The Effect of Inhaled Budesonide on the Maximal Degree of Airway Narrowing to Leukotriene D4and Methacholine in Normal SubjectsIn Vivo

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Abstract
In normal humans in vivo, maximal airway narrowing to LTD4 is more severe than to methacholine. Moreover, LTD4 heightens the maximal response to methacholine for several days. To investigate whether or not this is due to inflammatory changes in the airway wall, we studied the effects of the corticosteroid budesonide on the dose-response curves to inhaled LTD4 and to methacholine. In a two-period, double-blind, placebo-controlled design, budesonide (400 µg twice a day) or placebo was inhaled by eight normal subjects on six consecutive days, with a 3-wk washout. Complete dose-response curves to LTD4 (0.36 to 43 nmol) were performed on Day 5, and to methacholine (1.28 to 655 µmol) on Days 4 and 6 of each period using a validated method. The response was measured by FEV1 and standardized partial expiratory flow-volume curves ( 40p), and was expressed as the percent fall from baseline. A maximal response plateau was considered if more than two doses fell within a 5% response range. All subjects reached plateaus to methacholine and to LTD4. Budesonide reduced the maximal response to LTD4 (mean difference with placebo, 7.9% fall for FEV1, and 8.4% fall for 40p; p < 0.05). During placebo the maximal response to methacholine 24 h after LTD4 was higher than 24 h before (mean change, 2.7% fall in FEV1 and 5.5% fall in 40p; p < 0.05), but not during budesonide (mean change, −2.5% fall in FEV1 and −0.1% fall in 40p; p > 0.2), the changes being significantly different between the two periods (p < 0.05). Budesonide did not affect the position of the respective dose-response curves. We conclude that inhaled steroids reduce the maximal degree of airway narrowing to LTD4 and protect against the LTD4-induced increase in maximal response to methacholine. This is in support of the hypothesis that inflammatory changes account for the excessive airway narrowing observed in asthma.