Airway effects of purine nucleosides and nucleotides and release with bronchial provocation in asthma

Adenosine, AMP, and ADP all caused similar concentration-related bronchoconstriction when inhaled by patients with asthma, whereas the adenosine hydrolysis product inosine had no effect. Geometric mean provocation concentrations of adenosine AMP and ADP causing a 20% fall in forced expiratory volume in 1 s (PCf20) were 2.34, 4.27, and 2.19 mumol/ml and 40% fall in specific airway conductance (PCs40) 3.16, 5.01, and 2.0 mumol/ml. Bronchoconstriction was rapid in onset, reaching a maximum 2-5 min after a single inhalation of AMP. In 31 asthmatic subjects a positive correlation was established between airway responsiveness to histamine, as an index of non-specific responsiveness, and airway reactivity to adenosine (PCf20, r = 0.60; PCs40, r = 0.64; P less than 0.01). Following bronchial provocation with allergen in nine subjects, plasma levels of adenosine increased from a mean base line of 5.4 +/- 0.9 to 9.6 +/- 2.0 ng/ml at 15 min (P less than 0.01) in parallel with a fall in forced expiratory volume in 1 s. With methacholine provocation bronchoconstriction reached maximum 2-5 min postchallenge being followed by, but not accompanied by, significant increases in plasma levels of adenosine. These data suggest that adenosine is a specific bronchoconstrictor that may contribute to airflow obstruction in asthma.     

Effect of long-term treatment with salmeterol on asthma control: a double blind,randomised crossover study.

OBJECTIVES: To determine the effect of adding salmeterol 50 micrograms twice daily for six months to current treatment in subjects with asthma who control their inhaled corticosteroid dose according to a management plan. DESIGN: A double blind, randomised crossover study. SETTING: Nottingham. SUBJECTS: 101 subjects with mild or moderate asthma taking at least 200 micrograms twice daily of beclomethasone dipropionate or budesonide. INTERVENTIONS: Salmeterol 50 micrograms twice daily and placebo for six months each, with a one month washout. Subjects adjusted inhaled steroid dose according to guidelines. MAIN OUTCOME MEASURE: Reduction in inhaled steroid use, exacerbations of asthma, and use of oral steroids. RESULTS: Data were available for 87 subjects. When compared with placebo salmeterol treatment was associated with a 17% reduction in inhaled steroid use (95% confidence interval 12% to 22%) with no significant difference in the number of subjects who had an exacerbation (placebo 25%, salmeterol 16%) or use of oral steroids. For secondary end points salmeterol treatment was associated with higher morning and evening peak expiratory flow and forced expiratory volume in one second; a reduction in symptoms, bronchodilator use and airway responsiveness to methacholine; and no effect on serum potassium concentration, 24 hour heart rate, or the final forced expiratory volume in one second achieved during a salbutamol dose-response study. CONCLUSIONS: In subjects who adjusted their inhaled steroid treatment according to guidelines the addition of salmeterol 50 micrograms twice daily was associated with a reduction in inhaled steroid use and improved lung function and symptom control.     

Airway responsiveness to methacholine: effects of deep inhalations and airway inflammation.

We determined the dose-response curves to inhaled methacholine (MCh) in 16 asthmatic and 8 healthy subjects with prohibition of deep inhalations (DIs) and with 5 DIs taken after each MCh dose. Flow was measured on partial expiratory flow-volume curves at an absolute lung volume (plethysmographically determined) equal to 25% of control forced vital capacity (FVC). Airway inflammation was assessed in asthmatic subjects by analysis of induced sputum. Even when DIs were prohibited, the dose of MCh causing a 50% decrease in forced partial flow at 25% of control FVC (PD(50)MCh) was lower in asthmatic than in healthy subjects (P < 0.0001). In healthy but not in asthmatic subjects, repeated DIs significantly decreased the maximum response to MCh [from 90 +/- 4 to 62 +/- 8 (SD) % of control, P < 0.001], increased PD(50)MCh (P < 0.005), without affecting the dose causing 50% of maximal response. In asthmatic subjects, neither PD(50)MCh when DIs were prohibited nor changes in PD(50)MCh induced by DIs were significantly correlated with inflammatory cell numbers or percentages in sputum. We conclude that 1) even when DIs are prohibited, the responsiveness to MCh is greater in asthmatic than in healthy subjects; 2) repeated DIs reduce airway responsiveness in healthy but not in asthmatic subjects; and 3) neither airway hyperresponsiveness nor the inability of DIs to relax constricted airways in asthmatic subjects is related to the presence of inflammatory cells in the airways.     

