Simvastatin attenuates acrolein-induced mucin production in rats: Involvement of the Ras/extracellular signal-regulated kinase pathway
Simvastatin attenuates acrolein-induced mucin production in rats: Involvement of the Ras/extracellular signal-regulated kinase pathway
复制标题
DOI：
10.1016/j.intimp.2010.03.012
复制
发表时间：
2010-06-01
影响因子：
5.6
通讯作者：
Wen, Fu-Qiang
中科院分区：
文献类型：
--
作者：
Chen, Ya-Juan;Chen, Peng;Wen, Fu-Qiang
气道粘液过度产生是气道炎症性疾病的主要特征，例如慢性阻塞性肺病和囊性纤维化。由于已知小 G 蛋白 Ras 可以调节肺部细胞功能，因此我们试图研究 Ras 抑制剂辛伐他汀是否可以减弱大鼠气道中丙烯醛诱导的粘蛋白产生。大鼠首先单独用辛伐他汀或辛伐他汀与甲羟戊酸联合胃内预处理 24 小时，然后暴露于丙烯醛 12 天，甲羟戊酸可防止 Ras 激活所需的异戊二烯化。分析肺组织的细胞外信号调节激酶（ERK）活性、杯状细胞化生和粘蛋白产生。为了更详细地分析辛伐他汀对粘蛋白产生的影响，单独用辛伐他汀或与甲羟戊酸一起预处理暴露于丙烯醛的人气道上皮NCI-H292细胞。收集培养基以检测粘蛋白分泌，并检查细胞裂解物的Ras-GTP酶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丙烯醛诱导的支气管上皮杯状细胞增生和化生，并抑制大鼠肺匀浆中的 ERK 磷酸化。此外，辛伐他汀在肺部 mRNA 和蛋白质水平上抑制 Muc5AC 粘蛋白合成。在体外，辛伐他汀预处理减弱了丙烯醛诱导的 MUC5AC 粘蛋白表达、Ras-GTPase 活性和 EGFR/ERK 磷酸化的显着增加。辛伐他汀的这些抑制作用在体外和体内均被甲羟戊酸中和。我们的结果表明，辛伐他汀可能通过阻断 Ras 蛋白异戊二烯化介导的 ERK 激活来减弱气道中丙烯醛诱导的粘蛋白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来确定辛伐他汀治疗气道粘液过多的潜在安全性和有效性。 (C) 2010 Elsevier B.V. 保留所有权利。
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. (C) 2010 Elsevier B.V. All rights reserved.