Variations of airway responsiveness to methacholine and exercise in asthmatic and normal subjects over a 12-month period

This study looked at seasonal fluctuations of airway responsiveness (AR) to methacholine and exercise in ten mild asthmatic and seven normal subjects. Each subject had a monthly methacholine inhalation test. An exercise challenge with measurement of expiratory flows was performed initially in the fall (F), then in winter (W), and in summer (S). Throughout the study, the subjects were asked to record on a diary card twice daily peak flow rates and respiratory symptoms, one week a month. Airway responsiveness to exercise and methacholine remained generally stable throughout the year, although an increase in respiratory symptoms occurred during fall and winter. The overall AR to methacholine was not significantly different during the different seasons (F, W, S and Spring) with the methacholine concentration producing a 20% fall in FEV1, PC20 (mg/ml) values, respectively, of 1.7 +/- 1.2 mg/ml, 1.8 +/- 1.1, 2.1 +/- 1.2, and 2.0 +/- 1.9 for asthmatics and 79.0 +/- 1.2 mg/ml, 66.8 +/- 1.0, 87.3 +/- 1.0, and 73.1 +/- 1.0 for normals. However, short term variations in AR were associated to exposure to antigens and cold weather. Mean daily peak expiratory flows remained generally stable through the seasons. On the three exercise tests, the VO2 max and the mean % fall in FEV1 after maximal exercise showed large variations; these, however, were not significantly different (mean fall: 16.2% (F), 16.6% (W), and 14.7% (S) in asthmatics). In conclusion, although it may increase transiently, overall airway responsiveness to methacholine and exercise remains generally stable in asthmatic and normal subjects throughout the year.     

Airway responses to inhaled ouabain in subjects with and without asthma

Challenges with ouabain and histamine were performed a week apart in 10 patients with asthma and 5 normal subjects. Concentrations were increased cumulatively until specific airway conductance decreased by 30% or the maximal concentration of 1.0% was reached. At low concentrations, ouabain induced bronchodilatation in six patients who had asthma. Bronchodilatation gradually decreased with increasing concentrations and was followed by bronchoconstriction in two patients with asthma who had high airway sensitivity to histamine. Ouabain caused only bronchoconstriction in three patients with severe asthma. The normal subjects showed mild bronchodilatation or no response to ouabain. Several possible biochemical mechanisms may be responsible for the bronchodilatory response to low doses of ouabain, such as stimulation of adenylate cyclase or (Na+,K+)-adenosine triphosphatase. The absence of a bronchodilatory response to ouabain in patients with severe asthma suggests an impairment in the activity of these enzymes.     

Sodium cromoglycate in histamine and methacholine reactivity in asthma

The effect of increasing concentrations of inhaled sodium cromoglycate (SCG) (2, 10, 20 and 40 g/l) on histamine and methacholine bronchial reactivity was studied in nine patients with extrinsic bronchial asthma. The responses to histamine and methacholine were expressed in terms of provocative concentrations producing 20% fall in the FEV1 (PC20). The PC20 for histamine and methacholine was unaffected by all the concentrations of SCG used in the study. These results suggest that the effect of SCG on the bronchial smooth muscle or on the muscarinic receptors is minimal.     

Bronchial responsiveness to methacholine during airway cooling in normal subjects

In order to investigate the effects of airway cooling on bronchial responsiveness in normal subjects, we measured bronchial responsiveness to inhaled methacholine with and without the inhalation of cold air. Two out of seven subjects showed an increase in baseline respiratory resistance (Rrs) during cooling of the airway but the other five subjects showed little change in their baseline Rrs. All subjects increased bronchial responsiveness to methacholine. Additionally, the threshold dose of methacholine decreased to one-third of the control dose with cooling of the airway. We speculate that airway cooling increased bronchial responsiveness to methacholine in normal subjects presumably due to increased vagal tone, increased alpha-adrenergic activity and/or a release of chemical mediators.     

