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PubMed2001

Inflammatory and mechanical factors of allergen-induced bronchoconstriction in mild asthma and rhinitis.

We studied whether different bronchial responses to allergen in asthma and rhinitis are associated with different bronchial inflammation and remodeling or airway mechanics. Nine subjects with mild asthma and eight with rhinitis alone underwent methacholine and allergen inhalation challenges. The latter was preceded and followed by bronchoalveolar lavage and bronchial biopsy. The response to methacholine was positive in all asthmatic but in only two rhinitic subjects. The response to allergen was positive in all asthmatic and most, i.e., five, rhinitic subjects. No significant differences between groups were found in airway inflammatory cells or basement membrane thickness either at baseline or after allergen. The ability of deep inhalation to dilate methacholine-constricted airways was greater in rhinitis than in asthma, but it was progressively reduced in rhinitis during allergen challenge. We conclude that 1) rhinitic subjects may develop similar airway inflammation and remodeling as the asthmatic subjects do and 2) the difference in bronchial response to allergen between asthma and rhinitis is associated with different airway mechanics.

Adult↗
PubMed2004

Acetaldehyde induces histamine release from human airway mast cells to cause bronchoconstriction.

BACKGROUND: Approximately half of the Japanese asthmatics experience exacerbation of asthma after alcohol consumption. We previously reported that this phenomenon is probably caused by histamine release from mast cells by acetaldehyde stimulation. However, no reports have described the effects of acetaldehyde on human airway mast cells. The purpose of the present study was to demonstrate acetaldehyde-induced histamine release from human airway mast cells with subsequent airway smooth muscle contraction and to investigate the ensuing mechanisms. METHODS: Human tissue samples were prepared from the lungs resected from patients with lung cancer. The effect of acetaldehyde on airway muscle tone and the concentration of chemical mediators released in the organ bath were measured before and after acetaldehyde stimulation. Mast cells were prepared from lung parenchyma by the immunomagnetic method and then stimulated with acetaldehyde to determine the chemical mediators released. RESULTS: Acetaldehyde (>3 x 10(-4) M) increased airway muscle tone, which was associated with a significant increase in the release of histamine, but not thromboxane B2 or cysteinyl-leukotrienes. A histamine (H1 receptor) antagonist completely inhibited acetaldehyde-induced bronchial smooth muscle contraction. Acetaldehyde also induced a significant histamine release from human lung mast cells and degranulation of mast cells. CONCLUSIONS: The present results strongly suggest that acetaldehyde stimulates human airway mast cells to release histamine, which may be involved in bronchial smooth muscle contraction following alcohol consumption.

Acetaldehyde↗
PubMed1994

Bronchoconstriction occurring during exercise in asthmatic subjects.

To demonstrate physiologic changes associated with asthma symptoms that many patients with asthma develop during exercise, we used sustained constant-load and interval exercise protocols with subjects breathing dry room temperature air. In constant-load exercise, subjects pedaled a stationary bicycle at 50% of their maximal power capacity for 36 min. In interval protocols, subjects pedaled at 60% of maximal capacity for 6 min and then 40% of maximal for 6 min; the 12-min cycle was repeated three times for a total exercise time of 36 min. Maximal expiratory flow versus volume maneuvers (MEFV) were obtained before, at 6-min intervals during, and at 5-min intervals after exercise. Changes in peak expiratory flow (PEF), forced expiratory volume in 1 s (FEV1), and forced expiratory flow at 50% of pre-exercise vital capacity (FEF50) were compared with pre-exercise values. Within 15 min after a maximal 1-min incremental exercise protocol, mean flows decreased compared with pre-exercise (PEF, mean -22%, range -46 to 5%; FEV1, mean -21%, range -42 to -3%; FEF50, mean -41%, range -80 to 3%; all p < 0.05). There were no significant changes in MEFV flows until 18 min of constant-load exercise, when FEV1 and FEF50 fell (FEV1, mean -6%, range -15 to 2%; FEF50, mean -14%, range -32 to 6%; both p < 0.05), although changes in PEF were minimal and were not significantly different compared with pre-exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Reversal of bronchoconstriction by inhaled nitric oxide. Histamine versus methacholine.

