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Effect of curcumin (Curcuma longa extract) on LPS-induced acute lung injury is mediated by the activation of AMPK

Abstract

Purpose

Curcumin, a biphenolic compound extracted from turmeric (Curcuma longa), possesses potent anti-inflammatory activity. The present study investigated whether curcumin could increase 5′ adenosine monophosphate-activated protein kinase (AMPK) activity in macrophages and modulate the severity of lipopolysaccharide (LPS)-induced acute lung injury.

Methods

Macrophages were treated with curcumin and then exposed (or not) to LPS. Acute lung injury was induced by intratracheal administration of LPS in BALB/c mice.

Results

Curcumin increased phosphorylation of AMPK and acetyl-CoA carboxylase (ACC), a downstream target of AMPK, in a time- and concentration-dependent manner. Curcumin did not increase phosphorylation of liver kinase B1, a primary kinase upstream of AMPK. STO-609, an inhibitor of calcium2+/calmodulin-dependent protein kinase kinase, diminished curcumin-induced AMPK phosphorylation, but transforming growth factor-beta-activated kinase 1 inhibitor did not. Curcumin also diminished the LPS-induced increase in phosphorylation of inhibitory κB-alpha and the production of tumor necrosis factor alpha (TNF-α), macrophage inflammatory protein (MIP)-2, and interleukin (IL)-6 by macrophages. Systemic administration of curcumin significantly decreased the production of TNF-α, MIP-2, and IL-6 as well as neutrophil accumulation in bronchoalveolar lavage fluid, and also decreased pulmonary myeloperoxidase levels and the wet/dry weight ratio in mice subjected to LPS treatment.

Conclusion

These results suggest that the protective effect of curcumin on LPS-induced acute lung injury is associated with AMPK activation.

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References

  1. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334–49.

    Article  CAS  PubMed  Google Scholar 

  2. Steinberg KP, Milberg JA, Martin TR, Maunder RJ, Cockrill BA, Hudson LD. Evolution of bronchoalveolar cell populations in the adult respiratory distress syndrome. Am J Respir Crit Care Med. 1994;150:113–22.

    Article  CAS  PubMed  Google Scholar 

  3. Bao Z, Ye Q, Gong W, Xiang Y, Wan H. Humanized monoclonal antibody against the chemokine CXCL-8 (IL-8) effectively prevents acute lung injury. Int Immunopharmacol. 2010;10:259–63.

    Article  CAS  PubMed  Google Scholar 

  4. Folkesson HG, Matthay MA, Hébert CA, Broaddus VC. Acid aspiration-induced lung injury in rabbits is mediated by interleukin-8-dependent mechanisms. J Clin Invest. 1995;96:107–16.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  5. Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res. 2007;100:328–41.

    Article  CAS  PubMed  Google Scholar 

  6. Tsoyi K, Jang HJ, Nizamutdinova IT, Kim YM, Lee YS, Kim HJ, Seo HG, Lee JH, Chang KC. Metformin inhibits HMGB1 release in LPS-treated RAW 264.7 cells and increases survival rate of endotoxaemic mice. Br J Pharmacol. 2011;162:1498–508.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  7. Bae HB, Zmijewski JW, Deshane JS, Tadie JM, Chaplin DD, Takashima S, Abraham E. AMP-activated protein kinase enhances the phagocytic ability of macrophages and neutrophils. FASEB J. 2011;25:4358–68.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  8. Zhao X, Zmijewski JW, Lorne E, Liu G, Park YJ, Tsuruta Y, Abraham E. Activation of AMPK attenuates neutrophil proinflammatory activity and decreases the severity of acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2008;295:L497–504.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  9. Sag D, Carling D, Stout RD, Suttles J. Adenosine 5′-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J Immunol. 2008;181:8633–41.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  10. Jurenka JS. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Altern Med Rev. 2009;14:141–53.

  11. Abe Y, Hashimoto S, Horie T. Curcumin inhibition of inflammatory cytokine production by human peripheral blood monocytes and alveolar macrophages. Pharmacol Res. 1999;39:41–7.

    Article  CAS  PubMed  Google Scholar 

  12. Tu CT, Yao QY, Xu BL, Zhang SC. Curcumin protects against concanavalin A-induced hepatitis in mice through inhibiting the cytoplasmic translocation and expression of high mobility group box 1. Inflammation. 2013;36:206–15.

