MCh-induced Bronchoconstriction Research Articles

Elevation in lung volume and preventing catastrophic airway closure in asthmatics during bronchoconstriction.

BackgroundAsthma exacerbations cause lung hyperinflation, elevation in load to inspiratory muscles, and decreased breathing capacity that, in severe cases, may lead to inspiratory muscle fatigue and respiratory failure. Hyperinflation has been attributed to a passive mechanical origin; a respiratory system time-constant too long for full exhalation. However, because the increase in volume is also concurrent with activation of inspiratory muscles during exhalation it is unclear whether hyperinflation in broncho-constriction is a passive phenomenon or is actively controlled to avoid airway closure.MethodsUsing CT scanning, we measured the distensibility of individual segmental airways relative to that of their surrounding parenchyma in seven subjects with asthma and nine healthy controls. With this data we tested whether the elevation of lung volume measured after methacholine (MCh) provocation was associated with airway narrowing, or to the volume required to preventing airway closure. We also tested whether the reduction in FVC post-MCh could be attributed to gas trapped behind closed segmental airways.FindingsThe changes in lung volume by MCh in subjects with and without asthma were inversely associated with their reduction in average airway lumen. This finding would be inconsistent with hyperinflation by passive elevation of airway resistance. In contrast, the change in volume of each subject was associated with the lung volume estimated to cause the closure of the least stable segmental airway of his/her lungs. In addition, the measured drop in FVC post MCh was associated with the estimated volume of gas trapped behind closed segmental airways at RV.ConclusionsOur data supports the concept that hyperinflation caused by MCh-induced bronchoconstriction is the result of an actively controlled process where parenchymal distending forces on airways are increased to counteract their closure. To our knowledge, this is the first imaging-based study that associates inter-subject differences in whole lung behavior with the interdependence between individual airways and their surrounding parenchyma.

Role of prostaglandin I2 in the bronchoconstriction-triggered cough response in guinea pigs

Purpose/Aim of the study: Methacholine chloride (MCh) inhalation causes bronchoconstriction and cough. Following MCh-induced bronchoconstriction, metabolic products of prostaglandin I2 (PGI2) increase in bronchoalveolar lavage fluid (BALF), suggesting that PGI2 plays a role in the cough response. Accordingly, we used an experimental guinea pig model to evaluate the role of PGI2 in the bronchoconstriction-triggered cough response. Materials and Methods: Experiment 1: The concentration of PGF1α, a stable metabolite of PGI2, in BALF was assessed in animals exposed to nebulized MCh and animals exposed to nebulized saline. Experiment 2: Bronchoconstriction and cough were assessed in 3 groups of animals after MCh inhalation (a saline group, low-dose PGI2 group, and high-dose PGI2 group). Enhanced pause (Penh) was used as a measure of bronchoconstriction. Experiment 3: Bronchoconstriction and cough were assessed in 3 groups of animals (groups administered saline, a low dose of a specific antagonist of the PGI2 receptor (IP antagonist), and a high dose of a specific IP antagonist). Results: The PGF1α concentration in BALF was significantly higher in the bronchoconstriction group than in the control group. In animals administered high-dose PGI2, the MCh-induced increase in Penh was significantly suppressed, and the number of coughs induced by bronchoconstriction was significantly decreased. In animals treated with a high dose of an IP antagonist, the MCh-induced increase in Penh was not affected, and the number of coughs increased. Conclusions: Our results suggest that PGI2 ameliorates a bronchoconstriction-triggered cough. The measurement and administration of PGI2 may assist in the diagnosis and treatment, respectively, of the cough response triggered by bronchoconstriction.

Mucins and Their Sugars. Critical Mediators of Hyperreactivity and Inflammation.

