Inhibition of HMGCoA reductase by simvastatin protects mice from injurious mechanical ventilation

Respiratory Research

Nikolaos A Maniatis²  Apostolos Armaganidis²  Spyros G Zakynthinos³  Ioanna Dimopoulou²  Christina Magkou¹  Ilias Siempos³  Ioanna Nikitopoulou³  Anastasia Kotanidou³  Stylianos E Orfanos²  Nikolaos Manitsopoulos³ 

[1] Department of Pathology, Evangelismos Hospital, Athens, Greece;2nd Department of Critical Care, University of Athens Medical School, Attikon Hospital, Haidari, Greece;1st Department of Critical Care Medicine and Pulmonary Services, GP Livanos and M Simou Laboratories, University of Athens Medical School, Evangelismos Hospital, Athens, Greece

关键词: Endothelial permeability;    Lung compliance;    Lung function;    Statin;    Pulmonary edema;    Acute lung injury;    Acute respiratory distress syndrome;    Ventilator lung injury;   

Others  :  1133338
DOI  :  10.1186/s12931-015-0173-y

 received in 2014-09-23, accepted in 2015-01-17,  发布年份 2015

【 摘 要 】

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.

Conclusion

High-dose simvastatin prevents experimental hyperinflation lung injury by angioprotective and anti-inflammatory effects.

