Mannitol triggers mast cell-dependent contractions of human small bronchi and prostacyclin bronchoprotection.

BACKGROUND: Clinical research supports that exercise-induced bronchoconstriction (EIB) is caused by hyperosmolar triggering of mast cells. The reaction can be mimicked by inhalation of mannitol, but it has paradoxically previously not been possible to replicate this mode of action of mannitol in isolated airways. OBJECTIVE: We sought to establish an ex vivo model of EIB in human small bronchi. METHODS: Small bronchi (inner diameter, 0.5-2 mm) from macroscopically healthy human lung tissue were obtained from 48 patients and mounted in organ baths. Contractions and mediator release were analyzed after challenge with hyperosmolar mannitol (850 mOsm). RESULTS: Ten minutes of exposure to mannitol caused a small initial contraction (12% ± 1% of maximum) that was followed by a second and much larger contraction (maximum effect [Emax], 47% ± 5%) when mannitol was washed out. The mast cell stabilizer cromolyn reduced the second contraction (Emax, 27% ± 3%). Furthermore, this main contraction was abolished by the combination of antagonists of histamine and cysteinyl leukotrienes in the presence of indomethacin. Mannitol increased the release of the mast cell mediators histamine (9.0-fold), cysteinyl leukotrienes (4.5-fold), and prostaglandin (PG) D2 (5.4-fold), as well as PGE2 (6.3-fold) and the prostacyclin metabolite 6-keto PGF1α (5.7-fold). In contrast, indomethacin alone enhanced the bronchoconstriction (Emax, 68% ± 6%). Likewise, receptor antagonists for PGE2 (EP2 and EP4) and prostacyclin (IP) also enhanced the mannitol-induced bronchoconstriction (Emax, 67% ± 5%, 66% ± 4%, and 68% ± 3%, respectively). In bronchi precontracted by carbachol, the IP receptor agonist cicaprost induced profound relaxation. CONCLUSION: This new protocol established an in vitro model for studies of EIB in isolated human bronchi. The IP receptor might be a new target for asthma treatment.

An open-label study examining the effect of pharmacological treatment on mannitol- and exercise-induced airway hyperresponsiveness in asthmatic children and adolescents with exercise-induced bronchoconstriction.

BACKGROUND: Mannitol- and exercise bronchial provocation tests are both used to diagnose exercise-induced bronchoconstriction. The study aim was to compare the short-term treatment response to budesonide and montelukast on airway hyperresponsiveness to mannitol challenge test and to exercise challenge test in children and adolescents with exercise-induced bronchoconstriction. METHODS: Patients were recruited from a paediatric asthma rehabilitation clinic located in the Swiss Alps. Individuals with exercise-induced bronchoconstriction and a positive result in the exercise challenge test underwent mannitol challenge test on day 0. All subjects then received a treatment with 400 µg budesonide and bronchodilators as needed for 7 days, after which exercise- and mannitol-challenge tests were repeated (day 7). Montelukast was then added to the previous treatment and both tests were repeated again after 7 days (day 14). RESULTS: Of 26 children and adolescents with exercise-induced bronchoconstriction, 14 had a positive exercise challenge test at baseline and were included in the intervention study. Seven of 14 (50%) also had a positive mannitol challenge test. There was a strong correlation between airway responsiveness to exercise and to mannitol at baseline (r = 0.560, p = 0.037). Treatment with budesonide and montelukast decreased airway hyperresponsiveness to exercise challenge test and to a lesser degree to mannitol challenge test. The fall in forced expiratory volume in one second during exercise challenge test was 21.7% on day 0 compared to 6.7% on day 14 (p = 0.001) and the mannitol challenge test dose response ratio was 0.036%/mg on day 0 compared to 0.013%/mg on day 14 (p = 0.067). CONCLUSION: Short-term treatment with an inhaled corticosteroid and an additional leukotriene receptor antagonist in children and adolescents with exercise-induced bronchoconstriction decreases airway hyperresponsiveness to exercise and to mannitol.

Swimming pool-induced asthma.