Excessive mucus causes severe airflow obstruction in fatal asthma. It is also present in mild to moderate disease, but is poorly understood and treated. Mucus overproduction is associated with dysregulated expression of the mucins MUC5AC and MUC5B. Whereas increased MUC5AC is a consistent finding, MUC5B varies-remaining stably produced in some patients but strongly repressed in others (>90%). Patients with lower MUC5B display worsened asthma phenotypes including airway hyperreactivity (AHR) to methacholine (MCh) and eosinophilic inflammation. To better understand the roles of mucins in asthma, we generated Muc5ac and Muc5b knockout ((-/-)) mice. AHR to MCh was abolished in antigen-challenged Muc5ac(-/-) mice, due to prevention of heterogeneous mucous plugging that occurred in allergic wild-type mice during MCh-induced bronchoconstriction. Thus, in addition to the established role of smooth muscle-mediated airway narrowing, Muc5ac is an essential noncontractile AHR component. We also found that, unlike Muc5ac(-/-) mice, Muc5b-deficient mice were not protected from asthma phenotypes. Furthermore, whereas inflammation was unaffected by Muc5ac deficiency, it was exaggerated in the absence of Muc5b. On the basis of these differential effects, we are now determining how asthma phenotypes are regulated by mucin isoform specificity. Glycosylation is dramatically different: Muc5ac is heavily fucosylated whereas Muc5b is mainly sialylated. Fucosylation increases mucus viscoelasticity, and FUT2, the enzyme that catalyzes mucin α1,2-fucosylation, is associated with severe asthma exacerbation risk. Sialylation is required for binding to siglec (sialic acid-binding immunoglobulin-like lectin) receptors on leukocytes. Eosinophils express Siglec-F (mouse) or Siglec-8 (human). Engagement by sialoside ligands induces eosinophil apoptosis, and Muc5b via sialylated termini that require the α2,3-sialyltransferase ST3Gal3 for synthesis binds Siglec-F and induces apoptosis in mouse eosinophils. Because Muc5b is required for host defense in mouse lungs, inhibiting MUC5AC while preserving or enhancing MUC5B functions may be effective for treating asthma.

Bronchoconstriction induced by inhaled methacholine delays desflurane uptake and elimination in a piglet model

Bronchoconstriction is a hallmark of asthma and impairs gas exchange. We hypothesized that pharmacokinetics of volatile anesthetics would be affected by bronchoconstriction. Ventilation/perfusion (VA/Q) ratios and pharmacokinetics of desflurane in both healthy state and during inhalational administration of methacholine (MCh) to double peak airway pressure were studied in a piglet model.In piglets, MCh administration by inhalation (100μg/ml, n=6) increased respiratory resistance, impaired VA/Q distribution, increased shunt, and decreased paO2 in all animals. The uptake and elimination of desflurane in arterial blood was delayed by nebulization of MCh, as determined by Micropore Membrane Inlet Mass Spectrometry (wash-in time to P50, healthy vs. inhalation: 0.5min vs. 1.1min, to P90: 4.0min vs. 14.8min). Volatile elimination was accordingly delayed.Inhaled methacholine induced severe bronchoconstriction and marked inhomogeneous VA/Q distribution in pigs, which is similar to findings in human asthma exacerbation. Furthermore, MCh-induced bronchoconstriction delayed both uptake and elimination of desflurane. These findings might be considered when administering inhalational anesthesia to asthmatic patients.

Sevoflurane and desflurane protect cholinergic-induced bronchoconstriction of hyperreactive airways in rabbits

The potential of desflurane to alter respiratory mechanics in the presence of bronchial hyperresponsiveness (BHR) is still a subject of debate. Accordingly, we evaluated the bronchoprotective potential of desflurane compared with sevoflurane following cholinergic lung constriction in rabbits with normal and hyperreactive airways. The input impedance of the respiratory system (Zrs) was measured during midazolam-based anesthesia before and during intravenous infusions of increasing doses of methacholine (MCh). The rabbits in the control group (Group C) were then randomized to receive either sevoflurane 1 MAC followed by desflurane 1 MAC or vice versa, whereas ovalbumin-sensitized rabbits received sevoflurane followed by desflurane (Group S-SD) or vice versa (Group S-DS). Baseline Zrs measurements and the MCh provocations were repeated under the maintenance of each volatile agent. Airway resistance (Raw), tissue damping (G), and elastance data were obtained from Zrs by model fitting. Similar bronchoprotective effects of sevoflurane and desflurane against MCh-induced bronchoconstriction were observed independently of the severity of the bronchospasm and the presence of BHR. With sevoflurane, the decreases in Raw ranged from 22 (8.8)% to 44 (12)%, and with desflurane, they ranged from 22 (8.7)% to 50 (12)%. The increases in G reflecting the enhanced ventilation heterogeneities in the lung periphery were not affected by the volatile agents. If the contractile stimulus is cholinergic in origin, sevoflurane and desflurane exert similar bronchoprotective potentials to act against lung constriction independent of the presence of BHR. These volatile anesthetics otherwise lack a potential to improve the enhanced ventilation heterogeneities that develop particularly in the presence of BHR.

