Simvastatin Therapy and Bronchoalveolar Lavage Fluid Biomarkers in Chronic Obstructive Pulmonary Disease

  • Iwona Patyk
  • Cezary Rybacki
  • Agata Kalicka
  • Agnieszka Rzeszotarska
  • Jolanta Korsak
  • Andrzej ChciałowskiEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1150)


Chronic obstructive pulmonary disease (COPD) is a progressive disease underlain by airway inflammation. Despite trials with new generations of anti-inflammatory drugs to alleviate the disease burden, the effective curative treatment remains elusive. In this context, the aim of this study was to assess the influence of simvastatin, a leading member of the family of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, known to display anti-inflammatory and immunomodulatory activity, on symptoms and lung function, as well as the proportion of inflammatory cells, cytokines, proteolytic enzymes, and surfactant protein D (SP-D) content in bronchoalveolar lavage fluid (BALF) in COPD patients. There were 50 patients with moderate-to-severe airway obstructions included into the study, subdivided into simvastatin-treated (Zocor – MSD; 40 mg daily) and control simvastatin-untreated groups, other treatment being equal. Pulmonary functions tests and bronchofiberoscopy with BALF procedure were performed before and after 3–month–long treatment in both groups. The major finding was that simvastatin treatment caused a distinct increase in the airway content of SP-D. Further effects, albeit smaller in magnitude, consisted of reductions in the proportion of airway neutrophils and in MMP-9 content, all with a benefit of improved score in the disease activity assessment test. There were no appreciable changes noted in lung function or dyspnea perception, which could be ascribed to simvastatin treatment. We conclude that statin’s anti-inflammatory and surfactant homeostasis preserving properties may offer promise as an adjunctive treatment in COPD patients. The SP-D content in BALF has a potential to become a marker of COPD inflammatory activity and treatment monitoring.


COPD Cytokines Fiber-optic bronchoscopy Matrix Metalloproteinases Pulmonary function Statins Surfactant protein 


Conflicts of Interest

The authors declare no conflicts of interest in relation to this article.


