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Experimental Study of the Protective Effect of Simvastatin on Lung Injury in Rats with Sepsis

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Abstract

Simvastatin, which is primarily prescribed to lower cholesterol, may also mitigate lung injury caused by sepsis, although the mechanisms remain elusive. This study aimed to evaluate the protective effect of simvastatin on acute lung injury in rats with sepsis and to investigate possible mechanisms. Male Wistar rats were pretreated with simvastatin (0.2 μg/g) for 1 week before cecal ligation and puncture. Treatment with simvastatin demonstrated significant decreases in the concentration of protein, TNF-α, IL-1β, IL-6, and lipocalin 2, and the number of polymorphonuclear neutrophils in bronchoalveolar lavage fluid in septic rats. In addition, simvastatin also reduced levels of Evans blue, malondialdehyde, 8-hydroxy-2′-deoxyguanosine, and wet/dry lung weight ratios, and increased the activity of superoxide dismutase in lung tissue. Furthermore, expression levels of TLR4, NF-κB p65, and active caspase-3 proteins and Bax mRNA were also decreased by simvastatin. H&E staining showed that severe lung injury occurred in the sepsis group and that lung injury was reduced by treatment with simvastatin. In conclusion, simvastatin improved endothelial permeability and mitigated the inflammatory response of lung tissue, the oxidative stress response, and cell apoptosis by inhibiting the TLR4/NF-κB signaling pathway, thereby alleviating sepsis-induced acute lung injury in rats.

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References

  1. Li, G., C.L. Zhou, Q.S. Zhou, and H.D. Zou. 2016. Galantamine protects against lipopolysaccharide-induced acute lung injury in rats. Brazilian Journal of Medical and Biological Research 49: e5008. https://doi.org/10.1590/1414-431X20155008.

    CAS  PubMed  Google Scholar 

  2. Do–Umehara, H.C., C. Chen, D. Urich, L. Zhou, J. Qiu, S. Jang, A. Zander, M.A. Baker, M. Eilers, et al. 2013. Suppression of inflammation and acute lung injury by Mizl via repression of C/EBP-δ. Nature Immunology 14: 46l–469.

    Google Scholar 

  3. Tauseef, M., N. Knezevic, K.R. Chava, M. Smith, S. Sukriti, N. Gianaris, A.G. Obukhov, S.M. Vogel, D.E. Schraufnagel, A. Dietrich, et al. 2012. TLR4 activation of TRPC-6-dependent calcium signaling mediates endotoxin-induced lung vascular permeability and inflammation. The Journal of Experimental Medicine 209: 1953–1968.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. He, Z., X. Chen, S. Wang, and Z. Zou. 2014. Toll-like receptor 4 monoclonal antibody attenuates lipopolysaccharide-induced acute lung injury in mice. Experimental and Therapeutic Medicine 8: 871–876.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Deng, Y., Z. Yng, Y. Gao, H. Xu, B. Zheng, M. Jiang, J. Xu, Z. He, and X. Wang. 2013. Toll-like receptor 4 mediates acute lung injury induced by high mobility group box-1. PloS One 8: e64357. https://doi.org/10.1371/journal.pone.0064375.

    Article  Google Scholar 

  6. Zhang, M., L. Zou, Y. Feng, Y.J. Chen, Q. Zhou, F. Ichinose, and W. Chao. 2014. Toll-like receptor 4 is essential to preserving cardiac function and survival in low grade polymicrobial sepsis. Anesthesiology 121: 1270–1280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hackam, D.G., M. Mamdani, P. Li, and D.A. Redelmeier. 2006. Statins and sepsis in patients with cardiovascular disease, a population-based cohort analysis. Lancet 367: 413–418.

    Article  CAS  PubMed  Google Scholar 

  8. Koptertides, P., and M.E. Falagas. 2009. Statins for sepsis: a critical and updated review. Clinical Microbiology and Infection 15: 325–334.

    Article  Google Scholar 

  9. Zhang, S., M. Rahman, S. Zhang, Z. Qi, and H. Thorlacius. 2011. Simvastatin antagonizes CD40L secretion, CXC chemokine formation, and pulmonary infiltration of neutrophils in abdominal sepsis. Journal of Leukocyte Biology 89: 735–742.

    Article  CAS  PubMed  Google Scholar 

  10. Rittirsch, D., M.S. Huber-Lang, M.A. Flierl, and P.A. Ward. 2009. Immunodesign of experimental sepsis by cecal ligation and puncture. Nature Protocols 4: 31–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Han, J., R. Ding, D. Zhao, Z. Zhang, and X. Ma. 2013. Unfractionated heparin attenuates lung vascular leak in a mouse model of sepsis: role of RhoA/Rho kinase pathway. Thrombosis Research 132: 42–47.

    Article  Google Scholar 

  12. Wu, R., W. Dong, M. Zhou, F. Zhang, C.P. Marini, T.S. Ravikumar, and P. Wang. 2007. Ghrelin attenuates sepsis-induced acute lung injury and mortality in rats. American Journal of Respiratory and Critical Care Medicine 176: 805–813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Angus, D.C., and T. van der Poll. 2013. Severe sepsis and septic shock. The New England Journal of Medicine 369: 840–851.

    Article  CAS  PubMed  Google Scholar 

  14. Tasaka, S., H. Koh, W. Yamada, M. Shimizu, Y. Ogawa, N. Hasegawa, K. Yamaguchi, Y. Ishii, S.E. Richer, C.M. Doerschuk, et al. 2005. Attenuation of endotoxin-induced acute lung injury by the Rho-associated kinase inhibitor. Y-27632. American Journal of Respiratory Cell and Molecular Biology 32: 504–5l0.

