPD). Airways in those conditions are exposed to excessive mechanical strain during periods of acute exacerbations. We recently reported that mechanical strain of human airway smooth muscle (HASM) led to an increase in their proliferation and migration. Sustained growth in airway smooth muscle in vivo requires an increase in the nutritional supply to these muscles, hence angiogenesis. In this study, we examined the hypothesis that cyclic mechanical strain of HASM produces factors promoting angiogenic events in the surrounding vascular endothelial cells. Our results show: 1) a significant increase in human lung microvascular endothelial cell (HMVEC-L) proliferation, migration, and tube formation following incubation in conditioned media (CM) from HASM cells exposed to mechanical strain; 2) mechanical strain of HASM cells induced VEGF expression and release; 3) VEGF neutralizing antibodies inhibited the proliferation, migration, and tube formations of HMVEC-L induced by the strained airway smooth muscle CM; 4) mechanical strain of HASM induced a significant increase in hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA and protein, a transcription factor required for VEGF gene transcription; and 5) mechanical strain of HASM induced HIF-1alpha/VEGF through dual phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and ERK pathways. In conclusion, exposing HASM cells to mechanical strain induces signal transduction pathway through PI3K/Akt/mTOR and ERK pathways that lead to an increase in HIF-1alpha, a transcription factor required for VEGF expression. VEGF release by mechanical strain of HASM may contribute to the angiogenesis seen with repeated exacerbation of asthma and COPD. PMID:17693481

  12. Dramatic dilatation of the upper airway secondary to a Valsalva manoeuvre in a lateral cephalometric teleradiograph of a child.

    PubMed

    Varela, M; Quiñones, D; Martínez-Pérez, D

    2010-12-01

    Radiographs are routinely used by orthodontists for the planning of treatment for their patients and they can, in some cases, play a decisive role in the early diagnosis of some unexpected medical or surgical disorders. This report presents the case of a substantial dilatation of the upper airway in a 10-year-old girl, which was attributed to a forced Valsalva manoeuvre. The diagnosis was confirmed upon repetition of the teleradiograph with the mouth open. PMID:21062946

  13. Dramatic dilatation of the upper airway secondary to a Valsalva manoeuvre in a lateral cephalometric teleradiograph of a child

    PubMed Central

    Varela, M; Quiñones, D; Martínez-Pérez, D

    2010-01-01

    Radiographs are routinely used by orthodontists for the planning of treatment for their patients and they can, in some cases, play a decisive role in the early diagnosis of some unexpected medical or surgical disorders. This report presents the case of a substantial dilatation of the upper airway in a 10-year-old girl, which was attributed to a forced Valsalva manoeuvre. The diagnosis was confirmed upon repetition of the teleradiograph with the mouth open. PMID:21062946

  14. The Pivotal Role of Airway Smooth Muscle in Asthma Pathophysiology

    PubMed Central

    Ozier, Annaïg; Allard, Benoit; Bara, Imane; Girodet, Pierre-Olivier; Trian, Thomas; Marthan, Roger; Berger, Patrick

    2011-01-01

    Asthma is characterized by the association of airway hyperresponsiveness (AHR), inflammation, and remodelling. The aim of the present article is to review the pivotal role of airway smooth muscle (ASM) in the pathophysiology of asthma. ASM is the main effector of AHR. The mechanisms of AHR in asthma may involve a larger release of contractile mediators and/or a lower release of relaxant mediators, an improved ASM cell excitation/contraction coupling, and/or an alteration in the contraction/load coupling. Beyond its contractile function, ASM is also involved in bronchial inflammation and remodelling. Whereas ASM is a target of the inflammatory process, it can also display proinflammatory and immunomodulatory functions, through its synthetic properties and the expression of a wide range of cell surface molecules. ASM remodelling represents a key feature of asthmatic bronchial remodelling. ASM also plays a role in promoting complementary airway structural alterations, in particular by its synthetic function. PMID:22220184

  15. Increase in passive stiffness at reduced airway smooth muscle length: potential impact on airway responsiveness.

    PubMed

    Bossé, Ynuk; Solomon, Dennis; Chin, Leslie Y M; Lian, Kevin; Paré, Peter D; Seow, Chun Y

    2010-03-01

    The amplitude of strain in airway smooth muscle (ASM) produced by oscillatory perturbations such as tidal breathing or deep inspiration (DI) influences the force loss in the muscle and is therefore a key determinant of the bronchoprotective and bronchodilatory effects of these breathing maneuvers. The stiffness of unstimulated ASM (passive stiffness) directly influences the amplitude of strain. The nature of the passive stiffness is, however, not clear. In this study, we measured the passive stiffness of ovine ASM at different muscle lengths (relative to in situ length, which was used as a reference length, L(ref)) and states of adaptation to gain insights into the origin of this muscle property. The results showed that the passive stiffness was relatively independent of muscle length, possessing a constant plateau value over a length range from 0.62 to 1.25 L(ref). Following a halving of ASM length, passive stiffness decreased substantially (by 71%) but redeveloped over time ( approximately 30 min) at the shorter length to reach 65% of the stiffness value at L(ref), provided that the muscle was stimulated to contract at least once over a approximately 30-min period. The redevelopment and maintenance of passive stiffness were dependent on the presence of Ca(2+) but unaffected by latrunculin B, an inhibitor of actin filament polymerization. The maintenance of passive stiffness was also not affected by blocking myosin cross-bridge cycling using a myosin light chain kinase inhibitor or by blocking the Rho-Rho kinase (RhoK) pathway using a RhoK inhibitor. Our results suggest that the passive stiffness of ASM is labile and capable of redevelopment following length reduction. Redevelopment and maintenance of passive stiffness following muscle shortening could contribute to airway hyperresponsiveness by attenuating the airway wall strain induced by tidal breathing and DI. PMID:20008114

  16. Airway smooth muscle growth from the perspective of animal models.

    PubMed

    Martin, James G; Ramos-Barbón, David

    2003-09-16

    Airway smooth muscle maintains airway tone and may assist in adjusting ventilation distribution within the normal lung. Alterations in the properties or the quantity of ASM are likely responsible for some instances of airways hyperresponsiveness to bronchoconstrictive stimuli that is a characteristic of diseases such as asthma. Morphometric studies have shown an increase in the mass of ASM in human asthmatic airways. Animal models have been developed that confirm that ASM can be induced to grow by allergic sensitization and challenge. Growth is in large part by hyperplasia as measured by incorporation of bromodeoxyuridine as a marker of the S-phase of the cell cycle. T cells, in particular CD4+ cells, may participate in the stimulation of growth of ASM by allergen challenge. The growth factors responsible for the increase in ASM are as yet unidentified but two mediators associated with allergic airway responses, cysteinyl leukotrienes and endothelin, have been implicated using specific receptor antagonists. The links between T cells and the biochemical mediators of growth have not been established. PMID:14516730

  17. Characterization of muscarinic receptors mediating relaxation and contraction in the rat iris dilator muscle.

    PubMed Central

    Masuda, Y; Yamahara, N S; Tanaka, M; Ryang, S; Kawai, T; Imaizumi, Y; Watanabe, M

    1995-01-01

    1. The characteristics of muscarinic receptors mediating relaxation and/or contraction in the rat iris dilator muscle were examined. 2. Relaxation was induced in a dilator muscle by application of acetylcholine (ACh) at low doses (3 microM or less) and contraction was induced by high doses. Methacholine and carbachol also showed biphasic effects similar to those of ACh; in contrast, bethanechol, arecoline, pilocarpine and McN-A-343 induced mainly relaxation but no substantial contraction. 3. After parasympathetic denervation by ciliary ganglionectomy, the relaxant response to muscarinic agonists disappeared upon nerve stimulation. Application of McN-A-343 and pilocarpine induced only small contractions in denervated dilator muscles, indicating that these are partial agonists for contraction. 4. pA2 values of pirenzepine, methoctramine, AF-DX 116, himbacine, and 4-DAMP for antagonism to pilocarpine-induced relaxation in normal dilator muscles and those for antagonism to ACh-induced contraction in denervated dilator muscles were determined. The pA2 values for antagonism to relaxation of all these antagonists were most similar to those for M3-type muscarinic receptors. 5. Although pA2 values for contraction of these antagonists, except for methoctramine, were very close to those for relaxation, contraction was not significantly antagonized by methoctramine. Contraction might be mediated by M3-like receptors which have a very low affinity for methoctramine. 6. In conclusion, ACh-induced biphasic responses in rat iris dilator muscles were clearly distinguished from each other by specific muscarinic agonists and parasympathetic denervation, whereas muscarinic receptors could not be subclassified according to the pA2 values of 5 specific antagonists only. PMID:7539696

  18. Does the length dependency of airway smooth muscle force contribute to airway hyperresponsiveness?

    PubMed

    Lee-Gosselin, Audrey; Pascoe, Chris D; Couture, Christian; Paré, Peter D; Bossé, Ynuk

    2013-11-01

    Airway wall remodeling and lung hyperinflation are two typical features of asthma that may alter the contractility of airway smooth muscle (ASM) by affecting its operating length. The aims of this study were as follows: 1) to describe in detail the "length dependency of ASM force" in response to different spasmogens; and 2) to predict, based on morphological data and a computational model, the consequence of this length dependency of ASM force on airway responsiveness in asthmatic subjects who have both remodeled airway walls and hyperinflated lungs. Ovine tracheal ASM strips and human bronchial rings were isolated and stimulated to contract in response to increasing concentrations of spasmogens at three different lengths. Ovine tracheal strips were more sensitive and generated greater force at longer lengths in response to acetylcholine (ACh) and K(+). Equipotent concentrations of ACh were approximately a log less for ASM stretched by 30% and approximately a log more for ASM shortened by 30%. Similar results were observed in human bronchi in response to methacholine. Morphometric and computational analyses predicted that the ASM of asthmatic subjects may be elongated by 6.6-10.4% (depending on airway generation) due to remodeling and/or hyperinflation, which could increase ACh-induced force by 1.8-117.8% (depending on ASM length and ACh concentration) and enhance the increased resistance to airflow by 0.4-4,432.8%. In conclusion, elongation of ASM imposed by airway wall remodeling and/or hyperinflation may allow ASM to operate at a longer length and to consequently generate more force and respond to lower concentration of spasmogens. This phenomenon could contribute to airway hyperresponsiveness. PMID:23970527

  19. Airway compliance and dynamics explain the apparent discrepancy in length adaptation between intact airways and smooth muscle strips.

    PubMed

    Dowie, Jackson; Ansell, Thomas K; Noble, Peter B; Donovan, Graham M

    2016-01-01

    Length adaptation is a phenomenon observed in airway smooth muscle (ASM) wherein over time there is a shift in the length-tension curve. There is potential for length adaptation to play an important role in airway constriction and airway hyper-responsiveness in asthma. Recent results by Ansell et al., 2015 (JAP 2014 10.1152/japplphysiol.00724.2014) have cast doubt on this role by testing for length adaptation using an intact airway preparation, rather than strips of ASM. Using this technique they found no evidence for length adaptation in intact airways. Here we attempt to resolve this apparent discrepancy by constructing a minimal mathematical model of the intact airway, including ASM which follows the classic length-tension curve and undergoes length adaptation. This allows us to show that (1) no evidence of length adaptation should be expected in large, cartilaginous, intact airways; (2) even in highly compliant peripheral airways, or at more compliant regions of the pressure-volume curve of large airways, the effect of length adaptation would be modest and at best marginally detectable in intact airways; (3) the key parameters which control the appearance of length adaptation in intact airways are airway compliance and the relaxation timescale. The results of this mathematical simulation suggest that length adaptation observed at the level of the isolated ASM may not clearly manifest in the normal intact airway. PMID:26376002

  20. The Dilator Naris Muscle as a Reporter of Facial Nerve Regeneration in a Rat Model

    PubMed Central

    Weinberg, Julie S.; Kleiss, Ingrid J.; Knox, Christopher J.; Heaton, James T.; Hadlock, Tessa A.

    2015-01-01

    Objective Many investigators study facial nerve regeneration using the rat whisker pad model, though widely standardized outcomes measures of facial nerve regeneration in the rodent have not yet been developed. The intrinsic whisker pad “sling” muscles producing whisker protraction, situated at the base of each individual whisker, are extremely small and difficult to study en bloc. Here, we compare the functional innervation of two potential reporter muscles for whisker pad innervation: the dilator naris and the levator labii superioris, to characterize facial nerve regeneration. Methods Motor supply of the dilator naris and levator labii superioris was elucidated by measuring contraction force and compound muscle action potentials during stimulation of individual facial nerve branches, and by measuring whisking amplitude before and after dilator naris distal tendon release. Results The pattern of dilator naris innervation matched that of the intrinsic whisker pad musculature (i.e. via the buccal and marginal mandibular branches of the facial nerve), whereas the levator labii superioris appeared to be innervated almost entirely by the zygomatic branch, whose primary target is the orbicularis oculi muscle. Conclusion While the levator labii superioris has been commonly used as a reporter muscle of whisker pad innervation, the present data show that its innervation pattern does not overlap substantially with the muscles producing whisker protraction. The dilator naris muscle may serve as a more appropriate reporter for whisker pad innervation because it is innervated by the same facial nerve branches as the intrinsic whisker pad musculature, making structure\\function correlations more accurate, and more relevant to investigators studying facial nerve regeneration. PMID:25643189

  1. Impact of obstructive apnea syndrome on upper airway respiratory muscles.

    PubMed

    Svanborg, Eva

    2005-07-28

    This article reviews studies of upper airway muscles in humans, with emphasis on muscle fiber structural and electrophysiological changes observed in patients with obstructive sleep apnea syndrome (OSAS). The concept of OSAS as a progressive disease is discussed and also possible causes. These include local nervous lesions in the upper airway, both motor and sensory. Previous muscle biopsy studies have given evidence for motor neuron lesions such as, e.g., the phenomenon of type grouping in histological sections. New data obtained with concentric needle EMG recordings from the palatopharyngeus muscles are also presented. In 10/12 OSAS patients there were typical findings indicating motor neuropathy (reduced EMG activity at maximal voluntary effort, long and polyphasic motor-unit potentials and, in two cases, spontaneous denervation activity), whereas such findings were only present in 3/15 patients with habitual snoring. This supports the hypothesis that progression from habitual snoring to the clinical disease of OSAS could be attributed to peripheral neurogenic lesions. PMID:16054444

  2. Mechanisms of BDNF regulation in asthmatic airway smooth muscle.

    PubMed

    Aravamudan, Bharathi; Thompson, Michael A; Pabelick, Christina M; Prakash, Y S

    2016-08-01

    Brain-derived neurotrophic factor (BDNF), a neurotrophin produced by airway smooth muscle (ASM), enhances inflammation effects on airway contractility, supporting the idea that locally produced growth factors influence airway diseases such as asthma. We endeavored to dissect intrinsic mechanisms regulating endogenous, as well as inflammation (TNF-α)-induced BDNF secretion in ASM of nonasthmatic vs. asthmatic humans. We focused on specific Ca(2+) regulation- and inflammation-related signaling cascades and quantified BDNF secretion. We find that TNF-α enhances BDNF release by ASM cells, via several mechanisms relevant to asthma, including transient receptor potential channels TRPC3 and TRPC6 (but not TRPC1), ERK 1/2, PI3K, PLC, and PKC cascades, Rho kinase, and transcription factors cAMP response element binding protein and nuclear factor of activated T cells. Basal BDNF expression and secretion are elevated in asthmatic ASM and increase further with TNF-α exposure, involving many of these regulatory mechanisms. We conclude that airway BDNF secretion is regulated at multiple levels, providing a basis for autocrine effects of BDNF under conditions of inflammation and disease, with potential downstream influences on contractility and remodeling. PMID:27317689

  3. Effect of gender on rat upper airway muscle contractile properties.

    PubMed

    Cantillon, D; Bradford, A

    1998-08-01

    Obstructive sleep apnoea arises due to upper airway (UA) collapse which is normally counteracted by contraction of UA muscles such as the sternohyoids and geniohyoids. The disorder has a marked male predominance but the effect of gender on UA muscle contractile properties is unknown and these properties have not been compared for the sternohyoid and geniohyoid muscles in the same species. Isometric contractile characteristics were determined using strips of sternohyoid and geniohyoid muscle from male and female rats in Krebs solution at 30 degrees C. For both muscles, there were no differences between male and female contractile kinetics, twitch or tetanic tension, tension-length or tension-frequency relationship or endurance. In both males and females, sternohyoid twitch and tetanic tension was greater than geniohyoid. Sternohyoid endurance was less than geniohyoid but contractile kinetics, tension-length and tension-frequency relationships were similar. Therefore, gender does not affect UA muscle contractile properties and sternohyoid tension is greater and endurance less than that of the geniohyoid. PMID:9832233

  4. Pre- and postsynaptic effects of brimonidine on isolated rabbit iris dilator muscles

    PubMed Central

    Tatsui, Sonoko; Ishikawa, Hitoshi; Shimizu, Kimiya; Mashimo, Kimiyo

    2016-01-01

    Purpose Brimonidine is an imidazoline compound used for the treatment of glaucoma, but having very little effect on pupil diameter. Like para-aminoclonidine, most imidazoline compounds interact with postsynaptic α-adrenoceptors and cause pupil dilatation. Therefore, as part of an investigation of the mechanism of action of brimonidine on pupil diameter, the present study was initiated to measure, in vitro, the relative potency of brimonidine on the pre- and postsynaptic α-adrenoceptors of rabbit iris dilator muscle. Methods The contractile activity of brimonidine and its effect on twitch contraction evoked by electrical field stimulation were studied in isolated rabbit iris dilator muscles by isometric tension recording. Results Brimonidine significantly inhibited the twitch contraction of the dilator muscle caused by field stimulation, without affecting the response to exogenously applied phenylephrine. Compared to phenylephrine, brimonidine caused only a small contractile response with % maximum contraction values of <10%. Conclusion These results suggest that brimonidine may act on nerve endings to inhibit adrenergic neurotransmission with very little effect on postsynaptic α-adrenoceptors. This may indicate that brimonidine reduced the pupil diameter just a little, thus improving night vision. PMID:27274189

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

    PubMed Central

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

    2008-01-01

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

  6. IL-6 trans-signaling increases expression of airways disease genes in airway smooth muscle.

    PubMed

    Robinson, Mac B; Deshpande, Deepak A; Chou, Jeffery; Cui, Wei; Smith, Shelly; Langefeld, Carl; Hastie, Annette T; Bleecker, Eugene R; Hawkins, Gregory A

    2015-07-15

    Genetic data suggest that IL-6 trans-signaling may have a pathogenic role in the lung; however, the effects of IL-6 trans-signaling on lung effector cells have not been investigated. In this study, human airway smooth muscle (HASM) cells were treated with IL-6 (classical) or IL-6+sIL6R (trans-signaling) for 24 h and gene expression was measured by RNAseq. Intracellular signaling and transcription factor activation were assessed by Western blotting and luciferase assay, respectively. The functional effect of IL-6 trans-signaling was determined by proliferation assay. IL-6 trans-signaling had no effect on phosphoinositide-3 kinase and Erk MAP kinase pathways in HASM cells. Both classical and IL-6 trans-signaling in HASM involves activation of Stat3. However, the kinetics of Stat3 phosphorylation by IL-6 trans-signaling was different than classical IL-6 signaling. This was further reflected in the differential gene expression profile by IL-6 trans-signaling in HASM cells. Under IL-6 trans-signaling conditions 36 genes were upregulated, including PLA2G2A, IL13RA1, MUC1, and SOD2. Four genes, including CCL11, were downregulated at least twofold. The expression of 112 genes was divergent between IL-6 classical and trans-signaling, including the genes HILPDA, NNMT, DAB2, MUC1, WWC1, and VEGFA. Pathway analysis revealed that IL-6 trans-signaling induced expression of genes involved in regulation of airway remodeling, immune response, hypoxia, and glucose metabolism. Treatment of HASM cells with IL-6+sIL6R induced proliferation in a dose-dependent fashion, suggesting a role for IL-6 trans-signaling in asthma pathogenesis. These novel findings demonstrate differential effect of IL-6 trans-signaling on airway cells and identify IL-6 trans-signaling as a potential modifier of airway inflammation and remodeling. PMID:26001777

  7. AMPK Dilates Resistance Arteries via Activation of SERCA and BKCa Channels in Smooth Muscle.

    PubMed

    Schneider, Holger; Schubert, Kai Michael; Blodow, Stephanie; Kreutz, Claus-Peter; Erdogmus, Serap; Wiedenmann, Margarethe; Qiu, Jiehua; Fey, Theres; Ruth, Peter; Lubomirov, Lubomir T; Pfitzer, Gabriele; Mederos Y Schnitzler, Michael; Hardie, D Grahame; Gudermann, Thomas; Pohl, Ulrich

    2015-07-01

    The protective effects of 5'-AMP-activated protein kinase (AMPK) on the metabolic syndrome may include direct effects on resistance artery vasomotor function. However, the precise actions of AMPK on microvessels and their potential interaction are largely unknown. Thus, we set to determine the effects of AMPK activation on vascular smooth muscle tone and the underlying mechanisms. Resistance arteries isolated from hamster and mouse exhibited a pronounced endothelium-independent dilation on direct pharmacological AMPK activation by 2 structurally unrelated compounds (PT1 and A769662). The dilation was associated with a decrease of intracellular-free calcium [Ca(2+)]i in vascular smooth muscle cell. AMPK stimulation induced activation of BKCa channels as assessed by patch clamp studies in freshly isolated hamster vascular smooth muscle cell and confirmed by direct proof of membrane hyperpolarization in intact arteries. The BKCa channel blocker iberiotoxin abolished the hyperpolarization but only partially reduced the dilation and did not affect the decrease of [Ca(2+)]i. By contrast, the sarcoplasmic/endoplasmic Ca(2+)-ATPase (SERCA) inhibitor thapsigargin largely reduced these effects, whereas combined inhibition of SERCA and BKCa channels virtually abolished them. AMPK stimulation significantly increased the phosphorylation of the SERCA modulator phospholamban at the regulatory T17 site. Stimulation of smooth muscle AMPK represents a new, potent vasodilator mechanism in resistance vessels. AMPK directly relaxes vascular smooth muscle cell by a decrease of [Ca(2+)]i. This is achieved by calcium sequestration via SERCA activation, as well as activation of BKCa channels. There is in part a mutual compensation of both calcium-lowering mechanisms. However, SERCA activation which involves an AMPK-dependent phosphorylation of phospholamban is the predominant mechanism in resistance vessels. PMID:26034200

  8. Functional effects of KCNQ K+ channels in airway smooth muscle

    PubMed Central

    Evseev, Alexey I.; Semenov, Iurii; Archer, Crystal R.; Medina, Jorge L.; Dube, Peter H.; Shapiro, Mark S.; Brenner, Robert

    2013-01-01

    KCNQ (Kv7) channels underlie a voltage-gated K+ current best known for control of neuronal excitability, and its inhibition by Gq/11-coupled, muscarinic signaling. Studies have indicated expression of KCNQ channels in airway smooth muscle (ASM), a tissue that is predominantly regulated by muscarinic receptor signaling. Therefore, we investigated the function of KCNQ channels in rodent ASM and their interplay with Gq/11-coupled M3 muscarinic receptors. Perforated-patch clamp of dissociated ASM cells detected a K+ current inhibited by the KCNQ antagonist, XE991, and augmented by the specific agonist, flupirtine. KCNQ channels begin to activate at voltages near resting potentials for ASM cells, and indeed XE991 depolarized resting membrane potentials. Muscarinic receptor activation inhibited KCNQ current weakly (~20%) at concentrations half-maximal for contractions. Thus, we were surprised to see that KCNQ had no affect on membrane voltage or muscle contractility following muscarinic activation. Further, M3 receptor-specific antagonist J104129 fumarate alone did not reveal KCNQ effects on muscarinic evoked depolarization or contractility. However, a role for KCNQ channels was revealed when BK-K+ channel activities are reduced. While KCNQ channels do control resting potentials, they appear to play a redundant role with BK calcium-activated K+ channels during ASM muscarinic signaling. In contrast to effect of antagonist, we observe that KCNQ agonist flupirtine caused a significant hyperpolarization and reduced contraction in vitro irrespective of muscarinic activation. Using non-invasive whole animal plethysmography, the clinically approved KCNQ agonist retigabine caused a transient reduction in indexes of airway resistance in both wild type and BK β1 knockout (KO) mice treated with the muscarinic agonist. These findings indicate that KCNQ channels can be recruited via agonists to oppose muscarinic evoked contractions and may be of therapeutic value as bronchodilators

  9. Functional effects of KCNQ K(+) channels in airway smooth muscle.

    PubMed

    Evseev, Alexey I; Semenov, Iurii; Archer, Crystal R; Medina, Jorge L; Dube, Peter H; Shapiro, Mark S; Brenner, Robert

    2013-01-01

    KCNQ (Kv7) channels underlie a voltage-gated K(+) current best known for control of neuronal excitability, and its inhibition by Gq/11-coupled, muscarinic signaling. Studies have indicated expression of KCNQ channels in airway smooth muscle (ASM), a tissue that is predominantly regulated by muscarinic receptor signaling. Therefore, we investigated the function of KCNQ channels in rodent ASM and their interplay with Gq/11-coupled M3 muscarinic receptors. Perforated-patch clamp of dissociated ASM cells detected a K(+) current inhibited by the KCNQ antagonist, XE991, and augmented by the specific agonist, flupirtine. KCNQ channels begin to activate at voltages near resting potentials for ASM cells, and indeed XE991 depolarized resting membrane potentials. Muscarinic receptor activation inhibited KCNQ current weakly (~20%) at concentrations half-maximal for contractions. Thus, we were surprised to see that KCNQ had no affect on membrane voltage or muscle contractility following muscarinic activation. Further, M3 receptor-specific antagonist J104129 fumarate alone did not reveal KCNQ effects on muscarinic evoked depolarization or contractility. However, a role for KCNQ channels was revealed when BK-K(+) channel activities are reduced. While KCNQ channels do control resting potentials, they appear to play a redundant role with BK calcium-activated K(+) channels during ASM muscarinic signaling. In contrast to effect of antagonist, we observe that KCNQ agonist flupirtine caused a significant hyperpolarization and reduced contraction in vitro irrespective of muscarinic activation. Using non-invasive whole animal plethysmography, the clinically approved KCNQ agonist retigabine caused a transient reduction in indexes of airway resistance in both wild type and BK β1 knockout (KO) mice treated with the muscarinic agonist. These findings indicate that KCNQ channels can be recruited via agonists to oppose muscarinic evoked contractions and may be of therapeutic value as

  10. Effect of inflammatory mediators on airway nerves and muscle

    SciTech Connect

    Daniel, E.E.; O'Byrne, P. )

    1991-03-01

    The neuromuscular mechanisms underlying airway hyperresponsiveness have been reviewed on the basis of studies of the changes induced by ozone inhalation in dogs. In vivo, there is increased, nonspecific airway hyperresponsiveness based on studies of the response to inhaled acetylcholine or histamine. The underlying inflammatory mechanism involves release of LTB4 and/or other chemotactic agents from epithelial or lumenal cells, ingress of macrophages, neutrophils, and platelets from the blood vessels between the muscle and epithelium, and migration of mast cells into the epithelium. The hyperresponsiveness seems to depend upon the influx of neutrophils and actions of thromboxane A2 released from the neutrophils. In vitro, there is increased responsiveness to field stimulation of cholinergic nerves and to acetylcholine (not to KCI) in tracheal strips. These effects can be mimicked by a thromboxane A2 analog (U44619). In the sucrose gap, the TxA2 analog does not affect the excitatory junction potential, but in low concentration it increases and prolongs a series of fading membrane oscillations closely related to the contractions. We consider these oscillations to reflect ongoing release and/or action of acetylcholine. In high concentrations the analog causes a small depolarization and a tonic contraction, but it does not enhance the sensitivity to acetylcholine. TxA2 may be acting either presynaptically or postsynaptically or both to produce these effects; however, changes in release of an epithelial-derived relaxing factor do not seem to be involved. We conclude that TxA2 actions probably underlie hyperresponsiveness developed in vivo and in vitro after ozone inhalation.

  11. Sensorimotor function of the upper-airway muscles and respiratory sensory processing in untreated obstructive sleep apnea.

    PubMed

    Eckert, Danny J; Lo, Yu L; Saboisky, Julian P; Jordan, Amy S; White, David P; Malhotra, Atul

    2011-12-01

    Numerous studies have demonstrated upper-airway neuromuscular abnormalities during wakefulness in snorers and obstructive sleep apnea (OSA) patients. However, the functional role of sensorimotor impairment in OSA pathogenesis/disease progression and its potential effects on protective upper-airway reflexes, measures of respiratory sensory processing, and force characteristics remain unclear. This study aimed to gain physiological insight into the potential role of sensorimotor impairment in OSA pathogenesis/disease progression by comparing sensory processing properties (respiratory-related evoked potentials; RREP), functionally important protective reflexes (genioglossus and tensor palatini) across a range of negative pressures (brief pulses and entrained iron lung ventilation), and tongue force and time to task failure characteristics between 12 untreated OSA patients and 13 controls. We hypothesized that abnormalities in these measures would be present in OSA patients. Upper-airway reflexes (e.g., genioglossus onset latency, 20 ± 1 vs. 19 ± 2 ms, P = 0.82), early RREP components (e.g., P1 latency 25 ± 2 vs. 25 ± 1 ms, P = 0.78), and the slope of epiglottic pressure vs. genioglossus activity during iron lung ventilation (-0.68 ± 1.0 vs. -0.80 ± 2.0 cmH(2)O/%max, P = 0.59) were not different between patients and controls. Maximal tongue protrusion force was greater in OSA patients vs. controls (35 ± 2 vs. 27 ± 2 N, P < 0.01), but task failure occurred more rapidly (149 ± 24 vs. 254 ± 23 s, P < 0.01). Upper-airway protective reflexes across a range of negative pressures as measured by electromyography and the early P1 component of the RREP are preserved in OSA patients during wakefulness. Consistent with an adaptive training effect, tongue protrusion force is increased, not decreased, in untreated OSA patients. However, OSA patients may be vulnerable to fatigue of upper-airway dilator muscles, which could contribute to disease progression. PMID:21885797

  12. [Influence of nanosize particles of cobalt ferrite on contractile responses of smooth muscle segment of airways].

    PubMed

    Kapilevich, L V; Zaĭtseva, T N; Nosarev, A V; D'iakova, E Iu; Petlina, Z R; Ogorodova, L M; Ageev, B G; Magaeva, A A; Itin, V I; Terekhova, O G; Medvedev, M A

    2012-02-01

    Contractile responses of airways segments of porpoises inhaling nanopowder CoFe2O4 were stidued by means of a mechanographic method. Inhalation of the nanosize particles of CoFe2O4 in vivo and in vitro testing the nanomaterial on isolated smooth muscles led to potentiation histaminergic, cholinergic contractile activity in airways of porpoises and to strengthening of adrenergic relaxing answers. Nanosize particles vary amplitude of hyperpotassium reductions in smooth muscle segments of airways similarly to the effect of depolymerizing drug colchicine. PMID:22650066

  13. Tonic activity in inspiratory muscles during continuous negative airway pressure.

    PubMed

    Meessen, N E; van der Grinten, C P; Folgering, H T; Luijendijk, S C

    1993-05-01

    We studied tonic inspiratory activity (TIA) induced by continuous negative airway pressure (CNAP) in anaesthetized, spontaneously breathing cats. TIA in the diaphragm and parasternal intercostal muscles (ICM) was quantified in response to tracheal pressure (PTR) = -0.3 to -1.2 kPa. To differentiate between reflexes from rapidly adapting receptors (RARs), slowly adapting receptors (SARs) and C-fiber endings different temperatures of the vagus nerves (TVG) were used between 4 and 37 degrees C. At PTR = -1.2 kPa mean TIA values were 41% and 62% of peak inspiratory EMG activity of control breaths for the diaphragm and ICM, respectively. After vagotomy and for TVG < 6 degrees C CNAP did not induce TIA anymore. Changes in inspiratory and expiratory time during vagal cooling down to 4 degrees C confirmed the selective block of conductance in vagal afferents of the three types of lung receptors. We conclude that CNAP-induced TIA results from stimulation of RARs. Our data strongly indicate that stimulation of SARs suppresses TIA, whereas C-fiber endings are not involved in TIA at all. The results suggest that part of the hyperinflation in bronchial asthma may be caused by TIA in response to mechanical stimulation of RARs. PMID:8327788

  14. Perturbed equilibrium of myosin binding in airway smooth muscle and its implications in bronchospasm.

    PubMed

    Fredberg, J J; Inouye, D S; Mijailovich, S M; Butler, J P

    1999-03-01

    In asthma, the mechanisms relating airway obstruction, hyperresponsiveness, and inflammation remain rather mysterious. We show here that regulation of airway smooth muscle length corresponds to a dynamically equilibrated steady state, not the static mechanical equilibrium that had been previously assumed. This dynamic steady state requires as an essential feature a continuous supply of external mechanical energy (derived from tidal lung inflations) that acts to perturb the interactions of myosin with actin, drive the molecular state of the system far away from thermodynamic equilibrium, and bias the muscle toward lengthening. This mechanism leads naturally to the suggestion that excessive airway narrowing in asthma may be associated with the destabilization of that dynamic process and its resulting collapse back to static equilibrium. With this collapse the muscle undergoes a phase transition and virtually freezes at its static equilibrium length. This mechanism may help to elucidate several unexplained phenomena including the multifactorial origins of airway hyperresponsiveness, how allergen sensitization leads to airway hyperresponsiveness, how hyperresponsiveness can persist long after airway inflammation is resolved, and the inability in asthma of deep inspirations to relax airway smooth muscle. PMID:10051279

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

    PubMed

    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. PMID:25583659

  16. The impact of vitamin D on asthmatic human airway smooth muscle.

    PubMed

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

    2016-02-01

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

  17. Tempol ameliorates pharyngeal dilator muscle dysfunction in a rodent model of chronic intermittent hypoxia.

    PubMed

    Skelly, J Richard; Edge, Deirdre; Shortt, Christine M; Jones, James F X; Bradford, Aidan; O'Halloran, Ken D

    2012-02-01

    Respiratory muscle dysfunction is implicated in the pathophysiology of obstructive sleep apnea syndrome (OSAS), an oxidative stress disorder prevalent in men. Pharmacotherapy for OSAS is an attractive option, and antioxidant treatments may prove beneficial. We examined the effects of chronic intermittent hypoxia (CIH) on breathing and pharyngeal dilator muscle structure and function in male and female rats. Additionally, we tested the efficacy of antioxidant treatment in preventing (chronic administration) or reversing (acute administration) CIH-induced effects in male rats. Adult male and female Wistar rats were exposed to alternating cycles of normoxia and hypoxia (90 s each; Fi(O(2)) = 5% O(2) at nadir; Sa(O(2)) ∼ 80%) or sham treatment for 8 h/d for 9 days. Tempol (1 mM, superoxide dismutase mimetic) was administered to subgroups of sham- and CIH-treated animals. Breathing was assessed by whole-body plethysmography. Sternohyoid muscle contractile and endurance properties were examined in vitro. Muscle fiber type and cross-sectional area and the activity of key metabolic enzymes were determined. CIH decreased sternohyoid muscle force in male rats only. This was not attributable to fiber transitions or alterations in oxidative or glycolytic enzyme activity. Muscle weakness after CIH was prevented by chronic Tempol supplementation and was reversed by acute antioxidant treatment in vitro. CIH increased normoxic ventilation in male rats only. Sex differences exist in the effects of CIH on the respiratory system, which may contribute to the higher prevalence of OSAS in male subjects. Antioxidant treatment may be beneficial as an adjunct OSAS therapy. PMID:21868712

  18. Airway smooth muscle changes in the nitrofen-induced congenital diaphragmatic hernia rat model.

    PubMed

    Belik, Jaques; Davidge, Sandra T; Zhang, Wei; Pan, Jingyi; Greer, John J

    2003-05-01

    In the fetal rat, nitrofen induces congenital diaphragmatic hernia (CDH) and pulmonary vascular remodeling similar to what is observed in the human condition. Airway hyperactivity is common in infants with CDH and attributed to the ventilator-induced airway damage. The purpose of this study was to test the hypothesis that airway smooth muscle mechanical properties are altered in the nitrofen-induced CDH rat model. Lungs from nitrofen-exposed fetuses with hernias (CDH) or intact diaphragm (nitrofen) and untreated fetuses (control) were studied on gestation d 21. The left intrapulmonary artery and bronchi were removed and mounted on a wire myograph, and lung expression, content, and immunolocalization of cyclooxygenases COX-1 and COX-2 were evaluated. Pulmonary artery muscle in the CDH group had significantly (p < 0.01) lower force generation compared with control and nitrofen groups. In contrast, the same generation bronchial smooth muscle of the CDH and nitrofen groups developed higher force compared with control. Whereas no differences were found in endothelium-dependent pulmonary vascular muscle tone, the epithelium-dependent airway muscle relaxation was significantly decreased (p < 0.01) in the CDH and nitrofen groups. The lung mRNA levels of COX-1 and COX-2 were increased in the CDH and nitrofen groups. COX-1 vascular and airway immunostaining, as well as COX-1 and COX-2 lung protein content, were increased in the CDH group. This is the first report of airway smooth muscle abnormalities in the nitrofen-induced fetal rat model of CDH. We speculate that congenital airway muscle changes may be present in the human form of this disease. PMID:12612200

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

    PubMed

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

    2016-05-01

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

  20. Large conducting potassium channel reconstituted from airway smooth muscle.

    PubMed

    Savaria, D; Lanoue, C; Cadieux, A; Rousseau, E

    1992-03-01

    Microsomal fractions were prepared from canine and bovine airway smooth muscle (ASM) by differential and gradient centrifugations. Surface membrane vesicles were characterized by binding assays and incorporated into planar lipid bilayers. Single-channel activities were recorded in symmetric or asymmetric K+ buffer systems and studied under voltage and Ca2+ clamp conditions. A large-conductance K(+)-selective channel (greater than 220 pS in 150 mM K+) displaying a high Ca2+, low Ba2+, and charybdotoxin (CTX) sensitivity was identified. Time analysis of single-channel recordings revealed a complex kinetic behavior compatible with the previous schemes proposed for Ca(2+)-activated K+ channels in a variety of biological surface membranes. We now report that the open probability of the channel at low Ca2+ concentration is enhanced on in vitro phosphorylation, which is mediated via an adenosine 3',5'-cyclic monophosphate-dependent protein kinase. In addition to this characterization at the molecular level, a second series of pharmacological experiments were designed to assess the putative role of this channel in ASM strips. Our results show that 50 nM CTX, a specific inhibitor of the large conducting Ca(2+)-dependent K+ channel, prevents norepinephrine transient relaxation on carbamylcholine-precontracted ASM strips. It was also shown that CTX reversed the steady-state relaxation induced by vasoactive intestinal peptide and partially antagonized further relaxation induced by cumulative doses of this potent bronchodilatator. Thus it is proposed that the Ca(2+)-activated K+ channels have a physiological role because they are indirectly activated on stimulation of various membrane receptors via intracellular mechanisms. PMID:1372487

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

    NASA Astrophysics Data System (ADS)

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

    2016-03-01

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

  2. Lingual Muscle Activity Across Sleep–Wake States in Rats with Surgically Altered Upper Airway

    PubMed Central

    Rukhadze, Irma; Kalter, Julie; Stettner, Georg M.; Kubin, Leszek

    2014-01-01

    Obstructive sleep apnea (OSA) patients have increased upper airway muscle activity, including such lingual muscles as the genioglossus (GG), geniohyoid (GH), and hyoglossus (HG). This adaptation partially protects their upper airway against obstructions. Rodents are used to study the central neural control of sleep and breathing but they do not naturally exhibit OSA. We investigated whether, in chronically instrumented, behaving rats, disconnecting the GH and HG muscles from the hyoid (H) apparatus would result in a compensatory increase of other upper airway muscle activity (electromyogram, EMG) and/or other signs of upper airway instability. We first determined that, in intact rats, lingual (GG and intrinsic) muscles maintained stable activity levels when quantified based on 2 h-long recordings conducted on days 6 through 22 after instrumentation. We then studied five rats in which the tendons connecting the GH and HG muscles to the H apparatus were experimentally severed. When quantified across all recording days, lingual EMG during slow-wave sleep (SWS) was modestly but significantly increased in rats with surgically altered upper airway [8.6 ± 0.7% (SE) vs. 6.1 ± 0.7% of the mean during wakefulness; p = 0.012]. Respiratory modulation of lingual EMG occurred mainly during SWS and was similarly infrequent in both groups, and the incidence of sighs and central apneas also was similar. Thus, a weakened action of selected lingual muscles did not produce sleep-disordered breathing but resulted in a relatively elevated activity in other lingual muscles during SWS. These results encourage more extensive surgical manipulations with the aim to obtain a rodent model with collapsible upper airway. PMID:24803913

  3. c-Myc regulates proliferation and Fgf10 expression in airway smooth muscle after airway epithelial injury in mouse.

    PubMed

    Volckaert, Thomas; Campbell, Alice; De Langhe, Stijn

    2013-01-01

    During lung development, Fibroblast growth factor 10 (Fgf10), which is expressed in the distal mesenchyme and regulated by Wnt signaling, acts on the distal epithelial progenitors to maintain them and prevent them from differentiating into proximal (airway) epithelial cells. Fgf10-expressing cells in the distal mesenchyme are progenitors for parabronchial smooth muscle cells (PSMCs). After naphthalene, ozone or bleomycin-induced airway epithelial injury, surviving epithelial cells secrete Wnt7b which then activates the PSMC niche to induce Fgf10 expression. This Fgf10 secreted by the niche then acts on a subset of Clara stem cells to break quiescence, induce proliferation and initiate epithelial repair. Here we show that conditional deletion of the Wnt target gene c-Myc from the lung mesenchyme during development does not affect proper epithelial or mesenchymal differentiation. However, in the adult lung we show that after naphthalene-mediated airway epithelial injury c-Myc is important for the activation of the PSMC niche and as such induces proliferation and Fgf10 expression in PSMCs. Our data indicate that conditional deletion of c-Myc from PSMCs inhibits airway epithelial repair, whereas c-Myc ablation from Clara cells has no effect on airway epithelial regeneration. These findings may have important implications for understanding the misregulation of lung repair in asthma and COPD. PMID:23967208

  4. Eugenol dilates rat cerebral arteries by inhibiting smooth muscle cell voltage-dependent calcium channels

    PubMed Central

    Peixoto-Neves, Dieniffer; Leal-Cardoso, Jose Henrique; Jaggar, Jonathan H.

    2014-01-01

    Plants high in eugenol, a phenylpropanoid compound, are used as folk medicines to alleviate diseases including hypertension. Eugenol has been demonstrated to relax conduit and ear arteries and reduce systemic blood pressure, but mechanisms involved are unclear. Here, we studied eugenol regulation of resistance-size cerebral arteries that control regional brain blood pressure and flow and investigated mechanisms involved. We demonstrate that eugenol dilates arteries constricted by either pressure or membrane depolarization (60 mM K+) in a concentration-dependent manner. Experiments performed using patch-clamp electrophysiology demonstrated that eugenol inhibited voltage-dependent calcium (Ca2+) currents, when using Ba2+ as a charge carrier, in isolated cerebral artery smooth muscle cells. Eugenol inhibition of voltage-dependent Ca2+ currents involved pore block, a hyperpolarizing shift ( ~−10 mV) in voltage-dependent inactivation, an increase in the proportion of steady-state inactivating current, and acceleration of inactivaiton rate. In summary, our data indicate that eugenol dilates cerebral arteries via multi-modal inhibition of voltage-dependent Ca2+ channels. PMID:24921632

  5. Increased vascular thromboxane generation impairs dilation of skeletal muscle arterioles of obese Zucker rats with reduced oxygen tension

    PubMed Central

    Goodwill, Adam G.; James, Milinda E.; Frisbee, Jefferson C.

    2008-01-01

    This study determined if altered vascular prostacyclin (PGI2) and/or thromboxane A2 (TxA2) production with reduced Po2 contributes to impaired hypoxic dilation of skeletal muscle resistance arterioles of obese Zucker rats (OZRs) versus lean Zucker rats (LZRs). Mechanical responses were assessed in isolated gracilis muscle arterioles following reductions in Po2 under control conditions and following pharmacological interventions inhibiting arachidonic acid metabolism and nitric oxide synthase and alleviating elevated vascular oxidant stress. The production of arachidonic acid metabolites was assessed using pooled arteries from OZRs and LZRs in response to reduced Po2. Hypoxic dilation, endothelium-dependent in both strains, was attenuated in OZRs versus LZRs. Nitric oxide synthase inhibition had no significant impact on hypoxic dilation in either strain. Cyclooxygenase inhibition dramatically reduced hypoxic dilation in LZRs and abolished responses in OZRs. Treatment of arterioles from OZRs with polyethylene glycol-superoxide dismutase improved hypoxic dilation, and this improvement was entirely cyclooxygenase dependent. Vascular PGI2 production with reduced Po2 was similar between strains, although TxA2 production was increased in OZRs, a difference that was attenuated by treatment of vessels from OZRs with polyethylene glycol-superoxide dismutase. Both blockade of PGH2/TxA2 receptors and inhibition of thromboxane synthase increased hypoxic dilation in OZR arterioles. These results suggest that a contributing mechanism underlying impaired hypoxic dilation of skeletal muscle arterioles of OZRs may be an increased vascular production of TxA2, which competes against the vasodilator influences of PGI2. These results also suggest that the elevated vascular oxidant stress inherent in metabolic syndrome may contribute to the increased vascular TxA2 production and may blunt vascular sensitivity to PGI2. PMID:18689495

  6. Increased vascular thromboxane generation impairs dilation of skeletal muscle arterioles of obese Zucker rats with reduced oxygen tension.

    PubMed

    Goodwill, Adam G; James, Milinda E; Frisbee, Jefferson C

    2008-10-01

    This study determined if altered vascular prostacyclin (PGI(2)) and/or thromboxane A(2) (TxA(2)) production with reduced Po(2) contributes to impaired hypoxic dilation of skeletal muscle resistance arterioles of obese Zucker rats (OZRs) versus lean Zucker rats (LZRs). Mechanical responses were assessed in isolated gracilis muscle arterioles following reductions in Po(2) under control conditions and following pharmacological interventions inhibiting arachidonic acid metabolism and nitric oxide synthase and alleviating elevated vascular oxidant stress. The production of arachidonic acid metabolites was assessed using pooled arteries from OZRs and LZRs in response to reduced Po(2). Hypoxic dilation, endothelium-dependent in both strains, was attenuated in OZRs versus LZRs. Nitric oxide synthase inhibition had no significant impact on hypoxic dilation in either strain. Cyclooxygenase inhibition dramatically reduced hypoxic dilation in LZRs and abolished responses in OZRs. Treatment of arterioles from OZRs with polyethylene glycol-superoxide dismutase improved hypoxic dilation, and this improvement was entirely cyclooxygenase dependent. Vascular PGI(2) production with reduced Po(2) was similar between strains, although TxA(2) production was increased in OZRs, a difference that was attenuated by treatment of vessels from OZRs with polyethylene glycol-superoxide dismutase. Both blockade of PGH(2)/TxA(2) receptors and inhibition of thromboxane synthase increased hypoxic dilation in OZR arterioles. These results suggest that a contributing mechanism underlying impaired hypoxic dilation of skeletal muscle arterioles of OZRs may be an increased vascular production of TxA(2), which competes against the vasodilator influences of PGI(2). These results also suggest that the elevated vascular oxidant stress inherent in metabolic syndrome may contribute to the increased vascular TxA(2) production and may blunt vascular sensitivity to PGI(2). PMID:18689495

  7. How the airway smooth muscle in cystic fibrosis reacts in proinflammatory conditions: implications for airway hyper-responsiveness and asthma in cystic fibrosis.

    PubMed

    McCuaig, Sarah; Martin, James G

    2013-04-01

    Among patients with cystic fibrosis there is a high prevalence (40-70%) of asthma signs and symptoms such as cough and wheezing and airway hyper-responsiveness to inhaled histamine or methacholine. Whether these abnormal airway responses are due to a primary deficiency in the cystic fibrosis transmembrane conductance regulator (CFTR) or are secondary to the inflammatory environment in the cystic fibrosis lungs is not clear. A role for the CFTR in smooth muscle function is emerging, and alterations in contractile signalling have been reported in CFTR-deficient airway smooth muscle. Persistent bacterial infection, especially with Pseudomonas aeruginosa, stimulates interleukin-8 release from the airway epithelium, resulting in neutrophilic inflammation. Increased neutrophilia and skewing of CFTR-deficient T-helper cells to type 2 helper T cells creates an inflammatory environment characterised by high concentrations of tumour necrosis factor α, interleukin-8, and interleukin-13, which might all contribute to increased contractility of airway smooth muscle in cystic fibrosis. An emerging role of interleukin-17, which is raised in patients with cystic fibrosis, in airway smooth muscle proliferation and hyper-responsiveness is apparent. Increased understanding of the molecular mechanisms responsible for the altered smooth muscle physiology in patients with cystic fibrosis might provide insight into airway dysfunction in this disease. PMID:24429094

  8. Airway smooth muscle NOX4 is upregulated and modulates ROS generation in COPD.

    PubMed

    Hollins, Fay; Sutcliffe, Amanda; Gomez, Edith; Berair, Rachid; Russell, Richard; Szyndralewiez, Cédric; Saunders, Ruth; Brightling, Christopher

    2016-01-01

    The burden of oxidative stress is increased in chronic obstructive pulmonary disease (COPD). However, whether the intra-cellular mechanisms controlling the oxidant/anti-oxidant balance in structural airway cells such as airway smooth muscle in COPD is altered is unclear. We sought to determine whether the expression of the NADPH oxidase (NOX)-4 is increased in airway smooth muscle in COPD both in vivo and primary cells in vitro and its role in hydrogen peroxide-induced reactive oxygen species generation. We found that in vivo NOX4 expression was up-regulated in the airway smooth muscle bundle in COPD (n = 9) and healthy controls with >20 pack year history (n = 4) compared to control subjects without a significant smoking history (n = 6). In vitro NOX4 expression was increased in airway smooth muscle cells from subjects with COPD (n = 5) compared to asthma (n = 7) and upregulated following TNF-α stimulation. Hydrogen peroxide-induced reactive oxygen species generation by airway smooth muscle cells in COPD (n = 5) was comparable to healthy controls (n = 9) but lower than asthma (n = 5); and was markedly attenuated by NOX4 inhibition. Our findings demonstrate that NOX4 expression is increased in vivo and in vitro in COPD and although we did not observe an intrinsic increase in oxidant-induced reactive oxygen species generation in COPD, it was reduced markedly by NOX4 inhibition supporting a potential therapeutic role for NOX4 in COPD. PMID:27435477

  9. A novel bronchial ring bioassay for the evaluation of small airway smooth muscle function in mice.

    PubMed

    Liu, John Q; Yang, Dennis; Folz, Rodney J

    2006-08-01

    Advances in our understanding of murine airway physiology have been hindered by the lack of suitable, ex vivo, small airway bioassay systems. In this study, we introduce a novel small murine airway bioassay system that permits the physiological and pharmacological study of intrapulmonary bronchial smooth muscle via a bronchial ring (BR) preparation utilizing BR segments as small as 200 microm in diameter. Using this ex vivo BR bioassay, we characterized small airway smooth muscle contraction and relaxation in the presence and absence of bronchial epithelium. In control BRs, the application of mechanical stretch is followed by spontaneous bronchial smooth muscle relaxation. BRs pretreated with methacholine (MCh) partially attenuate this stretch-induced relaxation by as much as 42% compared with control. MCh elicited a dose-dependent bronchial constriction with a maximal tension (E(max)) of 8.7 +/- 0.2 mN at an EC(50) of 0.33 +/- 0.02 microM. In the presence of nifedipine, ryanodine, 2-aminoethoxydiphenyl borate, and SKF-96365, E(max) to MCh was significantly reduced. In epithelium-denuded BRs, MCh-induced contraction was significantly enhanced to 11.4 +/- 1.0 mN with an EC(50) of 0.16 +/- 0.04 microM (P < 0.01). Substance P relaxed MCh-precontracted BR by 62.1%; however, this bronchial relaxation effect was completely lost in epithelium-denuded BRs. Papaverine virtually abolished MCh-induced constriction in both epithelium-intact and epithelium-denuded bronchial smooth muscle. In conclusion, this study introduces a novel murine small airway BR bioassay that allows for the physiological study of smooth muscle airway contractile responses that may aid in our understanding of the pathophysiology of asthma. PMID:16648239

  10. Cigarette smoke enhances proliferation and extracellular matrix deposition by human fetal airway smooth muscle

    PubMed Central

    Vogel, Elizabeth R.; VanOosten, Sarah K.; Holman, Michelle A.; Hohbein, Danielle D.; Thompson, Michael A.; Vassallo, Robert; Pandya, Hitesh C.; Prakash, Y. S.

    2014-01-01

    Cigarette smoke is a common environmental insult associated with increased risk of developing airway diseases such as wheezing and asthma in neonates and children. In adults, asthma involves airway remodeling characterized by increased airway smooth muscle (ASM) cell proliferation and increased extracellular matrix (ECM) deposition, as well as airway hyperreactivity. The effects of cigarette smoke on remodeling and contractility in the developing airway are not well-elucidated. In this study, we used canalicular-stage (18–20 wk gestational age) human fetal airway smooth muscle (fASM) cells as an in vitro model of the immature airway. fASM cells were exposed to cigarette smoke extract (CSE; 0.5–1.5% for 24–72 h), and cell proliferation, ECM deposition, and intracellular calcium ([Ca2+]i) responses to agonist (histamine 10 μM) were used to evaluate effects on remodeling and hyperreactivity. CSE significantly increased cell proliferation and deposition of ECM molecules collagen I, collagen III, and fibronectin. In contrast, [Ca2+]i responses were not significantly affected by CSE. Analysis of key signaling pathways demonstrated significant increase in extracellular signal-related kinase (ERK) and p38 activation with CSE. Inhibition of ERK or p38 signaling prevented CSE-mediated changes in proliferation, whereas only ERK inhibition attenuated the CSE-mediated increase in ECM deposition. Overall, these results demonstrate that cigarette smoke may enhance remodeling in developing human ASM through hyperplasia and ECM production, thus contributing to development of neonatal and pediatric airway disease. PMID:25344066

  11. O3-induced mucosa-linked airway muscle hyperresponsiveness in the guinea pig

    SciTech Connect

    Murlas, C.G.; Murphy, T.P.; Chodimella, V. )

    1990-07-01

    We investigated the effects of ozone exposure (3.0 ppm, 2 h) on the responsiveness of guinea pig airway muscle in vitro from animals developing bronchial hyperreactivity. Muscarinic reactivity in vivo was determined by measuring specific airway resistance (sRaw) in response to increasing concentrations of aerosolized acetylcholine (ACh) administered before and 30 min after exposure. Immediately after reactivity testing, multiple tracheal rings from ozone- and air-exposed animals were prepared and the contractile responses to increasing concentrations of substance P, ACh, or KCl were assessed in the presence of 10 microM indomethacin with or without 1 microM phosphoramidon, an inhibitor of neutral endopeptidase. Isometric force generation in vitro was measured on stimulation by cumulative concentrations of the agonists, and force generation (in g/cm2) was calculated after determination of muscle cross-sectional area. The smooth muscle of mucosa-intact airways from guinea pigs with ozone-induced bronchial hyper-reactivity proved to be hyperresponsive in vitro to substance P and ACh but not to KCl. Pretreatment with phosphoramidon abolished the increase in substance P responsiveness but had no effect on muscarinic hyperresponsiveness after ozone exposure. Furthermore, substance P responsiveness was not augmented in ozone-exposed airways in which the mucosa had been removed before testing in vitro. Likewise, muscarinic hyperresponsiveness was not present in ozone-exposed airways without mucosa. Our data indicate that airway smooth muscle responsiveness is increased in guinea pigs with ozone-induced bronchial hyperreactivity and suggest that this hyperresponsiveness may be linked to non-cyclooxygenase mucosa-derived factors.

  12. Sex differences of continuous positive airway pressure treatment on flow-mediated dilation in patients with obstructive sleep apnea syndrome

    PubMed Central

    Kallianos, Anastasios; Panoutsopoulos, Athanasios; Mermigkis, Christoforos; Kostopoulos, Konstantinos; Papamichail, Chrysanthi; Kokkonouzis, Ioannis; Kostopoulos, Christoforos; Nikolopoulos, Ioannis; Papaiwannou, Antonis; Lampaki, Sofia; Organtzis, John; Pitsiou, Georgia; Zarogoulidis, Paul; Trakada, Georgia

    2015-01-01

    Introduction There is growing research evidence suggesting the presence of endothelial dysfunction and systemic inflammation in patients with obstructive sleep apnea syndrome (OSAS). Continuous positive airway pressure (CPAP) is the most effective method for treating OSAS; nonetheless, the effects of CPAP on the aforementioned pathophysiologic pathways as well as on the systemic disease that result or coexist with the OSAS remain elusive. Aim To assess the effect of 3-month CPAP therapy on endothelial-dependent dilation, plasma levels of inflammatory markers, blood pressure (BP), and glucose control on male and female patients with OSAS. Methods Our study group consisted of 40 (24 males and 16 females) patients with no prior history of cardiovascular disease, with an apnea–hypopnea index ≥15, who were assigned to receive CPAP treatment. Measurements of flow-mediated dilation (FMD), 24-hour ambulatory BP, and blood analysis were performed at baseline and 3 months after CPAP therapy. Results Baseline FMD values were negatively correlated with the apnea–hypopnea index (r=−0.55, P=0.001). After 3 months of CPAP, there was an increase in the FMD values (5.40%±2.91% vs 3.13%±3.15%, P<0.05) and a significant reduction in the patients’ 24-hour systolic BP (122.82±11.88 mmHg vs 130.24±16.75 mmHg, P<0.05), diastolic BP (75.44±9.14 mmHg vs 79.68±11.09 mmHg, P<0.05), and pulse pressure (47.38±9.77 mmHg vs 52.72±11.38 mmHg, P<0.05); daytime systolic BP (125.76±12.69 mmHg vs 132.55±17.00 mmHg, P<0.05) and diastolic BP (77.88±10.39 mmHg vs 82.25±11.01 mmHg, P<0.05); nighttime systolic BP (118.17±13.16 mmHg vs 126.22±17.42 mmHg, P<0.05) and pulse pressure (46.61±10.76 mmHg vs 52.66±11.86 mmHg, P<0.05); and C-reactive protein and HbA1c levels (0.40 [0.40–0.70] mg/L vs 0.60 [0.40–0.84] mg/L and 5.45%±0.70% vs 5.95%±1.08%, respectively; P<0.05). When divided by sex, only male patients produced similar statistically significant results, while female

  13. Human airway smooth muscle cells secrete amphiregulin via bradykinin/COX-2/PGE2, inducing COX-2, CXCL8, and VEGF expression in airway epithelial cells

    PubMed Central

    Knox, Alan J.

    2015-01-01

    Human airway smooth muscle cells (HASMC) contribute to asthma pathophysiology through an increased smooth muscle mass and elevated cytokine/chemokine output. Little is known about how HASMC and the airway epithelium interact to regulate chronic airway inflammation and remodeling. Amphiregulin is a member of the family of epidermal growth factor receptor (EGFR) agonists with cell growth and proinflammatory roles and increased expression in the lungs of asthma patients. Here we show that bradykinin (BK) stimulation of HASMC increases amphiregulin secretion in a mechanism dependent on BK-induced COX-2 expression, increased PGE2 output, and the stimulation of HASMC EP2 and EP4 receptors. Conditioned medium from BK treated HASMC induced CXCL8, VEGF, and COX-2 mRNA and protein accumulation in airway epithelial cells, which were blocked by anti-amphiregulin antibodies and amphiregulin siRNA, suggesting a paracrine effect of HASMC-derived amphiregulin on airway epithelial cells. Consistent with this, recombinant amphiregulin induced CXCL8, VEGF, and COX-2 in airway epithelial cells. Finally, we found that conditioned media from amphiregulin-stimulated airway epithelial cells induced amphiregulin expression in HASMC and that this was dependent on airway epithelial cell COX-2 activity. Our study provides evidence of a dynamic axis of interaction between HASMC and epithelial cells that amplifies CXCL8, VEGF, COX-2, and amphiregulin production. PMID:26047642

  14. Effects of upper airway pressure on abdominal muscle activity in conscious dogs.

    PubMed

    Plowman, L; Lauff, D C; McNamara, F; Berthon-Jones, M; Sullivan, C E

    1991-12-01

    We have examined arousal and abdominal muscle electromyogram (EMGabd) responses to upper airway pressure stimuli during physiological sleep in four dogs with permanent side-hole tracheal stomata. The dogs were trained to sleep with a tightly fitting snout mask, hermetically sealed in place, while breathing through a cuffed endotracheal tube inserted through the tracheostomy. Sleep stage was determined by behavioral and electroencephalographic criteria. EMGabd activity was measured using bipolar fine-wire electrodes inserted into the abdominal muscle layers. Static increases or decreases in upper airway pressure (+/- 6 cmH2O), when applied at the snout mask or larynx (upper trachea), caused an immediate decrease in EMGabd on the first two to three breaths; EMGabd usually returned to control levels within the 1-min test interval. In contrast, oscillatory pressure waves at 30 Hz and +/- 3 cmH2O amplitude (or -2 to -8 cmH2O amplitude) produced an immediate and sustained reduction in IMGabd in all sleep states. Inhibition of EMGabd could be maintained over many minutes when the oscillatory pressure stimulus was pulsed by using a cycle of 0.5 s on and 0.5 s off. Oscillatory upper airway pressures were also found to be powerful arousal-promoting stimuli, producing arousal in 94% of tests in drowsiness and 66% of tests in slowwave sleep. The results demonstrate the presence of breath-by-breath upper airway control of abdominal muscle activity. PMID:1778951

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

    SciTech Connect

    Liu, Wenrui; Kong, Hui; Zeng, Xiaoning; Wang, Jingjing; Wang, Zailiang; Yan, Xiaopei; Wang, Yanli; Xie, Weiping Wang, Hong

    2015-08-15

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

  16. Peripheral Airway Smooth Muscle, but Not the Trachealis, Is Hypercontractile in an Equine Model of Asthma.

    PubMed

    Matusovsky, Oleg S; Kachmar, Linda; Ijpma, Gijs; Bates, Genevieve; Zitouni, Nedjma; Benedetti, Andrea; Lavoie, Jean-Pierre; Lauzon, Anne-Marie

    2016-05-01

    Heaves is a naturally occurring equine disease that shares many similarities with human asthma, including reversible antigen-induced bronchoconstriction, airway inflammation, and remodeling. The purpose of this study was to determine whether the trachealis muscle is mechanically representative of the peripheral airway smooth muscle (ASM) in an equine model of asthma. Tracheal and peripheral ASM of heaves-affected horses under exacerbation, or under clinical remission of the disease, and control horses were dissected and freed of epithelium to measure unloaded shortening velocity (Vmax), stress (force/cross-sectional area), methacholine effective concentration at which 50% of the maximum response is obtained, and stiffness. Myofibrillar Mg(2+)-ATPase activity, actomyosin in vitro motility, and contractile protein expression were also measured. Horses with heaves had significantly greater Vmax and Mg(2+)-ATPase activity in peripheral airway but not in tracheal smooth muscle. In addition, a significant correlation was found between Vmax and the time elapsed since the end of the corticosteroid treatment for the peripheral airways in horses with heaves. Maximal stress and stiffness were greater in the peripheral airways of the horses under remission compared with controls and the horses under exacerbation, potentially due to remodeling. Actomyosin in vitro motility was not different between controls and horses with heaves. These data demonstrate that peripheral ASM is mechanically and biochemically altered in heaves, whereas the trachealis behaves as in control horses. It is therefore conceivable that the trachealis muscle may not be representative of the peripheral ASM in human asthma either, but this will require further investigation. PMID:26473389

  17. Orai channel-mediated Ca2+ signals in vascular and airway smooth muscle.

    PubMed

    Spinelli, Amy M; Trebak, Mohamed

    2016-03-15

    Orai (Orai1, Orai2, and Orai3) proteins form a family of highly Ca(2+)-selective plasma membrane channels that are regulated by stromal-interacting molecules (STIM1 and STIM2); STIM proteins are Ca(2+) sensors located in the membrane of the endoplasmic reticulum. STIM and Orai proteins are expressed in vascular and airway smooth muscle and constitute the molecular components of the ubiquitous store-operated Ca(2+) entry pathway that mediate the Ca(2+) release-activated Ca(2+) current. STIM/Orai proteins also encode store-independent Ca(2+) entry pathways in smooth muscle. Altered expression and function of STIM/Orai proteins have been linked to vascular and airway pathologies, including restenosis, hypertension, and atopic asthma. In this review we discuss our current understanding of Orai proteins and the store-dependent and -independent signaling pathways mediated by these proteins in vascular and airway smooth muscle. We also discuss the current studies linking altered expression and function of Orai proteins with smooth muscle-related pathologies. PMID:26718630

  18. Matrix stiffness-modulated proliferation and secretory function of the airway smooth muscle cells.

    PubMed

    Shkumatov, Artem; Thompson, Michael; Choi, Kyoung M; Sicard, Delphine; Baek, Kwanghyun; Kim, Dong Hyun; Tschumperlin, Daniel J; Prakash, Y S; Kong, Hyunjoon

    2015-06-01

    Multiple pulmonary conditions are characterized by an abnormal misbalance between various tissue components, for example, an increase in the fibrous connective tissue and loss/increase in extracellular matrix proteins (ECM). Such tissue remodeling may adversely impact physiological function of airway smooth muscle cells (ASMCs) responsible for contraction of airways and release of a variety of bioactive molecules. However, few efforts have been made to understand the potentially significant impact of tissue remodeling on ASMCs. Therefore, this study reports how ASMCs respond to a change in mechanical stiffness of a matrix, to which ASMCs adhere because mechanical stiffness of the remodeled airways is often different from the physiological stiffness. Accordingly, using atomic force microscopy (AFM) measurements, we found that the elastic modulus of the mouse bronchus has an arithmetic mean of 23.1 ± 14 kPa (SD) (median 18.6 kPa). By culturing ASMCs on collagen-conjugated polyacrylamide hydrogels with controlled elastic moduli, we found that gels designed to be softer than average airway tissue significantly increased cellular secretion of vascular endothelial growth factor (VEGF). Conversely, gels stiffer than average airways stimulated cell proliferation, while reducing VEGF secretion and agonist-induced calcium responses of ASMCs. These dependencies of cellular activities on elastic modulus of the gel were correlated with changes in the expression of integrin-β1 and integrin-linked kinase (ILK). Overall, the results of this study demonstrate that changes in matrix mechanics alter cell proliferation, calcium signaling, and proangiogenic functions in ASMCs. PMID:25724668

  19. HB-EGF-Promoted Airway Smooth Muscle Cells and Their Progenitor Migration Contribute to Airway Smooth Muscle Remodeling in Asthmatic Mouse.

    PubMed

    Wang, Qing; Li, Hequan; Yao, Yinan; Lu, Guohua; Wang, Yuehong; Xia, Dajing; Zhou, Jianying

    2016-03-01

    The airway smooth muscle (ASM) cells' proliferation, migration, and their progenitor's migration are currently regarded as causative factors for ASM remodeling in asthma. Heparin-binding epidermal growth factor (HB-EGF), a potent mitogen and chemotactic factor, could promote ASM cell proliferation through MAPK pathways. In this study, we obtained primary ASM cells and their progenitors from C57BL/6 mice and went on to explore the role of HB-EGF in these cells migration and the underlying mechanisms. We found that recombinant HB-EGF (rHB-EGF) intratracheal instillation accelerated ASM layer thickening in an OVA-induced asthmatic mouse. Modified Boyden chamber assay revealed that rHB-EGF facilitate ASM cell migration in a dose-dependent manner and ASM cells from asthmatic mice had a greater migration ability than that from normal counterparts. rHB-EGF could stimulate the phosphorylation of ERK1/2 and p38 in ASM cells but further migration assay showed that only epidermal growth factor receptor inhibitor (AG1478) or p38 inhibitor (SB203580), but not ERK1/2 inhibitor (PD98059), could inhibit rHB-EGF-mediated ASM cells migration. Actin cytoskeleton experiments exhibited that rHB-EGF could cause actin stress fibers disassembly and focal adhesions formation of ASM cells through the activation of p38. Finally, airway instillation of rHB-EGF promoted the recruitment of bone marrow-derived smooth muscle progenitor cells, which were transferred via caudal vein, migrating into the airway from the circulation. These observations demonstrated that ASM remodeling in asthma might have resulted from HB-EGF-mediated ASM cells and their progenitor cells migration, via p38 MAPK-dependent actin cytoskeleton remodeling. PMID:26826248

  20. Steroids augment relengthening of contracted airway smooth muscle: potential additional mechanism of benefit in asthma.

