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Modulation of Pulmonary Leukotriene B₄ Production by Cyclooxygenase-2 Inhibitors and Lipopolysaccharide

¹ Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California; and ² Division of Pulmonary and Critical Care Medicine, VA San Diego Healthcare System and the University of California, San Diego, California

Purpose: 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) B₄ synthesis in the lungs of active smokers, as part of a pilot lung cancer chemoprevention study with celecoxib (Celebrex), an oral COX-2 inhibitor.

Experimental Design: 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 LTB₄ 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 LTB₄ production from smokers’ AMs was markedly increased by 10.6-fold. In addition, smokers’ AMs were twice as responsive in producing LTB₄ 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 LTB₄ in a dose-responsive manner. Finally, cycloheximide increased the production of LTB₄ 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 LTB₄ production in the lung microenvironment, under physiologic conditions, this effect is probably not functionally significant.

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