Skip to main content
SpringerLink
Log in

Suppression of MAPK and NF-κB Pathways by Limonene Contributes to Attenuation of Lipopolysaccharide-Induced Inflammatory Responses in Acute Lung Injury

Inflammation Aims and scope Submit manuscript

Cite this article

An Erratum to this article was published on 16 March 2013

Abstract

The present study aimed to investigate the protective role of limonene in lipopolysaccharide (LPS)-induced acute lung injury (ALI). ALI was induced in mice by intratracheal instillation of LPS (0.5 mg/kg), and limonene (25, 50, and 75 mg/kg) was injected intraperitoneally 1 h prior to LPS administration. After 12 h, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. Limonene pretreatment at doses of 25, 50, and 75 mg/kg decreased LPS-induced evident lung histopathological changes, lung wet-to-dry weight ratio, and lung myeloperoxidase activity. In addition, pretreatment with limonene inhibited inflammatory cells and proinflammatory cytokines including tumor necrosis factor-α, interleukin-1β, and interleukin-6 in BALF. Furthermore, we demonstrated that limonene blocked the phosphorylation of IκBα, nuclear factor-κB (NF-κB) p65, p38 mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase, and extracellular signal-regulated kinase in LPS-induced ALI. The results presented here suggest that the protective mechanism of limonene may be attributed partly to decreased production of proinflammatory cytokines through the inhibition of NF-κB and MAPK activation.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Repine, J.E. 1992. Scientific perspectives on adult respiratory distress syndrome. Lancet 339: 466e9.

    Article  Google Scholar 

  2. Ware, L.B., and M.A. Matthay. 2000. The acute respiratory distress syndrome. The New England Journal of Medicine 342: 1334e49.

    Article  Google Scholar 

  3. Sato, K., M.B. Kadiiska, A.J. Ghio, et al. 2002. In vivo lipid-derived free radical formation by NADPH oxidase in acute lung injury induced by lipopolysaccharide: a model for ARDS. The FASEB Journal 16: 1713–1720.

    Article  CAS  Google Scholar 

  4. Matthay, M.A., G.A. Zimmerman, C. Esmon, J. Bhattacharya, B. Coller, C.M. Doerschuk, J. Floros, and M.A. Gimbrone. 2003. Future research directions in acute lung injury. American Journal of Respiratory and Critical Care Medicine 167: 1027–1035.

    Article  PubMed  Google Scholar 

  5. Rubenfeld, G.D., E. Caldwell, E. Peabody, J. Weaver, D.P. Martin, M. Neff, et al. 2005. Incidence and outcomes of acute lung injury. The New England Journal of Medicine 353: 1685–1693.

    Article  PubMed  CAS  Google Scholar 

  6. Pahl, H.L. 1999. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18: 6853–6866.

    Article  PubMed  CAS  Google Scholar 

  7. Chen, Z., X. Zhang, X. Chu, X. Zhang, K. Song, Y. Jiang, L. Yu, and X. Deng. 2010. Preventive effects of valnemulin on lipopolysaccharide-induced acute lung injury in mice. Inflammation 33: 306–314.

    Article  PubMed  CAS  Google Scholar 

  8. Yang, Ruhui, Lina Yang, Xiangchun Shen, Wenyuan Cheng, Bohua Zhao, Kazi Hamid Ali, Zhiyu Qian, and Hui Ji. 2012. Suppression of NF-κB pathway by crocetin contributes to attenuation of lipopolysaccharide-induced acute lung injury in mice. European Journal of Pharmacology 674: 391–396.

    Article  PubMed  CAS  Google Scholar 

  9. Di, R., M.T. Huang, and C.T. Ho. 2011. Anti-inflammatory activities of mogrosides from Momordica grosvenori in murine macrophages and a murine ear edema model. Journal of Agricultural and Food Chemistry 59: 7474–7481.

    Article  PubMed  CAS  Google Scholar 

  10. Kim, E.K., and E.J. Choi. 2010. Pathological roles of MAPK signaling pathways in human diseases. Biochimica et Biophysica Acta 1802: 396–405.

    Article  PubMed  CAS  Google Scholar 

  11. Song, H.Y., J.A. Lee, S.M. Ju, K.Y. Yoo, M.H. Won, H.J. Kwon, et al. 2008. Topical transduction of superoxide dismutase mediated by HIV-1 Tat protein transduction domain ameliorates 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation in mice. Biochemical Pharmacology 75: 1348–1357.

    Article  PubMed  CAS  Google Scholar 

  12. Yoon, Weon-Jong, Nam Ho Lee, and Chang-Gu Hyun. 2010. Limonene suppresses lipopolysaccharide-induced production of nitric oxide, prostaglandin E2, and proinflammatory cytokines in RAW 264.7 macrophages. Journal of Oleo Science 59: 415–421.

