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Molecular Medicine

, Volume 21, Issue 1, pp 637–644 | Cite as

Stimulation of Brain AMP-Activated Protein Kinase Attenuates Inflammation and Acute Lung Injury in Sepsis

  • Nikhil Mulchandani
  • Weng-Lang Yang
  • Mohammad Moshahid Khan
  • Fangming Zhang
  • Philippe Marambaud
  • Jeffrey Nicastro
  • Gene F. Coppa
  • Ping Wang
Research Article

Abstract

Sepsis and septic shock are enormous public health problems with astronomical financial repercussions on health systems worldwide. The central nervous system (CNS) is closely intertwined in the septic process but the underlying mechanism is still obscure. AMP-activated protein kinase (AMPK) is a ubiquitous energy sensor enzyme and plays a key role in regulation of energy homeostasis and cell survival. In this study, we hypothesized that activation of AMPK in the brain would attenuate inflammatory responses in sepsis, particularly in the lungs. Adult C57BL/6 male mice were treated with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR, 20 ng), an AMPK activator, or vehicle (normal saline) by intracerebroventricular (ICV) injection, followed by cecal ligation and puncture (CLP) at 30 min post-ICV. The septic mice treated with AICAR exhibited elevated phosphorylation of AMPKα in the brain along with reduced serum levels of aspartate aminotransferase, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), compared with the vehicle. Similarly, the expressions of TNF-α, IL-1β, keratinocyte-derived chemokine and macrophage inflammatory protein-2 as well as myeloperoxidase activity in the lungs of AICAR-treated mice were significantly reduced. Moreover, histological findings in the lungs showed improvement of morphologic features and reduction of apoptosis with AICAR treatment. We further found that the beneficial effects of AICAR on septic mice were diminished in AMPKα2 deficient mice, showing that AMPK mediates these effects. In conclusion, our findings reveal a new functional role of activating AMPK in the CNS to attenuate inflammatory responses and acute lung injury in sepsis.

Notes

Acknowledgments

Supported in part by National Institutes of Health (NIH) grants GM057468 and GM053008 (to P Wang). The authors thank Benoit Viollet (INSERM, Institut Cochin, Paris, France) for generously providing the AMPKα2 knockout mice.