    Article  CAS  PubMed  Google Scholar 

  13. Kim JH, Park JM, Kim EK, Lee JO, Lee SK, Jung JH, You GY, Park SH, Suh PG, Kim HS. Curcumin stimulates glucose uptake through AMPK-p38 MAPK pathways in L6 myotube cells. J Cell Physiol. 2010;223:771–8.

    CAS  PubMed  Google Scholar 

  14. Na LX, Zhang YL, Li Y, Liu LY, Li R, Kong T, Sun CH. Curcumin improves insulin resistance in skeletal muscle of rats. Nutr Metab Cardiovasc Dis. 2011;21:526–33.

    Article  CAS  PubMed  Google Scholar 

  15. Pan W, Yang H, Cao C, Song X, Wallin B, Kivlin R, Lu S, Hu G, Di W, Wan Y. AMPK mediates curcumin-induced cell death in CaOV3 ovarian cancer cells. Oncol Rep. 2008;20:1553–9.

    CAS  PubMed  Google Scholar 

  16. Bae HB, Li M, Son JK, Seo CS, Chung SH, Kim SJ, Jeong CW, Lee HG, Kim W, Park HC, Kwak SH. Sauchinone, a lignan from Saururus chinensis, reduces tumor necrosis factor-alpha production through the inhibition of c-raf/MEK1/2/ERK 1/2 pathway activation. Int Immunopharmacol. 2010;10:1022–8.

  17. Han HJ, Li M, Son JK, Seo CS, Song SW, Kwak SH, Bae HB. Sauchinone, a lignan from Saururus chinensis, attenuates neutrophil pro-inflammatory activity and acute lung injury. Int Immunopharmacol. 2013;17:471–7.

  18. Asti C, Ruggieri V, Porzio S, Chiusaroli R, Melillo G, Caselli GF. Lipopolysaccharide-induced lung injury in mice. I. Concomitant evaluation of inflammatory cells and haemorrhagic lung damage. Pulm Pharmacol Ther. 2000;13:61–9.

    Article  CAS  PubMed  Google Scholar 

  19. Wang S, Song P, Zou MH. AMP-activated protein kinase, stress responses and cardiovascular diseases. Clin Sci (Lond). 2012;122:555–73.

    Article  CAS  Google Scholar 

  20. Xie Z, Dong Y, Scholz R, Neumann D, Zou MH. Phosphorylation of LKB1 at serine 428 by protein kinase C-ζ is required for metformin-enhanced activation of the AMP-activated protein kinase in endothelial cells. Circulation. 2008;117:952–62.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  21. Jeong HW, Hsu KC, Lee JW, Ham M, Huh JY, Shin HJ, Kim WS, Kim JB. Berberine suppresses proinflammatory responses through AMPK activation in macrophages. Am J Physiol Endocrinol Metab. 2009;296:E955–64.

    Article  CAS  PubMed  Google Scholar 

  22. Puneet P, Moochhala S, Bhatia M. Chemokines in acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol. 2005;288:L3–15.

    Article  CAS  PubMed  Google Scholar 

  23. Bhatia M, Zemans RL, Jeyaseelan S. Role of chemokines in the pathogenesis of acute lung injury. Am J Respir Cell Mol Biol. 2012;46:566–72.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  24. Zhou H, Beevers CS, Huang S. The targets of curcumin. Curr Drug Targets. 2011;12:332–47.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  25. Kunnumakkara AB, Anand P, Aggarwal BB. Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Lett. 2008;269:199–225.

    Article  CAS  PubMed  Google Scholar 

  26. Olszanecki R, Gebska A, Korbut R. The role of haem oxygenase-1 in the decrease of endothelial intercellular adhesion molecule-1 expression by curcumin. Basic Clin Pharmacol Toxicol. 2007;101:411–5.

    Article  CAS  PubMed  Google Scholar 

  27. Dhandapani KM, Mahesh VB, Brann DW. Curcumin suppresses growth and chemoresistance of human glioblastoma cells via AP-1 and NFkappaB transcription factors. J Neurochem. 2007;102:522–38.

