Potential bronchoconstrictor stimuli in acid fog.

PubMed Central

Balmes, J R; Fine, J M; Gordon, T; Sheppard, D

1989-01-01

Acid fog is complex and contains multiple stimuli that may be capable of inducing bronchoconstriction. These stimuli include sulfuric and niric acids, the principal inorganic acids present; sulfites, formed in the atmosphere as a reaction product of sulfur dioxide and water droplets; fog water itself, a hypoosmolar aerosol; the organic acid hydroxymethanesulfonate, the bisulfite adduct of formaldehyde; and gaseous pollutants, e.g., sulfur dioxide, oxides of nitrogen, ozone. Given this complexity, evaluation of the respiratory health effects of naturally occurring acid fog requires assessment of the bronchoconstrictor potency of each component stimulus and possible interactions among these stimuli. We summarize the results of three studies that involve characterization of the bronchoconstrictor potency of acid fog stimuli and/or their interaction in subjects with asthma. The results of the first study indicate that titratable acidity appears to be a more important stimulus to bronchoconstriction than is pH. The results of the second study demonstrate that sulfite species are capable of inducing bronchoconstriction, especially when inhaled at acid pH. The results of the third study suggest that acidity can potentiate hypoosmolar fog-induced bronchoconstriction. PMID:2539989

Vagal afferents contribute to exacerbated airway responses following ozone and allergen challenge.

PubMed

Schelegle, Edward S; Walby, William F

2012-05-31

Brown-Norway rats (n=113) sensitized and challenged with nDer f 1 allergen were used to examine the contribution of lung sensory nerves to ozone (O(3)) exacerbation of asthma. Prior to their third challenge rats inhaled 1.0ppm O(3) for 8h. There were three groups: (1) control; (2) vagus perineural capsaicin treatment (PCT) with or without hexamethonium; and (3) vagotomy. O(3) inhalation resulted in a significant increase in lung resistance (R(L)) and an exaggerated response to subsequent allergen challenge. PCT abolished the O(3)-induced increase in R(L) and significantly reduced the increase in R(L) induced by a subsequent allergen challenge, while hexamethonium treatment reestablished bronchoconstriction induced by allergen challenge. Vagotomy resulted in a significant increase in the bronchoconstriction induced by O(3) inhalation and subsequent challenge with allergen. In this model of O(3) exacerbation of asthma, vagal C-fibers initiate reflex bronchoconstriction, vagal myelinated fibers initiate reflex bronchodilation, and mediators released within the airway initiate bronchoconstriction. Copyright © 2012 Elsevier B.V. All rights reserved.

A critical role of acute bronchoconstriction in the mortality associated with high-dose sarin inhalation: Effects of epinephrine and oxygen therapies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gundavarapu, Sravanthi; Zhuang, Jianguo; Barrett, Edward G.

Sarin is an organophosphate nerve agent that is among the most lethal chemical toxins known to mankind. Because of its vaporization properties and ease and low cost of production, sarin is the nerve agent with a strong potential for use by terrorists and rouge nations. The primary route of sarin exposure is through inhalation and, depending on the dose, sarin leads to acute respiratory failure and death. The mechanism(s) of sarin-induced respiratory failure is poorly understood. Sarin irreversibly inhibits acetylcholine esterase, leading to excessive synaptic levels of acetylcholine and, we have previously shown that sarin causes marked ventilatory changes includingmore » weakened response to hypoxia. We now show that LD{sub 50} sarin inhalation causes severe bronchoconstriction in rats, leading to airway resistance, increased hypoxia-induced factor-1α, and severe lung epithelium injury. Transferring animals into 60% oxygen chambers after sarin exposure improved the survival from about 50% to 75% at 24 h; however, many animals died within hours after removal from the oxygen chambers. On the other hand, if LD{sub 50} sarin-exposed animals were administered the bronchodilator epinephrine, > 90% of the animals survived. Moreover, while both epinephrine and oxygen treatments moderated cardiorespiratory parameters, the proinflammatory cytokine surge, and elevated expression of hypoxia-induced factor-1α, only epinephrine consistently reduced the sarin-induced bronchoconstriction. These data suggest that severe bronchoconstriction is a critical factor in the mortality induced by LD{sub 50} sarin inhalation, and epinephrine may limit the ventilatory, inflammatory, and lethal effects of sarin. - Highlights: • Inhalation exposure of rats to LD{sub 50} sarin causes death through respiratory failure. • Severe bronchoconstriction is the major cause of sarin-induced respiratory failure. • Transfer of sarin exposed rats to 60% oxygen improves the mortality temporarily. • Epinephrine improves bronchoconstriction and mortality in LD{sub 50} sarin-exposed rats. • Both epinephrine and oxygen moderate the sarin-induced lung inflammatory response.« less

Self-reported Symptoms after Induced and Inhibited Bronchoconstriction in Athletes

PubMed Central

SIMPSON, ANDREW J.; ROMER, LEE M.; KIPPELEN, PASCALE

2015-01-01

ABSTRACT Purpose A change in the perception of respiratory symptoms after treatment with inhaled beta2 agonists is often used to aid diagnosis of exercise-induced bronchoconstriction (EIB). Our aim was to test the association between subjective ratings of respiratory symptoms and changes in airway caliber after induced and inhibited bronchoconstriction in athletes with EIB. Methods Eighty-five athletes with diagnosed or suspected EIB performed a eucapnic voluntary hyperpnea (EVH) challenge with dry air. Of the 45 athletes with hyperpnea-induced bronchoconstriction [i.e., post-EVH fall in forced expiratory volume in 1 s (FEV1) ≥10%, EVH−], 36 were randomized in a double-blind, placebo-controlled, crossover study. Terbutaline (0.5 mg) or placebo was administered by inhalation 15 min before EVH. Spirometry (for FEV1) was performed before and after EVH, and respiratory symptoms were recorded 15 min after EVH on visual analog scales. Results Terbutaline inhibited bronchoconstriction (i.e., maximal fall in FEV1 <10% after EVH) in 83% of the EVH-positive athletes, with an average degree of bronchoprotection of 53% (95% confidence interval [CI], 45% to 62%). Terbutaline reduced group mean symptom scores (P < 0.01), but the degree of bronchoprotection did not correlate with individual differences in symptom scores between terbutaline and placebo. Of the 29 athletes who had less than 10% FEV1 fall after EVH in the terbutaline condition, almost half (48%) rated at least one respiratory symptom higher under terbutaline, and more than one quarter (28%) had a higher total symptom score under terbutaline. Conclusion Self-reports of respiratory symptoms in conditions of induced and inhibited bronchoconstriction do not correlate with changes in airway caliber in athletes with EIB. Therefore, subjective ratings of respiratory symptoms after treatment with inhaled beta2 agonists should not be used as the sole diagnostic tool for EIB in athletes. PMID:25710876

Cigarette smoke-inhibition of neurogenic bronchoconstriction in guinea-pigs in vivo: involvement of exogenous and endogenous nitric oxide

PubMed Central

Emms, Joanne C; Rogers, Duncan F

1997-01-01

We investigated the effect of acute inhalation of cigarette smoke on subsequent non-adrenergic, non-cholinergic (NANC) neural bronchoconstriction in anaesthetized guinea-pigs in vivo by use of pulmonary insufflation pressure (PIP) as an index of airway tone. The contribution of endogenous nitric oxide (NO) was investigated with the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). The contribution of plasma exudation to the response was investigated with Evans blue dye as a plasma marker. Inhalation of 50 tidal volumes of cigarette smoke or air had no significant effect on baseline PIP. In the presence of propranolol and atropine (1 mg kg−1 each), electrical stimulation of the vagus nerves in animals given air 30 min previously induced a frequency-dependent increase in PIP above sham stimulated controls (16 fold increase at 2.5 Hz, 24 fold increase at 10 Hz). In contrast, in smoke-exposed animals, the increase in subsequent vagally-induced PIP was markedly less than in the air controls (90% less at 2.5 Hz, 76% less at 10 Hz). L-NAME (10 mg kg−1), given 10 min before air or smoke, potentiated subsequent vagally-induced (2.5 Hz) NANC bronchoconstriction by 338% in smoke-exposed animals, but had no significant effect in air-exposed animals. The inactive enantiomer D-NAME (10 mg kg−1) had no effect, and the potentiation by L-NAME was partially reversed by the NO-precursor L-arginine (100 mg kg−1). Vagal stimulation did not affect the magnitude of vagally-induced bronchoconstriction 30 min later. Cigarette smoke exposure reduced the magnitude of subsequent bronchoconstriction induced by neurokinin A (NKA) by 37% compared with the effect of NKA in air-exposed animals. L-NAME had no significant effect on the smoke-induced inhibition of NKA-induced bronchoconstriction. Vagally-induced plasma exudation in the main bronchi was greater in smoke-exposed animals compared with air-exposed animals (120% greater at 2.5 Hz, 82% greater at 10 Hz). We conclude that cigarette smoke-induced inhibition of subsequent NANC neurogenic bronchoconstriction is not associated with inhibition of airway plasma exudation and is mediated in part via exogenous smoke-derived NO, or another bronchoprotective molecule, and by endogenous NO. PMID:9375977

Practical approach to exercise-induced bronchoconstriction in athletes.

PubMed

Ansley, Les; Rae, Glen; Hull, James H

2013-03-01

Exercise-induced bronchoconstriction (EIB) is highly prevalent in athletes of all abilities and can impact on their health and performance. The majority of athletes with exertional dyspnoea will be initially assessed and managed in primary care. This report provides a practical and pragmatic approach to the assessment and management of a young athlete presenting with suspected EIB in this setting.

Role of nitric oxide and septide-insensitive NK1 receptors in bronchoconstriction induced by aerosolised neurokinin A in guinea-pigs

PubMed Central

Ricciardolo, Fabio L M; Trevisani, Marcello; Geppetti, Pierangelo; Nadel, Jay A; Amadesi, Silvia; Bertrand, Claude

2000-01-01

The tachykinin, neurokinin A (NKA), contracts guinea-pig airways both in vitro and in vivo, preferentially activating smooth muscle NK2 receptors, although smooth muscle NK1 receptors may also contribute. In vitro evidence suggests that NKA activates epithelial NK1 receptors, inducing the release of nitric oxide (NO) and subsequent smooth muscle relaxation. A number of selective NK1 receptor agonists have been reported to activate both smooth muscle and epithelial NK1 receptors, however septide appears only to activate smooth muscle NK1 receptors. The aim of the present study was to investigate whether NKA-induced bronchoconstriction in guinea-pigs in vivo may be limited by NO release via NK1 receptor activation, and whether selective NK1 receptor agonists may activate this mechanism differently. Aerosolized NKA caused an increase in total pulmonary resistance (RL) that was markedly reduced by the NK2 receptor antagonist, SR 48968, and abolished by the combination of SR 48968 and the NK1 receptor antagonist, CP-99,994. The increase in RL evoked by NKA was potentiated by pretreatment with the NO synthase (NOs) inhibitor, L-NAME, but not by the inactive enantiomer D-NAME. Potentiation by L-NAME of NKA-induced increase in RL was reversed by L-Arginine, but not by D-Arginine. Pretreatment with L-NAME did not affect the increase in RL induced by the selective NK2 receptor agonist, [β-Ala8]NKA(4-10), and by the selective NK1 receptor agonist, septide, whereas it markedly potentiated the increase in RL caused by a different NK1 selective agonist, [Sar9,Met(O2)11]SP. Dose-response curves showed that septide was a more potent bronchoconstrictor than [Sar9,Met(O2)11]SP to cause bronchoconstriction. Pretreatment with the NK1 receptor antagonist, CP-96,994, abolished the ability of L-NAME to increase bronchoconstriction to aerosolized NKA. Bronchoconstriction to aerosolized NKA was increased by L-NAME, after pretreatment with the NK3 receptor antagonist, SR 142801. The present study shows that in vivo bronchoconstriction in response to the aerosolized naturally occurring tachykinin, NKA, is limited by its own ability to release relaxant NO via NK1 receptor activation. This receptor is apparently insensitive to septide, thus justifying, at least in part, the high potency of septide to cause bronchoconstriction in guinea-pigs. PMID:10696090

Role of nitric oxide and septide-insensitive NK(1) receptors in bronchoconstriction induced by aerosolised neurokinin A in guinea-pigs.

PubMed

Ricciardolo, F L; Trevisani, M; Geppetti, P; Nadel, J A; Amadesi, S; Bertrand, C

2000-03-01

The tachykinin, neurokinin A (NKA), contracts guinea-pig airways both in vitro and in vivo, preferentially activating smooth muscle NK(2) receptors, although smooth muscle NK(1) receptors may also contribute. In vitro evidence suggests that NKA activates epithelial NK(1) receptors, inducing the release of nitric oxide (NO) and subsequent smooth muscle relaxation. A number of selective NK(1) receptor agonists have been reported to activate both smooth muscle and epithelial NK(1) receptors, however septide appears only to activate smooth muscle NK(1) receptors. The aim of the present study was to investigate whether NKA-induced bronchoconstriction in guinea-pigs in vivo may be limited by NO release via NK(1) receptor activation, and whether selective NK(1) receptor agonists may activate this mechanism differently. Aerosolized NKA caused an increase in total pulmonary resistance (RL) that was markedly reduced by the NK(2) receptor antagonist, SR 48968, and abolished by the combination of SR 48968 and the NK(1) receptor antagonist, CP-99, 994. The increase in RL evoked by NKA was potentiated by pretreatment with the NO synthase (NOs) inhibitor, L-NAME, but not by the inactive enantiomer D-NAME. Potentiation by L-NAME of NKA-induced increase in RL was reversed by L-Arginine, but not by D-Arginine. Pretreatment with L-NAME did not affect the increase in RL induced by the selective NK(2) receptor agonist, [beta-Ala(8)]NKA(4-10), and by the selective NK(1) receptor agonist, septide, whereas it markedly potentiated the increase in RL caused by a different NK(1) selective agonist, [Sar(9),Met(O(2))(11)]SP. Dose-response curves showed that septide was a more potent bronchoconstrictor than [Sar(9),Met(O(2))(11)]SP to cause bronchoconstriction. Pretreatment with the NK(1) receptor antagonist, CP-96,994, abolished the ability of L-NAME to increase bronchoconstriction to aerosolized NKA. Bronchoconstriction to aerosolized NKA was increased by L-NAME, after pretreatment with the NK(3) receptor antagonist, SR 142801. The present study shows that in vivo bronchoconstriction in response to the aerosolized naturally occurring tachykinin, NKA, is limited by its own ability to release relaxant NO via NK(1) receptor activation. This receptor is apparently insensitive to septide, thus justifying, at least in part, the high potency of septide to cause bronchoconstriction in guinea-pigs.

Case reports - When bronchial obstruction in the young adult is not asthma and inhalers do not help.

PubMed

Sigvard, Anne; Bødtger, Uffe

2016-08-01

Localised bronchial obstruction is a rare differential diagnosis to asthma. We describe two younger patients treated unsuccessfully for asthma and eventually diagnosed with localised bronchoconstriction. Bronchoscopy revealed bronchoconstriction: Tracheobronchomalacia in case 1 and fixed obstruction in case 2. A systematic approach to the asthma patient with absent response to therapy facilitates rational use of therapeutic and diagnostic resources.

The PDE4 inhibitor CHF-6001 and LAMAs inhibit bronchoconstriction-induced remodeling in lung slices.

PubMed

Kistemaker, Loes E M; Oenema, Tjitske A; Baarsma, Hoeke A; Bos, I Sophie T; Schmidt, Martina; Facchinetti, Fabrizio; Civelli, Maurizio; Villetti, Gino; Gosens, Reinoud

2017-09-01

Combination therapy of PDE4 inhibitors and anticholinergics induces bronchoprotection in COPD. Mechanical forces that arise during bronchoconstriction may contribute to airway remodeling. Therefore, we investigated the impact of PDE4 inhibitors and anticholinergics on bronchoconstriction-induced remodeling. Because of the different mechanism of action of PDE4 inhibitors and anticholinergics, we hypothesized functional interactions of these two drug classes. Guinea pig precision-cut lung slices were preincubated with the PDE4 inhibitors CHF-6001 or roflumilast and/or the anticholinergics tiotropium or glycopyorrolate, followed by stimulation with methacholine (10 μM) or TGF-β 1 (2 ng/ml) for 48 h. The inhibitory effects on airway smooth muscle remodeling, airway contraction, and TGF-β release were investigated. Methacholine-induced protein expression of smooth muscle-myosin was fully inhibited by CHF-6001 (0.3-100 nM), whereas roflumilast (1 µM) had smaller effects. Tiotropium and glycopyrrolate fully inhibited methacholine-induced airway remodeling (0.1-30 nM). The combination of CHF-6001 and tiotropium or glycopyrrolate, in concentrations partially effective by themselves, fully inhibited methacholine-induced remodeling in combination. CHF-6001 did not affect airway closure and had limited effects on TGF-β 1 -induced remodeling, but rather, it inhibited methacholine-induced TGF-β release. The PDE4 inhibitor CHF-6001, and to a lesser extent roflumilast, and the LAMAs tiotropium and glycopyrrolate inhibit bronchoconstriction-induced remodeling. The combination of CHF-6001 and anticholinergics was more effective than the individual compounds. This cooperativity might be explained by the distinct mechanisms of action inhibiting TGF-β release and bronchoconstriction. Copyright © 2017 the American Physiological Society.

Effects of carbamazepine on plasma extravasation and bronchoconstriction induced by substance P, capsaicin, acetaldehyde and histamine in guinea-pig lower airways.

PubMed

Bianchi, M; Rossoni, G; Maggi, R; Panerai, A E; Berti, F

1998-01-01

We evaluated the in vivo effects of the pretreatment with carbamazepine (CBZ) at different doses (10, 20 and 40 mg/kg p.o.) on the Evans-blue extravasation and on bronchoconstriction induced by different substances in guinea-pig tracheal tissue. The drug dose-dependently inhibited the extravasation induced by substance P (SP), capsaicin and acetaldehyde, but not that induced by histamine. At the highest dose (40 mg/kg) CBZ inhibited the bronchoconstriction induced by SP, capsaicin and acetaldehyde, but not that produced by histamine administration. The in vitro study with guinea-pig tracheal preparation indicates that the drug does not interfere with the binding of SP to its receptors. Our results suggest that CBZ exerts a protective activity against the pro-inflammatory action of SP.

Pulmonary Stress Induced by Hyperthermia: Role of Airway Sensory Nerves

DTIC Science & Technology

2012-10-01

conclusions: 1) Airway hyperresponsiveness developed in Ova-sensitized mice was less pronounced in TRPV1 -null mice, indicating an important role of TRPV1 ...expression of the transient receptor potential vanilloid type 1 ( TRPV1 ) channel is up-regulated in the airway mucosa of patients with mild asthma... TRPV1 channel in triggering the bronchoconstriction caused by airway hyperthermia, and to determine whether this acute bronchoconstrictive effect was

Substance P antagonists and the role of tachykinins in non-cholinergic bronchoconstriction.

PubMed

Karlsson, J A; Finney, M J; Persson, C G; Post, C

1984-12-24

Electrical field stimulation of guinea-pig isolated hilus bronchi induced tetrodotoxin-sensitive contractions of which only a minor part could be inhibited by atropine. The remaining non-cholinergic bronchoconstriction was antagonized by a heptapeptide and an undecapeptide substance P (SP) analogue (Arg5, D-Trp7,9) SP5-11, IC50 = 24.0 microM and (D-Pro2, D-Trp 7,9) SP, IC50 = 10.0 microM. Of the exogenously added tachykinins, both eledoisin (8 times) and physalaemin (3 times) were more potent bronchoconstrictors than SP. Pretreatment with the SP-analogues shifted concentration-response curves to the tachykinins to the right, eledoisin being most readily antagonized. (Arg5, D-Trp 7,9) SP 5-11 also antagonized the neural response more readily than that of SP. In addition, in the frog isolated sciatic nerve preparation the two SP-analogues were found to possess potent lidocaine-like neurodepressant actions which further complicated the interpretation of the neural inhibitory effects of these compounds. It is concluded that if a tachykinin contributes to non-cholinergic bronchoconstriction, an eledoisin-like peptide is a more likely candidate than SP itself. Since SP-antagonists may have local anaesthetic properties their value as tools in neurophysiology seems limited. Inferentially, the non-cholinergic bronchoconstrictive neurotransmitter remains to be identified.

[Mechanisms of tolerance to sulfur dioxide and sodium metabisulfite].

PubMed

Atzori, L; Corriga, A M; Cannas, E; Congiu, L

1997-01-01

Inhalation of sulphur dioxide (250 ppm), (SO2) or sodium metabisulfite (80 mM) (MBS) aerosol or perfusion with MBS (3 mM) induced a reduction in compliance and conductance in the isolated, perfused and ventilated guinea pig lung. Pretreatment of the lung with sodium sulfite (3 mM), a dissolution product of SO2 and MBS, reduced the bronchoconstriction induced by SO2 and MBS. Bronchoconstriction induced by SO2 and MBS in associated to increased levels of Calcitonin gene-Related Peptide (CGRP) in the perfusate effinent, indicating activation of sensory nerves. The release of CGRP induced by SO2 and MBS was not affected by sodium sulfite. Sulfite treatment did not modify lung reactivity towards acethylcholine, bradykinin, serotonin, histamine and substance P (fragment 5-11). An inhibitory effect by sulfite was observed on bronchoconstriction induced by neurokinin A (fragment 4-10). Since bronchoconstriction induced by SO2 and MBS appears to be mediated by neurokinin A release and action, sulfite may act by affecting its signal transduction pathway. In conclusion, the results indicate that during exposure to some environmental and occupational pollutants, e.g. SO2 and MBS, critical modifications of sulfhydryl groups on smooth muscle receptors may occur. We hypothesise this as a possible step in the development of tolerance and hyperreactivity.

The effect of substance P on the antigen-induced bronchoconstriction in guinea pigs.

PubMed

Nagai, H; Tsuji, F; Koda, A

1990-03-01

The effect of substance P (SP) on the antigen-induced bronchoconstriction in vitro and in vivo was investigated in guinea pigs. SP caused the contraction of isolated non-sensitized guinea pig tracheal muscle at concentrations between 10(-9) to 10(-7) g/ml. The elimination of epithelium in the tracheal muscle produced a slight enhancement of SP response as compared to control. Antigen-induced contraction of isolated sensitized guinea pig tracheal muscle was slightly enhanced by the pretreatment with SP at a concentration of 10(-9) g/ml. The SP-induced enhancement of antigen-induced contraction was significantly augmented by the elimination of epithelium of sensitized tracheal muscle. Moreover, the clear bronchoconstriction was observed by the infusion of SP (1 micrograms/min) intravenously, but not by the infusion of SP at the rates between 0.1 and 0.01 micrograms/min. Antigen-induced asthmatic respiratory disorder was accelerated temporarily by the infusion of subthreshold SP (0.1 microgram/min). The reactivity of bronchial smooth muscle measured by repeated injection of acetylcholine was significantly potentiated by the infusion of subthreshold SP (0.1 microgram/min). These results suggest that SP has dual actions in the contractile response of guinea pig airway smooth muscle. One is the direct contractile activity, and the other one is enhancing activity of antigen- and acetylcholine-induced bronchoconstriction.

Bronchoconstriction induced by hyperventilation with humidified hot air: role of TRPV1-expressing airway afferents.

PubMed

Lin, Ruei-Lung; Hayes, Don; Lee, Lu-Yuan

2009-06-01

A recent study by our laboratory has shown that an increase in intrathoracic temperature activates vagal pulmonary C-fibers. Because these afferents are known to elicit reflex bronchoconstriction upon stimulation, this study was carried out to investigate if an increase in airway temperature within the physiological range alters bronchomotor tone. Adult guinea pigs were anesthetized and mechanically ventilated via a tracheal tube. After the lung had been hyperventilated with humidified hot air (HHA) for 4 min, the tracheal temperature was elevated from 36.4 to 40.5 degrees C, which induced an immediate bronchoconstriction, increasing total pulmonary resistance (R(L)) to 177 +/- 10% and decreasing dynamic lung compliance to 81 +/- 6% of their respective baselines. The increase in R(L) returned spontaneously toward the baseline in <10 min and was reproducible in the same animals. There were no difference in the responses whether the humidity was generated from distilled water or isotonic saline. In contrast, hyperventilation with humidified air at room temperature did not cause any increase in R(L). The increase in R(L) caused by HHA was attenuated by 65.9% after a pretreatment with atropine alone and by 72.0% after a pretreatment with a combination of atropine and neurokinin receptor type 1 and 2 antagonists. In addition, capsazepine, a selective transient receptor potential vanilloid type 1 (TRPV1) antagonist, reduced the HHA-induced increase in R(L) by 64.1% but did not abolish it. However, pretreatment with formoterol, a beta(2)-agonist, completely prevented the HHA-induced bronchoconstriction. These results indicate that the increase in airway temperature induced transient airway constriction in guinea pigs. Approximately two-thirds of the increase in bronchomotor tone was mediated through the cholinergic reflex, which was probably elicited by the activation of TRPV1-expressing airway afferents. The remaining bronchoconstriction was caused by other, yet unidentified factors.

Effects of two novel tachykinin antagonists, FK224 and FK888, on neurogenic airway plasma exudation, bronchoconstriction and systemic hypotension in guinea-pigs in vivo.

PubMed Central

Hirayama, Y.; Lei, Y. H.; Barnes, P. J.; Rogers, D. F.

1993-01-01

1. We compared the effects of two novel tachykinin receptor antagonists, FK888 (selective at the tachykinin NK1 receptor) and FK224 (dual antagonist at NK1 and NK2 tachykinin receptors) on stimulus-evoked airway plasma exudation, bronchoconstriction and systemic hypotension in guinea-pigs in vivo. Plasma exudation was induced by substance P (SP), synthetic tachykinin receptor agonists, platelet activating factor (PAF), electrical stimulation of the cervical vagus nerves or by inhalation of cigarette smoke. Changes in airway tone and in carotid artery blood pressure (BP) were induced by synthetic tachykinin agonists, PAF and vagal stimulation. 2. Both FK224 and FK888 dose-dependently inhibited SP-induced plasma exudation in the lower trachea and main bronchi (ID50 values respectively of 1.1 and 0.1 mumol kg-1 in lower trachea, and of 0.5 and 0.1 mumol kg-1 in main bronchi) with complete inhibition at both airway levels at 10 mumol kg-1 for FK224 and at 2 mumol kg-1 for FK888. 3. The NK1-selective tachykinin receptor agonist, [Sar9,Met(O2)11]substance P ([Sar]SP), induced plasma exudation, a response which was blocked by both FK888 and FK224. The NK2-selective agonist, [beta-Ala8]neurokinin A-(4-10) ([beta-Ala]NKA), did not induce plasma exudation: neither FK888 nor FK224 affected this lack of response to [beta-Ala]NKA. 4. [beta-Ala]NKA induced bronchoconstriction, a response which was blocked by FK224 but which was completely unaffected by FK888. [Sar]SP induced a small but significant bronchoconstriction which was completely inhibited by both tachykinin antagonists. 5. In animals pretreated with capsaicin to deplete sensory neuropeptides, PAF induced both plasma exudation and bronchoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7682142

Antitussive and antibronchoconstriction actions of fenspiride in guinea-pigs.

PubMed

Laude, E A; Bee, D; Crambes, O; Howard, P

1995-10-01

Fenspiride is a nonsteroidal anti-inflammatory agent, which we have previously shown to have an in vivo antibronchoconstrictor action in guinea pigs. We have currently studied this action using the constrictors Substance P, neurokinin A, citric acid and capsaicin in anaesthetized guinea-pigs. Fenspiride has also been reported to produce a subjective improvement in cough in patients. We have used a conscious guinea-pig model of cough as a more definitive method to study the effect of fenspiride on capsaicin- and citric acid-induced cough. Aerosolized fenspiride (1 mg.mL-1) caused a 58% reversal of capsaicin-induced bronchoconstriction; and i.v. fenspiride (1mg.kg-1) a 45% reversal of citric acid induced bronchoconstriction. Substance P- and neurokinin A-induced bronchoconstriction were unaffected by 1 mg.kg-1 i.v. fenspiride. Aerosolized fenspiride (1, 3 and 10 mg.mL-1) administered for 4 min reduced citric acid (300 mM) induced cough, but 0.1 mg.mL-1 was without effect. Pretreatment with aerosolized fenspiride (10 mg.mL-1) caused a shift in the citric acid dose response curve to the right. For citric acid-induced cough, the duration of action of aerosolized fenspiride (10 mg.mL-1) was found to be 5 and 15 min post-treatment. Aerosolized capsaicin (30 microM) induced cough was also reduced by 3 and 10 mg.mL-1 aerosolized fenspiride, but no significant effect was found with 1 mg.mL-1. We conclude that aerosolized fenspiride reduces capsaicin- and citric acid-induced bronchoconstriction as well as induced cough in guinea-pigs in vivo. Whether a pathway common to both cough and bronchoconstriction is the site of action of fenspiride remains to be established. We postulate that fenspiride, acting as an antitussive and antibronchoconstrictor agent, would be beneficial in the clinical situation for those patients with hyperresponsive airways.

Bronchoprotection in conscious guinea pigs by budesonide and the NO-donating analogue, TPI 1020, alone and combined with tiotropium or formoterol

PubMed Central

Turner, DL; Ferrari, N; Ford, WR; Kidd, EJ; Nevin, B; Paquet, L; Renzi, P; Broadley, KJ

2012-01-01

BACKGROUND AND PURPOSE Inhaled corticosteroids, anticholinergics and β2-adrenoceptor agonists are frequently combined for treating chronic respiratory diseases. We examine the corticosteroid, budesonide, and novel NO-donating derivative, TPI 1020, against histamine- and methacholine-induced bronchoconstriction and whether they enhance the β2-adrenoceptor agonist formoterol or muscarinic antagonist tiotropium in conscious guinea pigs. EXPERIMENTAL APPROACH Dunkin-Hartley guinea pigs received inhaled histamine (3 mM) or methacholine (1.5 mM) and specific airway conductance (sGaw) was measured before and 15 or 75 min after treatment with budesonide, TPI 1020, tiotropium or formoterol alone or in combinations. KEY RESULTS Formoterol (0.7–10 µM) and budesonide (0.11–0.7 mM) inhibited histamine-induced bronchoconstriction and tiotropium (2–20 µM) inhibited methacholine-induced bronchoconstriction by up to 70.8 ± 16.6%, 34.9 ± 4.4% and 85.1 ± 14.3%, respectively. Formoterol (2.5 µM) or tiotropium (2 µM) alone exerted small non-significant bronchoprotection. However, when co-administered with TPI 1020 0.11 mM, which alone had no significant effect, there was significant inhibition of the bronchoconstriction (45.7 ± 12.2% and 79.7 ± 21.4%, respectively). Co-administering budesonide (0.11 mM) with tiotropium (2 µM), which alone had no effect, also significantly inhibited the methacholine bronchoconstriction (36.5 ± 13.0%), but there was no potentiation of formoterol against histamine. The NO scavenger, CPTIO, prevented the bronchoprotection by SNAPand TPI 1020. CONCLUSIONS AND IMPLICATIONS TPI 1020 potentiated the bronchoprotection by formoterol and tiotropium. Budesonide also enhanced the effects of tiotropium but not formoterol. Combination of TPI 1020 with a long-acting β2-adrenoceptor agonist or muscarinic receptor antagonist may therefore be a more potent therapeutic approach for treatment of chronic respiratory diseases. PMID:22563753

Exercise-induced bronchoconstriction and atopy in Tunisian athletes

PubMed Central

Sallaoui, Ridha; Chamari, Karim; Mossa, Abbas; Tabka, Zouhair; Chtara, Moktar; Feki, Youssef; Amri, Mohamed

2009-01-01

Background This study is a cross sectional analysis, aiming to evaluate if atopy is as a risk factor for exercise induced bronchoconstriction (EIB) among Tunisian athletes. Methods Atopy was defined by a skin prick test result and EIB was defined as a decrease of at least 15% in forced expiratory volume in one second (FEV1) after 8-min running at 80–85% HRmaxTheo. The study population was composed of 326 athletes (age: 20.8 ± 2.7 yrs – mean ± SD; 138 women and 188 men) of whom 107 were elite athletes. Results Atopy was found in 26.9% (88/326) of the athletes. Post exercise spirometry revealed the presence of EIB in 9.8% of the athletes including 13% of the elite athletes. Frequency of atopy in athletes with EIB was significantly higher than in athletes without EIB [62.5% vs 23.1%, respectively]. Conclusion This study showed that atopic Tunisian athletes presented a higher risk of developing exercise induced bronchoconstriction than non-atopic athletes. PMID:19196480

Tachykinin receptors and noncholinergic bronchoconstriction in the guinea-pig isolated bronchi.

PubMed

Maggi, C A; Patacchini, R; Rovero, P; Santicioli, P

1991-08-01

The aim of the study was to assess which type(s) of tachykinin receptor mediate the noncholinergic bronchoconstriction produced by activation (electrical field stimulation) of capsaicin-sensitive primary afferents in epithellum-denuded guinea-pig isolated bronchi. Experiments with natural and synthetic tachykinin agonists indicated the presence of both NK-1 and NK-2 receptors at this level. Experiments with the putative NK-1 (L668, 169) or NK-2 (MEN 10,207, MEN 10,376, L659,877, and R396) selective antagonists against NK-1 and NK-2 selective agonists further supported this conclusion. All the tachykinin antagonists tested reduced the noncholinergic bronchoconstriction to field stimulation with the order of potency MEN 10,207 = MEN 10,376 greater than L659,877 greater than L668,169 congruent to R396. In the presence of peptidase inhibitors, the activity of MEN 10,376 toward the noncholinergic bronchoconstriction was slightly reduced, whereas that of L668,169 was increased. These findings demonstrate that both NK-1 and NK-2 receptors mediate the noncholinergic constriction produced by endogenous tachykinins in guinea-pig bronchi and that the relative contribution of NK-2 receptors is greater than that of NK-1. These findings implicate a major role for neurokinin A rather than for substance P as an endogenous bronchoconstrictor in the guinea-pig isolated bronchi. In the presence of peptidase inhibitors, the relative contribution of NK-1 receptors is increased.

Cyclooxygenase-2-dependent bronchoconstriction in perfused rat lungs exposed to endotoxin.

PubMed

Uhlig, S; Nüsing, R; von Bethmann, A; Featherstone, R L; Klein, T; Brasch, F; Müller, K M; Ullrich, V; Wendel, A

1996-05-01

Lipopolysaccharides (LPS), widely used to study the mechanisms of gram-negative sepsis, increase airway resistance by constriction of terminal bronchioles. The role of the cyclooxygenase (COX) isoenzymes and their prostanoid metabolites in this process was studied. Pulmonary resistance, the release of thromboxane (TX) and the expression of COX-2 mRNA were measured in isolated blood-free perfused rat lungs exposed to LPS. LPS induced the release of TX and caused increased airway resistance after about 30 min. Both TX formation and LPS-induced bronchoconstriction were prevented by treatment with the unspecific COX inhibitor acetyl salicylic acid, the specific COX-2 inhibitor CGP-28238, dexamethasone, actinomycin D, or cycloheximide. LPS-induced bronchoconstriction was also inhibited by the TX receptor antagonist BM-13177. The TX-mimetic compound, U-46619, increased airway resistance predominantly by constricting terminal bronchioles. COX-2-specific mRNA in lung tissue was elevated after LPS exposure, and this increase was attenuated by addition of dexamethasone or of actinomycin D. In contrast to LPS, platelet-activating factor (PAF) induced immediate TX release and bronchoconstriction that was prevented by acetyl salicylic acid, but not by CGP-28238. LPS elicits the following biochemical and functional changes in rat lungs: (i) induction of COX-2; (ii) formation of prostaglandins and TX; (iii) activation of the TX receptor on airway smooth muscle cells; (iv) constriction of terminal bronchioles; and (v) increased airway resistance. In contrast to LPS, the PAF-induced TX release is likely to depend on COX-1.

Role of tachykinins in ozone-induced airway hyperresponsiveness to cigarette smoke in guinea pigs.

PubMed

Wu, Z X; Morton, R F; Lee, L Y

1997-09-01

Acute exposure to ozone (O3) induces airway hyperresponsiveness to various inhaled bronchoactive substances. Inhalation of cigarette smoke, a common inhaled irritant in humans, is known to evoke a transient bronchoconstrictive effect. To examine whether O3 increases airway responsiveness to cigarette smoke, effects of smoke inhalation challenge on total pulmonary resistance (RL) and dynamic lung compliance (Cdyn) were compared before and after exposure to O3 (1.5 ppm, 1 h) in anesthetized guinea pigs. Before O3 exposure, inhalation of two breaths of cigarette smoke (7 ml) at a low concentration (33%) induced a mild and reproducible bronchoconstriction that slowly developed and reached its peak (DeltaRL = 67 +/- 19%, DeltaCdyn = -29 +/- 6%) after a delay of >1 min. After exposure to O3 the same cigarette smoke inhalation challenge evoked an intense bronchoconstriction that occurred more rapidly, reaching its peak (DeltaRL = 620 +/- 224%, DeltaCdyn = -35 +/- 7%) within 20 s, and was sustained for >2 min. By contrast, sham exposure to room air did not alter the bronchomotor response to cigarette smoke challenge. Pretreatment with CP-99994 and SR-48968, the selective antagonists of neurokinin type 1 and 2 receptors, respectively, completely blocked the enhanced responses of RL and Cdyn to cigarette smoke challenge induced by O3. These results show that O3 exposure induces airway hyperresponsiveness to inhaled cigarette smoke and that the enhanced responses result primarily from the bronchoconstrictive effect of endogenous tachykinins.

Propofol preferentially relaxes neurokinin receptor-2-induced airway smooth muscle contraction in guinea pig trachea.

PubMed

Gleason, Neil R; Gallos, George; Zhang, Yi; Emala, Charles W

2010-06-01

Propofol is the anesthetic of choice for patients with reactive airway disease and is thought to reduce intubation- or irritant-induced bronchoconstriction by decreasing the cholinergic component of vagal nerve activation. However, additional neurotransmitters, including neurokinins, play a role in irritant-induced bronchoconstriction. We questioned the mechanistic assumption that the clinically recognized protective effect of propofol against irritant-induced bronchoconstriction during intubation was due to attenuation of airway cholinergic reflexes. Muscle force was continuously recorded from isolated guinea pig tracheal rings in organ baths. Rings were subjected to exogenous contractile agonists (acetylcholine, histamine, endothelin-1, substance P, acetyl-substance P, and neurokinin A) or to electrical field stimulation (EFS) to differentiate cholinergic or nonadrenergic, noncholinergic nerve-mediated contraction with or without cumulatively increasing concentrations of propofol, thiopental, etomidate, or ketamine. Propofol did not attenuate the cholinergic component of EFS-induced contraction at clinically relevant concentrations. In contrast, propofol relaxed nonadrenergic, noncholinergic-mediated EFS contraction at concentrations within the clinical range (20-100 mum, n = 9; P < 0.05), and propofol was more potent against an exogenous selective neurokinin-2 receptor versus neurokinin-1 receptor agonist contraction (n = 6, P < 0.001). Propofol, at clinically relevant concentrations, relaxes airway smooth muscle contracted by nonadrenergic, noncholinergic-mediated EFS and exogenous neurokinins but not contractions elicited by the cholinergic component of EFS. These findings suggest that the mechanism of protective effects of propofol against irritant-induced bronchoconstriction involves attenuation of tachykinins released from nonadrenergic, noncholinergic nerves acting at neurokinin-2 receptors on airway smooth muscle.

Effect of active sensitization on the bronchopulmonary responses to tachykinins in the guinea pig. Modulation by peptidase inhibitors.

PubMed

Capaz, F R; Ruffié, C; Lefort, J; Manzini, S; Vargaftig, B B; Pretolani, M

1993-08-01

The i.v. administration of substance P (SP, 0.25-16 micrograms/kg) or of the selective metabolic stable NK-1 agonist, [Glp6,Pro9]SP-(6-11) (septide, 0.03-0.25 microgram) to atropine-treated guinea pigs or to isolated perfused lungs triggered a dose-dependent bronchoconstriction, which was enhanced in animals actively sensitized to ovalbumin. In vivo, bronchial hyper-responsiveness was restricted to SP and to septide, inasmuch as neurokinin A (0.06-1 microgram/kg)- or capsaicin (0.5-32 micrograms/kg)-induced bronchoconstriction were not modified. In contrast, isolated lungs from sensitized guinea pigs exhibited an increased bronchoconstriction also in response to capsaicin (0.01-10 micrograms), which was inhibited by atropine in the medium. Pretreatment of actively sensitized guinea pigs either with indomethacin plus mepyramine, the lipoxygenase inhibitor BW A4C or with the platelet-activating factor antagonist SR 27417, did not modify bronchial hyper-reactivity to SP. Captopril (5 mg/kg i.v.), but not thiorphan (0.8 mg/kg i.v.), increased the SP-induced bronchoconstriction in actively sensitized animals, whereas both inhibitors were equally effective in nonsensitized guinea pigs. Thiorphan, however, did not modify the in vivo response to septide. Our results demonstrate that guinea pigs sensitized to ovalbumin exhibit bronchial hyperreactivity to SP, but not to neurokinin A, as compared to nonsensitized animals, suggesting a decrease in the neutral endopeptidase activity in the airways brought by the immunization. However, the results obtained by using septide indicate that other mechanisms may be involved in the bronchial hyper-reactivity to SP.

Mechanisms of exercise-induced bronchoconstriction in athletes: Current perspectives and future challenges.

PubMed

Couto, M; Kurowski, M; Moreira, A; Bullens, D M A; Carlsen, K-H; Delgado, L; Kowalski, M L; Seys, S F

2018-01-01

The evidence of exercise-induced bronchoconstriction (EIB) without asthma (EIBw A ) occurring in athletes led to speculate about different endotypes inducing respiratory symptoms within athletes. Classical postulated mechanisms for bronchial obstruction in this population include the osmotic and the thermal hypotheses. More recently, the presence of epithelial injury and inflammation in the airways of athletes was demonstrated. In addition, neuronal activation has been suggested as a potential modulator of bronchoconstriction. Investigation of these emerging mechanisms is of major importance as EIB is a significant problem for both recreational and competitive athletes and is the most common chronic condition among Olympic athletes, with obvious implications for their competing performance, health and quality of life. Hereby, we summarize the latest achievements in this area and identify the current gaps of knowledge so that future research heads toward better defining the etiologic factors and mechanisms involved in development of EIB in elite athletes as well as essential aspects to ultimately propose preventive and therapeutic measures. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

Vegetable dust and airway disease: inflammatory mechanisms.

PubMed Central

Cooper, J A; Buck, M G; Gee, J B

1986-01-01

Exposure to cotton or grain dust causes an obstructive bronchitis in certain subjects, mechanisms of which are poorly understood. A difficulty encountered in discerning mechanisms of this airway disease is the lack of knowledge of the active components of these dusts. Clinical features suggest common but not exact mechanisms of the airway disease associated with these vegetable dusts. Human and animal studies show evidence of acellular and cellular inflammatory mechanisms of the bronchoconstriction and inflammation associated with these disorders. Potential cellular sources include alveolar macrophages, polymorphonuclear leukocytes, mast cells, basophils, eosinophils and lymphocytes. Acellular origins include the complement and humoral antibody systems, both of which have been implicated, although their pathogenic role in grain or cotton dust disorders is uncertain. In this review we critically address potential inflammatory mechanisms of airway alterations resulting from cotton or grain dust exposure. General mechanisms of bronchoconstriction are first presented, then specific studies dealing with either of the two dusts are discussed. We believe this area of research may be fruitful in dissecting mechanisms of bronchoconstriction and airway inflammation, especially as more human studies are undertaken. PMID:3519205

Update on montelukast and its role in the treatment of asthma, allergic rhinitis and exercise-induced bronchoconstriction.

PubMed

Storms, William

2007-09-01

Montelukast sodium (Singulair, Merck and Co., Inc., Whitehouse Station, NJ) is a selective and orally-active leukotriene receptor antagonist with demonstrated effectiveness for treating allergic asthma and allergic rhinitis in adults and children as young as 12 months of age for allergic asthma and 6 months of age for allergic rhinitis. It was recently approved in the US for prevention of exercise-induced bronchoconstriction in patients who are > or = 15 years of age. This paper updates a prior review of the data on the clinical efficacy of montelukast published in this journal.

Protective Role of Eosinophils and TNFa after Ozone Inhalation.

PubMed

Fryer, Allison D; Jacoby, David B; Wicher, Sarah A

2017-03-01

Exposure to ozone induces deleterious responses in the airways that include shortness of breath, inflammation, and bronchoconstriction. People with asthma have increased airway sensitivity to ozone and other irritants. Dr. Allison Fryer and colleagues addressed how exposure to ozone affects the immune and physiological responses in guinea pigs. Guinea pigs are considered a useful animal model for studies of respiratory and physiological responses in humans; their response to airborne allergens is similar to that in humans and shares some features of allergic asthma. Fryer and colleagues had previously observed that within 24 hours of exposure, ozone not only induced bronchoconstriction but also stimulated the production of new cells in the bone marrow, where all white blood cells develop. As a result of ozone exposure, increased numbers of newly synthesized white blood cells, particularly eosinophils, moved into the blood and lungs. The central hypothesis of the current study was that newly synthesized eosinophils recruited to the lungs 3 days after ozone exposure were beneficial to the animals because they reduced ozoneinduced bronchoconstriction. The investigators also hypothesized that the beneficial effect seen in normal (nonsensitized) animals was lost in animals that had been injected with an allergen, ovalbumin (sensitized). They also planned to explore the effects of inhibitors of certain cytokines (cellsignaling molecules). Immune responses in sensitized animals are dominated by a Th2 pattern, which is characterized by the synthesis of cytokines (interleukin [IL]-4, IL-5, and IL-13) and the Th2 subset of CD4+ T lymphocytes and the cells they activate (predominantly eosinophils, and B lymphocytes that switch to making immunoglobulin E [IgE]). Thus, sensitized animals were used as a model of allergic humans, whose immune responses tend to be dominated by IgE. Fryer and colleagues exposed normal and sensitized (allergic) guinea pigs to 2 ppm ozone or filtered air for 4 hours and measured changes in cell numbers and airway responses 1 or 3 days later. They counted the numbers of eosinophils and other white blood cells (macrophages, neutrophils, and lymphocytes) in bone marrow, blood, and bronchoalveolar lung lavage fluid. The investigators also measured important physiological responses, including bronchoconstriction. Some animals were pretreated with etanercept and monoclonal anti-IL-5, which block tumor necrosis factor-a (TNFa) and IL-5, respectively. TNFa and IL-5 blockers have been used to treat patients with asthma. A key feature of the study was a technique to distinguish which white blood cells were synthesized after exposure from those that already existed, by injecting animals with bromodeoxyuridine (BrdU). BrdU is a thymidine analogue that is incorporated into the DNA of dividing cells, serving as a marker of newly produced cells. Therefore, a snapshot can be obtained of the proportion of newly synthesized (BrdU-positive) versus pre-existing (BrdU-negative) cell types. 1. Allergic and normal animals differed in the time course of bronchoconstriction and changes in cell types after ozone exposure. In normal animals, bronchoconstriction increased substantially at day 1 but decreased by day 3 after ozone exposure. In contrast, in allergic animals bronchoconstriction remained high at day 3. Ozone also increased the percentage of newly formed, BrdU2 positive eosinophils in the bone marrow and lungs of normal but not allergic animals. 2. Pretreatment with the TNFa blocker etanercept had complex effects, which differed between normal and allergic animals. In normal animals, etanercept decreased ozone-induced new synthesis of eosinophils in the bone marrow and blocked eosinophil migration to the lung; it also increased bronchoconstriction at day 3 (relative to day 1 without etanercept). In allergic animals, etanercept had no effect on any cell type in the bone marrow or lung after exposure to ozone and did not change bronchoconstriction compared with allergic animals not treated with etanercept. Etanercept tended to increase the numbers of blood monocytes and lymphocytes in air- and ozone-exposed normal and allergic animals at day 3, but had no effect on eosinophils in blood at this time point. This was one of the few statistically significant findings in the blood of exposed animals in the study. 3. Anti-IL-5 reduced bronchoconstriction at day 3 after exposure of allergic animals to ozone. In contrast, bronchoconstriction was greatly increased in normal animals treated with anti-IL-5. Fryer and colleagues explored the airway and cellular responses in guinea pigs exposed to ozone. The HEI Review Committee, which conducted an independent review of the study, agreed that the findings supported the authors’ hypothesis (1) that exposure to ozone stimulates production of eosinophils in bone marrow, (2) that these newly formed eosinophils migrate to the lungs, and (3) that those eosinophils play a delayed but potentially beneficial role in reducing ozone-induced inflammation in the airways of healthy normal animals, but not in allergen-sensitized animals. The Committee also agreed that guinea pigs were a good model for studying responses to an allergen, because a major subtype of asthma (the high Th2 or allergic type) is associated with high levels of eosinophils in the blood. A novel finding was that the TNFa blocker etanercept decreased ozone-induced formation of eosinophils in the bone marrow and blocked eosinophil migration to the lung in normal animals. However, because injecting etanercept had little effect on eosinophils and did not decrease bronchoconstriction in allergic guinea pigs, the potential for treating patients with allergic asthma with TNFa blockers is uncertain. This is consistent with the poor performance of TNFa blockers in clinical studies of asthma treatment. Blocking the cytokine IL-5 with an anti-IL-5 antibody substantially decreased bronchoconstriction in sensitized animals. This suggests that therapies targeting IL-5 and eosinophils would be promising in at least some types of asthma. The Committee expressed caution toward experiments with cytokine blockers, both in animal models and humans, because such blockers are often not specific to a particular cell type and may differ at different sites in the body. Without further detailed confirmation of the effects of the blockers, interpreting these experiments can be challenging. The Committee concluded that the study by Fryer and colleagues raises several intriguing directions for future research, including exploring ways in which newly formed eosinophils differ from pre-existing ones, and how such findings apply to humans with allergy or asthma.

Anti-inflammatory and bronchodilatory constituents of leaf extracts of Anacardium occidentale L. in animal models.

PubMed

Awakan, Oluwakemi Josephine; Malomo, Sylvia Omonirume; Adejare, Abdullahi Adeyinka; Igunnu, Adedoyin; Atolani, Olubunmi; Adebayo, Abiodun Humphrey; Owoyele, Bamidele Victor

2018-01-01

Anacardium occidentale L. leaf is useful in the treatment of inflammation and asthma, but the bioactive constituents responsible for these activities have not been characterized. Therefore, this study was aimed at identifying the bioactive constituent(s) of A. occidentale ethanolic leaf extract (AOEL) and its solvent-soluble portions, and evaluating their effects on histamine-induced paw edema and bronchoconstriction. The bronchodilatory effect was determined by measuring the percentage protection provided by plant extracts in the histamine-induced bronchoconstriction model in guinea pigs. The anti-inflammatory effect of the extracts on histamine-induced paw edema in rats was determined by measuring the increase in paw diameter, after which the percent edema inhibition was calculated. The extracts were analyzed using gas chromatography-mass spectrometry to identify the bioactive constituents. Column chromatography and Fourier transform infrared spectroscopy were used respectively to isolate and characterize the constituents. The bronchodilatory and anti-inflammatory activities of the isolated bioactive constituent were evaluated. Histamine induced bronchoconstriction in the guinea pigs and edema in the rat paw. AOEL, hexane-soluble portion of AOEL, ethyl acetate-soluble portion of AOEL, and chloroform-soluble portion of AOEL significantly increased bronchodilatory and anti-inflammatory activities (P < 0.05). Oleamide (9-octadecenamide) was identified as the most abundant compound in the extracts and was isolated. Oleamide significantly increased bronchodilatory and anti-inflammatory activities by 32.97% and 98.41%, respectively (P < 0.05). These results indicate that oleamide is one of the bioactive constituents responsible for the bronchodilatory and anti-inflammatory activity of A. occidentale leaf, and can therefore be employed in the management of bronchoconstriction and inflammation. Copyright © 2017 Shanghai Changhai Hospital. Published by Elsevier B.V. All rights reserved.

Cross refractoriness between sodium metabisulphite and exercise induced asthma.

PubMed Central

Pavord, I.; Lazarowicz, H.; Inchley, D.; Baldwin, D.; Knox, A.; Tattersfield, A.

1994-01-01

BACKGROUND--Exercise and inhaled sodium metabisulphite are thought to cause bronchoconstriction in asthma through different mechanisms. The response to both stimuli becomes refractory with repeat challenge. The mechanism of refractoriness is unclear, although depletion of mast cell derived mediators or neurotransmitters has been suggested. Recent studies suggest a common mechanism involving release of inhibitory prostaglandins. If this is true, exercise and sodium metabisulphite induced bronchoconstriction should show cross refractoriness. METHODS--Thirteen subjects with mild asthma and previously established exercise and sodium metabisulphite induced bronchoconstriction performed two sodium metabisulphite challenges (giving a single dose previously shown to cause a 20% fall in FEV1) on one study day, and two exercise tests on another. The second challenge proceeded after recovery (FEV1 > 95% baseline) from the first. Subjects then attended on two further occasions when an exercise test was performed after sodium metabisulphite and a sodium metabisulphite challenge after exercise. RESULTS--When expressed as the percentage reduction in the area under the change in percentage FEV1 curve over 20 minutes (AUC) the response to exercise was reduced by a mean 62.3% (95% CI 46.5% to 78.1%) following a first exercise challenge, and by 50.7% (95% CI 27.8% to 73.6%) following a sodium metabisulphite challenge. The response to a sodium metabisulphite challenge was reduced by a mean of 80.2% (95% CI 68.9% to 91.5%) when it followed a sodium metabisulphite challenge, and by 37.3% (95% CI 15.1% to 59.5%) following an exercise challenge. CONCLUSION--This study shows some cross refractoriness between exercise and sodium metabisulphite induced bronchoconstriction, in keeping with a partially shared mechanism of refractoriness. PMID:8202881

Inhibition of neutral endopeptidase potentiates bronchoconstriction induced by neurokinin A in asthmatic patients.

PubMed

Crimi, N; Palermo, F; Oliveri, R; Polosa, R; Magrì, S; Mistretta, A

1994-02-01

The endogenous tachykinins exhibit a range of properties which may be relevant in the pathophysiology of asthma. Their effects on the airways seem to be modulated by a variety of lung peptidases, including neutral endopeptidase (NEP). In order to evaluate the potential role of endogenous NEP activity in modulating tachykinins-induced bronchoconstriction in man in vivo, six atopic asthmatic patients, with a mean FEV1 value of 3.38 +/- 0.76 l, and a histamine PD20 mean value of 0.024 mg, were studied. The influence of inhaled phosphoramidon (a potent NEP inhibitor) was examined against the NKA-induced bronchospasm in a double-blind, placebo-controlled randomized study. Changes in airway calibre were followed as FEV1 and agonists responsiveness expressed as PD20 and PD15 for histamine and NKA respectively. Patients received nebulized phosphoramidon sodium salt (10(-5) M) or a control solution 10 min prior to the bronchoprovocation test with NKA. No significant difference was noticed between any of the study days and after inhaled phosphoramidon on baseline FEV1 values (3.29 +/- 0.90 l) in comparison with the control solution (3.31 +/- 0.79 l). Inhaled NKA produced a dose-dependent fall in FEV1 values in all the subjects studied with a mean PD15 value of 20.91 x 10(-9) mol. Phosphoramidon administered by inhalation elicited a significant (P < 0.01 vs baseline and control solution) potentiation in the airway responsiveness to inhaled NKA, the NKA PD15 value decreasing to 9.45 x 10(-9) mol. The present study confirms that inhaled NKA induces a dose-related bronchoconstriction in asthmatic patients and demonstrates that inhaled phosphoramidon potentiates NKA-induced bronchoconstriction.

Mechanisms of leukotriene D4-induced constriction in human small bronchioles

PubMed Central

Snetkov, V A; Hapgood, K J; McVicker, C G; Lee, T H; Ward, J P T

2001-01-01

We examined the mechanisms underlying leukotriene D4- (LTD4) induced constriction of human small (300 – 500 μm i.d.) bronchioles, and the effect of LTD4 on ion currents and Ca2+ transients in smooth muscle cells (SMC) isolated from these bronchioles. LTD4 caused a concentration-dependent bronchoconstriction with an EC50=0.58±0.05 nM (n=7) which was not easily reversible upon washout. This bronchoconstriction was entirely dependent on extracellular Ca2+. Blockade of L-type Ca2+ channels with nifedipine (10 μM) reduced LTD4 response by 39±2% (n=8), whilst La3+, Gd3+ and SK&F 96,365 abolished LTD4-induced bronchoconstriction completely and reversibly, suggesting the majority of Ca2+ entry was via non-selective cation channels. Antagonists of PI-PLC (U73,122 and ET-18-OCH3), PLD (propranolol) and PKC (cheleretrine and Ro31-8220) were without any effect on LTD4-induced bronchoconstriction, whilst the PC-PLC inhibitor D609 caused complete relaxation. Inhibition of protein tyrosine kinase with tyrphostin A23 (100 μM) caused about 50% relaxation, although the inactive analogue tyrphostin A1 was without effect. In freshly isolated SMC from human small bronchioles LTD4 caused a slow increase of intracellular Ca2+ concentration, with a consequent rise of the activity of large conductance Ca2+-dependent K+ channels and the amplitude of depolarization-induced outward whole-cell current. Again, no effect of LTD4 could be observed in the absence of extracellular Ca2+. We conclude that LTD4 causes constriction of these small bronchioles primarily by activating Ca2+ entry via non-voltage gated channels, possibly by a PC-PLC mediated pathway. PMID:11350860

Cutting edge: guinea pigs with a natural C3a-receptor defect exhibit decreased bronchoconstriction in allergic airway disease: evidence for an involvement of the C3a anaphylatoxin in the pathogenesis of asthma.

PubMed

Bautsch, W; Hoymann, H G; Zhang, Q; Meier-Wiedenbach, I; Raschke, U; Ames, R S; Sohns, B; Flemme, N; Meyer zu Vilsendorf, A; Grove, M; Klos, A; Köhl, J

2000-11-15

Asthma is a major cause of morbidity worldwide with prevalence and severity still increasing at an alarming pace. Hallmarks of this disease include early-phase bronchoconstriction with subsequent eosinophil infiltration, symptoms that may be mimicked in vivo by the complement-derived C3a anaphylatoxin, following its interaction with the single-copy C3aR. We analyzed the pathophysiological role of the C3a anaphylatoxin in a model of experimental OVA-induced allergic asthma, using an inbred guinea pig strain phenotypically unresponsive to C3a. Molecular analysis of this defect revealed a point mutation within the coding region of the C3aR that creates a stop codon, thereby effectively inactivating gene function. When challenged by OVA inhalation, sensitized animals of this strain exhibited a bronchoconstriction decreased by approximately 30% in comparison to the corresponding wild-type strain. These data suggest an important role of C3a in the pathogenesis of asthma and define a novel target for drug intervention strategies.

Phosphoramidon potentiates the bronchoconstriction induced by inhaled bombesin in guinea pigs.

PubMed

Lagente, V; Boichot, E; Mencia-Huerta, J M; Braquet, P

1993-01-01

The effect of the neutral endopeptidase inhibitor, phosphoramidon, on the bronchoconstriction induced by aerosolized bombesin in the guinea pig was investigated. Administered by aerosol for 1 min, bombesin (0.01 or 0.1 mg/ml) induced a dose-dependent increase in pulmonary inflation pressure. Pretreatment of the guinea-pigs with phosphoramidon (0.1 mM), administered by aerosol for 15 min, 15 min prior to challenge, markedly potentiated the increase in pulmonary inflation pressure induced by bombesin (0.01 mg/ml) and substance P (0.1 mg/ml). This result suggests a local hydrolysis of bombesin by airway neutral endopeptidase reducing the activity of this peptide on smooth muscle.

Leukotriene B4 receptor type 2 protects against pneumolysin-dependent acute lung injury.

PubMed

Shigematsu, Misako; Koga, Tomoaki; Ishimori, Ayako; Saeki, Kazuko; Ishii, Yumiko; Taketomi, Yoshitaka; Ohba, Mai; Jo-Watanabe, Airi; Okuno, Toshiaki; Harada, Norihiro; Harayama, Takeshi; Shindou, Hideo; Li, Jian-Dong; Murakami, Makoto; Hoka, Sumio; Yokomizo, Takehiko

2016-10-05

Although pneumococcal infection is a serious problem worldwide and has a high mortality rate, the molecular mechanisms underlying the lethality caused by pneumococcus remain elusive. Here, we show that BLT2, a G protein-coupled receptor for leukotriene B 4 and 12(S)-hydroxyheptadecatrienoic acid (12-HHT), protects mice from lung injury caused by a pneumococcal toxin, pneumolysin (PLY). Intratracheal injection of PLY caused lethal acute lung injury (ALI) in BLT2-deficient mice, with evident vascular leakage and bronchoconstriction. Large amounts of cysteinyl leukotrienes (cysLTs), classically known as a slow reactive substance of anaphylaxis, were detected in PLY-treated lungs. PLY-dependent vascular leakage, bronchoconstriction, and death were markedly ameliorated by treatment with a CysLT1 receptor antagonist. Upon stimulation by PLY, mast cells produced cysLTs that activated CysLT1 expressed in vascular endothelial cells and bronchial smooth muscle cells, leading to lethal vascular leakage and bronchoconstriction. Treatment of mice with aspirin or loxoprofen inhibited the production of 12-HHT and increased the sensitivity toward PLY, which was also ameliorated by the CysLT1 antagonist. Thus, the present study identifies the molecular mechanism underlying PLY-dependent ALI and suggests the possible use of CysLT1 antagonists as a therapeutic tool to protect against ALI caused by pneumococcal infection.

Leukotriene B4 receptor type 2 protects against pneumolysin-dependent acute lung injury

PubMed Central

Shigematsu, Misako; Koga, Tomoaki; Ishimori, Ayako; Saeki, Kazuko; Ishii, Yumiko; Taketomi, Yoshitaka; Ohba, Mai; Jo-Watanabe, Airi; Okuno, Toshiaki; Harada, Norihiro; Harayama, Takeshi; Shindou, Hideo; Li, Jian-Dong; Murakami, Makoto; Hoka, Sumio; Yokomizo, Takehiko

2016-01-01

Although pneumococcal infection is a serious problem worldwide and has a high mortality rate, the molecular mechanisms underlying the lethality caused by pneumococcus remain elusive. Here, we show that BLT2, a G protein-coupled receptor for leukotriene B4 and 12(S)-hydroxyheptadecatrienoic acid (12-HHT), protects mice from lung injury caused by a pneumococcal toxin, pneumolysin (PLY). Intratracheal injection of PLY caused lethal acute lung injury (ALI) in BLT2-deficient mice, with evident vascular leakage and bronchoconstriction. Large amounts of cysteinyl leukotrienes (cysLTs), classically known as a slow reactive substance of anaphylaxis, were detected in PLY-treated lungs. PLY-dependent vascular leakage, bronchoconstriction, and death were markedly ameliorated by treatment with a CysLT1 receptor antagonist. Upon stimulation by PLY, mast cells produced cysLTs that activated CysLT1 expressed in vascular endothelial cells and bronchial smooth muscle cells, leading to lethal vascular leakage and bronchoconstriction. Treatment of mice with aspirin or loxoprofen inhibited the production of 12-HHT and increased the sensitivity toward PLY, which was also ameliorated by the CysLT1 antagonist. Thus, the present study identifies the molecular mechanism underlying PLY-dependent ALI and suggests the possible use of CysLT1 antagonists as a therapeutic tool to protect against ALI caused by pneumococcal infection. PMID:27703200

Administration of SIN-1 induces guinea pig airway hyperresponsiveness through inactivation of airway neutral endopeptidase.

PubMed

Kanazawa, H; Hirata, K; Yoshikawa, J

1999-12-01

Peroxynitrite plays an important role in the pathogenesis of airway inflammation. We have already found that peroxynitrite may contribute to decreased beta(2)-adrenoceptor responses in airway smooth muscle. However, it is not known whether peroxynitrite can alter neutral endopeptidase (EC 3.4.24.11; NEP) activity in the airways. This study was designed to determine whether peroxynitrite induces airway hyperresponsiveness to substance P (SP) and endothelin-1 (ET-1) through the inactivation of airway NEP. We examined whether the administration of S-morpholinosydnonimine (SIN-1), a compound that releases peroxynitrite, increased bronchoconstrictor responses to SP and ET-1 in anesthetized guinea pigs. In addition, we assayed NEP activity in the airways of SIN-1-exposed guinea pigs. Though SIN-1 (10(-7) M) alone had no effect on pulmonary resistance, pretreatment with SIN-1 significantly enhanced SP- and ET-1-induced bronchoconstriction. Pretreatment with phosphoramidon, an NEP inhibitor, also enhanced SP- and ET-1-induced bronchoconstriction. However, simultaneous administration of phosphoramidon and SIN-1 had no additive effect on SP- and ET-1-induced bronchoconstriction. Peroxynitrite formation by SIN-1 was completely inhibited by N-acetylcysteine (NAC) and glutathione (GSH) in vitro, and pretreatment with NAC and GSH significantly reversed the potentiation by SIN-1 of SP-induced bronchoconstriction. In addition, the NEP activity of the trachea after SIN-1 exposure was significantly reduced compared to the level in control guinea pigs (solvent for SIN-1: 30.0+/-4.2 fmol.min(-1).mg tissue(-1); 10(-7) M SIN-1; 15.5+/-4.5 fmol.min(-1).mg tissue(-1), p<0.05). These findings suggest that peroxynitrite induces airway hyperresponsiveness to SP and ET-1 through the inactivation of airway NEP, and that peroxynitrite is an important mediator of the alterations in airway functions.

Toll-like receptor 7 agonists are potent and rapid bronchodilators in guinea pigs

PubMed Central

Kaufman, Elad H.; Fryer, Allison D.; Jacoby, David B.

2011-01-01

Background Respiratory tract viral infections result in asthma exacerbations. Toll-like receptor (TLR) 7 is a receptor for viral single-stranded RNA and is expressed at high levels in the lungs. Objective Because TLR7 polymorphisms are associated with asthma, we examined the effects of TLR7 agonists in guinea pig airways. Methods We induced bronchoconstriction in guinea pigs in vivo by means of electrical stimulation of the vagus nerve or intravenous administration of acetylcholine and measured the effect of a TLR7 agonist administered intravenously. We induced contraction of airway smooth muscle in segments of isolated guinea pig tracheas in vitro and measured the effect of TLR7 agonists, antagonists, and pharmacologic inhibitors of associated signaling pathways administered directly to the bath. Results TLR7 agonists acutely inhibited bronchoconstriction in vivo and relaxed contraction of airway smooth muscle in vitro within minutes of administration. Airway relaxation induced by the TLR7 agonist R837 (imiquimod) was partially blocked with a TLR7 antagonist and was also blocked by inhibitors of large-conductance, calcium-activated potassium channels; prostaglandin synthesis; and nitric oxide generation. Another TLR7 agonist, 21-mer single-stranded phosphorothioated polyuridylic acid (PolyUs), mediated relaxation that was completely blocked by a TLR7 antagonist. Conclusions These data demonstrate a novel protective mechanism to limit bronchoconstriction and maintain airflow during respiratory tract viral infections. The fast time frame is inconsistent with canonical TLR7 signaling. R837 mediates bronchodilation by means of TLR7-dependent and TLR7-independent mechanisms, whereas PolyUs does so through only the TLR7-dependent mechanism. TLR7-independent mechanisms involve prostaglandins and large-conductance, calcium-activated potassium channels, whereas TLR7-dependent mechanisms involve nitric oxide. TLR7 is an attractive therapeutic target for its ability to reverse bronchoconstriction within minutes. PMID:21167577

Benzalkonium Chloride: A Bronchoconstricting Preservative in Continuous Albuterol Nebulizer Solutions.

PubMed

Prabhakaran, Sreekala; Abu-Hasan, Mutasim; Hendeles, Leslie

2017-05-01

For convenience, many pediatric hospitals are preparing solutions for continuous nebulized albuterol using the 0.5% 20-ml multidose albuterol dropper bottle. This product contains benzalkonium chloride (BAC) that, by itself, produces bronchospasm that is dose dependent and cumulative. The bronchoconstrictive effects of BAC are greater in patients with more severe airway obstruction and increased airway responsiveness. Use of BAC-containing albuterol during severe acute asthma exacerbations may antagonize the bronchodilator response to albuterol, prolong treatment, and increase the risk of albuterol-related systemic adverse effects. Such a deleterious effect of BAC is difficult to detect because some patients improve slowly or may even worsen during treatment. We recommend that only preservative-free albuterol products be used. © 2017 Pharmacotherapy Publications, Inc.

Anaesthetic management in asthma.

PubMed

Burburan, S M; Xisto, D G; Rocco, P R M

2007-06-01

Anaesthetic management in asthmatic patients has been focused on avoiding bronchoconstriction and inducing bronchodilation. However, the definition of asthma has changed over the past decade. Asthma has been defined as a clinical syndrome characterized by an inflammatory process that extends beyond the central airways to the distal airways and lung parenchyma. With this concept in mind, and knowing that asthma is a common disorder with increasing prevalence rates and severity worldwide, a rational choice of anaesthetic agents and procedures is mandatory. Thus, we pursued an update on the pharmacologic and technical anaesthetic approach for the asthmatic patient. When feasible, regional anaesthesia should be preferred because it reduces airway irritation and postoperative complications. If general anaesthesia is unavoidable, a laryngeal mask airway is safer than endotracheal intubation. Lidocaine inhalation, alone or combined with albuterol, minimizes histamine-induced bronchoconstriction. Propofol and ketamine inhibit bronchoconstriction, decreasing the risk of bronchospasm during anaesthesia induction. Propofol yields central airway dilation and is more reliable than etomidate or thiopental. Halothane, enflurane, and isoflurane are potent bronchodilators and can be helpful even in status asthmaticus. Sevoflurane has shown controversial results in asthmatic patients. Vecuronium, rocuronium, cisatracurium, and pancuronium do not induce bronchospasm, while atracurium and mivacurium can dose-dependently release histamine and should be cautiously administered in those patients. Further knowledge about the sites of action of anaesthetic agents in the lung, allied with our understanding of asthma pathophysiology, will establish the best anaesthetic approach for people with asthma.

Exercise and Asthma

MedlinePlus

... Treatments ▸ Library ▸ Asthma Library ▸ Exercise and Asthma Share | Exercise and Asthma This article has been reviewed by Thanai Pongdee, MD, FAAAAI Exercise-induced bronchoconstriction (EIB) , also called exercise-induced asthma, ...