Changes in airway dead space in response to methacholine provocation in normal subjects

Measurements of bronchial hyper-responsiveness rely on sensitive techniques for measurement of bronchoconstriction, ideally based on tidal breathing. A potentially useful technique is measurement of airway dead space (V_Daw), which reflects the volume of the conducting airways. The aim of this study was to evaluate measurements of V_Daw with the single breath test for CO₂ (SBT-CO₂), compared to spirometric measurements, as a method of measuring bronchial response to methacholine challenge. Nineteen healthy adults were studied. Dosimetric methacholine challenge tests were performed on two study days. Forced expirations or the SBT-CO₂ were used to assess the response. There were dose-dependent reductions in the spirometric measurements, with a 10 ± 10% reduction from the baseline value of forced expiratory volume at the highest dose of methacholine. There was a dose-dependent reduction from the baseline value of V_Daw by 19 ± 9% at the highest dose. There was also a dose-dependent increase in the slope of the alveolar plateau of the SBT-CO₂. This study provides support for measurement of V_Daw as a means of evaluating bronchial responsiveness after methacholine challenge. In a group of healthy adults, this method shows a greater response but with similar dispersion as measurement of forced expiratory volume after methacholine challenge.     

Efficacy of budesonide in inhaled corticosteroid-naive patients and patients with mild persistent asthma

BACKGROUND: Patients with mild intermittent or mild persistent asthma represent 70% of asthma sufferers. Inhaled corticosteroids (ICSs) are the mainstay of treatment for persistent asthma, although many of the early clinical studies of these drugs included only patients with moderate to severe asthma. OBJECTIVE: This article reviews the literature on the efficacy of budesonide in the treatment of mild persistent asthma, including newly diagnosed ICS-naive patients. METHODS: Published data were identified by a MEDLINE search of the English-language literature from 1992 to 2002 using the terms budesonide plus efficacy or safety, both with and without the termsfluticasone or beclomethasone. An AstraZeneca reference database was also used to identify publications from the same period. Controlled, randomized studies that included patients with mild persistent asthma and early-treatment intervention were selected for inclusion. RESULTS: Inhaled budesonide has been used for almost 20 years in the treatment and control of moderate to severe asthma. Studies involving patients with mild persistent asthma have demonstrated significant improvements in peak expiratory flow (PEF) rates (P < 0.01) and forced expiratory volume in I second (P < 0.016) values for adult, adolescent, and pediatric patients treated with budesonide compared with placebo. Budesonide therapy is effective when given once or twice daily via dry powder inhaler or nebulizer, even at a low starting dose (200 microg/d). No significant adverse events have been reported with budesonide within the dose range used to treat mild persistent asthma (200 to 400 microg/d). Significant improvements in PEF rates (P < 0.01) and significant reductions in the risk of exacerbations and the number of days with poorly controlled asthma have been reported for ICS-naive patients treated with budesonide compared with placebo (both P < 0.001). In the primary care setting, mild persistent asthma may be undertreated. Patients with mild persistent asthma benefit significantly from early treatment with budesonide (P < 0.05). CONCLUSIONS: Budesonide is effective and well tolerated in the treatment of mild persistent asthma in adults and children, including many patients whose primary care physicians do not think they require daily ICS treatment.     

Variability in airway conductance and lung volume in subjects with asthma

Summary. Variability in airway conductance (G_aw) and lung volume (TGV) was studied in 26 subjects with moderately severe asthma during a 9-week period. Specific airway conductance (SG_aw) was calculated as G_aw:TGV. There was considerable inter-individual variability in airway conductance, and a smaller variability in TGV. Airway conductance (SG_aw) showed an eight-fold difference and TGV a three-fold difference between smallest and largest values. The intra-individual variability was less, with a range of ±55% (SG_aw) and ±12% (TGV) of the grand mean, respectively. The error of the method contributed only marginally to the variations in airway conductance. These data for spontaneous variability of conductance facilitate, for example, the assessment of the clinical importance of changes in lung function seen after exposure to air pollutants in chamber studies. Furthermore, the substantial inter-individual variability in conductance argues against comparing samples of asthmatic subjects in polluted and non-polluted areas, and in favour of prospective studies of cohorts of subjects with asthma.     

