Skip to main content
SpringerLink
Log in

Simvastatin prevents lipopolysaccharide-induced septic shock in rats

  • Published:
Journal of Huazhong University of Science and Technology [Medical Sciences] Aims and scope Submit manuscript

Summary

Simvastatin is a hypolipidemic drug that inhibits hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase to control elevated cholesterol, or hypercholesterolemia. Previous studies have shown that simvastatin may attenuate inflammation in ischemia-reperfusion injury and sepsis. Herein, we hypothesized that simvastatin may prevent rats from lipopolysaccharide (LPS)-induced septic shock. In our study, rats were divided into a saline group, an LPS group and an LPS plus simvastatin group. Male Sprague-Dawley (SD) rats were pretreated with simvastatin (1 mg/kg) for 30 min before the addition of LPS (8 mg/kg), with variations in left ventricular pressure recorded throughout. Ninety min after LPS injection, whole blood was collected from the inferior vena cava, and neutrophils were separated from the whole blood using separating medium. The neutrophils were then lysed for Western blotting to detect the levels of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1). In addition, mesentery microcirculations of inlet diameter, outlet diameter and blood flow rate were measured in all three groups. The results indicated that simvastatin significantly promoted heart systolic function and increased the level of uPA while simultaneously inhibited the expression of PAI-1 as compared with LPS group. Moreover, simvastatin reversed the LPS-induced inhibition of mesentery microcirculation. Taken together, it was suggested that simvastatin can effectively protect the rats from LPS-induced septic shock.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Rudiger A, Singer M. The heart in sepsis: from basic mechanisms to clinical management. Curr Vasc Pharmacol, 2013,11(2):187–195

    CAS  PubMed  Google Scholar 

  2. Hernandez G, Bruhn A, Ince C. Microcirculation in sepsis: new perspectives. Curr Vasc Pharmacol, 2013,11(2):161–169

    CAS  PubMed  Google Scholar 

  3. Borregaard N, Cowland JB. Granules of the human neutrophilic polymorphonuclear leukocyte. Blood, 1997,89(10):3503–3521

    CAS  PubMed  Google Scholar 

  4. Rao XQ, Zhong JX, Sun QH. The heterogenic properties of monocytes/macrophages and neutrophils in inflammatory response in diabetes. Life Sci, 2014,116(2):59–66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hardaway RM. A review of septic shock. Am Surg, 2000,66(1):22–29

    CAS  PubMed  Google Scholar 

  6. Mondino A, Blasi F. uPA and uPAR in fibrinolysis, immunity and pathology. Trends Immunol, 2004,25(8):450–455

    Article  CAS  PubMed  Google Scholar 

  7. Asakura H, Wada H, Okamoto K, et al. Evaluation of haemostatic molecular markers for diagnosis of disseminated intravascular coagulation in patients with infections. Thromb Haemost, 2006,95(2):282–287

    CAS  PubMed  Google Scholar 

  8. Iwaki T, Urano T, Umemura K. PAI-1, progress in understanding the clinical problem and its aetiology. Brit J Haematol, 2012,157(3):291–298

    Article  CAS  Google Scholar 

  9. Skibsted S, Jones AE, Puskarich MA, et al. Biomarkers of endothelial cell activation in early sepsis. Shock, 2013,39(5):427–432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Madach K, Aladzsity I, Szilagyi A, et al. 4G/5G polymorphism of PAI-1 gene is associated with multiple organ dysfunction and septic shock in pneumonia induced severe sepsis: prospective, observational, genetic study. Crit Care, 2010,14(2):R279

    Article  Google Scholar 

  11. McGown CC, Brookes ZL. Beneficial effects of statins on the microcirculation during sepsis: the role of nitric oxide. Br J Anaesth, 2007,98(2):163–175

    Article  CAS  PubMed  Google Scholar 

  12. Dobesh PP, Klepser DG, McGuire TR, et al. Reduction in mortality associated with statin therapy in patients with severe sepsis. Pharmacotherapy, 2009,29(6):621–630

    Article  CAS  PubMed  Google Scholar 

  13. Rinaldi B, Donniacuo M, Esposito E, et al. PPAR alpha mediates the anti-inflammatory effect of simvastatin in an experimental model of zymosan-induced multiple organ failure. Brit J Pharmacol, 2011,163(3):609–623

    Article  CAS  Google Scholar 

  14. Den Uil CA, Klijn E, Lagrand WK, et al. The microcirculation in health and critical disease. Prog Cardiovasc Dis, 2008,51(2):161–170

    Article  PubMed  Google Scholar 

  15. Podoprigora GI, Blagosklonov O, Angoue O, et al. Assessment of microcirculatory effects of glycine by intravital microscopy in rats. Conf Proc IEEE Eng Med BiolSoc, 2012, 2012: 2651–2654

    Google Scholar 

  16. Li Y, Wu XL, Zhao YC, et al. Hemodynamic monitoring with pulse-indicator continuors cardiac output (PICCO) in piglets with sepsis after nitiric oxide inhalation. Acta Med Univ Sci Technol Huazhong (Chinese), 2015,44(1):785

    Google Scholar 

  17. Merx MW, Liehn EA, Graf J, et al. Statin treatment after onset of sepsis in a murine model improves survival. Circulation, 2005,112(1):117–124

