The role of inflammation in the pathogenesis of severe asthma chronically treated with high doses of glucocorticoids is poorly understood. Despite this, treatment has been aimed at advancing anti-inflammatory and immunomodulator therapy. This study was designed to evaluate both the presence and type of airway inflammation in patients with severe asthma. A prospective bronchoscopic study evaluated 14 severe, high-dose oral glucocorticoid dependent asthmatics. Bronchoalveolar lavage fluid was analyzed for cytology and inflammatory mediators. Endobronchial and transbronchial biopsies were performed in selected patients for morphometric evaluation of macrophage/monocytes, neutrophils, eosinophils and lymphocytes. These results were compared with lavage and endo- and transbronchial biopsy studies in normal controls and patients with moderate asthma. The concentration of eosinophils in bronchoalveolar lavage fluid was highest in the moderate asthmatics not on glucocorticoids, with very little difference between normal controls and severe asthmatics (significant difference among the groups, P=0.007). In contrast, the severe asthmatics demonstrated a twofold higher concentration of neutrophils in lavage than either the mild-moderate asthmatics, or the normal controls (P=0.032 among the groups, P<0.05 between the severe asthmatics and both controls). Similar results were obtained in the endobronchial and transbronchial biopsy specimens, which consistently showed significantly higher numbers of neutrophils in the severe asthmatics than in the control groups. The eicosanoid mediators, thromboxane and leukotriene B4, were also highest in the severe asthma group (differences among the groups, P=0.019 and P=0.023, respectively). These findings suggest that inflammation remains in severe symptomatic asthmatics despite treatment with high dose glucocorticoids which may be due to the severity of disease, glucocorticoid treatment, or other as yet undefined factors.
A study of 14 healthy adult subjects was undertaken to determine whether brief exposure to 0.5-0.6 ppM of ozone would increase bronchial reactivity to inhaled irritants, as reflected by the rise in airway resistance provoked by aerosol challenge with weak solutions of histamine or methacholine. An additional study of 9 subjects with nonasthmatic allergic diseases was also undertaken to determine the effects on ozone on bronchial reactivity in atopic subjects. Subjects from both the non-atopic groups were exposed to ozone on several occasions to determine whether tolerance develops to the sensitizing effects of ozone on bronchial responsiveness. The results indicate that exposure to 0.6 ppM of ozone for 2 hours increases bronchial reactivity to histamine in both normal and atopic subjects and that the increase in responsiveness is blocked by pretreatment with atropine, suggesting that postganglionic cholinergic mechanisms are involved. Bronchial reactivity returned to control levels in 1-7 days in most subjects, but tolerance to repeated exposures to ozone was not observed.
Whether short-term exposure to low levels of nitrogen dioxide (NO2) enhances airway responsiveness in asthmatic subjects is controversial. Because it is well established that asthma is associated with increased airway responsiveness to another common air pollutant, sulfur dioxide (SO2), we examined whether short-term exposure of asthmatic subjects to 0.3 ppm NO2 potentiates airway responsiveness to inhaled SO2. We exposed nine subjects with clinically stable asthma to 0.3 ppm NO2 or filtered air in an environmental room for 30 min on 2 separate days at least 1 wk apart in a double-blind, randomized fashion. A questionnaire about common symptoms related to inhaled irritants was completed before and immediately after each exposure. Each subject exercised (60 to 80 W) on a cycloergometer during the first 20 min of each exposure. We measured specific airway resistance (SRaw) and FEV1/FVC before, 5 min after, and 1 h after completion of the air or NO2 exposures. The single-breath nitrogen test (SBN2) was also performed before and 1 h after completion of the air or NO2 exposures and closing volume was determined; subsequently, SO2 dose-response curves (0.25 to 4.0 ppm) were performed via a mouthpiece. Each dose of SO2 was inhaled at a minute ventilation of 20 L/min for 4 min and was doubled until SRaw increased by at least 8 U above baseline. The dose of SO2 required to provoke an increase in SRaw of 8 U above baseline was determined by linear interpolation from the dose-response curve (PD8USO2). We found that exposure to NO2 was not associated with any change in the reported symptoms or in the measured pulmonary function tests. The mean SRaw was 7.1 ± 2.2 before and 9.5 ± 2.6 L × cm H2O/L/s after air exposure, and 7.1 ± 2.2 before and 9.7 ± 3.5 L × cm H2O/L/s after NO2 exposure but FEV1/FVC did not change. Mean SRaw, FEV1/FVC, and closing volume measured 60 min after air or NO2 exposures did not differ from baseline. The mean PD8USO2 was similar after air (1.25 ± 0.70 ppm) and NO2 (1.31 ± 0.75 ppm) exposures. We conclude that in exercising individuals with clinically stable asthma, a controlled 30-min exposure to 0.3 ppm NO2 is not associated with a greater change in pulmonary function than that observed after exposure to filtered air and does not potentiate airway responsiveness to inhaled SO2.