Evaluation of the efficacy of inhaled glucocorticosteroids in mild bronchial asthma

AIM: To develop a procedure for evaluating the efficacy of antiinflammatory agents in mild persistent bronchial asthma. MATERIALS AND METHODS: 76 patients with mild bronchial asthma were given long acting theophylline. If a complete clinical and functional effect was absent, the inhaled glucocorticosteroid budesonide was added to the therapy. Before and after therapy, the forced expiratory volume per second and forced vital capacity (FVC) were measured many times within 24 hours, by using two procedures: 1) that involving morning and diurnal tests using short acting beta 2-agonists and 2) that without a bronchodilator. The time of onset of the plateau of values of different functional indices obtained during monitoring and their dispersion in the stable state were automatically calculated. The reliability of indices for evaluating the efficiency of antiinflammatory therapy was compared. RESULTS: There were great differences in the patients' response to therapy: a complete clinical and functional effect of therapy with long acting theophylline alone (n = 9) and in combination with budesonide (n = 56). Moreover, therapy-resistant patients (n = 11) were identified. When a complete therapeutic effect was achieved, the clinical symptoms of the disease disappeared before the onset of the plateau of values of the most reliable functional indices. A comparative analysis of the indices has indicated that the ratio of the morning value of FVC measured just after awakening to its best personal value throughout the study was most convenient for the patients and reliable. CONCLUSION: The authors propose to use the index "ratio of the morning value of FVC measured just after awakening to its best personal value the percentage", by calculating the dispersion of this index, which characterizes the steady state of the expiratory respiratory system in order to evaluate the efficiency of antiinflammatory therapy for bronchial asthma and to solve other problems that require functional monitoring.     

Effect of inhaled methacholine on gas mixing efficiency

1. Pulmonary function tests, including alveolar mixing efficiency by the single-breath and multi-breath methods, and ventilation scans were performed on 16 volunteer subjects. The tests were repeated after the inhalation of a methacholine aerosol in sufficient dosage to increase airways resistance. 2. After inhalation of methacholine there was a significant fall in mean series dead space of 31 ml (P less than 0.05), and mean multi-breath alveolar mixing efficiency fell from 68% to 36% (P less than 0.001), a fall occurring in all subjects. Mean single-breath alveolar mixing efficiency measured on the first breath of the nitrogen washout fell from 76% to 70%, but this change did not reach statistical significance (0.1 greater than P greater than 0.05). 3. In eight of the subjects, technically adequate lung scans and pulmonary function tests were obtained both before and not more than 30 min after methacholine inhalation. In seven there were obvious visible defects on the ventilation scans, and in five of these the computer-calculated underventilation score became abnormal. 4. Thus inhalation of methacholine causes maldistribution of ventilation, a fall in alveolar mixing efficiency and a fall in series dead space, presumably brought about by bronchoconstriction. The parallel component of this maldistribution of ventilation, as judged by 81mKr ventilation scanning, does not of itself seem to be sufficient to explain the fall in alveolar mixing efficiency, and therefore a degree of diffusion limitation is probably involved as well.     

