Time course of the increase in airway responsiveness associated with late asthmatic reactions to toluene diisocyanate in sensitized subjects

To understand better the mechanism of the increase in airway responsiveness associated with late asthmatic reactions, we determined the time course of toluene diisocyanate (TDI) effect on airway responsiveness in six sensitized subjects who exhibited a late asthmatic response after TDI exposure (0.018 +/- 0.005 ppm, 30 min) in the laboratory. Airway responsiveness was assessed before TDI exposure and then at 8 hr, 1 day, 1 wk, and 1 mo after TDI exposure. To assess responsiveness we determined the provocative dose of methacholine causing a decrease in FEV1 of 20% (PD20FEV1). The methacholine PD20 decreased from 0.50 mg geometric standard error of the mean (GSEM = 1.54) to 0.06 mg (GSEM = 1.55) (p less than 0.001) at 8 hr after exposure to TDI, was still decreased to 0.15 mg (GSEM = 1.93) (p less than 0.05) at 1 day, returned to 0.26 mg (GSEM = 1.91) (p greater than 0.05) at 1 wk, and returned to 0.43 mg (GSEM = 1.71) at 1 mo, indicating that full recovery occurred within 1 to 4 wk. These results demonstrate that TDI-induced late asthmatic response is associated with a reversible increase in airway responsiveness to methacholine and suggest that the TDI effect is linked to an acute inflammatory response in the airways.     

The role of alpha and beta adrenoceptors in airway hyperresponsiveness to histamine

The effect of a specific alpha 1-adrenoceptor antagonist, prazosin, on histamine-induced bronchoconstriction was compared to a beta 2-adrenoceptor agonist, salbutamol, in 16 subjects with nonspecific bronchial hyperresponsiveness whose PC20H ranged from 0.10 to 5.12 mg/ml. PC20H was calculated from a histamine inhalation test performed before and after 0.5 mg of prazosin by dry powder inhalation and 200 mcg of salbutamol by pressurized aerosol. PC20H was also measured in six subjects before and after placebo (20 mg lactose) by dry powder inhalation in a randomized double-blind study with prazosin. Mean (+/- SE) PC20H before and after placebo was 1.77 (0.32) and 1.57 (0.38) mg/ml, respectively, an 0.89-fold change. Mean (+/- SE) PC20H before and after prazosin for the 16 subjects was 1.92 (0.34) and 3.10 (0.72) mg/ml, a 1.51-fold change (p less than 0.001), and PC20H before and after salbutamol was 2.08 (0.33) and 9.54 (2.51) mg/ml, a 4.08-fold change (p less than 0.001). There was a positive correlation between the prazosin and salbutamol responses (r = 0.55, p less than 0.05). A dose response for salbutamol was performed in eight subjects, and PC20H was determined by use of increasing doses of salbutamol until PC20H was more than 16 mg/ml. The dose of salbutamol required varied widely between subjects and did not relate to baseline PC20H. The results suggest a role for alpha-adrenoceptors in addition to beta-adrenoceptors in histamine-induced bronchoconstriction.     

Changes in bronchial hyperreactivity induced by 4 weeks of treatment with antiasthmatic drugs in patients with allergic asthma: a comparison between budesonide and terbutaline

We performed a double-blind crossover study to compare the effects of long-term treatment of inhaled budesonide and terbutaline on bronchial hyperreactivity in 17 patients with allergic asthma. Both drugs were administered for 4 weeks with a placebo-treatment period before and after each active-treatment period. To assess bronchial hyperreactivity, standardized inhalation provocation tests with histamine and propranolol were performed every 2 weeks. Before each inhalation provocation the drugs were withheld for at least 12 hours. Before the budesonide treatment the FEV1 value (percent predicted) was 85.3 +/- 4.1% (mean +/- SEM). After 2 and 4 weeks of treatment with this drug, the value increased significantly to 89.4 +/- 4.1% and 96.2 +/- 3.8%, respectively (p less than 0.05 and p less than 0.005). The histamine provocation concentrations causing a decrease in FEV1 of 20% (PC20) on the same days were 4.0, 7.2, and 9.5 mg/ml, respectively (both p less than 0.001). The PC20 values for propranolol, which were measured 1 hour after the histamine provocation, were 11.7, 13.3, and 14.0 mg/ml (ns). The FEV1 values before and after 2 and 4 weeks of treatment with terbutaline were 86.2 +/- 4.0%, 84.8 +/- 4.1%, and 87.0 +/- 4.6%, respectively. The histamine PC20 values on the same days were 4.7, 3.1 (p less than 0.05), and 3.8 mg/ml, respectively. The propranolol PC20 values were 14.2, 8.7, and 10.1 mg/ml (p less than 0.001 and p less than 0.05, respectively. We conclude that budesonide improves bronchial hyperreactivity, possibly by a dampening of late allergic reactions, whereas treatment with terbutaline may lead to a temporary increase of bronchial hyperreactivity, possibly as a result of beta-receptor desensitization.     