    PubMed

    Lakser, O J; Dowell, M L; Hoyte, F L; Chen, B; Lavoie, T L; Ferreira, C; Pinto, L H; Dulin, N O; Kogut, P; Churchill, J; Mitchell, R W; Solway, J

    2008-11-01

    Breathing (especially deep breathing) antagonises development and persistence of airflow obstruction during bronchoconstrictor stimulation. Force fluctuations imposed on contracted airway smooth muscle (ASM) in vitro result in its relengthening, a phenomenon called force fluctuation-induced relengthening (FFIR). Because breathing imposes similar force fluctuations on contracted ASM within intact lungs, FFIR represents a likely mechanism by which breathing antagonises bronchoconstriction. While this bronchoprotective effect appears to be impaired in asthma, corticosteroid treatment can restore the ability of deep breaths to reverse artificially induced bronchoconstriction in asthmatic subjects. It has previously been demonstrated that FFIR is physiologically regulated through the p38 mitogen-activated protein kinase (MAPK) signalling pathway. While the beneficial effects of corticosteroids have been attributed to suppression of airway inflammation, the current authors hypothesised that alternatively they might exert their action directly on ASM by augmenting FFIR as a result of inhibiting p38 MAPK signalling. This possibility was tested in the present study by measuring relengthening in contracted canine tracheal smooth muscle (TSM) strips. The results indicate that dexamethasone treatment significantly augmented FFIR of contracted canine TSM. Canine tracheal ASM cells treated with dexamethasone demonstrated increased MAPK phosphatase-1 expression and decreased p38 MAPK activity, as reflected in reduced phosphorylation of the p38 MAPK downstream target, heat shock protein 27. These results suggest that corticosteroids may exert part of their therapeutic effect through direct action on airway smooth muscle, by decreasing p38 mitogen-activated protein kinase activity and thus increasing force fluctuation-induced relengthening. PMID:18768574

  1. The TLR7 agonist imiquimod induces bronchodilation via a nonneuronal TLR7-independent mechanism: a possible role for quinoline in airway dilation.

    PubMed

    Larsson, Olivia J; Manson, Martijn L; Starkhammar, Magnus; Fuchs, Barbara; Adner, Mikael; Kumlien Georén, Susanna; Cardell, Lars-Olaf

    2016-06-01

    Toll-like receptor (TLR) 7 agonists are known to reduce allergic airway inflammation. Their recently reported ability to rapidly relax airways has further increased their interest in the treatment of pulmonary disease. However, the mechanisms behind this effect are not fully understood. The present study, therefore, aimed to determine whether airway smooth muscle (ASM)-dependent mechanisms could be identified. TLR7 agonists were added to guinea pig airways following precontraction with carbachol in vitro or histamine in vivo. Pharmacological inhibitors were used to dissect conventional pathways of bronchodilation; tetrodotoxin was used or bilateral vagotomy was performed to assess neuronal involvement. Human ASM cells (HASMCs) were employed to determine the effect of TLR7 agonists on intracellular Ca(2+) ([Ca(2+)]i) mobilization. The well-established TLR7 agonist imiquimod rapidly relaxed precontracted airways in vitro and in vivo. This relaxation was demonstrated to be independent of nitric oxide, carbon monoxide, and cAMP signaling, as well as neuronal activity. A limited role for prostanoids could be detected. Imiquimod induced [Ca(2+)]i release from endoplasmic reticulum stores in HASMCs, inhibiting histamine-induced [Ca(2+)]i The TLR7 antagonist IRS661 failed to inhibit relaxation, and the structurally dissimilar agonist CL264 did not relax airways or inhibit [Ca(2+)]i This study shows that imiquimod acts directly on ASM to induce bronchorelaxation, via a TLR7-independent release of [Ca(2+)]i The effect is paralleled by other bronchorelaxant compounds, like chloroquine, which, like imiquimod, but unlike CL264, contains the chemical structure quinoline. Compounds with quinoline moieties may be of interest in the development of multifunctional drugs to treat pulmonary disease. PMID:27084847

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

    PubMed

    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. PMID:23428645

  3. Differential Expression of Lipid and Carbohydrate Metabolism Genes in Upper Airway versus Diaphragm Muscle

    PubMed Central

    van Lunteren, Erik; Spiegler, Sarah; Moyer, Michelle

    2010-01-01

    Study Objectives: Contractile properties of upper airway muscles influence upper airway patency, an issue of particular importance for subjects with obstructive sleep apnea. Expression of genes related to cellular energetics is, in turn, critical for the maintenance of contractile integrity over time during repetitive activation. We tested the hypothesis that sternohyoid has lower expression of genes related to lipid and carbohydrate energetic pathways than the diaphragm. Methods: Sternohyoid and diaphragm from normal adult rats were examined with gene expression arrays. Analysis focused on genes belonging to Gene Ontology (GO) groups carbohydrate metabolism and lipid metabolism. Results: There were 433 genes with at least ± 2-fold significant differential expression between sternohyoid and diaphragm, of which 192 had sternohyoid > diaphragm and 241 had diaphragm > sternohyoid expression. Among genes with higher sternohyoid expression, there was over-representation of the GO group carbohydrate metabolism (P = 0.0053, n = 13 genes, range of differential expression 2.1- to 6.2-fold) but not lipid metabolism (P = 0.44). Conversely, among genes with higher diaphragm expression, there was over-representation of the GO group lipid metabolism (P = 0.0000065, n = 32 genes, range of differential expression 2.0- to 37.9-fold) but not carbohydrate metabolism (P = 0.23). Nineteen genes with diaphragm > sternohyoid expression were related to fatty acid metabolism (P = 0.000000058), in particular fatty acid β oxidation and biosynthesis in the mitochondria. Conclusions: Sternohyoid has much lower gene expression than diaphragm for mitochondrial enzymes that participate in fatty acid oxidation and biosynthesis. This likely contributes to the lower fatigue resistance of pharyngeal upper airway muscles compared with the diaphragm. Citation: van Lunteren E; Spiegler S; Moyer M. Differential expression of lipid and carbohydrate metabolism genes in upper airway versus diaphragm

  4. Endobronchial Ultrasound Reliably Quantifies Airway Smooth Muscle Remodeling in an Equine Asthma Model.

    PubMed

    Bullone, Michela; Beauchamp, Guy; Godbout, Mireille; Martin, James G; Lavoie, Jean-Pierre

    2015-01-01

    Endobronchial ultrasonography (EBUS) revealed differences in the thickness of the layer representing subepithelial tissues (L2) between human asthmatics and controls, but whether this measurement correlates with airway smooth muscle (ASM) remodeling in asthma is unknown. In this study, we sought to determine the ability of EBUS to predict histological ASM remodeling in normal and equine asthmatic airways. We studied 109 isolated bronchi from the lungs of 13 horses. They underwent EBUS examination using a 30 MHz radial probe before being processed for histology. ASM remodeling parameters were evaluated in EBUS images (L2 thickness, L2 area, L2 area/internal perimeter [Pi] and L2 area/Pi2) and histological cuts (ASM area/Pi2), and compared. EBUS was then performed ex vivo on the lungs of 4 horses with heaves, an asthma-like condition of horses, and 7 controls to determine whether central bronchial remodeling could be detected with this technique. An optimized approach was developed based on data variability within airways, subjects, and groups, and then validated in 7 horses (3 controls, 4 with heaves) that underwent EBUS in vivo. L2 area was significantly associated to ASM area in isolated lungs (p<0.0001), in the absence of significant bias related to the airway size. Bronchial size significantly affected EBUS ASM-related parameters, except for L2 area/Pi2. L2 area/Pi2 was increased in the airways of asthmatic horses compared to controls, both ex vivo and in vivo (p<0.05). Bronchial histology confirmed our findings (AASM/Pi2 was increased in asthmatic horses compared to controls, p<0.05). In both horses with heaves and controls, L2 was composed of ASM for the outer 75% of its thickness and by ECM for the remaining inner 25%. In conclusion, EBUS reliably allows assessment of asthma-associated ASM remodeling of central airways in a non-invasive way. PMID:26348727

  5. Endobronchial Ultrasound Reliably Quantifies Airway Smooth Muscle Remodeling in an Equine Asthma Model

    PubMed Central

    Bullone, Michela; Beauchamp, Guy; Godbout, Mireille; Martin, James G.; Lavoie, Jean-Pierre

    2015-01-01

    Endobronchial ultrasonography (EBUS) revealed differences in the thickness of the layer representing subepithelial tissues (L2) between human asthmatics and controls, but whether this measurement correlates with airway smooth muscle (ASM) remodeling in asthma is unknown. In this study, we sought to determine the ability of EBUS to predict histological ASM remodeling in normal and equine asthmatic airways. We studied 109 isolated bronchi from the lungs of 13 horses. They underwent EBUS examination using a 30 MHz radial probe before being processed for histology. ASM remodeling parameters were evaluated in EBUS images (L2 thickness, L2 area, L2 area/internal perimeter [Pi] and L2 area/Pi2) and histological cuts (ASM area/Pi2), and compared. EBUS was then performed ex vivo on the lungs of 4 horses with heaves, an asthma-like condition of horses, and 7 controls to determine whether central bronchial remodeling could be detected with this technique. An optimized approach was developed based on data variability within airways, subjects, and groups, and then validated in 7 horses (3 controls, 4 with heaves) that underwent EBUS in vivo. L2 area was significantly associated to ASM area in isolated lungs (p<0.0001), in the absence of significant bias related to the airway size. Bronchial size significantly affected EBUS ASM-related parameters, except for L2 area/Pi2. L2 area/Pi2 was increased in the airways of asthmatic horses compared to controls, both ex vivo and in vivo (p<0.05). Bronchial histology confirmed our findings (AASM/Pi2 was increased in asthmatic horses compared to controls, p<0.05). In both horses with heaves and controls, L2 was composed of ASM for the outer 75% of its thickness and by ECM for the remaining inner 25%. In conclusion, EBUS reliably allows assessment of asthma-associated ASM remodeling of central airways in a non-invasive way. PMID:26348727

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

    PubMed Central

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

    2016-01-01

    Background Adult human airway smooth muscle (ASM) produce cytokines involved in recruitment and survival of leukocytes within airway walls. Cytokine generation by adult ASM is glucocorticoid-sensitive. Whether developing lung ASM produces cytokines in a glucocorticoid-sensitive fashion is unknown. Methods Cultured fetal human ASM cells stimulated with TNF-α (0–20 ng/ml) were incubated with TNF-α receptor-blocking antibodies, fluticasone (1 and 100 nm), or vehicle. Supernatants and cells were assayed for the production of CCL5, CXCL10, and CXCL8 mRNA and protein and glucocorticoid receptor phosphorylation. Results CCL5, CXCL10, and CXCL8 mRNA and protein production by fetal ASM cell was significantly and dose-dependently following TNF-α treatment. Cytokine mRNA and protein production were effectively blocked by TNF-α R1 and R2 receptor neutralizing antibodies but variably inhibited by fluticasone. TNF-α-induced TNF-R1 and R2 receptor mRNA expression was only partially attenuated by fluticasone. Glucocorticoid receptor phosphorylation at serine (Ser) 211 but not at Ser 226 was enhanced by fluticasone. Conclusion Production of CCL5, CXCL10, and CXCL8 by fetal ASM appears to involve pathways that are both qualitatively and mechanistically distinct to those described for adult ASM. The findings imply developing ASM has potential to recruit leukocyte into airways and, therefore, of relevance to childhood airway diseases. PMID:26331770

  7. IL-1β: a key modulator in asthmatic airway smooth muscle hyper-reactivity.

    PubMed

    Liao, Zhi; Xiao, Hong-tao; Zhang, Yuan; Tong, Rong-Sheng; Zhang, Li-Juan; Bian, Yuan; He, Xia

    2015-08-01

    Asthma is a chronic inflammatory disorder of the airway. It is characterized by airway hyper-reactivity, which can be attributed to the chronically inflamed airway. However, the molecular mechanism is still under investigation. In this article, we have shown that IL-1β is a key molecule that can orchestrate both Toll-like receptor and muscarinic receptor pathways, and that antagonizing the function of IL-1β has a promising future as a potential drug target for asthma treatment. IL-1β can activate NF-κB pathways via Toll-like receptors, and NF-κB will eventually transactivate the genes of cytokines, chemokines, proteins of the complement system, adhesion molecules and immune receptors involved in inflammation. IL-1β can activate eosinophils, which can release major basic protein (MBP) to antagonize the M2 receptors leading to excessive acetylcholine release. Acetylcholine has an effect on M3 receptors, which are related to airway smooth muscle contraction and mucus production. IL-1β is reported to activate COX-2 resulting in heterologous desensitization of adenylate cyclase and impairs relaxation of the ASM. IL-1β is involved in mediation of neutrophilic inflammation. Identification of the prominent role of IL-1β in asthma could lead to successful use of anti-IL1β agents. PMID:26134749

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

    PubMed Central

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

    2016-01-01

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

  9. Triptolide inhibits TGF-β1-induced cell proliferation in rat airway smooth muscle cells by suppressing Smad signaling

    SciTech Connect

    Chen, Ming; Lv, Zhiqiang; Huang, Linjie; Zhang, Wei; Lin, Xiaoling; Shi, Jianting; Zhang, Wei; Liang, Ruiyun; Jiang, Shanping

    2015-02-15

    Background: We have reported that triptolide can inhibit airway remodeling in a murine model of asthma via TGF-β1/Smad signaling. In the present study, we aimed to investigate the effect of triptolide on airway smooth muscle cells (ASMCs) proliferation and the possible mechanism. Methods: Rat airway smooth muscle cells were cultured and made synchronized, then pretreated with different concentration of triptolide before stimulated by TGF-β1. Cell proliferation was evaluated by MTT assay. Flow cytometry was used to study the influence of triptolide on cell cycle and apoptosis. Signal proteins (Smad2, Smad3 and Smad7) were detected by western blotting analysis. Results: Triptolide significantly inhibited TGF-β1-induced ASMC proliferation (P<0.05). The cell cycle was blocked at G1/S-interphase by triptolide dose dependently. No pro-apoptotic effects were detected under the concentration of triptolide we used. Western blotting analysis showed TGF-β1 induced Smad2 and Smad3 phosphorylation was inhibited by triptolide pretreatment, and the level of Smad7 was increased by triptolide pretreatment. Conclusions: Triptolide may function as an inhibitor of asthma airway remodeling by suppressing ASMCs proliferation via negative regulation of Smad signaling pathway. - Highlights: • In this study, rat airway smooth muscle cells were cultured and made synchronized. • Triptolide inhibited TGF-β1-induced airway smooth muscle cells proliferation. • Triptolide inhibited ASMCs proliferation via negative regulation of Smad signaling pathway.

  10. Sex Steroids Influence Brain-Derived Neurotropic Factor Secretion From Human Airway Smooth Muscle Cells.

    PubMed

    Wang, Sheng-Yu; Freeman, Michelle R; Sathish, Venkatachalem; Thompson, Michael A; Pabelick, Christina M; Prakash, Y S

    2016-07-01

    Brain derived neurotropic factor (BDNF) is emerging as an important player in airway inflammation, remodeling, and hyperreactivity. Separately, there is increasing evidence that sex hormones contribute to pathophysiology in the lung. BDNF and sex steroid signaling are thought to be intricately linked in the brain. There is currently little information on BDNF and sex steroid interactions in the airway but is relevant to understanding growth factor signaling in the context of asthma in men versus women. In this study, we assessed the effect of sex steroids on BDNF expression and secretion in human airway smooth muscle (ASM). Human ASM was treated with estrogen (E2 ) or testosterone (T, 10 nM each) and intracellular BDNF and secreted BDNF measured. E2 and T significantly reduced secretion of BDNF; effects prevented by estrogen and androgen receptor inhibitor, ICI 182,780 (1 μM), and flutamide (10 μM), respectively. Interestingly, no significant changes were observed in intracellular BDNF mRNA or protein expression. High affinity BDNF receptor, TrkB, was not altered by E2 or T. E2 (but not T) significantly increased intracellular cyclic AMP levels. Notably, Epac1 and Epac2 expression were significantly reduced by E2 and T. Furthermore, SNARE complex protein SNAP25 was decreased. Overall, these novel data suggest that physiologically relevant concentrations of E2 or T inhibit BDNF secretion in human ASM, suggesting a potential interaction of sex steroids with BDNF in the airway that is different from brain. The relevance of sex steroid-BDNF interactions may lie in their overall contribution to airway diseases such as asthma. J. Cell. Physiol. 231: 1586-1592, 2016. © 2015 Wiley Periodicals, Inc. PMID:26566264

  11. Inflammatory responses of airway smooth muscle cells and effects of endothelin receptor antagonism.

    PubMed

    Knobloch, Jürgen; Lin, Yingfeng; Konradi, Jürgen; Jungck, David; Behr, Juergen; Strauch, Justus; Stoelben, Erich; Koch, Andrea

    2013-07-01

    Endothelin receptor antagonists (ETRAs), authorized for pulmonary hypertension, have failed to prove their utility in chronic lung diseases with corticosteroid-resistant airway inflammation when applied at late disease stages with emphysema/fibrosis. Earlier administration might prove effective by targeting the interaction between airway inflammation and tissue remodeling. We hypothesized that human airway smooth muscle cells (HASMCs) participate in linking inflammation with remodeling and that associated genes become differentially suppressed by ambrisentan (A-receptor selective ETRA) and bosentan (nonselective/dual ETRA). Inflammatory responses of ex vivo-cultivated HASMCs to TNF-α were investigated by whole-genome microarray analyses. qRT-PCR and ELISA were used to test inflammatory and remodeling genes for sensitivity to bosentan and ambrisentan and to investigate differential sensitivities mechanistically. ETRA and corticosteroid effects were compared in HASMCs from patients with chronic obstructive pulmonary disease. TNF-α induced the expression of 18 cytokines/chemokines and five tissue remodeling genes involved in severe, corticosteroid-insensitive asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and/or pulmonary hypertension. Thirteen cytokines/chemokines, MMP13, and WISP1 were suppressed by ETRAs. Eight genes had differential sensitivity to bosentan and ambrisentan depending on the endothelin-B receptor impact on transcriptional regulation and mRNA stabilization. Chemokine (C-C motif) ligands 2 and 5, granulocyte macrophage colony-stimulating factor, and MMP13 had increased sensitivity to bosentan or bosentan/dexamethasone combination versus dexamethasone alone. Suppression of cytokine and remodeling gene expression by ETRAs was confirmed in TNF-α-activated human bronchial epithelial cells. HASMCs and human bronchial epithelial cells participate in the interaction of inflammation and tissue remodeling. This interaction is

  12. The effects of in utero vitamin D deficiency on airway smooth muscle mass and lung function.

    PubMed

    Foong, Rachel E; Bosco, Anthony; Jones, Anya C; Gout, Alex; Gorman, Shelley; Hart, Prue H; Zosky, Graeme R

    2015-11-01

    We have previously demonstrated increased airway smooth muscle (ASM) mass and airway hyperresponsiveness in whole-life vitamin D-deficient female mice. In this study, we aimed to uncover the molecular mechanisms contributing to altered lung structure and function. RNA was extracted from lung tissue of whole-life vitamin D-deficient and -replete female mice, and gene expression patterns were profiled by RNA sequencing. The data showed that genes involved in embryonic organ development, pattern formation, branching morphogenesis, Wingless/Int signaling, and inflammation were differentially expressed in vitamin D-deficient mice. Network analysis suggested that differentially expressed genes were connected by the hubs matrix metallopeptidase 9; NF-κ light polypeptide gene enhancer in B cells inhibitor, α; epidermal growth factor receptor; and E1A binding protein p300. Given our findings that developmental pathways may be altered, we investigated if the timing of vitamin D exposure (in utero vs. postnatal) had an impact on lung health outcomes. Gene expression was measured in in utero or postnatal vitamin D-deficient mice, as well as whole-life vitamin D-deficient and -replete mice at 8 weeks of age. Baseline lung function, airway hyperresponsiveness, and airway inflammation were measured and lungs fixed for lung structure assessment using stereological methods and quantification of ASM mass. In utero vitamin D deficiency was sufficient to increase ASM mass and baseline airway resistance and alter lung structure. There were increased neutrophils but decreased lymphocytes in bronchoalveolar lavage. Expression of inflammatory molecules S100A9 and S100A8 was mainly increased in postnatal vitamin D-deficient mice. These observations suggest that in utero vitamin D deficiency can alter lung structure and function and increase inflammation, contributing to symptoms in chronic diseases, such as asthma. PMID:25867172

  13. Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells.

    PubMed

    Sharma, Pawan; Panebra, Alfredo; Pera, Tonio; Tiegs, Brian C; Hershfeld, Alena; Kenyon, Lawrence C; Deshpande, Deepak A

    2016-02-15

    Airway remodeling is a hallmark feature of asthma and chronic obstructive pulmonary disease. Clinical studies and animal models have demonstrated increased airway smooth muscle (ASM) mass, and ASM thickness is correlated with severity of the disease. Current medications control inflammation and reverse airway obstruction effectively but have limited effect on remodeling. Recently we identified the expression of bitter taste receptors (TAS2R) on ASM cells, and activation with known TAS2R agonists resulted in ASM relaxation and bronchodilation. These studies suggest that TAS2R can be used as new therapeutic targets in the treatment of obstructive lung diseases. To further establish their effectiveness, in this study we aimed to determine the effects of TAS2R agonists on ASM growth and promitogenic signaling. Pretreatment of healthy and asthmatic human ASM cells with TAS2R agonists resulted in a dose-dependent inhibition of ASM proliferation. The antimitogenic effect of TAS2R ligands was not dependent on activation of protein kinase A, protein kinase C, or high/intermediate-conductance calcium-activated K(+) channels. Immunoblot analyses revealed that TAS2R agonists inhibit growth factor-activated protein kinase B phosphorylation without affecting the availability of phosphatidylinositol 3,4,5-trisphosphate, suggesting TAS2R agonists block signaling downstream of phosphatidylinositol 3-kinase. Furthermore, the antimitogenic effect of TAS2R agonists involved inhibition of induced transcription factors (activator protein-1, signal transducer and activator of transcription-3, E2 factor, nuclear factor of activated T cells) and inhibition of expression of multiple cell cycle regulatory genes, suggesting a direct inhibition of cell cycle progression. Collectively, these findings establish the antimitogenic effect of TAS2R agonists and identify a novel class of receptors and signaling pathways that can be targeted to reduce or prevent airway remodeling as well as

  14. Influence of upper airway sensory receptors on respiratory muscle activation in humans.

    PubMed

    Redline, S; Strohl, K P

    1987-07-01

    We reasoned that neural information from upper airway (UA) sensory receptors could influence the relationship between UA and diaphragmatic neuromuscular responses to hypercapnia. In this study, the electromyographic (EMG) activities of the alae nasi (AN), genioglossus (GG), and chest wall (CW) or diaphragm (Di) to ventilatory loading were assessed in six laryngectomized, tracheostomized human subjects and in six subjects breathing with an intact UA before and after topical UA anesthesia. The EMG activities of the UA and thoracic muscles increased at similar rates with increasing hypercapnia in normal subjects, in subjects whose upper airways were anesthetized, and in laryngectomized subjects breathing with a cervical tracheostomy. Furthermore, in the laryngectomized subjects, respiratory muscle EMG activation increased with resistive inspiratory loading (15 cmH2O X l-1 X s) applied at the level of a cervical tracheostomy. At an average expired CO2 fraction of 7.0%, resistive loading resulted in a 93 +/- 26.3% (SE) increase in peak AN EMG activity, a 39 +/- 2.0% increase in peak GG EMG activity, and a 43.2 +/- 16.5% increase in peak CW (Di) EMG activity compared with control values. We conclude that the ventilatory responses of the UA and thoracic muscles to ventilatory loading are not substantially influenced by laryngectomy or UA anesthesia. PMID:3624139

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

    PubMed

    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 < 0.05). As for EFS-induced contractions, Kidsolone had no direct effect but Xyzal could inhibit it, with increasing basal tension. In conclusion, using glucocorticoids alone had no spasmolytic effect but they can be synergized with 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. PMID:25115316

  16. Ovalbumin sensitization of guinea pig at birth prevents the ontogenetic decrease in airway smooth muscle responsiveness

    PubMed Central

    Chitano, Pasquale; Wang, Lu; Degan, Simone; Worthington, Charles L.; Pozzato, Valeria; Hussaini, Syed H.; Turner, Wesley C.; Dorscheid, Delbert R.; Murphy, Thomas M.

    2014-01-01

    Abstract Airway smooth muscle (ASM) displays a hyperresponsive phenotype at young age and becomes less responsive in adulthood. We hypothesized that allergic sensitization, which causes ASM hyperresponsiveness and typically occurs early in life, prevents the ontogenetic loss of the ASM hyperresponsive phenotype. We therefore studied whether neonatal allergic sensitization, not followed by later allergen challenges, alters the ontogenesis of ASM properties. We neonatally sensitized guinea pigs to ovalbumin and studied them at 1 week, 3 weeks, and 3 months (adult). A Schultz‐Dale response in isolated tracheal rings confirmed sensitization. The occurrence of inflammation was evaluated in the blood and in the submucosa of large airways. We assessed ASM function in tracheal strips as ability to produce force and shortening. ASM content of vimentin was also studied. A Schultz‐Dale response was observed in all 3‐week or older sensitized animals. A mild inflammatory process was characterized by eosinophilia in the blood and in the airway submucosa. Early life sensitization had no effect on ASM force generation, but prevented the ontogenetic decline of shortening velocity and the increase in resistance to shortening. Vimentin increased with age in control but not in sensitized animals. Allergic sensitization at birth without subsequent allergen exposures is sufficient to prevent normal ASM ontogenesis, inducing persistence to adulthood of an ASM hyperresponsive phenotype. PMID:25501429

  17. Studying airway smooth muscle in vivo with PS-OCT (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    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.

  18. Cigarette smoke-induced mitochondrial fragmentation and dysfunction in human airway smooth muscle

    PubMed Central

    Aravamudan, Bharathi; Kiel, Alexander; Freeman, Michelle; Delmotte, Philippe; Thompson, Michael; Vassallo, Robert; Sieck, Gary C.; Pabelick, Christina M.

    2014-01-01

    The balance between mitochondrial fission and fusion is crucial for mitochondria to perform its normal cellular functions. We hypothesized that cigarette smoke (CS) disrupts this balance and enhances mitochondrial dysfunction in the airway. In nonasthmatic human airway smooth muscle (ASM) cells, CS extract (CSE) induced mitochondrial fragmentation and damages their networked morphology in a concentration-dependent fashion, via increased expression of mitochondrial fission protein dynamin-related protein 1 (Drp1) and decreased fusion protein mitofusin (Mfn) 2. CSE effects on Drp1 vs. Mfn2 and mitochondrial network morphology involved reactive oxygen species (ROS), activation of extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), protein kinase C (PKC) and proteasome pathways, as well as transcriptional regulation via factors such as NF-κB and nuclear erythroid 2-related factor 2. Inhibiting Drp1 prevented CSE effects on mitochondrial networks and ROS generation, whereas blocking Mfn2 had the opposite, detrimental effect. In ASM from asmatic patients, mitochondria exhibited substantial morphological defects at baseline and showed increased Drp1 but decreased Mfn2 expression, with exacerbating effects of CSE. Overall, these results highlight the importance of mitochondrial networks and their regulation in the context of cellular changes induced by insults such as inflammation (as in asthma) or CS. Altered mitochondrial fission/fusion proteins have a further potential to influence parameters such as ROS and cell proliferation and apoptosis relevant to airway diseases. PMID:24610934

  19. Effects of miRNA-145 on airway smooth muscle cells function.

    PubMed

    Liu, Yun; Sun, Xiuzhen; Wu, Yuanyuan; Fang, Ping; Shi, Hongyang; Xu, Jing; Li, Manxiang

    2015-11-01

    The pathological changes of airway smooth muscle (ASM) contribute to airway remodeling during asthma. Here, we investigated the effect of miR-145 on ASM function. We found that miR-145 was aberrantly more highly expressed in ASM cells exposed to cytokine stimulation that mimic the airway conditions of patients with asthma. Repression of miR-145 resulted in decreased ASM cell proliferation and migration in a dose-dependent manner and down-regulation of type I collagen and contractile protein MHC in ASM cells. qRT-PCR and Western blot analysis demonstrated that miR-145 negatively regulated the expression of downstream target Krüppel-like factor 4 (KLF4) protein, and overexpression of KLF4 attenuated the effects of miR-145 on ASM cells. Further studies showed that KLF4 significantly up-regulated the expression of p21 and down-regulated matrix metalloproteinase (MMP-2 and MMP-9). In conclusion, miR-145 overexpression in ASM cells significantly inhibited KLF4, and subsequently affected downstream p21, MMP-2, and MMP-9 expressions, eventually leading to enhanced proliferation and migration of ASM cells in vitro. PMID:26197891

  20. Effect of airway inflammation on smooth muscle shortening and contractility in guinea pig trachealis.

    PubMed

    Mitchell, R W; Ndukwu, I M; Arbetter, K; Solway, J; Leff, A R

    1993-12-01

    We studied the effect of either 1) immunogenic inflammation caused by aerosolized ovalbumin or 2) neurogenic inflammation caused by aerosolized capsaicin in vivo on guinea pig tracheal smooth muscle (TSM) contractility in vitro. Force-velocity relationships were determined for nine epithelium-intact TSM strips from ovalbumin-sensitized (OAS) vs. seven sham-sensitized controls and TSM strips for seven animals treated with capsaicin aerosol (Cap-Aer) vs. eight sham controls. Muscle strips were tethered to an electromagnetic lever system, which allowed isotonic shortening when load clamps [from 0 to maximal isometric force (Po)] were applied at specific times after onset of contraction. Contractions were elicited by supramaximal electrical field stimulation (60 Hz, 10-s duration, 18 V). Optimal length for each muscle was determined during equilibration. Maximal shortening velocity (Vmax) was increased in TSM from OAS (1.72 +/- 0.46 mm/s) compared with sham-sensitized animals (0.90 +/- 0.15 mm/s, P < 0.05); Vmax for TSM from Cap-Aer (0.88 +/- 0.11 mm/s) was not different from control TSM (1.13 +/- 0.08 mm/s, P = NS). Similarly, maximal shortening (delta max) was augmented in TSM from OAS (1.01 +/- 0.15 mm) compared with sham-sensitized animals (0.72 +/- 0.14 mm, P < 0.05); delta max for TSM from Cap-Aer animals (0.65 +/- 0.11 mm) was not different from saline aerosol controls (0.71 +/- 0.15 mm, P = NS). We demonstrate Vmax and delta max are augmented in TSM after ovalbumin sensitization; in contrast, neurogenic inflammation caused by capsaicin has no effect on isolated TSM contractility in vitro. These data suggest that airway hyperresponsiveness in vivo that occurs in association with immunogenic or neurogenic inflammation may result from different effects of these types of inflammation on airway smooth muscle. PMID:8279571

  1. Airway hyperresponsiveness in asthma: a problem of limited smooth muscle relaxation with inspiration.

    PubMed Central

    Skloot, G; Permutt, S; Togias, A

    1995-01-01

    We hypothesized that hyperresponsiveness in asthma is caused by an impairment in the ability of inspiration to stretch airway smooth muscle. If the hypothesis was correct, we reasoned that the sensitivity to inhaled methacholine in normal and asthmatic subjects should be the same if the challenge was carried out under conditions where deep inspirations were prohibited. 10 asthmatic and 10 normal subjects received increasing concentrations of inhaled methacholine under conditions where forced expirations from a normal end-tidal inspiration were performed. When no deep inspirations were allowed, the response to methacholine was similar in the normal and asthmatic subjects, compatible with the hypothesis we propose. Completely contrary to our expectations, however, was the marked responsivity to methacholine that remained in the normal subjects after deep breaths were initiated. 6 of the 10 normal subjects had > 20% reduction in forced expiratory volume in one second (FEV 1) at doses of methacholine < 8 mg/ml, whereas there was < 15% reduction with 75 mg/ml during routine challenge. The ability of normal subjects to develop asthmatic responses when the modulating effects of increases in lung volume was voluntarily suppressed suggests that an intrinsic impairment of the ability of inspiration to stretch airway smooth muscle is a major feature of asthma. PMID:7593627

  2. A Synthetic Chloride Channel Relaxes Airway Smooth Muscle of the Rat

    PubMed Central

    Yau, Kwok-hei; Mak, Judith Choi-wo; Leung, Susan Wai-sum; Yang, Dan; Vanhoutte, Paul M.

    2012-01-01

    Synthetic ion channels may have potential therapeutic applications, provided they possess appropriate biological activities. The present study was designed to examine the ability of small molecule-based synthetic Cl– channels to modulate airway smooth muscle responsiveness. Changes in isometric tension were measured in rat tracheal rings. Relaxations to the synthetic chloride channel SCC-1 were obtained during sustained contractions to KCl. The anion dependency of the effect of SCC-1 was evaluated by ion substitution experiments. The sensitivity to conventional Cl– transport inhibitors was also tested. SCC-1 caused concentration-dependent relaxations during sustained contractions to potassium chloride. This relaxing effect was dependent on the presence of extracellular Cl– and HCO3−. It was insensitive to conventional Cl– channels/transport inhibitors that blocked the cystic fibrosis transmembrane conductance regulator and calcium-activated Cl– channels. SCC-1 did not inhibit contractions induced by carbachol, endothelin-1, 5-hydroxytryptamine or the calcium ionophore A23187. SCC-1 relaxes airway smooth muscle during contractions evoked by depolarizing solutions. The Cl– conductance conferred by this synthetic compound is distinct from the endogenous transport systems for chloride anions. PMID:23049786

  3. M2 Muscarinic acetylcholine receptor modulates rat airway smooth muscle cell proliferation

    PubMed Central

    2013-01-01

    Airways chronic inflammatory conditions in asthma and COPD are characterized by tissue remodeling, being smooth muscle hyperplasia, the most important feature. Non-neuronal and neuronal Acetylcholine acting on muscarinic receptors (MAChRs) has been postulated as determinant of tissue remodeling in asthma and COPD by promoting proliferation and phenotypic changes of airway smooth muscle cells (ASMC). The objective was to evaluate proliferative responses to muscarinic agonist as carbamylcholine (Cch) and to identify the MAchR subtype involved. ASMC were isolated from tracheal fragments of Sprague–Dawley rats by enzymatic digestion. Proliferation assays were performed by MTS-PMS method. Viability was confirmed by trypan blue exclusion method. Mitogens as, epidermal growth factor (EGF), Tumor necrosis factor-alpha (TNF-α) and fetal bovine serum (FBS) increased ASMC proliferation (p < 0.05, n = 5). Cch alone increased ASMC proliferation at 24 and 48 hrs. However, combination of Cch with other mitogens exhibited a dual effect, synergistic proliferation effect in the presence of EGF (5 ng/mL) and 5% FBS and inhibiting the proliferation induced by 10% FBS, EGF (10 ng/mL) and TNF-α (10 ng/mL). To determine the MAChR subtype involved in these biological responses, a titration curve of selective muscarinic antagonists were performed. The Cch stimulatory and inhibitory effects on ASCM proliferation was blocked by AF-DX-116 (M2AChR selective antagonist), in greater proportion than 4-DAMP (M3AChR selective antagonist), suggesting that the modulation of muscarinic agonist-induced proliferation is M2AChR mediated responses. Thus, M2AChR can activate multiple signal transduction systems and mediate both effects on ASMC proliferation depending on the plethora and variable airway microenvironments existing in asthma and COPD. PMID:24377382

  4. Aging impairs PI3K/Akt signaling and NO-mediated dilation in soleus muscle feed arteries.

    PubMed

    Trott, Daniel W; Luttrell, Meredith J; Seawright, John W; Woodman, Christopher R

    2013-08-01

    We tested the hypothesis that impaired nitric oxide (NO)-mediated, endothelium-dependent dilation in aged soleus muscle feed arteries (SFA) is due to an age-related decline in the potential for PI3-kinase (PI3K)/protein kinase B (Akt)-dependent phosphorylation of endothelial NO synthase (eNOS) on serine residue 1177 (p-eNOS(ser1177)). SFA from young (4 months) and old (24 months) Fischer 344 rats were cannulated for examination of endothelium-dependent [flow or acetylcholine (ACh)] and endothelium-independent [sodium nitroprusside (SNP)] vasodilator function. To determine the mechanism by which aging affected vasodilation to flow and ACh, vasodilator responses were assessed in the presence of N (ω)-nitro-L-arginine (L-NNA, to inhibit NOS), LY-294002 (to inhibit PI3K), or 1L6-hydroxymethyl-chiro-inositol-2-(R)-2-O-methyl-3-O-octadecyl-sn-glycerocarbonate (AktI, to inhibit Akt). Flow- and ACh-induced vasodilator responses were significantly impaired in old SFA, whereas endothelium-independent dilation to SNP was not compromised. Age-group differences in flow- and ACh-induced dilations were abolished in the presence of L-NNA, LY-294002, or AktI. In a separate experiment, SFA were cannulated and stimulated with ACh (10(-4) M, 3 min), flow (60 μl/min, 5 min), or remained unstimulated (3 min). SFA were removed from the pipettes and immunoblot analysis was used to assess ACh- and flow-stimulated phosphorylation of eNOS on ser(1177). Stimulation with ACh or flow increased phosphorylation of eNOS on ser(1177) in young (not old) SFA. Preincubation of young SFA with LY-294002, abolished the ACh-induced phosphorylation of eNOS in young SFA. Collectively, these results indicate that impaired NO-mediated, endothelium-dependent dilation in old SFA is due, in part, to an impaired potential for PI3K/Akt-dependent phosphorylation of eNOS on ser(1177). PMID:23563601

  5. Hereditary dilated cardiomyopathy in Holstein-Friesian cattle in Japan: association with hereditary myopathy of the diaphragmatic muscles.

    PubMed

    Furuoka, H; Yagi, S; Murakami, A; Honma, A; Kobayashi, Y; Matsui, T; Miyahara, K; Taniyama, H

    2001-01-01

    This report deals with the pathology and genetic basis of dilated cardiomyopathy in 10 Holstein-Friesian cows aged 3-6 years, a disease similar to that reported in Simmental-Red Holstein and Holstein-Friesian cattle in several other countries. The main clinical signs were associated with systemic circulatory failure, and at necropsy the animals showed cardiomegaly, severe congestion and fibrosis of the liver, and systemic cardiac oedema. Histologically, hypertrophy and vacuolation of the cardiac muscle fibres and severe fibrosis were noted. Electron microscopically, the sarcoplasm of the hypertrophic fibres was seen to be filled with fine structures of low electron-density, together with thin filamentous material, suggesting myofibrillar lysis. The mitochondria showed increased size, an abnormal cristae pattern and vacuolation due to partial loss of cristae. Pedigree analysis of the affected cattle indicated an autosomal recessive mode of inheritance. The family line of this cardiomyopathy overlapped with that of hereditary myopathy of the diaphragmatic muscles in Holstein-Friesian cattle, the pathological aspects and inheritance mode of which were reported previously. The available evidence suggested a genetic association between these two pathologically distinct diseases. PMID:11578132

  6. Laryngeal mask airway without muscle relaxant in femoral head replacement in elderly patients

    PubMed Central

    KONG, MING; LI, BEIPING; TIAN, YUNPING

    2016-01-01

    The number of elderly patients undergoing femoral head replacement surgeries is on the increase. These patients often suffer from comorbidity such as cardiovascular and cerebrovascular complications, which limits the ability of medical teams to employ anesthesia. Thus, alternative methods are required. The aim of this study was to examine the advantage of laryngeal mask airway (LMA) in the absence of muscle relaxant in elderly patients undergoing femoral head replacement operations. Fifty patients (27 males and 23 females) undergoing femoral head replacements were selected for the study between March 2013 and May 2014. The mean value for the age in this group was 74.6±12.5 years. The patients were randomly distributed into two groups of 25. One group was designated as the treatment group and the second group as the control group. For the treatment group, LMA without muscle relaxant was used, and the control group received routine anesthesia. Variations in heart rate (HR), mean arterial pressure (MAP) and oxygen saturation (SPO2) in the two groups were monitored at different times. Clinical efficacy and muscle relaxation effects were also analyzed. For the treatment group, the HR, MAP and SPO2 measurements did not reveal any significant variation while these values in the control group demonstrated important dissimilarities. Time to recovery, time to extubation and incidence of throat pain in the treatment group were all markedly decreased as compared to those in control group. The operation time in the treatment group was not significantly different to that of control group. The satisfaction of the muscle relaxation effect in the treatment group was significantly higher than that in the control group while the incidence of adverse reactions was not considerably different. In conclusion, the use of LMA without using muscle relaxant in femoral head replacement surgeries performed on elderly patients showed to be effective and safe. PMID:26889218

  7. Hyaluronic acid influence on platelet-induced airway smooth muscle cell proliferation

    SciTech Connect

    Svensson Holm, Ann-Charlotte B.; Bengtsson, Torbjoern; Grenegard, Magnus; Lindstroem, Eva G.

    2012-03-10

    Hyaluronic acid (HA) is one of the main components of the extracellular matrix (ECM) and is expressed throughout the body including the lung and mostly in areas surrounding proliferating and migrating cells. Furthermore, platelets have been implicated as important players in the airway remodelling process, e.g. due to their ability to induce airway smooth muscle cell (ASMC) proliferation. The aim of the present study was to investigate the role of HA, the HA-binding surface receptor CD44 and focal adhesion kinase (FAK) in platelet-induced ASMC proliferation. Proliferation of ASMC was measured using the MTS-assay, and we found that the CD44 blocking antibody and the HA synthase inhibitor 4-Methylumbelliferone (4-MU) significantly inhibited platelet-induced ASMC proliferation. The interaction between ASMC and platelets was studied by fluorescent staining of F-actin. In addition, the ability of ASMC to synthesise HA was investigated by fluorescent staining using biotinylated HA-binding protein and a streptavidin conjugate. We observed that ASMC produced HA and that a CD44 blocking antibody and 4-MU significantly inhibited platelet binding to the area surrounding the ASMC. Furthermore, the FAK-inhibitor PF 573228 inhibited platelet-induced ASMC proliferation. Co-culture of ASMC and platelets also resulted in increased phosphorylation of FAK as detected by Western blot analysis. In addition, 4-MU significantly inhibited the increased FAK-phosphorylation. In conclusion, our findings demonstrate that ECM has the ability to influence platelet-induced ASMC proliferation. Specifically, we propose that HA produced by ASMC is recognised by platelet CD44. The platelet/HA interaction is followed by FAK activation and increased proliferation of co-cultured ASMC. We also suggest that the mitogenic effect of platelets represents a potential important and novel mechanism that may contribute to airway remodelling.

  8. Three Paradigms of Airway Smooth Muscle Hyperresponsiveness in Young Guinea Pigs

    PubMed Central

    Chitano, Pasquale; Wang, Lu; Murphy, Thomas M.

    2008-01-01

    Evidence for contributions of airway smooth muscle (ASM) to the hyperresponsiveness of newborn and juvenile airways continues to accumulate. In our laboratory three novel paradigms of hyperresponsiveness of newborn and young ASM have recently emerged using a guinea pig model of maturation in three age groups-- 1 week (newborn); 3 week (juvenile) and 2−3 months (adult). These include 1) evidence for a natural decline after newborn and juvenile life of the shortening velocity of ASM shortening associated with a decrease in regulatory myosin light chain (MLC) phosphorylation and a parallel decline in the content of MLC kinase. Associated with the decrease in ASM shortening with age is an increase in the internal resistance to shortening. This relationship can be approximated as dP/dtmax ≈ dP/dLpassive × dL/dtmax (the maximal rate of increase of active stress generation ≈ the passive stiffness × the maximal shortening velocity V0). 2) The second paradigm demonstrates that newborn ASM, unlike that in adults, does not relax with prolonged electrical field stimulation. The impaired relaxation is related to changes in prostaglandin synthesis and acetylcholinesterase function; 3) the third paradigm demonstrates that while oscillatory strain serves to relax adult ASM, the response in newborns is the potentiation of active stress. This is related to developmental changes in the cytoskeleton. Oscillatory stiffness is shown to relate inversely to the expression of myosin light chain kinase. This suggests that developmental changes in shortening relate inversely to the stiffness of the ASM early in shortening, suggesting a dynamic role for the cytoskeleton in facilitating and opposing ASM shortening. Together these paradigms demonstrate that ASM contributes by multiple mechanisms to the natural hyperresponsiveness of newborn and juvenile airways. Future studies will elaborate the mechanisms and extend these paradigms relate to ASM hyperresponsiveness that is increased

  9. Tensile strength and dilatational elasticity of giant sarcolemmal vesicles shed from rabbit muscle.

    PubMed Central

    Nichol, J A; Hutter, O F

    1996-01-01

    1. Mechanical properties of the surface membrane of skeletal muscle were determined on sarcolemmal vesicles (mean diameter, 71 microns) shed by rabbit psoas muscle swelling in 140 mM KC1 containing collagenase. 2. Vesicles were stressed by partial aspiration into parallel bore pipettes. The isotropic membrane tension so created caused an increase in membrane area which expresses itself in an elongation of the vesicle projection into the pipette. 3. For individual vesicles, a linear relationship between membrane tension and membrane area increase was found up to the point when the vesicle burst, i.e. sarcolemmal vesicles behaved as perfectly elastic structures. 4. The maximum tension sarcolemmal vesicles could sustain before bursting was 12.4 +/- 0.2 mN m-1 (median +/- 95% confidence interval), and the corresponding fractional increase in membrane area was 0.026 +/- 0.005 (median +/- 95% confidence interval). The elastic modulus of area expansion was 490 +/- 88 mN m-1 (mean +/- S.D.). 5. In conformity with cited comparable work on red blood cells and artificial lipid vesicles, the strength and area elasticity of the skeletal muscle membrane are considered properties of the fluid lipid matrix of the membrane and of the degree to which the bilayer is perturbed by lipid-protein interaction. Images Figure 2 PMID:8735704

  10. Effects of cigarette smoke extract on human airway smooth muscle cells in COPD.

    PubMed

    Chen, Ling; Ge, Qi; Tjin, Gavin; Alkhouri, Hatem; Deng, Linghong; Brandsma, Corry-Anke; Adcock, Ian; Timens, Wim; Postma, Dirkje; Burgess, Janette K; Black, Judith L; Oliver, Brian G G

    2014-09-01

    We hypothesised that the response to cigarette smoke in airway smooth muscle (ASM) cells from smokers with chronic obstructive pulmonary disease (COPD) would be intrinsically different from smokers without COPD, producing greater pro-inflammatory mediators and factors relating to airway remodelling. ASM cells were obtained from smokers with or without COPD, and then stimulated with cigarette smoke extract (CSE) or transforming growth factor-β1. The production of chemokines and matrix metalloproteinases (MMPs) were measured by ELISA, and the deposition of collagens by extracellular matrix ELISA. The effects of CSE on cell attachment and wound healing were measured by toluidine blue attachment and cell tracker green wound healing assays. CSE increased the release of CXCL8 and CXCL1 from human ASM cells, and cells from smokers with COPD produced more CSE-induced CXCL1. The production of MMP-1, -3 and -10, and the deposition of collagen VIII alpha 1 (COL8A1) were increased by CSE, especially in the COPD group which had higher production of MMP-1 and deposition of COL8A1. CSE decreased ASM cell attachment and wound healing in the COPD group only. ASM cells from smokers with COPD were more sensitive to CSE stimulation, which may explain, in part, why some smokers develop COPD. PMID:24969654

  11. Baicalin inhibits PDGF-induced proliferation and migration of airway smooth muscle cells

    PubMed Central

    Yang, Guang; Li, Jian-Qiang; Bo, Jian-Ping; Wang, Bei; Tian, Xin-Rui; Liu, Tan-Zhen; Liu, Zhuo-La

    2015-01-01

    Airway smooth muscle (ASM) cell proliferation and migration play important roles in airway remodeling in asthma. In vitro platelet-derived growth factor (PDGF) induced ASM cell proliferation and migration. Baicalin is one of flavonoid extracts from Scutellaria baicalensis, which has an anti-asthma effect. However, little is known about its role in PDGF-induced proliferation and migration in rat ASM (RASM) cells. In this study, we aimed to investigate the effects of baicalin on PDGF-induced RASM cell proliferation and migration. We also identified the signaling pathway by which baicalin influences RASM cell proliferation and migration. In the current study, we demonstrated that baicalin suppressed PDGF-induced RASM cell proliferation, arrested PDGF-induced cell-cycle progression. It also suppressed PDGF-induced RASM cell migration. Furthermore, baicalin suppressed PDGF-induced expression of phosphorylated p38, ERK1/2 and JNK in RASM cells. In summary, our study is the first to show that baicalin pretreatment can significantly inhibit PDGF-induced RASM cell proliferation and migration by suppressing the MAPK signaling pathway, and baicalin may be a useful chemotherapeutic agent for asthma. PMID:26884970

  12. Olfactory Receptors Modulate Physiological Processes in Human Airway Smooth Muscle Cells.

    PubMed

    Kalbe, Benjamin; Knobloch, Jürgen; Schulz, Viola M; Wecker, Christine; Schlimm, Marian; Scholz, Paul; Jansen, Fabian; Stoelben, Erich; Philippou, Stathis; Hecker, Erich; Lübbert, Hermann; Koch, Andrea; Hatt, Hanns; Osterloh, Sabrina

    2016-01-01

    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 Ca(2+) 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. PMID:27540365

  13. Olfactory Receptors Modulate Physiological Processes in Human Airway Smooth Muscle Cells

    PubMed Central

    Kalbe, Benjamin; Knobloch, Jürgen; Schulz, Viola M.; Wecker, Christine; Schlimm, Marian; Scholz, Paul; Jansen, Fabian; Stoelben, Erich; Philippou, Stathis; Hecker, Erich; Lübbert, Hermann; Koch, Andrea; Hatt, Hanns; Osterloh, Sabrina

    2016-01-01

    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. PMID:27540365

  14. Prostaglandin E2 induces expression of MAPK phosphatase 1 (MKP-1) in airway smooth muscle cells.

    PubMed

    Rumzhum, Nowshin N; Ammit, Alaina J

    2016-07-01

    Prostaglandin E2 (PGE2) is a prostanoid with diverse actions in health and disease. In chronic respiratory diseases driven by inflammation, PGE2 has both positive and negative effects. An enhanced understanding of the receptor-mediated cellular signalling pathways induced by PGE2 may help us separate the beneficial properties from unwanted actions of this important prostaglandin. PGE2 is known to exert anti-inflammatory and bronchoprotective actions in human airways. To date however, whether PGE2 increases production of the anti-inflammatory protein MAPK phosphatase 1 (MKP-1) was unknown. We address this herein and use primary cultures of human airway smooth muscle (ASM) cells to show that PGE2 increases MKP-1 mRNA and protein upregulation in a concentration-dependent manner. We explore the signalling pathways responsible and show that PGE2-induces CREB phosphorylation, not p38 MAPK activation, in ASM cells. Moreover, we utilize selective antagonists of EP2 (PF-04418948) and EP4 receptors (GW 627368X) to begin to identify EP-mediated functional outcomes in ASM cells in vitro. Taken together with earlier studies, our data suggest that PGE2 increases production of the anti-inflammatory protein MKP-1 via cAMP/CREB-mediated cellular signalling in ASM cells and demonstrates that EP2 may, in part, be involved. PMID:27108790

  15. Relaxant Action of Plumula Nelumbinis Extract on Mouse Airway Smooth Muscle

    PubMed Central

    Tan, Li; Chen, Weiwei; Wei, Ming-Yu; Shen, Jinhua; Yu, Meng-Fei; Yang, Guangzhong; Guo, Donglin; Qin, Gangjian; Ji, Guangju; Liu, Qing-Hua

    2015-01-01

    The traditional herb Plumula Nelumbinis is widely used in the world because it has many biological activities, such as anti-inflammation, antioxidant, antihypertension, and butyrylcholinesterase inhibition. However, the action of Plumula Nelumbinis on airway smooth muscle (ASM) relaxation has not been investigated. A chloroform extract of Plumula Nelumbinis (CEPN) was prepared, which completely inhibited precontraction induced by high K+ in a concentration-dependent manner in mouse tracheal rings, but it had no effect on resting tension. CEPN also blocked voltage-dependent L-type Ca2+ channel- (VDCC-) mediated currents. In addition, ACh-induced precontraction was also completely blocked by CEPN and partially inhibited by nifedipine or pyrazole 3. Besides, CEPN partially reduced ACh-activated nonselective cation channel (NSCC) currents. Taken together, our data demonstrate that CEPN blocked VDCC and NSCC to inhibit Ca2+ influx, resulting in relaxation of precontracted ASM. This finding indicates that CEPN would be a candidate of new potent bronchodilators. PMID:25763092

  16. Role of Dystrophin in Airway Smooth Muscle Phenotype, Contraction and Lung Function

    PubMed Central

    Sharma, Pawan; Basu, Sujata; Mitchell, Richard W.; Stelmack, Gerald L.; Anderson, Judy E.; Halayko, Andrew J.

    2014-01-01

    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. PMID:25054970

  17. Biomechanical effects of environmental and engineered particles on human airway smooth muscle cells

    PubMed Central

    Berntsen, P.; Park, C. Y.; Rothen-Rutishauser, B.; Tsuda, A.; Sager, T. M.; Molina, R. M.; Donaghey, T. C.; Alencar, A. M.; Kasahara, D. I.; Ericsson, T.; Millet, E. J.; Swenson, J.; Tschumperlin, D. J.; Butler, J. P.; Brain, J. D.; Fredberg, J. J.; Gehr, P.; Zhou, E. H.

    2010-01-01

    The past decade has seen significant increases in combustion-generated ambient particles, which contain a nanosized fraction (less than 100 nm), and even greater increases have occurred in engineered nanoparticles (NPs) propelled by the booming nanotechnology industry. Although inhalation of these particulates has become a public health concern, human health effects and mechanisms of action for NPs are not well understood. Focusing on the human airway smooth muscle cell, here we show that the cellular mechanical function is altered by particulate exposure in a manner that is dependent upon particle material, size and dose. We used Alamar Blue assay to measure cell viability and optical magnetic twisting cytometry to measure cell stiffness and agonist-induced contractility. The eight particle species fell into four categories, based on their respective effect on cell viability and on mechanical function. Cell viability was impaired and cell contractility was decreased by (i) zinc oxide (40–100 nm and less than 44 μm) and copper(II) oxide (less than 50 nm); cell contractility was decreased by (ii) fluorescent polystyrene spheres (40 nm), increased by (iii) welding fumes and unchanged by (iv) diesel exhaust particles, titanium dioxide (25 nm) and copper(II) oxide (less than 5 μm), although in none of these cases was cell viability impaired. Treatment with hydrogen peroxide up to 500 μM did not alter viability or cell mechanics, suggesting that the particle effects are unlikely to be mediated by particle-generated reactive oxygen species. Our results highlight the susceptibility of cellular mechanical function to particulate exposures and suggest that direct exposure of the airway smooth muscle cells to particulates may initiate or aggravate respiratory diseases. PMID:20356875

  18. Effect of different bronchodilators on airway smooth muscle responsiveness to contractile agents.

    PubMed

    Gustafsson, B; Persson, C G

    1991-05-01

    "Functional antagonism" is often used to describe the general relaxant effect of beta 2 agonists and xanthines and their ability to protect the airways against bronchoconstrictor stimuli. This study in guinea pig isolated trachea addresses the question of whether the capacity of these drugs to protect against constrictor stimuli is related to smooth muscle relaxation. Three antimuscarinic drugs were also examined to determine whether antagonism of mediators other than muscarinic agonists might contribute to bronchodilatation by these antimuscarinic drugs. Terbutaline (1.1 x 10(-7), 2.2 x 10(-7) M), theophylline (2.2 x 10(-4), 4.4 x 10(-4) M), and enprofylline (5.2 x 10(-5), 1.0 x 10(-4) M) relaxed the tracheal tension that remained after indomethacin treatment. They did not, however, alter the carbachol concentration-response curve significantly. In addition, neither theophylline (2.2 x 10(-4) M) nor terbutaline (1.1 x 10(-7) M) altered histamine induced contraction. Atropine sulphate, glycopyrrolate, and ipratropium bromide had EC50 values of 10(-9) - 10(-8) M for relaxation of carbachol induced contractions, whereas concentrations of 10(-6) - 10(-3) M or greater were required to relax contractions induced by allergen and nine other non-muscarinic mediators. It is suggested that bronchodilatation by antimuscarinic drugs in vivo is due to inhibition of acetylcholine induced bronchoconstriction alone and that beta 2 agonists and xanthines have poor ability to protect airway smooth muscle against constrictor stimuli. Hence mechanisms other than bronchodilatation and "functional antagonism" should be considered to explain the protection against constrictor stimuli in asthma seen with beta 2 agonists and xanthines. PMID:2068693

  19. Diacylglycerol-containing docosahexaenoic acid in acyl chain modulates airway smooth muscle tone.

    PubMed

    Hichami, Aziz; Morin, Caroline; Rousseau, Eric; Khan, Naim A

    2005-10-01

    We synthesized and assessed the role of a diacylglycerol (DAG)-containing docosahexaenoic acid (DHA), that is, 1-stearoyl-2-docosahexaenoyl-sn-glycerol (SDHG), in the contraction of guinea pig airway smooth muscle (ASM). We compared its action with 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG) and 1,2-dioctanoyl-sn-glycerol (1,2-DiC8), a stable DAG analog. The three DAGs (SAG, SDHG, and 1,2-DiC8) induced reversible concentration-dependent contraction of ASM. SDHG induced higher guinea pig ASM contraction than did SAG and 1,2-DiC8. The effects of SDHG were blocked, to different extents, by nifedipine (L-type Ca2+ channel blocker). By employing GF-109203X (protein kinase C [PKC] inhibitor) and lanthanum (La3+), a nonselective cation channel blocker, we observed that SDHG evoked ASM contractile response via PKC-dependent and PKC-independent (but Ca2+-dependent) pathways. Interestingly, SAG exerted its action only by increasing [Ca2+]i and did not require PKC activation. To probe the implication of calcium mobilization, we employed thapsigargin (TG), which also induced ASM contraction in a calcium-dependent manner. SDHG and 1,2-DiC8, in a PKC-dependent manner, induced the phosphorylation of CPI-17 (myosin light chain phosphatase inhibitor of 17 kD). Furthermore, SAG and TG failed to phosphorylate CPI-17 in ASM cells. Our results suggest that different DAG species, produced during a dietary supplementation with fatty acids, could modulate the reactivity of airway smooth muscles in a PKC-dependent and -independent manner, and hence, may play a critical role in health and disease. PMID:15961724

  20. IL-9-mediated induction of eotaxin1/CCL11 in human airway smooth muscle cells.

    PubMed

    Gounni, Abdelilah Soussi; Hamid, Qutayba; Rahman, Sahidur M; Hoeck, Jutta; Yang, Jie; Shan, Lianyu

    2004-08-15

    Recent work has shown the potential importance of IL-9 in allergic diseases. The development of transgenic mice overexpressing IL-9 has suggested a key role for this cytokine in the development of the asthmatic phenotype including airway eosinophilia. In this study, we evaluated the expression of the IL-9R and the effects of IL-9 on human ASM cells by examining the release of Th2-associated chemokines (eotaxin1/CCL11 and thymus- and activation-regulated chemokine (TARC)/CCL17). IL-9R alpha-chain mRNA and surface expression were detected in cultured human airway smooth muscle (ASM) cells. In addition, primary cultured ASM cells, as well as bronchial smooth muscle cells within biopsies of asthmatics and not control subjects, revealed IL-9R protein expression. IL-9 stimulation of human ASM cells resulted in release of eotaxin1/CCL11, but had no effect on the release of TARC/CCL17, in time- and dose-dependent manner. Moreover, in vitro chemotaxis assay demonstrated that conditioned medium from IL-9-stimulated ASM cells attracted human eosinophils. Neutralizing Abs to IL-9, but not to IL-4 or IL-13, reduced significantly IL-9-induced production of eotaxin1/CCL11 from ASM cells. Interestingly, real-time RT-PCR showed that IL-9 up-regulated eotaxin1/CCL11 mRNA expression, but had no effect on TARC/CCL17. Treatment with Act D abrogates IL-9-induced eotaxin1/CCL11 mRNA and protein release by ASM cells. Finally, transfection study using eotaxin1/CCL11 promoter luciferase construct confirmed that IL-9 induced eotaxin1/CCL11 at the transcriptional level. Taken together, these data provide new evidence demonstrating that IL-9-dependent activation of ASM cells contributes to eosinophilic inflammation observed in asthma. PMID:15294996

  1. Biomechanical effects of environmental and engineered particles on human airway smooth muscle cells.

    PubMed

    Berntsen, P; Park, C Y; Rothen-Rutishauser, B; Tsuda, A; Sager, T M; Molina, R M; Donaghey, T C; Alencar, A M; Kasahara, D I; Ericsson, T; Millet, E J; Swenson, J; Tschumperlin, D J; Butler, J P; Brain, J D; Fredberg, J J; Gehr, P; Zhou, E H

    2010-06-01

    The past decade has seen significant increases in combustion-generated ambient particles, which contain a nanosized fraction (less than 100 nm), and even greater increases have occurred in engineered nanoparticles (NPs) propelled by the booming nanotechnology industry. Although inhalation of these particulates has become a public health concern, human health effects and mechanisms of action for NPs are not well understood. Focusing on the human airway smooth muscle cell, here we show that the cellular mechanical function is altered by particulate exposure in a manner that is dependent upon particle material, size and dose. We used Alamar Blue assay to measure cell viability and optical magnetic twisting cytometry to measure cell stiffness and agonist-induced contractility. The eight particle species fell into four categories, based on their respective effect on cell viability and on mechanical function. Cell viability was impaired and cell contractility was decreased by (i) zinc oxide (40-100 nm and less than 44 microm) and copper(II) oxide (less than 50 nm); cell contractility was decreased by (ii) fluorescent polystyrene spheres (40 nm), increased by (iii) welding fumes and unchanged by (iv) diesel exhaust particles, titanium dioxide (25 nm) and copper(II) oxide (less than 5 microm), although in none of these cases was cell viability impaired. Treatment with hydrogen peroxide up to 500 microM did not alter viability or cell mechanics, suggesting that the particle effects are unlikely to be mediated by particle-generated reactive oxygen species. Our results highlight the susceptibility of cellular mechanical function to particulate exposures and suggest that direct exposure of the airway smooth muscle cells to particulates may initiate or aggravate respiratory diseases. PMID:20356875

  2. Human airway smooth muscle maintain in situ cell orientation and phenotype when cultured on aligned electrospun scaffolds

    PubMed Central

    Morris, G. E.; Bridge, J. C.; Eltboli, O. M. I.; Lewis, M. P.; Knox, A. J.; Aylott, J. W.; Brightling, C. E.; Ghaemmaghami, A. M.

    2014-01-01

    Human airway smooth muscle (HASM) contraction plays a central role in regulating airway resistance in both healthy and asthmatic bronchioles. In vitro studies that investigate the intricate mechanisms that regulate this contractile process are predominantly conducted on tissue culture plastic, a rigid, 2D geometry, unlike the 3D microenvironment smooth muscle cells are exposed to in situ. It is increasingly apparent that cellular characteristics and responses are altered between cells cultured on 2D substrates compared with 3D topographies. Electrospinning is an attractive method to produce 3D topographies for cell culturing as the fibers produced have dimensions within the nanometer range, similar to cells' natural environment. We have developed an electrospun scaffold using the nondegradable, nontoxic, polymer polyethylene terephthalate (PET) composed of uniaxially orientated nanofibers and have evaluated this topography's effect on HASM cell adhesion, alignment, and morphology. The fibers orientation provided contact guidance enabling the formation of fully aligned sheets of smooth muscle. Moreover, smooth muscle cells cultured on the scaffold present an elongated cell phenotype with altered contractile protein levels and distribution. HASM cells cultured on this scaffold responded to the bronchoconstrictor bradykinin. The platform presented provides a novel in vitro model that promotes airway smooth muscle cell development toward a more in vivo-like phenotype while providing topological cues to ensure full cell alignment. PMID:24793171

  3. Effects of genetic obesity on rat upper airway muscle and diaphragm contractile properties.

    PubMed

    van Lunteren, E

    1996-10-01

    The contractile properties of pharyngeal respiratory muscle are altered in sleep apnoea and in conditions associated with sleep apnoea, such as ageing. We hypothesized that the contractile properties of the pharyngeal musculature are also altered by obesity, another factor associated with sleep apnoea. Studies compared a pharyngeal muscle, the sternohyoid, with the diaphragm. These were chosen as representative muscles whose contraction has opposing effects on upper airway patency. Both muscles were removed from nine lean and nine obese male Zucker rats (a genetic model of obesity), and isometric contractile properties were studied in vitro at 37 degrees C. For the sternohyoid muscle, in obese compared to lean animals there were no significant differences in isometric contraction time (15.2 +/- 0.3 vs 14.2 +/- 0.6 ms, respectively), half-relaxation time (13.6 +/- 0.5 vs 12.6 +/- 0.9 ms, respectively), twitch-to-tetanic tension ratio (0.22 +/- 0.02 vs 0.24 +/- 0.02, respectively), force-frequency relationship, fatigue resistance (2 min fatigue index 0.20 +/- 0.03 vs 0.18 +/- 0.02, respectively), or maximal degree of force potentiation during repetitive stimulation (52 +/- 11 vs 74 +/- 20% increase, respectively). For the diaphragm, the only significant effect of obesity was a lowering of the twitch-to-tetanic tension ratio (0.25 +/- 0.01 vs 0.29 +/- 0.02, respectively). In obese, as in lean animals, the sternohyoid had faster isometric twitch kinetics, a larger degree of force potentiation, and lower resistance to fatigue, than the diaphragm. In lean, but not obese, animals the sternohyoid twitch-to-tetanic tension ratio was lower than and the force frequency relationship was located to the right of that of the diaphragm. In this study, genetic obesity in rats was not associated with any significant alterations in the contractile properties of the pharyngeal muscle, and only small changes in the relationship between the contractile properties of the sternohyoid and

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

    PubMed Central

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

    2014-01-01

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

  5. TLR3 activation increases chemokine expression in human fetal airway smooth muscle cells.

    PubMed

    Faksh, Arij; Britt, Rodney D; Vogel, Elizabeth R; Thompson, Michael A; Pandya, Hitesh C; Martin, Richard J; Pabelick, Christina M; Prakash, Y S

    2016-01-15

    Viral infections, such as respiratory syncytial virus and rhinovirus, adversely affect neonatal and pediatric populations, resulting in significant lung morbidity, including acute asthma exacerbation. Studies in adults have demonstrated that human airway smooth muscle (ASM) cells modulate inflammation through their ability to secrete inflammatory cytokines and chemokines. The role of ASM in the developing airway during infection remains undefined. In our study, we used human fetal ASM cells as an in vitro model to examine the effect of Toll-like receptor (TLR) agonists on chemokine secretion. We found that fetal ASM express multiple TLRs, including TLR3 and TLR4, which are implicated in the pathogenesis of respiratory syncytial virus and rhinovirus infection. Cells were treated with TLR agonists, polyinosinic-polycytidylic acid [poly(I:C)] (TLR3 agonist), lipopolysaccharide (TLR4 agonist), or R848 (TLR7/8 agonist), and IL-8 and chemokine (C-C motif) ligand 5 (CCL5) secretion were evaluated. Interestingly, poly(I:C), but neither lipopolysaccharide nor R848, increased IL-8 and chemokine (C-C motif) ligand 5 secretion. Examination of signaling pathways suggested that the poly(I:C) effects in fetal ASM involve TLR and ERK signaling, in addition to another major inflammatory pathway, NF-κB. Moreover, there are variations between fetal and adult ASM with respect to poly(I:C) effects on signaling pathways. Pharmacological inhibition suggested that ERK pathways mediate poly(I:C) effects. Overall, our data show that poly(I:C) initiates activation of proinflammatory pathways in developing ASM, which may contribute to immune responses to infection and exacerbation of asthma. PMID:26589477

  6. Development and characterization of a 3D multicell microtissue culture model of airway smooth muscle

    PubMed Central

    Zaman, Nishat; Cole, Darren J.; Walker, Matthew J.; Legant, Wesley R.; Boudou, Thomas; Chen, Christopher S.; Favreau, John T.; Gaudette, Glenn R.; Cowley, Elizabeth A.; Maksym, Geoffrey N.