A meta-analysis of the dose-response relationship of inhaled corticosteroids in adolescents and adults with mild to moderate persistent asthma

BACKGROUND: Although inhaled corticosteroids (ICS) are commonly used in the treatment of persistent asthma, the relationship between dose and clinical response remains unclear. OBJECTIVE: This study investigated whether ICS exhibit a dose-response relationship in the treatment of mild to moderate persistent asthma. METHODS: This was a meta-analysis of published randomized clinical trials concerning the relationship between ICS dose and response in asthma. Relevant studies were identified through a search of PubMed and MEDLINE for articles on asthma and ICS published between January 1996 and January 2001. The search was limited to publications classified as clinical trials that included the text words asthma and corticosteroids, glucocorticoids, beclomethasone, budesonide, fluticasone, flunisolide, mometasone, or triamcinolone acetonide. Five clinical measures were considered: morning peak expiratory flow rate (AM PEFR), evening PEFR (PM PEFR), forced expiratory volume in 1 second (FEV(1)), beta-agonist use, and asthma symptom score (severity of symptoms on a given day, as evaluated by patients). RESULTS: Forty-three studies were identified, of which 16 met the criteria for inclusion in the meta-analysis. These studies involved 4 agents: fluticasone propionate, triamcinolone acetonide, budesonide, and mometasone furoate. A statistically significant dose response in AM PEFR was observed with fluticasone propionate, triamcinolone acetonide, and budesonide (respective 95% CIs, 4.9 to 11.5, 4.7 to 18.0, and 5.8 to 24.9). A statistically significant dose response to fluticasone propionate and triamcinolone acetonide was also observed in PM PEFR (95% CIs, 2.0 to 8.7 and 2.4 to 13.7) and asthma symptom score (95% CI, -0.069 to -0.002 and -0.60 to -0.10). In terms of FEV(1), the dose response was statistically significant only with budesonide (95% CI, 0.025 to 0.17). Dose-response relationships were not disproportionately driven by the highest doses, and the greatest effects on response were seen at doses below or at the low end of the recommended range, suggesting that use of high doses of ICS may contribute only marginally to efficacy. CONCLUSIONS: Dose-response relationships were not uniformly observed with all drugs or for all measures of response. Use of higher doses of ICS in patients with mild to moderate persistent asthma does not appear to increase the efficacy of these drugs.     

Exhaled particles as markers of small airway inflammation in subjects with asthma

Exhaled breath contains suspended particles of respiratory tract lining fluid from the small airways. The particles are formed when closed airways open during inhalation. We have developed a method called Particles in Exhaled air (PExA^®) to measure and sample these particles in the exhaled aerosol. Here, we use the PExA^® method to study the effects of birch pollen exposure on the small airways of individuals with asthma and birch pollen allergy. We hypothesized that birch pollen‐induced inflammation could change the concentrations of surfactant protein A and albumin in the respiratory tract lining fluid of the small airways and influence the amount of exhaled particles. The amount of exhaled particles was reduced after birch pollen exposure in subjects with asthma and birch pollen allergy, but no significant effect on the concentrations of surfactant protein A and albumin in exhaled particles was found. The reduction in the number of exhaled particles may be due to inflammation in the small airways, which would reduce their diameter and potentially reduce the number of small airways that open and close during inhalation and exhalation.     

A single-blind, partial crossover clinical trial of the effects of inhaled fluticasone propionate and nedocromil sodium on airway hyperresponsiveness to methacholine

