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Published ahead of print on September 10, 2004, doi:10.1164/rccm.200402-200OC

Am. J. Respir. Crit. Care Med., Volume 170, Number 12, December 2004, 1331-1339

A more recent version of this article appeared on December 15, 2004
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Submitted on February 19, 2004
Accepted on September 7, 2004

Azithromycin Blocks Neutrophil Recruitment in Pseudomonas Endobronchial Infection

Wan C Tsai1*, Michael L Rodriguez1, Katherine S Young1, Jane C Deng2, Victor J Thannickal2, Kazuhiro Tateda3, Marc B Hershenson1, and Theodore J Standiford2

1 Department of Pediatrics, Divisions of Pulmonary and Critical Care Medicine, The University of Michigan Medical School, Ann Arbor, MI, USA, 2 Department of Medicine, Divisions of Pulmonary and Critical Care Medicine, The University of Michigan Medical School, Ann Arbor, MI, USA, 3 Department of Microbiology, Toho University School of Medicine, Tokyo, Japan

* To whom correspondence should be addressed. 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 to untreated mice. This effect was associated with significant decreases in lung levels of tumor necrosis factor-alpha and keratinocyte-derived chemokine in azithromycin-treated mice compared to 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: macrolides, chemotaxis, neutrophils, airway inflammation




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