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A Neutrophil Elastase Inhibitor, Sivelestat, Reduces Lung Injury Following Endotoxin-Induced Shock in Rats by Inhibiting HMGB1

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Abstract

Neutrophil elastase (NE) plays an important role in the progression of acute lung injury (ALI). Sivelestat sodium hydrate (Sivelestat) is a highly specific synthetic inhibitor of NE. High mobility group box 1 (HMGB1) is one of the key mediators in the development of sepsis. The aim of this study was to evaluate the effect of sivelestat and to determine whether it can reduce lipopolysaccharide (LPS)-induced acute lung injury in rats. Rats were randomly divided into a negative control group, an LPS-induced sepsis group, and a group treated with sivelestat prior to LPS administration. Animals in the sivelestat group received a bolus of 10 mg/kg of sivelestat injected into the intraperitoneal cavity before the LPS treatment. Furthermore, rats were administered sivelestat at 0, 1, 3, and 6 h following LPS treatment. We measured cytokine and HMGB1 levels in the serum after the induction of sepsis. In addition, we observed histopathology, wet/dry weight ratio, inducible nitric oxide synthase and HMGB1 expression in the lung tissue. Lung histopathology was significantly improved in the sivelestat group compared to the LPS group. Serum and pulmonary HMGB1 levels were lower over time among sivelestat-treated animals. Furthermore, inhibition of NF-κB activity was observed with the administration of sivelestat. These results suggest that sivelestat reduces LPS-induced lung injury at least partially by inhibiting inflammation and NF-κB activity.

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References

  1. Schlichting, D., and J. S. McCollam. 2007. Recognizing and managing severe sepsis: a common and deadly threat. South Med. J. 100(6):594–600.

    PubMed  Google Scholar 

  2. Costa, E. L., I. A. Schettino, and G. P. Schettino. 2006. The lung in sepsis: guilty or innocent? Endocr. Metab. Immune. Disord. Drug Targets 6(2):213–216.

    PubMed  CAS  Google Scholar 

  3. Andrews, P., E. Azoulay, M. Antonelli, L. Brochard, C. Brun-Buisson, G. Dobb, J. Y. Fagon, H. Gerlach, J. Groeneveld, J. Mancebo, P. Metnitz, S. Nava, J. Pugin, M. Pinsky, P. Radermacher, C. Richard, and R. Tasker. 2006. Year in review in intensive care medicine, 2005. II. Infection and sepsis, ventilator-associated pneumonia, ethics, haematology and haemostasis, ICU organisation and scoring, brain injury. Intensive. Care Med. 32:380–390.

    Article  PubMed  Google Scholar 

  4. Andrews, P., E. Azoulay, M. Antonelli, L. Brochard, C. Brun-Buisson, G. Dobb, J. Y. Fagon, H. Gerlach, J. Groeneveld, J. Mancebo, P. Metnitz, S. Nava, J. Pugin, M. Pinsky, P. Radermacher, C. Richard, R. Tasker, and B. Vallet. 2005. Year in review in intensive care medicine, 2004. I. Respiratory failure, infection, and sepsis. Intensive. Care Med. 31:28–40.

    Article  PubMed  Google Scholar 

  5. Weiss, S. J. 1989. Tissue destruction by neutrophils. N. Engl. J. Med. 320:365–376.

    PubMed  CAS  Google Scholar 

  6. Vender, R. L. 1996. Therapeutic potential of neutrophil-elastase inhibition in pulmonary disease. J. Invest. Med. 44:531–539.

    CAS  Google Scholar 

  7. Moreas, T. J., C. W. Chow, and G. P. Downey. 2003. Proteases and lung injury. Crit. Care Med. 31:S189–S194.

    Article  CAS  Google Scholar 

  8. Kawabata, K., M. Suzuki, M. Sugitani, K. Imaki, M. Toda, and T. Miyamoto. 1991. ONO-5046, a novel inhibitor of human neutrophil elastase. Biochem. Biophys. Res. Commun. 177:814–820.

    Article  PubMed  CAS  Google Scholar 

  9. Bellomo, R., S. Uchino, T. Naka, and L. Wan. 2004. Hidden evidence to the West: multicentre, randomised, controlled trials in sepsis and systemic inflammatory response syndrome in Japanese journals. Intensive. Care Med. 30:911–917.