Effect of normobaric hyperoxia on airways of normal subjects

Airway responsiveness to inhaled cholinergic agonist during the early stage of pulmonary O2 toxicity was examined to determine whether normobaric hyperoxia alters airway function. Eight healthy nonsmoking males with moderate base-line methacholine responsiveness breathed normobaric O2 (greater than or equal to 95%) over 12 h and on another occasion breathed air in an identical protocol. Vital capacity, expiratory flow, airway responsiveness to methacholine, and respiratory symptoms were measured at 0, 4, 8, and 12 h while subjects breathed O2 and 12 h afterwards. After 12 h, forced vital capacity was significantly decreased with O2 breathing but not with air breathing. At 4, 8, or 12 h of exposure and 12 h after exposure, there was no difference in methacholine sensitivity or reactivity between O2 and air-exposure trials. The earliest manifestations of pulmonary normobaric O2 toxicity in normal adults include diminished vital capacity and the onset of respiratory symptoms, but early O2 toxicity does not produce altered responsiveness to inhaled methacholine.     

Refractoriness for ultrasonically nebulized distilled water and histamine after histamine challenge

Refractoriness for bronchial provocation frequently occurs after different challenge tests used to assess bronchial hyperresponsiveness in asthmatic patients. We investigated whether histamine inhalation could cause refractoriness for bronchoconstriction induced by ultrasonically nebulized distilled water (UNDW) and whether histamine causes tachyphylaxis for a subsequent histamine challenge in nine stable asthmatic patients. Preinhalation of histamine induced a significant diminished bronchoconstrictor response to UNDW cumulative dose of inhaled UNDW causing a 20% fall in forced expired volume in 1 s. The mean increased from 3.5 +/- 0.8 to 11.8 +/- 2.6 (SE) ml after histamine challenge (P less than 0.01). However, repeated inhalation of histamine did not change the bronchoconstrictor response to histamine within 1 h after rechallenge (P greater than 0.5). The magnitude of refractoriness for UNDW inhalation after preinhalation of histamine was correlated to the bronchoconstrictor response to histamine (r = 0.73, P less than 0.05). We conclude that inhaled histamine can induce refractoriness for UNDW, which seems to be related to the degree of bronchial hyperresponsiveness.     

Airway reactivity in infants: a positive response to methacholine and metaproterenol

Because the presence of bronchial smooth muscle reactivity in infants remains controversial, airway reactivity was assessed in 10 normal, asymptomatic male infants less than 15 mo of age by measuring the changes that occurred in the maximal expiratory flows at functional residual capacity (VmaxFRC) during a methacholine bronchial challenge test. Sleeping infants inhaled doubling concentrations of methacholine by 2 min of tidal breathing, starting with a concentration of 0.075 mg/ml, and the bronchial challenge was stopped when VmaxFRC decreased by at least 40%. The threshold concentration of methacholine required to produce a decrease in VmaxFRC by 2 SD's of the control value was 0.43 mg/ml (0.11-0.90). By a methacholine concentration of 1.2 mg/ml, all infants decreased VmaxFRC by at least 40% (range 40-75%), and the mean dose required to produce a 40% decrease was 0.72 mg/ml. The airway reactivity was not related to base-line flows. During the methacholine challenge, no infant developed wheezing, but the percent oxygen saturation for the group decreased significantly (P less than 0.05) from 94 to 92%. Following the methacholine, the infants inhaled the bronchodilator metaproterenol, and 10 min later, VmaxFRC returned to base line. This study demonstrates that infants exhibit airway reactivity as evidenced by bronchoconstriction with methacholine and the subsequent bronchodilation with metaproterenol.     