A 13-year-old elite swimmer presented with wheezing after indoor swimming training. On the basis of her clinical history and the tests performed, exercise-induced asthma and mold-induced asthma were ruled out and a diagnosis of chlorine-induced asthma was made.

Doping and respiratory system.

Historically many different drugs have been used to enhance sporting performances. The magic elixir is still elusive and the drugs are still used despite the heavy adverse effects. The respiratory system is regularly involved in this research probably because of its central location in the body with several connections to the cardiovascular system. Moreover people are aware that O2 consumption and its delivery to mitochondria firstly depend on ventilation and on the respiratory exchanges. The second step consists in the tendency to increase V'O2 max and to prolong its availability with the aim of improving the endurance time and to relieve the fatigue. Many methods and substances had been used in order to gain an artificial success. Additional oxygen, autologous and homologous transfusion and erythropoietin, mainly the synthetic type, have been administered with the aim of increasing the amount of oxygen being delivered to the tissues. Some compounds like stimulants and caffeine are endowed of excitatory activity on the CNS and stimulate pulmonary ventilation. They did not prove to have any real activity in supporting the athletic performances. Beta-adrenergic drugs, particularly clenbuterol, when administered orally or parenterally develop a clear illicit activity on the myosin fibres and on the muscles as a whole. Salbutamol, terbutaline, salmeterol and formoterol are legally admitted when administrated by MDI in the treatment of asthma. The prevalence of asthma and bronchial hyperactivity is higher in athletes than amongst the general population. This implies that clear rules must be provided to set a correct diagnosis of asthma in the athletes and a correct therapy to align with the actual guidelines according to the same rights of the "other" asthmatic patients.

Dietary sodium intake and asthma: an epidemiological and clinical review.

The changes in diet associated with the development of a more affluent lifestyle have been considered one of the environmental factors that may have contributed to the rise in the prevalence of asthma over the past few decades, and dietary sodium has been considered to be a dietary constituent which may be implicated in this phenomenon. The data presented in this review demonstrate that adoption of a low sodium diet for a period of 2-5 weeks may improve lung function and decrease bronchial reactivity in adults with asthma, while sodium loading appears to have a detrimental effect. Similarly, a low sodium diet maintained for 1-2 weeks decreases bronchoconstriction in response to exercise in individuals with asthma. There is no data as to the longer-term effect of a low sodium diet on either the prevalence or severity of asthma or on exercise-induced bronchoconstriction. As a low sodium diet has other beneficial health effects, it can be considered as a therapeutic option for adults with asthma, although it should be considered as an adjunctive intervention to supplement optimal pharmacological management of asthma and not as an alternative. If the relationship between higher sodium intake and increased prevalence and severity of asthma is causal, then there are potential population benefits for asthma as well as cardiovascular disease to be derived from public health measures to reduce sodium consumption.

Endogenous and exogenous sex steroid hormones and asthma and wheeze in young women.

BACKGROUND: Emerging evidence suggests that both endogenous and exogenous sex steroid hormones may influence the occurrence of asthma and wheeze among women. OBJECTIVE: We investigated the associations between exogenous sex hormone (oral contraceptive [OC]) use and wheezing in young women with and without asthma history. To investigate the role of endogenous sex hormones, we examined the association between age at menarche and the development of asthma after puberty. METHODS: We conducted a study among 905 women who had undergone menarche. Subjects were between 13 and 28 years of age and had participated in the Children's Health Study. RESULTS: In women without asthma, OC use was associated with higher risk of current wheeze (odds ratio [OR], 1.75; 95% CI, 1.15-2.65). In contrast, OC use was associated with a markedly reduced prevalence of current wheeze in women with a history of asthma (OR, 0.18; 95% CI, 0.06-0.56; P value for interaction = .003). These associations showed significant trends with duration of OC use. Age at menarche was associated with new-onset asthma after puberty. Compared with women who had menarche after age 12 years, women with menarche before age 12 years had a 2.08-fold (95% CI, 1.05-4.12) higher risk of asthma after puberty. CONCLUSION: Both endogenous and exogenous sex steroid hormones affect asthma and wheeze occurrences in young women. CLINICAL IMPLICATIONS: Because women have higher asthma risk after puberty, and OC use is common among young women, clinicians may inform women with asthma about the potential effects of OC on asthma-related respiratory symptoms.

