EFFECT OF 5-LIPOXYGENASE INHIBITION ON BRONCHOCONSTRICTION AND AIRWAY INFLAMMATION IN NOCTURNAL ASTHMA

To investigate the contribution of leukotrienes (LTs) to inflammation and bronchoconstriction in nocturnal asthma, we performed a randomized trial in 12 asthmatic patients and 6 normal control subjects. This study involved pulmonary function testing, methacholine challenge, bronchoscopy for cell counts, LT and thromboxane (TX) levels in bronchoalveolar lavage (BAL) fluid, and collection of urine for LTs at 4:00 P.M. and 4:00 A.M. At 4:00 P.M. BAL fluid LTB(4) and sulfidopeptide LT levels in asthmatic and control subjects were not statistically different. At 4:00 A.M. alone, LTB(4) and cysteinyl LT levels increased to become significantly greater in asthmatic than in control subjects, LTB(4) levels correlating significantly (r = -0.66, p < 0.0001) with nocturnal fall in FEV(1). Nocturnal asthmatic urinary LTE(4) levels were also significantly higher than those of control subjects. The 4:00 A.M. testing was repeated during treatment with a 5-lipoxygenase inhibitor, zileuton. In asthmatic subjects, zileuton decreased BAL fluid LTB(4) (p = 0.01) and urinary LTE(4) (p = 0.01) while showing a trend for improving nocturnal FEV(1) (p = 0.086). These decreases in LTB(4) levels and improvement in FEV(1) were associated with significant reductions in 4 A.M. BAL fluid and blood eosinophil percentages on zileuton compared with placebo administration. These findings demonstrate the importance of LTs in both the inflammation and the physiology of nocturnal asthma.