    2013-01-01

    Airway smooth muscle (ASM) cellular and molecular biology is typically studied with single-cell cultures grown on flat 2D substrates. However, cells in vivo exist as part of complex 3D structures, and it is well established in other cell types that altering substrate geometry exerts potent effects on phenotype and function. These factors may be especially relevant to asthma, a disease characterized by structural remodeling of the airway wall, and highlights a need for more physiologically relevant models of ASM function. We utilized a tissue engineering platform known as microfabricated tissue gauges to develop a 3D culture model of ASM featuring arrays of ∼0.4 mm long, ∼350 cell “microtissues” capable of simultaneous contractile force measurement and cell-level microscopy. ASM-only microtissues generated baseline tension, exhibited strong cellular organization, and developed actin stress fibers, but lost structural integrity and dissociated from the cantilevers within 3 days. Addition of 3T3-fibroblasts dramatically improved survival times without affecting tension development or morphology. ASM-3T3 microtissues contracted similarly to ex vivo ASM, exhibiting reproducible responses to a range of contractile and relaxant agents. Compared with 2D cultures, microtissues demonstrated identical responses to acetylcholine and KCl, but not histamine, forskolin, or cytochalasin D, suggesting that contractility is regulated by substrate geometry. Microtissues represent a novel model for studying ASM, incorporating a physiological 3D structure, realistic mechanical environment, coculture of multiple cells types, and comparable contractile properties to existing models. This new model allows for rapid screening of biochemical and mechanical factors to provide insight into ASM dysfunction in asthma. PMID:23125251

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

    PubMed Central

    Dileepan, Mythili; Sarver, Anne E.; Rao, Savita P.; Panettieri, Reynold A.; Subramanian, Subbaya; Kannan, Mathur S.

    2016-01-01

    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. PMID:26998837

  8. Airway smooth muscle inflammation is regulated by microRNA-145 in COPD.

    PubMed

    O'Leary, Lawrence; Sevinç, Kenan; Papazoglou, Ilektra M; Tildy, Bernadett; Detillieux, Karen; Halayko, Andrew J; Chung, Kian Fan; Perry, Mark M

    2016-05-01

    Chronic obstructive pulmonary disease (COPD) is a common, highly debilitating disease of the airways, primarily caused by smoking. Chronic inflammation and structural remodelling are key pathological features of this disease, in part caused by the aberrant function of airway smooth muscle (ASM) cells under the regulation of transforming growth factor (TGF)-β. miRNA are short, noncoding gene transcripts involved in the negative regulation of specific target genes, through their interactions with mRNA. Previous studies have proposed that mRNA-145 (miR-145) may interact with SMAD3, an important downstream signalling molecule of the TGF-β pathway. TGF-β was used to stimulate primary human ASM cells isolated from healthy nonsmokers, healthy smokers and COPD patients. This resulted in a TGF-β-dependent increase in CXCL8 and IL-6 release, most notably in the cells from COPD patients. TGF-β stimulation increased SMAD3 expression, only in cells from COPD patients, with a concurrent increased miR-145 expression. Regulation of miR-145 was found to be negatively controlled by pathways involving the MAP kinases, MEK-1/2 and p38 MAPK. Subsequent, overexpression of miR-145 (using synthetic mimics) in ASM cells from patients with COPD suppressed IL-6 and CXCL8 release, to levels comparable to the nonsmoker controls. Therefore, this study suggests that miR-145 negatively regulates pro-inflammatory cytokine release from ASM cells in COPD by targeting SMAD3. PMID:27060571

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

    PubMed Central

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

    2014-01-01

    In asthma, the airway smooth muscle (ASM) produces CXCL10 which may attract CXCR3+ mast/T cells to it. Our aim was to investigate the effects of mast cell products on ASM cell CXCL10 production. ASM cells from people with and without asthma were stimulated with IL-1β, TNF-α, and/or IFNγ and treated with histamine (1–100 μM) ± chlorpheniramine (H1R antagonist; 1 μM) or ranitidine (H2R antagonist; 50 μM) or tryptase (1 nM) ± leupeptin (serine protease inhibitor; 50 μM), heat-inactivated tryptase, or vehicle for 4 h or 24 h. Human lung mast cells (MC) were isolated and activated with IgE/anti-IgE and supernatants were collected after 2 h or 24 h. The supernatants were added to ASM cells for 48 h and ASM cell CXCL10 production detected using ELISA (protein) and real-time PCR (mRNA). Histamine reduced IL-1β/TNF-α-induced CXCL10 protein, but not mRNA, levels independent of H1 and H2 receptor activation, whereas tryptase and MC 2 h supernatants reduced all cytokine-induced CXCL10. Tryptase also reduced CXCL10 levels in a cell-free system. Leupeptin inhibited the effects of tryptase and MC 2 h supernatants. MC 24 h supernatants contained TNF-α and amplified IFNγ-induced ASM cell CXCL10 production. This is the first evidence that MC can regulate ASM cell CXCL10 production and its degradation. Thus MC may regulate airway myositis in asthma. PMID:24648846

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

    PubMed

    Dileepan, Mythili; Sarver, Anne E; Rao, Savita P; Panettieri, Reynold A; Subramanian, Subbaya; Kannan, Mathur S

    2016-01-01

    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. PMID:26998837

  11. Assays for in vitro monitoring of proliferation of human airway smooth muscle (ASM) and human pulmonary arterial vascular smooth muscle (VSM) cells.

    PubMed

    Goncharova, Elena A; Lim, Poay; Goncharov, Dmitry A; Eszterhas, Andrew; Panettieri, Reynold A; Krymskaya, Vera P

    2006-01-01

    Vascular and airway remodeling, which are characterized by airway smooth muscle (ASM) and pulmonary arterial vascular smooth muscle (VSM) proliferation, contribute to the pathology of asthma, pulmonary hypertension, restenosis and atherosclerosis. To evaluate the proliferation of VSM and ASM cells in response to mitogens, we perform a [3H]thymidine incorporation assay. The proliferation protocol takes approximately 48 h and includes stimulating cells synchronized in G0/G1 phase of the cell cycle with agonists, labeling cells with [3H]thymidine and examining levels of [3H]thymidine incorporation by scintillation counting. Although using radiolabeled [3H]thymidine incorporation is a limitation, the greatest benefit of the assay is providing reliable and statistically significant data. PMID:17406550

  12. Chrysin inhibits human airway smooth muscle cells proliferation through the extracellular signal-regulated kinase 1/2 signaling pathway.

    PubMed

    Yao, Jing; Zhang, Yun-Shi; Feng, Gan-Zhu; Du, Qiang

    2015-11-01

    Asthma is a chronic airway inflammatory disease characterized by an increased mass of airway smooth muscle (ASM). Chrysin (5,7-dihydroxyflavone), a natural flavonoid, has been shown to exert multiple biological activities, including anti-inflammatory, anti-proliferative and anti-oxidant effects, as well as the potency to ameliorate asthma in animal models. The objective of the present study was to identify the underlying mechanism of the therapeutic effects of chrysin. The impact of chrysin on basal and platelet-derived growth factor (PDGF)-induced proliferation and apoptosis of human airway smooth muscle cells (HASMCs) was investigated. Furthermore, the activation of the extracellular signal-regulated protein kinase (ERK) signaling pathway was evaluated in HASMCs. The results revealed that chrysin significantly inhibited basal as well as PDGF-induced HASMC proliferation, most likely through the suppression of ERK1/2 phosphorylation. However, chrysin did not significantly reduce PDGF-induced apoptosis of HASMCs. The present study indicated that chrysin may be a promising medication for controlling airway remodeling and clinical manifestations of asthma. PMID:26502995

  13. The effect of hyperpolarization-activated cyclic nucleotide-gated ion channel inhibitors on the vagal control of guinea pig airway smooth muscle tone

    PubMed Central

    McGovern, Alice E; Robusto, Jed; Rakoczy, Joanna; Simmons, David G; Phipps, Simon; Mazzone, Stuart B

    2014-01-01

    BACKGROUND AND PURPOSE Subtypes of the hyperpolarization-activated cyclic nucleotide-gated (HCN) family of cation channels are widely expressed on nerves and smooth muscle cells in many organ systems, where they serve to regulate membrane excitability. Here we have assessed whether HCN channel inhibitors alter the function of airway smooth muscle or the neurons that regulate airway smooth muscle tone. EXPERIMENTAL APPROACH The effects of the HCN channel inhibitors ZD7288, zatebradine and Cs+ were assessed on agonist and nerve stimulation-evoked changes in guinea pig airway smooth muscle tone using tracheal strips in vitro, an innervated tracheal tube preparation ex vivo or in anaesthetized mechanically ventilated guinea pigs in vivo. HCN channel expression in airway nerves was assessed using immunohistochemistry, PCR and in situ hybridization. KEY RESULTS HCN channel inhibition did not alter airway smooth muscle reactivity in vitro to exogenously administered smooth muscle spasmogens, but significantly potentiated smooth muscle contraction evoked by the sensory nerve stimulant capsaicin and electrical field stimulation of parasympathetic cholinergic postganglionic neurons. Sensory nerve hyperresponsiveness was also evident in in vivo following HCN channel blockade. Cs+, but not ZD7288, potentiated preganglionic nerve-dependent airway contractions and over time induced autorhythmic preganglionic nerve activity, which was not mimicked by inhibitors of potassium channels. HCN channel expression was most evident in vagal sensory ganglia and airway nerve fibres. CONCLUSIONS AND IMPLICATIONS HCN channel inhibitors had a previously unrecognized effect on the neural regulation of airway smooth muscle tone, which may have implications for some patients receiving HCN channel inhibitors for therapeutic purposes. PMID:24762027

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

    NASA Astrophysics Data System (ADS)

    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.

  15. Hydrogen sulphide inhibits Ca2+ release through InsP3 receptors and relaxes airway smooth muscle

    PubMed Central

    Castro-Piedras, Isabel; Perez-Zoghbi, Jose F

    2013-01-01

    Hydrogen sulphide (H2S) is a signalling molecule that appears to regulate diverse cell physiological process in several organs and systems including vascular and airway smooth muscle cell (SMC) contraction. Decreases in endogenous H2S synthesis have been associated with the development of cardiovascular diseases and asthma. Here we investigated the mechanism of airway SMC relaxation induced by H2S in small intrapulmonary airways using mouse lung slices and confocal and phase-contrast video microscopy. Exogenous H2S donor Na2S (100 μm) reversibly inhibited Ca2+ release and airway contraction evoked by inositol-1,4,5-trisphosphate (InsP3) uncaging in airway SMCs. Similarly, InsP3-evoked Ca2+ release and contraction was inhibited by endogenous H2S precursor l-cysteine (10 mm) but not by l-serine (10 mm) or either amino acid in the presence of dl-propargylglycine (PPG). Consistent with the inhibition of Ca2+ release through InsP3 receptors (InsP3Rs), Na2S reversibly inhibited acetylcholine (ACh)-induced Ca2+ oscillations in airway SMCs. In addition, Na2S, the H2S donor GYY-4137, and l-cysteine caused relaxation of airways pre-contracted with either ACh or 5-hydroxytryptamine (5-HT). Na2S-induced airway relaxation was resistant to a guanylyl cyclase inhibitor (ODQ) and a protein kinase G inhibitor (Rp-8-pCPT-cGMPS). The effects of H2S on InsP3-evoked Ca2+ release and contraction as well as on the relaxation of agonist-contracted airways were mimicked by the thiol-reducing agent dithiothreitol (DTT, 10 mm) and inhibited by the oxidizing agent diamide (30 μm). These studies indicate that H2S causes airway SMC relaxation by inhibiting Ca2+ release through InsP3Rs and consequent reduction of agonist-induced Ca2+ oscillations in SMCs. The results suggest a novel role for endogenously produced H2S that involves the modulation of InsP3-evoked Ca2+ release – a cell-signalling system of critical importance for many physiological and pathophysiological processes. PMID

  16. Hydrogen sulphide inhibits Ca2+ release through InsP3 receptors and relaxes airway smooth muscle.

    PubMed

    Castro-Piedras, Isabel; Perez-Zoghbi, Jose F

    2013-12-01

    Hydrogen sulphide (H2S) is a signalling molecule that appears to regulate diverse cell physiological process in several organs and systems including vascular and airway smooth muscle cell (SMC) contraction. Decreases in endogenous H2S synthesis have been associated with the development of cardiovascular diseases and asthma. Here we investigated the mechanism of airway SMC relaxation induced by H2S in small intrapulmonary airways using mouse lung slices and confocal and phase-contrast video microscopy. Exogenous H2S donor Na2S (100 μm) reversibly inhibited Ca(2+) release and airway contraction evoked by inositol-1,4,5-trisphosphate (InsP3) uncaging in airway SMCs. Similarly, InsP3-evoked Ca(2+) release and contraction was inhibited by endogenous H2S precursor l-cysteine (10 mm) but not by l-serine (10 mm) or either amino acid in the presence of dl-propargylglycine (PPG). Consistent with the inhibition of Ca(2+) release through InsP3 receptors (InsP3Rs), Na2S reversibly inhibited acetylcholine (ACh)-induced Ca(2+) oscillations in airway SMCs. In addition, Na2S, the H2S donor GYY-4137, and l-cysteine caused relaxation of airways pre-contracted with either ACh or 5-hydroxytryptamine (5-HT). Na2S-induced airway relaxation was resistant to a guanylyl cyclase inhibitor (ODQ) and a protein kinase G inhibitor (Rp-8-pCPT-cGMPS). The effects of H2S on InsP3-evoked Ca(2+) release and contraction as well as on the relaxation of agonist-contracted airways were mimicked by the thiol-reducing agent dithiothreitol (DTT, 10 mm) and inhibited by the oxidizing agent diamide (30 μm). These studies indicate that H2S causes airway SMC relaxation by inhibiting Ca(2+) release through InsP3Rs and consequent reduction of agonist-induced Ca(2+) oscillations in SMCs. The results suggest a novel role for endogenously produced H2S that involves the modulation of InsP3-evoked Ca(2+) release - a cell-signalling system of critical importance for many physiological and pathophysiological processes

  17. Reactive oxygen species induce a Ca(2+)-spark increase in sensitized murine airway smooth muscle cells.

    PubMed

    Tuo, Qing-Rong; Ma, Yun-Fei; Chen, Weiwei; Luo, Xiao-Jing; Shen, Jinhua; Guo, Donglin; Zheng, Yun-Min; Wang, Yong-Xiao; Ji, Guangju; Liu, Qing-Hua

    2013-05-10

    The level of reactive oxygen species (ROS) and the activity of spontaneous, transient, localized Ca(2+) increases (known as Ca(2+) sparks) in tracheal smooth muscle cells (TSMCs) in an experimental allergic asthma mouse model has not yet been investigated. We used laser confocal microscopy and fluorescent dyes to measure ROS levels and Ca(2+) sparks, and we found that both events were significantly increased in TSMCs obtained from ovalbumin (OVA)-sensitized/-challenged mice compared with control mice. ROS levels began to increase in TSMCs after the first OVA challenge, and this increase was sustained. However, this elevation and Ca(2+)-spark increase was abolished after the administration of the ROS scavenger N-acetylcysteine amide (NACA) for 5days. Furthermore, a similar inhibition was also observed following the direct perfusion of NACA into cells isolated from the (OVA)-sensitized mice that were not treated with NACA. Moreover, we used 0.1-mM caffeine treatment to increase the Ca(2+) sparks in single TSMCs and observed cell shortening. In addition, we did not find increases in the mRNA levels of ryanodine (RyRs) and inositol 1,4,5-trisphosphate (IP3Rs) receptors in the tracheal smooth muscle cells of (OVA)-sensitized mice compared with controls. We concluded that ROS and Ca(2+) sparks increased in (OVA)-sensitized TSMCs. We found that ROS induces Ca(2+) sparks, and increased Ca(2+) sparks resulted in the contraction of (OVA)-sensitized TSMCs, resulting in the generation of airway hyperresponsiveness (AHR). This effect may represent a novel mechanism for AHR pathogenesis and might provide insight into new methods for the clinical prevention and treatment of asthma and asthmatic AHR. PMID:23583396

  18. A novel role for RhoA GTPase in the regulation of airway smooth muscle contraction.

    PubMed

    Zhang, Wenwu; Huang, Youliang; Wu, Yidi; Gunst, Susan J

    2015-02-01

    Recent studies have demonstrated a novel molecular mechanism for the regulation of airway smooth muscle (ASM) contraction by RhoA GTPase. In ASM tissues, both myosin light chain (MLC) phosphorylation and actin polymerization are required for active tension generation. RhoA inactivation dramatically suppresses agonist-induced tension development and completely inhibits agonist-induced actin polymerization, but only slightly reduces MLC phosphorylation. The inhibition of MLC phosphatase does not reverse the effects of RhoA inactivation on contraction or actin polymerization. Thus, RhoA regulates ASM contraction through its effects on actin polymerization rather than MLC phosphorylation. Contractile stimulation of ASM induces the recruitment and assembly of paxillin, vinculin, and focal adhesion kinase (FAK) into membrane adhesion complexes (adhesomes) that regulate actin polymerization by catalyzing the activation of cdc42 GTPase by the G-protein-coupled receptor kinase-interacting target (GIT) - p21-activated kinase (PAK) - PAK-interacting exchange factor (PIX) complex. Cdc42 is a necessary and specific activator of the actin filament nucleation activator, N-WASp. The recruitment and activation of paxillin, vinculin, and FAK is prevented by RhoA inactivation, thus preventing cdc42 and N-WASp activation. We conclude that RhoA regulates ASM contraction by catalyzing the assembly and activation of membrane adhesome signaling modules that regulate actin polymerization, and that the RhoA-mediated assembly of adhesome complexes is a fundamental step in the signal transduction process in response to a contractile agonist. PMID:25531582

  19. Effects of acute ethanol exposure on cytokine production by primary airway smooth muscle cells.

    PubMed

    Kaphalia, Lata; Kalita, Mridul; Kaphalia, Bhupendra S; Calhoun, William J

    2016-02-01

    Both chronic and binge alcohol abuse can be significant risk factors for inflammatory lung diseases such as acute respiratory distress syndrome and chronic obstructive pulmonary disease. However, metabolic basis of alcohol-related lung disease is not well defined, and may include key metabolites of ethanol [EtOH] in addition to EtOH itself. Therefore, we investigated the effects of EtOH, acetaldehyde [ACE], and fatty acid ethyl esters [FAEEs] on oxidative stress, endoplasmic reticulum (ER) stress, AMP-activated protein kinase (AMPK) signaling and nuclear translocation of phosphorylated (p)-NF-κB p65 in primary human airway smooth muscle (HASM) cells stimulated to produce cytokines using LPS exposure. Both FAEEs and ACE induced evidence of cellular oxidative stress and ER stress, and increased p-NF-κB in nuclear extracts. EtOH and its metabolites decreased p-AMPKα activation, and induced expression of fatty acid synthase, and decreased expression of sirtuin 1. In general, EtOH decreased secretion of IP-10, IL-6, eotaxin, GCSF, and MCP-1. However, FAEEs and ACE increased these cytokines, suggesting that both FAEEs and ACE as compared to EtOH itself are proinflammatory. A direct effect of EtOH could be consistent with blunted immune response. Collectively, these two features of EtOH exposure, coupled with the known inhibition of innate immune response in our model might explain some clinical manifestations of EtOH exposure in the lung. PMID:26721307

  20. Spatial and temporal traction response in human airway smooth muscle cells

    NASA Technical Reports Server (NTRS)

    Tolic-Norrelykke, Iva Marija; Butler, James P.; Chen, Jianxin; Wang, Ning

    2002-01-01

    Tractions that cells exert on their substrates are essential in cell spreading, migration, and contraction. These tractions can be determined by plating the cells on a flexible gel and measuring the deformation of the gel by using fluorescent beads embedded just below the surface of the gel. In this article we describe the image correlation method (ICM) optimized for determining the displacement field of the gel under a contracting cell. For the calculation of the traction field from the displacement field we use the recently developed method of Fourier transform traction cytometry (FTTC). The ICM and FTTC methods are applied to human airway smooth muscle cells during stimulation with the contractile agonist histamine or the relaxing agonist isoproterenol. The overall intensity of the cell contraction (the median traction magnitude, the energy transferred from the cell to the gel, and the net contractile moment) increased after activation with histamine, and decreased after treatment with isoproterenol. Cells exhibited regional differences in the time course of traction during the treatment. Both temporal evolution and magnitude of traction increase induced by histamine varied markedly among different cell protrusions, whereas the nuclear region showed the smallest response. These results suggest that intracellular mediators of cell adhesion and contraction respond to contractile stimuli with different rates and intensities in different regions of the cell.

  1. Glucocorticoid and TNF signaling converge at A20 (TNFAIP3) to repress airway smooth muscle cytokine expression.

    PubMed

    Sasse, Sarah K; Altonsy, Mohammed O; Kadiyala, Vineela; Cao, Gaoyuan; Panettieri, Reynold A; Gerber, Anthony N

    2016-08-01

    Airway smooth muscle is a major target tissue for glucocorticoid (GC)-based asthma therapies, however, molecular mechanisms through which the GC receptor (GR) exerts therapeutic effects in this key airway cell type have not been fully elucidated. We previously identified the nuclear factor-κB (NF-κB) inhibitor, A20 (TNFAIP3), as a mediator of cytokine repression by glucocorticoids (GCs) in airway epithelial cells and defined cooperative regulation of anti-inflammatory genes by GR and NF-κB as a key mechanistic underpinning of airway epithelial GR function. Here, we expand on these findings to determine whether a similar mechanism is operational in human airway smooth muscle (HASM). Using HASM cells derived from normal and fatal asthma samples as an in vitro model, we demonstrate that GCs spare or augment TNF-mediated induction of A20 (TNFAIP3), TNIP1, and NFKBIA, all implicated in negative feedback control of NF-κB-driven inflammatory processes. We applied chromatin immunoprecipitation and reporter analysis to show that GR and NF-κB directly regulate A20 expression in HASM through cooperative induction of an intronic enhancer. Using overexpression, we show for the first time that A20 and its interacting partner, TNIP1, repress TNF signaling in HASM cells. Moreover, we applied small interfering RNA-based gene knockdown to demonstrate that A20 is required for maximal cytokine repression by GCs in HASM. Taken together, our data suggest that inductive regulation of A20 by GR and NF-κB contributes to cytokine repression in HASM. PMID:27371733

  2. Biological characteristics of tracheal smooth muscle cells regulated by NK-1R in asthmatic rat with airway remodeling

    PubMed Central

    Wei, Bing; Liu, Yali; Yue, Xiaozhe; Li, Yinping; Shang, Yunxiao

    2015-01-01

    This study aims to investigate the biological characteristic changes of infant rat tracheal smooth muscle cells in asthma airway remodeling and the impact of NK-1R on the mechanism. Ovalbumin (OVA) was used to excited juvenile SD rats by 8 w. Immunofluorescence, MTT assay, transwell chambers, real time quantitative PCR, Western blot and other methods were used to observe the proliferation, migration, synthesis and secretion changes of infant airway remodeling in rat tracheal smooth muscle cell and the Neurokinin 1 receptor (NK-1R) expression. 1. NK-1R mRNA, protein expression of airway smooth muscle cell (ASMC) of each asthma group were higher than that of the control group, especially the asthma 8 w group had highest expression (P<0.01). 2. The average A value of 8 w asthma group measured by MTT method were significantly higher than that of the control group (P<0.05), WIN62577 10-8 mol/L group had the strongest inhibition of ASMC proliferation (P<0.01). 3. The number of cell migration in the asthma group significantly increased than that in the control group. The number of migrating cells in the NK-1R antagonist group significantly reduced compared with the asthma 8 w group (P<0.05). 4. The average gray value of type III collagen in each asthma group were higher than that of the control group, and the asthma 8 w group had the highest (P<0.01). After NK-1R blocking, the average gray value of type III collagen was significantly lower (P<0.05). ASMC proliferation, migration, synthesis and secretion function increased in the airway remodeling group, and NK-1R played an important role. PMID:26628953

  3. Does smooth muscle in an intact airway undergo length adaptation during a sustained change in transmural pressure?

    PubMed

    Ansell, Thomas K; McFawn, Peter K; McLaughlin, Robert A; Sampson, David D; Eastwood, Peter R; Hillman, David R; Mitchell, Howard W; Noble, Peter B

    2015-03-01

    In isolated airway smooth muscle (ASM) strips, an increase or decrease in ASM length away from its current optimum length causes an immediate reduction in force production followed by a gradual time-dependent recovery in force, a phenomenon termed length adaptation. In situ, length adaptation may be initiated by a change in transmural pressure (Ptm), which is a primary physiological determinant of ASM length. The present study sought to determine the effect of sustained changes in Ptm and therefore, ASM perimeter, on airway function. We measured contractile responses in whole porcine bronchial segments in vitro before and after a sustained inflation from a baseline Ptm of 5 cmH2O to 25 cmH2O, or deflation to -5 cmH2O, for ∼50 min in each case. In one group of airways, lumen narrowing and stiffening in response to electrical field stimulation (EFS) were assessed from volume and pressure signals using a servo-controlled syringe pump with pressure feedback. In a second group of airways, lumen narrowing and the perimeter of the ASM in situ were determined by anatomical optical coherence tomography. In a third group of airways, active tension was determined under isovolumic conditions. Both inflation and deflation reduced the contractile response to EFS. Sustained Ptm change resulted in a further decrease in contractile response, which returned to baseline levels upon return to the baseline Ptm. These findings reaffirm the importance of Ptm in regulating airway narrowing. However, they do not support a role for ASM length adaptation in situ under physiological levels of ASM lengthening and shortening. PMID:25729015

  4. The Oligo Fucoidan Inhibits Platelet-Derived Growth Factor-Stimulated Proliferation of Airway Smooth Muscle Cells

    PubMed Central

    Yang, Chao-Huei; Tsao, Chiung-Fang; Ko, Wang-Sheng; Chiou, Ya-Ling

    2016-01-01

    In the pathogenesis of asthma, the proliferation of airway smooth muscle cells (ASMCs) is a key factor in airway remodeling and causes airway narrowing. In addition, ASMCs are also the effector cells of airway inflammation. Fucoidan extracted from marine brown algae polysaccharides has antiviral, antioxidant, antimicrobial, anticlotting, and anticancer properties; however, its effectiveness for asthma has not been elucidated thus far. Platelet-derived growth factor (PDGF)-treated primary ASMCs were cultured with or without oligo-fucoidan (100, 500, or 1000 µg/mL) to evaluate its effects on cell proliferation, cell cycle, apoptosis, and Akt, ERK1/2 signaling pathway. We found that PDGF (40 ng/mL) increased the proliferation of ASMCs by 2.5-fold after 48 h (p < 0.05). Oligo-fucoidan reduced the proliferation of PDGF-stimulated ASMCs by 75%–99% after 48 h (p < 0.05) and induced G1/G0 cell cycle arrest, but did not induce apoptosis. Further, oligo-fucoidan supplementation reduced PDGF-stimulated extracellular signal-regulated kinase (ERK1/2), Akt, and nuclear factor (NF)-κB phosphorylation. Taken together, oligo-fucoidan supplementation might reduce proliferation of PDGF-treated ASMCs through the suppression of ERK1/2 and Akt phosphorylation and NF-κB activation. The results provide basis for future animal experiments and human trials. PMID:26761017

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

    PubMed

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

    2005-09-01

    Airway smooth muscle (ASM) proliferation and migration are major components of airway remodeling in asthma. Asthmatic airways are exposed to mechanical strain, which contributes to their remodeling. Matrix metalloproteinase (MMP) plays an important role in remodeling. In the present study, we examined if the mechanical strain of human ASM (HASM) cells contributes to their proliferation and migration and the role of MMPs in this process. HASM were exposed to mechanical strain using the FlexCell system. HASM cell proliferation, migration and MMP release, activation, and expression were assessed. Our results show that cyclic strain increased the proliferation and migration of HASM; cyclic strain increased release and activation of MMP-1, -2, and -3 and membrane type 1-MMP; MMP release was preceded by an increase in extracellular MMP inducer; Prinomastat [a MMP inhibitor (MMPI)] significantly decreased cyclic strain-induced proliferation and migration of HASM; and the strain-induced increase in the release of MMPs was accompanied by an increase in tenascin-C release. In conclusion, cyclic mechanical strain plays an important role in HASM cell proliferation and migration. This increase in proliferation and migration is through an increase in MMP release and activation. Pharmacological MMPIs should be considered in the pursuit of therapeutic options for airway remodeling in asthma. PMID:16014803

  6. The Pro-Proliferative Effects of Nicotine and Its Underlying Mechanism on Rat Airway Smooth Muscle Cells

    PubMed Central

    He, Fang; Li, Bing; Zhao, Zhuxiang; Zhou, Yumin; Hu, Guoping; Zou, Weifeng; Hong, Wei; Zou, Yimin; Jiang, Changbin; Zhao, Dongxing; Ran, Pixin

    2014-01-01

    Recent studies have shown that nicotine, a major component of cigarette smoke, can stimulate the proliferation of non-neuronal cells. Cigarette smoking can promote a variety of pulmonary and cardiovascular diseases, such as chronic obstructive pulmonary disease (COPD), atherosclerosis, and cancer. A predominant feature of COPD is airway remodeling, which includes increased airway smooth muscle (ASM) mass. The mechanisms underlying ASM remodeling in COPD have not yet been fully elucidated. Here, we show that nicotine induces a profound and time-dependent increase in DNA synthesis in rat airway smooth muscle cells (RASMCs) in vitro. Nicotine also significantly increased the number of RASMCs, which was associated with the increased expression of Cyclin D1, phosphorylation of the retinoblastoma protein (RB) and was dependent on the activation of Akt. The activation of Akt by nicotine occurred within minutes and depended upon the nicotinic acetylcholine receptors (nAchRs). Activated Akt increased the phosphorylation of downstream substrates such as GSK3β. Our data suggest that the binding of nicotine to the nAchRs on RASMCs can regulate cellular proliferation by activating the Akt pathway. PMID:24690900

  7. Dietary obesity increases NO and inhibits BKCa-mediated, endothelium-dependent dilation in rat cremaster muscle artery: association with caveolins and caveolae.

    PubMed

    Howitt, Lauren; Grayson, T Hilton; Morris, Margaret J; Sandow, Shaun L; Murphy, Timothy V

    2012-06-15

    Obesity is a risk factor for hypertension and other vascular disease. The aim of this study was to examine the effect of diet-induced obesity on endothelium-dependent dilation of rat cremaster muscle arterioles. Male Sprague-Dawley rats (213 ± 1 g) were fed a cafeteria-style high-fat or control diet for 16-20 wk. Control rats weighed 558 ± 7 g compared with obese rats 762 ± 12 g (n = 52-56; P < 0.05). Diet-induced obesity had no effect on acetylcholine (ACh)-induced dilation of isolated, pressurized (70 mmHg) arterioles, but sodium nitroprusside (SNP)-induced vasodilation was enhanced. ACh-induced dilation of arterioles from control rats was abolished by a combination of the K(Ca) blockers apamin, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), and iberiotoxin (IBTX; all 0.1 μmol/l), with no apparent role for nitric oxide (NO). In arterioles from obese rats, however, IBTX had no effect on responses to ACh while the NO synthase (NOS)/guanylate cyclase inhibitors N(ω)-nitro-L-arginine methyl ester (L-NAME; 100 μmol/l)/1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 μmol/l) partially inhibited ACh-induced dilation. Furthermore, NOS activity (but not endothelial NOS expression) was increased in arteries from obese rats. L-NAME/ODQ alone or removal of the endothelium constricted arterioles from obese but not control rats. Expression of caveolin-1 and -2 oligomers (but not monomers or caveolin-3) was increased in arterioles from obese rats. The number of caveolae was reduced in the endothelium of arteries, and caveolae density was increased at the ends of smooth muscle cells from obese rats. Diet-induced obesity abolished the contribution of large-conductance Ca(2+)-activated K(+) channel to ACh-mediated endothelium-dependent dilation of rat cremaster muscle arterioles, while increasing NOS activity and inducing an NO-dependent component. PMID:22492718

  8. Vitamin D Modulates Expression of the Airway Smooth Muscle Transcriptome in Fatal Asthma

    PubMed Central

    Johnson, Martin; Nikolos, Christina; Jester, William; Klanderman, Barbara; Litonjua, Augusto A.; Tantisira, Kelan G.; Truskowski, Kevin; MacDonald, Kevin; Panettieri, Reynold A.; Weiss, Scott T.

    2015-01-01

    Globally, asthma is a chronic inflammatory respiratory disease affecting over 300 million people. Some asthma patients remain poorly controlled by conventional therapies and experience more life-threatening exacerbations. Vitamin D, as an adjunct therapy, may improve disease control in severe asthma patients since vitamin D enhances glucocorticoid responsiveness and mitigates airway smooth muscle (ASM) hyperplasia. We sought to characterize differences in transcriptome responsiveness to vitamin D between fatal asthma- and non-asthma-derived ASM by using RNA-Seq to measure ASM transcript expression in five donors with fatal asthma and ten non-asthma-derived donors at baseline and with vitamin D treatment. Based on a Benjamini-Hochberg corrected p-value <0.05, 838 genes were differentially expressed in fatal asthma vs. non-asthma-derived ASM at baseline, and vitamin D treatment compared to baseline conditions induced differential expression of 711 and 867 genes in fatal asthma- and non-asthma-derived ASM, respectively. Functional gene categories that were highly represented in all groups included extracellular matrix, and responses to steroid hormone stimuli and wounding. Genes differentially expressed by vitamin D also included cytokine and chemokine activity categories. Follow-up qPCR and individual analyte ELISA experiments were conducted for four cytokines (i.e. CCL2, CCL13, CXCL12, IL8) to measure TNFα-induced changes by asthma status and vitamin D treatment. Vitamin D inhibited TNFα-induced IL8 protein secretion levels to a comparable degree in fatal asthma- and non-asthma-derived ASM even though IL8 had significantly higher baseline levels in fatal asthma-derived ASM. Our findings identify vitamin D-specific gene targets and provide transcriptomic data to explore differences in the ASM of fatal asthma- and non-asthma-derived donors. PMID:26207385

  9. Bidirectional counter-regulation of human lung mast cell and airway smooth muscle β2-adrenoceptors

    PubMed Central

    Newby, Chris; Amrani, Yassine; Bradding, Peter

    2015-01-01

    Human lung mast cells (HLMCs) play a central role in asthma pathogenesis through their relocation to the airway smooth muscle (ASM) bundles. β2 adrenoceptor (β2-AR)-agonists are used to relieve bronchoconstriction in asthma, but may reduce asthma control, particularly when used as monotherapy. We hypothesised that HLMC and human ASM cell (HASMC) responsiveness to β2-AR agonists would be attenuated when HLMCs are in contact with HASMCs. Cells were cultured in the presence of the short-acting β2-agonist albuterol, and the long-acting β2-agonists formoterol and olodaterol. Constitutive and FcεRI-dependent HLMC histamine release, HASMC contraction, and β2-AR phosphorylation at tyrosine 350 (Tyr350) were assessed. Constitutive HLMC histamine release was increased in HLMC-HASMC co-culture and this was enhanced by β2-AR agonists. Inhibition of FcεRI-dependent HLMC mediator release by β2-agonists was greatly reduced in HLMC-HASMC co-culture. These effects were reversed by neutralisation of stem cell factor (SCF) or cell adhesion molecule 1 (CADM1). β2-AR agonists did not prevent HASMC contraction when HLMCs were present, but this was reversed by fluticasone. β2-AR phosphorylation at Tyr350 occurred within 5 minutes in both HLMCs and HASMCs when the cells were co-cultured, and was inhibited by neutralising SCF or CADM1. HLMC interactions with HASMCs via CADM1 and Kit inhibit the potentially beneficial effects of β2-AR agonists on these cells via phosphorylation of the β2-AR. These results may explain the potentially adverse effects of β2-ARs agonists when used for asthma therapy. Targeting SCF and CADM1 may enhance β2-AR efficacy, particularly in corticosteroid-resistant patients. PMID:26608913

  10. A deterministic model predicts the properties of stochastic calcium oscillations in airway smooth muscle cells.

    PubMed

    Cao, Pengxing; Tan, Xiahui; Donovan, Graham; Sanderson, Michael J; Sneyd, James

    2014-08-01

    The inositol trisphosphate receptor ([Formula: see text]) is one of the most important cellular components responsible for oscillations in the cytoplasmic calcium concentration. Over the past decade, two major questions about the [Formula: see text] have arisen. Firstly, how best should the [Formula: see text] be modeled? In other words, what fundamental properties of the [Formula: see text] allow it to perform its function, and what are their quantitative properties? Secondly, although calcium oscillations are caused by the stochastic opening and closing of small numbers of [Formula: see text], is it possible for a deterministic model to be a reliable predictor of calcium behavior? Here, we answer these two questions, using airway smooth muscle cells (ASMC) as a specific example. Firstly, we show that periodic calcium waves in ASMC, as well as the statistics of calcium puffs in other cell types, can be quantitatively reproduced by a two-state model of the [Formula: see text], and thus the behavior of the [Formula: see text] is essentially determined by its modal structure. The structure within each mode is irrelevant for function. Secondly, we show that, although calcium waves in ASMC are generated by a stochastic mechanism, [Formula: see text] stochasticity is not essential for a qualitative prediction of how oscillation frequency depends on model parameters, and thus deterministic [Formula: see text] models demonstrate the same level of predictive capability as do stochastic models. We conclude that, firstly, calcium dynamics can be accurately modeled using simplified [Formula: see text] models, and, secondly, to obtain qualitative predictions of how oscillation frequency depends on parameters it is sufficient to use a deterministic model. PMID:25121766

  11. A-kinase-anchoring proteins coordinate inflammatory responses to cigarette smoke in airway smooth muscle

    PubMed Central

    Heijink, Irene H.; Holtzer, Laura J.; Skroblin, Philipp; Klussmann, Enno; Halayko, Andrew J.; Timens, Wim; Maarsingh, Harm; Schmidt, Martina

    2015-01-01

    β2-Agonist inhibitors can relieve chronic obstructive pulmonary disease (COPD) symptoms by stimulating cyclic AMP (cAMP) signaling. A-kinase-anchoring proteins (AKAPs) compartmentalize cAMP signaling by establishing protein complexes. We previously reported that the β2-agonist fenoterol, direct activation of protein kinase A (PKA), and exchange factor directly activated by cAMP decrease cigarette smoke extract (CSE)-induced release of neutrophil attractant interleukin-8 (IL-8) from human airway smooth muscle (ASM) cells. In the present study, we tested the role of AKAPs in CSE-induced IL-8 release from ASM cells and assessed the effect of CSE on the expression levels of different AKAPs. We also studied mRNA and protein expression of AKAPs in lung tissue from patients with COPD. Our data show that CSE exposure of ASM cells decreases AKAP5 and AKAP12, both capable of interacting with β2-adrenoceptors. In lung tissue of patients with COPD, mRNA levels of AKAP5 and AKAP12 were decreased compared with lung tissue from controls. Using immunohistochemistry, we detected less AKAP5 protein in ASM of patients with COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II compared with control subjects. St-Ht31, which disrupts AKAP-PKA interactions, augmented CSE-induced IL-8 release from ASM cells and diminished its suppression by fenoterol, an effect mediated by disturbed ERK signaling. The modulatory role of AKAP-PKA interactions in the anti-inflammatory effects of fenoterol in ASM cells and the decrease in expression of AKAP5 and AKAP12 in response to cigarette smoke and in lungs of patients with COPD suggest that cigarette smoke-induced changes in AKAP5 and AKAP12 in patients with COPD may affect efficacy of pharmacotherapy. PMID:25637608

  12. A-kinase-anchoring proteins coordinate inflammatory responses to cigarette smoke in airway smooth muscle.

    PubMed

    Poppinga, Wilfred J; Heijink, Irene H; Holtzer, Laura J; Skroblin, Philipp; Klussmann, Enno; Halayko, Andrew J; Timens, Wim; Maarsingh, Harm; Schmidt, Martina

    2015-04-15

    β2-Agonist inhibitors can relieve chronic obstructive pulmonary disease (COPD) symptoms by stimulating cyclic AMP (cAMP) signaling. A-kinase-anchoring proteins (AKAPs) compartmentalize cAMP signaling by establishing protein complexes. We previously reported that the β2-agonist fenoterol, direct activation of protein kinase A (PKA), and exchange factor directly activated by cAMP decrease cigarette smoke extract (CSE)-induced release of neutrophil attractant interleukin-8 (IL-8) from human airway smooth muscle (ASM) cells. In the present study, we tested the role of AKAPs in CSE-induced IL-8 release from ASM cells and assessed the effect of CSE on the expression levels of different AKAPs. We also studied mRNA and protein expression of AKAPs in lung tissue from patients with COPD. Our data show that CSE exposure of ASM cells decreases AKAP5 and AKAP12, both capable of interacting with β2-adrenoceptors. In lung tissue of patients with COPD, mRNA levels of AKAP5 and AKAP12 were decreased compared with lung tissue from controls. Using immunohistochemistry, we detected less AKAP5 protein in ASM of patients with COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II compared with control subjects. St-Ht31, which disrupts AKAP-PKA interactions, augmented CSE-induced IL-8 release from ASM cells and diminished its suppression by fenoterol, an effect mediated by disturbed ERK signaling. The modulatory role of AKAP-PKA interactions in the anti-inflammatory effects of fenoterol in ASM cells and the decrease in expression of AKAP5 and AKAP12 in response to cigarette smoke and in lungs of patients with COPD suggest that cigarette smoke-induced changes in AKAP5 and AKAP12 in patients with COPD may affect efficacy of pharmacotherapy. PMID:25637608

  13. Bidirectional Counterregulation of Human Lung Mast Cell and Airway Smooth Muscle β2 Adrenoceptors.

    PubMed

    Lewis, Rebecca J; Chachi, Latifa; Newby, Chris; Amrani, Yassine; Bradding, Peter

    2016-01-01

    Human lung mast cells (HLMCs) play a central role in asthma pathogenesis through their relocation to the airway smooth muscle (ASM) bundles. β2 adrenoceptor (β2-AR)-agonists are used to relieve bronchoconstriction in asthma, but may reduce asthma control, particularly when used as monotherapy. We hypothesized that HLMC and human ASM cell (HASMC) responsiveness to β2-AR agonists would be attenuated when HLMCs are in contact with HASMCs. Cells were cultured in the presence of the short-acting β2-agonist albuterol, and the long-acting β2-agonists formoterol and olodaterol. Constitutive and FcεRI-dependent HLMC histamine release, HASMC contraction, and β2-AR phosphorylation at Tyr(350) were assessed. Constitutive HLMC histamine release was increased in HLMC-HASMC coculture and this was enhanced by β2-AR agonists. Inhibition of FcεRI-dependent HLMC mediator release by β2-agonists was greatly reduced in HLMC-HASMC coculture. These effects were reversed by neutralization of stem cell factor (SCF) or cell adhesion molecule 1 (CADM1). β2-AR agonists did not prevent HASMC contraction when HLMCs were present, but this was reversed by fluticasone. β2-AR phosphorylation at Tyr(350) occurred within 5 min in both HLMCs and HASMCs when the cells were cocultured, and was inhibited by neutralizing SCF or CADM1. HLMC interactions with HASMCs via CADM1 and Kit inhibit the potentially beneficial effects of β2-AR agonists on these cells via phosphorylation of the β2-AR. These results may explain the potentially adverse effects of β2-ARs agonists when used for asthma therapy. Targeting SCF and CADM1 may enhance β2-AR efficacy, particularly in corticosteroid-resistant patients. PMID:26608913

  14. Acute response of airway muscle to extreme temperature includes disruption of actin-myosin interaction.

    PubMed

    Dyrda, Peter; Tazzeo, Tracy; DoHarris, Lindsay; Nilius, Berndt; Roman, Horia Nicolae; Lauzon, Anne-Marie; Aziz, Tariq; Lukic, Dusan; Janssen, Luke J

    2011-02-01

    Despite the emerging use of bronchial thermoplasty in asthma therapy, the response of airway smooth muscle (ASM) to extreme temperatures is unknown. We investigated the immediate effects of exposing ASM to supraphysiologic temperatures. Isometric contractions were studied in bovine ASM before and after exposure to various thermal loads and/or pharmacologic interventions. Actin-myosin interactions were investigated using a standard in vitro motility assay. We found steep thermal sensitivity for isometric contractions evoked by acetylcholine, with threshold and complete inhibition at less than 50°C and greater than 55°C, respectively. Contractile responses to serotonin or KCl were similarly affected, whereas isometric relaxations evoked by the nitric oxide donor S-nitrosyl-N-acetylpenicillamine or the β-agonist isoproterenol were unaffected. This thermal sensitivity developed within 15 minutes, but did not evolve further over the course of several days (such a rapid time-course rules out heat shock proteins, apoptosis, autophagy, and necrosis). Although heat-sensitive transient receptor potential (TRPV2) channels and the calmodulin-dependent (Cam) kinase-II-induced inactivation of myosin light chain kinase are both acutely thermally sensitive, with a temperature producing half-maximal effect (T(1/2)) of 52.5°C, the phenomenon we describe was not prevented by blockers of TRPV2 channels (e.g., ruthenium red, gadolinium, zero-Ca(2+) or zero-Na(+)/zero-Ca(2+) media, and cromakalim) or of Cam kinase-II (e.g., W7, trifluoperazine, and KN-93). However, direct measurements of actin-myosin interactions showed the same steep thermal profile. The functional changes preceded any histologic evidence of necrosis or apoptosis. We conclude that extreme temperatures (such as those used in bronchial thermoplasty) directly disrupt actin-myosin interactions, likely through a denaturation of the motor protein, leading to an immediate loss of ASM cell function. PMID:20395634

  15. Myosin filament polymerization and depolymerization in a model of partial length adaptation in airway smooth muscle.

    PubMed

    Ijpma, Gijs; Al-Jumaily, Ahmed M; Cairns, Simeon P; Sieck, Gary C

    2011-09-01

    Length adaptation in airway smooth muscle (ASM) is attributed to reorganization of the cytoskeleton, and in particular the contractile elements. However, a constantly changing lung volume with tidal breathing (hence changing ASM length) is likely to restrict full adaptation of ASM for force generation. There is likely to be continuous length adaptation of ASM between states of incomplete or partial length adaption. We propose a new model that assimilates findings on myosin filament polymerization/depolymerization, partial length adaptation, isometric force, and shortening velocity to describe this continuous length adaptation process. In this model, the ASM adapts to an optimal force-generating capacity in a repeating cycle of events. Initially the myosin filament, shortened by prior length changes, associates with two longer actin filaments. The actin filaments are located adjacent to the myosin filaments, such that all myosin heads overlap with actin to permit maximal cross-bridge cycling. Since in this model the actin filaments are usually longer than myosin filaments, the excess length of the actin filament is located randomly with respect to the myosin filament. Once activated, the myosin filament elongates by polymerization along the actin filaments, with the growth limited by the overlap of the actin filaments. During relaxation, the myosin filaments dissociate from the actin filaments, and then the cycle repeats. This process causes a gradual adaptation of force and instantaneous adaptation of shortening velocity. Good agreement is found between model simulations and the experimental data depicting the relationship between force development, myosin filament density, or shortening velocity and length. PMID:21659490

  16. Airway smooth muscle dysfunction precedes teratogenic congenital diaphragmatic hernia and may contribute to hypoplastic lung morphogenesis.

    PubMed

    Featherstone, Neil C; Connell, Marilyn G; Fernig, David G; Wray, Susan; Burdyga, Theodor V; Losty, Paul D; Jesudason, Edwin C

    2006-11-01

    Fetal intervention aims to improve lung growth and survival in congenital diaphragmatic hernia (CDH). Airway smooth muscle (ASM) is important in lung development: ASM progenitors produce a key growth factor for lung morphogenesis (fibroblast growth factor 10); ASM contractility is also coupled to growth. ASM hyperreactivity occurs in postnatal CDH and may exacerbate barotrauma via impaired lung compliance. We hypothesize that ASM hyperreactivity and its sequelae are based on an early developmental lesion of ASM activity in hypoplastic lung. Sprague-Dawley rats were fed 100 mg nitrofen on Day 9.5 of pregnancy to induce lung hypoplasia in offspring (controls had vehicle alone). Normal and hypoplastic lung primordia were cultured from Day 13.5 of gestation at 37 degrees C in 5% CO(2) and loaded at 54 or 78 h with Ca(2+)-sensitive indicators: Fluo-4 for confocal imaging and Indo-1 or Fura-2 for photometric measurements of [Ca(2+)](i). Hypoplastic lung features spontaneous propagating ASM Ca(2+) transients with reduced frequency, increased amplitude, and significantly prolonged plateau duration, relative to control lung. Nonetheless, hypoplastic lung exhibits normal requirement for extracellular calcium entry and intracellular calcium release in initiation and regulation of ASM Ca(2+) waves. Early ASM dysfunction in lung hypoplasia is apparent as specific anomalies of Ca(2+) transients that indicate a problem with plasmalemmal ion channels/action potential generation. Elucidation of such an ASM lesion may allow pharmacologic amelioration not only of ASM hyperreactivity and its sequelae, but also of hypoplastic lung growth itself. PMID:16728706

  17. Nonadrenergic, noncholinergic responses stabilize smooth muscle tone, with and without parasympathetic activation, in guinea-pig isolated airways.

    PubMed

    Lindén, A; Löfdahl, C G; Ullman, A; Skoogh, B E

    1993-03-01

    In guinea-pig isolated airways, nonadrenergic, noncholinergic (NANC) neural responses converge towards a similar level of smooth muscle tone, via a contraction when the tone is low prior to stimulation, and via a relaxation when the tone is high prior to stimulation. We wanted to assess the effect of simultaneous parasympathetic activation on these converging NANC responses, with and without the addition of sympathetic activation. In guinea-pig isolated airways, the spontaneous airway tone was initially abolished by indomethacin (10 microM). In one series, adrenergic depletion by guanethidine (10 microM) was then established, with and without cholinergic blockade by atropine (1 microM). In another series, either cholinergic blockade by atropine (1 microM) or no blockade was utilized. Responses to electrical field stimulation (1,200 mA, 0.5 ms, 3 Hz for 240 s) were studied with no induced tone, at a moderate (0.3 microM) and at a near-maximum (6 microM), histamine-induced tone. The mean level of the tonus equilibrium (% of maximum tone) was higher with the simultaneous NANC and parasympathetic activation than with NANC activation alone (75% compared with 44%, in the main bronchus, n = 8). The level of the tonus equilibrium was also higher with the simultaneous NANC, sympathetic and parasympathetic activation than with NANC and sympathetic activation only (49% compared with 21%, in the main bronchus, n = 8). The pattern was similar in the distal trachea. In conclusion, NANC neural responses can stabilize smooth muscle tone, and this stabilizing effect can be modulated by both parasympathetic and sympathetic activation, in guinea-pig isolated airways. PMID:8472834

  18. Computational simulation of human upper airway collapse using a pressure-/state-dependent model of genioglossal muscle contraction under laminar flow conditions

    PubMed Central

    Huang, Yaqi; Malhotra, Atul; White, David P.

    2012-01-01

    A three-element, pressure- and state (sleep and wake) -dependent contraction model of the genioglossal muscle was developed based on the microstructure of skeletal muscle and the cross-bridge theory. This model establishes a direct connection between the contractile forces generated in muscle fibers and the measured electromyogram signals during various upper airway conditions. This effectively avoids the difficulty of determining muscle shortening velocity during complex pharyngeal conditions when modeling the muscle’s contractile behaviors. The activation of the genioglossal muscle under different conditions was then simulated. A sensitivity analysis was performed to determine the effects of varying each modeled parameter on the muscle’s contractile behaviors. This muscle contraction model was then incorporated into our anatomically correct, two-dimensional computational model of the pharyngeal airway to perform a finite-element analysis of air flow, tissue deformation, and airway collapse. The model-predicted muscle deformations are consistent with previous observations regarding upper airway behavior in normal subjects. PMID:15831800

  19. Real-time imaging of ATP release induced by mechanical stretch in human airway smooth muscle cells.

    PubMed

    Takahara, Norihiro; Ito, Satoru; Furuya, Kishio; Naruse, Keiji; Aso, Hiromichi; Kondo, Masashi; Sokabe, Masahiro; Hasegawa, Yoshinori

    2014-12-01

    Airway smooth muscle (ASM) cells within the airway walls are continually exposed to mechanical stimuli, and exhibit various functions in response to these mechanical stresses. ATP acts as an extracellular mediator in the airway. Moreover, extracellular ATP is considered to play an important role in the pathophysiology of asthma and chronic obstructive pulmonary disease. However, it is not known whether ASM cells are cellular sources of ATP secretion in the airway. We therefore investigated whether mechanical stretch induces ATP release from ASM cells. Mechanical stretch was applied to primary human ASM cells cultured on a silicone chamber coated with type I collagen using a stretching apparatus. Concentrations of ATP in cell culture supernatants measured by luciferin-luciferase bioluminescence were significantly elevated by cyclic stretch (12 and 20% strain). We further visualized the stretch-induced ATP release from the cells in real time using a luminescence imaging system, while acquiring differential interference contrast cell images with infrared optics. Immediately after a single uniaxial stretch for 1 second, strong ATP signals were produced by a certain population of cells and spread to surrounding spaces. The cyclic stretch-induced ATP release was significantly reduced by inhibitors of Ca(2+)-dependent vesicular exocytosis, 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester, monensin, N-ethylmaleimide, and bafilomycin. In contrast, the stretch-induced ATP release was not inhibited by a hemichannel blocker, carbenoxolone, or blockade of transient receptor potential vanilloid 4 by short interfering RNA transfection or ruthenium red. These findings reveal a novel property of ASM cells: mechanically induced ATP release may be a cellular source of ATP in the airway. PMID:24885163

  20. Kv7 potassium channels in airway smooth muscle cells: signal transduction intermediates and pharmacological targets for bronchodilator therapy.

    PubMed

    Brueggemann, Lioubov I; Kakad, Priyanka P; Love, Robert B; Solway, Julian; Dowell, Maria L; Cribbs, Leanne L; Byron, Kenneth L

    2012-01-01

    Expression and function of Kv7 (KCNQ) voltage-activated potassium channels in guinea pig and human airway smooth muscle cells (ASMCs) were investigated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), patch-clamp electrophysiology, and precision-cut lung slices. qRT-PCR revealed expression of multiple KCNQ genes in both guinea pig and human ASMCs. Currents with electrophysiological and pharmacological characteristics of Kv7 currents were measured in freshly isolated guinea pig and human ASMCs. In guinea pig ASMCs, Kv7 currents were significantly suppressed by application of the bronchoconstrictor agonists methacholine (100 nM) or histamine (30 μM), but current amplitudes were restored by addition of a Kv7 channel activator, flupirtine (10 μM). Kv7 currents in guinea pig ASMCs were also significantly enhanced by another Kv7.2-7.5 channel activator, retigabine, and by celecoxib and 2,5-dimethyl celecoxib. In precision-cut human lung slices, constriction of airways by histamine was significantly reduced in the presence of flupirtine. Kv7 currents in both guinea pig and human ASMCs were inhibited by the Kv7 channel blocker XE991. In human lung slices, XE991 induced robust airway constriction, which was completely reversed by addition of the calcium channel blocker verapamil. These findings suggest that Kv7 channels in ASMCs play an essential role in the regulation of airway diameter and may be targeted pharmacologically to relieve airway hyperconstriction induced by elevated concentrations of bronchoconstrictor agonists. PMID:21964407

  1. Kv7 potassium channels in airway smooth muscle cells: signal transduction intermediates and pharmacological targets for bronchodilator therapy

    PubMed Central

    Brueggemann, Lioubov I.; Kakad, Priyanka P.; Love, Robert B.; Solway, Julian; Dowell, Maria L.; Cribbs, Leanne L.

    2012-01-01

    Expression and function of Kv7 (KCNQ) voltage-activated potassium channels in guinea pig and human airway smooth muscle cells (ASMCs) were investigated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), patch-clamp electrophysiology, and precision-cut lung slices. qRT-PCR revealed expression of multiple KCNQ genes in both guinea pig and human ASMCs. Currents with electrophysiological and pharmacological characteristics of Kv7 currents were measured in freshly isolated guinea pig and human ASMCs. In guinea pig ASMCs, Kv7 currents were significantly suppressed by application of the bronchoconstrictor agonists methacholine (100 nM) or histamine (30 μM), but current amplitudes were restored by addition of a Kv7 channel activator, flupirtine (10 μM). Kv7 currents in guinea pig ASMCs were also significantly enhanced by another Kv7.2–7.5 channel activator, retigabine, and by celecoxib and 2,5-dimethyl celecoxib. In precision-cut human lung slices, constriction of airways by histamine was significantly reduced in the presence of flupirtine. Kv7 currents in both guinea pig and human ASMCs were inhibited by the Kv7 channel blocker XE991. In human lung slices, XE991 induced robust airway constriction, which was completely reversed by addition of the calcium channel blocker verapamil. These findings suggest that Kv7 channels in ASMCs play an essential role in the regulation of airway diameter and may be targeted pharmacologically to relieve airway hyperconstriction induced by elevated concentrations of bronchoconstrictor agonists. PMID:21964407

  2. YAP is up-regulated in the bronchial airway smooth muscle of the chronic asthma mouse model.

    PubMed

    Zhou, Jing; Xu, Fei; Yu, Jing Jing; Zhang, Wei

    2015-01-01

    Asthma is characterized by leukocytic infiltration and tissue remodeling with structural changes including subepithelial fibrosis and ASM cells proliferation. The Hippo pathway is a key regulatory point involved in cell proliferation, fibroblasts, and smooth muscle cell differentiation. In order to disclose the relation between asthma and the Hippo pathway, expression of the Yes-associated protein (YAP), a key gene in the Hippo pathway, in the bronchial smooth muscle of chronic asthma model (CAM) was studied. 40 mice were randomly divided into control (wide type) and experimental group to construct CAM using chicken ovalbumin (OVA). Pathological changes of the lung tissues were observed in the CAM mice compared with the control using HE staining method. Immunohistochemistry (IHC) was used to detect if YAP protein is expressed in the lung tissues. The pathological changes of the CAM group showed that a large number of inflammatory cells infiltration including mainly lymphocytes and a small amount of eosinophilic, with the presence of certain airway smooth muscle hyperplasia, was observed in comparison with the control. IHC results showed that the YAP protein was significantly increased compared with the control groups (P < 0.01). This result was further confirmed by quantitative real-time PCR (qPCR) assay which detected the up-regulation of the YAP gene (P < 0.01) and Western blot. In conclusion, the YAP protein was significantly expressed in the bronchial airway tissues of the CAM mice, and could be used as an indicator for asthma. PMID:26617833

  3. Selective visualisation of sensory receptors in the smooth muscle layer of ex-vivo airway whole-mounts by styryl pyridinium dyes.

    PubMed

    De Proost, Ian; Pintelon, Isabel; Brouns, Inge; Timmermans, Jean-Pierre; Adriaensen, Dirk

    2007-09-01

    Recently, we established the location, morphology and neurochemical coding of vagal smooth-muscle-associated airway receptors (SMARs) in rat lungs. These receptors were characterised as branching laminar terminals that originated from myelinated nerve fibres and were intercalated between airway smooth-muscle bundles. To allow the direct physiological examination of these receptors, the present investigation aimed at visualising SMARs in airway whole-mounts of rat and mouse lungs ex vivo. Short incubation with various styryl pyridinium dyes (AM1-43, FM2-10, FM4-64 or 4-Di-2-ASP) gave a highly selective fluorescent visualisation of both laminar nerve terminals and myelinated fibres from which they originated throughout the intrapulmonary airway tree in mouse and in rat. The reliable and specific labelling of SMARs ex vivo with these lipophilic membrane dyes was confirmed via immunostaining for protein gene-product 9.5 and vesicular glutamate transporters. Similar to the intrapulmonary location of NEBs, these SMARs appeared to be even more explicitly located near airway bifurcations. Both the trachealis muscle and the smooth-muscle bundles of extrapulmonary bronchi were also shown to contain laminar nerve terminals that were morphologically similar to the SMARs reported in the intrapulmonary airways. Thus, this study provides an in-vitro model enabling, for the first time, the fast and reliable visualisation of SMARs and the myelinated nerve fibres from which they originate in airway whole-mount preparations ex vivo. As such, this model opens up further perspectives and creates a valid basis for direct physiological measurement and manipulation of the individually identified airway receptors. PMID:17522895

  4. CXCL8 histone H3 acetylation is dysfunctional in airway smooth muscle in asthma: regulation by BET

    PubMed Central

    Clifford, Rachel L.; Patel, Jamie K.; John, Alison E.; Tatler, Amanda L.; Mazengarb, Lisa; Brightling, Christopher E.

    2015-01-01

    Asthma is characterized by airway inflammation and remodeling and CXCL8 is a CXC chemokine that drives steroid-resistant neutrophilic airway inflammation. We have shown that airway smooth muscle (ASM) cells isolated from asthmatic individuals secrete more CXCL8 than cells from nonasthmatic individuals. Here we investigated chromatin modifications at the CXCL8 promoter in ASM cells from nonasthmatic and asthmatic donors to further understand how CXCL8 is dysregulated in asthma. ASM cells from asthmatic donors had increased histone H3 acetylation, specifically histone H3K18 acetylation, and increased binding of histone acetyltransferase p300 compared with nonasthmatic donors but no differences in CXCL8 DNA methylation. The acetylation reader proteins Brd3 and Brd4 were bound to the CXCL8 promoter and Brd inhibitors inhibited CXCL8 secretion from ASM cells by disrupting Brd4 and RNA polymerase II binding to the CXCL8 promoter. Our results show a novel dysregulation of CXCL8 transcriptional regulation in asthma characterized by a promoter complex that is abnormal in ASM cells isolated from asthmatic donors and can be modulated by Brd inhibitors. Brd inhibitors may provide a new therapeutic strategy for steroid-resistant inflammation. PMID:25713319

  5. Arachidonate-Regulated Ca2+ Influx in Human Airway Smooth Muscle

    PubMed Central

    Thompson, Michael A.; Prakash, Y. S.

    2014-01-01

    Plasma membrane Ca2+ influx, especially store-operated Ca2+ entry triggered by sarcoplasmic reticulum (SR) Ca2+ release, is a key component of intracellular calcium concentration ([Ca2+]i) regulation in airway smooth muscle (ASM). Agonist-induced Ca2+ oscillations in ASM that involve both influx and SR mechanisms have been previously demonstrated. In nonexcitable cells, [Ca2+]i oscillations involve Ca2+ influx via arachidonic acid (AA) –stimulated channels, which show similarities to store-operated Ca2+ entry, although their molecular identity remains undetermined. Little is known about AA-regulated Ca2+ channels or their regulation in ASM. In enzymatically dissociated human ASM cells loaded with the Ca2+ indicator, fura-2, AA (1–10 μM) triggered [Ca2+]i oscillations that were inhibited by removal of extracellular Ca2+. Other fatty acids, such as the diacylglycerol analog, 1-oleoyl-2-acetyl-SN-glycerol, oleic acid, and palmitic acid (10 μM each), failed to elicit similar [Ca2+]i responses. Preincubation with LaCl3 (1 μM or 1 mM) inhibited AA-induced oscillations. Inhibition of receptor-operated channels (SKF96,365 [10 μM]), lipoxygenase (zileuton [10 μM]), or cyclooxygenase (indomethacin [10 μM]) did not affect oscillation parameters. Inhibition of SR Ca2+ release (ryanodine [10 μM] or inositol 1,4,5-trisphosphate receptor inhibitor, xestospongin C [1 μM]) decreased [Ca2+]i oscillation frequency and amplitude. Small interfering RNA against caveolin-1, stromal interaction molecule 1, or Orai3 (20 nM each) reduced the frequency and amplitude of AA-induced [Ca2+]i oscillations. In ASM cells derived from individuals with asthma, AA increased oscillation amplitude, but not frequency. These results are highly suggestive of a novel AA-mediated Ca2+–regulatory mechanism in human ASM, reminiscent of agonist-induced oscillations. Given the role of AA in ASM intracellular signaling, especially with inflammation, AA-regulated Ca2+ channels could potentially

  6. IgE induces proliferation in human airway smooth muscle cells: role of MAPK and STAT3 pathways.

    PubMed

    Redhu, Naresh Singh; Shan, Lianyu; Al-Subait, Duaa; Ashdown, Heather L; Movassagh, Hesam; Lamkhioued, Bouchaib; Gounni, Abdelilah S

    2013-01-01

    Airway remodeling is not specifically targeted by current asthma medications, partly owing to the lack of understanding of remodeling mechanisms, altogether posing great challenges in asthma treatment. Increased airway smooth muscle (ASM) mass due to hyperplasia/hypertrophy contributes significantly to overall airway remodeling and correlates with decline in lung function. Recent evidence suggests that IgE sensitization can enhance the survival and mediator release in inflammatory cells. Human ASM (HASM) cells express both low affinity (FcεRII/CD23) and high affinity IgE Fc receptors (FcεRI), and IgE can modulate the contractile and synthetic function of HASM cells. IgE was recently shown to induce HASM cell proliferation but the detailed mechanisms remain unknown. We report here that IgE sensitization induces HASM cell proliferation, as measured by 3H-thymidine, EdU incorporation, and manual cell counting. As an upstream signature component of FcεRI signaling, inhibition of spleen tyrosine kinase (Syk) abrogated the IgE-induced HASM proliferation. Further analysis of IgE-induced signaling depicted an IgE-mediated activation of Erk 1/2, p38, JNK MAPK, and Akt kinases. Lastly, lentiviral-shRNA-mediated STAT3 silencing completely abolished the IgE-mediated HASM cell proliferation. Collectively, our data provide mechanisms of a novel function of IgE which may contribute, at least in part, to airway remodeling observed in allergic asthma by directly inducing HASM cell proliferation. PMID:24499258

  7. Nuclear factor-κB mediates the phenotype switching of airway smooth muscle cells in a murine asthma model

    PubMed Central

    Qiu, Chen; Zhang, Jian; Su, Meiping; Fan, Xiujun

    2015-01-01

    Airway smooth muscle cells (ASMCs) phenotype modulation, characterized by reversible switching between contractile and proliferative phenotypes, is considered to contribute to airway proliferative diseases such as allergic asthma. Nuclear Factor-κB (NF-κB) has been reported as a key regulator for the occurrence and development of asthma. However, little is known regarding its role in ASM cell phenotypic modulation. To elucidate the role of NF-κB in regulating ASM cells phenotypic modulation, we investigated the effects of NF-κB on ASM cells contractile marker protein expression, and its impact on proliferation and apoptosis. We found that chronic asthma increased the activation of NF-κB in the primary murine ASM cells with a concomitant marked decrease in the expression of contractile phenotypic marker protein including smooth muscle alpha-actin (α-SMA). Additionally, we used the normal ASM cells under different processing to build the phenotype switching when we found the activation of NF-κB. Meanwhile, the expression of α-SMA in asthma was significantly increased by the NF-κB blocker. NF-κB blocker also suppressed asthma mouse ASM cell proliferation and promoted apoptosis. These findings highlight a novel role for the NF-κB in murine ASM cell phenotypic modulation and provide a potential target for therapeutic intervention for asthma. PMID:26722396

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

    SciTech Connect

    Xu, Guang-Ni; Yang, Kai; Xu, Zu-Peng; Zhu, Liang; Hou, Li-Na; Qi, Hong; Chen, Hong-Zhuan Cui, Yong-Yao

    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.

  9. Effect of subchronic in vivo exposure to nitrogen dioxide on lung tissue inflammation, airway microvascular leakage, and in vitro bronchial muscle responsiveness in rats.