    Article  PubMed  CAS  Google Scholar 

  13. Chaudhary, S.C., M.S. Siddiqui, M. Athar, Sarwar, and M. Alam. 2012. D-Limonene modulates inflammation, oxidative stress and Ras–ERK pathway to inhibit murine skin tumorigenesis. Human and Experimental Toxicology 31: 798–811.

    Article  PubMed  CAS  Google Scholar 

  14. Hirota, Ryoji, Ngatu Nlandu Roger, Hiroyuki Nakamura, Hee-sun Song, Masayoshi Sawamura, and Narufumi Suganuma. 2010. Anti-inflammatory effects of limonene from yuzu (Citrus junos Tanaka) essential oil on eosinophils. Journal of Food Science 75: 87–92.

    Article  Google Scholar 

  15. Matthay, M.A., G.A. Zimmerman, C. Esmon, J. Bhattacharya, B. Coller, C.M. Doerschuk, et al. 2003. Future research directions in acute lung injury: summary of a National Heart, Lung, and Blood Institute working group. American Journal of Respiratory and Critical Care Medicine 167: 1027–1035.

    Article  PubMed  Google Scholar 

  16. Rubenfeld, G.D. 2003. Epidemiology of acute lung injury. Critical Care Medicine 31: 276–284.

    Article  Google Scholar 

  17. Knapp, S., S. Florquin, D.T. Golenbock, and T. van der Poll. 2006. Pulmonary lipopolysaccharide (LPS)-binding protein inhibits the LPS-induced lung inflammation in vivo. Journal of Immunology 176: 3189–3195.

    CAS  Google Scholar 

  18. Chen, H., C. Bai, and X. Wang. 2010. The value of the lipopolysaccharide-induced acute lung injury model in respiratory medicine. Expert Review of Respiratory Medicine 4: 773–783.

    Article  PubMed  CAS  Google Scholar 

  19. Cepkova, M., and M.A. Matthay. 2006. Pharmacotherapy of acute lung injury and the acute respiratory distress syndrome. Journal of Intensive Care Medicine 21: 119–143.

    Article  PubMed  Google Scholar 

  20. Teder, P., R.W. Vandivier, D. Jiang, J. Liang, L. Cohn, E. Pure, P.M. Henson, and P.W. Noble. 2002. Resolution of lung inflammation by CD44. Science 296: 155–158.

    Article  PubMed  CAS  Google Scholar 

  21. Abraham, E. 2003. Neutrophils and acute lung injury. Critical Care Medicine 31: 195–199.

    Article  Google Scholar 

  22. Bachofen, M., and E.R. Weibel. 1982. Structural alterations of lung parenchyma in the adult respiratory distress syndrome. Clinics in Chest 3: 35–56.

    CAS  Google Scholar 

  23. Klebanoff, S.J. 2005. Myeloperoxidase: friend and foe. Journal of Leukemia Biology 77: 598–625.

    Article  CAS  Google Scholar 

  24. Zhang, X.M., K.J. Song, H.Z. Xiong, H.Y. Li, X. Chu, and X.M. Deng. 2009. Protective effect of florfenicol on acute lung injury induced by lipopolysaccharide in mice. International Immunopharmacology 9: 1525–1529.

    Article  PubMed  CAS  Google Scholar 

  25. Bhatia, M., and S. Moochhala. 2004. Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. The Journal of Pathology 202: 145–156.

    Article  PubMed  CAS  Google Scholar 

  26. Minamino, T., and I. Komuro. 2006. Regeneration of the endothelium as a novel therapeutic strategy for acute lung injury. The Journal of Clinical Investigation 116: 2316–2319.

    Article  PubMed  CAS  Google Scholar 

  27. Ganter, M.T., J. Roux, B. Miyazawa, M. Howard, J.A. Frank, G. Su, et al. 2008. Interleukin-1beta causes acute lung injury via alphavbeta5 and alphavbeta6 integrin-dependent mechanisms. Circulation Research 102: 804–812.

    Article  PubMed  CAS  Google Scholar 

  28. Giebelen, I.A., D.J. van Westerloo, G.J. LaRosa, et al. 2007. Local stimulation of a7 cholinergic receptors inhibits LPS-induced TNF-a release in the mouse lung. Shock 28: 700.

    PubMed  CAS  Google Scholar 

  29. Marsh, C.B., and M.D. Wewers. 1996. The pathogenesis of sepsis. Factors that modulate the response to gram-negative bacterial infection. Clinics in Chest Medicine 17: 183–197.

    Article  PubMed  CAS  Google Scholar 

  30. Bouros, D., M.G. Alexandrakis, K.M. Antoniou, et al. 2004. The clinical significance of serum and bronchoalveolar lavage inflammatory cytokines in patients at risk for acute respiratory distress syndrome. BMC Pulmonary Medicine 4: 6.

    Article  PubMed  Google Scholar 

  31. Goodman, R.B., J. Pugin, J.S. Lee, and M.A. Matthay. 2003. Cytokine-mediated inflammation in acute lung injury. Cytokine & Growth Factor Reviews 14: 523–535.

