Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
Int Immunopharmacol. 2010 Jun;10(6):685-93. doi: 10.1016/j.intimp.2010.03.012. Epub 2010 Mar 30.
Airway mucus overproduction is a cardinal feature of airway inflammatory diseases, such as chronic obstructive pulmonary disease and cystic fibrosis. Since the small G-protein Ras is known to modulate cellular functions in the lung, we sought to investigate whether the Ras inhibitor simvastatin could attenuate acrolein-induced mucin production in rat airways. Rats were exposed to acrolein for 12 days, after first being pretreated intragastrically for 24 h with either simvastatin alone or simvastatin in combination with mevalonate, which prevents the isoprenylation needed for Ras activation. Lung tissue was analyzed for extracellular signal-regulated kinase (ERK) activity, goblet cell metaplasia and mucin production. To analyze the effect of simvastatin on mucin production in more detail, acrolein-exposed human airway epithelial NCI-H292 cells were pretreated with simvastatin alone or together with mevalonate. Culture medium was collected to detect mucin secretion, and cell lysates were examined for Ras-GTPase activity and epidermal growth factor receptor (EGFR)/ERK phosphorylation. In vivo, simvastatin treatment dose-dependently suppressed acrolein-induced goblet cell hyperplasia and metaplasia in bronchial epithelium and inhibited ERK phosphorylation in rat lung homogenates. Moreover, simvastatin inhibited Muc5AC mucin synthesis at both the mRNA and protein levels in the lung. In vitro, simvastatin pretreatment attenuated the acrolein-induced significant increase in MUC5AC mucin expression, Ras-GTPase activity and EGFR/ERK phosphorylation. These inhibitory effects of simvastatin were neutralized by mevalonate administration both in vitro and in vivo. Our results suggest that simvastatin may attenuate acrolein-induced mucin protein synthesis in the airway and airway inflammation, possibly by blocking ERK activation mediated by Ras protein isoprenylation. Thus, the evidence from the experiment suggests that human trials are warranted to determine the potential safety and efficacy of simvastatin for treatment of over production of airway mucus.
气道黏液过度产生是气道炎症性疾病（如慢性阻塞性肺疾病和囊性纤维化）的主要特征。由于小 G 蛋白 Ras 已知可调节肺部的细胞功能，我们试图研究 Ras 抑制剂辛伐他汀是否可以减轻丙烯醛诱导的大鼠气道黏液产生。大鼠先经口给予辛伐他汀预处理 24 h，然后再用丙烯醛处理 12 天，辛伐他汀预处理同时还给予了法呢基焦磷酸（mevalonate），法呢基焦磷酸可阻止 Ras 激活所需的异戊烯化。分析肺组织细胞外信号调节激酶（ERK）活性、杯状细胞化生和黏液产生。为了更详细地分析辛伐他汀对黏液产生的影响，用辛伐他汀单独或与法呢基焦磷酸一起预处理暴露于丙烯醛的人气道上皮细胞系 NCI-H292 细胞。收集培养基以检测黏液分泌，并检查细胞裂解物中 Ras-GTPase 活性和表皮生长因子受体（EGFR）/ERK 磷酸化。在体内，辛伐他汀治疗剂量依赖性地抑制了支气管上皮细胞中丙烯醛诱导的杯状细胞增生和化生，并抑制了大鼠肺匀浆中 ERK 的磷酸化。此外，辛伐他汀还抑制了肺中的 Muc5AC 黏蛋白合成在 mRNA 和蛋白质水平上。在体外，辛伐他汀预处理可减弱丙烯醛诱导的 MUC5AC 黏蛋白表达、Ras-GTPase 活性和 EGFR/ERK 磷酸化的显著增加。辛伐他汀的这些抑制作用在体内和体外均被法呢基焦磷酸中和。我们的结果表明，辛伐他汀可能通过阻断 Ras 蛋白异戊烯化介导的 ERK 激活来减轻气道中的丙烯醛诱导的黏液蛋白合成和气道炎症。因此，实验证据表明，有必要进行人体试验以确定辛伐他汀治疗气道黏液过度产生的潜在安全性和疗效。