Effect of IL‐1β and TNF‐αvs IL‐13 on bronchial hyperresponsiveness, β2‐adrenergic responses and cellularity of bronchial alveolar lavage fluid

1 Levels of IL-13, IL-1β and TNF-α are increased in bronchial lavage fluid of asthmatics and induce certain significant features of bronchial asthma including airway hyper-responsiveness (AHR). In this study, we have investigated the effect of these cytokines in naïve mice and those sensitized to ovalbumin (OVA) on bronchoconstrictions to methacholine (MCh) and the functional antagonism induced by β2 -adrenoceptor agonism. 2 Naïve or OVA-sensitized mice were treated for 3 days with IL-1β (250 U), TNF-α (150 ng), IL-13 (5 μg) or combinations of IL-1β with TNF-α or IL-1β with IL-13. MCh-induced bronchoconstriction and its sensitivity to albuterol, a β2-adrenoceptor agonist, was assessed 24 h after the last cytokine administration. 3 In naïve mice, responsiveness to MCh was significantly increased by the combination of IL-1β and TNF-α, IL-13 alone or in combination with IL-1β, but not by treatment with IL-1β or TNF-α alone. Similar results were obtained in OVA-sensitized mice except that treatment with IL-13 alone did not increase sensitivity to MCh. 4 In naïve mice, albuterol sensitivity was only significantly attenuated by treatment with IL-1β and TNF-α in combination. In mice sensitized to OVA, albuterol sensitivity was significantly attenuated by treatment with TNF-α, IL-13 or IL-13 in combination with IL-1β. 5 Inflammatory cell influx was increased by all cytokines and combinations except IL-13 in OVA-sensitized mice. 6 Our data do not support a link between inflammatory cell influx and AHR. In addition, the mechanism of IL-13-induced AHR might involve decreased β2-adrenoceptor responsiveness.

Impaired response to deep inspiration in obesity.

Deep inspirations modulate airway caliber and airway closure and their effects are impaired in asthma. The association between asthma and obesity raises the question whether the deep inspiration (DI) effect is also impaired in the latter condition. We assessed the DI effects in obese and nonobese nonasthmatics. Thirty-six subjects (17 obese, 19 nonobese) underwent routine methacholine (Mch) challenge and 30 of them also had a modified bronchoprovocation in the absence of DIs. Lung function was monitored with spirometry and forced oscillation (FO) [resistance (R) at 5 Hz (R5), at 20 Hz (R20), R5-R20 and the integrated area of low-frequency reactance (AX)]. The response to Mch, assessed with area under the dose-response curves (AUC), was consistently greater in the routine challenge in the obese (mean ± SE, obese vs. nonobese AUC: R5: 15.7 ± 2.3 vs. 2.4 ± 2.0, P < 0.0005; R20: 5.6 ± 1.4 vs. 1.4 ± 1.2, P = 0.027; R5-R20: 10.2 ± 1.6 vs. 0.9 ± 0.1.4, P < 0.0005; AX: 115.6 ± 22.0 vs. 1.5 ± 18.9, P < 0.0005), but differences between groups in the modified challenge were smaller, indicating reduced DI effects in obesity. Given that DI has bronchodilatory and bronchoprotective effects, we further assessed these components separately. In the obese subjects, DI prior to Mch enhanced Mch-induced bronchoconstriction, but DI after Mch resulted in bronchodilation that was of similar magnitude as in the nonobese. We conclude that obesity is characterized by increased Mch responsiveness, predominantly of the small airways, due to a DI effect that renders the airways more sensitive to the stimulus.