Using high-resolution CT (HRCT), which measures changes in innervated airways greater than 1 mm in diameter, we compared the ability of nitric oxide (NO) to dilate airways preconstricted with histamine and methacholine in five anesthetized dogs. After the airways were preconstricted, NO was inhaled in concentrations of 100, 200, and 400 ppm. Additionally, histamine was given with and without atropine and methylene blue. Data were analyzed by one-way analysis of variance. Histamine and methacholine decreased airway area to a similar extent: 60 +/- 3% (mean +/- SEM) and 63 +/- 3% of control, respectively (p = 0.85). Atropine completely reversed the histamine-induced constriction (255 +/- 19%). NO also completely reversed histamine-induced airway constriction in a dose-related fashion. The airway area went from 60 +/- 3% during histamine infusion to 85 +/- 5, 102 +/- 5, and 111 +/- 10% of control, respectively (p < 0.01), after doses of 100, 200, and 400 ppm NO. Methylene blue partially inhibited the reversal by 200 ppm NO of histamine-induced constriction. In contrast, NO only partially reversed methacholine-induced constriction. NO at 100, 200, and 400 ppm partially attenuated the methacholine-induced airway constriction. Airway area went from 63 +/- 3 to 67 +/- 3, 75 +/- 3, and 75 +/- 2% of control, respectively (p < 0.01). We conclude that NO relaxes canine conducting airways by indirect mechanisms as well as by directly relaxing the airway smooth muscle.

Administration, Inhalation↗
PubMed1994

Nonbronchodilator effects of inhaled beta 2 agonists. Greater protection against adenosine monophosphate- than methacholine-induced bronchoconstriction in asthma.

There has been controversy about possible beneficial effects of beta agonists on airway function in asthma, in addition to their effects on airway smooth muscle. We compared the protective effects of terbutaline on bronchoconstrictor responses to methacholine, which constricts smooth muscle directly, adenosine 5'-monophosphate (AMP), which acts indirectly by mast cell activation, and sodium metabisulfite (MBS), which stimulates sensory nerves, in 15 mild asthmatic subjects in a randomized double-blind study carried out in two phases. In the first phase 12 subjects inhaled two doses of 0.5 and 2.5 mg terbutaline or placebo administered as a dry power (Tubohaler) 20 min before challenge with methacholine and AMP. Each subject received increasing doubling doses of methacholine and AMP nebulized from a dosimeter. Challenges were terminated when FEV1 fell by 20% from baseline (PC20). In the second phase 10 subjects (seven of whom had participated in Phase 1) inhaled 0.5 mg terbutaline or placebo before similar challenge with methacholine and MBS. In Phase 1 terbutaline inhibited the bronchoconstrictor response to methacholine by 2.1 and 3.3 doubling doses but caused a significantly greater inhibition of the response to AMP of 3.4 and 4.8 doubling doses after 0.5 and 2.5 mg, respectively. In the second phase 0.5 mg terbutaline had equivalent effects on responses to both methacholine and MBS of 2.6 and 2.2 doubling dilutions, respectively. This effect on methacholine and MBS implies functional antagonism of airway smooth muscle. The enhanced effect on AMP implies an additional non-smooth muscle action that may involve suppression of airway mast cell function.

Adenosine Monophosphate↗
PubMed1995

Association between late allergic bronchoconstriction in the rat and allergen-stimulated lymphocyte proliferation in vitro.

T lymphocytes are potentially of importance in determining the inflammatory response in the airways after allergen challenge. We hypothesized that the proliferative response of lymphocytes on exposure to allergen in vitro would be associated with the magnitude of the airway response in vivo after inhalational challenge. We studied Brown Norway rats that were actively sensitized with ovalbumin (OA) in aluminum hydroxide gel using Bordetella pertussis as an adjuvant. Two weeks later, blood mononuclear cells were isolated, and their proliferative response to culture with OA was measured with 3H-thymidine incorporation. Subsequently, the animals were anesthetized and challenged with aerosolized OA. Early allergic response (ER) and late (LR) allergic response were determined from the changes in pulmonary resistance (RL). Both significant ER and LR were observed in sensitized and challenged animals. The LR (measured as the area under the curve of RL against time) had a median value of 15.2 and ranged from 0.1 to 81.1 units. Lymphocyte proliferation occurred on exposure to OA (34,336 +/- 7,447 cpm) but less than after the mitogen Concanavalin A (250,685 +/- 76,676 cpm). The stimulation index (OA-stimulated 3H-thymidine incorporation standardized for baseline incorporation) was positively correlated with the magnitude of the late response. Interleukin-2 was significantly increased in the supernatant of cultured mononuclear cells exposed to OA, confirming T-cell activation. We conclude that the capacity of sensitized peripheral blood lymphocytes to respond to allergens may determine the magnitude of late airway responses.