  1. Abeles AM, Pillinger MH (2006) Statins as anti-inflammatory and immunomodulatory agents: a future in rheumatologic therapy? Arthritis Rheum 54(2):393–407CrossRefGoogle Scholar
  2. Arnaud C, Burger F, Steffens S, Veillard NR, Nguyen TH, Trono D, Mach F (2005) Statins reduce interleukin–6– induced C–reactive protein in human hepatocytes: new evidence for direct antiinflammatory effects of statins. Arterioscler Thromb Vasc Biol 25:1231–1236CrossRefGoogle Scholar
  3. Barnes PJ, Celli BR (2009) Systemic manifestations and comorbidities of COPD. Eur Respir J 33:1165–1185CrossRefGoogle Scholar
  4. Bellosta S, Via D, Canavesi M, Pfister P, Fumagalli R, Paoletti R, Bernini F (1998) HMG–CoA reductase inhibitors reduce MMP–9 secretion by macrophages. Arterioscler Thromb Vasc Biol 18:1671–1678CrossRefGoogle Scholar
  5. Chciałowski A, Chorostowska–Wynimko J, Fal A, Domagała Kulawik J, Pawłowicz R (2011) Recommendation of the polish respiratory society for bronchoalveolar lavage (BAL) sampling, processing and analysis methods. Pneumonol Alergol Pol 79:75–89 (Article in Polish)PubMedGoogle Scholar
  6. Churg A, Zhou S, Wright JL (2011) Series “matrix metalloproteinases in lung health and disease”: matrix metalloproteinases in COPD. Eur Respir J 39(1):197–209CrossRefGoogle Scholar
  7. Davis BB, Zeki AA, Bratt JM, Wang L, Filosto S, Walby WF, Kenyon NJ, Goldkorn T, Schelegle ES, Pinkerton KE (2013) Simvastatin inhibits smoke-induced airway epithelial injury: implications for COPD therapy. Eur Respir J 42:350–361CrossRefGoogle Scholar
  8. Duvoix A, Dickens J, Haq I, Mannino D, Miller B, Tal–Singer R, Lomas DA (2012) Blood fibrinogen as a biomarker of chronic obstructive pulmonary disease. Thorax 68(7):670–676CrossRefGoogle Scholar
  9. Ferrari R, Tanni SE, Caram LM (2013) Three–year follow–up of Interleukin 6 and C–reactive protein in chronic obstructive pulmonary disease. Thorax 68:691–694CrossRefGoogle Scholar
  10. Ferro D, Parrotto S, Basili S, Alessandri C, Violi F (2000) Simvastatin inhibits the monocyte expression of proinflammatory cytokines in patients with hypercholesterolemia. J Am Coll Cardiol 36:427–431CrossRefGoogle Scholar
  11. Finlay GA, Russell KJ, McMahon KJ, D’arcy EM, Masterson JB, FitzGerald MX, O’Connor CM (1997) Elevated levels of matrix metalloproteinases in bronchoalveolar lavage fluid of emphysematous patients. Thorax 52(6):502–506CrossRefGoogle Scholar
  12. Haslam PL, Baughman RP (1992) Report of ERS task force: guidelines for measurement of acellular components and standardization of BAL. Eur Respir J 14:245–248CrossRefGoogle Scholar
  13. Hill J, Heslop C, Man SF, Frohlich J, Connett JE, Anthonisen NR, Wise RA, Tashkin DP, Sin DD (2011) Circulating surfactant protein–D and the risk of cardiovascular morbidity and mortality. Eur Heart J 32(15):1918–1925CrossRefGoogle Scholar
  14. Hogg JC (2004) Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet 364(9435):709–721CrossRefGoogle Scholar
  15. Holz O, Waschki B, Roepcke S, Watz H, Lauer G, Faulenbach C, Hohlfeld JM (2014) Potential prognostic value of biomarkers in lavage, sputum and serum in a five year clinical follow–up of smokers with and without COPD. BMC Pulm Med 14:30CrossRefGoogle Scholar
  16. Honda Y, Takahashi H, Kuroki Y, Akino T, Abe S (1996) Decreased contents of surfactant proteins A and D in BAL fluids of healthy smokers. Chest 109(4):1006–1009CrossRefGoogle Scholar
  17. Hothersall E, McSharry C, Thomson NC (2006) Potential therapeutic role for statins in respiratory disease. Thorax 61(8):729–734CrossRefGoogle Scholar
  18. Ikeda U, Shimpo M, Ohki R, Inaba H, Takahashi M, Yamamoto K, Shimada K (2000) Fluvastatin inhibits matrix metalloproteinase–1 expression in human vascular endothelial cells. Hypertension 36:325–329CrossRefGoogle Scholar
