Bronchial effects of leukotriene D4 inhalation in normal human lung

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Abstract
1. The aim of the study was to investigate whether inhaled leukotriene (LT) D4 could mimic the characteristics of asthmatic patients after allergen-induced attack, i.e. a prolonged subclinical bronchial obstruction, an increased reactivity of the airways and a late reaction. The effects of LTD4 were compared with those of histamine and the mechanism of action sought. 2. Thirty-three non-atopic individuals participated in the study. The two drugs were inhaled as an aerosol of small particles causing a relative peripheral deposition pattern in order to mimic the preferential involvement of peripheral airways in asthmatic patients out of attack. 3. LTD4, caused a dose-dependent obstruction of the airways as measured by partial flow-volume curves and volume of trapped gas, yet only minor changes in forced expiratory volume in 1 s (FEV1) and peak expiratory flow rate. LTD4 was 1900-7000 times more potent than histamine. LTD4 inhalations were almost symptomless as opposed to the irritative and dyspnoeic symptoms seen after inhalation of histamine. 4. The time duration for the induced change in partial flow-volume curves was the same for the two drugs. Approximatelk 30 min elapsed until the bronchial obstruction had decreased by 50% of the maximum effect, and no delayed reaction was observed within 10 h. 5. The reactivity of the airways did not change during 10 h after inhalation of LTD4 as tested by repeated exercise challenges. 6. Pretreatment with ipratropium bromide prevented the effect of LTD4 on FEV1, yet not on partial flow-volume curves. Pretreatment with either cimetidine and mepyramine or with indomethacin, did not affect the bronchial obstruction after LTD4. 7. In conclusion, peripheral deposition of LTD4 in non-atopic subjects causes symptomless reduction in airflow with changes in lung function imitating that found in asthmatic patients out of attack. Unlike an allergen-induced asthmatic attack, inhalation of LTD4 does not seem to induce bronchial hyper-reactivity to exercise nor a late reaction. These findings are compatible with LTD4 as a mediator involved in bronchial asthma.