Unilateral nasal allergen challenge leads to bilateral release of prostaglandin D2

BACKGROUND: Multiple mediators including prostaglandin D2 and leukotriene B4 have been shown to increase in nasal secretions during the early response to nasal challenge with antigen. OBJECTIVE: Our objective was to investigate the time course of prostanoid and leukotriene B4 release into nasal secretions on both the ipsilateral and contralateral side after a unilateral nasal allergen challenge. METHODS: We performed a controlled, randomized trial. Six volunteers were challenged unilaterally with antigen or diluent in a randomized order and discs were used to collect nasal secretions from both nostrils at 2 min intervals for 20 min after the challenge. Prostanoids and leukotriene B4 (LTB4) in recovered nasal secretions were measured by combined capillary gas chromatography-negative ion chemical ionization mass spectrometry (GC/MS). RESULTS: Nasal allergen challenge resulted in a significant and immediate increase in symptoms and sneezing. PGD2 was significantly elevated above diluent values (0.6 +/- 0.6 pg) 30 s after removal of the allergen disc (P < 0.05), reached its peak (423.2 +/- 182.4 pg) at 2 min and then slowly decreased. PGD2 also increased on the contralateral side after unilateral allergen challenge, reaching peak values about six times lower than on the ipsilateral side (70.8 +/- 21.7 pg at 6 min). Levels of 9a, 11b-PGF2 after antigen provocation became significantly higher than after diluent (0 +/- 0 pg) on the ipsilateral side at 2 min (17.2 +/- 5.9 pg), and reached peak levels at 4 min (25.1 +/- 8.0 pg). LTB4 also increased significantly on the side of challenge. For the other prostanoids measured (PGF2, PGF2 alpha, TxB2, 6kPGF1 alpha), no significant changes in either ipsilateral or contralateral secretions were observed after allergen challenge. CONCLUSIONS: Our study described the kinetics of PGD2 and LTB4 release as well as the contralateral release of PGD2.     

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

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.     

Successful myoblast transplantation in primates depends on appropriate cell delivery and induction of regeneration in the host muscle

In a double-blind, cross-over study, we examined the effect of inhaled budesonide (800 microgram twice daily via Turbohaler) on lung function and various markers of airway inflammation including airway responsiveness to methacholine (PC20), exhaled nitric oxide (NO), eosinophils in induced sputum, bronchoalveolar lavage (BAL), and airway biopsies from 14 patients with mild asthma needing beta2- agonist therapy only. After inhaled steroids, there was a significant increase in FEV1 and PC20, and reduction in exhaled NO. Eosinophils in induced sputum and airway biopsy sections were also significantly decreased, although BAL eosinophil counts remained unchanged. At baseline, significant correlations were observed between exhaled NO and PC20 methacholine (r = 0.64, p < 0.05), exhaled NO and peak expiratory flow rate (PEFR) variability (r = 0. 65, p < 0.05), sputum eosinophils and FEV1 (r = -0.63, p = 0.05), and sputum eosinophils and log PC20 methacholine (r = -0.67, p < 0. 05). After treatment with inhaled steroids, there was a significant correlation between eosinophils in biopsy sections, and BAL, with log PC20 methacholine. It is likely that these parameters represent different aspects of the inflammatory process, which are all inhibited by inhaled steroids.     

Effects of inhaled nitric oxide on methacholine-induced bronchoconstriction: a concentration response study in rabbits