    PubMed Central

    Chitano, P; Rado, V; Di Stefano, A; Papi, A; Boniotti, A; Zancuoghi, G; Boschetto, P; Romano, M; Salmona, M; Ciaccia, A; Fabbri, L M; Mapp, C E

    1996-01-01

    OBJECTIVES: In a previous study on bronchoalveolar lavage fluid from rats exposed in vivo for seven days to 10 ppm nitrogen dioxide (NO2), it has been shown that there is an influx of macrophages into the airways. The present study investigated the effect of seven day exposure to 10 ppm NO2, on: (a) lung tissue inflammation and morphology; (b) airway microvascular leakage; (c) in vitro contractile response of main bronchi. METHODS: Lung tissue was studied by light microscopy, after fixing the lungs by inflation with 4% formalin at a pressure of 20 cm H2O. Microvascular leakage was measured by extravasation of Evans blue dye in the larynx, trachea, main bronchi, and intrapulmonary airways. Smooth muscle responsiveness was evaluated by concentration-responses curves to acetylcholine (10(-9)-10(-3) M), serotonin (10(-9)-10(-4) M), and voltage-response curves (12-28 V) to electrical field stimulation. RESULTS: Histology showed an increased total inflammation at the level of respiratory bronchioles and alveoli. No influx of inflammatory cells was found in the main bronchi. A loss of cilia in the epithelium of small airways and ectasia of alveolar capillaries was also found. By contrast, no alterations to microvascular permeability or modification of bronchial smooth muscle responsiveness was found. CONCLUSIONS: Subchronic exposure to 10 ppm NO2 causes airway inflammation and structural damage, but does not cause any persistent alteration to microvascular permeability or bronchial smooth muscle responsiveness in rats. Images Figure 1 PMID:8758032

  10. Differentiated muscles are mandatory for gas-filling of the Drosophila airway system

    PubMed Central

    Wang, Yiwen; Cruz, Tina; Irion, Uwe; Moussian, Bernard

    2015-01-01

    ABSTRACT At the end of development, organs acquire functionality, thereby ensuring autonomy of an organism when it separates from its mother or a protective egg. In insects, respiratory competence starts when the tracheal system fills with gas just before hatching of the juvenile animal. Cellular and molecular mechanisms of this process are not fully understood. Analyses of the phenotype of Drosophila embryos with malformed muscles revealed that they fail to gas-fill their tracheal system. Indeed, we show that major regulators of muscle formation like Lame duck and Blown fuse are important, while factors involved in the development of subsets of muscles including cardiac and visceral muscles are dispensable for this process, suggesting that somatic muscles (or parts of them) are essential to enable tracheal terminal differentiation. Based on our phenotypic data, we assume that somatic muscle defect severity correlates with the penetrance of the gas-filling phenotype. This argues that a limiting molecular or mechanical muscle-borne signal tunes tracheal differentiation. We think that in analogy to the function of smooth muscles in vertebrate lungs, a balance of physical forces between muscles and the elasticity of tracheal walls may be decisive for tracheal terminal differentiation in Drosophila. PMID:26621831

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

    PubMed Central

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

    2015-01-01

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

  12. Abnormal Histone Methylation is Responsible for Increased VEGF165a Secretion from Airway Smooth Muscle Cells in Asthma

    PubMed Central

    Clifford, Rachel L.; John, Alison E.; Brightling, Christopher E.; Knox, Alan J.

    2012-01-01

    Vascular Endothelial Growth Factor (VEGF), a key angiogenic molecule, is aberrantly expressed in several diseases including asthma where it contributes to bronchial vascular remodelling and chronic inflammation. Asthmatic human airway smooth muscle (HASM) cells hypersecrete VEGF but the mechanism is unclear. Here we defined the mechanism in HASM cells from non-asthmatic (NA) and asthmatic (A) patients. We found that asthmatic cells lacked a repression complex at the VEGF promoter which was present in non-asthmatic cells. Recruitment of G9A, trimethylation of histone H3 at lysine 9 (H3K9me3) and a resultant decrease in RNA polymerase II (RNA pol II) at the VEGF promoter was critical to repression of VEGF secretion in non-asthmatic cells. At the asthmatic promoter H3K9me3 was absent due to failed recruitment of G9a; RNA pol II binding, in association with TAF1, was increased, H3K4me3 was present and Sp1 binding was exaggerated and sustained. In contrast DNA methylation and histone acetylation were similar in A and NA cells. This is the first study to show that airway cells in asthma have altered epigenetic regulation of remodelling gene(s). Histone methylation at genes such as VEGF may be an important new therapeutic target. PMID:22689881

  13. [Role of bronchodilators in therapy for COPD-mechanisms of LABA and LAMA on airway smooth muscle].

    PubMed

    Kume, Hiroaki

    2016-05-01

    Long-acting β2-adrenergic receptor agonists (LABAs) and anticholinergics (LAMAs) are widely used clinically as therpy for COPD. Clinical reports have demonstrated that LABAs (salmeterol, formoterol, indacaterol, olodaterol, vilanterol) and LAMAs (tiotropium, glycopyrronium, umeclidinium, aclidinium) are useful to improving symptoms and lung function, and to reducing exacerbation and hospitarization. LABAs expect salmeterol are strong partial agonists, and LAMAs are non-specific antagonists. Ca2+ dynamics and Ca2+ sensitization contribute to relaxation of airway smooth muscle in these bronchodilators. LABAs act on orthosteric and allosteric sites on the β2-adrenergic receptors. In contrast, LAMAs act not only on orthosteric site on the muscarinic receptors, but also allosteric site on the β2-adrenergic receptors, leading to enhancing β2-adrenergic action. Allosteric GPCR modulation is involved in the synergistic effects between LABAs and LAMAs. PMID:27254952

  14. Vasoactive peptides upregulate mRNA expression and secretion of vascular endothelial growth factor in human airway smooth muscle cells.

    PubMed

    Alagappan, Vijay K T; Willems-Widyastuti, Anna; Seynhaeve, Ann L B; Garrelds, Ingrid M; ten Hagen, Timo L M; Saxena, Pramod R; Sharma, Hari S

    2007-01-01

    Airway remodeling and associated angiogenesis are documented features of asthma, of which the molecular mechanisms are not fully understood. Angiotensin (ANG)II and endothelin (ET)-1 are potent vasoconstricting circulatory hormones implicated in asthma. We investigated the effects of ANG II and ET-1 on human airway smooth muscle (ASM) cells proliferation and growth and examined the mRNA expression and release of the angiogenic peptide, vascular endothelial growth factor (VEGF). Serum deprived (48 h) human ASM cells were incubated with ANG II (100 nM) or ET-1 (10 nM) for 30 min, 1, 2, 4, 8, 16, and 24 h and the endogenous synthesis of VEGF was examined in relation to control cells receiving serum free culture medium. ET-1 induced time dependent DNA biosynthesis as determined by [3H]-thymidine incorporation assay. Using northern blot hybridization, we detected two mRNA species of 3.9 and 1.7 kb encoding VEGF in the cultured smooth muscle cells. Both ANG II and ET-1 induced the mRNA expression (two- to threefold) and secretion (1.8- to 2.8-fold) of VEGF reaching maximal levels between 4-8 h of incubation. Induced expression and release of VEGF declined after 8 h of ANG II incubation while levels remained elevated in the case of ET-1. The conditioned medium derived from ET-1-treated ASM cells induced [3H]-thymidine incorporation and cell number in porcine pulmonary artery endothelial as well as human umbilical vein endothelial cells. Moreover, the VEGF tyrosine kinase receptor inhibitor blocked the conditioned medium induced mitogenesis in endothelial cells. Our results suggest a potential role for ANG II and ET-1 in ASM cell growth and upregulation of VEGF that may participate in endothelial cell proliferation via paracrine mechanisms and thus causing pathological angiogenesis and vascular remodelling seen during asthma. PMID:17406064

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

    PubMed

    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. PMID:26215306

  16. Dilated cardiomyopathy

    MedlinePlus

    Hare JM. The dilated, restrictive, and infiltrative cardiomyopathies. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine . 9th ed. Philadelphia, PA: Elsevier Saunders; 2011:chap 68.

  17. Contractile and electrical properties of sternohyoid muscle in streptozotocin diabetic rats.

    PubMed

    McGuire, M; Dumbleton, M; MacDermott, M; Bradford, A

    2001-03-01

    1. The effects of diabetes on the electrical and contractile function of skeletal muscle are variable, depending on muscle fibre type distribution. The muscles of the upper airway have a characteristic fibre distribution that differs from previously studied muscles, but the effects of diabetes on upper airway muscle function are unknown. Normally, contraction of upper airway muscles, such as the sternohyoids, dilates and/or stabilizes the upper airway, thereby preventing its collapse. Diabetes is associated with obstructive sleep apnoea in which there is collapse of the upper airway due to failure of the upper airway musculature to maintain airway patency. Therefore, the purpose of the present study was to determine the effects of diabetes on the electrical and contractile characteristics of upper airway muscle. 2. Rats were treated with vehicle (sodium citrate buffer; pH 4.5) or with streptozotocin to induce diabetes, confirmed by the presence of hyperglycaemia, and the contractile and electrical properties of the sternohyoid were compared in these two groups. Isometric contractile properties and membrane potentials were determined in isolated sternohyoid muscles in physiological saline solution at 25 degrees C. 3. Streptozotocin had no effect on sternohyoid muscle fatigue, the tension-frequency relationship or membrane potentials, but did increase contraction time, half-relaxation time, twitch tension and tetanic tension. 4. Streptozotocin-induced diabetes has no effect on sternohyoid muscle fatigue or the tension-frequency relationship, but does reduce contractile kinetics and increases force generation. These effects are not due to changes in resting membrane potential. These data are evidence that the association of sleep apnoea and diabetes is not due to effects on upper airway muscle contractile properties. PMID:11207673

  18. Acute and chronic responses of the upper airway to inspiratory loading in healthy awake humans: an MRI study.

    PubMed

    How, Stephen C; McConnell, Alison K; Taylor, Bryan J; Romer, Lee M

    2007-08-01

    We assessed upper airway responses to acute and chronic inspiratory loading. In Experiment I, 11 healthy subjects underwent T(2)-weighted magnetic resonance imaging (MRI) of upper airway dilator muscles (genioglossus and geniohyoid) before and up to 10 min after a single bout of pressure threshold inspiratory muscle training (IMT) at 60% maximal inspiratory mouth pressure (MIP). T(2) values for genioglossus and geniohyoid were increased versus control (p<0.001), suggesting that these airway dilator muscles are activated in response to acute IMT. In Experiment II, nine subjects underwent 2D-Flash sequence MRI of the upper airway during quiet breathing and while performing single inspirations against resistive loads (10%, 30% and 50% MIP); this procedure was repeated after 6 weeks of IMT. Lateral narrowing of the upper airway occurred at all loads, whilst anteroposterior narrowing occurred at the level of the laryngopharynx at loads > or =30% MIP. Changes in upper airway morphology and narrowing after IMT were undetectable using MRI. PMID:17341450

  19. T-bet is induced by interferon-γ to mediate chemokine secretion and migration in human airway smooth muscle cells

    PubMed Central

    2011-01-01

    An inappropriate balance between T-helper (Th)1 and Th2 cytokine production underlies inflammatory changes that result in airway disease. Expression of the T-box transcription factor T-bet regulates differentiation of Th cells and production of Th1 cytokines, particularly IFNγ. T-bet-deficient mice develop airway hyperreactivity, undergo airway remodeling, and exhibit defects in IFNγ production while overproducing Th2 cytokines. T-bet is also reduced in the airways of asthmatic patients, suggesting loss of T-bet expression or activity promotes development of inflammatory airway disease. We present novel data demonstrating T-bet expression is induced in human airway smooth muscle cells (ASMC) by IFNγ. This IFNγ-stimulated expression of T-bet is dependent on signaling through JAK2 and signal transducers and activators of transcription 1 (STAT1) and activates T-bet-dependent DNA binding activity. Expression of T-bet stimulates IFNγ-stimulated IFNγ expression, secretion, and promoter activity, while inhibiting IFNγ-stimulated release of chemokines including monocyte chemoattractant protein (MCP)-1/CCL2, regulated on activation normal T-expressed and secreted (RANTES)/CCL5, and eotaxin/CCL11. This is accompanied by changes in expression of the chemokine receptors CCR3 and IL12Rβ2 and TNFα. T-bet expression also reduces chemotactic migration of ASMC in response to serum and PDGF, which contributes to airway hyperplasia. These results are the first to identify T-bet expression and activity in a structural cell of the lung and may provide new insights into therapeutic targets for inflammatory airway disease. PMID:21239533

  20. Parabronchial smooth muscle constitutes an airway epithelial stem cell niche in the mouse lung after injury.

    PubMed

    Volckaert, Thomas; Dill, Erik; Campbell, Alice; Tiozzo, Caterina; Majka, Susan; Bellusci, Saverio; De Langhe, Stijn P

    2011-11-01

    During lung development, parabronchial SMC (PSMC) progenitors in the distal mesenchyme secrete fibroblast growth factor 10 (Fgf10), which acts on distal epithelial progenitors to promote their proliferation. β-catenin signaling within PSMC progenitors is essential for their maintenance, proliferation, and expression of Fgf10. Here, we report that this Wnt/Fgf10 embryonic signaling cascade is reactivated in mature PSMCs after naphthalene-induced injury to airway epithelium. Furthermore, we found that this paracrine Fgf10 action was essential for activating surviving variant Clara cells (the cells in the airway epithelium from which replacement epithelial cells originate) located at the bronchoalveolar duct junctions and adjacent to neuroendocrine bodies. After naphthalene injury, PSMCs secreted Fgf10 to activate Notch signaling and induce Snai1 expression in surviving variant Clara cells, which subsequently underwent a transient epithelial to mesenchymal transition to initiate the repair process. Epithelial Snai1 expression was important for regeneration after injury. We have therefore identified PSMCs as a stem cell niche for the variant Clara cells in the lung and established that paracrine Fgf10 signaling from the niche is critical for epithelial repair after naphthalene injury. These findings also have implications for understanding the misregulation of lung repair in asthma and cancer. PMID:21985786

  1. Airway occlusion pressure and diaphragm global electromyogram analysis for evaluation of inspiratory muscle drive and neuromechanical coupling in cattle.

    PubMed

    Desmecht, D J; Linden, A S; Rollin, F A; Lekeux, P M

    1994-06-01

    Although healthy and diseased bovine respiratory tracts have been intensively studied during the last years, to the authors' knowledge, there have been no attempts to objectively examine the inspiratory drive from the brain to the nerves and muscles and its transformation in pressure. Such technique would be useful in assessing the possibility of altered ventilatory drive or inspiratory muscle fatigue in the context of an animal with ventilatory failure. The relation among ventilation, airway opening occlusion pressure generated 100 milliseconds after onset of inspiration (Pawo100ms) and 6 indexes describing diaphragmatic electromyographic activity (EMGdi) recorded via implanted fishhooks was evaluated during free and impeded CO2 rebreathing in 6 young bulls. The best significant linear correlations (r > 0.8) with inspiratory center afferent stimulation, as judged by end-tidal CO2 concentration in expired air, were found for Pawo100ms, peak moving time average or variance EMGdi, and mean integrated EMGdi, whatever had been the respiratory impedance. However, with an inspiratory load, Pawo100ms responses systematically had greater increase for a given change in the driving EMGdi, implying dependence of the former not only on neural input, but also on configurational factors that determine inspiratory muscle excitation-pressure generation couplings. The reproducibility of EMGdi absolute values and changes was satisfactory up to 10 hours, but could not be repeated from one day to the other. It was concluded that, provided the constancy of the electrical coupling of the recording system to the tissue being studied is ensured, specific EMGdi and Pawo100ms values correlate reliably with amount of CO2 during free and loaded breathing.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7944009

  2. L-thyroxine promotes a proliferative airway smooth muscle phenotype in the presence of TGF-β1.

    PubMed

    Dekkers, Bart G J; Naeimi, Saeideh; Bos, I Sophie T; Menzen, Mark H; Halayko, Andrew J; Hashjin, Goudarz Sadeghi; Meurs, Herman

    2015-02-01

    Hypothyroidism may reduce, whereas hyperthyroidism may aggravate, asthma symptoms. The mechanisms underlying this relationship are largely unknown. Since thyroid hormones have central roles in cell growth and differentiation, we hypothesized that airway remodeling, in particular increased airway smooth muscle (ASM) mass, may be involved. To address this hypothesis, we investigated the effects of triiodothyronine (T3) and l-thyroxine (T4) in the absence and presence of the profibrotic transforming growth factor (TGF)-β1 on human ASM cell phenotype switching. T3 (1-100 nM) and T4 (1-100 nM) did not affect basal ASM proliferation. However, when combined with TGF-β1 (2 ng/ml), T4 synergistically increased the proliferative response, whereas only a minor effect was observed for T3. In line with a switch from a contractile to a proliferative ASM phenotype, T4 reduced the TGF-β1-induced contractile protein expression by ∼50%. Cotreatment with T3 reduced TGF-β1-induced contractile protein expression by ∼25%. The synergistic increase in proliferation was almost fully inhibited by the integrin αvβ3 antagonist tetrac (100 nM), whereas no significant effects of the thyroid receptor antagonist 1-850 (3 μM) were observed. Inhibition of MEK1/2, downstream of the integrin αvβ3, also inhibited the T4- and TGF-β1-induced proliferative responses. Collectively, the results indicate that T4, and to a lesser extent T3, promotes a proliferative ASM phenotype in the presence of TGF-β1, which is predominantly mediated by the membrane-bound T4 receptor αvβ3. These results indicate that thyroid hormones may enhance ASM remodeling in asthma, which could be of relevance for hyperthyroid patients with this disease. PMID:25480330

  3. BET Bromodomains Regulate Transforming Growth Factor-β-induced Proliferation and Cytokine Release in Asthmatic Airway Smooth Muscle*

    PubMed Central

    Perry, Mark M.; Durham, Andrew L.; Austin, Philip J.; Adcock, Ian M.; Chung, Kian Fan

    2015-01-01

    Airway smooth muscle (ASM) mass is increased in asthma, and ASM cells from patients with asthma are hyperproliferative and release more IL-6 and CXCL8. The BET (bromo- and extra-terminal) family of proteins (Brd2, Brd3, and Brd4) govern the assembly of histone acetylation-dependent chromatin complexes. We have examined whether they modulate proliferation and cytokine expression in asthmatic ASM cells by studying the effect of BET bromodomain mimics JQ1/SGCBD01 and I-BET762. ASM cells from healthy individuals and nonsevere and severe asthmatics were pretreated with JQ1/SGCBD01 and I-BET762 prior to stimulation with FCS and TGF-β. Proliferation was measured by BrdU incorporation. IL-6 and CXCL8 release was measured by ELISA, and mRNA expression was measured by quantitative RT-PCR. ChIP using a specific anti-Brd4 antibody and PCR primers directed against the transcriptional start site of IL-6 and CXCL8 gene promoters was performed. Neither JQ1/SGCBD01 nor I-BET762 had any effect on ASM cell viability. JQ1/SGCBD01 and I-BET762 inhibited FCS+TGF-β-induced ASM cell proliferation and IL-6 and CXCL8 release in healthy individuals (≥ 30 nm) and in nonsevere and severe asthma patients (≥100 nm), with the latter requiring higher concentrations of these mimics. JQ1/SGCBD01 reduced Brd4 binding to IL8 and IL6 promoters induced by FCS+TGF-β. Mimics of BET bromodomains inhibit aberrant ASM cell proliferation and inflammation with lesser efficiency in those from asthmatic patients. They may be effective in reducing airway remodeling in asthma. PMID:25697361

  4. A new nitrosyl ruthenium complex nitric oxide donor presents higher efficacy than sodium nitroprusside on relaxation of airway smooth muscle.

    PubMed

    Castro, Patrícia F S; Pereira, Amanda de C; Rogrigues, Gerson J; Batista, Aline C; da Silva, Roberto S; Bendhack, Lusiane M; Rocha, Matheus L

    2011-08-17

    Nitric oxide (NO) has been demonstrated to be the primary agent in relaxing airways in humans and animals. We investigated the mechanisms involved in the relaxation induced by NO-donors, ruthenium complex [Ru(terpy)(bdq)NO(+)](3+) (TERPY) and sodium nitroprusside (SNP) in isolated trachea of rats contracted with carbachol in an isolated organs chamber. For instance, we verified the contribution of K(+) channels, the importance of sGC/cGMP pathway, the influence of the extra and intracellular Ca(2+) sources and the contribution of the epithelium on the relaxing response. Additionally, we have used confocal microscopy in order to analyze the action of the NO-donors on cytosolic Ca(2+) concentration. The results demonstrated that both compounds led to the relaxation of trachea in a dependent-concentration way. However, the maximum effect (E(max)) of TERPY is higher than the SNP. The relaxation induced by SNP (but not TERPY) was significantly reduced by pretreatment with ODQ (sGC inhibitor). Only TERPY-induced relaxation was reduced by tetraethylammonium (K(+) channels blocker) and by pre-contraction with 75mM KCl (membrane depolarization). The response to both NO-donors was not altered by the presence of thapsigargin (sarcoplasmic reticulum Ca(2+)-ATPase inhibitor). The epithelium removal has reduced the relaxation only to SNP, and it has no effect on TERPY. The both NO-donors reduced the contraction evoked by Ca(2+) influx, while TERPY have shown a higher inhibitory effect on contraction. Moreover, the TERPY was more effective than SNP in reducing the cytosolic Ca(2+) concentration measured by confocal microscopy. In conclusion, these results show that TERPY induces airway smooth muscle relaxation by cGMP-independent mechanisms, it involves the fluxes of Ca(2+) and K(+) across the membrane, it is more effective in reducing cytosolic Ca(2+) concentration and inducing relaxation in the rat trachea than the standard drug, SNP. PMID:21605670

  5. The Role of Inflammation Resolution Speed in Airway Smooth Muscle Mass Accumulation in Asthma: Insight from a Theoretical Model

    PubMed Central

    Chernyavsky, Igor L.; Croisier, Huguette; Chapman, Lloyd A. C.; Kimpton, Laura S.; Hiorns, Jonathan E.; Brook, Bindi S.; Jensen, Oliver E.; Billington, Charlotte K.; Hall, Ian P.; Johnson, Simon R.

    2014-01-01

    Despite a large amount of in vitro data, the dynamics of airway smooth muscle (ASM) mass increase in the airways of patients with asthma is not well understood. Here, we present a novel mathematical model that describes qualitatively the growth dynamics of ASM cells over short and long terms in the normal and inflammatory environments typically observed in asthma. The degree of ASM accumulation can be explained by an increase in the rate at which ASM cells switch between non-proliferative and proliferative states, driven by episodic inflammatory events. Our model explores the idea that remodelling due to ASM hyperplasia increases with the frequency and magnitude of these inflammatory events, relative to certain sensitivity thresholds. It highlights the importance of inflammation resolution speed by showing that when resolution is slow, even a series of small exacerbation events can result in significant remodelling, which persists after the inflammatory episodes. In addition, we demonstrate how the uncertainty in long-term outcome may be quantified and used to design an optimal low-risk individual anti-proliferative treatment strategy. The model shows that the rate of clearance of ASM proliferation and recruitment factors after an acute inflammatory event is a potentially important, and hitherto unrecognised, target for anti-remodelling therapy in asthma. It also suggests new ways of quantifying inflammation severity that could improve prediction of the extent of ASM accumulation. This ASM growth model should prove useful for designing new experiments or as a building block of more detailed multi-cellular tissue-level models. PMID:24632688

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

    PubMed Central

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

    2015-01-01

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

  7. Effects of sustained hypoxia on sternohyoid and diaphragm muscle during development.

    PubMed

    Carberry, Jayne C; McMorrow, Clodagh; Bradford, Aidan; Jones, James F X; O'Halloran, Ken D

    2014-04-01

    Sustained hypoxia is a dominant feature of respiratory disease. Despite the clinical significance, the effects of sustained hypoxia on the form and function of respiratory muscle during development are relatively underexplored. Wistar rats were exposed to 1 week of sustained hypoxia (ambient pressure 450 mmHg) or normoxia at various time points during development. Sternohyoid and diaphragm muscle contractile and endurance properties were assessed in vitro. Muscle succinate dehydrogenase and myosin heavy chain composition were determined. The role of reactive oxygen species in hypoxia-induced muscle remodelling was assessed. Sustained hypoxia increased sternohyoid muscle force and fatigue in early but not late development, effects that persisted after return to normoxia. Hypoxia-induced sternohyoid muscle fatigue was not attributable to fibre type transitions or to a decrease in oxidative capacity. Chronic supplementation with the superoxide scavenger tempol did not prevent hypoxia-induced sternohyoid muscle fatigue, suggesting that mechanisms unrelated to oxidative stress underpin hypoxia-induced maladaptation in sternohyoid muscle. Sustained hypoxia had no effect on diaphragm muscle fatigue. We conclude that there are critical windows during development for hypoxia-induced airway dilator muscle maladaptation. Sustained hypoxia-induced impairment of upper airway muscle endurance may persist into later life. Upper airway muscle dysfunction could have deleterious consequences for the control of pharyngeal airway calibre in vivo. PMID:23766332

  8. A mannose receptor mediates mannosyl-rich glycoprotein-induced mitogenesis in bovine airway smooth muscle cells.

    PubMed Central

    Lew, D B; Songu-Mize, E; Pontow, S E; Stahl, P D; Rattazzi, M C

    1994-01-01

    The putative mannose receptor (MR), previously implicated in mannosyl-rich glycoprotein-induced mitogenesis in bovine airway smooth muscle (ASM) cells, was studied to determine its properties. Specific binding of the mitogenic neoglycoprotein, mannosylated bovine serum albumin (Man-BSA) to ASM cells was saturable, with an apparent Kd = 5.0 x 10(-8) M. Cell-bound ManBSA-colloidal gold conjugate was localized by electron microscopy to clathrin-coated pits on the cell surface, and was found to undergo internalization to endosomes; this was inhibitable by weak bases and swainsonine, that also inhibited ligand-induced mitogenesis. The ASM-MR, isolated by mannose-affinity chromatography, had the same apparent molecular mass as the macrophage (Mø) MR (M(r) = 175 kD), and was immunoprecipitated by an anti-MøMR immune serum. This antiserum blocked 125I-labeled-ManBSA binding to intact ASM cells, stimulated mitogenesis, and immunolocalized the ASM-MR in cytoplasmic vesicles compatible with endosomes. A monoclonal antibody directed against the MøMR also reacted with the ASM-MR; like the polyclonal antibodies, it stimulated mitogenesis as effectively as beta-hexosaminidases. These data indicate that the ASM-MR shares a number of functional and structural properties with the MøMR and suggest that similar receptors may have different main functions in different cells. Images PMID:7962531

  9. Nanotubes connect CD4+ T cells to airway smooth muscle cells: novel mechanism of T cell survival.

    PubMed

    Al Heialy, Saba; Zeroual, Melissa; Farahnak, Soroor; McGovern, Toby; Risse, Paul-André; Novali, Mauro; Lauzon, Anne-Marie; Roman, Horia N; Martin, James G

    2015-06-15

    Contact between airway smooth muscle (ASM) cells and activated CD4(+) T cells, a key interaction in diseases such as asthma, triggers ASM cell proliferation and enhances T cell survival. We hypothesized that direct contact between ASM and CD4(+) T cells facilitated the transfer of anti-apoptotic proteins via nanotubes, resulting in increased survival of activated CD4(+) T cells. CD4(+) T cells, isolated from PBMCs of healthy subjects, when activated and cocultured with ASM cells for 24 h, formed nanotubes that were visualized by immunofluorescence and atomic force microscopy. Cell-to-cell transfer of the fluorescent dye calcein-AM confirmed cytoplasmic communication via nanotubes. Immunoreactive B cell lymphoma 2 (Bcl-2) and induced myeloid leukemia cell differentiation protein (Mcl-1), two major anti-apoptotic proteins, were present within the nanotubes. Downregulation of Mcl-1 by small interfering RNA in ASM cells significantly increased T cell apoptosis, whereas downregulation of Bcl-2 had no effect. Transfer of GFP-tagged Mcl-1 from ASM cells to CD4(+) T cells via the nanotubes confirmed directionality of transfer. In conclusion, activated T cells communicate with ASM cells via nanotube formation. Direct transfer of Mcl-1 from ASM to CD(+) T cells via nanotubes is involved in T cell survival. This study provides a novel mechanism of survival of CD4(+) T cells that is dependent on interaction with a structural cell. PMID:25934863

  10. Selective targeting of the α5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling

    PubMed Central

    Yocum, Gene T.; Siviski, Matthew E.; Yim, Peter D.; Fu, Xiao Wen; Poe, Michael M.; Cook, James M.; Harrison, Neil; Perez-Zoghbi, Jose; Emala, Charles W.

    2015-01-01

    The clinical need for novel bronchodilators for the treatment of bronchoconstrictive diseases remains a major medical issue. Modulation of airway smooth muscle (ASM) chloride via GABAA receptor activation to achieve relaxation of precontracted ASM represents a potentially beneficial therapeutic option. Since human ASM GABAA receptors express only the α4- and α5-subunits, there is an opportunity to selectively target ASM GABAA receptors to improve drug efficacy and minimize side effects. Recently, a novel compound (R)-ethyl8-ethynyl-6-(2-fluorophenyl)-4-methyl-4H-benzo[f]imidazo[1,5-a][1,4] diazepine-3-carboxylate (SH-053-2′F-R-CH3) with allosteric selectivity for α5-subunit containing GABAA receptors has become available. We questioned whether this novel GABAA α5-selective ligand relaxes ASM and affects intracellular calcium concentration ([Ca2+]i) regulation. Immunohistochemical staining localized the GABAA α5-subunit to human ASM. The selective GABAA α5 ligand SH-053-2′F-R-CH3 relaxes precontracted intact ASM; increases GABA-activated chloride currents in human ASM cells in voltage-clamp electrophysiology studies; and attenuates bradykinin-induced increases in [Ca2+]i, store-operated Ca2+ entry, and methacholine-induced Ca2+ oscillations in peripheral murine lung slices. In conclusion, selective subunit targeting of endogenous α5-subunit containing GABAA receptors on ASM may represent a novel therapeutic option to treat severe bronchospasm. PMID:25659897

  11. Selective targeting of the α5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling.

    PubMed

    Gallos, George; Yocum, Gene T; Siviski, Matthew E; Yim, Peter D; Fu, Xiao Wen; Poe, Michael M; Cook, James M; Harrison, Neil; Perez-Zoghbi, Jose; Emala, Charles W

    2015-05-01

    The clinical need for novel bronchodilators for the treatment of bronchoconstrictive diseases remains a major medical issue. Modulation of airway smooth muscle (ASM) chloride via GABAA receptor activation to achieve relaxation of precontracted ASM represents a potentially beneficial therapeutic option. Since human ASM GABAA receptors express only the α4- and α5-subunits, there is an opportunity to selectively target ASM GABAA receptors to improve drug efficacy and minimize side effects. Recently, a novel compound (R)-ethyl8-ethynyl-6-(2-fluorophenyl)-4-methyl-4H-benzo[f]imidazo[1,5-a][1,4] diazepine-3-carboxylate (SH-053-2'F-R-CH3) with allosteric selectivity for α5-subunit containing GABAA receptors has become available. We questioned whether this novel GABAA α5-selective ligand relaxes ASM and affects intracellular calcium concentration ([Ca(2+)]i) regulation. Immunohistochemical staining localized the GABAA α5-subunit to human ASM. The selective GABAA α5 ligand SH-053-2'F-R-CH3 relaxes precontracted intact ASM; increases GABA-activated chloride currents in human ASM cells in voltage-clamp electrophysiology studies; and attenuates bradykinin-induced increases in [Ca(2+)]i, store-operated Ca(2+) entry, and methacholine-induced Ca(2+) oscillations in peripheral murine lung slices. In conclusion, selective subunit targeting of endogenous α5-subunit containing GABAA receptors on ASM may represent a novel therapeutic option to treat severe bronchospasm. PMID:25659897

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

    SciTech Connect

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

    2011-10-07

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

  13. A New Approach for the Study of Lung Smooth Muscle Phenotypes and Its Application in a Murine Model of Allergic Airway Inflammation

    PubMed Central

    Paez-Cortez, Jesus; Krishnan, Ramaswamy; Arno, Anneliese; Aven, Linh; Ram-Mohan, Sumati; Patel, Kruti R.; Lu, Jining; King, Oliver D.; Ai, Xingbin; Fine, Alan

    2013-01-01

    Phenotypes of lung smooth muscle cells in health and disease are poorly characterized. This is due, in part, to a lack of methodologies that allow for the independent and direct isolation of bronchial smooth muscle cells (BSMCs) and vascular smooth muscle cells (VSMCs) from the lung. In this paper, we describe the development of a bi-fluorescent mouse that permits purification of these two cell populations by cell sorting. By subjecting this mouse to an acute allergen based-model of airway inflammation that exhibits many features of asthma, we utilized this tool to characterize the phenotype of so-called asthmatic BSMCs. First, we examined the biophysical properties of single BSMCs from allergen sensitized mice and found increases in basal tone and cell size that were sustained ex vivo. We then generated for the first time, a comprehensive characterization of the global gene expression changes in BSMCs isolated from the bi-fluorescent mice with allergic airway inflammation. Using statistical methods and pathway analysis, we identified a number of differentially expressed mRNAs in BSMCs from allergen sensitized mice that code for key candidate proteins underlying changes in matrix formation, contractility, and immune responses. Ultimately, this tool will provide direction and guidance for the logical development of new markers and approaches for studying human lung smooth muscle. PMID:24040256

  14. Effects of age on muscarinic agonist-induced contraction an IP accumulation in airway smooth muscle

    SciTech Connect

    Wills-Karp, M. )

    1991-01-01

    The effects of age on carbachol-stimulated force development and ({sup 3}H)inositol phosphate production was studied in tracheal rings from guinea pigs aged 1 month and 25 months of age. The pD{sub 2} for the contractile response to carbachol was significantly reduced in tracheal tissues from old animals as compared to that of the young tissues, respectively. In contrast, inositol phosphate formation was not altered with increasing age when stimulated by carbachol or NaF, a direct activator of G proteins. Carbachol-induced inositol phosphate accumulation was inhibited by treatment with 1{mu}g/ml pertussis toxin, suggesting that IP1 accumulation is coupled to a pertussis-toxin-sensitive protein. The pD{sub 2} values for contraction were significantly different from the pD{sub 2} values for IP1 accumulation, in both young and old tissues, respectively. These data suggest that IP1 accumulation is not responsible for the decreased contractile ability in tracheal smooth muscle during aging.

  15. The Dilated Cardiomyopathy-Causing Mutation ACTC E361G in Cardiac Muscle Myofibrils Specifically Abolishes Modulation of Ca2+ Regulation by Phosphorylation of Troponin I

    PubMed Central

    Vikhorev, Petr G.; Song, Weihua; Wilkinson, Ross; Copeland, O’Neal; Messer, Andrew E.; Ferenczi, Michael A.; Marston, Steven B.

    2014-01-01

    Phosphorylation of troponin I by protein kinase A (PKA) reduces Ca2+ sensitivity and increases the rate of Ca2+ release from troponin C and the rate of relaxation in cardiac muscle. In vitro experiments indicate that mutations that cause dilated cardiomyopathy (DCM) uncouple this modulation, but this has not been demonstrated in an intact contractile system. Using a Ca2+-jump protocol, we measured the effect of the DCM-causing mutation ACTC E361G on the equilibrium and kinetic parameters of Ca2+ regulation of contractility in single transgenic mouse heart myofibrils. We used propranolol treatment of mice to reduce the level of troponin I and myosin binding protein C (MyBP-C) phosphorylation in their hearts before isolating the myofibrils. In nontransgenic mouse myofibrils, the Ca2+ sensitivity of force was increased, the fast relaxation phase rate constant, kREL, was reduced, and the length of the slow linear phase, tLIN, was increased when the troponin I phosphorylation level was reduced from 1.02 to 0.3 molPi/TnI (EC50 P/unP = 1.8 ± 0.2, p < 0.001). Native myofibrils from ACTC E361G transgenic mice had a 2.4-fold higher Ca2+ sensitivity than nontransgenic mouse myofibrils. Strikingly, the Ca2+ sensitivity and relaxation parameters of ACTC E361G myofibrils did not depend on the troponin I phosphorylation level (EC50 P/unP = 0.88 ± 0.17, p = 0.39). Nevertheless, modulation of the Ca2+ sensitivity of ACTC E361G myofibrils by sarcomere length or EMD57033 was indistinguishable from that of nontransgenic myofibrils. Overall, EC50 measured in different conditions varied over a 7-fold range. The time course of relaxation, as defined by tLIN and kREL, was correlated with EC50 but varied by just 2.7- and 3.3-fold, respectively. Our results confirm that troponin I phosphorylation specifically alters the Ca2+ sensitivity of isometric tension and the time course of relaxation in cardiac muscle myofibrils. Moreover, the DCM-causing mutation ACTC E361G blunts this

  16. Bronchodilator and anti-inflammatory activities of glaucine: In vitro studies in human airway smooth muscle and polymorphonuclear leukocytes.

    PubMed

    Cortijo, J; Villagrasa, V; Pons, R; Berto, L; Martí-Cabrera, M; Martinez-Losa, M; Domenech, T; Beleta, J; Morcillo, E J

    1999-08-01

    1. Selective phosphodiesterase 4 (PDE4) inhibitors are of potential interest in the treatment of asthma. We examined the effects of the alkaloid S-(+)-glaucine, a PDE4 inhibitor, on human isolated bronchus and granulocyte function. 2. Glaucine selectively inhibited PDE4 from human bronchus and polymorphonuclear leukocytes (PMN) in a non-competitive manner (Ki=3.4 microM). Glaucine displaced [3H]-rolipram from its high-affinity binding sites in rat brain cortex membranes (IC50 approximately 100 microM). 3. Glaucine inhibited the spontaneous and histamine-induced tone in human isolated bronchus (pD2 approximately 4.5). Glaucine (10 microM) did not potentiate the isoprenaline-induced relaxation but augmented cyclic AMP accumulation by isoprenaline. The glaucine-induced relaxation was resistant to H-89, a protein kinase A inhibitor. Glaucine depressed the contractile responses to Ca2+ (pD'2 approximately 3.62) and reduced the sustained rise of [Ca2+]i produced by histamine in cultured human airway smooth muscle cells (-log IC50 approximately 4.3). 4. Glaucine augmented cyclic AMP levels in human polymorphonuclear leukocytes challenged with N-formyl-Met-Leu-Phe (FMLP) or isoprenaline, and inhibited FMLP-induced superoxide generation, elastase release, leukotriene B4 production, [Ca2+]i signal and platelet aggregation as well as opsonized zymosan-, phorbol myristate acetate-, and A23187-induced superoxide release. The inhibitory effect of glaucine on superoxide generation by FMLP was reduced by H-89. 5. In conclusion, Ca2+ channel antagonism by glaucine appears mainly responsible for the relaxant effect of glaucine in human isolated bronchus while PDE4 inhibition contributes to the inhibitory effects of glaucine in human granulocytes. The very low PDE4/binding site ratio found for glaucine makes this compound attractive for further structure-activity studies. PMID:10455321

  17. Bronchodilator and anti-inflammatory activities of glaucine: In vitro studies in human airway smooth muscle and polymorphonuclear leukocytes

    PubMed Central

    Cortijo, J; Villagrasa, V; Pons, R; Berto, L; Martí-Cabrera, M; Martinez-Losa, M; Domenech, T; Beleta, J; Morcillo, E J

    1999-01-01

    Selective phosphodiesterase 4 (PDE4) inhibitors are of potential interest in the treatment of asthma. We examined the effects of the alkaloid S-(+)-glaucine, a PDE4 inhibitor, on human isolated bronchus and granulocyte function.Glaucine selectively inhibited PDE4 from human bronchus and polymorphonuclear leukocytes (PMN) in a non-competitive manner (Ki=3.4 μM). Glaucine displaced [3H]-rolipram from its high-affinity binding sites in rat brain cortex membranes (IC50∼100 μM).Glaucine inhibited the spontaneous and histamine-induced tone in human isolated bronchus (pD2∼4.5). Glaucine (10 μM) did not potentiate the isoprenaline-induced relaxation but augmented cyclic AMP accumulation by isoprenaline. The glaucine-induced relaxation was resistant to H-89, a protein kinase A inhibitor. Glaucine depressed the contractile responses to Ca2+ (pD'2∼3.62) and reduced the sustained rise of [Ca2+]i produced by histamine in cultured human airway smooth muscle cells (−log IC50∼4.3).Glaucine augmented cyclic AMP levels in human polymorphonuclear leukocytes challenged with N-formyl-Met-Leu-Phe (FMLP) or isoprenaline, and inhibited FMLP-induced superoxide generation, elastase release, leukotriene B4 production, [Ca2+]i signal and platelet aggregation as well as opsonized zymosan-, phorbol myristate acetate-, and A23187-induced superoxide release. The inhibitory effect of glaucine on superoxide generation by FMLP was reduced by H-89.In conclusion, Ca2+ channel antagonism by glaucine appears mainly responsible for the relaxant effect of glaucine in human isolated bronchus while PDE4 inhibition contributes to the inhibitory effects of glaucine in human granulocytes. The very low PDE4/binding site ratio found for glaucine makes this compound attractive for further structure-activity studies. PMID:10455321

  18. Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction.

    PubMed

    Yocum, Gene T; Gallos, George; Zhang, Yi; Jahan, Rajwana; Stephen, Michael Rajesh; Varagic, Zdravko; Puthenkalam, Roshan; Ernst, Margot; Cook, James M; Emala, Charles W

    2016-04-01

    We previously demonstrated that airway smooth muscle (ASM) cells express γ-aminobutyric acid A receptors (GABAARs), and that GABAAR agonists acutely relax ASM. Among the GABAAR α subunits, human ASM cells express only α4 and α5, providing the opportunity for selective pharmacologic targeting. Novel GABAAR-positive allosteric modulators designed for enhanced α4/α6 subunit selectivity were synthesized using iterative computational analyses (CMD-45 and XHe-III-74). Studies using oocyte heterologous expression systems confirmed that CMD-45 and XHe-III-74 led to significantly greater augmentation of currents induced by a 3% maximal effective concentration (EC3) of GABA [EC3]-induced currents in oocytes expressing α4 or α6 subunits (along with β3 and γ2) compared with other α subunits. CMD-45 and XHe-III-74 also led to greater ex vivo relaxation of contracted wild-type mouse tracheal rings compared with tracheal rings from GABAAR α4 subunit (Gabra4) knockout mice. Furthermore, CMD-45 and XHe-III-74 significantly relaxed precontracted human ASM ex vivo, and, at a low concentration, both ligands led to a significant leftward shift in albuterol-mediated ASM relaxation. In vivo, inhaled XHe-III-74 reduced respiratory system resistance in an asthmatic mouse model. Pretreatment of human ASM cells with CMD-45 and XHe-III-74 inhibited histamine-induced increases in intracellular calcium concentrations in vitro, an effect that was lost when calcium was omitted from the extracellular buffer, suggesting that inhibition of calcium influx due to alterations in plasma membrane potential may play a role in the mechanism of ASM relaxation. Selective targeting of the GABAAR α4 subunit with inhaled ligands may be a novel therapeutic pathway to treat bronchoconstriction, while avoiding sedative central nervous system effects, which are largely mediated by α1-3 subunit-containing GABAARs in the brain. PMID:26405827

  19. Dilation of the oropharynx via selective stimulation of the hypoglossal nerve

    NASA Astrophysics Data System (ADS)

    Huang, Jingtao; Sahin, Mesut; Durand, Dominique M.

    2005-12-01

    The functional effects of selective hypoglossal nerve (HG) stimulation with a multi-contact peripheral nerve electrode were assessed using images of the upper airways and the tongue in anesthetized beagles. A biphasic pulse train of 50 Hz frequency and 2 s duration was applied through each one of the tripolar contact sets of the nerve electrode while the pharyngeal images were acquired into a computer. The stimulation current was limited to 20% above the activation threshold for maximum selectivity. The images showed that various contact sets could generate several different activation patterns of the tongue muscles resulting in medial and/or lateral dilation and closing of the airways at the tongue root. Some of these patterns translated into an increase in the oropharyngeal size while others did not have any effect. The pharyngeal sizes were not statistically different during stimulation either between the two different positions of the head (30° and 60°), or when the lateral contacts were compared with the medial ones. The contacts that had the least effect generated an average of 53 ± 15% pharyngeal dilation relative to the best contacts, indicating that the results are marginally sensitive to the contact position around the HG nerve trunk. These results suggest that selective HG nerve stimulation can be a useful technique to produce multiple tongue activation patterns that can dilate the pharynx. This may in turn increase the size of the patient population who can benefit from HG nerve stimulation as a treatment method for obstructive sleep apnea.

  20. Dilation of the oropharynx via selective stimulation of the hypoglossal nerve.

    PubMed

    Huang, Jingtao; Sahin, Mesut; Durand, Dominique M

    2005-12-01

    The functional effects of selective hypoglossal nerve (HG) stimulation with a multi-contact peripheral nerve electrode were assessed using images of the upper airways and the tongue in anesthetized beagles. A biphasic pulse train of 50 Hz frequency and 2 s duration was applied through each one of the tripolar contact sets of the nerve electrode while the pharyngeal images were acquired into a computer. The stimulation current was limited to 20% above the activation threshold for maximum selectivity. The images showed that various contact sets could generate several different activation patterns of the tongue muscles resulting in medial and/or lateral dilation and closing of the airways at the tongue root. Some of these patterns translated into an increase in the oropharyngeal size while others did not have any effect. The pharyngeal sizes were not statistically different during stimulation either between the two different positions of the head (30 degrees and 60 degrees), or when the lateral contacts were compared with the medial ones. The contacts that had the least effect generated an average of 53 +/- 15% pharyngeal dilation relative to the best contacts, indicating that the results are marginally sensitive to the contact position around the HG nerve trunk. These results suggest that selective HG nerve stimulation can be a useful technique to produce multiple tongue activation patterns that can dilate the pharynx. This may in turn increase the size of the patient population who can benefit from HG nerve stimulation as a treatment method for obstructive sleep apnea. PMID:16317230

  1. Snoring-Induced Nerve Lesions in the Upper Airway

    PubMed Central

    Poothrikovil, Rajesh P; Al Abri, Mohammed A

    2012-01-01

    The prevalence of habitual snoring is extremely high in the general population, and is reported to be roughly 40% in men and 20% in women. The low-frequency vibrations of snoring may cause physical trauma and, more specifically, peripheral nerve injuries, just as jobs which require workers to use vibrating tools over the course of many years result in local nerve lesions in the hands. Histopathological analysis of upper airway (UA) muscles have shown strong evidence of a varying severity of neurological lesions in groups of snoring patients. Neurophysiological assessment shows evidence of active and chronic denervation and re-innervation in the palatopharyngeal muscles of obstructive sleep apnoea (OSA) patients. Neurogenic lesions of UA muscles induced by vibration trauma impair the reflex dilation abilities of the UA, leading to an increase in the possibility of UA collapse. The neurological factors which are partly responsible for the progressive nature of OSAS warrant the necessity of early assessment in habitual snorers. PMID:22548134

  2. Calcineurin/Nuclear Factor of Activated T Cells–Coupled Vanilliod Transient Receptor Potential Channel 4 Ca2+ Sparklets Stimulate Airway Smooth Muscle Cell Proliferation

    PubMed Central

    Zhao, Limin; Sullivan, Michelle N.; Chase, Marlee; Gonzales, Albert L.

    2014-01-01

    Proliferation of airway smooth muscle cells (ASMCs) contributes to the remodeling and irreversible obstruction of airways during severe asthma, but the mechanisms underlying this disease process are poorly understood. Here we tested the hypothesis that Ca2+ influx through the vanilliod transient receptor potential channel (TRPV) 4 stimulates ASMC proliferation. We found that synthetic and endogenous TRPV4 agonists increase proliferation of primary ASMCs. Furthermore, we demonstrate that Ca2+ influx through individual TRPV4 channels produces Ca2+ microdomains in ASMCs, called “TRPV4 Ca2+ sparklets.” We also show that TRPV4 channels colocalize with the Ca2+/calmodulin–dependent protein phosphatase calcineurin in ASMCs. Activated calcineurin dephosphorylates nuclear factor of activated T cells (NFAT) transcription factors cytosolic (c) to allow nuclear translocation and activation of synthetic transcriptional pathways. We show that ASMC proliferation in response to TRPV4 activity is associated with calcineurin-dependent nuclear translocation of the NFATc3 isoform tagged with green florescent protein. Our findings suggest that Ca2+ microdomains created by TRPV4 Ca2+ sparklets activate calcineurin to stimulate nuclear translocation of NFAT and ASMC proliferation. These findings further suggest that inhibition of TRPV4 could diminish asthma-induced airway remodeling. PMID:24392954

  3. Effect of the plant derivative Compound A on the production of corticosteroid-resistant chemokines in airway smooth muscle cells.

    PubMed

    Gavrila, Adelina; Chachi, Latifa; Tliba, Omar; Brightling, Christopher; Amrani, Yassine

    2015-11-01

    Preclinical models of human conditions including asthma showed the therapeutic potential of Compound A (CpdA), a dissociated glucocorticoid (GC) receptor (GRα) ligand. Whether CpdA inhibits GC resistance, a central feature of severe asthma, has not been addressed. We investigated whether CpdA modulates cytokine-induced GC resistance in human airway smooth muscle (ASM) cells. Healthy and asthmatic ASM cells were treated with TNF-α/IFN-γ for 24 hours in the presence or absence of CpdA. ELISA and quantitative PCR assays were used to assess the effect of CpdA on chemokine expression. Activation of GRα by CpdA was assessed by quantitative PCR, immunostaining, and receptor antagonism using RU486. An effect of CpdA on the transcription factor interferon regulatory factor 1 (IRF-1) was investigated using immunoblot, immunostaining, and small interfering RNA (siRNA) knockdown. CpdA inhibited production of fluticasone-resistant chemokines CCL5, CX3CL1, and CXCL10 at protein and mRNA levels in both asthmatic and healthy cells. CpdA failed to induce expression of GC-induced Leucine Zipper while transiently inducing mitogen-activated protein kinase phosphatase 1 (MKP-1) at both mRNA and protein levels. CpdA inhibitory action was not associated with GRα nuclear translocation, nor was it prevented by RU486 antagonism. Activation of IRF-1 by TNF-α/IFN-γ was inhibited by CpdA. IRF-1 siRNA knockdown reduced cytokine-induced CCL5 and CX3CL1 production. siRNA MKP-1 prevented the inhibitory effect of CpdA on cytokine-induced CXCL10 production. For the first time, we show that CpdA inhibits the production of GC-resistant chemokines via GRα-independent mechanisms involving the inhibition of IRF-1 and up-regulation of MKP-1. Thus, targeting CpdA-sensitive pathways in ASM cells represents an alternative therapeutic approach to treat GC resistance in asthma. PMID:25897650

  4. Dilating Eye Drops

    MedlinePlus

    ... Frequently Asked Questions Español Condiciones Chinese Conditions Dilating Eye Drops En Español Read in Chinese What are dilating eye drops? Dilating eye drops contain medication to enlarge ( ...

  5. Effects of Gestational and Postnatal Exposure to Chronic Intermittent Hypoxia on Diaphragm Muscle Contractile Function in the Rat

    PubMed Central

    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

  6. Effects of Gestational and Postnatal Exposure to Chronic Intermittent Hypoxia on Diaphragm Muscle Contractile Function in the Rat.

    PubMed

    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

  7. Dilating Eye Drops

    MedlinePlus

    ... Conditions Most Common Searches Adult Strabismus Amblyopia Cataract Conjunctivitis Corneal Abrasions Dilating Eye Drops Lazy eye (defined) ... Loading... Most Common Searches Adult Strabismus Amblyopia Cataract Conjunctivitis Corneal Abrasions Dilating Eye Drops Lazy eye (defined) ...

  8. The role of arousal related brainstem reflexes in causing recovery from upper airway occlusion in infants.

    PubMed

    Wulbrand, Henning; McNamara, Frances; Thach, Bradley T

    2008-06-01

    During obstructive sleep apnea (OSA) in adults upper airway reopening coincides with a sudden burst in activity of pharyngeal dilating muscles. This has been attributed to arousal from sleep as indicated by increased EEG activity. Recovery from OSA in infants often occurs in the absence of cortical arousal. To investigate mechanisms involved in recovery, we performed experimental airway occlusions in sleeping infants. Based on past work, our hypothesis was that a sleep startle combined with an augmented breath and heart rate acceleration would occur during the occlusion, and that such brainstem mediated reflexes might provide an explanation for recovery from OSA in the absence of cortical arousal. However, this is contrary to expectations, since lung inflation is believed to be necessary for occurrence of an augmented breath. We studied 16 healthy infants during sleep. We recorded EEG, EOG, ECG, oxygen saturation, diaphragmatic, nuchal and limb electromyograms, face mask pressure, and airflow. A startle, accompanied by neck extension, limb and nuchal EMG activation, as well as heart rate acceleration occurred during all airway occlusions. The startle occurred simultaneously with a large biphasic inspiratory effort, having characteristics of an augmented breath (sigh). In more than a third of cases, this occurred without any evidence of cortical arousal activity. The magnitude of startles as well as the increase in heart rate correlated positively with peak airway negative pressure, indicating that arousal processes are graded in intensity. We conclude that the neck extension and pharyngeal dilating muscle activity associated with the startle and augmented breath may account for recovery of airway patency in infants as they do adults. Lung inflation is not a prerequisite for the reflex to occur. PMID:18548828

  9. Cardiomyopathy, familial dilated

    PubMed Central

    Taylor, Matthew RG; Carniel, Elisa; Mestroni, Luisa

    2006-01-01

    Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by ventricular dilatation and impaired systolic function. Patients with DCM suffer from heart failure, arrhythmia, and are at risk of premature death. DCM has a prevalence of one case out of 2500 individuals with an incidence of 7/100,000/year (but may be under diagnosed). In many cases the disease is inherited and is termed familial DCM (FDC). FDC may account for 20–48% of DCM. FDC is principally caused by genetic mutations in FDC genes that encode for cytoskeletal and sarcomeric proteins in the cardiac myocyte. Family history analysis is an important tool for identifying families affected by FDC. Standard criteria for evaluating FDC families have been published and the use of such criteria is increasing. Clinical genetic testing has been developed for some FDC genes and will be increasingly utilized for evaluating FDC families. Through the use of family screening by pedigree analysis and/or genetic testing, it is possible to identify patients at earlier, or even presymptomatic stages of their disease. This presents an opportunity to invoke lifestyle changes and to provide pharmacological therapy earlier in the course of disease. Genetic counseling is used to identify additional asymptomatic family members who are at risk of developing symptoms, allowing for regular screening of these individuals. The management of FDC focuses on limiting the progression of heart failure and controlling arrhythmia, and is based on currently accepted treatment guidelines for DCM. It includes general measures (salt and fluid restriction, treatment of hypertension, limitation of alcohol intake, control of body weight, moderate exercise) and pharmacotherapy. Cardiac resynchronization, implantable cardioverter defibrillators and left ventricular assist devices have progressively expanding usage. Patients with severe heart failure, severe reduction of the functional capacity and depressed left ventricular ejection

  10. Sexual Dimorphism in the Regulation of Estrogen, Progesterone, and Androgen Receptors by Sex Steroids in the Rat Airway Smooth Muscle Cells

    PubMed Central

    Zarazúa, Abraham; González-Arenas, Aliesha; Ramírez-Vélez, Gabriela; Bazán-Perkins, Blanca; Guerra-Araiza, Christian; Campos-Lara, María G.

    2016-01-01

    The role of sex hormones in lung is known. The three main sex steroid receptors, estrogen, progesterone, and androgen, have not been sufficiently studied in airway smooth muscle cells (ASMC), and the sex hormone regulation on these receptors is unknown. We examined the presence and regulation of sex hormone receptors in female and male rat ASMC by Western blotting and flow cytometry. Gonadectomized rats were treated with 17β-estradiol, progesterone, 17β-estradiol + progesterone, or testosterone. ASMC were enzymatically isolated from tracheas and bronchi. The experiments were performed with double staining flow cytometry (anti-α-actin smooth muscle and antibodies to each hormone receptor). ERα, ERβ, tPR, and AR were detected in females or males. ERα was upregulated by E2 and T and downregulated by P4 in females; in males, ERα was downregulated by P4, E + P, and T. ERβ was downregulated by each treatment in females, and only by E + P and T in males. tPR was downregulated by P4, E + P, and T in females. No hormonal regulation was observed in male receptors. AR was downregulated in males treated with E + P and T. We have shown the occurrence of sex hormone receptors in ASMC and their regulation by the sex hormones in female and male rats. PMID:27110242

  11. Sexual Dimorphism in the Regulation of Estrogen, Progesterone, and Androgen Receptors by Sex Steroids in the Rat Airway Smooth Muscle Cells.

    PubMed

    Zarazúa, Abraham; González-Arenas, Aliesha; Ramírez-Vélez, Gabriela; Bazán-Perkins, Blanca; Guerra-Araiza, Christian; Campos-Lara, María G

    2016-01-01

    The role of sex hormones in lung is known. The three main sex steroid receptors, estrogen, progesterone, and androgen, have not been sufficiently studied in airway smooth muscle cells (ASMC), and the sex hormone regulation on these receptors is unknown. We examined the presence and regulation of sex hormone receptors in female and male rat ASMC by Western blotting and flow cytometry. Gonadectomized rats were treated with 17β-estradiol, progesterone, 17β-estradiol + progesterone, or testosterone. ASMC were enzymatically isolated from tracheas and bronchi. The experiments were performed with double staining flow cytometry (anti-α-actin smooth muscle and antibodies to each hormone receptor). ERα, ERβ, tPR, and AR were detected in females or males. ERα was upregulated by E2 and T and downregulated by P4 in females; in males, ERα was downregulated by P4, E + P, and T. ERβ was downregulated by each treatment in females, and only by E + P and T in males. tPR was downregulated by P4, E + P, and T in females. No hormonal regulation was observed in male receptors. AR was downregulated in males treated with E + P and T. We have shown the occurrence of sex hormone receptors in ASMC and their regulation by the sex hormones in female and male rats. PMID:27110242

  12. Upregulation of TRPM7 augments cell proliferation and interleukin-8 release in airway smooth muscle cells of rats exposed to cigarette smoke.

    PubMed

    Lin, Xiaoling; Yang, Cheng; Huang, Linjie; Chen, Ming; Shi, Jianting; Ouyang, Lihua; Tang, Tiantian; Zhang, Wei; Li, Yiqun; Liang, Ruiyun; Jiang, Shanping

    2016-06-01

    Proliferation and synthetic function (i.e. the capacity to release numerous chemokines and cytokines) of airway smooth muscle cells (ASMCs) are important in airway remodeling induced by cigarette smoke exposure. However, the molecular mechanism has not been clarified. Transient receptor potential cation channel subfamily M member 7 (TRPM7) is expressed ubiquitously and is crucial for the cellular physiological function of many cell types. The present study aimed to detect the expression of TRPM7 in ASMCs from smoke‑exposed rats and determine the importance of TRPM7 in proliferation and interleukin‑8 (IL‑8) release. ASMCs were isolated and cultured from smoke‑exposed rats. Expression levels of TRPM7 were determined by reverse transcription‑polymerase chain reaction, western blot analysis and immunofluorescence. TRPM7 was silenced with TRPM7‑short hairpin RNA lentivirus vector. DNA synthesis, cell number and IL‑8 release of ASMCs induced by cigarette smoke extract (CSE) and tumor necrosis factor‑α (TNF‑α) were assessed using [3H]-thymidine incorporation assay, hemocytometer and enzyme‑linked immunosorbent assay, respectively. It was determined that mRNA and protein expression levels of TRPM7 were increased in ASMCs from smoke‑exposed rats. Stimulation with CSE or TNF‑α elevated DNA synthesis, cell number and IL‑8 release were more marked in ASMCs from smoke‑exposed rats. Silencing of TRPM7 reduced DNA synthesis, cell number and IL‑8 release induced by CSE or TNF‑α in ASMCs from smoke-exposed rats. In conclusion, expression of TRPM7 increased significantly in ASMCs from smoke‑exposed rats and the upregulation of TRPM7 led to augmented cell proliferation and IL-8 release in ASMCs from rats exposed to cigarette smoke. PMID:27108806

  13. Upregulation of TRPM7 augments cell proliferation and interleukin-8 release in airway smooth muscle cells of rats exposed to cigarette smoke

    PubMed Central

    LIN, XIAOLING; YANG, CHENG; HUANG, LINJIE; CHEN, MING; SHI, JIANTING; OUYANG, LIHUA; TANG, TIANTIAN; ZHANG, WEI; LI, YIQUN; LIANG, RUIYUN; JIANG, SHANPING

    2016-01-01

    Proliferation and synthetic function (i.e. the capacity to release numerous chemokines and cytokines) of airway smooth muscle cells (ASMCs) are important in airway remodeling induced by cigarette smoke exposure. However, the molecular mechanism has not been clarified. Transient receptor potential cation channel subfamily M member 7 (TRPM7) is expressed ubiquitously and is crucial for the cellular physiological function of many cell types. The present study aimed to detect the expression of TRPM7 in ASMCs from smoke-exposed rats and determine the importance of TRPM7 in proliferation and interleukin-8 (IL-8) release. ASMCs were isolated and cultured from smoke-exposed rats. Expression levels of TRPM7 were determined by reverse transcription-polymerase chain reaction, western blot analysis and immunofluorescence. TRPM7 was silenced with TRPM7-short hairpin RNA lentivirus vector. DNA synthesis, cell number and IL-8 release of ASMCs induced by cigarette smoke extract (CSE) and tumor necrosis factor-α (TNF-α) were assessed using [3H]-thymidine incorporation assay, hemocytometer and enzyme-linked immunosorbent assay, respectively. It was determined that mRNA and protein expression levels of TRPM7 were increased in ASMCs from smoke-exposed rats. Stimulation with CSE or TNF-α elevated DNA synthesis, cell number and IL-8 release were more marked in ASMCs from smoke-exposed rats. Silencing of TRPM7 reduced DNA synthesis, cell number and IL-8 release induced by CSE or TNF-α in ASMCs from smoke-exposed rats. In conclusion, expression of TRPM7 increased significantly in ASMCs from smoke-exposed rats and the upregulation of TRPM7 led to augmented cell proliferation and IL-8 release in ASMCs from rats exposed to cigarette smoke. PMID:27108806

  14. Chronic effects of mechanical force on airways.

    PubMed

    Tschumperlin, Daniel J; Drazen, Jeffrey M

    2006-01-01

    Airways are embedded in the mechanically dynamic environment of the lung. In utero, this mechanical environment is defined largely by fluid secretion into the developing airway lumen. Clinical, whole lung, and cellular studies demonstrate pivotal roles for mechanical distention in airway morphogenesis and cellular behavior during lung development. In the adult lung, the mechanical environment is defined by a dynamic balance of surface, tissue, and muscle forces. Diseases of the airways modulate both the mechanical stresses to which the airways are exposed as well as the structure and mechanical behavior of the airways. For instance, in asthma, activation of airway smooth muscle abruptly changes the airway size and stress state within the airway wall; asthma also results in profound remodeling of the airway wall. Data now demonstrate that airway epithelial cells, smooth muscle cells, and fibroblasts respond to their mechanical environment. A prominent role has been identified for the epithelium in transducing mechanical stresses, and in both the fetal and mature airways, epithelial cells interact with mesenchymal cells to coordinate remodeling of tissue architecture in response to the mechanical environment. PMID:16460284

  15. Induction of cyclo-oxygenase-2 by cytokines in human cultured airway smooth muscle cells: novel inflammatory role of this cell type

    PubMed Central

    Belvisi, Maria G; Saunders, Michael A; Haddad, El-Bdaoui; Hirst, Stuart J; Yacoub, Magdi H; Barnes, Peter J; Mitchell, Jane A

    1997-01-01

    Cyclo-oxygenase (COX) is the enzyme that converts arachidonic acid to prostaglandin H2 (PGH2) which can then be further metabolized to prostanoids which modulate various airway functions. COX exists in at least two isoforms. COX-1 is expressed constitutively, whereas COX-2 is expressed in response to pro-inflammatory stimuli. Prostanoids are produced under physiological and pathophysiological conditions by many cell types in the lung. However, the regulation of the different COX isoforms in human airway smooth muscle (HASM) cells has not yet been determined.COX-1 and COX-2 protein were measured by Western blot analysis with specific antibodies for COX-1 and COX-2. COX-2 mRNA levels were assessed by Northern blot analysis by use of a COX-2 cDNA probe. COX activity was determined by measuring conversion of either endogenous or exogenous arachidonic acid to three metabolites, PGE2, thromboxane B2 or 6-ketoPGF1α by radioimmunoassay.Under control culture conditions HASM cells expressed COX-1, but not COX-2, protein. However, a mixture of cytokines (interleukin-1β (IL-1β), tumour necrosis factor α (TNFα) and interferon γ (IFNγ) each at 10 ng ml−1) induced COX-2 mRNA expression, which was maximal at 12 h and inhibited by dexamethasone (1 μM; added 30 min before the cytokines). Furthermore, COX-2 protein was detected 24 h after the cytokine treatment and the expression of this protein was also inhibited by dexamethasone (1 μM) and cyclohexamide (10 μg ml−1; added 30 min before the cytokines).Untreated HASM cells released low or undetectable amounts of all COX metabolites measured over a 24 h period. Incubation of the cells with the cytokine mixture (IL-1β, TNFα, IFNγ each at 10 ng ml−1 for 24 h) caused the accumulation of PGE2 and 6-keto-PGF1α.In experiments where COX-2 metabolized endogenous stores of arachidonic acid, treatment of HASM cells with IL-1β in combination with TNFα caused a similar release of PGE2 to that when

  16. Functional Effects of WNT1-Inducible Signaling Pathway Protein-1 on Bronchial Smooth Muscle Cell Migration and Proliferation in OVA-Induced Airway Remodeling.

    PubMed

    Yang, Mingjin; Du, Yuejun; Xu, Zhibo; Jiang, Youfan

    2016-02-01

    Upregulation of WISP1 has been demonstrated in lung remodeling. Moreover, it has been recently found that some signaling components of WNT pathway can activate GSK3β signaling to mediate remodeling of airway smooth muscle (ASM) in asthma. Therefore, we hypothesized that WISP1, a signaling molecule downstream of the WNT signaling pathway, is involved in PI3K/GSK3β signaling to mediate ASM remodeling in asthma. Our results showed that WISP1 depletion partly suppressed OVA-induced ASM hypertrophy in vivo. In vitro, WISP1 could induce hBSMC hypertrophy and proliferation, accompanied by upregulation of levels of PI3K, p-Akt, p-GSK3β, and its own expression. TGF-β treatment could increase expression of PI3K, p-Akt, p-GSK3β, and WISP1. SH-5 treatment could partly suppress TGF-β-induced hypertrophy and proliferation of hBSMC, and depress expression of p-GSK3β and WISP1. In conclusion, WISP1 may be a potential inducer of ASM proliferation and hypertrophy in asthma. The pro-remodeling effect of WISP1 is likely due to be involved in PI3K-GSK3β-dependent noncanonical TGF-β signaling. PMID:26242865

  17. Short-term variability in respiratory impedance and effect of deep breath in asthmatic and healthy subjects with airway smooth muscle activation and unloading.

    PubMed

    Gobbi, Alessandro; Pellegrino, Riccardo; Gulotta, Carlo; Antonelli, Andrea; Pompilio, Pasquale; Crimi, Claudia; Torchio, Roberto; Dutto, Luca; Parola, Paolo; Dellacà, Raffaele L; Brusasco, Vito

    2013-09-01

    Inspiratory resistance (RINSP) and reactance (XINSP) were measured for 7 min at 5 Hz in 10 subjects with mild asymptomatic asthma and 9 healthy subjects to assess the effects of airway smooth muscle (ASM) activation by methacholine (MCh) and unloading by chest wall strapping (CWS) on the variability of lung function and the effects of deep inspiration (DI). Subjects were studied at control conditions, after MCh, with CWS, and after MCh with CWS. In all experimental conditions XINSP was significantly more negative in subjects with asthma than in healthy subjects, suggesting greater inhomogeneity in the former. However, the variability in both RINSP and XINSP was increased by either ASM activation or CWS, without significant difference between groups. DI significantly reversed MCh-induced changes in RINSP both in subjects with asthma and healthy subjects, but XINSP in the former only. This effect was impaired by CWS more in subjects with asthma than in healthy subjects. The velocity of RINSP and XINSP recovery after DI was faster in subjects with asthma than healthy subjects. In conclusion, these results support the opinion that the short-term variability in respiratory impedance is related to ASM tone or operating length, rather than to the disease. Nevertheless, ASM in individuals with asthma differs from that in healthy individuals in an increased velocity of shortening and a reduced sensitivity to mechanical stress when strain is reduced. PMID:23766502

  18. Differential effects of respiratory and electrical stimulation-induced dilator muscle contraction on mechanical properties of the pharynx in the pig.