Tidal Airway Closure During Bronchoconstriction in Asthma: Usefulness of Lung Volume Measurements

Background. The presence and extent of tidal airway closure is not routinely assessed in asthma. The objective of this study was to provide a simple functional tool able to detect tidal airway closure during bronchoconstriction in asthma. Methods. In 20 subjects with mild persistent asthma, we sequentially performed the measurement of functional residual capacity (FRC) by body plethysmography (pleth) and multibreath helium dilutional technique (He) and then computed residual volume (RV) and total lung capacity (TLC) at baseline, at the end of methacholine (MCh) challenge and after bronchodilator (albuterol). Measurements and main results. Despite substantial bronchoconstriction (fall in FEV1 = 35 ± 7%), TLC,pleth did not change following MCh challenge, but FRC,pleth because of dynamic pulmonary hyperinflation (+0.68 ± 0.54 L) and RV,pleth because of air trapping (+0.65 ± 0.37 L), invariably increased (on average by 22% and 46%, respectively). In contrast, FRC,He (and RV,He and TLC,He) could either increase, as seen in 13 subjects (Group I), or decrease, as seen in 7 subjects (Group II). Hence, the difference between FRC,pleth and FRC,He (Diff. FRC,pleth – FRC,He) was much greater in Group II (1.03 ± 0.41 L) than in Group I (0.22 ± 0.20 L) (p < .01). No functional differences were found between the two groups, including baseline PD20FEV1 and absolute and percent change in forced vital capacity (FVC) at the end of the MCh challenge. Conclusions. Comparison between FRC,pleth and FRC,He is useful to identify asthmatics prone to tidal airway closure during MCh-induced bronchoconstriction and Diff. FRC,pleth – FRC,He can be used to measure the overall unventilated lung volume upstream of the airways closed at end-expiratory lung volume (EELV).

HIGHLIGHTS FROM THE LITERATURE

HIGHLIGHTS FROM THE LITERATURE

Effects of Obesity on Perceptual and Mechanical Responses to Bronchoconstriction in Asthma

The influence of obesity on the perception of respiratory discomfort during acute bronchoconstriction in asthma is unknown. We hypothesized that the respiratory impairment associated with an increased body mass index (BMI) would predispose to greater perceived symptom intensity during acute airway narrowing. We therefore compared relationships between induced changes in dyspnea intensity and lung function during methacholine (MCh) bronchoprovocation in obese (OBA) and normal-weight (NWA) individuals with asthma of mild to moderate severity. High-dose MCh challenge tests to a maximum 50% decrease in FEV(1) were conducted in 51 NWA (BMI, 18.5-24.9 kg/m(2); 29% male) and 45 OBA (BMI, 30.1-51.4 kg/m(2); 33% male) between 20 and 60 years of age. Serial spirometry, inspiratory capacity (IC), plethysmographic end-expiratory lung volume (EELV) and dyspnea intensity using the Borg scale were measured throughout bronchoprovocation. Spirometry and airway sensitivity were similar in both groups; baseline EELV was lower (P < 0.0005) and IC was higher (P = 0.007) in OBA compared with NWA. From baseline to PC(20), EELV increased more in OBA (20% predicted) than NWA (13% predicted) (P = 0.008) with concomitant greater reductions in IC (P < 0.0005). Dyspnea ratings were not different for a given FEV(1) or IC across groups. By mixed effects regression analysis, relationships between induced dyspnea and changes in lung function parameters were not influenced by BMI, sex, or their interaction. Perceptual responses to MCh-induced bronchoconstriction and lung hyperinflation were similar in obese and normal-weight individuals with asthma despite significant group differences in baseline lung volumes.

BRONCHOCONSTRICTION-TRIGGERED COUGH IN CONSCIOUS GUINEA PIGS

The aim of the present study was to investigate the relation between bronchoconstriction and cough induced by methacholine (Mch) inhalation and to elucidate the role of C-fibers and rapidly adapting irritant receptors (RARs) in these reactions in conscious guinea pigs. The authors measured enhanced pause (Penh) as an index of bronchoconstriction and also measured the number of coughs induced by Mch inhalation in conscious guinea pigs. The authors also examined the effects of pretreatment with procaterol, capsaicin desensitization and moguisteine on these responses. There was a significant positive correlation between the increase in Penh and the number of coughs induced by Mch inhalation. Procaterol (0.1 mg/kg, intraperitoneal [i.p.]) completely abolished both the Mch-induced increase in Penh and cough. Capsaicin desensitization had no effect on Penh or the number of coughs. Moguisteine (0.02, 0.2, or 2 mg/kg, i.p.) dose-dependently inhibited the number of coughs but not the increase in Penh induced by Mch inhalation. Bronchoconstriction causes cough via RARs, but not C-fibers. Neither RARs nor C-fibers are involved in Mch-induced bronchoconstriction itself.

