Macrolides attenuate mucus hypersecretion in rat airways through inactivation of NF-kappaB |
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Authors: | Ou Xue-Mei Feng Yu-Ling Wen Fu-Qiang Wang Ke Yang Jie Deng Zhi-Pin Liu Dai-Shun Li Yan-Ping |
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Institution: | Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, and;Department of Respiratory Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, China |
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Abstract: | 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)‐κB, 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‐1β, IL‐8 and tumour necrosis factor (TNF)‐α 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‐1β, IL‐8 and TNF‐α, and increased neutrophil numbers in BAL. Moreover, LPS increased staining for NF ‐ κB in the cytoplasm as well as nuclear translocation of NF ‐ κB in airway epithelial cells. Upregulated expression of Muc5ac mRNA correlated positively with NF ‐ κB activation and the levels of cytokines (P < 0.05). Roxithromycin (5 and 10 mg/kg) significantly attenuated bronchial Muc5ac expression and NF ‐ κB 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 ‐ κB 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 ‐ κB activation, neutrophil infiltration and release of inflammatory cytokines in the lung. |
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Keywords: | airway LPS macrolide mucus NF-κB |
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