title: Simvastatin inhibits goblet cell hyperplasia and lung arginase in a mouse model of allergic asthma: a novel treatment for airway remodeling?
abstract: Airway remodeling in asthma contributes to airway hyperreactivity, loss of lung function, and persistent symptoms. Current therapies do not adequately treat the structural airway changes associated with asthma. The statins are cholesterol-lowering drugs that inhibit the enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase, which is the rate-limiting step of cholesterol biosynthesis in the mevalonate (MA) pathway. These drugs have been associated with improved respiratory health, and ongoing clinical trials are testing their therapeutic potential in asthma. We hypothesized that simvastatin treatment of ovalbumin (OVA)-exposed mice would attenuate early features of airway remodeling by a mevalonate-dependent mechanism. BALB/c mice initially were sensitized to OVA and then exposed to 1% OVA aerosol for 2 weeks after sensitization for 6 exposures. Simvastatin (40 mg/kg) or simvastatin plus MA (20 mg/kg) were injected intraperitoneally before each OVA exposure. Treatment with simvastatin attenuated goblet cell hyperplasia, arginase-1 protein expression, and total arginase enzyme activity, but it did not alter airway hydroxyproline content or transforming growth factor-β1. Inhibition of goblet cell hyperplasia by simvastatin was mevalonate-dependent. No appreciable changes to airway smooth muscle cells were observed in any control or treatment groups. In conclusion, in an acute mouse model of allergic asthma, simvastatin inhibited early hallmarks of airway remodeling, which are indicators that can lead to airway thickening and fibrosis. Statins are potentially novel treatments for airway remodeling in asthma. Additional studies using subchronic or chronic allergen exposure models are needed to extend these initial findings.
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Department of Internal Medicine, Center for Comparative Respiratory Biology & Medicine, Davis, CA 95616, USA.
authors.forename: Amir A
authors.initials: AA
authors.lastname: Zeki
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Bratt
authors.forename: Michelle
authors.initials: M
authors.lastname: Rabowsky
authors.forename: Jerold A
authors.initials: JA
authors.lastname: Last
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Kenyon
mesh_terms: D000336:Aerosols; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors; D001120:Arginine / Q000378:metabolism; D001249:Asthma / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D015153:Blotting, Western; D004396:Coloring Agents; D004195:Disease Models, Animal; D020397:Goblet Cells / Q000187:drug effects / Q000473:pathology*; D006909:Hydroxyproline / Q000378:metabolism; D006965:Hyperplasia / Q000517:prevention & control; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010047:Ovalbumin / Q000008:administration & dosage / Q000494:pharmacology; D019821:Simvastatin / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000336:Aerosols; D004396:Coloring Agents; D009566:Nitrates; D009573:Nitrites; D053773:Transforming Growth Factor beta1; D010047:Ovalbumin; D001120:Arginine; D019821:Simvastatin; D001119:Arginase; D006909:Hydroxyproline