In vivo PAF-induced airway eosinophil accumulation reduces bronchial responsiveness to inhaled histamine

Chronic eosinophilic bronchitis and bronchial hyperresponsiveness have been considered to be the fundamental features of bronchial asthma. However, the role of airway eosinophils in bronchial responsiveness in vivo has not been fully discussed. The aim of this study was to investigate the direct effect of airway eosinophil accumulation on bronchial responsiveness in vivo. Guinea pigs were transnasally treated with platelet activating factor (PAF) or vehicle twice a week for a total of 3 weeks. Anesthetized guinea pigs were surgically cannulated and artificially ventilated 48 h after the last administration of PAF or vehicle. Ten minutes after the installation of artificial ventilation, ascending doses of histamine were inhaled. In a subsequent study, selective inhibitors of diamine oxidase and histamine N-methyltransferase were intravenously administered before the histamine inhalation in the PAF-treated animals. Next study was conducted 20 min after treatment with indomethacin in this study line. Finally, ascending doses of methacholine were inhaled in our animal model. Proportion of eosinophils and the number of nuclear segmentation in bronchoalveolar lavage fluid significantly increased in guinea pigs treated with PAF compared with vehicle and this finding was confirmed histologically. Nevertheless, bronchial responsiveness to inhaled histamine, but not methacholine, was significantly decreased by the PAF treatment. This bronchoprotective effect induced by PAF remained following aminoguanidine and histamine N-methyltransferase administration, but abolished by treatment of indomethacin. These results suggest that in vivo airway eosinophils may reduce nonspecific bronchial responsiveness through production of inhibitory or bronchoprotective prostanoids, but not through histaminase production.     

Tachyphylaxis to inhaled methacholine in normal but not asthmatic subjects

Methacholine inhalation tests measure airway responsiveness in asthmatic and normal subjects. Tachyphylaxis occurs with repeated methacholine inhalations in normal subjects. The purpose of this study was to examine the time course and mechanisms of methacholine tachyphylaxis in normal subjects and to determine whether this occurs in mildly asthmatic subjects. Fifteen normal and nine asthmatic subjects were studied on 2 study days, at least 48 h apart. Each day, two inhalation tests were carried out. On one day, subjects performed two methacholine inhalation tests 3 h later by a methacholine test. Results were expressed as the provocation concentration causing a 20% fall in forced expiratory volume in 1 s (FEV1), (PC20). All normal subjects developed methacholine tachyphylaxis. The mean PC20 increased from 47.3 mg/ml (%SE 1.34) to 115.6 (%SE 1.51) (P less than 0.0001) in a 3-h interval. This increase lasted for greater than or equal to 6 h (P = 0.012). Asthmatic subjects did not develop methacholine tachyphylaxis. Their mean methacholine PC20s were 1.6 mg/ml (%SE 1.4) and 1.5 (%SE 1.4) (P = 0.75) 3 h later. In two other series of experiments, normal subjects were pretreated with the cyclooxygenase inhibitors indomethacin (100 mg/day) or flurbiprofen (150 mg/day) or a placebo for 3 days before two methacholine tests 3 h apart. Both indomethacin and flurbiprofen significantly inhibited the development of methacholine tachyphylaxis. These results confirm that methacholine tachyphylaxis occurs in normal subjects, lasts greater than or equal to 6 h, and may occur through the release of inhibitory prostaglandins. By contrast, methacholine tachyphylaxis does not occur in asthmatic subjects.     