Background: Airway inflammation plays a central role in the pathogenesis of asthma, even in the mildest forms and at the earliest stages. Therapeutic strategies now aim to relieve bronchoconstriction as well as focus primarily on controlling the underlying inflammatory process. Clinical trials of children and adults with asthma have demonstrated that inhaled corticosteroids and cromones (such as nedocromil sodium [NS]) improve symptoms and lung function, as well as decrease nonspecific bronchial hyperresponsiveness.Objective: The aim of this study was to compare the effects of various anti-inflammatory therapeutic regimens using inhaled fluticasone propionate (FP) and/or NS on airway hyperresponsiveness to methacholine.Methods: Patients with mild, persistent asthma, who tested positive to a Dermatophagoides pteronyssinus skin prick test, were randomly assigned to 1 of 4 treatment groups: (1) FP for 16 weeks; (2) FP for 8 weeks, followed by NS for 8 weeks; (3) NS for 8 weeks, followed by FP for 8 weeks; or (4) NS for 16 weeks. Each patient was evaluated every 4 weeks.Results: Thirty-two patients with asthma (16 men and 16 women; age range, 18-48 years) were included in the study; 8 patients were randomly assigned to each of the 4 treatment groups. During treatment with FP alone, the provocative dose of methacholine required to induce a 20% decrease in forced expiratory volume in 1 second (PD₂₀) was significantly higher than that recorded during treatment with NS alone (P < 0.05 at weeks 12 and 16). However, both drugs induced progressive increases in PD₂₀ versus baseline values throughout the study. Moreover, when FP was administered as the second drug (after NS), a further increase in PD₂₀ compared with the values at week 8 occurred at both week 12 (P < 0.01) and week 16 (P < 0.001). In contrast, when NS was administered after 8 weeks of treatment with FP, methacholine PD₂₀ decreased significantly compared with week 8 (P < 0.001 and P < 0.01 at weeks 12 and 16, respectively).Conclusions: Our results suggest that, in this limited population of asthmatic patients who were treated for 16 weeks, FP was effective in increasing the PD₂₀ and that NS exerted an effective, progressive protective action against bronchial hyperresponsiveness to methacholine, thereby partially limiting the negative consequences of FP withdrawal on airway inflammation.     

The effect of regular inhaled salbutamol on the airway responsiveness of normal subjects

1. Airway responses to inhaled salbutamol were measured in two groups of six normal non-atopic subjects. In each group there was a dose-dependent increase in specific airways conductance after salbutamol inhaled in cumulative doses from 25 to 600 micrograms. 2. In the first group these studies were repeated weekly during and after the subjects had taken regular inhaled salbutamol for 4 weeks, in doses increasing to 500 micrograms four times daily by week 5. Then, while subjects were continuing to receive regular salbutamol, the studies were repeated after 48 h of inhaled sodium cromoglycate (20 mg four times daily) and again after 48 h of beclomethasone dipropionate (200 micrograms four times daily). 3. In the second group the studies were repeated after 10 days of regular inhaled salbutamol (500 micrograms four times daily). 4. There was no change in airway response to inhaled salbutamol after 4 weeks or 10 days regular salbutamol therapy, or after 48 h of sodium cromoglycate or beclomethasone dipropionate therapy. 5. This study did not show the development of resistance to beta-agonists in the airways of normal subjects. These findings are discussed in the context of other studies which have shown the development of resistance, and we suggest that there may be a spectrum of susceptibility to the development of impaired airway responsiveness following regular treatment with beta-adrenergic drugs.     

Comparison of airway conductance and FEV1 as measures of airway responsiveness to methacholine

When defining bronchial responsiveness in healthy, non‐asthmatic, subjects exposed in different working situations, it is not clear whether different outcome measures yield similar results. Therefore, the concentration and dose of methacholine that caused a 20% decrease in forced expiratory volume in 1 s (FEV₁) (PC20_FEV1 and PD20_FEV1), the corresponding change in Gaw and the relationship between the dose–response slope (DRS) for FEV₁ and Gaw was studied in different working populations and healthy control subjects (n=1038). The two outcome measures were compared in groups of subjects in whom differences in bronchial responsiveness could be anticipated [atopics (n=72) and non‐atopics (n= 207) and subjects exposed (n=54) and not exposed (n=32) to saw dust]. A bronchial challenge was also made before and after exposure in a swine confinement building, an exposure known to increase bronchial responsiveness (n=37). PD20_FEV1 was 1·7 mg in atopics and 4·9 mg in non‐atopics, 7·1 mg in saw dust exposed and >20 mg in non‐exposed subjects and 5·3 mg before and 0·79 mg after exposure to organic dust. There was a correlation between DRS_FEV1 and DRS_Gaw, r=0·87 (P<0·001). In subjects who were highly sensitive to methacholine a 20% change in FEV₁ corresponded to <40% change in Gaw, while a 20% decrease in FEV₁ corresponded to none or a minor decrease in Gaw in subjects with less methacholine‐sensitive airways. The ability to detect differences in bronchial responsiveness between groups, or to detect changes in bronchial responsiveness following exposure was approximately the same for FEV₁ and Gaw. The reproducibility was similar for both variables and a second measurement was within one doubling of the methacholine concentration of the first provocation in ≈95% of all measurements (n=41). In conclusion, with our methacholine provocation method, FEV₁ and Gaw had similar sensitivity in detecting small differences in bronchial responsiveness in healthy subjects.     