Adenosine 5'-monophosphate in asthma: gas exchange and sputum cellular responses

Adenosine 5'-monophosphate (AMP) bronchoprovocation reproduces the lung function abnormalities that occur spontaneously during acute asthma and detects peripheral airway inflammation better than direct bronchoconstrictive agents. Pulmonary gas exchange disturbances may reflect changes in small airways related to airway inflammation rather than bronchoconstriction alone. The present authors investigated whether AMP induced a greater imbalance in the ventilation/perfusion ratio than methacholine (MCh), at an equivalent degree of bronchoconstriction, with and without salbutamol pre-medication. In total, 36 asthmatics were studied in three randomised, double-blind, crossover studies: 1) before and after AMP or MCh; 2) before and 30 min after salbutamol or placebo, followed by AMP; or 3) MCh challenge. Sputum was collected before and 4 h post-challenge. Compared with MCh, AMP provoked similar pulmonary gas exchange abnormalities at an equivalent degree of intense bronchoconstriction (forced expiratory volume in one second decrease of 28-44%). While salbutamol blocked AMP- or MCh-induced bronchoconstriction, arterial oxygen tension (P(a,O(2))) and alveolar-arterial oxygen tension difference (P(A-a,O(2))) disturbances induced by AMP and MCh were only partially blocked (P(a,O(2)) by 46 and 42%, respectively; P(A-a,O(2)) by 58 and 57%, respectively). Compared with MCh, AMP increased the percentage of neutrophils (mean+/-se increased from 28+/-4% to 38+/-4%), but this increase did not occur after salbutamol pre-treatment. Both adenosine 5'-monophosphate and methacholine induced similar peripheral airway dysfunction. The fully inhibited adenosine 5'-monophosphate-induced neutrophilia with residual hypoxaemia observed after salbutamol treatment is probably related to beta(2)-agonists acting on both bronchial and pulmonary circulation.

Glucocorticoids reverse IL‐1β‐induced impairment of β‐adrenoceptor‐mediated relaxation and up‐regulation of G‐protein‐coupled receptor kinases

1. The aim of the present study was to examine the effects of glucocorticoid dexamethasone on airway responsiveness to albuterol after intratracheal instillation of saline or IL-1beta in Brown-Norway rats in vivo and to elucidate the molecular mechanism of this effect. 2. IL-1beta caused a significant reduction in albuterol-mediated relaxation to protect against MCh-induced bronchoconstriction. Dexamethasone attenuated the IL-1beta-induced impaired relaxation while alone had no effect when compared to rats treated identically with saline. 3. The density of beta(2)-adrenoceptors was significantly reduced in lung membranes harvested from IL-1beta-treated rats, which was associated with impaired isoproterenol- and forskolin-stimulated cyclic AMP accumulation and adenylyl cyclase (AC) activity ex vivo. Dexamethasone did not prevent IL-1beta-induced down-regulation of beta(2)-adrenoceptors but completely blocked IL-1beta-induced impairment of cyclic AMP accumulation and AC activity stimulated by isoproterenol and forskolin. 4. The inhibitory G-protein subtypes, G(ialpha1), G(ialpha2) and G(ialpha3), were detected in lung membranes prepared from all groups of rats but the intensity of G(ialpha1) and G(ialpha2) was markedly increased in IL-1beta-treated rats, which were not prevented by dexamethasone. 5. The activity of cytosolic GRK and the expression of GRK2 and GRK5 were elevated in the lung of IL-1beta-treated rats, which were completely abolished by dexamethasone. 6. These results indicate that treatment of rats with IL-1beta results in desensitization of pulmonary beta(2)-adrenoceptors. In light of data obtained in this study, we propose that both the decrease in AC activity and the increase in GRK activity, which are reversed by dexamethasone, may underlie beta(2)-adrenoceptor desensitization.

