Patrick J. Manning

Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4-receptor antagonist.

BACKGROUND Exercise is a common stimulus of bronchoconstriction in subjects with asthma, who also have bronchoconstriction after inhaling the sulfidopeptide leukotriene D4 (LTD4). The purpose of this study was to investigate the importance of LTD4 as a mediator of exercise-induced bronchoconstriction. METHODS In a double-blind, randomized, crossover study, 12 subjects with stable asthma were treated intravenously with MK-571 (160 mg), a selective and potent LTD4-receptor antagonist, or placebo, 20 minutes before each of two challenges involving exercise at a level previously demonstrated to cause a fall of at least 20 percent in the forced expiratory volume in one second (FEV1). The two exercise challenges were separated by one week. The results of the challenges were expressed as both the maximal fall in FEV1 after exercise and the time to recovery from bronchoconstriction. RESULTS Treatment with MK-571 attenuated exercise-induced bronchoconstriction in all the subjects. The mean (+/- SEM) maximal percent decrease in FEV1 after exercise was 25.2 +/- 3.5 percent in the subjects taking placebo and 9.2 +/- 2.5 percent in the subjects taking MK-571 (P less than 0.001). The mean percent inhibition for the entire group was 69.5 percent. The mean time to recovery after exercise was 33.4 +/- 4.0 minutes in the placebo group and 8.4 +/- 2.5 minutes in the MK-571 group (P less than 0.001). CONCLUSIONS This study demonstrates that pretreatment with a potent and selective LTD4 antagonist markedly attenuates exercise-induced bronchoconstriction, and it suggests that LTD4 is a major mediator of this type of bronchoconstriction.

Urinary leukotriene E4 levels during early and late asthmatic responses

The sulphidopeptide leukotrienes C4 and D4 (LTC4, LTD4) are potent bronchoconstrictor mediators, released from human lung fragments after challenge with specific allergens in vitro. The purpose of this study was to measure urinary LTE4 (metabolite of LTC4 and LTD4) in subjects undergoing inhalation challenges with allergens or occupational sensitizing agents in the laboratory. Eighteen subjects with previously documented isolated early asthmatic responses (EARs), isolated late asthmatic responses (LARs), or dual (both early and late) asthmatic responses were studied. Urinary LTE4 levels increased in subjects who developed either isolated EARs (mean fall in FEV1, 27.98%) or early responses preceding LARs (mean fall in FEV1, 15.01%). The baseline levels of LTE4 were 150.26 (SEM, 49.5) pg/mg of creatinine in the isolated responders and 66.60 (SEM, 13.5) pg/mg of creatinine in the dual responders. These levels increased to 1816 (SEM, 606.1) pg/mg of creatinine (p = 0.041) and 174.80 (SEM, 40.1) pg/mg of creatinine (p = 0.025), respectively, after the EAR. The degree of maximal bronchoconstriction during the EAR correlated with the levels of LTE4 (r = 0.68; p = 0.001). No significant increase in urinary LTE4 levels occurred during the LAR. These results suggest that the LTE4 precursors, LTC4 and LTD4, are important bronchoconstrictor mediators causing EARs after allergen inhalation.

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.

The effect of oral prostaglandin E1 on airway responsiveness in asthmatic subjects.

Prostaglandin E1 (PGE1) is a bronchodilator in humans, but the effect of this prostaglandin on airway responsiveness in asthmatic subjects is not known. The purpose of this study was to examine the effect of oral PGE1 treatment on airway responsiveness to inhaled histamine and methacholine in asthmatic subjects. The subjects had inhalation tests performed on separate study days over a period of 2 weeks. PGE1 (200 micrograms 4 times daily) or placebo was taken in a double-blind fashion for 4 consecutive days. Each week, after three days of treatment, a histamine or methacholine inhalation test was performed on one day, followed by an inhalation test with the alternative agonist the following day. Baseline forced expired volume in 1 s (FEV1) values were similar before each inhalation test on each study day (P = 0.81). However, both histamine and methacholine airway responsiveness decreased following PGE1 treatment. The mean provocative concentration of histamine causing a 20% fall in FEV1 (PC20 histamine) on the placebo day was 1.47 mg/ml (%SD 3.05) and was 2.35 mg/ml (%SD 2.72) (p less than 0.005) during PGE1 treatment period. Similarly the PC20 methacholine was 1.84 mg/ml (%SD 2.30) on the placebo day and was 2.53 mg/ml (%SD 2.06) during PGE1 treatment period (p = 0.025). This study demonstrates that oral PGE1, administered in doses which did not change airway caliber, can reduce airway responsiveness in mild asthmatics.

The inhibitory influence of tracheal mucosa mounted in close proximity to canine trachealis

Reduced smooth muscle contractile responses to agonists occur in the presence of epithelium, perhaps due to the release of an epithelium-derived relaxing factor (EpDRF). It is not clear whether the release of EpDRF requires the direct attachment of the epithelium to the smooth muscle. In the present study, using isolated canine tracheal smooth muscle strips, we examined whether the inhibitory effects of airway mucosa require the attachment of the mucosa to smooth muscle. The smooth muscle contractile responses to acetylcholine and histamine were reduced in the presence of airway mucosa, whether the mucosa was attached or in close proximity. The inhibitory effect mediated by the airway mucosa therefore is not dependent on mucosal attachment to smooth muscle. This phenomenon appears to be due to the release of a soluble, short-acting mediator from the airway mucosa.