Modulation of pulmonary leukotriene B4 production by cyclooxygenase-2 inhibitors and lipopolysaccharide.
OBJECTIVE
Emerging data continue to link carcinogenesis to inflammatory events involving the eicosanoid metabolic pathways. We therefore evaluated the effects of cyclooxygenase (COX)-2 inhibition on leukotriene (LT) B(4) synthesis in the lungs of active smokers, as part of a pilot lung cancer chemoprevention study with celecoxib (Celebrex), an oral COX-2 inhibitor.


METHODS
Bronchoalveolar lavage was performed before celecoxib treatment and after 1 month of celecoxib treatment to recover alveolar macrophages (AMs) and lining fluid for study. After harvest, AMs were immediately stimulated in vitro with the calcium ionophore A23187. AMs obtained from smokers before treatment and from ex-smoker control subjects were also cultured overnight with SC58236, a selective COX-2 inhibitor, with or without lipopolysaccharide stimulation.


RESULTS
Treatment with oral celecoxib only modestly increased LTB(4) levels in bronchoalveolar lavage, without increasing the mRNA transcription of 5-lipoxygenase (5-LOX) or 5-LOX-activating protein in AMs, whereas the acute calcium ionophore-stimulated LTB(4) production from smokers' AMs was markedly increased by 10.6-fold. In addition, smokers' AMs were twice as responsive in producing LTB(4) when exposed to lipopolysaccharide compared with ex-smokers' AMs. Concomitant COX-2 inhibition with SC58236, however, did not significantly impact these changes, whereas the 5-LOX inhibitor Zileuton blocked the generation of LTB(4) in a dose-responsive manner. Finally, cycloheximide increased the production of LTB(4) under all conditions, suggesting a shunting phenomenon and/or the presence of pathway inhibitors.


CONCLUSIONS
Our findings suggest that whereas oral celecoxib is capable of modulating LTB(4) production in the lung microenvironment, under physiologic conditions, this effect is probably not functionally significant.
Mao
Jenny T
JT
Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California 90095-1690, USA. jmao@mednet.ucla.edu
Tsu
I-Hsien
IH
Dubinett
Steven M
SM
Adams
Bradley
B
Sarafian
Theodore
T
Baratelli
Felicita
F
Roth
Michael D
MD
Serio
Kenneth J
KJ
D000284:Administration, Oral; D000368:Aged; D018893:Bronchoalveolar Lavage; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007975:Leukotriene B4 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000502:physiology; D016676:Macrophages, Alveolar; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012907:Smoking; D013449:Sulfonamides / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; D007975:Leukotriene B4; D000068579:Celecoxib