Effects of methacholine infusion on desflurane pharmacokinetics in piglets☆

PubMed Central

Kozian, Alf; Kretzschmar, Moritz; Baumgardner, James E.; Schreiber, Jens; Hedenstierna, Göran; Larsson, Anders; Hachenberg, Thomas; Schilling, Thomas

2015-01-01

The data of a corresponding animal experiment demonstrates that nebulized methacholine (MCh) induced severe bronchoconstriction and significant inhomogeneous ventilation and pulmonary perfusion (V̇A/Q̇) distribution in pigs, which is similar to findings in human asthma. The inhalation of MCh induced bronchoconstriction and delayed both uptake and elimination of desflurane (Kretzschmar et al., 2015) [1]. The objective of the present data is to determine V̇A/Q̇ matching by Multiple Inert Gas Elimination Technique (MIGET) in piglets before and during methacholine- (MCh-) induced bronchoconstriction, induced by MCh infusion, and to assess the blood concentration profiles for desflurane (DES) by Micropore Membrane Inlet Mass Spectrometry (MMIMS). Healthy piglets (n=4) under general anesthesia were instrumented with arterial, central venous, and pulmonary artery lines. The airway was secured via median tracheostomy with an endotracheal tube, and animals were mechanically ventilated with intermittent positive pressure ventilation (IPPV) with a FiO2 of 0.4, tidal volume (VT)=10 ml/kg and PEEP of 5cmH2O using an open system. The determination of V.A/Q. was done by MIGET: before desflurane application and at plateau in both healthy state and during MCh infusion. Arterial blood was sampled at 0, 1, 2, 5, 10, 20, and 30 min during wash-in and washout, respectively. Bronchoconstriction was established by MCH infusion aiming at doubling the peak airway pressure, after which wash-in and washout of the anesthetic gas was repeated. Anesthesia gas concentrations were measured by MMIMS. Data were analyzed by ANOVA, paired t-test, and by nonparametric Friedman׳s test and Wilcoxon׳s matched pairs test. We measured airway pressures, pulmonary resistance, and mean paO2 as well as hemodynamic variables in all pigs before desflurane application and at plateau in both healthy state and during methacholine administration by infusion. By MIGET, fractional alveolar ventilation and pulmonary perfusion in relation to the V.A/Q. compartments, data of logSDQ̇ and logSDV̇ (the second moments describing global dispersion, i.e. heterogeneity of distribution) were estimated prior to and after MCh infusion. The uptake and elimination of desflurane was determined by MMIMS. PMID:26702425

Guinea pig models of asthma.

PubMed

McGovern, Alice E; Mazzone, Stuart B

2014-12-01

Described in this unit are methods for establishing guinea pig models of asthma. Sufficient detail is provided to enable investigators to study bronchoconstriction, cough, airway hyperresponsiveness, inflammation, and remodeling. Copyright © 2014 John Wiley & Sons, Inc.

Exercise-Induced Bronchoconstriction Quiz

MedlinePlus

... the AAAAI Foundation Donate Utility navigation Español Journals Pollen Counts Annual Meeting Member Login / My Membership Search ... have a viral infection, temperatures are low, or pollen and air pollution levels are high. Learn more ...

An RGS4-mediated phenotypic switch of bronchial smooth muscle cells promotes fixed airway obstruction in asthma.

PubMed

Damera, Gautam; Druey, Kirk M; Cooper, Philip R; Krymskaya, Vera P; Soberman, Roy J; Amrani, Yassine; Hoshi, Toshinori; Brightling, Christopher E; Panettieri, Reynold A

2012-01-01

In severe asthma, bronchodilator- and steroid-insensitive airflow obstruction develops through unknown mechanisms characterized by increased lung airway smooth muscle (ASM) mass and stiffness. We explored the role of a Regulator of G-protein Signaling protein (RGS4) in the ASM hyperplasia and reduced contractile capacity characteristic of advanced asthma. Using immunocytochemical staining, ASM expression of RGS4 was determined in endobronchial biopsies from healthy subjects and those from subjects with mild, moderate and severe asthma. Cell proliferation assays, agonist-induced calcium mobilization and bronchoconstriction were determined in cultured human ASM cells and in human precision cut lung slices. Using gain- and loss-of-function approaches, the precise role of RGS proteins was determined in stimulating human ASM proliferation and inhibiting bronchoconstriction. RGS4 expression was restricted to a subpopulation of ASM and was specifically upregulated by mitogens, which induced a hyperproliferative and hypocontractile ASM phenotype similar to that observed in recalcitrant asthma. RGS4 expression was markedly increased in bronchial smooth muscle of patients with severe asthma, and expression correlated significantly with reduced pulmonary function. Whereas RGS4 inhibited G protein-coupled receptor (GPCR)-mediated bronchoconstriction, unexpectedly RGS4 was required for PDGF-induced proliferation and sustained activation of PI3K, a mitogenic signaling molecule that regulates ASM proliferation. These studies indicate that increased RGS4 expression promotes a phenotypic switch of ASM, evoking irreversible airway obstruction in subjects with severe asthma.

Vitamins C and E for asthma and exercise-induced bronchoconstriction.

PubMed

Wilkinson, Mark; Hart, Anna; Milan, Stephen J; Sugumar, Karnam

2014-06-17

The association between dietary antioxidants and asthma or exercise-induced bronchoconstriction (EIB) is not fully understood. Vitamin C and vitamin E are natural antioxidants that are predominantly present in fruits and vegetables; inadequate vitamin E intake is associated with airway inflammation. It has been postulated that the combination may be more beneficial than either single antioxidant for people with asthma and exercise-induced bronchoconstriction. To assess the effects of supplementation of vitamins C and E versus placebo (or no vitamin C and E supplementation) on exacerbations and health-related quality of life (HRQL) in adults and children with chronic asthma. To also examine the potential effects of vitamins C and E on exercise-induced bronchoconstriction in people with asthma and in people without a diagnosis of asthma who experience symptoms only on exercise. Trials were identified from the Cochrane Airways Review Group Specialised Register and from trial registry websites. Searches were conducted in September 2013. We included randomised controlled trials of adults and children with a diagnosis of asthma. We separately considered trials in which participants had received a diagnosis of exercise-induced bronchoconstriction (or exercise-induced asthma). Trials comparing vitamin C and E supplementation versus placebo were included. We included trials in which asthma management for treatment and control groups included similar background therapy. Short-term use of vitamins C and E at the time of exacerbation or for cold symptoms in people with asthma is outside the scope of this review. Two review authors independently screened the titles and abstracts of potential studies and subsequently screened full-text study reports for inclusion. We used standard methods as expected by The Cochrane Collaboration. It was not possible to aggregate the five included studies (214 participants). Four studies (206 participants) addressed the question of whether differences in outcomes were seen when vitamin C and E supplementation versus placebo was provided for participants with asthma, and only one of those studies (160 children) included a paediatric population; the remaining three studies included a combined total of just 46 adults. An additional study considered the question of whether differences in outcomes were noted when vitamin C and E supplementation was compared with placebo for exercise-induced asthma; this trial included only eight participants. The randomisation process of the trials were unclear leading us to downgrade the quality of the evidence. Four of the studies were double blind while the other study was single blind.None of these studies provided data on our two prespecified primary outcome measures: exacerbations and HRQL. Lung function data obtained from the studies were inconclusive. The only studies that provided any suggestion of an effect, and only with some outcomes, were the paediatric study, especially for children with moderate to severe asthma, and the small study on exercise-induced asthma. Even so, this evidence was judged to be at moderate/low quality. Only one study contributed data on asthma symptoms and adverse events, reporting no evidence of an effect of the intervention for symptoms and that one participant in the treatment group dropped out due to cystitis. It is not possible to draw firm conclusions from this review with respect to the comparison of vitamin C and E supplementation versus placebo in the management of asthma or exercise-induced bronchoconstriction. We found only one study relevant to exercise-induced bronchoconstriction; most included participants came from studies designed to assess the effect of vitamin supplementation on the impact of atmospheric pollutants (such as ozone). Evidence is lacking on the comparison of vitamin C and E supplementation versus placebo for asthma with respect to outcomes such as HRQL and exacerbations, which were not addressed by any of the included studies.When compared with lung function tests alone, HRQL scores and exacerbation frequency are better indicators of the severity of asthma, its impact on daily activities and its response to treatment in a patient population. These end points are well recognised in good quality studies of asthma management. However, clinical studies of vitamins C and E in the management of asthma using these important end points of exacerbations and effects on quality of life are not available, and evidence is insufficient to support robust conclusions on the role of vitamin C and E supplementation in asthma and exercise-induced breathlessness.

Exercise-Induced Bronchoconstriction (EIB)

MedlinePlus

... the AAAAI Foundation Donate Utility navigation Español Journals Pollen Counts Annual Meeting Member Login / My Membership Search navigation ... navigation Donate Annual meeting Browse your conditions Check pollen counts Continuing education center Find an allergist / immunologist Journals ...

Degradative enzymes modulate airway responses to intravenous neurokinins A and B.

PubMed

Shore, S A; Drazen, J M

1989-12-01

We studied the effects of the neutral endopeptidase (NEP) inhibitor thiorphan (1.7 mg/kg iv) and the angiotensin-converting enzyme (ACE) inhibitor captopril (5.7 mg/kg iv) on airway responses to rapid intravenous infusions of neurokinin A (NKA) and neurokinin B (NKB) in anesthetized, mechanically ventilated guinea pigs. The dose of NKA required to decrease pulmonary conductance to 50% of its base-line value (ED50GL) was fivefold less (P less than 0.0001) in animals treated with thiorphan compared with controls. NKA1-8, a product resulting from cleavage of NKA by NEP, had no bronchoconstrictor activity. Similar results were obtained by using NKB as the bronchoconstricting agent. Captopril had no significant effect on airway responses to NKA or NKB. In contrast, both thiorphan and captopril decrease the ED50GL for substance P (SP). We also compared the relative bronchoconstrictor potency of NKA, NKB, and SP. In control animals, the rank order of ED50GL values was NKA much less than NKB = SP. NKA also caused a more prolonged bronchoconstriction than SP or NKB. Thiorphan had no effect on the rank order of bronchoconstrictor potency, but in animals treated with captopril, the rank order of ED50GL values was altered to NKA less than SP less than NKB. These results suggest that degradation of NKA and NKB by NEP but not by ACE is an important determinant of the bronchoconstriction induced by these peptides. The degradation by ACE of SP but not NKA or NKB influences the observed relative potency of the three tachykinins as bronchoactive agents.

AIR POLLUTION AND EXERCISE-INDUCED BRONCHOCONSTRICTION

EPA Science Inventory

If ambient PM is toxic, a statistical relationship might be expected between personal exposure to ambient PM and health effects due to ambient PM. However, some exposure analysts seem to believe that there cannot be a meaningful relationship between ambient concentrations of PM ...

MECHANISTIC CONSIDERATIONS FOR FORMALDEHYDE-INDUCED BRONCHOCONSTRICTION INVOLVING S-NITROSOGLUTATHIONE REDUCTASE

EPA Science Inventory

Inhalation of formaldehyde vapor has long been suspected of producing airway pathophysiology such as asthma and hyperresponsivity, presumably via irritant mechanisms. Recent studies on asthma and airway biology implicate changes in nitric oxide (NO) disposition in the adverse eff...

NEUROSENSORY LINKS BETWEEN BRONCHOCONSTRICTION AND CARDIAC RHYTHM

EPA Science Inventory

Reports in the literature have attributed altered heart rate, heart rate variability, and rhythm to inhaled particulate matter (PM) in humans. Whereas the changes in heart rate are very small, analysis of ECG tracings indicate changes in HRV suggesting altered autonomic balance. ...

Newly divided eosinophils limit ozone-induced airway hyperreactivity in nonsensitized guinea pigs

PubMed Central

Jacoby, David B.

2017-01-01

Ozone causes vagally mediated airway hyperreactivity and recruits inflammatory cells, including eosinophils, to lungs, where they mediate ozone-induced hyperreactivity 1 day after exposure but are paradoxically protective 3 days later. We aimed to test the role of newly divided eosinophils in ozone-induced airway hyperreactivity in sensitized and nonsensitized guinea pigs. Nonsensitized and sensitized guinea pigs were treated with 5-bromo-2-deoxyuridine (BrdU) to label newly divided cells and were exposed to air or ozone for 4 h. Later (1 or 3 days later), vagally induced bronchoconstriction was measured, and inflammatory cells were harvested from bone marrow, blood, and bronchoalveolar lavage. Ozone induced eosinophil hematopoiesis. One day after ozone, mature eosinophils dominate the inflammatory response and potentiate vagally induced bronchoconstriction. However, by 3 days, newly divided eosinophils have reached the lungs, where they inhibit ozone-induced airway hyperreactivity because depleting them with antibody to IL-5 or a TNF-α antagonist worsened vagally induced bronchoconstriction. In sensitized guinea pigs, both ozone-induced eosinophil hematopoiesis and subsequent recruitment of newly divided eosinophils to lungs 3 days later failed to occur. Thus mature eosinophils dominated the ozone-induced inflammatory response in sensitized guinea pigs. Depleting these mature eosinophils prevented ozone-induced airway hyperreactivity in sensitized animals. Ozone induces eosinophil hematopoiesis and recruitment to lungs, where 3 days later, newly divided eosinophils attenuate vagally mediated hyperreactivity. Ozone-induced hematopoiesis of beneficial eosinophils is blocked by a TNF-α antagonist or by prior sensitization. In these animals, mature eosinophils are associated with hyperreactivity. Thus interventions targeting eosinophils, although beneficial in atopic individuals, may delay resolution of airway hyperreactivity in nonatopic individuals. PMID:28258108

Prostaglandin E2 Prevents Hyperosmolar-Induced Human Mast Cell Activation through Prostanoid Receptors EP2 and EP4

PubMed Central

Torres-Atencio, Ivonne; Ainsua-Enrich, Erola; de Mora, Fernando; Picado, César; Martín, Margarita

2014-01-01

Background Mast cells play a critical role in allergic and inflammatory diseases, including exercise-induced bronchoconstriction (EIB) in asthma. The mechanism underlying EIB is probably related to increased airway fluid osmolarity that activates mast cells to the release inflammatory mediators. These mediators then act on bronchial smooth muscle to cause bronchoconstriction. In parallel, protective substances such as prostaglandin E2 (PGE2) are probably also released and could explain the refractory period observed in patients with EIB. Objective This study aimed to evaluate the protective effect of PGE2 on osmotically activated mast cells, as a model of exercise-induced bronchoconstriction. Methods We used LAD2, HMC-1, CD34-positive, and human lung mast cell lines. Cells underwent a mannitol challenge, and the effects of PGE2 and prostanoid receptor (EP) antagonists for EP1–4 were assayed on the activated mast cells. Beta-hexosaminidase release, protein phosphorylation, and calcium mobilization were assessed. Results Mannitol both induced mast cell degranulation and activated phosphatidyl inositide 3-kinase and mitogen-activated protein kinase (MAPK) pathways, thereby causing de novo eicosanoid and cytokine synthesis. The addition of PGE2 significantly reduced mannitol-induced degranulation through EP2 and EP4 receptors, as measured by beta-hexosaminidase release, and consequently calcium influx. Extracellular-signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 phosphorylation were diminished when compared with mannitol activation alone. Conclusions Our data show a protective role for the PGE2 receptors EP2 and EP4 following osmotic changes, through the reduction of human mast cell activity caused by calcium influx impairment and MAP kinase inhibition. PMID:25329458

Bronchoconstriction induced by increasing airway temperature in ovalbumin-sensitized rats: role of tachykinins.

PubMed

Hsu, Chun-Chun; Lin, Ruei-Lung; Lin, You Shuei; Lee, Lu-Yuan

2013-09-01

This study was carried out to determine the effect of allergic inflammation on the airway response to increasing airway temperature. Our results showed the following: 1) In Brown-Norway rats actively sensitized by ovalbumin (Ova), isocapnic hyperventilation with humidified warm air (HWA) for 2 min raised tracheal temperature (Ttr) from 33.4 ± 0.6°C to 40.6 ± 0.1°C, which induced an immediate and sustained (>10 min) increase in total pulmonary resistance (Rl) from 0.128 ± 0.004 to 0.212 ± 0.013 cmH2O·ml(-1)·s (n = 6, P < 0.01). In sharp contrast, the HWA challenge caused the same increase in Ttr but did not generate any increase in Rl in control rats. 2) The increase in Rl in sensitized rats was reproducible when the same HWA challenge was repeated 60-90 min later. 3) This bronchoconstrictive effect was temperature dependent: a slightly smaller increase in peak Ttr (39.6 ± 0.2°C) generated a significant but smaller increase in Rl in sensitized rats. 4) The HWA-induced bronchoconstriction was not generated by the humidity delivered by the HWA challenge alone, because the same water content delivered by saline aerosol at room temperature had no effect. 5) The HWA-evoked increase in Rl in sensitized rats was not blocked by atropine but was completely prevented by pretreatment either with a combination of neurokinin (NK)-1 and NK-2 antagonists or with formoterol, a β2 agonist, before the HWA challenge. This study showed that increasing airway temperature evoked a pronounced and reversible increase in airway resistance in sensitized rats and that tachykinins released from the vagal bronchopulmonary C-fiber endings were primarily responsible.

Effect of inspired air conditions on exercise-induced bronchoconstriction and urinary CC16 levels in athletes.

PubMed

Bolger, C; Tufvesson, E; Anderson, S D; Devereux, G; Ayres, J G; Bjermer, L; Sue-Chu, M; Kippelen, P

2011-10-01

Injury to the airway epithelium has been proposed as a key susceptibility factor for exercise-induced bronchoconstriction (EIB). Our goals were to establish whether airway epithelial cell injury occurs during EIB in athletes and whether inhalation of warm humid air inhibits this injury. Twenty-one young male athletes (10 with a history of EIB) performed two 8-min exercise tests near maximal aerobic capacity in cold dry (4°C, 37% relative humidity) and warm humid (25°C, 94% relative humidity) air on separate days. Postexercise changes in urinary CC16 were used as a biomarker of airway epithelial cell perturbation and injury. Bronchoconstriction occurred in eight athletes in the cold dry environment and was completely blocked by inhalation of warm humid air [maximal fall in forced expiratory volume in 1 s = 18.1 ± 2.1% (SD) in cold dry air and 1.7 ± 0.8% in warm humid air, P < 0.01]. Exercise caused an increase in urinary excretion of CC16 in all subjects (P < 0.001), but this rise in CC16 was blunted following inhalation of warm humid air [median CC16 increase pre- to postchallenge = 1.91 and 0.35 ng/μmol in cold dry and warm humid air, respectively, in athletes with EIB (P = 0.017) and 1.68 and 0.48 ng/μmol in cold dry and warm humid air, respectively, in athletes without EIB (P = 0.002)]. The results indicate that exercise hyperpnea transiently disrupts the airway epithelium of all athletes (not only in those with EIB) and that inhalation of warm moist air limits airway epithelial cell perturbation and injury.

Newly divided eosinophils limit ozone-induced airway hyperreactivity in nonsensitized guinea pigs.

PubMed

Wicher, Sarah A; Jacoby, David B; Fryer, Allison D

2017-06-01

Ozone causes vagally mediated airway hyperreactivity and recruits inflammatory cells, including eosinophils, to lungs, where they mediate ozone-induced hyperreactivity 1 day after exposure but are paradoxically protective 3 days later. We aimed to test the role of newly divided eosinophils in ozone-induced airway hyperreactivity in sensitized and nonsensitized guinea pigs. Nonsensitized and sensitized guinea pigs were treated with 5-bromo-2-deoxyuridine (BrdU) to label newly divided cells and were exposed to air or ozone for 4 h. Later (1 or 3 days later), vagally induced bronchoconstriction was measured, and inflammatory cells were harvested from bone marrow, blood, and bronchoalveolar lavage. Ozone induced eosinophil hematopoiesis. One day after ozone, mature eosinophils dominate the inflammatory response and potentiate vagally induced bronchoconstriction. However, by 3 days, newly divided eosinophils have reached the lungs, where they inhibit ozone-induced airway hyperreactivity because depleting them with antibody to IL-5 or a TNF-α antagonist worsened vagally induced bronchoconstriction. In sensitized guinea pigs, both ozone-induced eosinophil hematopoiesis and subsequent recruitment of newly divided eosinophils to lungs 3 days later failed to occur. Thus mature eosinophils dominated the ozone-induced inflammatory response in sensitized guinea pigs. Depleting these mature eosinophils prevented ozone-induced airway hyperreactivity in sensitized animals. Ozone induces eosinophil hematopoiesis and recruitment to lungs, where 3 days later, newly divided eosinophils attenuate vagally mediated hyperreactivity. Ozone-induced hematopoiesis of beneficial eosinophils is blocked by a TNF-α antagonist or by prior sensitization. In these animals, mature eosinophils are associated with hyperreactivity. Thus interventions targeting eosinophils, although beneficial in atopic individuals, may delay resolution of airway hyperreactivity in nonatopic individuals. Copyright © 2017 the American Physiological Society.

Relative bronchoconstrictor activity of neurokinin A and neurokinin A fragments in guinea pigs.

PubMed

Shore, S A; Drazen, J M

1991-08-01

We examined the effect of rapid intravenous infusion of neurokinin A (NKA) and selected COOH-terminal NKA fragments on pulmonary conductance (GL) and dynamic compliance in anesthetized mechanically ventilated guinea pigs. The rank order of the dose of peptide required to reduce GL by 50% (ED50GL) was NKA = NKA2-10 = NKA3-10 = NKA4-10 less than NKA5-10 much less than NKA6-10. The time course of bronchoconstriction induced by NKA2-10, NKA3-10, and NKA4-10 was similar to that induced by NKA, whereas NKA5-10 and NKA6-10 each had a shorter duration of action than NKA for a similar induced maximal change in GL. To determine whether degradation of these NKA fragments by neutral endopeptidase (NEP) modulates their bronchoconstrictor activity as it does for native NKA, we examined the effect of the NEP inhibitor SCH32615 on NKA3-10-, NKA5-10-, and NKA6-10-induced changes in GL. We have previously reported that the ED50GL for NKA was approximately 20-fold lower in animals pretreated with SCH32615 (1 mg/kg) than in control guinea pigs. SCH32615 caused a 16-fold decrease in ED50GL for NKA3-10 (P less than 0.001) but had no effect on airway responses to NKA5-10 or NKA6-10. The results demonstrate that the magnitude and duration of bronchoconstriction induced by potential aminopeptidase degradation products of NKA are similar to those of the native peptide. Aminopeptidases do not, therefore, have the capacity to modulate the bronchoconstriction induced by this peptide.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of an inhaled neutral endopeptidase inhibitor, thiorphan, on airway responses to neurokinin A in normal humans in vivo.

PubMed

Cheung, D; Bel, E H; Den Hartigh, J; Dijkman, J H; Sterk, P J

1992-06-01

Neuropeptides such as neurokinin A (NKA) have been proposed as important mediators of bronchoconstriction and airway hyperresponsiveness in asthma. Inhaled NKA causes bronchoconstriction in patients with asthma, but not in normal subjects. This is possibly due to the activity of an endogenous neuropeptide-degrading enzyme: neutral endopeptidase (NEP). We investigated whether a NEP-inhibitor, thiorphan, reveals bronchoconstriction to NKA or NKA-induced changes in airway responsiveness to methacholine in normal humans in vivo. Eight normal male subjects participated in a double-blind crossover study, using thiorphan as pretreatment to NKA challenge. Dose-response curves to inhaled NKA (8 to 1,000 micrograms/ml, 0.5 ml/dose) were recorded on 2 randomized days 1 wk apart, and methacholine tests were performed 48 h before and 24 h after the NKA challenge. Ten minutes prior to NKA challenge the subjects inhaled either thiorphan (2.5 mg/ml, 0.5 ml) or placebo. To detect a possible nonspecific effect of thiorphan, we investigated the effect of the same pretreatment with thiorphan or placebo on the dose-response curve to methacholine in a separate set of experiments. The response was measured by the flow from standardized partial expiratory flow-volume curves (V40p), expressed in percent fall from baseline. NKA log dose-response curves were analyzed using the area under the curve (AUC) and the response to the highest dose of 1,000 micrograms/ml (V40p,1000). The methacholine dose-response curves were characterized by their position (PC40V40p) and the maximal-response plateau (MV40p). Baseline V40p was not affected by either pretreatment (p greater than 0.15).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of inhaled furosemide and torasemide on bronchial response to ultrasonically nebulized distilled water in asthmatic subjects.

PubMed

Foresi, A; Pelucchi, A; Mastropasqua, B; Cavigioli, G; Carlesi, R M; Marazzini, L

1992-08-01

Inhaled furosemide has been shown to reduce the bronchoconstriction induced by several indirect stimuli, including ultrasonically nebulized distilled water (UNDW). Because the protective effect could be due to the inhibition of the Na(+)-2Cl(-)-K+ cotransport system of bronchial epithelium, we have compared the protective effect of inhaled furosemide with that of inhaled torasemide, a new and more potent loop diuretic, on UNDW-induced bronchoconstriction in a group of 12 asthmatic subjects. UNDW challenge was performed by constructing a stimulus-response curve with five increasing volume outputs of distilled water (from 0.5 to 5.2 ml/min) and the bronchial response expressed as the provocative output causing a 20% fall in FEV1 (PO20UNDW). On different days, each subject inhaled an equal dose (28 mg) of furosemide and torasemide in a randomized, double-blind, placebo-controlled study 5 min prior to an UNDW challenge. Furosemide and torasemide had no significant effect on resting lung function. The geometric mean value of PO20UNDW measured after placebo was 1.73 ml/min. This was significantly lower than that recorded after furosemide (4.25 ml/min; p < 0.025), but not after torasemide (3.05 ml/min; p = 0.07). Inhaled furosemide totally blocked bronchial response to UNDW in five subjects. In two of five subjects the response was also blocked by inhaled torasemide. A remarkable increase in diuresis was noted only after torasemide in most subjects. We conclude that inhaled furosemide has a better protective effect than does inhaled torasemide against UNDW-induced bronchoconstriction. However, the protective effect of furosemide is variable, with some asthmatic patients showing no change in bronchial response to UNDW.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of inhaled formyl-methionyl-leucyl-phenylalanine on airway function.

PubMed Central

Berend, N; Peters, M J; Armour, C L; Black, J L; Ward, H E

1988-01-01

Formyl-methionyl-leucyl-phenylalanine (FMLP), a synthetic, acylated tripeptide analogous to bacterial chemotactic factors, has been shown to cause bronchoconstriction in guinea pig, rabbit, and human airways in vitro. To determine whether FMLP causes bronchoconstriction in man in vivo, a preliminary study was undertaken in which five non-smokers (mean age 35 years, FEV1 94% (SEM 5%) predicted) and five smokers (mean age 34 years, FEV1 93% (6%) predicted) inhaled aerosols of FMLP. None of the subjects showed airway hyperresponsiveness to histamine (the provocative concentrations of histamine causing a fall of greater than or equal to 20% in FEV1 (PC20) were over 8 mg/ml). FMLP dissolved in 50% dimethylsulphoxide and 50% saline in concentrations of 0, 0.06, 0.12, 0.25, 0.5, 1.0, 2.0, and 4.0 mg/ml was administered to the subjects by means of a French-Rosenthal dosimeter, FEV1 being recorded after inhalation of each concentration. Dose dependent falls in FEV1 occurred in five non-smokers (geometric mean 1.76, 95% confidence limits 0.87-3.53 mg/ml) and three smokers (0.23, 0.07-0.78 mg/ml), with two smokers not responding by 20% to the highest concentration of FMLP. On a separate day the FMLP dose-response curves were repeated after nebulisation of 500 micrograms of ipratropium bromide. The PC20 FMLP in the responders more than doubled. In six additional normal subjects a histamine inhalation test was performed before and four and 24 hours after inhalation of FMLP. All subjects remained unresponsive to histamine. These results show that FMLP is a potent bronchoconstrictor in some non-asthmatic individuals in vivo and this may be important in bronchoconstriction related to infection in patients with chronic obstructive lung disease. PMID:2965425

Vital capacities in acute and chronic airway obstruction: dependence on flow and volume histories.

PubMed

Brusasco, V; Pellegrino, R; Rodarte, J R

1997-06-01

The aim of this study was to investigate whether measurements of vital capacity (VC) are affected by the direction of the manoeuvre (inspiratory vs expiratory) and by the rate of expiratory flow. The study was performed on 25 individuals with chronic airway obstruction (CAO) and a forced expiratory volume in one second (FEV1) (expressed in standardized residuals (SR)) of -2.0+/-1.4 SD (CAO group), and 10 asthmatic subjects with methacholine (MCh)-induced bronchoconstriction (FEV1 -23+/-1.02 SR) (MCh group). VCs were measured during fast inspiration following both slow (FIVCse) and forced (FIVCfe) expiration from end-tidal inspiration to residual volume (RV), and during slow (EVC) or forced (FVC) expiration from total lung capacity (TLC). In the CAO group, FVC was the smallest volume (3.75+/-1.03 L) and significantly different from the other three estimates of VC; FIVCse (4.03+/-0.91 L) was the largest volume and significantly different from FVC and FIVCfe (3.83+/-0.98 L). In the MCh group, FVC (4.16+/-0.94 L) and EVC (4.19+/-0.89 L) were the largest volumes, although only the difference between FVC and FIVCfe (3.76+/-0.81 L) reached statistical significance. These data suggest that both flow and volume histories contribute to decreased vital capacities during bronchoconstriction. However, whereas increasing expiratory flow always tends to decrease vital capacity, the volume history of full inflation has different effects in chronic and acute bronchoconstriction, probably due to different effects on airway calibre. These results stress the importance of using standardized manoeuvres in order to obtain comparable values of vital capacity.

Endogenous cannabinoid receptor agonists inhibit neurogenic inflammations in guinea pig airways.

PubMed

Yoshihara, Shigemi; Morimoto, Hiroshi; Ohori, Makoto; Yamada, Yumi; Abe, Toshio; Arisaka, Osamu

2005-09-01

Although neurogenic inflammation via the activation of C fibers in the airway must have an important role in the pathogenesis of asthma, their regulatory mechanism remains uncertain. The pharmacological profiles of endogenous cannabinoid receptor agonists on the activation of C fibers in airway tissues were investigated and the mechanisms how cannabinoids regulate airway inflammatory reactions were clarified. The effects of endogenous cannabinoid receptor agonists on electrical field stimulation-induced bronchial smooth muscle contraction, capsaicin-induced bronchoconstriction and capsaicin-induced substance P release in guinea pig airway tissues were investigated. The influences of cannabinoid receptor antagonists and K+ channel blockers to the effects of cannabinoid receptor agonists on these respiratory reactions were examined. Both endogenous cannabinoid receptor agonists, anandamide and palmitoylethanolamide, inhibited electrical field stimulation-induced guinea pig bronchial smooth muscle contraction, but not neurokinin A-induced contraction. A cannabinoid CB2 antagonist, SR 144528, reduced the inhibitory effect of endogenous agonists, but not a cannabinoid CB1 antagonist, SR 141716A. Inhibitory effects of agonists were also reduced by the pretreatment of large conductance Ca2+ -activated K+ channel (maxi-K+ channel) blockers, iberiotoxin and charybdotoxin, but not by other K+ channel blockers, dendrotoxin or glibenclamide. Anandamide and palmitoylethanolamide blocked the capsaicin-induced release of substance P-like immunoreactivity from guinea pig airway tissues. Additionally, intravenous injection of palmitoylethanolamide dose-dependently inhibited capsaicin-induced guinea pig bronchoconstriction, but not neurokinin A-induced reaction. However, anandamide did not reduce capsaicin-induced guinea pig bronchoconstriction. These findings suggest that endogenous cannabinoid receptor agonists inhibit the activation of C fibers via cannabinoid CB2 receptors and maxi-K+ channels in guinea pig airways. Copyright (c) 2005 S. Karger AG, Basel.

Sensitivity of disease parameters to flexible budesonide/formoterol treatment in an allergic rat model.

PubMed

Brange, Charlotte; Smailagic, Amir; Jansson, Anne-Helene; Middleton, Brian; Miller-Larsson, Anna; Taylor, John D; Silberstein, David S; Lal, Harbans

2009-02-01

Clinical studies show that flexible dosing (maintenance and symptom-driven dose adjustments) of budesonide and formoterol (BUD/FORM) improves control of asthma exacerbations as compared to fixed maintenance dosing protocols (maintenance therapy) even when the latter utilize higher BUD/FORM doses. This suggests that dose-response relationships for certain pathobiologic mechanisms in asthma shift over time. Here, we have conducted animal studies to address this issue. (1) To test in an animal asthma-like model whether it is possible to achieve the same or greater pharmacological control over bronchoconstriction and airway/lung inflammation, and with less total drug used, by flexible BUD/FORM dosing (upward adjustment of doses) in association with allergen challenges. (2) To determine whether the benefit requires adjustment of both drug components. Rats sensitized on days 0 and 7 were challenged intratracheally with ovalbumin on days 14 and 21. On days 13-21, rats were treated intratracheally with fixed maintenance or flexible BUD/FORM combinations. On day 22, rats were challenged with methacholine and lungs were harvested for analysis. A flexible BUD/FORM dosing regimen (using 3.3 times less total drug than the fixed maintenance high dose regimen), delivered the same or greater reductions of excised lung gas volume (a measure of gas trapped in lung by bronchoconstriction) and lung weight (a measure of inflammatory oedema). When either BUD or FORM alone was increased on days of challenge, the benefit of the flexible dose upward adjustment was lost. Flexible dosing of the BUD/FORM combination improves the pharmacological inhibition of allergen-induced bronchoconstriction and an inflammatory oedema in an allergic asthma-like rat model.

Nitrogen Dioxide Exposure and Airway Responsiveness in Individuals with Asthma

EPA Science Inventory

Controlled human exposure studies evaluating the effect of inhaled NO2 on the inherent responsiveness of the airways to challenge by bronchoconstricting agents have had mixed results. In general, existing meta-analyses show statistically significant effects of NO2 on the airway r...

Computational Modeling of Airway and Pulmonary Vascular Structure and Function: Development of a “Lung Physiome”

PubMed Central

Tawhai, M. H.; Clark, A. R.; Donovan, G. M.; Burrowes, K. S.

2011-01-01

Computational models of lung structure and function necessarily span multiple spatial and temporal scales, i.e., dynamic molecular interactions give rise to whole organ function, and the link between these scales cannot be fully understood if only molecular or organ-level function is considered. Here, we review progress in constructing multiscale finite element models of lung structure and function that are aimed at providing a computational framework for bridging the spatial scales from molecular to whole organ. These include structural models of the intact lung, embedded models of the pulmonary airways that couple to model lung tissue, and models of the pulmonary vasculature that account for distinct structural differences at the extra- and intra-acinar levels. Biophysically based functional models for tissue deformation, pulmonary blood flow, and airway bronchoconstriction are also described. The development of these advanced multiscale models has led to a better understanding of complex physiological mechanisms that govern regional lung perfusion and emergent heterogeneity during bronchoconstriction. PMID:22011236

Eucapnic Voluntary Hyperventilation to Detect Exercise-Induced Bronchoconstriction in Cystic Fibrosis.

PubMed

Kirkby, Stephen E; Hayes, Don; Parsons, Jonathan P; Wisely, Clayton E; Kopp, Ben; McCoy, Karen S; Mastronarde, John G

2015-10-01

Exercise-induced bronchoconstriction (EIB) has not been well studied in cystic fibrosis (CF), and eucapnic voluntary hyperventilation (EVH) testing has not been used as an objective assessment of EIB in CF to date. A prospective cohort pilot study was completed where standard EVH testing was completed by 10 CF patients with forced expiratory volume in 1 s (FEV1) ≥70% of predicted. All patients also completed a cardiopulmonary exercise test (CPET) with pre- and post-CPET spirometry as a comparative method of detecting EIB. No adverse events occurred with EVH testing. A total of 20% (2/10) patients were diagnosed with EIB by means of EVH. Both patients had clinical symptoms consistent with EIB. No patient had a CPET-based exercise challenge consistent with EIB. EVH testing was safe and effective in the objective assessment for EIB in patients with CF who had well-preserved lung function. It may be a more sensitive method of detecting EIB then exercise challenge.

Formalin produces depolarizations in human airway smooth muscle in vitro.

PubMed

Richards, Ira S; DeHate, Robin B

2006-03-01

Respiratory irritants may result in airway smooth muscle (ASM) depolarization and bronchoconstriction. We examined the effect of formalin on membrane potentials in human ASM in two types of in vitro preparations: strip preparations, which contain functional sensory and motor nerve endings and cultured cells, which lack these nerve endings due to the tissue dissociation process. Depolarizations occurred in atropine-treated strip preparations in response to formalin exposures, but not in similarly-treated cultured cells, suggesting a role for non-cholinergic mediators in formalin-induced depolarization. It is suggested that formalin may act as an irritant to produce bronchoconstriction that is mediated by the release of endogenous substance P (SP) from peripheral sensory nerve endings. This is supported by our observation that exogenous SP produced depolarizations of a magnitude similar to those produced by formalin in both strip preparations and cultured cells. In addition, capsaicin, which releases endogenous SP from nerve endings, produced depolarizations of a magnitude similar to formalin in strip preparations, but was without effect in cultured cells.

Comparison of the efficacy of preservative free ipratropium bromide and Atrovent nebuliser solution.

PubMed Central

Rafferty, P; Beasley, R; Holgate, S T

1988-01-01

The paradoxical bronchoconstriction observed with commercially available isotonic ipratropium bromide nebuliser solution (Atrovent) in patients with asthma results from an adverse reaction to the preservatives, benzalkonium chloride and ethylenediaminetetra-acetic acid (EDTA). The airway response to inhaled Atrovent and preservative free ipratropium bromide nebuliser solutions has been examined in a double blind study. On separate occasions 30 asthmatic subjects inhaled 2 ml of the solutions and airway calibre was measured in terms of FEV1 for 45 minutes. Atrovent nebuliser solution provoked a greater than 20% fall in FEV1 in five of the 30 subjects, whereas this did not occur after preservative free ipratropium bromide. Inhalation of the preservative free solution resulted in more rapid and greater overall bronchodilatation than Atrovent, with mean maximum increases in FEV1 of 29.2% and 18.5% respectively. It is concluded that the risk of paradoxical bronchoconstriction with ipratropium bromide is considerably reduced by removal of benzalkonium chloride and EDTA and that preservative free ipratropium bromide is a more potent bronchodilator than the currently available Atrovent solution. PMID:2971274

Discovery of olodaterol, a novel inhaled beta2-adrenoceptor agonist with a 24 h bronchodilatory efficacy.

PubMed

Bouyssou, Thierry; Hoenke, Christoph; Rudolf, Klaus; Lustenberger, Philipp; Pestel, Sabine; Sieger, Peter; Lotz, Ralf; Heine, Claudia; Büttner, Frank H; Schnapp, Andreas; Konetzki, Ingo

2010-02-15

Compound 4p was identified from a series of 6-hydroxy-4H-benzo[1,4]oxazin-3-ones as potent agonist of the human beta2-adrenoceptor with a high beta1/beta2-selectivity. A complete reversal of acetylcholine-induced bronchoconstriction which lasted over the whole study period of 5h was demonstrated for 4p in a guinea pig in vivo model without any signs of cardiovascular effects up to 10-fold above the first dose reaching 100% bronchoprotection. The enantiomerically pure (R)-form of 4p exerted a bronchodilatory efficacy over 24 h in dogs and guinea pigs in the absence of systemic pharmacodynamic effects. Formoterol which was tested as comparator in the same in vivo models of acetylcholine-induced bronchoconstriction did not retain efficacy after 24 h. In summary, the preclinical profile of compound (R)-4p (olodaterol, also known as BI 1744 CL) suggests a potential for once-daily dosing in man accompanied with an improved safety profile. Copyright 2010 Elsevier Ltd. All rights reserved.

Responses to sulfur dioxide and exercise by medication-depend asthmatics: Effect of varying medication levels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Linn, W.S.; Shamoo, D.A.; Peng, R.C.

Twenty-one volunteers with moderate to severe asthma were exposed to sulfur dioxide (SO{sub 2}) at concentrations of O (control), 0.3, and 0.6 ppm in each of three medication states: (1) low (much of their usual asthma medication withheld), (2) normal (each subject on his own usual medication schedule), and (3) high (usual medication supplemented by inhaled metaproterenol before exposure). Theophylline, the medication usually taken by subjects, was often supplemented by beta-adrenergics. Exposures were for 10 min and were accompanied by continuous heavy exercise (ventilation {approximately} 50 1/min). Lung function and symptoms were measured before and after exposure. With normal medication,more » symptomatic bronchoconstriction occurred with exercise and was exacerbated by 0.6 ppm SO{sub 2}, as reported for mildly unmedicated asthmatics studied previously. Both baseline and post-exposure lung function were noticeably worse in the low-medication state. High medication improved baseline lung function and prevented most broncho-constrictive effect of SO{sup 2}/exercise. High medication also increased heart rate and apparently induced tremor or nervousness in some individuals.« less

Deposition in the distal parts of the bovine respiratory tract: assessment of equipment suitable for drug inhalation.

PubMed

Genicot, B; Votion, D; Munsters, K; Close, R; Lindsey, J K; Lekeux, P

1996-03-30

The efficiency of equipment suitable for the inhalation of drugs by calves was assessed in six animals which inhaled radioisotopically labelled particles while suffering from reversible diffuse bronchoconstriction induced experimentally with 5-hydroxytryptamine and while they were breathing normally. Respiratory rates and data from pulmonary function tests and scintiscans were recorded during both investigations. After the first investigation, a mean (se) wash-out period of 9.8 (3.2) days was allowed. Under diffuse bronchoconstriction, the respiratory rate, the oscillatory resistance and the compliance of the respiratory system reached 282.1 (22.0), 161.1 (10.8) and 68.8 (2.7) per cent of their respective baseline values. When the calves were breathing normally these parameters did not change over time. The ratios (Cp/Ct) of the counts of gamma-disintegrations in the peripheral part (Cp) of the lungs and in the total lung area (Ct) were not significantly different when comparing the results from the two investigations. The ratios of Cp/Ct in the left lungs did not differ significantly from those in the right lungs.

Cough reflex testing with inhaled capsaicin and TRPV1 activation in asthma and comorbid conditions.

PubMed

Couto, M; de Diego, A; Perpiñi, M; Delgado, L; Moreira, A

2013-01-01

A high parasympathetic tone leading to bronchoconstriction and neurogenic inflammation is thought to have a major role in the pathogenesis of asthma. Transient receptor potential vanilloid 1 (TRPV1) is the hub of almost all neuronal inflammatory signaling pathways. A critical determinant of neurogenic inflammation, TRPV1 functions as a sensor for detecting irritants in the lung by transmitting noxious stimuli to the central nervous system and inducing the release of a variety of proinflammatory neuropeptides at the peripheral terminals. Challenge with inhaled capsaicin, an exogenous agonist of TRPV1, has been used to measure the sensitivity of the cough reflex. However, inhalation of capsaicin is also associated with parasympathetic bronchoconstriction, mucus hypersecretion, vasodilatation, and the sensation of dyspnea. Therefore, inhaled capsaicin challenge is expected to have other potential applications in asthma and comorbid conditions, such as rhinitis and gastroesophageal reflux disease, both of which produce cough. Capsaicin challenge has established itself as a useful objective method for evaluating airway hypersensitivity; however, it is potentially valuable in many other situations, which will be reviewed in this paper.

Hypothermia augments non-cholinergic neuronal bronchoconstriction in pithed guinea-pigs.

PubMed

Rechtman, M P; King, R G; Boura, A L

1991-08-16

Electrical stimulation at C4-C7 in the spinal canal of pithed guinea-pigs injected with atropine, d-tubocurarine and pentolinium caused frequency-dependent bronchoconstriction. Such non-cholinergic responses to electrical stimulation, unlike responses to substance P, were abolished by pretreatment with capsaicin but not by mepyramine or propranolol. Bronchoconstrictor responses to electrical stimulation were inversely related to rectal temperature (between 30-40 degrees C) whereas responses to substance P increased with increasing temperature over the same range. Ouabain (i.v.) augmented responses to electrical stimulation at 35-37 degrees C but depressed those at 30-32 degrees C. Both morphine and the alpha 2-adrenoceptor agonist B-HT920 (i.v.) inhibited non-cholinergic-mediated bronchoconstrictor responses at 30-32 degrees C. These results stress the importance of adequate control of body temperature in this preparation. Lowered body temperature may increase neuronal output of neuropeptides whilst depressing bronchial smooth muscle sensitivity. The data support previous conclusions regarding the role of Na+/K+ activated ATPase in temperature-induced changes in sensitivity to bronchoconstrictor stimuli.

Pulmonary function in obese vs non-obese cats.

PubMed

García-Guasch, Laín; Caro-Vadillo, Alicia; Manubens-Grau, Jordi; Carretón, Elena; Camacho, Aparecido A; Montoya-Alonso, José Alberto

2015-06-01

Obesity is a risk factor in the development of several respiratory diseases. Lung volumes tend to be decreased, especially expiratory reserve volume, increasing expiratory flow limitation during tidal breathing. Barometric whole-body plethysmography is a non-invasive pulmonary function test that allows a dynamic study of breathing patterns. The objective of this study was to compare pulmonary function variables between obese and non-obese cats through the use of barometric whole-body plethysmography. Nine normal-weight and six obese cats were placed in the plethysmograph chamber, and different respiratory variables were measured. There was a significant decrease in tidal volume per kilogram (P = 0.003), minute volume per kilogram (P = 0.001) and peak inspiratory and expiratory flows per kilogram (P = 0.001) in obese cats compared with non-obese cats. Obesity failed to demonstrate a significant increase in bronchoconstriction index variable enhanced pause (Penh), as previously reported in humans and dogs. The results show that feline obesity impairs pulmonary function in cats, although a significant increase in bronchoconstriction indexes was not observed. Non-invasive barometric whole-body plethysmography can help characterise mechanical dysfunction of the airways in obese cats. © ISFM and AAFP 2014.

Ionotropic and metabotropic proton-sensing receptors involved in airway inflammation in allergic asthma.

PubMed

Aoki, Haruka; Mogi, Chihiro; Okajima, Fumikazu

2014-01-01

An acidic microenvironment has been shown to evoke a variety of airway responses, including cough, bronchoconstriction, airway hyperresponsiveness (AHR), infiltration of inflammatory cells in the lung, and stimulation of mucus hyperproduction. Except for the participation of transient receptor potential vanilloid-1 (TRPV1) and acid-sensing ion channels (ASICs) in severe acidic pH (of less than 6.0)-induced cough and bronchoconstriction through sensory neurons, the molecular mechanisms underlying extracellular acidic pH-induced actions in the airways have not been fully understood. Recent studies have revealed that ovarian cancer G protein-coupled receptor 1 (OGR1)-family G protein-coupled receptors, which sense pH of more than 6.0, are expressed in structural cells, such as airway smooth muscle cells and epithelial cells, and in inflammatory and immune cells, such as eosinophils and dendritic cells. They function in a variety of airway responses related to the pathophysiology of inflammatory diseases, including allergic asthma. In the present review, we discuss the roles of ionotropic TRPV1 and ASICs and metabotropic OGR1-family G protein-coupled receptors in the airway inflammation and AHR in asthma and respiratory diseases.

Emergent structure-function relations in emphysema and asthma.

PubMed

Winkler, Tilo; Suki, Béla

2011-01-01

Structure-function relationships in the respiratory system are often a result of the emergence of self-organized patterns or behaviors that are characteristic of certain respiratory diseases. Proper description of such self-organized behavior requires network models that include nonlinear interactions among different parts of the system. This review focuses on 2 models that exhibit self-organized behavior: a network model of the lung parenchyma during the progression of emphysema that is driven by mechanical force-induced breakdown, and an integrative model of bronchoconstriction in asthma that describes interactions among airways within the bronchial tree. Both models suggest that the transition from normal to pathologic states is a nonlinear process that includes a tipping point beyond which interactions among the system components are reinforced by positive feedback, further promoting the progression of pathologic changes. In emphysema, the progressive destruction of tissue is irreversible, while in asthma, it is possible to recover from a severe bronchoconstriction. These concepts may have implications for pulmonary medicine. Specifically, we suggest that structure-function relationships emerging from network behavior across multiple scales should be taken into account when the efficacy of novel treatments or drug therapy is evaluated. Multiscale, computational, network models will play a major role in this endeavor.

An official American Thoracic Society clinical practice guideline: exercise-induced bronchoconstriction.

PubMed

Parsons, Jonathan P; Hallstrand, Teal S; Mastronarde, John G; Kaminsky, David A; Rundell, Kenneth W; Hull, James H; Storms, William W; Weiler, John M; Cheek, Fern M; Wilson, Kevin C; Anderson, Sandra D

2013-05-01

Exercise-induced bronchoconstriction (EIB) describes acute airway narrowing that occurs as a result of exercise. EIB occurs in a substantial proportion of patients with asthma, but may also occur in individuals without known asthma. To provide clinicians with practical guidance, a multidisciplinary panel of stakeholders was convened to review the pathogenesis of EIB and to develop evidence-based guidelines for the diagnosis and treatment of EIB. The evidence was appraised and recommendations were formulated using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Recommendations for the treatment of EIB were developed. The quality of evidence supporting the recommendations was variable, ranging from low to high. A strong recommendation was made for using a short-acting β(2)-agonist before exercise in all patients with EIB. For patients who continue to have symptoms of EIB despite the administration of a short-acting β(2)-agonist before exercise, strong recommendations were made for a daily inhaled corticosteroid, a daily leukotriene receptor antagonist, or a mast cell stabilizing agent before exercise. The recommendations in this Guideline reflect the currently available evidence. New clinical research data will necessitate a revision and update in the future.

Substance P-induced bronchoconstriction in the guinea pig. Enhancement by inhibitors of neutral metalloendopeptidase and angiotensin-converting enzyme.

PubMed

Shore, S A; Stimler-Gerard, N P; Coats, S R; Drazen, J M

1988-02-01

We tested the effects of the neutral metalloendopeptidase (NEP) inhibitor, thiorphan (0.17, 0.5, and 1.7 mg i.v), and the angiotensin-converting enzyme (ACE) inhibitor, captopril (0.5, 1.7, and 5.0 mg i.v.), on the bronchoconstrictor response to rapid intravenous infusions of substance P (0.1 to 30 nmol/kg) in anesthetized, mechanically ventilated guinea pigs. The decreases in pulmonary conductance and dynamic compliance caused by substance P were greater in animals treated with either thiorphan or captopril than in control animals. Thiorphan (0.5 mg) had no effect on airway responsiveness to intravenously administered methacholine, whereas captopril (1.7 mg) caused a small increase in methacholine responsiveness. Both drugs significantly increased the recovery of immunoreactive substance P in arterial plasma after exogenous administration of the peptide. We conclude that degradation of substance P by both NEP and ACE is important for determining the magnitude of the bronchoconstriction caused by intravenous administration of this neuropeptide. These data suggest that conditions associated with diminished peptidase activity could result in enhanced responses to stimuli which cause the release of endogenous substance P.

Modelling responses of the inert-gas washout and MRI to bronchoconstriction.

PubMed

Foy, Brody H; Kay, David; Bordas, Rafel

2017-01-01

Many lung diseases lead to an increase in ventilation heterogeneity (VH). Two clinical practices for the measurement of patient VH are in vivo imaging, and the inert gas multiple breath washout (MBW). In this study computational modelling was used to compare the responses of MBW indices LCI and s cond and MRI measured global and local ventilation indices, σ r and σ local , to constriction of airways in the conducting zone of the lungs. The simulations show that s cond , LCI and σ r behave quite similarly to each other, all being sensitive to increases in the severity of constriction, while exhibiting little sensitivity to the depth at which constriction occurs. In contrast, the local MRI index σ local shows strong sensitivity to depth of constriction, but lowered sensitivity to constriction severity. We finish with an analysis of the sensitivity of MRI indices to grid sizes, showing that results should be interpreted with reference to the image resolution. Overall we conclude that the application of both local and global VH measures may help to classify different types of bronchoconstriction. Copyright © 2016 Elsevier B.V. All rights reserved.

Design and synthesis of novel sulfonamide-containing bradykinin hB2 receptor antagonists. 2. Synthesis and structure-activity relationships of alpha,alpha-cycloalkylglycine sulfonamides.

PubMed

Fattori, Daniela; Rossi, Cristina; Fincham, Christopher I; Caciagli, Valerio; Catrambone, Fernando; D'Andrea, Piero; Felicetti, Patrizia; Gensini, Martina; Marastoni, Elena; Nannicini, Rossano; Paris, Marielle; Terracciano, Rosa; Bressan, Alessandro; Giuliani, Sandro; Maggi, Carlo A; Meini, Stefania; Valenti, Claudio; Quartara, Laura

2007-02-08

Recently we reported on the design and synthesis of a novel class of selective nonpeptide bradykinin (BK) B2 receptor antagonists (J. Med. Chem. 2006, 3602-3613). This work led to the discovery of MEN 15442, an antagonist with subnanomolar affinity for the human B2 receptor (hB2R), which also displayed significant and prolonged activity in vivo (for up to 210 min) against BK-induced bronchoconstriction in the guinea-pig at a dose of 300 nmol/kg (it), while demonstrating only a slight effect on BK-induced hypotension. Here we describe the further optimization of this series of compounds aimed at maximizing the effect on bronchoconstriction and minimizing the effect on hypotension, with a view to developing topically delivered drugs for airway diseases. The work led to the discovery of MEN 16132, a compound which, after intratracheal or aerosol administration, inhibited, in a dose-dependent manner, BK-induced bronchoconstricton in the airways, while showing minimal systemic activity. This compound was selected as a preclinical candidate for the topical treatment of airway diseases involving kinin B2 receptor stimulation.

Enhanced neutrophil chemotactic activity after bronchial challenge in subjects with grain dust-induced asthma.

PubMed

Park, H S; Jung, K S

1998-03-01

There have been few reports suggesting involvement of neutrophils in induction of bronchoconstriction after inhalation of grain dust. To understand the role of neutrophils in pathogenesis of grain dust-induced asthma. We observed serum neutrophil chemotactic activity during grain dust-bronchoprovocation tests in six asthmatic subjects with positive bronchial challenges (group I). They were compared with those of six symptomatic subjects from the same workplace with negative bronchial challenges (group II). After grain dust inhalation, serum neutrophil chemotactic activity significantly increased at 30 minutes (P = .028), and then decreased to baseline level at 240 minutes (P = .028) in five subjects of group I having isolated early asthmatic responses. Enhanced neutrophil chemotactic activity was persistent for up to 240 minutes in one asthmatic subject having both early and late asthmatic responses. There was, however, no significant change in serum neutrophil chemotactic activity during bronchial challenges in subjects of group II. Pre-incubation of sera with anti-interleukin-8 (IL-8) antibody did not affect the neutrophil chemotactic activity results of group I subjects. These results suggest that enhanced neutrophil chemotactic activity distinct from IL-8 may contribute to significant bronchoconstriction induced by grain dust.

Implication of dipeptidylpeptidase IV activity in human bronchial inflammation and in bronchoconstriction evaluated in anesthetized rabbits.

PubMed

Landis, B N; Grouzmann, E; Monod, M; Busso, N; Petak, F; Spiliopoulos, A; Robert, J H; Szalay-Quinodoz, I; Morel, D R; Lacroix, J S

2008-01-01

Decreased dipeptidylpeptidase IV (DPPIV) activity within the human nasal mucosa has previously been shown to contribute to the severity of chronic inflammatory rhinosinusitis. To investigate and correlate the role of DPPIV activity with regard to bronchial inflammation. DPPIV/CD26 activity/concentration was investigated in the bronchial tissue of human subjects suffering from chronic bronchial inflammation. In addition, the effect of a recombinant Aspergillus fumigatus DPPIV (fuDPPIV) was investigated on histamine-induced bronchoconstriction in anesthetized rabbits. DPPIV/CD26 was present in submucosal seromucous glands, in leukocytes and to a very low degree in endothelial cells of human bronchi. DPPIV activity was correlated with tissue CD26 content measured by immunoassay. As previously reported for the nasal mucosa, DPPIV/CD26 activity was inversely correlated with the degree of airway inflammation. Systemic pretreatment with recombinant fuDPPIV markedly reduced the increase in histamine-induced airway resistance in rabbits. In conclusion, DPPIV activity modulates lower airway tone by degrading unknown peptidic substrates released by histamine in response to an allergen. Contrasting with our observations in the nose, this modulation is apparently not mediated via a neurokinin (NK1) receptor. (c) 2007 S. Karger AG, Basel.

Effects of omega-conotoxin GVIA on the activation of capsaicin-sensitive afferent sensory nerves in guinea pig airway tissues.

PubMed

Morimoto, H; Matsuda, A; Ohori, M; Fujii, T

1996-06-01

We examined the effects of Ca2+ channel antagonists on various respiratory reactions induced by the activation of capsaicin-sensitive afferent sensory nerves. Intravenous (i.v.) injection of the N-type Ca2+ channel antagonist omega-conotoxin GVIA (CgTX) (1-20 micrograms/kg) dose-dependently inhibited capsaicin-induced guinea pig bronchoconstriction, whereas i.v. administration of the L-type antagonist nicardipine (100 micrograms/kg), the P-type antagonist omega-agatoxin IVA (AgaTX) (20 micrograms/kg) or the OPQ family-type antagonist omega-conotoxin MVIIC (CmTX) (20 micrograms/kg) had no effect. However, CgTX (20 micrograms/kg) failed to inhibit substance P-induced guinea pig bronchoconstriction. CgTX (20 micrograms/kg) significantly inhibited cigarette smoke-induced guinea pig tracheal plasma extravasation, but not the substance P-induced reaction. CgTX also reduced electrical field stimulation-induced guinea pig bronchial smooth muscle contraction (0.01-10 microM) and capsaicin-induced substance P-like immunoreactivity release from guinea pig lung (0.14 microM). This evidence suggests that N-type Ca2+ channels modulate tachykinin release from capsaicin-sensitive afferent sensory nerve endings in guinea pig airway tissue.

Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides as potent and long acting muscarinic antagonists.

PubMed

Prat, Maria; Buil, María Antonia; Fernández, Maria Dolors; Tort, Laia; Monleón, Juan Manuel; Casals, Gaspar; Ferrer, Manuel; Castro, Jordi; Gavaldà, Amadeu; Miralpeix, Montserrat; Ramos, Israel; Vilella, Dolors; Huerta, Josep Maria; Espinosa, Sònia; Hernández, Begoña; Segarra, Victor; Córdoba, Mònica

2015-04-15

Novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides have been identified as potent M3 muscarinic antagonists with a long duration of action in an in vivo model of bronchoconstriction. The synthesis, structure-activity relationships and biological evaluation of this series of compounds are reported. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pulmonary Stress Induced by Hyperthermia: Role of Airway Sensory Nerves

DTIC Science & Technology

2011-10-01

patients with mild asthma, allergic rhinitis and upper respiratory infection, which makes these patients more susceptible to the bronchoconstriction...and other respiratory dysfunctions induced by thermal stress. There are two specific aims for the first year of this translational project: 1) To...dyspnea, airway constriction, cough, etc) in healthy volunteers, and in patients with mild asthma, allergic rhinitis and post upper respiratory

Swine confinement buildings: effects of airborne particles and settled dust on airway smooth muscles.

PubMed

Demanche, Annick; Bonlokke, Jakob; Beaulieu, Marie-Josee; Assayag, Evelyne; Cormier, Yvon

2009-01-01

Swine confinement workers are exposed to various contaminants. These agents can cause airway inflammation and bronchoconstriction. This study was undertaken to evaluate if the bronchoconstrictive effects of swine barn air and settled dust are mediated by endotoxin, and if these effects are directly mediated on airway smooth muscles. Mouse tracheas where isolated and mounted isometrically in organ baths. Tracheas, with or without epithelium, were attached to a force transducer and tension was recorded. Concentrated swine building air at 68 EU/ml or settled dust extract at 0.01 g/ml were added for 20 minutes and tracheal smooth muscle contraction was measured. Direct role of LPS was assessed by removing it from air concentrates with an endotoxin affinity resin. Swine barn air and settled dust extract caused contraction of tracheal smooth muscle by 26 and 20%, respectively, of the maximal induced by methacholine. Removal of epithelium did not affect the contractile effects. LPS alone and LPS with peptidoglycans did not induce contraction. However, when endotoxin was removed from swine barn air concentrates, it lost 24% of its contractile effect. Concentrated swine barn air and settled dust have direct effects on airway smooth muscles. This effect is partially due to LPS but a synergy with other components of the environment of swine confinement buildings is required.

Substance P in the nucleus of the solitary tract augments bronchopulmonary C fiber reflex output.

PubMed

Mutoh, T; Bonham, A C; Joad, J P

2000-10-01

Bronchopulmonary C fibers defend the lungs against injury from inhaled agents by a central nervous system reflex consisting of apnea, cough, bronchoconstriction, hypotension, and bradycardia. Glutamate is the putative neurotransmitter at the first central synapses in the nucleus of the solitary tract (NTS), but substance P, also released in the NTS, may modulate the transmission. To test the hypothesis that substance P in the NTS augments bronchopulmonary C fiber input and hence reflex output, we stimulated the C fibers with left atrial capsaicin (LA CAP) injections and compared the changes in phrenic nerve discharge, tracheal pressure (TP), arterial blood pressure (ABP), and heart rate (HR) in guinea pigs before and after substance P injections (200 microM, 25 nl) in the NTS. Substance P significantly augmented LA CAP-evoked increases in expiratory time by 10-fold and increases in TP and decreases in ABP and HR by threefold, effects prevented by neurokinin-1 (NK1) receptor antagonism. Thus substance P acting at NTS NK1 receptors can exaggerate bronchopulmonary C fiber reflex output. Because substance P synthesis in vagal airway C fibers may be enhanced in pathological conditions such as allergic asthma, the findings may help explain some of the associated respiratory symptoms including cough and bronchoconstriction.

Passive smoke effects on cough and airways in young guinea pigs: role of brainstem substance P.

PubMed

Joad, Jesse P; Munch, Paul A; Bric, John M; Evans, Samuel J; Pinkerton, Kent E; Chen, Chao-Yin; Bonham, Ann C

2004-02-15

Children raised with extended exposure to environmental tobacco smoke (ETS) experience increased cough and wheeze. This study was designed to determine whether extended ETS exposure enhances citric acid-induced cough and bronchoconstriction in young guinea pigs via a neurokinin-1 (NK-1) receptor mechanism at the first central synapse of lung afferent neurons, the nucleus tractus solitarius. Guinea pigs were exposed to ETS from 1 to 6 weeks of age. At 5 weeks of age, guide cannulae were implanted bilaterally in the medial nucleus tractus solitarius at a site that produced apnea in response to the glutamate agonist D,L-homocysteic acid. At 6 weeks of age, either vehicle or a NK-1 receptor antagonist, SR 140333, was injected into the nucleus tractus solitarius of the conscious guinea pigs who were then exposed to citric acid aerosol. ETS exposure significantly enhanced citric acid-induced cough by 56% and maximal Penh (a measure of airway obstruction) by 43%, effects that were attenuated by the NK-1 receptor antagonist in the nucleus tractus solitarius. We conclude that in young guinea pigs extended exposure to ETS increases citric acid-induced cough and bronchoconstriction in part by an NK-1 receptor mechanism in the nucleus tractus solitarius.

Genetic control of indirect airway responsiveness in the rat.

PubMed

Pauwels, R A; Germonpré, P R; Kips, J C; Joos, G F

1995-11-01

Many of the airway responses to endogenous and exogenous stimuli are caused by indirect mechanisms such as the activation of neurons and/or inflammatory cells. In the present study we compare the bronchoconstrictor and the plasma protein extravasation response to adenosine and tachykinins in two highly inbred rat strains, F344 and BDE. BDE-rats have a bronchoconstrictor response to adenosine at lower doses. Challenge with the A3-adenosine receptor agonist APNEA demonstrates that the difference in airway responsiveness to adenosine between BDE- and F344-rats is probably related to a higher number of A3-receptors on the airway mast cells of BDE-rats. In contrast, F344-rats have a higher airway responsiveness to tachykinins than BDE-rats. Tachykinins cause bronchoconstriction in F344-rats mainly by an indirect mechanism, involving stimulation of NK1-receptors and mast cell activation. In BDE-rats they cause bronchoconstriction by a direct effect on airway smooth muscle via activation of NK2-receptors. Finally we also observed a difference between F344- and BDE-rats with regard to the mechanisms involved in the plasma protein extravasation in the airways caused by substance P or capsaicin. In F344-rats but not in BDE-rats mast cell activation and the release of 5-hydroxytryptamine is partly responsible for this plasma protein extravasation.

Inhibition by calcitonin gene-related peptide of agonist-induced bronchoconstriction in various mammals including man.

PubMed

Cadieux, A; Lanoue, C

1990-01-01

The effect of calcitonin gene-related peptide (CGRP) on the smooth muscle of mammalian airways has been investigated in vitro. CGRP itself lacked contractile activity but reduced responses evoked by bronchoconstrictor agents via a post-junctional action. The inhibitory effect of CGRP was concentration-related and greatest in distal airways. The results suggest that CGRP may contribute to regulating muscular tone in the tracheobronchial tree.

Common causes of dyspnoea in athletes: a practical approach for diagnosis and management

PubMed Central

Mohseni, Zahra S.; Berwager, Jeffrey D.; Hegedus, Eric J.

2016-01-01

Key points “Dyspnoea” during exercise is a common complaint in seemingly otherwise healthy athletes, which may be associated with fatigue and underperformance. Because dyspnoea is an general term and may be caused by numerous factors, ranging from poor aerobic fitness to serious, potentially fatal respiratory and nonrespiratory pathologies, it is important for clinicians to obtain an appropriate case history and ask relevant exercise-specific questions to fully characterise the nature of the complaint so that a targeted diagnostic plan can be developed. Exercise-induced bronchoconstriction and exercise-induced laryngeal obstruction are two common causes of dyspnoea in athletes, and both are regularly misdiagnosed and mismanaged due to poor adherence to available practice parameters. Aside from airway dysfunction, iron deficiency and anaemia, infectious disease, and musculoskeletal conditions are common problems in athletes which ultimately may lead to complaints of dyspnoea. Educational aims To inform readers of the common causes of dyspnoea encountered in athletes. To highlight that airway diseases, such as asthma and exercise-induced bronchoconstriction, are commonly misdiagnosed and mismanaged. To introduce readers to common nonairway causes of dyspnoea in athletes, including clinical features and general principles of diagnosis, and management. To emphasise the importance of a detailed case history and proper adherence to established protocols in evaluating and managing the dyspnoeic athlete. To provide readers with a general framework of appropriate questions that are useful for developing a targeted diagnostic plan for evaluating dyspnoeic athletes. Dyspnoea during exercise is a common chief complaint in athletes and active individuals. It is not uncommon for dyspnoeic athletes to be diagnosed with asthma, “exercise-induced asthma” or exercise-induced bronchoconstriction based on their symptoms, but this strategy regularly leads to misdiagnosis and improper patient management. Dyspnoea during exercise can ultimately be caused by numerous respiratory and nonrespiratory conditions, ranging from nonpathological to potentially fatal in severity. As, such it is important for healthcare providers to be familiar with the many factors that can cause dyspnoea during exercise in seemingly otherwise-healthy individuals and have a general understanding of the clinical approach to this patient population. This article reviews common conditions that ultimately cause athletes to report dyspnoea and associated symptoms, and provides insight for developing an efficient diagnostic plan. PMID:27408644

Selective inhibition by dactinomycin of NANC sensory bronchoconstriction and [125I]NKA binding due to NK-2 receptor antagonism.

PubMed

Lou, Y P; Delay-Goyet, P; Lundberg, J M

1992-03-01

In the present study, dactinomycin (10(-5) M) inhibited the non-adrenergic, non-cholinergic bronchoconstriction upon antidromic vagal nerve stimulation (1 Hz for 1 min) in the isolated perfused guinea-pig lung by 84%. The release of calcitonin gene-related peptide was unchanged, however, suggesting a postjunctional action. Dactinomycin (10(-5), 5 x 10(-5) M) also reduced non-adrenergic non-cholinergic bronchial contractions (maximally by 75%) induced by electrical field stimulation or capsaicin, while the cholinergic component and non-adrenergic non-cholinergic relaxation remained intact. The neurokinin-2 receptor antagonist L-659,877 (10(-6) M) had a similar effect as dactinomycin, inhibiting the non-adrenergic non-cholinergic bronchial contractions by 69%, while the neurokinin-1 receptor antagonist CP-96,345 (10(-6) M) had no effect. The bronchoconstriction evoked by neurokinin A, the selective neurokinin-2 receptor agonist Nle10neurokinin A (4-10) and capsaicin was markedly inhibited by dactinomycin while the contraction induced by substance P (SP), the selective neurokinin-1 receptor agonist Sar9Met(O2)11SP, endothelin-1 and acetylcholine was not affected. In autoradiographic experiments on guinea-pig lung, [125I]neurokinin A-labelled sections showed dense binding in the bronchial smooth muscle layer. Dactinomycin inhibited the specific binding of [125I]neurokinin A in a concentration-dependent manner (IC50 = 6.3 x 10(-6) M) and 66% of [125I]neurokinin A total binding was inhibited by 10(-4) M dactinomycin. In the rat colon, [125I]neurokinin A binding to neurokinin-2 sites on circular smooth muscle was inhibited by dactinomycin with an IC50 value of 7.9 x 10(-6) M. Dactinomycin failed to reduce increased nerve-evoked contractions or those caused by Nle10neurokinin A (4-10) per se in the rat vas deferens, which are considered to be mediated by neurokinin-2 receptor activation. In the rat portal vein, dactinomycin did not influence the contractions caused by the neurokinin-3 selective agonist Pro7neurokinin B. In conclusion, dactinomycin selectively inhibited neurokinin-2 receptor activation in guinea-pig lung and rat colon, but not in rat vas deferens, which may depend on the existence of different neurokinin-2 receptor subtypes. Neurokinin A is most likely the main endogenous excitatory non-adrenergic non-cholinergic transmitter in guinea-pig bronchi.

Length oscillation induces force potentiation in infant guinea pig airway smooth muscle.

PubMed

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

2005-12-01

Deep inspiration counteracts bronchospasm in normal subjects but triggers further bronchoconstriction in hyperresponsive airways. Although the exact mechanisms for this contrary response by normal and hyperresponsive airways are unclear, it has been suggested that the phenomenon is related to changes in force-generating ability of airway smooth muscle after mechanical oscillation. It is known that healthy immature airways of both humans and animals exhibit hyperresponsiveness. We hypothesize that the profile of active force generation after mechanical oscillation changes with maturation and that this change contributes to the expression of airway hyperresponsiveness in juveniles. We examined the effect of an acute sinusoidal length oscillation on the force-generating ability of tracheal smooth muscle from 1 wk, 3 wk, and 2- to 3-mo-old guinea pigs. We found that the length oscillation produced 15-20% initial reduction in active force equally in all age groups. This was followed by a force recovery profile that displayed striking maturation-specific features. Unique to tracheal strips from 1-wk-old animals, active force potentiated beyond the maximal force generated before oscillation. We also found that actin polymerization was required in force recovery and that prostanoids contributed to the maturation-specific force potentiation in immature airway smooth muscle. Our results suggest a potentiated mechanosensitive contractile property of hyperresponsive airway smooth muscle. This can account for further bronchoconstriction triggered by deep inspiration in hyperresponsive airways.

Effect of the NEP inhibitor SCH32615 on airway responses to intravenous substance P in guinea pigs.

PubMed

Shore, S A; Martins, M A; Drazen, J M

1992-11-01

We examined the effects of the selective neutral endopeptidase (NEP) inhibitor SCH32615 on airway responses to rapid intravenous infusions of substance P (SP) and neurokinin A (NKA) and on recovery of administered tachykinins from arterial blood in anesthetized mechanically ventilated guinea pigs. SCH32615, in doses that cause a marked increase in the magnitude of bronchoconstriction induced by infused NKA, had little effect on the changes in pulmonary conductance (GL) or dynamic compliance induced by SP. In animals in which SCH32615 (1 mg/kg) was administered in combination with the angiotensin-converting enzyme (ACE) inhibitor captopril (5.7 mg/kg), the dose of SP required to decrease GL by 50% was fourfold less than in animals that received captopril alone (P < 0.005). SP measured in arterial blood withdrawn within 45 s of intravenous administration of this tachykinin was not different in control and SCH32615-treated animals, whereas captopril caused an approximately threefold increase in SP concentrations (P < 0.005). When SCH32615 and captopril were administered together, significantly more SP was recovered than when captopril or SCH32615 was administered alone (P < 0.0005). Our results are consistent with the hypothesis that both NEP and ACE contribute to the degradation of intravenously infused SP. ACE degradation of SP is sufficient to limit SP-induced bronchoconstriction even in the presence of specific NEP inhibition.