    Article  CAS  PubMed  Google Scholar 

  15. Ge, Q.M., C.M. Huang, X.Y. Zhu, F. Bian, and S.M. Pan. 2017. Differentially expressed miRNAs in sepsis-induced acute kidney injury target oxidative stress and mitochondrial dysfunction pathways. PloS One 12: e0173292. https://doi.org/10.1371/journal.pone.0173292.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Prauchner, C.A. 2017. Oxidative stress in sepsis: pathophysiological implications justifying antioxidant co-therapy. Burns 43: 471–485.

    Article  PubMed  Google Scholar 

  17. Gil, H.W., S.J. Seok, D.S. Jeong, J.O. Yang, E.Y. Lee, and S.Y. Hong. 2010. Plasma level of malondialdehyde in the case of acute qaraquat intoxicatin. Clinical Toxicology (Philadelphia, Pa.) 48: 149–152.

    Article  Google Scholar 

  18. Byrd-Leikr, C.A., E.F. Block, K. Takeda, S. Akira, and A. Ding. 2001. The role of MyD88 and TLR4 in the LPS-mimetic activity of Taxol. European Journal of Immunology 31: 2448–2457.

    Article  Google Scholar 

  19. Ran, S. 2015. The role of TLR4 in chemotherapy-driven metastasis. Cancer Research 75: 2405–2410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sun, S.C., J.H. Chang, and J. Jin. 2013. Regulation of nuclear factor-kappaB in autoimmunity. Trends in Immunology 34: 282–289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hu, R., H. Xu, H. Jiang, Y. Zhang, and Y. Sun. 2013. The role of TLR4 in the pathogenesis of indirect acute lung injury. Frontiers in Bioscience 18: 1244–1255.

    Article  CAS  Google Scholar 

  22. Li, W.C., Z.J. Zou, M.C. Zhou, L. Chen, L. Zhou, Y.K. Zheng, and Z.J. He. 2015. Effects of simvastatin on the expression of inducible NOS in acute lung injury in septic rats. International Journal of Clinical and Experimental Pathology 8: 15106–15111.

    PubMed  PubMed Central  Google Scholar 

  23. Gil, M., Y.K. Kim, S.B. Hong, and K.J. Lee. 2016. Naringin decreases TNF-α and HMGB1 release from LPS-stimulated macrophages and improves survival in a CLP-induced sepsis mice. PloS One 11: e0164186.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Borregaard, N., and J.B. Cowland. 2006. Neutrophil gelatinase-associated lipocalin, a siderophore-binding eukaryotic protein. Biology of Metals 19: 211–215.

    CAS  Google Scholar 

  25. Aigner, F., H.T. Maier, H.G. Schwelberger, E.A. Wallnöfer, A. Amberger, P. Obrist, T. Berger, T.W. Mak, M. Maglione, R. Margreiter, et al. 2007. Lipocalin-2 regulates the inflammatory response during ischemia and reperfusion of the transplanted heart. American Journal of Transplantation 7: 779–788.

    Article  CAS  PubMed  Google Scholar 

  26. Roudkenar, M.H., Y. Kuwahara, T. Baba, A.M. Roushandeh, S. Ebishima, S. Abe, Y. Ohkubo, and M. Fukumoto. 2007. Oxidative stress induced lipocalin 2 gene expression: addressing its expression under the harmful conditions. Journal of Radiation Research 48: 39–44.

    Article  CAS  PubMed  Google Scholar 

  27. Connor, A.J., J.D. Laskin, and D.L. Laskin. 2012. Ozone-induced lung injury and sterile inflammation. Role of toll-like receptor 4. Experimental and Molecular Pathology 92: 229–235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shapiro, N.I., S. Trzeciak, J.E. Hollander, R. Birkhahn, R. Otero, T.M. Osborn, E. Moretti, H.B. Nguyen, K.J. Gunnerson, D. Milzman, et al. 2009. A prospective, muhicenter derivation of a biomarker panel to assess risk of organ dysfunction, shock, and death in emergency department patients with suspected sepsis. Critical Care Medicine 37: 96–104.

    Article  PubMed  Google Scholar 

  29. Sultan, S., M. Pascucci, S. Ahmad, I.A. Malik, A. Bianchi, P. Ramadori, G. Ahmad, and G. Ramadori. 2012. Lipocalin-2 is a major acute-phase protein in a rat and mouse model of sterile abscess. Shock 37: 191–196.

    CAS  PubMed  Google Scholar 

  30. Hai, Y., X. Zhou, Q. Dai, Y. Fan, and X. Huang. 2015. Hydrogen rich saline ameliorates lung injury associated with cecal ligation and puncture induced sepsis in rats. Experimental and Molecular Pathology 98: 268–276.

    Article  Google Scholar 

  31. Bannerman, D.D., and S.E. Goldblum. 2003. Mechanisms of bacterial lipopolysaccharide–induced endothelial apoptosis. American Journal of Physiology-Lung Cellular and Molecular Physiology 284: L899–L914.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was funded in part by Liaoning Science and Technology Project of China (Grant No.2015020527). We thank all the people who helped us to carry out this work.

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Authors and Affiliations

  1. Emergency Department, Shengjing Hospital of China Medical University, No. 36 Sanhao street, Heping district, Shenyang, Liaoning Province, 110004, China

    Yu Wang, Wenping Yang, Xin Zhao & Rong Zhang

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  1. Yu Wang
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  2. Wenping Yang
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  3. Xin Zhao
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Correspondence to Yu Wang.

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Wang, Y., Yang, W., Zhao, X. et al. Experimental Study of the Protective Effect of Simvastatin on Lung Injury in Rats with Sepsis. Inflammation 41, 104–113 (2018). https://doi.org/10.1007/s10753-017-0668-4

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