Interaction of inhaled LTC4 with histamine and PGD2 on airway caliber in asthma

To investigate possible mediator interaction in asthma, the effect of inhaled leukotriene (LT) C4 on bronchoconstriction provoked by histamine and prostaglandin (PG) D2 was studied in nine asthmatic subjects. The provocation doses of histamine, PGD2, and LTC4 required to produce a 12.5% decrease in baseline forced expiratory volume in 1 s (FEV1, PD12.5) and to further this fall to 25% (PD25-12.5) were determined. On three subsequent occasions, subjects inhaled either the PD12.5 LTC4 plus vehicle or vehicle plus the PD25-12.5 of either histamine or PGD2, and FEV1 and maximal flow at 70% of vital capacity below total lung capacity after a forced partial expiratory maneuver (Vp30) followed for 45 min. From these results, predicted time-course curves for LTC4 with histamine and LTC4 with PGD2 were calculated. On two final occasions, airway caliber was followed for 45 min after inhalation of the PD12.5 LTC4 followed by the PD25-12.5 of either histamine or PGD2. During the first 9 min after LTC4-histamine and LTC4-PGD2, the decreases in airway caliber were greater than the calculated predicted response. This interaction, although small, was significant with LTC4-PGD2 for both FEV1 (P = 0.01) and Vp30 (P less than 0.05) and with LTC4-histamine for Vp30 (P less than 0.05) but not for FEV1 (P less than 0.05). We conclude that inhaled LTC4 interacts synergistically with histamine and PGD2 and that this effect, although small, may be a relevant interaction in asthma.     

Effects of rapid saline infusion on lung mechanics and airway responsiveness in humans.

Lung mechanics and airway responsiveness to methacholine (MCh) were studied in seven volunteers before and after a 20-min intravenous infusion of saline. Data were compared with those of a time point-matched control study. The following parameters were measured: 1-s forced expiratory volume, forced vital capacity, flows at 40% of control forced vital capacity on maximal (Vm(40)) and partial (Vp(40)) forced expiratory maneuvers, lung volumes, lung elastic recoil, lung resistance (Rl), dynamic elastance (Edyn), and within-breath resistance of respiratory system (Rrs). Rl and Edyn were measured during tidal breathing before and for 2 min after a deep inhalation and also at different lung volumes above and below functional residual capacity. Rrs was measured at functional residual capacity and at total lung capacity. Before MCh, saline infusion caused significant decrements of forced expiratory volume in 1 s, Vm(40), and Vp(40), but insignificantly affected lung volumes, elastic recoil, Rl, Edyn, and Rrs at any lung volume. Furthermore, saline infusion was associated with an increased response to MCh, which was not associated with significant changes in the ratio of Vm(40) to Vp(40). In conclusion, mild airflow obstruction and enhanced airway responsiveness were observed after saline, but this was not apparently due to altered elastic properties of the lung or inability of the airways to dilate with deep inhalation. It is speculated that it was likely the result of airway wall edema encroaching on the bronchial lumen.     

Airway responses to methacholine in asymptomatic nonatopic cigarette smokers

We prospectively performed methacholine bronchoprovocation challenges on 46 young smokers to examine the effects of cigarette smoking on airway responsiveness. The subjects, ages 18-35 yr, had no past or present history or physical examination findings of asthma or other lung diseases, rhinitis, allergic diseases, or respiratory infections; were skin test negative to 29 common aeroallergens; and had base-line pulmonary function values greater than 80% predicted. Sixteen of 46 (35%) subjects had a 20% or greater drop in forced expiratory volume in 1 s at a provocative methacholine concentration less than or equal to 25 mg/ml. The degree of methacholine responsiveness was not dependent upon base-line pulmonary function values or the amount of cigarettes consumed, and there was no association between the amount of cigarettes consumed and base-line pulmonary function values. These data suggest that many young asymptomatic nonatopic smokers have increased airway responsiveness to inhaled methacholine without clinically significant hyperreactive airway disease.     