Potentiation of pulmonary reflex response to capsaicin 24h following whole-body acrolein exposure is mediated by TRPV1.

PubMed

Hazari, Mehdi S; Rowan, William H; Winsett, Darrell W; Ledbetter, Allen D; Haykal-Coates, Najwa; Watkinson, William P; Costa, Daniel L

2008-02-01

Pulmonary C-fibers are stimulated by irritant air pollutants producing apnea, bronchospasm, and decrease in HR. Chemoreflex responses resulting from C-fiber activation are sometimes mediated by TRPV1 and release of substance P. While acrolein has been shown to stimulate C-fibers, the persistence of acrolein effects and the role of C-fibers in these responses are unknown. These experiments were designed to determine the effects of whole-body acrolein exposure and pulmonary chemoreflex response post-acrolein. Rats were exposed to either air or 3 ppm acrolein for 3 h while ventilatory function and HR were measured; 1-day later response to capsaicin challenge was measured in anesthetized rats. Rats experienced apnea and decrease in HR upon exposure to acrolein, which was not affected by either TRPV1 antagonist or NK(1)R antagonist pretreatment. Twenty-four hours later, capsaicin caused apnea and bronchoconstriction in control rats, which was potentiated in rats exposed to acrolein. Pretreatment with TRPV1 antagonist or NK(1)R antagonist prevented potentiation of apneic response and bronchoconstriction 24h post-exposure. These data suggest that although potentiation of pulmonary chemoreflex response 24h post-acrolein is mediated by TRPV1 and release of substance P, cardiopulmonary inhibition during whole-body acrolein exposure is mediated through other mechanisms.

Use of steroidal antiinflammatory drug provides further evidence for a potential role of PAF-acether in bronchial anaphylaxis.

PubMed

Chignard, M; Le Còuedic, J P; Andersson, P; Brange, C

1986-01-01

We presently demonstrate that PAF-acether (1-O-alkyl-2-O-acetyl-sn-glycerol-3-phosphoryl-choline) is formed by sensitized guinea pig lungs upon in vitro antigenic challenge. Pretreatment of the animals with a steroidal antiinflammatory drug, budesonide, almost totally suppresses this biosynthesis. Since budesonide inhibits the anaphylactic bronchoconstriction in actively sensitized guinea pigs, these data strongly support the assumption that PAF-acether is a mediator of bronchial anaphylaxis.

The 5-lipoxygenase inhibitor RF-22c potently suppresses leukotriene biosynthesis in cellulo and blocks bronchoconstriction and inflammation in vivo.

PubMed

Schaible, Anja M; Filosa, Rosanna; Krauth, Verena; Temml, Veronika; Pace, Simona; Garscha, Ulrike; Liening, Stefanie; Weinigel, Christina; Rummler, Silke; Schieferdecker, Sebastian; Nett, Markus; Peduto, Antonella; Collarile, Selene; Scuotto, Maria; Roviezzo, Fioretina; Spaziano, Giuseppe; de Rosa, Mario; Stuppner, Hermann; Schuster, Daniela; D'Agostino, Bruno; Werz, Oliver

2016-07-15

5-Lipoxygenase (5-LO) catalyzes the first two steps in leukotriene (LT) biosynthesis. Because LTs play pivotal roles in allergy and inflammation, 5-LO represents a valuable target for anti-inflammatory drugs. Here, we investigated the molecular mechanism, the pharmacological profile, and the in vivo effectiveness of the novel 1,2-benzoquinone-featured 5-LO inhibitor RF-22c. Compound RF-22c potently inhibited 5-LO product synthesis in neutrophils and monocytes (IC50⩾22nM) and in cell-free assays (IC50⩾140nM) without affecting 12/15-LOs, cyclooxygenase (COX)-1/2, or arachidonic acid release, in a specific and reversible manner, supported by molecular docking data. Antioxidant or iron-chelating properties were not evident for RF-22c and 5-LO-regulatory cofactors like Ca(2+) mobilization, ERK-1/2 activation, and 5-LO nuclear membrane translocation and interaction with 5-LO-activating protein (FLAP) were unaffected. RF-22c (0.1mg/kg; i.p.) impaired (I) bronchoconstriction in ovalbumin-sensitized mice challenged with acetylcholine, (II) exudate formation in carrageenan-induced paw edema, and (III) zymosan-induced leukocyte infiltration in air pouches. Taken together, RF-22c is a highly selective and potent 5-LO inhibitor in intact human leukocytes with pronounced effectiveness in different models of inflammation that warrants further preclinical analysis of this agent as anti-inflammatory drug. Copyright © 2016 Elsevier Inc. All rights reserved.

4-D segmentation and normalization of 3He MR images for intrasubject assessment of ventilated lung volumes

NASA Astrophysics Data System (ADS)

Contrella, Benjamin; Tustison, Nicholas J.; Altes, Talissa A.; Avants, Brian B.; Mugler, John P., III; de Lange, Eduard E.

2012-03-01

Although 3He MRI permits compelling visualization of the pulmonary air spaces, quantitation of absolute ventilation is difficult due to confounds such as field inhomogeneity and relative intensity differences between image acquisition; the latter complicating longitudinal investigations of ventilation variation with respiratory alterations. To address these potential difficulties, we present a 4-D segmentation and normalization approach for intra-subject quantitative analysis of lung hyperpolarized 3He MRI. After normalization, which combines bias correction and relative intensity scaling between longitudinal data, partitioning of the lung volume time series is performed by iterating between modeling of the combined intensity histogram as a Gaussian mixture model and modulating the spatial heterogeneity tissue class assignments through Markov random field modeling. Evaluation of the algorithm was retrospectively applied to a cohort of 10 asthmatics between 19-25 years old in which spirometry and 3He MR ventilation images were acquired both before and after respiratory exacerbation by a bronchoconstricting agent (methacholine). Acquisition was repeated under the same conditions from 7 to 467 days (mean +/- standard deviation: 185 +/- 37.2) later. Several techniques were evaluated for matching intensities between the pre and post-methacholine images with the 95th percentile value histogram matching demonstrating superior correlations with spirometry measures. Subsequent analysis evaluated segmentation parameters for assessing ventilation change in this cohort. Current findings also support previous research that areas of poor ventilation in response to bronchoconstriction are relatively consistent over time.

Prevention of abnormal pulmonary mechanics in the postmortem guinea pig lung.

PubMed

Reynolds, A M; McEvoy, R D

1988-04-01

Severe postmortem bronchoconstriction has been shown previously in guinea pig lungs and linked to pulmonary blood loss during exsanguination (Lai et al., J. Appl. Physiol. 56: 308-314, 1984). To reexamine this phenomenon we measured postmortem airway function in anesthetized open-chest guinea pigs after sudden circulatory arrest. Animals were divided into 4 groups of 10 and ventilated for 15 min postmortem with different gases: 1) room air, 2) conditioned air, 3) dry 5% CO2-21% O2-74% N2, and 4) conditioned 5% CO2-21% O2-74% N2. In room air-ventilated lungs there was a 50% decrease in dynamic compliance (Cdyn) by 15 min and marked gas trapping compared with control lungs. Conditioning the room air did not attenuate these changes, but when 5% CO2 was added to the conditioned postmortem inspirate, gas trapping was eliminated and the fall in Cdyn was almost abolished. Ventilation with a dry 5% CO2 gas mixture at room temperature resulted in a 31% fall in Cdyn at 15 min but no gas trapping. We conclude that marked abnormalities of airway function occur postmortem in room air-ventilated guinea pig lungs in the absence of pulmonary blood loss. The changes are mainly due to airway hypocarbia, a known cause of bronchoconstriction, but a reduction in Cdyn can also occur if there is marked airway cooling and drying. Acute postmortem airway dysfunction can be prevented in the guinea pig by maintaining normal airway gas composition.

KF19514, a phosphodieterase 4 and 1 inhibitor, inhibits PAF-induced lung inflammatory responses by inhaled administration in guinea pigs.

PubMed

Manabe, H; Akuta, K; Okamura, K; Ohmori, K

1997-12-01

Phosphodiesterase (PDE) 4 inhibitors are well known for their inhibitory effect on bronchoconstriction and inflammation and may be promising anti-asthma drugs. Platelet-activating factor (PAF) has been proposed as an inflammatory mediator to be relevant to asthma. It causes bronchoconstriction, airway microvascular leakage, inflammatory cell accumulation in the lung and hyperresponsiveness. In this study, we therefore have investigated the anti-asthmatic effects of the inhaled KF19514 [5-phenyl-3'-(3-pyridyl)methyl-3H-imidazo(4,5-c)(1,8) naphthyridin-4(5H)-one], a PDE 4 and 1 inhibitor, on PAF-induced lung inflammatory responses in guinea pigs. The inhaled KF19514 (0.0001-0.01%) significantly inhibited PAF-induced eosinophil and neutrophil accumulation into the airway and hyperresponsiveness in guinea pigs. The IC50 value of KF19514 against eosinophil accumulation was 14.8 microM (0.00063%). Moreover, the effect of KF19514 on the electrical field stimulation-induced bronchial contraction was examined using the main bronchi of guinea pigs in vitro. KF19514 inhibited both cholinergic and tachykininergic contraction and, in particular, produced a potent inhibitory effect on tachykininergic contraction (IC50 = 0.49 microM). The mechanism by which KF19514 inhibited the PAF-induced hyperresponsiveness may in part be the suppression of the tachykinin release. Based on these results, it was demonstrated that the inhaled KF19514 might have a significant potential effect on the inflammatory cell accumulation and hyperresponsiveness induced by PAF.

Effect of the glucocorticosteroid budesonide and a novel phosphodiesterase type 4 inhibitor CDP840 on antigen-induced airway responses in neonatally immunised rabbits.

PubMed Central

Gozzard, N.; el-Hashim, A.; Herd, C. M.; Blake, S. M.; Holbrook, M.; Hughes, B.; Higgs, G. A.; Page, C. P.

1996-01-01

1. The effects of the inhaled corticosteroid budesonide and a novel PDE 4 inhibitor CDP840 given systematically, were evaluated in a model of antigen-induced airway inflammation in the rabbit. 2. Adult litter-matched NZW rabbits (2.4-3.5 kg) immunised within 24 h of birth with Alternaria tenuis antigen were pretreated with budesonide (total dose 100 micrograms, inhaled over 2 days) or CDP840 (total dose 7 mg kg-1, i.p. over 3 days), before antigen challenge. For each drug-treated group a parallel group of rabbits was pretreated with the appropriate vehicle. In all groups airway responsiveness to inhaled histamine was assessed and bronchoalveolar lavage (BAL) performed 24 h before and after antigen challenge. 3. Basal lung function in terms of total lung resistance (RL; cmH2O l 1s-1) and dynamic compliance (Cdyn; ml cmH2O-1) were unaltered by pretreatment with budesonide or CDP840 compared to their respective vehicles 24 h before or after antigen challenge. 4. The RL component of the acute bronchoconstriction induced by inhaled Alternaria tenuis aerosol was unaffected by pretreatment with budesonide. However, budesonide prevented the fall in Cdyn due to antigen. Treatment with CDP840 significantly reduced antigen-induced acute bronchoconstriction in terms of both RL and Cdyn. 5. Airway hyperresponsiveness (AHR) to inhaled histamine was indicated by reduced RL PC50 (2.4-4.5 fold) and Cdyn PC35 (2.1-3.9 fold) values 24 h after antigen challenge. Treatment with either budesonide or CDP840 abolished the antigen-induced increase in responsiveness to inhaled histamine. 6. Total cells recovered per ml of BAL fluid increased 24 h after antigen challenge. Antigen-induced pulmonary eosinophilia was reduced (93%) in budesonide and (85%) in CDP840 treated rabbits. Antigen-induced increases in neutrophil numbers were reduced (76%) with budesonide but not CDP840 pretreatment. 7. Inhalation of Alternaria tenuis aerosol elicited an acute bronchoconstriction, followed 24 hours later by an increased responsiveness to inhaled histamine and pulmonary neutrophil and eosinophil recruitment. CDP840 was more effective than budesonide in preventing the antigen-induced increase in total lung resistance (RL); however, both drugs prevented the antigen-induced reduction in dynamic compliance (Cdyn). CDP840 and budesonide also prevented antigen-induced AHR and eosinophilia in the immunised rabbit. PMID:8818344

Exercise-induced bronchoconstriction alters airway nitric oxide exchange in a pattern distinct from spirometry.

PubMed

Shin, Hye-Won; Schwindt, Christina D; Aledia, Anna S; Rose-Gottron, Christine M; Larson, Jennifer K; Newcomb, Robert L; Cooper, Dan M; George, Steven C

2006-12-01

Exhaled nitric oxide (NO) is altered in asthmatic subjects with exercise-induced bronchoconstriction (EIB). However, the physiological interpretation of exhaled NO is limited because of its dependence on exhalation flow and the inability to distinguish completely proximal (large airway) from peripheral (small airway and alveolar) contributions. We estimated flow-independent NO exchange parameters that partition exhaled NO into proximal and peripheral contributions at baseline, postexercise challenge, and postbronchodilator administration in steroid-naive mild-intermittent asthmatic subjects with EIB (24-43 yr old, n = 9) and healthy controls (20-31 yr old, n = 9). The mean +/- SD maximum airway wall flux and airway diffusing capacity were elevated and forced expiratory flow, midexpiratory phase (FEF(25-75)), forced expiratory volume in 1 s (FEV(1)), and FEV(1)/forced vital capacity (FVC) were reduced at baseline in subjects with EIB compared with healthy controls, whereas the steady-state alveolar concentration of NO and FVC were not different. Compared with the response of healthy controls, exercise challenge significantly reduced FEV(1) (-23 +/- 15%), FEF(25-75) (-37 +/- 18%), FVC (-12 +/- 12%), FEV(1)/FVC (-13 +/- 8%), and maximum airway wall flux (-35 +/- 11%) relative to baseline in subjects with EIB, whereas bronchodilator administration only increased FEV(1) (+20 +/- 21%), FEF(25-75) (+56 +/- 41%), and FEV(1)/FVC (+13 +/- 9%). We conclude that mild-intermittent steroid-naive asthmatic subjects with EIB have altered airway NO exchange dynamics at baseline and after exercise challenge but that these changes occur by distinct mechanisms and are not correlated with alterations in spirometry.

Airway constriction in asthma during sustained emotional stimulation with films.

PubMed

Ritz, Thomas; Rosenfield, David; Wilhelm, Frank H; Roth, Walton T

2012-09-01

Individuals with asthma have been shown to respond to unpleasant stimuli with bronchoconstriction, but little is known about the time course of responding during sustained emotional stimulation and whether it varies with patients' experience. To examine the time course of oscillatory resistance (R(os)) during emotionally evocative films in 15 asthma patients and 14 healthy controls. Participants viewed unpleasant, surgery, and neutral films, each ranging 3-5min in duration. R(os) and the respiratory pattern (respiration rate, tidal volume, minute ventilation) were monitored continuously. Following each film, participants rated their affective response and symptoms. The time course of R(os) during films was explored using multilevel modeling. Compared to neutral film sequences, unpleasant films (including those with surgery scenes) elicited a uniform pattern of initial increases in R(os) with peaks within the first 1-2min, followed by a gradual decline. Increases were more pronounced in asthma and during surgery films. Including additional respiratory parameters as time-varying covariates did not affect the temporal course of R(os) change. The rate of decline in R(os) (after the initial increase) was less in participants who experienced greater arousal and in patients who reported more shortness of breath. Patients more susceptible to psychological triggers in daily life showed slower rates of decline in R(os). The temporal course of bronchoconstriction to unpleasant stimulation is highly uniform in asthma, with strong constriction in early stages of stimulation. More sustained constriction in emotion-induced asthma could be a risk factor for developing asthma exacerbation in daily life. Copyright © 2012 Elsevier B.V. All rights reserved.

Smooth muscle in the maintenance of increased airway resistance elicited by methacholine in humans.

PubMed

Chapman, David G; Pascoe, Chris D; Lee-Gosselin, Audrey; Couture, Christian; Seow, Chun Y; Paré, Peter D; Salome, Cheryl M; King, Gregory G; Bossé, Ynuk

2014-10-15

Airway narrowing is maintained for a prolonged period after acute bronchoconstriction in humans in the absence of deep inspirations (DIs). To determine whether maintenance of airway smooth muscle (ASM) shortening is responsible for the persistence of airway narrowing in healthy subjects following transient methacholine (MCh)-induced bronchoconstriction. On two separate visits, five healthy subjects underwent MCh challenges until respiratory system resistance (Rrs) had increased by approximately 1.5 cm H2O/L/s. Subjects took a DI either immediately after or 30 minutes after the last dose. The extent of renarrowing following the bronchodilator effect of DI was used to assess the continued action of MCh (calculated as percent change in Rrs from the pre-DI Rrs). We then used human bronchial rings to determine whether ASM can maintain shortening during a progressive decrease of carbachol concentration. The increased Rrs induced by MCh was maintained for 30 minutes despite waning of MCh concentration over that period, measured as attenuated renarrowing when the DI was taken 30 minutes after compared with immediately after the last dose (7 min post-DI, -36.2 ± 11.8 vs. 14.4 ± 13.2%; 12 min post-DI, -39.5 ± 9.8 vs. 15.2 ± 17.8%). Ex vivo, ASM shortening was largely maintained during a progressive decrease of carbachol concentration, even down to concentrations that would not be expected to induce shortening. The maintenance of airway narrowing despite MCh clearance in humans is attributed to an intrinsic ability of ASM to maintain shortening during a progressive decrease of contractile stimulation.

Roflumilast attenuates allergen-induced inflammation in mild asthmatic subjects.

PubMed

Gauvreau, Gail M; Boulet, Louis-Philippe; Schmid-Wirlitsch, Christine; Côté, Johanne; Duong, Mylinh; Killian, Kieran J; Milot, Joanne; Deschesnes, Francine; Strinich, Tara; Watson, Richard M; Bredenbröker, Dirk; O'Byrne, Paul M

2011-10-26

Phosphodiesterase 4 (PDE4) inhibitors increase intracellular cyclic adenosine monophosphate (cAMP), leading to regulation of inflammatory cell functions. Roflumilast is a potent and targeted PDE4 inhibitor. The objective of this study was to evaluate the effects of roflumilast on bronchoconstriction, airway hyperresponsiveness (AHR), and airway inflammation in mild asthmatic patients undergoing allergen inhalation challenge. 25 subjects with mild allergic asthma were randomized to oral roflumilast 500 mcg or placebo, once daily for 14 days in a double-blind, placebo-controlled, crossover study. Allergen challenge was performed on Day 14, and FEV1 was measured until 7 h post challenge. Methacholine challenge was performed on Days 1 (pre-dose), 13 (24 h pre-allergen), and 15 (24 h post-allergen), and sputum induction was performed on Days 1, 13, 14 (7 h post-allergen), and 15. Roflumilast inhibited the allergen-induced late phase response compared to placebo; maximum % fall in FEV1 (p = 0.02) and the area under the curve (p = 0.01). Roflumilast had a more impressive effect inhibiting allergen-induced sputum eosinophils, neutrophils, and eosinophil cationic protein (ECP) at 7 h post-allergen (all p = 0.02), and sputum neutrophils (p = 0.04), ECP (p = 0.02), neutrophil elastase (p = 0.0001) and AHR (p = 0.004) at 24 h post-allergen. This study demonstrates a protective effect of roflumilast on allergen-induced airway inflammation. The observed attenuation of sputum eosinophils and neutrophils demonstrates the anti-inflammatory properties of PDE4 inhibition and supports the roles of both cell types in the development of late phase bronchoconstriction and AHR. ClinicalTrials.gov: NCT01365533.

Allergies and Exercise-Induced Bronchoconstriction in a Youth Academy and Reserve Professional Soccer Team.

PubMed

Bougault, Valérie; Drouard, François; Legall, Franck; Dupont, Grégory; Wallaert, Benoit

2017-09-01

A high prevalence of respiratory allergies and exercise-induced bronchoconstriction (EIB) has been reported among endurance athletes. This study was designed to analyze the frequency of sensitization to respiratory allergens and EIB in young soccer players. Prospective cohort design. Youth academy and reserve professional soccer team during the seasons 2012 to 2013 and 2013 to 2014. Eighty-five soccer players (mean age: 20 ± 4 years) participated. Players underwent skin prick tests (SPTs) during the seasons 2012 to 2013 and 2013 to 2014. Spirometry and a eucapnic voluntary hyperpnea test were performed on soccer players during the first season 2012 to 2013 (n = 51) to detect EIB. Two self-administered questionnaires on respiratory history and allergic symptoms (European Community Respiratory Health Survey and Allergy Questionnaire for Athletes) were also distributed during both seasons (n = 59). The number of positive SPTs, exercise-induced respiratory symptoms, presence of asthma, airway obstruction, and EIB. Forty-nine percent of players were sensitized to at least one respiratory allergen, 33% reported an allergic disease, 1 player presented airway obstruction at rest, and 16% presented EIB. Factors predictive of EIB were self-reported exercise-induced symptoms and sensitization to at least 5 allergens. Questioning players about exercise-induced respiratory symptoms and allergies as well as spirometry at the time of the inclusion medical checkup would improve management of respiratory health of soccer players and would constitute inexpensive preliminary screening to select players requiring indirect bronchial provocation test or SPTs. This study showed that despite low frequencies, EIB and allergies are underdiagnosed and undertreated in young soccer players.

Neutrophil infiltration and release of IL-8 in airway mucosa from subjects with grain dust-induced occupational asthma.

PubMed

Park, H S; Jung, K S; Hwang, S C; Nahm, D H; Yim, H E

1998-06-01

The immuno-pathological mechanism for occupational asthma induced by grain dust (GD) remains to be clarified. There have been few reports suggesting the involvement of neutrophils inducing bronchoconstriction after inhalation of GD. To further understand the role of neutrophil in the pathogenesis of GD-induced asthma. We studied the phenotype of leucocytes of the bronchial mucosa in patients with GD-induced asthma. Bronchial biopsy specimens were obtained by fibreoptic bronchoscopy from six subjects with GD-induced asthma. Six allergic asthma patients sensitive to house dust mite were enrolled as controls. Bronchial biopsy specimens were examined by immunohistochemistry with a panel of monoclonal antibodies to tryptase-containing mast cell (AA1), activated eosinophil (EG2), pan T-lymphocyte (CD3) and neutrophil elastase (NE). Induced sputum was collected before and after the GD-bronchoprovocation test. The IL-8 level in the sputum was measured using ELISA. There was a significant increase in the number of AA1+ and NE+ cells in bronchial mucosa of GD-induced asthma, compared with those of allergic asthma (P=0.01, P=0.01, respectively). No significant differences were observed in the number of EG2+ and CD3+ cells (P = 0.13, P=0.15, respectively). IL-8 was abundant in the sputum of all GD-induced asthma patients and significantly increased after the bronchial challenges compared with the baseline value (P = 0.03). These findings support the view that neutrophil recruitment together with mast cells may contribute to the bronchoconstriction induced by GD. A possible involvement of IL-8 was suggested.

Thoracic vagal efferent nerve stimulation evokes substance P-induced early airway bronchonstriction and late proinflammatory and oxidative injury in the rat respiratory tract.

PubMed

Li, Ping-Chia; Li, Sheng-Chung; Lin, Yuan-Ju; Liang, Jin-Tung; Chien, Chiang-Ting; Shaw, Chen-Fu

2005-01-01

Electrical stimulation of efferent thoracic vagus nerve (TVN) evoked neurogenic inflammation in respiratory tract of atropine-treated rats by an undefined mechanism. We explored whether efferent TVN stimulation via substance P facilitates neurogenic inflammation via action of nuclear factor-kappaB (NF-kappaB) activation and reactive oxygen species (ROS) production. Our results showed that increased frequency of TVN stimulation concomitantly increased substance P-enhanced hypotension, and bronchoconstriction (increases in smooth muscle electromyographic activity and total pulmonary resistance). The enhanced SP release evoked the appearance of endothelial gap in silver-stained leaky venules, India-ink labeled extravasation, and accumulations of inflammatory cells in the respiratory tract, contributing to trachea plasma extravasation as well as increases in blood O (2)(-) and H(2)O(2) ROS amount. L-732138 (NK(1) receptor antagonist), SR-48968 (NK(2) receptor antagonist), dimethylthiourea (H(2)O(2) scavenger) or catechins (O (2)(-) and H(2)O(2) scavenger) pretreatment reduced efferent TVN stimulation-enhanced hypotension, bronchoconstriction, and plasma extravasation. Increased frequency of TVN stimulation significantly upregulated the expression of nuclear factor-kappaB (NF-kappaB) in nuclear protein and intercellular adhesion molecule-1 (ICAM-1) in total protein of the lower respiratory tract tissue. The upregulation of NF-kappaB and ICAM-1 was attenuated by NK receptor antagonist and antioxidants. In conclusion, TVN efferent stimulation increases substance P release to trigger NF-kappaB mediated ICAM-1 expression and O (2)(-) and H(2)O(2) ROS production in the respiratory tract.

Effects of sodium metabisulphite on guinea pig contractile airway smooth muscle responses in vitro.

PubMed

Sun, J; Sakamoto, T; Chung, K F

1995-08-01

Sodium metabisulphite (MBS) is known to induce bronchoconstriction in asthmatic patients. The effects of MBS on guinea pig airway smooth muscle and on neurally mediated contraction in vitro have been examined. Tracheal and bronchial airway segments were placed in oxygenated buffer solution and electrical field stimulation was performed in the presence of indomethacin (10(-5) M) and propranolol (10(-6) M) for the measurement of isometric tension. Atropine (10(-6) M) was added to bronchial tissues. Concentrations of MBS up to 10(-3) M had no direct effect on airway smooth muscle contraction and did not alter either tracheal smooth muscle contraction induced by electrical field stimulation at all frequencies or acetylcholine-induced tracheal smooth muscle contraction. There was a similar response in the absence of epithelium, except for potentiation of the response induced by electrical field stimulation at 0.5 Hz (24 (10)% increase). However, MBS (10(-5), 10(-6) and 10(-7) M) augmented neurally-mediated non-adrenergic non-cholinergic contractile responses in the bronchi (13.3 (3.2)%, 23.8 (9.6)%, and 6.4 (1.6)%, respectively). MBS had no effect on the contractile response induced by substance P, but at higher concentrations (10(-3) M and 10(-4) M) it caused a time-dependent attenuation of responses induced by either electrical field stimulation or exogenously applied acetylcholine or substance P. MBS had no direct contractile responses but enhanced bronchoconstriction induced by activation of non-cholinergic neural pathways in the bronchus, probably through increased release of neuropeptides. At high concentrations MBS inhibited contractile responses initiated by receptor or neural stimulation.

Asthma, surgery, and general anesthesia: a review.

PubMed

Tirumalasetty, Jyothi; Grammer, Leslie C

2006-05-01

Over 20 million Americans are affected with asthma. Many will require some type of surgical procedure during which their asthma management should be optimized. Preoperative assessment of asthma should include a specialized history and physical as well as pulmonary function testing. In many asthmatic patients, treatment with systemic corticosteroids and bronchodilators is indicated to prevent the inflammation and bronchoconstriction associated with endotracheal intubation. The use of corticosteroids has not been shown to adversely affect wound healing or increase the rate of infections postoperatively. Preoperative systemic corticosteroids may be used safely in the majority of patients to decrease asthma-related morbidity.

Hypothesis: Hemolytic Transfusion Reactions Represent an Alternative Type of Anaphylaxis

PubMed Central

Hod, Eldad A.; Sokol, Set A.; Zimring, James C.; Spitalnik, Steven L.

2009-01-01

Classical anaphylaxis is the most severe, and potentially fatal, type of allergic reaction, manifested by hypotension, bronchoconstriction, and vascular permeability. Similarly, a hemolytic transfusion reaction (HTR) is the most feared consequence of blood transfusion. Evidence for the existence of an alternative, IgG-mediated pathway of anaphylaxis may be relevant for explaining the pathophysiology of IgG-mediated-HTRs. The purpose of this review is to summarize the evidence for this alternative pathway of anaphylaxis and to present the hypothesis that an IgG-mediated HTR is one example of this type of anaphylaxis. PMID:18830382

Phospholipase A2 in experimental allergic bronchitis: a lesson from mouse and rat models.

PubMed

Mruwat, Rufayda; Yedgar, Saul; Lavon, Iris; Ariel, Amiram; Krimsky, Miron; Shoseyov, David

2013-01-01

Phospholipases A2 (PLA2) hydrolyzes phospholipids, initiating the production of inflammatory lipid mediators. We have previously shown that in rats, sPLA2 and cPLA2 play opposing roles in the pathophysiology of ovalbumin (OVA)-induced experimental allergic bronchitis (OVA-EAB), an asthma model: Upon disease induction sPLA2 expression and production of the broncho-constricting CysLTs are elevated, whereas cPLA2 expression and the broncho-dilating PGE2 production are suppressed. These were reversed upon disease amelioration by treatment with an sPLA2 inhibitor. However, studies in mice reported the involvement of both sPLA2 and cPLA2 in EAB induction. To examine the relevance of mouse and rat models to understanding asthma pathophysiology. OVA-EAB was induced in mice using the same methodology applied in rats. Disease and biochemical markers in mice were compared with those in rats. As in rats, EAB in mice was associated with increased mRNA of sPLA2, specifically sPLA2gX, in the lungs, and production of the broncho-constricting eicosanoids CysLTs, PGD2 and TBX2 in bronchoalveolar lavage (BAL). In contrast, EAB in mice was associated also with elevated cPLA2 mRNA and PGE2 production. Yet, treatment with an sPLA2 inhibitor ameliorated the EAB concomitantly with reverting the expression of both cPLA2 and sPLA2, and eicosanoid production. In both mice and rats sPLA2 is pivotal in OVA-induced EAB. Yet, amelioration of asthma markers in mouse models, and human tissues, was observed also upon cPLA2 inhibition. It is plausible that airway conditions, involving multiple cell types and organs, require the combined action of more than one, essential, PLA2s.

Btk Inhibitor RN983 Delivered by Dry Powder Nose-only Aerosol Inhalation Inhibits Bronchoconstriction and Pulmonary Inflammation in the Ovalbumin Allergic Mouse Model of Asthma.

PubMed

Phillips, Jonathan E; Renteria, Lorena; Burns, Lisa; Harris, Paul; Peng, Ruoqi; Bauer, Carla M T; Laine, Dramane; Stevenson, Christopher S

2016-06-01

In allergen-induced asthma, activated mast cells start the lung inflammatory process with degranulation, cytokine synthesis, and mediator release. Bruton's tyrosine kinase (Btk) activity is required for the mast cell activation during IgE-mediated secretion. This study characterized a novel inhaled Btk inhibitor RN983 in vitro and in ovalbumin allergic mouse models of the early (EAR) and late (LAR) asthmatic response. RN983 potently, selectively, and reversibly inhibited the Btk enzyme. RN983 displayed functional activities in human cell-based assays in multiple cell types, inhibiting IgG production in B-cells with an IC50 of 2.5 ± 0.7 nM and PGD2 production from mast cells with an IC50 of 8.3 ± 1.1 nM. RN983 displayed similar functional activities in the allergic mouse model of asthma when delivered as a dry powder aerosol by nose-only inhalation. RN983 was less potent at inhibiting bronchoconstriction (IC50(RN983) = 59 μg/kg) than the β-agonist salbutamol (IC50(salbutamol) = 15 μg/kg) in the mouse model of the EAR. RN983 was more potent at inhibiting the antigen induced increase in pulmonary inflammation (IC50(RN983) = <3 μg/kg) than the inhaled corticosteroid budesonide (IC50(budesonide) = 27 μg/kg) in the mouse model of the LAR. Inhalation of aerosolized RN983 may be effective as a stand-alone asthma therapy or used in combination with inhaled steroids and β-agonists in severe asthmatics due to its potent inhibition of mast cell activation.

Aspirin provocation increases 8-iso-PGE2 in exhaled breath condensate of aspirin-hypersensitive asthmatics.

PubMed

Mastalerz, Lucyna; Januszek, Rafał; Kaszuba, Marek; Wójcik, Krzysztof; Celejewska-Wójcik, Natalia; Gielicz, Anna; Plutecka, Hanna; Oleś, Krzysztof; Stręk, Paweł; Sanak, Marek

2015-09-01

Isoprostanes are bioactive compounds formed by non-enzymatic oxidation of polyunsaturated fatty acids, mostly arachidonic, and markers of free radical generation during inflammation. In aspirin exacerbated respiratory disease (AERD), asthmatic symptoms are precipitated by ingestion of non-steroid anti-inflammatory drugs capable for pharmacologic inhibition of cyclooxygenase-1 isoenzyme. We investigated whether aspirin-provoked bronchoconstriction is accompanied by changes of isoprostanes in exhaled breath condensate (EBC). EBC was collected from 28 AERD subjects and 25 aspirin-tolerant asthmatics before and after inhalatory aspirin challenge. Concentrations of 8-iso-PGF2α, 8-iso-PGE2, and prostaglandin E2 were measured using gas chromatography/mass spectrometry. Leukotriene E4 was measured by immunoassay in urine samples collected before and after the challenge. Before the challenge, exhaled 8-iso-PGF2α, 8-iso-PGE2, and PGE2 levels did not differ between the study groups. 8-iso-PGE2 level increased in AERD group only (p=0.014) as a result of the aspirin challenge. Urinary LTE4 was elevated in AERD, both in baseline and post-challenge samples. Post-challenge airways 8-iso-PGE2 correlated positively with urinary LTE4 level (p=0.046), whereas it correlated negatively with the provocative dose of aspirin (p=0.027). A significant increase of exhaled 8-iso-PGE2 after inhalatory challenge with aspirin was selective and not present for the other isoprostane measured. This is a novel finding in AERD, suggesting that inhibition of cyclooxygenase may elicit 8-iso-PGE2 production in a specific mechanism, contributing to bronchoconstriction and systemic overproduction of cysteinyl leukotrienes. Copyright © 2015 Elsevier Inc. All rights reserved.

Hypotonic and isotonic aerosols increase bronchial reactivity in basenji-greyhound dogs.

PubMed

Osborne, M L; Evans, T W; Sommerhoff, C P; Chung, K F; Hirshman, C A; Boushey, H A; Nadel, J A

1987-02-01

Because basenji-greyhound dogs have greater bronchial reactivity to a range of inhaled stimuli than mongrel dogs do, and because bronchial hyperreactivity to nonspecific stimuli is characteristic of asthma, we asked whether basenji-greyhound dogs have greater bronchial reactivity to hypotonic and isotonic aerosols than mongrel dogs do. We assessed bronchial reactivity by measuring both the total pulmonary resistance and the bronchial response to an acetylcholine aerosol, before and after delivery of hypotonic and isotonic aerosols. Bronchial reactivity as measured by a change in total pulmonary resistance increased 9-fold after delivery of hypotonic and 5-fold after delivery of isotonic aerosols in 5 anesthetized basenji-greyhound dogs, but not in 3 similarly challenged mongrel dogs (p less than 0.01). Bronchial reactivity as measured by an increased bronchial response to acetylcholine aerosol increased 3-fold in basenji-greyhound dogs but not in mongrel dogs. Thus, hypotonic and isotonic aerosols increase bronchial reactivity in basenji-greyhound dogs. We also asked whether vagal or nonvagal pathways are involved in the increase in total pulmonary resistance induced by a hypotonic aerosol. Both vagal and nonvagal pathways appear to be involved, since blockade of the vagal pathway by intravenously administered atropine only partially inhibited the bronchoconstriction induced by a hypotonic aerosol (54%). Disodium cromoglycate, which inhibits vagal and nonvagal pathways, partially inhibited the bronchoconstriction (57%), but even in combination with atropine, did not completely inhibit it (68%). Our observations in basenji-greyhound dogs are similar to results in asthmatic subjects, suggesting that basenji-greyhound dogs are useful experimental animals in which to study the mechanisms by which hypotonic and isotonic aerosols increase bronchial reactivity.

The effect of peptidase inhibitors on bradykinin-induced bronchoconstriction in guinea-pigs in vivo.

PubMed Central

Ichinose, M.; Barnes, P. J.

1990-01-01

1. Bradykinin (BK) instilled directly into the airway lumen caused bronchoconstriction in anaesthetized, mechanically ventilated guinea-pigs in the presence of propranolol (1 mg kg-1 i.v.). The geometric mean dose of BK required to produce 100% increase in airway opening pressure (PD100) was 22.9 nmol (95% c.i. 11.7-44.6 nmol). 2. The dose-response curve for the effect of instilled BK was significantly shifted to the left by the angiotensin converting enzyme (ACE) inhibitor, captopril (5 and 50 nmol instillation, PD100 = 3.0, 95% c.i. 0.98-8.9, and 2.0 nmol, 95% c.i. 0.65-6.2 nmol, respectively). 3. The neutral endopeptidase (NEP) inhibitor, phosphoramidon (5 and 50 nmol instillation) also shifted the dose-response curve for the effect of instilled BK; the PD100 values = 2.2 (95% c.i. 0.40-11.7) and 1.8 nmol (95% c.i. 0.87-3.5 nmol), respectively. 4. After pretreatment with captopril (50 nmol) and phosphoramidon (50 nmol) in combination, the dose-response curve for the effect of instilled BK (PD100 = 1.1 nmol, 95% c.i. 0.37-3.2 nmol) was similar to that obtained in the presence of each inhibitor used alone. 5. The kinase I inhibitor, DL-2-mercaptomethyl-3-guanidinoethylthiopropionic acid (50 nmol instillation) failed to alter the dose-response curve to instilled BK (PD100 = 14.6 nmol, 95% c.i. 6.7-32.0 nmol). 6. These data suggest that both ACE and NEP degrade BK in the airway lumen, but that kininase I is not involved. PMID:2282470

Paradoxical Lung Function Response to Beta2-agonists: Radiologic Correlates and Clinical Implications

PubMed Central

Bhatt, Surya P.; Wells, James M.; Kim, Victor; Criner, Gerard J.; Hersh, Craig P.; Hardin, Megan; Bailey, William C.; Nath, Hrudaya; il-Kim, Young; Foreman, Marilyn G.; Stinson, Douglas S.; Wilson, Carla G.; Rennard, Stephen I.; Silverman, Edwin K.; Make, Barry J.; Dransfield, Mark T.

2014-01-01

Background Bronchodilator response is seen in a significant proportion of patients with chronic obstructive pulmonary disease (COPD). However, there are also reports of a paradoxical response (PR) to beta2-agonists, resulting in bronchoconstriction. Asymptomatic bronchoconstriction is likely far more common but there has been no systematic study of this phenomenon.We assessed theprevalence of PR in current and former smokers with and without COPD, and its radiologic correlates and clinical implications. Methods Subjects from a large multicenter study (COPDGene) were categorized into two groups based on PR defined as at least a 12% and 200mLreduction in FEV1 and/or FVC after administration of a short-acting beta2-agonist (180ucg albuterol). Predictors of PR and associations with respiratory morbidity and computed tomographic measures of emphysema and airway disease were assessed. Findings 9986 subjects were included. PR was seen in 4.54% and the frequency was similar in those with COPD and smokers without airflow obstruction. Compared to Caucasians, PR was twice as common in African-Americans (6.9% vs. 3.4%;p <0.001). On multivariate analyses, African- American race (adjusted OR 1.89, 95%CI 1.50 to 2.39), lesspercent emphysema (OR 0.96, 95%CI 0.92 to 0.99) and increased wall-area% of segmental airways (OR 1.04,95%CI 1.01 to 1.08) were independently associated with PR.PR was independently associated with worse dyspnea, lower six-minute-walk distance, higher BODE index, and a greater frequency of exacerbations(increased by a factor of 1.35, 95%CI 1.003 to 1.81). Interpretation Paradoxical response to beta2-agonists is associated with respiratory morbidity and is more common in African Americans. PMID:25217076

Prevalence of exercise-induced bronchoconstriction and exercise-induced laryngeal obstruction in a general adolescent population.

PubMed

Johansson, Henrik; Norlander, Katarina; Berglund, Lars; Janson, Christer; Malinovschi, Andrei; Nordvall, Lennart; Nordang, Leif; Emtner, Margareta

2015-01-01

Exercise-induced respiratory symptoms are common among adolescents. Exercise is a known stimulus for transient narrowing of the airways, such as exercise-induced bronchoconstriction (EIB) and exercise-induced laryngeal obstruction (EILO). Our aim was to investigate the prevalence of EIB and EILO in a general population of adolescents. In this cross-sectional study, a questionnaire on exercise-induced dyspnoea was sent to all adolescents born in 1997 and 1998 in Uppsala, Sweden (n=3838). A random subsample of 146 adolescents (99 with self-reported exercise-induced dyspnoea and 47 without this condition) underwent standardised treadmill exercise tests for EIB and EILO. The exercise test for EIB was performed while breathing dry air; a positive test was defined as a decrease of ≥10% in FEV1 from baseline. EILO was investigated using continuous laryngoscopy during exercise. The estimated prevalence of EIB and EILO in the total population was 19.2% and 5.7%, respectively. No gender differences were found. In adolescents with exercise-induced dyspnoea, 39.8% had EIB, 6% had EILO and 4.8% had both conditions. In this group, significantly more boys than girls had neither EIB nor EILO (64.7% vs 38.8%; p=0.026). There were no significant differences in body mass index, lung function, diagnosed asthma or medication between the participants with exercise-induced dyspnoea who had or did not have a positive EIB or EILO test result. Both EIB and EILO are common causes of exercise-induced dyspnoea in adolescents. EILO is equally common among girls and boys and can coexist with EIB. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

A Halotyrosine Antibody that Detects Increased Protein Modifications in Asthma Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jin, Hongjun; Hallstrand, Teal S.; Daly, Don S.

Background-Airway inflammation plays an important pathophysiological role in asthma. Eosinophils produce hypobromite and bromotyrosine while neutrophils produce hypochlorite and chlorotyrosine. Objective-To evaluate halotyrosine modifications of individual airway proteins as a marker of inflammation in asthma using an antibody-based assay. Methods-We developed a novel monoclonal antibody (BTK-94C) that binds halogenated tyrosine residues, and used this antibody in a custom enzyme-linked immunosorbent assay (ELISA) microarray platform to examine halotyrosine levels in 23 proteins in three independent sets of sputum samples (52 samples total). Results-In 15 subjects with either no asthma, or with asthma characterized by high or low sputum eosinophil counts, wemore » found associations between increased halotyrosine levels of at least three proteins and severity of airway hyperresponsiveness (AHR). Treatment with mepolizumab in 17 patients with sputum eosinophilia markedly reduced the sputum eosinophilia and significantly reduced halotyrosine levels in one sputum protein. Further analysis of 10 subjects with neutrophilic asthma and 10 health controls demonstrated a broad increase in halotyrosine in the patients with airway neutrophilia. Conclusions-Significantly higher levels of halotyrosine are associated with asthma in the asthma phenotypes we examined. The halotyrosine levels correlated with indirect AHR in the form of exercise-induced bronchoconstriction. Clinical Implication-An antibody-based assay for tyrosine halogenation in specific proteins may prove useful for assessing airway inflammation in asthma. Capsule Summary-An antibody to measure protein monobrominated tyrosine and other halotyrosine modifications was developed and used to evaluate halogenation in specific proteins in the airways for the first time. Associations were found between levels of halotyrosine and exercise-induced bronchoconstriction, and eosinophil and neutrophil inflammation in sputum from asthma patients. The ELISA developed here can be easily translated into a clinical test.« less

Btk Inhibitor RN983 Delivered by Dry Powder Nose-only Aerosol Inhalation Inhibits Bronchoconstriction and Pulmonary Inflammation in the Ovalbumin Allergic Mouse Model of Asthma

PubMed Central

Renteria, Lorena; Burns, Lisa; Harris, Paul; Peng, Ruoqi; Bauer, Carla M.T.; Laine, Dramane; Stevenson, Christopher S.

2016-01-01

Abstract Background: In allergen-induced asthma, activated mast cells start the lung inflammatory process with degranulation, cytokine synthesis, and mediator release. Bruton's tyrosine kinase (Btk) activity is required for the mast cell activation during IgE-mediated secretion. Methods: This study characterized a novel inhaled Btk inhibitor RN983 in vitro and in ovalbumin allergic mouse models of the early (EAR) and late (LAR) asthmatic response. Results: RN983 potently, selectively, and reversibly inhibited the Btk enzyme. RN983 displayed functional activities in human cell-based assays in multiple cell types, inhibiting IgG production in B-cells with an IC50 of 2.5 ± 0.7 nM and PGD2 production from mast cells with an IC50 of 8.3 ± 1.1 nM. RN983 displayed similar functional activities in the allergic mouse model of asthma when delivered as a dry powder aerosol by nose-only inhalation. RN983 was less potent at inhibiting bronchoconstriction (IC50(RN983) = 59 μg/kg) than the β-agonist salbutamol (IC50(salbutamol) = 15 μg/kg) in the mouse model of the EAR. RN983 was more potent at inhibiting the antigen induced increase in pulmonary inflammation (IC50(RN983) = <3 μg/kg) than the inhaled corticosteroid budesonide (IC50(budesonide) = 27 μg/kg) in the mouse model of the LAR. Conclusions: Inhalation of aerosolized RN983 may be effective as a stand-alone asthma therapy or used in combination with inhaled steroids and β-agonists in severe asthmatics due to its potent inhibition of mast cell activation. PMID:27111445

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

The contribution of airway smooth muscle to airway narrowing and airway hyperresponsiveness in disease.

PubMed

Martin, J G; Duguet, A; Eidelman, D H

2000-08-01

Airway hyperresponsiveness (AHR), the exaggerated response to constrictor agonists in asthmatic subjects, is incompletely understood. Changes in either the quantity or properties of airway smooth muscle (ASM) are possible explanations for AHR. Morphometric analyses demonstrate structural changes in asthmatic airways, including subepithelial fibrosis, gland hyperplasia/hypertrophy, neovascularization and an increase in ASM mass. Mathematical modelling of airway narrowing suggests that, of all the changes in structure, the increase in ASM mass is the most probable cause of AHR. An increase in ASM mass in the large airways is more closely associated with a greater likelihood of dying from asthma than increases in ASM mass in other locations within the airway tree. ASM contraction is opposed by the elastic recoil of the lungs and airways, which appears to limit the degree of bronchoconstriction in vivo. The cyclical nature of tidal breathing applies stresses to the airway wall that enhance the bronchodilating influence of the lung tissues on the contracting ASM, in all probability by disrupting cross-bridges. However, the increase in ASM mass in asthma may overcome the limitation resulting from the impedances to ASM shortening imposed by the lung parenchyma and airway wall tissues. Additionally, ASM with the capacity to shorten rapidly may achieve shorter lengths and cause a greater degree of bronchoconstriction when stimulated to contract than slower ASM. Changes in ASM properties are induced by the process of sensitization and allergen-exposure such as enhancement of phospholipase C activity and inositol phosphate turnover, and increases in myosin light chain kinase activity. Whether changes in ASM mass or biochemical/biomechanical properties form the basis for asthma remains to be determined.

Effects of sodium metabisulphite on guinea pig contractile airway smooth muscle responses in vitro.

PubMed Central

Sun, J.; Sakamoto, T.; Chung, K. F.

1995-01-01

BACKGROUND--Sodium metabisulphite (MBS) is known to induce bronchoconstriction in asthmatic patients. The effects of MBS on guinea pig airway smooth muscle and on neurally mediated contraction in vitro have been examined. METHODS--Tracheal and bronchial airway segments were placed in oxygenated buffer solution and electrical field stimulation was performed in the presence of indomethacin (10(-5) M) and propranolol (10(-6) M) for the measurement of isometric tension. Atropine (10(-6) M) was added to bronchial tissues. RESULTS--Concentrations of MBS up to 10(-3) M had no direct effect on airway smooth muscle contraction and did not alter either tracheal smooth muscle contraction induced by electrical field stimulation at all frequencies or acetylcholine-induced tracheal smooth muscle contraction. There was a similar response in the absence of epithelium, except for potentiation of the response induced by electrical field stimulation at 0.5 Hz (24 (10)% increase). However, MBS (10(-5), 10(-6) and 10(-7) M) augmented neurally-mediated non-adrenergic non-cholinergic contractile responses in the bronchi (13.3 (3.2)%, 23.8 (9.6)%, and 6.4 (1.6)%, respectively). MBS had no effect on the contractile response induced by substance P, but at higher concentrations (10(-3) M and 10(-4) M) it caused a time-dependent attenuation of responses induced by either electrical field stimulation or exogenously applied acetylcholine or substance P. CONCLUSIONS--MBS had no direct contractile responses but enhanced bronchoconstriction induced by activation of non-cholinergic neural pathways in the bronchus, probably through increased release of neuropeptides. At high concentrations MBS inhibited contractile responses initiated by receptor or neural stimulation. Images PMID:7570440

Tachykinin control of ferret airways: mucus secretion, bronchoconstriction and receptor mapping.

PubMed

Meini, S; Mak, J C; Rohde, J A; Rogers, D F

1993-02-01

The effects of synthetic tachykinin receptor agonists on mucus secretion by ferret trachea was determined in vitro in Ussing chambers using 35SO4 as a mucus marker and the synthetic peptides [Sar9,Met(O2)11]substance P (SarSP), [beta Ala8]neurokinin A-(4-10) and [MePhe7] neurokinin B which are selective for NK1, NK2 and NK3 tachykinin-receptors respectively. The bronchomotor effects of the same agonists were also studied in vitro and tachykinin receptors were localized by autoradiographic mapping. SarSP was the only synthetic agonist able to elicit a concentration-dependent increase in mucus secretion and was much more potent than SP. The EC50 for SarSP was 1.7 x 10(-6) M. Moreover, the maximal increase in release of 35SO4 produced by SarSP 10(-5) M was 95% of the increase produced by methacholine 10(-4) M indicating that this concentration of SarSP induced a near maximal secretory response. There was no significant difference in the secretory action of SP administered from the luminal or the submucosal side of the tissue. Only the NK2 agonist was able to produce a concentration-dependent contractility of bronchial ring preparations and its effect was relatively weak (EC50 6.4 x 10(-6) M). Capsaicin (10(-5) M) produced only a slight increase in tracheal mucus secretion (28 +/- 5%; n = 6) and was completely ineffective in inducing bronchoconstriction. Binding sites for [125I]-Bolton Hunter SP were more evident than sites for [125I]-NKA on submucosal glands and epithelium. In contrast, only binding sites to NKA could be observed over the smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin converting enzyme inhibitors potentiate the bronchoconstriction induced by substance P in the guinea-pig.

PubMed Central

Subissi, A.; Guelfi, M.; Criscuoli, M.

1990-01-01

1. The effects of intravenous captopril and enalaprilic acid on the increase in pulmonary inflation pressure induced by different bronchoconstrictor agents were evaluated in the anaesthetized guinea-pig. 2. Captopril and enalaprilic acid (1.6-200 micrograms kg-1) enhanced dose-dependently the bronchoconstriction (BC) induced by substance P. The threshold effective dose was 1.6 micrograms kg-1 and maximal potentiation over the control response was more than 400% for both agents. Enalaprilic acid was also assayed for serum and lung angiotensin converting enzyme (ACE) inhibition in anaesthetized guinea-pigs. This drug produced a dose-dependent inhibition of ACE in both tissues, with ED50 s of 7.6 and 9.4 micrograms kg-1, respectively: this inhibitory activity was positively correlated to substance P potentiation. 3. Captopril (8-1000 micrograms kg-1) enhanced dose-dependently the BC induced by capsaicin. The threshold effective dose was 40 micrograms kg-1 and maximal potentiation about 90%. 4. Captopril (200-1000 micrograms kg-1) did not affect BC induced by bradykinin. However, this response was markedly enhanced (about 200%) by captopril 200 micrograms kg-1 in propranolol-pretreated animals. 5. Captopril and enalaprilic acid (200-1000 micrograms kg-1) slightly (20-40%) but significantly enhanced the BC induced by 5-hydroxytryptamine. However, this response was potentiated to the same extent by a dose of prazosin, which produced a degree of hypotension similar to that observed after administration of the ACE inhibitors. 6. In conclusion, ACE inhibitors potentiate the BC induced by substance P and, to a minor extent, that induced by capsaicin in the anaesthetized guinea-pig.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1697196

Long-term effects of substance P on the isolated guinea pig trachea.

PubMed

Schreiber, J; Slapke, J; Nieber, K; Oehme, P

1988-01-01

The undecapeptide substance P(SP) and its C-terminal sequence SP-5-11 induced a dose-dependent contraction of the isolated guinea pig trachea. SP-5-11 had a more potent bronchoconstrictive action than SP-1-11. The distal part of the isolated guinea pig trachea showed a greater reagibility to SP-5-11 than the proximal one. There was a continuous increase of the amplitude of the SP-1-11-induced contractions when the neuropeptide was added several times at one-hour intervals. Incubation with 10(-6) M SP-1-11 for 5 h reduced the reagibility of the isolated guinea pig trachea to acetylcholine.

[Effectiveness of fenspiride in patients with chronic obstructive bronchitis].

PubMed

Shorokhova, T D; Medvedeva, I V; Lapik, S V; Solov'eva, O G; Gracheva, E Iu; Iusupova, R S

2001-01-01

Patients with chronic obstructive pulmonary disease of moderate severity were investigated for two months for assessment of fenspiride activity. Examination of the patients (age 42.6 +/- 5.3) took place before and after fenspiride therapy. In comparison to the control group, fenspiride patients showed improvement of external respiration function: FEV 1, FVC, FEF 50-75, PEF increased. Dienic conjugates, malonic dialdehyde levels decreased, alpha-tocopherol in platelet membranes rose, functional activity of platelets fell. Side effects were rare and not serious. It is concluded that fenspiride has an antiinflammatory effect, reduces bronchoconstriction and depresses platelet aggregation, is well tolerated. Fenspiride is an effective drug for the treatment of moderate chronic obstructive bronchitis.

[Anti-cholinergic effect of Pluchea ovalis (pers.) Dc. (asteraceae) root extract on isolated Wistar rat tracheae].

PubMed

Agbonon, A; Aklikokou, K; Kwashie, E-G; Gbéassor, M

2004-09-01

Ethanolic extract of Pluchea ovalis roots inhibit acetylcholine-induced bronchoconstriction observed in asthma. To understand the mechanism of P. ovalis root extract on airway smooth muscle contraction, we investigated the anti-cholinergic effect of the ethanolic extract on isolated isolated tracheae of the Wistar rat. For this purpose, three experimental conditions of incubation were used: idomethacin, indomethacin+propranolol or indomethacin+propranolo+ promethazine. The extract was applied in all three conditions at 0.25 mg/ml for 10 minutes prior to cumulative doses of acetylcholine (10(-8) to 5.10(-4) g/ml). The extract reduced acetylcholine-induced contraction and could have an antagonistic effect on muscarinic receptors of the rat trachea.

Air quality and exercise-induced bronchoconstriction in elite athletes.

PubMed

Rundell, Kenneth W; Sue-Chu, Malcolm

2013-08-01

A higher prevalence of airway hyperresponsiveness, airway remodeling, and asthma has been identified among athletes who compete and train in environmental conditions of cold dry air and/or high air pollution. Repeated long-duration exposure to cold/dry air at high minute ventilation rates can cause airway damage. Competition or training at venues close to busy roadways, or in indoor ice arenas or chlorinated swimming pools, harbors a risk for acute and chronic airway disorders from high pollutant exposure. This article discusses the effects of these harsh environments on the airways, and summarizes potential mechanisms and prevalence of airway disorders in elite athletes. Copyright © 2013 Elsevier Inc. All rights reserved.

Adenosine receptor subtypes in the airways responses to 5'-adenosine monophosphate inhalation of sensitized guinea-pigs.

PubMed

Smith, N; Broadley, K J

2008-09-01

Endogenous adenosine levels are raised in the lungs during asthma attacks. 5'-adenosine monophosphate (5'-AMP) inhalation in asthmatics causes bronchoconstriction and in sensitized guinea-pigs induces early (EAR) and late asthmatic responses (LAR), airway hyper-reactivity (AHR) and inflammatory cell recruitment to the lungs. The aim of this study was to investigate the roles of A(1), A(2A), A(2B) and A(3) adenosine receptors in these responses to inhaled 5'-AMP in sensitized guinea-pigs. Comparisons were made with the effect of dexamethasone treatment on 5'-AMP-induced responses. Functional airways responses to inhaled 5'-AMP (3 and 300 mM) of actively sensitized, conscious guinea-pigs were determined by whole-body plethysmography following administration of selective adenosine receptor antagonists or their vehicles. AHR to inhaled histamine (1 mM) and inflammatory cell influx in bronchoalveolar lavage fluid were determined. 5'-AMP at 3 mM caused an immediate bronchoconstriction (EAR), whereas 300 mM caused bronchodilatation. Both responses were followed at 6 h by a LAR, together with inflammatory cell influx and AHR to histamine. The A(2A) receptor antagonist, ZM241385, further enhanced cell influx after 5'-AMP inhalation (3 and 300 mM), and blocked the immediate bronchodilator response to 300 mM 5'-AMP, exposing an EAR. The A(2B) receptor antagonist, MRS1706 (in the presence of ZM241385), inhibited the LAR, AHR and cell influx, following inhalation of 5'-AMP (300 mM). The A(3) receptor antagonist, MRS1220, inhibited 5'-AMP-induced inflammatory cell influx. The A(1) receptor antagonist, DPCPX (in the presence of ZM241385), inhibited the EAR following 5'-AMP inhalation (300 mM). Dexamethasone inhibited the LAR, AHR and cell influx following inhalation of 5'-AMP (300 mM). All four adenosine receptor subtypes play various roles in the airways responses to inhaled 5'-AMP in sensitized guinea-pigs.

Speed of onset of bronchodilator response to salbutamol inhaled via different devices in asthmatics: a bioassay based on functional antagonism

PubMed Central

Lavorini, Federico; Geri, Pietro; Mariani, Laura; Marmai, Cecilia; Maluccio, Nazzarena Maria; Pistolesi, Massimo; Fontana, Giovanni A

2006-01-01

Aims To evaluate the speed of onset of bronchodilation following salbutamol administered via a metered-dose inhaler with a spacer (pMDI + Volumatic) and a dry-powder inhaler (Diskus), as well as the relative potencies of these devices in asthmatic patients with methacholine-induced bronchoconstriction. Methods Eighteen patients inhaled methacholine (MCh) until FEV1 decreased by 35% of control. Following administration of placebo, 200 µg salbutamol or 400 µg salbutamol through the pMDI + Volumatic or the Diskus, we calculated the time elapsed from drug administration and the appearance of a 90% increase in post-MCh forced vital capacity (FVC), FEV1 and volume-adjusted mid-expiratory flow (recovery times). The salbutamol doses to be delivered by the two inhalation devices to achieve similar recovery times and the relative potencies of the devices were calculated by using the 2-by-2 Finney parallel regression method. Results For all functional variables, recovery times were significantly (P < 0.01) shorter in pMDI + Volumatic than Diskus trials. The salbutamol doses to be delivered by the Diskus to achieve recovery times for FVC, FEV1 and volume-adjusted mid-expiratory flow similar to those obtained with 200 µg salbutamol administered via the pMDI + Volumatic were 558 (95% CI 537, 579) µg, 395 (95% CI 388, 404) µg and 404 (95% CI 393, 415) µg, respectively, and corresponded to relative potencies of 2.79 (95% CI 2.68, 2.90), 1.98 (95% CI 1.94, 2.02), and 2.02 (95% CI 1.96, 2.07). Conclusions Administration of salbutamol via the pMDI + Volumatic provides faster reversal of induced bronchoconstriction than via the Diskus. The salbutamol dose targeting the lungs with the pMDI + Volumatic is approximately twice that with the Diskus. PMID:16995861

The effect of nebulized salbutamol or isotonic saline on exercise-induced bronchoconstriction in elite skaters following a 1,500-meter race: study protocol for a randomized controlled trial.

PubMed

Driessen, Jean M M; Gerritsma, Margryt; Westbroek, Jaap; ten Hacken, Nick H T; de Jongh, Frans H C

2013-07-09

Prevalence of exercise-induced bronchoconstriction (EIB) is high in elite athletes, especially after many years training in cold and dry air conditions. The primary treatment of EIB is inhaling a short-acting beta-2-agonist such as salbutamol. However, professional speed skaters also inhale nebulized isotonic saline or tap water before and after a race or intense training. The use of nebulized isotonic saline or tap water to prevent EIB has not been studied before, raising questions about safety and efficacy. The aim of this study is to analyze the acute effect of nebulized isotonic saline or salbutamol on EIB in elite speed skaters following a 1,500-meter race. This randomized controlled trial compares single dose treatment of 1 mg nebulized salbutamol in 4 mL of isotonic saline, or with 5 mL of isotonic saline. A minimum of 13 participants will be allocated in each treatment group. Participants should be between 18 and 35 years of age and able to skate 1,500 m in less than 2 min 10 s (women) or 2 min 05 s (men). Repeated measurements of spirometry, forced oscillation technique, and electromyography will be performed before and after an official 1,500-m race. Primary outcome of the study is the difference in fall in FEV1 after exercise in the different treatment groups. The trial is currently enrolling participants. Elite athletes run the risk of pulmonary inflammation and remodeling as a consequence of their frequent exercise, and thus increased ventilation in cold and dry environments. Although inhalation of nebulized isotonic saline is commonplace, no study has ever investigated the safety or efficacy of this treatment. This trial protocol was registered with the Dutch trial registration for clinical trials under number NTR3550.

Inhibition of excitatory non-adrenergic non-cholinergic bronchoconstriction in guinea-pig airways in vitro by activation of an atypical 5-HT receptor.

PubMed Central

Ward, J. K.; Fox, A. J.; Barnes, P. J.; Belvisi, M. G.

1994-01-01

1. The effect of 5-hydroxytryptamine (5-HT) was studied on excitatory neurally mediated non-adrenergic non-cholinergic (NANC) contractions evoked by electrical field stimulation (EFS) in guinea-pig isolated bronchi. 2. 5-HT (0.1-100 microM) produced a concentration-dependent inhibition of the excitatory NANC response with 50.9 +/- 5.0% (n = 5, P < 0.01) inhibition at 100 microM. This inhibition was not significantly affected by the 5-HT2 antagonist, ketanserin (1 microM) when inhibitions (+/- ketanserin) at each concentration of 5-HT were compared by unpaired t tests; however, this concentration appeared to produce a leftward shift (approximately 10 fold) of the 5-HT concentration-inhibition curve. Ketanserin (1 microM) was effective in blocking bronchoconstriction evoked by activation of 5-HT2A receptors on airway smooth muscle. In the presence of ketanserin (1 microM) 5-HT (100 microM) evoked an inhibition of 57.4 +/- 5.9% (n = 5, P < 0.01) with an EC50 of 0.57 microM. 3. Inhibition evoked by 5-HT (0.1-100 microM) was unaffected by the alpha-adrenoceptor antagonist phentolamine (1 microM), the beta 2-adrenoceptor antagonist, ICI 118551 (0.1 microM), the 5-HT1A/B antagonist, cyanopindolol (1 microM) or the 5-HT3/4 antagonist, ICS 205-930 (1 microM). 4. Methiothepin (0.1 microM) produced an insurmountable inhibition of the effect of 5-HT (0.1-100 microM), reducing the maximum inhibition produced by 5-HT (100 microM) to 30.2 +/- 5.0% (n = 5, P < 0.001) and suggesting a non-competitive antagonism. Methiothepin inhibited the effect of 5-HT (10 microM) in a concentration-dependent manner with an IC50 of 81 nM.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7518294

Sch 37224, an experimental antiallergy compound, inhibits the neuropeptide component of hyperventilation- and nicotine-induced bronchoconstriction in guinea pigs.

PubMed

Mauser, P J; Rasquinha, C; Hey, J A; Kreutner, W; Egan, R W; Sherwood, J E; Anthes, J; Greenfeder, S; Chapman, R W

1997-01-01

Sch 37224 is an experimental antiallergy compound that inhibits hyperventilation-induced bronchoconstriction (HIB) in guinea pigs and cold air bronchospasm in human asthmatics. HIB in guinea pigs may involve the release of tachykinins such as neurokinin A (NKA) and substance P (SP), and the action of Sch 37224 in this model may relate to inhibition of these neuropeptides. We studied the effect of Sch 37224 on the neuropeptide component of HIB that was enhanced in guinea pigs treated with the neutral endopeptidase inhibitors, thiorphan and phosphoramidon. Pulmonary resistance (RL) and dynamic lung compliance (CDyn) were measured in anesthetized, mechanically ventilated guinea pigs. RL and CDyn were measured at baseline (1 ml/100 g tidal volume and 50 breaths/min) and after a 10-min period of hyperventilation (1 ml/100 g, 150 breaths/min). Hyperventilation produced modest changes in RL (+41 +/- 12%) and CDyn (-12 +/- 3%) which were markedly enhanced by treatment with 3 mg/kg of either thiorphan or phosphoramidon (RL + 269 +/- 43% for thiorphan, + 292 +/- 63% for phosphoramidon and CDyn -65 +/- 3% for thiorphan, -51 +/- 13% for phosphoramidon). In the presence of thiorphan or phosphoramidon, the bronchospasm to hyperventilation was significantly reduced (> 70%) with 5 mg/kg, p.o., of Sch 37224. In other studies, the peptidergic (conducted in the presence of ipratropium bromide and phosphoramidon) bronchoconstrictor response to intravenous nicotine (1 mg/kg) was also inhibited by Sch 37224 (0.3-10 mg/kg, p.o.). However, Sch 37224 (5 mg/kg, p.o.) had no effect on the bronchoconstrictor response to intravenous NKA. These results indicate that Sch 37224 inhibits the neuropeptide component of HIB and nicotine in guinea pigs and this effect appears to be mediated by the inhibition of the release of tachykinins from airway C fibers.

Combination of budesonide/formoterol on demand improves asthma control by reducing exercise-induced bronchoconstriction

PubMed Central

Lazarinis, Nikolaos; Jørgensen, Leif; Ekström, Tommy; Bjermer, Leif; Dahlén, Barbro; Pullerits, Teet; Hedlin, Gunilla; Carlsen, Kai-Håkon; Larsson, Kjell

2014-01-01

Background In mild asthma exercise-induced bronchoconstriction (EIB) is usually treated with inhaled short-acting β2 agonists (SABAs) on demand. Objective The hypothesis was that a combination of budesonide and formoterol on demand diminishes EIB equally to regular inhalation of budesonide and is more effective than terbutaline inhaled on demand. Methods Sixty-six patients with asthma (>12 years of age) with verified EIB were randomised to terbutaline (0.5 mg) on demand, regular budesonide (400 μg) and terbutaline (0.5 mg) on demand, or a combination of budesonide (200 μg)  + formoterol (6 μg) on demand in a 6-week, double-blind, parallel-group study (ClinicalTrials.gov identifier: NCT00989833). The patients were instructed to perform three to four working sessions per week. The main outcome was EIB 24 h after the last dosing of study medication. Results After 6 weeks of treatment with regular budesonide or budesonide+formoterol on demand the maximum post-exercise forced expiratory volume in 1 s fall, 24 h after the last medication, was 6.6% (mean; 95% CI −10.3 to −3.0) and 5.4% (−8.9 to −1.8) smaller, respectively. This effect was superior to inhalation of terbutaline on demand (+1.5%; −2.1 to +5.1). The total budesonide dose was approximately 2.5 times lower in the budesonide+formoterol group than in the regular budesonide group. The need for extra medication was similar in the three groups. Conclusions The combination of budesonide and formoterol on demand improves asthma control by reducing EIB in the same order of magnitude as regular budesonide treatment despite a substantially lower total steroid dose. Both these treatments were superior to terbutaline on demand, which did not alter the bronchial response to exercise. The results question the recommendation of prescribing SABAs as the only treatment for EIB in mild asthma. PMID:24092567

The role of inspiratory muscle training in the management of asthma and exercise-induced bronchoconstriction.

PubMed

Shei, Ren-Jay; Paris, Hunter L R; Wilhite, Daniel P; Chapman, Robert F; Mickleborough, Timothy D

2016-11-01

Asthma is a pathological condition comprising of a variety of symptoms which affect the ability to function in daily life. Due to the high prevalence of asthma and associated healthcare costs, it is important to identify low-cost alternatives to traditional pharmacotherapy. One of these low cost alternatives is the use of inspiratory muscle training (IMT), which is a technique aimed at increasing the strength and endurance of the diaphragm and accessory muscles of respiration. IMT typically consists of taking voluntary inspirations against a resistive load across the entire range of vital capacity while at rest. In healthy individuals, the most notable benefits of IMT are an increase in diaphragm thickness and strength, a decrease in exertional dyspnea, and a decrease in the oxygen cost of breathing. Due to the presence of expiratory flow limitation in asthma and exercise-induced bronchoconstriction, dynamic lung hyperinflation is common. As a result of varying operational lung volumes, due in part to hyperinflation, the respiratory muscles may operate far from the optimal portion of the length-tension curve, and thus may be forced to operate against a low pulmonary compliance. Therefore, the ability of these muscles to generate tension is reduced, and for any given level of ventilation, the work of breathing is increased as compared to non-asthmatics. Evidence that IMT is an effective treatment for asthma is inconclusive, due to limited data and a wide variation in study methodologies. However, IMT has been shown to decrease dyspnea, increase inspiratory muscle strength, and improve exercise capacity in asthmatic individuals. In order to develop more concrete recommendations regarding IMT as an effective low-cost adjunct in addition to traditional asthma treatments, we recommend that a standard treatment protocol be developed and tested in a placebo-controlled clinical trial with a large representative sample.

Perception of Exercise-Induced Bronchoconstriction in College Athletes.

PubMed

Burnett, David M; Vardiman, John P; Deckert, Jake A; Ward, Jaimie L; Sharpe, Matthew R

2016-07-01

Exercise-induced bronchoconstriction (EIB) can lead to long-term respiratory illness and even death. EIB prevalence rates are both high and variable in college athletes. Also, prevalence rates may be underestimated due to ineffective screening. The purpose of this study is to investigate the prevalence of EIB and the perceived impact of EIB in college athletes via a self-report questionnaire. A self-report EIB questionnaire was administered to college athletes on 8 different sports teams. Information collected was used to identify athletes who self-reported: (1) a history of EIB and/or asthma, (2) respiratory symptoms during exercise, (3) medication use, and (4) concern about EIB. Results showed that 56 of 196 athletes (28.6%) self-reported a history of EIB or asthma. Over half (52%) reported a history of EIB/asthma or current EIB symptoms. Forty-six of the 140 athletes (32.9%) who did not report a history of EIB or asthma indicated symptoms of EIB during sports, training, or exercise. Fourteen of 56 athletes (25%) self-reporting a history of EIB or asthma did not report the use of a respiratory medication. Nineteen of 196 athletes (9.7%) reported being concerned that EIB was adversely affecting their sports performance. College athletes self-report a high prevalence of EIB or asthma. Although college athletes may not report a history of EIB or asthma, they indicate symptoms of EIB. A majority of athletes reported a history or current symptoms related to EIB or asthma. Many athletes with a history of EIB or asthma are not taking any asthma medication. Last, athletes report concern about EIB adversely affecting their sports performance. More work is needed using a combination of a screening questionnaire and standardized EIB testing to develop a validated tool for accurately screening and diagnosing EIB in college athletes. Copyright © 2016 by Daedalus Enterprises.

Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia.

