Effects of telithromycin in in vitro and in vivo models of lipopolysaccharide-induced airway inflammation

Abstract

Background: The ketolide antibiotic telithromycin (TEL) exerts immunomodulatory and antiinflammatory effects in vitro and in a mouse model of septic shock. We studied the antiinflamma-tory activity of TEL in in vitro and in vivo models of airway inflammation induced by lipopolysaccharide (LPS). Methods: We measured the effects of TEL on the response of RAW 264.7 macrophages to LPS and of murine lung epithelial (MLE)-12 cells to supernatants of LPS-stimulated RAW 264.7 macrophages. Macrophage inflammatory protein (MIP)-2 and tumor necrosis factor (TNF)-α production, nuclear factor (NF)-κB activation, and apoptosis were determined. Acute airway inflammation was induced in untreated and TEL-treated BALB/c mice by nebulization with LPS. Total number of leukocytes, macrophages, and neutrophils, the protein concentration, and nitrite and cytokine levels were determined in the 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-κB activation was inhibited and apoptosis was increased in both cell lines by TEL. The LPS-induced influx of neutrophils in BAL fluid was decreased by TEL pretreatment. TEL also reduced protein, nitrite, MIP-2, and TNF-a levels in the BAL fluid of LPS-nebulized animals. Conclusions: We have provided evidence that TEL exerts potent antiinflammatory effects in LPS-induced airways injury. We propose that TEL acts in the early phase of inflammation by reducing the release of inflammatory mediators through NF-κB inhibition, and in the later phase through enhancement of inflammatory cell apoptosis. Copyright © 2008 by American College of Chest Physicians.