Inhaled nitric oxide (NO), at a concentration of 80 ppm, counters the increase in respiratory resistance (Rrs) induced by methacholine, but fails to prevent a reduction in lung compliance (Crs) in a rabbit model. This study reports the effects of 3, 30 and 300 ppm of inhaled NO. New Zealand White rabbits were intubated and mechanically ventilated with 30% oxygen during neurolept anaesthesia. Methacholine (3 mg.ml-1) was nebulized, with or without NO inhalation. Inhalation of 3 and 30 ppm NO had no effect on the induced bronchoconstriction, whereas 300 ppm fully blocked the increase in Rrs. The decrease in Crs due to methacholine was not countered by 3, 30 or 300 ppm NO. On the contrary, inhalation of 300 ppm NO in itself decreased Crs from 5.0 +/- 0.1 to 4.3 +/- 0.1 ml.cmH2O-1. Also, mean arterial pressure (60 +/- 7 to 54 +/- 5 mmHg), alveolar-arterial oxygen tension gradient (0.8 +/- 0.8 to 2.3 +/- 1.8 kPa) and methaemoglobin (0.5 +/- 0.2 to 1.5 +/- 0.5%) changed significantly on inhalation of NO 300 ppm prior to methacholine challenge. We conclude that 3 and 30 ppm NO inhalation does not alter methacholine-induced bronchoconstriction. Inhalation of 300 ppm NO blocks an increase in resistance but fails to counter the reduction in compliance due to methacholine. This suggests that the bronchodilating effects of NO in rabbits in vitro are confined to the large airways.     

Effect of inhaled PGE2 on exercise-induced bronchoconstriction in asthmatic subjects

Previous studies have suggested that the endogenous release of inhibitory prostanoids limits the bronchoconstrictor response to repeated exercise. The aim of our study was to determine whether inhaled prostaglandin (PG)E2 attenuates exercise-induced bronchoconstriction or methacholine airway responsiveness in asthmatic subjects. Eight subjects with mild stable asthma and exercise bronchoconstriction were studied on 4 separate days, 48 h apart. Subjects inhaled PGE2 or placebo in a randomized, crossover, double-blind fashion, 30 min prior to an exercise challenge or a methacholine challenge. PGE2 inhalation significantly attenuated exercise bronchoconstriction. The mean maximal %fall in FEV1 after exercise was 26% (SEM 3.7%) after placebo, and was 9.7% (SEM 2.7%) after PGE2 (p < 0.001). PGE2 also significantly reduced the duration of exercise bronchoconstriction (p = 0.034). However, PGE2 did not significantly attenuate methacholine airway responsiveness. The geometric mean methacholine provocative concentration causing a 20% fall in FEV1 (PC20) was 0.77 (%SEM 1.48) after placebo day, and 1.41 (%SEM 2.20) after PGE2 (p = 0.30). These results demonstrate that inhaled PGE2 markedly attenuates exercise bronchoconstriction in asthmatic subjects and suggest that this effect is not occurring through functional antagonism of airway smooth muscle.     

Beclomethasone given after the early asthmatic response inhibits the late response and the increased methacholine responsiveness and cromolyn does not

BACKGROUND: Single doses of inhaled beclomethasone or inhaled cromolyn, given before allergen inhalation, inhibit allergen-induced late asthmatic responses (LARs) and increased airway responsiveness (delta log methacholine PC20). We hypothesized that when given 2 hours after allergen, beclomethasone might work better than cromolyn. METHODS: In 10 patients with mild, stable, atopic asthma with LARs or delta log PC20 or both, we performed a double-blind, double-dummy, random-order trial comparing a single dose of inhaled beclomethasone (500 micrograms), cromolyn (20 mg), and placebo, administered 2 hours after allergen challenge on LAR and delta log PC20. RESULTS: The treatment effect on LAR was significant (p < 0.001). The LAR after beclomethasone (7.3% +/- 6.1%) was significantly less than after cromolyn (20.4% +/- 15.2%) or placebo (26.4% +/- 8.2%); cromolyn was not different from placebo. There was a borderline treatment effect on delta log PC20 (p = 0.056) with beclomethasone (0.12 +/- 0.31) less than placebo (0.37 +/- 0.39) but not less than cromolyn (0.34 +/- 0.18). CONCLUSION: Beclomethasone (500 micrograms) administered 2 hours after allergen challenge markedly inhibited the LAR and had a small effect on allergen-induced airway responsiveness. Cromolyn (20 mg) was not effective on maximal LAR; a small effect on the early part of the LAR was suggested.     