References

  1. 1.
    Gaieski DF, Edwards JM, Kallan MJ, Carr BG. (2013) Benchmarking the incidence and mortality of severe sepsis in the United States. Crit. Care Med. 41:1167–74.CrossRefGoogle Scholar
  2. 2.
    Khan MM, Yang WL, Wang P. (2015) Endoplasmic reticulum stress in sepsis. Shock. 44:294–304.CrossRefGoogle Scholar
  3. 3.
    Hu Z, et al. (2015) Ursolic acid improves survival and attenuates lung injury in septic rats induced by cecal ligation and puncture. J. Surg. Res. 194:528–36.CrossRefGoogle Scholar
  4. 4.
    Sharma A, Matsuo S, Yang WL, Wang Z, Wang P. (2014) Receptor-interacting protein kinase 3 deficiency inhibits immune cell infiltration and attenuates organ injury in sepsis. Crit. Care. 18:R142.CrossRefGoogle Scholar
  5. 5.
    Neumann B, et al. (1999) Mechanisms of acute inflammatory lung injury induced by abdominal sepsis. Int. Immunol. 11:217–27.CrossRefGoogle Scholar
  6. 6.
    Ayala A, et al. (2002) Shock-induced neutrophil mediated priming for acute lung injury in mice: divergent effects of TLR-4 and TLR-4/FasL deficiency. Am. J. Pathol. 161:2283–94.CrossRefGoogle Scholar
  7. 7.
    Lomas-Neira JL, Chung CS, Wesche DE, Perl M, Ayala A. (2005) In vivo gene silencing (with siRNA) of pulmonary expression of MIP-2 versus KC results in divergent effects on hemorrhage-induced, neutrophil-mediated septic acute lung injury. J. Leukoc. Biol. 77:846–53.CrossRefGoogle Scholar
  8. 8.
    Filgueiras LR, Capelozzi VL, Martins JO, Jancar S. (2014) Sepsis-induced lung inflammation is modulated by insulin. BMC Pulm. Med. 14:177.CrossRefGoogle Scholar
  9. 9.
    Mannam P, et al. (2014) MKK3 regulates mitochondrial biogenesis and mitophagy in sepsis-induced lung injury. Am. J. Physiol Lung Cell. Mol. Physiol. 306:L604–19.CrossRefGoogle Scholar
  10. 10.
    Aziz M, Jacob A, Yang WL, Matsuda A, Wang P. (2013) Current trends in inflammatory and immunomodulatory mediators in sepsis. J. Leukoc. Biol. 93:329–42.CrossRefGoogle Scholar
  11. 11.
    Botha AJ, et al. (1995) Early neutrophil sequestration after injury: a pathogenic mechanism for multiple organ failure. J. Trauma. 39:411–7.CrossRefGoogle Scholar
  12. 12.
    Hardie DG. (2003) Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology. 144:5179–83.CrossRefGoogle Scholar
  13. 13.
    Zhao X, et al. (2008) Activation of AMPK attenuates neutrophil proinflammatory activity and decreases the severity of acute lung injury. Am. J. Physiol. Lung Cell. Mol. Physiol. 295:L497–504.CrossRefGoogle Scholar
  14. 14.
    Viollet B, et al. (2003) The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity. J. Clin. Invest. 111:91–8.CrossRefGoogle Scholar
  15. 15.
    Mihaylova MM, Shaw RJ. (2011) The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat. Cell Biol. 13:1016–23.CrossRefGoogle Scholar
  16. 16.
    Li XN, et al. (2009) Activation of the AMPK-FOXO3 pathway reduces fatty acid-induced increase in intracellular reactive oxygen species by upregulating thioredoxin. Diabetes. 58:2246–57.CrossRefGoogle Scholar
  17. 17.
    Dolinsky VW, Dyck JR. (2006) Role of AMP-activated protein kinase in healthy and diseased hearts. Am. J. Physiol. Heart Circ. Physiol. 291: H2557–69.CrossRefGoogle Scholar
  18. 18.
    Salminen A, Hyttinen JM, Kaarniranta K. (2011) AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan. J. Mol. Med. (Berl). 89:667–76.CrossRefGoogle Scholar
  19. 19.
    Sullivan JE, et al. (1994) Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell-permeable activator of AMP-activated protein kinase. FEBS Lett. 353:33–6.CrossRefGoogle Scholar
  20. 20.
    Bai A, et al. (2010) AMPK agonist downregulates innate and adaptive immune responses in TNBS-induced murine acute and relapsing colitis. Biochem. Pharmacol. 80:1708–17.CrossRefGoogle Scholar