    Article  CAS  PubMed  Google Scholar 

  28. Yang K, Xu C, Li X, Jiang H. Combination of D942 with curcumin protects cardiomyocytes from ischemic damage through promoting autophagy. J Cardiovasc Pharmacol Ther. 2013;18:570–81.

    Article  CAS  PubMed  Google Scholar 

  29. Nath N, Khan M, Paintlia MK, Singh I, Hoda MN, Giri S. Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis. J Immunol. 2009;182:8005–14.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  30. Ji G, Zhang Y, Yang Q, Cheng S, Hao J, Zhao X, Jiang Z. Genistein suppresses LPS-induced inflammatory response through inhibiting NF-κB following AMP kinase activation in RAW 264.7 macrophages. PLoS One. 2012;7:e53101.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  31. Misra J, Chanda D, Kim DK, Li T, Koo SH, Back SH, Chiang JY, Choi HS. Curcumin differentially regulates endoplasmic reticulum stress through transcriptional corepressor SMILE (small heterodimer partner-interacting leucine zipper protein)-mediated inhibition of CREBH (cAMP responsive element-binding protein H). J Biol Chem. 2011;286:41972–84.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  32. Takikawa M, Kurimoto Y, Tsuda T. Curcumin stimulates glucagon-like peptide-1 secretion in GLUTag cells via Ca2+/calmodulin-dependent kinase II activation. Biochem Biophys Res Commun. 2013;435:165–70.

    Article  CAS  PubMed  Google Scholar 

  33. Lu HF, Lai KC, Hsu SC, Lin HJ, Yang MD, Chen YL, Fan MJ, Yang JS, Cheng PY, Kuo CL, Chung JG. Curcumin induces apoptosis through FAS and FADD, in caspase-3-dependent and -independent pathways in the N18 mouse-rat hybrid retina ganglion cells. Oncol Rep. 2009;22:97–104.

    CAS  PubMed  Google Scholar 

  34. Huang S, Paulauskis JD, Godleski JJ, Kobzik L. Expression of macrophage inflammatory protein-2 and KC mRNA in pulmonary inflammation. Am J Pathol. 1992;141:981–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Schmal H, Shanley TP, Jones ML, Friedl HP, Ward PA. Role for macrophage inflammatory protein-2 in lipopolysaccharide-induced lung injury in rats. J Immunol. 1996;156:1963–72.

    CAS  PubMed  Google Scholar 

  36. Remick DG, Strieter RM, Eskandari MK, Nguyen DT, Genord MA, Raiford CL, Kunkel SL. Role of tumor necrosis factor-alpha in lipopolysaccharide-induced pathologic alterations. Am J Pathol. 1990;136:49–60.

    PubMed Central  CAS  PubMed  Google Scholar 

  37. Wang Y, Thorlacius H. Mast cell-derived tumour necrosis factor-alpha mediates macrophage inflammatory protein-2-induced recruitment of neutrophils in mice. Br J Pharmacol. 2005;145:1062–8.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  38. Greenberger MJ, Strieter RM, Kunkel SL, Danforth JM, Laichalk LL, McGillicuddy DC, Standiford TJ. Neutralization of macrophage inflammatory protein-2 attenuates neutrophil recruitment and bacterial clearance in murine Klebsiella pneumonia. J Infect Dis. 1996;173:159–65.

  39. Antoine F, Simard JC, Girard D. Curcumin inhibits agent-induced human neutrophil functions in vitro and lipopolysaccharide-induced neutrophilic infiltration in vivo. Int Immunopharmacol. 2013;17:1101–7.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by a grant (CRI13021-1) from the Chonnam National University Hospital Research Institute of Clinical Medicine.

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Authors

Corresponding author

Correspondence to Hong-Beom Bae.

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Conflict of interest

There is no conflict of interest.

Additional information

J. Kim and S.-W. Jeong contributed equally to this study.

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Cite this article

Kim, J., Jeong, SW., Quan, H. et al. Effect of curcumin (Curcuma longa extract) on LPS-induced acute lung injury is mediated by the activation of AMPK. J Anesth 30, 100–108 (2016). https://doi.org/10.1007/s00540-015-2073-1

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  • DOI: https://doi.org/10.1007/s00540-015-2073-1

Keywords

  • AMPK
  • CaMKK
  • Curcumin
  • LPS
  • Macrophage