    Article  CAS  PubMed  Google Scholar 

  18. Sari AN, Korkmaz B, Serin MS, et al. Effects of 5,14-HEDGE, a 20-HETE mimetic, on lipopolysaccharideinduced changes in MyD88/TAK1/IKK beta/I kappa Balpha/ NF-kappa B pathway and circulating miR-150, miR-223, and miR-297 levels in a rat model of septic shock. Inflamm Res, 2014,63(9):741–756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tunctan B, Korkmaz B, Sari AN, et al. Contribution of iNOS/sGC/PKG pathway, COX-2, CYP4A1, and gp91(phox) to the protective effect of 5,14-HEDGE, a 20-HETE mimetic, against vasodilation, hypotension, tachycardia, and inflammation in a rat model of septic shock. Nitric Oxide-Biol Ch, 2013, 33: 18–41

    Article  CAS  Google Scholar 

  20. Herzig DS, Luan LM, Bohannon JK, et al. The role of CXCL10 in the pathogenesis of experimental septic shock. Crit Care, 2014,18(3):R113

    Article  PubMed  PubMed Central  Google Scholar 

  21. Anuar F, Whiteman M, Bhatia M, et al. Flurbiprofen and its nitric oxide-releasing derivative protect against septic shock in rats. Inflamm Res, 2006,55(11):498–503

    Article  CAS  PubMed  Google Scholar 

  22. Xu T, Yang JH, Long D, et al. The mechanism of edaraone’s rat brain-protective effect. Mil Med J S Chin, 2010,24(1):34–36

    CAS  Google Scholar 

  23. de Backer D, Donadello K, Sakr Y, et al. Microcirculatory alterations in patients with severe sepsis: impact of time of assessment and relationship with outcome. Crit Care Med, 2013,41(3):791–799

    Article  PubMed  Google Scholar 

  24. Sakr Y, Dubois MJ, de Backer D, et al. Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med, 2004,32(9):1825–1831

    Article  PubMed  Google Scholar 

  25. de Backer D, Creteur J, Preiser JC, et al. Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med, 2002,166(1):98–104

    Article  PubMed  Google Scholar 

  26. Brown GT, Narayanan P, Li W, et al. Lipopolysaccharide stimulates platelets through an IL-1 beta autocrine loop. J Immunol, 2013,191(10):5196–5203

    Article  CAS  PubMed  Google Scholar 

  27. Abraham E, Gyetko MR, Kuhn K, et al. Urokinase-type plasminogen activator potentiates lipopolysaccharideinduced neutrophil activation. J Immunol, 2003,170(11):5644–5651

    Article  CAS  PubMed  Google Scholar 

  28. Zhang G, Han J, Welch EJ, et al. Lipopolysaccharide stimulates platelet secretion and potentiates platelet aggregation via TLR4/MyD88 and the cGMP-dependent protein kinase pathway. J Immunol, 2009,182(12):7997–29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Polanowska-Grabowska RK, Ley K. Plateletneutrophil-interactions: linking hemostasis and inflammation. Blood Rev, 2007,21(2):99–111

    Article  PubMed  Google Scholar 

  30. Futosi K, Fodor S, Mocsai A. Reprint of neutrophil cell surface receptors and their intracellular signal transduction pathways. Int Immunopharmac, 2013,17(4):1185–1197

    Article  CAS  Google Scholar 

  31. Zhao YL, Feng QZ, Huang ZJ, et al. Simvastatin inhibits inflammation in ischemia-reperfusion injury. Inflammation, 2014,37(5):1865–1875

    Article  CAS  PubMed  Google Scholar 

  32. Moraes AL, Vaiyapuri S, Sasikumar P, et al. Antithrombotic actions of statins involve PECAM-1 signaling. Blood, 2013,122(18):3188–3196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Plesner T, Ploug M, Ellis V, et al. The receptor for urokinase-type plasminogen activator and urokinase is translocated from two distinct intracellular compartments to the plasma membrane on stimulation of human neutrophils. Blood, 1994,83(3):808–815

    CAS  PubMed  Google Scholar 

  34. Reichel CA, Uhl B, Lerchenberger M, et al. Urokinase-type plasminogen activator promotes paracellular transmigration of neutrophils via Mac-1, but independently of urokinasetype plasminogen activator receptor. Circulation, 2011, 124(17):1849–1193

    Article  Google Scholar 

  35. Kwak SH, Wang XQ, He Q, et al. Plasminogen activator inhibitor-1 potentiates LPS-induced neutrophil activation through a JNK-mediated pathway. Thromb Haemost, 2006,95(5):829–835

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Intensive Care Unit, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, China

    Li Yu  (喻 莉), Xiao-ling Wu  (武晓灵) & Ding Long  (龙 鼎)

  2. Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Xing-wen Da  (达兴文) & Ao-di He  (何奥迪)

Authors
  1. Li Yu  (喻 莉)
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xing-wen Da  (达兴文)
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiao-ling Wu  (武晓灵)
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ao-di He  (何奥迪)
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ding Long  (龙 鼎)
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Li Yu  (喻 莉).

Additional information

These two authors contributed equally to this work and should be considered co-first authors.

This project was supported by the Wuhan Science and Technology Project, China (No. 2013060602010252).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, L., Da, Xw., Wu, Xl. et al. Simvastatin prevents lipopolysaccharide-induced septic shock in rats. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 37, 226–230 (2017). https://doi.org/10.1007/s11596-017-1719-7

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11596-017-1719-7

Key words

Search

Navigation