  21. 21.
    Hoogendijk AJ, Pinhancos SS, van der Poll T, Wieland CW. (2013) AMP-activated protein kinase activation by 5-aminoimidazole-4-carbox-amide-1-beta-D-ribofuranoside (AICAR) reduces lipoteichoic acid-induced lung inflammation. J. Biol. Chem. 288:7047–52.CrossRefGoogle Scholar
  22. 22.
    Giri S, et al. (2004) 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside inhibits proinflammatory response in glial cells: a possible role of AMP-activated protein kinase. J. Neurosci. 24:479–87.CrossRefGoogle Scholar
  23. 23.
    Tracey KJ. (2007) Physiology and immunology of the cholinergic antiinflammatory pathway. J. Clin. Invest. 117:289–96.CrossRefGoogle Scholar
  24. 24.
    Huston JM, et al. (2007) Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis. Crit. Care Med. 35:2762–8.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Boeckxstaens G. (2013) The clinical importance of the anti-inflammatory vagovagal reflex. Handb. Clin. Neurol. 117:119–34.CrossRefGoogle Scholar
  26. 26.
    Park J, Kang JW, Lee SM. (2013) Activation of the cholinergic anti-inflammatory pathway by nicotine attenuates hepatic ischemia/reperfusion injury via heme oxygenase-1 induction. Eur. J. Pharmacol. 707:61–70.CrossRefGoogle Scholar
  27. 27.
    Cai D, Liu T. (2011) Hypothalamic inflammation: a double-edged sword to nutritional diseases. Ann. N. Y. Acad. Sci. 1243:E1–39.CrossRefGoogle Scholar
  28. 28.
    Ronnett GV, Aja S. (2008) AMP-activated protein kinase in the brain. Int. J. Obes. (Lond). 32 Suppl 4: S42–8.CrossRefGoogle Scholar
  29. 29.
    Turnley AM, et al. (1999) Cellular distribution and developmental expression of AMP-activated protein kinase isoforms in mouse central nervous system. J. Neurochem. 72:1707–16.CrossRefGoogle Scholar
  30. 30.
    Amato S, Man HY. (2011) Bioenergy sensing in the brain: the role of AMP-activated protein kinase in neuronal metabolism, development and neurological diseases. Cell Cycle. 10:3452–60.CrossRefGoogle Scholar
  31. 31.
    Giangola MD, et al. (2013) Growth arrest-specific protein 6 attenuates neutrophil migration and acute lung injury in sepsis. Shock. 40:485–91.CrossRefGoogle Scholar
  32. 32.
    Hirano Y, et al. (2015) Neutralization of osteopontin attenuates neutrophil migration in sepsis-induced acute lung injury. Crit. Care. 19:782.CrossRefGoogle Scholar
  33. 33.
    Hudson LD. (1995) New therapies for ARDS. Chest. 108:79S–91S.CrossRefGoogle Scholar
  34. 34.
    Oberholzer C, Oberholzer A, Clare-Salzler M, Moldawer LL. (2001) Apoptosis in sepsis: a new target for therapeutic exploration. FASEB J. 15:879–92.CrossRefGoogle Scholar
  35. 35.
    Liu D, Zienkiewicz J, DiGiandomenico A, Hawiger J. (2009) Suppression of acute lung inflammation by intracellular peptide delivery of a nuclear import inhibitor. Mol. Ther. 17:796–802.CrossRefGoogle Scholar
  36. 36.
    Schmal H, Shanley TP, Jones ML, Friedl HP, Ward PA. (1996) Role for macrophage inflammatory protein-2 in lipopolysaccharide-induced lung injury in rats. J. Immunol. 156:1963–72.PubMedGoogle Scholar
  37. 37.
    Lomas JL, et al. (2003) Differential effects of macrophage inflammatory chemokine-2 and keratinocyte-derived chemokine on hemorrhage-induced neutrophil priming for lung inflammation: assessment by adoptive cells transfer in mice. Shock. 19:358–65.CrossRefGoogle Scholar
  38. 38.
    Chong DL, Sriskandan S. (2011) Pro-inflammatory mechanisms in sepsis. Contrib. Microbiol. 17:86–107.CrossRefGoogle Scholar
  39. 39.
    Escobar DA, et al. (2015) Adenosine monophosphate-activated protein kinase activation protects against sepsis-induced organ injury and inflammation. J. Surg. Res. 194:262–72.CrossRefGoogle Scholar
  40. 40.