Mechanism of hypoxemia after methacholine challenge

Hypoxemia after the treatment of asthmatic attack continues for a while, and can even become worse after the treatment. This hypoxemia has been attributed to inhomogeneity of ventilation-to-perfusion ratios in the lungs of asthmatic patients. We studied post-hyperventilation hypoxemia in subjects with hypoxemia after a methacholine challenge test. Nineteen subjects who were hyperresponsive and hypoxemic after a methacholine challenge were studied. The methacholine challenge with incremental doses was stopped when the respiratory resistance doubled. Thereafter, oxygen and carbon dioxide concentrations in the expired air, mouth flow (VE), and oxygen saturation (using a pulse oximeter, SpO2) were monitored continuously. End-tidal PCO2 (PETCO2) as well as respiratory exchange ratio (R) were thus obtained. In 14 subjects, VE significantly increased from 8.6 +/- 1.2 (mean +/- SD) to 13.4 +/- 2.6 l/min and then decreased gradually, while PETCO2 significantly decreased from 38.5 +/- 2.3 to 29.1 +/- 4.4 Torr and then increased gradually, SpO2 decreased from 97 +/- 1.3 to 89 +/- 2.4% concomitant with a significant decrease in R from 0.86 +/- 0.04 to 0.67 +/- 0.05. In contrast, in 5 subjects VE significantly increased from 7.5 +/- 2.8 to 12.4 +/- 1.6 l/min and then remained unchanged, while PETCO2 significantly decreased from 37.9 +/- 1.3 to 31.3 +/- 3.9 Torr and then remained unchanged, SpO2 decreased from 98 +/- 1.1 to 92 +/- 1.9% with no change in R (from 0.84 +/- 0.06 to 0.87 +/- 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)     

TRFK-5 reverses established airway eosinophilia but not established hyperresponsiveness in a murine model of chronic asthma

We studied the effects of an anti-interleukin (IL)-5 monoclonal antibody (TRFK-5) or dexamethasone (DEX) to reverse already established airway hyperresponsiveness (AHR) and tissue eosinophilia in a Schistosoma mansoni antigen-sensitized and airway-challenged mouse model of chronic asthma. In this model at 4 d after antigen challenge there is dramatic bronchoalveolar lavage fluid (BAL) eosinophilia, AHR to intravenous methacholine (MCh), and histologic evidence of peribronchial eosinophilic infiltration and mucoid cell hyperplasia. These changes persist for up to 2 wk after antigen challenge. Treatment with DEX from Days 4 through 10 significantly reduced established airway eosinophilia compared with animals sham-treated with saline from Days 4 -10 (120 +/- 29 eosinophils/microl BAL for DEX-treated mice versus 382 +/- 60 eosinophils/microl BAL for sham-treated animals, p < 0.01). DEX-treated mice also had dramatically reduced mucoid cell hyperplasia, and airway responsiveness returned to normal. In contrast, TRFK-5 given during the same time period reduced airway eosinophilia (86 +/- 32 eosinophils/microl BAL versus 382 +/- 60 eosinophils/microl BAL, p < 0.01) but did not reduce goblet cell hyperplasia or reverse already established AHR. Treatment with DEX but not TRFK-5 also inhibited interferon gamma (IFN-gamma) content of BAL fluid (0.49 +/- 0.09 ng/ml BAL fluid for DEX versus 1.50 +/- 0.24 ng/ml BAL fluid and 1.36 +/- 0.13 ng/ml BAL fluid for TRFK-5 and sham-treated mice, respectively, both p < 0.001 versus DEX). Thus, treatment with DEX reduces established eosinophilic airway inflammation and AHR in S. mansoni-sensitized and airway-challenged mice but treatment with TRFK-5 reversed established eosinophilia without ameliorating established AHR. Together, these data suggest that once airway inflammation develops, neutralizing the effects of IL-5 or reducing eosinophilia alone may not result in inhibiting established AHR in atopic asthma.     

