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Simvastatin attenuates lipopolysaccharide-induced airway mucus hypersecretion in rats
作者单位: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 
基金项目:National Natural Science Foundation of China to Dr. WEN Fu-qing,No. 30425007, 30370627, 30670921;China Medical Board of New York to Dr. WEN Fu-qiang,No. 0-722;
摘    要: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)-α 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-α 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

关 键 词:脂多糖  粘液分泌过多  RhoA  分裂素  病原体

Simvastatin attenuates lipopolysaccharide-induced airway mucus hypersecretion in rats
Authors:OU Xue-mei  WANG Bai-ding  WEN Fu-qiang  FENG Yu-lin  HUANG Xiang-yang  XIAO Jun
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 610041,China
Abstract: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)-a 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-α 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-traated 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.
Keywords:mucus hypersecretion  lipopolysaccharide  simvastatin  RhoA  mitogen-activated protein kinases p38
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