PubMed

Baral, Pankaj; Umans, Benjamin D; Li, Lu; Wallrapp, Antonia; Bist, Meghna; Kirschbaum, Talia; Wei, Yibing; Zhou, Yan; Kuchroo, Vijay K; Burkett, Patrick R; Yipp, Bryan G; Liberles, Stephen D; Chiu, Isaac M

2018-05-01

Lung-innervating nociceptor sensory neurons detect noxious or harmful stimuli and consequently protect organisms by mediating coughing, pain, and bronchoconstriction. However, the role of sensory neurons in pulmonary host defense is unclear. Here, we found that TRPV1 + nociceptors suppressed protective immunity against lethal Staphylococcus aureus pneumonia. Targeted TRPV1 + -neuron ablation increased survival, cytokine induction, and lung bacterial clearance. Nociceptors suppressed the recruitment and surveillance of neutrophils, and altered lung γδ T cell numbers, which are necessary for immunity. Vagal ganglia TRPV1 + afferents mediated immunosuppression through release of the neuropeptide calcitonin gene-related peptide (CGRP). Targeting neuroimmunological signaling may be an effective approach to treat lung infections and bacterial pneumonia.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weinstein, L.; Droegemueller, W.; Cornette, J.

A single intra-amniotic injection of (15S)-15 methyl prostaglandin F/sub 2/..cap alpha.. (THAM) was used to induce second trimester abortion in five patients. Serial levels of (15S)-15 methyl prostaglandin F/sub 2/..cap alpha.. were subsequently measured in amniotic fluid and plasma by radioimmunoassay. The slow removal of this drug from the amniotic fluid was documented. Plasma levels of (15S)-15 methyl prostaglandin F/sub 2/..cap alpha.. increased fourfold to sevenfold after clinical rupture of the membranes in three patients, supporting the fact that prostaglandins are well absorbed from the vagina. Because this analogue of prostaglandin can cause marked peripheral bronchoconstriction when administered systemically, itmore » is best to avoid its use in patients with a history of asthma.« less

Airway smooth muscle: a potential target for asthma therapy.

PubMed

Dowell, Maria L; Lavoie, Tera L; Solway, Julian; Krishnan, Ramaswamy

2014-01-01

Asthma is a major public health problem that afflicts nearly one in 20 people worldwide. Despite available treatments, asthma symptoms remain poorly controlled in a significant minority of asthma patients, especially those with severe disease. Accordingly, much ongoing effort has been directed at developing new therapeutic strategies; these efforts are described in detail below. Although mucus hypersecretion is an important component of asthma pathobiology, the primary mechanism of morbidity and mortality in asthma is excessive narrowing of the airway. The key end- effector of excessive airway narrowing is airway smooth muscle (ASM) contraction; overcoming ASM contraction is therefore a prominent therapeutic strategy. Here, we review exciting new advances aimed at ASM relaxation. Exciting advances in ASM biology have identified new therapeutic targets for the prevention or reversal of bronchoconstriction in asthma.

Recent advances in the search for novel 5-lipoxygenase inhibitors for the treatment of asthma.

PubMed

Bruno, Ferdinando; Spaziano, Giuseppe; Liparulo, Angela; Roviezzo, Fiorentina; Nabavi, Seyed Mohammed; Sureda, Antoni; Filosa, Rosanna; D'Agostino, Bruno

2018-06-10

The products of 5-lipoxygenase are synthesized and released in the airway when an asthmatic reaction occurs. 5-lipoxygenase via arachidonic acid metabolism produces leukotrienes that mediate bronchoconstriction and inflammatory modifications essential in the pathophysiology of asthma. Until to now, only one approved 5-LO inhibitor, zileuton, can be found as a potential therapy for asthma. With the increasing number of indications for anti-leukotriene (anti-LT) drugs, the development of 5-LO inhibitor agents becomes increasingly important. The present MiniReview reports an update on 5-LO inhibitors currently under clinical investigation. In addition, the latest advances focused on the development of new 5-lipoxygenase inhibitors as asthma anti-inflammatory agents are also discussed. Copyright © 2017. Published by Elsevier Masson SAS.

CysLT2 receptor activation is involved in LTC4-induced lung air-trapping in guinea pigs.

PubMed

Sekioka, Tomohiko; Kadode, Michiaki; Yonetomi, Yasuo; Kamiya, Akihiro; Fujita, Manabu; Nabe, Takeshi; Kawabata, Kazuhito

2017-01-05

CysLT 1 receptors are known to be involved in the pathogenesis of asthma. However, the functional roles of CysLT 2 receptors in this condition have not been determined. The purpose of this study is to develop an experimental model of CysLT 2 receptor-mediated LTC 4 -induced lung air-trapping in guinea pigs and use this model to clarify the mechanism underlying response to such trapping. Because LTC 4 is rapidly converted to LTD 4 by γ-glutamyltranspeptidase (γ-GTP) under physiological conditions, S-hexyl GSH was used as a γ-GTP inhibitor. In anesthetized artificially ventilated guinea pigs with no S-hexyl GSH treatment, i.v. LTC 4 -induced bronchoconstriction was almost completely inhibited by montelukast, a CysLT 1 receptor antagonist, but not by BayCysLT 2 RA, a CysLT 2 receptor antagonist. The inhibitory effect of montelukast was diminished by treatment with S-hexyl GSH, whereas the effect of BayCysLT 2 RA was enhanced with increasing dose of S-hexyl GSH. Macroscopic and histological examination of lung tissue isolated from LTC 4 -/S-hexyl-GSH-treated guinea pigs revealed air-trapping expansion, particularly at the alveolar site. Inhaled LTC 4 in conscious guinea pigs treated with S-hexyl GSH increased both airway resistance and airway hyperinflation. On the other hand, LTC 4 -induced air-trapping was only partially suppressed by treatment with the bronchodilator salmeterol. Although montelukast inhibition of LTC 4 -induced air-trapping was weak, treatment with BayCysLT 2 RA resulted in complete suppression of this air-trapping. Furthermore, BayCysLT 2 RA completely suppressed LTC 4 -induced airway vascular hyperpermeability. In conclusion, we found in this study that CysLT 2 receptors mediate LTC 4 -induced bronchoconstriction and air-trapping in S-hexyl GSH-treated guinea pigs. It is therefore believed that CysLT 2 receptors contribute to asthmatic response involving air-trapping. Copyright © 2016 Elsevier B.V. All rights reserved.

Exercise-induced dehydration alters pulmonary function but does not modify airway responsiveness to dry air in athletes with mild asthma

PubMed Central

Romer, L. M.

2017-01-01

Local airway water loss is the main physiological trigger for exercise-induced bronchoconstriction (EIB). Our aim was to investigate the effects of whole body water loss on airway responsiveness and pulmonary function in athletes with mild asthma and/or EIB. Ten recreational athletes with a medical diagnosis of mild asthma and/or EIB completed a randomized, crossover study. Pulmonary function tests, including spirometry, whole body plethysmography, and diffusing capacity of the lung for carbon monoxide (DlCO), were conducted before and after three conditions: 1) 2 h of exercise in the heat with no fluid intake (dehydration), 2) 2 h of exercise with ad libitum fluid intake (control), and 3) a time-matched rest period (rest). Airway responsiveness was assessed 2 h postexercise/rest via eucapnic voluntary hyperpnea (EVH) to dry air. Exercise in the heat with no fluid intake induced a state of mild dehydration, with a body mass loss of 2.3 ± 0.8% (SD). After EVH, airway narrowing was not different between conditions: median (interquartile range) maximum fall in forced expiratory volume in 1 s was 13 (7–15)%, 11 (9–24)%, and 12 (7–20)% in dehydration, control, and rest conditions, respectively. Dehydration caused a significant reduction in forced vital capacity (300 ± 190 ml, P = 0.001) and concomitant increases in residual volume (260 ± 180 ml, P = 0.001) and functional residual capacity (260 ± 250 ml, P = 0.011), with no change in DlCO. Mild exercise-induced dehydration does not exaggerate airway responsiveness to dry air in athletes with mild asthma/EIB but may affect small airway function. NEW & NOTEWORTHY This study is the first to investigate the effect of whole body dehydration on airway responsiveness. Our data suggest that the airway response to dry air hyperpnea in athletes with mild asthma and/or exercise-induced bronchoconstriction is not exacerbated in a state of mild dehydration. On the basis of alterations in lung volumes, however, exercise-induced dehydration appears to compromise small airway function. PMID:28280109

Exercise-induced dehydration alters pulmonary function but does not modify airway responsiveness to dry air in athletes with mild asthma.

PubMed

Simpson, A J; Romer, L M; Kippelen, P

2017-05-01

Local airway water loss is the main physiological trigger for exercise-induced bronchoconstriction (EIB). Our aim was to investigate the effects of whole body water loss on airway responsiveness and pulmonary function in athletes with mild asthma and/or EIB. Ten recreational athletes with a medical diagnosis of mild asthma and/or EIB completed a randomized, crossover study. Pulmonary function tests, including spirometry, whole body plethysmography, and diffusing capacity of the lung for carbon monoxide (Dl CO ), were conducted before and after three conditions: 1 ) 2 h of exercise in the heat with no fluid intake (dehydration), 2 ) 2 h of exercise with ad libitum fluid intake (control), and 3 ) a time-matched rest period (rest). Airway responsiveness was assessed 2 h postexercise/rest via eucapnic voluntary hyperpnea (EVH) to dry air. Exercise in the heat with no fluid intake induced a state of mild dehydration, with a body mass loss of 2.3 ± 0.8% (SD). After EVH, airway narrowing was not different between conditions: median (interquartile range) maximum fall in forced expiratory volume in 1 s was 13 (7-15)%, 11 (9-24)%, and 12 (7-20)% in dehydration, control, and rest conditions, respectively. Dehydration caused a significant reduction in forced vital capacity (300 ± 190 ml, P = 0.001) and concomitant increases in residual volume (260 ± 180 ml, P = 0.001) and functional residual capacity (260 ± 250 ml, P = 0.011), with no change in Dl CO Mild exercise-induced dehydration does not exaggerate airway responsiveness to dry air in athletes with mild asthma/EIB but may affect small airway function. NEW & NOTEWORTHY This study is the first to investigate the effect of whole body dehydration on airway responsiveness. Our data suggest that the airway response to dry air hyperpnea in athletes with mild asthma and/or exercise-induced bronchoconstriction is not exacerbated in a state of mild dehydration. On the basis of alterations in lung volumes, however, exercise-induced dehydration appears to compromise small airway function. Copyright © 2017 the American Physiological Society.

Intravenous colforsin daropate, a water-soluble forskolin derivative, prevents thiamylal-fentanyl-induced bronchoconstriction in humans.

PubMed

Wajima, Zen'ichiro; Yoshikawa, Tatsusuke; Ogura, Akira; Imanaga, Kazuyuki; Shiga, Toshiya; Inoue, Tetsuo; Ogawa, Ryo

2002-04-01

Forskolin, a direct activator of adenylate cyclase, can relax airway smooth muscle, similar to other agents that increase intracellular cyclic adenine monophosphate. However, the potential usefulness of forskolin in treating bronchospasm is limited by its poor water solubility. Colforsin daropate is a novel and potent water-soluble forskolin derivative. No clinical data have been published on the bronchorelaxant effects of this drug. The aim of this study was to investigate whether intravenous colforsin daropate prevents thiamylal-fentanyl-induced bronchoconstriction. Double-blind, prospective, placebo-controlled randomized study. University teaching hospital. Thirty-six patients were allocated randomly to two groups: the control group (n = 18) and colforsin daropate group (n = 18). Intravenous administration of colforsin daropate or placebo (normal saline). Anesthesia was induced with thiamylal 5 mg/kg and vecuronium 0.3 mg/kg. A 15 mg x kg(-1) x hr(-1) continuous infusion of thiamylal followed anesthetic induction. Controlled ventilation was maintained, delivering 50% nitrous oxide in oxygen. Twenty minutes after the induction of anesthesia, the control group patients started to receive 7.5 mL/hr continuous infusion of normal saline, and the colforsin daropate group patients started to receive 0.75 microg x kg(-1) x min(-1) (7.5 mL/hr) continuous infusion of colforsin daropate for 60 min. After that, both groups received fentanyl 5 microg/kg. Systolic and diastolic arterial pressure, heart rate, mean airway resistance (Rawm), expiratory airway resistance (Rawe), and dynamic lung compliance (Cdyn) were measured at the baseline, just before the administration of fentanyl (T30), at three consecutive 6-min intervals after fentanyl injection (T36, T42, and T48) and 30 min after fentanyl injection (T60). At baseline, both groups had comparable Rawm, Rawe, and Cdyn values. In the control group, Rawm increased significantly at T36-60 compared with the baseline, Rawe increased significantly at T36-48 compared with the baseline, and Cdyn decreased significantly at T36-60 compared with the baseline. In the colforsin daropate group, there were no changes in Rawm, Rawe or Cdyn at T36-60. These observations suggest that intravenous colforsin daropate has a bronchodilator effect in humans.

Labeled carbon dioxide (C18O2): an indicator gas for phase II in expirograms.

PubMed

Schulz, Holger; Schulz, Anne; Eder, Gunter; Heyder, Joachim

2004-11-01

Carbon dioxide labeled with 18O (C18O2) was used as a tracer gas for single-breath measurements in six anesthetized, mechanically ventilated beagle dogs. C18O2 is taken up quasi-instantaneously in the gas-exchanging region of the lungs but much less so in the conducting airways. Its use allows a clear separation of phase II in an expirogram even from diseased individuals and excludes the influence of alveolar concentration differences. Phase II of a C18O2 expirogram mathematically corresponds to the cumulative distribution of bronchial pathways to be traversed completely in the course of exhalation. The derivative of this cumulative distribution with respect to respired volume was submitted to a power moment analysis to characterize volumetric mean (position), standard deviation (broadness), and skewness (asymmetry) of phase II. Position is an estimate of dead space volume, whereas broadness and skewness are measures of the range and asymmetry of functional airway pathway lengths. The effects of changing ventilatory patterns and of changes in airway size (via carbachol-induced bronchoconstriction) were studied. Increasing inspiratory or expiratory flow rates or tidal volume had only minor influence on position and shape of phase II. With the introduction of a postinspiratory breath hold, phase II was continually shifted toward the airway opening (maximum 45% at 16 s) and became steeper by up to 16%, whereas skewness showed a biphasic response with a moderate decrease at short breath holding and a significant increase at longer breath holds. Stepwise bronchoconstriction decreased position up to 45 +/- 2% and broadness of phase II up to 43 +/- 4%, whereas skewness was increased up to twofold at high-carbachol concentrations. Under all circumstances, position of phase II by power moment analysis and dead space volume by the Fowler technique agreed closely in our healthy dogs. Overall, power moment analysis provides a more comprehensive view on phase II of single-breath expirograms than conventional dead space volume determinations and may be useful for respiratory physiology studies as well as for the study of diseased lungs.

Efficiency and limitations of the upper airway mucosa as an air conditioner evaluated from the mechanisms of bronchoconstriction in asthmatic subjects.

PubMed

Konno, A; Terada, N; Okamoto, Y; Togawa, K

1985-01-01

To elucidate a limit to the efficiency of the upper airway mucosa as an air conditioner, the temperatures of the inspiratory air and mucosa were measured in the cervical trachea. Both of them were affected only minimally by change of atmospheric air temperature during resting nose breathing, but were affected greatly by change of mode of breathing. During hyperventilation through the mouth, when the atmospheric air temperature was 1 degree C, a temperature difference of 9 degrees C was noted between inspiratory air in the cervical trachea and body temperature, together with a mucosal temperature fall by 1.86 +/- 0.61 degree C. Wearing of a mask caused a rise of 3 degrees C in the inspiratory air temperature in the cervical trachea.

[Bronchial inflammation during chronic bronchitis, importance of fenspiride].

PubMed

Melloni, B

2002-09-01

PATHOPHYSIOLOGY OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD): Chronic inflammation of the upper airways, pulmonary parenchyma and pulmonary vasculature is the characteristic feature of COPD. Two mechanisms besides inflammation are also involved: oxidative stress and imbalance between proteinases and antiproteinases. Cellular infiltration of the upper airways involved neutrophils, macrophages, T lymphocytes and eosinophils. Inflammatory mediators appear to play a crucial role in the interaction between inflammation and obstruction. PROPERTIES OF FENSPIRIDE: A nonsteroidal drug, fenspiride, exhibits interesting properties documented in vitro: anti-bronchoconstriction activity, anti-secretory activity, and anti-inflammatory activity (reduction in the activity of phospholipase A2 and release of proinflammatory leukotriens). Two french clinical trials have studied the efficacy of fenspiride in patients with acute excerbation or stable COPD and have demonstrated an improvement in the group treated with fenspiride compared with the placebo group.

Volumetric capnography curves as lung function test to confirm bronchoconstriction after carbachol challenge in sedated dogs.

PubMed

Scheffzek, S; Mosing, M; Hirt, R; Iff, I; Moens, Y

2012-12-01

This study investigated volumetric capnography (VC) in detecting airway responsiveness following airway challenge using carbachol in seven sedated dogs via face mask. Nebulised saline was administered, followed by increasing concentrations of nebulised carbachol until airflow limitation occurred (EP). Dead space (DS) variables and shape indices of the VC curve were calculated automatically after entering arterial carbon dioxide tension. Airway DS, airway DS to tidal volume (VT) ratio and the intercept of slope 2 of the VC curve decreased significantly at EP by 10%, 13% and 16%, respectively, minute ventilation, VT and alveolar DS increased significantly at EP by 49%, 22% and 200%, respectively. We conclude that VC and derived indices may be used to verify a reaction to airway challenge caused by carbachol in sedated dogs. Copyright © 2012 Elsevier Ltd. All rights reserved.

Hyperventilation in Panic Disorder and Asthma: Empirical Evidence and Clinical Strategies

PubMed Central

Meuret, Alicia E.; Ritz, Thomas

2010-01-01

Sustained or spontaneous hyperventilation has been associated with a variety of physical symptoms and has been linked to a number of organic illnesses and mental disorders. Theories of panic disorder hold that hyperventilation either produces feared symptoms of hypocapnia or protects against feared suffocation symptoms of hypercapnia. Although the evidence for both theories is inconclusive, findings from observational, experimental, and therapeutic studies suggest an important role of low carbon dioxide (CO2) levels in this disorder. Similarly, hypocapnia and associated hyperpnia are linked to bronchoconstriction, symptom exacerbation, and lower quality of life in patients with asthma. Raising CO2 levels by means of therapeutic capnometry has proven beneficial effects in both disorders, and the reversing of hyperventilation has emerged as a potent mediator for reductions in panic symptom severity and treatment success. PMID:20685222

Response localization of the pharmacological agents histamine and salbutamol along the respiratory system by forced oscillations in asthmatic subjects.

PubMed

Wouters, E F; Polko, A H; Visser, B F

1989-01-01

The bronchodilating effect of 1 mg and 0.4 mg salbutamol on the impedance of the respiratory system was studied in 25 asthmatic subjects after histamine-induced bronchoconstriction. Histamine caused an increase of respiratory resistance (Rrs) at lower frequencies and a frequency dependence of Rrs. Respiratory reactance (Xrs) decreased at all frequencies after histamine challenge. These changes can be explained by peripheral airway obstruction. Impedance measurements performed 5 min after inhalation of 1 mg and 0.4 mg salbutamol showed a decrease of Rrs values at lower frequencies, a disappearance of the frequency dependence of Rrs, and a significant increase of Xrs values. No significant differences in absolute changes of Rrs and Xrs are observed between the salbutamol regimens. These changes after inhalation of salbutamol can be explained by supposing a predominant action on the peripheral airways.

Quantifying parenchymal tethering in a finite element simulation of a human lung slice under bronchoconstriction.

PubMed

Breen, Barbara J; Donovan, Graham M; Sneyd, James; Tawhai, Merryn H

2012-08-15

Airway hyper-responsiveness (AHR), a hallmark of asthma, is a highly complex phenomenon characterised by multiple processes manifesting over a large range of length and time scales. Multiscale computational models have been derived to embody the experimental understanding of AHR. While current models differ in their derivation, a common assumption is that the increase in parenchymal tethering pressure P(teth) during airway constriction can be described using the model proposed by Lai-Fook (1979), which is based on intact lung experimental data for elastic moduli over a range of inflation pressures. Here we reexamine this relationship for consistency with a nonlinear elastic material law that has been parameterised to the pressure-volume behaviour of the intact lung. We show that the nonlinear law and Lai-Fook's relationship are consistent for small constrictions, but diverge when the constriction becomes large. Copyright © 2012 Elsevier B.V. All rights reserved.

Exposure to formaldehyde: effects on pulmonary function.

PubMed

Alexandersson, R; Hedenstierna, G; Kolmodin-Hedman, B

1982-01-01

Forty-seven subjects exposed to formaldehyde (mean air concentration 0.45 mg/m3) and 20 unexposed subjects, all of whom were employed at a carpentry shop, were studied with regard to symptoms and pulmonary function. Symptoms involving eyes and throat as well as chest oppression were significantly more common in the exposed subjects than in the unexposed controls. Spirometry and single breath nitrogen washout were normal Monday morning before exposure to formaldehyde. A reduction in forced expiratory volume in 1 sec by an average of 0.2 L (P = .002), percent forced expiratory volume by 2% (P = .04), maximum midexpiratory flow by 0.3 L/sec (P = .04) and an increase in closing volume in percentage of vital capacity by 3.4% (P - .002) were seen after a day of work and exposure to formaldehyde, suggesting bronchoconstriction. Smokers and nonsmokers displayed similar changes in spirometry and nitrogen washout.

Neutrophilic inflammation is associated with altered airway hydration in stable asthmatics.

PubMed

Loughlin, Ceila E; Esther, Charles R; Lazarowski, Eduardo R; Alexis, Neil E; Peden, David B

2010-01-01

Airway dehydration is a potential trigger of bronchoconstriction in exercise-induced asthma; however, its role in stable asthma has not been explored. Using sputum percent solids, as an indicator of airway hydration, we sought relationships between airway hydration and other known markers of neutrophilic (TH1) and allergic (TH2) inflammation in stable asthma. Thirty-seven atopic subjects with stable asthma and 15 healthy controls underwent sputum induction. Sputum was analyzed for percent solids, cell counts, cellular and biochemical markers of inflammation and purines. Sputum percent solids was significantly elevated in stable asthmatics vs. controls and positively correlated with markers of neutrophilic/TH1-type inflammation (neutrophils, IL-8 and AMP). Sputum percent solids were not correlated with markers of allergic/TH2-type inflammation. These data suggest a direct relationship between neutrophil inflammation and airway hydration in stable asthmatics. Copyright 2009 Elsevier Ltd. All rights reserved.

Nedocromil sodium modulates nonadrenergic, noncholinergic bronchoconstrictor nerves in guinea pig airways in vitro.

PubMed

Verleden, G M; Belvisi, M G; Stretton, C D; Barnes, P J

1991-01-01

Nonadrenergic, noncholinergic (NANC) neural bronchoconstrictor responses in guinea pig airways are due to the release of tachykinins from sensory nerves. We have performed an in vitro study using electrical field stimulation (EFS; 40 V, 0.5 ms, 8 Hz for 20 s) in guinea pig bronchi to investigate the effect of nedocromil sodium (NS) on NANC bronchoconstrictor responses. NS inhibited NANC bronchoconstriction in bronchi in a concentration-dependent manner, with a maximum inhibition of 40 +/- 4% (p less than 0.001, n = 6) at 100 microM. Cromolyn sodium, however, produced only 9 +/- 8% inhibition at the same molar concentration (p less than 0.05). NS did not affect the contractile response to substance P, nor did it modulate the cholinergic bronchoconstrictor response to EFS in tracheal smooth muscle. These results indicate that NS may modulate the release of tachykinins from airway sensory nerves.

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

PubMed

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

2016-01-01

Background: COPD is a progressive lung disease characterized by emphysema and enhanced bronchoconstriction. Current treatments focused on bronchodilation can delay disease progression to some extent, but recovery or normalization of loss of lung function is impossible. Therefore, novel therapeutic targets are needed. The importance of the parenchyma in airway narrowing is increasingly recognized. In COPD, the parenchyma and extracellular matrix are altered, possibly affecting airway mechanics and enhancing bronchoconstriction. Our aim was to set up a comprehensive ex vivo Precision Cut Lung Slice (PCLS) model with a pathophysiology resembling that of COPD and integrate multiple readouts in order to study the relationship between parenchyma, airway functionality, and lung repair processes. Methods: Lungs of C57Bl/6J mice were sliced and treated ex vivo with elastase (2.5 μg/ml) or H 2 O 2 (200 μM) for 16 h. Following treatment, parenchymal structure, airway narrowing, and gene expression levels of alveolar Type I and II cell repair were assessed. Results: Following elastase, but not H 2 O 2 treatment, slices showed a significant increase in mean linear intercept (Lmi), reflective of emphysema. Only elastase-treated slices showed disorganization of elastin and collagen fibers. In addition, elastase treatment lowered both alveolar Type I and II marker expression, whereas H 2 O 2 stimulation lowered alveolar Type I marker expression only. Furthermore, elastase-treated slices showed enhanced methacholine-induced airway narrowing as reflected by increased pEC50 (5.87 at basal vs. 6.50 after elastase treatment) and Emax values (47.96 vs. 67.30%), and impaired chloroquine-induced airway opening. The increase in pEC50 correlated with an increase in mean Lmi. Conclusion: Using this model, we show that structural disruption of elastin fibers leads to impaired alveolar repair, disruption of the parenchymal compartment, and altered airway biomechanics, enhancing airway contraction. This finding may have implications for COPD, as the amount of elastin fiber and parenchymal tissue disruption is associated with disease severity. Therefore, we suggest that PCLS can be used to model certain aspects of COPD pathophysiology and that the parenchymal tissue damage observed in COPD contributes to lung function decline by disrupting airway biomechanics. Targeting the parenchymal compartment may therefore be a promising therapeutic target in the treatment of COPD.

Treatment of exercise-induced asthma, respiratory and allergic disorders in sports and the relationship to doping: Part II of the report from the Joint Task Force of European Respiratory Society (ERS) and European Academy of Allergy and Clinical Immunology (EAACI) in cooperation with GA(2)LEN.

PubMed

Carlsen, K H; Anderson, S D; Bjermer, L; Bonini, S; Brusasco, V; Canonica, W; Cummiskey, J; Delgado, L; Del Giacco, S R; Drobnic, F; Haahtela, T; Larsson, K; Palange, P; Popov, T; van Cauwenberge, P

2008-05-01

The aims of part II is to review the current recommended treatment of exercise-induced asthma (EIA), respiratory and allergic disorders in sports, to review the evidence on possible improvement of performance in sports by asthma drugs and to make recommendations for their treatment. The literature cited with respect to the treatment of exercise induced asthma in athletes (and in asthma patients) is mainly based upon the systematic review given by Larsson et al. (Larsson K, Carlsen KH, Bonini S. Anti-asthmatic drugs: treatment of athletes and exercise-induced bronchoconstriction. In: Carlsen KH, Delgado L, Del Giacco S, editors. Diagnosis, prevention and treatment of exercise-related asthma, respiratory and allergic disorders in sports. Sheffield, UK: European Respiratory Journals Ltd, 2005:73-88) during the work of the Task Force. To assess the evidence of the literature regarding use of beta(2)-agonists related to athletic performance, the Task Force searched Medline for relevant papers up to November 2006 using the present search words: asthma, bronchial responsiveness, exercise-induced bronchoconstriction, athletes, sports, performance and beta(2)-agonists. Evidence level and grades of recommendation were assessed according to Sign criteria. Treatment recommendations for EIA and bronchial hyper-responsiveness in athletes are set forth with special reference to controller and reliever medications. Evidence for lack of improvement of exercise performance by inhaled beta(2)-agonists in healthy athletes serves as a basis for permitting their use. There is a lack of evidence of treatment effects of asthma drugs on EIA and bronchial hyper-responsiveness in athletes whereas extensive documentation exists in treatment of EIA in patients with asthma. The documentation on lack of improvement on performance by common asthma drugs as inhaled beta(2)-agonists with relationship to sports in healthy individuals is of high evidence, level (1+). Exercise induced asthma should be treated in athletes along same principles as in ordinary asthma patients with relevance to controller and reliever treatment after careful diagnosis. There is very high level of evidence for the lack of improvement in athletic performance by inhaled beta2-agonists.

Inhibition of excitatory non-adrenergic non-cholinergic bronchoconstriction in guinea-pig airways in vitro by activation of an atypical 5-HT receptor.

PubMed

Ward, J K; Fox, A J; Barnes, P J; Belvisi, M G

1994-04-01

1. The effect of 5-hydroxytryptamine (5-HT) was studied on excitatory neurally mediated non-adrenergic non-cholinergic (NANC) contractions evoked by electrical field stimulation (EFS) in guinea-pig isolated bronchi. 2. 5-HT (0.1-100 microM) produced a concentration-dependent inhibition of the excitatory NANC response with 50.9 +/- 5.0% (n = 5, P < 0.01) inhibition at 100 microM. This inhibition was not significantly affected by the 5-HT2 antagonist, ketanserin (1 microM) when inhibitions (+/- ketanserin) at each concentration of 5-HT were compared by unpaired t tests; however, this concentration appeared to produce a leftward shift (approximately 10 fold) of the 5-HT concentration-inhibition curve. Ketanserin (1 microM) was effective in blocking bronchoconstriction evoked by activation of 5-HT2A receptors on airway smooth muscle. In the presence of ketanserin (1 microM) 5-HT (100 microM) evoked an inhibition of 57.4 +/- 5.9% (n = 5, P < 0.01) with an EC50 of 0.57 microM. 3. Inhibition evoked by 5-HT (0.1-100 microM) was unaffected by the alpha-adrenoceptor antagonist phentolamine (1 microM), the beta 2-adrenoceptor antagonist, ICI 118551 (0.1 microM), the 5-HT1A/B antagonist, cyanopindolol (1 microM) or the 5-HT3/4 antagonist, ICS 205-930 (1 microM). 4. Methiothepin (0.1 microM) produced an insurmountable inhibition of the effect of 5-HT (0.1-100 microM), reducing the maximum inhibition produced by 5-HT (100 microM) to 30.2 +/- 5.0% (n = 5, P < 0.001) and suggesting a non-competitive antagonism. Methiothepin inhibited the effect of 5-HT (10 microM) in a concentration-dependent manner with an IC50 of 81 nM. 5. Selective 5-HT receptor agonists were also tested on excitatory NANC responses. 5-Carboxamidotryptamine (5-CT, 0.1-100 MicroM) was the most potent, producing a concentration-dependent inhibition with an EC50 of 0.13 MicroM. Calculation of approximate IC25 values (concentration of the agonist required to give a 25% inhibition of the excitatory NANC response) gave a rank order of potency 5-CT > 5-HT> > 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) >alpha-methyl-5-hydroxytryptamine (alpha-Me-5HT). Sumatriptan, 5-methoxytryptamine (5-MeOT) and 2-methyl-5-hydroxytryptamine (2-Me-5HT) were essentially inactive with IC25> 100 MicroM.6. 5-HT (10 microM) did not significantly affect contractile responses to exogenously applied substance P(1 nM-10 Microm).7. The effect of 5-HT was unchanged after incubation with the nitric oxide (NO) synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME, 100 Microm). However, pretreatment with charybdotoxin (ChTX,0.1-30 nM), a blocker of the large conductance Ca2+-activated K+channel (K+ca), produced a concentration-dependent inhibition of the effect of 5-HT (10 MicroM).8. 5-HT evokes a concentration-dependent inhibition of e-NANC bronchoconstriction in guinea-pig isolated bronchi but does not affect cumulative concentration-dependent contractile responses to substance P, suggesting that inhibition is via a prejunctional receptor. Effects of selective antagonists and agonists suggest that an atypical 5-HT receptor mediates this inhibition. The inhibitory effect of 5-HT does not involve the production of NO, but may involve the opening a ChTX-sensitive K+ca channel.These data suggest that an atypical 5-HT receptor inhibits the release of neuropeptides from sensory C fibres and may act as other inhibitory neuromodulators via the opening of a common K'channel.

Bronchial provocation tests in clinical practice.

PubMed

Borges, Marcos de Carvalho; Ferraz, Erica; Vianna, Elcio Oliveira

2011-01-01

Bronchial hyperresponsiveness, which consists of an exaggerated response of the airways to bronchoconstrictor stimuli, is one of the main characteristics of asthma, presented in nearly all asthmatic patients. Bronchial hyperresponsiveness may also be present in other diseases, such as allergic rhinitis, chronic obstructive pulmonary disease, cystic fibrosis, heart failure and respiratory infection, and with some medications, such as β-blockers. Bronchial provocation tests (also known as bronchial challenges) are used to evaluate bronchial responsiveness. These tests have become increasingly used over the last 20 years, with the development and validation of accurate, safe and reproducible tests, and with the publication of well-detailed protocols. Several stimuli can be used in a bronchial challenge, and they are classified as direct and indirect stimuli. There are many indications for a bronchial challenge. In this review, we discuss the main differences between direct and indirect stimuli, and the use of bronchial challenges in clinical practice, especially for confirming diagnoses of asthma, exercise-induced bronchoconstriction and cough-variant asthma, and for use among elite-level athletes.

Exercise induced asthma and endogenous opioids.

PubMed Central

Gaillard, R C; Bachman, M; Rochat, T; Egger, D; de Haller, R; Junod, A F

1986-01-01

Concentrations of endogenous opioid peptides in the plasma are increased during exercise and these substances have been implicated in the pathogenesis of asthma induced by chloropropramide and alcohol in diabetic patients. This work was undertaken to determine whether exercise induced asthma might be mediated by endogenous opioids. Plasma beta endorphin, met-enkephalin, and adrenocorticotrophic hormone (ACTH) concentrations were measured in five asthmatic patients and five normal volunteers breathing cold air during exercise. In four of the patients the effect of an infusion of naloxone on FEV1 was also measured during exercise induced asthma. Exercise produced acute bronchoconstriction in all asthmatics, characterised by a fall in FEV1; whereas no change occurred in normal subjects. There was no difference in plasma met-enkephalin, beta endorphin, and ACTH concentration between the two groups. Infusion of naloxone neither prevented nor worsened exercise induced asthma. These data suggest that endogenous opioids probably do not play a part in the development of exercise induced asthma. PMID:2944240

Human mast cell and airway smooth muscle cell interactions: implications for asthma.

PubMed

Page, S; Ammit, A J; Black, J L; Armour, C L

2001-12-01

Asthma is characterized by inflammation, hyperresponsiveness, and remodeling of the airway. Human mast cells (HMCs) play a central role in all of these changes by releasing mediators that cause exaggerated bronchoconstriction, induce human airway smooth muscle (HASM) cell proliferation, and recruit and activate inflammatory cells. Moreover, the number of HMCs present on asthmatic HASM is increased compared with that on nonasthmatic HASM. HASM cells also have the potential to actively participate in the inflammatory process by synthesizing cytokines and chemokines and expressing surface molecules, which have the capacity to perpetuate the inflammatory mechanisms present in asthma. This review specifically examines how the mediators of HMCs have the capacity to modulate many functions of HASM; how the synthetic function of HASM, particularly through the release and expression of stem cell factor, has the potential to influence HMC number and activation in an extraordinarily potent and proinflammatory manner; and how these interactions between HMCs and HASM have potential consequences for airway structure and inflammation relevant to the disease process of asthma.

[Anaesthesia for patients with obstructive airway diseases].

PubMed

Groeben, H; Keller, V; Silvanus, M T

2014-01-01

Obstructive lung diseases like asthma or chronic obstructive lung diseases have a high prevalence and are one of the four most frequent causes of death. Obstructive lung diseases can be significantly influenced by the choice of anesthetic techniques and anesthetic agents. Basically, the severity of the COPD and the degree of bronchial hyperreactivity will determine the perioperative anesthetic risk. This risk has to be assessed by a thorough preoperative evaluation and will give the rationale on which to decide for the adequate anaesthetic technique. In particular, airway instrumentation can cause severe reflex bronchoconstriction. The use of regional anaesthesia alone or in combination with general anaesthesia can help to avoid airway irritation and leads to reduced postoperative complications. Prophylactic antiobstructive treatment, volatile anesthetics, propofol, opioids, and an adequate choice of muscle relaxants minimize the anesthetic risk, when general anesthesia is required In case, despite all precautions intra-operative bronchospasm occurs, deepening of anaesthesia, repeated administration of beta2-adrenergic agents and parasympatholytics, and a single systemic dose of corticosteroids represent the main treatment options.

Asthma Management in Sickle Cell Disease

PubMed Central

Morris, Claudia R.

2013-01-01

Asthma is a common comorbid factor in sickle cell disease (SCD). However, the incidence of asthma in SCD is much higher than expected compared to rates in the general population. Whether “asthma” in SCD is purely related to genetic and environmental factors or rather is the consequence of the underlying hemolytic and inflammatory state is a topic of recent debate. Regardless of the etiology, hypoxemia induced by bronchoconstriction and inflammation associated with asthma exacerbations will contribute to a cycle of sickling and subsequent complications of SCD. Recent studies confirm that asthma predisposes to complications of SCD such as pain crises, acute chest syndrome, and stroke and is associated with increased mortality. Early recognition and aggressive standard of care management of asthma may prevent serious pulmonary complications and reduce mortality. However, data regarding the management of asthma in SCD is very limited. Clinical trials are needed to evaluate the effectiveness of current asthma therapy in patients with SCD and coincident asthma, while mechanistic studies are needed to delineate the underlying pathophysiology. PMID:24324967

Calculated ventilation and effort distribution as a measure of respiratory disease and Heliox effectiveness.

PubMed

Pozin, N; Montesantos, S; Katz, I; Pichelin, M; Grandmont, C; Vignon-Clementel, I

2017-07-26

In spite of numerous clinical studies, there is no consensus on the benefit Heliox mixtures can bring to asthmatic patients in terms of work of breathing and ventilation distribution. In this article we use a 3D finite element mathematical model of the lung to study the impact of asthma on effort and ventilation distribution along with the effect of Heliox compared to air. Lung surface displacement fields extracted from computed tomography medical images are used to prescribe realistic boundary conditions to the model. Asthma is simulated by imposing bronchoconstrictions to some airways of the tracheo-bronchial tree based on statistical laws deduced from the literature. This study illuminates potential mechanisms for patient responsiveness to Heliox when affected by obstructive pulmonary diseases. Responsiveness appears to be function of the pathology severity, as well as its distal position in the tracheo-bronchial tree and geometrical position within the lung. Copyright © 2017 Elsevier Ltd. All rights reserved.

Treatment options for the management of exercise-induced asthma and bronchoconstriction.

PubMed

Millward, David T; Tanner, Lindsay G; Brown, Mark A

2010-12-01

Treatment for exercise-induced bronchospasm and exercise-induced asthma includes both pharmacologic and nonpharmacologic options. Pharmacologic agents that have been proven to be effective for treating these conditions include short- and long-acting β2-adrenoceptor agonists, mast cell-stabilizing agents, anticholinergics, leukotriene receptor antagonists, and inhaled corticosteroids (ICS). When selecting the most appropriate medication, factors to consider include the effectiveness of each, the duration of action, frequency of administration, potential side effects, and tolerance level. Long-acting β2-adrenoceptor agonists should not be used without ICS. Nonpharmacologic treatments include physical conditioning, incorporating a warm-up before and a cool-down period after exercise, performing nasal breathing, avoiding cold weather or environmental allergens, using a face mask or other aid to warm and humidify inhaled air, and modifying dietary intake. The data to support nonpharmacologic treatments are limited; however, they are routinely recommended because of the low risk associated with their use. This article highlights the advantages and limitations of each treatment option.

Effect of isoprenaline and cigarette smoking on airways.

PubMed

Mahajan, K K; Reghunandan, V; Maini, B K; Mahajan, S K

1983-01-01

After two hours of abstinence from smoking pulmonary functions were assessed in twenty-seven asymptomatic male smokers by spirometry and Wright Peak Flow Meter, recording FVC, FEV1, FEV1%, FEF25-75%, and FEF75-85% of FVC, MVV and PEFR. These tests were repeated immediately after smoking and again after one hr. Only PEFR decreased significantly (P less than 0.01) and returned to nearly basal level after one hr. Sixteen of these smokers were subjected to further study. Isoprenaline inhalation in these smokers caused a significant improvement in most of the flow rates. Smoking of cigarettes at this stage decreased flow rates. After one hr the effect of smoking was over and most of the parameters were between basal and post-isoprenaline levels. Smoking affects the flow rates more than other parameters. An improvement in FEV1, FEV1%, FEF25-75% and FEF75-85% of FVC, after bronchodilator inhalation suggests the presence of some reversible bronchoconstriction specially of smaller airways basically present in chronic smokers.

Respiratory response of guinea pigs to sulfuric acid mist

DOE Office of Scientific and Technical Information (OSTI.GOV)

Amdur, M.O.

1958-01-01

Guinea pigs were exposed to 23 to 42 mg/m/sup 3/ acid mist with a mass median diameter of 0.8, 2.5, or 7 ..mu..m for 1-h periods. Significant increase in resistance at all levels and sizes was observed. There was a concurrent decrease in compliance for 2.5- and 7-..mu..m sizes with exception of lowest level of exposure. Dose-effect with resistance vs concentration shows smaller sizes were more deleterious. The 2.5 ..mu..m were more harmful at higher concentrations (above approx. 15 mg/m/sup 3/). The 0.8-..mu..m particles produced a rapid response suggesting bronchoconstriction as the mechanism (change in resistance proportionately greater than changemore » in compliance). This was similar to irritant gases. Conversely, 2.5- and 7-..mu..m particles acted slower and change in resistance paralleled the drop in compliance. High concentrations evoked edema and atelectasis. This was interpreted as closure of main bronchi rather than general constriction. Response was consistent with expected penetration.« less

[Specific aspects and care of lung involvement in adults with cystic fibrosis].

PubMed

Pin, I; Grenet, D; Scheid, P; Domblides, P; Stern, M; Hubert, D

2000-08-01

Respiratory impairment is present in almost all adult cystic fibrosis patients and makes the prognosis. Viscous, infected and abundant secretions, inflammation and bronchial oedema, bronchoconstriction and respiratory muscle fatigue lead to airway obstruction, bronchiectasis and respiratory failure. The disease is preferentially located in the upper lobes. Exacerbations of the disease are due to bronchial infections and are often responsible for drops of the respiratory function. Regular spirometric surveillance is fundamental for the prognosis and the assessment of the effects of the treatment. Among adult patients chronic colonisation with mucoid and often multiresistant strains of Pseudomonas Aeruginosa are common. It is treated with i.v. high doses antibiotic courses and nebulized antibiotics between i.v. courses. Respiratory failure may require long term oxygen and non invasive mechanical ventilation. Systemic hypervascularization around the bronchiectasis may lead to moderate to severe hemoptysis, which may require embolization. Pneumothorax are associated with poor prognosis and are treated by pleural drainage and if failure by thoracoscopy.

Nociceptin effects in the airways.

PubMed

Peiser, C; Undem, B J; Fischer, A

2000-07-01

The opioid-like heptadecapeptide nociceptin (NC) has the following effects in the airways (investigated in isolated tracheae and bronchi from guinea pig or rat): the electric field stimulation (EFS)-induces release of acetylcholine (ACh), the tachykinin substance P (SP) and calcitonin gene-related peptide (CGRP) is reduced after pretreatment with NC, and EFS-induced tachykinergic nonadrenergic-noncholinergic (NANC) bronchoconstriction is inhibited by NC. Both the NC-mediated inhibition of neurotransmission and of smooth muscle contraction occurred in a concentration-dependent manner. Because these effects were naloxone-insensitive, were blocked by the NC receptor antagonist [F/G]NC(1-13)NH(2), and could be mimicked by the NC analogs, NCNH(2) and NC(1-13)NH(2), it is thought that they are distinct from the classic opioid receptors. That these pharmacological actions of NC are of relevance for airway physiology is highly probable given the presence of NC-immunoreactivity in the nerve fibers of the airways and of opioid-like receptor (ORL-1) transcripts in the jugular ganglia, from where the tachykinin-containing afferents arise.

The effect of cisatracurium and rocuronium on lung function in anesthetized children.

PubMed

Yang, Charles I; Fine, Gavin F; Jooste, Edmund H; Mutich, Rebecca; Walczak, Stephen A; Motoyama, Etsuro K

2013-12-01

Neuromuscular blocking drugs have been implicated in intraoperative bronchoconstrictive episodes. We examined the effects of clinically relevant doses of cisatracurium and rocuronium on the lung mechanics of pediatric subjects. We hypothesized that cisatracurium and rocuronium would have bronchoconstrictive effects. We studied ASA physical status I and II pediatric subjects having elective dental or urological procedures, requiring general anesthesia with endotracheal intubations with either cisatracurium or rocuronium. Pulmonary function tests were performed before and after neuromuscular blocking drug dosing and again after albuterol administration. Using forced deflation and passive deflation techniques, forced vital capacity (FVC) and maximum expiratory flow rate at 10% (MEF10) of FVC were obtained. Fractional changes from the baseline were used to compare subjects. Changes in MEF10 of >30% were considered clinically significant. A Shapiro-Wilk test, paired t test, and Wilcoxon rank sum test were used to analyze the data. Twenty-five subjects (median age = 5.25 years; range = 9 months-9.9 years) were studied; 12 subjects received cisatracurium and 13 subjects received rocuronium. Data are shown as mean proportional change ± SD or, in the case of not normally distributed, median proportional change (first, third quartile) with P values. In the cisatracurium group, there were no differences between baseline and postneuromuscular blocker administration in the fractional change from the baselines of FVC (1.00 ± 0.04, P = 0.5), but there was a significant decrease in MEF10 (0.80 ± 0.18, P = 0.002). In the rocuronium group, there were small yet significant decreases of FVC (0.99 [first quartile 0.97, third quartile 1], P = 0.02) and significant decreases in MEF10 (0.78 ± 0.26, P = 0.008). After administration of albuterol in the cisatracurium group, FVC increased slightly but significantly from baseline values (1.02 ± 0.02, P = 0.005). MEF10 increased significantly beyond baseline values (1.24 ± 0.43, P =0.04). In the rocuronium group, there were also significant differences between baseline and postalbuterol administration from the baseline value of FVC (1.02 ± 0.02, P = 0.004) and MEF10 (1.23 ± 0.29, P = 0.01). At clinically relevant doses, both cisatracurium and rocuronium caused changes in lung function, indicating constriction of smaller airways. In general, these changes were mild and not clinically detectable. However, in the rocuronium group, 3 of 13 patients showed more noticeable decreases in MEF10 (≤50%), demonstrating the potential for significant broncho-bronchiolar constriction in susceptible patients.

Caveolin-1: Functional Insights into Its Role in Muscarine- and Serotonin-Induced Smooth Muscle Constriction in Murine Airways

PubMed Central

Keshavarz, Maryam; Schwarz, Heike; Hartmann, Petra; Wiegand, Silke; Skill, Melanie; Althaus, Mike; Kummer, Wolfgang; Krasteva-Christ, Gabriela

2017-01-01

An increased bronchoconstrictor response is a hallmark in the progression of obstructive airway diseases. Acetylcholine and 5-hydroxytryptamine (5-HT, serotonin) are the major bronchoconstrictors. There is evidence that both cholinergic and serotonergic signaling in airway smooth muscle (ASM) involve caveolae. We hypothesized that caveolin-1 (cav-1), a structural protein of caveolae, plays an important regulatory role in ASM contraction. We analyzed airway contraction in different tracheal segments and extra- and intrapulmonary bronchi in cav-1 deficient (cav-1−/−) and wild-type mice using organ bath recordings and videomorphometry of methyl-beta-cyclodextrin (MCD) treated and non-treated precision-cut lung slices (PCLS). The presence of caveolae was investigated by electron microscopy. Receptor subtypes driving 5-HT-responses were studied by RT-PCR and videomorphometry after pharmacological inhibition with ketanserin. Cav-1 was present in tracheal epithelium and ASM. Muscarine induced a dose dependent contraction in all airway segments. A significantly higher Emax was observed in the caudal trachea. Although, caveolae abundancy was largely reduced in cav-1−/− mice, muscarine-induced airway contraction was maintained, albeit at diminished potency in the middle trachea, in the caudal trachea and in the bronchus without changes in the maximum efficacy. MCD-treatment of PLCS from cav-1−/− mice reduced cholinergic constriction by about 50%, indicating that cholesterol-rich plasma domains account for a substantial portion of the muscarine-induced bronchoconstriction. Notably, cav-1-deficiency fully abrogated 5-HT-induced contraction of extrapulmonary airways. In contrast, 5-HT-induced bronchoconstriction was fully maintained in cav-1-deficient intrapulmonary bronchi, but desensitization upon repetitive stimulation was enhanced. RT-PCR analysis revealed 5-HT1B, 5-HT2A, 5-HT6, and 5-HT7 receptors as the most prevalent subtypes in the airways. The 5-HT-induced-constriction in PCLS could be antagonized by ketanserin, a 5-HT2A receptor inhibitor. In conclusion, the role of cav-1, caveolae, and cholesterol-rich plasma domains in regulation of airway tone are highly agonist-specific and dependent on airway level. Cav-1 is indispensable for serotonergic contraction of extrapulmonary airways and modulates cholinergic constriction of the trachea and main bronchus. Thus, cav-1/caveolae shall be considered in settings such as bronchial hyperreactivity in common airway diseases and might provide an opportunity for modulation of the constrictor response. PMID:28555112

The role of the adenosinergic system in lung fibrosis.

PubMed

Della Latta, Veronica; Cabiati, Manuela; Rocchiccioli, Silvia; Del Ry, Silvia; Morales, Maria-Aurora

2013-10-01

Adenosine (ADO) is a retaliatory metabolite that is expressed in conditions of injury or stress. During these conditions ATP is released at the extracellular level and is metabolized to adenosine. For this reason, adenosine is defined as a "danger signal" for cells and organs, in addition to its important role as homeostatic regulator. Its physiological functions are mediated through interaction with four specific transmembrane receptors called ADORA1, ADORA2A, ADORA2B and ADORA3. In the lungs of mice and humans all four adenosine receptors are expressed with different roles, having pro- and anti-inflammatory roles, determining bronchoconstriction and regulating lung inflammation and airway remodeling. Adenosine receptors can also promote differentiation of lung fibroblasts into myofibroblasts, typical of the fibrotic event. This last function suggests a potential involvement of adenosine in the fibrotic lung disease processes, which are characterized by different degrees of inflammation and fibrosis. Idiopathic pulmonary fibrosis (IPF) is the pathology with the highest degree of fibrosis and is of unknown etiology and burdened by lack of effective treatments in humans. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effects of inhalational anaesthetics in experimental allergic asthma.

PubMed

Burburan, S M; Silva, J D; Abreu, S C; Samary, C S; Guimarães, I H L; Xisto, D G; Morales, M M; Rocco, P R M

2014-06-01

We evaluated whether isoflurane, halothane and sevoflurane attenuate the inflammatory response and improve lung morphofunction in experimental asthma. Fifty-six BALB/c mice were sensitised and challenged with ovalbumin and anaesthetised with isoflurane, halothane, sevoflurane or pentobarbital sodium for one hour. Lung mechanics and histology were evaluated. Gene expression of pro-inflammatory (tumour necrosis factor-α), pro-fibrogenic (transforming growth factor-β) and pro-angiogenic (vascular endothelial growth factor) mediators, as well as oxidative process modulators, were analysed. These modulators included nuclear factor erythroid-2 related factor 2, sirtuin, catalase and glutathione peroxidase. Isoflurane, halothane and sevoflurane reduced airway resistance, static lung elastance and atelectasis when compared with pentobarbital sodium. Sevoflurane minimised bronchoconstriction and cell infiltration, and decreased tumour necrosis factor-α, transforming growth factor-β, vascular endothelial growth factor, sirtuin, catalase and glutathione peroxidase, while increasing nuclear factor erythroid-2-related factor 2 expression. Sevoflurane down-regulated inflammatory, fibrogenic and angiogenic mediators, and modulated oxidant-antioxidant imbalance, improving lung function in this model of asthma. © 2014 The Association of Anaesthetists of Great Britain and Ireland.

[Comparison of epidural anesthesia and general anesthesia for patients with bronchial asthma].

PubMed

Kasaba, T; Suga, R; Matsuoka, H; Iwasaki, T; Hidaka, N; Takasaki, M

2000-10-01

We prospectively investigated the incidence of asthmatic attacks in 94 patients (1.5%) who were diagnosed as definite asthma. We separated the patients into three groups: epidural anesthesia (n = 10) including combined spinal/epidural anesthesia (n = 7), combined epidural and general anesthesia (n = 23), and general anesthesia (n = 54). General anesthesia was induced with propofol or midazolam and maintained with N2O and O2 with sevoflurane in adults. Patients who underwent epidural anesthesia and combined spinal and epidural anesthesia showed no asthmatic attacks. The incidence of bronchospasm with combined epidural and general anesthesia was 2/23. The incidence of bronchospasm with general anesthesia was 4/54. Bronchoconstriction occurred after tracheal intubation in 5 patients except in one patient, in whom it occurred after induction of anesthesia with midazolam. All episodes of bronchospasm in the operative period were treated successfully. The frequency of bronchospasm did not depend on the severity of asthmatic symptoms or the chronic use of bronchodilators before operation. These findings suggest that tracheal intubation, not the choice of anesthetic, plays an important role in the pathogenesis of bronchospasm.

Breathing hot humid air induces airway irritation and cough in patients with allergic rhinitis.

PubMed

Khosravi, Mehdi; Collins, Paul B; Lin, Ruei-Lung; Hayes, Don; Smith, Jaclyn A; Lee, Lu-Yuan

2014-07-01

We studied the respiratory responses to an increase in airway temperature in patients with allergic rhinitis (AR). Responses to isocapnic hyperventilation (40% of maximal voluntary ventilation) for 4min of humidified hot air (HA; 49°C) and room air (RA; 21°C) were compared between AR patients (n=7) and healthy subjects (n=6). In AR patients, cough frequency increased pronouncedly from 0.10±0.07 before to 2.37±0.73 during, and 1.80±0.79coughs/min for the first 8min after the HA challenge, but not during the RA challenge. In contrast, neither HA nor RA had any significant tussive effect in healthy subjects. The HA challenge also caused respiratory discomfort (mainly throat irritation) measured by the handgrip dynamometry in AR patients, but not in healthy subjects. Bronchoconstriction was not detected after the HA challenge in either group of subjects. In conclusion, hyperventilation of HA triggered vigorous cough response and throat irritation in AR patients, indicating the involvement of sensory nerves innervating upper airways. Copyright © 2014 Elsevier B.V. All rights reserved.

Improvement in bronchial hyper-responsiveness in patients with moderate asthma after treatment with a hypnotic technique: a randomised controlled trial.

PubMed Central

Ewer, T C; Stewart, D E

1986-01-01

A prospective, randomised, single blind, and controlled trial of a hypnotic technique was undertaken in 39 adults with mild to moderate asthma graded for low and high susceptibility to hypnosis. After a six week course of hypnotherapy 12 patients with a high susceptibility score showed a 74.9% improvement (p less than 0.01) in the degree of bronchial hyper-responsiveness to a standardised methacholine challenge test. Daily home recordings of symptoms improved by 41% (p less than 0.01), peak expiratory flow rates improved by 5.5% (p less than 0.01), and use of bronchodilators decreased by 26.2% (p less than 0.05). The improvement in bronchial hyper-reactivity occurred without a change in subjective appreciation of the degree of bronchoconstriction. A control group 17 patients and 10 patients undergoing treatment with low susceptibility to hypnosis had no change in either bronchial hyper-responsiveness or any of the symptoms recorded at home. This study shows the efficacy of a hypnotic technique in adult asthmatics who are moderately to highly susceptible to hypnosis. PMID:3094804

Impact of air pollutants on athletic performance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pierson, W.E.

Human controlled and observational studies both lead to the conclusion of air pollution adversely affecting athletic performance during training and competition. The dosage of various air pollutants during exercise is much higher due to the marked increase in ventilatory rate and concomitant nasal and oral breathing. This is particularly true for sulfur dioxide which is a highly water-soluble gas and is normally absorbed in the upper airway during nasal breathing. With heavy exercise, oral pharyngeal breathing is the predominant mode of breathing and much larger amounts of sulfur dioxide are delivered to the lower airway resulting in significant impact uponmore » the lower respiratory tract. More recently, several controlled human studies have shown that a combination of exercise and air pollutants such as ozone (O3) or sulfur dioxides (SO2) cause a significant increase in bronchoconstriction and air flow obstruction when compared to the same exposure at rest. In strenuous athletic competition such as the Olympic Games where small increments of time often determine the ultimate success of athletes, the impact of air pollutants and subsequent adverse ventilatory changes can affect athletic performance. 62 references.« less

Pathogenic Mechanisms and In Vitro Diagnosis of AERD

PubMed Central

Schäfer, Dirk; Maune, Steffen

2012-01-01

Aspirin-exacerbated respiratory disease (AERD) refers to chronic rhinosinusitis, nasal polyposis, bronchoconstriction, and/or eosinophilic inflammation in asthmatics following the exposure to nonsteroidal anti-inflammatory drugs (NSAIDs). A key pathogenic mechanism associated with AERD is the imbalance of eicosanoid metabolism focusing on prostanoid and leukotriene pathways in airway mucosa as well as blood cells. Genetic and functional metabolic studies on vital and non-vital cells pointed to the variability and the crucial role of lipid mediators in disease susceptibility and their response to medication. Eicosanoids, exemplified by prostaglandin E2 (PGE2) and peptidoleukotrienes (pLT), are potential metabolic biomarkers contributing to the AERD phenotype. Also other mediators are implicated in the progress of AERD. Considering the various pathogenic mechanisms of AERD, a multitude of metabolic and genetic markers is suggested to be implicated and were introduced as potential biomarkers for in vitro diagnosis during the past decades. Deduced from an eicosanoid-related pathogenic mechanism, functional tests balancing PGE2 and pLT as well as other eicosanoids from preferentially vital leukocytes demonstrated their applicability for in vitro diagnosis of AERD. PMID:22654920

[Acetylsalicylic acid and food additive intolerance in urticaria, bronchial asthma and rhinopathy].

PubMed

Wüthrich, B; Fabro, L

1981-09-26

Adverse reactions (urticaria, angio-edema, bronchoconstriction, purpura) to Aspirin (ASS) and food-and-drug additives such as the yellow dye tartrazine and the preservative benzoate are observed all over the world. Since the exact pathogenetic mechanisms of this condition is unknown, it is described as intolerance or pseudo-allergy and has been related to an imbalance of prostaglandin synthesis. Among 620 patients with urticaria, bronchial asthma or chronic rhinitis, oral provocation tests with ASS, tartrazine or benzoic acid revealed in 165 (26.6%) intolerance to ASS or additives. Frequency of intolerance to tartrazine varied between 6.1% in urticaria (n=308), 7.3% in asthma (n=96) and 14.5% in urticaria and asthma patients, while intolerance to benzoate varied from 2.5% in rhinitis (n=40) to 11.5% in asthma. More than two thirds of the intolerant patients were improved by an elimination diet and by the avoidance of "aspirin-like" drugs. More than one third of chronic urticaria patients became symptomfree. In Switzerland exact declaration of all food additives is urgently needed. Moreover, azo-dyes must no longer be used for colouring of drugs.

Chloride channel blockers promote relaxation of TEA-induced contraction in airway smooth muscle.

PubMed

Yim, Peter D; Gallos, George; Perez-Zoghbi, Jose F; Trice, Jacquelyn; Zhang, Yi; Siviski, Matthew; Sonett, Joshua; Emala, Charles W

2013-01-01

Enhanced airway smooth muscle (ASM) contraction is an important component in the pathophysiology of asthma. We have shown that ligand gated chloride channels modulate ASM contractile tone during the maintenance phase of an induced contraction, however the role of chloride flux in depolarization-induced contraction remains incompletely understood. To better understand the role of chloride flux under these conditions, muscle force (human ASM, guinea pig ASM), peripheral small airway luminal area (rat ASM) and airway smooth muscle plasma membrane electrical potentials (human cultured ASM) were measured. We found ex vivo guinea pig airway rings, human ASM strips and small peripheral airways in rat lungs slices relaxed in response to niflumic acid following depolarization-induced contraction induced by K(+) channel blockade with tetraethylammonium chloride (TEA). In isolated human airway smooth muscle cells TEA induce depolarization as measured by a fluorescent indicator or whole cell patch clamp and this depolarization was reversed by niflumic acid. These findings demonstrate that ASM depolarization induced contraction is dependent on chloride channel activity. Targeting of chloride channels may be a novel approach to relax hypercontractile airway smooth muscle in bronchoconstrictive disorders.

Right upper lobe atelectasis after tracheal extubation in a morbidly obese patient

PubMed Central

Uzman, Sinan; Toptaş, Mehmet; Yanaral, Tumay Uludag

2012-01-01

Summary Background: Acute lobar collapse caused by a reflex bronchoconstriction was previously reported to occur during the induction of anesthesia, however there are no reports on its occurrence during the emergence period. Case Report: A 56-year-old morbidly obese woman was scheduled for surgery due to a gastric ulcer perforation. Anesthesia was induced with thiopental 500 mg, fentanyl and rocuronium, and maintained with sevoflurane in a N2O/O2 mixture. The operative procedure and anesthesia were uneventful; however, the patient developed a sudden decrease in SaO2 and blurring of consciousness after extubation. She was re-intubated and ventilated with 100% O2. Arterial blood gas analysis at that time showed respiratory acidosis and hypoxemia. Further work-up revealed a bronchospasm-induced right upper lobe atelectasis, which occurred immediately after tracheal extubation. The patient was successfully treated using mechanical ventilation and bronchodilators. Conclusions: Bronchospasm may cause acute lobar atelectasis immediately after tracheal extubation. Morbid obesity and the use of 100% oxygen may facilitate atelectasis formation during emergence from anesthesia. PMID:23569513

Environmental Causes of Asthma.

PubMed

Cockcroft, Donald W

2018-02-01

Environmental factors which cause asthma are those that induce airway inflammation with eosinophils (more common) or neutrophils along with airway hyperresponsiveness (AHR). The most common of these (indeed the most common cause of asthma) are IgE-mediated inhalant allergen exposures. Allergen-induced AHR and inflammation are both associated with the allergen-induced late asthmatic response (LAR). Although allergens were previously recognized only as causes of symptoms and bronchoconstriction in asthmatics, we now appreciate them as causes of the fundamental pathophysiologic features of asthma. Low-molecular-weight chemical sensitizers, causes of occupational asthma, also cause asthma in a manner analogous to allergen. Acute irritant-induced asthma (reactive airways dysfunction syndrome) following a very heavy irritant exposure and chronic irritant-induced asthma following repeated high exposures can also induce persistent or permanent changes (inflammation and AHR) consistent with asthma. Textile dust exposure produces a different form of airway disease (byssinosis) which is less frequently observed currently. Environmental exposure to tobacco smoke facilitates the development of asthma in children. Personal smoking and environmental air pollution have an inconsistent and likely generally small effect in causing asthma. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abraham, W.M.; Kim, C.S.; King, M.M.

The airway effects of a 4-hr exposure (via a Plexiglas hood) to 1.6 ppm nitric acid vapor were evaluated in seven normal and seven allergic sheep, i.e., animals that have a history of reacting with bronchospasm to inhalation challenge with Ascaris suum antigen. The nitric acid vapor was generated by ultrasonic nebulization of a 2% nitric acid solution. Airway effects were assessed by measuring the change in specific pulmonary flow resistance before and after a standard inhalation challenge with 2.5% carbachol aerosol. Nitric acid exposure did not produce bronchoconstriction in either group. Pre-exposure increases in specific pulmonary flow resistance aftermore » carbachol inhalation were 68% (SD+/- 13%) and 82% (SD+/- 35%) for the normal and allergic sheep, respectively. Within 24 hr, the largest post-exposure increases in specific pulmonary flow resistance for the normal and allergic sheep were 108% (SD+/- 51%(P<.06)) and 175% (SD+/- 87% (p<.02)), respectively. We conclude that a short-term exposure to nitric acid vapor at levels below the industrial threshold limit (2 ppm), produces airway hyperreactivity to aerosolized carbachol in allergic sheep.« less

Asthma due to aluminium soldering flux

PubMed Central

Sterling, G. M.

1967-01-01

Two patients have been studied who complained of dyspnoea after the inhalation of fumes from a new soldering flux recently developed for use in jointing aluminium which has been replacing copper as a material for electric cables. A previous survey of respiratory complaints after the use of this particular flux had failed to show any objective change in lung function, and the present cases are the first to be reported. Both subjects have been investigated by means of serial spirometry, peak flow rates, and body plethysmography following inhalation of small amounts of flux fumes; delayed and prolonged bronchoconstriction has been demonstrated. Similar results have been obtained after the inhalation of one of the main constituents of the flux, namely amino-ethyl ethanolamine, which is presumably the active allergic agent. The bronchial response is unusual in being delayed in onset but otherwise resembles pollen-sensitivity asthma rather than the infiltrative process seen in farmer's lung. The type of immune mechanism involved is speculative, but it is possible that some alteration of the amino-ethyl ethanolamine is needed before it can react with reaginic antibody fixed in the bronchial tissues. PMID:6076508

Airliner cabin ozone: An updated review. Final report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Melton, C.E.

1989-12-01

The recent literature pertaining to ozone contamination of airliner cabins is reviewed. Measurements in airliner cabins without filters showed that ozone levels were about 50 percent of atmospheric ozone. Filters were about 90 percent effective in destroying ozone. Ozone (0.12 to 0.14 ppmv) caused mild subjective respiratory irritation in exercising men, but 0.20 to 0.30 ppmv did not have adverse effects on patients with chronic heart or lung disease. Ozone (1.0 to 2.0 ppmv) decreased survival time of influenza-infected rats and mice and suppressed the capacity of lung macrophages to destroy Listeria. Airway responses to ozone are divided into anmore » early parasympathetically mediated bronchoconstrictive phase and a later histamine-mediated congestive phase. Evidence indicates that intracellular free radicals are responsible for ozone damage and that the damage may be spread to other cells by toxic intermediate products: Antioxidants provide some protection to cells in vitro from ozone but dietary intake of antioxidant vitamins by humans has only a weak effect, if any. This review indicates that earlier findings regarding ozone toxicity do not need to be corrected. Compliance with existing FAA ozone standards appears to provide adequate protection to aircrews and passengers.« less

Safety assessment of bacterial choline oxidase protein introduced in transgenic crops for tolerance against abiotic stress.

PubMed

Singh, Abinav K; Singh, Bhanu P; Prasad, G B K S; Gaur, Shailendra N; Arora, Naveen

2008-12-24

Genetically modified crops have resistance to abiotic stress by introduction of choline oxidase protein. In the present study, the safety of choline oxidase protein derived from Arthrobacter globiformis was assessed for toxicity and allergenicity. The protein was stable at 90 degrees C for 1 h. Toxicity studies of choline oxidase in mice showed no significant difference (p > 0.05) from control in terms of growth, body weight, food consumption, and blood biochemical indices. Histology of gut tissue of mice fed protein showed normal gastric mucosal lining and villi in jejunum and ileum sections. Specific IgE in serum and IL-4 release in splenic culture supernatant were low in choline oxidase treated mice, comparable to control. Intravenous challenge with choline oxidase did not induce any adverse reaction, unlike ovalbumin group mice. Histology of lung tissues from choline oxidase sensitized mice showed normal airways, whereas ovalbumin-sensitized mice showed inflamed airways with eosinophilic infiltration and bronchoconstriction. ELISA carried out with food allergic patients' sera revealed no significant IgE affinity with choline oxidase. Also, choline oxidase did not show any symptoms of toxicity and allergenicity in mice.

Morphological and functional determinants of fluoxetine (Prozac)-induced pulmonary disease in an experimental model.

PubMed

Capelozzi, Marco A; Leick-Maldonado, Edna A; Parra, Edwin R; Martins, Mílton A; Tibério, Iolanda F L C; Capelozzi, Vera L

2007-05-14

Fluoxetine treatment effects were determined by evaluating respiratory mechanics (elastance/resistance) and exhaled nitric oxide, as well as mononuclear and polymorphonuclear cell recruitment into the lungs, in an experimental guinea pig model. Guinea pigs were divided into four groups: Fl (fluoxetine only, n=7); Fl+Sw (fluoxetine and forced swimming, n=7); Ns+Sw (normal saline and forced swimming, n=8); and Ns (normal saline only, n=8). Treated animals received oral fluoxetine (10 mg/(kg day)) for 30 consecutive days. On day 31, all animals were anesthetized and mechanically ventilated so that respiratory system elastance and resistance, as well exhaled nitric oxide, could be determined. The lungs were then excised en bloc for histological and immunohistochemical evaluation. Forced swimming induced bronchodilation in untreated animals and bronchoconstriction in fluoxetine-treated animals. Fluoxetine treatment was also associated with mononuclear infiltration (predominantly into alveolar walls) and neutrophil recruitment. In addition, levels of exhaled nitric oxide, an inflammatory marker, were higher in fluoxetine-treated animals. Swimming-induced stress also amplified mononuclear cell recruitment to the lungs. These results show that, in this experimental model, fluoxetine treatment reproduces the pathology of chronic interstitial pneumonia in humans.

Effect of ozone exposure on antigen-induced airway hyperresponsiveness in guinea pigs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vargas, M.H.; Segura, P.; Campos, M.G.

1994-12-31

Airway hyperresponsiveness can be induced by several stimuli including antigen and ozone, both of which may be present in the air of polluted cities. Though the effect of ozone on the bronchoconstrictor response to antigen has been well described, the combined effect of these stimuli on airway hyperresponsiveness has not yet been studied. Sensitized guinea pigs with or without ozone exposure for 1 h at 3 ppm, 18 h prior to study, were challenged with a dose-response curve to histamine (0.01-1.8 {mu}g/kg, iv), and then by a second histamine dose-response curve 1 h later. Airway responses were measured as themore » increase in pulmonary insufflation pressure. In sensitized guinea pigs, the histamine ED50 significantly decreased after antigen challenge, demonstrating the development of airway hyperresponsiveness. Sensitized guinea pigs exposed to ozone showed airway hyperresponsiveness to histamine when compared with nonexposed animals, and such hyperresponsiveness was further enhanced after antigen challenge. We conclude that in this guinea pig model of acute allergic bronchoconstriction both antigen challenge and ozone induce airway hyperresponsiveness, while ozone exposure does not modify the development of antigen-induced hyperresponsiveness. 25 refs., 1 fig., 1 tab.« less

Implications of air pollution effects on athletic performance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pierson, W.E.; Covert, D.S.; Koenig, J.Q.

Both controlled human studies and observational studies suggest that air pollution adversely affects athletic performance during both training and competition. The air pollution dosage during exercise is much higher than during rest because of a higher ventilatory rate and both nasal and oral breathing in the former case. For example, sulfur dioxide, which is a highly water-soluble gas, is almost entirely absorbed in the upper respiratory tract during nasal breathing. However, with oral pharyngeal breathing, the amount of sulfur dioxide that is absorbed is significantly less, and with exercise and oral pharyngeal breathing a significant decrease in upper airway absorptionmore » occurs, resulting in a significantly larger dosage of this pollutant being delivered to the tracheobronchial tree. Recently, several controlled human studies have shown that the combination of exercise and pollutant exposure (SO/sub 2/ or O/sub 3/) caused a marked bronchoconstriction and reduced ventilatory flow when compared to pollution exposure at rest. In a situation like the Olympic Games where milliseconds and millimeters often determine the success of athletes, air pollution can be an important factor in affecting their performance. This paper examines possible impacts of air pollution on athletic competition.« less

Chloride channel blockers promote relaxation of TEA-induced contraction in airway smooth muscle

PubMed Central

Yim, Peter D.; Gallos, George; Perez-zoghbi, Jose F.; Trice, Jacquelyn; Zhang, Yi; Siviski, Matthew; Sonett, Joshua; Emala, Charles W.