Poststorage diastolic abnormalities of heart transplants: is vascular dysfunction or myocardial contracture the culprit?

We tested the hypothesis that mast cells contribute to platelet-activating factor (PAF)-induced airways hyperreactivity and hyperpermeability in mice. Airways reactivity to acetylcholine (ACh) and lung permeability to Evans blue (EB) dye were measured before and after PAF challenge in genetically mast cell-deficient (WBB6F1 W/Wv) and normal congenic (WBB6F1 +/+) mice, as well as mast cell-reconstituted (BMT W/Wv) mice. In addition, prostaglandin D2 (PGD2), a mast cell-specific mediator, was measured in the bronchoalveolar lavage (BAL) from +/+ and W/Wv mice to determine if lung mast cell activation was a consequence of PAF challenge. Genetically PAF-sensitive AKR/J mice were also treated with the mast cell stabilizer nedocromil prior to assessment of PAF effects on ACh reactivity. Intravenous PAF (10 micrograms/kg) induced a significant (P < 0.05) increase in airways reactivity to ACh (25 micrograms/kg) in both +/+ (371 +/- 52%) and W/Wv (122 +/- 24%) mice. There was a significantly greater increase in +/+ compared with W/Wv mice. PAF-induced hyperreactivity to ACh in BMT W/Wv mice (191 +/- 44%) was significantly (P < 0.05) greater than age-matched W/Wv mice (80 +/- 16%), but not significantly different from age-matched +/+ mice (153 +/- 44%). PAF (10 micrograms/kg) also significantly (P < 0.5) increased lung permeability in +/+ and W/Wv mice, but there was no significant difference between groups. BAL PGD2 increased significantly in +/+ mice following PAF challenge (559 +/- 24 ng/ml) compared with vehicle controls (152 +/- 8 pg/ml). There was no significant increase in BAL PGD2 from W/Wv mice. Nedocromil pretreatment significantly (P < 0.05) decreased PAF-induced hyperreactivity in AKR/J mice but not in W/Wv mice (P > 0.05). We conclude that mast cells contribute significantly to PAF-induced hyperreactivity but not hyperpermeability in mice.     

The effect of salmeterol on nocturnal symptoms, airway function, and inflammation in asthma

STUDY OBJECTIVE: To determine the efficacy of salmeterol alone in a group of patients with moderate asthma with nocturnal worsening of symptoms. DESIGN: Double-blind, randomized, placebo-controlled crossover study. SETTING: Tertiary care hospital specializing in respiratory diseases. PARTICIPANTS: Ten patients with nocturnal asthma. INTERVENTIONS: Subjects were randomized to salmeterol, 100 micrograms twice daily, or placebo for 6 weeks with a 1-week washout between treatment periods. Symptoms, nocturnal awakenings, and beta 2-agonist use were recorded daily. Spirometry was performed at weeks 1 and 6 of each period at bedtime and at 4 AM, and methacholine challenge was performed at 4 AM followed by bronchoscopy with BAL. BAL fluid analysis included cell count and differential count, eosinophil cationic protein, Charcot-Leyden crystal protein, leukotriene B4, and thromboxane B2. RESULTS: The percentage of nights with awakenings decreased significantly with salmeterol (69.8 +/- 8.7% vs 30.6 +/- 10.8% for placebo and salmeterol, respectively; p = 0.02). The percentage of 24-h days with supplemental inhaled beta 2-agonist use significantly decreased with salmeterol (85.9 +/- 9.4% vs 70.4 +/- 10.1% for placebo and salmeterol, respectively; p = 0.04). There were no significant differences in bronchial reactivity, 4 AM FEV1, overnight percentage change in FEV1, or indexes of airway inflammation. CONCLUSIONS: Salmeterol alone improves the number of nocturnal awakenings and supplemental 24-h beta 2-agonist use in nocturnal asthma without significantly altering lung function and airway inflammation.     