Bronchoconstrictor and antibronchoconstrictor properties of inhaled prostacyclin in asthma

Prostacyclin (PGI2) is generated in appreciable amounts during allergic reactions in human lung tissue. To define its activity on human airways we have studied the effects of doubling concentrations of inhaled PGI2 and its hydrolysis product 6-oxoprostaglandin F1 alpha (6-oxo-PGF1 alpha) on specific airway conductance (sGaw), maximum expiratory flow at 30% vital capacity (Vmax30), forced expiratory volume in 1 s (FEV1), and static lung volumes in subjects with mild allergic asthma. In a second study the effect of inhaled PGI2 on bronchoconstriction provoked by increasing concentrations of inhaled prostaglandin (PG) D2 and methacholine was observed. Inhalation of PGI2 up to a concentration of 500 micrograms/ml had no significant effect on sGaw but produced a concentration-related decrease in FEV1 and Vmax30 in all subjects. In two of four subjects inhalation of PGI2 also increased residual volume and decreased vital capacity but had no effect on total lung capacity. PGI2, but not 6-oxo-PGF1 alpha, protected against bronchoconstriction provoked by either PGD2 or methacholine whether airway caliber was measured as sGaw, FEV1, or Vmax30. The apparent disparity between the bronchoconstrictor and antibronchoconstrictor effects of PGI2 might be explained by its potent vasodilator effect in causing airway narrowing through mucosal engorgement and reducing the spasmogenic effects of other inhaled mediators by increasing their clearance from the airways.     

Antigen sensitization and methacholine responses in dogs with hyperreactive airways

Antigen sensitization was induced in six Basenji-Greyhound (BG) dogs by weekly aerosol exposure to Ascaris suum. The effects on airway responsiveness to inhaled methacholine were studied before and at least 2 wk following Ascaris sensitization. All dogs developed detectable serum levels of Ascaris-specific immunoglobulin E (IgE), and five out of six dogs developed airway responsiveness to antigen over the 4- to 6-mo period. This was accompanied by a decrease rather than an increase in airway responsiveness to inhaled methacholine. When dogs were challenged with methacholine 30 min after Ascaris antigen aerosol challenge, however, dogs reactive to Ascaris became hyperresponsive to methacholine. The magnitude of the response to antigen correlated (r = 0.85) inversely with the dose of methacholine increasing pulmonary resistance 200%. These data show that in BG dogs airway responsiveness to methacholine is increased by acute antigen exposure but that sensitization of previously unsensitized dogs does not increase nonspecific airway responsiveness.     

Effect of inhaled corticosteroids on episodes of wheezing associated with viral infection in school age children: randomised double blind placebo controlled trial.

OBJECTIVES: To determine the effect of regular prophylactic inhaled corticosteroids on wheezing episodes associated with viral infection in school age children. DESIGN: Randomised, double blind, placebo controlled trial. SETTING: Community based study in Southampton. SUBJECTS: 104 children aged 7 to 9 years who had had wheezing in association with symptoms of upper and lower respiratory tract infection in the preceding 12 months. INTERVENTIONS: After a run in period of 2-6 weeks children were randomly allocated twice daily inhaled beclomethasone dipropionate 200 micrograms or placebo through a Diskhaler for 6 months with a wash out period of 2 months. Children were assessed monthly. MAIN OUTCOME MEASURES: Forced expiratory volume in 1 second (FEV1); bronchial responsiveness to methacholine (PD20); percentage of days with symptoms of upper and lower respiratory tract infection with frequency, severity, and duration of episodes of upper and lower respiratory symptoms and of reduced peak expiratory flow rate. RESULTS: During the treatment period there was a significant increase in mean FEV1 (1.63 v 1.53 1; adjusted difference 0.09 1 (95% confidence interval 0.04 to 0.14); P = 0.001) and methacholine PD20 12.8 v 7.2 mumol/l; adjusted ratio of means 1.7 (1.2 to 2.4); P = 0.007) in children receiving beclomethasone dipropionate compared with placebo. There were, however, no significant differences in the percentage of days with symptoms or in the frequency, severity, or duration of episodes of upper or lower respiratory symptoms or of reduced peak expiratory flow rate during the treatment period between the two groups. CONCLUSIONS: Although lung function is improved with regular beclomethasone dipropionate 400 micrograms/day, this treatment offers no clinically significant benefit in school age children with wheezing episodes associated with viral infection.     