Adenosine level in exhaled breath increases during exercise-induced bronchoconstriction.

In asthmatic patients, airway obstruction provoked by exercise challenge is accompanied by an increase in plasma adenosine level. In this study, the current authors investigated if exercise-induced bronchoconstriction was associated with local changes of adenosine concentration in the airways. Oral exhaled breath condensate (EBC) collection (5-min duration) and forced expiratory volume in one second (FEV1) measurements were performed at rest (baseline) and 4-8 times after treadmill exercise challenge in healthy and asthmatic subjects. Adenosine concentration in EBC was determined by HPLC. Observations indicated that physical exercise results in bronchoconstriction together with a significant increase of adenosine level in EBC in asthmatic patients (mean+/-sd maximal fall in FEV1 27+/-13%; associated increase in adenosine 110+/-76% as compared to baseline), but not in healthy control subjects. Exercise-induced changes in adenosine concentration correlated significantly with the fall in FEV1 values in asthmatic patients. In conclusion, the observed increase in adenosine concentration of oral exhaled breath condensate most probably reflects changes in the airways during exercise-induced bronchoconstriction. Due to its known bronchoconstrictor property in asthma, adenosine may contribute to the development of bronchospasm.

Dietary salt intake as a potential modifier of airway responsiveness in bronchial asthma.

While pharmacologic treatment of chronic asthma is usually highly effective, medications often have significant side-effects or exhibit tachyphylaxis. Alternative and/or complementary treatments that reduce dependence on pharmacologic medications are of interest in reducing the severity of asthma. This review analyzes the literature that has evaluated dietary salt intake as a potential modifier of the severity of asthma and airway responsiveness. High dietary intakes of salt, greater than 9 g/d, are common in Western civilizations, as is asthma. The question is whether reducing dietary salt intake potentially would improve pulmonary function and airway responsiveness in individuals with asthma. This review details the existing studies in this regard and includes the studies that have evaluated dietary salt on the severity of exercise-induced asthma (exercise-induced bronchoconstriction [E1B]). From a critical analysis of the existing literature, the data that support a role for dietary salt reduction for reducing severity of asthma and airway responsiveness in individuals with asthma is considered encouraging but not clinically convincing. The existing studies have suffered from a variety of experimental and population limitations. In contrast, the data from studies that have altered dietary salt and evaluated severity of EIB in nonatopic individuals is much more convincing. In each study so far, lowering dietary salt has reduced the severity of EIB to subclinical levels. Correspondingly, the supplementing of diets to higher than normal salt intake increased EIB significantly. This review concludes that the data are sufficient to warrant a clinical trial that is properly controlled and randomized to further investigate the influence of dietary salt intake on pulmonary function, airway responsiveness, symptoms, quality of life, and medication requirements in asthma and EIB.

[A model for exercise-induced asthma in guinea pigs with lipopolysaccharide and metyrapone].

OBJECTIVE: To investigate the relationship between airway inflammation and exercise-induced asthma (EIA), an experimental model for EIA in guinea pigs was developed. METHOD: 27 guinea pigs was divided into 4 groups. A) LPS + MET exercise group (n = 7) had been pretreated with lipopolysaccharide (LPS 1 mg/kg, i.p.) and metyrapone (MET 50 mg/kg, i.p.) on the first day. Then lung resistance (RL) and dynamic compliance (Cdyn) were measured before and after exercise on the fourth day. B) LPS + MET non exercise group (n = 6) that pretreated with LPS and MET had nonexercise on the 4th day. C) NS exercise group (n = 7) pretreated with normal saline (NS 1 mg/kg, i.p.) on the 1st day. RL and Cdyn were measured before and after exercise on the 4th day. D) NS nonexercise group (n = 7) that pretreated with NS had no exercise on the 4th day. RESULT: In LPS+MET exercise group RL increased and Cdyn reduced significantly after exercise. In another 3 control groups there were no such changes either in RL or in Cdyn. CONCLUSION: These observations suggest that the treatment with LPS and MET could make a model for exercise-induced asthma.