Allergen-induced increase in bronchial responsiveness to histamine: relationship to the late asthmatic response and change in airway caliber

Allergen-induced late asthmatic responses are associated with an increase in bronchial responsiveness to histamine. We have examined the relationship between the magnitude of the late asthmatic response and the magnitude and duration of increased histamine responsiveness. Allergen inhalation tests were carried out in 12 asthmatic subjects to induce a mild early asthmatic response (16% to 40% reduction in FEV₁ in the first hour after allergen inhalation); the response was followed over 8 hr to identify the occurrence and magnitude of any late asthmatic response (maximum fall in FEV₁ from baseline between 3 and 8 hr). The provocation concentration of histamine causing a decrease in FEV₁ of 20% (PC₂₀) was measured before and after inhalation of allergen. The magnitude of decrease in PC₂₀ correlated with the magnitude of the late asthmatic response as measured by the percent fall in FEV₁ (r = 0.8, p < 0.002). The duration of decrease in PC₂₀ was from 2 to 74 days and this also correlated with the magnitude of the late response (r = 0.53, p < 0.05). Total lung capacity (TLC), residual volume (RV), FEV₁, maximal expiratory flow-volume curves (on air and He-O₂), and histamine responsiveness were also measured before and at intervals after allergen inhalation. Four of seven subjects still had a reduction in PC₂₀ when the TLC, RV, FEV₁, maximal expiratory flow-volume rates on air (V?₅₀air) and He-O₂ (V?₅₀He-O₂) (measured at an absolute volume corresponding plus 50% of control vital capacity) and ratio of V?₅₀He-O₂ to V?₅₀air were back t preallergen inhalation levels. In two of these subjects volume of isoflow was also back to ±10% of preallergen inhalation levels when the PC₂₀ was still significantly reduced. The results suggest that allergen-induced late asthmatic responses can be associated with an increase in bronchial responsiveness to histamine by mechanisms other than a reduction in baseline airway caliber alone.     

Nifedipine in bronchial asthma

In 11 patients with bronchial asthma and regular overnight falls in PEFR of greater than 15%, we demonstrated significant bronchodilation restricted only to large airways after the administration of a single dose of 10 mg of nifedipine. A statistically significant increase in PEFR, SGaw, and FEV1 was noticed at 1 and especially 2 hr after nifedipine administration. During 4 days of nifedipine treatment (10 mg t.i.d.), the overnight fall in mean PEFR was statistically significant (p less than 0.02) and less than the mean fall of PEFR during the 4 days of placebo treatment. Thus nifedipine does modify the basal bronchial tone of patients with asthma and diminishes the circadian swing of airway resistance.     

Combined alveolitis and asthma due to hexamethylene diisocyanate (HDI), with demonstration of crossed respiratory and immunologic reactivities to diphenylmethane diisocyanate (MDI)

A worker exposed intermittently to hexamethylene diisocyanate (HDI) developed episodes of dyspnea, wheezing, and fever on working days. Complete lung function tests performed when the subject was asymptomatic were normal except for increased airway responsiveness to histamine, which significantly improved after a 3 wk period off work. At that time, specific inhalation challenges with HDI were carried out. After being exposed for 5 min, the subject developed general malaise, cough, fever, and leukocytosis, together with a mixed restrictive and obstructive breathing defect. We demonstrated a subsequent increase in airway hyperexcitability, which lasted for 2 mo. The subject was also challenged with diphenylmethane diisocyanate (MDI) for 15 min. A late obstructive reaction was documented. Increased levels of specific IgG antibodies against HDI-human serum albumin (HSA) and MDI-HSA were demonstrated.