Effects of 5-lipoxygenase inhibitor zileuton on airway responses to inhaled swine house dust in healthy subjects.
BACKGROUND
Inhalation of swine house dust induces acute airway inflammation and increased bronchial responsiveness in healthy subjects.


OBJECTIVE
The aim of the study was to investigate whether 5-lipoxygenase products such as leukotrienes may have a role in this reaction.


METHODS
Twenty-three healthy subjects were randomised into two groups receiving treatment with either zileuton (600 mg) or placebo four times a day. After 5 days of treatment, all subjects were exposed for 3h in a swine barn. Bronchial responsiveness, exhaled nitric oxide (NO), and mediators in nasal lavage (NAL), blood and urine were measured before and after the exposure.


RESULTS
The exposure induced an increased bronchial responsiveness to methacholine in both groups with 2-3 doubling concentration steps, no significant difference between treatments. Leukotriene E(4) in urine increased significantly following exposure in the placebo group from 37.3 (29.1-45.6) (mean (95% confidence interval)) ng/mmol creatinine to 47.7 (36.3-59.0) ng/mmol creatinine (P<0.05), but not in the zileuton group. The post-exposure increase of LTB(4) levels in NAL fluid was totally abolished in the zileuton group (P<0.05 vs. the placebo). The levels of exhaled NO increased significantly (P<0.01), two-fold in both groups. The PGD(2) metabolite 9alpha, 11beta-PGF(2) increased in placebo-treated subjects (P<0.01; P<0.05 vs. zileuton), strengthening mast cell participation. Neutrophil counts and levels of IL-6 in peripheral blood increased in both groups, with a significantly larger increase in zileuton treated subjects (P<0.05 and P<0.001, respectively compared to placebo).


CONCLUSIONS
Pre-treatment with clinically recommended doses of the 5-lipoxygenase inhibitor zileuton did not affect the increase of bronchial reactivity induced by swine dust exposure. The intervention totally abolished the LTB(4) release in NAL fluid, but only partially inhibited the formation of leukotrienes as monitored by urinary levels. The enhanced increase of neutrophils and IL-6 in peripheral blood in the zileuton group, suggests that inhibition of 5-lipoxygenase may have pro-inflammatory effects.
Larsson
Britt-Marie
BM
Lung and Allergy Research, Division of Physiology, The National Institute of Environmental Medicine, Karolinska Institutet, P.O. Box 287, SE-171 77 Stockholm, Sweden.
Kumlin
Maria
M
Sundblad
Britt-Marie
BM
Larsson
Kjell
K
Dahlén
Sven-Erik
SE
Palmberg
Lena
L
D000328:Adult; D000818:Animals; D001980:Bronchi / Q000187:drug effects*; D001985:Bronchial Provocation Tests; D016207:Cytokines / Q000378:metabolism; D004391:Dust; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology; D019570:Inhalation Exposure; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D017817:Nasal Lavage Fluid / Q000737:chemistry; D009569:Nitric Oxide / Q000032:analysis; D012129:Respiratory Function Tests; D013552:Swine
D016207:Cytokines; D004391:Dust; D016859:Lipoxygenase Inhibitors; D009569:Nitric Oxide; C063449:zileuton; D006918:Hydroxyurea