    PubMed

    Brodsky, A; Dotan, Y; Samri, M; Schwartz, A R; Oliven, A

    2016-09-01

    Respiratory stimulation (RS) during sleep often fails to discontinue flow limitation, whereas electrical stimulation (ES) of the hypoglossus (HG) nerve frequently prevents obstruction. The present work compares the effects of RS and HG-ES on pharyngeal mechanics and the relative contribution of tongue muscles and thoracic forces to pharyngeal patency. We determined the pressure-area relationship of the collapsible segment of the pharynx in anesthetized pigs under the following three conditions: baseline (BL), RS induced by partial obstruction of the tracheostomy tube, and HG-ES. Parameters were obtained also after transection of the neck muscles and the trachea (NMT) and after additional bilateral HG transection (HGT). In addition, we measured the force produced by in situ isolated geniohyoid (GH) during RS and HG-ES. Intense RS was recognized by large negative intrathoracic pressures and triggered high phasic genioglossus and GH EMG activity. GH contraction produced during maximal RS less than a quarter of the force obtained during HG-ES. The major finding of the study was that RS and ES differed in the mechanism by which they stabilized the pharynx: RS lowered the pressure-area slope, i.e., reduced pharyngeal compliance (14.1 ± 2.9 to 9.2 ± 1.9 mm(2)/cmH2O, P < 0.01). HG-ES shifted the slope toward lower pressures, i.e., lowered the calculated extraluminal pressure (17.4 ± 5.8 to 9.2 ± 7.4 cmH2O, P < 0.01). Changes during RS and HG-ES were not affected by NMT, but the effect of RS decreased significantly after HGT. In conclusion, HG-ES and RS affect the pharyngeal site of collapse differently. Tongue muscle contraction contributes to pharyngeal stiffening during RS. PMID:27311440

  19. Airway Management and Endoscopic Treatment of Subglottic and Tracheal Stenosis: The Laryngeal Mask Airway Technique

    PubMed Central

    Vorasubin, Nopawan; Vira, Darshni; Jamal, Nausheen; Chhetri, Dinesh K.

    2015-01-01

    Objectives The objective is to present clinical outcomes of subglottic and tracheal stenosis treated by flexible bronchoscopic delivery of carbon dioxide (CO2) laser via laryngeal mask airway (LMA). Methods All consecutive, nontracheotomy dependent cases of subglottic and tracheal stenosis treated endoscopically over a 4-year period were retrospectively reviewed. The surgical approach consisted of radial incisions using a flexible fiber-based CO2 laser, balloon dilation, and topical application of mitomycin C. Ventilation during the procedure occurred through the LMA, and the CO2 laser fiber was delivered through the working channel of a flexible bronchoscope passed through the LMA. Number of dilations, period between dilations, and operative times were reviewed. Results Eleven patients who underwent airway intervention during the study period were identified. Average follow-up was 28 months. Etiologies of airway stenosis included intubation injury (6), idiopathic (4), or autoimmune disease (1), requiring an average of 1.3, 1.5, and 3 dilations, respectively. Average operative time was 67 minutes. Autoimmune etiology correlated with more frequent dilations. Conclusion LMA is an effective way to manage ventilation while simultaneously allowing unencumbered flexible bronchoscopic access for laser surgery, balloon dilation, and mitomycin C application for airway stenosis. Long-term success in treating stenosis is achievable using this technique. PMID:24671485

  20. Viscoelastic and dynamic nonlinear properties of airway smooth muscle tissue: roles of mechanical force and the cytoskeleton.

    PubMed

    Ito, Satoru; Majumdar, Arnab; Kume, Hiroaki; Shimokata, Kaoru; Naruse, Keiji; Lutchen, Kenneth R; Stamenovic, Dimitrije; Suki, Béla

    2006-06-01

    The viscoelastic and dynamic nonlinear properties of guinea pig tracheal smooth muscle tissues were investigated by measuring the storage (G') and loss (G") moduli using pseudorandom small-amplitude length oscillations between 0.12 and 3.5 Hz superimposed on static strains of either 10 or 20% of initial length. The G" and G' spectra were interpreted using a linear viscoelastic model incorporating damping (G) and stiffness (H), respectively. Both G and H were elevated following an increase in strain from 10 to 20%. There was no change in harmonic distortion (K(d)), an index of dynamic nonlinearity, between 10 and 20% strains. Application of methacholine at 10% strain significantly increased G and H while it decreased K(d). Cytochalasin D, isoproterenol, and HA-1077, a Rho-kinase inhibitor, significantly decreased both G and H but increased K(d). Following cytochalasin D, G, H, and K(d) were all elevated when mean strain increased from 10 to 20%. There were no changes in hysteresivity, G/H, under any condition. We conclude that not all aspects of the viscoelastic properties of tracheal smooth muscle strips are similar to those previously observed in cultured cells. We attribute these differences to the contribution of the extracellular matrix. Additionally, using a network model, we show that the dynamic nonlinear behavior, which has not been observed in cell culture, is associated with the state of the contractile stress and may derive from active polymerization within the cytoskeleton. PMID:16414980

  1. Activity of the oxidation products of oleum terebinthinae "Landes" on guinea pig airway smooth muscle in vivo and in vitro.

    PubMed

    Bermudez, J; Burgess, M F; Cassidy, F; Clarke, G D

    1987-11-01

    The oxidation products of Oleum Terebinthinae "Landes" (Ozothin; in the following briefly called Ox. O. T. L.) have been described in many studies as being of benefit in the treatment of disturbed tracheobronchial function in obstructive airways diseases. Previous literature has dealt mainly with the influence of Ox. O. T. L. on the visco-elastic properties of mucus. However, the purpose of the present work was to study the bronchospasmolytic component. Using a standard methodology for the measurement of bronchospasmolytic effects, it could be demonstrated that Ox.O.T.L., given orally or as an aerosol, protected conscious guinea pigs against histamine-induced bronchoconstriction. The potency was lower than that of isoprenaline but was significant and reproducible. These results in vivo are paralleled by effects observed on guinea pig lung strips and tracheal spiral preparations. Ox.O.T.L. relaxed, in a dose-dependent fashion, guinea pig lung strip preparations contracted with histamine. Potency and efficacy was, however, less than that of isoprenaline. Similarly, in guinea pig tracheal spiral preparations, Ox.O.T.L. was less potent than isoprenaline in counteracting carbachol-elevated tone. However, efficacy equalled that of isoprenaline. Ox.O.T.L. was approximately 3 times more potent in the isolated tracheal spiral preparation than in lung strips. The activity of non-oxidised turpentine oil and terpin hydrate against histamine-induced bronchoconstriction in conscious animals and in the isolated organ preparations was substantially lower than that of the oxidation products of O.T.L. PMID:3440034

  2. Surgical Airway

    PubMed Central

    Patel, Sapna A; Meyer, Tanya K

    2014-01-01

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

  3. Effects of estrogen on genioglossal muscle contractile properties and fiber-type distribution in chronic intermittent hypoxia rats.

    PubMed

    Liu, Yue-Hua; Huang, Yan; Shao, Xiao

    2009-12-01

    Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a highly prevalent disorder that is characterized by recurrent sleep-induced collapse of the upper airway. Genioglossus is an important pharyngeal dilator muscle that helps to maintain the patency of the upper airway. The effect of female hormones on pharyngeal dilator muscle activity may be one possible explanation for the differences observed in the prevalence of OSAHS between genders. The aim of this research was to investigate the influence of estrogen on genioglossus activity in rats exposed to chronic intermittent hypoxia (CIH). Eight-wk-old female rats were ovariectomized or sham-operated, received 5-wk of estrogen replacement therapy, and/or were exposed to CIH. The contractile properties of the genioglossus were measured. ATPase staining was performed to determine the per cent fiber-type distribution and to measure the cross-sectional area (CSA) of muscle fibers. Myosin heavy chain phenotypes were determined by gel electrophoresis. Chronic intermittent hypoxia reduced the contractile properties of the genioglossus muscle, decreased the CSA of type IIA fibers, and decreased the proportion of myosin heavy chain IIA, and ovariectomy exacerbated this effect. However, estrogen replacement can partially reverse the effect of CIH in ovariectomized rats. It is concluded that a low female hormone level and CIH may increase fatigue and alter genioglossus structure and function, and may compromise the maintenance of upper airway patency, while estrogen may help to reverse this effect. PMID:20121931

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

    NASA Astrophysics Data System (ADS)

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

    2006-03-01

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

  5. [Lethal vascular erosion after percutaneous dilatation tracheostomy].

    PubMed

    Hürter, H; Post-Stanke, A; Tolksdorf, W

    2000-10-01

    We report on a patient who underwent dilatational tracheostomy (Ciaglia technique) because of ARDS. 29 days after the procedure she died of hemorrhage from an arrosion of the bracheocephalic trunk, caused by the cuff of the tracheal cannula. This complication has, so far, been reported only after surgical tracheostomy. The fracture of tracheal cartilages is considered to be the specific cause of this fatal complication. The consequent loss of circular stability of the trachea demands increased cuff insufflation and pressure to tighten the airway. Prevention and therapy consist in control of the cuff pressure and caudal placement of the tracheal cannula. PMID:11116502

  6. Divergent modulation of Rho‐kinase and Ca2+ influx pathways by Src family kinases and focal adhesion kinase in airway smooth muscle

    PubMed Central

    Shaifta, Yasin; Irechukwu, Nneka; Prieto‐Lloret, Jesus; MacKay, Charles E; Marchon, Keisha A; Ward, Jeremy P T

    2015-01-01

    Background and Purpose The importance of tyrosine kinases in airway smooth muscle (ASM) contraction is not fully understood. The aim of this study was to investigate the role of Src‐family kinases (SrcFK) and focal adhesion kinase (FAK) in GPCR‐mediated ASM contraction and associated signalling events. Experimental Approach Contraction was recorded in intact or α‐toxin permeabilized rat bronchioles. Phosphorylation of SrcFK, FAK, myosin light‐chain‐20 (MLC20) and myosin phosphatase targeting subunit‐1 (MYPT‐1) was evaluated in cultured human ASM cells (hASMC). [Ca2+]i was evaluated in Fura‐2 loaded hASMC. Responses to carbachol (CCh) and bradykinin (BK) and the contribution of SrcFK and FAK to these responses were determined. Key Results Contractile responses in intact bronchioles were inhibited by antagonists of SrcFK, FAK and Rho‐kinase, while after α‐toxin permeabilization, they were sensitive to inhibition of SrcFK and Rho‐kinase, but not FAK. CCh and BK increased phosphorylation of MYPT‐1 and MLC20 and auto‐phosphorylation of SrcFK and FAK. MYPT‐1 phosphorylation was sensitive to inhibition of Rho‐kinase and SrcFK, but not FAK. Contraction induced by SR Ca2+ depletion and equivalent [Ca2+]i responses in hASMC were sensitive to inhibition of both SrcFK and FAK, while depolarization‐induced contraction was sensitive to FAK inhibition only. SrcFK auto‐phosphorylation was partially FAK‐dependent, while FAK auto‐phosphorylation was SrcFK‐independent. Conclusions and Implications SrcFK mediates Ca2+‐sensitization in ASM, while SrcFK and FAK together and individually influence multiple Ca2+ influx pathways. Tyrosine phosphorylation is therefore a key upstream signalling event in ASM contraction and may be a viable target for modulating ASM tone in respiratory disease. PMID:26294392

  7. Tumor Necrosis Factor Alpha Inhibits L-Type Ca2+ Channels in Sensitized Guinea Pig Airway Smooth Muscle through ERK 1/2 Pathway

    PubMed Central

    Reyes-García, Jorge; Flores-Soto, Edgar; Solís-Chagoyán, Héctor; Sommer, Bettina; Díaz-Hernández, Verónica; García-Hernández, Luz María

    2016-01-01

    Tumor necrosis factor alpha (TNF-α) is a potent proinflammatory cytokine that plays a significant role in the pathogenesis of asthma by inducing hyperresponsiveness and airway remodeling. TNF-α diminishes the L-type voltage dependent Ca2+ channel (L-VDCC) current in cardiac myocytes, an observation that seems paradoxical. In guinea pig sensitized tracheas KCl responses were lower than in control tissues. Serum from sensitized animals (Ser-S) induced the same phenomenon. In tracheal myocytes from nonsensitized (NS) and sensitized (S) guinea pigs, an L-VDCC current (ICa) was observed and diminished by Ser-S. The same decrease was detected in NS myocytes incubated with TNF-α, pointing out that this cytokine might be present in Ser-S. We observed that a small-molecule inhibitor of TNF-α (SMI-TNF) and a TNF-α receptor 1 (TNFR1) antagonist (WP9QY) reversed ICa decrease induced by Ser-S in NS myocytes, confirming the former hypothesis. U0126 (a blocker of ERK 1/2 kinase) also reverted the decrease in ICa. Neither cycloheximide (a protein synthesis inhibitor) nor actinomycin D (a transcription inhibitor) showed any effect on the TNF-α-induced ICa reduction. We found that CaV1.2 and CaV1.3 mRNA and proteins were expressed in tracheal myocytes and that sensitization did not modify them. In cardiac myocytes, ERK 1/2 phosphorylates two sites of the L-VDCC, augmenting or decreasing ICa; we postulate that, in guinea pig tracheal smooth muscle, TNF-α diminishes ICa probably by phosphorylating the L-VDCC site that reduces its activity through the ERK1/2 MAP kinase pathway. PMID:27445440

  8. Schisandrin B inhibits the proliferation of airway smooth muscle cells via microRNA-135a suppressing the expression of transient receptor potential channel 1.

    PubMed

    Zhang, Xiao-Yu; Zhang, Luo-Xian; Guo, Ya-Li; Zhao, Li-Min; Tang, Xue-Yi; Tian, Cui-Jie; Cheng, Dong-Jun; Chen, Xian-Liang; Ma, Li-Jun; Chen, Zhuo-Chang

    2016-07-01

    Airway smooth muscle cell (ASMC) was known to involve in the pathophysiology of asthma. Schisandrin B was reported to have anti-asthmatic effects in a murine asthma model. However, the molecular mechanism involving in the effect of Schisandrin B on ASMCs remains poorly understood. Sprague-Dawley rats were divided into three groups: rats as the control (Group 1), sensitized rats (Group 2), sensitized rats and intragastric-administrated Schisandrin B (Group 3). The expression of miR-135a and TRPC1 was detected in the rats from three groups. Platelet-derived growth factor (PDGF)-BB was used to induce the proliferation of isolated ASMCs, and the expression of miR-135a and TRPC1 was detected in PDGF-BB-treated ASMCs. Cell viability was examined in ASMCs transfected with miR-135a inhibitor or si-TRPC1. The expression of TRPC1 was examined in A10 cells pretreated with miR-135a inhibitor or miR-135a mimic. In this study, we found that Schisandrin B attenuated the inspiratory and expiratory resistances in sensitized rats. Schisandrin B upregulated the mRNA level of miR-135a and decreased the expression of TRPC1 in sensitized rats. In addition, Schisandrin B reversed the expression of miR-135a and TRPC1 in PDGF-BB-induced ASMCs. Si-TRPC1 abrogated the increasing proliferation of ASMCs induced by miR-135a inhibitor. We also found that miR-135a regulated the expression of TRPC1 in the A10 cells. These results demonstrate that Schisandrin B inhibits the proliferation of ASMCs via miR-135a suppressing the expression of TRPC1. PMID:26916957

  9. Theophylline Represses IL-8 Secretion from Airway Smooth Muscle Cells Independently of Phosphodiesterase Inhibition. Novel Role as a Protein Phosphatase 2A Activator.

    PubMed

    Patel, Brijeshkumar S; Rahman, Md Mostafizur; Rumzhum, Nowshin N; Oliver, Brian G; Verrills, Nicole M; Ammit, Alaina J

    2016-06-01

    Theophylline is an old drug experiencing a renaissance owing to its beneficial antiinflammatory effects in chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease. Multiple modes of antiinflammatory action have been reported, including inhibition of the enzymes that degrade cAMP-phosphodiesterase (PDE). Using primary cultures of airway smooth muscle (ASM) cells, we recently revealed that PDE4 inhibitors can potentiate the antiinflammatory action of β2-agonists by augmenting cAMP-dependent expression of the phosphatase that deactivates mitogen-activated protein kinase (MAPK)-MAPK phosphatase (MKP)-1. Therefore, the aim of this study was to address whether theophylline repressed cytokine production in a similar, PDE-dependent, MKP-1-mediated manner. Notably, theophylline did not potentiate cAMP release from ASM cells treated with the long-acting β2-agonist formoterol. Moreover, theophylline (0.1-10 μM) did not increase formoterol-induced MKP-1 messenger RNA expression nor protein up-regulation, consistent with the lack of cAMP generation. However, theophylline (at 10 μM) was antiinflammatory and repressed secretion of the neutrophil chemoattractant cytokine IL-8, which is produced in response to TNF-α. Because theophylline's effects were independent of PDE4 inhibition or antiinflammatory MKP-1, we then wished to elucidate the novel mechanisms responsible. We investigated the impact of theophylline on protein phosphatase (PP) 2A, a master controller of multiple inflammatory signaling pathways, and show that theophylline increases TNF-α-induced PP2A activity in ASM cells. Confirmatory results were obtained in A549 lung epithelial cells. PP2A activators have beneficial effects in ex vivo and in vivo models of respiratory disease. Thus, our study is the first to link theophylline with PP2A activation as a novel mechanism to control respiratory inflammation. PMID:26574643

  10. Inositol 1,4,5-trisphosphate activates TRPC3 channels to cause extracellular Ca2+ influx in airway smooth muscle cells.

    PubMed

    Song, Tengyao; Hao, Qiongyu; Zheng, Yun-Min; Liu, Qing-Hua; Wang, Yong-Xiao

    2015-12-15

    Transient receptor potential-3 (TRPC3) channels play a predominant role in forming nonselective cation channels (NSCCs) in airway smooth muscle cells (ASMCs) and are significantly increased in their activity and expression in asthmatic ASMCs. To extend these novel findings, we have explored the regulatory mechanisms that control the activity of TRPC3 channels. Our data for the first time reveal that inositol 1,4,5-trisphosphate (IP3), an important endogenous signaling molecule, can significantly enhance the activity of single NSCCs in ASMCs. The analog of diacylglycerol (DAG; another endogenous signaling molecule), 1-oleyl-2-acetyl-sn-glycerol (OAG), 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG), and 1-stearoyl-2-linoleoyl-sn-glycerol (SLG) all augment NSCC activity. The effects of IP3 and OAG are fully abolished by lentiviral short-hairpin (sh)RNA-mediated TRPC3 channel knockdown (KD). The stimulatory effect of IP3 is eliminated by heparin, an IP3 receptor (IP3R) antagonist that blocks the IP3-binding site, but not by xestospongin C, the IP3R antagonist that has no effect on the IP3-binding site. Lentiviral shRNA-mediated KD of IP3R1, IP3R2, or IP3R3 does not alter the excitatory effect of IP3. TRPC3 channel KD greatly inhibits IP3-induced increase in intracellular Ca(2+) concentration. IP3R1 KD produces a similar inhibitory effect. TRPC3 channel and IP3R1 KD both diminish the muscarinic receptor agonist methacholine-evoked Ca(2+) responses. Taking these findings together, we conclude that IP3, the important intracellular second messenger, may activate TRPC3 channels to cause extracellular Ca(2+) influx, in addition to opening IP3Rs to induce intracellular Ca(2+) release. This novel extracellular Ca(2+) entry route may play a significant role in mediating IP3-mediated numerous cellular responses in ASMCs and other cells. PMID:26453517

  11. The small heat shock-related protein, HSP20, is a cAMP-dependent protein kinase substrate that is involved in airway smooth muscle relaxation

    PubMed Central

    Komalavilas, Padmini; Penn, Raymond B.; Flynn, Charles R.; Thresher, Jeffrey; Lopes, Luciana B.; Furnish, Elizabeth J.; Guo, Manhong; Pallero, Manuel A.; Murphy-Ullrich, Joanne E.; Brophy, Colleen M.

    2009-01-01

    Activation of the cAMP/cAMP-dependent PKA pathway leads to relaxation of airway smooth muscle (ASM). The purpose of this study was to examine the role of the small heat shock-related protein HSP20 in mediating PKA-dependent ASM relaxation. Human ASM cells were engineered to constitutively express a green fluorescent protein-PKA inhibitory fusion protein (PKI-GFP) or GFP alone. Activation of the cAMP-dependent signaling pathways by isoproterenol (ISO) or forskolin led to increases in the phosphorylation of HSP20 in GFP but not PKI-GFP cells. Forskolin treatment in GFP but not PKI-GFP cells led to a loss of central actin stress fibers and decreases in the number of focal adhesion complexes. This loss of stress fibers was associated with dephosphorylation of the actin-depolymerizing protein cofilin in GFP but not PKI-GFP cells. To confirm that phosphorylated HSP20 plays a role in PKA-induced ASM relaxation, intact strips of bovine ASM were precontracted with serotonin followed by ISO. Activation of the PKA pathway led to relaxation of bovine ASM, which was associated with phosphorylation of HSP20 and dephosphorylation of cofilin. Finally, treatment with phosphopeptide mimetics of HSP20 possessing a protein transduction domain partially relaxed precontracted bovine ASM strips. In summary, ISO-induced phosphorylation of HSP20 or synthetic phosphopeptide analogs of HSP20 decreases phosphorylation of cofilin and disrupts actin in ASM, suggesting that one possible mechanism by which HSP20 mediates ASM relaxation is via regulation of actin filament dynamics. PMID:17993590

  12. Tumor Necrosis Factor Alpha Inhibits L-Type Ca(2+) Channels in Sensitized Guinea Pig Airway Smooth Muscle through ERK 1/2 Pathway.

    PubMed

    Reyes-García, Jorge; Flores-Soto, Edgar; Solís-Chagoyán, Héctor; Sommer, Bettina; Díaz-Hernández, Verónica; García-Hernández, Luz María; Montaño, Luis M

    2016-01-01

    Tumor necrosis factor alpha (TNF-α) is a potent proinflammatory cytokine that plays a significant role in the pathogenesis of asthma by inducing hyperresponsiveness and airway remodeling. TNF-α diminishes the L-type voltage dependent Ca(2+) channel (L-VDCC) current in cardiac myocytes, an observation that seems paradoxical. In guinea pig sensitized tracheas KCl responses were lower than in control tissues. Serum from sensitized animals (Ser-S) induced the same phenomenon. In tracheal myocytes from nonsensitized (NS) and sensitized (S) guinea pigs, an L-VDCC current (ICa) was observed and diminished by Ser-S. The same decrease was detected in NS myocytes incubated with TNF-α, pointing out that this cytokine might be present in Ser-S. We observed that a small-molecule inhibitor of TNF-α (SMI-TNF) and a TNF-α receptor 1 (TNFR1) antagonist (WP9QY) reversed ICa decrease induced by Ser-S in NS myocytes, confirming the former hypothesis. U0126 (a blocker of ERK 1/2 kinase) also reverted the decrease in ICa. Neither cycloheximide (a protein synthesis inhibitor) nor actinomycin D (a transcription inhibitor) showed any effect on the TNF-α-induced ICa reduction. We found that CaV1.2 and CaV1.3 mRNA and proteins were expressed in tracheal myocytes and that sensitization did not modify them. In cardiac myocytes, ERK 1/2 phosphorylates two sites of the L-VDCC, augmenting or decreasing ICa; we postulate that, in guinea pig tracheal smooth muscle, TNF-α diminishes ICa probably by phosphorylating the L-VDCC site that reduces its activity through the ERK1/2 MAP kinase pathway. PMID:27445440

  13. Sinuplasty (Balloon Catheter Dilation)

    MedlinePlus

    ... development of the balloon dilating catheter and its adaptation to sinus surgery. In the 1980s, the field ... used in endoscopic sinus surgery. It is the adaptation or application of minimally-invasive balloon technology to ...

  14. Geniohyoid muscle properties and myosin heavy chain composition are altered after short-term intermittent hypoxic exposure.

    PubMed

    Pae, Eung-Kwon; Wu, Jennifer; Nguyen, Daniel; Monti, Ryan; Harper, Ronald M

    2005-03-01

    Patients with obstructive sleep apnea (OSA) often exhibit fatigued or inefficient upper airway dilator and constrictor muscles; an upper airway dilator, the geniohyoid (GH) muscle, is a particular example. Intermittent hypoxia (IH) is a frequent concomitant of OSA, and it may trigger muscle fiber composition changes that are characteristic of a fatigable nature. We examined effects of short-term IH on diaphragmatic and GH muscle fiber composition and fatigue properties by exposing 24 rats to alternating 10.3% O(2)-balance N(2) and room air every 480 s (240 s duty cycle) for a total duration of 5, 10, 15, 20, or 30 h. Sternohyoid fiber composition was also examined. Control animals were exposed to room air on the same schedule. Single-fiber analyses showed that GH muscle fiber types changed completely from myosin heavy chain (MHC) type 2A to MHC type 2B after 10 h of exposure, and the conversion was maintained for at least 30 h. Sternohyoid muscle fibers showed a delayed transition from MHC type 2A/2B to MHC type 2B. In contrast, major fiber types of the diaphragm were not significantly altered. The GH muscles showed similar tension-frequency relationships in all groups, but an increased fatigability developed, proportional to the duration of IH treatment. We conclude that short-term IH exposure alters GH muscle composition and physical properties toward more fatigable, fast-twitch types and that it may account for the fatigable upper airway fiber types found in sleep-disturbed breathing. PMID:15557011

  15. Analysis of the interplay between neurochemical control of respiration and upper airway mechanics producing upper airway obstruction during sleep in humans.

    PubMed

    Longobardo, G S; Evangelisti, C J; Cherniack, N S

    2008-02-01

    Increased loop gain (a function of both controller gain and plant gain), which results in instability in feedback control, is of major importance in producing recurrent central apnoeas during sleep but its role in causing obstructive apnoeas is not clear. The purpose of this study was to investigate the role of loop gain in producing obstructive sleep apnoeas. Owing to the complexity of factors that may operate to produce obstruction during sleep, we used a mathematical model to sort them out. The model used was based on our previous model of neurochemical control of breathing, which included the effects of chemical stimuli and changes in alertness on respiratory pattern generator activity. To this we added a model of the upper airways that contained a narrowed section which behaved as a compressible elastic tube and was tethered during inspiration by the contraction of the upper airway dilator muscles. These muscles in the model, as in life, responded to changes in hypoxia, hypercapnia and alertness in a manner similar to the action of the chest wall muscles, opposing the compressive action caused by the negative intraluminal pressure generated during inspiration which was magnified by the Bernoulli Effect. As the velocity of inspiratory airflow increased, with sufficiently large increase in airflow velocity, obstruction occurred. Changes in breathing after sleep onset were simulated. The simulations showed that increases in controller gain caused the more rapid onset of obstructive apnoeas. Apnoea episodes were terminated by arousal. With a constant controller gain, as stiffness decreased, obstructed breaths appeared and periods of obstruction recurred longer after sleep onset before disappearing. Decreased controller gain produced, for example, by breathing oxygen eliminated the obstructive apnoeas resulting from moderate reductions in constricted segment stiffness. This became less effective as stiffness was reduced more. Contraction of the upper airway muscles

  16. Systems-level airway models of bronchoconstriction.

    PubMed

    Donovan, Graham M

    2016-09-01

    Understanding lung and airway behavior presents a number of challenges, both experimental and theoretical, but the potential rewards are great in terms of both potential treatments for disease and interesting biophysical phenomena. This presents an opportunity for modeling to contribute to greater understanding, and here, we focus on modeling efforts that work toward understanding the behavior of airways in vivo, with an emphasis on asthma. We look particularly at those models that address not just isolated airways but many of the important ways in which airways are coupled both with each other and with other structures. This includes both interesting phenomena involving the airways and the layer of airway smooth muscle that surrounds them, and also the emergence of spatial ventilation patterns via dynamic airway interaction. WIREs Syst Biol Med 2016, 8:459-467. doi: 10.1002/wsbm.1349 For further resources related to this article, please visit the WIREs website. PMID:27348217

  17. Physiologic, metabolic, and muscle fiber type characteristics of musculus uvulae in sleep apnea hypopnea syndrome and in snorers.

    PubMed

    Sériès, F; Côté, C; Simoneau, J A; Gélinas, Y; St Pierre, S; Leclerc, J; Ferland, R; Marc, I

    1995-01-01

    Upper airway dilator muscles play an important role in the pathophysiology of sleep apnea hypopnea syndrome (SAHS). The mechanical and structural characteristics of these muscles remain unknown. The aim of this study was to compare the physiologic, metabolic, and fiber type characteristics of one upper airway dilator muscle (musculus uvulae, MU) in 11 SAHS and in seven nonapneic snorers. The different analyses were done on MU obtained during uvulo-palato-pharyngoplasty. Snorers and SAHS differed only in their apnea + hypopnea indices (11.5 +/- 5.9 and 34.2 +/- 14.6/h, respectively, mean +/- SD). Absolute twitch and tetanic tension production of MU was significantly greater in SAHS than in snorers while the fatigability index was similar in the two groups. Protein content and anaerobic enzyme activities of MU were significantly greater in SAHS than in snorers; no difference was observed for aerobic enzyme activities. The total muscle fiber cross-sectional area of MU was significantly higher in SAHS (2.2 +/- 0.9 mm2) than in snorers (1.1 +/- 0.7 mm2). The surface occupied by type IIA muscle fibers of MU was larger in SAHS (2.00 +/- 0.96) than in snorers (0.84 +/- 0.63 mm2). We conclude that the capacity for tension production and the anaerobic metabolic activity of MU are greater in SAHS than in snorers. PMID:7814616

  18. Compression of adjacent anatomical structures by pulmonary artery dilation.

    PubMed

    Dakkak, Wael; Tonelli, Adriano R

    2016-06-01

    Pulmonary hypertension is the commonest condition leading to dilated pulmonary artery. We describe three different types of compression of adjacent anatomical structures by dilated pulmonary arteries. We included involvement of the left main coronary artery, left recurrent laryngeal nerve and tracheobronchial tree. Compression of these structures can cause major complications such as myocardial ischemia, hoarseness and major airway stenosis. We present a case for each scenario and review the literature for each of these complications, focusing on patients' characteristics and contemporary management. PMID:26898826

  19. Suppression of the increasing level of acetylcholine-stimulated intracellular Ca2+ in guinea pig airway smooth muscle cells by mabuterol

    PubMed Central

    SONG, XIRUI; ZHAO, CHAO; DAI, CAILING; REN, YANXIN; AN, NAN; WEN, HUIMIN; PAN, LI; CHENG, MAOSHENG; ZHANG, YUYANG

    2015-01-01

    The present study aimed to establish an effective method for the in vitro culture of guinea pig airway smooth muscle (ASM) cells, and also investigate the suppressive effect of mabuterol hydrochloride (Mab) on the increased level of intracellular Ca2+ in ASM cells induced with acetylcholine (Ach). Two different methods, i.e. with or without collagenase to pretreat tracheal tissues, were applied to the manufacture of ASM cells. Cell viability was determined with the 3-(4,5-dimethylthinazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Immunocytochemistry and immunofluorescence were used for the identification of ASM cells. Different concentration levels (10−3, 10−4, 10−5, 10−6 and 10−7 mmol/l) of Mab were administered 5 min before Ach (10−4 M) treatment, respectively. The Ca2+ fluorescent probe, Fura-2/AM or Fluo-3/AM were applied to the inspection of Ca2+ fluorescent intensity with Varioskan Flash, immunocytometry systems and an inverted system microscope, respectively. The results showed that the fresh method, in which isolated tracheal tissues were previously treated with collagenase for 20 min, was more advantageous for the preparation of guinea pig ASM cells compared to when the enzyme was not used. The time for the ASM cells to initially migrate out of the ‘tissue blocks’ and the culture having to be generated due to the thick cell density was significantly less. On identification with immunocytochemistry or immunofluorescent staining, >95% of the cells were ASM cells. Mab (10−3−10−7 mmol/l) significantly suppressed the elevation of intracellular Ca2+ induced by Ach in a concentration-dependent manner. The inhibitory rates of intracellular Ca2+ by different concentrations of Mab, from low to high, were 14.93, 24.73, 40.06, 48.54 and 57.13%, respectively, when Varioskan Flash was used for determination. In conclusion, this novel method has a shorter harvesting period for ASM cells. Mab can suppress the increasing level of intracellular Ca2

  20. Upper airway collapsibility, and contractile and metabolic characteristics of musculus uvulae.

    PubMed

    Sériès, F; Côté, C; Simoneau, J A; St Pierre, S; Marc, I

    1996-06-01

    Physiologic, metabolic, and histochemical characteristics of one upper airway (UA) dilator muscle (musculus uvulae; MU) differ between sleep apnea hypopnea syndrome (SAHS) and nonapneic snorers. We hypothesized that these differences in MU characteristics could result from the cumulative effects of the diurnal and nocturnal intermittent contractions of UA muscles in order to compensate for a permanent increase in UA collapsibility. The aim of this study was to determine the influence of UA collapsibility on MU characteristics. Seventeen SAHS and three nonapneic snorers, who underwent an uvulo-palato-pharyngoplasty as a treatment for snoring or SAHS, participated in the study. Awake and sleeping UA critical pressure (Pcrit) was measured during continuous positive or negative airway pressure trials by analysis of the relationship between maximal inspiratory flow and the upstream pressure of flow-limited breathing cycles. Maximum isometric twitch (Pt) and tetanic tension (Po), fatigability measurements, activities of marker enzymes for anaerobic and aerobic-oxidative profile, and fiber type proportions and areas of MU were determined. There was a significant positive relationship between Pt, Po, and Pcrit measured during wakefulness and sleep. The fatigability index was negatively correlated with awake Pcrit values (r = -0.79). Activity level of the anaerobic enzymes as well as the percentage of surface occupied by type I and type IIA muscle fibers as correlated witb awake Pcrit. We conclude that the differences in awake UA collapsibility help to determine the contractile properties and metabolic and histochemical characteristics of MU. PMID:8666167

  1. Multum non multa: airway distensibility by forced oscillations.

    PubMed

    Mermigkis, Charalampos; Schiza, Sophia E; Panagou, Panagiotis

    2016-01-01

    Airway distensibility although appears to be unaffected by airway smooth muscle tone probably related to airway remodelling, after bronchodilator treatment is significantly increased in subjects with asthma. We assessed airway distensibity and its first moment derivative in two patients with mild intermittent asthma and normal spirometry. The increase in airway distensibility after bronchodilation measured at the tidal volume range during quiet breathing by forced oscillations was not accompanied by a change in its first moment, while the latter showed a significant increase in a second patient after anti-inflammatory treatment. It appears that airway distensibility is sensitive to reduction of bronchial smooth muscle tone after bronchodilation, but in addition its first moment might provide information on a change of both bronchial smooth muscle tone and small airways inflammation. PMID:27374218

  2. Prospective randomized comparison of progressive dilational vs forceps dilational percutaneous tracheostomy.

    PubMed

    Kaiser, E; Cantais, E; Goutorbe, P; Salinier, L; Palmier, B

    2006-02-01

    This trial prospectively compares two methods of percutaneous tracheostomy, both routinely used in ICU: the Ciaglia progressive dilational tracheostomy and the Griggs forceps dilational tracheostomy. One hundred patients were randomized using a single-blinded envelope method to receive progressive or forceps percutaneous tracheostomy performed at the bedside. Operative time, the occurrence of hypoxaemia or hypercapnia and complications were recorded. The progressive technique took longer than the forceps technique (median 7 (range 2-26) vs. 4 (1-16) minutes, P = 0.0005). Hypercapnia occurred in both groups but was more marked with the progressive technique (56 (16) vs. 49 (13) mmHg, P = 0.0082). Minor complications (minor bleeding, transient hypoxaemia, damage to posterior tracheal wall without emphysema) were also more frequent with the progressive technique (31 vs. 9 complications, P < 0.0001). Six major complications occurred with the progressive technique, none with the forceps technique (P = 0.0085): tension pneumothorax, posterior tracheal wall injury with subcutaneous emphysema, loss of airway with hypoxaemia, loss of stoma with impossible re-catheterization, and two conversions to another technique. In conclusion, progressive dilational tracheostomy took longer, caused more hypercapnia and more minor and major difficulties than forceps dilational tracheostomy. PMID:16494150

  3. Airway clearance in neuromuscular weakness.

    PubMed

    Gauld, Leanne Maree

    2009-05-01

    Impaired airway clearance leads to recurrent chest infections and respiratory deterioration in neuromuscular weakness. It is frequently the cause of death. Cough is the major mechanism of airway clearance. Cough has several components, and assessment tools are available to measure the different components of cough. These include measuring peak cough flow, respiratory muscle strength, and inspiratory capacity. Each is useful in assessing the ability to generate an effective cough, and can be used to guide when techniques of assisting airway clearance may be effective for the individual and which are most effective. Techniques to assist airway clearance include augmenting inspiration by air stacking, augmenting expiration by assisting the cough, and augmenting both inspiration and expiration with the mechanical insufflator-exsufflator or by direct suctioning via a tracheostomy. Physiotherapists are invaluable in assisting airway clearance, and in teaching patients and their families how to use these techniques. Use of the mechanical insufflator-exsufflator has gained popularity in recent times, but several simpler, more economical methods are available to assist airway clearance that can be used effectively alone or in combination. This review examines the literature available on the assessment and management of impaired airway clearance in neuromuscular weakness. PMID:19379290

  4. Respiratory control and sternohyoid muscle structure and function in aged male rats: decreased susceptibility to chronic intermittent hypoxia.

    PubMed

    Skelly, J Richard; Edge, Deirdre; Shortt, Christine M; Jones, James F X; Bradford, Aidan; O'Halloran, Ken D

    2012-03-15

    Obstructive sleep apnoea syndrome (OSAS) is a common respiratory disorder characterized by chronic intermittent hypoxia (CIH). We have shown that CIH causes upper airway muscle dysfunction in the rat due to oxidative stress. Ageing is an independent risk factor for the development of OSAS perhaps due to respiratory muscle remodelling and increased susceptibility to hypoxia. We sought to examine the effects of CIH on breathing and pharyngeal dilator muscle structure and function in aged rats. Aged (18-20 months), male Wistar rats were exposed to alternating cycles of normoxia and hypoxia (90 s each; F(I)O(2)=5% O(2) at nadir) or sham treatment for 8h/day for 9 days. Following CIH exposure, breathing was assessed by whole-body plethysmography. In addition, sternohyoid muscle contractile and endurance properties were examined in vitro. Muscle fibre type and cross-sectional area, and the activity of key oxidative and glycolytic enzymes were determined. CIH had no effect on basal breathing or ventilatory responses to hypoxia or hypercapnia. CIH did not alter succinate dehydrogenase or glycerol phosphate dehydrogenase enzyme activities, myosin heavy chain fibre areal density or cross-sectional area. Sternohyoid muscle force and endurance were unaffected by CIH exposure. Since we have established that this CIH paradigm causes sternohyoid muscle weakness in adult male rats, we conclude that aged rats have decreased susceptibility to CIH-induced stress. We suggest that structural remodelling with improved hypoxic tolerance in upper airway muscles may partly compensate for impaired neural regulation of the upper airway and increased propensity for airway collapse in aged mammals. PMID:22122888

  5. Pediatric airway reconstruction with a prefabricated auricular cartilage and radial forearm free flap.

    PubMed

    Ahmad, Faisal I; O'Dell, Karla; Peck, Jessica J; Wax, Mark K; Milczuk, Henry A

    2015-08-01

    Prefabricated composite free flaps for complex airway reconstruction have been described for an adult series at our institution. We extended this approach to a pediatric patient with lifelong subglottic stenosis who had failed previous open airway reconstructions. A staged procedure was utilized in which a composite graft was created using conchal cartilages and a radial forearm free flap. This reconstruction improved the patency of her airway and decreased her dependency on intermittent airway dilations. Airway reconstruction with prefabricated conchal cartilage composite free flaps may be used as a salvage procedure for complex pediatric airway reconstruction when other methods have failed. PMID:25645935

  6. Effects of lung inflation on airway heterogeneity during histaminergic bronchoconstriction.

    PubMed

    Kaczka, David W; Mitzner, Wayne; Brown, Robert H

    2013-09-01

    Lung inflation has been shown to dilate airways by altering the mechanical equilibrium between opposing airway and parenchymal forces. However, it is not known how heterogeneously such dilation occurs throughout the airway tree. In six anesthetized dogs, we measured the diameters of five to six central airway segments using high-resolution computed tomography, along with respiratory input impedance (Zrs) during generalized aerosol histamine challenge, and local histamine challenge in which the agonist was instilled directly onto the epithelia of the imaged central airways. Airway diameters and Zrs were measured at 12 and 25 cmH2O. The Zrs spectra were fitted with a model that incorporated continuous distributions of airway resistances. Airway heterogeneity was quantified using the coefficient of variation for predefined airway distribution functions. Significant reductions in average central airway diameter were observed at 12 cmH2O for both aerosolized and local challenges, along with significant increases upon inflation to 25 cmH2O. No significant differences were observed for the coefficient of variation of airway diameters under any condition. Significant increases in effective airway resistance as measured by Zrs were observed only for the aerosolized challenge at 12 cmH2O, which was completely reversed upon inflation. We conclude that the lung periphery may be the most dominant contributor to increases in airway resistance and tissue elastance during bronchoconstriction induced by aerosolized histamine. However, isolated constriction of only a few central airway segments may also affect tissue stiffness via interdependence with their surrounding parenchyma. PMID:23813528

  7. Chronic sustained hypoxia-induced redox remodeling causes contractile dysfunction in mouse sternohyoid muscle.

    PubMed

    Lewis, Philip; Sheehan, David; Soares, Renata; Varela Coelho, Ana; O'Halloran, Ken D

    2015-01-01

    Chronic sustained hypoxia (CH) induces structural and functional adaptations in respiratory muscles of animal models, however the underlying molecular mechanisms are unclear. This study explores the putative role of CH-induced redox remodeling in a translational mouse model, with a focus on the sternohyoid-a representative upper airway dilator muscle involved in the control of pharyngeal airway caliber. We hypothesized that exposure to CH induces redox disturbance in mouse sternohyoid muscle in a time-dependent manner affecting metabolic capacity and contractile performance. C57Bl6/J mice were exposed to normoxia or normobaric CH (FiO2 = 0.1) for 1, 3, or 6 weeks. A second cohort of animals was exposed to CH for 6 weeks with and without antioxidant supplementation (tempol or N-acetyl cysteine in the drinking water). Following CH exposure, we performed 2D redox proteomics with mass spectrometry, metabolic enzyme activity assays, and cell-signaling assays. Additionally, we assessed isotonic contractile and endurance properties ex vivo. Temporal changes in protein oxidation and glycolytic enzyme activities were observed. Redox modulation of sternohyoid muscle proteins key to contraction, metabolism and cellular homeostasis was identified. There was no change in redox-sensitive proteasome activity or HIF-1α content, but CH decreased phospho-JNK content independent of antioxidant supplementation. CH was detrimental to sternohyoid force- and power-generating capacity and this was prevented by chronic antioxidant supplementation. We conclude that CH causes upper airway dilator muscle dysfunction due to redox modulation of proteins key to function and homeostasis. Such changes could serve to further disrupt respiratory homeostasis in diseases characterized by CH such as chronic obstructive pulmonary disease. Antioxidants may have potential use as an adjunctive therapy in hypoxic respiratory disease. PMID:25941492

  8. Chronic sustained hypoxia-induced redox remodeling causes contractile dysfunction in mouse sternohyoid muscle

    PubMed Central

    Lewis, Philip; Sheehan, David; Soares, Renata; Varela Coelho, Ana; O'Halloran, Ken D.

    2015-01-01

    Chronic sustained hypoxia (CH) induces structural and functional adaptations in respiratory muscles of animal models, however the underlying molecular mechanisms are unclear. This study explores the putative role of CH-induced redox remodeling in a translational mouse model, with a focus on the sternohyoid—a representative upper airway dilator muscle involved in the control of pharyngeal airway caliber. We hypothesized that exposure to CH induces redox disturbance in mouse sternohyoid muscle in a time-dependent manner affecting metabolic capacity and contractile performance. C57Bl6/J mice were exposed to normoxia or normobaric CH (FiO2 = 0.1) for 1, 3, or 6 weeks. A second cohort of animals was exposed to CH for 6 weeks with and without antioxidant supplementation (tempol or N-acetyl cysteine in the drinking water). Following CH exposure, we performed 2D redox proteomics with mass spectrometry, metabolic enzyme activity assays, and cell-signaling assays. Additionally, we assessed isotonic contractile and endurance properties ex vivo. Temporal changes in protein oxidation and glycolytic enzyme activities were observed. Redox modulation of sternohyoid muscle proteins key to contraction, metabolism and cellular homeostasis was identified. There was no change in redox-sensitive proteasome activity or HIF-1α content, but CH decreased phospho-JNK content independent of antioxidant supplementation. CH was detrimental to sternohyoid force- and power-generating capacity and this was prevented by chronic antioxidant supplementation. We conclude that CH causes upper airway dilator muscle dysfunction due to redox modulation of proteins key to function and homeostasis. Such changes could serve to further disrupt respiratory homeostasis in diseases characterized by CH such as chronic obstructive pulmonary disease. Antioxidants may have potential use as an adjunctive therapy in hypoxic respiratory disease. PMID:25941492

  9. A systematic study on the influence of the main ingredients of an ivy leaves dry extract on the β2-adrenergic responsiveness of human airway smooth muscle cells.

    PubMed

    Greunke, Christian; Hage-Hülsmann, Anne; Sorkalla, Thomas; Keksel, Nelli; Häberlein, Felix; Häberlein, Hanns

    2015-04-01

    The bronchospasmolytic and secretolytic effects of ivy leaves dry extracts can be explained by an increased β2-adrenergic responsiveness of the bronchi. Recently, it was shown that α-hederin inhibits the internalization of β2-adrenergic receptors (ß2AR) under stimulating conditions. α-Hederin pretreated alveolar type II cells and human airway smooth muscle cells revealed an increased ß2AR binding and an elevated intracellular cAMP level, respectively. In order to identify whether additional compounds also mediate an increased β2-adrenergic responsiveness, we examined the ingredients of an ivy leaves dry extract (EA 575) protocatechuic acid, neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, rutin, kaempferol-3-O-rutinoside, 3,4-, 3,5- and 4,5-dicaffeoylquinic acid, hederacoside B, and β-hederin. Within all the tested substances, only β-hederin inhibited the internalization of GFP-tagged ß2AR in stably transfected HEK293 cells. Using fluorescence correlation spectroscopy β-hederin (1 μM, 24 h) pretreated HASM cells showed a statistically significant increase in the ß2AR binding from 33.0 ± 8.9% to 44.1 ± 11.5% which was distributed with 36.0 ± 9.5% for τbound1 and 8.1 ± 2.6% for τbound2, respectively (n = 8, p < 0.05). The increased binding was selectively found for the receptor-ligand complex with unrestricted lateral mobility (τbound1 of 0.9 ± 0.1 ms, D1 = 9.1 ± 0.2 μm(2)/s, n = 8), whereas the binding of ß2AR with hindered lateral mobility (τbound2 of 64.2 ± 47.6 ms, D2 = 0.15 ± 0.02 μm(2)/s, n = 8) was not affected. Compared to control cells, a statistically significant increase of 17.5 ± 6.4% (n = 4, p < 0.05) and 24.2 ± 5.8% (n = 4, p < 0.001) in the cAMP formation was found for β-hederin pretreated HASM cells after stimulation with 10 μM of terbutaline and simultaneous stimulation with 10 μM terbutaline and 10 μM forskolin, respectively. Within this systematic study

  10. Dilation and Curettage (D&C)

    MedlinePlus

    ... Advocacy For Patients About ACOG Dilation and Curettage (D&C) Home For Patients Search FAQs Dilation and ... FAQ062, February 2016 PDF Format Dilation and Curettage (D&C) Special Procedures What is dilation and curettage ( ...

  11. Airway and Extracellular Matrix Mechanics in COPD

    PubMed Central

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

    2015-01-01

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

  12. 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

    PubMed Central

    Belleau, Joseph T; Gandhi, Radha K; McPherson, Holly M; Lew, D Betty

    2005-01-01

    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 for new therapeutic options

  13. Bootstrapping Time Dilation Decoherence

    NASA Astrophysics Data System (ADS)

    Gooding, Cisco; Unruh, William G.

    2015-10-01

    We present a general relativistic model of a spherical shell of matter with a perfect fluid on its surface coupled to an internal oscillator, which generalizes a model recently introduced by the authors to construct a self-gravitating interferometer (Gooding and Unruh in Phys Rev D 90:044071, 2014). The internal oscillator evolution is defined with respect to the local proper time of the shell, allowing the oscillator to serve as a local clock that ticks differently depending on the shell's position and momentum. A Hamiltonian reduction is performed on the system, and an approximate quantum description is given to the reduced phase space. If we focus only on the external dynamics, we must trace out the clock degree of freedom, and this results in a form of intrinsic decoherence that shares some features with a proposed "universal" decoherence mechanism attributed to gravitational time dilation (Pikovski et al in Nat Phys, 2015). We note that the proposed decoherence remains present in the (gravity-free) limit of flat spacetime, emphasizing that the effect can be attributed entirely to proper time differences, and thus is not necessarily related to gravity. Whereas the effect described in (Pikovski et al in Nat Phys, 2015) vanishes in the absence of an external gravitational field, our approach bootstraps the gravitational contribution to the time dilation decoherence by including self-interaction, yielding a fundamentally gravitational intrinsic decoherence effect.

  14. Unwarranted Administration of Acetylcholinesterase Inhibitors Can Impair Genioglossus and Diaphragm Muscle Function

    PubMed Central

    Eikermann, Matthias; Fassbender, Philipp; Malhotra, Atul; Takahashi, Masaya; Kubo, Shigeto; Jordan, Amy S.; Gautam, Shiva; White, David P.; Chamberlin, Nancy L.

    2012-01-01

    Background It is standard practice to administer a cholinesterase inhibitor (e.g., neostigmine) at the end of a surgical case to reverse suspected effects of neuromuscular blocking agents regardless of whether such residual effects are present. The authors hypothesized that cholinesterase inhibition when given the in absence of neuromuscular blockade (NB) would decrease upper airway dilatory muscle activity and consequently upper airway volume. Methods The authors measured genioglossus and diaphragm electromyograms during spontaneous ventilation in anesthetized, tracheostomized rats before and after administration of neostigmine (0.03, 0.06, or 0.12 mg/kg), after recovery of the train-of-four ratio (quadriceps femoris muscle) to unity after NB (n = 18). For comparison, the authors made the same measurements in rats that had no previous NB (n = 27). In intact anesthetized rats, the authors measured upper airway volume and end-expiratory lung volume by magnetic resonance imaging before and after 0.12 mg/kg neostigmine (n = 9). Results Neostigmine treatment in rats that had fully recovered from NB based on the train-of-four ratio caused dose-dependent decreases in genioglossus electromyogram (to 70.3 = 7.6, 49.2 = 3.2, and 39.7 = 2.3% of control, respectively), decreases in diaphragm electromyogram (to 103.1 ± 6.5, 83.1 ± 4.7, and 68.7 ± 7.3% of control), and decreases in minute ventilation to a nadir value of 79.6 ± 6% of preneostigmine baseline. Genioglossus electromyogram effects were the same when neostigmine was given with no previous NB. Neostigmine caused a decrease in upper airway volume to 83 ± 3% of control, whereas end-expiratory lung volume remained constant. Conclusions The cholinesterase inhibitor neostigmine markedly impairs upper airway dilator volume, genioglossus muscle function, diaphragmatic function, and breathing when given after recovery from vecuronium-induced neuromuscular block. PMID:17893459

  15. A quantitative histological analysis of the dilated ureter of childhood.

    PubMed

    Lee, B R; Partin, A W; Epstein, J I; Quinlan, D M; Gosling, J A; Gearhart, J P

    1992-11-01

    A quantitative histological study of the dilated ureter of childhood was performed on 26 ureters. The specimens were from 15 male and 11 female patients 10 days to 12 years old (mean age 2.0 years). A color image analysis system was used to examine and compare collagen and smooth muscle components of the muscularis layers to normal control ureters of similar age. In comparing primary obstructed (12) to primary refluxing (14) megaureters and control ureters (6), there was a statistically different collagen-to-smooth muscle ratio (p < 0.001) between the primary obstructed and primary refluxing megaureter groups. For patients with primary refluxing megaureter there was a 2-fold increase in the tissue matrix ratio of collagen-to-smooth muscle when compared to patients with primary obstructed megaureter. In the primary obstructed megaureters the amount of collagen and smooth muscle was not statistically different from controls (p > 0.01). The increased tissue matrix ratio of 2.0 +/- 0.35 (collagen-to-smooth muscle) in the refluxing megaureter group compared to 0.78 +/- 0.22 in the obstructed megaureter group and 0.52 +/- 0.12 in controls was found to be due not only to a marked increase in collagen but also a significant decrease in the smooth muscle component of the tissue. Primary obstructed and normal control ureters had similar quantitative amounts of smooth muscle with 60 +/- 5% and 61 +/- 6%, respectively, while refluxing megaureters had only 40 +/- 5% smooth muscle. The percentage collagen was 36 +/- 5 in the obstructed megaureter group and 30 +/- 5 in controls, with refluxing megaureters having 58 +/- 5% collagen on analysis. Our findings emphasize the significant differences in the structural components (collagen and smooth muscle) of the dilated ureter of childhood, and provide us with further insight into the pathological nature of these dilated ureters and their surgical repair. PMID:1433552

  16. Emergency airway puncture

    MedlinePlus

    Emergency airway puncture is the placement of a hollow needle through the throat into the airway. It ... Emergency airway puncture is done in an emergency situation, when someone is choking and all other efforts ...

  17. Blockage of upper airway

    MedlinePlus

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

  18. Bronchoconstriction and airway biology: potential impact and therapeutic opportunities.

    PubMed

    Gosens, Reinoud; Grainge, Chris

    2015-03-01

    Recent work has demonstrated that mechanical forces occurring in the airway as a consequence of bronchoconstriction are sufficient to not only induce symptoms but also influence airway biology. Animal and human in vitro and in vivo work demonstrates that the airways are structurally and functionally altered by mechanical stress induced by bronchoconstriction. Compression of the airway epithelium and mechanosensing by the airway smooth muscle trigger the activation and release of growth factors, causing cell proliferation, extracellular matrix protein accumulation, and goblet cell differentiation. These effects of bronchoconstriction are of major importance to asthma pathophysiology and appear sufficient to induce remodeling independent of the inflammatory response. We review these findings in detail and discuss previous studies in light of this new evidence regarding the influence of mechanical forces in the airways. Furthermore, we highlight potential impacts of therapies influencing mechanical forces on airway structure and function in asthma. PMID:25732446

  19. Regulation of airway neurogenic inflammation by neutral endopeptidase.

    PubMed

    Di Maria, G U; Bellofiore, S; Geppetti, P

    1998-12-01

    Airway neurogenic inflammation is caused by tachykinins released from peripheral nerve endings of sensory neurons within the airways, and is characterized by plasma protein extravasation, airway smooth muscle contraction and increased secretion of mucus. Tachykinins are degraded and inactivated by neutral endopeptidase (NEP), a membrane-bound metallopeptidase, which is located mainly at the surface of airway epithelial cells, but is also present in airway smooth muscle cells, submucosal gland cells and fibroblasts. The key role of NEP in limiting and regulating the neurogenic inflammation provoked by different stimuli has been demonstrated in a large series of studies published in recent years. It has also been shown that a variety of factors, which are relevant for airway diseases, including viral infections, allergen exposure, inhalation of cigarette smoke and other respiratory irritants, is able to reduce NEP activity, thus enhancing the effects of tachykinins within the airways. On the basis of these observations, the reduction of neutral endopeptidase activity may be regarded as a factor that switches neurogenic airway responses from their physiological and protective functions to a detrimental role that increases and perpetuates airway inflammation. However, further studies are needed to assess the role of neutral endopeptidase down regulation in the pathogenesis of asthma and other inflammatory airway diseases. PMID:9877509

  20. A case of pregnancy complicated with dilated cardiomyopathy 1X

    PubMed Central

    Oki, Shinya; Nagamatsu, Takeshi; Iriyama, Takayuki; Komatsu, Atsushi; Osuga, Yutaka; Fujii, Tomoyuki

    2015-01-01

    Dilated cardiomyopathy 1X (CMD1X) is characterized by dilated cardiomyopathy (DCM) with mildest limb-girdle muscle symptoms and normal intelligence. Compound heterozygous mutation in fukutin gene is known as its genetic cause. Here, we report a pregnancy case complicated with CMD1X. A 25-year-old primiparous woman, who had been diagnosed as CMD1X at the age of 19, was referred to our hospital at 6 weeks of gestation. In early pregnancy, the evaluation of her cardiac function showed ejection fraction 47% and NYHA class II. Worsening of cardiac function was observed from 30 weeks, manifesting reduced cardiac load with left ventricular dilatation and in-hospital bed rest was necessary. Elective cesarean section was performed at 35 weeks to prevent deterioration of cardiac function. The parameters of her cardiac function returned to the pre-pregnancy status in a month after delivery, whereas she realized persistent worsening of muscular weakness at postpartum. PMID:26566449

  1. Dilatancy in Slow Granular Flows

    NASA Astrophysics Data System (ADS)

    Kabla, Alexandre J.; Senden, Tim J.

    2009-06-01

    When walking on wet sand, each footstep leaves behind a temporarily dry impression. This counterintuitive observation is the most common illustration of the Reynolds principle of dilatancy: that is, a granular packing tends to expand as it is deformed, therefore increasing the amount of porous space. Although widely called upon in areas such as soil mechanics and geotechnics, a deeper understanding of this principle is constrained by the lack of analytical tools to study this behavior. Using x-ray radiography, we track a broad variety of granular flow profiles and quantify their intrinsic dilatancy behavior. These measurements frame Reynolds dilatancy as a kinematic process. Closer inspection demonstrates, however, the practical importance of flow induced compaction which competes with dilatancy, leading more complex flow properties than expected.

  2. Dilatancy in slow granular flows.

    PubMed

    Kabla, Alexandre J; Senden, Tim J

    2009-06-01

    When walking on wet sand, each footstep leaves behind a temporarily dry impression. This counterintuitive observation is the most common illustration of the Reynolds principle of dilatancy: that is, a granular packing tends to expand as it is deformed, therefore increasing the amount of porous space. Although widely called upon in areas such as soil mechanics and geotechnics, a deeper understanding of this principle is constrained by the lack of analytical tools to study this behavior. Using x-ray radiography, we track a broad variety of granular flow profiles and quantify their intrinsic dilatancy behavior. These measurements frame Reynolds dilatancy as a kinematic process. Closer inspection demonstrates, however, the practical importance of flow induced compaction which competes with dilatancy, leading more complex flow properties than expected. PMID:19658906

  3. A long-acting β2-adrenergic agonist increases the expression of muscarine cholinergic subtype-3 receptors by activating the β2-adrenoceptor cyclic adenosine monophosphate signaling pathway in airway smooth muscle cells

    PubMed Central

    LIU, YUAN-HUA; WU, SONG-ZE; WANG, GANG; HUANG, NI-WEN; LIU, CHUN-TAO

    2015-01-01

    The persistent administration of β2-adrenergic (β2AR) agonists has been demonstrated to increase the risk of severe asthma, partly due to the induction of tolerance to bronchoprotection via undefined mechanisms. The present study investigated the potential effect of the long-acting β2-adrenergic agonist, formoterol, on the expression of muscarinic M3 receptor (M3R) in rat airway smooth muscle cells (ASMCs). Primary rat ASMCs were isolated and characterized following immunostaining with anti-α-smooth muscle actin antibodies. The protein expression levels of M3R and phospholipase C-β1 (PLCβ1) were characterized by western blot analysis and the production of inositol 1,4,5-trisphosphate (IP3) was determined using an enzyme-linked immunosorbent assay. Formoterol increased the protein expression of M3R in rat ASMCs in a time- and dose-dependent manner, which was significantly inhibited by the β2AR antagonist, ICI118,551 and the cyclic adenosine monophosphate (cAMP) inhibitor, SQ22,536. The increased protein expression of M3R was positively correlated with increased production of PLCβ1 and IP3. Furthermore, treatment with the glucocorticoid, budesonide, and the PLC inhibitor, U73,122, significantly suppressed the formoterol-induced upregulated protein expression levels of M3R and PLCβ1 and production of IP3. The present study demonstrated that formoterol mediated the upregulation of M3R in the rat ASMCs by activating the β2AR-cAMP signaling pathway, resulting in increased expression levels of PLCβ1 and IP3, which are key to inducing bronchoprotection tolerance. Administration of glucocorticoids or a PLC antagonist prevented formoterol-induced bronchoprotection tolerance by suppressing the protein expression of M3R. PMID:25672589

  4. Sensory neuropeptides and airway function.

    PubMed

    Solway, J; Leff, A R

    1991-12-01

    Sensory nerves synthesize tachykinins and calcitonin-gene related peptide and package these neuropeptides together in synaptic vesicles. Stimulation of these C-fibers by a range of chemical and physical factors results in afferent neuronal conduction that elicits central parasympathetic reflexes and in antidromic conduction that results in local release of neuropeptides through the axon reflex. In the airways, sensory neuropeptides act on bronchial smooth muscle, the mucosal vasculature, and submucosal glands to promote airflow obstruction, hyperemia, microvascular hyperpermeability, and mucus hypersecretion. In addition, tachykinins potentiate cholinergic neurotransmission. Proinflammatory effects of these peptides also promote the recruitment, adherence, and activation of granulocytes that may further exacerbate neurogenic inflammation (i.e., neuropeptide-induced plasma extravasation and vasodilation). Enzymatic degradation limits the physiological effects of tachykinins but may be impaired by respiratory infection or other factors. Given their sensitivity to noxious compounds and physical stimuli and their potent effects on airway function, it is possible that neuropeptide-containing sensory nerves play an important role in mediating airway responses in human disease. Supporting this view are the striking phenomenological similarities between hyperpnea-induced bronchoconstriction (HIB) in guinea pigs and HIB in patients with exercise-induced asthma. Endogenous tachykinins released from airway sensory nerves mediate HIB in guinea pigs and also cause hyperpnea-induced bronchovascular hyperpermeability in these animals. On the basis of these observations, it is reasonable to speculate that sensory neuropeptides participate in the pathogenesis of hyperpnea-induced airflow obstruction in human asthmatic subjects as well. PMID:1663932

  5. Dilatational band formation in bone

    PubMed Central

    Poundarik, Atharva A.; Diab, Tamim; Sroga, Grazyna E.; Ural, Ani; Boskey, Adele L.; Gundberg, Caren M.; Vashishth, Deepak

    2012-01-01

    Toughening in hierarchically structured materials like bone arises from the arrangement of constituent material elements and their interactions. Unlike microcracking, which entails micrometer-level separation, there is no known evidence of fracture at the level of bone’s nanostructure. Here, we show that the initiation of fracture occurs in bone at the nanometer scale by dilatational bands. Through fatigue and indentation tests and laser confocal, scanning electron, and atomic force microscopies on human and bovine bone specimens, we established that dilatational bands of the order of 100 nm form as ellipsoidal voids in between fused mineral aggregates and two adjacent proteins, osteocalcin (OC) and osteopontin (OPN). Laser microdissection and ELISA of bone microdamage support our claim that OC and OPN colocalize with dilatational bands. Fracture tests on bones from OC and/or OPN knockout mice (OC−/−, OPN−/−, OC-OPN−/−;−/−) confirm that these two proteins regulate dilatational band formation and bone matrix toughness. On the basis of these observations, we propose molecular deformation and fracture mechanics models, illustrating the role of OC and OPN in dilatational band formation, and predict that the nanometer scale of tissue organization, associated with dilatational bands, affects fracture at higher scales and determines fracture toughness of bone. PMID:23129653

  6. Airway wall eosinophilia is not a feature of equine heaves.

    PubMed

    Dubuc, J; Lavoie, J-P

    2014-11-01

    The objective of this study was to determine whether eosinophils infiltrate the airway wall of horses with heaves. Eosinophils were evaluated using paraffin embedded lung tissues from six heaves-affected horses in crisis and six aged-matched controls. Slides were stained using Luna's method and eosinophils enumerated using histomorphometric techniques. Total eosinophil counts (expressed per mm(2) of basement membrane) were significantly higher in the airways of controls horses than in horses with heaves. Intraluminal, intraepithelial, and airway smooth muscle eosinophils counts were also increased in control horses. The results suggest that eosinophils do not contribute to the persistent airway obstruction in heaves. PMID:25239297

  7. Dynamics of airway response in lung microsections: a tool for studying airway-extra cellular matrix interactions.

    PubMed

    Khan, Mohammad Afzal

    2016-01-01

    The biological configuration of extracellular matrix (ECM) plays a key role in how mechanical interactions of the airway with its parenchymal attachments affect the dynamics of airway responses in different pulmonary disorders including asthma, emphysema and chronic bronchitis. It is now recognized that mechanical interactions between airway tissue and ECM play a key regulatory role on airway physiology and kinetics that can lead to the reorganization and remodeling of airway connective tissue. A connective tissue is composed of airway smooth muscle cells (ASM) and the ECM, which includes variety of glycoproteins and therefore the extent of interactions between ECM and ASM affects airway dynamics during exacerbations of major pulmonary disorders. Measurement of the velocity and magnitude of airway closure or opening provide important insights into the functions of the airway contractile apparatus and the interactions with its surrounding connective tissues. This review highlights suitability of lung microsection technique in studying measurements of airway dynamics (narrowing/opening) and associated structural distortions in airway compartments. PMID:27176036

  8. Long-term effects of acupuncture treatment on airway smooth muscle in a rat model of smoke-induced chronic obstructive pulmonary disease

    PubMed Central

    Li, Jia; Wu, Song; Tang, Hongtu; Huang, Wei; Wang, Lushan; Zhou, Huanjiao; Zhou, Miao; Wang, Hua; Li, Jing

    2016-01-01

    Background Chronic obstructive pulmonary disease (COPD) is one of the most common lung diseases. It is a chronic inflammatory process characterised by airway obstruction and progressive lung inflammation, associated with difficulty breathing and insensitivity to corticosteroid therapy. Although there is some preliminary evidence to suggest a beneficial effect of acupuncture on COPD, its mechanism of action has not been investigated. Our aim was to examine the anti-inflammatory effects of acupuncture in a rat model of COPD induced by exposure to cigarette smoke (CS). Methods Sixty Sprague–Dawley rats were exposed to the smoke of 15 cigarettes for 1 h/day, 6 days/week for 3 months to induce COPD and treated with acupuncture at BL13 (Feishu), BL23 (Shenshu) and Dingchuan (COPD+Acupuncture, n=15), sham acupuncture (COPD+Sham, n=15) or left untreated (n=15). Exposed rats were compared with controls not exposed to CS (control, n=15). Pulmonary function was measured, and tumour necrosis factor-α (TNF-α) and interleukin-8 (IL-8) levels were determined in bronchoalveolar lavage fluid by ELISA. Histone deacetylase 2 (HDAC2) protein and mRNA expression were examined in lung tissue and in bronchus. Results Acupuncture treatment appeared to protect pulmonary function and reduce the COPD-induced inflammatory response by decreasing cell inflammation and the production of TNF-α and IL-8. Acupuncture also enhanced HDAC2 mRNA and protein expression, suggesting a possible direct effect on protein structure through post-translational modifications. Conclusions Our results suggest that acupuncture regulates inflammatory cytokines and contributes to lung protection in a rat model of smoke-induced COPD by modulating HDAC2. PMID:26345700

  9. Overexpression of Smad2 Drives House Dust Mite–mediated Airway Remodeling and Airway Hyperresponsiveness via Activin and IL-25

    PubMed Central

    Gregory, Lisa G.; Mathie, Sara A.; Walker, Simone A.; Pegorier, Sophie; Jones, Carla P.; Lloyd, Clare M.