  19. Ilumets H, Rytilä P, Demedts I, Brusselle GG, Sovijärvi A, Myllärniemi M, Sorsa T, Kinnula VL (2007) Matrix metalloproteinases–8, −9, −12 in smokers and patients with Stage 0 COPD. Int J Chron Obstruct Pulmon Dis 2(3):369–379PubMedPubMedCentralGoogle Scholar
  20. Imai K, Dalal SS, Chen ES, Downey R, Schulman LL, Ginsburg M, D’Armiento J (2001) Human Collagenase (Matrix Metalloproteinase–1) Expression in the Lungs of Patients with Emphysema. Am J Respir Crit Care Med 163(3 Pt 1):786–791CrossRefGoogle Scholar
  21. Kamio K, Liu XD, Sugiura H, Togo S, Kawasaki S, Wang XY, Hogaboam AC, Rennard SI (2010) Statins inhibit matrix metalloproteinase release from human lung fibroblasts. Eur Respir J 35:637–646CrossRefGoogle Scholar
  22. Kim SE, Thanh Thuy TT, Lee JH, Ro JY, Bae YA, Kong Y, Ahn JY, Lee DS, Oh YM, Lee SD, Lee YS (2009) Simvastatin inhibits induction of matrix metalloproteinase–9 in rat alveolar macrophages exposed to cigarette smoke extract. Exp Mol Med 41(4):277–287CrossRefGoogle Scholar
  23. Lee JH, Lee DS, Kim EK, Choe KH, Oh YM, Shim TS, Kim SE, Lee YS, Lee SD (2005) Simvastatin inhibits cigarette smoking-induced emphysema and pulmonary hypertension in rat lungs. Am J Respir Crit Care Med 172:987–993CrossRefGoogle Scholar
  24. Lee TM, Lin MS, Chang NC (2008) Usefulness of C–reactive protein and interleukin–6 as predictors of outcomes in patients with chronic obstructive pulmonary disease receiving pravastatin. Am J Cardiol 101:530–535CrossRefGoogle Scholar
  25. Lentsch AB, Shanley TP, Sarma V, Ward PA (1997) In vivo suppression of NF–kappa B and preservation of I kappa B alpha by interleukin–10 and interleukin–13. Clin Invest 100(10):2443–2448CrossRefGoogle Scholar
  26. Liao JK, Laufs U (2005) Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 45:89–118CrossRefGoogle Scholar
  27. Löfdahl JM, Cederlund K, Nathell L, Eklund A, Sköld CM (2005) Bronchoalveolar lavage in COPD: fluid recovery correlates with the degree of emphysema. Eur Respir J 25(2):275–281CrossRefGoogle Scholar
  28. Luan Z, Chase AJ, Newby AC (2003) Statins inhibit secretion of metalloproteinases–1, 2, 3 and 9 from vascular smooth muscle cells and macrophages. Arterioscler Thromb Vasc Biol 23:769–775CrossRefGoogle Scholar
  29. Maher BM, Ni Dhonnchu T, Burke JP, Soo A, Wood AE, Watson RW (2009) Statins alter neutrophil migration by modulating cellular Rho activity – a potential mechanism for statins-mediated pleiotropic effects? J Leukoc Biol 85:186–193CrossRefGoogle Scholar
  30. Mahler D, Wells C (1988) Evaluation of clinical methods for rating dyspnea. Chest 93:580–586CrossRefGoogle Scholar
  31. Maneechotesuwan K, Wongkajornsilp A, Adcock IM, Barnes PJ (2015) Simvastatin suppresses airway IL–17 and upregulates IL–10 in patients with stable COPD. Chest 148(5):1164–1176CrossRefGoogle Scholar
  32. Martin TR, Raghu G, Maunder RJ, Springmeyer S (1985) The effects of chronic bronchitis and chronic air–flow obstruction on lung cell populations recovered by bronchoalveolar lavage. Am Rev Respir Dis 132:254–260PubMedGoogle Scholar
  33. May SM, Li JT (2015) Burden of chronic obstructive pulmonary disease: healthcare costs and beyond. Allergy Asthma Proc 36(1):4–10CrossRefGoogle Scholar
  34. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J, ATS/ERS Task Force (2005) Standardisation of spirometry. Eur Respir J 26(2):319–338CrossRefGoogle Scholar
  35. Moré JM, Voelker DR, Silveira LJ, Edwards MG, Chan ED, Bowler RP (2010) Smoking reduces surfactant protein D and phospholipids in patients with and without chronic obstructive pulmonary disease. BMC Pulm Med 10:53CrossRefGoogle Scholar