The bronchoprotective efficacy of salbutamol inhaled from a new metered-dose powder inhaler compared with a conventional pressurized metered-dose inhaler connected to a spacer

The aim of this study was to compare the efficacy of 100 μg of salbutamol inhaled from a new metered-dose powder inhaler (MDPI, Leiras Taifun ®, Finland) with that of a same dose of salbutamol inhaled from a conventional pressurized metered-dose inhaler with a large volume spacer (pMDI+S) in protecting against methacholine (Mch) induced bronchoconstriction. This was a 3 day, randomized, cross-over, partly blinded, placebo-controlled multicentre study where the pMDI+S was used as an open control. Twenty-six asthmatic outpatients with a baseline FEV 1≥60% of predicted and with bronchial hyperreactivity (PD 20FEV 1≤890 μg of Mch) were studied. On each study day the patients underwent an Mch provocation 30 min after inhaling placebo from the MDPI or a dose of 100 μg of salbutamol from the MDPI and from the pMDI+S. PD 20 FEV 1 and dose-response slope [DRS; maximal change in FEV 1 (%)/dose of Mch (μmol)] were used to evaluate efficacy. The median values of PD 20 FEV 1 were 250, 622 and 1737 μg after placebo MDPI, salbutamol pMDI+S and salbutamol MDPI, respectively. The corresponding DRS values were − 11.0%, − 4.5% and − 2.0% μmol −1. With both parameters, all differences were statistically significant ( P<0·05). In conclusion, 100 μg of salbutamol inhaled from Leiras Taifun ® MDPI offers better protection against Mch-induced bronchoconstriction than 100 μg of salbutamol from a pMDI connected to a large volume spacer device.

Partitioning airway and lung tissue resistances in humans: effects of bronchoconstriction.

The contribution of airway resistance (Raw) and tissue resistance (Rti) to total lung resistance (RL) during breathing in humans is poorly understood. We have recently developed a method for separating Raw and Rti from measurements of RL and lung elastance (EL) alone. In nine healthy, awake subjects, we applied a broad-band optimal ventilator waveform (OVW) with energy between 0.156 and 8.1 Hz that simultaneously provides tidal ventilation. In four of the subjects, data were acquired before and during a methacholine (MCh)-bronchoconstricted challenge. The RL and EL data were first analyzed by using a model with a homogeneous airway compartment leading to a viscoelastic tissue compartment consisting of tissue damping and elastance parameters. Our OVW-based estimates of Raw correlated well with estimates obtained by using standard plethysmography and were responsive to MCh-induced bronchoconstriction. Our data suggest that Rti comprises approximately 40% of total RL at typical breathing frequencies, which corresponds to approximately 60% of intrathoracic RL. During mild MCh-induced bronchoconstriction, Raw accounts for most of the increase in RL. At high doses of MCh, there was a substantial increase in RL at all frequencies and in EL at higher frequencies. Our analysis showed that both Raw and Rti increase, but most of the increase is due to Raw. The data also suggest that widespread peripheral constriction causes airway wall shunting to produce additional frequency dependence in EL.

Inhalation of nitric oxide modulates adult human bronchial tone.

We studied whether nitric oxide (NO), added at 80 ppm to inspired gas, can exert a bronchodilatory effect in humans. Four groups were studied: (1) healthy adult volunteers (n = 6), (2) adult subjects with hyperreactive airways (n = 6) during provocation with inhaled methacholine (MCh), (3) patients with bronchial asthma (n = 13), and (4) patients with chronic obstructive pulmonary disease (COPD, n = 6). All subjects were studied in a body plethysmograph, measuring volume-corrected specific airway conductance (SGaw). No patient or volunteer reacted with bronchoconstriction during NO inhalation. Nitric oxide did not affect SGaw in healthy volunteers or in patients with COPD. Inhaled NO modulated the MCh-induced bronchoconstriction toward dilatation. In patients with bronchial asthma, SGaw increased (p < 0.05) from 0.4 +/- 0.1 to 0.6 +/- 0.2 (kPa.s)-1. In a succeeding test with inhalation of a beta 2-agonist immediately after NO inhalation, a more marked increase in SGaw was seen, to 1.2 +/- 0.3 (kPa.s)-1 (p < 0.001). We conclude that NO inhaled at 80 ppm has no effect on airway tone in healthy volunteers, but modulates the response to MCh provocation toward bronchodilation. It exerts a weak bronchodilatory effect in bronchial asthma, but not in COPD.

Expiratory airflow limitation and hyperinflation during methacholine-induced bronchoconstriction.