    Article  PubMed  Google Scholar 

  10. Sakamaki, F., A. Ishizaka, T. Urano, K. Sayama, H. Nakamura, T. Terashima, Y. Waki, S. Tasaka, N. Hasegawa, K. Sato, N. Nakagawa, T. Obata, and M. Kanazawa. 1996. Effect of a specific neutrophil elastase inhibitor, ONO-5046, on endotoxin-induced acute lung injury. Am. J. Respir. Crit. Care Med. 153(1):391–397.

    PubMed  CAS  Google Scholar 

  11. Wakayama, F., I. Fukuda, Y. Suzuki, and N. Kondo. 2007. Neutrophil elastase inhibitor, sivelestat, attenuates acute lung injury after cardiopulmonary bypass in the rabbit endotoxemia model. Ann. Thorac. Surg. 83(1):153–160.

    Article  PubMed  Google Scholar 

  12. Wang, H., O. Bloom, M. Zhang, J. M. Vishnubhakat, M. Ombrellino, J. Che, A. Frazier, H. Yang, S. Ivanova, L. Borovikova, K. R. Manogue, E. Faist, E. Abraham, J. Andersson, U. Andersson, P. E. Molina, N. N. Abumrad, A. Sama, and K. J. Tracey. 1999. HMG-1 as a late mediator of endotoxin lethality in mice. Science 285:248–251.

    Article  PubMed  CAS  Google Scholar 

  13. Ueno, H., T. Matsuda, S. Hashimoto, F. Amaya, Y. Kitamura, M. Tanaka, A. Kobayashi, I. Maruyama, S. Yamada, N. Hasegawa, J. Soejima, H. Koh, and A. Ishizaka. 2004. Contributions of high mobility group box protein in experimental and clinical acute lung injury. Am. J. Respir. Crit. Care Med. 170:1310–1316.

    Article  PubMed  Google Scholar 

  14. Yu, M., H. Wang, A. Ding, D. T. Golenbock, E. Latz, C. J. Czura, M. J. Fenton, K. J. Tracey, and H. Yang. 2006. HMGB1 signals through toll-like receptor (TLR) 4 and TLR2. Shock 26:174–179.

    Article  PubMed  CAS  Google Scholar 

  15. Park, J. S., F. Gamboni-Robertson, Q. He, D. Svetkauskaite, J. Y. Kim, D. Strassheim, J. W. Sohn, S. Yamada, I. Maruyama, A. Banerjee, A. Ishizaka, and E. Abraham. 2006. High Mobility Group Box 1 protein (HMGB1) interacts with multiple Toll like receptors. Am. J. Physiol. Cell Physiol. 290:917–924.

    Article  CAS  Google Scholar 

  16. Sunden-Cullberg, J., A. Norrby-Teglund, and C. J. Treutiger. 2006. The role of high mobility group box-1 protein in severe sepsis. Curr. Opin. Infect. Dis. 19:231–236.

    Article  PubMed  CAS  Google Scholar 

  17. Hatada, T., H. Wada, T. Nobori, K. Okabayashi, K. Maruyama, Y. Abe, S. Uemoto, S. Yamada, and I. Maruyama. 2005. Plasma concentrations and importance of High Mobility Group Box protein in the prognosis of organ failure in patients with disseminated intravascular coagulation. Thromb. Haemost. 94:975–979.

    PubMed  CAS  Google Scholar 

  18. Sunden-Cullberg, J., A. Norrby-Teglund, A. Rouhiainen, H. Rauvala, G. Herman, K. J. Tracey, M. L. Lee, J. Andersson, L. Tokics, and C. J. Treutiger. 2005. Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock. Crit. Care Med. 33:564–573.

    Article  PubMed  CAS  Google Scholar 

  19. Wang, H., H. Yang, C. J. Czura, A. E. Sama, and K. J. Tracey. 2001. HMGB1 as a late mediator of lethal systemic inflammation. Am. J. Respir. Crit. Care Med. 164:1768–1773.

    PubMed  CAS  Google Scholar 

  20. Poltorak, A., X. He, I. Smirnova, M. Y. Liu, C. Van Huffel, X. Du, D. Birdwell, E. Alejos, M. Silva, C. Galanos, M. Freudenberg, P. Ricciardi-Castagnoli, B. Layton, and B. Beutler. 1998. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–2088.

    Article  PubMed  CAS  Google Scholar 

  21. Jiang, W., and D. S. Pisetsky. 2006. The role of IFN-alpha and nitric oxide in the release of HMGB1 by RAW 264.7 cells stimulated with polyinosinic-polycytidylic acid or lipopolysaccharide. J. Immunol. 1;177(5):3337–3343.

