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Azithromycin Blocks Neutrophil Recruitment in Pseudomonas Endobronchial Infection

Departments of Pediatrics and Medicine, Divisions of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan; and Department of Microbiology, Toho University School of Medicine, Tokyo, Japan

Correspondence and requests for reprints should be addressed to Wan C. Tsai, M.D., University of Michigan Medical Center, Division of Pediatric Pulmonary Medicine, 6301 MSRB III, Box 0642, Ann Arbor, MI 48109–0642. E-mail: wctsai{at}med.umich.edu

Macrolides exert their effects on the host by modulation of immune responses. In this study, we assessed the therapeutic efficacy of azithromycin in a murine model of mucoid Pseudomonas aeruginosa endobronchial infection. The clearance of Pseudomonas from the airway of mice treated with the macrolide azithromycin was not different than untreated mice challenged with Pseudomonas beads. However, the azithromycin-treated mice showed a remarkable reduction in lung cellular infiltrate in response to Pseudomonas beads, as compared with untreated mice. This effect was associated with significant decreases in lung levels of tumor necrosis factor- and keratinocyte-derived chemokine in azithromycin-treated mice compared with untreated mice. Furthermore, there was a significant reduction in the response of both mouse and human neutrophils to chemokine-dependent and -independent chemoattractants when studied in vitro. Inhibition of chemotaxis correlated with azithromycin-mediated inhibition of extracellular signal–regulated kinase-1 and -2 activation. This study indicates that the azithromycin treatment in vivo results in significant reduction in airway-specific inflammation, which occurs in part by inhibition of neutrophil recruitment to the lung through reduction in proinflammatory cytokine expression and inhibition of neutrophil migration via the extracellular signal–regulated kinase-1 and -2 signal transduction pathway.

Key Words: airway inflammation • chemotaxis • macrolides • neutrophils

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