Inhaled PAF stimulates leukotriene and thromboxane A2 production in humans.

Platelet-activating factor (PAF) is a potent bronchoconstrictor in humans and has been implicated as an inflammatory mediator in asthma. This study was performed to evaluate whether PAF-induced bronchoconstriction in vivo could be mediated through the release of the bronchoconstrictor eicosanoids, thromboxane (Tx) A2 and the cysteinyl leukotrienes. Ten asthmatic subjects were studied on three occasions after bronchial challenges with aerosolized PAF, methacholine, or isotonic saline. PAF caused bronchoconstriction in all 10 subjects (mean maximal percent fall in specific airway conductance 48.2 +/- 4.6) and was matched by methacholine challenge. Saline caused no changes in specific airway conductance. Urinary leukotriene E4 was significantly elevated after inhaled PAF (366.0 +/- 66.9 ng/mmol creatinine, P less than 0.01) compared with methacholine (41.6 +/- 13.3) and saline (33.6 +/- 4.6). The major urinary TxA2 metabolite 2,3-dinor TxB2 was elevated after inhaled PAF (41.3 +/- 7.1 ng/mmol creatinine, P less than 0.01) compared with methacholine (14.0 +/- 2.7) and saline (17.1 +/- 3.9). Urinary 2,3-dinor 6-oxo-prostaglandin F1 alpha after PAF (22.2 +/- 1.4) was raised with respect to the methacholine challenge (13.9 +/- 1.8, P less than 0.02), although no significant increase was observed compared with the saline control (18.6 +/- 3.3). Inhaled PAF leads to the secondary generation of cysteinyl leukotrienes and TxA2, and it is possible that these mediate some of the acute effects of inhaled PAF in vivo.     

The occurrence of refractoriness and mast cell mediator release following mannitol-induced bronchoconstriction

For several hours after exercise-induced bronchoconstriction, there is diminished responsiveness to repeated challenge. The mechanism causing this refractoriness is unclear. Inhalation of dry powder mannitol is a new bronchial provocation test that has been suggested as a surrogate for an exercise challenge. Refractoriness to repeated mannitol challenge has however not been established. Our objective was to investigate if repeated challenge with mannitol is associated with refractoriness and diminished release of mast cell mediators of bronchoconstriction. Sixteen subjects with asthma underwent repeated inhalation of mannitol 90 min apart. Lung function was assessed by forced expiratory volume in 1 s (FEV?). The urinary excretion (ng/mmol creatinine) of the mediators 9α,11β-prostaglandin (PG) F? and leukotriene (LT) E? were measured. The group mean fall in FEV? after the second challenge was 48.5 ± 5.8% of the first (P < 0.001). The protection afforded by the initial challenge, however, varied considerably between subjects (range 88-0%). Furthermore, the urinary excretion of the two mediators was increased after both challenges. The average excretion of mediators after the challenges was significantly higher for the six most refractory subjects. This was observed both for LTE? (95.6 ± 5.2 vs. 58.0 ± 2.4 for the 6 least refractory) (P < 0.001) and for 9α,11β-PGF? (137.6 ± 6.7 vs. 50.1 ± 1.1 for the 6 least refractory) (P = 0.002). As occurs with exercise-induced bronchoconstriction, repeated inhalation of mannitol induced refractoriness. We propose that refractoriness is due to tachyphylaxis at the level of the airway smooth muscle responsiveness to mediators of bronchoconstriction rather than due to fatigue of their release from mast cells.     

Potent bronchoprotective effect of deep inspiration and its absence in asthma.