Inhalation of dry-powder mannitol increases mucociliary clearance

Inhalation of hypertonic saline stimulates mucociliary clearance (MCC) in healthy subjects and those with obstructive lung disease. We investigated the effect of inhaling the osmotic agent mannitol on MCC. We used a dry-powder preparation of mannitol British Pharmacopea (BP) which was encapsulated and delivered using a Dinkihaler. MCC was measured for 75 min in six asthmatic and six healthy subjects on two occasions before and after the mannitol inhalation or its control, using 99mTc-sulphur colloid and a gamma camera. The inhaled dose of mannitol was 267+/-171 mg (mean+/-SD) and 400 mg and the percentage fall in forced expiratory volume in one second (FEV1) was 22+/-3 and 4+/-2% in the asthmatic and healthy subjects, respectively. The total clearance in the whole right lung for the 60 min from the start of inhalation of mannitol was greater by 263+/-11.9% in the asthmatic and 18.1+/-4.9% in the healthy subjects compared to the control. The total clearance over 75 min was 54.7+/-9.6% and 33.6+/-9.4% on the mannitol and control day (p<0.002), respectively, in the asthmatic subjects and 40.5+/-7.1% and 24.8+/-7.8% (p<0.002) in the healthy subjects. In conclusion, inhalation of dry-powder mannitol increases mucociliary clearance in asthmatic and healthy subjects and may benefit patients with abnormal mucociliary clearance.     

Characterization of the inhibitory prostanoid receptors on human neutrophils

1. We have evaluated the effects of various prostanoid agonists on the release of leukotriene B4 (LTB4) and superoxide anions (O2-) from human neutrophils stimulated with opsonized zymosan (OZ) and formyl-methionyl-leucyl-phenylalanine (FMLP), respectively. 2. Prostaglandin E2 (PGE2) and PGD2 inhibited both OZ-induced LTB4 release (EC50 0.72 microM and 0.91 microM respectively), and FMLP-induced O2- release (EC50 0.42 microM and 0.50 microM respectively). PGF2 alpha, the TP-receptor agonist, U46619, and the IP-receptor agonist, iloprost, were also active, but were all at least an order of magnitude less potent than PGE2 and PGD2. 3. The EP2/EP3-receptor agonist, misoprostol, and the selective EP2-agonist, AH13205, were both effective inhibitors of LTB4 release, being approximately equipotent with and 16-times less potent than PGE2, respectively. In contrast, the EP1/EP3-receptor agonist, sulprostone, had no inhibitory activity at concentrations of up to 10 microM. 4. The selective DP-receptor agonist, BW245C, inhibited LTB4 release, (EC50 0.006 microM) being approximately 50 times more potent than PGD2. BW245C also inhibited O2- release, and this inhibition was antagonized competitively by the DP-receptor blocking drug, AH6809 (pA2 6.6). 5. These data indicate the presence of both inhibitory EP- and DP-receptors on the human neutrophil. The rank order of potency of EP-receptor agonists suggest that the EP-receptors are of the EP2-subtype.     

