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Therapeutic effects of lysophosphatidylcholine in experimental sepsis

Nature Medicine volume 10, pages 161–167 (2004)Cite this article

Abstract

Sepsis represents a major cause of death in intensive care units. Here we show that administration of lysophosphatidylcholine (LPC), an endogenous lysophospholipid, protected mice against lethality after cecal ligation and puncture (CLP) or intraperitoneal injection of Escherichia coli. In vivo treatment with LPC markedly enhanced clearance of intraperitoneal bacteria and blocked CLP-induced deactivation of neutrophils. In vitro, LPC increased bactericidal activity of neutrophils, but not macrophages, by enhancing H2O2 production in neutrophils that ingested E. coli. Incubation with an antibody to the LPC receptor, G2A, inhibited LPC-induced protection from CLP lethality and inhibited the effects of LPC in neutrophils. G2A-specific antibody also blocked the inhibitory effects of LPC on certain actions of lipopolysaccharides (LPS), including lethality and the release of tumor necrosis factor-α (TNF-α) from neutrophils. These results suggest that LPC can effectively prevent and treat sepsis and microbial infections.

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Figure 1: LPC protects against sepsis-induced lethality.
Figure 2: Effects of 18:0 LPC on various cytokines in peritoneal lavage fluid of CLP-treated mice.
Figure 3: LPC enhances bacterial clearance in vivo and blocks CLP-induced deactivation of neutrophils.
Figure 4: LPC increases bactericidal activity in neutrophils by enhancing H2O2 production.
Figure 5: Inhibitory effects of LPC on actions of LPS.

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References

  1. Hoyert, D.L., Kochanek, K.D. & Murphy, S.L. Deaths: final data for 1997. Natl. Vital Stat. Rep. 47, 1–104 (1999).

    PubMed  Google Scholar 

  2. Huber-Lang, M.S. et al. Complement-induced impairment of innate immunity during sepsis. J. Immunol. 169, 3223–3231 (2002).

    Article  CAS  Google Scholar 

  3. Czermak, B.J. et al. Protective effects of C5a blockade in sepsis. Nat. Med. 5, 788–792 (1999).

    Article  CAS  Google Scholar 

  4. Docke, W.D. et al. Monocyte deactivation in septic patients: restoration by IFN-γ treatment. Nat. Med. 3, 678–681 (1997).

    Article  CAS  Google Scholar 

  5. Wang, S.D., Huang, K.J., Lin, Y.S. & Lei, H.Y. Sepsis-induced apoptosis of the thymocytes in mice. J. Immunol. 152, 5014–5021 (1994).

    CAS  PubMed  Google Scholar 

  6. Ayala, A. et al. Increased mucosal B-lymphocyte apoptosis during polymicrobial sepsis is a Fas ligand but not an endotoxin-mediated process. Blood 91, 1362–1372 (1998).

    CAS  PubMed  Google Scholar 

  7. Hotchkiss, R.S. et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J. Immunol. 166, 6952–6963 (2001).

    Article  CAS  Google Scholar 

  8. Hotchkiss, R.S. & Karl, I.E. The pathophysiology and treatment of sepsis. N. Engl. J. Med. 348, 138–150 (2003).

    Article  CAS  Google Scholar 

  9. Bone, R.C. Sir Isaac Newton, sepsis, SIRS, and CARS. Crit. Care Med. 24, 1125–1128 (1996).

    Article  CAS  Google Scholar 

  10. Huber-Lang, M.S. et al. Protective effects of anti-C5a peptide antibodies in experimental sepsis. FASEB J. 15, 568–570 (2001).

    Article  CAS  Google Scholar 

  11. Hotchkiss, R.S. et al. Prevention of lymphocyte cell death in sepsis improves survival in mice. Proc. Natl. Acad. Sci. USA 96, 14541–14546 (1999).

    Article  CAS  Google Scholar 

  12. Kabarowski, J.H., Xu, Y. & Witte, O.N. Lysophosphatidylcholine as a ligand for immunoregulation. Biochem. Pharmacol. 64, 161–167 (2002).

    Article  CAS  Google Scholar 

  13. Quinn, M.T., Parthasarathy, S. & Steinberg, D. Lysophosphatidylcholine: a chemotactic factor for human monocytes and its potential role in atherogenesis. Proc. Natl. Acad. Sci. USA 85, 2805–2809 (1988).