In the absence of deep inspirations, healthy individuals develop bronchoconstriction with methacholine inhalation. One hypothesis is that deep inspiration results in bronchodilation. In this study, we tested an alternative hypothesis, that deep inspiration acts as a bronchoprotector. Single-dose methacholine bronchoprovocations were performed after 20 min of deep breath inhibition, in nine healthy subjects and in eight asthmatics, to establish the dose that reduces forced expiratory volume in 1 s by >15%. The provocation was repeated with two and five deep inspirations preceding methacholine. Additional studies were carried out to assess optimization and reproducibility of the protocol and to rule out the possibility that bronchoprotection may result from changes in airway geometry or from differential spasmogen deposition. In healthy subjects, five deep inspirations conferred 85% bronchoprotection. The bronchoprotective effect was reproducible and was not attributable to increased airway caliber or to differential deposition of methacholine. Deep inspirations did not protect the bronchi of asthmatics. We demonstrated that bronchoprotection is a potent physiologic function of lung inflation and established its absence, even in mild asthma. This observation deepens our understanding of airway dysfunction in asthma.     

Effect of triiodothyronine-induced thyrotoxicosis on airway hyperresponsiveness

To determine whether thyrotoxicosis has an effect on the asthmatic state in subjects with mild asthma, airway responsiveness, lung function, and exercise capacity were measured in a randomized double-blind placebo-controlled trial before and after liothyronine (triiodothyronine, T3)-induced thyrotoxicosis. Baseline evaluation of 15 subjects with mild asthma included clinical evaluation, thyroid and routine pulmonary function tests, airway responsiveness assessment by methacholine inhalation challenge, and a symptom-limited maximal exercise test. For all subjects, the initial testing revealed that the dose of methacholine which provoked a 20% fall in forced expiratory volume in 1s (PD20) was in a range consistent with symptomatic asthma. There was no significant change in pulmonary function tests, airway reactivity (PD20), or exercise capacity in either the placebo or the T3-treated groups. Thyroid function tests confirmed mild sustained thyrotoxicosis in the T3-treated groups. We conclude that mild T3-induced thyrotoxicosis of 4-wk duration had no effect on lung function, airway responsiveness, or exercise capacity in subjects with mild asthma.     

Threshold of airway response to inhaled methacholine in healthy men and women

Threshold of airway response to inhaled methacholine was determined using maximum expiratory partial flow-volume curves in 21 men and 36 women with similar age distribution, all of them healthy nonsmokers. Mean threshold was on average 1.3 doubling dose lower in women than men. There were no sex differences in the increase of maximum expiratory flows after a full inspiration when the airways were constricted by methacholine.     

Effect of inhaled platelet-activating factor on circulating neutrophils and platelets in vivo and ex vivo in man

We studied the effect of five successive inhalations of platelet-activating factor (PAF) on airway calibre, circulating neutrophil and platelet counts and the activation of these cells ex vivo in normal subjects. PAF (24 ug) caused a mean maximal fall of the expiratory flow rate at 70% vital capacity from a partial manoeuvre (Vp30) of 46.4 +/- 6.2% (p less than 0.001); there was a tachyphylactic response to further doses of PAF. Circulating neutrophil counts fell by 54.3 +/- 10.6% (p less than 0.005) with immediate recovery and with a rebound neutrophilia by the fifth inhalation. Platelet counts showed no significant changes. Aggregation of platelets in platelet-rich plasma to PAF and ADP in vitro at 15 min after the first, second and fifth PAF inhalations was not significantly altered. Chemiluminescence responses of neutrophils to PAF (0.01, 0.1, 1 and 10 microM) in vitro were reduced at 15 min after the fifth PAF inhalation, but this was only significant at 1 microM PAF. Methacholine inhalation did not cause any changes in responsiveness of neutrophils to PAF ex vivo. We conclude that ex vivo platelet desensitisation cannot be used as an index of endogenous PAF release, but reduced responsiveness of neutrophils ex vivo is not a sensitive indicator.