    2010-01-01

    Rationale: Airway hyperreactivity and remodeling are characteristic features of asthma. Interactions between the airway epithelium and environmental allergens are believed to be important in driving development of pathology, particularly because altered epithelial gene expression is common in individuals with asthma. Objectives: To investigate the interactions between a modified airway epithelium and a common aeroallergen in vivo. Methods: We used an adenoviral vector to generate mice overexpressing the transforming growth factor-β signaling molecule, Smad2, in the airway epithelium and exposed them to house dust mite (HDM) extract intranasally. Measurements and Main Results: Smad2 overexpression resulted in enhanced airway hyperreactivity after allergen challenge concomitant with changes in airway remodeling. Subepithelial collagen deposition was increased and smooth muscle hyperplasia was evident resulting in thickening of the airway smooth muscle layer. However, there was no increase in airway inflammation in mice given the Smad2 vector compared with the control vector. Enhanced airway hyperreactivity and remodeling did not correlate with elevated levels of Th2 cytokines, such as IL-13 or IL-4. However, mice overexpressing Smad2 in the airway epithelium showed significantly enhanced levels of IL-25 and activin A after HDM exposure. Blocking activin A with a neutralizing antibody prevented the increase in lung IL-25 and inhibited subsequent collagen deposition and also the enhanced airway hyperreactivity observed in the Smad2 overexpressing HDM-exposed mice. Conclusions: Epithelial overexpression of Smad2 can specifically alter airway hyperreactivity and remodeling in response to an aeroallergen. Moreover, we have identified novel roles for IL-25 and activin A in driving airway hyperreactivity and remodeling. PMID:20339149

  10. Early Life Exposure to Chronic Intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle during Adulthood.

    PubMed

    McDonald, Fiona B; Dempsey, Eugene M; O'Halloran, Ken D

    2016-01-01

    Intermittent hypoxia is a feature of apnea of prematurity (AOP), chronic lung disease, and sleep apnea. Despite the clinical relevance, the long-term effects of hypoxic exposure in early life on respiratory control are not well defined. We recently reported that exposure to chronic intermittent hypoxia (CIH) during postnatal development (pCIH) causes upper airway muscle weakness in both sexes, which persists for several weeks. We sought to examine if there are persistent sex-dependent effects of pCIH on respiratory muscle function into adulthood and/or increased susceptibility to re-exposure to CIH in adulthood in animals previously exposed to CIH during postnatal development. We hypothesized that pCIH would cause long-lasting muscle impairment and increased susceptibility to subsequent hypoxia. Within 24 h of delivery, pups and their respective dams were exposed to CIH: 90 s of hypoxia reaching 5% O2 at nadir; once every 5 min, 8 h per day for 3 weeks. Sham groups were exposed to normoxia in parallel. Three groups were studied: sham; pCIH; and pCIH combined with adult CIH (p+aCIH), where a subset of the pCIH-exposed pups were re-exposed to the same CIH paradigm beginning at 13 weeks. Following gas exposures, sternohyoid and diaphragm muscle isometric contractile and endurance properties were examined ex vivo. There was no apparent lasting effect of pCIH on respiratory muscle function in adults. However, in both males and females, re-exposure to CIH in adulthood in pCIH-exposed animals caused sternohyoid (but not diaphragm) weakness. Exposure to this paradigm of CIH in adulthood alone had no effect on muscle function. Persistent susceptibility in pCIH-exposed airway dilator muscle to subsequent hypoxic insult may have implications for the control of airway patency in adult humans exposed to intermittent hypoxic stress during early life. PMID:26973537

  11. Early Life Exposure to Chronic Intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle during Adulthood

    PubMed Central

    McDonald, Fiona B.; Dempsey, Eugene M.; O'Halloran, Ken D.

    2016-01-01

    Intermittent hypoxia is a feature of apnea of prematurity (AOP), chronic lung disease, and sleep apnea. Despite the clinical relevance, the long-term effects of hypoxic exposure in early life on respiratory control are not well defined. We recently reported that exposure to chronic intermittent hypoxia (CIH) during postnatal development (pCIH) causes upper airway muscle weakness in both sexes, which persists for several weeks. We sought to examine if there are persistent sex-dependent effects of pCIH on respiratory muscle function into adulthood and/or increased susceptibility to re-exposure to CIH in adulthood in animals previously exposed to CIH during postnatal development. We hypothesized that pCIH would cause long-lasting muscle impairment and increased susceptibility to subsequent hypoxia. Within 24 h of delivery, pups and their respective dams were exposed to CIH: 90 s of hypoxia reaching 5% O2 at nadir; once every 5 min, 8 h per day for 3 weeks. Sham groups were exposed to normoxia in parallel. Three groups were studied: sham; pCIH; and pCIH combined with adult CIH (p+aCIH), where a subset of the pCIH-exposed pups were re-exposed to the same CIH paradigm beginning at 13 weeks. Following gas exposures, sternohyoid and diaphragm muscle isometric contractile and endurance properties were examined ex vivo. There was no apparent lasting effect of pCIH on respiratory muscle function in adults. However, in both males and females, re-exposure to CIH in adulthood in pCIH-exposed animals caused sternohyoid (but not diaphragm) weakness. Exposure to this paradigm of CIH in adulthood alone had no effect on muscle function. Persistent susceptibility in pCIH-exposed airway dilator muscle to subsequent hypoxic insult may have implications for the control of airway patency in adult humans exposed to intermittent hypoxic stress during early life. PMID:26973537

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

    PubMed

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

    2012-12-01

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

  13. Upper airway test (image)

    MedlinePlus

    An upper airway biopsy is obtained by using a flexible scope called a bronchoscope. The scope is passed down through ... may be performed when an abnormality of the upper airway is suspected. It may also be performed as ...

  14. Platelet-derived-growth-factor stimulation of the p42/p44 mitogen-activated protein kinase pathway in airway smooth muscle: role of pertussis-toxin-sensitive G-proteins, c-Src tyrosine kinases and phosphoinositide 3-kinase.

    PubMed Central

    Conway, A M; Rakhit, S; Pyne, S; Pyne, N J

    1999-01-01

    The mechanism used by the platelet-derived growth factor receptor (PDGFR) to activate the mitogen-activated- protein-kinase (p42/p44 MAPK) pathway was investigated in cultured airway smooth muscle (ASM) cells. We have found that pertussis toxin (PTX, which was used to inactivate the heterotrimeric G-protein Gi) induced an approx. 40-50% decrease in the activation of c-Src and p42/p44 MAPK by PDGF. An essential role for c-Src was confirmed using the c-Src inhibitor, PP1, which abolished p42/p44 MAPK activation (PP1 and PTX were without effect on PDGFR tyrosine phosphorylation). Furthermore, the PTX-dependent decrease in c-Src and p42/p44 MAPK activation appeared correlated. These findings suggest that the PDGFR can utilize the PTX-sensitive G-protein, Gi, to regulate c-Src and subsequent p42/p44 MAPK activation. Phosphoinositide 3-kinase (PI3K) has been shown by others to be involved in p42/p44 MAPK activation. This is confirmed here by experiments which showed that PI3K inhibitors (wortmannin and LY294002) reduced the activation of p42/p44 MAPK by PDGF. PI3K activity was increased in Grb-2 immunoprecipitates from PDGF-stimulated cells and was decreased by pretreating these cells with PTX. These findings show that Gi might also promote Grb-2-PI3K complex formation and that Grb-2 may be a site at which PI3K is integrated into the p42/p44 MAPK cascade. In conclusion, our results demonstrate that Gi enables the PDGFR to signal more efficiently to p42/p44 MAPK, and this appears to be achieved through the regulation of c-Src and Grb-2/PI3K, which are intermediates in the p42/p44 MAPK cascade. PMID:9882612

  15. Sphingosine 1-phosphate stimulation of the p42/p44 mitogen-activated protein kinase pathway in airway smooth muscle. Role of endothelial differentiation gene 1, c-Src tyrosine kinase and phosphoinositide 3-kinase.

    PubMed Central

    Rakhit, S; Conway, A M; Tate, R; Bower, T; Pyne, N J; Pyne, S

    1999-01-01

    We report here that cultured airway smooth muscle cells contain transcripts of endothelial differentiation gene 1 (EDG-1), a prototypical orphan Gi-coupled receptor whose natural ligand is sphingosine 1-phosphate (S1P). This is consistent with data that showed that S1P activated both c-Src and p42/p44 mitogen-activated protein kinase (p42/p44 MAPK) in a pertussis toxin (PTX)-sensitive manner in these cells. An essential role for c-Src was confirmed by using the c-Src inhibitor, PP1, which markedly decreased p42/p44 MAPK activation. We have also shown that phosphoinositide 3-kinase (PI-3K) inhibitors (wortmannin and LY294002) decreased p42/p44 MAPK activation. An essential role for PI-3K was supported by experiments that showed that PI-3K activity was increased in Grb-2 immunoprecipitates from S1P-stimulated cells. Significantly, Grb-2 associated PI-3K activity was decreased by pretreatment of cells with PTX. Finally, we have shown that the co-stimulation of cells with platelet-derived growth factor (PDGF) and S1P (which failed to stimulate DNA synthesis) elicited a larger p42/p44 MAPK activation over a 30 min stimulation compared with each agonist alone. This was associated with a S1P-dependent increase in PDGF-stimulated DNA synthesis. These results demonstrate that S1P activates c-Src and Grb-2-PI-3K (intermediates in the p42/p44 MAPK cascade) via a PTX-sensitive mechanism. This action of S1P is consistent with the stimulation of EDG-1 receptors. S1P might also function as a co-mitogen with PDGF, producing a more robust activation of a common permissive signal transduction pathway linked to DNA synthesis. PMID:10051434

  16. Careers in Airway Science.

    ERIC Educational Resources Information Center

    Federal Aviation Administration (DOT), Washington, DC.

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

  17. Trichobezoar Causing Airway Compromise during Esophagogastroduodenoscopy.

    PubMed

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

    2015-01-01

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

  18. Trichobezoar Causing Airway Compromise during Esophagogastroduodenoscopy

    PubMed Central

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

    2015-01-01

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

  19. Exercise-induced airways constriction 1

    PubMed Central

    Simonsson, Bo G.; Skoogh, B-E.; Ekström-Jodal, B.

    1972-01-01

    Airway conductance was measured in a body plethysmograph at different lung volumes before and after graded exercise. In 14 out of 19 patients, mostly asthmatics, airway conductance fell significantly after exercise. These subjects also showed other signs of an increased bronchial reactivity to different stimuli, including forced breathing, hyperventilation, and cold air, but they had no exogenous allergy. The exercise-induced bronchoconstriction could be blocked by atropine in six of the nine patients tested. Exercise-induced bronchoconstriction in patients with clinical and physiological evidence of increased airway reactivity thus seems to be primarily mediated via a vagal reflex, probably from hyperresponsive airway mechanoreceptors reacting to increased ventilatory flow or lung distension. No relation was found between PaCO2 or pH and the severity of airways constriction. Cromoglycic acid failed to block the exercise reaction in five of the six hyperreactive patients tested. In addition to or following the vagal reflex a disturbed relation between beta and alpha receptors in bronchial muscles or a release of humoral spasmogens may contribute to the progression of post-exercise airways constriction. PMID:4624586

  20. Mechanical Properties of the Upper Airway

    PubMed Central

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

    2013-01-01

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

  1. Airway Surgery in Tracheostomised Patients with Wegener Granulomatosis Leading to Subglottic Stenosis.

    PubMed

    Altun, Demet; Sivrikoz, Nükhet; Çamcı, Emre

    2015-10-01

    Wegener granulomatosis (WG) is a multisystemic disorder characterised by granulomatous inflammation of the respiratory system. The growing of proliferative tissue towards the larynx and trachea may cause airway obstruction on account of subglottic stenosis. In this situation, the surgical goal is to eliminate the airway obstruction by providing natural airway anatomy. While mild lesions do not require surgical intervention, in fixed lesions, surgical intervention is required, such as tracheostomy, laser resection and dilatation. In tracheostomised patients, granuloma formation surrounding the tracheostomy cannula may occur in the trachea. Inflammation and newly formed granulation tissue result in severe stenosis in the airways. During surgical treatment of such patients, airway management is important. In this case report, we will discuss gas exchange and airway management with jet ventilation (JV) during excision of the granulation tissue with endolaryngeal laser surgery, leading to subglottic stenosis in tracheostomised patients in WG. PMID:27366530

  2. Current Treatment of Dilated Cardiomyopathy

    PubMed Central

    Massin, Edward K.

    1991-01-01

    Within the last decade, the treatment for patients with dilated cardiomyopathy has changed. Clinical management of these patients is aimed at controlling congestive heart failure, treating arrhythmias, preventing pulmonary and systemic emboli, and managing chest pain. The goals of treatment for patients with dilated cardiomyopathy are to make the patient feel better and live longer. To achieve this, we direct treatment to improving left ventricular function and cardiac output and controlling arrhythmias and thromboemboli. Basic treatment begins with inotropic therapy, preload reduction, and afterload reduction. For patients with symptomatic disease, we recommend diuretics, digoxin, and converting enzyme inhibitors for first-line therapy. Patients with arrhythmias may be treated by the addition of amiodarone, a pacemaker, or an automatic implantable cardioverter-defibrillator; and most such patients need to be anticoagulated. All patients need close follow-up for possible drug toxicity associated with their regimens. Heart transplantation can be considered for patients refractory to medical treatment. Although the incidence of dilated cardiomyopathy continues to increase, we are learning better ways to treat it. In the future, new drugs with fewer side effects should be available to treat, and perhaps impede, the development of dilated cardiomyopathy. (Texas Heart Institute Journal 1991;18:41-9) PMID:15227507

  3. Long-Acting Beta Agonists Enhance Allergic Airway Disease

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  5. Upper Airway Elasticity Estimation in Pediatric Down Syndrome Sleep Apnea Patients Using Collapsible Tube Theory.

    PubMed

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

    2016-05-01

    Elasticity of the soft tissues surrounding the upper airway lumen is one of the important factors contributing to upper airway disorders such as snoring and obstructive sleep apnea. The objective of this study is to calculate patient specific elasticity of the pharynx from magnetic resonance (MR) images using a 'tube law', i.e., the relationship between airway cross-sectional area and transmural pressure difference. MR imaging was performed under anesthesia in children with Down syndrome (DS) and obstructive sleep apnea (OSA). An airway segmentation algorithm was employed to evaluate changes in airway cross-sectional area dilated by continuous positive airway pressure (CPAP). A pressure-area relation was used to make localized estimates of airway wall stiffness for each patient. Optimized values of patient specific Young's modulus for tissue in the velopharynx and oropharynx, were estimated from finite element simulations of airway collapse. Patient specific deformation of the airway wall under CPAP was found to exhibit either a non-linear 'hardening' or 'softening' behavior. The localized airway and tissue elasticity were found to increase with increasing severity of OSA. Elasticity based patient phenotyping can potentially assist clinicians in decision making on CPAP and airway or tissue elasticity can supplement well-known clinical measures of OSA severity. PMID:26314989

  6. Medical management considerations for upper airway disease.

    PubMed

    Spaulding, G L

    1992-06-01

    The conducting airways, also commonly referred to as the upper airways, provide for the passage of air to and from the atmosphere and lungs. Anatomical components include the nasal passages, pharynx, larynx, trachea, and mainstem bronchi. Clinical problems involving the conducting airways can be manifested by relatively mild clinical signs of stertorous breathing, by life-threatening dyspnea, or by chronic bouts of inspiratory stridor and cough. Concurrent disease of the lower respiratory system (ie, chronic bronchitis) as well as other organ systems (ie, cardiovascular, nervous, endocrine) may significantly contribute to the etiology and pathophysiology of upper airway disease. Diagnosis of the diseases of the conducting airways is primarily based on history and physical examination. The dynamic nature of some conditions, related to the phases of respiration, can make diagnosis more difficult. In addition to direct visualization, radiographic and endoscopic evaluation are often useful. Many upper airway problems, especially congenital conditions, lend themselves to surgical palliation that should be performed as early in life as possible. Medical management is often directed at treating underlying diseases and the relief of clinical signs. Historically, the use of variety of drugs have been advocated and frequently include decongestants, cough suppressants, bronchodilators, glucocorticoids, and antibiotics. However, their use may be detrimental and contraindicated. In addition, therapy for some conditions (ie, laryngeal paralysis and intrathoracic tracheal collapse) may be better directed at increasing airway muscle tone in order to stabilized airway patency. Therapeutic agents that may be useful include aspirin and digitalis. The overall objective to medical management must be to balance potential therapeutic benefit against untoward effects in order to minimize clinical signs and to improve the animal's quality of life. PMID:1643322

  7. Genetics Home Reference: familial dilated cardiomyopathy

    MedlinePlus

    ... Related Dilated Cardiomyopathy Genetic Testing Registry (1 link) Primary dilated cardiomyopathy ClinicalTrials.gov (1 link) ClinicalTrials.gov Scientific articles on PubMed (1 link) PubMed OMIM (36 links) ...

  8. What Is a Comprehensive Dilated Eye Exam?

    MedlinePlus

    ... su oculista What is a comprehensive dilated eye exam? You may think your eyes are healthy, but ... eye care professional for a comprehensive dilated eye exam is the only way to really be sure. ...

  9. The Physiologically Difficult Airway.

    PubMed

    Mosier, Jarrod M; Joshi, Raj; Hypes, Cameron; Pacheco, Garrett; Valenzuela, Terence; Sakles, John C

    2015-12-01

    Airway management in critically ill patients involves the identification and management of the potentially difficult airway in order to avoid untoward complications. This focus on difficult airway management has traditionally referred to identifying anatomic characteristics of the patient that make either visualizing the glottic opening or placement of the tracheal tube through the vocal cords difficult. This paper will describe the physiologically difficult airway, in which physiologic derangements of the patient increase the risk of cardiovascular collapse from airway management. The four physiologically difficult airways described include hypoxemia, hypotension, severe metabolic acidosis, and right ventricular failure. The emergency physician should account for these physiologic derangements with airway management in critically ill patients regardless of the predicted anatomic difficulty of the intubation. PMID:26759664

  10. The Physiologically Difficult Airway

    PubMed Central

    Mosier, Jarrod M.; Joshi, Raj; Hypes, Cameron; Pacheco, Garrett; Valenzuela, Terence; Sakles, John C.

    2015-01-01

    Airway management in critically ill patients involves the identification and management of the potentially difficult airway in order to avoid untoward complications. This focus on difficult airway management has traditionally referred to identifying anatomic characteristics of the patient that make either visualizing the glottic opening or placement of the tracheal tube through the vocal cords difficult. This paper will describe the physiologically difficult airway, in which physiologic derangements of the patient increase the risk of cardiovascular collapse from airway management. The four physiologically difficult airways described include hypoxemia, hypotension, severe metabolic acidosis, and right ventricular failure. The emergency physician should account for these physiologic derangements with airway management in critically ill patients regardless of the predicted anatomic difficulty of the intubation. PMID:26759664

  11. Usefulness of sugammadex in a patient with Becker muscular dystrophy and dilated cardiomyopathy.

    PubMed

    Shimauchi, Tsukasa; Yamaura, Ken; Sugibe, Sayaka; Hoka, Sumio

    2014-09-01

    A 54-year-old patient with Becker muscular dystrophy and dilated cardiomyopathy underwent laparoscopic cholecystectomy under total intravenous anesthesia. Muscle relaxation was induced by rocuronium (0.4 mg/kg body weight) under train-of-four (TOF) ratio monitoring. The TOF ratio was 0 at intubation, and 0.2 at the end of surgery. Residual muscle relaxant activity was successfully reversed by sugammadex (2 mg/kg body weight) without any hemodynamic adverse effects (TOF ratio 1.0 at extubation). The clinical and hemodynamic findings suggest that sugammadex can be safely used in patients with Becker muscular dystrophy and dilated cardiomyopathy. PMID:25199695

  12. Noninvasive clearance of airway secretions.

    PubMed

    Hardy, K A; Anderson, B D

    1996-06-01

    or airway malacia. Use of positive pressure to maintain airway patency in these children allows cephalad clearance of secretions. Patients with segmental atelectasis, particularly related to asthma, may benefit from intrapulmonary percussive ventilator, positive expiratory pressure, or PDPV. Prevention of postoperative atelectasis is particularly well suited to positive expiratory pressure, which is not as painful as techniques using oscillations. Neurologically abnormal patients who are unable to cooperate with any active method are also treated using intrapulmonary percussive ventilator, PDPV, and suctioning, if necessary. Musculoskeletal abnormalities, muscular dystrophies, myasthenia gravis, poliomyelitis, or other similar diseases require stabilization of bellows function. Optimizing ventilation in patients with such abnormalities may require positive pressure ventilation either during sleep or continuously. Externally applied pressure, such as with the In-Exsufflator or the cyclically inflated pneumatic belt, can augment the patient's own efforts and is sometimes helpful. Normalizing the vital capacity and functional residual capacity typically helps to improve the ability to cough and clear secretions. Assisted cough devices or maneuvers are described in other papers by Bach and Hill. Not all patients who have weak muscles require nocturnal or continuous support, and may benefit from positive expiratory pressure mask treatments. Further studies are sorely needed for this population. Long-term controlled trials are urgently needed to help establish the best types of treatment for patients with CF and bronchiectasis. Such studies will become more complicated by the introduction of new treatments, such as DNase and other therapies that alter secretions, and may begin to change mucociliary or cough clearance. The selection of appropriate outcome measures is central to studying these questions, and it is unclear which are the most important. (ABSTRACT TRUNCATED

  13. Clinical management of dilated cardiomyopathy: current knowledge and future perspectives.

    PubMed

    Merlo, Marco; Cannatá, Antonio; Vitagliano, Alice; Zambon, Elena; Lardieri, Gerardina; Sinagra, Gianfranco

    2016-01-01

    Dilated cardiomyopathy (DCM) is a primary heart muscle disease characterized by a progressive dilation and dysfunction of either the left or both ventricles. The management of DCM is currently challenging for clinicians. The persistent lack of knowledge about the etiology and pathophysiology of this disease continues to determine important fields of uncertainty in managing this condition. Molecular cardiology and genetics currently represent the most crucial horizon of increasing knowledge. Understanding the mechanisms underlying the disease allows clinicians to treat this disease more effectively and to further improve outcomes of DCM patients through advancements in etiologic characterization, prognostic stratification and individualized therapy. Left ventricular reverse remodeling predicts a lower rate of major cardiac adverse events independently from other factors. Optimized medical treatment and device implantation are pivotal in inducing left ventricular reverse remodeling. Newly identified targets, such as angiotensin-neprilysin inhibition, phosphodiesterase inhibition and calcium sensitizing are important in improving prognosis in patients affected by DCM. PMID:26606394

  14. X-Linked Dilated Cardiomyopathy: A Cardiospecific Phenotype of Dystrophinopathy

    PubMed Central

    Nakamura, Akinori

    2015-01-01

    X-linked dilated cardiomyopathy (XLDCM) is a distinct phenotype of dystrophinopathy characterized by preferential cardiac involvement without any overt skeletal myopathy. XLDCM is caused by mutations of the Duchenne muscular dystrophy (DMD) gene and results in lethal heart failure in individuals between 10 and 20 years. Patients with Becker muscular dystrophy, an allelic disorder, have a milder phenotype of skeletal muscle involvement compared to Duchenne muscular dystrophy (DMD) and sometimes present with dilated cardiomyopathy. The precise relationship between mutations in the DMD gene and cardiomyopathy remain unclear. However, some hypothetical mechanisms are being considered to be associated with the presence of some several dystrophin isoforms, certain reported mutations, and an unknown dystrophin-related pathophysiological mechanism. Recent therapy for Duchenne muscular dystrophy, the severe dystrophinopathy phenotype, appears promising, but the presence of XLDCM highlights the importance of focusing on cardiomyopathy while elucidating the pathomechanism and developing treatment. PMID:26066469

  15. Characteristic adaptations of the extracellular matrix in dilated cardiomyopathy.

    PubMed

    Louzao-Martinez, Laura; Vink, Aryan; Harakalova, Magdalena; Asselbergs, Folkert W; Verhaar, Marianne C; Cheng, Caroline

    2016-10-01

    Dilated cardiomyopathy (DCM) is a relatively common heart muscle disease characterized by the dilation and thinning of the left ventricle accompanied with left ventricular systolic dysfunction. Myocardial fibrosis is a major feature in DCM and therefore it is inevitable that corresponding extracellular matrix (ECM) changes are involved in DCM onset and progression. Increasing our understanding of how ECM adaptations are involved in DCM could be important for the development of future interventions. This review article discusses the molecular adaptations in ECM composition and structure that have been reported in both animal and human studies of DCM. Furthermore, we provide a transcriptome-based catalogue of ECM genes that are associated with DCM, generated by using NCBI Gene Expression Omnibus database sets for DCM. Based on this in silico analysis, many novel ECM components involved in DCM are identified and discussed in this review. With the information gathered, we propose putative pathways of ECM adaptations in onset and progression of DCM. PMID:27391006

  16. GENETIC CAUSES OF DILATED CARDIOMYOPATHY

    PubMed Central

    Mestroni, Luisa; Brun, Francesca; Spezzacatene, Anita; Sinagra, Gianfranco; Taylor, Matthew RG

    2014-01-01

    Dilated cardiomyopathy is a disease of the myocardium characterized by left ventricular dilatation and/or dysfunction, affecting both adult and pediatric populations. Almost half of cases are genetically determined with an autosomal pattern of inheritance. Up to 40 genes have been identified affecting proteins of a wide variety of cellular structures such as the sarcomere, the nuclear envelope, the cytoskeleton, the sarcolemma and the intercellular junction. Novel gene mutations have been recently identified thanks to advances in next-generation sequencing technologies. Genetic screening is an essential tool for early diagnosis, risk assessment, prognostic stratification and, possibly, adoption of primary preventive measures in affected patients and their asymptomatic relatives. The purpose of this article is to review the genetic basis of DCM, the known genotype-phenotype correlations, the role of current genetic sequencing techniques in the discovery of novel pathogenic gene mutations and new therapeutic perspectives. PMID:25584016

  17. Multisensory signalling enhances pupil dilation.

    PubMed

    Rigato, Silvia; Rieger, Gerulf; Romei, Vincenzo

    2016-01-01

    Detecting and integrating information across the senses is an advantageous mechanism to efficiently respond to the environment. In this study, a simple auditory-visual detection task was employed to test whether pupil dilation, generally associated with successful target detection, could be used as a reliable measure for studying multisensory integration processing in humans. We recorded reaction times and pupil dilation in response to a series of visual and auditory stimuli, which were presented either alone or in combination. The results indicated faster reaction times and larger pupil diameter to the presentation of combined auditory and visual stimuli than the same stimuli when presented in isolation. Moreover, the responses to the multisensory condition exceeded the linear summation of the responses obtained in each unimodal condition. Importantly, faster reaction times corresponded to larger pupil dilation, suggesting that also the latter can be a reliable measure of multisensory processes. This study will serve as a foundation for the investigation of auditory-visual integration in populations where simple reaction times cannot be collected, such as developmental and clinical populations. PMID:27189316

  18. Multisensory signalling enhances pupil dilation

    PubMed Central

    Rigato, Silvia; Rieger, Gerulf; Romei, Vincenzo

    2016-01-01

    Detecting and integrating information across the senses is an advantageous mechanism to efficiently respond to the environment. In this study, a simple auditory-visual detection task was employed to test whether pupil dilation, generally associated with successful target detection, could be used as a reliable measure for studying multisensory integration processing in humans. We recorded reaction times and pupil dilation in response to a series of visual and auditory stimuli, which were presented either alone or in combination. The results indicated faster reaction times and larger pupil diameter to the presentation of combined auditory and visual stimuli than the same stimuli when presented in isolation. Moreover, the responses to the multisensory condition exceeded the linear summation of the responses obtained in each unimodal condition. Importantly, faster reaction times corresponded to larger pupil dilation, suggesting that also the latter can be a reliable measure of multisensory processes. This study will serve as a foundation for the investigation of auditory-visual integration in populations where simple reaction times cannot be collected, such as developmental and clinical populations. PMID:27189316

  19. Modeling the pressure-dilatation correlation

    NASA Technical Reports Server (NTRS)

    Sarkar, S.

    1991-01-01

    It is generally accepted that pressure dilatation, which is an additional compressibility term in turbulence transport equations, may be important for high speed flows. Recent direct simulations of homogeneous shear turbulence have given concrete evidence that the pressure dilatation is important insofar that it contributes to the reduced growth of turbulent kinetic energy due to compressibility effects. The problem of modeling pressure dilatation is addressed. A component of the pressure dilatation is isolated which exhibits temporal oscillations and, using direct numerical simulations of homogeneous shear turbulence and isotropic turbulence, show that it has a negligible contribution to the evolution of turbulent kinetic energy. Then, an analysis for the case of homogeneous turbulence is performed to obtain a model for the nonoscillatory pressure dilatation. This model algebraically relates the pressure dilatation to quantities traditionally obtained in incompressible turbulence closures. The model is validated by direct comparison with the pressure dilatation data obtained from the simulations.

  20. Link between vitamin D and airway remodeling

    PubMed Central

    Berraies, Anissa; Hamzaoui, Kamel; Hamzaoui, Agnes

    2014-01-01

    In the last decade, many epidemiologic studies have investigated the link between vitamin D deficiency and asthma. Most studies have shown that vitamin D deficiency increases the risk of asthma and allergies. Low levels of vitamin D have been associated with asthma severity and loss of control, together with recurrent exacerbations. Remodeling is an early event in asthma described as a consequence of production of mediators and growth factors by inflammatory and resident bronchial cells. Consequently, lung function is altered, with a decrease in forced expiratory volume in one second and exacerbated airway hyperresponsiveness. Subepithelial fibrosis and airway smooth muscle cell hypertrophy are typical features of structural changes in the airways. In animal models, vitamin D deficiency enhances inflammation and bronchial anomalies. In severe asthma of childhood, major remodeling is observed in patients with low vitamin D levels. Conversely, the antifibrotic and antiproliferative effects of vitamin D in smooth muscle cells have been described in several experiments. In this review, we briefly summarize the current knowledge regarding the relationship between vitamin D and asthma, and focus on its effect on airway remodeling and its potential therapeutic impact for asthma. PMID:24729717

  1. Laparoscopic Heller Myotomy for Non-Dilated Esophageal Achalasia in Children with Intraoperative Stepped Dilation Under Image Guidance: Attempting Complete Myotomy.

    PubMed

    Miyano, Go; Miyake, Hiromu; Koyama, Mariko; Morita, Keiichi; Kaneshiro, Masakatsu; Nouso, Hiroshi; Yamoto, Masaya; Fukumoto, Koji; Urushihara, Naoto

    2016-05-01

    This study presents a modified surgical approach to laparoscopic myotomy for achalasia using stepped dilation with a Rigiflex balloon and contrast medium under image guidance. A 10-year-old boy with persistent dysphagia and vomiting had ingested only liquids for 3 months, losing >10 kg in body weight. Barium swallow and esophageal manometry diagnosed esophageal achalasia with mild esophageal dilatation. After failed pneumatic dilatation, laparoscopic Heller myotomy with Dor fundoplication was performed. Prior to surgery, a Rigiflex balloon dilator was placed within the esophagus near the diaphragmatic hiatus. A four-port technique was used, and mobilization of the esophagus was limited to the anterior aspect. A 5-cm Heller myotomy was performed, extending another 2 cm onto the anterior gastric wall. During myotomy, the Rigiflex balloon was serially dilated from 30 to 50 mL, and filled with contrast medium under fluoroscopic image guidance in order to maintain appropriate tension on the esophagus to facilitate myotomy, and to confirm adequate myotomy with sufficient release of lower esophageal sphincter by resecting residual circular muscle fibers. Residual circular muscle fibers can be simultaneously visualized under both fluoroscopic image guidance and direct observation through the laparoscope, and they were cut precisely until the residual notch fully disappeared. Dor fundoplication was completed. The operative time was 180 minutes, and oral intake was started after esophagography on postoperative day 1. As of the 12-month follow-up, the patient has not shown any symptoms, and his postoperative course appeared satisfactory. PMID:26845662

  2. Engineering Airway Epithelium

    PubMed Central

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

    2012-01-01

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

  3. Balloon dilator versus telescopic metal dilators for tract dilatation during percutaneous nephrolithotomy for staghorn stones and calyceal stones

    PubMed Central

    El-Shazly, Mohamed; Salem, Shady; Allam, Adel; Hathout, Badawy

    2015-01-01

    Objective To compare the results of balloon dilatation (BD) vs. telescopic metal dilators (TMDs) in establishing the tract for percutaneous nephrolithotomy (PCNL) in patients with calyceal stones or staghorn stones, but with no hydronephrosis. Patients and methods Data from selected patients over 4 years were recorded retrospectively. Patients with complex staghorn stones, an undilated targeted calyx, or the stone filling the targeted calyx, were included in the study. In all, 97 patients were included, of 235 undergoing PCNL between March 2010 and March 2014, and were divided into two groups according to the technique of primary tract dilatation. Group A included patients who had BD and group B those treated using TMDs. Results In group A (BD, 55 patients) dilatation was successful in 34 (62%). The dilatation failed or there was a need for re-dilatation using TMD in 21 patients (38%). In one of these 21 patients the dilatation failed due to extravasation. In group B (TMD, 42 patients) dilatation was successful in 38 (90%) patients, with incomplete dilatation and a need for re-dilatation in four (10%) patients, and no failed procedures. Group A had a significantly higher failure rate than group B (P < 0.001). Differences in operative duration, blood loss, stone-removal success rate and complication rate were statistically insignificant. Conclusion BD has a higher failure rate than TMD when establishing access for calyceal stones or staghorn stones that have little space around them. PMID:26413325

  4. Reconstructive procedures for impaired upper airway function: laryngeal respiration

    PubMed Central

    Müller, Andreas

    2005-01-01

    The larynx is the "bottleneck" of the human airway. For this reason, the effects of stenosing laryngeal pathologies on the vital factor respiratory gas exchange are particularly critical. Internal stabilization is a prerequisite for recovery of the laryngeal respiratory function in severe forms of inspiratory collapse (laryngomalacia). Effective laser surgery techniques have been developed to this end in recent years. Glottis-dilating surgery in cases of bilateral vocal cord motion impairment is now moving in the direction of endoscopic laser cordotomy or cordectomy, whereas arytenoidectomy and open surgical procedures are now used only rarely due to higher secondary morbidity rates. In individual cases, in particular if functional recovery is expected, temporary laterofixation of a vocal cord using an endoscopic suturing technique can be a helpful approach. Extensive laryngeal defects can be covered by means of composite grafts with mucosal lining, a supporting skeleton and their own vascularization. Autologous transplantation of the larynx, with its complex surgical and immunological problems, has become a manageable procedure. The problems of post-transplantation reinnervation and risk assessment of immunosuppression-induced recurrence of the tumor are still under consideration. Reanimation of the bilaterally paralyzed larynx by means of neurorrhaphy (neurosuture), neural grafting and, more recently, functional electrostimulation (pacemaker) represents a challenge for the coming years. In most cases of paralysis of the recurrent laryngeal nerve, a part of the muscles is maintained by synkinetic reinnervation when therapy is carried out, which however also prevents effective vocal cord movement due to simultaneous activity of agonists and antagonists. Modulation of reinnervation by means of electrostimulation and modern genetic therapy approaches justify hopes of better outcomes in the future. PMID:22073057

  5. Conquering the difficult airway.

    PubMed

    Gandy, William E

    2008-01-01

    Every medic should practice regularly for the inevitable difficult airway case. Practice should include review of the causes of difficult airways, as well as skill practice. Having a preassembled airway kit can make your response to an unexpected difficult situation easier. Of all the devices mentioned, the bougie is the airway practitioner's best friend. Using the BURP technique, if not contraindicated, together with the bougie will enable you to intubate many difficult patients with confidence. Remember, "If your patient cannot breathe, nothing else matters. PMID:18251307

  6. Motor innervation of respiratory muscles and an opercular display muscle in Siamese fighting fish Betta splendens.

    PubMed

    Gorlick, D L

    1989-12-15

    Horseradish peroxidase was used to identify motor neurons projecting to the adductor mandibulae, levator hyomandibulae, levator operculi, adductor operculi, and dilator operculi muscles in Siamese fighting fish, Betta splendens. These muscles participate in the production of respiratory and feeding movements in teleost fishes. The dilator operculi is also the effector muscle for gill-cover erection behavior that is part of Betta's aggressive display. The motor innervation of these muscles in Betta was compared to that previously described for carp. Motor neurons of the adductor mandibulae, levator hyomandibulae, and dilator operculi are located in the trigeminal motor nucleus, and motor neurons of the adductor operculi and levator operculi are located in the facial motor nucleus in Betta and in carp. The trigeminal motor nucleus in both species is divided into rostral and caudal subnuclei. However, there are substantial differences in the organization of the subnuclei, and in the distribution of motor neurons within them. In Betta, the rostral trigeminal subnucleus consists of a single part but the caudal subnucleus is divided into two parts. Motor neurons for the dilator operculi and levator hyomandibulae muscles are located in the lateral part of the caudal subnucleus; the medial part of the caudal subnucleus contains only dilator operculi motor neurons. The single caudal subnucleus in carp is located laterally, and contains motor neurons of both the dilator operculi and levator hyomandibulae muscles. Differences in the organization of the trigeminal motor nucleus may relate to the use of the dilator operculi muscle for aggressive display behavior by perciform fishes such as Betta but not by cypriniform fishes such as carp. Five species of perciform fishes that perform gill-cover erection behavior had a Betta-like pattern of organization of the caudal trigeminal nucleus and a similar distribution of dilator operculi motor neurons. Goldfish, which like carp are

  7. Antarctic analog for dilational bands on Europa

    NASA Astrophysics Data System (ADS)

    Hurford, T. A.; Brunt, K. M.

    2014-09-01

    Europa's surface shows signs of extension, which is revealed as lithospheric dilation expressed along ridges, dilational bands and ridged bands. Ridges, the most common tectonic feature on Europa, comprise a central crack flanked by two raised banks a few hundred meters high on each side. Together these three classes may represent a continuum of formation. In Tufts' Dilational Model ridge formation is dominated by daily tidal cycling of a crack, which can be superimposed with regional secular dilation. The two sources of dilation can combine to form the various band morphologies observed. New GPS data along a rift on the Ross Ice Shelf, Antarctica is a suitable Earth analog to test the framework of Tufts' Dilational Model. As predicted by Tufts' Dilational Model, tensile failures in the Ross Ice Shelf exhibit secular dilation, upon which a tidal signal can be seen. From this analog we conclude that Tufts' Dilational Model for Europan ridges and bands may be credible and that the secular dilation is most likely from a regional source and not tidally driven.

  8. Antarctic Analog for Dilational Bands on Europa

    NASA Technical Reports Server (NTRS)

    Hurford, T. A.; Brunt, K. M.

    2014-01-01

    Europa's surface shows signs of extension, which is revealed as lithospheric dilation expressed along ridges, dilational bands and ridged bands. Ridges, the most common tectonic feature on Europa, comprise a central crack flanked by two raised banks a few hundred meters high on each side. Together these three classes may represent a continuum of formation. In Tufts' Dilational Model ridge formation is dominated by daily tidal cycling of a crack, which can be superimposed with regional secular dilation. The two sources of dilation can combine to form the various band morphologies observed. New GPS data along a rift on the Ross Ice Shelf, Antarctica is a suitable Earth analog to test the framework of Tufts' Dilational Model. As predicted by Tufts' Dilational Model, tensile failures in the Ross Ice Shelf exhibit secular dilation, upon which a tidal signal can be seen. From this analog we conclude that Tufts' Dilational Model for Europan ridges and bands may be credible and that the secular dilation is most likely from a regional source and not tidally driven.

  9. Brachycephalic airway syndrome: management.

    PubMed

    Lodato, Dena L; Hedlund, Cheryl S

    2012-08-01

    Brachycephalic airway syndrome (BAS) is a group of primary and secondary abnormalities that result in upper airway obstruction. Several of these abnormalities can be addressed medically and/or surgically to improve quality of life. This article reviews potential complications, anesthetic considerations, recovery strategies, and outcomes associated with medical and surgical management of BAS. PMID:22935992

  10. Simvastatin Inhibits Airway Hyperreactivity

    PubMed Central

    Zeki, Amir A.; Franzi, Lisa; Last, Jerold; Kenyon, Nicholas J.

    2009-01-01

    Rationale: Statin use has been linked to improved lung health in asthma and chronic obstructive pulmonary disease. We hypothesize that statins inhibit allergic airway inflammation and reduce airway hyperreactivity via a mevalonate-dependent mechanism. Objectives: To determine whether simvastatin attenuates airway inflammation and improves lung physiology by mevalonate pathway inhibition. Methods: BALB/c mice were sensitized to ovalbumin over 4 weeks and exposed to 1% ovalbumin aerosol over 2 weeks. Simvastatin (40 mg/kg) or simvastatin plus mevalonate (20 mg/kg) was injected intraperitoneally before each ovalbumin exposure. Measurements and Main Results: Simvastatin reduced total lung lavage leukocytes, eosinophils, and macrophages (P < 0.05) in the ovalbumin-exposed mice. Cotreatment with mevalonate, in addition to simvastatin, reversed the antiinflammatory effects seen with simvastatin alone (P < 0.05). Lung lavage IL-4, IL-13, and tumor necrosis factor-α levels were all reduced by treatment with simvastatin (P < 0.05). Simvastatin treatment before methacholine bronchial challenge increased lung compliance and reduced airway hyperreactivity (P = 0.0001). Conclusions: Simvastatin attenuates allergic airway inflammation, inhibits key helper T cell type 1 and 2 chemokines, and improves lung physiology in a mouse model of asthma. The mevalonate pathway appears to modulate allergic airway inflammation, while the beneficial effects of simvastatin on lung compliance and airway hyperreactivity may be independent of the mevalonate pathway. Simvastatin and similar agents that modulate the mevalonate pathway may prove to be treatments for inflammatory airway diseases, such as asthma. PMID:19608720

  11. Contribution of Different Anatomical and Physiologic Factors to Iris Contour and Anterior Chamber Angle Changes During Pupil Dilation: Theoretical Analysis

    PubMed Central

    Jouzdani, Sara; Amini, Rouzbeh; Barocas, Victor H.

    2013-01-01

    Purpose. To investigate the contribution of three anatomical and physiologic factors (dilator thickness, dynamic pupillary block, and iris compressibility) to changes in iris configuration and anterior chamber angle during pupil dilation. Methods. A mathematical model of the anterior segment based on the average values of ocular dimensions was developed to simulate pupil dilation. To change the pupil diameter from 3.0 to 5.4 mm in 10 seconds, active dilator contraction was applied by imposing stress in the dilator region. Three sets of parameters were varied in the simulations: (1) a thin (4 μm, 1% of full thickness) versus a thick dilator (covering the full thickness iris) to quantify the effects of dilator anatomy, (2) in the presence (+PB) versus absence of pupillary block (−PB) to quantify the effect of dynamic motion of aqueous humor from the posterior to the anterior chamber, and (3) a compressible versus an incompressible iris to quantify the effects of iris volume change. Changes in the apparent iris–lens contact and angle open distance (AOD500) were calculated for each case. Results. The thin case predicted a significant increase (average 700%) in iris curvature compared with the thick case (average 70%), showing that the anatomy of dilator plays an important role in iris deformation during dilation. In the presence of pupillary block (+PB), AOD500 decreased 25% and 36% for the compressible and incompressible iris, respectively. Conclusions. Iris bowing during dilation was driven primarily by posterior location of the dilator muscle and by dynamic pupillary block, but the effect of pupillary block was not as large as that of the dilator anatomy according to the quantified values of AOD500. Incompressibility of the iris, in contrast, had a relatively small effect on iris curvature but a large effect on AOD500; thus, we conclude that all three effects are important. PMID:23482467

  12. Controversies in Pediatric Perioperative Airways

    PubMed Central

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

    2015-01-01

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

  13. Mechanisms of flow and ACh-induced dilation in rat soleus arterioles are altered by hindlimb unweighting

    NASA Technical Reports Server (NTRS)

    Schrage, William G.; Woodman, Christopher R.; Laughlin, M. Harold

    2002-01-01

    The purpose of this study was to test the hypothesis that endothelium-dependent dilation (flow-induced dilation and ACh-induced dilation) in rat soleus muscle arterioles is impaired by hindlimb unweighting (HLU). Male Sprague-Dawley rats (approximately 300 g) were exposed to HLU or weight-bearing control (Con) conditions for 14 days. Soleus first-order (1A) and second-order (2A) arterioles were isolated, cannulated, and exposed to step increases in luminal flow at constant pressure. Flow-induced dilation was not impaired by HLU in 1A or 2A arterioles. The cyclooxygenase inhibitor indomethacin (Indo; 50 microM) did not alter flow-induced dilation in 1As or 2As. Inhibition of nitric oxide synthase (NOS) with N(omega)-nitro-L-arginine (L-NNA; 300 microM) reduced flow-induced dilation by 65-70% in Con and HLU 1As. In contrast, L-NNA abolished flow-induced dilation in 2As from Con rats but had no effect in HLU 2As. Combined treatment with L-NNA + Indo reduced tone in 1As and 2As from Con rats, but flow-induced dilation in the presence of L-NNA + Indo was not different from responses without inhibitors in either Con or HLU 1As or 2As. HLU also did not impair ACh-induced dilation (10(-9)-10(-4) M) in soleus 2As. L-NNA reduced ACh-induced dilation by approximately 40% in Con 2As but abolished dilation in HLU 2As. Indo did not alter ACh-induced dilation in Con or HLU 2As, whereas combined treatment with L-NNA + Indo abolished ACh-induced dilation in 2As from both groups. We conclude that flow-induced dilation (1As and 2As) was preserved after 2 wk HLU, but HLU decreased the contribution of NOS in mediating flow-induced dilation and increased the contribution of a NOS- and cyclooxygenase-independent mechanism (possibly endothelium-derived hyperpolarizing factor). In soleus 2As, ACh-induced dilation was preserved after 2-wk HLU but the contribution of NOS in mediating ACh-induced dilation was increased.

  14. [Monitoring cervical dilatation by impedance].

    PubMed

    Salvat, J; Lassen, M; Sauze, C; Baud, S; Salvat, F

    1992-01-01

    Several different physics procedures have been tried to mechanize the recording of partograms. Can a measure of impedance of tissue Z using potential difference V, according to Ohm's law V = Z1, and 1 is a constant, be correlated with a measure of cervical dilatation using vaginal examination? This was our hypothesis. The tissue impedance meter was made to our design and applied according to a bipolar procedure. Our work was carried out on 28 patients. 10 patients were registered before labour started in order to test the apparatus and to record the impedance variations without labour taking place, and 18 patients were registered in labour to see whether there was any correlation. The level of impedance in the cervix without labour was 302.7 Ohms with a deviation of 8.2. Using student's t tests it was found that there was a significant correlation (p less than 0.001) in four measurements between the impedance measure and measures obtained by extrapolating the degrees of dilatation calculated from vaginal examination. This is a preliminary study in which we have defined the conditions that are necessary to confirm these first results and to further develop the method. PMID:1401774

  15. Interplay between the effects of a Protein Kinase C phosphomimic (T204E) and a dilated cardiomyopathy mutation (K211Δ or R206W) in rat cardiac troponin T blunts the magnitude of muscle length-mediated crossbridge recruitment against the β-myosin heavy chain background.

    PubMed

    Michael, John Jeshurun; Gollapudi, Sampath K; Chandra, Murali

    2016-06-01

    Failing hearts of dilated cardiomyopathy (DCM)-patients reveal systolic dysfunction and upregulation of several Protein Kinase C (PKC) isoforms. Recently, we demonstrated that the functional effects of T204E, a PKC phosphomimic of cardiac troponin T (TnT), were differently modulated by α- and β-myosin heavy chain (MHC) isoforms. Therefore, we hypothesized that the interplay between the effects of T204E and a DCM-linked mutation (K211Δ or R206W) in TnT would modulate contractile parameters linked-to systolic function in an MHC-dependent manner. To test our hypothesis, five TnT variants (wildtype, K211Δ, K211Δ + T204E, R206W, and R206W + T204E) were generated and individually reconstituted into demembranated cardiac muscle fibers from normal (α-MHC) and propylthiouracil-treated (β-MHC) rats. Steady-state and mechano-dynamic measurements were performed on reconstituted fibers. Myofilament Ca(2+) sensitivity (pCa50) was decreased by both K211Δ and R206W to a greater extent in α-MHC fibers (~0.15 pCa units) than in β-MHC fibers (~0.06 pCa units). However, T204E exacerbated the attenuating influence of both mutants on pCa50 only in β-MHC fibers. Moreover, the magnitude of muscle length (ML)-mediated crossbridge (XB) recruitment was decreased by K211Δ + T204E (~47 %), R206W (~34 %), and R206W + T204E (~36 %) only in β-MHC fibers. In relevance to human hearts, which predominantly express β-MHC, our data suggest that the interplay between the effects of DCM mutations, PKC phosphomimic in TnT, and β-MHC lead to systolic dysfunction by attenuating pCa50 and the magnitude of ML-mediated XB recruitment. PMID:27411801

  16. Cervical dilation in second-trimester abortion.

    PubMed

    Hayes, Jennifer L; Fox, Michelle C

    2009-06-01

    Dilation and evacuation, the most common method performed for second-trimester abortion in the United States, requires sufficient cervical dilation to reduce the risk of complications such as cervical laceration or uterine perforation. The cervix may be prepared with osmotic dilators such as laminaria, Lamicel, or Dilapan-S, or with pharmacologic agents such as misoprostol. Dilapan-S and Lamicel achieve their maximum dilation faster than laminaria, making same-day procedures possible. Misoprostol has limited data supporting its use in this setting. Decisions regarding which method is best are clinician-dependent, and factors such as gestational age and time allowed for preparation should be considered. PMID:19407523

  17. Airway dysfunction in swimmers.

    PubMed

    Bougault, Valérie; Boulet, Louis-Philippe

    2012-05-01

    Elite competitive swimmers are particularly affected by airway disorders that are probably related to regular and intense training sessions in a chlorinated environment. Upper and lower airway respiratory symptoms, rhinitis, airway hyper-responsiveness, and exercise-induced bronchoconstriction are highly prevalent in these athletes, but their influence on athletic performance is still unclear. The authors reviewed the main upper and lower respiratory ailments observed in competitive swimmers who train in indoor swimming pools, their pathophysiology, clinical significance and possible effects on performance. Issues regarding the screening of these disorders, their management and preventive measures are addressed. PMID:22247299

  18. Meteorological conditions along airways

    NASA Technical Reports Server (NTRS)

    Gregg, W R

    1927-01-01

    This report is an attempt to show the kind of meteorological information that is needed, and is in part available, for the purpose of determining operating conditions along airways. In general, the same factors affect these operating conditions along all airways though in varying degree, depending upon their topographic, geographic, and other characteristics; but in order to bring out as clearly as possible the nature of the data available, a specific example is taken, that of the Chicago-Dallas airway on which regular flying begins this year (1926).

  19. On turbulence in dilatant dispersions

    NASA Astrophysics Data System (ADS)

    Baumert, Helmut Z.; Wessling, Bernhard

    2016-07-01

    This paper presents a new theory on the behaviour of shear-thickening (dilatant) fluids under turbulent conditions. The structure of a dilatant colloidal fluid in turbulent motion may be characterized by (at least) four characteristic length scales: (i) the ‘statistically largest’ turbulent scale, {λ }0, labeling the begin of the inertial part of the wavenumber spectrum; (ii) the energy-containing scale, { L }; (iii) Kolmogorov’s micro-scale, {λ }{ K }, related with the size of the smallest vortices existing for a given kinematic viscosity and forcing; (iv) the inner (‘colloidal’) micro-scale, {λ }i, typically representing a major stable material property of the colloidal fluid. In particular, for small ratios r={λ }i/{λ }{ K }∼ { O }(1), various interactions between colloidal structures and smallest turbulent eddies can be expected. In the present paper we discuss particularly that for ρ ={λ }0/{λ }{ K }\\to { O }(1) turbulence (in the narrow, inertial sense) is strangled and chaotic but less mixing fluid motions remain. We start from a new stochastic, micro-mechanical turbulence theory without empirical parameters valid for inviscid fluids as seen in publications by Baumert in 2013 and 2015. It predicts e.g. von Karman’s constant correctly as 1/\\sqrt{2 π }=0.399. In its generalized version for non-zero viscosity and shear-thickening behavior presented in this contribution, it predicts two solution branches for the steady state: The first characterizes a family of states with swift (inertial) turbulent mixing and small {λ }{ K }, potentially approaching {λ }i. The second branch characterizes a state family with ρ \\to { O }(1) and thus strangled turbulence, ρ ≈ { O }(1). Stability properties and a potential dynamic commuting between the two solution branches had to be left for future research.

  20. Nonlinear Compliance Modulates Dynamic Bronchoconstriction in a Multiscale Airway Model

    PubMed Central

    Hiorns, Jonathan E.; Jensen, Oliver E.; Brook, Bindi S.

    2014-01-01

    The role of breathing and deep inspirations (DI) in modulating airway hyperresponsiveness remains poorly understood. In particular, DIs are potent bronchodilators of constricted airways in nonasthmatic subjects but not in asthmatic subjects. Additionally, length fluctuations (mimicking DIs) have been shown to reduce mean contractile force when applied to airway smooth muscle (ASM) cells and tissue strips. However, these observations are not recapitulated on application of transmural pressure (PTM) oscillations (that mimic tidal breathing and DIs) in isolated intact airways. To shed light on this paradox, we have developed a biomechanical model of the intact airway, accounting for strain-stiffening due to collagen recruitment (a large component of the extracellular matrix (ECM)), and dynamic actomyosin-driven force generation by ASM cells. In agreement with intact airway studies, our model shows that PTM fluctuations at particular mean transmural pressures can lead to only limited bronchodilation. However, our model predicts that moving the airway to a more compliant point on the static pressure-radius relationship (which may involve reducing mean PTM), before applying pressure fluctuations, can generate greater bronchodilation. This difference arises from competition between passive strain-stiffening of ECM and force generation by ASM yielding a highly nonlinear relationship between effective airway stiffness and PTM, which is modified by the presence of contractile agonist. Effectively, the airway at its most compliant may allow for greater strain to be transmitted to subcellular contractile machinery. The model predictions lead us to hypothesize that the maximum possible bronchodilation of an airway depends on its static compliance at the PTM about which the fluctuations are applied. We suggest the design of additional experimental protocols to test this hypothesis. PMID:25517167

  1. 21 CFR 874.3900 - Nasal dilator.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Nasal dilator. 874.3900 Section 874.3900 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Prosthetic Devices § 874.3900 Nasal dilator. (a) Identification. A...

  2. 21 CFR 874.3900 - Nasal dilator.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Nasal dilator. 874.3900 Section 874.3900 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Prosthetic Devices § 874.3900 Nasal dilator. (a) Identification. A...

  3. 21 CFR 874.3900 - Nasal dilator.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Nasal dilator. 874.3900 Section 874.3900 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Prosthetic Devices § 874.3900 Nasal dilator. (a) Identification. A...

  4. 21 CFR 874.3900 - Nasal dilator.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Nasal dilator. 874.3900 Section 874.3900 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Prosthetic Devices § 874.3900 Nasal dilator. (a) Identification. A...

  5. 21 CFR 874.3900 - Nasal dilator.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Nasal dilator. 874.3900 Section 874.3900 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Prosthetic Devices § 874.3900 Nasal dilator. (a) Identification. A...

  6. 21 CFR 876.5450 - Rectal dilator.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Rectal dilator. 876.5450 Section 876.5450 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES GASTROENTEROLOGY-UROLOGY DEVICES Therapeutic Devices § 876.5450 Rectal dilator. (a) Identification. A...

  7. 21 CFR 876.5470 - Ureteral dilator.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Ureteral dilator. 876.5470 Section 876.5470 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES GASTROENTEROLOGY-UROLOGY DEVICES Therapeutic Devices § 876.5470 Ureteral dilator....

  8. 21 CFR 876.5520 - Urethral dilator.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Urethral dilator. 876.5520 Section 876.5520 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES GASTROENTEROLOGY-UROLOGY DEVICES Therapeutic Devices § 876.5520 Urethral dilator....

  9. 21 CFR 876.5365 - Esophageal dilator.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Esophageal dilator. 876.5365 Section 876.5365 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES GASTROENTEROLOGY-UROLOGY DEVICES Therapeutic Devices § 876.5365 Esophageal dilator....

  10. 21 CFR 876.5470 - Ureteral dilator.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Ureteral dilator. 876.5470 Section 876.5470 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES GASTROENTEROLOGY-UROLOGY DEVICES Therapeutic Devices § 876.5470 Ureteral dilator....

  11. 21 CFR 876.5450 - Rectal dilator.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Rectal dilator. 876.5450 Section 876.5450 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES GASTROENTEROLOGY-UROLOGY DEVICES Therapeutic Devices § 876.5450 Rectal dilator. (a) Identification. A...

  12. The Role of the Extracellular Matrix Protein Mindin in Airway Response to Environmental Airways Injury

    PubMed Central

    Frush, Sarah; Li, Zhuowei; Potts, Erin N.; Du, Wanglei; Eu, Jerry P.; Garantziotis, Stavros; He, You-Wen; Foster, W. Michael

    2011-01-01

    mindin in airway smooth muscle contractility after exposure to ozone. PMID:21684833

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

    PubMed Central

    Zhong, Xiaoning; He, Zhiyi; Wei, Lianghong; Zheng, Xiaozhen; Zhang, Jianquan; Bai, Jing; Zhong, Wei; Zhong, Dengjun

    2014-01-01

    Background. Noncystic fibrosis bronchiectasis (NCFB) is characterized by airway expansion and recurrent acute exacerbations. Macrolide has been shown to exhibit anti-inflammatory effects in some chronic airway diseases. Objective. To assess the efficacy of roxithromycin on airway inflammation and remodeling in patients with NCFB under steady state. Methods. The study involved an open-label design in 52 eligible Chinese patients with NCFB, who were assigned to control (receiving no treatment) and roxithromycin (receiving 150 mg/day for 6 months) groups. At baseline and 6 months, the inflammatory markers such as interleukin- (IL-)8, neutrophil elastase (NE), matrix metalloproteinase- (MMP)9, hyaluronidase (HA), and type IV collagen in sputum were measured, along with the detection of dilated bronchus by throat computed tomography scan, and assessed the exacerbation. Results. Forty-three patients completed the study. The neutrophil in the sputum was decreased in roxithromycin group compared with control (P < 0.05). IL-8, NE, MMP-9, HA, and type IV collagen in sputum were also decreased in roxithromycin group compared with the control group (all P < 0.01). Airway thickness of dilated bronchus and exacerbation were reduced in roxithromycin group compared with the control (all P < 0.05). Conclusions. Roxithromycin can reduce airway inflammation and airway thickness of dilated bronchus in patients with NCFB. PMID:25580060

  14. LIGHT is a crucial mediator of airway remodeling.

    PubMed

    Hung, Jen-Yu; Chiang, Shyh-Ren; Tsai, Ming-Ju; Tsai, Ying-Ming; Chong, Inn-Wen; Shieh, Jiunn-Min; Hsu, Ya-Ling

    2015-05-01

    Chronic inflammatory airway diseases like asthma and chronic obstructive pulmonary disease are major health problems globally. Airway epithelial cells play important role in airway remodeling, which is a critical process in the pathogenesis of diseases. This study aimed to demonstrate that LIGHT, an inflammatory factor secreted by T cells after allergen exposure, is responsible for promoting airway remodeling. LIGHT increased primary human bronchial epithelial cells (HBECs) undergoing epithelial-mesenchymal transition (EMT) and expressing MMP-9. The induction of EMT was associated with increased NF-κB activation and p300/NF-κB association. The interaction of NF-κB with p300 facilitated NF-κB acetylation, which in turn, was bound to the promoter of ZEB1, resulting in E-cadherin downregulation. LIGHT also stimulated HBECs to produce numerous cytokines/chemokines that could worsen airway inflammation. Furthermore, LIGHT enhanced HBECs to secrete activin A, which increased bronchial smooth muscle cell (BSMC) migration. In contrast, depletion of activin A decreased such migration. The findings suggest a new molecular determinant of LIGHT-mediated pathogenic changes in HBECs and that the LIGHT-related vicious cycle involving HBECs and BSMCs may be a potential target for the treatment of chronic inflammation airway diseases with airway remodeling. PMID:25251281

  15. Patient-Specific Airway Wall Remodeling in Chronic Lung Disease.

    PubMed

    Eskandari, Mona; Kuschner, Ware G; Kuhl, Ellen

    2015-10-01

    Chronic lung disease affects more than a quarter of the adult population; yet, the mechanics of the airways are poorly understood. The pathophysiology of chronic lung disease is commonly characterized by mucosal growth and smooth muscle contraction of the airways, which initiate an inward folding of the mucosal layer and progressive airflow obstruction. Since the degree of obstruction is closely correlated with the number of folds, mucosal folding has been extensively studied in idealized circular cross sections. However, airflow obstruction has never been studied in real airway geometries; the behavior of imperfect, non-cylindrical, continuously branching airways remains unknown. Here we model the effects of chronic lung disease using the nonlinear field theories of mechanics supplemented by the theory of finite growth. We perform finite element analysis of patient-specific Y-branch segments created from magnetic resonance images. We demonstrate that the mucosal folding pattern is insensitive to the specific airway geometry, but that it critically depends on the mucosal and submucosal stiffness, thickness, and loading mechanism. Our results suggests that patient-specific airway models with inherent geometric imperfections are more sensitive to obstruction than idealized circular models. Our models help to explain the pathophysiology of airway obstruction in chronic lung disease and hold promise to improve the diagnostics and treatment of asthma, bronchitis, chronic obstructive pulmonary disease, and respiratory failure. PMID:25821112

  16. Spreading dilatation to luminal perfusion of ATP and UTP in rat isolated small mesenteric arteries

    PubMed Central

    Winter, Polly; Dora, Kim A

    2007-01-01

    Levels of ATP achieved within the lumen of vessels suggest a key autacoid role. P2Y receptors on the endothelium may represent the target for ATP, leading to hyperpolarization and associated relaxation of vascular smooth muscle through the endothelium-dependent hyperpolarizing factor (EDHF) pathway. EDHF signals radially from the endothelium to cause dilatation, and appears mechanistically distinct from the axial spread of dilatation, which we showed occurs independently of a change in endothelial cell Ca2+ in rat mesenteric arteries. Here we have investigated the potential of P2Y receptor stimulation to evoke spreading dilatation in rat resistance small arteries under physiological pressure and flow. Triple cannulation of isolated arteries enables focal application of purine and pyrimidine nucleotides to the endothelium, avoiding potential complicating actions of these agents on the smooth muscle. Nucleotides were locally infused through one branch of a bifurcation, causing near maximal local dilatation attributable to EDHF. Dilatation then spread rapidly into the adjacent feed artery and upstream against the direction of luminal flow, sufficient to increase flow into the feed artery. The rate of decay of this spreading dilatation was identical between nucleotides, and matched that to ACh, which acts only on the endothelium. In contrast, focal abluminal application of either ATP or UTP at the downstream end of cannulated arteries evoked constriction, which only in the case of ATP was also associated with modest spread of dilatation. The non-hydrolysable ADP analogue, ADPβS, acting at P2Y1 receptors, caused robust local and spreading dilatation responses whether applied to the luminal or abluminal surface of pressurized arteries. Dilatation to nucleotides was sensitive to inhibition with apamin and TRAM-34, selective blockers of small- and intermediate-conductance Ca2+-activated K+ channels, respectively. These data demonstrate that direct luminal stimulation of P

  17. Genetics Home Reference: dilated cardiomyopathy with ataxia syndrome

    MedlinePlus

    ... dilated cardiomyopathy with ataxia syndrome dilated cardiomyopathy with ataxia syndrome Enable Javascript to view the expand/collapse ... Open All Close All Description Dilated cardiomyopathy with ataxia (DCMA) syndrome is an inherited condition characterized by ...

  18. Airway management in trauma.

    PubMed

    Langeron, O; Birenbaum, A; Amour, J

    2009-05-01

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

  19. Influence of posterior cricoarytenoid muscle activity on pressure-flow relationship of the larynx.

    PubMed

    Tully, A; Brancatisano, A; Loring, S H; Engel, L A

    1991-05-01

    We examined the effect of posterior cricoarytenoid (PCA) muscle activity on the pressure-flow (PV) relationship of the larynx in five anesthetized tracheostomized dogs. The PCA activity was recorded using bipolar fine-wire electrodes, expressed as a percentage of the quiet breathing level and altered by mechanical ventilation, changes in lung volume, and chest wall compression. Subglottic pressure was recorded while a constant flow of air was passed through the upper airway. In the absence of PCA activity the PV relationship was alinear and could be described by a power function (P = K0Va, where K0 and a are constants). The slope of the log P-log V plots in the absence of PCA and thyroarytenoid activity was 1.83 +/- 0.02 (SD), whereas with increasing PCA activity it was 1.88 +/- 0.11. An effective hydraulic diameter (DH) was calculated for 20% increments of PCA activity, and in two dogs glottic diameter (Dg) was calculated from glottic area measurements obtained by fiber-optic laryngoscopy. Both DH and Dg increased linearly with increasing PCA activity. Denervation of the cricothyroid muscle had no systematic effect on laryngeal resistance. The results indicate that the PV relationship of the larynx may be described by a power function with a single exponent, the magnitude of which is independent of glottic dilator muscle activity and consistent with orifice flow. However, laryngeal diameter increases linearly with PCA activity in the range studied. PMID:1864806

  20. Gastric dilatation and volvulus in a brachycephalic dog with hiatal hernia.

    PubMed

    Aslanian, M E; Sharp, C R; Garneau, M S

    2014-10-01

    A brachycephalic dog was presented with an acute onset of retching and abdominal discomfort. The dog had a chronic history of stertor and exercise intolerance suggestive of brachycephalic airway obstructive syndrome. Radiographs were consistent with a Type II hiatal hernia. The dog was referred and within hours of admission became acutely painful and developed tympanic abdominal distension. A right lateral abdominal radiograph confirmed gastric dilatation and volvulus with herniation of the pylorus through the hiatus. An emergency exploratory coeliotomy was performed, during which the stomach was derotated, and an incisional gastropexy, herniorrhaphy and splenectomy were performed. A staphylectomy was performed immediately following the exploratory coeliotomy. The dog recovered uneventfully. Gastric dilatation and volvulus is a potentially life-threatening complication that can occur in dogs with Type II hiatal hernia and should be considered a surgical emergency. PMID:24871205

  1. Your Muscles

    MedlinePlus

    ... Homework? Here's Help White House Lunch Recipes Your Muscles KidsHealth > For Kids > Your Muscles Print A A ... and skeletal (say: SKEL-uh-tul) muscle. Smooth Muscles Smooth muscles — sometimes also called involuntary muscles — are ...