Treatment of recurrent corneal erosion using phototherapeutic keratectomy with the excimer laser

Tachyphylaxis to methacholine has been reported in nonasthmatic subjects. In a recent study on the prevalence of airway hyperresponsiveness (AHR) and atopy, we performed duplicate methacholine inhalation tests at a 60-min interval, in subjects with symptomatic asthma (n = 33), asymptomatic AHR (AAHR) (n = 72) and in a group of normal subjects (n = 130); 135/235 subjects were atopic. All subjects had a respiratory questionnaire, allergy skin prick tests, blood eosinophil counts and determination of total serum IgE level. In asthmatic subjects, PC20 just failed to be significantly higher on a second methacholine challenge (p = 0.09); when they were stratified according to severity of AHR and use of inhaled corticosteroids, we observed a significant increase in PC20 on the second test in asthmatic subjects with mild AHR not using corticosteroids (p < 0.01). In normal controls, PC20 methacholine was slightly increased on rechallenge (p < 0.01) as it was in those with AAHR (p < 0.01). There was no relationship between the magnitude of the change in PC20 and age, sex, baseline airway responsiveness, percent fall in FEV1 on the first challenge, atopic score, blood eosinophil counts and serum IgE levels. In conclusion, tachyphylaxis to methacholine is observed in normal or mild asthmatic subjects not using inhaled corticosteroids and in subjects with AAHR; however, in most subjects this change is of a small magnitude.     

Cross-tachyphylactic airway response to inhaled bradykinin, kallidin and [desArg9]-bradykinin in asthmatic subjects

Kinins are oligopeptides that may act as mediators in the pathogenesis of bronchial asthma by interacting with specific cell surface receptors designated B1 and B2. When administered by inhalation to asthmatic subjects, bradykinin and kallidin, but not [desArg9]-bradykinin, provoke potent bronchoconstriction, thus suggesting a specific effect compatible with the stimulation of B2 receptors. To characterize further the receptor(s) mediating this bronchospastic response we have carried out cross-tachyphylactic studies with inhaled bradykinin, kallidin, and [desArg9]-bradykinin, administered in a randomized double-blind fashion in a group of 10 asthmatic subjects. Inhalation of bradykinin and kallidin, but not [desArg9]-bradykinin, elicited concentration-related falls in forced expiratory volume in one second (FEV1) in all the subjects studied. The geometric mean provocation concentrations of inhaled agonists reducing FEV1 by 20% of baseline (PC20) were 0.12 and 0.28 mg.ml-1 for bradykinin and kallidin, respectively. When inhaled at concentrations up to 10.62 mg.ml-1, [desArg9]-bradykinin failed to provoke any significant fall in FEV1 from baseline in any of the subjects studied. Following recovery from the second bradykinin challenge, provocation with kallidin revealed a reduced response to this agonist, the PC20 value increasing from 0.28 to 1.23 mg.ml-1. Similarly, once the airways had recovered from the second kallidin challenge, provocation with bradykinin also showed a reduced response, the PC20Bk increasing from 0.12 to 0.94 mg.ml-1. Surprisingly, despite failing to cause bronchoconstriction, repeated exposures with inhaled [desArg9]-bradykinin reduced the airway response to bradykinin, the PC20Bk increasing from 0.12 to 0.41 mg.ml-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

BAL neutrophilia in asthmatic patients. A by-product of eosinophil recruitment?

Although neutrophil number may be increased in the airways of patients with asthma, its pathogenetic role in this disorder remains unclear. We evaluated BAL of 8 normal control subjects, 30 +/- 2 years of age, and 24 patients with mild asthma: 17 patients with allergic asthma, 24 +/- 1 years of age, and 7 patients with nonallergic asthma, 30 +/- 1 years of age. The BAL of asthmatic patients showed increased numbers of neutrophils (p < 0.01), eosinophils (p < 0.01), and ciliated epithelial cells (p < 0.05) and increased concentrations of myeloperoxidase (MPO) (p < 0.01) compared with control subjects. Positive correlations were observed between the number of BAL neutrophils and eosinophils (Rs = 0.780, p < 0.0001) and between BAL neutrophil numbers and BAL MPO levels (Rs = 0.40, p < 0.05). No correlations were found between the following: (1) BAL eosinophils or neutrophils and BAL epithelial cells (p > 0.05, each comparison); (2) BAL neutrophils or eosinophils and log Pd15 methacholine (MCh) (p > 0.05, each comparison); or (3) BAL epithelial cells or log Pd15 MCh and BAL MPO (p > 0.05, each comparison). Dividing the patient population into two groups, allergic asthmatics and nonallergic asthmatics, similar BAL neutrophil, eosinophil, and epithelial cell numbers and similar MPO levels were found (p > 0.05, each comparison). In addition, the correlations between BAL neutrophils and eosinophils showed similar significance in the two patient subgroups (p > 0.05, each comparison). These results suggest that, both in allergic and nonallergic asthma, airway recruitment and activation of neutrophils occur as does parallel eosinophil migration. However, airway neutrophils do not seem to contribute significantly to epithelial cell injury or to airway hyperresponsiveness in the steady state.     