The combined effects of two pairs of mediators, adenosine with methacholine and prostaglandin D2 with histamine, on airway calibre in asthma

Mediators released from mast cells and secondary effector cells in the airways contribute to bronchoconstriction of allergic asthma. This study investigates methods for defining the effect of two inflammatory mediators on airway calibre in asthma. In an initial study on three asthmatic subjects, subconstrictor (subthreshold) concentrations of two mast cell derived mediators, histamine and prostaglandin (PG) D2, produced similar displacement to the left of a histamine concentration-specific airways conductance (sGaw) response curve. With both agonists enhancement of histamine-induced bronchoconstriction was greater at low histamine concentrations. Since potentiation of histamine-induced bronchoconstriction was independent of the class of subconstrictor agent given, it is likely to represent a physiological rather than a pharmacological interaction. During provoked asthma different constrictor mediators are likely to be released simultaneously into the airways. A method was therefore devised to investigate the combined effect of equiconstrictor concentrations of two mediators on airway calibre. Two pairs of inhaled bronchoconstrictor agonists were chosen for study: adenosine with methacholine and PGD2 with histamine. For each agonist, concentration-sGaw response curves were constructed, from which were derived the provocation concentrations of agonist causing a 25% fall in sGaw from baseline (PC25) and required to further this to 50% (PC50-25). On separate days, eight subjects received paired inhalations of methacholine-adenosine, methacholine-methacholine and adenosine-adenosine. The concentration used for the first inhalation was the PC25 value and for the second inhalation the PC50-25 value. Before, immediately after the first inhalation, and at regular intervals after the second inhalation, sGaw was followed for 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reagin-mediated asthma in rhesus monkeys and relation to bronchial cell histamine release and airway reactivity to carbocholine.

Rhesus monkeys with persistent immediate-type cutaneous and respiratory responses (RR) to ascaris antigen (AA) were compared with rhesus monkeys with skin reactivity and no respiratory responses, and animals with no skin reactivity and no respiratory responses to inhaled antigen (NR). The RR group could not be distinguished from the nonresponding (NR) group by the cutaneous skin test titers, serum, or respiratory secretion IgE concentration. Leukocyte histamine (H) release due to anti-IgE was similar with peripheral blood leukocytes and bronchial lumen mast cells (MC) from RR and NR animals. The RR group of animals could be distinguished from the NR group by their degree of sensitivity to inhaled carbocholine and H release from respiratory MC exposed to AA. The RR group demonstrates consistent, persistent respiratory responses suitable for immunologic, pharmacologic, and physiologic studies. Finally, it was found that the IgE concentration in respiratory secretions of rhesus monkeys was comparatively higher than in serum, evidence for IgE as a secretory Ig in the respiratory tract of this species.     

Hyperosmolar solution effects in guinea pig airways. IV. Lipopolysaccharide-induced alterations in airway reactivity and epithelial bioelectric responses to methacholine and hyperosmolarity