[Swimming-induced asthma]. / Svømmeindusert astma.

Swimming is said to have low asthmogeneity especially when compared with other physical activities. Four young athletes who participated in heavy swimming exercise are reported as having symptoms of exercise-induced asthma (EIA). Three of them started to develop the symptoms after several years of training and had no former history of asthma. In the fourth, the asthma was diagnosed in childhood but the EIA-symptoms here exacerbated by swimming. All four experienced more symptoms when the air in the swimming pool was warm, or when there was a strong smell of chlorine. Two of the athletes reported having no symptoms when they swam in outdoor pools and had only minor symptoms, or none at all, when they did other formes of physical exercise, including running. In all four their swimming performance was hampered by their respiratory symptoms. Two of the swimmers improved when they inhaled steroids and adrenerg-beta 2 agonists, and continued their swimming carrier. The cases suggest that an irritant may provoke asthma symptoms in susceptible swimmers. Volatile compounds from chlorination of the pools are suspected as possible irritant agents.

Pre-exposure to ozone does not enhance or produce exercise-induced asthma.

We evaluated whether acute exposure to ozone (O3) enhances or produces exercise-induced asthma (EIA) in asthmatic subjects who have or do not have EIA, according to standardized exercise challenge. Twenty-one otherwise healthy asthmatic subjects, 19 to 40 yr of age, with forced expiratory volume in one second (FEV1) greater than 70% of predicted and methacholine hyperresponsiveness, underwent three 1-h exposures on separate days to 0.10 ppm ozone in filtered air (FA), 0.25 ppm ozone in FA, and FA alone (randomized order, single-blinded, crossover design). Of these subjects, 12 underwent an additional exposure to 0.40 ppm ozone in FA. The subjects performed intermittent light exercise (with mean ventilation of 27 L/min) while in an environmentally controlled chamber (21 degrees C and 40% relative humidity). After each exposure, the subjects rested 1 h in clean air and performed serial postexposure spirometry. The subjects then underwent a standardized exercise challenge in clean air, followed by serial spirometry for 60 min. No significant changes in FEV1 or forced vital capacity (FVC) were found following 1-h exposures to 0, 0.10, and 0.25 ppm ozone (regardless of EIA status). The 12 subjects who underwent all four exposures showed a significant excess reduction in FEV1 (-0.35 +/- 0.37 L or -9.6%) after 1-h exposure to 0.40 ppm O3 (p = 0.017), regardless of EIA status. Postexposure FEV1 returned to baseline levels within 1 h. Postexposure changes in FVC showed similar magnitude and time course but were not statistically significant across exposure conditions or EIA status.(ABSTRACT TRUNCATED AT 250 WORDS)

Methacholine airway responsiveness decreases during exercise in asthmatic subjects.

In many asthmatic subjects, bronchoconstriction develops 2 to 5 min after exercise, reaches a maximum at approximately 10 min, and declines over the next 60 min. However, bronchodilation is typically observed during and immediately after exercise. We measured the bronchoconstrictor responses to increasing concentrations of inhaled methacholine at rest and during two levels of exercise in seven asthmatic subjects to determine the protection against bronchoconstriction afforded by exercise. On the first day, an incremental Stage 1 exercise test was performed to determine the work capacity (Wcap) of each subject. On the second, third, and fourth days, methacholine was inhaled at rest or during steady-state exercise at one-third or two-thirds of Wcap. The bronchoconstrictor response to methacholine was significantly reduced during exercise (p less than 0.0001). The concentration of methacholine required to produce a 20% reduction in FEV1 (PC20) increased from 2.80 mg/ml (%SEM, 1.62) at rest to 7.29 mg/ml (%SEM, 1.43) during exercise at one-third Wcap, and to 31.03 mg/ml (%SEM, 1.74) during exercise at two-thirds Wcap (p less than 0.001). This study has demonstrated that there is greater than tenfold protection against bronchoconstriction by methacholine during exercise, and the magnitude of the protection depends on the intensity of exercise performed. The mechanism of this protection is not known, but may have clinical utility.

