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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

BackgroundThe 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).

MethodsWe 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.

ResultsTEL 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.

ConclusionsWe 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