2014-01-01

Enhanced airway smooth muscle (ASM) contraction is an important component in the pathophysiology of asthma. We have shown that ligand gated chloride channels modulate ASM contractile tone during the maintenance phase of an induced contraction, however the role of chloride flux in depolarization-induced contraction remains incompletely understood. To better understand the role of chloride flux under these conditions, muscle force (human ASM, guinea pig ASM), peripheral small airway luminal area (rat ASM) and airway smooth muscle plasma membrane electrical potentials (human cultured ASM) were measured. We found ex vivo guinea pig airway rings, human ASM strips and small peripheral airways in rat lungs slices relaxed in response to niflumic acid following depolarization-induced contraction induced by K+ channel blockade with tetraethylammonium chloride (TEA). In isolated human airway smooth muscle cells TEA induce depolarization as measured by a fluorescent indicator or whole cell patch clamp and this depolarization was reversed by niflumic acid. These findings demonstrate that ASM depolarization induced contraction is dependent on chloride channel activity. Targeting of chloride channels may be a novel approach to relax hypercontractile airway smooth muscle in bronchoconstrictive disorders. PMID:24662476

Airway smooth muscle in asthma: linking contraction and mechanotransduction to disease pathogenesis and remodelling.

PubMed

Noble, Peter B; Pascoe, Chris D; Lan, Bo; Ito, Satoru; Kistemaker, Loes E M; Tatler, Amanda L; Pera, Tonio; Brook, Bindi S; Gosens, Reinoud; West, Adrian R

2014-12-01

Asthma is an obstructive airway disease, with a heterogeneous and multifactorial pathogenesis. Although generally considered to be a disease principally driven by chronic inflammation, it is becoming increasingly recognised that the immune component of the pathology poorly correlates with the clinical symptoms of asthma, thus highlighting a potentially central role for non-immune cells. In this context airway smooth muscle (ASM) may be a key player, as it comprises a significant proportion of the airway wall and is the ultimate effector of acute airway narrowing. Historically, the contribution of ASM to asthma pathogenesis has been contentious, yet emerging evidence suggests that ASM contractile activation imparts chronic effects that extend well beyond the temporary effects of bronchoconstriction. In this review article we describe the effects that ASM contraction, in combination with cellular mechanotransduction and novel contraction-inflammation synergies, contribute to asthma pathogenesis. Specific emphasis will be placed on the effects that ASM contraction exerts on the mechanical properties of the airway wall, as well as novel mechanisms by which ASM contraction may contribute to more established features of asthma such as airway wall remodelling. Copyright © 2014 Elsevier Ltd. All rights reserved.

Allergic inflammation induces a persistent mechanistic switch in thromboxane-mediated airway constriction in the mouse

PubMed Central

Cyphert, Jaime M.; Allen, Irving C.; Church, Rachel J.; Latour, Anne M.; Snouwaert, John N.; Coffman, Thomas M.

2012-01-01

Actions of thromboxane (TXA2) to alter airway resistance were first identified over 25 years ago. However, the mechanism underlying this physiological response has remained largely undefined. Here we address this question using a novel panel of mice in which expression of the thromboxane receptor (TP) has been genetically manipulated. We show that the response of the airways to TXA2 is complex: it depends on expression of other G protein-coupled receptors but also on the physiological context of the signal. In the healthy airway, TXA2-mediated airway constriction depends on expression of TP receptors by smooth muscle cells. In contrast, in the inflamed lung, the direct actions of TXA2 on smooth muscle cell TP receptors no longer contribute to bronchoconstriction. Instead, in allergic lung disease, TXA2-mediated airway constriction depends on neuronal TP receptors. Furthermore, this mechanistic switch persists long after resolution of pulmonary inflammation. Our findings demonstrate the powerful ability of lung inflammation to modify pathways leading to airway constriction, resulting in persistent changes in mechanisms of airway reactivity to key bronchoconstrictors. Such alterations are likely to shape the pathogenesis of asthmatic lung disease. PMID:21984570

Selectivity of beta-adrenergic stimulating and blocking agents.

PubMed

Löfdahl, C G; Svedmyr, N

1984-01-01

Studies have been performed to answer two questions: whether there are subgroups of beta 2-receptors separating effects in bronchial and skeletal muscle and whether beta 1-receptors in asthmatic airways mediate bronchoconstriction. Asthmatic patients have been studied in randomised cross-over trials. Effects on FEV1, heart rate and skeletal muscle tremor have been monitored. In some experimental studies, two new compounds, D2343 and QH-25, have shown a selectivity for beta 2-receptors in bronchial muscle compared to skeletal muscle. Studies in asthmatics did not confirm this. Thus, the beta 2-receptors in the two organs appear to be identical. The clinical effect of beta 1-receptors in the the airways was studied by giving selective beta 1-receptor blocking agents. It was shown that pafenolol , a beta-blocker more beta 1-selective than metoprolol, had less effect on FEV1 than metoprolol given in equipotent beta 1-blocking doses. Beta 1-receptor stimulation with a new selective beta 1-stimulating agent, prenalterol, did not give bronchodilation in doses which gave a significant increase of heart rate. Thus, beta 1-receptors do not contribute to bronchodilation in asthmatic patients.

β-Agonist-mediated Relaxation of Airway Smooth Muscle Is Protein Kinase A-dependent*

PubMed Central

Morgan, Sarah J.; Deshpande, Deepak A.; Tiegs, Brian C.; Misior, Anna M.; Yan, Huandong; Hershfeld, Alena V.; Rich, Thomas C.; Panettieri, Reynold A.; An, Steven S.; Penn, Raymond B.

2014-01-01

Inhaled β-agonists are effective at reversing bronchoconstriction in asthma, but the mechanism by which they exert this effect is unclear and controversial. PKA is the historically accepted effector, although this assumption is made on the basis of associative and not direct evidence. Recent studies have asserted that exchange protein activated by cAMP (Epac), not PKA, mediates the relaxation of airway smooth muscle (ASM) observed with β-agonist treatment. This study aims to clarify the role of PKA in the prorelaxant effects of β-agonists on ASM. Inhibition of PKA activity via expression of the PKI and RevAB peptides results in increased β-agonist-mediated cAMP release, abolishes the inhibitory effect of isoproterenol on histamine-induced intracellular calcium flux, and significantly attenuates histamine-stimulated MLC-20 phosphorylation. Analyses of ASM cell and tissue contraction demonstrate that PKA inhibition eliminates most, if not all, β-agonist-mediated relaxation of contracted smooth muscle. Conversely, Epac knockdown had no effect on the regulation of contraction or procontractile signaling by isoproterenol. These findings suggest that PKA, not Epac, is the predominant and physiologically relevant effector through which β-agonists exert their relaxant effects. PMID:24973219

Occupational asthma and IgE sensitization to grain dust.

PubMed

Park, H S; Nahm, D H; Suh, C H; Kwon, O Y; Kim, K S; Lee, S W; Chung, H K

1998-06-01

To evaluate type I hypersensitivity to grain dust (GD), its prevalence and relationship to respiratory dysfunction, we studied clinical and immunologic features, including skin prick tests (SPT), serum specific IgE, and bronchoprovocation tests of 43 employees working in the animal feed industry. To further characterize IgE-mediated reaction, SDS-PAGE and electroblot studies were performed. Our survey revealed that 15 (34.9%) subjects had work-related skin response (> or =2+ of A/H ratio) to GD, thirteen (30.2%) had high specific IgE antibody against GD. The specific IgE antibody was detected more frequently in symptomatic workers (40%) than in asymptomatic workers (11%). Significant association was found between specific IgE antibody and atopy or smoking (p<0.05). The ELISA inhibition test of GD revealed significant inhibitions by GD extract and minimal inhibitions by the house dust mite, storage mite and corn dust. Immunoblot analysis showed 8 IgE binding components within GD ranging from 13.5 to 142.5 kDa. Two bands (13.5, 33 kDa) were bound to the IgE from more than 50% of the 14 sera tested. In conclusion, these findings suggest that GD inhalation could induce IgE-mediated bronchoconstriction in exposed workers.

Effect of ONO-1078, a leukotriene antagonist, on capsaicin- and substance P-induced bronchoconstriction and airway microvascular leakage in guinea pigs.

PubMed

Wei, E Q; Liu, J W; Zhang, L F; Zhang, W P; Bian, R L

1996-05-01

To study the effect of 4-oxo-8-[p-(4-phenylbutyloxy) benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyran hemihydrate (ONO-1078), a specific leukotriene antagonist, on capsaicin (Cap)-sensitive sensory nerve functions in the airways, and clarify the modulating roles of endogenous peptido-leukotrienes. Changes in intrapulmonary pressure (IPP), Evans blue extravasation in airways, and contraction of bronchial smooth muscles of guinea pigs induced by Cap, substance P (SP) and leukotriene C4 (LTC4) were observed. Cap (0.05 mg.kg-1, i.v.), SP (1 microgram.kg-1, i.v.) and LTC4 (0.5 microgram.kg-1, i.v.) enhanced IPP, and Evans blue extravasation in bronchi and intrapulmonary airways. ONO-1078 0.03 mg.kg-1, i.v. completely blocked the responses to LTC4, attenuated those to Cap, but had no effect to SP. In isolated bronchial smooth muscles, ONO-1078 (1 mumol.L-1) inhibited the contractile response to Cap, but not to SP. ONO-1078 partly inhibits Cap-sensitive sensory nerve actions in airways, but has no direct effect on SP, a sensory neuropeptide.

A spectrum of pharmacological activity in some biologically active peptides

PubMed Central

Bisset, G. W.; Lewis, G. P.

1962-01-01

The actions of bradykinin, angiotensin, oxytocin, vasopressin and substance P have been examined both on isolated smooth muscle preparations and in vivo. It was found that the isolated rat uterus and guinea-pig ileum can be used to distinguish between oxytocin and bradykinin and that the isolated rat colon and hen rectal caecum are almost specific test preparations for substance P. All the peptides were active on peripheral blood vessels, bradykinin, substance P and oxytocin causing vasodilatation and vasopressin and angiotensin vasoconstriction; bradykinin, substance P and angiotensin also caused an increase in capillary permeability in guinea-pigs. Only bradykinin and substance P were active in low concentrations in producing pain when applied to an exposed blister base. These two peptides were also active in causing bronchoconstriction. Oxytocin and vasopressin were the only peptides having milk-ejecting or antidiuretic activity which could be dissociated from cardiovascular effects. The spectrum of activity displayed by these peptides is in agreement with those functions which have been established for vasopressin and oxytocin and with those suggested, but not yet fully accepted, for bradykinin and angiotensin. It also indicates a possible function for substance P based on its vascular and permeability effects. ImagesFig. 6 PMID:13869527

Fullerene carbon-70 derivatives dampen anaphylaxis and allergic asthma pathogenesis in mice

NASA Astrophysics Data System (ADS)

Norton, Sarah Brooke

Fullerenes are carbon nanospheres that can be solublized by the addition of polar chemical groups to the carbon cage, forming fullerene derivatives. One specifically derivatized fullerene compound, termed C 70-Tetragylocolate (C70-TGA), has been shown to stabilize mast cell responses in vitro thus we hypothesized it may have an effect on mast cell-driven diseases such as asthma and systemic anaphylaxis. To observe the effects of C70-TGA on systemic anaphylaxis, mice were subjected to a model of passive systemic anaphylaxis. In this model, mice were injected with DNP-specific IgE 16 hours prior to challenge, then treated with C 70-TGA. Immediately prior to DNP challenge, mice were subjected to a second injection of C70-TGA. Following DNP challenge, body temperature was recorded and blood was collected for quantitation of histamine levels. Treatment with C70-TGA significantly reduced body temperature drop associated with systemic anaphylaxis and serum histamine levels. To observe the effects of C70-TGA on chronic features of asthma in vivo, we utilized a heavily MC influenced model of asthma pathogenesis. Mice were sensitized by intraperitoneal (i.p.) injection of ovalbumin (OVA) in saline, challenged intranasally (i.n.) with OVA, and one of two treatment strategies was pursued. In one, C70-TGA was given i.n. throughout disease development. In the other, C70-TGA was given following an initial set of challenges to allow disease to develop prior to treatment; mice were then re-challenged with OVA to assess the effect on established disease. We found that C70-TGA treatment significantly reduced airway inflammation and eosinophilia and dramatically reduced bronchoconstriction in either model. Cytokines IL-4 and IL-5 and serum IgE levels are significantly reduced in C70-TGA treated animals. Interestingly, we also saw an increase in the anti-inflammatory eicosanoid 11, 12-epoxyeicosatreinoic acid (11,12-EET) in the BAL fluid, suggesting the involvement of this mediator in C70-TGA inhibition. Further experiments utilizing an inhibitor of 11,12-EET formation (6-(2-Propargyloxyphenyl)hexanoic acid) and a structural analog of 14,15-EET (14,15-EE-5(Z)-E) in vivo indicate that these mediators are closely associated with C70-TGA mediated inhibition as their inhibition reverses the anti-inflammatory effects of C70-TGA. Importantly, mice did not exhibit any acute toxicity following C70-TGA treatment and liver and kidney function were normal. Collectively, these results show that the fullerene C70 derivative C70-TGA is capable of dampening severe allergic responses including systemic anaphylaxis, airway inflammation, and bronchoconstriction. The mechanism of inhibition is through the upregulation of the anti-inflammatory EETs, which may dampen mast cell degranulation in vivo, thus contributing to the inhibitory effect of C70-TGA on allergic disease

Airway and Parenchymal Strains during Bronchoconstriction in the Precision Cut Lung Slice

PubMed Central

Hiorns, Jonathan E.; Bidan, Cécile M.; Jensen, Oliver E.; Gosens, Reinoud; Kistemaker, Loes E. M.; Fredberg, Jeffrey J.; Butler, Jim P.; Krishnan, Ramaswamy; Brook, Bindi S.

2016-01-01

The precision-cut lung slice (PCLS) is a powerful tool for studying airway reactivity, but biomechanical measurements to date have largely focused on changes in airway caliber. Here we describe an image processing tool that reveals the associated spatio-temporal changes in airway and parenchymal strains. Displacements of sub-regions within the PCLS are tracked in phase-contrast movies acquired after addition of contractile and relaxing drugs. From displacement maps, strains are determined across the entire PCLS or along user-specified directions. In a representative mouse PCLS challenged with 10−4M methacholine, as lumen area decreased, compressive circumferential strains were highest in the 50 μm closest to the airway lumen while expansive radial strains were highest in the region 50–100 μm from the lumen. However, at any given distance from the airway the strain distribution varied substantially in the vicinity of neighboring small airways and blood vessels. Upon challenge with the relaxant agonist chloroquine, although most strains disappeared, residual positive strains remained a long time after addition of chloroquine, predominantly in the radial direction. Taken together, these findings establish strain mapping as a new tool to elucidate local dynamic mechanical events within the constricting airway and its supporting parenchyma. PMID:27559314

Bronchial biopsy evidence for leukocyte infiltration and upregulation of leukocyte-endothelial cell adhesion molecules 6 hours after local allergen challenge of sensitized asthmatic airways.

PubMed Central

Montefort, S; Gratziou, C; Goulding, D; Polosa, R; Haskard, D O; Howarth, P H; Holgate, S T; Carroll, M P

1994-01-01

We have examined the mucosal changes occurring in bronchial biopsies from six atopic asthmatics 5-6 h after local endobronchial allergen challenge and compared them with biopsies from saline-challenged segments from the same subjects at the same time point. All the subjects developed localized bronchoconstriction in the allergen-challenged segment and had a decrease in forced expiratory volume in 1 s (FEV1) (P < 0.01) and a decrease in their methacholine provocative concentration of agonist required to reduce FEV1 from baseline by 20% (P < 0.05) 24 h postchallenge. At 6 h we observed an increase in neutrophils (P = 0.03), eosinophils (P = 0.025), mast cells (P = 0.03), and CD3+ lymphocytes (P = 0.025), but not in CD4+ or CD8+ lymphocyte counts. We also detected an increase in endothelial intercellular adhesion molecule type 1 (P < 0.05) and E-selectin (P < 0.005), but not vascular cell adhesion molecule type 1 expression with a correlative increase in submucosal and epithelial LFA+ leucocytes (P < 0.01). Thus, in sensitized asthmatics, local endobronchial allergen instillation leads to an increased inflammatory cell infiltrate of the airway mucosa that involves upregulation of specific adhesion molecules expressed on the microvasculature. Images PMID:7512980

cAMP Regulation of Airway Smooth Muscle Function

PubMed Central

Billington, Charlotte K.; Ojo, Oluwaseun O.; Penn, Raymond B.; Ito, Satoru

2013-01-01

Agonists activating β2-adrenoceptors (β2ARs) on airway smooth muscle (ASM) are the drug of choice for rescue from acute bronchoconstriction in patients with both asthma and chronic obstructive pulmonary disease (COPD). Moreover, the use of long-acting β-agonists combined with inhaled corticosteroids constitutes an important maintenance therapy for these diseases. β-Agonists are effective bronchodilators due primarily to their ability to antagonize ASM contraction. The presumed cellular mechanism of action involves the generation of intracellular cAMP, which in turn can activate the effector molecules cAMP-dependent protein kinase (PKA) and Epac. Other agents such as prostaglandin E2 and phosphodiesterase inhibitors that also increase intracellular cAMP levels in ASM, can also antagonize ASM contraction, and inhibit other ASM functions including proliferation and migration. Therefore, β2ARs and cAMP are key players in combating the pathophysiology of airway narrowing and remodeling. However, limitations of β-agonist therapy due to drug tachyphylaxis related to β2AR desensitization, and recent findings regarding the manner in which β2ARs and cAMP signal, have raised new and interesting questions about these well-studied molecules. In this review we discuss current concepts regarding β2ARs and cAMP in the regulation of ASM cell functions and their therapeutic roles in asthma and COPD. PMID:22634112

β-Agonist-mediated relaxation of airway smooth muscle is protein kinase A-dependent.

PubMed

Morgan, Sarah J; Deshpande, Deepak A; Tiegs, Brian C; Misior, Anna M; Yan, Huandong; Hershfeld, Alena V; Rich, Thomas C; Panettieri, Reynold A; An, Steven S; Penn, Raymond B

2014-08-15

Inhaled β-agonists are effective at reversing bronchoconstriction in asthma, but the mechanism by which they exert this effect is unclear and controversial. PKA is the historically accepted effector, although this assumption is made on the basis of associative and not direct evidence. Recent studies have asserted that exchange protein activated by cAMP (Epac), not PKA, mediates the relaxation of airway smooth muscle (ASM) observed with β-agonist treatment. This study aims to clarify the role of PKA in the prorelaxant effects of β-agonists on ASM. Inhibition of PKA activity via expression of the PKI and RevAB peptides results in increased β-agonist-mediated cAMP release, abolishes the inhibitory effect of isoproterenol on histamine-induced intracellular calcium flux, and significantly attenuates histamine-stimulated MLC-20 phosphorylation. Analyses of ASM cell and tissue contraction demonstrate that PKA inhibition eliminates most, if not all, β-agonist-mediated relaxation of contracted smooth muscle. Conversely, Epac knockdown had no effect on the regulation of contraction or procontractile signaling by isoproterenol. These findings suggest that PKA, not Epac, is the predominant and physiologically relevant effector through which β-agonists exert their relaxant effects. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Endothelial gaps and adherent leukocytes in allergen-induced early- and late-phase plasma leakage in rat airways.

PubMed Central

Baluk, P.; Bolton, P.; Hirata, A.; Thurston, G.; McDonald, D. M.

1998-01-01

Exposure of sensitized individuals to antigen can induce allergic responses in the respiratory tract, manifested by early and late phases of vasodilatation, plasma leakage, leukocyte influx, and bronchoconstriction. Similar responses can occur in the skin, eye, and gastrointestinal tract. The early-phase response involves mast cell mediators and the late-phase response is leukocyte dependent, but the mechanism of leakage is not understood. We sought to identify the leaky blood vessels, to determine whether these vessels contained endothelial gaps, and to analyze the relationship of the gaps to adherent leukocytes, using biotinylated lectins or silver nitrate to stain the cells in situ and Monastral blue as a tracer to quantify plasma leakage. Most of the leakage occurred in postcapillary venules (< 40-microns diameter), whereas most of the leukocyte migration (predominantly neutrophils) occurred in collecting venules. Capillaries and arterioles did not leak. Endothelial gaps were found in the leaky venules, both by silver nitrate staining and by scanning electron microscopy, and 94% of the gaps were distinct from sites of leukocyte adhesion or migration. We conclude that endothelial gaps contribute to both early and late phases of plasma leakage induced by antigen, but most leakage occurs upstream to sites of leukocyte adhesion. Images Figure 3 Figure 5 Figure 6 Figure 7 PMID:9626051

Changes in cross-sectional airway areas induced by methacholine, histamine, and LTC4 in asthmatic subjects.

PubMed

Molfino, N A; Slutsky, A S; Hoffstein, V; McClean, P A; Rebuck, A S; Drazen, J M; Zamel, N

1992-09-01

To examine whether leukotrienes, histamine, and methacholine have different sites of bronchoconstrictor action, we studied 8 stable asthmatic subjects (mean age +/- SD, 26 +/- 5 yr) on 3 different days. On each day, a randomized challenge with LTC4, methacholine, or histamine was performed until the dose that provoked a fall of 20% in FEV1 (PC20) was obtained. Complete and partial flow-volume curves as well as area-distance profiles generated by the acoustic reflection technique (ART) at a fixed lung volume were obtained in all subjects before and after each inhalation challenge. No significant differences were found in pulmonary function or baseline cross-sectional airway areas for the different study days. The three agonists provoked significant (p less than 0.05) bronchoconstriction at the level of the main bronchi when identical falls of FEV1 were achieved. Similarly, equal reductions of V30p were elicited by the three agonists. However, LTC4 and methacholine induced additional tracheal constriction but histamine inhalation did not. These differences in the degree of tracheal constriction were statistically significant (p less than 0.05; ANOVA). These results may be explained by distinct pharmacologic properties of the agents used and may have relevance in the understanding of the pathophysiology of asthma.

Sensitivity of bronchopulmonary receptors to cold and heat mediated by transient receptor potential cation channel subtypes in an ex vivo rat lung preparation.

PubMed

Zhou, Yun; Sun, Biying; Li, Qian; Luo, Pin; Dong, Li; Rong, Weifang

2011-08-15

Changes in airway temperature can result in respiratory responses such as cough, bronchoconstriction and mucosal secretion after cold exposure and hyperventilation after heat exposure. In the present investigation, we examined the activity of bronchopulmonary receptors in response to activators of thermo-sensitive transient receptor potential (TS-TRP) cation channels using an ex vivo rat lung preparation. Receptive fields in small bronchioles were probed with von Frey hair monofilaments, warm (50°C) or cold (8°C) saline or saline containing TS-TRP agonists. Among 233 fibers tested, 159 (68.2%) responded to heat (50°C). A large proportion of heat-responsive receptors (107/145) were also activated by capsaicin. Heat and capsaicin-evoked responses were both blocked by TRPV1 antagonist, capsazepine. Only 15.3% of airway receptors responded to cold, which was associated with sensitivity to TRPM8 agonist menthol but not to TRPA1 agonist cinnamaldehyde (CA). Moreover, cold-evoked responses was unaffected by TRPA1 antagonist HC-03001. Our observations suggest that TRPV1 and TRPM8 are involved in transducing heat and cold in the lower respiratory tract, respectively. Copyright © 2011 Elsevier B.V. All rights reserved.

Occupational asthma and IgE sensitization to grain dust.

PubMed Central

Park, H. S.; Nahm, D. H.; Suh, C. H.; Kwon, O. Y.; Kim, K. S.; Lee, S. W.; Chung, H. K.

1998-01-01

To evaluate type I hypersensitivity to grain dust (GD), its prevalence and relationship to respiratory dysfunction, we studied clinical and immunologic features, including skin prick tests (SPT), serum specific IgE, and bronchoprovocation tests of 43 employees working in the animal feed industry. To further characterize IgE-mediated reaction, SDS-PAGE and electroblot studies were performed. Our survey revealed that 15 (34.9%) subjects had work-related skin response (> or =2+ of A/H ratio) to GD, thirteen (30.2%) had high specific IgE antibody against GD. The specific IgE antibody was detected more frequently in symptomatic workers (40%) than in asymptomatic workers (11%). Significant association was found between specific IgE antibody and atopy or smoking (p<0.05). The ELISA inhibition test of GD revealed significant inhibitions by GD extract and minimal inhibitions by the house dust mite, storage mite and corn dust. Immunoblot analysis showed 8 IgE binding components within GD ranging from 13.5 to 142.5 kDa. Two bands (13.5, 33 kDa) were bound to the IgE from more than 50% of the 14 sera tested. In conclusion, these findings suggest that GD inhalation could induce IgE-mediated bronchoconstriction in exposed workers. PMID:9681805

Air pollutants and cough.

PubMed

Joad, Jesse P; Sekizawa, Shin-ichi; Chen, Chao-Yin; Bonham, Ann C

2007-01-01

Epidemiological studies have shown that exposure to air pollution is associated with respiratory symptoms and decreases in lung function. This paper reviews recent literature showing that exposure to particulate matter, irritant gases, environmental tobacco smoke (ETS), mixed pollutants, and molds is associated with an increase in cough and wheeze. Some pollutants, like particulate matter and mixed pollutants, appear to increase cough at least as much as wheeze. Others, like irritant gases, appear to increase wheeze more than cough. For ETS, exposure during childhood is associated with cough and wheeze in adulthood, suggesting that the pollutant permanently alters some important aspect of the lungs, immune system or nervous system. We have shown in animal studies that pollutants change the neural control of airways and cough. Second hand smoke (SHS) exposure lengthened stimulated apnoea, increased the number of stimulated coughs, and augmented the degree of stimulated bronchoconstriction. The mechanisms included enhanced reactivity of the peripheral sensory neurones and second-order neurones in the nucleus tractus solitarius (NTS). NTS effects were due to a substance P mechanism at least in part. Ozone and allergen increased the intrinsic excitability of second-order neurones in the NTS. The animal studies suggest that the cough and wheeze experienced by humans exposed to pollutants may involve plasticity in the nervous system.

Inhalation of substance P and thiorphan: acute toxicity and effects on respiration in conscious guinea pigs.

PubMed

Koch, B L; Edvinsson, A A; Koskinen, L O

1999-01-01

Substance P is a tachykinin and a biologically active neuropeptide. The peptide produces salivation, neuronal excitation, vasodilatation, increased vascular permeability and contraction of smooth muscles in the respiratory tract. The study was designed to evaluate the acute effects in guinea pigs of inhaled aerosolized Substance P (SP). Apart from the acute toxic effect of the peptide, the distribution in different organs was also investigated. The acute inhalation toxicity of SP (LC50, 15 min) when co-administrated with the neutral endopeptidase inhibitor thiorphan was 368 microg m(-3). The peptide caused an increase in respiratory rate proceeding a decrease in tidal volume. As the exposure proceeded, a decrease in both respiratory rate and further decreases in tidal volume were observed until either the animal died or the exposure was terminated. The decreases in respiratory rate and tidal volume were probably due to bronchoconstriction caused by SP. Eighteen per cent of the inhaled amount of radioactive SP was retained in the body, and the highest concentrations of radioactivity were found in the kidney, lung and liver. Substance P in combination with thiorphan administered as an aerosol is extremely toxic and highly potent. Exposure to the substance at extremely low air concentrations may result in incapacitation in humans.

Effect of vagotomy and vagal cooling on bronchoconstrictor response to substance P in sheep.

PubMed

Corcoran, B M; Haigh, A L

1995-10-01

The bronchoconstrictor effect of intravenous substance P can be antagonised by atropine pre-treatment in several species, and we have previously reported this finding in anaesthetised sheep. In the present study, we have assessed the effect of cooling the right vagus after sectioning the left vagus (n = 6), and bilateral vagotomy (n = 7) on the bronchoconstrictor response to a single intravenous dose of substance P (SP) (0.3-1.0 mumol/kg) in anaesthetized female sheep aged 6 to 12 months. Respiratory parameters including tidal volume, flow and transpulmonary pressure pressure were measured, from which pulmonary resistance (RL; cmH2O.1(-1).s) and dynamic compliance (CDyn; ml.cmH2O(-1) were calculated. Systemic arterial pressures were also measured. Vagal cooling significantly attenuated the bronchoconstrictor response to SP at 7 degrees C (RL P < 0.01; Cdyn P < 0.001). A further reduction in the response to SP occurred at 3 degrees C, but this was not statistically significantly different from the response at 7 degrees C. Vagotomy abolished the response to SP. SP caused mild, but statistically insignificant, hypotension (119.7 vs. 107.7 mmHg). These results suggest SP causes bronchoconstriction in the anaesthetised sheep by vagal reflex mechanisms, involving stimulation of myelinated nerve fibre endings.

Variability of breath condensate pH may contribute to the better understanding of non-allergic seasonal respiratory diseases

NASA Astrophysics Data System (ADS)

Kullmann, Tamás; Szipőcs, Annamária

2017-09-01

The seasonal variability of certain non-allergic respiratory diseases is not clearly understood. Analysis of the breath condensate, the liquid that can be collected by breathing into a cold tube, has been proposed to bring closer to the understanding of airway pathologies. It has been assumed, that (1) airway lining fluid was a stable body liquid and (2) the breath condensate samples were representative of the airway lining fluid. Research was focussed on the identification of biomarkers indicative of respiratory pathologies. Despite 30 years of extended investigations breath condensate analysis has not gained any clinical implementation so far. The pH of the condensate is the characteristic that can be determined with the highest reproducibility. The present paper shows, that contrary to the initial assumptions, breath condensate is not a representative of the airway lining fluid, and the airway lining fluid is not a stable body liquid. Condensate pH shows baseline variability and it is influenced by drinking and by the ambient temperature. The changes in condensate pH are linked to changes in airway lining fluid pH. The variability of airway lining fluid pH may explain seasonal incidence of certain non-allergic respiratory diseases such as the catching of a common cold and the increased incidence of COPD exacerbations and exercise-induced bronchoconstriction in cold periods.

Nitrogen Dioxide Exposure and Airway Responsiveness in ...

EPA Pesticide Factsheets

Controlled human exposure studies evaluating the effect of inhaled NO2 on the inherent responsiveness of the airways to challenge by bronchoconstricting agents have had mixed results. In general, existing meta-analyses show statistically significant effects of NO2 on the airway responsiveness of individuals with asthma. However, no meta-analysis has provided a comprehensive assessment of clinical relevance of changes in airway responsiveness, the potential for methodological biases in the original papers, and the distribution of responses. This paper provides analyses showing that a statistically significant fraction, 70% of individuals with asthma exposed to NO2 at rest, experience increases in airway responsiveness following 30-minute exposures to NO2 in the range of 200 to 300 ppb and following 60-minute exposures to 100 ppb. The distribution of changes in airway responsiveness is log-normally distributed with a median change of 0.75 (provocative dose following NO2 divided by provocative dose following filtered air exposure) and geometric standard deviation of 1.88. About a quarter of the exposed individuals experience a clinically relevant reduction in their provocative dose due to NO2 relative to air exposure. The fraction experiencing an increase in responsiveness was statistically significant and robust to exclusion of individual studies. Results showed minimal change in airway responsiveness for individuals exposed to NO2 during exercise. A variety of fa

Absence of bronchodilation during desflurane anesthesia: a comparison to sevoflurane and thiopental.

PubMed

Goff, M J; Arain, S R; Ficke, D J; Uhrich, T D; Ebert, T J

2000-08-01

Bronchospasm is a potential complication in anyone undergoing general anesthesia. Because volatile anesthetics relax bronchial smooth muscle, the effects of two newer volatile anesthetics, desflurane and sevoflurane, on respiratory resistance were evaluated. The authors hypothesized that desflurane would have greater bronchodilating effects because of its ability to increase sympathetic nervous system activity. Informed consent was obtained from patients undergoing elective surgery with general anesthesia. We recorded airway flow and pressure after thiopental induction and tracheal intubation (baseline) and for 10 min after beginning volatile anesthesia ( approximately 1 minimum alveolar concentration inspired). Respiratory system resistance was determined using the isovolume technique. Fifty subjects were randomized to receive sevoflurane (n = 20), desflurane (n = 20), or thiopental infusion (n = 10, 0.25 mg. kg-1. h-1). There were no differences between groups for age, height, weight, smoking history, and American Society of Anesthesiologists physical class. On average, sevoflurane reduced respiratory resistance 15% below baseline, whereas both desflurane (+5%) and thiopental (+10%) did not decrease respiratory resistance. The respiratory resistance changes did not differ in patients with and without a history of smoking during sevoflurane or thiopental. In contrast, administration of desflurane to smokers resulted in the greatest increase in respiratory resistance. Sevoflurane causes moderate bronchodilation that is not observed with desflurane or sodium thiopental. The bronchoconstriction produced by desflurane was primarily noted in patients who currently smoked. (Key words: Bronchospasm; respiratory resistance; volatile anesthetics.)

Safety and efficacy of Regadenoson in myocardial perfusion imaging (MPI) stress tests: A review

NASA Astrophysics Data System (ADS)

Ahmed, Ambereen

2018-02-01

Myocardial perfusion imaging (MPI) tests are often used to help diagnose coronary heart disease (CAD). The tests usually involve applying stress, such as hard physical exercise together with administration of vasodilators, to the patients. To date, many of these tests use non-selective A2A adenosine receptor agonists which, however, can be associated with highly undesirable and life-threatening side effects such as chest pain, dyspnea, severe bronchoconstriction and atrioventricular conduction anomalies. Regadenoson is a relatively new, highly selective A2A adenosine receptor agonist, suitable for use in MPI tests which exhibits far fewer adverse side effects and, unlike others testing agents, can be used without the necessity of excessive concomitant exercise. Also, the dose of regadenoson required is not dependent upon patient weight or renal impairment, and it can be rapidly administered by i.v. Injection. Regadenoson use in MPI testing thus has the potential as a simplified, relatively safe, time-saving and cost-effective method for helping diagnose CAD. The present study was designed to review several articles on the safety, efficacy, and suitability of regadenoson in MPI testing for CAD. Overall, the combined studies demonstrated that use of regadenoson in conjunction with low-level exercise in MPI is a highly efficient and relatively safe test for CAD, especially for more severe health-compromised patients.

Anesthesia and ventilation strategies in children with asthma: part II - intraoperative management.

PubMed

Regli, Adrian; von Ungern-Sternberg, Britta S

2014-06-01

As asthma is a frequent disease especially in children, anesthetists are increasingly providing anesthesia for children requiring elective surgery with well controlled asthma but also for those requiring urgent surgery with poorly controlled or undiagnosed asthma. This second part of this two-part review details the medical and ventilatory management throughout the perioperative period in general but also includes the perioperative management of acute bronchospasm and asthma exacerbations in children with asthma. Multiple observational trials assessing perioperative respiratory adverse events in healthy and asthmatic children provide the basis for identifying risk reduction strategies. Mainly, animal experiments and to a small extent clinical data have advanced our understanding of how anesthetic agents effect bronchial smooth muscle tone and blunt reflex bronchoconstriction. Asthma treatment outside anesthesia is well founded on a large body of evidence.Perioperative prevention strategies have increasingly been studied. However, evidence on the perioperative management, including mechanical ventilation strategies of asthmatic children, is still only fair, and further research is required. To minimize the considerable risk of perioperative respiratory adverse events in asthmatic children, perioperative management should be based on two main pillars: the preoperative optimization of asthma treatment (please refer to the first part of this two-part review) and - the focus of this second part of this review - the optimization of anesthesia management in order to optimize lung function and minimize bronchial hyperreactivity in the perioperative period.

Treatment of asthma patients with herbal medicine TJ-96: a randomized controlled trial.

PubMed

Urata, Y; Yoshida, S; Irie, Y; Tanigawa, T; Amayasu, H; Nakabayashi, M; Akahori, K

2002-06-01

Alternative medicine use has increased at a remarkable pace all over the world in recent years. Although herbal medicine for the treatment of asthma is becoming the focus of public attention, randomized studies had not been performed, even in Eastern countries including Japan. This study was designed to investigate whether one of the Japanese government approved herbal complexes Saiboku-to (TJ-96) is effective for the treatment of atopic asthma, and to investigate whether this protective activity is associated with a reduction in eosinophilic inflammation. A double-blind, randomized, crossover design was used. Subjects received 2.5 g of TJ-96 or placebo orally 3 times daily for 4 weeks and then, after a washout period of at least 4 weeks, crossed over to receive the alternative treatment. We assessed the effects of pretreatment with TJ-96 on bronchoconstriction precipitated by inhalation of methacholine. Furthermore, eosinophil counts and measurement of eosinophilic cationic protein (ECP) were performed. After 4 weeks of treatment with TJ-96, values of PC20 -methacholine significantly improved in the treatment with TJ-96. Also, patients' symptoms, blood eosinophils, serum ECP, sputum eosinophils, and sputum ECP were significantly decreased. Our results suggest that TJ-96 has an antiinflammatory effect on bronchial eosinophilic infiltration. This study raises further interesting therapeutic possibilities and argues for further trials of new approaches to the treatment of asthma.

Sarin (GB, O-isopropyl methylphosphonofluoridate) neurotoxicity: critical review

PubMed Central

Abou-Donia, Mohamed B.; Siracuse, Briana; Gupta, Natasha; Sokol, Ashly Sobel

2017-01-01

Sarin (GB, O-isopropyl methylphosphonofluoridate) is a potent organophosphorus (OP) nerve agent that inhibits acetylcholinesterase (AChE) irreversibly. The subsequent build-up of acetylcholine (ACh) in the central nervous system (CNS) provokes seizures and, at sufficient doses, centrally-mediated respiratory arrest. Accumulation of ACh at peripheral autonomic synapses leads to peripheral signs of intoxication and overstimulation of the muscarinic and nicotinic receptors, which is described as “cholinergic crisis” (i.e. diarrhea, sweating, salivation, miosis, bronchoconstriction). Exposure to high doses of sarin can result in tremors, seizures, and hypothermia. More seriously, build-up of ACh at neuromuscular junctions also can cause paralysis and ultimately peripherally-mediated respiratory arrest which can lead to death via respiratory failure. In addition to its primary action on the cholinergic system, sarin possesses other indirect effects. These involve the activation of several neurotransmitters including gamma-amino-butyric acid (GABA) and the alteration of other signaling systems such as ion channels, cell adhesion molecules, and inflammatory regulators. Sarin exposure is associated with symptoms of organophosphate-induced delayed neurotoxicity (OPIDN) and organophosphate-induced chronic neurotoxicity (OPICN). Moreover, sarin has been involved in toxic and immunotoxic effects as well as organophosphate-induced endocrine disruption (OPIED). The standard treatment for sarin-like nerve agent exposure is post-exposure injection of atropine, a muscarinic receptor antagonist, accompanied by an oxime, an AChE reactivator, and diazepam. PMID:27705071

Comparison of non-invasive measures of cholinergic and allergic airway responsiveness in rats.

PubMed

Glaab, T; Hecker, H; Stephan, M; Baelder, R; Braun, A; Korolewitz, R; Krug, N; Hoymann, H G

2006-04-01

Non-invasive analysis of tidal expiratory flow parameters such as Tme/TE (time needed to reach peak expiratory flow divided by total expiratory time) or midexpiratory tidal flow (EF50) has been shown useful for phenotypic characterization of lung function in humans and animal models. In this study, we aimed to compare the utility of two non-invasive measures, EF50 and Tme/TE, to monitor bronchoconstriction to inhaled cholinergic and allergic challenges in Brown-Norway rats. Non-invasive measurements of Tme/TE and EF50 were paralleled by invasive recordings of Tme/TE, EF50 and pulmonary conductance (GL). First, dose-response studies with acetylcholine were performed in naive rats, showing that EF50 better than Tme/TE reflected the dose-related changes as observed with the classical invasive outcome parameter GL. The subsequent determination of allergen-specific early airway responsiveness (EAR) showed that ovalbumin-sensitized and -challenged rats exhibited airway inflammation and allergen-specific EAR. Again, EF50 was more sensitive than Tme/TE in detecting the allergen-specific EAR recorded with invasive and non-invasive lung function methods and agreed well with classical GL measurements. We conclude that non-invasive assessment of EF50 is significantly superior to Tme/TE and serves as a suitable and valid tool for phenotypic screening of cholinergic and allergic airway responsiveness in rats.

β2 Agonists.

PubMed

Billington, Charlotte K; Penn, Raymond B; Hall, Ian P

2017-01-01

History suggests β agonists, the cognate ligand of the β 2 adrenoceptor, have been used as bronchodilators for around 5,000 years, and β agonists remain today the frontline treatment for asthma and chronic obstructive pulmonary disease (COPD). The β agonists used clinically today are the products of significant expenditure and over 100 year's intensive research aimed at minimizing side effects and enhancing therapeutic usefulness. The respiratory physician now has a therapeutic toolbox of long acting β agonists to prophylactically manage bronchoconstriction, and short acting β agonists to relieve acute exacerbations. Despite constituting the cornerstone of asthma and COPD therapy, these drugs are not perfect; significant safety issues have led to a black box warning advising that long acting β agonists should not be used alone in patients with asthma. In addition there are a significant proportion of patients whose asthma remains uncontrolled. In this chapter we discuss the evolution of β agonist use and how the understanding of β agonist actions on their principal target tissue, airway smooth muscle, has led to greater understanding of how these drugs can be further modified and improved in the future. Research into the genetics of the β 2 adrenoceptor will also be discussed, as will the implications of individual DNA profiles on the clinical outcomes of β agonist use (pharmacogenetics). Finally we comment on what the future may hold for the use of β agonists in respiratory disease.

cAMP regulation of airway smooth muscle function.

PubMed

Billington, Charlotte K; Ojo, Oluwaseun O; Penn, Raymond B; Ito, Satoru

2013-02-01

Agonists activating β(2)-adrenoceptors (β(2)ARs) on airway smooth muscle (ASM) are the drug of choice for rescue from acute bronchoconstriction in patients with both asthma and chronic obstructive pulmonary disease (COPD). Moreover, the use of long-acting β-agonists combined with inhaled corticosteroids constitutes an important maintenance therapy for these diseases. β-Agonists are effective bronchodilators due primarily to their ability to antagonize ASM contraction. The presumed cellular mechanism of action involves the generation of intracellular cAMP, which in turn can activate the effector molecules cAMP-dependent protein kinase (PKA) and Epac. Other agents such as prostaglandin E(2) and phosphodiesterase inhibitors that also increase intracellular cAMP levels in ASM, can also antagonize ASM contraction, and inhibit other ASM functions including proliferation and migration. Therefore, β(2)ARs and cAMP are key players in combating the pathophysiology of airway narrowing and remodeling. However, limitations of β-agonist therapy due to drug tachyphylaxis related to β(2)AR desensitization, and recent findings regarding the manner in which β(2)ARs and cAMP signal, have raised new and interesting questions about these well-studied molecules. In this review we discuss current concepts regarding β(2)ARs and cAMP in the regulation of ASM cell functions and their therapeutic roles in asthma and COPD. Copyright © 2012 Elsevier Ltd. All rights reserved.

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

Leukotriene E(4) in urine in patients with asthma and COPD--the effect of smoking habit.

PubMed

Gaki, E; Papatheodorou, G; Ischaki, E; Grammenou, V; Papa, I; Loukides, S

2007-04-01

Leukotriene E(4) (LTE(4)) is implicated in asthma pathophysiology and possibly in chronic obstructive pulmonary disease (COPD) as one of the causes of persistent bronchoconstriction and mucus hypersecretion. Cigarette smoking stimulates cysteinyl leukotrienes (CysLTs) production. We investigated whether LTE(4) is equally increased in asthma and COPD and whether smoking significantly affects LTE(4) levels. Secondary outcomes involved correlations with inflammatory and functional parameters. We studied 40 patients with COPD [20 smokers], 40 asthmatics [20 smokers] and 30 healthy subjects [15 smokers]. Spirometry (FEV(1)% pred., FEV(1)/FVC) was performed, urine was collected for measurement of LTE(4) and creatinine, induced sputum was collected for differential cell counts and serum for ECP. LTE(4)/creatinine levels (pg/mg) [mean (sd)] were increased in asthmatic patients compared to COPD and controls, [125.6(54.5) vs. 54.5(19) vs. 55.9(18.9)pg/mg, respectively, P<0.0001 for asthma]. Smoking significantly affects LTE(4) levels only in asthmatic patients [164 (48) vs. 87 (26.3), P<0.0001 for smokers]. The only significant correlation was between eosinophils in induced sputum and LTE(4)/creatinine levels in asthmatics. In conclusion, patients with asthma presented higher LTE(4) values compared to normals and patients with COPD. Smoking significantly affects LTE(4) values only in asthmatics indicating a different underlying CysLTs inflammatory process in this condition.

Effect of fenspiride, a non-steroidal antiinflammatory agent, on neurogenic mucus secretion in ferret trachea in vitro.

PubMed

Khawaja, A M; Liu, Y C; Rogers, D F

1999-01-01

Neural mechanisms contribute to control of mucus secretion in the airways. Fenspiride is a non-steroidal antiinflammatory agent which has a variety of actions, including inhibition of neurogenic bronchoconstriction. The effect of fenspiride on neurally-mediated mucus secretion was investigated in vitro in electrically-stimulated ferret trachea, using(35)SO(4)as a mucus marker. Cholinergic secretory responses were isolated using adrenoceptor and tachykinin receptor antagonists. Tachykinin responses were isolated using cholinoceptor and adrenoceptor antagonists. Electrical stimulation increased cholinergic secretion by;90% and tachykininergic secretion by;40%. Fenspiride (1 microM-1 mM) tended to inhibit cholinergic secretion in a concentration-dependent manner, although only at 1 mM was inhibition (by 87%) significant. Inhibition by fenspiride of tachykininergic secretion was not concentration-dependent, and again significant inhibition (by 85%) was only at 1 mM. Inhibition was not due to loss of tissue viability, as assessed by restitution of secretory response after washout. Fenspiride also inhibited secretion induced by acetylcholine, but did not inhibit substance P-induced secretion. Histamine receptor antagonists increased basal secretion by 164%, whereas fenspiride did not affect basal secretion. We conclude that, in ferret trachea in vitro, fenspiride inhibits neurally-mediated mucus secretion, with antimuscarinic action the most plausible mechanism of action, but not necessarily the only mechanism. Copyright 1999 Academic Press.

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.

Loop diuretics inhibit cholinergic and noncholinergic nerves in guinea pig airways.

PubMed

Elwood, W; Lötvall, J O; Barnes, P J; Chung, K F

1991-06-01

Furosemide, a loop diuretic, is known to inhibit the response to a variety of indirect bronchial challenges in humans but does not inhibit bronchoconstriction induced by inhaled methacholine or histamine. We have investigated the effects of the two loop diuretics, furosemide (10(-6) to 10(-3) M) and bumetanide (10(-7) to 10(-4) M), on airway smooth muscle contraction in vitro induced by electrical field stimulation (EFS), or exogenously applied acetylcholine (ACh) or substance P (SP) in guinea pig tracheal and bronchial smooth muscle strips pretreated with indomethacin (10(-5) M) and propranolol (10(-6) M). Both furosemide and bumetanide caused a concentration-dependent inhibition of cholinergically mediated neural contraction in the trachea. The effect of furosemide was not influenced by the presence of airway epithelium. Furthermore, both furosemide and bumetanide inhibited in a concentration-dependent fashion nonadrenergic, noncholinergic (NANC) contraction induced by electrical field stimulation of bronchi pretreated with atropine (10(-5) M). Neither drug at the highest concentration inhibited the responses to exogenous acetylcholine (10(-8) to 10(-2) M) or substance P (10(-9) to 10(-5) M). Thus loop diuretics inhibit the neurally induced contraction of guinea pig airways without a direct effect on airway smooth muscle. We conclude that loop diuretics inhibit both cholinergic and excitatory NANC neurotransmission in guinea pig airways and that this effect may be related to their inhibitory effects on the sodium-potassium-chloride cotransporter.

Repeated allergen exposure enhances excitatory nonadrenergic noncholinergic nerve-mediated bronchoconstriction in sensitized guinea-pigs.

PubMed

Kageyama, N; Ichinose, M; Igarashi, A; Miura, M; Yamauchi, H; Sasaki, Y; Ishikawa, J; Tomaki, M; Shirato, K

1996-07-01

The effect of repeated allergen inhalation challenge on the airway excitatory nonadrenergic noncholinergic (e-NANC) nerve-mediated bronchoconstrictor response was studied in ovalbumin (OA) sensitized guinea-pigs. Three weeks after sensitization, OA inhalation, 0.03% for 3 min (challenged group), or saline inhalation (control group) was repeated every day for 4 weeks. The e-NANC nerve function was examined in vitro by means of isometric tension measurement of main bronchi. After pretreatment with atropine (10(-6) M) and propranolol (10(-6) M), we performed electrical field stimulation (EFS) or exogenous neurokinin A (NKA) administration. In the challenged group, EFS-induced main bronchial contraction was significantly greater than that of the control group (p < 0.05 or p < 0.01), but exogenous NKA-mediated responses were almost the same in both groups. The e-NANC-induced main bronchial contractions after EFS were enhanced by pretreatment with the neutral endopeptidase inhibitor, phosphoramidon, to the same degree in the control and challenged groups, indicating that the peptide degradation mechanisms were not impaired even in the challenged group. Substance P immunoreactivities in the lung of the challenged group were significantly higher than those of the control group. These results suggest that chronic airway inflammation after repeated allergen challenge increases excitatory nonadrenergic noncholinergic nerve function, possibly by enhancing sensory neuropeptide production and/or release.

Pulmonary epithelial cancer cells and their exosomes metabolize myeloid cell-derived leukotriene C4 to leukotriene D4[S

PubMed Central

Lukic, Ana; Ji, Jie; Idborg, Helena; Samuelsson, Bengt; Palmberg, Lena

2016-01-01

Leukotrienes (LTs) play major roles in lung immune responses, and LTD4 is the most potent agonist for cysteinyl LT1, leading to bronchoconstriction and tissue remodeling. Here, we studied LT crosstalk between myeloid cells and pulmonary epithelial cells. Monocytic cells (Mono Mac 6 cell line, primary dendritic cells) and eosinophils produced primarily LTC4. In coincubations of these myeloid cells and epithelial cells, LTD4 became a prominent product. LTC4 released from the myeloid cells was further transformed by the epithelial cells in a transcellular manner. Formation of LTD4 was rapid when catalyzed by γ-glutamyl transpeptidase (GGT)1 in the A549 epithelial lung cancer cell line, but considerably slower when catalyzed by GGT5 in primary bronchial epithelial cells. When A549 cells were cultured in the presence of IL-1β, GGT1 expression increased about 2-fold. Also exosomes from A549 cells contained GGT1 and augmented LTD4 formation. Serine-borate complex (SBC), an inhibitor of GGT, inhibited conversion of LTC4 to LTD4. Unexpectedly, SBC also upregulated translocation of 5-lipoxygenase (LO) to the nucleus in Mono Mac 6 cells, and 5-LO activity. Our results demonstrate an active role for epithelial cells in biosynthesis of LTD4, which may be of particular relevance in the lung. PMID:27436590

Interleukin 13 and the beta-adrenergic blockade theory of asthma revisited 40 years later.

PubMed

Townley, Robert G

2007-09-01

Beta2-Adrenergic agonists are the most potent agents clinically used in inhibiting and preventing the immediate response to bronchoconstricting agents and in inhibiting mast cell mediator release. This raises the possibility that an abnormality in beta-adrenergic receptor function or circulating catecholamine levels could contribute to airway hyperresponsiveness. To link interleukin 13 (IL-13) to the pathogenesis of asthma. Almost 4 decades ago, Andor Szentivanyi published a beta-adrenergic theory of atopic abnormality in bronchial asthma. He proposed 9 characteristics to define bronchial asthma. Because he published these 9 tenets of the beta-adrenergic blockade theory of asthma in 1968, it is appropriate and important to evaluate their relevance in light of advances in pharmacology, inflammation, and immunology. We describe the effects of the allergic reaction on beta-adrenergic responses and airway responsiveness. Both IL-1beta and tumor necrosis factor a have been detected in increased amounts in bronchial lavage fluids in allergic airway inflammation. Both IL-13 and the proinflammatory cytokines IL-1beta and tumor necrosis factor a have been demonstrated in airway smooth muscle to cause a decreased relaxation response to beta-adrenergic agonist. However, IL-13 has been shown to be necessary and sufficient to produce the characteristics of asthma. The decreased adrenergic bronchodilator activity and associated hypersensitivity to mediators put forth by Szentivanyi can be elicited with IL-13 and support its role in the pathogenesis of asthma.

Ozone-Induced Hypertussive Responses in Rabbits and Guinea Pigs

PubMed Central

Clay, Emlyn; Patacchini, Riccardo; Trevisani, Marcello; Preti, Delia; Branà, Maria Pia; Spina, Domenico

2016-01-01

Cough remains a major unmet clinical need, and preclinical animal models are not predictive for new antitussive agents. We have investigated the mechanisms and pharmacological sensitivity of ozone-induced hypertussive responses in rabbits and guinea pigs. Ozone induced a significant increase in cough frequency and a decrease in time to first cough to inhaled citric acid in both conscious guinea pigs and rabbits. This response was inhibited by the established antitussive drugs codeine and levodropropizine. In contrast to the guinea pig, hypertussive responses in the rabbit were not inhibited by bronchodilator drugs (β2 agonists or muscarinic receptor antagonists), suggesting that the observed hypertussive state was not secondary to bronchoconstriction in this species. The ozone-induced hypertussive response in the rabbit was inhibited by chronic pretreatment with capsaicin, suggestive of a sensitization of airway sensory nerve fibers. However, we could find no evidence for a role of TRPA1 in this response, suggesting that ozone was not sensitizing airway sensory nerves via activation of this receptor. Whereas the ozone-induced hypertussive response was accompanied by a significant influx of neutrophils into the airway, the hypertussive response was not inhibited by the anti-inflammatory phosphodiesterase 4 inhibitor roflumilast at a dose that clearly exhibited anti-inflammatory activity. In summary, our results suggest that ozone-induced hypertussive responses to citric acid may provide a useful model for the investigation of novel drugs for the treatment of cough, but some important differences were noted between the two species with respect to sensitivity to bronchodilator drugs. PMID:26837703

Life Event, Stress and Illness

PubMed Central

Salleh, Mohd. Razali

2008-01-01

The relationship between stress and illness is complex. The susceptibility to stress varies from person to person. Among the factors that influenced the susceptibility to stress are genetic vulnerability, coping style, type of personality and social support. Not all stress has negative effect. Studies have shown that short-term stress boosted the immune system, but chronic stress has a significant effect on the immune system that ultimately manifest an illness. It raises catecholamine and suppressor T cells levels, which suppress the immune system. This suppression, in turn raises the risk of viral infection. Stress also leads to the release of histamine, which can trigger severe broncho-constriction in asthmatics. Stress increases the risk for diabetes mellitus, especially in overweight individuals, since psychological stress alters insulin needs. Stress also alters the acid concentration in the stomach, which can lead to peptic ulcers, stress ulcers or ulcerative colitis. Chronic stress can also lead to plaque buildup in the arteries (atherosclerosis), especially if combined with a high-fat diet and sedentary living. The correlation between stressful life events and psychiatric illness is stronger than the correlation with medical or physical illness. The relationship of stress with psychiatric illness is strongest in neuroses, which is followed by depression and schizophrenia. There is no scientific evidence of a direct cause-and-effect relationship between the immune system changes and the development of cancer. However, recent studies found a link between stress, tumour development and suppression of natural killer (NK) cells, which is actively involved in preventing metastasis and destroying small metastases. PMID:22589633

Inhaled glycopyrrolate for the treatment of chronic obstructive pulmonary disease.

PubMed

Tashkin, Donald P; Gross, Nicholas J

2018-01-01

Long-acting muscarinic antagonists (LAMAs), along with long-acting β 2 -agonists (LABAs), are the mainstay for treatment of patients with COPD. Glycopyrrolate, or glycopyrronium bromide, like other LAMAs, inhibits parasympathetic nerve impulses by selectively blocking the binding of acetylcholine to muscarinic receptors. Glycopyrrolate is unusual in that it preferentially binds to M 3 over M 2 muscarinic receptors, thereby specifically targeting the primary muscarinic receptor responsible for bronchoconstriction occurring in COPD. Inhaled glycopyrrolate is slowly absorbed from the lungs and rapidly eliminated from the bloodstream, most likely by renal excretion in its unmetabolized form, limiting the potential for systemic adverse events. Inhaled glycopyrrolate is a fast-acting, efficacious treatment option for patients with moderate-severe COPD. It improves lung function, reduces the risk of exacerbations, and alleviates the symptoms of breathlessness, which in turn may explain the improvement seen in patients' quality of life. Inhaled formulations containing glycopyrrolate are well tolerated, and despite being an anticholinergic, few cardiovascular-related events have been reported. Inhaled glycopyrrolate is thus of value as both monotherapy and in combination with other classes of medication for maintenance treatment of COPD. This review covers the mechanism of action of inhaled glycopyrrolate, including its pharmacokinetic, pharmacodynamic, and safety profiles, and effects on mucus secretion. It also discusses the use of inhaled glycopyrrolate in the treatment of COPD, as monotherapy and in fixed-dose combinations with LABAs and inhaled corticosteroid-LABAs, including a triple therapy recently approved in Europe.

Mast cell stabilization, lipoxygenase inhibition, hyaluronidase inhibition, antihistaminic and antispasmodic activities of Aller-7, a novel botanical formulation for allergic rhinitis.

PubMed

Amit, A; Saxena, V S; Pratibha, N; D'Souza, P; Bagchi, M; Bagchi, D; Stohs, S J

2003-01-01

Allergic rhinitis, also known as hay fever, rose fever or summer catarrh, is a major challenge to health professionals. A large number of the world's population, including approximately 40 million Americans, suffers from allergic rhinitis. A novel, botanical formulation (Aller-7) has been developed for the treatment of allergic rhinitis using a combination of extracts from seven medicinal plants, including Phyllanthus emblica, Terminalia chebula, T. bellerica, Albizia lebbeck, Piper nigrum, Zingiber officinale and P. longum, which have a proven history of efficacy and health benefits. The clinical manifestations of allergy are due to a number of mediators that are released from mast cells. The effect of Aller-7 on rat mesenteric mast cell degranulation was studied by incubating different concentrations of Aller-7 and challenging them with a degranulating agent, compound 48/80. The inhibitory activity of Aller-7 was determined against lipoxygenase and hyaluronidase, the key enzymes involved in the initiation and maintenance of inflammatory responses. Furthermore, most of these manifestations are due to histamine, which causes vasodilatation, increasing capillary permeability and leading to bronchoconstriction. Hence, the antihistaminic activity of Aller-7 was determined is isolated guinea pig ileum substrate using cetirizine as a positive control. The antispasmodic effect of Aller-7 on contractions of guinea pig tracheal chain was determined using papaverine and cetirizine as controls. Aller-7 exhibited potent activity in all these in vitro models tested, thus demonstrating the novel anti-allergic potential of Aller-7.

Anti-asthmatic effect of Shirishadi compound through nasal spray actuation

PubMed Central

Kajaria, Divya; Tripathi, Jyotishankar; Tiwari, Shrikant

2014-01-01

Background: Increasing morbidity and mortality of Asthma placed it among the most dreaded diseases. Prediction says that asthma along with chronic obstructive pulmonary disease become third leading cause of death by the year 2020. Despite the availability of a wide range of antiasthmatic drugs, incidence of asthma is increasing alarmingly because the relief offered by these drugs is mainly symptomatic and short-lived. Moreover, their side effects are also quite distressing. Hence, a continuous search is needed to identify effective and safe remedies to treat bronchial asthma. Aims: The present clinical study was conducted to evaluate the efficacy of Shirishadi Polyherbal compound (given through nebulizer in Aerosol form) in the management of acute and chronic uncomplicated Bronchial Asthma and to propose a novel and safer Ayurvedic treatment modality. Methods and Materials: It is a randomized, open, control clinical trial in which the effect of the drug was compared with contemporary treatment and placebo medication (normal saline) in 60 adults with mild to moderate asthma. Results: There was a (t>0.001) found in pulmonary function tests (including FEV1, FVC and PEFR)in the group treated with polyherbal drug. Improvement remain constant in consecutive follow-ups signifies that there is no reverse broncho-constriction after discontinuation of the drug. Conclusion: This study signifies that polyherbal drug - Shirishadi compound may prove beneficial future alternative remedy for asthma, and its effect is similar to that of modern contemporary drug when given through nasal route. PMID:26664235

Effects on symptoms and lung function in humans experimentally exposed to diesel exhaust.

PubMed

Rudell, B; Ledin, M C; Hammarström, U; Stjernberg, N; Lundbäck, B; Sandström, T

1996-10-01

Diesel exhaust is a common air pollutant made up of several gases, hydrocarbons, and particles. An experimental study was carried out which was designed to evaluate if a particle trap on the tail pipe of an idling diesel engine would reduce effects on symptoms and lung function caused by the diesel exhaust, compared with exposure to unfiltered exhaust. Twelve healthy non-smoking volunteers (aged 20-37) were investigated in an exposure chamber for one hour during light work on a bicycle ergometer at 75 W. Each subject underwent three separate double blind exposures in a randomised sequence: to air and to diesel exhaust with the particle trap at the tail pipe and to unfiltered diesel exhaust. Symptoms were recorded according to the Borg scale before, every 10 minutes during, and 30 minutes after the exposure. Lung function was measured with a computerised whole body plethysmograph. The ceramic wall flow particle trap reduced the number of particles by 46%, whereas other compounds were relatively constant. It was shown that the most prominent symptoms during exposure to diesel exhaust were irritation of the eyes and nose and an unpleasant smell increasing during exposure. Both airway resistance (R(aw)) and specific airway resistance (SR(aw)) increased significantly during the exposures to diesel exhaust. Despite the 46% reduction in particle numbers by the trap effects on symptoms and lung function were not significantly attenuated. Exposure to diesel exhaust caused symptoms and bronchoconstriction which were not significantly reduced by a particle trap.

COPD Exacerbation and Cholinesterase Therapy in Dementia Patients.

PubMed

Mahan, Rebecca J; Blaszczyk, Amie Taggart

2016-04-01

Chronic obstructive pulmonary disease (COPD) is a nonreversible inflammatory condition of the lungs. Acetylcholine is a neurotransmitter involved in autonomic regulation of the airways, resulting in bronchoconstriction and mucous production. Cholinesterase inhibitors (ChEIs), a cornerstone therapy of dementia treatment, increase acetylcholine. Theoretically, ChEI use in patients with COPD can place patients at increased risk of exacerbation secondary to increased acetylcholine activity. A retrospective chart review was performed comparing veterans with dementia and COPD who received ChEIs with those who did not at the Veterans Affairs North Texas Health Care System. Frequency of exacerbation in the first 90 days following ChEI initiation was compared. Secondary outcomes assessed exacerbation severity and a potential protective effect of inhaled anticholinergics. A total of 94 patients were eligible for the study; 52 received a ChEI and 42 did not. The risk of exacerbation over 90 days was higher in the ChEI users with 10 (19%) experiencing an exacerbation compared with 3 (7%) in the nonusers (P = 0.133), showing a clinically significant trend. Of the patients experiencing an exacerbation, 2 patients on ChEIs had multiple exacerbations over the 90 days. The use of inhaled anticholinergics was not found to decrease the risk of exacerbation. The use of ChEIs may increase the risk of COPD exacerbation in the first 90 days of therapy in patients with dementia and COPD. This finding is clinically significant as previous studies have indicated no risk.

Chloride channel blockade relaxes airway smooth muscle and potentiates relaxation by β-agonists

PubMed Central

Yim, Peter; Rinderspacher, Alison; Fu, Xiao Wen; Zhang, Yi; Landry, Donald W.; Emala, Charles W.

2014-01-01

Severe bronchospasm refractory to β-agonists continues to cause significant morbidity and mortality in asthmatic patients. We questioned whether chloride channels/transporters are novel targets for the relaxation of airway smooth muscle (ASM). We have screened a library of compounds, derivatives of anthranilic and indanyloxyacetic acid, that were originally developed to antagonize chloride channels in the kidney. We hypothesized that members of this library would be novel calcium-activated chloride channel blockers for the airway. The initial screen of this compound library identified 4 of 20 compounds that relaxed a tetraethylammonium chloride-induced contraction in guinea pig tracheal rings. The two most effective compounds, compounds 1 and 13, were further studied for their potential to either prevent the initiation of or relax the maintenance phase of an acetylcholine (ACh)-induced contraction or to potentiate β-agonist-mediated relaxation. Both relaxed an established ACh-induced contraction in human and guinea pig ex vivo ASM. In contrast, the prevention of an ACh-induced contraction required copretreatment with the sodium-potassium-chloride cotransporter blocker bumetanide. The combination of compound 13 and bumetanide also potentiated relaxation by the β-agonist isoproterenol in guinea pig tracheal rings. Compounds 1 and 13 hyperpolarized the plasma cell membrane of human ASM cells and blocked spontaneous transient inward currents, a measure of chloride currents in these cells. These functional and electrophysiological data suggest that modulating ASM chloride flux is a novel therapeutic target in asthma and other bronchoconstrictive diseases. PMID:24879056

Effects of obesity on lung function and airway reactivity in healthy dogs.

PubMed

Manens, J; Bolognin, M; Bernaerts, F; Diez, M; Kirschvink, N; Clercx, C

2012-07-01

The present study investigated the effects of bodyweight (BW) gain on respiratory function and airway responsiveness in healthy Beagles using barometric whole body plethysmography (BWBP). Six adult dogs were examined before and after a fattening diet. The high-energy diet induced a mean increase in BW of 41±6%. BWBP basal parameters were recorded prior to airway reactivity testing (using increasing concentrations of histamine nebulisations). An airway responsiveness index (H-Penh300) was calculated as the histamine concentration necessary to reach 300% of basal enhanced pause (Penh, bronchoconstriction index). The same dogs underwent a doxapram hydrochloride (Dxp) stimulation testing 2 weeks later. Basal measurements showed that obese dogs had tidal volume per kg (TV/BW) that was significantly decreased whilst respiratory rate (RR) increased significantly. H-Penh300 decreased significantly in obese Beagles, indicating increased bronchoreactivity. Dxp administration induced a significant increase in TV/BW, minute volume per kg (MV/BW), peak inspiratory and expiratory flows per kg (PIF/BW and PEF/BW) in both normal and obese dogs although the TV/BW increase was significantly less marked in the obese group. In conclusion, obesity induced changes in basal respiratory parameters, increased bronchoreactivity and a blunted response to Dxp-induced respiratory stimulation. This combination of basal respiratory parameters, bronchoreactivity testing and pharmacological stimulation testing using non-invasive BWBP can help characterize pulmonary function and airway responsiveness in obese dogs. Copyright © 2011 Elsevier Ltd. All rights reserved.

Local small airway epithelial injury induces global smooth muscle contraction and airway constriction

PubMed Central

Zhou, Jian; Alvarez-Elizondo, Martha B.; Botvinick, Elliot

2012-01-01

Small airway epithelial cells form a continuous sheet lining the conducting airways, which serves many functions including a physical barrier to protect the underlying tissue. In asthma, injury to epithelial cells can occur during bronchoconstriction, which may exacerbate airway hyperreactivity. To investigate the role of epithelial cell rupture in airway constriction, laser ablation was used to precisely rupture individual airway epithelial cells of small airways (<300-μm diameter) in rat lung slices (∼250-μm thick). Laser ablation of single epithelial cells using a femtosecond laser reproducibly induced airway contraction to ∼70% of the original cross-sectional area within several seconds, and the contraction lasted for up to 40 s. The airway constriction could be mimicked by mechanical rupture of a single epithelial cell using a sharp glass micropipette but not with a blunt glass pipette. These results suggest that soluble mediators released from the wounded epithelial cell induce global airway contraction. To confirm this hypothesis, the lysate of primary human small airway epithelial cells stimulated a similar airway contraction. Laser ablation of single epithelial cells triggered a single instantaneous Ca2+ wave in the epithelium, and multiple Ca2+ waves in smooth muscle cells, which were delayed by several seconds. Removal of extracellular Ca2+ or decreasing intracellular Ca2+ both blocked laser-induced airway contraction. We conclude that local epithelial cell rupture induces rapid and global airway constriction through release of soluble mediators and subsequent Ca2+-dependent smooth muscle shortening. PMID:22114176

Local small airway epithelial injury induces global smooth muscle contraction and airway constriction.

PubMed

Zhou, Jian; Alvarez-Elizondo, Martha B; Botvinick, Elliot; George, Steven C

2012-02-01

Small airway epithelial cells form a continuous sheet lining the conducting airways, which serves many functions including a physical barrier to protect the underlying tissue. In asthma, injury to epithelial cells can occur during bronchoconstriction, which may exacerbate airway hyperreactivity. To investigate the role of epithelial cell rupture in airway constriction, laser ablation was used to precisely rupture individual airway epithelial cells of small airways (<300-μm diameter) in rat lung slices (∼250-μm thick). Laser ablation of single epithelial cells using a femtosecond laser reproducibly induced airway contraction to ∼70% of the original cross-sectional area within several seconds, and the contraction lasted for up to 40 s. The airway constriction could be mimicked by mechanical rupture of a single epithelial cell using a sharp glass micropipette but not with a blunt glass pipette. These results suggest that soluble mediators released from the wounded epithelial cell induce global airway contraction. To confirm this hypothesis, the lysate of primary human small airway epithelial cells stimulated a similar airway contraction. Laser ablation of single epithelial cells triggered a single instantaneous Ca(2+) wave in the epithelium, and multiple Ca(2+) waves in smooth muscle cells, which were delayed by several seconds. Removal of extracellular Ca(2+) or decreasing intracellular Ca(2+) both blocked laser-induced airway contraction. We conclude that local epithelial cell rupture induces rapid and global airway constriction through release of soluble mediators and subsequent Ca(2+)-dependent smooth muscle shortening.

Compact Eucapnic Voluntary Hyperpnoea Apparatus for Exercise-Induced Respiratory Disease Detection

PubMed Central

Wang, Lulu; Al-Jumaily, Ahmed

2017-01-01

Eucapnic voluntary hyperpnoea (EVH) challenge provides objective criteria for exercise-induced asthma (EIA) or exercise-induced bronchoconstriction (EIB), and it was recommended to justify the use of inhaled β2-agonists by athletes for the Olympics. This paper presents the development of a compact and easy-to-use EVH apparatus for assessing EIB in human subjects. The compact apparatus has been validated on human subjects and the results have been compared to the conventional EVH system. Twenty-two swimmers, including eleven healthy subjects and eleven subjects who had been physician-diagnosed with asthma, were recruited from sport and recreation centers throughout Auckland, New Zealand. Each subject performed two EVH challenge tests using the proposed breathing apparatus and the conventional Phillips EVH apparatus on separate days, respectively. Forced expiratory volume in one second (FEV1) was measured before and after the challenges. A reduction in FEV1 of 10% or more was considered positive. Of the eleven subjects who were previously diagnosed with asthma, EIB was present in all subjects (100%) in the compact EVH group, while it was presented in ten subjects (90.91%) in the conventional EVH challenge group. Of the eleven healthy subjects, EIB was present in one subject (4.55%) in the compact EVH group, while it was not present in the conventional EVH group. Experimental results showed that the compact EVH system has potential to become an alternative tool for EIB detection. PMID:28509868

Role of substance P in cough.