    Article  CAS  Google Scholar 

  14. Nakano, T., Raines, E.W., Abraham, J.A., Klagsbrun, M. & Ross, R. Lysophosphatidylcholine upregulates the level of heparin-binding epidermal growth factor-like growth factor mRNA in human monocytes. Proc. Natl. Acad. Sci. USA 91, 1069–1073 (1994).

    Article  CAS  Google Scholar 

  15. Liu-Wu, Y., Hurt-Camejo, E. & Wiklund, O. Lysophosphatidylcholine induces the production of IL-1β by human monocytes. Atherosclerosis 137, 351–357 (1998).

    Article  CAS  Google Scholar 

  16. Coutant, F. et al. Mature dendritic cell generation promoted by lysophosphatidylcholine. J. Immunol. 169, 1688–1695 (2002).

    Article  CAS  Google Scholar 

  17. Sakai, M. et al. Lysophosphatidylcholine plays an essential role in the mitogenic effect of oxidized low density lipoprotein on murine macrophages. J. Biol. Chem. 269, 31430–31435 (1994).

    CAS  PubMed  Google Scholar 

  18. Gomez-Munoz, A., O'Brien, L., Hundal, R. & Steinbrecher, U.P. Lysophosphatidylcholine stimulates phospholipase D activity in mouse peritoneal macrophages. J. Lipid Res. 40, 988–993 (1999).

    CAS  PubMed  Google Scholar 

  19. De Vries, H.E. et al. Acute effects of oxidized low density lipoprotein on metabolic responses in macrophages. FASEB J. 12, 111–118 (1998).

    Article  CAS  Google Scholar 

  20. Ngwenya, B.Z. & Yamamoto, N. Effects of inflammation products on immune systems. Lysophosphatidylcholine stimulates macrophages. Cancer Immunol. Immunother. 21, 174–182 (1986).

    Article  CAS  Google Scholar 

  21. Ramos, M.A. et al. Induction of macrophage VEGF in response to oxidized LDL and VEGF accumulation in human atherosclerotic lesions. Arterioscler. Thromb. Vasc. Biol. 18, 1188–1196 (1998).

    Article  CAS  Google Scholar 

  22. McMurray, H.F., Parthasarathy, S. & Steinberg, D. Oxidatively modified low density lipoprotein is a chemoattractant for human T lymphocytes. J. Clin. Invest. 92, 1004–1008 (1993).

    Article  CAS  Google Scholar 

  23. Asaoka, Y., Oka, M., Yoshida, K. & Nishizuka, Y. Lysophosphatidylcholine as a possible second messenger synergistic to diacylglycerol and calcium ion for T-lymphocyte activation. Biochem. Biophys. Res. Commun. 178, 1378–1385 (1991).

    Article  CAS  Google Scholar 

  24. Nishi, E. et al. Lysophosphatidylcholine increases expression of heparin-binding epidermal growth factor-like growth factor in human T lymphocytes. Circ. Res. 80, 638–644 (1997).

    Article  CAS  Google Scholar 

  25. Nishi, E. et al. Lysophosphatidylcholine enhances cytokine-induced interferon gamma expression in human T lymphocytes. Circ. Res. 83, 508–515 (1998).

    Article  CAS  Google Scholar 

  26. Asaoka, Y., Oka, M., Yoshida, K., Sasaki, Y. & Nishizuka, Y. Role of lysophosphatidylcholine in T-lymphocyte activation: involvement of phospholipase A2 in signal transduction through protein kinase C. Proc. Natl. Acad. Sci. USA 89, 6447–6451 (1992).

    Article  CAS  Google Scholar 

  27. Savage, J.E., Theron, A.J. & Anderson, R. Activation of neutrophil membrane-associated oxidative metabolism by ultraviolet radiation. J. Invest. Dermatol. 101, 532–536 (1993).

    Article  CAS  Google Scholar 

  28. Nishioka, H., Horiuchi, H., Arai, H. & Kita, T. Lysophosphatidylcholine generates superoxide anions through activation of phosphatidylinositol 3-kinase in human neutrophils. FEBS Lett. 441, 63–66 (1998).

    Article  CAS  Google Scholar 

  29. Silliman, C.C. et al. Lysophosphatidylcholines prime the NADPH oxidase and stimulate multiple neutrophil functions through changes in cytosolic calcium. J. Leukoc. Biol. 73, 511–524 (2003).

