This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mao, J. T. Articles by Serio, K. J. Search for Related Content PubMed PubMed Citation Articles by Mao, J. T. Articles by Serio, K. J.

Differential Modulation of Leukotriene B₄ Synthesis and Degradation in Human Bronchoalveolar Lavage Cells by Lipopolysaccharide and Tobacco Smoke

Authors' Affiliations: ¹ Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California and ² Scripps Green Hospital, La Jolla, California

Requests for reprints: Jenny T. Mao, Division of Pulmonary and Critical Care, CHS 37-131, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095-1690. Phone: 310-825-3100; Fax: 310-206-8622; E-mail: jmao{at}mednet.ucla.edu.

Leukotrienes have been implicated to play a prominent inductive role in carcinogenesis. We previously reported that bronchoalveolar lavage (BAL) cells from smokers manifested higher levels of leukotriene B₄ (LTB₄) production than ex-smokers. This study aims to elucidate the underlying mechanism(s). BAL cells from current and former smokers were exposed to lipopolysaccharide (LPS) for up to 7 days. LPS induced the release of LTB₄ from BAL cells and down-regulated 5-lipoxygenase (5-LOX) mRNA expression in a dose-dependent manner, followed by a decrease in 5-LOX protein production and normalization of LTB₄ levels. Exogenous LTB₄ inhibited LPS-induced 5-LOX activity and accentuated the down-regulation of 5-LOX mRNA, whereas suppression of 5-LOX abrogated the LPS-induced changes, suggesting a negative feedback mechanism. LPS concomitantly induced expression and activity of the LTB₄ metabolizing enzyme LTB₄ -hydroxylase (LTB₄OH) in ex-smokers' BAL cells, but not in smokers' BAL cells. In vitro smoke exposure of ex-smokers' BAL cells also abrogated the LPS-induced up-regulation of LTB₄OH mRNA expression. Furthermore, ex-smokers' BAL cells expressed significantly higher LTB₄OH mRNA levels than smokers' BAL cells. Such differential modulation of LTB₄ synthesis and degradation by LPS in the setting of tobacco smoke exposure suggests that mechanisms responsible for sustained elevation of LTB₄ levels in the lung microenvironment may contribute to the pathogenesis of tobacco-related respiratory diseases such as lung cancer. By regulating the balance of LTB₄ in the lung, LTB₄OH may function as a suppressor of lung carcinogenesis.

Key Words: 5-lipoxygenase • LTB₄ -hydroxylase