Evaluation of the Anti-inflammatory Activity of Atorvastatin and its Effect on Alveolar Diameter in a Model of Elastase-induced Emphysema in Rats

Abstract

Statins are cholesterol-lowering agents and some of them, like simvastatin, have anti-inflammatory effects. In this study, we evaluated the effect of atorvastatin on nitric oxide (NO) release, leukocytes levels and alveolar diameter related to the inflammatory process associated with elastase-induced emphysema in rats. 32 rats were divided into 4 groups, n=8: control (C), atorvastatin (A), emphysema (E), and emphysema+atorvastatin (EA). On day 0 (zero), groups C and A received intratracheal instillation of saline (0.2 ml), and groups E and EA received elastase (0.2 ml). Groups A and EA received atorvastatin (20 mg/kg) and C and E received vehicle, by gavage, for 25 days. Animals were euthanized, slices of lung stained and the alveolar diameters measured. Data obtained show that the treatment with atorvastatin (EA group) did not reduce the alveolar diameter (35.3 vs. 32.3), NO (2.7 vs. 3.0 μM) or the leukocyte count (111 vs. 136) compared with the E group, indicating that different statins, like simvastatin or atorvastatin, have different behavior in inflammatory processes like in elastase-induced development of emphysema in rats.

Key words

statin - COPD - emphysema - inflammation - leukocytes - lung

• References

• 1 Yoshida T, Tuder RM. Pathobiology of cigarette smoke-induced chronic obstructive disease. Physiol Rev 2007; 87: 1047-1082
• 2 Rubio ML, Martin-Mosquero MC, Ortega M et al. Elastase-induced pulmonary emphysema in rats. Chest 2004; 125: 1500-1506
• 3 Manchini MT, Boiati RF, Sousa DWN et al. Evaluation of the effect of prednisolone on the inflammatory process and alveolar diameter in elastase- induced pulmonary emphysema in rats. Lat Am J Pharm 2012; 31: 947-952
• 4 Barnes PJ. Mediators of chronic obstructive pulmonary disease. Pharmacol Rev 2004; 56: 515-548
• 5 Taraseviciene-Stewart L, Voelkel NF. Molecular pathogenesis of emphysema. J Clin Invest 2008; 118: 394-402
• 6 Takahashi S, Nakamura H, Seki M et al. Reversal of elastase-induced pulmonary emphysema and promotion of alveolar epithelial cell proliferation by simvastatin in mice. Am J Physiol Lung Cell Mol Physiol 2008; 294: L882-L890
• 7 Mennickent S, Bravo M, Calvo C et al. Pleiotropic effects of statins. Rev Méd Chile 2008; 136: 775-782
• 8 Moini A, Azimi G, Farivar A. Evaluation of atorvastatin for treatment of patients with asthma: A double-blind randomized clinical trial. Allergy Asthma Immunol Res 2012; 4: 290-294
• 9 Castro PF, Miranda R, Verdejo HE et al. Pleiotropic effects of atorvastatin in heart failure: Role in oxidative stress, inflammation, endothelial function, and exercise capacity. J Heart and Lung Transpl 2008; 27: 14-23
• 10 Dulak J, Loboda A, Jazwa A et al. Atorvastatin affects several angiogenic mediators in human endothelial cells. Endothelium 2005; 12: 233-241
• 11 Guide For The Care and Use Of Laboratory Animals . National Research Council Of The National. 8^th edn. National Academies Press; (US), Washington, D.C: 2011
• 12 Onclinx C, De Maertelaer V, Gustin P et al. Elastase-induced pulmonary emphysema in rats: Comparison of computed density and microscopic morphometry. Radiology 2006; 241: 763-770
• 13 Lüthje L, Raupach T, Michels H et al. Exercise intolerance and systemic manifestations of pulmonary emphysema in a mouse model. Respiratory Research 2009; 10: 1-10
• 14 Weibel ER. Principles and methods for the morphometric study of de lung and others organs. Lab Invest 1963; 12: 131-137
• 15 Gillooly M, Lamb D, Farrow ASJ. New automated technique for assessing emphysema on histological sections. J Clin Pathol 1991; 44: 1007-1011
• 16 Archer S. Measurement of nitric oxide in biological models. FASEB J 1993; 7: 349-360
• 17 Hogg JC, Senior RM. Chronic obstructive pulmonary disease c2: Pathology and biochemistry of emphysema. Thorax 2002; 57: 830-834
• 18 Inoue K, Koike E, Takano H. Comprehensive analysis of elastase-induced pulmonary emphysema in mice: Effects of ambient existing particulate matters. Int Immunopharmacol 2010; 10: 1380-1389
• 19 Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005; 45: 89-118
• 20 Bonetti PO, Lerman LO, Napoli C et al. Statin effects beyond lipid lowering: are they clinically relevant?. Eur Heart J 2003; 24: 225-248
• 21 Jacobson TA. Toward “pain-free” statin prescribing: Clinical algorithm for diagnosis management of myalgia. Mayo Clin Proc 2008; 83: 687-700
• 22 McKay A, Leung BP, McInnes IB et al. A novel anti-inflamatory role of simvastatin in a murine model of allergic asthma. J Immunol 2004; 172: 2903-2908
• 23 Mak JCW. Pathogenesis of COPD. Parte II. Oxidative-antioxidative imbalance. Int J Tuber Lung Dis 2008; 12: 115-127
• 24 Laufs U, La Fata V, Liao JK. Inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia-mediated down-regulation of endothelial nitric oxide synthase. J Biol Chem 1997; 272: 31725-31729
• 25 Lee J, Lee D, Kim E et al. Simvastatin Inhibits Cigarette Smoking–induced Emphysema and Pulmonary Hypertension in Rat Lungs. Am J Resp Crit Care Med 2005; 172: 987-983