A controlled trial of the effect of the 5-lipoxygenase inhibitor, zileuton, on lung inflammation produced by segmental antigen challenge in human beings.
BACKGROUND
Segmental antigen challenge (SAC) and bronchoalveolar lavage (BAL) have been proven useful for investigating IgE-mediated lung inflammation in volunteers with allergies.


OBJECTIVE
This model was used to evaluate the pulmonary antiinflammatory effects of an experimental 5-lipoxygenase inhibitor (zileuton) in subjects allergic to ragweed. We hypothesized that decreased generation of leukotrienes by inhibition of the 5-lipoxygenase pathway of arachidonic acid metabolism would diminish the subsequent inflammatory response resulting from antigen challenge.


METHODS
Ten subjects with allergies received zileuton or placebo, 600 mg administered orally four times a day for 8 days, and then underwent bronchoscopy, BAL of a control segment, and SAC in the contralateral lung followed by BAL of the challenged segment 24 hours later in a double-blind, placebo-controlled, crossover protocol. Urinary excretion of leukotriene E4 induced by antigen challenge plus total and differential cell counts and the amount of total protein, albumin, urea, and eosinophil cationic protein in BAL fluid were determined.


RESULTS
A significant inhibition of leukotriene production (approximately 86%) was observed in subjects receiving zileuton. In addition, there was a statistically significant increase in eosinophils after antigen challenge (0.6 +/- 0.2 x 10(4) eosinophils/ml increasing to 49.0 +/- 25.0 x 10(4) in subjects receiving placebo, whereas the influx of eosinophils in subjects receiving zileuton was not statistically different from baseline (1.1 +/- 0.7 x 10(4) eosinophils/ml increasing to 16.5 +/- 4.1 x 10(4); analysis of variance for repeated measures with post hoc comparisons).


CONCLUSIONS
Treatment with zileuton altered the inflammatory response after antigen challenge. Products of the 5-lipoxygenase pathway appear to be important in recruiting eosinophils to the lung after SAC.
Kane
G C
GC
Jefferson Medical College, Department of Medicine, Philadelphia, PA 19107-5083, USA.
Pollice
M
M
Kim
C J
CJ
Cohn
J
J
Dworski
R T
RT
Murray
J J
JJ
Sheller
J R
JR
Fish
J E
JE
Peters
S P
SP
D000328:Adult; D000941:Antigens / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002452:Cell Count / Q000187:drug effects; D004311:Double-Blind Method; D004804:Eosinophils / Q000473:pathology; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006967:Hypersensitivity / Q000276:immunology; D017999:Leukotriene E4 / Q000652:urine; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use; D008297:Male; D011014:Pneumonia / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D011058:Pollen
D000941:Antigens; D016859:Lipoxygenase Inhibitors; D017999:Leukotriene E4; C063449:zileuton; D006918:Hydroxyurea