  2. Treatment of eosinophilic esophagitis by dilation.

    PubMed

    Schoepfer, Alain

    2014-01-01

    Treatment options for eosinophilic esophagitis (EoE) include drugs, diets and esophageal dilation. Esophageal dilation can be performed using either through-the-scope balloons or wire-guided bougies. Dilation can lead to long-lasting symptom improvement in EoE patients presenting with esophageal strictures. Esophageal strictures are most often diagnosed when the 8- to 9-mm outer diameter adult gastroscope cannot be passed any further or only against resistance. A defined esophageal diameter to be targeted by dilation is missing, but the majority of patients have considerable symptomatic improvement when a diameter of 16-18 mm has been reached. A high complication rate, especially regarding esophageal perforations, has been reported in small case series until 2006. Several large series were published in 2007 and later that demonstrated that the complication risk (especially esophageal perforation) was much lower than what was reported in earlier series. The procedure can therefore be regarded as safe when some simple precautions are followed. It is noteworthy that esophageal dilation does not influence the underlying eosinophil-predominant inflammation. Patients should be informed before the procedure that postprocedural retrosternal pain may occur for some days, but that it usually responds well to over-the-counter analgesics such as paracetamol. Dilation-related superficial lacerations of the mucosa should not be regarded and reported as complications, but instead represent a desired effect of the therapy. Patient tolerance and acceptance for esophageal dilation have been reported to be good. PMID:24603396

  3. Role of upper airway ultrasound in airway management.

    PubMed

    Osman, Adi; Sum, Kok Meng

    2016-01-01

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

  4. Modulation of lung inflammation by vessel dilator in a mouse model of allergic asthma

    PubMed Central

    Wang, Xiaoqin; Xu, Weidong; Kong, Xiaoyuan; Chen, Dongqing; Hellermann, Gary; Ahlert, Terry A; Giaimo, Joseph D; Cormier, Stephania A; Li, Xu; Lockey, Richard F; Mohapatra, Subhra; Mohapatra, Shyam S

    2009-01-01

    Background Atrial natriuretic peptide (ANP) and its receptor, NPRA, have been extensively studied in terms of cardiovascular effects. We have found that the ANP-NPRA signaling pathway is also involved in airway allergic inflammation and asthma. ANP, a C-terminal peptide (amino acid 99–126) of pro-atrial natriuretic factor (proANF) and a recombinant peptide, NP73-102 (amino acid 73–102 of proANF) have been reported to induce bronchoprotective effects in a mouse model of allergic asthma. In this report, we evaluated the effects of vessel dilator (VD), another N-terminal natriuretic peptide covering amino acids 31–67 of proANF, on acute lung inflammation in a mouse model of allergic asthma. Methods A549 cells were transfected with pVD or the pVAX1 control plasmid and cells were collected 24 hrs after transfection to analyze the effect of VD on inactivation of the extracellular-signal regulated receptor kinase (ERK1/2) through western blot. Luciferase assay, western blot and RT-PCR were also performed to analyze the effect of VD on NPRA expression. For determination of VD's attenuation of lung inflammation, BALB/c mice were sensitized and challenged with ovalbumin and then treated intranasally with chitosan nanoparticles containing pVD. Parameters of airway inflammation, such as airway hyperreactivity, proinflammatory cytokine levels, eosinophil recruitment and lung histopathology were compared with control mice receiving nanoparticles containing pVAX1 control plasmid. Results pVD nanoparticles inactivated ERK1/2 and downregulated NPRA expression in vitro, and intranasal treatment with pVD nanoparticles protected mice from airway inflammation. Conclusion VD's modulation of airway inflammation may result from its inactivation of ERK1/2 and downregulation of NPRA expression. Chitosan nanoparticles containing pVD may be therapeutically effective in preventing allergic airway inflammation. PMID:19615076

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

    PubMed

    Bates, Jason H T

    2016-09-01

    Fresh air entering the mouth and nose is brought to the blood-gas barrier in the lungs by a repetitively branching network of airways. Provided the individual airway branches remain patent, this airway tree achieves an enormous amplification in cross-sectional area from the trachea to the terminal bronchioles. Obstructive lung diseases such as asthma occur when airway patency becomes compromised. Understanding the pathophysiology of these obstructive diseases thus begins with a consideration of the factors that determine the caliber of an individual airway, which include the force balance between the inward elastic recoil of the airway wall, the outward tethering forces of its parenchymal attachments, and any additional forces due to contraction of airway smooth muscle. Other factors may also contribute significantly to airway narrowing, such as thickening of the airway wall and accumulation of secretions in the lumen. Airway obstruction becomes particularly severe when these various factors occur in concert. However, the effect of airway abnormalities on lung function cannot be fully understood only in terms of what happens to a single airway because narrowing throughout the airway tree is invariably heterogeneous and interdependent. Obstructive lung pathologies thus manifest as emergent phenomena arising from the way in which the airway tree behaves a system. These emergent phenomena are studied with clinical measurements of lung function made by spirometry and by mechanical impedance measured with the forced oscillation technique. Anatomically based computational models are linking these measurements to underlying anatomic structure in systems physiology terms. WIREs Syst Biol Med 2016, 8:423-437. doi: 10.1002/wsbm.1347 For further resources related to this article, please visit the WIREs website. PMID:27340818

  6. From electrocautery, balloon dilatation, neodymium-doped:yttrium-aluminum-garnet (Nd:YAG) laser to argon plasma coagulation and cryotherapy.

    PubMed

    Sachdeva, Ashutosh; Pickering, Edward M; Lee, Hans J

    2015-12-01

    Over the past decade, there has been significant advancement in the development/application of therapeutics in thoracic diseases. Ablation methods using heat or cold energy in the airway is safe and effective for treating complex airway disorders including malignant and non-malignant central airway obstruction (CAO) without limiting the impact of future definitive therapy. Timely and efficient use of endobronchial ablative therapies combined with mechanical debridement or stent placement results in immediate relief of dyspnea for CAO. Therapeutic modalities reviewed in this article including electrocautery, balloon dilation (BD), neodymium-doped:yttrium-aluminum-garnet (Nd:YAG) laser, argon plasma coagulation (APC), and cryotherapy are often combined to achieve the desired results. This review aims to provide a clinically oriented review of these technologies in the modern era of interventional pulmonology (IP). PMID:26807284

  7. From electrocautery, balloon dilatation, neodymium-doped:yttrium-aluminum-garnet (Nd:YAG) laser to argon plasma coagulation and cryotherapy

    PubMed Central

    Pickering, Edward M.; Lee, Hans J.

    2015-01-01

    Over the past decade, there has been significant advancement in the development/application of therapeutics in thoracic diseases. Ablation methods using heat or cold energy in the airway is safe and effective for treating complex airway disorders including malignant and non-malignant central airway obstruction (CAO) without limiting the impact of future definitive therapy. Timely and efficient use of endobronchial ablative therapies combined with mechanical debridement or stent placement results in immediate relief of dyspnea for CAO. Therapeutic modalities reviewed in this article including electrocautery, balloon dilation (BD), neodymium-doped:yttrium-aluminum-garnet (Nd:YAG) laser, argon plasma coagulation (APC), and cryotherapy are often combined to achieve the desired results. This review aims to provide a clinically oriented review of these technologies in the modern era of interventional pulmonology (IP). PMID:26807284

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

    PubMed Central

    Johnson, Kathleen N; Botros, Daniel B; Groban, Leanne; Bryan, Yvon F

    2015-01-01

    There are many anatomical, physiopathological, and cognitive changes that occur in the elderly that affect different components of airway management: intubation, ventilation, oxygenation, and risk of aspiration. Anatomical changes occur in different areas of the airway from the oral cavity to the larynx. Common changes to the airway include tooth decay, oropharyngeal tumors, and significant decreases in neck range of motion. These changes may make intubation challenging by making it difficult to visualize the vocal cords and/or place the endotracheal tube. Also, some of these changes, including but not limited to, atrophy of the muscles around the lips and an edentulous mouth, affect bag mask ventilation due to a difficult face-mask seal. Physiopathologic changes may impact airway management as well. Common pulmonary issues in the elderly (eg, obstructive sleep apnea and COPD) increase the risk of an oxygen desaturation event, while gastrointestinal issues (eg, achalasia and gastroesophageal reflux disease) increase the risk of aspiration. Finally, cognitive changes (eg, dementia) not often seen as related to airway management may affect patient cooperation, especially if an awake intubation is required. Overall, degradation of the airway along with other physiopathologic and cognitive changes makes the elderly population more prone to complications related to airway management. When deciding which airway devices and techniques to use for intubation, the clinician should also consider the difficulty associated with ventilating the patient, the patient’s risk of oxygen desaturation, and/or aspiration. For patients who may be difficult to bag mask ventilate or who have a risk of aspiration, a specialized supralaryngeal device may be preferable over bag mask for ventilation. Patients with tumors or decreased neck range of motion may require a device with more finesse and maneuverability, such as a flexible fiberoptic broncho-scope. Overall, geriatric-focused airway

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

    PubMed

    Johnson, Kathleen N; Botros, Daniel B; Groban, Leanne; Bryan, Yvon F

    2015-01-01

    There are many anatomical, physiopathological, and cognitive changes that occur in the elderly that affect different components of airway management: intubation, ventilation, oxygenation, and risk of aspiration. Anatomical changes occur in different areas of the airway from the oral cavity to the larynx. Common changes to the airway include tooth decay, oropharyngeal tumors, and significant decreases in neck range of motion. These changes may make intubation challenging by making it difficult to visualize the vocal cords and/or place the endotracheal tube. Also, some of these changes, including but not limited to, atrophy of the muscles around the lips and an edentulous mouth, affect bag mask ventilation due to a difficult face-mask seal. Physiopathologic changes may impact airway management as well. Common pulmonary issues in the elderly (eg, obstructive sleep apnea and COPD) increase the risk of an oxygen desaturation event, while gastrointestinal issues (eg, achalasia and gastroesophageal reflux disease) increase the risk of aspiration. Finally, cognitive changes (eg, dementia) not often seen as related to airway management may affect patient cooperation, especially if an awake intubation is required. Overall, degradation of the airway along with other physiopathologic and cognitive changes makes the elderly population more prone to complications related to airway management. When deciding which airway devices and techniques to use for intubation, the clinician should also consider the difficulty associated with ventilating the patient, the patient's risk of oxygen desaturation, and/or aspiration. For patients who may be difficult to bag mask ventilate or who have a risk of aspiration, a specialized supralaryngeal device may be preferable over bag mask for ventilation. Patients with tumors or decreased neck range of motion may require a device with more finesse and maneuverability, such as a flexible fiberoptic broncho-scope. Overall, geriatric-focused airway

  10. 21 CFR 876.5365 - Esophageal dilator.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... and weighted with mercury or a metal olive-shaped weight that slides on a guide, such as a string or... esophageal or gastrointestinal bougies and the esophageal dilator (metal olive). (b) Classification. Class...

  11. 21 CFR 876.5365 - Esophageal dilator.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... and weighted with mercury or a metal olive-shaped weight that slides on a guide, such as a string or... esophageal or gastrointestinal bougies and the esophageal dilator (metal olive). (b) Classification. Class...

  12. 21 CFR 876.5365 - Esophageal dilator.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... and weighted with mercury or a metal olive-shaped weight that slides on a guide, such as a string or... esophageal or gastrointestinal bougies and the esophageal dilator (metal olive). (b) Classification. Class...

  13. 21 CFR 876.5365 - Esophageal dilator.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... and weighted with mercury or a metal olive-shaped weight that slides on a guide, such as a string or... esophageal or gastrointestinal bougies and the esophageal dilator (metal olive). (b) Classification. Class...

  14. Stem Cell Therapy for Pediatric Dilated Cardiomyopathy

    PubMed Central

    Selem, Sarah M.; Kaushal, Sunjay; Hare, Joshua M.

    2014-01-01

    Dilated cardiomyopathy is a serious and life-threatening disorder in children. It is the most common form of pediatric cardiomyopathy. Therapy for this condition has varied little over the last several decades and mortality continues to be high. Currently, children with dilated cardiomyopathy are treated with pharmacological agents and mechanical support, but most require heart transplantation and survival rates are not optimal. The lack of common treatment guidelines and inadequate survival rates after transplantation necessitates more therapeutic clinical trials. Stem cell and cell-based therapies offer an innovative approach to restore cardiac structure and function towards normal, possibly reducing the need for aggressive therapies and cardiac transplantation. Mesenchymal stem cells and cardiac stem cells may be the most promising cell types for treating children with dilated cardiomyopathy. The medical community must begin a systematic investigation of the benefits of current and novel treatments such as stem cell therapies for treating pediatric dilated cardiomyopathy. PMID:23666883

  15. An Erupted Dilated Odontoma: A Rare Presentation

    PubMed Central

    Sharma, Gaurav; Nagra, Amritpreet; Singh, Gurkeerat; Nagpal, Archna; Soin, Atul; Bhardwaj, Vishal

    2016-01-01

    A dilated odontoma is an extremely rare developmental anomaly represented as a dilatation of the crown and root as a consequence of a deep, enamel-lined invagination and is considered a severe variant of dens invaginatus. An oval shape of the tooth lacking morphological characteristics of a crown or root implies that the invagination happened in the initial stages of morphodifferentiation. Spontaneous eruption of an odontoma is a rare occurrence and the occurrence of a dilated odontoma in a supernumerary tooth is even rarer with only a few case reports documented in the English literature. We present an extremely rare case of erupted dilated odontoma occurring in the supernumerary tooth in anterior maxillary region in an 18-year-old male, which, to the best of our knowledge, is the first ever case reported in English literature. PMID:26989523

  16. An Erupted Dilated Odontoma: A Rare Presentation.

    PubMed

    Sharma, Gaurav; Nagra, Amritpreet; Singh, Gurkeerat; Nagpal, Archna; Soin, Atul; Bhardwaj, Vishal

    2016-01-01

    A dilated odontoma is an extremely rare developmental anomaly represented as a dilatation of the crown and root as a consequence of a deep, enamel-lined invagination and is considered a severe variant of dens invaginatus. An oval shape of the tooth lacking morphological characteristics of a crown or root implies that the invagination happened in the initial stages of morphodifferentiation. Spontaneous eruption of an odontoma is a rare occurrence and the occurrence of a dilated odontoma in a supernumerary tooth is even rarer with only a few case reports documented in the English literature. We present an extremely rare case of erupted dilated odontoma occurring in the supernumerary tooth in anterior maxillary region in an 18-year-old male, which, to the best of our knowledge, is the first ever case reported in English literature. PMID:26989523

  17. Cushing's Disease Presented by Reversible Dilated Cardiomyopathy.

    PubMed

    Aydoğan, Berna İmge; Gerede, Demet Menekşe; Canpolat, Asena Gökçay; Erdoğan, Murat Faik

    2015-01-01

    Introduction. Dilated cardiomyopathy is rarely reported among CS patients especially without hypertension and left ventricular hypertrophy. Materials and Methods. We hereby report a Cushing's syndrome case presenting with dilated cardiomyopathy. Results. A 48-year-old female patient was admitted to our clinic with severe proximal myopathy and dilated cardiomyopathy without ventricular hypertrophy. Cushing's disease was diagnosed and magnetic-resonance imaging of the pituitary gland revealed a microadenoma. Under diuretic and ketoconazole treatments, she underwent a successful transnasal/transsphenoidal adenomectomy procedure. Full recovery of symptoms and echocardiographic features was achieved after six months of surgery. Conclusion. Cushing's syndrome must be kept in mind as a reversible cause of dilated cardiomyopathy. Recovery of cardiomyopathy is achieved with successful surgery. PMID:26649206

  18. Cushing's Disease Presented by Reversible Dilated Cardiomyopathy

    PubMed Central

    Aydoğan, Berna İmge; Gerede, Demet Menekşe; Canpolat, Asena Gökçay; Erdoğan, Murat Faik

    2015-01-01

    Introduction. Dilated cardiomyopathy is rarely reported among CS patients especially without hypertension and left ventricular hypertrophy. Materials and Methods. We hereby report a Cushing's syndrome case presenting with dilated cardiomyopathy. Results. A 48-year-old female patient was admitted to our clinic with severe proximal myopathy and dilated cardiomyopathy without ventricular hypertrophy. Cushing's disease was diagnosed and magnetic-resonance imaging of the pituitary gland revealed a microadenoma. Under diuretic and ketoconazole treatments, she underwent a successful transnasal/transsphenoidal adenomectomy procedure. Full recovery of symptoms and echocardiographic features was achieved after six months of surgery. Conclusion. Cushing's syndrome must be kept in mind as a reversible cause of dilated cardiomyopathy. Recovery of cardiomyopathy is achieved with successful surgery. PMID:26649206

  19. Acute Gastric Dilatation in Anorexia Nervosa

    PubMed Central

    Jennings, K. P.; Klidjian, A. M.

    1974-01-01

    Two patients with anorexia nervosa were treated on a general surgical unit for acute gastric dilatation. In both cases the dilatation rapidly followed an increase in the usual low dietary intake of the patients, and the ingestion of extra food may have initiated the acute episode. Conservative treatment with parenteral fluids, nasogastric intubation, and then a gradual return to a normal diet proved a satisfactory method of management. In one patient the anorexia itself was improved. PMID:4834098

  20. Resveratrol Inhibits Aortic Root Dilatation in the Fbn1C1039G/+ Marfan Mouse Model

    PubMed Central

    Hibender, Stijntje; Franken, Romy; van Roomen, Cindy; ter Braake, Anique; van der Made, Ingeborg; Schermer, Edith E.; Gunst, Quinn; van den Hoff, Maurice J.; Lutgens, Esther; Pinto, Yigal M.; Groenink, Maarten; Zwinderman, Aeilko H.; Mulder, Barbara J.M.; de Vries, Carlie J.M.

    2016-01-01

    Objective— Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene. Patients with MFS are at risk of aortic aneurysm formation and dissection. Usually, blood pressure–lowering drugs are used to reduce aortic events; however, this is not sufficient for most patients. In the aorta of smooth muscle cell–specific sirtuin-1–deficient mice, spontaneous aneurysm formation and senescence are observed. Resveratrol is known to enhance sirtuin-1 activity and to reduce senescence, which prompted us to investigate the effectiveness of resveratrol in inhibition of aortic dilatation in the Fbn1C1039G/+ MFS mouse model. Approach and Results— Aortic senescence strongly correlates with aortic root dilatation rate in MFS mice. However, although resveratrol inhibits aortic dilatation, it only shows a trend toward reduced aortic senescence. Resveratrol enhances nuclear localization of sirtuin-1 in the vessel wall and, in contrast to losartan, does not affect leukocyte infiltration nor activation of SMAD2 and extracellular signal–regulated kinases 1/2 (ERK1/2). Interestingly, specific sirtuin-1 activation (SRT1720) or inhibition (sirtinol) in MFS mice does not affect aortic root dilatation rate, although senescence is changed. Resveratrol reduces aortic elastin breaks and decreases micro-RNA-29b expression coinciding with enhanced antiapoptotic Bcl-2 expression and decreased number of terminal apoptotic cells. In cultured smooth muscle cells, the resveratrol effect on micro-RNA-29b downregulation is endothelial cell and nuclear factor κB-dependent. Conclusions— Resveratrol inhibits aortic root dilatation in MFS mice by promoting elastin integrity and smooth muscle cell survival, involving downregulation of the aneurysm-related micro-RNA-29b in the aorta. On the basis of these data, resveratrol holds promise as a novel intervention strategy for patients with MFS. PMID:27283746

  1. [The dilatation of auditive tube (Bougirage tubaire) by dilators in XIX century].

    PubMed

    Kierzek, Andrzej

    2006-01-01

    The treatment of auditiory tube chronic catarrh in XIX century by pharmagological drugs, by special apparatuses of surprising technical sophistication, by electrisation and faradisation is discussed first of all. The dilatation of auditory tube by dilators was the diagnostical and therapeutical methods, especially preferenced by Victor Urbantschitsch, Hermann Schwartze, Jean P. Bonnafonte, Albert Calmettes and Bronisław Taczanowski, Teodor Heiman and Samuel Meyerson. The dilators were building of celluloid, whale-bone, silver and were absorbed by argentum nitrate, vaseline. The technique, difficulties and effects of dilatation are described in more detail. The complications of this operation is presented finally. PMID:17131853

  2. On Demand Urethral Dilatation Versus Intermittent Urethral Dilatation: Results and Complications in Women With Urethral Stricture

    PubMed Central

    Heidari, Fatemeh; Abbaszadeh, Shahin; Ghadian, Alireza; Tehrani Kia, Farahnaz

    2014-01-01

    Background: The treatment of urethral stricture in female patients is through dilatation of the urethra by tubes of increasing diameter. There are two main methods: intermittent dilatation and on demand dilatation. Objectives: The main aim of this study was to compare the results of these two methods, and to determine the best one. Patients and Methods: In this clinical trial study, we reviewed the documents of women diagnosed with urethral stricture, who came to the Baqiyatallah Clinic from 2007 and 2012. According to the method of dilatation, the patients were divided into two groups: intermittent dilatation and on demand dilatation. Patients’ data were then collected and analyzed. Results: Eighty-six patients were enrolled in the study. The mean age of the participants was 48.13 years (between 44 and 79 years). The mean urinary residual and maximum urinary flow speed changes, before and after on demand dilatation, were higher than in the intermittent method. Conclusions: For treating urethral stricture, on demand urethral dilatation is more effective than intermittent dilatation. PMID:24783171

  3. Supraglottic airway devices.

    PubMed

    Ramachandran, Satya Krishna; Kumar, Anjana M

    2014-06-01

    Supraglottic airway devices (SADs) are used to keep the upper airway open to provide unobstructed ventilation. Early (first-generation) SADs rapidly replaced endotracheal intubation and face masks in > 40% of general anesthesia cases due to their versatility and ease of use. Second-generation devices have further improved efficacy and utility by incorporating design changes. Individual second-generation SADs have allowed more dependable positive-pressure ventilation, are made of disposable materials, have integrated bite blocks, are better able to act as conduits for tracheal tube placement, and have reduced risk of pulmonary aspiration of gastric contents. SADs now provide successful rescue ventilation in > 90% of patients in whom mask ventilation or tracheal intubation is found to be impossible. However, some concerns with these devices remain, including failing to adequately ventilate, causing airway damage, and increasing the likelihood of pulmonary aspiration of gastric contents. Careful patient selection and excellent technical skills are necessary for successful use of these devices. PMID:24891199

  4. Knock-in mouse model of dilated cardiomyopathy caused by troponin mutation.

    PubMed

    Du, Cheng-Kun; Morimoto, Sachio; Nishii, Kiyomasa; Minakami, Reiko; Ohta, Mika; Tadano, Naoto; Lu, Qun-Wei; Wang, Yuan-Yuan; Zhan, Dong-Yun; Mochizuki, Misato; Kita, Satomi; Miwa, Yoshikazu; Takahashi-Yanaga, Fumi; Iwamoto, Takahiro; Ohtsuki, Iwao; Sasaguri, Toshiyuki

    2007-07-20

    We created knock-in mice in which a deletion of 3 base pairs coding for K210 in cardiac troponin (cTn)T found in familial dilated cardiomyopathy patients was introduced into endogenous genes. Membrane-permeabilized cardiac muscle fibers from mutant mice showed significantly lower Ca(2+) sensitivity in force generation than those from wild-type mice. Peak amplitude of Ca(2+) transient in cardiomyocytes was increased in mutant mice, and maximum isometric force produced by intact cardiac muscle fibers of mutant mice was not significantly different from that of wild-type mice, suggesting that Ca(2+) transient was augmented to compensate for decreased myofilament Ca(2+) sensitivity. Nevertheless, mutant mice developed marked cardiac enlargement, heart failure, and frequent sudden death recapitulating the phenotypes of dilated cardiomyopathy patients, indicating that global functional defect of the heart attributable to decreased myofilament Ca(2+) sensitivity could not be fully compensated by only increasing the intracellular Ca(2+) transient. We found that a positive inotropic agent, pimobendan, which directly increases myofilament Ca(2+) sensitivity, had profound effects of preventing cardiac enlargement, heart failure, and sudden death. These results verify the hypothesis that Ca(2+) desensitization of cardiac myofilament is the absolute cause of the pathogenesis of dilated cardiomyopathy associated with this mutation and strongly suggest that Ca(2+) sensitizers are beneficial for the treatment of dilated cardiomyopathy patients affected by sarcomeric regulatory protein mutations. PMID:17556660

  5. Ultrasound: A promising tool for contemporary airway management.

    PubMed

    Garg, Rakesh; Gupta, Anju

    2015-11-16

    Airway evaluation and its management remains an ever emerging clinical science. Present airway management tools are static and do not provide dynamic airway management option. Visualized procedures like ultrasound (US) provide point of care real time dynamic views of the airway in perioperative, emergency and critical care settings. US can provide dynamic anatomical assessment which is not possible by clinical examination alone. US aids in detecting gastric contents and the nature of gastric contents (clear fluid, thick turbid or solid) as well. US can help in predicting endotracheal tube size by measuring subglottic diameter and diameter of left main stem bronchus. US was found to be a sensitive in detecting rotational malposition of LMA in children. Also, US is the fastest and highly sensitive tool to rule out a suspected intraoperative pneumothorax. In intensive care units, US helps torule out causes of inadequate ventilation, determine the tracheal width and distance from the skin to predict tracheotomy tube size and shape and assist with percutaneous dilatational tracheostomy. US can help in confirming the correct tracheal tube placement by dynamic visualisation of the endotracheal tube insertion, widening of vocal cords (children), and bilateral lung-sliding and diaphragmatic movement. Thus, ultrasonography has brought a paradigm shift in the practise of airway management. With increasing awareness, portability, accessibility and further sophistication in technology, it is likely to find a place in routine airway management. We are not far from the time when all of us will be carrying a pocket US machine like stethoscopes to corroborate our clinical findings at point of care. PMID:26601094

  6. Ultrasound: A promising tool for contemporary airway management

    PubMed Central

    Garg, Rakesh; Gupta, Anju

    2015-01-01

    Airway evaluation and its management remains an ever emerging clinical science. Present airway management tools are static and do not provide dynamic airway management option. Visualized procedures like ultrasound (US) provide point of care real time dynamic views of the airway in perioperative, emergency and critical care settings. US can provide dynamic anatomical assessment which is not possible by clinical examination alone. US aids in detecting gastric contents and the nature of gastric contents (clear fluid, thick turbid or solid) as well. US can help in predicting endotracheal tube size by measuring subglottic diameter and diameter of left main stem bronchus. US was found to be a sensitive in detecting rotational malposition of LMA in children. Also, US is the fastest and highly sensitive tool to rule out a suspected intraoperative pneumothorax. In intensive care units, US helps torule out causes of inadequate ventilation, determine the tracheal width and distance from the skin to predict tracheotomy tube size and shape and assist with percutaneous dilatational tracheostomy. US can help in confirming the correct tracheal tube placement by dynamic visualisation of the endotracheal tube insertion, widening of vocal cords (children), and bilateral lung-sliding and diaphragmatic movement. Thus, ultrasonography has brought a paradigm shift in the practise of airway management. With increasing awareness, portability, accessibility and further sophistication in technology, it is likely to find a place in routine airway management. We are not far from the time when all of us will be carrying a pocket US machine like stethoscopes to corroborate our clinical findings at point of care. PMID:26601094

  7. Effect of nanodisperse ferrite cobalt (CoFe2O4) particles on contractile reactions in guinea pigs airways.

    PubMed

    Kapilevich, L V; D'yakova, E Yu; Nosarev, A V; Zaitseva, T N; Petlina, Z R; Ogorodova, L M; Ageev, B G; Magaeva, A A; Itin, V I; Terekhova, O G

    2010-07-01

    The effect of nanopowder CoFe(2)O(4)on contractile responses of smooth-muscle segments of guinea pigs airways was studied by mechanography. Both in vivo inhalation of nanopowder aerosol or in vitro application of nanopowder to isolated airway segments increased the amplitude of contractile responses to histamine and potentiated the dilatory reaction to adrenergic salbutamol. PMID:21113462

  8. Viral myocarditis and dilated cardiomyopathy: mechanisms, manifestations, and management

    PubMed Central

    Kearney, M; Cotton, J; Richardson, P; Shah, A

    2001-01-01

    Viral infection of the heart is relatively common and usually of little consequence. It can, however, lead to substantial cardiac damage and severe acute heart failure. It can also evolve into the progressive syndrome of chronic heart failure. Recent studies have gone some way towards unravelling the complex mechanisms underlying the heart muscle damage that occurs after viral infection. These studies have lent support to both immune and viral mediated (independent of an immune response) cardiac damage. Acute myocarditis can present in various ways, and it may be a cause of sudden death in an otherwise healthy young adult. New treatments for viral heart disease are awaited. In the meanwhile, the haemodynamic support of patients with acute left ventricular failure caused by myocarditis should be aggressive, to allow for the possibility of spontaneous recovery. Contemporary trials of treatment in chronic heart failure secondary to dilated cardiomyopathy support the use of angiotensin converting enzyme inhibitors, β adrenoceptor blockers, and spironolactone in such patients.


Keywords: myocarditis; heart failure; coxsackie B virus; dilated cardiomyopathy PMID:11123385

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

    PubMed

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

    2015-10-01

    Ozone causes airway hyperresponsiveness (AHR) and pulmonary inflammation. Rho kinase (ROCK) is a key regulator of smooth muscle cell contraction and inflammatory cell migration. To determine the contribution of the two ROCK isoforms ROCK1 and ROCK2 to ozone-induced AHR, we exposed wild-type, ROCK1(+/-), and ROCK2(+/-) mice to air or ozone (2 ppm for 3 h) and evaluated mice 24 h later. ROCK1 or ROCK2 haploinsufficiency did not affect airway responsiveness in air-exposed mice but significantly reduced ozone-induced AHR, with a greater reduction in ROCK2(+/-) mice despite increased bronchoalveolar lavage (BAL) inflammatory cells in ROCK2(+/-) mice. Compared with wild-type mice, ozone-induced increases in BAL hyaluronan, a matrix protein implicated in ozone-induced AHR, were lower in ROCK1(+/-) but not ROCK2(+/-) mice. Ozone-induced increases in other inflammatory moieties reported to contribute to ozone-induced AHR (IL-17A, osteopontin, TNFα) were not different in wild-type vs. ROCK1(+/-) or ROCK2(+/-) mice. We also observed a dose-dependent reduction in ozone-induced AHR after treatment with the ROCK1/ROCK2 inhibitor fasudil, even though fasudil was administered after induction of inflammation. Ozone increased pulmonary expression of ROCK2 but not ROCK1 or RhoA. A ROCK2 inhibitor, SR3677, reduced contractile forces in primary human airway smooth muscle cells, confirming a role for ROCK2 in airway smooth muscle contraction. Our results demonstrate that ozone-induced AHR requires ROCK. Whereas ROCK1-dependent changes in hyaluronan may contribute to ROCK1's role in O3-induced AHR, the role of ROCK2 is downstream of inflammation, likely at the level of airway smooth muscle contraction. PMID:26276827

  10. Issues of critical airway management (Which anesthesia; which surgical airway?).

    PubMed

    Bonanno, Fabrizio Giuseppe

    2012-10-01

    Which anesthesia for patients with critical airway? Safe and effective analgesia and anesthesia in critical airway is a skilled task especially after severe maxillofacial injury combined with head injury and hemorrhagic shock. If on one side sedation is wanted, on the other hand it may worsen the airway and hemodynamic situation to a point where hypoventilation and decrease of blood pressure, common side-effect of many opioids, may prejudice the patient's level of consciousness and hemodynamic compensation, compounding an already critical situation. What to do when endotracheal intubation fails and blood is trickling down the airways in an unconscious patient or when a conscious patient has to sit up to breathe? Which surgical airway in critical airway? Comparative studies among the various methods of emergency surgical airway would be unethical; furthermore, operator's training and experience is relevant for indications and performance. PMID:23248494

  11. Cervical dilatation by Lamicel before first trimester abortion: a clinical and experimental study.

    PubMed

    Norström, A; Bryman, I; Hansson, H A

    1988-04-01

    Twenty women were treated with Lamicel tents for 4 h and 20 women for 16 h before vacuum aspiration in the first trimester of pregnancy. The shorter time of treatment was as effective as the longer time with respect to cervical softening and dilatation. In comparison with an untreated control group, Lamicel treatment was followed by an increased collagenolytic activity and increased sensitivity to prostaglandin E2 of the cervical smooth muscle. PMID:3164206

  12. Exercise and airway injury in athletes.

    PubMed

    Couto, Mariana; Silva, Diana; Delgado, Luis; Moreira, André

    2013-01-01

    Olympic level athletes present an increased risk for asthma and allergy, especially those who take part in endurance sports, such as swimming or running, and in winter sports. Classical postulated mechanisms behind EIA include the osmotic, or airway-drying, hypothesis. Hyperventilation leads to evaporation of water and the airway surface liquid becomes hyperosmolar, providing a stimulus for water to move from any cell nearby, which results in the shrinkage of cells and the consequent release of inflammatory mediators that cause airway smooth muscle contraction. But the exercise-induced asthma/bronchoconstriction explanatory model in athletes probably comprises the interaction between environmental training factors, including allergens and ambient conditions such as temperature, humidity and air quality; and athlete's personal risk factors, such as genetic and neuroimmuneendocrine determinants. After the stress of training and competitions athletes experience higher rate of upper respiratory tract infections (URTI), compared with lesser active individuals. Increasing physical activity in non-athletes is associated with a decreased risk of URTI. Heavy exercise induces marked immunodepression which is multifactorial in origin. Prolonged, high intensity exercise temporarily impairs the immune competence while moderate activity may enhance immune function. The relationship between URTI and exercise is affected by poorly known individual determinants such genetic susceptibility, neurogenic mediated immune inflammation and epithelial barrier dysfunction. Further studies should better define the aetiologic factors and mechanisms involved in the development of asthma in athletes, and propose relevant preventive and therapeutic measures. PMID:23697359

  13. Role of Central Neurotransmission and Chemoreception on Airway Control

    PubMed Central

    Kc, Prabha; Martin, Richard J.

    2010-01-01

    This review summarizes work on central neurotransmission, chemoreception and CNS control of cholinergic outflow to the airways. First, we describe the neural transmission of bronchoconstrictive signals from airway afferents to the airway-related vagal preganglionic neurons (AVPNs) via the nucleus of the solitary tract (nTS) and, second, we characterize evidence for a modulatory effect of excitatory glutamatergic, and inhibitory GABAergic, noradrenergic and serotonergic pathways on AVPN output. Excitatory signals arising from bronchopulmonary afferents and/or the peripheral chemosensory system activate second order neurons within the nTS, via a glutamate-AMPA (alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid) receptor signaling pathway. These nTS neurons, using the same neurotransmitter-receptor unit, transmit information to the AVPNs, which in turn convey the central command through descending fibers and airway intramural ganglia to airway smooth muscle, submucosal secretory glands, and the vasculature. The strength and duration of this reflex-induced bronchoconstriction is modulated by GABAergic-inhibitory inputs. In addition, central noradrenergic and serotonergic inhibitory pathways appear to participate in the regulation of cholinergic drive to the tracheobronchial system. Down-regulation of these inhibitory influences results in a shift from inhibitory to excitatory drive, which may lead to increased excitability of AVPNs, heightened airway responsiveness, greater cholinergic outflow to the airways and consequently bronchoconstriction. In summary, centrally coordinated control of airway tone and respiratory drive serve to optimize gas exchange and work of breathing under normal homeostatic conditions. Greater understanding of this process should enhance our understanding of its disruption under pathophysiologic states. PMID:20359553

  14. Total airway reconstruction.

    PubMed

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

    2013-02-01

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

  15. Epithelial hyperplasia, airways

    Cancer.gov

    Number of respiratory epithelial cells is increased diffusely or focally. Frequently luminal protrusions are observed, sometimes forming papillae. Mucous (goblet) cell metaplastic hyperplasia is a variant, in which the respiratory epithelium of conducting airways is replaced by mucous cells either as a single or a pseudostratified layer.

  16. Advances in prehospital airway management

    PubMed Central

    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. PMID:24741499

  17. Methods of airway resistance assessment.

    PubMed

    Urbankowski, Tomasz; Przybyłowski, Tadeusz

    2016-01-01

    Airway resistance is the ratio of driving pressure to the rate of the airflow in the airways. The most frequent methods used to measure airway resistance are whole-body plethysmography, the interrupter technique and the forced oscillation technique. All these methods allow to measure resistance during respiration at the level close to tidal volume, they do not require forced breathing manoeuvres or deep breathing during measurement. The most popular method for measuring airway resistance is whole-body plethysmography. The results of plethysmography include among others the following parameters: airway resistance (Raw), airway conductance (Gaw), specific airway resistance (sRaw) and specific airway conductance (sGaw). The interrupter technique is based on the assumption that at the moment of airway occlusion, air pressure in the mouth is equal to the alveolar pressure . In the forced oscillation technique (FOT), airway resistance is calculated basing on the changes in pressure and flow caused by air vibration. The methods for measurement of airway resistance that are described in the present paper seem to be a useful alternative to the most common lung function test - spirometry. The target group in which these methods may be widely used are particularly the patients who are unable to perform spirometry. PMID:27238174

  18. Supraglottic airway devices in children

    PubMed Central

    Ramesh, S; Jayanthi, R

    2011-01-01

    Modern anaesthesia practice in children was made possible by the invention of the endotracheal tube (ET), which made lengthy and complex surgical procedures feasible without the disastrous complications of airway obstruction, aspiration of gastric contents or asphyxia. For decades, endotracheal intubation or bag-and-mask ventilation were the mainstays of airway management. In 1983, this changed with the invention of the laryngeal mask airway (LMA), the first supraglottic airway device that blended features of the facemask with those of the ET, providing ease of placement and hands-free maintenance along with a relatively secure airway. The invention and development of the LMA by Dr. Archie Brain has had a significant impact on the practice of anaesthesia, management of the difficult airway and cardiopulmonary resuscitation in children and neonates. This review article will be a brief about the clinical applications of supraglottic airways in children. PMID:22174464

  19. Investigation of the dilated urinary tract.

    PubMed

    Parkhouse, H F; Barratt, T M

    1988-01-01

    Dilatation of the urinary tract does not necessarily imply obstruction, and other factors may be operative: maldevelopment, infection, reflux, and polyuria. Obstruction of the urinary tract in intra-uterine life is associated with renal dysplasia: the original obstructive lesion may be transient but the consequent dysplasia and dilatation may be permanent. Routine antenatal ultrasound identifies a new population of infants with urinary tract dilatation, many of whom remain asymptomatic and would not otherwise have come to medical attention: the natural history and appropriate schedules of investigation and management of this group are still being evaluated. Anatomical imaging by ultrasound establishes the presence and extent of dilatation. Micturating cystourethrography, intravenous urography and antegrade pyelography establish the site but not the functional significance of an obstructive lesion. Isotope renal scanning with 99mTc-DTPA may identify an acutely obstructed kidney with a decrease renal uptake, prolonged parenchymal transit time, and delayed clearance of the isotope from the renal pelvis after furosemide. However, such analyses often give equivocal results in infants with poor renal function and markedly dilated urinary tracts. Obstructive uropathy should be seen as a disturbance of the normal pressure-flow relationships in the urinary tract, and be defined and investigated as such. Antegrade perfusion with renal pelvic pressure measurements has technical pitfalls, but is the definitive method of establishing upper tract obstruction. Videocystourethrography is the established method of investigating the lower urinary tract in older children but needs further development to be applicable to infants. PMID:3153000

  20. Management of the Traumatized Airway.

    PubMed

    Jain, Uday; McCunn, Maureen; Smith, Charles E; Pittet, Jean-Francois

    2016-01-01

    There is a lack of evidence-based approach regarding the best practice for airway management in patients with a traumatized airway. General recommendations for the management of the traumatized airway are summarized in table 5. Airway trauma may not be readily apparent, and its evaluation requires a high level of suspicion for airway disruption and compression. For patients with facial trauma, control of the airway may be significantly impacted by edema, bleeding, inability to clear secretions, loss of bony support, and difficulty with face mask ventilation. With the airway compression from neck swelling or hematoma, intubation attempts can further compromise the airway due to expanding hematoma. For patients with airway disruption, the goal is to pass the tube across the injured area without disrupting it or to insert the airway distal to the injury using a surgical approach. If airway injury is extensive, a surgical airway distal to the site of injury may be the best initial approach. Alternatively, if orotracheal intubation is chosen, spontaneous ventilation may be maintained or RSI may be performed. RSI is a common approach. Thus, some of the patients intubated may subsequently require tracheostomy. A stable patient with limited injuries may not require intubation but should be watched carefully for at least several hours. Because of a paucity of evidence-based data, the choice between these approaches and the techniques utilized is a clinical decision depending on the patient's condition, clinical setting, injuries to airway and other organs, and available personnel, expertise, and equipment. Inability to obtain a definitive airway is always an absolute indication for an emergency cricothyroidotomy or surgical tracheostomy. PMID:26517857

  1. A new rodent model for obstructive sleep apnea: effects on ATP-mediated dilations in cerebral arteries

    PubMed Central

    Crossland, Randy F.; Durgan, David J.; Lloyd, Eric E.; Phillips, Sharon C.; Reddy, Anilkumar K.; Marrelli, Sean P.

    2013-01-01

    Obstructive sleep apnea (OSA), a condition in which the upper airway collapses during sleep, is strongly associated with metabolic and cardiovascular diseases. Little is known how OSA affects the cerebral circulation. The goals of this study were 1) to develop a rat model of chronic OSA that involved apnea and 2) to test the hypothesis that 4 wk of apneas during the sleep cycle alters endothelium-mediated dilations in middle cerebral arteries (MCAs). An obstruction device, which was chronically implanted into the trachea of rats, inflated to obstruct the airway 30 times/h for 8 h during the sleep cycle. After 4 wk of apneas, MCAs were isolated, pressurized, and exposed to luminally applied ATP, an endothelial P2Y2 receptor agonist that dilates through endothelial-derived nitric oxide (NO) and endothelial-dependent hyperpolarization (EDH). Dilations to ATP were attenuated ∼30% in MCAs from rats undergoing apneas compared with those from a sham control group (P < 0.04 group effect; n = 7 and 10, respectively). When the NO component of the dilation was blocked to isolate the EDH component, the response to ATP in MCAs from the sham and apnea groups was similar. This finding suggests that the attenuated dilation to ATP must occur through reduced NO. In summary, we have successfully developed a novel rat model for chronic OSA that incorporates apnea during the sleep cycle. Using this model, we demonstrate that endothelial dysfunction occurred by 4 wk of apnea, likely increasing the vulnerability of the brain to cerebrovascular related accidents. PMID:23761641

  2. A surprising cause of reversible dilated cardiomyopathy

    PubMed Central

    Vlot, Mariska; de Jong, Margriet; de Ronde, Pim; Tukkie, Raymond

    2014-01-01

    This case report describes two cases of dilated cardiomyopathy due to hypocalcaemia as a result of hypoparathyroidism. Patient A suffered from dilated cardiomyopathy due to secondary hypoparathyroidism as a result of previous neck surgery. Patient B suffered from dilated cardiomyopathy with congestive heart failure due to primary hypoparathyroidism. Hypoparathyroidism can exist for years before being recognised, especially after neck surgery. Besides standard treatment of heart failure, restoration of serum calcium levels with calcium and vitamin D supplementation can lead to rapid improvement of cardiac function and should be continued lifelong. Both patients were responding very well to heart failure therapy and calcium supplementation as ejection fraction improved after restoration of plasma calcium levels. This case report emphasises that hypocalcaemia should be in the differential diagnosis of heart failure. PMID:24879729

  3. Myocardial gallium-67 imaging in dilated cardiomyopathy

    PubMed Central

    O'Connell, John B.; Henkin, Robert E.

    1985-01-01

    The use of gallium-67, an isotope that is avid for areas of inflammation in patients with dilated cardiomyopathy, is described and compared with endomyocardial biopsy in 68 consecutive patients with dilated cardiomyopathy. Myocarditis was diagnosed in 8% on biopsy and the likelihood of a positive biopsy when the gallium scan was positive for inflammation, rose to 36%. It is concluded that gallium scanning is a useful adjunct to biopsy in detecting myocarditis in patients with dilated cardiomyopathy and in following patients with evidence of myocarditis on biopsy. Disadvantages of gallium-67 imaging include the radiation dose accumulated with multiple scans and 72h delay from initial injection of the isotope to imaging. It is suggested that definitive conclusions regarding the technique should await the results of a large multicentre trial evaluating gallium in comparison with endomyocardial biopsy in the diagnosis of myocarditis. ImagesFigure 1Figure 2

  4. Parallelized Dilate Algorithm for Remote Sensing Image

    PubMed Central

    Zhang, Suli; Hu, Haoran; Pan, Xin

    2014-01-01

    As an important algorithm, dilate algorithm can give us more connective view of a remote sensing image which has broken lines or objects. However, with the technological progress of satellite sensor, the resolution of remote sensing image has been increasing and its data quantities become very large. This would lead to the decrease of algorithm running speed or cannot obtain a result in limited memory or time. To solve this problem, our research proposed a parallelized dilate algorithm for remote sensing Image based on MPI and MP. Experiments show that our method runs faster than traditional single-process algorithm. PMID:24955392

  5. Understanding the dilation and dilation relaxation behavior of graphite-based lithium-ion cells

    NASA Astrophysics Data System (ADS)

    Bauer, Marius; Wachtler, Mario; Stöwe, Hendrik; Persson, Jon V.; Danzer, Michael A.

    2016-06-01

    The dilation of lithium-ion cells is sensitive towards swelling phenomena caused by both graphite staging processes and lithium plating on graphite anodes. In this work, the dilation behavior of graphite/NMC pouch cells is studied with a focus on relaxation phenomena occurring after current pulses. In order to prevent misleading interpretations due to thermal effects, thermal expansion is quantified and a method for the thermal compensation of dilation data is developed. Dilation data are recorded for quasi-equilibrium cycling as well as for current pulses at high rates. In the quasi-equilibrium case, the staging behavior is characterized based on dilation and voltage data. By comparison with a graphite half-cell measurement, the major effects in full cell dilation are confirmed to be anode related. In the high rate case, the dilation responses to the actual pulse and the subsequent relaxation phases are recorded systematically. Positive and negative relaxation phenomena are observed depending on the SOC. They are ascribed to both graphite staging and lithium plating processes. A model is presented explaining the unexpected relaxation effects by a temporary coexistence of three or more staging compounds during high rate lithiation and delithiation. Our data thereby confirm the shrinking annuli model introduced by Heβ and Novák.

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

    PubMed

    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

    2009-06-01

    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. PMID:19458046

  7. Take the Wnt out of the inflammatory sails: modulatory effects of Wnt in airway diseases.

    PubMed

    Reuter, Sebastian; Beckert, Hendrik; Taube, Christian

    2016-02-01

    Bronchial asthma and chronic obstructive pulmonary disease (COPD) are chronic diseases that are associated with inflammation and structural changes in the airways and lungs. Recent findings have implicated Wnt pathways in critically regulating inflammatory responses, especially in asthma. Furthermore, canonical and noncanonical Wnt pathways are involved in structural changes such as airway remodeling, goblet cell metaplasia, and airway smooth muscle (ASM) proliferation. In COPD, Wnt pathways are not only associated with structural changes in the airways but also involved in the development of emphysema. The present review summarizes the role and function of the canonical and noncanonical Wnt pathway with regard to airway inflammation and structural changes in asthma and COPD. Further identification of the role and function of different Wnt molecules and pathways could help to develop novel therapeutic options for these diseases. PMID:26595171

  8. Limonene inhalation reduces allergic airway inflammation in Dermatophagoides farinae-treated mice.

    PubMed

    Hirota, Ryoji; Nakamura, Hiroyuki; Bhatti, Sabah Asif; Ngatu, Nlandu Roger; Muzembo, Basilua Andre; Dumavibhat, Narongpon; Eitoku, Masamitsu; Sawamura, Masayoshi; Suganuma, Narufumi

    2012-05-01

    Limonene is one of the main flavonoids which is reported to inhibit the inflammatory response by suppressing the production of reactive oxygen species. The aim of this study was to evaluate whether limonene can inhibit Dermatophagoides farinae-induced airway hyperresponsiveness (AHR), eosinophilic infiltration and other histological changes in the lung, T helper (Th) 2 cytokine production and airway remodeling in a mice model of asthma. Treatment with limonene significantly reduced the levels of IL-5, IL-13, eotaxin, MCP-1, and TGF-β₁ in bronchoalveolar lavage fluid. The goblet cell metaplasia, thickness of airway smooth muscle, and airway fibrosis were markedly decreased in limonene-treated mice. Furthermore, AHR to acetylcholine was significantly abrogated in limonene-treated mice. These results indicate that limonene has a potential to reduce airway remodeling and AHR in asthma model. PMID:22564095

  9. The Wnt/β-catenin signaling pathway regulates the development of airway remodeling in patients with asthma

    PubMed Central

    Kwak, Hyun Jung; Park, Dong Won; Seo, Ji-Young; Moon, Ji-Yong; Kim, Tae Hyung; Sohn, Jang Won; Shin, Dong Ho; Yoon, Ho Joo; Park, Sung Soo; Kim, Sang-Heon

    2015-01-01

    Airway remodeling is a key characteristic of chronic asthma, particularly in patients with a fixed airflow limitation. The mechanisms underlying airway remodeling are poorly understood, and no therapeutic option is available. The Wnt/β-catenin signaling pathway is involved in various physiological and pathological processes, including fibrosis and smooth muscle hypertrophy. In this study, we investigated the roles of Wnt/β-catenin signaling in airway remodeling in patients with asthma. Wnt7a mRNA expression was prominent in induced sputum from patients with asthma compared with that from healthy controls. Next, we induced a chronic asthma mouse model with airway remodeling features, including subepithelial fibrosis and airway smooth muscle hyperplasia. Higher expression of Wnt family proteins and β-catenin was detected in the lung tissue of mice with chronic asthma compared to control mice. Blocking β-catenin expression with a specific siRNA attenuated airway inflammation and airway remodeling. Decreased subepithelial fibrosis and collagen accumulation in the β-catenin siRNA-treated mice was accompanied by reduced expression of transforming growth factor-β. We further showed that suppressing β-catenin in the chronic asthma model inhibited smooth muscle hyperplasia by downregulating the tenascin C/platelet-derived growth factor receptor pathway. Taken together, these findings demonstrate that the Wnt/β-catenin signaling pathway is highly expressed and regulates the development of airway remodeling in chronic asthma. PMID:26655831

  10. Upper Airway Mechanics

    PubMed Central

    Verbraecken, Johan A.; De Backer, Wilfried A.

    2009-01-01

    This review discusses the pathophysiological aspects of sleep-disordered breathing, with focus on upper airway mechanics in obstructive and central sleep apnoea, Cheyne-Stokes respiration and obesity hypoventilation syndrome. These disorders constitute the end points of a spectrum with distinct yet interrelated mechanisms that lead to substantial pathology, i.e. increased upper airway collapsibility, control of breathing instability, increased work of breathing, disturbed ventilatory system mechanics and neurohormonal changes. Concepts are changing. Although sleep apnoea is considered more and more to be an increased loop gain disorder, the central type of apnoea is now considered as an obstructive event, because it causes pharyngeal narrowing, associated with prolonged expiration. Although a unifying concept for the pathogenesis is lacking, it seems that these patients are in a vicious circle. Knowledge of common patterns of sleep-disordered breathing may help to identify these patients and guide therapy. PMID:19478479

  11. Expression and function of a novel variant of estrogen receptor-α36 in murine airways.

    PubMed

    Jia, Shuping; Zhang, Xintian; He, David Z Z; Segal, Manav; Berro, Abdo; Gerson, Trevor; Wang, Zhaoyi; Casale, Thomas B

    2011-11-01

    Evidence suggests that estrogen signaling is involved in sex differences in the prevalence rates and control of asthma, but the expression patterns of estrogen receptor variants and estrogen function in the lung are not well established. We investigated the expression of major estrogen receptor variants occurring naturally and after the development of allergen-induced airway hyperreactivity in a murine model of allergic asthma, along with the role of estrogen signaling in small-airway ciliary motion and smooth muscle contraction. Female BALB/c mice were sensitized with ovalbumin, and estrogen receptor expression patterns were examined by immunofluorescence and Western blot analysis. Time-lapse video and photodiode-based displacement measurement systems were used to assess the effects of estrogen signaling on airway ciliary beat frequency and smooth muscle contraction. We found that a novel variant of estrogen receptor (ER)-α, ER-α36, is expressed in airway epithelial and smooth muscle cells. ER-α36 was predominately localized on the plasma membranes of airway cells. After sensitization to allergen, the expression levels of ER-α36 increased significantly (P < 0.01), whereas the expression of ER-β and ER-α66 did not significantly change. Estrogen treatment in vitro resulted in a rapid increase in airway cilia motion in a dose-dependent fashion, but did not exert any effect on airway smooth muscle contraction. We speculate that the up-regulation of estrogen receptor expression associated with allergen-induced airway hyperresponsiveness may constitute a protective mechanism to facilitate the clearance of mucus. The identification and localization of specific estrogen receptor subtypes in the lung could lead to newer therapeutic avenues aimed at addressing sex differences of asthma susceptibility. PMID:21642591

  12. Effect of intranasal rosiglitazone on airway inflammation and remodeling in a murine model of chronic asthma

    PubMed Central

    Lee, Hwa Young; Rhee, Chin Kook; Kang, Ji Young; Park, Chan Kwon; Lee, Sook Young; Kwon, Soon Suk; Kim, Young Kyoon; Yoon, Hyoung Kyu

    2016-01-01

    Background/Aims: Asthma is characterized by airway hyperresponsiveness, inflammation, and remodeling. Peroxisome proliferator-activated receptors have been reported to regulate inflammatory responses in many cells. In this study, we examined the effects of intranasal rosiglitazone on airway remodeling in a chronic asthma model. Methods: We developed a mouse model of airway remodeling, including smooth muscle thickening, in which ovalbumin (OVA)-sensitized mice were repeatedly exposed to intranasal OVA administration twice per week for 3 months. Mice were treated intranasally with rosiglitazone with or without an antagonist during OVA challenge. We determined airway inflammation and the degree of airway remodeling by smooth muscle actin area and collagen deposition. Results: Mice chronically exposed to OVA developed sustained eosinophilic airway inflammation, compared with control mice. Additionally, the mice developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Administration of rosiglitazone intranasally inhibited the eosinophilic inflammation significantly, and, importantly, airway smooth muscle remodeling in mice chronically exposed to OVA. Expression of Toll-like receptor (TLR)-4 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was increased in the OVA group and decreased in the rosiglitazone group. Co-treatment with GW9660 (a rosiglitazone antagonist) and rosiglitazone increased the expression of TLR-4 and NF-κB. Conclusions: These results suggest that intranasal administration of rosiglitazone can prevent not only air way inf lammation but also air way remodeling associated with chronic allergen challenge. This beneficial effect is mediated by inhibition of TLR-4 and NF-κB pathways. PMID:26767862

  13. Brachycephalic airway syndrome.

    PubMed

    Meola, Stacy D

    2013-08-01

    Brachycephalic airway syndrome is a common finding in brachycephalic breeds. A combination of primary and secondary changes can progress to life-threatening laryngeal collapse. Early recognition of primary anatomic abnormalities that include stenotic nares, elongated soft palate, and hypoplastic trachea would allow the clinician to make early recommendations for medical and surgical management, which can improve the quality of life in affected animals. PMID:24182996

  14. Upper airway resistance syndrome.

    PubMed

    Hasan, N; Fletcher, E C

    1998-07-01

    Many clinicians are familiar with the clinical symptoms and signs of obstructive sleep apnea (OSA). In its most blatant form, OSA is complete airway obstruction with repetitive, prolonged pauses in breathing, arterial oxyhemoglobin desaturation; followed by arousal with resumption of breathing. Daytime symptoms of this disorder include excessive daytime somnolence, intellectual dysfunction, and cardiovascular effects such as systemic hypertension, angina, myocardial infarction, and stroke. It has been recently recognized that increased pharyngeal resistance with incomplete obstruction can lead to a constellation of symptoms identical to OSA called "upper airway resistance syndrome" (UARS). The typical findings of UARS on sleep study are: (1) repetitive arousals from EEG sleep coinciding with a (2) waxing and waning of the respiratory airflow pattern and (3) increased respiratory effort as measured by esophageal pressure monitoring. There may be few, if any, obvious apneas or hypopneas with desaturation, but snoring may be a very prominent finding. Treatment with nasal positive airway pressure (NCPAP) eliminates the symptoms and confirms the diagnosis. Herein we describe two typical cases of UARS. PMID:9676067

  15. Airway closure in microgravity.

    PubMed

    Dutrieue, Brigitte; Verbanck, Sylvia; Darquenne, Chantal; Prisk, G Kim

    2005-08-25

    Recent single breath washout (SBW) studies in microgravity and on the ground have suggested an important effect of airway closure on gas mixing in the human lung, reflected particularly in the phase III slope of vital capacity SBW and bolus tests. In order to explore this effect, we designed a SBW in which subjects inspired 2-l from residual volume (RV) starting with a 150 ml bolus of He and SF6. In an attempt to vary the pattern of airways closure configuration before the test, the experiments were conducted in 1G and in microgravity during parabolic flight allowing the pre-test expiration to RV to be either in microgravity or at 1.8 G, with the actual test gas inhalation performed entirely in microgravity. Contrary to our expectations, the measured phase III slope and phase IV height and volume obtained from seven subjects in microgravity were essentially identical irrespective of the gravity level during the pre-test expiration to RV. The results suggest that airway closure configuration at RV before the test inspiration has no apparent impact on phases III and IV generation. PMID:15979418

  16. Hyaluronan mediates airway hyperresponsiveness in oxidative lung injury.

    PubMed

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

    2015-05-01

    Chlorine (Cl2) inhalation induces severe oxidative lung injury and airway hyperresponsiveness (AHR) that lead to asthmalike symptoms. When inhaled, Cl2 reacts with epithelial lining fluid, forming by-products that damage hyaluronan, a constituent of the extracellular matrix, causing the release of low-molecular-weight fragments (L-HA, <300 kDa), which initiate a series of proinflammatory events. Cl2 (400 ppm, 30 min) exposure to mice caused an increase of L-HA and its binding partner, inter-α-trypsin-inhibitor (IαI), in the bronchoalveolar lavage fluid. Airway resistance following methacholine challenge was increased 24 h post-Cl2 exposure. Intratracheal administration of high-molecular-weight hyaluronan (H-HA) or an antibody against IαI post-Cl2 exposure decreased AHR. Exposure of human airway smooth muscle (HASM) cells to Cl2 (100 ppm, 10 min) or incubation with Cl2-exposed H-HA (which fragments it to L-HA) increased membrane potential depolarization, intracellular Ca(2+), and RhoA activation. Inhibition of RhoA, chelation of intracellular Ca(2+), blockade of cation channels, as well as postexposure addition of H-HA, reversed membrane depolarization in HASM cells. We propose a paradigm in which oxidative lung injury generates reactive species and L-HA that activates RhoA and Ca(2+) channels of airway smooth muscle cells, increasing their contractility and thus causing AHR. PMID:25747964

  17. Hyaluronan mediates airway hyperresponsiveness in oxidative lung injury

    PubMed Central

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

    2015-01-01

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

  18. Management of achalasia: surgery or pneumatic dilation.

    PubMed

    Richter, Joel E; Boeckxstaens, Guy E

    2011-06-01

    Achalasia is an esophageal motility disorder of unknown cause, characterised by aperistalsis of the esophageal body and impaired lower esophageal sphincter relaxation. Patients present at all ages, primarily with dysphagia for solids/liquids and bland regurgitation. The diagnosis is suggested by barium esophagram or endoscopy and confirmed by esophageal manometry. Achalasia cannot be cured. Instead, our goal is to relieve symptoms, improve esophageal emptying and prevent the development of megaesophagus. The most successful therapies are pneumatic dilation and surgical myotomy. The advantages of pneumatic dilation include an outpatient procedure, minimal pain, return to work the next day, mild if any GERD, and can be performed in any age group and even during pregnancy. Pneumatic dilation does not hinder future myotomy, and all cost analyses find it less expensive than Heller myotomy. Laparoscopic myotomy with a partial fundoplication has the advantage of being a single procedure, dysphagia relief is longer at the cost of more troubling heartburn, and a myotomy may be more effective treatment in adolescents and younger adults, especially men. Over a two year horizon, the clinical success of pneumatic dilation and laparoscopic myotomy are comparable in a recent large European randomised trial. The prognosis for achalasia patients to return to near-normal swallowing and good quality of life are excellent, but few are "cured" with a single treatment and intermittent "touch up" procedures may be required. PMID:21303915

  19. Surface dilatational viscosity of Langmuir monolayers

    NASA Astrophysics Data System (ADS)

    Lopez, Juan; Vogel, Michael; Hirsa, Amir

    2003-11-01

    With increased interest in microfluidic systems, interfacial phenomena is receiving more attention. As the length scales of fluid problems decrease, the surface to volume ratio increases and the coupling between interfacial flow and bulk flow becomes increasingly dominated by effects due to intrinsic surface viscosities (shear and dilatational), in comparison to elastic effects (due to surface tension gradients). The surface shear viscosity is well-characterized, as cm-scale laboratory experiments are able to isolate its effects from other interfacial processes (e.g., in the deep-channel viscometer). The same is not true for the dilatational viscosity, because it acts in the direction of surface tension gradients. Their relative strength scale with the capillary number, and for cm-scale laboratory flows, surface tension effects tend to dominate. In microfluidic scale flows, the scaling favors viscosity. We have devised an experimental apparatus which is capable of isolating and enhancing the effects of dilatational viscosity at the cm scales by driving the interface harmonically in time, while keeping the interface flat. In this talk, we shall present both the theory for how this works as well as experimental measurements of surface velocity from which we deduce the dilatational viscosity of several monolayers on the air-water interface over a substantial range of surface concentrations. Anomalous behavior over some range of concentration, which superficially indicates negative viscosity, maybe explained in terms of compositional effects due to large spatial and temporal variations in concentration and corresponding viscosity.

  20. 21 CFR 876.5520 - Urethral dilator.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Urethral dilator. 876.5520 Section 876.5520 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL... flexibilities. The device may include a mechanism to expand the portion of the device in the urethra...

  1. A Symmetry Approach to Time Dilation.

    ERIC Educational Resources Information Center

    Dunne, Peter

    1995-01-01

    Outlines an approach to introduce students to special relativity using a discussion of stopclocks and measurement of the transmission of light pulses to produce a natural derivation of the time dilation factor. Aims at providing a frame of reference from which they can be tempted to explore special relativity at a more sophisticated level. (JRH)

  2. Pupils dilate for vocal or familiar music.

    PubMed

    Weiss, Michael W; Trehub, Sandra E; Schellenberg, E Glenn; Habashi, Peter

    2016-08-01

    Previous research reveals that vocal melodies are remembered better than instrumental renditions. Here we explored the possibility that the voice, as a highly salient stimulus, elicits greater arousal than nonvocal stimuli, resulting in greater pupil dilation for vocal than for instrumental melodies. We also explored the possibility that pupil dilation indexes memory for melodies. We tracked pupil dilation during a single exposure to 24 unfamiliar folk melodies (half sung to la la, half piano) and during a subsequent recognition test in which the previously heard melodies were intermixed with 24 novel melodies (half sung, half piano) from the same corpus. Pupil dilation was greater for vocal melodies than for piano melodies in the exposure phase and in the test phase. It was also greater for previously heard melodies than for novel melodies. Our findings provide the first evidence that pupillometry can be used to measure recognition of stimuli that unfold over several seconds. They also provide the first evidence of enhanced arousal to vocal melodies during encoding and retrieval, thereby supporting the more general notion of the voice as a privileged signal. (PsycINFO Database Record PMID:27123682

  3. Charged dilation black holes as particle accelerators

    NASA Astrophysics Data System (ADS)

    Pradhan, Parthapratim

    2015-03-01

    We examine the possibility of arbitrarily high energy in the center-of-mass (CM) frame of colliding neutral particles in the vicinity of the horizon of a charged dilation black hole (BH). We show that it is possible to achieve the infinite energy in the background of the dilation black hole without fine-tuning of the angular momentum parameter. It is found that the CM energy (Ecm) of collisions of particles near the infinite red-shift surface of the extreme dilation BHs are arbitrarily large while the non-extreme charged dilation BHs have the finite energy. We have also compared the Ecm at the horizon with the ISCO (Innermost Stable Circular Orbit) and MBCO (Marginally Bound Circular Orbit) for extremal Reissner-Nordstrøm (RN) BH and Schwarzschild BH. We find that for extreme RN BH the inequality becomes Ecm|r+ >Ecm|rmb >Ecm|rISCO i.e. Ecm|r+=M :Ecm | rmb =(3 +√{ 5 }/2) M :Ecm| rISCO = 4 M = ∞ : 3.23 : 2.6 . While for Schwarzschild BH the ratio of CM energy is Ecm| r+ = 2 M :Ecm| rmb = 4 M :Ecm| rISCO = 6 M =√{ 5 } :√{ 2 } :√{ 13 }/3 . Also for Gibbons-Maeda-Garfinkle-Horowitz-Strominger (GMGHS) BHs the ratio is being Ecm| r+ = 2 M :Ecm| rmb = 2 M :Ecm| rISCO = 2 M = ∞ : ∞ : ∞ .

  4. Difficult Airway Due to an Undiagnosed Subglottic Tumor

    PubMed Central

    Uzawa, Kohji; Tokumine, Joho; Lefor, Alan Kawarai; Takagi, Toshiyuki; Watanabe, Kunitaro; Yorozu, Tomoko

    2016-01-01

    Abstract The “cannot ventilate, cannot intubate” scenario during anesthesia induction can be lethal. We present a patient with an undiagnosed subglottic tumor who developed the “cannot ventilate, cannot intubate” situation after induction of general anesthesia, due to the presence of an undiagnosed subglottic tumor. A 93-year-old woman was brought to the operating room for repair of a femoral neck fracture. Both ventilation and intubation could not be accomplished, and the patient was awakened without complications after trials of maintaining the airway. In order to reverse muscle relaxation, sugammadex was useful to allow resumption of spontaneous breathing. A difficult airway can be caused by an undiagnosed subglottic tumor. Subglottic tumors can be misdiagnosed as asthma, because the clinical presentation can be very similar. If cricothyrotomy had been performed based on airway management algorithms, the airway may not have been controlled with a possibly fatal outcome. Ultrasound examination of the trachea may be useful to diagnose obstructive lesions in the airway. PMID:27082606

  5. Effects of pentobarbital on upper airway patency during sleep.

    PubMed

    Eikermann, M; Eckert, D J; Chamberlin, N L; Jordan, A S; Zaremba, S; Smith, S; Rosow, C; Malhotra, A

    2010-09-01

    We hypothesised that pentobarbital would improve upper airway mechanics based on an increase in latency to arousal and amplitude of the phasic genioglossus electromyogram (EMG), and a decrease in the active upper airway critical closing pressure (P(crit)). 12 healthy subjects received pentobarbital (100 mg) or placebo in a double-blind, crossover protocol. During wakefulness, we measured the genioglossus reflex response to negative pressure pulses. During sleep, carbon dioxide was insufflated into the inspired air. Airway pressure was then decreased in a stepwise fashion until arousal from sleep. With basal breathing during sleep: flow rate was lower in volunteers given pentobarbital; end-tidal CO(2) concentration and upper airway resistance were greater; and P(crit) was unaffected (pentobarbital mean ± SD -11.7 ± 4.5 versus placebo -10.25 ± 3.6 cmH(2)O; p = 0.11). Pentobarbital increased the time to arousal (297 ± 63s versus 232 ± 67 s; p<0.05), at which time phasic genioglossus EMG was higher (6.2 ± 4.8% maximal versus 3.1 ± 3%; p<0.05) as were CO(2) levels. The increase in genioglossus EMG after CO(2) administration was greater after pentobarbital versus placebo. Pentobarbital did not affect the genioglossus negative-pressure reflex. Pentobarbital increases the time to arousal and stimulates genioglossus muscle activity, but it also increases upper airway resistance during sleep. PMID:20032012

  6. Effects of pentobarbital on upper airway patency during sleep

    PubMed Central

    Eikermann, M.; Eckert, D.J.; Chamberlin, N.L.; Jordan, A.S.; Zaremba, S.; Smith, S.; Rosow, C.; Malhotra, A.

    2012-01-01

    We hypothesised that pentobarbital would improve upper airway mechanics based on an increase in latency to arousal and amplitude of the phasic genioglossus electromyogram (EMG), and a decrease in the active upper airway critical closing pressure (Pcrit). 12 healthy subjects received pentobarbital (100 mg) or placebo in a double-blind, crossover protocol. During wakefulness, we measured the genioglossus reflex response to negative pressure pulses. During sleep, carbon dioxide was insufflated into the inspired air. Airway pressure was then decreased in a stepwise fashion until arousal from sleep. With basal breathing during sleep: flow rate was lower in volunteers given pentobarbital; end-tidal CO2 concentration and upper airway resistance were greater; and Pcrit was unaffected (pentobarbital mean±sd -11.7±4.5 versus placebo -10.25±3.6 cmH2O; p=0.11). Pentobarbital increased the time to arousal (297±63s versus 232±67 s; p<0.05), at which time phasic genioglossus EMG was higher (6.2±4.8% maximal versus 3.1±3%; p<0.05) as were CO2 levels. The increase in genioglossus EMG after CO2 administration was greater after pentobarbital versus placebo. Pentobarbital did not affect the genioglossus negative-pressure reflex. Pentobarbital increases the time to arousal and stimulates genioglossus muscle activity, but it also increases upper airway resistance during sleep. PMID:20032012

  7. Airway Injury from Initiating Ventilation in Preterm Sheep

    PubMed Central

    Hillman, Noah H.; Kallapur, Suhas G.; Pillow, J. Jane; Moss, Timothy J. M.; Polglase, Graeme R.; Nitsos, Ilias; Jobe, Alan H.