Airway Resistance↗
PubMed1996

Inhaled PGE2 prevents aspirin-induced bronchoconstriction and urinary LTE4 excretion in aspirin-sensitive asthma.

Bronchial overproduction of leukotrienes and inhibition of prostaglandin synthesis are involved in the pathogenesis of aspirin-induced asthma. We investigated whether inhaled prostaglandin E2 (PGE2) attenuates the response to bronchial challenge with lysine acetylsalicylate (LASA) and the associated increase in urinary leukotriene E4 (u-LTE4) in seven aspirin-sensitive subjects with asthma. Each subject performed two challenges with a single dose of LASA that caused a decrease in FEV1 of 20% or more in a preliminary test, immediately after inhaling 100 micrograms PGE2 in 4 ml saline or placebo, according to a randomized double-blind protocol. FEV1 was recorded at 30-min intervals for 4 h. u-LTE4 was measured by combined high-performance liquid chromatography enzyme immunoassay at 2-h intervals. After placebo, LASA caused an obstructive reaction in all patients, with a maximum decrease in FEV1 of 35 +/- 5% with respect to baseline. u-LTE4 rose from 911 +/- 261 picograms (pg)/mg creatinine at baseline to a maximum value of 2249 +/- 748 after challenge. Inhaled PGE2 provided almost complete protection in all patients. Baseline u-LTE4 was 883 +/- 243 pg/mg creatinine and did not change significantly during the test, reaching a maximum value of 864 +/- 290 (p < 0.05 versus placebo). These results confirm that PGE2 is highly effective in preventing aspirin-induced asthma and suggest that this effect is mediated by inhibition of sulfidopeptide leukotriene production.

Administration, Inhalation↗
PubMed1996

Inhaled nitric oxide attenuates bronchoconstriction in canine peripheral airways.

Inhaled nitric oxide has been proposed as a bronchodilator because it relaxes vascular and airway smooth muscle and attenuates cholinergic reflexes. Although inhaled nitric oxide has been shown to act as a bronchodilator in central airways, effects on peripheral airways are largely unknown. To determine whether nitric oxide produces direct relaxation of peripheral airways, we investigated the ability of nitric oxide to attenuate hypocapnia- and acetylcholine-induced constriction in the peripheral airways of anesthetized dogs. Peripheral airway resistance (RP) was measured using a wedged bronchoscope technique. RP was increased by either hypocapnia (0% CO2 through the bronchoscope for 3 min) or by aerosolized acetylcholine (30 to 60 micrograms/ml for 1 to 3 min), in the presence or absence of nitric oxide. Nitric oxide was delivered directly to the lung periphery in the absence of O2. Nitric oxide (14.5 to 250 ppm) attenuated responses to hypocapnia by 38 +/- 0 to 74 +/- 0% (n = 6) and to acetylcholine by 36 +/- 0 to 52 +/- 0% (n = 6). The ability of inhaled nitric oxide (< 100 ppm) to attenuate Rp responses to two different direct-acting stimuli suggests that nitric oxide acts as a bronchodilator in the lung periphery. The mechanism for this effect may involve relaxation of airway and/or vascular smooth muscle.

Acetylcholine↗
PubMed1996

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

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.

Adult↗
PubMed1996

Inhaled misoprostol blocks guinea pig antigen-induced bronchoconstriction and airway inflammation.

Inhaled E-type prostaglandins (PGE) have been shown to modulate responses to both allergic and nonallergic provocation. Misoprostol, a PGE1 analog, was developed as an antiulcer agent because it prevents gastrointestinal ulceration. Little is known about the effect inhaled misoprostol has on the airway and whether its potential antiasthmatic activity would be similar to other PGEs. Nebulizied solutions of misoprostol and PGE2 effectively blocked the acute bronchospasm caused by a subsequent inhaled antigen challenge in actively sensitized guinea pigs. The minimal concentration to result in a significant reduction in specific airway resistance was 3 and 30 micrograms/ml for misoprostol and PGE2, respectively. Exposure to a 300 micrograms/ml nebulized misoprostol solution provided significant protection for 2 h. Eosinophil recovery in bronchoalveolar lavage performed 24 h after antigen challenge was significantly reduced by 72%. In a chronic model of antigen-induced airway inflammation in which guinea pigs are given multiple antigen exposures over a 3-wk period, both misoprostol and its free acid-active metabolite 5C-30695 significantly reduced bronchoalveolar lavage eosinophils by 50 to 55%. Treatment with TRFK5, a monoclonal antibody to interleukin-5, resulted in a 76% decrease in eosinophil recovery. The combination of antibronchoconstrictive and anti-inflammatory effects suggests that inhaled misoprostol may be an effective treatment for the acute and chronic symptoms of asthma.

