Simvastatin attenuates acrolein-induced mucin production in rats: involvement of the Ras/extracellular signal-regulated kinase pathway.
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.
Chen
Ya-Juan
YJ
Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
Chen
Peng
P
Wang
Hai-Xia
HX
Wang
Tao
T
Chen
Lei
L
Wang
Xun
X
Sun
Bei-Bei
BB
Liu
Dai-Shun
DS
Xu
Dan
D
An
Jing
J
Wen
Fu-Qiang
FQ
D000171:Acrolein / Q000633:toxicity; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000032:analysis / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000032:analysis / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000032:analysis / Q000378:metabolism; D020397:Goblet Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006965:Hyperplasia / Q000188:drug therapy; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008798:Mevalonic Acid / Q000627:therapeutic use; D055271:Mucin 5AC / Q000037:antagonists & inhibitors*; D010766:Phosphorylation / Q000187:drug effects; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy*; D054876:Prenylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000627:therapeutic use*; D018631:ras Proteins / Q000032:analysis / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D055271:Mucin 5AC; D000171:Acrolein; D019821:Simvastatin; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D020558:GTP Phosphohydrolases; D018631:ras Proteins; D008798:Mevalonic Acid