We investigated the in vivo and in vitro effects of lipopolysaccharide (LPS) treatment (4 mg/kg i.p.) on guinea pig airway smooth muscle reactivity and epithelial bioelectric responses to methacholine (MCh) and hyperosmolarity. Hyperosmolar challenge of the epithelium releases epithelium-derived relaxing factor (EpDRF). Using a two-chamber, whole body plethysmograph 18 h post-treatment, animals treated with LPS were hyporeactive to inhaled MCh aerosol. This could involve an increase in the release and/or actions of EpDRF, because LPS treatment enhanced EpDRF-induced smooth muscle relaxation in vitro in the isolated perfused trachea apparatus. In isolated perfused tracheas the basal transepithelial potential difference (Vt) was increased after LPS treatment. The increase in Vt was inhibited by amiloride and indomethacin. Concentration-response curves for changes in Vt in response to serosally and mucosally applied MCh were biphasic (hyperpolarization, <3 x 10(-7)M; depolarization, >3 x 10(-7)M); MCh was more potent when applied serosally. The hyperpolarization response to MCh, but not the depolarization response, was potentiated after LPS treatment. In both treatment groups, mucosally applied hyperosmolar solution (using added NaCl) depolarized the epithelium; this response was greater in tracheas from LPS-treated animals. The results of this study indicate that airway hyporeactivity in vivo after LPS treatment is accompanied by an increase in the release and/or actions of EpDRF in vitro. These changes may involve LPS-induced bioelectric alterations in the epithelium.     

孟鲁司特钠联合吸入性布地奈德对哮喘儿童小气道功能和呼出气一氧化氮浓度的影响

目的 评价孟鲁司特钠联合吸入性布地奈德治疗儿童哮喘的临床疗效及其对小气道功能和呼出气一氧化氮(FeNO)浓度的影响。方法 前瞻性选择典型哮喘儿童132例为研究对象,随机分为对照组和观察组,每组66例。对照组采用吸入性布地奈德混悬液,观察组在对照组基础上联合应用孟鲁司特钠颗粒,2组均连续应用4周。分析2组临床疗效、不良反应、大气道肺功能和小气道功能以及FeNO浓度;比较2组随访1年哮喘复发率。结果 对照组63例和观察组64例最终完成随访。观察组临床总有效率高于对照组,差异有统计学意义(P<0.05)。治疗前和治疗后,2组大气道肺功能相关指标比较,差异均无统计学意义(P>0.05)。治疗4周后,2组最大呼气中期流速(MMEF)、呼气流量峰值(PEF)和50%肺活量时最大呼气流速(MEF₅₀)均高于治疗前,且观察组高于对照组,差异有统计学意义(P<0.05); 2组FeNO浓度均低于治疗前,且观察组低于对照组,差异有统计学意义(P<0.05)。随访发现,观察组复发率低于对照组,差异有统计学意义(P<0.05)。结论 孟鲁司特钠联合吸入性布地...     

The peroxisome proliferator-activated receptor alpha agonist fenofibrate decreases airway reactivity to methacholine and increases endothelial nitric oxide synthase phosphorylation in mouse lung

In the present study, we have investigated the effect of the peroxisome proliferator-activated receptor α (PPARα) agonist fenofibrate on airway reactivity and the role of the endothelial nitric oxide synthase (eNOS)/NO pathway in this effect. Airway reactivity to methacholine was assessed in C57BL/6 mice treated or not with fenofibrate by whole-body plethysmography. In some experiments, animals were administered with the NOS inhibitor L-NAME, one hour before airway reactivity measurement. Expression and phosphorylation of eNOS were evaluated in lung homogenates from fenofibrate and control animals using Western blotting. Fenofibrate dose and time dependently decreased airway reactivity to methacholine in mice. A statistically significant (P < 0.05) reduction was observed after a treatment of 10 days with a dose of 3 or 15 mg/day fenofibrate. Mice treated with fenofibrate and administered with l-NAME exhibited similar reactivity to methacholine than vehicle-treated mice administered with the NOS inhibitor, suggesting that NO mediates fenofibrate-induced decrease in airway reactivity. eNOS levels remained unchanged in the lung from mice treated with fenofibrate, but phosphorylation of the enzyme at Ser-1177 was increased by 118% (P < 0.05). Taken together, our data demonstrate that fenofibrate downregulates airway reactivity to methacholine in the mouse and suggest that this effect could involve an increase in NO generation through an enhanced eNOS phosphorylation.