    Torgersen C, et al. (2009) Macroscopic post-mortem findings in 235 surgical intensive care patients with sepsis. Anesth. Analg. 108:1841–7.CrossRefGoogle Scholar
  41. 41.
    Weiss YG, et al. (2001) Adenoviral vector transfection into the pulmonary epithelium after cecal ligation and puncture in rats. Anesthesiology. 95:974–82.CrossRefGoogle Scholar
  42. 42.
    Aschkenasy G, Bromberg Z, Raj N, Deutschman CS, Weiss YG. (2011) Enhanced Hsp70 expression protects against acute lung injury by modulating apoptotic pathways. PLoS One. 6:e26956.CrossRefGoogle Scholar
  43. 43.
    Chopra M, Reuben JS, Sharma AC. (2009) Acute lung injury: apoptosis and signaling mechanisms. Exp. Biol. Med. (Maywood). 234:361–71.CrossRefGoogle Scholar
  44. 44.
    Kim JE, et al. (2008) AMPK activator, AICAR, inhibits palmitate-induced apoptosis in osteoblast. Bone. 43:394–404.CrossRefGoogle Scholar
  45. 45.
    Rossi A, Lord JM. (2013) Adiponectin inhibits neutrophil apoptosis via activation of AMP kinase, PKB and ERK 1/2 MAP kinase. Apoptosis. 18:1469–80.CrossRefGoogle Scholar
  46. 46.
    Kim J, Park YJ, Jang Y, Kwon YH. (2011) AMPK activation inhibits apoptosis and tau hyperphosphorylation mediated by palmitate in SH-SY5Y cells. Brain Res. 1418:42–51.CrossRefGoogle Scholar
  47. 47.
    Shanley TP, et al. (1997) Requirement for C-X-C chemokines (macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant) in IgG immune complex-induced lung injury. J. Immunol. 158:3439–48.PubMedGoogle Scholar
  48. 48.
    Schmekel B, et al. (1990) Myeloperoxidase in human lung lavage. I. A marker of local neutrophil activity. Inflammation. 14:447–54.CrossRefGoogle Scholar
  49. 49.
    Bellinger DL, et al. (2008) Sympathetic modulation of immunity: relevance to disease. Cell Immunol. 252:27–56.CrossRefGoogle Scholar
  50. 50.
    Cervi AL, Lukewich MK, Lomax AE. (2014) Neural regulation of gastrointestinal inflammation: role of the sympathetic nervous system. Auton. Neurosci. 182:83–8.CrossRefGoogle Scholar
  51. 51.
    Huston JM. (2012) The vagus nerve and the inflammatory reflex: wandering on a new treatment paradigm for systemic inflammation and sepsis. Surg. Infect. (Larchmt). 13:187–93.CrossRefGoogle Scholar
  52. 52.
    Ji H, et al. (2014) Central cholinergic activation of a vagus nerve-to-spleen circuit alleviates experimental colitis. Mucosal Immunol. 7:335–47.CrossRefGoogle Scholar
  53. 53.
    Smith SM, Vale WW. (2006) The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin. Neurosci. 8:383–95.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Silverman MN, Pearce BD, Biron CA, Miller AH. (2005) Immune modulation of the hypothalamic-pituitary-adrenal (HPA) axis during viral infection. Viral Immunol. 18:41–78.CrossRefGoogle Scholar
  55. 55.
    Bernik TR, et al. (2002) Pharmacological stimulation of the cholinergic antiinflammatory pathway. J. Exp. Med. 195:781–8.CrossRefGoogle Scholar
  56. 56.
    Santos GA, et al. (2013) Hypothalamic AMPK activation blocks lipopolysaccharide inhibition of glucose production in mice liver. Mol. Cell. Endocrinol. 381:88–96.CrossRefGoogle Scholar

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Authors and Affiliations

  • Nikhil Mulchandani
    • 1
  • Weng-Lang Yang
    • 1
    • 2
  • Mohammad Moshahid Khan
    • 2
  • Fangming Zhang
    • 2
  • Philippe Marambaud
    • 3
  • Jeffrey Nicastro
    • 1
  • Gene F. Coppa
    • 1
  • Ping Wang
    • 1
    • 2
  1. 1.Department of SurgeryHofstra North Shore-LIJ School of MedicineManhassetUSA
  2. 2.Center for Translational ResearchThe Feinstein Institute for Medical ResearchManhassetUSA
  3. 3.Litwin-Zucker Research Center for the Study of Alzheimer’s DiseaseThe Feinstein Institute for Medical ResearchManhassetUSA

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