【 授权许可】

   
2015 Manitsopoulos et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Matthay MA, Ware LB, Zimmerman GA: The acute respiratory distress syndrome. J Clin Invest 2012, 122(8):2731-40.
• [2]Slutsky AS, Ranieri VM: Ventilator-induced lung injury. N Engl J Med 2014, 370(10):980.
• [3]Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, et al.: Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012, 307(23):2526-33.
• [4]Siempos II, Maniatis NA, Kopterides P, Magkou C, Glynos C, Roussos C, et al.: Pretreatment with atorvastatin attenuates lung injury caused by high-stretch mechanical ventilation in an isolated rabbit lung model. Crit Care Med 2010, 38(5):1321-8.
• [5]Singla S, Jacobson JR: Statins as a novel therapeutic strategy in acute lung injury. Pulm circulation 2012, 2(4):397-406.
• [6]Jacobson JR, Barnard JW, Grigoryev DN, Ma SF, Tuder RM, Garcia JG: Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol 2005, 288(6):L1026-32.
• [7]Mathew B, Huang Y, Jacobson JR, Berdyshev E, Gerhold LM, Wang T, et al.: Simvastatin attenuates radiation-induced murine lung injury and dysregulated lung gene expression. Am J Respir Cell Mol Biol 2011, 44(3):415-22.
• [8]Muller HC, Hellwig K, Rosseau S, Tschernig T, Schmiedl A, Gutbier B, et al.: Simvastatin attenuates ventilator-induced lung injury in mice. Critical care (London, England) 2010, 14(4):R143. BioMed Central Full Text
• [9]Parihar SP, Guler R, Lang DM, Suzuki H, Marais AD, Brombacher F: Simvastatin enhances protection against Listeria monocytogenes infection in mice by counteracting Listeria-induced phagosomal escape. PLoS One 2013, 8(9):e75490.
• [10]Pruefer D, Makowski J, Schnell M, Buerke U, Dahm M, Oelert H, et al.: Simvastatin inhibits inflammatory properties of Staphylococcus aureus alpha-toxin. Circulation 2002, 106(16):2104-10.
• [11]Erkkila L, Jauhiainen M, Laitinen K, Haasio K, Tiirola T, Saikku P, et al.: Effect of simvastatin, an established lipid-lowering drug, on pulmonary Chlamydia pneumoniae infection in mice. Antimicrob Agents Chemother 2005, 49(9):3959-62.
• [12]Gluck B, Schmidtke M, Walther M, Meerbach A, Wutzler P: Simvastatin treatment showed no prophylactic effect in influenza virus-infected mice. J Med Virol 2013, 85(11):1978-82.
• [13]Belser JA, Szretter KJ, Katz JM, Tumpey TM: Simvastatin and oseltamivir combination therapy does not improve the effectiveness of oseltamivir alone following highly pathogenic avian H5N1 influenza virus infection in mice. Virology 2013, 439(1):42-6.
• [14]Craig TR, Duffy MJ, Shyamsundar M, McDowell C, O'Kane CM, Elborn JS, et al.: A randomized clinical trial of hydroxymethylglutaryl- coenzyme a reductase inhibition for acute lung injury (The HARP Study). Am J Respir Crit Care Med 2011, 183(5):620-6.
• [15]Papazian L, Roch A, Charles PE, Penot-Ragon C, Perrin G, Roulier P, et al.: Effect of statin therapy on mortality in patients with ventilator-associated pneumonia: a randomized clinical trial. JAMA 2013, 310(16):1692-700.
• [16]Truwit JD, Bernard GR, Steingrub J, Matthay MA, Liu KD, Albertson TE, et al.: Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med 2014, 370(23):2191-200.
• [17]McAuley DF, Laffey JG, O’Kane CM, Perkins GD, Mullan B, Trinder TJ, et al.: Simvastatin in the acute respiratory distress syndrome. N Engl J Med 2014, 371(18):1695-703.
• [18]Maniatis NA, Harokopos V, Thanassopoulou A, Oikonomou N, Mersinias V, Witke W, et al.: A critical role for gelsolin in ventilator-induced lung injury. Am J Respir Cell Mol Biol 2009, 41(4):426-32.
• [19]Maniatis NA, Letsiou E, Orfanos SE, Kardara M, Dimopoulou I, Nakos G, et al.: Inhaled activated protein C protects mice from ventilator-induced lung injury. Critical care (London, England) 2010, 14(2):R70. BioMed Central Full Text
• [20]Kotanidou A, Loutrari H, Papadomichelakis E, Glynos C, Magkou C, Armaganidis A, et al.: Inhaled activated protein C attenuates lung injury induced by aerosolized endotoxin in mice. Vascul Pharmacol 2006, 45(2):134-40.
• [21]Kallet RH, Hemphill JC 3rd, Dicker RA, Alonso JA, Campbell AR, Mackersie RC, et al.: The spontaneous breathing pattern and work of breathing of patients with acute respiratory distress syndrome and acute lung injury. Respir Care 2007, 52(8):989-95.
• [22]Girgis RE, Mozammel S, Champion HC, Li D, Peng X, Shimoda L, et al.: Regression of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Lung Cell Mol Physiol 2007, 292(5):L1105-10.
• [23]Liu CP, Kuo MS, Wu BN, Chai CY, Huang HT, Chung PW, et al.: NO-releasing xanthine KMUP-1 bonded by simvastatin attenuates bleomycin-induced lung inflammation and delayed fibrosis. Pulm Pharmacol Ther 2014, 27(1):17-28.
• [24]McKay A, Leung BP, McInnes IB, Thomson NC, Liew FY: A novel anti-inflammatory role of simvastatin in a murine model of allergic asthma. J Immunol 2004, 172(5):2903-8.
• [25]Rinaldi B, Donniacuo M, Esposito E, Capuano A, Sodano L, Mazzon E, et al.: PPARalpha mediates the anti-inflammatory effect of simvastatin in an experimental model of zymosan-induced multiple organ failure. Br J Pharmacol 2011, 163(3):609-23.
• [26]Zhang S, Rahman M, Zhang S, Qi Z, Herwald H, Thorlacius H: Simvastatin regulates CXC chemokine formation in streptococcal M1 protein-induced neutrophil infiltration in the lung. Am J Physiol Lung Cell Mol Physiol 2011, 300(6):L930-9.
• [27]Chen W, Sammani S, Mitra S, Ma SF, Garcia JG, Jacobson JR: Critical role for integrin-beta4 in the attenuation of murine acute lung injury by simvastatin. Am J Physiol Lung Cell Mol Physiol 2012, 303(4):L279-85.
• [28]Torii K, Iida K, Miyazaki Y, Saga S, Kondoh Y, Taniguchi H, et al.: Higher concentrations of matrix metalloproteinases in bronchoalveolar lavage fluid of patients with adult respiratory distress syndrome. Am J Respir Crit Care Med 1997, 155(1):43-6.
• [29]Ohbayashi H: Matrix metalloproteinases in lung diseases. Curr Protein Pept Sci 2002, 3(4):409-21.
• [30]Foda HD, Rollo EE, Drews M, Conner C, Appelt K, Shalinsky DR, et al.: Ventilator-induced lung injury upregulates and activates gelatinases and EMMPRIN: attenuation by the synthetic matrix metalloproteinase inhibitor, Prinomastat (AG3340). Am J Respir Cell Mol Biol 2001, 25(6):717-24.
• [31]Pugin J, Dunn I, Jolliet P, Tassaux D, Magnenat JL, Nicod LP, et al.: Activation of human macrophages by mechanical ventilation in vitro. Am J Physiol 1998, 275(6 Pt 1):L1040-50.
• [32]Kim JH, Suk MH, Yoon DW, Lee SH, Hur GY, Jung KH, et al.: Inhibition of matrix metalloproteinase-9 prevents neutrophilic inflammation in ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 2006, 291(4):L580-7.
• [33]Mehta D, Malik AB: Signaling mechanisms regulating endothelial permeability. Physiol Rev 2006, 86(1):279-367.