title: Inhibition of HMGCoA reductase by simvastatin protects mice from injurious mechanical ventilation.
abstract: BACKGROUND
  Mortality from severe acute respiratory distress syndrome exceeds 40% and there is no available pharmacologic treatment. Mechanical ventilation contributes to lung dysfunction and mortality by causing ventilator-induced lung injury. We explored the utility of simvastatin in a mouse model of severe ventilator-induced lung injury.
  
  
  METHODS
  Male C57BL6 mice (n = 7/group) were pretreated with simvastatin or saline and received protective (8 mL/kg) or injurious (25 mL/kg) ventilation for four hours. Three doses of simvastatin (20 mg/kg) or saline were injected intraperitoneally on days -2, -1 and 0 of the experiment. Lung mechanics, (respiratory system elastance, tissue damping and airway resistance), were evaluated by forced oscillation technique, while respiratory system compliance was measured with quasi-static pressure-volume curves. A pathologist blinded to treatment allocation scored hematoxylin-eosin-stained lung sections for the presence of lung injury. Pulmonary endothelial dysfunction was ascertained by bronchoalveolar lavage protein content and lung tissue expression of endothelial junctional protein Vascular Endothelial cadherin by immunoblotting. To assess the inflammatory response in the lung, we determined bronchoalveolar lavage fluid total cell content and neutrophil fraction by microscopy and staining in addition to Matrix-Metalloprotease-9 by ELISA. For the systemic response, we obtained plasma levels of Tumor Necrosis Factor-α, Interleukin-6 and Matrix-Metalloprotease-9 by ELISA. Statistical hypothesis testing was undertaken using one-way analysis of variance and Tukey's post hoc tests.
  
  
  RESULTS
  Ventilation with high tidal volume (HVt) resulted in significantly increased lung elastance by 3-fold and decreased lung compliance by 45% compared to low tidal volume (LVt) but simvastatin abrogated lung mechanical alterations of HVt. Histologic lung injury score increased four-fold by HVt but not in simvastatin-pretreated mice. Lavage pleocytosis and neutrophilia were induced by HVt but were significantly attenuated by simvastatin. Microvascular protein permeability increase 20-fold by injurious ventilation but only 4-fold with simvastatin. There was a 3-fold increase in plasma Tumor Necrosis Factor-α, a 7-fold increase in plasma Interleukin-6 and a 20-fold increase in lavage fluid Matrix-Metalloprotease-9 by HVt but simvastatin reduced these levels to control. Lung tissue vascular endothelial cadherin expression was significantly reduced by injurious ventilation but remained preserved by simvastatin.
  
  
  CONCLUSIONS
  High-dose simvastatin prevents experimental hyperinflation lung injury by angioprotective and anti-inflammatory effects.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Manitsopoulos
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Orfanos
authors.forename: Anastasia
authors.initials: A
authors.lastname: Kotanidou
authors.forename: Ioanna
authors.initials: I
authors.lastname: Nikitopoulou
authors.forename: Ilias
authors.initials: I
authors.lastname: Siempos
authors.forename: Christina
authors.initials: C
authors.lastname: Magkou
authors.forename: Ioanna
authors.initials: I
authors.lastname: Dimopoulou
authors.forename: Spyros G
authors.initials: SG
authors.lastname: Zakynthinos
authors.forename: Apostolos
authors.initials: A
authors.lastname: Armaganidis
authors.forename: Nikolaos A
authors.initials: NA
authors.lastname: Maniatis
mesh_terms: D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002199:Capillary Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D004548:Elasticity; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000097:blood; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008170:Lung Compliance / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011014:Pneumonia / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D011654:Pulmonary Edema / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D019821:Simvastatin / Q000494:pharmacology*; D013997:Time Factors; D055397:Ventilator-Induced Lung Injury / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D000893:Anti-Inflammatory Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D019821:Simvastatin
references.citation: Pulm Pharmacol Ther. 2014 Feb;27(1):17-28
references.pmid: 23518214
references.citation: Pulm Circ. 2012 Oct;2(4):397-406
references.pmid: 23372924
references.citation: JAMA. 2013 Oct 23;310(16):1692-700
references.pmid: 24108510
references.citation: J Immunol. 2004 Mar 1;172(5):2903-8
references.pmid: 14978092
references.citation: Crit Care. 2010;14(2):R70
references.pmid: 20403177
references.citation: Vascul Pharmacol. 2006 Aug;45(2):134-40
references.pmid: 16959545
references.citation: J Med Virol. 2013 Nov;85(11):1978-82
references.pmid: 23926054
references.citation: Br J Pharmacol. 2011 Jun;163(3):609-23
references.pmid: 21323892
references.citation: PLoS One. 2013;8(9):e75490
references.pmid: 24086542
references.citation: Crit Care Med. 2010 May;38(5):1321-8
references.pmid: 20308883
references.citation: JAMA. 2012 Jun 20;307(23):2526-33
references.pmid: 22797452
references.citation: Virology. 2013 Apr 25;439(1):42-6
references.pmid: 23453580
references.citation: Am J Physiol Lung Cell Mol Physiol. 2012 Aug 15;303(4):L279-85
references.pmid: 22683568
references.citation: Am J Physiol Lung Cell Mol Physiol. 2011 Jun;300(6):L930-9
references.pmid: 21441352
references.citation: Am J Physiol. 1998 Dec;275(6 Pt 1):L1040-50
references.pmid: 9843840
references.citation: N Engl J Med. 2014 Jun 5;370(23):2191-200
references.pmid: 24835849
references.citation: Antimicrob Agents Chemother. 2005 Sep;49(9):3959-62
references.pmid: 16127082
references.citation: Am J Respir Cell Mol Biol. 2001 Dec;25(6):717-24
references.pmid: 11726397
references.citation: Am J Respir Cell Mol Biol. 2009 Oct;41(4):426-32
references.pmid: 19202007
references.citation: Am J Physiol Lung Cell Mol Physiol. 2006 Oct;291(4):L580-7
references.pmid: 16698855
references.citation: Am J Respir Crit Care Med. 1997 Jan;155(1):43-6
references.pmid: 9001287
references.citation: Respir Care. 2007 Aug;52(8):989-95
references.pmid: 17650353
references.citation: Curr Protein Pept Sci. 2002 Aug;3(4):409-21
references.pmid: 12370004
references.citation: J Clin Invest. 2012 Aug;122(8):2731-40
references.pmid: 22850883
references.citation: N Engl J Med. 2014 Mar 6;370(10):980
references.pmid: 24597883
references.citation: Am J Respir Cell Mol Biol. 2011 Mar;44(3):415-22
references.pmid: 20508068
references.citation: Physiol Rev. 2006 Jan;86(1):279-367
references.pmid: 16371600
references.citation: Circulation. 2002 Oct 15;106(16):2104-10
references.pmid: 12379581
references.citation: Am J Physiol Lung Cell Mol Physiol. 2005 Jun;288(6):L1026-32
references.pmid: 15665042
references.citation: N Engl J Med. 2014 Oct 30;371(18):1695-703
references.pmid: 25268516
references.citation: Am J Respir Crit Care Med. 2011 Mar 1;183(5):620-6
references.pmid: 20870757
references.citation: Am J Physiol Lung Cell Mol Physiol. 2007 May;292(5):L1105-10
references.pmid: 17277047
references.citation: Crit Care. 2010;14(4):R143
references.pmid: 20673352