Macrolides attenuate mucus hypersecretion in rat airways through inactivation of NF-κB

Background and objective: To examine the effect of a 14-membered ring macrolide on airway mucus hypersecretion in rats treated with LPS. Methods: Mucus hypersecretion in rat airways was induced by intratracheal instillation of LPS. Rats treated with or without LPS were administered roxithromycin (1-10 mg/kg), josamycin (10 mg/kg) or amoxicillin (40 mg/kg), orally for 4 days. Expression of Muc5ac, nuclear factor (NF)-kappa B, and the mitogen-activated protein (MAP) kinases p38 and ERK1/2 in bronchial epithelium were detected by RT-PCR, immunohistochemistry or western blotting. Mucins, IL-1 beta, IL-8 and tumour necrosis factor (TNF)-alpha in BAL fluid were assayed by enzyme-linked lectin assay and ELISA. Results: LPS significantly induced the expression of Muc5ac mRNA and protein in bronchial epithelium, increased the release of mucins, IL-1 beta, IL-8 and TNF-alpha, and increased neutrophil numbers in BAL. Moreover, LPS increased staining for NF-kappa B in the cytoplasm as well as nuclear translocation of NF-kappa B in airway epithelial cells. Upregulated expression of Muc5ac mRNA correlated positively with NF-kappa B activation and the levels of cytokines (P < 0.05). Roxithromycin (5 and 10 mg/kg) significantly attenuated bronchial Muc5ac expression and NF-kappa B nuclear translocation stimulated by LPS, and reduced neutrophil numbers, mucins and inflammatory cytokines in BAL (P < 0.05). However, LPS-stimulated expression of p38 and ERK1/2 in airway epithelium was not affected by roxithromycin. Josamycin and amoxicillin had no effects on Muc5ac expression, NF-kappa B activation or cytokine release. Conclusions: Roxithromycin inhibits the pulmonary inflammatory response and airway mucus hypersecretion induced by LPS. The inhibitory effect of roxithromycin on airway mucus hypersecretion may be mediated through reduction of NF-kappa B activation, neutrophil infiltration and release of inflammatory cytokines in the lung.