    Google Scholar 

  22. Wang, H., J. M. Vishnubhakat, O. Bloom, M. Zhang, M. Ombrellino, A. Sama, and K. J. Tracey. 1999. Proinflammatory cytokines (tumor necrosis factor and interleukin 1) stimulate release of high mobility group protein-1 by pituicytes. Surgery 126:389–392.

    PubMed  CAS  Google Scholar 

  23. Murakami, K., R. McGuire, R. A. Cox, J. M. Jodoin, L. J. Bjertnaes, J. Katahira, L. D. Traber, F. C. Schmalstieg, H. K. Hawkins, D. N. Herndon, and D. L. Traber. 2002. Heparin nebulization attenuates acute lung injury in sepsis following smoke inhalation in sheep. Shock 18:236–241.

    Article  PubMed  Google Scholar 

  24. Tate, R. M., and J. E. Repine. 1983. Neutrophils and the adult respiratory distress syndrome. Am. Rev. Respir. Dis. 128:552–559.

    PubMed  CAS  Google Scholar 

  25. Chandra, A., P. Enkhbaatar, Y. Nakano, L. D. Traber, and D. L. Traber. 2006. Sepsis: emerging role of nitric oxide and selectins. Clinics 61:71–76.

    Article  PubMed  Google Scholar 

  26. Bhatia, M., and S. Moochhala. 2004. Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. J. Pathol. 202:145–156.

    Article  PubMed  CAS  Google Scholar 

  27. Jiang, W., and D. S. Pisetsky. 2006. The role of IFN-alpha and nitric oxide in the release of HMGB1 by RAW 264.7 cells stimulated with polyinosinic–polycytidylic acid or lipopolysaccharide. J. Immunol. 177(5):3337–3343.

    PubMed  CAS  Google Scholar 

  28. Schwartz, M. D., E. E. Moore, F. A. Moore, R. Shenkar, P. Moine, J. B. Haenel, and E. Abraham. 1996. Nuclear factor-kappa B is activated in alveolar macrophages from patients with acute respiratory distress syndrome. Crit. Care Med. 24:1285–1292.

    Article  PubMed  CAS  Google Scholar 

  29. Liu, S. F., and A. B. Malik. 2006. NF-kappa B activation as a pathological mechanism of septic shock and inflammation. Am. J. Physiol. Lung Cell Mol. Physiol. 290(4):L622–L645.

    Article  PubMed  CAS  Google Scholar 

  30. Pritts, T. A., M. R. Moon, Q. Wang, E. S. Hungness, A. L. Salzman, J. E. Fischer, and P. O. Hasselgren. 2000. Activation of NF-kappaB varies in different regions of the gastrointestinal tract during endotoxemia. Shock 14:118–122.

    Article  PubMed  CAS  Google Scholar 

  31. Kawai, T., O. Adachi, T. Ogawa, K. Takeda, and S. Akira. 1999. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity. 11(1):115–122.

    Article  PubMed  CAS  Google Scholar 

  32. Adcock, I. M. 1997. Transcription factors as activators of gene transcription: AP-1 and NF-kappa B. Monaldi. Arch. Chest Dis. 52:178–186.

    PubMed  CAS  Google Scholar 

  33. Kuwahara, I., E. P. Lillehoj, W. Lu, I. S. Singh, Y. Isohama, T. Miyata, and K. C. Kim. 2006. Neutrophil elastase induces IL-8 gene transcription and protein release through p38/NF-{kappa}B activation via EGFR transactivation in a lung epithelial cell line. Am. J. Physiol. Lung Cell Mol. Physiol. 291:L407–L416.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors wish to thank Dr. Tomohisa Uchida for giving us helpful advice and for scoring lung injuries.

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Authors and Affiliations

  1. Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, 1-1 Idaigaoka-Hasamamachi-Yufu, City-Oita, 879-5593, Japan

    Satoshi Hagiwara, Hideo Iwasaka, Kazumi Togo & Takayuki Noguchi

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  1. Satoshi Hagiwara
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  2. Hideo Iwasaka
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  3. Kazumi Togo
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  4. Takayuki Noguchi
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Correspondence to Satoshi Hagiwara.

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Hagiwara, S., Iwasaka, H., Togo, K. et al. A Neutrophil Elastase Inhibitor, Sivelestat, Reduces Lung Injury Following Endotoxin-Induced Shock in Rats by Inhibiting HMGB1. Inflammation 31, 227–234 (2008). https://doi.org/10.1007/s10753-008-9069-z

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