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Effects of Telithromycin in In Vitro and In Vivo Models of Lipopolysaccharide-Induced Airway Inflammation

From the Microbial Immunology Research Group, Departament of Microbiology, Faculty of Pharmacy, University of Granada, Spain

aruizbr{at}ugr.es

Abstract

Background: The ketolide antibiotic telithromycin (TEL) exerts immunomodulatory and anti-inflamatory effects in vitro, and in a mouse model of septic shock. We studied the anti-inflammatory activity of TEL in in vitro and in vivo models of airway inflammation induced with lipopolysaccharide (LPS).

Methods: We measured the effects of TEL on the response of RAW 264.7 macrophages to LPS and of MLE-12 epithelial cells to supernatants of LPS-stimulated RAW 264.7 macrophages. MIP-2 and TNF-a production, NF-kB activation, and apoptosis were determined. Acute airway inflammation was induced in untreated and TEL-treated BALB/c mice by nebulization with LPS. Total leukocyte number, macrophages, neutrophils, protein concentration, and nitrite and cytokine levels were determined in the bronchoalveolar lavage (BAL) fluid.

Results: TEL inhibited in a dose-dependent manner the production of MIP-2 and TNF-a by LPS-stimulated RAW 264.7 macrophages and the production of MIP-2 by MLE-12 epithelial cells to supernatants of LPS-stimulated RAW 264.7 macrophages. NF-kB activation was inhibited and apoptosis was increased in both cell lines by TEL. The LPS-induced influx of neutrophils in BAL was decreased by TEL pre-treatment. TEL also reduced protein, nitrite, MIP-2 and TNF-a levels in BAL of LPS-nebulized animals.

Conclusions: We have provided evidence that TEL exerts potent anti-inflammatory effects in LPS-induced airways injury. We propose that TEL acts in the early phase of inflammation by reducing release of inflammatory mediators through NF-kB inhibition, and in the later phase through enhancement of inflammatory cell apoptosis.

Key Words: Telithromycin • anti-inflammatory activity • airway inflammation • MIP-2 • neutrophil recruitment • NF-kB inhibition • apoptosis