Exercise-induced anaphylaxis: improvement after removal of amalgam in dental caries.

We present a case of exercise-induced anaphylaxis with improvement following the removal of dental amalgam. Although her symptoms were unresponsive to various kinds of therapy until removal of the amalgam, her symptoms related to exercise improved remarkably after the removal. The increase in plasma histamine levels for exercise provocation test also improved. This suggests that sensitivity to metals might cause exercise-induced asthma in some patients.

[Effect of nitrogen dioxide on exercise-induced bronchial asthma and the sensitivity of the respiratory tract to methacholine]. / Der Einfluss von Stickstoffdioxid auf das anstrengungsinduzierbare Asthma bronchiale und die Empfindlichkeit der Atemwege gegenüber Methacholin.

In patients with bronchial asthma, airway hyperreactivity may be further increased by exposure to low concentrations of nitrogen dioxide. We studied the effect of inhaled nitrogen dioxide in 11 patients with bronchial asthma who presented with normal lung function values. On two different days, 20 min tidal breathing of either filtered air or 0.25 ppm nitrogen dioxide was followed by bicycle exercise (average minute ventilation 30 l/min). One hour after the end of exercise, we performed a methacholine provocation challenge and determined PC100SRaw. The methacholine provocation challenge was repeated on another day (control day). Mean (SEM) SRaw increased by 79.8 (23.8) % and 82.4 (24.9) % after breathing of filtered air and nitrogen dioxide during exercise, respectively (n.s.). Mean (SEM) PC100SRaw was 0.409 (0.205), 0.407 (0.201) and 0.455 (0.181) mg/ml after breathing of filtered air, nitrogen dioxide and on the control day, respectively (n.s.). We conclude that in mild asthmatics short-term exposure to 0.25 ppm nitrogen dioxide does not enhance airway responsiveness to exercise or methacholine.

Prior exposure to ozone potentiates subsequent response to sulfur dioxide in adolescent asthmatic subjects.

The objective of this study was to test whether prior exposure to a low concentration of ozone (120 ppb) would condition airways in asthmatic subjects to respond to a subthreshold concentration of sulfur dioxide (100 ppb). Eight male and five female subjects 12 to 18 yr of age participated. They all had allergic asthma and exercise-induced bronchospasm. Subjects were exposed to three test atmosphere sequences during intermittent moderate exercise (a 45-min exposure to one pollutant followed by a 15-min exposure to the second pollutant). The sequences were: air followed by 100 ppb SO2, 120 ppb O3 followed by 120 ppb O3, and 120 ppb O3 followed by 100 ppb SO2. The pulmonary function measurements assessed were FEV1, total respiratory resistance (RT), and maximal flow (Vmax50). Air-SO2 and O3-O3 exposures did not cause significant changes in pulmonary function. On the other hand, exposure to 100 ppb SO2 after a 45-min exposure to 120 ppb O3 caused a significant (8%) decrease in FEV1 (p = 0.046), a significant (19%) increase in RT (p = 0.048), and a significant (15%) decrease in Vmax50 (p = 0.008). It is concluded that prior O3 exposure increased bronchial hyperresponsiveness in these subjects such that they responded to an ordinarily subthreshold concentration of SO2. These data suggest that assessment of pulmonary changes to single pollutant challenges overlooks the interactive effects of common coexisting or sequentially occurring air pollutants.

Health risks of short-term SO2 exposure to exercising asthmatics.

A method is described for quantifying health risks to asthmatics briefly exposed to elevated levels of SO2. By combining symptomological and physiological measurements, we have developed a dose-response surface that relates both severity and incidence of response to ambient air quality levels. The complete model to assess potentially avoidable risks includes power plant emission data; ambient SO2 background levels; demographic and activity patterns of asthmatics, the identified population at risk; and the dose-response surface. The estimated annual risk to persons experiencing an SO2-induced response due to a nearby power plant is quite small (response rates under 3 percent). Uncertainties due to modeling errors, variations in activity patterns, demographics and physiological response are discussed.