Administration, Inhalation↗
PubMed1999

Cholinergic contraction is altered in nNOS knockouts. Cooperative modulation of neural bronchoconstriction by nNOS and COX.

Endogenous nitric oxide (NO) is a bronchodilator but its physiologic role in small airways is not clear. In this study, we investigated the role of endogenous NO in the regulation of bronchiolar tone in the small airways of wild type and NO synthase (NOS) isoform (eNOS and nNOS)-knockout mice. Pretreatment with the cyclooxygenase inhibitor indomethacin significantly enhanced electrical field stimulation (EFS)-induced contraction in the airways from all types of mice by approximately 60 to 170% (n = 8 in each case), whereas pretreatment with the NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) did not (n = 8). Combined pretreatment with L-NAME and indomethacin enhanced airway contraction of wild-type and eNOS-knockout mice to a significantly greater extent (i.e., by 140 to 290%) than did indomethacin alone (n = 8 for each). This potentiation by L-NAME was not seen in nNOS knockout mice (n = 8). Neither indomethacin nor L-NAME alone affected carbachol (CCh) potency or maximal efficacy in the airways of wild-type mice, whereas the combined pretreatment slightly enhanced the maximal response without altering the potency of CCh (n = 6). Our results show that both NO and prostaglandins modulate neuronal contraction of murine small airways. NO is produced by nNOS, which may be located in nerves, and its overall effects are tonically inhibited by cyclooxygenase products.

Animals↗
PubMed1990

Formoterol, a new inhaled beta-2 adrenergic agonist, has a longer blocking effect than albuterol on hyperventilation-induced bronchoconstriction.

The duration of effect of inhaled formoterol (24 micrograms) was compared with that of a placebo and that of inhaled albuterol (200 micrograms) in 12 adult asthmatic subjects who underwent hyperventilation tests with cold dry air (-20 degrees C) on 4 study days. On the control day, they were subjected to four hyperventilation tests to ensure functional stability. On the 3 remaining days, after a first hyperventilation test, they inhaled placebo, albuterol, or formoterol in randomized, double-blind fashion. The hyperventilation test was repeated 1, 4, and 8 h and, if the blocking effect was still present, 12 and 24 h after the drug had been administered. The dose of hyperventilation of cold air causing a 20% fall in FEV1 (PD20) was interpolated on the dose-response curve. The magnitude of the blocking effect at each time interval on each study day was assessed by comparing the changes in PD20 from baseline with the within-day variability of PD20 (standardized change in PD20). The acute bronchodilator effect was not significantly different as assessed 15 min (21 +/- 14% for albuterol and 18 +/- 18% for formoterol) and 1 h (20 +/- 13% for albuterol and 18 +/- 17% for formoterol) after administering the medication. The duration of the blocking effect, defined as the return to 2 SD from the standardized change in PD20, was significantly more prolonged for formoterol (8.0 +/- 3.4 h) than for albuterol (3.0 +/- 1.7 h) (t = 4.2, p less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1991

Airway luminal liquid. Sources and role as an amplifier of bronchoconstriction.

The release of mediators from inflammatory cells into the airway lumen can initiate a series of events leading to airway obstruction, particularly smooth muscle contraction and alteration of endothelial and epithelial permeability leading to mucosal edema and subsequent influx of liquid into the airway lumen. In this report we briefly review the effects of several inflammatory mediators, including eicosanoids, platelet-activating factor, and histamine, as well as the effects of plasma proteins and tachykinins that may be secondarily released because of the presence of inflammatory mediators on endothelial and epithelial permeability. We then consider physical mechanisms whereby the resulting airway luminal liquid could amplify the response of an airway previously constricted because of smooth muscle contraction. Specifically, liquid in the interstices between epithelial projections that are formed during muscular contraction could amplify the degree of luminal compromise by (1) further decreasing luminal cross-sectional area by occupying space, and (2) providing an additional source of inward recoil because of the surface tension of the air-liquid interface.

Animals↗