Macrolides attenuate mucus hypersecretion in rat airways through inactivation of NF-kappaB.
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)-kappaB, 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-1beta, 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-1beta, IL-8 and TNF-alpha, and increased neutrophil numbers in BAL. Moreover, LPS increased staining for NF-kappaB in the cytoplasm as well as nuclear translocation of NF-kappaB in airway epithelial cells. Upregulated expression of Muc5ac mRNA correlated positively with NF-kappaB activation and the levels of cytokines (P < 0.05). Roxithromycin (5 and 10 mg/kg) significantly attenuated bronchial Muc5ac expression and NF-kappaB 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-kappaB 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-kappaB activation, neutrophil infiltration and release of inflammatory cytokines in the lung.
Ou
Xue-Mei
XM
Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China.
Feng
Yu-Ling
YL
Wen
Fu-Qiang
FQ
Wang
Ke
K
Yang
Jie
J
Deng
Zhi-Pin
ZP
Liu
Dai-Shun
DS
Li
Yan-Ping
YP
D000658:Amoxicillin / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015570:Josamycin / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008297:Male; D055271:Mucin 5AC; D009077:Mucins / Q000235:genetics / Q000378:metabolism; D009093:Mucus / Q000378:metabolism*; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism*; D015575:Roxithromycin / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D008070:Lipopolysaccharides; C524680:Muc5ac protein, rat; D055271:Mucin 5AC; D009077:Mucins; D016328:NF-kappa B; D012333:RNA, Messenger; D015575:Roxithromycin; D000658:Amoxicillin; D015570:Josamycin