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Celecoxib Modulates the Capacity for Prostaglandin E₂ and Interleukin-10 Production in Alveolar Macrophages from Active Smokers

¹ Division of Pulmonary and Critical Care Medicine and
² Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, and
³ Division of Pulmonary and Critical Care Medicine, VA San Diego Healthcare System and the University of California, San Diego, California

ABSTRACT

Purpose: Preclinical data suggest that the cyclooxygenase (COX)-2/prostaglandin (PG) E₂ signaling pathway plays an essential role in conferring the malignant phenotype in non-small cell lung cancer. We hypothesized that treatment with oral celecoxib, a selective COX-2 inhibitor, would favorably alter biomarkers of lung cancer risk. This study evaluated the feasibility of COX-2 inhibition as a form of chemoprevention for lung cancer.

Experimental Design: Heavy active smokers were enrolled into a pilot study and treated with celecoxib. Bronchoscopy with bronchoalveolar lavage was performed both before 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 nonsmoking control subjects were also cultured overnight with SC58236, a selective COX-2 inhibitor, with or without lipopolysaccharide stimulation.

Results: Treatment with celecoxib significantly reduced calcium ionophore-stimulated PGE₂ production from AMs recovered from smokers. AMs recovered from smokers, but not nonsmokers, were primed to produce high levels of PGE₂ and interleukin (IL-10) when stimulated with lipopolysaccharide, and SC58236 significantly abrogated the production of these factors. Moreover, both plasma and bronchoalveolar lavage fluid obtained from treated subjects significantly reduced the production of PGE₂ that resulted when a lung cancer cell line, A549, was stimulated with IL-1ß or A23187.

Conclusions: Our findings suggest that oral celecoxib is capable of inhibiting the overproduction of PGE₂, as well as modulating the production of IL-10 in the lung microenvironment in individuals at risk for lung cancer.

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