Simvastatin attenuates lipopolysaccharide-induced airway mucus hypersecretion in rats.
BACKGROUND
Mucus hypersecretion in the respiratory tract and goblet cell metaplasia in the airway epithelium contribute to the morbidity and mortality associated with airway inflammatory diseases. This study aimed to examine the effect and mechanisms of simvastatin on airway mucus hypersecretion in rats treated with lipopolysaccharide (LPS).


METHODS
Mucus hypersecretion in rat airways was induced by intra-tracheal instillation of LPS. Rats treated with or without LPS were administered intra-peritoneally simvastatin (5 and 20 mg/kg) for 4 days. Expression of Muc5ac, RhoA and mitogen-activated protein kinases (MAPK) p38 in lung were detected by real-time polymerase chain reaction (PCR), immunohistochemistry or Western blotting. Tumor necrosis factor (TNF)-alpha and IL-8 in bronchoalveolar lavage fluid (BALF) were assayed by an enzyme-linked lectin assay and enzyme linked immunosorbent assay (ELISA).


RESULTS
Simvastatin attenuated LPS-induced goblet cell hyperplasia in bronchial epithelium and Muc5ac hypersecretion at both the gene and protein levels in lung (P <0.05). Moreover, simvastatin inhibited neutrophil accumulation and the increased concentration of TNF-alpha and IL-8 in BALF follows LPS stimulation (P < 0.05). The higher dose of simvastatin was associated with a more significant reduction in Muc5ac mRNA expression, neutrophil accumulation and inflammatory cytokine release. Simultaneously, the increased expression of RhoA and p38 MAPK were observed in LPS-treated lung (P <0.05). Simvastatin inhibited the expression of RhoA and p38 phosphorylation in lung following LPS stimulation (P < 0.05). However, the increased expression of p38 protein in LPS-treated lung was not affected by simvastatin administration.


CONCLUSIONS
Simvastatin attenuates airway mucus hypersecretion and pulmonary inflammatory damage induced by LPS. The inhibitory effect of simvastatin on airway mucus hypersecretion may be through, at least in part, the suppression of neutrophil accumulation and inflammatory cytokine release via inactivation of RhoA and p38 signaling pathway.
Ou
Xue-Mei
XM
Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, and Department of Respiratory Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
Wang
Bai-Ding
BD
Wen
Fu-Qiang
FQ
Feng
Yu-Lin
YL
Huang
Xiang-Yang
XY
Xiao
Jun
J
D000818:Animals; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D055271:Mucin 5AC / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008070:Lipopolysaccharides; C524680:Muc5ac protein, rat; D055271:Mucin 5AC; D019821:Simvastatin; D048051:p38 Mitogen-Activated Protein Kinases; D020742:rhoA GTP-Binding Protein