Lung epithelial permeability and bronchial responsiveness in subjects with stable asthma

Lung epithelial permeability of asthmatic patients has been reported to be similar or lower than that of healthy subjects and to be correlated or not to bronchial hyperresponsiveness. To clarify these discrepancies, we evaluated 99mTc-DTPA pulmonary clearance in a group of carefully selected asthmatic patients with mild, stable asthma (n = 13; seven women; mean age +/- SD = 27.69 +/- 6.63 years), and compared them with a group of healthy, nonsmoking subjects (n = 8; six women; mean age +/- SD = 24.38 +/- 5.15 years). Selection criteria for asthmatics were as follows: baseline FEV1 > or = 80% of predicted values, no bronchial infections, and/or no asthma attacks during 4 weeks prior to study and peak expiratory flow rate variability lower than 20%, over a period of 3 weeks. Patients controlled symptoms with beta 2-adrenergic drugs only, regularly or on demand. Mean baseline FEV1 (+/-SD) as percent of predicted was 102.38 +/- 13.97 and 112.88 +/- 18.36, respectively (p < 0.05). In the asthmatic group, bronchial responsiveness to methacholine (PC20 M FEV1) ranged between 0.55 and 28.5 mg/mL. Mean value (+/-SD) of DTPA clearance from lungs to blood (evaluated on the first 10 min out of 30 min of the curves) in the asthmatic group was not different from that of control group (68.31 +/- 21.46 and 69.5 +/- 15.73). In the asthmatic patients, there was no correlation between PC20 M values and DTPA T1/2 min of the whole lung, nor between PC20 M and inner and outer lung clearance zones. Moreover, both in asthmatics and healthy subjects, DTPA clearance of outer (alveolar) zones was significantly faster than that of inner (bronchial) zones (57.69 +/- 19.94 vs 102.08 +/- 38.19, p < 0.001, and 59.75 +/- 12.49 vs 103.5 +/- 31.86, p < 0.003, respectively). Our data show that DTPA clearance in patients with stable asthma is similar to that found in healthy subjects; it is not correlated to degree of bronchial responsiveness and occurs more rapidly in the outer zones than in the inner zones, both in asthmatic patients and in healthy subjects. Thus, to date, DTPA clearance index is not a valid tool for identifying and/or monitoring asthmatic patients.     

Anti-inflammatory effects of inhaled beclomethasone dipropionate in nonatopic asthmatics

The effects of inhaled beclomethasone dipropionate (BDP) on asthma symptoms and infiltration of the bronchial mucosa by inflammatory cells were investigated in an open study of 10 patients with mild-to-moderate nonatopic bronchial asthma. Asthma scores were recorded in an asthma diary. Peak expiratory flow (PEF), PEF diurnal variation (PEF%), forced expiratory volume in one second (FEV1%), methacholine airway hypersensitivity (minimum dose of methacholine) (Dmin) were measured. Biopsy of the bronchial mucosa was performed before and after 8 weeks of treatment with BDP (400 micrograms.day-1). The following inflammatory cells were immunostained: eosinophils with anti-EG2; mast cells with AA1; neutrophils with NP57; T-lymphocytes with anti-CD3, CD4, and CD8; and activated T-lymphocytes with anti-CD25. There was a significant improvement in the asthma symptom score, PEF%, FEV1%, and Dmin after BDP therapy and the number of EG2-, AA1-, CD3-, CD4-, and CD25-positive cells decreased significantly. We conclude that inhaled beclomethasone dipropionate inhibited inflammatory cell infiltration of airway tissue and that associated with this there was an improvement of symptoms in this open study of inhaled beclomethasone dipropionate in a group of nonatopic asthmatic subjects.     