PubMed

Sekizawa, K; Jia, Y X; Ebihara, T; Hirose, Y; Hirayama, Y; Sasaki, H

1996-01-01

The sensory neuropeptide, substance P (SP), is present in human airway nerves, beneath and within the epithelium where the condensed localization of neutral endopeptidase (NEP), the major enzyme degrading SP, is observed. To test the hypothesis whether SP stimulates the cough reflex and NEP modifies the cough reflex, we studied the cough response to various stimuli in awake guinea-pigs. Inhibition of NEP with phosphoramidon caused cough, which was inhibited by systemic capsaicin treatment and by aerosols of a specific NK1 receptor antagonist FK 888. Aerosols of FK 888 also inhibited cough induced by bronchoconstricting agents such as acetylcholine and histamine in non-sensitized animals and by ovalbumin antigen in animals sensitized to ovalbumin. The number of coughs induced by histamine aerosols was inhibited by systemic capsaicin treatment and enhanced by pretreatment with a NEP inhibitor phosphoramidon. Likewise, FK 888 inhibited the augmented cough response to aerosolized capsaicin in female guinea-pigs treated with a long-term medication of an angiotensin-converting enzyme inhibitor, cilazapril. In humans, aerosols of SP did not cause cough in normal subjects, whereas it did in patients with common colds. The SP fragment a major metabolite of SP produced by NEP, was less effective compared with SP in these patients, suggesting that damaged epithelium may facilitate the penetration of SP. These findings suggest that SP released from sensory nerves in response to stimuli may mediate cough and NEP may have a role in modulating SP-induced effects.

Effect of fenspiride on pulmonary function in the rat and guinea pig.

PubMed

Bee, D; Laude, E A; Emery, C J; Howard, P

1995-03-01

1. Fenspiride is an anti-inflammatory agent that may have a role in reversible obstructive airways disease. Small, but significant, improvements have been seen in airways function and arterial oxygen tension in patients with mild chronic obstructive pulmonary disease. These changes have been attributed to the anti-inflammatory properties of the drug. However, airways function can be improved by other means, e.g. improved ventilation/perfusion ratio or reduced airways resistance. The possibility that fenspiride may have actions other than anti-inflammatory was investigated in two animal species. 2. In the rat, actions on the pulmonary circulation were investigated in the isolated perfused lung, but fenspiride proved to be a poor pulmonary vasodilator, showing only a small reversal of the raised pulmonary artery pressure induced by hypoxia. 3. Ventilation was measured in the anaesthetized rat using whole-body plethysmography. Fenspiride caused no increase in ventilation or changes in arterial blood gases. However, a profound hypotensive action was observed with high doses. 4. The possibility that a decrease in airways resistance (R(aw)) might occur with fenspiride was investigated in anaesthetized guinea pigs. Capsaicin (30 mumol/l) was used to increase baseline R(aw) through bronchoconstriction. Fenspiride gave a dose-dependent partial reversal of the raised R(aw), and its administration by aerosol proved as efficacious as the intravenous route. In addition, the hypotensive side-effect found with intravenous injection was alleviated by aerosolized fenspiride.(ABSTRACT TRUNCATED AT 250 WORDS)

Fibromyalgia as a cause of uncontrolled asthma: a case-control multicenter study.

PubMed

Martinez-Moragon, Eva; Plaza, Vicente; Torres, Isabel; Rosado, Ana; Urrutia, Isabel; Casas, Xavier; Hinojosa, Belen; Blanco-Aparicio, Marina; Delgado, Julio; Quirce, Santiago; Sabadell, Carles; Cebollero, Pilar; Muñoz-Fernández, Ana

2017-12-01

Fibromyalgia can affect the control of asthma when both diseases are present in a single patient. To characterize asthma in patients with concomitant fibromyalgia to assess whether fibromyalgia is an independent factor of asthma severity that influences poor asthma control. We also evaluated how dyspnea is perceived by patients in order to demonstrate that alterations in the perception of airway obstruction may be responsible for poor asthma control. This was a cross-sectional case-control multicenter study, in which 56 patients in the asthma and fibromyalgia group were matched to 36 asthmatics by sex, approximate age, and asthma severity level. All patients were women. Study variables included the Asthma Control Test (ACT), the Mini Asthma Quality of Life Questionnaire (MiniAQLQ), the Nijmegen hyperventilation syndrome questionnaire, the Hospital Anxiety and Depression Scale, and perception of dyspnea after acute bronchoconstriction. Although patients in both study groups showed similar asthma severity and use of anti-asthmatic drugs, patients in the asthma and fibromyalgia group showed lower scores on the ACT and MiniAQLQ questionnaires, and higher scores of anxiety and depression as well as hyperventilation compared to asthma patients without fibromyalgia. All these differences were statistically significant. Fibromyalgia in patients with asthma influences poor control of the respiratory disease and is associated with altered perception of dyspnea, hyperventilation syndrome, high prevalence of depression and anxiety, and impaired quality of life. Fibromyalgia may be considered a risk factor for uncontrolled asthma in patients suffering from asthma and fibromyalgia concomitantly.

Nebulized perflubron and carbon dioxide rapidly dilate constricted airways in an ovine model of allergic asthma.

PubMed

El Mays, Tamer Y; Choudhury, Parichita; Leigh, Richard; Koumoundouros, Emmanuel; Van der Velden, Joanne; Shrestha, Grishma; Pieron, Cora A; Dennis, John H; Green, Francis Hy; Snibson, Ken J

2014-09-16

The low toxicity of perfluorocarbons (PFCs), their high affinity for respiratory gases and their compatibility with lung surfactant have made them useful candidates for treating respiratory diseases such as adult respiratory distress syndrome. We report results for treating acute allergic and non-allergic bronchoconstriction in sheep using S-1226 (a gas mixture containing carbon dioxide and small volumes of nebulized perflubron). The carbon dioxide, which is highly soluble in perflubron, was used to relax airway smooth muscle. Sheep previously sensitized to house dust mite (HDM) were challenged with HDM aerosols to induce early asthmatic responses. At the maximal responses (characterised by an increase in lung resistance), the sheep were either not treated or treated with one of the following; nebulized S-1226 (perflubron + 12% CO2), nebulized perflubron + medical air, 12% CO2, salbutamol or medical air. Lung resistance was monitored for up to 20 minutes after cessation of treatment. Treatment with S-1226 for 2 minutes following HDM challenge resulted in a more rapid, more profound and more prolonged decline in lung resistance compared with the other treatment interventions. Video bronchoscopy showed an immediate and complete (within 5 seconds) re-opening of MCh-constricted airways following treatment with S-1226. S-1226 is a potent and rapid formulation for re-opening constricted airways. Its mechanism(s) of action are unknown. The formulation has potential as a rescue treatment for acute severe asthma.

Bronchodilatory effect of deep inspiration in freshly isolated sheep lungs.

PubMed

Wong, William D; Wang, Lu; Paré, Peter D; Seow, Chun Y

2017-02-01

Taking a big breath is known to reverse bronchoconstriction induced by bronchochallenge in healthy subjects; this bronchodilatory effect of deep inspiration (DI) is diminished in asthmatics. The mechanism underlying the DI effect is not clear. Observations from experiments using isolated airway smooth muscle (ASM) preparations and airway segments suggest that straining of ASM due to DI could lead to bronchodilation, possibly due to strain-induced reduction in ASM contractility. However, factors external to the lung cannot be excluded as potential causes for the DI effect. Neural reflex initiated by stretch receptors in the lung are known to inhibit the broncho-motor tone and enhance vasodilatation; the former directly reduces airway resistance, and the latter facilitates removal of contractile agonists through the bronchial circulation. If the DI effect is solely mediated by factors extrinsic to the lung, the DI effect would be absent in isolated, nonperfused lungs. Here we examined the DI effect in freshly isolated, nonperfused sheep lungs. We found that imposition of DI on isolated lungs resulted in significant bronchodilation, that this DI effect was present only after the lungs were challenged with a contractile agonist (acetylcholine or histamine), and that the effect was independent of the difference in lung volume observed pre- and post-DI. We conclude that a significant portion of the bronchodilatory DI effect stems from factors internal to the lung related to the activation of ASM. Copyright © 2017 the American Physiological Society.

Cysteinyl leukotrienes C4 and D4 downregulate human mast cell expression of toll-like receptors 1 through 7.

PubMed

Karpov, V; Ilarraza, R; Catalli, A; Kulka, M

2018-01-01

Cysteinyl leukotrienes (CysLT) are potent inflammatory lipid molecules that mediate some of the pathophysiological responses associated with asthma such as bronchoconstriction, vasodilation and increased microvascular permeability. As a result, CysLT receptor antagonists (LRA), such as montelukast, have been used to effectively treat patients with asthma. We have recently shown that mast cells are necessary modulators of innate immune responses to bacterial infection and an important component of this innate immune response may involve the production of CysLT. However, the effect of LRA on innate immune receptors, particularly on allergic effector cells, is unknown. This study determined the effect of CysLT on toll-like receptor (TLR) expression by the human mast cell line LAD2. Real-time PCR analysis determined that LTC4, LTD4 and LTE4 downregulated mRNA expression of several TLR. Specifically in human CD34+-derived human mast cells (HuMC), LTC4 inhibited expression of TLR1, 2, 4, 5, 6 and 7 while LTD4 inhibited expression of TLR1-7. Montelukast blocked LTC4-mediated downregulation of all TLR, suggesting that these effects were mediated by activation of the CysLT1 receptor (CysLT1R). Flow cytometry analysis confirmed that LTC4 downregulated surface expression of TLR2 which was blocked by montelukast. These data show that CysLT can modulate human mast cell expression of TLR and that montelukast may be beneficial for innate immune responses mediated by mast cells.

Enalapril and diltiazem co-administration and respiratory side effects of enalapril.

PubMed

Franová, S; Nosál'ová, G; Antosová, M; Nosál', S

2005-01-01

A persistent, chronic dry cough is the most common adverse effect of angiotensin converting enzyme (ACE) inhibitors therapy. The mechanism of this respiratory adverse effect is related to the inhibition of ACE and the accumulation of bradykinin, substance P, prostanoids and other inflammatory neuropeptides in the airways. The aim of this study was to follow the relationship between 15-day administration of enalapril and the defense reflexes (cough and bronchoconstriction) of the airways in experimental animals, as well as the possibility of their pharmacological restriction with simultaneous diltiazem administration. Cough reflex was investigated by the method of mechanical irritation of laryngopharyngeal and tracheobronchial area in non-anesthetized cats. The reactivity of tracheal smooth muscles of the airways to bronchoconstrictor mediators (histamine 10 nM - 1 mM, acetylcholine 10 nM - 1 mM and KCl 1 mM - 100 mM) was evaluated by an in vitro method in guinea pigs. Enalapril 5 mg/kg/day and diltiazem 30 mg/kg/day were administered perorally for 15 days. The results showed that long-lasting administration of enalapril resulted in a significant increase of measured cough parameters and increased reactivity of tracheal smooth muscle to histamine and KCl. Simultaneous administration of enalapril together with diltiazem significantly decreased the enalapril induced cough, and decreased enalapril induced hyperreactivity of tracheal smooth muscles to KCl. The results showed a partially protective effect of diltiazem and enalapril co-administration on the respiratory adverse effects induced by enalapril therapy.

A novel method for detecting airway narrowing using breath sound spectrum analysis in children.

PubMed

Tabata, Hideyuki; Hirayama, Mariko; Enseki, Mayumi; Nukaga, Mariko; Hirai, Kota; Furuya, Hiroyuki; Mochizuki, Hiroyuki

2016-01-01

Using a breath sound analyzer, we investigated new clinical parameters that are rarely affected by airflow in young children. A total of 65 children with asthma participated in this study (mean age 9.6 years). In Study 1, the intra- and inter-observer variability was measured. Common breath sound parameters, frequency at 99%, 75%, and 50% of the maximum frequency (F99, F75, and F50) and the highest frequency of inspiratory breath sounds were calculated. In addition, new parameters obtained using the ratio of sound spectra parameters, i.e., the spectrum curve indexes including the ratio of the third and fourth area to the total area and the ratio of power and frequency at F75 and F50, were calculated. In Study 2, 51 children underwent breath sound analyses. In Study 3, breath sounds were studied before and after methacholine inhalation. In Study 1, the data showed good inter- and intra-observer reliability. In Study 2, there were significant relationships between the airflow rate, age, height, and spirometric and common breath sound parameters. However, there were no significant relationships between the airflow rate and the spectrum curve indexes. Moreover, the spectrum curve indexes showed no relationships with age, height, or spirometric parameters. In Study 3, all parameters significantly changed after methacholine inhalation. Some spectrum curve indexes are not significantly affected by the airflow rate at the mouth, although they successfully indicate airway narrowing. These parameters may play a role in the assessment of bronchoconstriction in children. Copyright © 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Role of Inflammatory Reponse in Experimental Decompression Sickness

NASA Technical Reports Server (NTRS)

Butler, B. D.; Little, T.

1999-01-01

Decompression to altitude can result in gas bubble formation both in tissues and in the systemic veins. The venous gas emboli (VGE) are often monitored during decompression exposures to assess risk for decompression sickness (DCS). Astronauts are at risk for DCS during extravehicular activities (EVA), where decompression occurs from the Space Shuttle or Space Station atmospheric pressure of 14.7 pounds per square inch (PSI) to that of the space suit pressure of 4.3 PSI. DCS symptoms include diffuse pain, especially around joints, inflammation and edema. Pathophysiological effects include interstitial inflammatory responses and recurring injury to the vascular endothelium. Such responses can result in vasoconstriction and associated hemodynamic changes.The granulocyte cell activation and chemotaxin release results in the formation of vasoactive and microvascular permeability altering mediators, especially from the lungs which are the principal target organ for the venous bubbles, and from activated cells (neutrophils, platelets, macrophages). Such mediators include free arachidonic acid and the byproducts of its metabolism via the cyclooxygenase and lipoxygenase pathways (see figure). The cyclooxygenase pathway results in formation of prostacyclin and other prostaglandins and thromboxanes that cause vasoconstriction, bronchoconstriction and platelet aggregation. Leukotrienes produced by the alternate pathway cause pulmonary and bronchial smooth muscle contraction and edema. Substances directly affecting vascular tone such as nitric oxide may also play a role in the respose to DCS. We are studying the role and consequent effects of the release inflammatory bioactive mediators as a result of DCS and VGE. More recent efforts are focused on identifying the effects of the body's circadian rhythm on these physiological consequences to decompression stress. al

The in vivo pharmacology of CP-80, 633, a selective inhibitor of phosphodiesterase 4.

PubMed

Turner, C R; Cohan, V L; Cheng, J B; Showell, H J; Pazoles, C J; Watson, J W

1996-09-01

The following studies were conducted to characterize the bron-chodilatory and antiinflammatory activity of the novel, selective phosphodiesterase-IV inhibitor, CP-80,633 (2'S)5-[3-(2'-exobicyclo[2.2.1]heptyloxy-4-methoxy-phenyl]te trahydro- 2(1H)-pyrimidone, a compound in clinical development for atopic disease. In IgG1 passively sensitized guinea pigs, aerosolized ovalbumin challenge increases both pulmonary eosinophil peroxidase levels and airway obstruction. CP-80,633, administered before ovalbumin challenge, significantly attenuated both the increase in tissue eosinophil peroxidase levels (ED50 = 1.4 mg/kg, p.o.) and airway obstruction (ED50 = 0.93 +/- 0.14 mg/kg,p.o.) 10 to 30 times more potently than theophyl-line. Intraarterially administered CP-80,633 also reversed an established bronchoconstriction initiated by continuous infusion of histamine to guinea pigs (ED50 of 8.2 micrograms/kg vs. 5.6 mg/kg for theophylline). The antiinflammatory effect of CP-80,633 was also examined in atopic monkeys challenged with Ascaris suum (Ag) aerosol. CP-80,633 (1 mg/kg, qid, s.c., 1 hr before antigen challenge) significantly reduced antigen-induced increases in bronchoalveolar lavage neutrophils (72.8 +/- 15.8% inhibition) and eosinophils (61.1 +/- 5.7% inhibition) 4 hr postchallenge, but did not reduce leukocytes 24 hr postchallenge. CP-80,633 did not inhibit antigen-induced increases in BAL levels of interleukin-1 beta, -6 or -8 as measured by enzyme-linked immunosorbant assay. These results indicate that CP-80,633 possesses bronchodilatory activity in guinea pigs and some antiinflammatory effects in both guinea pigs and monkeys.

Is Wolbachia participating in the bronchial reactivity of cats with heartworm associated respiratory disease?

PubMed

García-Guasch, L; Caro-Vadillo, A; Manubens-Grau, J; Carretón, E; Morchón, R; Simón, F; Kramer, L H; Montoya-Alonso, J A

2013-09-01

Heartworm associated respiratory disease is a pulmonary syndrome in cats that results from the vascular and parenchymal inflammatory response associated with the arrival and death of Dirofilaria immitis worms into the distal pulmonary arteries. This parasite harbors intracellular Wolbachia, an endosymbiont bacteria. The association between the parasite and the bacteria is obligatory. Some studies suggest the involvement of Wolbachia in the development of the inflammatory reaction and in the polarization of the host immune response against the parasite. Barometric whole-body plethysmography is a non-invasive pulmonary function test that allows a dynamic study of breathing patterns and is useful to study airway disease and the response to different treatments. The aim of this prospective non-blinded study was to compare the influence of Wolbachia upon the respiratory function variables in a population of cats seropositive to D. immitis by use of Barometric whole-body plethysmography. Fourteen seropositive cats to Wolbachia and eight seronegative cats were put into the plethysmograph chamber and different respiratory variables were measured. The results were analyzed and compared between the two groups of animals. Significant differences were found for bronchoconstriction index variables PAU (pause) (P-value<0.05) and Penh (enhanced pause) (P-value<0.05). The results obtained in our study suggest that Wolbachia seems to produce a greater acute inflammatory response at bronchial, vascular and parenchymal level worsening the state of broncho-reactivity associated with the presence of seropositivity to D. immitis in cats. Copyright © 2013 Elsevier B.V. All rights reserved.

Bronchial hyperresponsiveness testing in athletes of the Swiss Paralympic team

PubMed Central

2013-01-01

Background The aim of this study was to assess airway hyperresponsiveness to eucapnic voluntary hyperventilation and dry powder mannitol challenge in athletes aiming to participate at the Paralympic Games 2008 in Beijing, especially in athletes with spinal cord injury. Methods Forty-four athletes with a disability (27 with paraplegia (group 1), 3 with tetraplegia (group 2) and 14 with other disabilities such as blindness or single limb amputations (group 3) performed spirometry, skin prick testing, measurement of exhaled nitric oxide, eucapnic voluntary hyperventilation challenge test (EVH) and mannitol challenge test (MCT). A fall in FEV1 of ≥10% in either challenge test was deemed positive for exercise-induced bronchoconstriction. Results Fourteen (32%) athletes were atopic and 7 (16%) had a history of physician-diagnosed asthma. Absolute lung function values were significantly lower in patients of group 1 and 2 compared to group 3. Nine (20%) athletes were positive to EVH (8 paraplegics, 1 tetraplegic), and 8 (18%) athletes were positive to MCT (7 paraplegics, 1 tetraplegic). Fourteen (22.7%) subjects were positive to at least one challenge; only three athletes were positive to both tests. None of the athletes in group 3 had a positive test. Both challenge tests showed a significant association with physician-diagnosed asthma status (p = 0.0001). The positive and negative predictive value to diagnose physician-diagnosed asthma was 89% and 91% for EHV, and 75% and 86% for MCT, respectively. Conclusion EVH and MCT can be used to identify, but especially exclude asthma in Paralympic athletes. PMID:23845126

Peri-adolescent asthma symptoms cause adult anxiety-related behavior and neurobiological processes in mice

PubMed Central

Caulfield, Jasmine I.; Caruso, Michael J.; Michael, Kerry C.; Bourne, Rebecca A.; Chirichella, Nicole R.; Klein, Laura C.; Craig, Timothy; Bonneau, Robert H.; August, Avery; Cavigelli, Sonia A.

2017-01-01

Human and animal studies have shown that physical challenges and stressors during adolescence can have significant influences on behavioral and neurobiological development associated with internalizing disorders such as anxiety and depression. Given the prevalence of asthma during adolescence and increased rates of internalizing disorders in humans with asthma, we used a mouse model to test if and which symptoms of adolescent allergic asthma (airway inflammation or labored breathing) cause adult anxiety- and depression-related behavior and brain function. To mimic symptoms of allergic asthma in young BALB/cJ mice (postnatal days [P] 7–57; N=98), we induced lung inflammation with repeated intranasal administration of house dust mite extract (most common aeroallergen for humans) and bronchoconstriction with aerosolized methacholine (non-selective muscarinic receptor agonist). Three experimental groups, in addition to a control group, included: (1) “Airway inflammation only”, allergen exposure 3 times/week, (2) “Labored breathing only”, methacholine exposure once/week, and (3) “Airway inflammation + Labored breathing”, allergen and methacholine exposure. Compared to controls, mice that experienced methacholine-induced labored breathing during adolescence displayed a ~20% decrease in time on open arms of the elevated plus maze in early adulthood (P60), a ~30% decrease in brainstem serotonin transporter (SERT) mRNA expression and a ~50% increase in hippocampal serotonin receptor 1a (5Htr1a) and corticotropin releasing hormone receptor 1 (Crhr1) expression in adulthood (P75). This is the first evidence that experimentally-induced clinical symptoms of adolescent asthma alter adult anxiety-related behavior and brain function several weeks after completion of asthma manipulations. PMID:28284954

Hazardous air pollutants and asthma.

PubMed

Leikauf, George D

2002-08-01

Asthma has a high prevalence in the United States, and persons with asthma may be at added risk from the adverse effects of hazardous air pollutants (HAPs). Complex mixtures (fine particulate matter and tobacco smoke) have been associated with respiratory symptoms and hospital admissions for asthma. The toxic ingredients of these mixtures are HAPs, but whether ambient HAP exposures can induce asthma remains unclear. Certain HAPs are occupational asthmagens, whereas others may act as adjuncts during sensitization. HAPs may exacerbate asthma because, once sensitized, individuals can respond to remarkably low concentrations, and irritants lower the bronchoconstrictive threshold to respiratory antigens. Adverse responses after ambient exposures to complex mixtures often occur at concentrations below those producing effects in controlled human exposures to a single compound. In addition, certain HAPs that have been associated with asthma in occupational settings may interact with criteria pollutants in ambient air to exacerbate asthma. Based on these observations and past experience with 188 HAPs, a list of 19 compounds that could have the highest impact on the induction or exacerbation of asthma was developed. Nine additional compounds were identified that might exacerbate asthma based on their irritancy, respirability, or ability to react with biological macromolecules. Although the ambient levels of these 28 compounds are largely unknown, estimated exposures from emissions inventories and limited air monitoring suggest that aldehydes (especially acrolein and formaldehyde) and metals (especially nickel and chromium compounds) may have possible health risk indices sufficient for additional attention. Recommendations for research are presented regarding exposure monitoring and evaluation of biologic mechanisms controlling how these substances induce and exacerbate asthma.

Aerosolized red-tide toxins (brevetoxins) and asthma.

PubMed

Fleming, Lora E; Kirkpatrick, Barbara; Backer, Lorraine C; Bean, Judy A; Wanner, Adam; Reich, Andrew; Zaias, Julia; Cheng, Yung Sung; Pierce, Richard; Naar, Jerome; Abraham, William M; Baden, Daniel G

2007-01-01

With the increasing incidence of asthma, there is increasing concern over environmental exposures that may trigger asthma exacerbations. Blooms of the marine microalgae, Karenia brevis, cause red tides (or harmful algal blooms) annually throughout the Gulf of Mexico. K brevis produces highly potent natural polyether toxins, called brevetoxins, which are sodium channel blockers, and possibly histamine activators. In experimental animals, brevetoxins cause significant bronchoconstriction. In humans, a significant increase in self-reported respiratory symptoms has been described after recreational and occupational exposures to Florida red-tide aerosols, particularly among individuals with asthma. Before and after 1 h spent on beaches with and without an active K brevis red-tide exposure, 97 persons >or= 12 years of age with physician-diagnosed asthma were evaluated by questionnaire and spirometry. Concomitant environmental monitoring, water and air sampling, and personal monitoring for brevetoxins were performed. Participants were significantly more likely to report respiratory symptoms after K brevis red-tide aerosol exposure than before exposure. Participants demonstrated small, but statistically significant, decreases in FEV(1), midexpiratory phase of forced expiratory flow, and peak expiratory flow after exposure, particularly among those participants regularly using asthma medications. No significant differences were detected when there was no Florida red tide (ie, during nonexposure periods). This study demonstrated objectively measurable adverse changes in lung function from exposure to aerosolized Florida red-tide toxins in asthmatic subjects, particularly among those requiring regular therapy with asthma medications. Future studies will assess these susceptible subpopulations in more depth, as well as the possible long-term effects of these toxins.

Aerosolized Red-Tide Toxins (Brevetoxins) and Asthma

PubMed Central

Fleming, Lora E.; Kirkpatrick, Barbara; Backer, Lorraine C.; Bean, Judy A.; Wanner, Adam; Reich, Andrew; Zaias, Julia; Cheng, Yung Sung; Pierce, Richard; Naar, Jerome; Abraham, William M.; Baden, Daniel G.

2009-01-01

Background With the increasing incidence of asthma, there is increasing concern over environmental exposures that may trigger asthma exacerbations. Blooms of the marine microalgae, Karenia brevis, cause red tides (or harmful algal blooms) annually throughout the Gulf of Mexico. K brevis produces highly potent natural polyether toxins, called brevetoxins, which are sodium channel blockers, and possibly histamine activators. In experimental animals, brevetoxins cause significant bronchoconstriction. In humans, a significant increase in self-reported respiratory symptoms has been described after recreational and occupational exposures to Florida red-tide aerosols, particularly among individuals with asthma. Methods Before and after 1 h spent on beaches with and without an active K brevis red-tide exposure, 97 persons ≥ 12 years of age with physician-diagnosed asthma were evaluated by questionnaire and spirometry. Concomitant environmental monitoring, water and air sampling, and personal monitoring for brevetoxins were performed. Results Participants were significantly more likely to report respiratory symptoms after K brevis red-tide aerosol exposure than before exposure. Participants demonstrated small, but statistically significant, decreases in FEV1, midexpiratory phase of forced expiratory flow, and peak expiratory flow after exposure, particularly among those participants regularly using asthma medications. No significant differences were detected when there was no Florida red tide (ie, during nonexposure periods). Conclusions This study demonstrated objectively measurable adverse changes in lung function from exposure to aerosolized Florida red-tide toxins in asthmatic subjects, particularly among those requiring regular therapy with asthma medications. Future studies will assess these susceptible subpopulations in more depth, as well as the possible long-term effects of these toxins. PMID:17218574

A maturational model for the study of airway smooth muscle adaptation to mechanical oscillation.

PubMed

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

2005-10-01

It has been shown that mechanical stretches imposed on airway smooth muscle (ASM) by deep inspiration reduce the subsequent contractile response of the ASM. This passive maneuver of lengthening and retraction of the muscle is beneficial in normal subjects to counteract bronchospasm. However, it is detrimental to hyperresponsive airways because it triggers further bronchoconstriction. Although the exact mechanisms for this contrary response by normal and hyperresponsive airways are unclear, it has been suggested that the phenomenon is related to changes in ASM adaptability to mechanical oscillation. Healthy immature airways of both human and animal exhibit hyperresponsiveness, but whether the adaptative properties of hyperresponsive airway differ from normal is still unknown. In this article, we review the phenomenon of ASM adaptation to mechanical oscillation and its relevance and implication to airway hyperresponsiveness. We demonstrate that the age-specific expression of ASM adaptation is prominent using an established maturational animal model developed in our laboratory. Our data on immature ASM showed potentiated contractile force shortly after a length oscillation compared with the maximum force generated before oscillation. Several potential mechanisms such as myogenic response, changes in actin polymerization, or changes in the quantity of the cytoskeletal regulatory proteins plectin and vimentin, which may underlie this age-specific force potentiation, are discussed. We suggest a working model of the structure of smooth muscle associated with force transmission, which may help to elucidate the mechanisms responsible for the age-specific expression of smooth muscle adaptation. It is important to study the maturational profile of ASM adaptation as it could contribute to juvenile hyperresponsiveness.

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.

Onset of diabetes modulates the airway smooth muscle reactivity of guinea pigs: role of epithelial mediators.

PubMed

Saidullah, Bano; Muralidhar, Kambadur; Fahim, Mohammad

2014-01-01

Diabetes induces lung dysfunction, leading to alteration in the pulmonary functions. Our aim was to investigate whether the early stage of diabetes alters the epithelium-dependent bronchial responses and whether nitric oxide (NO), KATP channels and cyclooxygenase (COX) pathways contribute in this effect. Guinea pigs were treated with a single injection of streptozotocin (180 mg/kg, i.p.) for induction of diabetes. Airway conductivity was assessed by inhaled histamine, using a non-invasive body plethysmography. The contractile responses of tracheal rings induced by acetylcholine (ACh) and relaxant responses of precontracted rings, induced by isoproterenol (IP) were compared in the presence and absence of the epithelium. Effects of N(ω)-Nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor), glybenclamide (a KATP channel inhibitor) and indomethacin (a COX inhibitor) were also assessed in diabetic guinea pigs. Early stage diabetes did not alter the airway conductivity. ACh-induced bronchoconstriction in epithelium intact tracheal rings was not affected by the onset of diabetes, however a reduction in the increased ACh responses due to epithelium removal, to L-NAME or to indomethacin was observed. The relaxation response to IP was impaired in trachea from guinea pigs in which diabetes had just developed. Early diabetes significantly reduced the IP response to glybenclamide and to indomethacin. Our results demonstrate that the early stage of diabetes, modulate the bronchial reactivity to both ACh and IP by disrupting the NO, KATP channels and COX pathways, without affecting the airway conductivity in guinea pigs.

Length oscillation mimicking periodic individual deep inspirations during tidal breathing attenuates force recovery and adaptation in airway smooth muscle.

PubMed

Raqeeb, Abdul; Solomon, Dennis; Paré, Peter D; Seow, Chun Y

2010-11-01

Airway smooth muscle (ASM) is able to generate maximal force under static conditions, and this isometric force can be maintained over a large length range due to length adaptation. The increased force at short muscle length could lead to excessive narrowing of the airways. Prolonged exposure of ASM to submaximal stimuli also increases the muscle's ability to generate force in a process called force adaptation. To date, the effects of length and force adaptation have only been demonstrated under static conditions. In the mechanically dynamic environment of the lung, ASM is constantly subjected to periodic stretches by the parenchyma due to tidal breathing and deep inspiration. It is not known whether force recovery due to muscle adaptation to a static environment could occur in a dynamic environment. In this study the effect of length oscillation mimicking tidal breathing and deep inspiration was examined. Force recovery after a length change was attenuated in the presence of length oscillation, except at very short lengths. Force adaptation was abolished by length oscillation. We conclude that in a healthy lung (with intact airway-parenchymal tethering) where airways are not allowed to narrow excessively, large stretches (associated with deep inspiration) may prevent the ability of the muscle to generate maximal force that would occur under static conditions irrespective of changes in mean length; mechanical perturbation on ASM due to tidal breathing and deep inspiration, therefore, is the first line of defense against excessive bronchoconstriction that may result from static length and force adaptation.

Ambient particulate matter air pollution and cardiopulmonary diseases.

PubMed

Thurston, George; Lippmann, Morton

2015-06-01

Population exposures to ambient outdoor particulate matter (PM) air pollution have been assessed to represent a major burden on global health. Ambient PM is a diverse class of air pollution, with characteristics and health implications that can vary depending on a host of factors, including a particle's original source of emission or formation. The penetration of inhaled particles into the thorax is dependent on their deposition in the upper respiratory tract during inspiration, which varies with particle size, flow rate and tidal volume, and in vivo airway dimensions. All of these factors can be quite variable from person to person, depending on age, transient illness, cigarette smoke and other short-term toxicant exposures that cause transient bronchoconstriction, and occupational history associated with loss of lung function or cumulative injury. The adverse effects of inhaled PM can result from both short-term (acute) and long-term (chronic) exposures to PM, and can range from relatively minor, such as increased symptoms, to very severe effects, including increased risk of premature mortality and decreased life expectancy from long-term exposure. Control of the most toxic PM components can therefore provide major health benefits, and can help guide the selection of the most human health optimal air quality control and climate change mitigation policy measures. As such, a continued improvement in our understanding of the nature and types of PM that are most dangerous to health, and the mechanism(s) of their respective health effects, is an important public health goal. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Effects on symptoms and lung function in humans experimentally exposed to diesel exhaust.

PubMed Central

Rudell, B; Ledin, M C; Hammarström, U; Stjernberg, N; Lundbäck, B; Sandström, T

1996-01-01

OBJECTIVES: Diesel exhaust is a common air pollutant made up of several gases, hydrocarbons, and particles. An experimental study was carried out which was designed to evaluate if a particle trap on the tail pipe of an idling diesel engine would reduce effects on symptoms and lung function caused by the diesel exhaust, compared with exposure to unfiltered exhaust. METHODS: Twelve healthy non-smoking volunteers (aged 20-37) were investigated in an exposure chamber for one hour during light work on a bicycle ergometer at 75 W. Each subject underwent three separate double blind exposures in a randomised sequence: to air and to diesel exhaust with the particle trap at the tail pipe and to unfiltered diesel exhaust. Symptoms were recorded according to the Borg scale before, every 10 minutes during, and 30 minutes after the exposure. Lung function was measured with a computerised whole body plethysmograph. RESULTS: The ceramic wall flow particle trap reduced the number of particles by 46%, whereas other compounds were relatively constant. It was shown that the most prominent symptoms during exposure to diesel exhaust were irritation of the eyes and nose and an unpleasant smell increasing during exposure. Both airway resistance (R(aw)) and specific airway resistance (SR(aw)) increased significantly during the exposures to diesel exhaust. Despite the 46% reduction in particle numbers by the trap effects on symptoms and lung function were not significantly attenuated. CONCLUSION: Exposure to diesel exhaust caused symptoms and bronchoconstriction which were not significantly reduced by a particle trap. PMID:8943829

Hazardous air pollutants and asthma.

PubMed Central

Leikauf, George D

2002-01-01

Asthma has a high prevalence in the United States, and persons with asthma may be at added risk from the adverse effects of hazardous air pollutants (HAPs). Complex mixtures (fine particulate matter and tobacco smoke) have been associated with respiratory symptoms and hospital admissions for asthma. The toxic ingredients of these mixtures are HAPs, but whether ambient HAP exposures can induce asthma remains unclear. Certain HAPs are occupational asthmagens, whereas others may act as adjuncts during sensitization. HAPs may exacerbate asthma because, once sensitized, individuals can respond to remarkably low concentrations, and irritants lower the bronchoconstrictive threshold to respiratory antigens. Adverse responses after ambient exposures to complex mixtures often occur at concentrations below those producing effects in controlled human exposures to a single compound. In addition, certain HAPs that have been associated with asthma in occupational settings may interact with criteria pollutants in ambient air to exacerbate asthma. Based on these observations and past experience with 188 HAPs, a list of 19 compounds that could have the highest impact on the induction or exacerbation of asthma was developed. Nine additional compounds were identified that might exacerbate asthma based on their irritancy, respirability, or ability to react with biological macromolecules. Although the ambient levels of these 28 compounds are largely unknown, estimated exposures from emissions inventories and limited air monitoring suggest that aldehydes (especially acrolein and formaldehyde) and metals (especially nickel and chromium compounds) may have possible health risk indices sufficient for additional attention. Recommendations for research are presented regarding exposure monitoring and evaluation of biologic mechanisms controlling how these substances induce and exacerbate asthma. PMID:12194881

Association of TRPV4 gene polymorphisms with chronic obstructive pulmonary disease.

PubMed

Zhu, Guohua; Gulsvik, Amund; Bakke, Per; Ghatta, Srinivas; Anderson, Wayne; Lomas, David A; Silverman, Edwin K; Pillai, Sreekumar G

2009-06-01

Chronic obstructive pulmonary disease (COPD) is characterized by airway epithelial damage, bronchoconstriction, parenchymal destruction and mucus hypersecretion. Upon activation by a broad range of stimuli, transient receptor potential vanilloid 4 (TRPV4) functions to control airway epithelial cell volume and epithelial and endothelial permeability; it also triggers bronchial smooth muscle contraction and participates in autoregulation of mucociliary transport. These functions of TRPV4 may be important for the regulation of COPD pathogenesis, so TRPV4 is a candidate gene for COPD. We genotyped 20 single nucleotide polymorphisms (SNPs) in TRPV4, and tested qualitative COPD and quantitative FEV(1) and FEV(1)/(F)VC phenotypes in two independent large populations. The family population had 606 pedigrees including 1891 individuals, and the case-control sample included 953 COPD cases and 956 controls. Family-based association tests were performed in the family data. Logistic regression and linear models were used in the case-control data to replicate the association results. In the family data, seven out of 20 SNPs tested were associated with COPD (2.5 x 10(-4) < or = P < or = 0.04) and six SNPs were associated with FEV(1)/VC (0.02 < or = P < or = 0.03) from family-based association tests (PBAT) analysis. Four out of the seven SNPs associated with COPD demonstrated replicated associations with the same effect directions in the case-control population (0.02 < or = P < or = 0.03). Significant haplotype associations supported the results of single SNP analyses. Thus, polymorphisms in the TRPV4 gene are associated with COPD.

Feasibility to apply eucapnic voluntary hyperventilation in young elite athletes.

PubMed

Van der Eycken, S; Schelpe, A; Marijsse, G; Dilissen, E; Troosters, T; Vanbelle, V; Aertgeerts, S; Dupont, L J; Peers, K; Bullens, D M; Seys, S F

2016-02-01

Exercise-induced bronchoconstriction (EIB) is more common in athletes compared to the general population. The eucapnic voluntary hyperventilation test is used to detect EIB in adult athletes. It is however unclear whether this technique is also applicable to young athletes. Young athletes (basketball (n = 13), football (n = 19), swimming (n = 12)) were recruited at the start of their elite sports career (12-14 years). Eight age-matched controls were also recruited. Eucapnic voluntary hyperventilation test was performed according to ATS guidelines in all subjects. A second (after 1 year, n = 32) and third (after 2 years, n = 39) measurement was performed in a subgroup of athletes and controls. At time of first evaluation, 3/13 basketball players, 4/19 football players, 5/11 swimmers and 1/8 controls met criteria for EIB (fall in FEV1≥10% after EVH). A ventilation rate of >85% of the maximal voluntary ventilation (MVV) is recommended by current guidelines (for adults) but was only achieved by a low number of individuals (first occasion: 27%, third occasion: 45%) However, MVV in young athletes corresponds to 30 times FEV1, which is equivalent to 85% of MVV in adults. A threshold of 70% of MVV (21 times FEV1) is feasible in the majority of young athletes. EIB is present in a substantial number of individuals at the age of 12-14 years, especially in swimmers. This underscores the importance of screening for EIB at this age. EVH is feasible in young elite athletes, however target ventilation needs to be adjusted accordingly. Copyright © 2016 Elsevier Ltd. All rights reserved.

Upregulation of Mas-related G Protein coupled receptor X2 in asthmatic lung mast cells and its activation by the novel neuropeptide hemokinin-1.

PubMed

Manorak, Wichayapha; Idahosa, Chizobam; Gupta, Kshitij; Roy, Saptarshi; Panettieri, Reynold; Ali, Hydar

2018-01-03

Hemokinin-1 (HK-1) is a novel neuropeptide produced by human bronchial cells and macrophages and causes contraction of human bronchi ex vivo. It is also generated by antigen/IgE-activated murine mast cells (MCs) and contributes to experimental chronic allergic airway inflammation via the activation of the neurokinin receptor-1 (NK-1R) expressed on murine MCs. We found elevated MC numbers in the lungs of individuals who died from asthma (asthma) when compared to lungs of individuals who died from other causes (non-asthma). Mas-related G Protein coupled receptor X2 (MRGPRX2) is a novel G-protein coupled receptor (GPCR) that is expressed predominantly on human MCs. We detected low level of MRGPRX2 in non-asthma lung MCs but its expression was significantly upregulated in asthma lung MCs. HK-1 caused degranulation in a human MC line (LAD2) and RBL-2H3 cells stably expressing MRGPRX2 and this response was resistant to inhibition by an NK-1R antagonist. However, knockdown of MRGPRX2 in LAD2 cells resulted in substantial inhibition of HK-1-induced degranulation. These findings suggest that while HK-1 contributes to the development of experimental asthma in mice via NK-1R on murine MCs the effect of this neuropeptide on human bronchoconstriction likely reflects the activation of MRGPRX2 on lung MCs. Thus, development of selective MRGPRX2 antagonists could serve as novel target for the modulation of asthma.

Leukotriene E4 induces airflow obstruction and mast cell activation through the cysteinyl leukotriene type 1 receptor.

PubMed

Lazarinis, Nikolaos; Bood, Johan; Gomez, Cristina; Kolmert, Johan; Lantz, Ann-Sofie; Gyllfors, Pär; Davis, Andy; Wheelock, Craig E; Dahlén, Sven-Erik; Dahlén, Barbro

2018-03-05

Leukotriene (LT) E 4 is the final active metabolite among the cysteinyl leukotrienes (CysLTs). Animal studies have identified a distinct LTE 4 receptor, suggesting that current cysteinyl leukotriene type 1 (CysLT 1 ) receptor antagonists can provide incomplete inhibition of CysLT responses. We tested this hypothesis by assessing the influence of the CysLT 1 antagonist montelukast on responses induced by means of inhalation of LTE 4 in asthmatic patients. Fourteen patients with mild intermittent asthma and 2 patients with aspirin-exacerbated respiratory disease received 20 mg of montelukast twice daily and placebo for 5 to 7 days in a randomized, double-blind, crossover study (NCT01841164). The PD 20 value was determined at the end of each treatment period based on an increasing dose challenge. Measurements included lipid mediators in urine and sputum cells 4 hours after LTE 4 challenge. Montelukast completely blocked LTE 4 -induced bronchoconstriction. Despite tolerating an at least 10 times higher dose of LTE 4 after montelukast, there was no difference in the percentage of eosinophils in sputum. Urinary excretion of all major lipid mediators increased after LTE 4 inhalation. Montelukast blocked release of the mast cell product prostaglandin (PG) D 2 , as well as release of PGF 2α and thromboxane (Tx) A 2 , but not increased excretion of PGE 2 and its metabolites or isoprostanes. LTE 4 induces airflow obstruction and mast cell activation through the CysLT 1 receptor. Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Intracarotid substance P infusion inhibits ventilation in the goat.

PubMed

Pizarro, J; Ryan, M L; Hedrick, M S; Xue, D H; Keith, I M; Bisgard, G E

1995-07-01

Substance P (SP) has been proposed as an excitatory neuromodulator of the carotid body (CB) response to hypoxia based on data from the cat and rat. The role of SP as a CB neuromodulator in the goat is unknown. Awake (n = 14) and chloralose anesthetized goats (n = 6) were used to investigate the effects of intracarotid (IC) SP infusions (1-6 micrograms.kg-1.min-1) and bolus injections (6 micrograms kg-1) to the CB intact and denervated (CBX) sides (control) on mean ventilation (VE) and mean blood pressure (MBP). In awake goats VE was decreased by infusion or bolus SP injection at a dose of 6 micrograms.kg-1 (P < 0.05) and occurred with infusions to the intact or CBX sides. MBP was elevated with SP infusion to either the CB intact or CBX sides at all SP doses. The SP antagonist CP-96,345 (0.1 mg.kg-1, IV) blocked the decrease in VE induced by SP in normoxia and significantly increased the hypoxic ventilatory response (PaO2 = 40 torr). In anesthetized goats, IC injections of SP (1 to 6 micrograms.kg-1) reduced phrenic activity and MBP before and after CBX. In only one of five goats airway pressure was increased suggesting that bronchoconstriction was not a cause for the reduced ventilatory and phrenic activity induced by SP. Immunohistochemistry provided evidence of SP in CB nerve fibers and terminals, carotid sinus nerve axons and petrosal ganglion cells, but not in type I glomus cells. Our results do not support the view that SP is an excitatory neuromodulator of CB chemotransduction in the goat.

Ginger (Zingiber officinale) as an Analgesic and Ergogenic Aid in Sport: A Systemic Review.

PubMed

Wilson, Patrick B

2015-10-01

Ginger is a popular spice used to treat a variety of maladies, including pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used by athletes to manage and prevent pain; unfortunately, NSAIDs contribute to substantial adverse effects, including gastrointestinal (GI) dysfunction, exercise-induced bronchoconstriction, hyponatremia, impairment of connective tissue remodeling, endurance competition withdrawal, and cardiovascular disease. Ginger, however, may act as a promoter of GI integrity and as a bronchodilator. Given these potentially positive effects of ginger, a systematic review of randomized trials was performed to assess the evidence for ginger as an analgesic and ergogenic aid for exercise training and sport. Among 7 studies examining ginger as an analgesic, the evidence indicates that roughly 2 g·d(-1) of ginger may modestly reduce muscle pain stemming from eccentric resistance exercise and prolonged running, particularly if taken for a minimum of 5 days. Among 9 studies examining ginger as an ergogenic aid, no discernable effects on body composition, metabolic rate, oxygen consumption, isometric force generation, or perceived exertion were observed. Limited data suggest that ginger may accelerate recovery of maximal strength after eccentric resistance exercise and reduce the inflammatory response to cardiorespiratory exercise. Major limitations to the research include the use of untrained individuals, insufficient reporting on adverse events, and no direct comparisons with NSAID ingestion. While ginger taken over 1-2 weeks may reduce pain from eccentric resistance exercise and prolonged running, more research is needed to evaluate its safety and efficacy as an analgesic for a wide range of athletic endeavors.

Adverse reactions to foods.

PubMed

Ring, J; Brockow, K; Behrendt, H

2001-05-25

Allergic reactions to foods represent a prominent, actual and increasing problem in clinical medicine. Symptoms of food allergy comprise skin reactions (urticaria, angioedema, eczema) respiratory (bronchoconstriction, rhinitis), gastrointestinal (cramping, diarrhea) and cardiovascular symptoms with the maximal manifestation of anaphylactic shock. They can be elicited by minute amounts of allergens. The diagnosis of food allergy is done by history, skin test, in vitro allergy diagnosis and--if necessary--oral provocation tests, if possible placebo-controlled. Avoidance of respective allergens for the allergic patient, however, is often complicated or impossible due to deficits in declaration regulations in many countries. Increasing numbers of cases including fatalities, due to inadvertent intake of food allergens are reported. It is therefore necessary to improve declaration laws and develop methods for allergen detection in foods. Allergens can be detected by serological methods (enzyme immunoassays, in vitro basophil histamine release or in vivo skin test procedures in sensitized individuals). The problem of diagnosis of food allergy is further complicated by cross-reactivity between allergens in foods and aeroallergens (pollen, animal epithelia, latex etc.). Elicitors of pseudo-allergic reactions with similar clinical symptomatology comprise low-molecular-mass chemicals (preservatives, colorings, flavor substances etc.). For some of them (e.g. sulfites) detection assays are available. In some patients classic allergic contact eczema can be elicited systemically after oral intake of low-molecular-mass contact allergens such as nickel sulfate or flavorings such as vanillin in foods. The role of xenobiotic components in foods (e.g. pesticides) is not known at the moment. In order to improve the situation of the food allergic patient, research programs to elucidate the pathophysiology and improve allergen detection strategies have to be implemented together with reinforced declaration regulations on a quantitative basis.

Peri-adolescent asthma symptoms cause adult anxiety-related behavior and neurobiological processes in mice.

PubMed

Caulfield, Jasmine I; Caruso, Michael J; Michael, Kerry C; Bourne, Rebecca A; Chirichella, Nicole R; Klein, Laura C; Craig, Timothy; Bonneau, Robert H; August, Avery; Cavigelli, Sonia A

2017-05-30

Human and animal studies have shown that physical challenges and stressors during adolescence can have significant influences on behavioral and neurobiological development associated with internalizing disorders such as anxiety and depression. Given the prevalence of asthma during adolescence and increased rates of internalizing disorders in humans with asthma, we used a mouse model to test if and which symptoms of adolescent allergic asthma (airway inflammation or labored breathing) cause adult anxiety- and depression-related behavior and brain function. To mimic symptoms of allergic asthma in young BALB/cJ mice (postnatal days [P] 7-57; N=98), we induced lung inflammation with repeated intranasal administration of house dust mite extract (most common aeroallergen for humans) and bronchoconstriction with aerosolized methacholine (non-selective muscarinic receptor agonist). Three experimental groups, in addition to a control group, included: (1) "Airway inflammation only", allergen exposure 3 times/week, (2) "Labored breathing only", methacholine exposure once/week, and (3) "Airway inflammation+Labored breathing", allergen and methacholine exposure. Compared to controls, mice that experienced methacholine-induced labored breathing during adolescence displayed a ∼20% decrease in time on open arms of the elevated plus maze in early adulthood (P60), a ∼30% decrease in brainstem serotonin transporter (SERT) mRNA expression and a ∼50% increase in hippocampal serotonin receptor 1a (5Htr1a) and corticotropin releasing hormone receptor 1 (Crhr1) expression in adulthood (P75). This is the first evidence that experimentally-induced clinical symptoms of adolescent asthma alter adult anxiety-related behavior and brain function several weeks after completion of asthma manipulations. Copyright © 2017 Elsevier B.V. All rights reserved.

Responsiveness to montelukast is associated with bronchial hyperresponsiveness and total immunoglobulin E but not polymorphisms in the leukotriene C4 synthase and cysteinyl leukotriene receptor 1 genes in Korean children with exercise-induced asthma (EIA).

PubMed

Lee, S-Y; Kim, H-B; Kim, J-H; Kim, B-S; Kang, M-J; Jang, S-O; Seo, H-J; Hong, S-J

2007-10-01

As previous studies have shown that cysteinyl leukotrienes are important mediators in exercise-induced bronchoconstriction (EIB), and leukotriene receptor antagonists (LTRAs) such as montelukast have been shown to improve post-exercise bronchoconstrictor responses, we herein investigated whether clinical responsiveness to montelukast was associated with polymorphisms in the genes encoding leukotriene C4 synthase (LTC4S) and cysteinyl leukotriene receptor 1 (CysLTR1) and/or clinical parameters in Korean asthmatic children with EIB. The study population consisted of 100 asthmatic children with EIB. The individuals studied were given exercise challenge tests before and after receiving montelukast (5 mg/day) for 8 weeks. Responders were defined as children showing>10% post-treatment improvement in forced expiratory volume in 1 s (FEV1). The LTC4S A(-444)C and CysLTR1 T(+927)C polymorphisms were genotyped by PCR-restriction fragment length polymorphism analysis. Of 100 enrolled children, 68 were classified as responders and 32 were classified as non-responders. No significant association was observed between montelukast responsiveness and LTC4S or CysLTR1 genotype, either alone or in combination. In contrast, montelukast-induced improvement in FEV(1) after exercise was correlated with higher pre-treatment PC20 (methacholine) values (r=0.210, P=0.036) and lower total IgE levels (r=-0.216, P=0.031). The LTC4S A(-444)C and CysLTR1 T(+927)C genotypes do not appear to be useful for predicting clinical responsiveness to montelukast, whereas bronchial hyperresponsiveness and total IgE appear to predict the degree of montelukast responsiveness in Korean asthmatic children with EIB.

Evaluation of Trigeminal Sensitivity to Ammonia in Asthmatics and Healthy Human Volunteers

PubMed Central

Petrova, Maja; Diamond, Jeanmarie; Schuster, Benno; Dalton, Pamela

2009-01-01

Background Asthmatics often report the triggering or exacerbation of respiratory symptoms following exposure to airborne irritants, which in some cases may result from stimulation of irritant receptors in the upper airways inducing reflexive broncho-constriction. Ammonia (NH3) is a common constituent of commercially available household products, and in high concentration has the potential to elicit sensory irritation in the eyes and upper respiratory tract of humans. The goal of the present study was to evaluate the irritation potential of ammonia in asthmatics and healthy volunteers and to determine whether differences in nasal or ocular irritant sensitivity to ammonia between these two groups could account for the exacerbation of symptoms reported by asthmatics following exposure to an irritant. Methods 25 healthy and 15 mild/moderate persistent asthmatic volunteers, with reported sensitivity to household cleaning products, were evaluated for their sensitivity to the ocular and nasal irritancy of NH3. Lung function was evaluated at baseline and multiple time points following exposure. Results Irritation thresholds did not differ between asthmatics and healthy controls, nor did ratings of odor intensity, annoyance and irritancy following exposure to NH3 concentrations at and above the irritant threshold for longer periods of time (30 sec).Importantly, no changes in lung function occurred following exposure to NH3 for any individuals in either group. Conclusion Despite heightened symptom reports to environmental irritants among asthmatics, the ocular and nasal trigeminal system of mild-moderate asthmatics does not appear to be more sensitive or more reactive than that of non-asthmatics, nor does short duration exposure to ammonia at irritant levels induce changes in lung function. At least in brief exposures, the basis for some asthmatics to experience adverse responses to volatile compounds in everyday life may arise from factors other than trigeminally-mediated reflexes. PMID:18728993

Modifications in forced vital capacity during adenosine monophosphate-induced bronchoconstriction in asthma: relationship with the response to methacholine and the effect of inhaled corticosteroids.

PubMed

Prieto, Luis; López, Victoria; Catalan, Pablo; Barato, Desiree; Marín, Julio

2009-05-01

The effect of adenosine monophosphate (AMP) on forced vital capacity (FVC) has never been systematically investigated. To compare methacholine- and AMP-induced changes in FVC, as a marker of air trapping, in asthmatic patients treated and not treated with inhaled corticosteroids (ICSs). Airway responsiveness to equipotent concentrations of AMP and methacholine was obtained in asthmatic patients treated (n = 32) and not treated (n = 18) with ICSs. The response was expressed by the provocation concentration of agonist that caused a decrease in forced expiratory volume in 1 second (FEV1) of 20% (PC20) and by the slope of the FVC values recorded at each step of the challenge against the corresponding FEV1 values (sFVC). Although methacholine and AMP PC20 values were similar in patients treated and not treated with ICSs, the mean (95% confidence interval) methacholine sFVC (but not AMP sFVC) was higher in those treated with ICSs (0.91; 0.77-1.06) than in those not taking ICSs (0.69; 0.57-0.81; P = .03). No significant correlation was found between sFVC and PC20 values obtained with either methacholine or AMP. Methacholine and AMP sFVC values were significantly related, but only in the group treated with ICSs (r = 0.60, P < .001). Although the AMP-induced decline in FVC in asthmatic patients is similar to that observed with equipotent concentrations of methacholine, the apparently different effect of ICSs on changes in FVC induced by each agonist suggests that the information provided by the 2 bronchoconstrictor agents is not interchangeable and that the information generated by the analysis of the effect of each agonist on FEV1 and FVC may be complementary.

Antagonist profile of ibodutant at the tachykinin NK2 receptor in guinea pig isolated bronchi.

PubMed

Santicioli, Paolo; Meini, Stefania; Giuliani, Sandro; Lecci, Alessandro; Maggi, Carlo Alberto

2013-10-24

In this study we have characterized the pharmacological profile of the non-peptide tachykinin NK 2 receptor antagonist ibodutant (MEN15596) in guinea pig isolated main bronchi contractility. The antagonist potency of ibodutant was evaluated using the selective NK 2 receptor agonist [βAla 8 ]NKA(4-10)-mediated contractions of guinea pig isolated main bronchi. In this assay ibodutant (30, 100 and 300nM) induced a concentration-dependent rightward shift of the [βAla 8 ]NKA(4-10) concentration-response curves without affecting the maximal contractile effect. The analysis of the results yielded a Schild-plot linear regression with a slope not different from unity (0.95, 95% c.l. 0.65-1.25), thus indicating a surmountable behaviour. The calculated apparent antagonist potency as pK B value was 8.31±0.05. Ibodutant (0.3-100nM), produced a concentration-dependent inhibition of the nonadrenergic-noncholinergic (NANC) contractile response induced by electrical field stimulation (EFS) of intrinsic airway nerves in guinea pig isolated main bronchi. At the highest concentration tested (100nM) ibodutant almost abolished the EFS-induced bronchoconstriction (95±4% inhibition), the calculated IC 50 value was 2.98nM (95% c.l. 1.73-5.16nM). In bronchi from ovalbumin (OVA) sensitized guinea pigs ibodutant (100nM) did not affect the maximal contractile response to OVA, but completely prevented the slowing in the fading of the motor response induced by phosphoramidon pretreatment linked to the endogenous neurokinin A release. Altogether, the present study demonstrate that ibodutant is a potent NK 2 receptor antagonist in guinea pig airways. © 2013 Published by Elsevier B.V.

Volcanic ash and respiratory symptoms in children on the island of Montserrat, British West Indies

PubMed Central

Forbes, L; Jarvis, D; Potts, J; Baxter, P

2003-01-01

Background: In July 1995 the volcano on the West Indian island of Montserrat erupted after being inactive for several hundred years. Since then, clouds of ash have been released intermittently from the volcano. Some of this ash is <10 µm in diameter and therefore respirable. Concerns were raised that the particles might cause respiratory problems. Aims: To evaluate whether ashfalls had any effect on the respiratory health of children in Montserrat. Methods: A survey of asthma diagnoses, respiratory symptoms, exercise induced bronchoconstriction (EIB), and current and previous exposure to volcanic ash was carried out in schools in Montserrat during February 1998. Results: Questionnaire information was available for nearly 80% of the 443 children on the school rolls. The prevalence of wheeze symptoms in the previous 12 months was 18% in children aged 12 years and under and 16% in children aged 13 years and over. In children aged 12 and under, the prevalence of wheeze was greater in those who had ever been heavily or moderately exposed to volcanic ash compared with the group who had only ever been exposed to low levels (wheeze in last 12 months: odds ratio (OR) 4.30; wheeze ever: OR 3.45). The prevalence of EIB in 8–12 year olds was about four times higher in those who were currently heavily exposed to volcanic ash (OR 3.85) compared to those currently exposed to low levels. Conclusions: Volcanic ash emissions adversely affected the respiratory health of Montserrat children. The findings emphasise the need to limit exposures of children to volcanic ash and ensure the appropriate management of respiratory symptoms. PMID:12598669

Study of pH Stability of R-Salbutamol Sulfate Aerosol Solution and Its Antiasthmatic Effects in Guinea Pigs.

PubMed

Liu, Qing; Li, Qingrui; Han, Ting; Hu, Tingting; Zhang, Xuemei; Hu, Junhua; Hu, Hui; Tan, Wen

2017-09-01

Currently, all commercial available nebulized salbutamol in China is in its racemic form. It is known that only R-salbutamol (eutomer) has therapeutic effects, while S-salbutamol (distomer) may exacerbate asthma after chronic use. Therefore, it is an unmet clinical need to develop R-salbutamol as a nebulized product that is more convenient for young and old patients. In our study, a stable aerosol solution of R-salbutamol sulfate was established, and its antiasthmatic effects were confirmed. The decomposition rate and racemization effect of the R-salbutamol sulfate solution were evaluated over a pH range from 1 to 10 (except pH=7, 8) at 60°C. The aerodynamic particle size of the R-salbutamol sulfate solution and commercial RS-salbutamol sulfate solution were both tested in vitro by Next-Generation Impactor (NGI) in 5°C. Laser diffractometer was used to characterize the droplet-size distribution (DSD) of both solutions. We next conducted an in vivo animal study to document the antiasthmatic effect of R-salbutamol aerosol sulfate solution and determine the relationship to RS-salbutamol. The results showed that the R-salbutamol sulfate solution was more stable at pH 6. In vitro comparison studies indicated that there was no distribution difference between R-salbutamol sulfate solution and the commercial RS-salbutamol solution. The animal results showed that R-salbutamol was more potent than RS-salbutamol against the same dose of histamine challenge. Unlike commercial RS-salbutamol, which was acidified to a pH of 3.5 to extend bench life but may cause bronchoconstriction in asthmatic patients, the neutralized R-salbutamol solution was more suitable for clinic use.

Effect of a 5-lipoxygenase inhibitor and leukotriene antagonist (PF 5901) on antigen-induced airway responses in neonatally immunized rabbits.

PubMed Central

Herd, C. M.; Donigi-Gale, D.; Shoupe, T. S.; Burroughs, D. A.; Yeadon, M.; Page, C. P.

1994-01-01

1. The effect of a single intratracheal dose (10 mg) of PF 5901 (2-[3(1-hydroxyhexyl) phenoxymethyl] quinoline hydrochloride, a specific inhibitor of the 5-lipoxygenase pathway of arachidonic acid metabolism and a leukotriene D4 antagonist) on airway changes induced in response to Alternaria tenuis aerosol challenge was assessed in adult rabbits neonatally immunized. Leukotriene generation was determined in vivo by measuring leukotriene B4 (LTB4) levels in bronchoalveolar lavage (BAL) fluid and ex vivo by measuring calcium ionophore-stimulated production of LTB4 in whole blood. 2. While PF 5901 (10 mg) had no significant effect on the acute bronchoconstriction induced by antigen, this dose was sufficient to inhibit significantly the increase in airway responsiveness to inhaled histamine 24 h following antigen challenge (P < 0.05). 3. Total leucocyte infiltration into the airways induced by antigen, as assessed by bronchoalveolar lavage, was significantly inhibited by pretreatment with PF 5901 (10 mg). However, the pulmonary infiltration of neutrophils and eosinophils induced by antigen was unaltered by prior treatment with PF 5901 (10 mg). 4. PF 5901 (10 mg) had no effect on ex vivo LTB4 synthesis in whole blood. However, the antigen-induced increase in LTB4 levels in BAL 24 h following challenge was significantly inhibited (P < 0.05). 5. We suggest from the results of the present study that the antigen-induced airway hyperresponsiveness to inhaled histamine in immunized rabbits is mediated, at least in part, by products of the 5-lipoxygenase metabolic pathway, and is not dependent on the extent of eosinophil or neutrophil influx into the airway lumen. PMID:8032653

Involvement of a phosphoramidon-sensitive endopeptidase in the processing of big endothelin-1 in the guinea-pig.

PubMed

Pons, F; Touvay, C; Lagente, V; Mencia-Huerta, J M; Braquet, P

1992-06-24

In anaesthetized and ventilated guinea-pigs, i.v. injection of 1 nmol/kg big endothelin-1 (big ET-1) did not evoke significant changes in pulmonary inflation pressure (PIP) and mean arterial blood pressure (MBP), whereas injection of the same dose of endothelin-1 (ET-1) induced marked and rapid bronchoconstrictor and pressor responses. Administered at the dose of 10 nmol/kg, big ET-1 provoked significant increases in PIP and MBP, which developed slowly and were long-lasting as compared to those evoked by ET-1. When big ET-1 was incubated for 45 min at 37 degrees C with alpha-chymotrypsin (2 mU/nmol) or pepsin (1 microgram/nmol) and then injected into guinea-pigs at the dose of 1 nmol/kg, marked bronchoconstrictor and pressor responses were observed, with kinetics similar to those noted after administration of the same dose of ET-1. The magnitude of the alpha-chymotrypsin- or pepsin-treated big ET-1 responses was similar to that induced by ET-1, incubated or not with the enzymes. Injected i.v. at the dose of 5 mg/kg, 5 min before the challenge, phosphoramidon almost totally inhibited the bronchoconstrictor and pressor responses induced by 10 nmol/kg big ET-1, whereas thiorphan (5 mg/kg) partially reduced the increase in PIP and exerted a minimal effect on the changes in MBP. Administered at the dose of 20 mg/kg per os, 1 h before i.v. administration of 10 nmol/kg big ET-1, enalapril maleate and captopril did not significantly alter the bronchoconstriction and the hypertensive response evoked by the peptide.(ABSTRACT TRUNCATED AT 250 WORDS)

Preexposure to ozone blocks the antigen-induced late asthmatic response of the canine peripheral airways

DOE Office of Scientific and Technical Information (OSTI.GOV)

Turner, C.R.; Kleeberger, S.R.; Spannhake, E.W.

1989-01-01

The influence of exposure of the airways to ozone on acute allergic responsiveness has been investigated in several species. Little is known, however, about the effect of this environmental pollutant on the late asthmatic response (LAR) in animals in which it is exhibited. The purpose of this study was to evaluate this effect in the canine peripheral airways and to assess the potential role of mast cells in modulating the effect. A series of experiments on seven mongrel dogs demonstrated that the numbers of mast cells at the base of the epithelial region of small subsegmental airways exposed to 1more » ppm ozone for 5 min were significantly (p less than .01) increased 3 h following exposure compared to air exposed or nonexposed control airways. In a second series of experiments performed on eight additional mongrel dogs with inherent sensitivity to Ascaris suum antigen, antigen aerosol was administered to the sublobar segment 3 h following ozone preexposure when mast cell numbers were presumed to be increased. These experiments were performed to determine whether ozone preexposure could enhance the late-phase response to antigen by virtue of acutely increasing the number of mast cells available to bind the antigen. Four of the eight dogs tested displayed a late-phase response to antigen following air-sham preexposure. In these four dogs, simultaneous ozone preexposure of a contralateral lobe completely blocked the late-phase response to antigen. These results indicate that the consequences of a single exposure to ozone persist beyond its effects on acute antigen-induced bronchoconstriction and extend to the complex processes involved with the late response. This attenuating effect of ozone is seen under conditions where mast-cell numbers in the airways are increased above baseline levels.« less

beta2-Agonist modulates epithelial gene expression involved in the T- and B-cell chemotaxis and induces airway sensitization in human isolated bronchi.

PubMed

Faisy, Christophe; Pinto, Francisco M; Blouquit-Laye, Sabine; Danel, Claire; Naline, Emmanuel; Buenestado, Amparo; Grassin Delyle, Stanislas; Burgel, Pierre-Régis; Chapelier, Alain; Advenier, Charles; Candenas, Maria-Luz; Devillier, Philippe

2010-02-01

Regular use of beta(2)-adrenoceptor agonists may enhance non-specific airway responsiveness and inflammation. In earlier experimental studies, we showed that prolonged in vitro fenoterol exposure induced airway sensitization via perturbed epithelial regulation of bronchoconstriction. The aim of the present work was to examine the involvement of inflammatory mediator genes and proinflammatory cells and to investigate the role of the bronchial epithelium in these untoward effects. Bronchial tissues were surgically removed from 17 ex-smokers. Bronchial rings and primary cultures of bronchial epithelial cells were incubated with 0.1microM fenoterol for 15h. Levels of mRNA-expression were analyzed using a real-time quantitative reverse transcription-polymerase chain reaction array. Bronchial rings were contracted with endothelin-1 and immune cell infiltration was assessed by immunohistochemistry. Compared to paired controls, fenoterol up-regulated the mRNAs of cytokines/proteins implicated in the recruitment of T and B cells or the activation and proliferation of bronchial epithelial cells (CCL20/MIP-3alpha, FOXA2, PPAR-gamma) in isolated bronchi and in cultured epithelial cells. Fenoterol exposure significantly enhanced CD8(+)-T and differentiated CD138(+)-B-cells infiltration into the bronchi, especially the subepithelial area. Increase in CD8 or CD138 labeling-intensity strongly correlated with rise in maximal contraction to endothelin-1 induced by fenoterol exposure. In summary, our results show that fenoterol modulates the T and B cells chemotaxis possibly via the epithelial chemokine secretion in isolated bronchi from ex-smokers. They also suggest that the infiltration of resident T and B cells into the subepithelial area is associated with an increase in airway responsiveness due to fenoterol exposure. Copyright 2009 Elsevier Ltd. All rights reserved.

Influence of menstrual cycle phase on pulmonary function in asthmatic athletes.

PubMed

Stanford, Kristin I; Mickleborough, Timothy D; Ray, Shahla; Lindley, Martin R; Koceja, David M; Stager, Joel M

2006-04-01

The main aim of this study was to investigate whether there is a relationship between menstrual cycle phase and exercise-induced bronchoconstriction (EIB) in female athletes with mild atopic asthma. Seven eumenorrheic subjects with regular 28-day menstrual cycles were exercised to volitional exhaustion on day 5 [mid-follicular (FOL)] and day 21 [mid-luteal (LUT)] of their menstrual cycle. Pulmonary function tests were conducted pre- and post-exercise. The maximal percentage decline in post-exercise forced expiratory volume in 1 s (FEV(1)) and forced expiratory flow from 25 to 75% of forced vital capacity (FEF(25-75%)) was significantly greater (P<0.05) on day 21 (mid-LUT phase) (-17.35+/-2.32 and -26.28+/-6.04%, respectively), when salivary progesterone concentration was highest, compared to day 5 (mid-FOL phase) (-12.81+/-3.35 and -17.23+/-8.20%, respectively), when salivary progesterone concentration was lowest. The deterioration in the severity of EIB during the mid-LUT phase was accompanied by worsening asthma symptoms and increased bronchodilator use. There was a negative correlation between the percent change in pre- to post-exercise FEV(1) and salivary progesterone concentration. However, no such correlation was found between salivary estradiol and the percentage change in pre- to post-exercise FEV(1). This study has shown for the first time that menstrual cycle phase is an important determinant of the severity of EIB in female athletes with mild atopic asthma. Female asthmatic athletes may need to adjust their training and competition schedules to their menstrual cycle and to consider the potential negative effects of the LUT phase of the menstrual cycle on exercise performance.

EFFECTS OF TITANIUM DIOXIDE NANOPARTICLE EXPOSURE ON NEUROIMMUNE RESPONSES IN RAT AIRWAYS

PubMed Central

Scuri, Mario; Chen, Bean T.; Castranova, Vincent; Reynolds, Jeffrey S.; Johnson, Victor J.; Samsell, Lennie; Walton, Cheryl; Piedimonte, Giovanni

2013-01-01

Exposure to ambient nanoparticles (defined as particulate matter [PM] having one dimension < 100 nm) is associated with increased risk of childhood and adult asthma. Nanomaterials feature a smaller aerodynamic diameter and a higher surface area per unit mass ratio compared to fine or coarse-sized particles, resulting in greater lung deposition efficiency and an increased potential for biological interaction. The neurotrophins nerve growth factor and brain-derived neurotrophic factor are key regulatory elements of neuronal development and responsiveness of airway sensory neurons. Changes in their expression are associated with bronchoconstriction, airway hyperresponsiveness, and airway inflammation. The neurogenic-mediated control of airway responses is a key pathophysiological mechanism of childhood asthma. However, the effects of nanoparticle exposure on neurotrophin-driven airway responses and their potential role as a predisposing factor for developing asthma have not been clearly elucidated. In this study, in vivo inhalation exposure to titanium dioxide nanoparticles (12 mg/m13; 5.6 h/d for 3 d) produced upregulation of lung neurotrophins in weanling (2-wk-old) and newborn (2-d-old) rats but not in adult (12-wk-old) animals compared to controls. This effect was associated with increased airway responsiveness and upregulation of growth-related oncogene/keratine-derived chemokine (GRO/KC; CXCL1, rat equivalent of human interleukin [IL]-8) in bronchoalveolar lavage fluid. These data show for the first time that exposure to nanoparticulate upregulates the expression of lung neurotrophins in an age-dependent fashion and that this effect is associated with airway hyperresponsiveness and inflammation. These results suggest the presence of a critical window of vulnerability in earlier stages of lung development, which may lead to a higher risk of developing asthma. PMID:20818535

Effect of a syringe aspiration technique versus a mechanical suction technique and use of N-butylscopolammonium bromide on the quantity and quality of bronchoalveolar lavage fluid samples obtained from horses with the summer pasture endophenotype of equine asthma.