    Article  CAS  Google Scholar 

  32. Li, Y.C., C.H. Yeh, M.L. Yang, and Y.H. Kuan. 2012. Luteolin suppresses inflammatory mediator expression by blocking the Akt/NFκB pathway in acute lung injury induced by lipopolysaccharide in mice. Evidence-Based Complementary and Alternative Medicine 2012: 383608.

    PubMed  Google Scholar 

  33. Sasaki, J., S. Fujishima, H. Iwamura, K. Wakitani, S. Aiso, and N. Aikawa. 2003. Prior burn insult induces lethal acute lung injury in endotoxemic mice: effects of cytokine inhibition. American Journal of Physiology. Lung Cellular and Molecular Physiology 284: 270–278.

    Google Scholar 

  34. Moine, P., R. McIntyre, M.D. Schwartz, et al. 2000. NF-kappaB regulatory mechanisms in alveolar macrophages from patients with acute respiratory distress syndrome. Shock 13: 85–91.

    Article  PubMed  CAS  Google Scholar 

  35. Baeuerle, P.A., and D. Baltimore. 1996. NF-κB: ten years after. Cell 87: 13–20.

    Article  PubMed  CAS  Google Scholar 

  36. Gilmore, T.D. 2006. Introduction to NF-kappaB: players, pathways, perspectives. Oncogene 25: 6680–6684.

    Article  PubMed  CAS  Google Scholar 

  37. Lee, J.C., and P.R. Young. 1996. Role of CSBP/p38/RK stress response kinase in LPS and cytokine signaling mechanisms. Journal of Leukocyte Biology 59: 152–157.

    PubMed  CAS  Google Scholar 

  38. Jarrar, D., J.F. Kuebler, L.W. Rue, S. Matalon, P. Wang, K.I. Bland, et al. 2002. Alveolar macrophage activation after trauma-hemorrhage and sepsis is dependent on NF-kappaB and MAPK/ERK mechanisms. American Journal of Physiology. Lung Cellular and Molecular Physiology 283: 799–805.

    Google Scholar 

  39. Candrian, S.S., V.F.J. Quesniaux, F. Di Padova, I. Maillet, N. Nicolas, I. Couillin, R. Moser, F. Erard, B.B. Vargaftig, B. Ryffel, and B. Schnyder. 2005. Dual effects of p38 MAPK on TNF-dependent bronchoconstriction and TNF-independent neutrophil recruitment in lipopolysaccharide-induced acute respiratory distress syndrome. Journal of Immunology 175: 262–269.

    Google Scholar 

  40. Kim, H.J., H.S. Lee, Y.H. Chong, and J.L. Kang. 2006. p38 Mitogen-activated protein kinase up-regulates LPS-induced NF-kappaB activation in the development of lung injury and RAW 264 7 macrophages. Toxicology 225: 36–47.

    Article  PubMed  CAS  Google Scholar 

  41. Pan, P., J. Cardinal, R. Dhupar, M.R. Rosengart, M.T. Lotze, D.A. Geller, et al. 2009. Low-dose cisplatin administration in murine cecal ligation and puncture prevents the systemic release of HMGB1 and attenuates lethality. Journal of Leukocyte Biology 86: 625–632.

    PubMed  CAS  Google Scholar 

  42. Song, G.Y., C.S. Chung, I.H. Chaudry, and A. Ayala. 2001. MAPK p38 antagonism as a novel method of inhibiting lymphoid immune suppression in polymicrobial sepsis. American Journal of Physiology. Cell Physiology 281: 662–669.

    Google Scholar 

  43. Schuh, K., and A. Pahl. 2009. Inhibition of the MAP kinase ERK protects from lipopolysaccharide-induced lung injury. Biochemical Pharmacology 77: 1827–1834.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Science and Technology Supporting Plan of China (No. 2006BAD31B03-4).

Author information

Authors and Affiliations

  1. College of Animal Science and Technology, Inner Mongolia National University, Tongliao, 028042, People’s Republic of China

    Gefu Chi

  2. Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Animal Science and Veterinary Medicine, Jilin University, 5333 Xi’an Road, Changchun, 130062, People’s Republic of China

    Miaomiao Wei, Xianxing Xie, L. W. Soromou & Fang Liu

  3. The Second Hospital of Jilin University, ZiqiangStreet 218#, Changchun, 130041, People’s Republic of China

    Miaomiao Wei & Shuhua Zhao

Authors
  1. Gefu Chi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miaomiao Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xianxing Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. W. Soromou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shuhua Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shuhua Zhao.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Chi, G., Wei, M., Xie, X. et al. Suppression of MAPK and NF-κB Pathways by Limonene Contributes to Attenuation of Lipopolysaccharide-Induced Inflammatory Responses in Acute Lung Injury. Inflammation 36, 501–511 (2013). https://doi.org/10.1007/s10753-012-9571-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-012-9571-1

KEY WORDS

search

Navigation