  36. Murphy DM, Forrest IA, Corris PA, Johnson GE, Small T, Jones D, Fisher AJ, Egan JJ, Cawston TE, Ward CH, Lordan JL (2008) Simvastatin attenuates release of neutrophilic and remodeling factors from primary bronchial epithelial cells derived from stable lung transplant recipients. Am J Physiol Lung Cell Mol Physiol 294:L592–L599CrossRefGoogle Scholar
  37. Mutti A, Corradi M, Goldoni M, Vettori MV, Bernard A, Apostoli P (2006) Exhaled metallic elements and serum pneumoproteins in asymptomatic smokers and patients with COPD or asthma. Chest 129(5):1288–1297CrossRefGoogle Scholar
  38. Pinto–Plata V, Casanova C, Müllerova H, Torres JP, Corado H, Varo N, Cordoba E, Zeineldine S, Paz H, Baz R, Divo M, Cortopassi F, Celli BR (2012) Inflammatory and repair serum biomarker pattern. Association to clinical outcomes in COPD. Respir Res 13(1):71CrossRefGoogle Scholar
  39. Sin DD, Leung R, Gan WQ, PaulMan SF (2007) Circulating surfactant protein D as a potential lung–specific biomarker of health outcomes in COPD: a pilot study. BMC Pulm Med 7:13CrossRefGoogle Scholar
  40. Sin DD, Pahlavan PS, Man SF (2008) Surfactant protein D: a lung specific biomarker in COPD? Ther Adv Respir Dis 2(2):65–74CrossRefGoogle Scholar
  41. Sinden NJ, Stockley RA (2010) Systemic inflammation and comorbidity in COPD: a result of ‘overspill’ of inflammatory mediators from the lungs? Review of the evidence. Thorax 65(10):930–936CrossRefGoogle Scholar
  42. Soler N, Ewig S, Torres A, Filella X, Gonzalez J, Zaubet A (1999) Airway inflammation and bronchial microbial patterns in patients with stable chronic obstructive pulmonary disease. Eur Respir J 14:1015–1022CrossRefGoogle Scholar
  43. Sorensen GL, Madsen J, Kejling K, Tornoe I, Nielsen O, Townsend P, Poulain F, Nielsen CH, Reid KB, Hawgood S, Falk E, Holmskov U (2006) Surfactant protein D is proatherogenic in mice. Am J Physiol Heart Circ Physiol 290(6):2286–2294CrossRefGoogle Scholar
  44. Vernooy JH, Lindeman JH, Jacobs JA, Hanemaaijer R, Wouters EF (2004) Increased activity of matrix metalloproteinase–8 and matrix metalloproteinase–9 in induced sputum from patients with COPD. Chest 126:1802–1810CrossRefGoogle Scholar
  45. Vestbo J, Hurd SS, Agustí AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, Stockley RA, Sin DD, Rodriguez–Roisin R (2013) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 187(4):347–365CrossRefGoogle Scholar
  46. Wang P, Wu P, Siegel MI, Egan RW, Billah MM (1995) Interleukin (IL)–10 inhibits nuclear factor κB (NFκB) activation in human monocytes IL–10 and IL–4 suppress cytokine synthesis by different mechanisms. J Biol Chem 270:9558–9563CrossRefGoogle Scholar
  47. Winkler C, Atochina–Vasserman EN, Holz O, Beers MF, Erpenbeck VJ, Krug N, Roepcke S, Lauer G, Elmlinger M, Hohlfeld JM (2011) Comprehensive characterisation of pulmonary and serum surfactant protein D in COPD. Respir Res 12:29CrossRefGoogle Scholar
  48. Wright JR (2005) Immunoregulatory functions of surfactant proteins. Nat Rev Immunol:558–568Google Scholar
  49. Young RP, Hopkins R, Eaton TE (2009) Pharmacological actions of statins: potential utility in COPD. Eur Respir Rev 18(114):222–232CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG  2018

Authors and Affiliations

  • Iwona Patyk
    • 1
  • Cezary Rybacki
    • 1
  • Agata Kalicka
    • 1
  • Agnieszka Rzeszotarska
    • 2
  • Jolanta Korsak
    • 2
  • Andrzej Chciałowski
    • 3
    Email author
  1. 1.Department of Pneumology and AllergologyTenth Military Clinical HospitalBydgoszczPoland
  2. 2.Department of Clinical TransfusiologyMilitary Institute of MedicineWarsawPoland
  3. 3.Department of Infectious Diseases and AllergologyMilitary Institute of MedicineWarsawPoland

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