PubMed

Bowser, Jacquelyn E; Costa, Lais R R; Rodil, Alba U; Lopp, Christine T; Johnson, Melanie E; Wills, Robert W; Swiderski, Cyprianna E

2018-03-01

OBJECTIVE To evaluate the effect of 2 bronchoalveolar lavage (BAL) sampling techniques and the use of N-butylscopolammonium bromide (NBB) on the quantity and quality of BAL fluid (BALF) samples obtained from horses with the summer pasture endophenotype of equine asthma. ANIMALS 8 horses with the summer pasture endophenotype of equine asthma. PROCEDURES BAL was performed bilaterally (right and left lung sites) with a flexible videoendoscope passed through the left or right nasal passage. During lavage of the first lung site, a BALF sample was collected by means of either gentle syringe aspiration or mechanical suction with a pressure-regulated wall-mounted suction pump. The endoscope was then maneuvered into the contralateral lung site, and lavage was performed with the alternate fluid retrieval technique. For each horse, BAL was performed bilaterally once with and once without premedication with NBB (21-day interval). The BALF samples retrieved were evaluated for volume, total cell count, differential cell count, RBC count, and total protein concentration. RESULTS Use of syringe aspiration significantly increased total BALF volume (mean volume increase, 40 mL [approx 7.5% yield]) and decreased total RBC count (mean decrease, 142 cells/μL), compared with use of mechanical suction. The BALF nucleated cell count and differential cell count did not differ between BAL procedures. Use of NBB had no effect on BALF retrieval. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that retrieval of BALF by syringe aspiration may increase yield and reduce barotrauma in horses at increased risk of bronchoconstriction and bronchiolar collapse. Further studies to determine the usefulness of NBB and other bronchodilators during BAL procedures in horses are warranted.

Initial Evaluation of the Effects of Aerosolized Florida Red Tide Toxins (Brevetoxins) in Persons with Asthma

PubMed Central

Fleming, Lora E.; Kirkpatrick, Barbara; Backer, Lorraine C.; Bean, Judy A.; Wanner, Adam; Dalpra, Dana; Tamer, Robert; Zaias, Julia; Cheng, Yung Sung; Pierce, Richard; Naar, Jerome; Abraham, William; Clark, Richard; Zhou, Yue; Henry, Michael S.; Johnson, David; Van De Bogart, Gayl; Bossart, Gregory D.; Harrington, Mark; Baden, Daniel G.

2005-01-01

Florida red tides annually occur in the Gulf of Mexico, resulting from blooms of the marine dinoflagellate Karenia brevis. K. brevis produces highly potent natural polyether toxins, known as brevetoxins, that activate voltage-sensitive sodium channels. In experimental animals, brevetoxins cause significant bronchoconstriction. A study of persons who visited the beach recreationally found a significant increase in self-reported respiratory symptoms after exposure to aerosolized Florida red tides. Anecdotal reports indicate that persons with underlying respiratory diseases may be particularly susceptible to adverse health effects from these aerosolized toxins. Fifty-nine persons with physician-diagnosed asthma were evaluated for 1 hr before and after going to the beach on days with and without Florida red tide. Study participants were evaluated with a brief symptom questionnaire, nose and throat swabs, and spirometry approved by the National Institute for Occupational Safety and Health. Environmental monitoring, water and air sampling (i.e., K. brevis, brevetoxins, and particulate size distribution), and personal monitoring (for toxins) were performed. Brevetoxin concentrations were measured by liquid chromatography mass spectrometry, high-performance liquid chromatography, and a newly developed brevetoxin enzyme-linked immunosorbent assay. Participants were significantly more likely to report respiratory symptoms after Florida red tide exposure. Participants demonstrated small but statistically significant decreases in forced expiratory volume in 1 sec, forced expiratory flow between 25 and 75%, and peak expiratory flow after exposure, particularly those regularly using asthma medications. Similar evaluation during nonexposure periods did not significantly differ. This is the first study to show objectively measurable adverse health effects from exposure to aerosolized Florida red tide toxins in persons with asthma. Future studies will examine the possible chronic effects of these toxins among persons with asthma and other chronic respiratory impairment. PMID:15866779

Bioequivalence of two formulations of montelukast sodium 4 mg oral granules in healthy adults

PubMed Central

2014-01-01

Montelukast is an effective and well-tolerated treatment for the prophylaxis and chronic treatment of asthma, acute prevention of exercise-induced bronchoconstriction and symptomatic relief of seasonal allergic rhinitis and perennial allergic rhinitis. The aim of the study was to compare bioavailability, and characterise the pharmacokinetic profile and safety of Sandoz generic montelukast 4 mg oral granules relative to Singulair® mini (Merck, Sharp & Dohme). An open-label, randomised, single-dose, two-treatment, two-period, two-sequence, two-way crossover bioequivalence study was conducted in healthy male volunteers aged 18–55 years, under fasting conditions. The duration of the clinical part of the trial was ≈ 11 days. Montelukast levels in plasma were quantified using a validated liquid chromatography tandem mass spectrometry method, and pharmacokinetic parameters calculated from the drug concentration–time profile using a non-compartmental model. A total of 40 subjects completed both study periods. The ratio test/reference of geometric least squares means was calculated for both formulations of montelukast for the In-transformed pharmacokinetic parameters; the 90% confidence intervals (CIs) were within the pre-defined limits of 80.00–125.00%: 92.2% (90% CI: 87.42–97.30%) for Cmax, 98.1% (90% CI: 94.49–101.81%) for AUC0–t and 97.6% (90% CI: 94.14–101.27%) for AUC0–∞. Two study subjects each reported one mild adverse event: dyspepsia (possibly related to study medication) and throat pain (not considered related to study medication). Sandoz montelukast 4 mg oral granules are bioequivalent to Singulair® 4 mg mini oral granules, with a similar safety profile. This suggests that these two preparations can be considered interchangeable in clinical practice. PMID:25250173

Spatial distribution of airway wall displacements during breathing and bronchoconstriction measured by ultrasound elastography using finite element image registration.

PubMed

Harvey, Brian C; Lutchen, Kenneth R; Barbone, Paul E

2017-03-01

With every breath, the airways within the lungs are strained. This periodic stretching is thought to play an important role in determining airway caliber in health and disease. Particularly, deep breaths can mitigate excessive airway narrowing in healthy subjects, but this beneficial effect is absent in asthmatics, perhaps due to an inability to stretch the airway smooth muscle (ASM) embedded within an airway wall. The heterogeneous composition throughout an airway wall likely modulates the strain felt by the ASM but the magnitude of ASM strain is difficult to measure directly. In this study, we optimized a finite element image registration method to measure the spatial distribution of displacements and strains throughout an airway wall during pressure inflation within the physiological breathing range before and after induced narrowing with acetylcholine (ACh). The method was shown to be repeatable, and displacements estimated from different image sequences of the same deformation agreed to within 5.3μm (0.77%). We found the magnitude and spatial distribution of displacements were radially and longitudinally heterogeneous. The region in the middle layer of the airway experienced the largest radial strain due to a transmural pressure (Ptm) increase simulating tidal breathing and a deep inspiration (DI), while the region containing the ASM (i.e., closest to the lumen) strained least. During induced narrowing with ACh, we observed temporal longitudinal heterogeneity of the airway wall. After constriction, the displacements and strain are much smaller than the relaxed airway and the pattern of strains changed, suggesting the airway stiffened heterogeneously. Copyright © 2016 Elsevier B.V. All rights reserved.

The relationship between wheezing and lung mechanics during methacholine-induced bronchoconstriction in asthmatic subjects.

PubMed

Spence, D P; Graham, D R; Jamieson, G; Cheetham, B M; Calverley, P M; Earis, J E

1996-08-01

Wheeze is a classic sign of airflow obstruction but relatively little is known of its mechanism of production or its relationship to the development of airflow obstruction. We studied eight asthmatic subjects age (mean +/- 5D) 42 +/- 5 yr, FEV1 2.46 +/- 0.36 L during an extended, symptom-limited methacholine challenge test. Breath sounds were detected by a microphone over the right upper anterior chest. Spectral analysis was by a fast Fourier transform algorithm. Mean FEV1 fell by 51 +/- 14% to 1.28 +/- 0.61 L during the challenge and airways resistance increased by 119 +/- 50%. There were no consistent changes in breathing pattern or tidal volume during the challenge. Wheeze occurred late in the challenge at the highest concentration of methacholine administered and only after expiratory tidal flow limitation had been reached. Five subjects developed wheeze on tidal breathing, the remaining three only wheezed on deep breathing. Wheezing sounds were reproducible between breaths, coefficient of variation of starting sound frequency was 4.2% and ending frequency 12%. Mean frequency of expiratory wheezes was 669 +/- 100 Hz and inspiratory wheezes 710 +/- 76 Hz. Expiratory wheeze fell in pitch during a breath (mean fall in sound frequency 187 +/- 43 Hz) but inspiratory wheezes were more variable. Expiratory wheezes occurred late in the respiratory cycle at a mean of 58% of the maximal tidal expiratory flow, whereas inspiratory wheezes occurred around maximal tidal inspiratory flows, suggesting that the mechanisms of production of inspiratory and expiratory wheezes may be different. In this model, the presence of wheeze during tidal breathing was a sign of severe airflow limitation.

Initial evaluation of the effects of aerosolized Florida red tide toxins (brevetoxins) in persons with asthma.

PubMed

Fleming, Lora E; Kirkpatrick, Barbara; Backer, Lorraine C; Bean, Judy A; Wanner, Adam; Dalpra, Dana; Tamer, Robert; Zaias, Julia; Cheng, Yung Sung; Pierce, Richard; Naar, Jerome; Abraham, William; Clark, Richard; Zhou, Yue; Henry, Michael S; Johnson, David; Van De Bogart, Gayl; Bossart, Gregory D; Harrington, Mark; Baden, Daniel G

2005-05-01

Florida red tides annually occur in the Gulf of Mexico, resulting from blooms of the marine dinoflagellate Karenia brevis. K. brevis produces highly potent natural polyether toxins, known as brevetoxins, that activate voltage-sensitive sodium channels. In experimental animals, brevetoxins cause significant bronchoconstriction. A study of persons who visited the beach recreationally found a significant increase in self-reported respiratory symptoms after exposure to aerosolized Florida red tides. Anecdotal reports indicate that persons with underlying respiratory diseases may be particularly susceptible to adverse health effects from these aerosolized toxins. Fifty-nine persons with physician-diagnosed asthma were evaluated for 1 hr before and after going to the beach on days with and without Florida red tide. Study participants were evaluated with a brief symptom questionnaire, nose and throat swabs, and spirometry approved by the National Institute for Occupational Safety and Health. Environmental monitoring, water and air sampling (i.e., K. brevis, brevetoxins, and particulate size distribution), and personal monitoring (for toxins) were performed. Brevetoxin concentrations were measured by liquid chromatography mass spectrometry, high-performance liquid chromatography, and a newly developed brevetoxin enzyme-linked immunosorbent assay. Participants were significantly more likely to report respiratory symptoms after Florida red tide exposure. Participants demonstrated small but statistically significant decreases in forced expiratory volume in 1 sec, forced expiratory flow between 25 and 75%, and peak expiratory flow after exposure, particularly those regularly using asthma medications. Similar evaluation during nonexposure periods did not significantly differ. This is the first study to show objectively measurable adverse health effects from exposure to aerosolized Florida red tide toxins in persons with asthma. Future studies will examine the possible chronic effects of these toxins among persons with asthma and other chronic respiratory impairment.

Activation of endogenous GABAA channels on airway smooth muscle potentiates isoproterenol-mediated relaxation.

PubMed

Gallos, George; Gleason, Neil R; Zhang, Yi; Pak, Sang-Woo; Sonett, J R; Yang, Jay; Emala, Charles W

2008-12-01

Reactive airway disease predisposes patients to episodes of acute smooth muscle mediated bronchoconstriction. We have for the first time recently demonstrated the expression and function of endogenous ionotropic GABA(A) channels on airway smooth muscle cells. We questioned whether endogenous GABA(A) channels on airway smooth muscle could augment beta-agonist-mediated relaxation. Guinea pig tracheal rings or human bronchial airway smooth muscles were equilibrated in organ baths with continuous digital tension recordings. After pretreatment with or without the selective GABA(A) antagonist gabazine (100 muM), airway muscle was contracted with acetylcholine or beta-ala neurokinin A, followed by relaxation induced by cumulatively increasing concentrations of isoproterenol (1 nM to 1 muM) in the absence or presence of the selective GABA(A) agonist muscimol (10-100 muM). In separate experiments, guinea pig tracheal rings were pretreated with the large conductance K(Ca) channel blocker iberiotoxin (100 nM) after an EC(50) contraction with acetylcholine but before cumulatively increasing concentrations of isoproterenol (1 nM to 1 uM) in the absence or presence of muscimol (100 uM). GABA(A) activation potentiated the relaxant effects of isoproterenol after an acetylcholine or tachykinin-induced contraction in guinea pig tracheal rings or an acetylcholine-induced contraction in human endobronchial smooth muscle. This muscimol-induced potentiation of relaxation was abolished by gabazine pretreatment but persisted after blockade of the maxi K(Ca) channel. Selective activation of endogenous GABA(A) receptors significantly augments beta-agonist-mediated relaxation of guinea pig and human airway smooth muscle, which may have important therapeutic implications for patients in severe bronchospasm.

Cooling-induced contraction in ovine airways smooth muscle.

PubMed

Mustafa, S M; Pilcher, C W; Williams, K I

1999-02-01

The mechanism of cold-induced bronchoconstriction is poorly understood. This prompted the present study whose aim was to determine the step-wise direct effect of cooling on smooth muscle of isolated ovine airways and analyse the role of calcium in the mechanisms involved. Isolated tracheal strips and bronchial segments were suspended in organ baths containing Krebs' solution for isometric tension recording. Tissue responses during stepwise cooling from 37 to 5 degrees C were examined. Cooling induced a rapid and reproducible contraction proportional to cooling temperature in ovine tracheal and bronchial preparations which was epithelium-independent. On readjustment to 37 degrees C the tone returned rapidly to basal level. Maximum contraction was achieved at a temperature of 5 degrees C for trachea and 15 degrees C for bronchiole. Cooling-induced contractions (CIC) was resistant to tetrodotoxin (1; 10 micrometer), and not affected by the muscarinic antagonist atropine (1 micrometer) or the alpha-adrenergic antagonist phentolamine (1 micrometer), or the histamine H1-antagonist mepyramine (1 micrometer) or indomethacin (1 micrometer). Ca2+ antagonists (nifedipine and verapamil) and Mn2+ raised tracheal but not bronchiolar tone and augmented CIC. Incubation in Ca2+-free, EGTA-containing Krebs' solution for 5 min had no effect on CIC, although it significantly reduced KCl-induced contraction by up to 75%. Cooling inhibited Ca2+ influx measured using 45Ca2+ uptake. Caffeine (100 micrometer) significantly inhibited CIC. The results show that cooling-induced contractions do not appear to involve activation of nerve endings, all surface reception systems or Ca2+ influx. However, CIC is mainly dependent on release of intracellular Ca2+. Copyright 1999 The Italian Pharmacological Society.

Neurokinin-neurotrophin interactions in airway smooth muscle

PubMed Central

Meuchel, Lucas W.; Stewart, Alecia; Smelter, Dan F.; Abcejo, Amard J.; Thompson, Michael A.; Zaidi, Syed I. A.; Martin, Richard J.

2011-01-01

Neurally derived tachykinins such as substance P (SP) play a key role in modulating airway contractility (especially with inflammation). Separately, the neurotrophin brain-derived neurotrophic factor (BDNF; potentially derived from nerves as well as airway smooth muscle; ASM) and its tropomyosin-related kinase receptor, TrkB, are involved in enhanced airway contractility. In this study, we hypothesized that neurokinins and neurotrophins are linked in enhancing intracellular Ca2+ concentration ([Ca2+]i) regulation in ASM. In rat ASM cells, 24 h exposure to 10 nM SP significantly increased BDNF and TrkB expression (P < 0.05). Furthermore, [Ca2+]i responses to 1 μM ACh as well as BDNF (30 min) effects on [Ca2+]i regulation were enhanced by prior SP exposure, largely via increased Ca2+ influx (P < 0.05). The enhancing effect of SP on BDNF signaling was blunted by the neurokinin-2 receptor antagonist MEN-10376 (1 μM, P < 0.05) to a greater extent than the neurokinin-1 receptor antagonist RP-67580 (5 nM). Chelation of extracellular BDNF (chimeric TrkB-Fc; 1 μg/ml), as well as tyrosine kinase inhibition (100 nM K252a), substantially blunted SP effects (P < 0.05). Overnight (24 h) exposure of ASM cells to 50% oxygen increased BDNF and TrkB expression and potentiated both SP- and BDNF-induced enhancement of [Ca2+]i (P < 0.05). These results suggest a novel interaction between SP and BDNF in regulating agonist-induced [Ca2+]i regulation in ASM. The autocrine mechanism we present here represents a new area in the development of bronchoconstrictive reflex response and airway hyperreactive disorders. PMID:21515660

Effects of vasoactive intestinal polypeptide on antigen-induced bronchoconstriction and thromboxane release in guinea-pig lung.

PubMed Central

Ciabattoni, G.; Montuschi, P.; Currò, D.; Togna, G.; Preziosi, P.

1993-01-01

1. Exogenous vasoactive intestinal polypeptide (VIP) infused into the pulmonary artery of isolated and ventilated lungs of guinea-pigs decreased, in a dose-dependent fashion (1.0-10.0 nmol), airway resistance and thromboxane B2 (TXB2, the stable hydrolysis product of TXA2) release in the perfusion medium. Prostacyclin (PGI2) synthesis, as reflected by the release of its stable hydrolysis product 6-oxo-PGF1 alpha, was unaffected. Pretreatment with the 5-lipoxygenase inhibitor BWA4c (3.5 x 10(-5) M) did not modify the bronchodilatory effect of VIP or its inhibitory action on TXB2 release. 2. Basal release of immunoreactive VIP from perfused lungs decreased from an initial value of 0.96 +/- 0.10 ng min-1 (mean +/- s.e.mean) in the first 2 min to an average of 0.58 +/- 0.10 ng min-1 in the following 15-20 min. 3. Antigen challenge with ovalbumin (0.1%) in sensitized lungs caused an anaphylactic reaction in 45% of tested lungs, concomitant with a 5 fold increase in both VIP and TXB2 release. Tetrodotoxin pretreatment (10(-6) M) reduced basal VIP release by > 80% and abolished the VIP increase observed during anaphylaxis, without modifying TXB2 release or the bronchoconstrictor response. 4. Indomethacin (10(-6) M) inhibited TXB2 synthesis and release by > 90%, delayed the bronchoconstrictor response and blunted the increased VIP release during lung anaphylaxis, without influencing basal VIP release. 5. The 5-lipoxygenase inhibitor BWA4c (3.5 x 10(-5) M) blunted the increase of TXB2 and VIP release from guinea-pig lung and attenuated the bronchoconstrictor response following ovalbumin challenge.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8495242

Athletes Do Not Condition Inspired Air More Effectively than Nonathletes during Hyperpnea.

PubMed

Boulet, Louis-Philippe; Moreau, Simon-Pierre; Villeneuve, HÉlÈNE; Turmel, Julie

2017-01-01

Endurance athletes have a high prevalence of airway diseases, some possibly representing adaptive mechanisms to the need of conditioning large volumes of inspired air during high ventilation in specific environments. The aim of this study is to assess the ability to condition (warm and humidify) inspired air in athletes by measuring the difference between inhaled and exhaled air temperature (ΔT) during and after eucapnic voluntary hyperpnea (EVH) test. Twenty-three endurance athletes from various sports, 12 with airway hyperresponsiveness (AHR) and/or exercise-induced bronchoconstriction (EIB) (A+), 11 without AHR and/or EIB (A-), 12 nonathletes with AHR and/or EIB (C+), and 11 nonathletes without AHR and/or EIB (C-) were recruited. All subjects attended the laboratory on three occasions, twice for baseline characterization, including questionnaires, pulmonary function, methacholine bronchoprovocation, allergy skin prick tests, exhaled nitric oxide measurement, and a standard EVH, and once to perform a modified EVH to assess ΔT. Inspired and expired air temperatures were measured with a high-precision probe during EVH and at regular intervals until 30 min after the end of the test. The global ΔT during the EVH was +5.8°C ± 1.5°C and +4.7°C ± 1.5°C during the 30 min after the EVH. No difference was found between groups for either the ΔT or the slope of ΔT, during and after the EVH. This study shows no evidence of improved capacity to condition inspired air in endurance athletes, which could have suggested an increased bronchial blood flow or another adaptive mechanism. The absence of an adaptive mechanism could therefore contribute to airway damage observed in athletes in allowing colder but mainly dryer air to penetrate deeper in the lung.

A Multi-Scale Approach to Airway Hyperresponsiveness: From Molecule to Organ

PubMed Central

Lauzon, Anne-Marie; Bates, Jason H. T.; Donovan, Graham; Tawhai, Merryn; Sneyd, James; Sanderson, Michael J.

2012-01-01

Airway hyperresponsiveness (AHR), a characteristic of asthma that involves an excessive reduction in airway caliber, is a complex mechanism reflecting multiple processes that manifest over a large range of length and time scales. At one extreme, molecular interactions determine the force generated by airway smooth muscle (ASM). At the other, the spatially distributed constriction of the branching airways leads to breathing difficulties. Similarly, asthma therapies act at the molecular scale while clinical outcomes are determined by lung function. These extremes are linked by events operating over intermediate scales of length and time. Thus, AHR is an emergent phenomenon that limits our understanding of asthma and confounds the interpretation of studies that address physiological mechanisms over a limited range of scales. A solution is a modular computational model that integrates experimental and mathematical data from multiple scales. This includes, at the molecular scale, kinetics, and force production of actin-myosin contractile proteins during cross-bridge and latch-state cycling; at the cellular scale, Ca2+ signaling mechanisms that regulate ASM force production; at the tissue scale, forces acting between contracting ASM and opposing viscoelastic tissue that determine airway narrowing; at the organ scale, the topographic distribution of ASM contraction dynamics that determine mechanical impedance of the lung. At each scale, models are constructed with iterations between theory and experimentation to identify the parameters that link adjacent scales. This modular model establishes algorithms for modeling over a wide range of scales and provides a framework for the inclusion of other responses such as inflammation or therapeutic regimes. The goal is to develop this lung model so that it can make predictions about bronchoconstriction and identify the pathophysiologic mechanisms having the greatest impact on AHR and its therapy. PMID:22701430

Characterization of the tachykinin NK2 receptor in the human bronchus: influence of amastatin-sensitive metabolic pathways.

PubMed Central

Astolfi, M.; Treggiari, S.; Giachetti, A.; Meini, S.; Maggi, C. A.; Manzini, S.

1994-01-01

1. The aim of this study was to characterize the tachykinin NK2 receptor subtype mediating the spasmogenic response in the human isolated bronchus. The motor response to neurokinin A (NKA) and the selective NK2 agonist [beta Ala8]NKA(4-10), as well as the antagonistic effects of cyclic (L659,877) and linear (MEN 10376) peptide NK2 antagonists were assessed in the presence or absence of amastatin (an inhibitor of aminopeptidases A and M). 2. NKA was more potent than [beta Ala8]NKA(4-10) in eliciting bronchoconstriction (pD2 being 7,43 and 6,87 respectively). In the presence of amastatin (1 microM), the estimated affinity of [beta Ala8]NKA(4-10), but not that of NKA, was significantly increased to yield a pD2 of 7,44. 3. L659,877 and MEN 10376 inhibited [beta Ala8]NKA(4-10)-induced contraction with similar affinities; pA2 values were 5.7 +/- 0.22 and 6.3 +/- 0.32, respectively. Amastatin (1 microM) increased the potency of MEN 10376 to 7.28 +/- 0.46, whereas that of L659,877 was unaffected. 4. In the presence of amastatin the pseudopeptide MDL 28,564 behaved as a partial agonist. 5. We conclude that the NK2 receptor subtype present in the human bronchus has properties similar to those described for the circular muscle of the human colon and thus may be classified as a 'NK2A' subtype. We show that the apparent potency of peptides, bearing N-terminal acidic residues, is influenced by an amastatin-sensitive peptidase, possibly aminopeptidase A. PMID:8004400

Characterization of the tachykinin NK2 receptor in the human bronchus: influence of amastatin-sensitive metabolic pathways.

PubMed

Astolfi, M; Treggiari, S; Giachetti, A; Meini, S; Maggi, C A; Manzini, S

1994-02-01

1. The aim of this study was to characterize the tachykinin NK2 receptor subtype mediating the spasmogenic response in the human isolated bronchus. The motor response to neurokinin A (NKA) and the selective NK2 agonist [beta Ala8]NKA(4-10), as well as the antagonistic effects of cyclic (L659,877) and linear (MEN 10376) peptide NK2 antagonists were assessed in the presence or absence of amastatin (an inhibitor of aminopeptidases A and M). 2. NKA was more potent than [beta Ala8]NKA(4-10) in eliciting bronchoconstriction (pD2 being 7,43 and 6,87 respectively). In the presence of amastatin (1 microM), the estimated affinity of [beta Ala8]NKA(4-10), but not that of NKA, was significantly increased to yield a pD2 of 7,44. 3. L659,877 and MEN 10376 inhibited [beta Ala8]NKA(4-10)-induced contraction with similar affinities; pA2 values were 5.7 +/- 0.22 and 6.3 +/- 0.32, respectively. Amastatin (1 microM) increased the potency of MEN 10376 to 7.28 +/- 0.46, whereas that of L659,877 was unaffected. 4. In the presence of amastatin the pseudopeptide MDL 28,564 behaved as a partial agonist. 5. We conclude that the NK2 receptor subtype present in the human bronchus has properties similar to those described for the circular muscle of the human colon and thus may be classified as a 'NK2A' subtype. We show that the apparent potency of peptides, bearing N-terminal acidic residues, is influenced by an amastatin-sensitive peptidase, possibly aminopeptidase A.

Neutral endopeptidase activity and airway hyperresponsiveness to neurokinin A in asthmatic subjects in vivo.

PubMed

Cheung, D; Timmers, M C; Zwinderman, A H; den Hartigh, J; Dijkman, J H; Sterk, P J

1993-12-01

In a previous study we have shown that inhibition of the endogenous neuropeptide-degrading enzyme, neutral endopeptidase (NEP), potentiates airway narrowing to neurokinin A (NKA) in normal humans in vivo. In the present study, we tested the hypothesis that hyperresponsiveness to NKA in asthma is caused by a reduction in endogenous NEP activity. To that end, we used the NEP inhibitor, thiorphan, or placebo as inhaled pretreatment to NKA challenge in eight atopic asthmatic men, who were controlled by on-demand usage of beta 2-agonists alone. The dose of thiorphan pretreatment was obtained from pilot experiments in which 0.5 ml of a 2.5-mg/ml concentration appeared to be the maximally effective nebulized dose. Dose-response curves to inhaled NKA (1 to 125 micrograms/ml, 0.5 ml/dose) were recorded on 2 randomized days 1 wk apart, in a cross-over study. To detect any effects of thiorphan on bronchoconstriction per se, we also investigated the effect of thiorphan or placebo on the dose-response curve to inhaled methacholine in a separate set of experiments. The response was measured by FEV1 and by partial expiratory flow-volume curves (V40p). The position of the dose-response curves was expressed as the concentration causing a 20% fall in FEV1 (PC20FEV1) or a 40% fall in V40p (PC40V40p). Baseline FEV1 and V40p were not affected by either pretreatment (p > 0.06). PC20FEV1 and PC40V40p to NKA were significantly lower after thiorphan pretreatment as compared with placebo (mean difference +/- SEM: 2.3 +/- 0.6 and 1.6 +/- 0.5 doubling dose, respectively; p < 0.015).(ABSTRACT TRUNCATED AT 250 WORDS)

Recovery benefits of using a heat and moisture exchange mask during sprint exercise in cold temperatures.

PubMed

Seifert, John G; Frost, Jeremy; St Cyr, John A

2017-01-01

Breathing cold air can lead to bronchoconstriction and peripheral vasoconstriction, both of which could impact muscular performance by affecting metabolic demands during exercise. Successful solutions dealing with these physiological changes during exercise in the cold has been lacking; therefore, we investigated the influence of a heat and moisture exchange mask during exercise in the cold. There were three trial arms within this study: wearing the heat and moisture exchange mask during the rest periods in the cold, no-mask application during the rest periods in the cold, and a trial at room temperature (22°C). Eight subjects cycled in four 35 kJ sprint sessions with each session separated by 20 min rest period. Workload was 4% of body mass. Mean sprint times were faster with heat and moisture exchange mask and room temperature trial than cold, no-mask trial (133.8 ± 8.6, 134.9 ± 8.8, and 138.0 ± 8.4 s (p = 0.001)). Systolic blood pressure and mean arterial pressure were greater during the cold trial with no mask (15% and 13%, respectively), and heart rate was 10 bpm less during the third rest or recovery period during cold, no mask compared to the heat and moisture exchange mask and room temperature trials. Subjects demonstrated significant decreases in vital capacity and peak expiratory flow rate during the cold with no mask applied during the rest periods. These negative responses to cold exposure were alleviated by the use of a heat and moisture exchange mask worn during the rest intervals by minimizing cold-induced temperature stress on the respiratory system with subsequent maintenance of cardiovascular function.

No effect of elevated operating lung volumes on airway function during variable workrate exercise in asthmatic humans.

PubMed

Klansky, Andrew; Irvin, Charlie; Morrison-Taylor, Adriane; Ahlstrand, Sarah; Labrie, Danielle; Haverkamp, Hans Christian

2016-07-01

In asthmatic adults, airway caliber fluctuates during variable intensity exercise such that bronchodilation (BD) occurs with increased workrate whereas bronchoconstriction (BC) occurs with decreased workrate. We hypothesized that increased lung mechanical stretch would prevent BC during such variable workrate exercise. Ten asthmatic and ten nonasthmatic subjects completed two exercise trials on a cycle ergometer. Both trials included a 28-min exercise bout consisting of alternating four min periods at workloads equal to 40 % (Low) and 70% (High) peak power output. During one trial, subjects breathed spontaneously throughout exercise (SVT), such that tidal volume (VT) and end-inspiratory lung volume (EILV) were increased by 0.5 and 0.6 liters during the high compared with the low workload in nonasthmatic and asthmatic subjects, respectively. During the second trial (MVT), VT and EILV were maintained constant when transitioning from the high to the low workload. Forced exhalations from total lung capacity were performed during each exercise workload. In asthmatic subjects, forced expiratory volume 1.0 s (FEV1.0) increased and decreased with the increases and decreases in workrate during both SVT (Low, 3.3 ± 0.3 liters; High, 3.6 ± 0.2 liters; P < 0.05) and MVT (Low, 3.3 ± 0.3 liters; High, 3.5 ± 0.2 liters; P < 0.05). Thus increased lung stretch during MVT did not prevent decreases in airway caliber when workload was reduced. We conclude that neural factors controlling airway smooth muscle (ASM) contractile activity during whole body exercise are more robust determinants of airway caliber than the ability of lung stretch to alter ASM actin-myosin binding and contraction. Copyright © 2016 the American Physiological Society.

Downregulation of the cough reflex by aclidinium and tiotropium in awake and anesthetized rabbits.

PubMed

Mutolo, Donatella; Cinelli, Elenia; Iovino, Ludovica; Pantaleo, Tito; Bongianni, Fulvia

2016-06-01

Long-acting muscarinic receptor antagonists (LAMAs) have been reported to attenuate cough in preclinical and clinical studies. The present study was performed on rabbits to compare aclidinium and tiotropium efficacy in the downregulation of the cough reflex. This reflex was evoked by citric acid inhalation in unanesthetized animals and by both citric acid inhalation and mechanical stimulation of the tracheobronchial tree in anesthetized animals 90 min following the inhalation of each drug (nebulizer output always at 1 mL/min). Aclidinium 4 mg/mL and tiotropium 200 μg/mL inhaled in 1 min proved to have similar protective effect on methacholine-induced bronchoconstriction in anesthetized animals. The total dosage employed for aclidinium and tiotropium was 4 mg and 200 μg, respectively. In awake animals, similar reductions in the cough number were observed following 10-min inhalation of each drug with a slight, not significant tendency to higher antitussive effects for aclidinium. In anesthetized animals, 1-min inhalation of each drug caused similar depressant effects on cough responses induced by both mechanical and chemical stimulation. A complete suppression of cough responses to mechanical stimuli was seen in some preparations. The results strongly suggest that the LAMA-induced downregulation of cough may be mediated not only by transient receptor potential vanilloid type 1 channels, as already reported, but also by acid-sensing ion channels and mechanoreceptors. The route of administration along with the more rapid hydrolysis of aclidinium into inactive metabolites minimize potential systemic side effects and give to this drug a very favorable safety profile. Copyright © 2016 Elsevier Ltd. All rights reserved.

Airway remodeling associated with cough hypersensitivity as a consequence of persistent cough: An experimental study.

PubMed

Nakaji, Hitoshi; Niimi, Akio; Matsuoka, Hirofumi; Iwata, Toshiyuki; Cui, Shilei; Matsumoto, Hisako; Ito, Isao; Oguma, Tsuyoshi; Otsuka, Kojiro; Takeda, Tomoshi; Inoue, Hideki; Tajiri, Tomoko; Nagasaki, Tadao; Kanemitsu, Yoshihiro; Chin, Kazuo; Mishima, Michiaki

2016-11-01

Chronic cough involves airway remodeling associated with cough reflex hypersensitivity. Whether cough itself induces these features remains unknown. Guinea pigs were assigned to receive treatment with citric acid (CA), saline (SA), or CA+dextromethorphan (DEX). All animals were exposed to 0.5M CA on days 1 and 22. On days 4-20, the CA and CA+DEX groups were exposed to CA, and the SA group to saline thrice weekly, during which the CA+DEX group was administered DEX pretreatment to inhibit cough. The number of coughs was counted during each 10-min CA or SA exposure. Terbutaline premedication was started to prevent bronchoconstriction. Bronchoalveolar lavage and pathology were examined on day 25. Average cough number for 10 CA exposures was examined as "cough index" in the CA group, which was divided into frequent (cough index>5) and infrequent (<5) cough subgroups for lavage and pathology analysis. The number of coughs significantly increased in the CA group from day 13 onwards. In the CA+DEX and SA groups, the number of coughs did not differ between days 1 and 22, while average number of coughs during days 4-20 was significantly lower than at days 1 and 22. Bronchoalveolar cell profiles were similar among the four groups. The smooth muscle area of small airways was significantly greater in the frequent-cough subgroup than in the other groups (in which it was similar), and highly correlated with cough index in CA group. Repeated cough induces airway smooth muscle remodeling associated with cough reflex hypersensitivity. Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Quality of Life in Adolescents With Mild Asthma

PubMed Central

Hallstrand, Teal S.; Curtis, J. Randall; Aitken, Moira L.; Sullivan, Sean D.

2007-01-01

Summary The majority of individuals with asthma have mild disease, often in conjunction with allergic rhinitis and exercise-induced bronchoconstriction (EIB). Although health-related quality-of-life (HRQoL) is reduced in moderate to severe asthma and allergic rhinitis, little is known about the effect of mild asthma, mild allergic rhinitis, and EIB on HRQoL outcomes. The objective of this study was to determine the effect of mild asthma, allergic rhinitis, and EIB on HRQoL. A cross-sectional study was conducted of 160 adolescent athletes participating in a screening program to detect EIB. Generic HRQoL was assessed with the teen version of the pediatric quality-of-life inventory (PedsQL™). Prior diagnoses of asthma, allergic rhinitis, and EIB, and current symptoms of dyspnea during exercise and asthma, were recorded. Lung function and the presence of EIB were determined by spirometry before and after an exercise challenge test. Adolescent athletes with a prior physician diagnosis of asthma had a lower HRQoL scale summary score (P < 0.01) and lower physical functioning, emotional functioning, and school functioning domain scores (P values, 0.01–0.02) in comparison to adolescent athletes with no prior diagnosis of these disorders. Athletes with a prior diagnosis of asthma reported dyspnea during exercise more frequently than did those without asthma (P < 0.001). Adolescent athletes with dyspnea during exercise had a lower scale summary score, and lower physical functioning, general well-being, and emotional functioning domain scores (P values, 0.02–0.03). These data show that mild asthma and dyspnea without asthma significantly affect HRQoL. Symptoms of dyspnea during exercise are common in asthma and are associated with lower HRQoL. The clinical significance of these differences in HRQoL is unclear. PMID:14618647

Effects of cigarette smoke on methacholine- and AMP-induced air trapping in asthmatics.

PubMed

Prieto, Luis; Palop, Julio; Llusar, Ruth; Herrera, Susana; Perez-Frances, Carmen; Lanuza, Amparo; Aguilar, Daniela

2015-02-01

Abstract Objective: No information is available on the effect of cigarette smoke on bronchoconstrictor-induced air trapping in asthma. The aim of this study was to evaluate the additional influence of smoking on methacholine- and adenosine 5'-monophosphate (AMP)-induced air trapping in subjects with asthma. Airway responsiveness to methacholine and AMP, bronchial (J'awNO) and alveolar (CANO) nitric oxide (NO) and exhaled breath condensate pH were measured in 68 adults (23 current smokers with asthma, 23 non-smokers with asthma and 22 current or former smokers with chronic obstructive pulmonary disease; COPD). The degree of air trapping induced by each bronchoconstrictor agent was expressed by the percent fall in forced vital capacity (FVC) at a 20% fall in forced expiratory volume in 1 s relative to FVC after saline inhalation (ΔFVC%). The ΔFVC% for AMP was higher in both smokers with asthma and patients with COPD than in non-smokers with asthma (p<0.001). By contrast, ΔFVC% for methacholine was similar in the three groups of subjects (p=0.69). In smokers with asthma, but not in the other two groups, there was a correlation between the residual volume/total lung capacity at baseline and the ΔFVC% induced by each bronchoconstrictor agent. Mean values for J'awNO were higher in non-smokers with asthma than in the other two groups (p<0.05). The results of this study suggest that factors underlying bronchoconstriction induced by indirect agonists are different in smokers and non-smokers with asthma. These observations might be clinically relevant, because triggers that frequently induce bronchial obstruction in the real world act by an indirect mechanism.

Inhaled ammonium persulphate inhibits non-adrenergic, non-cholinergic relaxations in the guinea pig isolated trachea.

PubMed

Dellabianca, A; Faniglione, M; De Angelis, S; Colucci, M; Cervio, M; Balestra, B; Tonini, S; Candura, S M

2010-01-01

Persulphates can act both as irritants and sensitizers in inducing occupational asthma. A dysfunction of nervous control regulating the airway tone has been hypothesized as a mechanism underlying bronchoconstriction in asthma. It was the aim of this study to investigate whether inhaled ammonium persulphate affects the non-adrenergic, non-cholinergic (NANC) inhibitory innervation, the cholinergic nerve-mediated contraction or the muscular response to the spasmogens, carbachol or histamine, in the guinea pig epithelium-free, isolated trachea. Male guinea pigs inhaled aerosols containing ammonium persulphate (10 mg/m(3) for 30 min for 5 days during 3 weeks). Control animals inhaled saline aerosol. NANC relaxations to electrical field stimulation at 3 Hz were evaluated in whole tracheal segments as intraluminal pressure changes. Drugs inactivating peptide transmission, nitric oxide synthase, carbon monoxide production by haem oxygenase-2 and soluble guanylyl cyclase were used to assess the involvement of various inhibitory neurotransmitters. Carbachol and histamine cumulative concentration-response curves were obtained. In both groups, nitric oxide and carbon monoxide participated to the same extent as inhibitory neurotransmitters. In exposed animals, the tracheal NANC relaxations were reduced to 45.9 +/- 12.1% (p < 0.01). The cholinergic nerve-mediated contractions to electrical field stimulation and the muscular response to histamine were not modified by ammonium persulphate exposure. The muscular response to carbachol was unaffected up to 1 microM. Conversely, the response to the maximal concentration of carbachol (3 microM) was increased (p < 0.01). Ammonium persulphate inhalation at high concentrations impairs the nervous NANC inhibitory control in the guinea pig airways. This may represent a novel mechanism contributing to persulphate-induced asthma. Copyright 2009 S. Karger AG, Basel.

Chronobiology and chronotherapy of allergic rhinitis and bronchial asthma.

PubMed

Smolensky, Michael H; Lemmer, Bjoern; Reinberg, Alain E

2007-08-31

Study of the chronobiology of allergic rhinitis (AR) and bronchial asthma (BA) and the chronopharmacology and chronotherapy of the medications used in their treatment began five decades ago. AR is an inflammatory disease of the upper airway tissue with hypersensitivity to specific environmental antigens, resulting in further local inflammation, vasomotor changes, and mucus hypersecretion. Symptoms include sneezing, nasal congestion, and runny and itchy nose. Approximately 25% of children and 40% of adults in USA are affected by AR during one or more seasons of the year. The manifestation and severity of AR symptoms exhibit prominent 24-h variation; in most persons they are worse overnight or early in the morning and often comprise nighttime sleep, resulting in poor daytime quality of life, compromised school and work performance, and irritability and moodiness. BA is also an inflammatory medical condition of the lower airways characterized by hypersensitivity to specific environmental antigens, resulting in greater local inflammation as well as bronchoconstriction, vasomotor change, and mucus hypersecretion. In USA an estimated 6.5 million children and 15.7 million adults have BA. The onset and worsening of BA are signaled by chest wheeze and/or croupy cough and difficult and labored breathing. Like AR, BA is primarily a nighttime medical condition. AR is treated with H1-antagonist, decongestant, and anti-inflammatory (glucocorticoid and leukotriene receptor antagonist and modifier) medications. Only H1-antagonist AR medications have been studied for their chronopharmacology and potential chronotherapy. BA is treated with some of the same medications and also theophylline and beta2-agonists. The chronopharmacology and chronotherapy of many classes of BA medications have been explored. This article reviews the rather extensive knowledge of the chronobiology of AR and BA and the chronopharmacology and chronotherapy of the various medications used in their treatment.

Respiratory response to toluene diisocyanate depends on prior frequency and concentration of dermal sensitization in mice.

PubMed

Vanoirbeek, Jeroen A J; Tarkowski, Maciej; Ceuppens, Jan L; Verbeken, Erik K; Nemery, Benoit; Hoet, Peter H M

2004-08-01

Occupational asthma is the principal cause of work-related respiratory disease in the industrial world. In the absence of satisfactory models for predicting the potential of low molecular weight chemicals to cause asthma, we verified that dermal sensitization prior to intranasal challenge influences the respiratory response using toluene diisocyanate (TDI), a known respiratory sensitizer. BALB/c mice received TDI or vehicle (acetone/olive oil) on each ear on three consecutive days (days 1, 2, and 3; 0.3 or 3% TDI) or only once (day 1, 1% TDI). On day 7, the mice received similar dermal applications of vehicle or the same concentration of TDI as before ("boost"). On day 10, they received an intranasal dose of TDI (0.1%) or vehicle. Ventilatory function was monitored by whole body plethysmography for 40 min after intranasal application, and reactivity to inhaled methacholine was assessed 24 h later. Pulmonary inflammation was assessed by bronchoalveolar lavage and histology. Mice that received an intranasal dose of TDI without having received a prior dermal application of TDI did not exhibit any ventilatory response or inflammatory changes compared to vehicle controls. In contrast, mice that had received prior application(s) of TDI, even if only on day 7, exhibited the following: ventilatory responses, compatible with bronchoconstriction, immediately after intranasal application with TDI; enhanced methacholine responsiveness 24 h later; and pulmonary inflammation characterized by neutrophils. This was, however, not the case in mice that received the highest dermal amount of TDI (3% on days 1, 2, and 3). These findings suggest that respiratory response to TDI depends on prior frequency and concentration of dermal sensitization in mice.

Lung Function Measurements in Rodents in Safety Pharmacology Studies

PubMed Central

Hoymann, Heinz Gerd

2012-01-01

The ICH guideline S7A requires safety pharmacology tests including measurements of pulmonary function. In the first step – as part of the “core battery” – lung function tests in conscious animals are requested. If potential adverse effects raise concern for human safety, these should be explored in a second step as a “follow-up study”. For these two stages of safety pharmacology testing, both non-invasive and invasive techniques are needed which should be as precise and reliable as possible. A short overview of typical in vivo measurement techniques is given, their advantages and disadvantages are discussed and out of these the non-invasive head-out body plethysmography and the invasive but repeatable body plethysmography in orotracheally intubated rodents are presented in detail. For validation purposes the changes in the respective parameters such as tidal midexpiratory flow (EF50) or lung resistance have been recorded in the same animals in typical bronchoconstriction models and compared. In addition, the technique of head-out body plethysmography has been shown to be useful to measure lung function in juvenile rats starting from day two of age. This allows safety pharmacology testing and toxicological studies in juvenile animals as a model for the young developing organism as requested by the regulatory authorities (e.g., EMEA Guideline 1/2008). It is concluded that both invasive and non-invasive pulmonary function tests are capable of detecting effects and alterations on the respiratory system with different selectivity and area of operation. The use of both techniques in a large number of studies in mice and rats in the last years have demonstrated that they provide useful and reliable information on pulmonary mechanics in safety pharmacology and toxicology testing, in investigations of respiratory disorders, and in pharmacological efficacy studies. PMID:22973226

Design and synthesis of novel sulfonamide-containing bradykinin hB2 receptor antagonists. 1. Synthesis and SAR of alpha,alpha-dimethylglycine sulfonamides.

PubMed

Fattori, Daniela; Rossi, Cristina; Fincham, Christopher I; Berettoni, Marco; Calvani, Federico; Catrambone, Fernando; Felicetti, Patrizia; Gensini, Martina; Terracciano, Rosa; Altamura, Maria; Bressan, Alessandro; Giuliani, Sandro; Maggi, Carlo A; Meini, Stefania; Valenti, Claudio; Quartara, Laura

2006-06-15

We recently published the extensive in vivo pharmacological characterization of MEN 16132 (J. Pharmacol. Exp. Ther. 2005, 616-623; Eur. J. Pharmacol. 2005, 528, 7), a member of the sulfonamide-containing human B(2) receptor (hB(2)R) antagonists. Here we report, in detail, how this family of compounds was designed, synthesized, and optimized to provide a group of products with subnanomolar affinity for the hB(2)R and high in vivo potency after topical administration to the respiratory tract. The series was designed on the basis of indications from the X-ray structures of the key structural motifs A and B present in known antagonists and is characterized by the presence of an alpha,alpha-dialkyl amino acid. The first lead (17) of the series was submitted to extensive chemical work to elucidate the structural requirements to increase hB(2) receptor affinity and antagonist potency in bioassays expressing the human B(2) receptor (hB(2)R). The following structural features were selected: a 2,4-dimethylquinoline moiety and a piperazine linker acylated with a basic amino acid. The representative lead compound 68 inhibited the specific binding of [(3)H]BK to hB(2)R with a pKi of 9.4 and antagonized the BK-induced inositolphosphate (IP) accumulation in recombinant cell systems expressing the hB(2)R with a pA(2) of 9.1. Moreover, compound 68 when administered (300 nmol/kg) intratracheally in the anesthetized guinea pig, was able to significantly inhibit BK-induced bronchoconstriction for up to 120 min after its administration, while having a lower and shorter lasting effect on hypotension.

β2-Agonist Induced cAMP Is Decreased in Asthmatic Airway Smooth Muscle Due to Increased PDE4D

PubMed Central

Trian, Thomas; Burgess, Janette K.; Niimi, Kyoko; Moir, Lyn M.; Ge, Qi; Berger, Patrick; Liggett, Stephen B.; Black, Judith L.; Oliver, Brian G.

2011-01-01

Background and Objective Asthma is associated with airway narrowing in response to bronchoconstricting stimuli and increased airway smooth muscle (ASM) mass. In addition, some studies have suggested impaired β-agonist induced ASM relaxation in asthmatics, but the mechanism is not known. Objective To characterize the potential defect in β-agonist induced cAMP in ASM derived from asthmatic in comparison to non-asthmatic subjects and to investigate its mechanism. Methods We examined β2-adrenergic (β2AR) receptor expression and basal β-agonist and forskolin (direct activator of adenylyl cyclase) stimulated cAMP production in asthmatic cultured ASM (n = 15) and non-asthmatic ASM (n = 22). Based on these results, PDE activity, PDE4D expression and cell proliferation were determined. Results In the presence of IBMX, a pan PDE inhibitor, asthmatic ASM had ∼50% lower cAMP production in response to isoproterenol, albuterol, formoterol, and forskolin compared to non-asthmatic ASM. However when PDE4 was specifically inhibited, cAMP production by the agonists and forskolin was normalized in asthmatic ASM. We then measured the amount and activity of PDE4, and found ∼2-fold greater expression and activity in asthmatic ASM compared to non-asthmatic ASM. Furthermore, inhibition of PDE4 reduced asthmatic ASM proliferation but not that of non-asthmatic ASM. Conclusion Decreased β-agonist induced cAMP in ASM from asthmatics results from enhanced degradation due to increased PDE4D expression. Clinical manifestations of this dysregulation would be suboptimal β-agonist-mediated bronchodilation and possibly reduced control over increasing ASM mass. These phenotypes appear to be “hard-wired” into ASM from asthmatics, as they do not require an inflammatory environment in culture to be observed. PMID:21611147

Trichostatin A Abrogates Airway Constriction, but Not Inflammation, in Murine and Human Asthma Models

PubMed Central

Trivedi, Chinmay M.; Damera, Gautam; Jiang, Meiqi; Jester, William; Hoshi, Toshinori; Epstein, Jonathan A.; Panettieri, Reynold A.

2012-01-01

Histone deacetylase (HDAC) inhibitors may offer novel approaches in the treatment of asthma. We postulate that trichostatin A (TSA), a Class 1 and 2 inhibitor of HDAC, inhibits airway hyperresponsiveness in antigen-challenged mice. Mice were sensitized and challenged with Aspergillus fumigatus antigen (AF) and treated with TSA, dexamethasone, or vehicle. Lung resistance (RL) and dynamic compliance were measured, and bronchial alveolar lavage fluid (BALF) was analyzed for numbers of leukocytes and concentrations of cytokines. Human precision-cut lung slices (PCLS) were treated with TSA and their agonist-induced bronchoconstriction was measured, and TSA-treated human airway smooth muscle (ASM) cells were evaluated for the agonist-induced activation of Rho and intracellular release of Ca2+. The activity of HDAC in murine lungs was enhanced by antigen and abrogated by TSA. TSA also inhibited methacholine (Mch)-induced increases in RL and decreases in dynamic compliance in naive control mice and in AF-sensitized and -challenged mice. Total cell counts, concentrations of IL-4, and numbers of eosinophils in BALF were unchanged in mice treated with TSA or vehicle, whereas dexamethasone inhibited the numbers of eosinophils in BALF and concentrations of IL-4. TSA inhibited the carbachol-induced contraction of PCLS. Treatment with TSA inhibited the intracellular release of Ca2+ in ASM cells in response to histamine, without affecting the activation of Rho. The inhibition of HDAC abrogates airway hyperresponsiveness to Mch in both naive and antigen-challenged mice. TSA inhibits the agonist-induced contraction of PCLS and mobilization of Ca2+ in ASM cells. Thus, HDAC inhibitors demonstrate a mechanism of action distinct from that of anti-inflammatory agents such as steroids, and represent a promising therapeutic agent for airway disease. PMID:22298527

Substance P acts via the neurokinin receptor 1 to elicit bronchoconstriction, oxidative stress, and upregulated ICAM-1 expression after oil smoke exposure.

PubMed

Li, Ping-Chia; Chen, Wen-Chung; Chang, Li-Ching; Lin, Shao-Chieh

2008-05-01

This study aimed to 1) assess whether substance P (SP) acts via neurokinin (NK)-1 and NK-2 receptors to stimulate neurogenic inflammation (indicated by formation of ICAM-1 expression and oxidative stress) following oil smoke exposure (OSE) in rats; and 2) determine if pretreatment with antioxidants ameliorates the deleterious effects of OSE. Rats were pretreated with NK-1 receptor antagonist CP-96345, NK-2 receptor antagonist SR-48968, vitamin C, or catechins. OSE was for 30-120 min. Rats were killed 0-8 h later. Total lung resistance (RL), airway smooth muscle activity (ASMA), lung ICAM-1 expression, neurogenic plasma extravasation (via India ink and Evans blue dye), bronchoalveolar lavage fluid SP concentrations, and reactive oxygen species formation [via lucigenin- and luminal-amplified chemiluminescence (CL)] were assessed. Lung histology was performed. SP concentrations increased significantly in nonpretreated rats following OSE in a dose-dependent manner. RL and total ASMA increased over time after OSE. Vitamin C and catechin pretreatments were associated with significantly reduced lucigenin CL 2 and 4 h after OSE. Pretreatment with catechins significantly reduced luminal CL counts 4 and 8 h after OSE. Evans blue levels were significantly reduced following 60 and 120 min of OSE in catechin- and CP-96345-pretreated rats. ICAM-1 protein expression was significantly decreased in all pretreatment groups after OSE. Thickening of the alveolar capillary membrane, focal hemorrhaging, interstitial pneumonitis, and peribronchiolar inflammation were apparent in OSE lungs. These findings suggest that SP acts via the NK-1 receptor to provoke neurogenic inflammation, oxidative stress, and ICAM-1 expression after OSE in rats.

In vitro and in vivo biological activities of SR140333, a novel potent non-peptide tachykinin NK1 receptor antagonist.

PubMed

Emonds-Alt, X; Doutremepuich, J D; Heaulme, M; Neliat, G; Santucci, V; Steinberg, R; Vilain, P; Bichon, D; Ducoux, J P; Proietto, V

1993-12-21

(S)1-(2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)pip eridin-3- yl]ethyl)-4-phenyl-1-azoniabicyclo[2.2.2]octane chloride (SR140333) is a new non-peptide antagonist of tachykinin NK1 receptors. SR140333 potently, selectively and competitively inhibited substance P binding to NK1 receptors from various animal species, including humans. In vitro, it was a potent antagonist in functional assays for NK1 receptors such as [Sar9,Met(O2)11]substance P-induced endothelium-dependent relaxation of rabbit pulmonary artery and contraction of guinea-pig ileum. Up to 1 microM, it had no effect in bioassays for NK2 ([beta Ala8]neurokinin A-induced contraction of endothelium-deprived rabbit pulmonary artery) and NK3 ([MePhe7]neurokinin B-induced contraction of rat portal vein) receptors. The antagonism exerted by SR140333 toward NK1 receptors was apparently non-competitive, with pD2' values (antagonism potency evaluated by the negative logarithm of the molar concentration of antagonist that produces a 50% reduction of the maximal response to the agonist) between 9.65 and 10.16 in the different assays. SR140333 also blocked in vitro [Sar9,Met(O2)11]substance P-induced release of acetylcholine from rat striatum. In vivo, SR140333 exerted highly potent antagonism toward [Sar9,Met(O2)11]substance P-induced hypotension in dogs (ED50 = 3 micrograms/kg i.v.), bronchoconstriction in guinea-pig (ED50 = 42 micrograms/kg i.v.) and plasma extravasation in rats (ED50 = 7 micrograms/kg i.v.). Finally, it also blocked the activation of rat thalamic neurons after nociceptive stimulation (ED50 = 0.2 micrograms/kg i.v.).

PKC-dependent regulation of Kv7.5 channels by the bronchoconstrictor histamine in human airway smooth muscle cells.

PubMed

Haick, Jennifer M; Brueggemann, Lioubov I; Cribbs, Leanne L; Denning, Mitchell F; Schwartz, Jeffrey; Byron, Kenneth L

2017-06-01

Kv7 potassium channels have recently been found to be expressed and functionally important for relaxation of airway smooth muscle. Previous research suggests that native Kv7 currents are inhibited following treatment of freshly isolated airway smooth muscle cells with bronchoconstrictor agonists, and in intact airways inhibition of Kv7 channels is sufficient to induce bronchiolar constriction. However, the mechanism by which Kv7 currents are inhibited by bronchoconstrictor agonists has yet to be elucidated. In the present study, native Kv7 currents in cultured human trachealis smooth muscle cells (HTSMCs) were observed to be inhibited upon treatment with histamine; inhibition of Kv7 currents was associated with membrane depolarization and an increase in cytosolic Ca 2+ ([Ca 2+ ] cyt ). The latter response was inhibited by verapamil, a blocker of L-type voltage-sensitive Ca 2+ channels (VSCCs). Protein kinase C (PKC) has been implicated as a mediator of bronchoconstrictor actions, although the targets of PKC are not clearly established. We found that histamine treatment significantly and dose-dependently suppressed currents through overexpressed wild-type human Kv7.5 (hKv7.5) channels in cultured HTSMCs, and this effect was inhibited by the PKC inhibitor Ro-31-8220 (3 µM). The PKC-dependent suppression of hKv7.5 currents corresponded with a PKC-dependent increase in hKv7.5 channel phosphorylation. Knocking down or inhibiting PKCα, or mutating hKv7.5 serine 441 to alanine, abolished the inhibitory effects of histamine on hKv7.5 currents. These findings provide the first evidence linking PKC activation to suppression of Kv7 currents, membrane depolarization, and Ca 2+ influx via L-type VSCCs as a mechanism for histamine-induced bronchoconstriction. Copyright © 2017 the American Physiological Society.

Dysfunctional breathing and reaching one’s physiological limit as causes of exercise-induced dyspnoea

PubMed Central

Everard, Mark L.

2016-01-01

Key points Excessive exercise-induced shortness of breath is a common complaint. For some, exercise-induced bronchoconstriction is the primary cause and for a small minority there may be an alternative organic pathology. However for many, the cause will be simply reaching their physiological limit or be due to a functional form of dysfunctional breathing, neither of which require drug therapy. The physiological limit category includes deconditioned individuals, such as those who have been through intensive care and require rehabilitation, as well as the unfit and the fit competitive athlete who has reached their limit with both of these latter groups requiring explanation and advice. Dysfunctional breathing is an umbrella term for an alteration in the normal biomechanical patterns of breathing that result in intermittent or chronic symptoms, which may be respiratory and/or nonrespiratory. This alteration may be due to structural causes or, much more commonly, be functional as exemplified by thoracic pattern disordered breathing (PDB) and extrathoracic paradoxical vocal fold motion disorder (pVFMD). Careful history and examination together with spirometry may identify those likely to have PDB and/or pVFMD. Where there is doubt about aetiology, cardiopulmonary exercise testing may be required to identify the deconditioned, unfit or fit individual reaching their physiological limit and PDB, while continuous laryngoscopy during exercise is increasingly becoming the benchmark for assessing extrathoracic causes. Accurate assessment and diagnosis can prevent excessive use of drug therapy and result in effective management of the cause of the individual’s complaint through cost-effective approaches such as reassurance, advice, breathing retraining and vocal exercises. This review provides an overview of the spectrum of conditions that can present as exercise-­induced breathlessness experienced by young subjects participating in sport and aims to promote understanding of the need for accurate assessment of an individual’s symptoms. We will highlight the high incidence of nonasthmatic causes, which simply require reassurance or simple interventions from respiratory physiotherapists or speech pathologists. PMID:27408630

Platelet–Eosinophil Interactions As a Potential Therapeutic Target in Allergic Inflammation and Asthma

PubMed Central

Shah, Sajeel A.; Page, Clive P.; Pitchford, Simon C.

2017-01-01

The importance of platelet activation during hemostasis is well understood. An understanding of these mechanisms has led to the use of several classes of anti-platelet drugs to inhibit aggregation for the prevention of thrombi during cardiovascular disease. It is now also recognized that platelets can function very differently during inflammation, as part of their role in the innate immune response against pathogens. This dichotomy in platelet function occurs through distinct physiological processes and alternative signaling pathways compared to that of hemostasis (leading to platelet aggregation) and is manifested as increased rheological interactions with leukocytes, the ability to undergo chemotaxis, communication with antigen-presenting cells, and direct anti-pathogen responses. Mounting evidence suggests platelets are also critical in the pathogenesis of allergic diseases such as asthma, where they have been associated with antigen presentation, bronchoconstriction, bronchial hyperresponsiveness, airway inflammation, and airway remodeling in both clinical and experimental studies. In particular, platelets have been reported bound to eosinophils in the blood of patients with asthma and the incidence of these events increases after both spontaneous asthma attacks in a biphasic manner, or after allergen challenge in the clinic. Platelet depletion in animal models of allergic airway inflammation causes a profound reduction in eosinophil recruitment to the lung, suggesting that the association of platelets with eosinophils is indeed an important event during eosinophil activation. Furthermore, in cases of severe asthma, and in animal models of allergic airways inflammation, platelet–eosinophil complexes move into the lung through a platelet P-selectin-mediated, eosinophil β1-integrin activation-dependent process, while platelets increase adherence of eosinophils to the vascular endothelium in vitro, demonstrating a clear interaction between these cell types in allergic inflammatory diseases. This review will explore non-thrombotic platelet activation in the context of allergy and the association of platelets with eosinophils, to reveal how these phenomena may lead to the discovery of novel therapeutic targets. PMID:28848732

Pulmonary function responses to ozone in smokers with a limited smoking history

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bates, Melissa L., E-mail: mlbates@pediatrics.wisc.edu; Department of Pediatrics, Critical Care Division, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792; John Rankin Laboratory of Pulmonary Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792

In non-smokers, ozone (O{sub 3}) inhalation causes decreases in forced expiratory volume (FEV{sub 1}) and dead space (V{sub D}) and increases the slope of the alveolar plateau (S{sub N}). We previously described a population of smokers with a limited smoking history that had enhanced responsiveness to brief O{sub 3} boluses and aimed to determine if responsiveness to continuous exposure was also enhanced. Thirty smokers (19 M, 11 F, 24 ± 4 years, 6 ± 4 total years smoking,4 ± 2 packs/week) and 30 non-smokers (17 M, 13 F, 25 ± 6 years) exercised for 1 h on a cycle ergometermore » while breathing 0.30 ppm O{sub 3}. Smokers and non-smokers were equally responsive in terms of FEV{sub 1} (− 9.5 ± 1.8% vs − 8.7 ± 1.9%). Smokers alone were responsive in terms of V{sub D} (− 6.1 ± 1.2%) and S{sub N} (9.1 ± 3.4%). There was no difference in total delivered dose. Dead space ventilation (V{sub D}/V{sub T}) was not initially different between the two groups, but increased in the non-smokers (16.4 ± 2.8%) during the exposure, suggesting that the inhaled dose may be distributed more peripherally in smokers. We also conclude that these cigarette smokers retain their airway responsiveness to O{sub 3} and, uniquely, experience changes in V{sub D} that lead to heterogeneity in airway morphometry and an increase in S{sub N}. - Highlights: • We previously found lung function responses to O{sub 3} bolus exposure in smokers. • Here, we describe their responsiveness to continuous O{sub 3} exposure with exercise. • Spirometry and capnography were used to assess pulmonary function changes. • Enhanced bronchoconstriction in smokers increases parenchymal delivery of O{sub 3}.« less

Gα12 facilitates shortening in human airway smooth muscle by modulating phosphoinositide 3-kinase-mediated activation in a RhoA-dependent manner.

PubMed

Yoo, Edwin J; Cao, Gaoyuan; Koziol-White, Cynthia J; Ojiaku, Christie A; Sunder, Krishna; Jude, Joseph A; Michael, James V; Lam, Hong; Pushkarsky, Ivan; Damoiseaux, Robert; Di Carlo, Dino; Ahn, Kwangmi; An, Steven S; Penn, Raymond B; Panettieri, Reynold A

2017-12-01

PI3K-dependent activation of Rho kinase (ROCK) is necessary for agonist-induced human airway smooth muscle cell (HASMC) contraction, and inhibition of PI3K promotes bronchodilation of human small airways. The mechanisms driving agonist-mediated PI3K/ROCK axis activation, however, remain unclear. Given that G 12 family proteins activate ROCK pathways in other cell types, their role in M 3 muscarinic acetylcholine receptor-stimulated PI3K/ROCK activation and contraction was examined. Gα 12 coupling was evaluated using co-immunoprecipitation and serum response element (SRE)-luciferase reporter assays. siRNA and pharmacological approaches, as well as overexpression of a regulator of G-protein signaling (RGS) proteins were applied in HASMCs. Phosphorylation levels of Akt, myosin phosphatase targeting subunit-1 (MYPT1), and myosin light chain-20 (MLC) were measured. Contraction and shortening were evaluated using magnetic twisting cytometry (MTC) and micro-pattern deformation, respectively. Human precision-cut lung slices (hPCLS) were utilized to evaluate bronchoconstriction. Knockdown of M 3 receptors or Gα 12 attenuated activation of Akt, MYPT1, and MLC phosphorylation. Gα 12 coimmunoprecipitated with M 3 receptors, and p115RhoGEF-RGS overexpression inhibited carbachol-mediated induction of SRE-luciferase reporter. p115RhoGEF-RGS overexpression inhibited carbachol-induced activation of Akt, HASMC contraction, and shortening. Moreover, inhibition of RhoA blunted activation of PI3K. Lastly, RhoA inhibitors induced dilation of hPCLS. Gα 12 plays a crucial role in HASMC contraction via RhoA-dependent activation of the PI3K/ROCK axis. Inhibition of RhoA activation induces bronchodilation in hPCLS, and targeting Gα 12 signaling may elucidate novel therapeutic targets in asthma. These findings provide alternative approaches to the clinical management of airway obstruction in asthma. © 2017 The British Pharmacological Society.

Bitter taste receptor agonists alter mitochondrial function and induce autophagy in airway smooth muscle cells.

PubMed

Pan, Shi; Sharma, Pawan; Shah, Sushrut D; Deshpande, Deepak A

2017-07-01

Airway remodeling, including increased airway smooth muscle (ASM) mass, is a hallmark feature of asthma and COPD. We previously identified the expression of bitter taste receptors (TAS2Rs) on human ASM cells and demonstrated that known TAS2R agonists could promote ASM relaxation and bronchodilation and inhibit mitogen-induced ASM growth. In this study, we explored cellular mechanisms mediating the antimitogenic effect of TAS2R agonists on human ASM cells. Pretreatment of ASM cells with TAS2R agonists chloroquine and quinine resulted in inhibition of cell survival, which was largely reversed by bafilomycin A1, an autophagy inhibitor. Transmission electron microscope studies demonstrated the presence of double-membrane autophagosomes and deformed mitochondria. In ASM cells, TAS2R agonists decreased mitochondrial membrane potential and increased mitochondrial ROS and mitochondrial fragmentation. Inhibiting dynamin-like protein 1 (DLP1) reversed TAS2R agonist-induced mitochondrial membrane potential change and attenuated mitochondrial fragmentation and cell death. Furthermore, the expression of mitochondrial protein BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (Bnip3) and mitochondrial localization of DLP1 were significantly upregulated by TAS2R agonists. More importantly, inhibiting Bnip3 mitochondrial localization by dominant-negative Bnip3 significantly attenuated cell death induced by TAS2R agonist. Collectively the TAS2R agonists chloroquine and quinine modulate mitochondrial structure and function, resulting in ASM cell death. Furthermore, Bnip3 plays a central role in TAS2R agonist-induced ASM functional changes via a mitochondrial pathway. These findings further establish the cellular mechanisms of antimitogenic effects of TAS2R agonists and identify a novel class of receptors and pathways that can be targeted to mitigate airway remodeling as well as bronchoconstriction in obstructive airway diseases. Copyright © 2017 the American Physiological Society.

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 bronchoconstriction in obstructive airway disease. Copyright © 2016 the American Physiological Society.

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

PubMed Central

Sharma, Pawan; Panebra, Alfredo; Pera, Tonio; Tiegs, Brian C.; Hershfeld, Alena; Kenyon, Lawrence C.

2015-01-01

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 bronchoconstriction in obstructive airway disease. PMID:26684251

ASM-024, a Piperazinium Compound, Promotes the In Vitro Relaxation of β2-Adrenoreceptor Desensitized Tracheas

PubMed Central

Israël-Assayag, Evelyne; Beaulieu, Marie-Josée; Cormier, Yvon

2015-01-01

Inhaled β2-adrenoreceptor agonists are widely used in asthma and chronic obstructive pulmonary disease (COPD) for bronchoconstriction relief. β2-adrenoreceptor agonists relax airway smooth muscle cells via cyclic adenosine monophosphate (cAMP) mediated pathways. However, prolonged stimulation induces functional desensitization of the β2-adrenoreceptors (β2-AR), potentially leading to reduced clinical efficacy with chronic or prolonged administration. ASM-024, a small synthetic molecule in clinical stage development, has shown activity at the level of nicotinic receptors and possibly at the muscarinic level and presents anti-inflammatory and bronchodilator properties. Aerosolized ASM-024 reduces airway resistance in mice and promotes in-vitro relaxation of tracheal and bronchial preparations from animal and human tissues. ASM-024 increased in vitro relaxation response to maximally effective concentration of short—acting beta-2 agonists in dog and human bronchi. Although the precise mechanisms by which ASM-024 promotes airway smooth muscle (ASM) relaxation remain unclear, we hypothesized that ASM-024 will attenuate and/or abrogate agonist-induced contraction and remain effective despite β2-AR tachyphylaxis. β2-AR tachyphylaxis was induced with salbutamol, salmeterol and formoterol on guinea pig tracheas. The addition of ASM-024 relaxed concentration-dependently intact or β2-AR desensitized tracheal rings precontracted with methacholine. ASM-024 did not induce any elevation of intracellular cAMP in isolated smooth muscle cells; moreover, blockade of the cAMP pathway with an adenylate cyclase inhibitor had no significant effect on ASM-024-induced guinea pig trachea relaxation. Collectively, these findings show that ASM-024 elicits relaxation of β2-AR desensitized tracheal preparations and suggest that ASM-024 mediates smooth muscle relaxation through a different target and signaling pathway than β2-adrenergic receptor agonists. These findings suggest ASM-024 could potentially provide clinical benefit when used adjunctively with inhaled β2-adrenoreceptor agonists in those patients exhibiting a reduced response to their chronic use. PMID:25799096

ASM-024, a piperazinium compound, promotes the in vitro relaxation of β2-adrenoreceptor desensitized tracheas.

PubMed

Israël-Assayag, Evelyne; Beaulieu, Marie-Josée; Cormier, Yvon

2015-01-01

Inhaled β2-adrenoreceptor agonists are widely used in asthma and chronic obstructive pulmonary disease (COPD) for bronchoconstriction relief. β2-Adrenoreceptor agonists relax airway smooth muscle cells via cyclic adenosine monophosphate (cAMP) mediated pathways. However, prolonged stimulation induces functional desensitization of the β2-adrenoreceptors (β2-AR), potentially leading to reduced clinical efficacy with chronic or prolonged administration. ASM-024, a small synthetic molecule in clinical stage development, has shown activity at the level of nicotinic receptors and possibly at the muscarinic level and presents anti-inflammatory and bronchodilator properties. Aerosolized ASM-024 reduces airway resistance in mice and promotes in-vitro relaxation of tracheal and bronchial preparations from animal and human tissues. ASM-024 increased in vitro relaxation response to maximally effective concentration of short-acting beta-2 agonists in dog and human bronchi. Although the precise mechanisms by which ASM-024 promotes airway smooth muscle (ASM) relaxation remain unclear, we hypothesized that ASM-024 will attenuate and/or abrogate agonist-induced contraction and remain effective despite β2-AR tachyphylaxis. β2-AR tachyphylaxis was induced with salbutamol, salmeterol and formoterol on guinea pig tracheas. The addition of ASM-024 relaxed concentration-dependently intact or β2-AR desensitized tracheal rings precontracted with methacholine. ASM-024 did not induce any elevation of intracellular cAMP in isolated smooth muscle cells; moreover, blockade of the cAMP pathway with an adenylate cyclase inhibitor had no significant effect on ASM-024-induced guinea pig trachea relaxation. Collectively, these findings show that ASM-024 elicits relaxation of β2-AR desensitized tracheal preparations and suggest that ASM-024 mediates smooth muscle relaxation through a different target and signaling pathway than β2-adrenergic receptor agonists. These findings suggest ASM-024 could potentially provide clinical benefit when used adjunctively with inhaled β2-adrenoreceptor agonists in those patients exhibiting a reduced response to their chronic use.