Metaproterenol responsiveness after methacholine- and histamine-induced bronchoconstriction

We investigated whether the bronchodilator response to a beta-adrenergic agonist is influenced by the mechanism of induced bronchoconstriction. Normal subjects and asymptomatic asthmatics inhaled a dry aerosol (mass median aerodynamic diameter, 1.5 microns) with increasing concentrations of methacholine or histamine to produce a 35% decrease in specific airway conductance (SGaw), followed by a single inhalation of a metaproterenol aerosol. By studying normal subjects and asthmatics, we were able to compare metaproterenol responsiveness after widely divergent doses of the bronchoprovocative agents but the same degree of bronchoconstriction. Airway deposition of methacholine, histamine, and metaproterenol was measured using a quinine fluorescence technique. Mean baseline SGaw, metaproterenol responsiveness, and metaproterenol mass deposited were similar in normal subjects and asthmatics. Likewise, mean SGaw after completion of methacholine and histamine challenge, and the subsequently deposited metaproterenol mass were similar in the two groups. After methacholine challenge (mean +/- SD provocative drug mass causing a 35% decrease in SGaw, PM35: 8.94 +/- 5.96 mumol in normal subject and 0.30 +/- 0.29 mumol in asthmatics), metaproterenol increased mean SGaw by 89 +/- 33% in normal subjects and by 190 +/- 55% in asthmatics (p < 0.05, two-way analysis of variance). After histamine challenge (PM35, 2.92 +/- 2.49 mumol in normal subjects and 0.17 +/- 0.29 mumol in asthmatics), metaproterenol increased mean SGaw by 111 +/- 38% in normal subjects and 113 +/- 69% in asthmatics (p = not significant). Thus, for the same degree of bronchoconstriction, metaproterenol responsiveness was influenced by the dose of methacholine but not the dose of histamine. The differential metaproterenol response could be related to a functional antagonism between muscarinic and beta-adrenergic agonists.     

Airway responsiveness to hyperosmolar saline challenge in cystic fibrosis: a pilot study

Hyperosmolar aerosols are used to assess airway responsiveness in subjects with asthma. Using a 10% NaCl aerosol, we investigated airway responsiveness in 23 cystic fibrosis (CF) subjects (12 females, 11 males; 19.1 +/- 3.3 years) who had asthma-like symptoms. The pre-challenge predicted forced expiratory volume in 1 second (FEV1) was 74.7 +/- 21.5. The aerosol was generated by a MistO2gen 143A ultrasonic nebulizer and inhaled for 0.5, 1, 2, 4, 8, 8, and 8 minutes or part thereof. Spirometry was performed before and 1 minute after each inhalation period. The challenge was stopped when a > or = 20% fall from the baseline FEV1 was recorded, after the last inhalation period, or when requested by the subject. We recorded different responses to 10% NaCl among subjects. In 7, the FEV1 fell progressively throughout the challenge in a manner similar to asthmatics. By contrast, in 15 subjects the FEV1 was higher at the completion of challenge compared to during challenge, i.e., the fall in FEV1 was transient. In 7 of these subjects, the final FEV1 at the end of the challenge was higher than the pre-challenge FEV1. We conclude that inhaled 10% hyperosmolar saline causes either progressive and sustained or transient airway narrowing during challenge in the majority of CF subjects. The cause of the transient airway narrowing requires further investigation.