    2009-01-01

    Premature infants exposed to ventilation are at risk of developing bronchopulmonary dysplasia (BPD) and persistent lung disease in childhood. We report where injury occurred within the lung following brief ventilation at birth. Preterm sheep (129d gestation) were ventilated with an escalating VT to 15mL/kg by 15 min to injure the lungs, with the placental circulation intact (Fetal) or after delivery (Newborn). Fetal lambs were returned to the uterus for 2h 45min, while Newborn lambs were maintained with gentle ventilatory support for the same period. The control group was not ventilated. Bronchoalveolar lavage fluid (BALF) and lung tissue were analysed. In both Fetal and Newborn lambs, ventilation caused bronchial epithelial disruption in medium-sized airways. Egr-1, MCP-1, IL-6, and IL-1β mRNA increased in lung tissue from Fetal and Newborn lambs. Egr-1, MCP-1 and IL-6 mRNA were induced in mesenchymal cells surrounding small airways, whereas IL-1β mRNA localized to the epithelium of medium/small airways. Ventilation caused loss of HSP70 mRNA from the bronchial epithelium, but induced mRNA in smooth muscle surrounding large airways. HSP70 protein decreased in lung tissue and increased in BALF with ventilation. Initiation of ventilation induced a stress response and inflammatory cytokines in small and medium-sized airways. PMID:19816239

  8. Cyclic stretch of airway epithelium inhibits prostanoid synthesis.

    PubMed

    Savla, U; Sporn, P H; Waters, C M

    1997-11-01

    Airway epithelial cells (AEC) metabolize arachidonic acid (AA) to biologically active eicosanoids, which contribute to regulation of airway smooth muscle tone and inflammatory responses. Although in vivo the airways undergo cyclical stretching during ventilation, the effect of cyclic stretch on airway epithelial AA metabolism is unknown. In this study, cat and human AEC were grown on flexible membranes and were subjected to cyclic stretch using the Flexercell strain unit. Cyclic stretch downregulated synthesis of prostaglandin (PG) E2, PGI2, and thromboxane A2 by both cell types in a frequency-dependent manner. The percent inhibition of prostanoid synthesis in both cell types ranged from 53 +/- 7 to 75 +/- 8% (SE; n = 4 and 5, respectively). Treatment of cat AEC with exogenous AA (10 micrograms/ml) had no effect on the stretch-induced inhibition of PGE2 synthesis, whereas treatment with exogenous PGH2 (10 micrograms/ml) overcame the stretch-induced decrease in PGE2 production. These results indicate that stretch inhibits prostanoid synthesis by inactivating cyclooxygenase. When cells were pretreated with the antioxidants catalase (100 micrograms/ml, 150 U/ml) and N-acetylcysteine (1 mM), there was a partial recovery of eicosanoid production, suggesting that cyclic stretch-induced inactivation of cyclooxygenase is oxidant mediated. These results may have important implications for inflammatory diseases in which airway mechanics are altered. PMID:9374729

  9. Muscle atrophy

    MedlinePlus

    Muscle wasting; Wasting; Atrophy of the muscles ... There are two types of muscle atrophy. Disuse atrophy occurs from a lack of physical activity. In most people, muscle atrophy is caused by not using the ...

  10. Muscle Disorders

    MedlinePlus

    Your muscles help you move and help your body work. Different types of muscles have different jobs. There are many problems that can affect muscles. Muscle disorders can cause weakness, pain or even ...

  11. Muscle atrophy

    MedlinePlus

    Muscle wasting; Wasting; Atrophy of the muscles ... There are two types of muscle atrophy: disuse and neurogenic. Disuse atrophy is caused by not using the muscles enough . This type of atrophy can often be ...

  12. Muscle Cramps

    MedlinePlus

    Muscle cramps are sudden, involuntary contractions or spasms in one or more of your muscles. They often occur after exercise or at night, ... to several minutes. It is a very common muscle problem. Muscle cramps can be caused by nerves ...

  13. NAD(P)H oxidase-derived reactive oxygen species contribute to age-related impairments of endothelium-dependent dilation in rat soleus feed arteries

    PubMed Central

    Trott, Daniel W.; Seawright, John W.; Luttrell, Meredith J.

    2011-01-01

    We tested the hypothesis that age-related endothelial dysfunction in rat soleus muscle feed arteries (SFA) is mediated in part by NAD(P)H oxidase-derived reactive oxygen species (ROS). SFA from young (4 mo) and old (24 mo) Fischer 344 rats were isolated and cannulated for examination of vasodilator responses to flow and acetylcholine (ACh) in the absence or presence of a superoxide anion (O2−) scavenger (Tempol; 100 μM) or an NAD(P)H oxidase inhibitor (apocynin; 100 μM). In the absence of inhibitors, flow- and ACh-induced dilations were attenuated in SFA from old rats compared with young rats. Tempol and apocynin improved flow- and ACh-induced dilation in SFA from old rats. In SFA from young rats, Tempol and apocynin had no effect on flow-induced dilation, and apocynin attenuated ACh-induced dilation. To determine the role of hydrogen peroxide (H2O2), dilator responses were assessed in the absence and presence of catalase (100 U/ml) or PEG-catalase (200 U/ml). Neither H2O2 scavenger altered flow-induced dilation, whereas both H2O2 scavengers blunted ACh-induced dilation in SFA from young rats. In old SFA, catalase improved flow-induced dilation whereas PEG-catalase improved ACh-induced dilation. Compared with young SFA, in response to exogenous H2O2 and NADPH, old rats exhibited blunted dilation and constriction, respectively. Immunoblot analysis revealed that the NAD(P)H oxidase subunit gp91phox protein content was greater in old SFA compared with young. These results suggest that NAD(P)H oxidase-derived reactive oxygen species contribute to impaired endothelium-dependent dilation in old SFA. PMID:21233343

  14. NAD(P)H oxidase-derived reactive oxygen species contribute to age-related impairments of endothelium-dependent dilation in rat soleus feed arteries.

    PubMed

    Trott, Daniel W; Seawright, John W; Luttrell, Meredith J; Woodman, Christopher R

    2011-05-01

    We tested the hypothesis that age-related endothelial dysfunction in rat soleus muscle feed arteries (SFA) is mediated in part by NAD(P)H oxidase-derived reactive oxygen species (ROS). SFA from young (4 mo) and old (24 mo) Fischer 344 rats were isolated and cannulated for examination of vasodilator responses to flow and acetylcholine (ACh) in the absence or presence of a superoxide anion (O(2)(-)) scavenger (Tempol; 100 μM) or an NAD(P)H oxidase inhibitor (apocynin; 100 μM). In the absence of inhibitors, flow- and ACh-induced dilations were attenuated in SFA from old rats compared with young rats. Tempol and apocynin improved flow- and ACh-induced dilation in SFA from old rats. In SFA from young rats, Tempol and apocynin had no effect on flow-induced dilation, and apocynin attenuated ACh-induced dilation. To determine the role of hydrogen peroxide (H(2)O(2)), dilator responses were assessed in the absence and presence of catalase (100 U/ml) or PEG-catalase (200 U/ml). Neither H(2)O(2) scavenger altered flow-induced dilation, whereas both H(2)O(2) scavengers blunted ACh-induced dilation in SFA from young rats. In old SFA, catalase improved flow-induced dilation whereas PEG-catalase improved ACh-induced dilation. Compared with young SFA, in response to exogenous H(2)O(2) and NADPH, old rats exhibited blunted dilation and constriction, respectively. Immunoblot analysis revealed that the NAD(P)H oxidase subunit gp91phox protein content was greater in old SFA compared with young. These results suggest that NAD(P)H oxidase-derived reactive oxygen species contribute to impaired endothelium-dependent dilation in old SFA. PMID:21233343

  15. Management of the artificial airway.

    PubMed

    Branson, Richard D; Gomaa, Dina; Rodriquez, Dario

    2014-06-01

    Management of the artificial airway includes securing the tube to prevent dislodgement or migration as well as removal of secretions. Preventive measures include adequate humidification and appropriate airway suctioning. Monitoring airway patency and removing obstruction are potentially life-saving components of airway management. Cuff pressure management is important for preventing aspiration and mucosal damage as well as assuring adequate ventilation. A number of new monitoring techniques have been introduced, and automated cuff pressure control is becoming more common. The respiratory therapist should be adept with all these devices and understand the appropriate application and management. PMID:24891202

  16. Laryngeal amyloidosis causing hoarseness and airway obstruction.

    PubMed

    Gallivan, Gregory J; Gallivan, Helen K

    2010-03-01

    Amyloidosis constitutes a fraction of 1% of benign localized laryngeal tumors and may occasionally be associated with systemic disease. A chronic, insidious, progressive, recurrent disease characterized by hoarseness, dyspnea, and stridor, it is caused by extracellular deposition of insoluble, abnormal tissue injurious fibrils. Submucosal lesions occur frequently in the vestibular folds and ventricles, less commonly in the subglottis and aryepiglottic folds and least on the vocal folds. Apple green birefrigence under polarized light after Congo red staining, electron microscopic fibrillar structure, and a beta-pleated sheet structure observed by x-ray diffraction are confirmatory. Two presented cases add to the small literature review of similar patients. Case 1 was a 70-year-old man with severe hoarseness, incomplete glottic closure, ovoid concentric stenosis of the inferior glottis and subglottis, who initially was not diagnosed by several laryngologists and speech therapists. He required multiple microlaryngoscopic excisions and dilations. Because low dose radiation induces plasma cell apoptosis in other diseases, external beam radiation therapy (EBRT) was hypothesized to eliminate amyloidogenic plasma cells. Case 2 was a 46-year-old welder with progressive dyspnea for 2-3 years and hoarseness, voice loss, and stridor over 6-7 months. Masses caused airway obstruction of the anterior commissure, vestibular, and vocal folds, with extension to the subglottis. Two phonomicrosurgical CO(2) laser-assisted resections relieved upper airway obstruction and restored voice. Conservative surgical intervention and long-term followup are essential. Further studies are needed to determine if a radiation dose response relationship exists to control laryngeal amyloidosis. PMID:19111441

  17. FIBERTOM Nd:YAG laser in treatment of post-inflammatory structures of lower airways

    NASA Astrophysics Data System (ADS)

    Pirozynski, Michal; Polubiec-Kownacka, Malgorzata; Strojecki, Krzysztof; Blachnio, Antoni; Pawlak, Wieslaw; Krusiewicz, Jan

    1996-03-01

    Introduction of the first laser by Maiman in 1960 led to a rapid increase in the biological application of this device. The first application of laser energy in the treatment of airway pathology was by Strong et al. In 1981 Toty et al described the first use of a neodymium:yttrium-aluminum garnet (Nd:YAG) laser for resection of a bronchial tumor. Subglottic and tracheal stenosis have been treated endoscopically for many years with electrocautery, cryosurgery, by mechanical dilatation, and more recently since the mid 1970s with the carbon-dioxide laser. Early series demonstrated a moderate success rate in about 60% of the cases. Recently a new modification of the Nd:YAG laser was made available by Dornier (formerly MBB - Germany). The FIBERTOMTM is a unique method of controlling the temperature at the tip of the light guide allowing precise, direct contact cutting. Eleven patients (age 35.1 plus or minus 20.7 years) with post inflammatory airway stenoses were treated. Thirty-six procedures were carried out. An immediate dilatation of the narrowed airway was produced in 86%. Endoscopic control carried out 52 weeks after the initial procedure confirmed restoration of the airway lumen in 82%. Clinical improvement was seen in all.

  18. Dilated common duct sign. A potential indicator of a sphincter of Oddi dyskinesia

    SciTech Connect

    DeRidder, P.; Fink-Bennett, D.

    1984-05-01

    The cholescintigraphic findings of a Sphincter of Oddi dyskinesia (SOD) in a 45-year-old woman with persistent right upper quadrant pain and biliary colic are reported. After an overnight fast, the patient was injected with 5 mCi of Tc-99 disofenin and .02 micrograms/kg of cholecystokinin (CCK) post maximal gallbladder filling. Pre and postcholescintiscans were obtained and gallbladder ejection fractions determined. The hepatobiliary scan was normal, except for a delay in biliary-bowel transit. The gallbladder responded normally to CCK, however, the Sphincter of Oddi responded abnormally, as there was a paradoxical response to CCK manifested by a marked dilatation of the common bile duct. It was postulate that this dilatation (the dilated common duct sign) was due to an inappropriate response of the smooth muscle of the Sphincter of Oddi (contraction vs relaxation) to CCK and was the cause of this patient's biliary colic. The dilated common duct sign should alert the physician to the possibility of a Sphincter of Oddi dyskinesia.

  19. Arteriolar dilation to endotoxin is increased in copper-deficient rats.

    PubMed

    Schuschke, D A; Saari, J T; Miller, F N

    1997-02-01

    We have previously reported that there is an altered response to mast cell-mediated inflammation in copper-deficient rats. In the current study we determined the microvascular reactivity to inflammatory stimuli with lipopolysacccharide (LPS) during dietary copper restriction. Male Sprague-Dawley rats were fed purified diets which were either copper-adequate (CuA, 6 micrograms Cu/g) or copper-deficient (CuD, 0.4 micrograms Cu/g) for 4 weeks. Rats were anesthetized and the cremaster muscle was prepared for in vivo television microscopy. Arteriolar diameters were measured and then 2.5 mg/kg LPS was injected i.p. In separate groups, animals were pretreated with the NO-synthase inhibitor L-NAME (2 x 10(-4) M), the cyclooxygenase inhibitor ibuprofen (9.6 x 10(-5) M) or the histamine receptor antagonist diphenhydramine (DPH, 10(-6) M). LPS caused arteriolar dilation in both dietary groups with the response being significantly greater in the CuD group. Ibuprofen and DPH but not L-NAME, each significantly reduced but did not block the dilation in the CuD group. Ibuprofen and DPH together blocked the dilation. These results suggest that dietary copper deficiency increases arteriolar dilation to LPS. The mechanism appears to involve a greater response to arachidonic acid metabolites and histamine but not NO. PMID:9179621

  20. 21 CFR 868.5110 - Oropharyngeal airway.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Therapeutic Devices § 868.5110 Oropharyngeal airway. (a... provide a patent airway. (b) Classification. Class I (general controls). The device is exempt from...

  1. 21 CFR 868.5110 - Oropharyngeal airway.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Therapeutic Devices § 868.5110 Oropharyngeal airway. (a... provide a patent airway. (b) Classification. Class I (general controls). The device is exempt from...

  2. Fetal Bowel Dilatation: A Sonographic Sign of Uncertain Prognosis

    PubMed Central

    Silva, Patrícia; Reis, Filipa; Alves, Paulo; Farinha, Luís; Gomes, Manuel Sousa; Câmara, Pilar

    2015-01-01

    Fetal bowel dilatation is an indirect sonographic sign of mechanical or functional bowel obstruction. The etiology of fetal bowel dilatation is a difficult prenatal diagnosis since ultrasound has limited accuracy for bowel evaluation. The authors describe a case of fetal bowel dilatation diagnosed in the third trimester. PMID:26819789

  3. 21 CFR 870.1310 - Vessel dilator for percutaneous catheterization.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Vessel dilator for percutaneous catheterization... Vessel dilator for percutaneous catheterization. (a) Identification. A vessel dilator for percutaneous catheterization is a device which is placed over the guide wire to enlarge the opening in the vessel, and which...

  4. Can clinicians accurately assess esophageal dilation without fluoroscopy?

    PubMed

    Bailey, A D; Goldner, F

    1990-01-01

    This study questioned whether clinicians could determine the success of esophageal dilation accurately without the aid of fluoroscopy. Twenty patients were enrolled with the diagnosis of distal esophageal stenosis, including benign peptic stricture (17), Schatski's ring (2), and squamous cell carcinoma of the esophagus (1). Dilation attempts using only Maloney dilators were monitored fluoroscopically by the principle investigator, the physician and patient being unaware of the findings. Physicians then predicted whether or not their dilations were successful, and they examined various features to determine their usefulness in predicting successful dilation. They were able to predict successful dilation accurately in 97% of the cases studied; however, their predictions of unsuccessful dilation were correct only 60% of the time. Features helpful in predicting passage included easy passage of the dilator (98%) and the patient feeling the dilator in the stomach (95%). Excessive resistance suggesting unsuccessful passage was an unreliable feature and was often due to the dilator curling in the stomach. When Maloney dilators are used to dilate simple distal strictures, if the physician predicts successful passage, he is reliably accurate without the use of fluoroscopy; however, if unsuccessful passage is suspected, fluoroscopy must be used for confirmation. PMID:2210278

  5. 21 CFR 870.4475 - Surgical vessel dilator.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Surgical vessel dilator. 870.4475 Section 870.4475...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Surgical Devices § 870.4475 Surgical vessel dilator. (a) Identification. A surgical vessel dilator is a device used to enlarge or calibrate a vessel....

  6. Effect of P2X4R on airway inflammation and airway remodeling in allergic airway challenge in mice

    PubMed Central

    CHEN, HONGXIA; XIA, QINGQING; FENG, XIAOQIAN; CAO, FANGYUAN; YU, HANG; SONG, YINLI; NI, XIUQIN

    2016-01-01

    P2X4 receptor (P2X4R) is the most widely expressed subtype of the P2XRs in the purinergic receptor family. Adenosine triphosphate (ATP), a ligand for this receptor, has been implicated in the pathogenesis of asthma. ATP-P2X4R signaling is involved in pulmonary vascular remodeling, and in the proliferation and differentiation of airway and alveolar epithelial cell lines. However, the role of P2X4R in asthma remains to be elucidated. This aim of the present study was to investigate the effects of P2X4R in a murine experimental asthma model. The asthmatic model was established by the inhalation of ovalbumin (OVA) in BALB/c mice. The mice were treated with P2X4R-specific agonists and antagonists to investigate the role of this receptor in vivo. Pathological changes in the bronchi and lung tissues were examined using hematoxylin and eosin staining, Masson's trichrome staining and Alcian blue staining. The inflammatory cells in the bronchoalveolar lavage fluid were counted, and the expression levels of P2X4R, α-smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) were detected using western blotting. In the OVA-challenged mice, inflammation, infiltration, collagen deposition, mucus production, and the expression levels of P2X4R and PCNA were all increased; however, the expression of α-SMA was decreased, compared with the mice in the control group. Whereas treatment with the P2X4R agonist, ATP, enhanced the allergic reaction, treatment with the P2X4R antagonist, 5-BDBD, attenuated the allergic reaction. The results suggested that ATP-P2X4R signaling may not only contribute to airway inflammation, but it may also contribute to airway remodeling in allergic asthma in mice. PMID:26648454

  7. Mechanical Properties of Respiratory Muscles

    PubMed Central

    Sieck, Gary C.; Ferreira, Leonardo F.; Reid, Michael B.; Mantilla, Carlos B.

    2014-01-01

    Striated respiratory muscles are necessary for lung ventilation and to maintain the patency of the upper airway. The basic structural and functional properties of respiratory muscles are similar to those of other striated muscles (both skeletal and cardiac). The sarcomere is the fundamental organizational unit of striated muscles and sarcomeric proteins underlie the passive and active mechanical properties of muscle fibers. In this respect, the functional categorization of different fiber types provides a conceptual framework to understand the physiological properties of respiratory muscles. Within the sarcomere, the interaction between the thick and thin filaments at the level of cross-bridges provides the elementary unit of force generation and contraction. Key to an understanding of the unique functional differences across muscle fiber types are differences in cross-bridge recruitment and cycling that relate to the expression of different myosin heavy chain isoforms in the thick filament. The active mechanical properties of muscle fibers are characterized by the relationship between myoplasmic Ca2+ and cross-bridge recruitment, force generation and sarcomere length (also cross-bridge recruitment), external load and shortening velocity (cross-bridge cycling rate), and cross-bridge cycling rate and ATP consumption. Passive mechanical properties are also important reflecting viscoelastic elements within sarcomeres as well as the extracellular matrix. Conditions that affect respiratory muscle performance may have a range of underlying pathophysiological causes, but their manifestations will depend on their impact on these basic elemental structures. PMID:24265238

  8. Brachycephalic airway obstructive syndrome.

    PubMed

    Wykes, P M

    1991-06-01

    This is a complex condition, recognized primarily in brachycephalic breeds, that results in varying degrees of upper airway obstruction. The signs consist of respiratory distress, stridor, reduced exercise tolerance, and in more severe cases, cyanosis and collapse. The inherent anatomy of the brachycephalic skull contributes to the development of these signs. Such anatomic features include: a shortened and distorted nasopharynx, stenotic nares, an elongated soft palate, and everted laryngeal saccules. The increased negative pressure created in the pharyngolaryngeal region, as a result of these obstructing structures, ultimately results in distortion and collapse of the arytenoid cartilages of the larynx. PMID:1802247

  9. Particle Deposition During Airway Closure

    NASA Astrophysics Data System (ADS)

    Tai, Cheng-Feng; Halpern, David; Grotberg, James B.

    2011-11-01

    Inhaled aerosol particles deposit in the lung and may be from environmental, toxic, or medical therapy sources. While much research focuses on inspiratory deposition, primarily at airway bifurcations due to inertial impaction, there are other mechanisms that allow the particles to reach the airway surface, such as gravitational settling and diffusion depending on particle size. We introduce a new mechanism not previously studied, i.e. aerosol deposition from airway closure. The airways are lined with a liquid layer. Due to the surface tension driven instability, a liquid plug can form from this layer which blocks the airway. This process of airway closure tends to occur toward the end of expiration. In this study, the efficiency of the impaction of the particles during airway closure will be investigated. The particles will be released from the upstream of the airway and convected by the air flow and deposited onto the closing liquid layer. We solve the governing equations using a finite volume approach in conjunction with a sharp interface method for the interfaces. Once the velocity field of the gas flow is obtained, the path of the particles will be calculated and the efficiency of the deposition can be estimated. We acknowledge support from the National Institutes of Health grant number NIH HL85156.

  10. Operative endoscopy of the airway

    PubMed Central

    Walters, Dustin M.

    2016-01-01

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

  11. Risk Stratification for Sudden Cardiac Death In Patients With Non-ischemic Dilated Cardiomyopathy

    PubMed Central

    Shekha, Karthik; Ghosh, Joydeep; Thekkoott, Deepak; Greenberg, Yisachar

    2005-01-01

    Non ischemic dilated cardiomyopathy (NIDCM) is a disorder of myocardium. It has varying etiologies. Albeit the varying etiologies of this heart muscle disorder, it presents with symptoms of heart failure, and rarely as sudden cardiac death (SCD). Manifestations of this disorder are in many ways similar to its counterpart, ischemic dilated cardiomyopathy (IDCM). A proportion of patients with NIDCM carries a grave prognosis and is prone to sudden cardiac death from sustained ventricular arrhythmias. Identification of this subgroup of patients who carry the risk of sudden cardiac death despite adequate medical management is a challenge .Yet another method is a blanket treatment of patients with this disorder with anti arrhythmic medications or anti tachyarrhythmia devices like implantable cardioverter defibrillators (ICD). However this modality of treatment could be a costly exercise even for affluent economies. In this review we try to analyze the existing data of risk stratification of NIDCM and its clinical implications in practice. PMID:16943952

  12. Becker Muscular Dystrophy (BMD) caused by duplication of exons 3-6 of the dystrophin gene presenting as dilated cardiomyopathy

    SciTech Connect

    Tsai, A.C.; Allingham-Hawkins, D.J.; Becker, L.

    1994-09-01

    X-linked dilated cardiomyopathy (XLCM) is a progressive myocardial disease presenting with congestive heart failure in teenage males without clinical signs of skeletal myopathy. Tight linkage of XLCM to the DMD locus has been demonstrated; it has been suggested that, at least in some families, XLCM is a {open_quotes}dystrophinopathy.{close_quotes} We report a 14-year-old boy who presented with acute heart failure due to dilated cardiomyopathy. He had no history of muscle weakness, but physical examination revealed pseudohypertrophy of the calf muscles. He subsequently received a heart transplantation. Family history was negative. Serum CK level at the time of diagnosis was 10,416. Myocardial biopsy showed no evidence of carditis. Dystrophin staining of cardiac and skeletal muscle with anti-sera to COOH and NH{sub 2}termini showed a patchy distribution of positivity suggestive of Becker muscular dystrophy. Analysis of 18 of the 79 dystrophin exons detected a duplication that included exons 3-6. The proband`s mother has an elevated serum CK and was confirmed to be a carrier of the same duplication. A mutation in the muscle promotor region of the dystrophin gene has been implicated in the etiology of SLCM. However, Towbin et al. (1991) argued that other 5{prime} mutations in the dystrophin gene could cause selective cardiomyopathy. The findings in our patient support the latter hypothesis. This suggests that there are multiple regions in the dystrophin gene which, when disrupted, can cause isolated dilated cardiomyopathy.

  13. The Diagnosis and Evaluation of Dilated Cardiomyopathy.

    PubMed

    Japp, Alan G; Gulati, Ankur; Cook, Stuart A; Cowie, Martin R; Prasad, Sanjay K

    2016-06-28

    Dilated cardiomyopathy (DCM) is best understood as the final common response of myocardium to diverse genetic and environmental insults. A rigorous work-up can exclude alternative causes of left ventricular (LV) dilation and dysfunction, identify etiologies that may respond to specific treatments, and guide family screening. A significant proportion of DCM cases have an underlying genetic or inflammatory basis. Measurement of LV size and ejection fraction remain central to diagnosis, risk stratification, and treatment, but other aspects of cardiac remodeling inform prognosis and carry therapeutic implications. Assessment of myocardial fibrosis predicts both risk of sudden cardiac death and likelihood of LV functional recovery, and has significant potential to guide patient selection for cardioverter-defibrillator implantation. Detailed mitral valve assessment is likely to assume increasing importance with the emergence of percutaneous interventions for functional mitral regurgitation. Detection of pre-clinical DCM could substantially reduce morbidity and mortality by allowing early instigation of cardioprotective therapy. PMID:27339497

  14. "Mustache sign" due to Stensen duct dilation.

    PubMed

    Yoruk, O; Kılıc, K; Kantarcı, M

    2013-12-01

    An 80-year-old woman presented with a 5-year history of painless swellings of the left and right cheeks. The degree of swelling did not change with mastication. On palpation, the cheeks were soft, well defined, and movable. Compression and massage of the swollen areas caused increased salivary discharge from the orifices of the Stensen ducts. Three-dimensional computed tomography showed well-bordered, 15- to 20-mm wide, bilateral, tube-like dilatations of the ducts. The ductal origin of the swellings was explained to the patient, but she refused invasive procedures, thus no sialogram or surgical procedure was performed. We describe the clinical and radiographic features of a case of bilateral, congenital Stensen duct dilatation with bilateral swelling of the cheeks. PMID:24209996

  15. Critically sampled wavelets with composite dilations.

    PubMed

    Easley, Glenn R; Labate, Demetrio

    2012-02-01

    Wavelets with composite dilations provide a general framework for the construction of waveforms defined not only at various scales and locations, as traditional wavelets, but also at various orientations and with different scaling factors in each coordinate. As a result, they are useful to analyze the geometric information that often dominate multidimensional data much more efficiently than traditional wavelets. The shearlet system, for example, is a particular well-known realization of this framework, which provides optimally sparse representations of images with edges. In this paper, we further investigate the constructions derived from this approach to develop critically sampled wavelets with composite dilations for the purpose of image coding. Not only do we show that many nonredundant directional constructions recently introduced in the literature can be derived within this setting, but we also introduce new critically sampled discrete transforms that achieve much better nonlinear approximation rates than traditional discrete wavelet transforms and outperform the other critically sampled multiscale transforms recently proposed. PMID:21843993

  16. Universal decoherence due to gravitational time dilation

    NASA Astrophysics Data System (ADS)

    Pikovski, Igor; Zych, Magdalena; Costa, Fabio; Brukner, Caslav

    2016-05-01

    The absence of quantum behavior on macroscopic scales is usually attributed to decoherence -- the suppression of quantum superpositions due to interaction with an environment. Here we show that time dilation provides a universal decoherence mechanism for any complex system. The effect takes place even for isolated particles that do not interact with any external environment and causes decoherence of position and momentum of the center of mass of the system. While time dilation is very weak on earth, it is already sufficient to decohere gram-scale objects and complex molecules. The results show that novel phenomena arise at the interplay between quantum theory and general relativity even in the low energy limit. Possible experimental verifications of the effect are briefly discussed.

  17. MiR-221 and miR-130a Regulate Lung Airway and Vascular Development

    PubMed Central

    Mujahid, Sana

    2013-01-01

    Epithelial-mesenchymal interactions play a crucial role in branching morphogenesis, but very little is known about how endothelial cells contribute to this process. Here, we examined how anti-angiogenic miR-221 and pro-angiogenic miR-130a affect airway and vascular development in the fetal lungs. Lung-specific effects of miR-130a and miR-221 were studied in mouse E14 whole lungs cultured for 48 hours with anti-miRs or mimics to miR-130a and miR-221. Anti-miR 221 treated lungs had more distal branch generations with increased Hoxb5 and VEGFR2 around airways. Conversely, mimic 221 treated lungs had reduced airway branching, dilated airway tips and decreased Hoxb5 and VEGFR2 in mesenchyme. Anti-miR 130a treatment led to reduced airway branching with increased Hoxa5 and decreased VEGFR2 in the mesenchyme. Conversely, mimic 130a treated lungs had numerous finely arborized branches extending into central lung regions with diffusely localized Hoxa5 and increased VEGFR2 in the mesenchyme. Vascular morphology was analyzed by GSL-B4 (endothelial cell-specific lectin) immunofluorescence. Observed changes in airway morphology following miR-221 inhibition and miR-130a enhancement were mirrored by changes in vascular plexus formation around the terminal airways. Mouse fetal lung endothelial cells (MFLM-91U) were used to study microvascular cell behavior. Mimic 221 treatment resulted in reduced tube formation and cell migration, where as the reverse was observed with mimic 130a treatment. From these data, we conclude that miR-221 and miR-130a have opposing effects on airway and vascular morphogenesis of the developing lung. PMID:23409087

  18. Charged Dilation Black Holes as Particle Accelerators

    NASA Astrophysics Data System (ADS)

    Pradhan, Parthapratim

    2016-07-01

    We examine the possibility of arbitrarily high energy in the Center-of-mass frame of colliding neutral particles in the vicinity of the horizon of a charged dilation black hole(BH). We show that it is possible to achieve the infinite energy in the background of the dilation black hole without fine-tuning of the angular momentum parameter. It is found that the center-of-mass energy (E_{cm}) of collisions of particles near the infinite red-shift surface of the extreme dilation BHs are arbitrarily large while the non-extreme charged dilation BHs have the finite energy. We have also compared the E_{cm} at the horizon with the ISCO(Innermost Stable Circular Orbit) and MBCO (Marginally Bound Circular Orbit) for extremal RN BH and Schwarzschild BH. We find that for extreme RN BH the inequality becomes E_{cm}mid_{r_{+}}>E_{cm}mid_{r_{mb}}> E_{cm}mid_{r_{ISCO}} i.e. E_{cm}mid_{r_{+}=M}: E_{cm}mid_{r_{mb}= ({3+√{5}}/{2})M} : E_{cm}mid_{r_{ISCO}=4M} =∞ : 3.23 : 2.6 . While for Schwarzschild BH the ratio of CM energy is E_{cm}mid_{r_{+}=2M}: E_{cm}mid_{r_{mb}=4M} : E_{cm}mid_{r_{ISCO}=6M} = √{5} : √{2} : {√{13}}/{3}. Also for Gibbons-Maeda-Garfinkle-Horowitz-Strominger (GMGHS) BHs the ratio is being E_{cm}mid_{r_{+}=2M}: E_{cm}mid_{r_{mb}=2M} : E_{cm}mid_{r_{ISCO}=2M}=∞ : ∞ : ∞.

  19. Functional characterization of muscarinic receptors in murine airways.

    PubMed Central

    Garssen, J.; Van Loveren, H.; Gierveld, C. M.; Van der Vliet, H.; Nijkamp, F. P.

    1993-01-01

    1. The effects of muscarinic receptor antagonists considered to be selective for M1 receptors (pirenzepine; PZ), M2 receptors (AFDX-116), and for M3 receptors (4-diphenyl acetoxy N-methyl-piperidine (4-DAMP)) were used to investigate the existence of muscarinic receptors subtypes in murine airways. Atropine was used as a nonselective antagonist. The effects of these antagonists were studied upon tracheal contractions induced either by EFS (electric field stimulation) or by application of an exogenous cholinoceptor agonist (arecoline). 2. The muscarinic receptor antagonists tested inhibited arecoline-induced tracheal contractions with the following rank order of potency: 4-DAMP = atropine > pirenzepine = AFDX-116. The rank order of potency of the muscarinic antagonists used in inhibiting EFS-induced tracheal contractions was: 4-DAMP = atropine > PZ > AFDX-116. The pA2 values for these antagonists were similar when compared to the pA2 values determined in guinea-pig and bovine airway smooth muscle. 3. In addition to in vitro studies, the effects of inhalation of the different muscarinic antagonists on lung function parameters in vivo were investigated. Inhalation of 4-DAMP induced a decrease in airway resistance and an increase in lung compliance. In contrast, inhalation of AFDX-116 induced an increase in airway resistance and almost no change in lung compliance. Apart from some minor effects of atropine on airway resistance, atropine, PZ, and pilocarpine failed to induce changes in lung mechanics as determined by in vivo lung function measurements. 4. The results provide evidence for the existence of M3 receptors on murine tracheae that are involved in the contraction of tracheal smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 6 Figure 7 PMID:8495246

  20. Bougie urethral dilators: revival or survival?

    PubMed Central

    Al–Adawi, Mohammad Ahmad

    2013-01-01

    Objectives To present our center's experience in managing bladder outlet obstruction (BOO) conditions using bougie dilators. We described the dilation technique methodically for teaching purpose. Patients and method Retrospectively, a total of 196 medical records over the last four years denoting BOO conditions in men, women, and children were retrieved for analysis. Data reviewed for common complications was namely: perforation, recurrence, urinary tract obstruction (UTI) and inability to overcome the obstruction. Results Among the 196 analyzed cases, 24 (12.2%) cases were cured, whereas 172 (87.8%) cases reported complications. Within the complicated cases analyzed, 134 (68.4%) cases had recurrent obstructions, 13 (6.6%) cases had perforations, 6 (3.0%) cases developed UTI, while in 19 (9.7%) cases, we failed to pass the obstruction. Conclusions In our center where urethral dilation technique has revived four years ago, it turned back to be the standard choice in managing BOO cases. We propose the technique to Urology training program directors, all over the world, to teach it as a compulsory skill for junior urologists to master. PMID:24757552

  1. Formation and interpretation of dilatant echelon cracks.

    USGS Publications Warehouse

    Pollard, D.D.; Segall, P.; Delaney, P.T.

    1982-01-01

    The relative displacements of the walls of many veins, joints, and dikes demonstrate that these structures are dilatant cracks. We infer that dilatant cracks propagate in a principal stress plane, normal to the maximum tensile or least compressive stress. Arrays of echelon crack segments appear to emerge from the peripheries of some dilatant cracks. Breakdown of a parent crack into an echelon array may be initiated by a spatial or temporal rotation of the remote principal stresses about an axis parallel to the crack propagation direction. Near the parent-crack tip, a rotation of the local principal stresses is induced in the same sense, but not necessarily through the same angle. Incipient echelon cracks form at the parent-crack tip normal to the local maximum tensile stress. Further longitudinal growth along surfaces that twist about axes parallel to the propagation direction realigns each echelon crack into a remote principal stress plane. The walls of these twisted cracks may be idealized as helicoidal surfaces. An array of helicoidal cracks sweeps out less surface area than one parent crack twisting through the same angle. Thus, many echelon cracks grow from a single parent because the work done in creating the array, as measured by its surface area decreases as the number of cracks increases. -from Authors

  2. Isolated cardiomyopathy caused by a DMD nonsense mutation in somatic mosaicism: genetic normalization in skeletal muscle.

    PubMed

    Juan-Mateu, J; Paradas, C; Olivé, M; Verdura, E; Rivas, E; González-Quereda, L; Rodríguez, M J; Baiget, M; Gallano, P

    2012-12-01

    X-linked dilated cardiomyopathy is a pure cardiac dystrophinopathy phenotype mainly caused by DMD mutations that present a specific transcription effect in cardiac tissue. We report a 26-year-old male who presented with severe dilated cardiomyopathy and high creatine kinase. The patient did not complain of skeletal muscle weakness. A muscle biopsy showed mild dystrophic changes and a low proportion of dystrophin-negative fibres. A molecular study identified a nonsense DMD mutation (p.Arg2098X) in somatic mosaicism. The ratio of mutant versus normal allele in blood and skeletal muscle suggests selective pressure against mutant muscle cells, a process known as genetic normalization. We hypothesize that this process may have mitigated skeletal muscle symptoms in this patient. This is the second report of a DMD somatic mosaic with evidence of genetic normalization in muscle. Somatic DMD mutations should be considered in patients presenting with idiopathic dilated cardiomyopathy. PMID:22092019

  3. The effects of inhaled corticosteroids on intrinsic responsiveness and histology of airways from infant monkeys exposed to house dust mite allergen and ozone

    SciTech Connect

    Joad, Jesse P. Kott, Kayleen S.; Bric, John M.; Schelegle, Edward S.; Gershwin, Laurel J.; Plopper, Charles G.; Peake, Janice L.; Pinkerton, Kent E.

    2008-01-15

    Inhaled corticosteroids (ICS) are recommended to treat infants with asthma, some with intermittent asthma. We previously showed that exposing infant monkeys to allergen/ozone resulted in asthma-like characteristics of their airways. We evaluated the effects of ICS on histology and intrinsic responsiveness of allergen/ozone-exposed and normal infant primate airways. Infant monkeys were exposed by inhalation to (1) filtered air and saline, (2) house dust mite allergen (HDMA) + ozone and saline, (3) filtered air and ICS (budesonide) or (4) HDMA + ozone and ICS. Allergen/ozone exposures started at 1 month and ICS at 3 months of age. At 6 months of age, methacholine-induced changes in luminal area of airways in proximal and distal lung slices were determined using videomicrometry, followed by histology of the same slices. Proximal airway responsiveness was increased by allergen/ozone and by ICS. Eosinophil profiles were increased by allergen/ozone in both proximal and distal airways, an effect that was decreased by ICS in distal airways. In both allergen/ozone- and air-exposed monkeys, ICS increased the number of alveolar attachments in distal airways, decreased mucin in proximal airways and decreased epithelial volume in both airways. ICS increased smooth muscle in air-exposed animals while decreasing it in allergen/ozone-exposed animals in both airways. In proximal airways, there was a small but significant positive correlation between smooth muscle and airway responsiveness, as well as between alveolar attachments and responsiveness. ICS change morphology and function in normal airways as well as allergen/ozone-exposed airways, suggesting that they should be reserved for infants with active symptoms.

  4. Skeletal muscle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    There are approximately 650-850 muscles in the human body these include skeletal (striated), smooth and cardiac muscle. The approximation is based on what some anatomists consider separate muscle or muscle systems. Muscles are classified based on their anatomy (striated vs. smooth) and if they are v...

  5. Rapid nongenomic actions of inhaled corticosteroids on long-acting β(2)-agonist transport in the airway.

    PubMed

    Horvath, Gabor; Mendes, Eliana S; Schmid, Nathalie; Schmid, Andreas; Conner, Gregory E; Fregien, Nevis L; Salathe, Matthias; Wanner, Adam

    2011-12-01

    Corticosteroids inhibit organic cation transporters (OCTs) that play an important role in drug absorption, tissue distribution and elimination. Corticosteroid sensitivity of bronchodilator trafficking in the airway tissue, however, is poorly understood. To assess the effects of inhaled corticosteroids on airway absorption and disposal mechanisms of long-acting β(2)-agonists, human airway epithelial and smooth muscle cell uptake of tritiated formoterol and salmeterol was measured in vitro. Corticosteroids caused a rapid, concentration-dependent inhibition of uptake of the cationic formoterol by airway smooth muscle cells, but not airway epithelial cells. Uptake of the non-charged lipophilic salmeterol was corticosteroid-insensitive in both cell types. In smooth muscle cells, inhaled corticosteroids inhibited formoterol uptake with a novel potency rank order: des-ciclesonide > budesonide > beclomethasone 17-monopropionate > beclomethasone dipropionate > ciclesonide > fluticasone. The inhibitory action was rapidly reversible, and was not enhanced by prolonged corticosteroid exposure or sensitive to a transcription inhibitor. Suppression of OCT3 expression using lentivirus-mediated production of shRNA reduced corticosteroid sensitivity of formoterol uptake by smooth muscle cells. Our data support a corticosteroid insensitive absorption and a corticosteroid-sensitive disposition mechanism for cationic long-acting β(2)-agonist bronchodilators in the airway. Potency rank order and other 'classical' features of anti-inflammatory effects do not apply to inhaled corticosteroids' rapid drug transport actions. PMID:21914487

  6. Putting the Squeeze on Airway Epithelia.

    PubMed

    Park, Jin-Ah; Fredberg, Jeffrey J; Drazen, Jeffrey M

    2015-07-01

    Asthma is characterized by chronic inflammation, airway hyperresponsiveness, and progressive airway remodeling. The airway epithelium is known to play a critical role in the initiation and perpetuation of these processes. Here, we review how excessive epithelial stress generated by bronchoconstriction is sufficient to induce airway remodeling, even in the absence of inflammatory cells. PMID:26136543

  7. Putting the Squeeze on Airway Epithelia

    PubMed Central

    Park, Jin-Ah; Fredberg, Jeffrey J.

    2015-01-01

    Asthma is characterized by chronic inflammation, airway hyperresponsiveness, and progressive airway remodeling. The airway epithelium is known to play a critical role in the initiation and perpetuation of these processes. Here, we review how excessive epithelial stress generated by bronchoconstriction is sufficient to induce airway remodeling, even in the absence of inflammatory cells. PMID:26136543

  8. [Ciaglia percutaneous dilatation tracheotomy with endoscopic control. Analysis of complication-fraught steps].

    PubMed

    Koitschev, A; Paasch, S; Plinkert, P K

    1998-07-01

    Since the first description by Ciaglia in 1985, percutaneous dilatational tracheostomy (PDT) has emerged worldwide to be a favored and frequently used technique for airway control. Advantages are the rapidity, simplicity and independence of the physician. These characteristics tempt clinicians to perform the procedure uncritically and thus produce complications. Based on our experiences with the technique and on a critical analysis of the literature the indications and optimal operative technique are discussed. Operative steps are illustrated and potential pitfalls (anatomic variations, injury to vital structures and bleeding) are defined. In our experience endoscopic control plays a crucial role in preventing intraoperative complications. ENT colleagues should know the technique because of their experience with tracheotomized patients and should offer their services to other disciplines. PMID:9736943

  9. Chrysin alleviates allergic inflammation and airway remodeling in a murine model of chronic asthma.

    PubMed

    Yao, Jing; Jiang, Mingzi; Zhang, Yunshi; Liu, Xing; Du, Qiang; Feng, Ganzhu

    2016-03-01

    Asthma is a chronic airway inflammatory disorder and progresses mainly due to airway remodeling. Chrysin, a natural flavonoid, has been reported to possess multiple biologic activities, including anti-inflammation, anti-oxidation and anti-proliferation. The present study aimed to investigate whether chrysin could relieve allergic airway inflammation and remodeling in a murine model of chronic asthma and the mechanism involved. The female BALB/c mice sensitized and challenged with ovalbumin (OVA) successfully developed airway hyperresponsiveness (AHR), inflammation and remodeling. The experimental data showed that chrysin could alleviate OVA-induced AHR. Chrysin could also reduce OVA-induced increases in the number of inflammatory cells, especially eosinophils, interleukin (IL) -4, and IL-13 in bronchoalveolar lavage fluid (BALF) and total IgE in serum. The decreased interferon-γ (IFN-γ) level in BALF was also upregulated by chrysin. In addition, inflammatory cell infiltration, goblet cell hyperplasia and the expression of α-smooth muscle actin (α-SMA) around bronchioles were suppressed by chrysin. Furthermore, the phosphorylation levels of Akt and extracellular signal-regulated kinase (ERK) could be decreased by chrysin, which are associated with airway smooth muscle cell (ASMC) proliferation. These results indicate the promising therapeutic effect of chrysin on chronic asthma, especially the progression of airway remodeling. PMID:26780233

  10. Chronic exposure to high levels of particulate air pollution and small airway remodeling.

    PubMed Central

    Churg, Andrew; Brauer, Michael; del Carmen Avila-Casado, Maria; Fortoul, Teresa I; Wright, Joanne L

    2003-01-01

    Recent evidence suggests that chronic exposure to high levels of ambient particulate matter (PM) is associated with decreased pulmonary function and the development of chronic airflow obstruction. To investigate the possible role of PM-induced abnormalities in the small airways in these functional changes, we examined histologic sections from the lungs of 20 women from Mexico City, a high PM locale. All subjects were lifelong residents of Mexico City, were never-smokers, never had occupational dust exposure, and never used biomass fuel for cooking. Twenty never-smoking, non-dust-exposed subjects from Vancouver, British Columbia, Canada, a low PM region, were used as a control. By light microscopy, abnormal small airways with fibrotic walls and excess muscle, many containing visible dust, were present in the Mexico City lungs. Formal grading analysis confirmed the presence of significantly greater amounts of fibrous tissue and muscle in the walls of the airways in the Mexico City compared with the Vancouver lungs. Electron microscopic particle burden measurements on four cases from Mexico City showed that carbonaceous aggregates of ultrafine particles, aggregates likely to be combustion products, were present in the airway mucosa. We conclude that PM penetrates into and is retained in the walls of small airways, and that, even in nonsmokers, long-term exposure to high levels of ambient particulate pollutants is associated with small airway remodeling. This process may produce chronic airflow obstruction. PMID:12727599

  11. Muscle Deoxygenation Causes Muscle Fatigue

    NASA Technical Reports Server (NTRS)

    Murthy, G.; Hargens, A. R.; Lehman, S.; Rempel, D.

    1999-01-01

    Muscle fatigue is a common musculoskeletal disorder in the work place, and may be a harbinger for more disabling cumulative trauma disorders. Although the cause of fatigue is multifactorial, reduced blood flow and muscle oxygenation may be the primary factor in causing muscle fatigue during low intensity muscle exertion. Muscle fatigue is defined as a reduction in muscle force production, and also occurs among astronauts who are subjected to postural constraints while performing lengthy, repetitive tasks. The objectives of this research are to: 1) develop an objective tool to study the role of decreased muscle oxygenation on muscle force production, and 2) to evaluate muscle fatigue during prolonged glovebox work.

  12. Muscle disorder

    MedlinePlus

    Blood tests sometimes show abnormally high muscle enzymes. If a muscle disorder might also affect other family members, genetic testing may be done. When someone has symptoms and signs of a muscle disorder, tests such as an electromyogram , ...

  13. Muscle aches

    MedlinePlus

    ... common cause of muscle aches and pain is fibromyalgia , a condition that causes tenderness in your muscles ... imbalance, such as too little potassium or calcium Fibromyalgia Infections, including the flu, Lyme disease , malaria , muscle ...

  14. Muscle disorder

    MedlinePlus

    Myopathic changes; Myopathy; Muscle problem ... Blood tests sometimes show abnormally high muscle enzymes. If a muscle disorder might also affect other family members, genetic testing may be done. When someone has symptoms and signs ...

  15. Irritant-induced airway disorders.

    PubMed

    Brooks, Stuart M; Bernstein, I Leonard

    2011-11-01

    Thousands of persons experience accidental high-level irritant exposures each year but most recover and few die. Irritants function differently than allergens because their actions proceed nonspecifically and by nonimmunologic mechanisms. For some individuals, the consequence of a single massive exposure to an irritant, gas, vapor or fume is persistent airway hyperresponsiveness and the clinical picture of asthma, referred to as reactive airways dysfunction syndrome (RADS). Repeated irritant exposures may lead to chronic cough and continual airway hyperresponsiveness. Cases of asthma attributed to repeated irritant-exposures may be the result of genetic and/or host factors. PMID:21978855

  16. Increased airway glucose increases airway bacterial load in hyperglycaemia

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  18. Dendritic cells and alveolar macrophages mediate IL-13–induced airway inflammation and chemokine production

    PubMed Central

    Crapster-Pregont, Margaret; Yeo, Janice; Sanchez, Raquel L.; Kuperman, Douglas A.

    2013-01-01

    Background IL-13 in the airway induces pathologies that are highly characteristic of asthma, including mucus metaplasia, airway hyperreactivity (AHR), and airway inflammation. As such, it is important to identify the IL-13–responding cell types that mediate each of the above pathologies. For example, IL-13’s effects on epithelium contribute to mucus metaplasia and AHR. IL-13’s effects on smooth muscle also contribute to AHR. However, it has been difficult to identify the cell types that mediate IL-13–induced airway inflammation. Objective We sought to determine which cell types mediate IL-13–induced airway inflammation. Methods We treated the airways of mice with IL-13 alone or in combination with IFN-γ. We associated the inhibitory effect of IFN-γ on IL-13–induced airway inflammation and chemokine production with cell types in the lung that coexpress IL-13 and IFN-γ receptors. We then evaluated IL-13–induced responses in CD11c promoter–directed diphtheria toxin receptor–expressing mice that were depleted of both dendritic cells and alveolar macrophages and in CD11b promoter–directed diphtheria toxin receptor– expressing mice that were depleted of dendritic cells. Results Dendritic cell and alveolar macrophage depletion protected mice from IL-13–induced airway inflammation and CCL11, CCL24, CCL22, and CCL17 chemokine production. Preferential depletion of dendritic cells protected mice from IL-13–induced airway inflammation and CCL22 and CCL17 chemokine production but not from IL-13–induced CCL11 and CCL24 chemokine production. In either case mice were not protected from IL-13–induced AHR and mucus metaplasia. Conclusions Pulmonary dendritic cells and alveolar macrophages mediate IL-13–induced airway inflammation and chemokine production. (J Allergy Clin Immunol 2012;129:1621-7.) PMID:22365581

  19. Sensory neuropeptides and the human lower airways: present state and future directions.

    PubMed

    Joos, G F; Germonpre, P R; Kips, J C; Peleman, R A; Pauwels, R A

    1994-06-01

    The sensory neuropeptides, substance P and neurokinin A, are present in human airway nerves, beneath and within the epithelium, around blood vessels and submucosal glands, and within the bronchial smooth muscle layer. Studies on autopsy tissue, bronchoalveolar lavage and sputum suggest that in asthma the substance P content of the airways may be increased. Neurokinin A is a more potent bronchoconstrictor than substance P. Asthmatics are hyperresponsive to neurokinin A and substance P. The neuropeptide degrading enzyme, neutral endopeptidase is present in the airways and is involved in the degradation of endogenously released and exogenously administered substance P and neurokinin A, both in normal and asthmatic subjects. As for other indirect bronchoconstrictor stimuli, the effect of neurokinin A on airway calibre in asthmatics can be inhibited by pretreatment with nedocromil sodium. Evidence is accumulating, not only from studies in animals but also from experiments on human airways, that tachykinins may also cause mucus secretion and plasma extravasation. They also have important proinflammatory effects, such as the chemoattraction of eosinophils and neutrophils, the adhesion of neutrophils, and the stimulation of lymphocytes, macrophages and mast cells. The tachykinins interact with the targets on the airways by specific tachykinin receptors. The NK1 and the NK2 receptor have been characterized in human airways, both pharmacologically and by cloning. The NK2 receptor is responsible for the in vitro contraction of normal airways, whilst the NK1 receptor is responsible for most of the other airway effects. Because of their presence in the airways and because of their ability to mimic the various pathophysiological features of asthma, substance P and neurokinin A are presently considered as possible mediators of asthma. The present development of potent and selective tachykinin antagonists will allow us to further define the role of tachykinins in the pathogenesis

  20. Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodeling.

    PubMed

    Rock, Jason R; Randell, Scott H; Hogan, Brigid L M

    2010-01-01

    The small airways of the human lung undergo pathological changes in pulmonary disorders, such as chronic obstructive pulmonary disease (COPD), asthma, bronchiolitis obliterans and cystic fibrosis. These clinical problems impose huge personal and societal healthcare burdens. The changes, termed 'pathological airway remodeling', affect the epithelium, the underlying mesenchyme and the reciprocal trophic interactions that occur between these tissues. Most of the normal human airway is lined by a pseudostratified epithelium of ciliated cells, secretory cells and 6-30% basal cells, the proportion of which varies along the proximal-distal axis. Epithelial abnormalities range from hypoplasia (failure to differentiate) to basal- and goblet-cell hyperplasia, squamous- and goblet-cell metaplasia, dysplasia and malignant transformation. Mesenchymal alterations include thickening of the basal lamina, smooth muscle hyperplasia, fibrosis and inflammatory cell accumulation. Paradoxically, given the prevalence and importance of airway remodeling in lung disease, its etiology is poorly understood. This is due, in part, to a lack of basic knowledge of the mechanisms that regulate the differentiation, maintenance and repair of the airway epithelium. Specifically, little is known about the proliferation and differentiation of basal cells, a multipotent stem cell population of the pseudostratified airway epithelium. This Perspective summarizes what we know, and what we need to know, about airway basal cells to evaluate their contributions to normal and abnormal airway remodeling. We contend that exploiting well-described model systems using both human airway epithelial cells and the pseudostratified epithelium of the genetically tractable mouse trachea will enable crucial discoveries regarding the pathogenesis of airway disease. PMID:20699479

  1. Rare Upper Airway Anomalies.

    PubMed

    Windsor, Alanna; Clemmens, Clarice; Jacobs, Ian N

    2016-01-01

    A broad spectrum of congenital upper airway anomalies can occur as a result of errors during embryologic development. In this review, we will describe the clinical presentation, diagnosis, and management strategies for a few select, rare congenital malformations of this system. The diagnostic tools used in workup of these disorders range from prenatal tests to radiological imaging, swallowing evaluations, indirect or direct laryngoscopy, and rigid bronchoscopy. While these congenital defects can occur in isolation, they are often associated with disorders of other organ systems or may present as part of a syndrome. Therefore workup and treatment planning for patients with these disorders often involves a team of multiple specialists, including paediatricians, otolaryngologists, pulmonologists, speech pathologists, gastroenterologists, and geneticists. PMID:26277452

  2. [Reactive airways dysfunction syndrome].

    PubMed

    Costa, R; Orriols, R

    2005-01-01

    Reactive airways dysfunction syndrome, better known as RADS, was described as a clinical entity consisting in the appearance of bronchial asthma due to massive toxic inhalation. The term was coined and recognised for the first time in 1985. Since then different publications have verified new cases as well as different causal agents. It usually arises from an accident at the work place and in closed or poorly ventilated spaces, where high concentrations of irritant products are inhaled in the form of gas, smoke or vapour. In the following minutes or hours symptoms of bronchial obstruction appear in an acute form, with bronchial hyperresponsiveness persisting for months or years. The affected patients do not show a recurrence of symptoms following exposure to non-toxic doses of the same agent that started the symptoms. This is why diagnosis is based on clinical manifestations as it is not reproducible through a provocation test. PMID:15915173

  3. Linkage of familial dilated cardiomyopathy with conduction defect and muscular dystrophy to chromosome 6q23.

    PubMed Central

    Messina, D N; Speer, M C; Pericak-Vance, M A; McNally, E M

    1997-01-01

    Inherited cardiomyopathies may arise from mutations in genes that are normally expressed in both heart and skeletal muscle and therefore may be accompanied by skeletal muscle weakness. Phenotypically, patients with familial dilated cardiomyopathy (FDC) show enlargement of all four chambers of the heart and develop symptoms of congestive heart failure. Inherited cardiomyopathies may also be accompanied by cardiac conduction-system defects that affect the atrioventricular node, resulting in bradycardia. Several different chromosomal regions have been linked with the development of autosomal dominant FDC, but the gene defects in these disorders remain unknown. We now characterize an autosomal dominant disorder involving dilated cardiomyopathy, cardiac conduction-system disease, and adult-onset limb-girdle muscular dystrophy (FDC, conduction disease, and myopathy [FDC-CDM]). Genetic linkage was used to exclude regions of the genome known to be linked to dilated cardiomyopathy and muscular dystrophy phenotypes and to confirm genetic heterogeneity of these disorders. A genomewide scan identified a region on the long arm of chromosome 6 that is significantly associated with the presence of myopathy (D6S262; maximum LOD score [Z(max)] 4.99 at maximum recombination fraction [theta(max)] .00), identifying FDC-CDM as a genetically distinct disease. Haplotype analysis refined the interval containing the genetic defect, to a 3-cM interval between D6S1705 and D6S1656. This haplotype analysis excludes a number of striated muscle-expressed genes present in this region, including laminin alpha2, laminin alpha4, triadin, and phospholamban. Images Figure 2 PMID:9382102

  4. Chlamydia muridarum Induction of Glandular Duct Dilation in Mice

    PubMed Central

    Sun, Xin; Yang, Zhangsheng; Zhang, Hongbo; Dai, Jin; Chen, Jianlin; Tang, Lingli; Rippentrop, Sheena; Xue, Min

    2015-01-01

    Although Chlamydia-induced hydrosalpinx in women and mice has been used as a surrogate marker for tubal infertility, the medical relevance of nontubal pathologies, such as uterine horn dilation, developed in mice following chlamydial infection remains unclear. We now report that the uterine horn dilation correlates with glandular duct dilation detected microscopically following Chlamydia muridarum infection. The dilated glandular ducts pushed the uterine horn lumen to closure or dilation and even broke through the myometrium to develop extrusion outside the uterine horn. The severity scores of uterine horn dilation observed macroscopically correlated well with the number of cross sections of the dilated glandular ducts counted under microscopy. Chlamydial infection was detected in the glandular epithelial cells, potentially leading to inflammation and dilation of the glandular ducts. Direct delivery of C. muridarum into the mouse uterus increased both uterine horn/glandular duct dilation and hydrosalpinx. However, the chlamydial plasmid, which is essential for the induction of hydrosalpinx, was not required for the induction of uterine horn/glandular duct dilation. Screening 12 strains of mice for uterine horn dilation following C. muridarum infection revealed that B10.D2, C57BL/10J, and C57BL/6J mice were most susceptible, followed by BALB/cJ and A/J mice. Deficiency in host genes involved in immune responses failed to significantly alter the C. muridarum induction of uterine horn dilation. Nevertheless, the chlamydial induction of uterine horn/glandular duct dilation may be used to evaluate plasmid-independent pathogenicity of Chlamydia in susceptible mice. PMID:25824829

  5. Origins of and implementation concepts for upper airway stimulation therapy for obstructive sleep apnea.

    PubMed

    Strohl M D, Kingman P; Baskin M D, Jonathan; Lance M D, Colleen; Ponsky M D, Diana; Weidenbecher M D, Mark; Strohl B A, Madeleine; Yamauchi M D, Motoo

    2016-07-01

    Upper airway stimulation, specifically hypoglossal (CN XII) nerve stimulation, is a new, alternative therapy for patients with obstructive sleep apnea hypopnea syndrome who cannot tolerate positive airway pressure, the first-line therapy for symptomatic patients. Stimulation therapy addresses the cause of inadequate upper airway muscle activation for nasopharyngeal and oropharyngeal airway collapse during sleep. The purpose of this report is to outline the development of this first-in-class therapy and its clinical implementation. Another practical theme is assessment of the features for considering a surgically implanted device and the insight as to how both clinical and endoscopic criteria increase the likelihood of safe and durable outcomes for an implant and how to more generally plan for management of CPAP-intolerant patients. A third theme is the team building required among sleep medicine and surgical specialties in the provision of individualized neurostimulation therapy. PMID:27424823

  6. A fungal protease allergen provokes airway hyper-responsiveness in asthma.

    PubMed

    Balenga, Nariman A; Klichinsky, Michael; Xie, Zhihui; Chan, Eunice C; Zhao, Ming; Jude, Joseph; Laviolette, Michel; Panettieri, Reynold A; Druey, Kirk M

    2015-01-01

    Asthma, a common disorder that affects >250 million people worldwide, is defined by exaggerated bronchoconstriction to inflammatory mediators including acetylcholine (ACh), bradykinin and histamine-also termed airway hyper-responsiveness. Nearly 10% of people with asthma have severe, treatment-resistant disease, which is frequently associated with immunoglobulin-E sensitization to ubiquitous fungi, typically Aspergillus fumigatus (Af). Here we show that a major Af allergen, Asp f13, which is a serine protease, alkaline protease 1 (Alp 1), promotes airway hyper-responsiveness by infiltrating the bronchial submucosa and disrupting airway smooth muscle (ASM) cell-extracellular matrix (ECM) interactions. Alp 1-mediated ECM degradation evokes pathophysiological RhoA-dependent Ca(2+) sensitivity and bronchoconstriction. These findings support a pathogenic mechanism in asthma and other lung diseases associated with epithelial barrier impairment, whereby ASM cells respond directly to inhaled environmental allergens to generate airway hyper-responsiveness. PMID:25865874

  7. CRAC ion channels and airway defense reflexes in experimental allergic inflammation.

    PubMed

    Sutovska, M; Adamkov, M; Kocmalova, M; Mesarosova, L; Oravec, M; Franova, S

    2013-01-01

    Calcium release-activated calcium channels (CRAC) play unambiguous role in secretory functions of mast cells, T cells, and eosinophils. Less knowledge exists about the role of CRAC, widely distributed in airway smooth muscle (ASM) cells, in airway contractility. The presented study seeks to determine the possible participation of CRAC in ASM-based inflammatory airway disorders in guinea pigs. The acute and long-term administration (14 days) of the CRAC antagonist 3-fluoropyridine-4-carboxylic acid was used to examine the ASM contractility and associated reflexes in the guinea pig model of allergic airway inflammation by the following methods: (i) evaluation of specific airway resistance in vivo; (ii) evaluation of the contractile response of isolated ASM strips in vitro; and (iii) citric acid-induced cough reflex; (iv) measurement of exhaled NO levels (E(NO)). Allergic airway inflammation was induced by repetitive exposure of guinea pigs to ovalbumin (10(-6) M). The CRAC antagonist administered in a single dose to guinea pigs with confirmed allergic inflammation significantly reduced the cough response and the airway resistance, which corresponded with the findings in vitro. Long-term application of the CRAC antagonist had more strongly expressed effects. The results confirm the role of CRAC in the pathophysiology of experimental animal asthma and have a potential meaning for anti-asthma therapy. PMID:22836617

  8. Pericytes contribute to airway remodeling in a mouse model of chronic allergic asthma.

    PubMed

    Johnson, Jill R; Folestad, Erika; Rowley, Jessica E; Noll, Elisa M; Walker, Simone A; Lloyd, Clare M; Rankin, Sara M; Pietras, Kristian; Eriksson, Ulf; Fuxe, Jonas

    2015-04-01

    Myofibroblast accumulation, subepithelial fibrosis, and vascular remodeling are complicating features of chronic asthma, but the mechanisms are not clear. Platelet-derived growth factors (PDGFs) regulate the fate and function of various mesenchymal cells and have been implicated as mediators of lung fibrosis. However, it is not known whether PDGF-BB signaling via PDGFRβ, which is critical for the recruitment of pericytes to blood vessels, plays a role in airway remodeling in chronic asthma. In the present study, we used a selective PDGFRβ inhibitor (CP-673451) to investigate the role of PDGFRβ signaling in the development of airway remodeling and lung dysfunction in an established mouse model of house dust mite-induced chronic allergic asthma. Unexpectedly, we found that pharmacological inhibition of PDGFRβ signaling in the context of chronic aeroallergen exposure led to exacerbated lung dysfunction and airway smooth muscle thickening. Further studies revealed that the inflammatory response to aeroallergen challenge in mice was associated with decreased PDGF-BB expression and the loss of pericytes from the airway microvasculature. In parallel, cells positive for pericyte markers accumulated in the subepithelial region of chronically inflamed airways. This process was exacerbated in animals treated with CP-673451. The results indicate that perturbed PDGF-BB/PDGFRβ signaling and pericyte accumulation in the airway wall may contribute to airway remodeling in chronic allergic asthma. PMID:25637607

  9. Pericytes contribute to airway remodeling in a mouse model of chronic allergic asthma

    PubMed Central

    Folestad, Erika; Rowley, Jessica E.; Noll, Elisa M.; Walker, Simone A.; Lloyd, Clare M.; Rankin, Sara M.; Pietras, Kristian; Eriksson, Ulf; Fuxe, Jonas

    2015-01-01

    Myofibroblast accumulation, subepithelial fibrosis, and vascular remodeling are complicating features of chronic asthma, but the mechanisms are not clear. Platelet-derived growth factors (PDGFs) regulate the fate and function of various mesenchymal cells and have been implicated as mediators of lung fibrosis. However, it is not known whether PDGF-BB signaling via PDGFRβ, which is critical for the recruitment of pericytes to blood vessels, plays a role in airway remodeling in chronic asthma. In the present study, we used a selective PDGFRβ inhibitor (CP-673451) to investigate the role of PDGFRβ signaling in the development of airway remodeling and lung dysfunction in an established mouse model of house dust mite-induced chronic allergic asthma. Unexpectedly, we found that pharmacological inhibition of PDGFRβ signaling in the context of chronic aeroallergen exposure led to exacerbated lung dysfunction and airway smooth muscle thickening. Further studies revealed that the inflammatory response to aeroallergen challenge in mice was associated with decreased PDGF-BB expression and the loss of pericytes from the airway microvasculature. In parallel, cells positive for pericyte markers accumulated in the subepithelial region of chronically inflamed airways. This process was exacerbated in animals treated with CP-673451. The results indicate that perturbed PDGF-BB/PDGFRβ signaling and pericyte accumulation in the airway wall may contribute to airway remodeling in chronic allergic asthma. PMID:25637607

  10. Cantilever and capacitor technique for measuring dilatation

    SciTech Connect

    Primak, W.; Monahan, E.

    1983-05-01

    The relationship of EerNisse's technique for measuring small dilatations caused by irradiation with short-range particles, which utilizes a metallized thin plate mounted as a cantilever below whose free end an electrode is placed (forming a capacitor), to a photoelastic technique and to an interferometric technique are derived. The effects of stray capacitance, the fringing field of the capacitor, the clamping stress on the cantilever plate, the electrical resistance of the metallic coating, the charging of the tank circuit of which the capacitor is an element, the flange bolting stress, and the beam heating are assessed, and examples of the manner in which they contaminate the data are given.

  11. Dilated cardiomyopathy following use of xenadrine EFX.

    PubMed

    Riccioni, Graziano; Speziale, Giuseppe; Scotti, Luca; Bucciarelli, Valentina; Cappetti, Silvia; Nasso, Giuseppe; Gallina, Sabina; Bucciarelli, Tonino

    2016-03-01

    We describe a case of a 35-year-old man presented at the emergency room of our institution with acute onset of dyspnea and dizziness. He was a body builder and had been using Xenadrine EFX for weight loss reduction. The laboratory analyses were normal. A chest radiograph showed an enlarged cardiac silhouette with clear lung fields. Transtoracic two-dimensional color Doppler echocardiography revealed a diffuse hypokinesia with a marked decreased in systolic function and a high teledyastolic diameter. This case document the possible relation to use of Xenadrine EFX for weight loss and the recurrence of dilated cardiomyopathy. PMID:26680256

  12. Dilated cardiomyopathy associated with toluene abuse.

    PubMed

    Vural, Mutlu; Ogel, Kultegin

    2006-01-01

    The use of paint thinner and glue to achieve an euphoric state has been associated with serious social and health problems in children and young adults. We present the case of a 21-year-old man with dilated cardiomyopathy occurring following abuse of paint thinner and glue containing toluene as main compound. After cessation of toluene abuse, the patient recovered rapidly and completely. Because of the increasing prevalence of toluene abuse, harmful effects of this volatile agent on the heart are also discussed. PMID:16479101

  13. Apoptosis and the Airway Epithelium

    PubMed Central

    White, Steven R.

    2011-01-01

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

  14. Extraglottic airway devices: A review

    PubMed Central

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

    2014-01-01

    Extraglottic