Characterization of tachykinin receptors mediating bronchomotor and vasodepressor responses to neuropeptide gamma and substance P in the anaesthetized rabbit.

PubMed

Yuan, L; Burcher, E; Nail, B S

1998-02-01

The effects of i.v. injections of two endogenous tachykinins, substance P (SP) and neuropeptide gamma and the highly selective tachykinin agonists [Sar9,Met(O2)11]-SP, [Lys5,MeLeu9, Nle10]-NKA(4-10) and senktide, on total lung resistance (RL), dynamic lung compliance (Cdyn) and systemic blood pressure, were compared in the anaesthetized rabbit. Senktide, the NK-3 receptor selective agonist, had no effect on RL, Cdyn or blood pressure. The other four agonists caused dose-dependent increases in RL and Cdyn, with [Sar9,Met(O2)11]-SP being the most potent agonist in producing changes in the absence of phosphoramidon. This suggested that NK-1 receptors play an important role in these responses. [Sar9, Met(O2)11]-SP, SP and neuropeptide gamma also decreased blood pressure. Phosphoramidon (1 mg/kg) potentiated the changes in RL and Cdyn evoked by [Sar9,Met(O2)11]-SP and SP, with very marked enhancement of responses to neuropeptide gamma. Responses to [Lys5, MeLeu9,Nle10]-NKA(4-10) were unaffected, suggesting that this NK-2 selective agonist may not be catabolized by neutral endopeptidase (NEP). In the presence of phosphoramidon, the non-peptide tachykinin NK-1 receptor selective antagonist CP 96345 (80 nmol/kg) reduced all responses to [Sar9,Met(O2)11]-SP and SP, whereas the NK-2 selective antagonist SR 48968 (40 nmol/kg) inhibited the bronchomotor but not the vasodepressor responses to neuropeptide gamma and [Lys5,MeLeu9, Nle10]-NKA(4-10). The fall in blood pressure induced by neuropeptide gamma was diminished by CP 96345, whereas bronchoconstriction was unaffected, indicating possible differences in NK-1 receptors in the vasculature and airways. Electrical stimulation of the distal ends of vagus nerves caused increases in RL which were abolished by atropine (1 mg/kg). Copyright 1998 Academic Press Limited

Intrathoracic airway measurement: ex-vivo validation

NASA Astrophysics Data System (ADS)

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

1997-05-01

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

Acute exposure to realistic acid fog: effects on respiratory function and airway responsiveness in asthmatics.

PubMed

Leduc, D; Fally, S; De Vuyst, P; Wollast, R; Yernault, J C

1995-11-01

Naturally occurring fogs in industrialized cities are contaminated by acidic air pollutants. In Brussels, Belgium, the pH of polluted fogwater may be as low as 3 with osmolarity as low as 30 mOsm. In order to explore short-term respiratory effects of a realistic acid-polluted fog, we collected samples of acid fog in Brussels, Belgium, which is a densely populated and industrialized city, we defined characteristics of this fog and exposed asthmatic volunteers at rest through a face mask to fogs with physical and chemical characteristics similar to those of natural fogs assessed in this urban area. Fogwater was sampled using a screen collector where droplets are collected by inertial impaction and chemical content of fogwater was assessed by measurement of conductivity, pH, visible colorimetry, high pressure liquid chromatography, and atomic absorption spectrophotometry over a period of one year. The fogwater composition was dominated by NH4+ and SO4- ions. First we evaluated the possible effect of fog acidity alone. For this purpose 14 subjects with asthma were exposed at rest for 1 hr [mass median aerodynamic diameter to a large-particle (MMAD), 9 microns] aerosol with H2SO4 concentration of 500 micrograms/m3 (pH 2.5) and osmolarity of 300 mOsm. We did not observe significant change in pulmonary function or bronchial responsiveness to metacholine. In the second part of the work, 10 asthmatic subjects were exposed to acid fog (MMAD, 7 microns) containing sulfate and ammonium ions (major ions recovered in naturally occurring fogs) with pH 3.5 and osmolarity 30 mOsm. Again, pulmonary function and bronchial reactivity were not modified after inhalation of this fog. It was concluded that short-term exposure to acid fog reproducing acidity and hypoosmolarity of natural polluted fogs does not induce bronchoconstriction and does not change bronchial responsiveness in asthmatics.

An Apparatus to Deliver Mannitol Powder for Bronchial Provocation in Children Under Six Years Old.

PubMed

Tang, Patricia; Leung, Sharon S Y; Hor, Eleanor; Ruzycki, Conor A; Carrigy, Nicholas B; Finlay, Warren H; Brannan, John D; Devadason, Sunalene; Anderson, Sandra D; Sly, Peter D; Samnick, Kevin; Chan, Hak-Kim

2015-12-01

Currently bronchial provocation testing (BPT) using mannitol powder cannot be performed in children under 6 years. A primary reason is it is challenging for children at this age to generate a consistent inspiratory effort to inhale mannitol efficiently from a dry powder inhaler. A prototype system, which does not require any inhalation training from the pediatric subject, is reported here. It uses an external source of compressed air to disperse mannitol powder into a commercial holding chamber. Then the subject uses tidal breathing to inhale the aerosol. The setup consists of a commercially available powder disperser and Volumatic™ holding chamber. Taguchi experimental design was used to identify the effect of dispersion parameters (flow rate of compressed air, time compressed air is applied, mass of powder, and the time between dispersion and inhalation) on the fine particle dose (FPD). The prototype was tested in vitro using a USP throat connected to a next generation impactor. The aerosols from the holding chamber were drawn at 10 L/min. A scaling factor for estimating the provoking dose to induce a 15% reduction in forced expiratory volume in 1 second (FEV1) (PD15) was calculated using anatomical dimensions of the human respiratory tract at various ages combined with known dosing values from the adult BPT. Consistent and doubling FPDs were successfully generated based on the Taguchi experimental design. The FPD was reliable over a range of 0.8 (±0.09) mg to 14 (±0.94) mg. The calculated PD15 for children aged 1-6 years ranged from 7.1-30 mg. The FPDs generated from the proposed set up are lower than the calculated PD15 and therefore are not expected to cause sudden bronchoconstriction. A prototype aerosol delivery system has been developed that is consistently able to deliver doubling doses suitable for bronchial provocation testing in young children.

Antiaggregant and antivasospastic properties of the new thromboxane A2 receptor antagonist sodium 4-[[1-[[[(4-chlorophenyl)sulfonyl]amino]methyl]cyclopentyl] methyl]benzeneacetate.

PubMed

Lardy, C; Rousselot, C; Chavernac, G; Depin, J C; Guerrier, D

1994-11-01

LCB 2853 (sodium 4-[[1-[[[(4-chlorophenyl)sulfonyl]amino]methyl]cyclopentyl] methyl]benzeneacetate, CAS 141335-11-7) was demonstrated to be a potent thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor antagonist in in vitro, ex vivo and in vivo experiments. The specific mechanism of action was studied in [3H]SQ 29548 receptor binding studies (pKi = 7.93) and was shown to be of competitive nature in U 46619-induced platelet aggregation (pA2 = 6.82). TXA2-dependent platelet rich plasma (PRP) aggregation (U 46619, arachidonic acid (AA), collagen, ADP or serotonin second phase) was inhibited in vitro in humans (IC50:0.037-0.65 mumol/l) and different animal species, as well as ex vivo i.v. rat and p.o. guinea-pig AA-induced aggregation (ED50 = 48 and 57 micrograms/kg). The U 46619-induced contractions of aorta, caudal artery and trachea were inhibited in a dose-dependent way (IC50 = 0.07, 0.02 and 0.5 mumol/l respectively). In vivo, both against platelet aggregation and vasoconstriction, LCB 2853 showed an ED50 lower than 1 mg/kg i.v. in rat AA-induced thrombocytopenia or U 46619-induced hypertension (ED50 = 0.25 and 0.16 mg/kg) as well as in AA-induced sudden death in the mouse (ED50 = 0.44 mg/kg). The U 46619-induced bronchoconstriction was blocked after i.v. administration of LCB 2853 (ED50 = 18.4 micrograms/kg). The duration of action observed in different models was 6 h by oral route and between 3 and 5 h by intravenous route. These properties in TXA2-dependent models led to further investigations of the antithrombotic activity of this novel TXA2 antagonist.

Grain dust induces IL-8 production from bronchial epithelial cells: the effect of dexamethasone on IL-8 production.

PubMed

Park, H S; Suh, J H; Kim, H Y; Kwon, O J; Choi, D C

1999-04-01

Recent publications have suggested an active participation of neutrophils to induce bronchoconstriction after inhalation of grain dust (GD). To further understand the role of neutrophils in the pathogenesis of GD-induced asthma, this investigation was designed to determine whether human bronchial epithelial cells could produce IL-8 production and to observe the effect of dexamethasone on IL-8 production. We cultured Beas-2B, a bronchial epithelial cell line. To observe GD-induced responses, four concentrations (1 to 200 microg/mL) of GD were incubated for 24 hours and compared with those without incubation of GD. To evaluate the effect of pro-inflammatory cytokines on IL-8 production, epithelial cells were incubated with peripheral blood mononuclear cell (PBMC) culture supernatant, which was derived from the culture of PBMC from a GD-induced asthmatic subject under the exposure to 10 microg/mL of GD, and compared with those cultured without addition of PBMC supernatant. The level of released IL-8 in the supernatant was measured by enzyme-linked immunosorbent assay. To evaluate the effect of dexamethasone on IL-8 production, four concentrations (5 to 5000 ng/mL) of dexamethasone were pre-incubated for 24 hours and the same experiments were repeated. There was significant production of IL-8 from bronchial epithelial cells with additions of GD in a dose-dependent manner (P < .05), which was significantly augmented with additions of PBMC supernatant (P < .05) at each concentration. Compared with the untreated sample, pretreatment of dexamethasone could induced a remarkable inhibitions (15% to 55%) of IL-8 production from bronchial epithelial cells in a dose-dependent manner. These results suggest that IL-8 production from bronchial epithelial cells may contribute to neutrophil recruitment occurring in GD-induced airway inflammation. The downregulation of IL-8 production by dexamethasone from bronchial epithelial cells may contribute to the efficacy of this compound in reducing cellular infiltration and ultimately to its anti-inflammatory property.

Positive interaction of the β2-agonist CHF 4226.01 with budesonide in the control of bronchoconstriction induced by acetaldehyde in the guinea-pigs

PubMed Central

Rossoni, Giuseppe; Manfredi, Barbara; Razzetti, Roberta; Civelli, Maurizio; Bongrani, Stefano; Berti, Ferruccio

2005-01-01

Pretreatment of anaesthetized guinea-pigs with either CHF 4226.01 (8-hydroxy-5-[(1R)-1-hydroxy-2-[N-[(1R)-2-(p-methoxyphenyl)-1-methylethyl]amino]ethyl] carbostyril hydrochloride), formoterol or budesonide reduced acetaldehyde (AcCHO)-evoked responses in the lungs with a rank order of potency CHF 4226.01 (ED50 values, from 1.88 to 3.31 pmol) > formoterol (ED50 values, from 3.03 to 5.51 pmol) ≫ budesonide (ED50 values, from 335 to 458 nmol). The duration of action of CHF 4226.01 in antagonizing the airway obstruction elicited by AcCHO was also substantially longer than formoterol (area under the curve) at 10 pmol, 763±58 and 480±34, respectively; P<0.01). Continuous infusion of a subthreshold dose of AcCHO enhanced the intratracheal pressure (ITP) increases caused by subsequent challenges with substance P (from 9.7±0.8 to 27.5±1.6 cm H2O as a peak, P<0.001). Pretreatment with either CHF 4226.01 or formoterol prevented the sensitizing effect of AcCHO on substance P responses (ED50 values, 2.85 and 6.11 pmol, respectively; P<0.01). The ED50 value of budesonide (396 nmol) in preventing AcCHO-evoked ITP increase was reduced when this glucocorticoid was combined with 0.1 pmol CHF 4226.01 (ED50 76 nmol; P<0.001). CHF 4226.01/budesonide was two-fold more effective (P<0.01) than the formoterol/budesonide combination. These results suggest that CHF 4226.01/budesonide, by optimizing each other's beneficial potential in the control of pulmonary changes caused by AcCHO in the guinea-pigs, may represent a new fixed combination in asthma. PMID:15655502

The protective effect of a beta 2 agonist against excessive airway narrowing in response to bronchoconstrictor stimuli in asthma and chronic obstructive lung disease.

PubMed Central

Bel, E. H.; Zwinderman, A. H.; Timmers, M. C.; Dijkman, J. H.; Sterk, P. J.

1991-01-01

Beta 2 agonists reduce airway hypersensitivity to bronchoconstrictor stimuli acutely in patients with asthma and chronic obstructive lung disease. To determine whether these drugs also protect against excessive airway narrowing, the effect of inhaled salbutamol on the position and shape of the dose-response curves for histamine or methacholine was investigated in 12 patients with asthma and 11 with chronic obstructive lung disease. After pretreatment with salbutamol (200 or 400 micrograms) or placebo in a double blind manner dose-response curves for inhaled histamine and methacholine were obtained by a standard method on six days in random order. Airway sensitivity was defined as the concentration of histamine or methacholine causing a 20% fall in FEV1 (PC20). A maximal response plateau on the log dose-response curve was considered to be present if two or more data points for FEV1 fell within a 5% response range. In the absence of a plateau, the test was continued until a predetermined level of severe bronchoconstriction was reached. Salbutamol caused an acute increase in FEV1 (mean increase 11.5% predicted in asthma, 7.2% in chronic obstructive lung disease), and increase in PC20 (mean 15 fold in asthma, fivefold in chronic obstructive lung disease), and an increase in the slope of the dose-response curves in both groups. In subjects in whom a plateau of FEV1 response could be measured salbutamol did not change the level of the plateau. In subjects without a plateau salbutamol did not lead to the development of a plateau, despite achieving a median FEV1 of 44% predicted in asthma and 39% in chronic obstructive lung disease. These results show that, although beta 2 agonists acutely reduce the airway response to a given strength of bronchoconstrictor stimulus, they do not protect against excessive airflow obstruction if there is exposure to relatively strong stimuli. This, together with the steepening of the dose-response curve, could be a disadvantage of beta 2 agonists in the treatment of moderate and severe asthma or chronic obstructive lung disease. PMID:1871705

Effects of tidal volume and methacholine on low-frequency total respiratory impedance in dogs.

PubMed

Lutchen, K R; Jackson, A C

1990-05-01

The frequency dependence of respiratory impedance (Zrs) from 0.125 to 4 Hz (Hantos et al., J. Appl. Physiol. 60: 123-132, 1986) may reflect inhomogeneous parallel time constants or the inherent viscoelastic properties of the respiratory tissues. However, studies on the lung alone or chest wall alone indicate that their impedance features are also dependent on the tidal volumes (VT) of the forced oscillations. The goals of this study were 1) to identify how total Zrs at lower frequencies measured with random noise (RN) compared with that measure with larger VT, 2) to identify how Zrs measured with RN is affected by bronchoconstriction, and 3) to identify the impact of using linear models for analyzing such data. We measured Zrs in six healthy dogs by use of a RN technique from 0.125 to 4 Hz or with a ventilator from 0.125 to 0.75 Hz with VT from 50 to 250 ml. Then methacholine was administered and the RN was repeated. Two linear models were fit to each separate set of data. Both models assume uniform airways leading to viscoelastic tissues. For healthy dogs, the respiratory resistance (Rrs) decreased with frequency, with most of the decrease occurring from 0.125 to 0.375 Hz. Significant VT dependence of Rrs was seen only at these lower frequencies, with Rrs higher as VT decreased. The respiratory compliance (Crs) was dependent on VT in a similar fashion at all frequencies, with Crs decreasing as VT decreased. Both linear models fit the data well at all VT, but the viscoelastic parameters of each model were very sensitive to VT. After methacholine, the minimum Rrs increased as did the total drop with frequency. Nevertheless the same models fit the data well, and both the airways and tissue parameters were altered after methacholine. We conclude that inferences based only on low-frequency Zrs data are problematic because of the effects of VT on such data (and subsequent linear modeling of it) and the apparent inability of such data to differentiate parallel inhomogeneities from normal viscoelastic properties of the respiratory tissues.

The Effects of Short-Term Propofol and Dexmedetomidine on Lung Mechanics, Histology, and Biological Markers in Experimental Obesity.

PubMed

Heil, Luciana Boavista Barros; Santos, Cíntia L; Santos, Raquel S; Samary, Cynthia S; Cavalcanti, Vinicius C M; Araújo, Mariana M P N; Poggio, Hananda; Maia, Lígia de A; Trevenzoli, Isis Hara; Pelosi, Paolo; Fernandes, Fatima C; Villela, Nivaldo R; Silva, Pedro L; Rocco, Patricia R M

2016-04-01

Administering anesthetics to the obese population requires caution because of a variety of reasons including possible interactions with the inflammatory process observed in obese patients. Propofol and dexmedetomidine have protective effects on pulmonary function and are widely used in short- and long-term sedation, particularly in intensive care unit settings in lean and obese subjects. However, the functional and biological effects of these drugs in obesity require further elucidation. In a model of diet-induced obesity, we compared the short-term effects of dexmedetomidine versus propofol on lung mechanics and histology, as well as biological markers of inflammation and oxidative stress modulation in obesity. Wistar rats (n = 56) were randomly fed a standard diet (lean) or experimental diet (obese) for 12 weeks. After this period, obese animals received sodium thiopental intraperitoneally and were randomly allocated into 4 subgroups: (1) nonventilated (n = 4) for molecular biology analysis only (control); (2) sodium thiopental (n = 8); (3) propofol (n = 8); and (4) dexmedetomidine (n = 8), which received continuous IV administration of the corresponding agents and were mechanically ventilated (tidal volume = 6 mL/kg body weight, fraction of inspired oxygen = 0.4, positive end-expiratory pressure = 3 cm H2O) for 1 hour. Compared with lean animals, obese rats did not present increased body weight but had higher total body and trunk fat percentages, airway resistance, and interleukin-6 levels in the lung tissue (P = 0.02, P = 0.0027, and P = 0.01, respectively). In obese rats, propofol, but not dexmedetomidine, yielded increased airway resistance, bronchoconstriction index (P = 0.016, P = 0.02, respectively), tumor necrosis factor-α, and interleukin-6 levels, as well as lower levels of nuclear factor-erythroid 2-related factor-2 and glutathione peroxidase (P = 0.001, Bonferroni-corrected t test). In this model of diet-induced obesity, a 1-hour propofol infusion yielded increased airway resistance, atelectasis, and lung inflammation, with depletion of antioxidative enzymes. However, unlike sodium thiopental and propofol, short-term infusion of dexmedetomidine had no impact on lung morphofunctional and biological variables.

Pharmacological characterization of the cysteinyl-leukotriene antagonists CGP 45715A (iralukast) and CGP 57698 in human airways in vitro

PubMed Central

Capra, Valérie; Bolla, Manlio; Angelo Belloni, Pier; Mezzetti, Maurizio; Carlo Folco, G; Nicosia, Simonetta; Enrico Rovati, G

1998-01-01

Cysteinyl-leukotrienes (cysteinyl-LTs) are important mediators in the pathogenesis of asthma. They cause bronchoconstriction, mucus hypersecretion, increase in microvascular permeability, plasma extravasation and eosinophil recruitment. We investigated the pharmacological profile of the cysteinyl-LT antagonists CGP 45715A (iralukast), a structural analogue of LTD4 and CGP 57698, a quinoline type antagonist, in human airways in vitro, by performing binding studies on human lung parenchyma membranes and functional studies on human isolated bronchial strips. Competition curves vs [3H]-LTD4 on human lung parenchyma membranes demonstrated that: (a) both antagonists were able to compete for the two sites labelled by [3H]-LTD4; (b) as in all the G-protein coupled receptors, iralukast and CGP 57698 did not discriminate between the high and the low affinity states of the CysLT receptor labelled by LTD4 (Ki1=Ki2=16.6 nM±36% CV and Ki1= Ki2=5.7 nM±19% CV, respectively); (c) iralukast, but not CGP 57698, displayed a slow binding kinetic, because preincubation (15 min) increased its antagonist potency. In functional studies: (a) iralukast and CGP 57698 antagonized LTD4-induced contraction of human bronchi, with pA2 values of 7.77±4.3% CV and 8.51±1.6% CV, respectively, and slopes not significantly different from unity; (b) the maximal LTD4 response in the presence of CGP 57698 was actually increased, thus clearly deviating from apparent simple competition. Both antagonists significantly inhibited antigen-induced contraction of human isolated bronchial strips in a concentration-dependent manner, lowering the upper plateau of the anti-IgE curves. In conclusion, the results of the present in vitro investigation indicate that iralukast and CGP 57698 are potent antagonists of LTD4 in human airways, with affinities in the nanomolar range, similar to those obtained for ICI 204,219 and ONO 1078, two of the most clinically advanced CysLT receptor antagonists. Thus, these compounds might be useful drugs for the therapy of asthma and other allergic diseases. PMID:9504401

Association of serum Clara cell protein CC16 with respiratory infections and immune response to respiratory pathogens in elite athletes.

PubMed

Kurowski, Marcin; Jurczyk, Janusz; Jarzębska, Marzanna; Moskwa, Sylwia; Makowska, Joanna S; Krysztofiak, Hubert; Kowalski, Marek L

2014-04-15

Respiratory epithelium integrity impairment caused by intensive exercise may lead to exercise-induced bronchoconstriction. Clara cell protein (CC16) has anti-inflammatory properties and its serum level reflects changes in epithelium integrity and airway inflammation. This study aimed to investigate serum CC16 in elite athletes and to seek associations of CC16 with asthma or allergy, respiratory tract infections (RTIs) and immune response to respiratory pathogens. The study was performed in 203 Olympic athletes. Control groups comprised 53 healthy subjects and 49 mild allergic asthmatics. Serum levels of CC16 and IgG against respiratory viruses and Mycoplasma pneumoniae were assessed. Allergy questionnaire for athletes was used to determine symptoms and exercise pattern. Current versions of ARIA and GINA guidelines were used when diagnosing allergic rhinitis and asthma, respectively. Asthma was diagnosed in 13.3% athletes, of whom 55.6% had concomitant allergic rhinitis. Allergic rhinitis without asthma was diagnosed in 14.8% of athletes. Mean CC16 concentration was significantly lower in athletes versus healthy controls and mild asthmatics. Athletes reporting frequent RTIs had significantly lower serum CC16 and the risk of frequent RTIs was more than 2-fold higher in athletes with low serum CC16 (defined as equal to or less than 4.99 ng/ml). Athletes had significantly higher anti-adenovirus IgG than healthy controls while only non-atopic athletes had anti-parainfluenza virus IgG significantly lower than controls. In all athletes weak correlation of serum CC16 and anti-parainfluenza virus IgG was present (R = 0.20, p < 0.01). In atopic athletes a weak positive correlations of CC16 with IgG specific for respiratory syncytial virus (R = 0.29, p = 0.009), parainfluenza virus (R = 0.31, p = 0.01) and adenovirus (R = 0.27, p = 0.02) were seen as well. Regular high-load exercise is associated with decrease in serum CC16 levels. Athletes with decreased CC16 are more susceptible to respiratory infections. Atopy may be an additional factor modifying susceptibility to infections in subjects performing regular high-load exercise.

Modeling of the Nitric Oxide Transport in the Human Lungs.

PubMed

Karamaoun, Cyril; Van Muylem, Alain; Haut, Benoît

2016-01-01

In the human lungs, nitric oxide (NO) acts as a bronchodilatator, by relaxing the bronchial smooth muscles and is closely linked to the inflammatory status of the lungs, owing to its antimicrobial activity. Furthermore, the molar fraction of NO in the exhaled air has been shown to be higher for asthmatic patients than for healthy patients. Multiple models have been developed in order to characterize the NO dynamics in the lungs, owing to their complex structure. Indeed, direct measurements in the lungs are difficult and, therefore, these models are valuable tools to interpret experimental data. In this work, a new model of the NO transport in the human lungs is proposed. It belongs to the family of the morphological models and is based on the morphometric model of Weibel (1963). When compared to models published previously, its main new features are the layered representation of the wall of the airways and the possibility to simulate the influence of bronchoconstriction (BC) and of the presence of mucus on the NO transport in lungs. The model is based on a geometrical description of the lungs, at rest and during a respiratory cycle, coupled with transport equations, written in the layers composing an airway wall and in the lumen of the airways. First, it is checked that the model is able to reproduce experimental information available in the literature. Second, the model is used to discuss some features of the NO transport in healthy and unhealthy lungs. The simulation results are analyzed, especially when BC has occurred in the lungs. For instance, it is shown that BC can have a significant influence on the NO transport in the tissues composing an airway wall. It is also shown that the relation between BC and the molar fraction of NO in the exhaled air is complex. Indeed, BC might lead to an increase or to a decrease of this molar fraction, depending on the extent of the BC and on the possible presence of mucus. This should be confirmed experimentally and might provide an interesting way to characterize the extent of BC in unhealthy patients.

[Measurement of bronchoconstrictive eicosanoids in chronic obstructive pulmonary disease].

PubMed

Gross-Sondej, Iwona; Soja, Jerzy; Sładek, Krzysztof; Pulka, Grażyna; Skucha, Wojciech; Niżankowska-Mogilnicka, Ewa

2012-01-01

The aim of the study was the evaluation of the concentration of 9α11β prostaglandin F(2) - a stable metabolite of prostaglandin D(2) (PGD(2)) and leukotriene E(4) (LTE(4)) in stable and exacerbated COPD patients. 29 COPD patients aged 73 ± 8.34, mean FEV1 = 48.64 ± 15.75% of predictive value and 29 healthy controls aged 57.48 ± 10.86, mean FEV1 = 97.17 ± 13.81% of predictive value participated in this study. Samples of urine and blood were taken from COPD patients during exacerbation and in stable state of the disease; LTE(4) was determined in urine using commercial enzyme immunoassay (EIA) and 9α11β prostaglandin F(2) (9α11βPGF(2)) - stable metabolite of PGD(2) was evaluated in blood and urine using GC/MS. LTE(4) concentration in urine (677.15 vs. 436.4 pg/mg of creatinine; p = 0.035) and 9α11βPGF(2) in blood serum (5.35 vs. 3.07 pg/ml; p = 0.007) were significantly higher in exacerbated COPD patients than in control group. There was no difference in LTE(4) level in urine and 9α11βPGF2 in blood serum between exacerbated and stable COPD. The urinary 9α11βPGF(2) concentration did not differ between all studied groups. We found a positive correlation between smoking history and the urine LTE(4) level (r = 0.395; p = 0.002) as well as blood 9α11βPGF(2) concentration (r = 0.603; p = 0.001) in COPD patients. 9α11βPGF(2) and LTE(4) level in urine did not differ between the stable COPD group and the control group. We also did not find any difference between LTE4 level in urine and 9α11βPGF(2) in blood and urine between exacerbated and stable COPD. Finally, LTE(4) concentration in urine and 9α11βPGF(2) in blood occurred to be significantly higher in exacerbated COPD patients than in control group.

Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Trifilieff, Alexandre; Ethell, Brian T.; Sykes, David A.

Long acting inhaled muscarinic receptor antagonists, such as tiotropium, are widely used as bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Although this class of compounds is generally considered to be safe and well tolerated in COPD patients the cardiovascular safety of tiotropium has recently been questioned. We describe a rat in vivo model that allows the concurrent assessment of muscarinic antagonist potency, bronchodilator efficacy and a potential for side effects, and we use this model to compare tiotropium with NVA237 (glycopyrronium bromide), a recently approved inhaled muscarinic antagonist for COPD. Anaesthetized Brown Norway rats were dosed intratracheally at 1more » or 6 h prior to receiving increasing doses of intravenous methacholine. Changes in airway resistance and cardiovascular function were recorded and therapeutic indices were calculated against the ED{sub 50} values for the inhibition of methacholine-induced bronchoconstriction. At both time points studied, greater therapeutic indices for hypotension and bradycardia were observed with glycopyrronium (19.5 and 28.5 fold at 1 h; > 200 fold at 6 h) than with tiotropium (1.5 and 4.2 fold at 1 h; 4.6 and 5.5 fold at 6 h). Pharmacokinetic, protein plasma binding and rat muscarinic receptor binding properties for both compounds were determined and used to generate an integrated model of systemic M{sub 2} muscarinic receptor occupancy, which predicted significantly higher M{sub 2} receptor blockade at ED{sub 50} doses with tiotropium than with glycopyrronium. In our preclinical model there was an improved safety profile for glycopyrronium when compared with tiotropium. - Highlights: • We use an in vivo rat model to study CV safety of inhaled muscarinic antagonists. • We integrate protein and receptor binding and PK of tiotropium and glycopyrrolate. • At ED{sub 50} doses for bronchoprotection we model systemic M{sub 2} receptor occupancy. • Glycopyrrolate demonstrates lower M{sub 2} occupancy at bronchoprotective doses. • Glycopyrrolate demonstrates an improved CV safety profile, versus tiotropium.« less

Dexmedetomidine's inhibitory effects on acetylcholine release from cholinergic nerves in guinea pig trachea: a mechanism that accounts for its clinical benefit during airway irritation.

PubMed

Mikami, Maya; Zhang, Yi; Kim, Benjamin; Worgall, Tilla S; Groeben, Harald; Emala, Charles W

2017-03-29

Airway instrumentation can evoke upper airway reflexes including bronchoconstriction and cough which can cause serious complications including airway trauma, laryngospasm or bronchospasm which may in turn lead to difficulty with ventilation and hypoxemia. These airway events are mediated in part by irritant-induced neuronal modulation of airway tone and cough responses. We investigated whether the commonly used anesthetic agents dexmedetomidine, lidocaine or remifentanil attenuated neuronal and airway smooth muscle responses in the upper airways of guinea pigs. The ability of dexmedetomidine, lidocaine or remifentanil to attenuate direct cholinergic nerve stimulation, C-fiber stimulation or direct smooth muscle contraction were studied using isolated tracheal rings from male guinea pigs under four paradigms; (1) the magnitude of contractile force elicited by cholinergic electrical field stimulation (EFS); (2) the amount of acetylcholine released during cholinergic EFS; (3) the direct airway smooth muscle relaxation of a sustained acetylcholine-induced contraction and (4) the magnitude of C-fiber mediated contraction. Dexmedetomidine (1-100 μM) and lidocaine (1 mM) attenuated cholinergic 30Hz EFS-induced tracheal ring contraction while remifentanil (10 μM) had no effect. Dexmedetomidine at 10 μM (p = 0.0047) and 100 μM (p = 0.01) reduced cholinergic EFS-induced acetylcholine release while lidocaine (10 μM-1 mM) and remifentanil (0.1-10 μM) did not. Tracheal ring muscle force induced by the exogenous addition of the contractile agonist acetylcholine or by a prototypical C-fiber analogue of capsaicin were also attenuated by 100 μM dexmedetomidine (p = 0.0061 and p = 0.01, respectively). The actual tracheal tissue concentrations of dexmedetomidine achieved (0.54-26 nM) following buffer application of 1-100 μM of dexmedetomidine were within the range of clinically achieved plasma concentrations (12 nM). The α2 adrenoceptor agonist dexmedetomidine reduced cholinergic EFS-induced contractions and acetylcholine release consistent with the presence of inhibitory α2 adrenoceptors on the prejunctional side of the postganglionic cholinergic nerve-smooth muscle junction. Dexmedetomidine also attenuated both exogenous acetylcholine-induced contraction and C-fiber mediated contraction, suggesting a direct airway smooth muscle effect and an underlying mechanism for cough suppression, respectively.

A xanthine-based epithelium-dependent airway relaxant KMUP-3 (7-[2-[4-(4-nitrobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine) increases respiratory performance and protects against tumor necrosis factor-alpha-induced tracheal contraction, involving nitric oxide release and expression of cGMP and protein kinase G.

PubMed

Lin, Rong-Jyh; Wu, Bin-Nan; Lo, Yi-Ching; An, Li-Mei; Dai, Zen-Kong; Lin, Young-Tso; Tang, Chao-Shun; Chen, Ing-Jun

2006-02-01

KMUP-3 (7-[2-[4-(4-nitrobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine) was investigated in guinea pig tracheal smooth muscle. Intratracheal instillation of tumor necrosis factor (TNF)-alpha (0.01 mg/kg/300 microl) induced bronchoconstriction, increases of lung resistance, and decreases of dynamic lung compliance. Instillation of KMUP-3 (0.5-2.0 mg/kg) reversed this situation. In isolated trachea precontracted with carbachol, KMUP-3 (10-100 microM)-caused relaxations were attenuated by epithelium removal and by pretreatments with an inhibitor of K(+) channel, tetraethylammonium (10 mm); K(ATP) channel, glibenclamide (1 microM); voltage-dependent K(+) channel, 4-aminopyridine (100 microM); Ca(2+)-dependent K(+) channel, charybdotoxin (0.1 microM) or apamin (1 microM); soluble guanylate cyclase (sGC), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1one (ODQ, 1 microM); nitric-oxide (NO) synthase, N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 microM); and adenylate cyclase, SQ 22536 [9-(terahydro-2-furanyl)-9H-purin-6-amine] (100 microM). KMUP-3 (0.01-100 microM) induced increases of cGMP and cAMP in primary culture of tracheal smooth muscle cells (TSMCs). The increase in cGMP by KMUP-3 was reduced by ODQ and L-NAME; the increase in cAMP was reduced by SQ 22536. Western blot analysis indicated that KMUP-3 (1 microM) induced expression of protein kinase A (PKA)(ri) and protein kinase G (PKG)(1alpha 1beta) in TSMCs.SQ 22536 inhibited KMUP-3-induced expression of (PKA)(ri). On the contrary, ODQ inhibited KMUP-3-induced expression of PKG(1alpha 1beta) In epithelium-intact trachea, KMUP-3 increased the NO release. Activation of sGC, NO release, and inhibition of phosphodiesterases in TSMCs by KMUP-3 may result in increases of intracellular cGMP and cAMP, which subsequently activate PKG and PKA, efflux of K(+) ion, and associated reduction in Ca(2+) influx in vitro, indicating the action mechanism to protect against TNF-alpha-induced airway dysfunction in vivo.

Bronchial hyperresponsiveness, word descriptors, and ethnicity: women with mild asthma.

PubMed

Hardie, Grace E; Brown, James K; Gold, Warren M

2012-02-01

Few studies have examined the ethnic differences in symptom reporting and airway hyperresponsiveness (AHR) for women with mild asthma during a methacholine (McH) challenge. The purpose of this sub-analysis was to determine: (1) whether AHR to McH varied by the ethnicity of women with mild asthma and (2) whether ethnic word descriptors (EWDs) varied by the ethnicity during induced bronchoconstriction. Specific inclusion criteria included the following: FEV(1) (forced expiratory volume in 1 second) ≥ 70% predicted normal, PC(30) ≤ 8 mg/McH, β(2) inhaler only, and self-reported ethnicity of African American (AFAM), Mexican American-Hispanic-Latino (MexAMLat), Asian-Pacific Islander (Asian PI), or white. Serial pulmonary function testing (PFT) and Borg, visual analogue scale (VAS), and EWDs were collected. A total of 44 women, mean age of 31.3 years old, with a mean baseline FEV(1) of 2.85 L comprised this sub-analysis. Ethnic-racial diversity included: 12 AFAMs, 5 MexAMLat, 13 Asian-PIs, and 14 whites. All had atopy ≥ 2 pinprick responses of 3 mm. At PC(30), Asian-PI women required a significantly (p < .05) smaller mean dose of McH 1.9 mg/mL. MexAMLat women required an McH dose of 1.6 mg/mL. At PC(30), McH dose was 2.9 mg/mL for AFAMs and 3.0 mg/mL for whites, respectively. Asian-PIs who used only upper airway EWDs at PC(30) vere itchy throat, itchy chin, and constricted throat (p < .001). AFAMs significant EWDs were itchy throat, itchy chin/face, and tight throat (p < .01). Lower airway EWD was used by both MexAMLat and whites. Significant EWD for Whites were tight chest (p < .01) and hard to inhale/lungs tight (p < .001). Asian-PI women required a significantly smaller dose (p < .05) of McH to induce a PC(30). AFAM and whites required a comparable dose of Mch at PC(30). Asian-PI and AFAM women used only upper airway EWD. Asian-PI women may be at a greater risk for acute asthma episodes that are not recognized or treated due to their upper airway symptom reporting.

MEN15596, a novel nonpeptide tachykinin NK2 receptor antagonist.

PubMed

Cialdai, Cecilia; Tramontana, Manuela; Patacchini, Riccardo; Lecci, Alessandro; Catalani, Claudio; Catalioto, Rose-Marie; Meini, Stefania; Valenti, Claudio; Altamura, Maria; Giuliani, Sandro; Maggi, Carlo Alberto

2006-11-07

The pharmacological profile of MEN15596 or (6-methyl-benzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-1R-{[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide), a novel potent and selective tachykinin NK2 receptor antagonist endowed with oral activity, is described. At the human recombinant tachykinin NK2 receptor, MEN15596 showed subnanomolar affinity (pKi 10.1) and potently antagonized (pKB 9.1) the neurokinin A-induced intracellular calcium release. MEN15596 selectivity for the tachykinin NK2 receptor was assessed by binding studies at the recombinant tachykinin NK1 (pKi 6.1) and NK3 (pKi 6.4) receptors, and at a number of 34 molecular targets including receptors, transporters and ion channels. In isolated smooth muscle preparations MEN15596 showed a marked species selectivity at the tachykinin NK2 receptor with the highest antagonist potency in guinea-pig colon, human and pig bladder (pKB 9.3, 9.2 and 8.8, respectively) whereas it was three orders of magnitude less potent in the rat and mouse urinary bladder (pKB 6.3 and 5.8, respectively). In agreement with binding experiments, MEN15596 showed low potency in blocking selective NK1 or NK3 receptor agonist-induced contractions of guinea-pig ileum preparations (pA2

Synthesis, docking study and relaxant effect of 2-alkyl and 2-naphthylchromones on rat aorta and guinea-pig trachea through phosphodiesterase inhibition.

PubMed

Rodríguez-Ramos, Fernando; Navarrete, Andrés; González-Andrade, Martín; Alarcón, Carlos; Aguilera-Cruz, Alejandro; Reyes-Ramírez, Adelfo

2013-10-01

Chromone (4), which form the base structure of various flavonoids isolated as natural products, is capable of relaxing smooth muscle. This is relevant to the treatment of high blood pressure, asthma and chronic obstructive pulmonary disease. The former disorder involves the contraction of vascular smooth muscle (VSM), and the latter two bronchoconstriction of airway smooth muscle (ASM). One of the principal mechanisms by which flavonoids relax muscle tissue is the inhibition of phosphodiesterases (PDEs), present in both VSM and ASM. Therefore, a study was designed to analyze the structure-activity relationship of chromone derivatives in vaso- and bronchorelaxation through the inhibition of PDE. Docking studies showed that these chromones bind at the catalytic site of PDEs. Consequently, we synthesized analogs of chromones substituted at position C-2 with alkyl and naphthyl groups. These compounds were synthesized from 2-hydroxyacetophenone and acyl chlorides in the presence of DBU and pyridine, modifying the methodology reported for the synthesis of 3-acylchromones by changing the reaction temperature from 80 to 30°C and using methylene chloride as solvent, yielding the corresponding phenolic esters 10a-10h. These compounds were cyclized with an equivalent of DBU, pyridine as solvent, and heated at reflux temperature, yielding the chromones 11a-11h. Evaluation of the vasorelaxant effect of 4, 11a-11h on rat aorta demonstrated that potency decreases with branched alkyl groups. Whereas the EC50 of compound 11d (substituted by an n-hexyl group) was 8.64±0.39 μM, that of 11f (substituted by an isobutyl group) was 14.58±0.64 μM. Contrarily, the effectiveness of the compound is directly proportional to the length of the alkyl chain, as evidenced by the increase in maximal effect of compound 11c versus 11d (66% versus 100%) and 11e versus 11f (60% versus 96%). With an aromatic group like naphthyl as the C-2 substituent, the effectiveness was only 43%. All compounds tested on guinea pig trachea showed less than 55% effectiveness. Compounds 4, 11a-11h were evaluated as PDE inhibitors in vitro, with 11d showing the greatest effect (73%), corroborating the importance of a long alkyl chain, which inhibits the decomposition of cGMP. Docking studies showed that the compound 11d was selective for the inhibition of PDE-5. Copyright © 2013 Elsevier Inc. All rights reserved.

Cough in the Athlete: CHEST Guideline and Expert Panel Report.

PubMed

Boulet, Louis-Philippe; Turmel, Julie; Irwin, Richard S

2017-02-01

Cough is a common symptom experienced by athletes, particularly after exercise. We performed a systematic review to assess the following in this population: (1) the main causes of acute and recurrent cough, either exercise-induced or not, (2) how cough is assessed, and (3) how cough is treated in this population. From the systematic review, suggestions for management were developed. This review was performed according to the CHEST methodological guidelines and Grading of Recommendations Assessment, Development and Evaluation framework until April 2015. To be included, studies had to meet the following criteria: participants had to be athletes and adults and adolescents aged ≥ 12 years and had to complain of cough, regardless of its duration or relationship to exercise. The Expert Cough Panel based their suggestions on the data extracted from the review and final grading by consensus according to a Delphi process. Only 60 reports fulfilled the inclusion criteria, and the results of our analysis revealed only low-quality evidence on the causes of cough and how to assess and treat cough specifically in athletes. Although there was no formal evaluation of causes of cough in the athletic population, the most common causes reported were asthma, exercise-induced bronchoconstriction, respiratory tract infection (RTI), upper airway cough syndrome (UACS) (mostly from rhinitis), and environmental exposures. Cough was also reported to be related to exercise-induced vocal cord dysfunction among a variety of less common causes. Although gastroesophageal reflux disease (GERD) is frequent in athletes, we found no publication on cough and GERD in this population. Assessment of the causes of cough was performed mainly with bronchoprovocation tests and suspected disease-specific investigations. The evidence to guide treatment of cough in the athlete was weak or nonexistent, depending on the cause. As data on cough in athletes were hidden in a set of other data (respiratory symptoms), evidence tables were difficult to produce and were done only for cough treatment in athletes. The causes of cough in the athlete appear to differ slightly from those in the general population. It is often associated with environmental exposures related to the sport training environment and occurs predominantly following intense exercise. Clinical history and specific investigations should allow identification of the cause of cough as well as targeting of the treatment. Until management studies have been performed in the athlete, current guidelines that exist for the general population should be applied for the evaluation and treatment of cough in the athlete, taking into account specific training context and anti-doping regulations. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Inhaled nebulised unfractionated heparin improves lung function in moderate to very severe COPD: A pilot study.

PubMed

Shute, Janis K; Calzetta, Luigino; Cardaci, Vittorio; di Toro, Stefania; Page, Clive P; Cazzola, Mario

2018-02-01

COPD is an inflammatory airway disease characterised by progressive airflow limitation and air trapping, leading to lung hyperinflation and exercise limitation. Acute worsening of symptoms, including dyspnea, cough and sputum production, occurs during exacerbations which are associated with significantly reduced health related quality of life, and increased morbidity and mortality. Chronic bronchial mucus production and productive cough are risk factors for exacerbations. Medicines targeting bronchoconstriction and airway inflammation are the current mainstays of COPD therapy. However, there is growing concern with an increased risk of pneumonia in patients with COPD receiving regular inhaled corticosteroids and there is therefore a need to find safer alternative treatments. Previous studies have indicated that inhalation of unfractionated heparin (UFH) treats local inflammation, mucus hypersecretion and lung injury, without systemic anticoagulation, and is safe. Therefore, our primary objective was to demonstrate that inhaled UFH significantly improves lung function (FEV 1 ) over 21 days of treatment in patients with COPD receiving pulmonary rehabilitation and that UFH provides a novel, safe and effective way of treating this complex disease. Forty patients with moderate to very severe COPD admitted to the IRCCS San Raffaele Pisana Hospital for 21 days pulmonary rehabilitation were randomised to receive nebulised inhaled UFH (75,000 or 150,000 IU BID) or placebo for 21 days. All patients also received nebulised salbutamol (1 mg) and beclomethasone dipropionate (400 μg) BID over the same period. Lung function was measured at day 0, 7, 14 and 21 of treatment and at a follow-up visit 7 days post-treatment. Exercise capacity (6MWT) and dyspnoea (Borg score) were measured before and after treatment. In pre-clinical studies, the ability of basic proteins found in COPD sputum to neutralise the anticoagulant activity of heparin was determined using the AMAX heparin assay kit. At both doses, UFH significantly increased FVC following 7 days of treatment and 150,000 IU BID significantly increased FEV1 (+249 ± 69 ml compared with placebo) at this time, an effect maintained to the 28 day follow-up. Clinically significant improvement in exercise capacity and dyspnoea were seen after 21 days of treatment with both doses of UFH. There were no serious adverse events or effects on systemic coagulation. Pre-clinical studies demonstrated that the basic proteins lactoferrin, platelet factor-4 (PF-4), IL-8 and polyarginine, as a model of the eosinophil cationic protein (ECP), found in COPD sputum neutralise the anticoagulant activity of heparin. Inhaled nebulised UFH is safe and provides additional clinical benefit for patients with moderate to very severe COPD through effects that are independent of its anticoagulant activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Characterization of NK1 and NK2 tachykinin receptors in guinea-pig and rat bronchopulmonary and vascular systems.

PubMed Central

Floch, A.; Fardin, V.; Cavero, I.

1994-01-01

1. NK1 and NK2 tachykinin receptors were characterized in guinea-pig and rat bronchopulmonary systems and in the vasculature of the rat by use of radioligand binding and/or functional studies. 2. The radioligands for NK1 and NK2 receptors ([3H]-SP and [3H]-pNKA, respectively) did not label tachykinin receptors in homogenates of rat lungs or bronchi. In contrast, in the guinea-pig, [3H]-SP bound with high affinity to these tissues (KD = 0.23 +/- 0.08 nM and 0.34 +/- 0.05 nM, for lungs and bronchi, respectively). The total number of binding sites was 4.6 fold greater in bronchus (Bmax = 135 +/- 27 fmol mg-1 protein) than in lung homogenates (Bmax = 29.3 +/- 0.1 fmol mg-1 protein). Furthermore, this binding was markedly displaced by CP-96,345 (pKi = 9.5 +/- 0.1) and RP 67580 (pKi = 7.6 +/- 0.1), antagonists of NK1 receptors, slightly displaced by SR 48968 (pKi = 6.6 +/- 0.1), but not affected by actinomycin D or L-659,877, antagonists of NK2 receptors. Specific binding of [3H]-pNKA, detected in guinea-pig bronchi (KD = 5.2 +/- 0.1 nM, and Bmax = 203 +/- 19 fmol mg-1 protein) but not in lungs, was similarly (40 to 53%) displaced by RP 67580 (1 microM), CP-96,345 (10 and 100 nM) or SR 48968 (10 and 100 nM). The displacement approximately doubled (87 to 91%) when SR 48968 (10 nM) was combined with either RP 67580 (1 microM) or CP-96,345 (10 nM), but not when RP 67580 was combined with CP-96,345. 3. In urethane-anaesthetized guinea-pigs, i.v. injections of the NK1 receptor agonists SP, [Pro9]-SP, [Sar9,Met(O2)11]-SP and septide, as well as the NK2 receptor agonists NKA and [Lys5,MeLeu9,NLeu10]-NKA(4-10) (0.1-10 micrograms kg-1, i.v.), dose-dependently increased lung inflation pressure. The most potent of these peptides were septide and [Lys5, MeLeu9,NLeu10]-NKA(4-10) (EC50 = 0.38 +/- 0.07 and 0.07 +/- 0.02 microgram kg-1, respectively). Interestingly, septide was 130 fold less potent than SP in displacing [3H]-SP from its binding sites in the guinea-pig lung, whereas it was 14 fold more potent than SP as a bronchoconstrictor. RP 67580 (0.3-5 mg kg-1, i.v.) and CP-96,345 (0.01-3 mg kg-1, i.v.) dose-dependently reduced the bronchoconstriction produced by the NK1 receptor agonists.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:7517328

Chronic β2 -adrenoceptor agonist treatment alters muscle proteome and functional adaptations induced by high intensity training in young men.

PubMed

Hostrup, Morten; Onslev, Johan; Jacobson, Glenn A; Wilson, Richard; Bangsbo, Jens

2018-01-15

While several studies have investigated the effects of exercise training in human skeletal muscle and the chronic effect of β 2 -agonist treatment in rodent muscle, their effects on muscle proteome signature with related functional measures in humans are still incompletely understood. Herein we show that daily β 2 -agonist treatment attenuates training-induced enhancements in exercise performance and maximal oxygen consumption, and alters muscle proteome signature and phenotype in trained young men. Daily β 2 -agonist treatment abolished several of the training-induced enhancements in muscle oxidative capacity and caused a repression of muscle metabolic pathways; furthermore, β 2 -agonist treatment induced a slow-to-fast twitch muscle phenotype transition. The present study indicates that chronic β 2 -agonist treatment confounds the positive effect of high intensity training on exercise performance and oxidative capacity, which is of interest for the large proportion of persons using inhaled β 2 -agonists on a daily basis, including athletes. Although the effects of training have been studied for decades, data on muscle proteome signature remodelling induced by high intensity training in relation to functional changes in humans remains incomplete. Likewise, β 2 -agonists are frequently used to counteract exercise-induced bronchoconstriction, but the effects β 2 -agonist treatment on muscle remodelling and adaptations to training are unknown. In a placebo-controlled parallel study, we randomly assigned 21 trained men to 4 weeks of high intensity training with (HIT+β 2 A) or without (HIT) daily inhalation of β 2 -agonist (terbutaline, 4 mg dose -1 ). Of 486 proteins identified by mass-spectrometry proteomics of muscle biopsies sampled before and after the intervention, 32 and 85 were changing (false discovery rate (FDR) ≤5%) with the intervention in HIT and HIT+β 2 A, respectively. Proteome signature changes were different in HIT and HIT+β 2 A (P = 0.005), wherein β 2 -agonist caused a repression of 25 proteins in HIT+β 2 A compared to HIT, and an upregulation of 7 proteins compared to HIT. β 2 -Agonist repressed or even downregulated training-induced enrichment of pathways related to oxidative phosphorylation and glycogen metabolism, but upregulated pathways related to histone trimethylation and the nucleosome. Muscle contractile phenotype changed differently in HIT and HIT+β 2 A (P ≤ 0.001), with a fast-to-slow twitch transition in HIT and a slow-to-fast twitch transition in HIT+β 2 A. β 2 -Agonist attenuated training-induced enhancements in maximal oxygen consumption (P ≤ 0.01) and exercise performance (6.1 vs. 11.6%, P ≤ 0.05) in HIT+β 2 A compared to HIT. These findings indicate that daily β 2 -agonist treatment attenuates the beneficial effects of high intensity training on exercise performance and oxidative capacity, and causes remodelling of muscle proteome signature towards a fast-twitch phenotype. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Comparative, general pharmacology of SDZ NKT 343, a novel, selective NK1 receptor antagonist

PubMed Central

Walpole, C S J; Brown, M C S; James, I F; Campbell, E A; McIntyre, P; Docherty, R; Ko, S; Hedley, L; Ewan, S; Buchheit, K-H; Urban, L A

1998-01-01

The in vitro and in vivo pharmacology of SDZ NKT 343 (2-nitrophenyl-carbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N-methylamide), a novel tachykinin NK1 receptor antagonist was investigated.SDZ NKT 343 inhibited [3H]-substance P binding to the human NK1 receptor in transfected Cos-7 cell membranes (IC50=0.62±0.11 nM). In comparison, in the same assay Ki values for FK888, CP 99,994, SR 140,333 and RPR 100,893 were 2.13±0.04 nM, 0.96±0.20 nM, 0.15±0.06 nM and 1.77±0.41 nM, respectively. SDZ NKT 343 showed a markedly lower affinity at rat NK1 receptors in whole forebrain membranes (IC50=451±139 nM).SDZ NKT 343 caused an increase in EC50 as well as reduction in the number of binding sites (Bmax) determined for [3H]-substance P, suggesting a non-competitive interaction at the human NK1 receptor. SDZ NKT 343 also caused a reduction in the maximum elevation of [Ca2+]i evoked by substance P (SP) in human U373MG cells and depressed the maximum [Sar9]SP sulphone-induced contraction of the guinea-pig isolated ileum. The antagonism of SP effects on U373MG cells by SDZ NKT 343 was reversible.SDZ NKT 343 showed weak affinity to human NK2 and NK3 receptors in transfected Cos-7 cells (Ki of 0.52±0.04 μM and 3.4±1.2 μM, respectively). SDZ NKT 343 was inactive in a broad array of binding assays including the bradykinin B2 receptor the histamine H1 receptor, opiate receptors and adrenoceptors. SDZ NKT 343 only weakly inhibited the voltage-activated Ca2+ and Na+currents in guinea-pig dorsal root ganglion neurones. The enantiomer of SDZ NKT 343, (R,R)-SDZ NKT 343 was about 1000 times less active at human NK1 receptors expressed in Cos-7 cell membranes.Contractions of the guinea-pig ileum by [Sar9]SP sulphone were inhibited by SDZ NKT 343 in a concentration-dependent manner, with an IC50=1.60±0.94 nM, while the enantiomer (R,R)-SDZ NKT 343 was 100 times less active (IC50=162±26 nM). In comparison, in the same assay IC50 values for other NK1 receptor antagonists CP 99,994, SR 140,333, RPR 100,893 and FK 888 were 2.90±07 nM, 0.14±0.02 nM, 11.4±2.9 nM and 2.4±0.83 nM, respectively.In anaesthetized guinea-pigs i.v. administered SDZ NKT 343 antagonized [Sar9]SP sulphone-evoked bronchoconstriction (70% reduction at 0.4 mg kg−1, i.v.). Basal airway resistance, mean arterial blood pressure and heart rate were not affected.In conclusion, SDZ NKT 343 is a highly selective NK1 receptor antagonist with high potency at the human and guinea-pig receptors. SDZ NKT 343 may be used as a potential novel therapeutic agent in human diseases where NK1 receptor hyperfunction is involved. PMID:9630347

Heart rate-lowering efficacy and respiratory safety of ivabradine in patients with obstructive airway disease: a randomized, double-blind, placebo-controlled, crossover study.

PubMed

Majewski, Sebastian; Slomka, Sebastian; Zielinska-Wyderkiewicz, Ewa; Ciebiada, Maciej; Gorski, Pawel

2012-06-01

There is substantial evidence that heart rate (HR) is a powerful predictor of mortality in both normal individuals and in patients with cardiovascular disease. The use of β-adrenoceptor antagonists (β-blockers) has confirmed the importance of lowering elevated HR in a patient's prognosis. However, these agents can have undesirable adverse effects (AEs) and due to the risk of bronchoconstriction are contraindicated in patients with obstructive airway disease. A selective bradycardic agent, without such undesirable effects, could be of therapeutic interest. Ivabradine, a new I(f) inhibitor that acts specifically on the sino-atrial node, is a pure HR-lowering agent. The objective of this study was to assess HR-lowering efficacy and respiratory safety of ivabradine in patients with asthma and chronic obstructive pulmonary disease (COPD). This was a randomized, single-center, double-blind, placebo-controlled, crossover trial. Enrolment began in May 2009, and the last patient completed the study in January 2011. The study was conducted in an ambulatory setting. A total of 40 patients completed the study (20 asthmatic patients and 20 COPD patients). Inclusion criteria were: documented diagnosis of asthma or COPD according to international guidelines, age 18-75 years, and mean HR on Holter ECG recording of ≥60 beats/min. Exclusion criteria included disease exacerbation in a previous month or inability to understand instructions on the study procedures. All patients received ivabradine 7.5 mg twice daily for 5 days and placebo twice daily for 5 days in a crossover manner, in one of the two arms of the study, with at least 2 days of washout between treatments. The main outcome measures included the difference in HR between ivabradine and placebo treatment and change in HR in comparison with baseline. Other evaluated outcomes were differences in the peak expiratory flow rate (PEFR), the daily symptom score, rescue medication consumption, and AEs. Ivabradine produced significantly lower mean HR than placebo in both groups of patients: asthma 67.4 ± 8.38 versus 82.85 ± 11.19 beats/min (p < 0.001) and COPD 69.75 ± 8.9 versus 81.05 ± 9.75 beats/min (p < 0.001). Similar results were observed for the minimal HR as well as for the maximal noted HR. In comparision with baseline, ivabradine significantly reduced HR in both groups of studied patients (all p < 0.05), whereas placebo did not have such an effect. No significant difference, in either the asthma or the COPD group, was found between ivabradine and placebo in morning and evening peak expiratory flow rate, peak expiratory flow diurnal variability, daily symptom scores, and rescue medication usage (all p > 0.05). Both treatments were well tolerated. The incidence of AEs was low and generally similar in both periods of treatment, except for visual symptoms during treatment with ivabradine, which was reported by 5% of the patients. Our study demonstrated that selective HR reduction with ivabradine is effective in patients with asthma and COPD, with no alteration in respiratory function or symptoms over the duration of the study. Ivabradine offers an interesting alternative, as an HR-lowering agent, in patients with respiratory disease and contraindications to β-blockers. Registered at www.clinicaltrials.gov (NCT01365286).

Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease.

PubMed

Chong, Jimmy; Leung, Bonnie; Poole, Phillippa

2017-09-19

Chronic obstructive pulmonary disease (COPD) is associated with cough, sputum production or dyspnoea and a reduction in lung function, quality of life and life expectancy. Apart from smoking cessation, there are no other treatments that slow lung function decline. Roflumilast and cilomilast are oral phosphodiesterase 4 (PDE 4 ) inhibitors proposed to reduce the airway inflammation and bronchoconstriction seen in COPD. This is an update of a Cochrane review first published in 2011 and updated in 2013. To evaluate the efficacy and safety of oral PDE 4 inhibitors in the management of stable COPD. We identified randomised controlled trials (RCTs) from the Cochrane Airways Trials Register (date of last search October 2016). We found other trials from web-based clinical trials registers. We included RCTs if they compared oral PDE 4 inhibitors with placebo in people with COPD. We allowed co-administration of standard COPD therapy. One review author extracted data and a second review author checked the data. We reported pooled data in Review Manager as mean differences (MD), standardised mean differences (SMD) or odds ratios (OR). We converted the odds ratios into absolute treatment effects in a 'Summary of findings' table. Thirty-four separate RCTs studying roflumilast (20 trials with 17,627 participants) or cilomilast (14 trials with 6457 participants) met the inclusion criteria, with a duration of between six weeks and one year. These included people across international study centres with moderate to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades II-IV), with a mean age of 64 years.We considered that the methodological quality of the 34 published and unpublished trials was acceptable overall. Treatment with a PDE 4 inhibitor was associated with a significant improvement in forced expiratory volume in one second (FEV 1 ) over the trial period compared with placebo (MD 51.53 mL, 95% confidence interval (CI) 43.17 to 59.90, 27 trials with 20,585 participants, moderate-quality evidence due to moderate levels of heterogeneity and risk of reporting bias). There were small improvements in quality of life (St George's Respiratory Questionnaire (SGRQ), MD -1.06 units, 95% CI -1.68 to -0.43, 11 trials with 7645 participants, moderate-quality evidence due to moderate levels of heterogeneity and risk of reporting bias) and COPD-related symptoms, but no significant change in exercise tolerance. Treatment with a PDE 4 inhibitor was associated with a reduced likelihood of COPD exacerbation (OR 0.78, 95% CI 0.73 to 0.83; 23 trials with 19,948 participants, high-quality evidence). For every 100 people treated with PDE 4 inhibitors, five more remained exacerbation-free during the study period compared with placebo (number needed to treat for an additional beneficial outcome (NNTB) 20, 95% CI 16 to 26). More participants in the treatment groups experienced non-serious adverse events compared with controls, particularly a range of gastrointestinal symptoms such as diarrhoea, nausea, vomiting or dyspepsia. For every 100 people treated with PDE 4 inhibitors, seven more suffered from diarrhoea during the study period compared with placebo (number needed to treat for an additional harmful outcome (NNTH) 15, 95% CI 13 to 17). Roflumilast in particular was associated with weight loss during the trial period and an increase in insomnia and depressive mood symptoms. There was no significant effect of treatment on non-fatal serious adverse events (OR 0.99, 95% CI 0.91 to 1.07) or mortality (OR 0.97, 95% CI 0.76 to 1.23), although mortality was a rare event during the trials. Participants treated with PDE 4 inhibitors were more likely to withdraw from the trials because of adverse effects; on average 14% in the treatment groups withdrew compared with 8% in the control groups. In people with COPD, PDE 4 inhibitors offered benefit over placebo in improving lung function and reducing the likelihood of exacerbations; however, they had little impact on quality of life or symptoms. Gastrointestinal adverse effects and weight loss were common, and safety data submitted to the US Food and Drug Administration (FDA) have raised concerns over psychiatric adverse events with roflumilast. The findings of this review give cautious support to the use of PDE 4 inhibitors in COPD. They may be best used as add-on therapy in a subgroup of people with persistent symptoms or exacerbations despite optimal COPD management. This is in accordance with the GOLD 2017 guidelines. Longer-term trials are needed to determine whether or not PDE 4 inhibitors modify FEV 1 decline, hospitalisation or mortality in COPD.

Home telemonitoring and remote feedback between clinic visits for asthma.

PubMed

Kew, Kayleigh M; Cates, Christopher J

2016-08-03

Asthma is a chronic disease that causes reversible narrowing of the airways due to bronchoconstriction, inflammation and mucus production. Asthma continues to be associated with significant avoidable morbidity and mortality. Self management facilitated by a healthcare professional is important to keep symptoms controlled and to prevent exacerbations.Telephone and Internet technologies can now be used by patients to measure lung function and asthma symptoms at home. Patients can then share this information electronically with their healthcare provider, who can provide feedback between clinic visits. Technology can be used in this manner to improve health outcomes and prevent the need for emergency treatment for people with asthma and other long-term health conditions. To assess the efficacy and safety of home telemonitoring with healthcare professional feedback between clinic visits, compared with usual care. We identified trials from the Cochrane Airways Review Group Specialised Register (CAGR) up to May 2016. We also searched www.clinicaltrials.gov, the World Health Organization (WHO) trials portal and reference lists of other reviews, and we contacted trial authors to ask for additional information. We included parallel randomised controlled trials (RCTs) of adults or children with asthma in which any form of technology was used to measure and share asthma monitoring data with a healthcare provider between clinic visits, compared with other monitoring or usual care. We excluded trials in which technologies were used for monitoring with no input from a doctor or nurse. We included studies reported as full-text articles, those published as abstracts only and unpublished data. Two review authors screened the search and independently extracted risk of bias and numerical data, resolving disagreements by consensus.We analysed dichotomous data as odds ratios (ORs) while using study participants as the unit of analysis, and continuous data as mean differences (MDs) while using random-effects models. We rated evidence for all outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation Working Group) approach. We found 18 studies including 2268 participants: 12 in adults, 5 in children and one in individuals from both age groups. Studies generally recruited people with mild to moderate persistent asthma and followed them for between three and 12 months. People in the intervention group were given one of a variety of technologies to record and share their symptoms (text messaging, Web systems or phone calls), compared with a group of people who received usual care or a control intervention.Evidence from these studies did not show clearly whether asthma telemonitoring with feedback from a healthcare professional increases or decreases the odds of exacerbations that require a course of oral steroids (OR 0.93, 95% confidence Interval (CI) 0.60 to 1.44; 466 participants; four studies), a visit to the emergency department (OR 0.75, 95% CI 0.36 to 1.58; 1018 participants; eight studies) or a stay in hospital (OR 0.56, 95% CI 0.21 to 1.49; 1042 participants; 10 studies) compared with usual care. Our confidence was limited by imprecision in all three primary outcomes. Evidence quality ratings ranged from moderate to very low. None of the studies recorded serious or non-serious adverse events separately from asthma exacerbations.Evidence for measures of asthma control was imprecise and inconsistent, revealing possible benefit over usual care for quality of life (MD 0.23, 95% CI 0.01 to 0.45; 796 participants; six studies; I(2) = 54%), but the effect was small and study results varied. Telemonitoring interventions may provide additional benefit for two measures of lung function. Current evidence does not support the widespread implementation of telemonitoring with healthcare provider feedback between asthma clinic visits. Studies have not yet proven that additional telemonitoring strategies lead to better symptom control or reduced need for oral steroids over usual asthma care, nor have they ruled out unintended harms. Investigators noted small benefits for quality of life, but these are subject to risk of bias, as the studies were unblinded. Similarly, some benefits for lung function are uncertain owing to possible attrition bias.Larger pragmatic studies in children and adults could better determine the real-world benefits of these interventions for preventing exacerbations and avoiding harms; it is difficult to generalise results from this review because benefits may be explained at least in part by the increased attention participants receive by taking part in clinical trials. Qualitative studies could inform future research by focusing on patient and provider preferences, or by identifying subgroups of patients who are more likely to attain benefit from closer monitoring, such as those who have frequent asthma attacks.

Respiratory medicine and research at McGill University: A historical perspective

PubMed Central

Martin, James G; Schwartzman, Kevin

2015-01-01

The history of respiratory medicine and research at McGill University (Montreal, Quebec) is tightly linked with the growth of academic medicine within its teaching hospitals. Dr Jonathan Meakins, a McGill medical graduate, was recruited to the Royal Victoria Hospital in 1924; as McGill’s first full-time clinical professor and Physician-in-Chief at the Royal Victoria Hospital. His focus on respiratory medicine led to the publication of his first book, Respiratory Function in Disease, in 1925. Meakins moved clinical laboratories from the Department of Pathology and placed them within the hospital. As such, he was responsible for the development of hospital-based research. Dr Ronald Christie was recruited as a postdoctoral fellow by Meakins in the early 1930s. After his fellowship, he returned to Britain but came back to McGill from St Bartholomew’s Hospital (London, United Kingdom) to become Chair of the Department of Medicine in 1955; he occupied the post for 10 years. He published extensively on the mechanical properties of the lung in common diseases such as emphysema and heart failure. Dr David Bates was among Dr Christie’s notable recruits; Bates in turn, recruited Drs Maurice McGregor, Margaret Becklake, William Thurlbeck, Joseph Milic-Emili, Nicholas Anthonisen, Charles Bryan and Peter Macklem. Bates published extensively in the area of respiratory physiology and, with Macklem and Christie, coauthored the book Respiratory Function in Disease, which integrated physiology into the analysis of disease. Dr JA Peter Paré joined the attending staff of the Royal Victoria Hospital and the Royal Edward Laurentian Hospital in 1949. A consummate clinician and teacher, he worked closely with Dr Robert Fraser, the Chair of Radiology, to write the reference text Diagnosis of Diseases of the Chest. This was a sentinel contribution in its focus on radiographic findings as the foundation for a systematic approach to diagnosis, and the correlation of these findings with pathological and clinical observations. Dr Margaret Becklake immigrated to Montreal from South Africa in 1957. Her research focused on occupational lung disease. She established the respiratory epidemiology research unit at McGill. She was renowned for her insistence on the importance of a clearly stated, relevant research question and for her clarity and insight. Dr William Thurlbeck, another South African, had developed an interest in emphysema and chronic bronchitis and applied a structure-function approach in collaboration with Peter Macklem and other respirologists. As chief of the Royal Victoria autopsy service, he used pathological specimens to develop a semiquantitative grading system of gross emphysema severity. He promoted the use of morphometry to quantify structural abnormalities. Dr James Hogg studied the functional consequences of pathological processes for lung function during his PhD studies under the joint supervision of Drs Macklem and Thurlbeck. His contributions to understanding the structural basis for chronic obstructive pulmonary disease (COPD) are numerous, reflecting his transdisciplinary knowledge of respiratory pathology and physiology. He trained other outstanding investigators such as Peter Paré Jr, with whom he founded the Pulmonary Research Laboratory in St Paul’s Hospital in Vancouver (British Columbia) in 1977. A signal event in the evolution of respiratory research at McGill was the construction of the Meakins-Christie Laboratories in 1972. These laboratories were directed by Dr Peter Macklem, a trainee of Dr Becklake’s. The research within the laboratory initially focused on respiratory mechanics, gas distribution within the lung and the contribution of airways of different sizes to the overall mechanical behaviour of the lungs. The effects of cigarette smoking on lung dysfunction, mechanisms of possible loss of lung elastic recoil in asthma and control of bronchomotor tone were all additional areas of active investigation. Dr Macklem pioneered the study of the physiological consequences of small airway pathology. Dr Joseph Milic-Emili succeeded Dr Macklem as director of the Meakins-Christie Laboratories in 1979. Milic-Emili was renowned for his work on ventilation distribution and the assessment of pleural pressure. He led the development of convenient tools for the assessment of respiratory drive. He clarified the physiological basis for carbon dioxide retention in patients with COPD placed on high inspired oxygen concentrations. Another area that captured many investigators’ attention in the 1980s was the notion of respiratory failure as a consequence of respiratory muscle fatigue. Dr Charalambos (‘Charis’) Roussos made seminal contributions in this field. These studies triggered a long-lasting interest in respiratory muscle training, in rehabilitation, and in noninvasive mechanical ventilation for acute and chronic respiratory failure. Dr Ludwig Engel obtained his PhD under the supervision of Peter Macklem and established himself in the area of ventilation distribution in health and in bronchoconstriction and the mechanics of breathing in asthma; he trained many investigators including one of the authors, Dr Jim Martin, who succeeded Milic-Emili as director of the Meakins Christie Laboratories from 1993 to 2008. Dr Martin developed small animal models of allergic asthma, and adopted a recruitment strategy that diversified the research programs at the Meakins Christie Laboratories. Dr Manuel Cosio built on earlier work with Macklem and Hogg in his development of key structure-function studies of COPD. He was instrumental in recruiting a new generation of young investigators with interests in sleep medicine and neuromuscular diseases. The 1970s and 1980s also witnessed the emergence of a topnotch respiratory division at the Montreal General Hospital, in large part reflecting the leadership of Dr Neil Colman, later a lead author of the revised Fraser and Paré textbook. At the Montreal General, areas of particular clinical strength and investigation included asthma, occupational and immunological lung diseases. In 1989, the Meakins Christie Laboratories relocated to its current site on Rue St Urbain, adjacent to the Montreal Chest Institute. Dr Qutayba Hamid, on faculty at the Brompton Hospital, joined the Meakins-Christie Labs in 1994. In addition to an outstanding career in the area of the immunopathology of human asthma, he broadened the array of techniques routinely applied at the labs and has ably led the Meakins-Christie Labs from 2008 to the present. The Meakins Christie Laboratories have had a remarkable track record that continues to this day. The basis for its enduring success is not immediately clear but it has almost certainly been linked to the balance of MD and PhD scientists that brought perspective and rigour. The diverse disciplines and research programs also facilitated adaptation to changing external research priorities. The late 1990s and the early 21st century also saw the flourishing of the Respiratory Epidemiology Unit, under the leadership of Drs Pierre Ernst, Dick Menzies and Jean Bourbeau. It moved from McGill University to the Montreal Chest Institute in 2004. This paved the way for expanded clinical and translational research programs in COPD, tuberculosis, asthma, respiratory sleep disorders and other pulmonary diseases. The faculty now comprises respiratory clinician-researchers and PhD scientists with expertise in epidemiological methods and biostatistics. Respiratory physiology and medicine at McGill benefitted from a strong start through the influence of Meakins and Christie, and a tight linkage between clinical observation and physiological research. The subsequent recruitment of talented and creative faculty members with absolute dedication to academic medicine continued the legacy. No matter how significant the scientific contributions of the individuals themselves, their most important impact resulted from the training of a large cohort of other gifted physicians and graduate students. Some of these are further described in the accompanying full-length online article. PMID:25664457