To investigate the role of airflow limitation on the increase of end-expiratory lung volume (EELV) during bronchoconstriction, nine stable asthmatic subjects and seven healthy subjects were challenged with inhaled methacholine (MCh). Changes in airway caliber were assessed by using forced expiratory volume in 1 s, partial forced expiratory flow at 50% of control forced vital capacity, and specific airway conductance. To detect airflow limitation, tidal flow-volume curves were superimposed on partial forced flow-volume curves at absolute lung volume. The electromyogram of the diaphragm was recorded by surface electrodes in four asthmatic and four healthy subjects, and the electrical diaphragmatic activity (DIA) during expiration was expressed as a percentage of the duration of expiratory time. In 10 subjects (9 asthmatic and 1 healthy) the partial forced expiratory flow recorded after some MCh dose impinged on tidal expiratory flow recorded before MCh. When this occurred it was associated with an increase in EELV by 0.54 +/- 0.07 (SE) liter (P < 0.001), which was larger than that occurring when lower MCh doses (0.11 +/- 0.04 liter, P < 0.05) were used, and with a moderate increase in DIA of 15 +/- 2.5% (P < 0.01). Six healthy subjects did not increase EELV after MCh despite a significant degree of bronchoconstriction; in these subjects tidal expiratory flow never impinged on forced expiratory flow, and DIA never increased. These results suggest that hyperinflation during MCh-induced bronchoconstriction is triggered by dynamic compression of the airways and is associated with moderate increase of DIA during expiration.

Effect of a thromboxane receptor antagonist on PGD2- and allergen-induced bronchoconstriction

In this study we investigated the effect of the selective and potent thromboxane A2 (TxA2) receptor antagonist GR32191 on smooth muscle contraction induced by the TxA2 analogue U46619, prostaglandin (PG) D2, PGF2 alpha, and methacholine (MCh) in guinea pig airways in vitro and the airways response provoked by inhaled PGD2 and MCh in asthmatic subjects in vivo. GR32191 antagonized competitively the contractile responses of all three prostanoids to a similar degree but had no effect on MCh-induced contractions. In asthmatic subjects GR32191, in a single oral dose of 80 mg, did not affect base-line airway caliber or MCh-induced broncho-constriction but caused significant inhibition of PGD2-induced bronchoconstriction, displacing the concentration-response curves to the right by greater than 10-fold. The effect of the same oral dose of GR32191 on allergen-induced immediate bronchoconstriction was subsequently investigated in allergic asthmatic subjects. In individual subjects, GR32191 inhibited to varying degrees the overall bronchoconstrictor response, with the maximum effect occurring between 10 and 30 min after allergen challenge. These studies suggest that prostanoids contribute to the immediate bronchoconstriction induced by inhaled allergen in allergic asthmatics, and that this effect is mediated by stimulation of a thromboxane receptor.

Effect of lung volume on interrupter resistance in cats challenged with methacholine.

To examine the effects of changes in lung volume on the magnitude of maximal bronchoconstriction, seven anesthetized, paralyzed, tracheostomized cats were challenged with aerosolized methacholine (MCh) and respiratory system resistance (Rss) was measured at different lung volumes using the interrupter technique. Analysis of the pressure changes following end-inspiratory interruptions allowed us to partition Rss into two quantities with the units of resistance, one (Rinit) corresponding to the resistance of the airways and the other (Rdif) reflecting the viscoelastic properties of the tissues of the respiratory system as well as gas redistribution following interruption of flow. Rinit and Rdif were used to construct concentration-response curves to MCh. Lung volume was increased by the application of 5, 10, and 15 cmH2O of positive end-expiratory pressure. The curve for Rinit reached a plateau in all cats, demonstrating a limit to the degree of MCh-induced bronchoconstriction. The mean value of Rinit (cmH2O.ml-1.s) for the group under control conditions was 0.011 and rose to 0.058 after maximal bronchoconstriction; the volume at which the flow was interrupted was 11.5 +/- 0.5 (SE) ml/kg above functional residual capacity (FRC). It then fell progressively to 0.029 at 21.2 +/- 0.8 ml/kg above FRC, 0.007 at 35.9 +/- 1.3 ml/kg above FRC, and 0.005 at 52.0 +/- 1.8 ml/kg above FRC. Cutting either the sympathetic or parasympathetic branches of the vagi had no significant effect on the lung volume-induced changes in MCh-induced bronchoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)