    Article  CAS  Google Scholar 

  30. Kabarowski, J.H., Zhu, K., Le, L.Q., Witte, O.N. & Xu, Y. Lysophosphatidylcholine as a ligand for the immunoregulatory receptor G2A. Science 293, 702–705 (2001).

    Article  CAS  Google Scholar 

  31. Muller Kobold, A.C. et al. Leukocyte activation in sepsis; correlations with disease state and mortality. Intensive Care Med. 26, 883–892 (2000).

    Article  CAS  Google Scholar 

  32. Solomkin, J.S., Jenkins, M.K., Nelson, R.D., Chenoweth, D. & Simmons, R.L. Neutrophil dysfunction in sepsis. II. Evidence for the role of complement activation products in cellular deactivation. Surgery 90, 319–327 (1981).

    CAS  PubMed  Google Scholar 

  33. Zhu, K. et al. Sphingosylphosphorylcholine and lysophosphatidylcholine are ligands for the G protein-coupled receptor GPR4. J. Biol. Chem. 276, 41325–41335 (2001).

    Article  CAS  Google Scholar 

  34. Okajima, F. et al. Stimulatory and inhibitory actions of lysophosphatidylcholine, depending on its fatty acid residue, on the phospholipase C/Ca2+ system in HL-60 leukaemia cells. Biochem. J. 336, 491–500 (1998).

    Article  CAS  Google Scholar 

  35. Zantl, N. et al. Essential role of gamma interferon in survival of colon ascendens stent peritonitis, a novel murine model of abdominal sepsis. Infect. Immun. 66, 2300–2309 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Tzianabos, A.O. et al. IL-2 mediates protection against abscess formation in an experimental model of sepsis. J. Immunol. 163, 893–897 (1999).

    CAS  PubMed  Google Scholar 

  37. Weighardt, H. et al. Impaired monocyte IL-12 production before surgery as a predictive factor for the lethal outcome of postoperative sepsis. Ann. Surg. 235, 560–567 (2002).

    Article  Google Scholar 

  38. Nakahata, E., Shindoh, Y., Takayama, T. & Shindoh, C. Interleukin-12 prevents diaphragm muscle deterioration in a septic animal model. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 130, 653–663 (2001).

    Article  CAS  Google Scholar 

  39. Remick, D.G. et al. Combination immunotherapy with soluble tumor necrosis factor receptors plus interleukin 1 receptor antagonist decreases sepsis mortality. Crit. Care Med. 29, 473–481 (2001).

    Article  CAS  Google Scholar 

  40. Matsumoto, T. et al. Contribution of neutrophils to lipopolysaccharide-induced tumor necrosis factor production and mortality in a carrageenan-pretreated mouse model. FEMS Immunol. Med. Microbiol. 17, 171–178 (1997).

    Article  CAS  Google Scholar 

  41. Drobnik, W. et al. Plasma ceramide and lysophosphatidylcholine inversely correlate with mortality in sepsis patients. J. Lipid Res. 44, 754–761 (2003).

    Article  CAS  Google Scholar 

  42. Macphee, C.H. Lipoprotein-associated phospholipase A2: a potential new risk factor for coronary artery disease and a therapeutic target. Curr. Opin. Pharmacol. 1, 121–125 (2001).

    Article  CAS  Google Scholar 

  43. Corr, P.B. et al. Pathophysiological concentrations of lysophosphatides and the slow response. Am. J. Physiol. 243, H187–H195 (1982).

    CAS  PubMed  Google Scholar 

  44. Kishimoto, T., Soda, Y., Matsuyama, Y. & Mizuno, K. An enzymatic assay for lysophosphatidylcholine concentration in human serum and plasma. Clin. Biochem. 35, 411–416 (2002).

    Article  CAS  Google Scholar 

  45. Szucs, S., Varga, C., Ember, I. & Kertai, P. The separation of the granulocytes from different rat strains. A comparative study. J. Immunol. Methods 167, 245–251 (1994)

    Article  CAS  Google Scholar 

  46. Qureshi, M.A. & Dietert, R.R. Bacterial uptake and killing by macrophages. in Methods in Immunotoxicology Vol. 2 (eds. Burleson, G.R., Dean, J.H. & Munson, A.E.) 119–131 (Wiley-Liss, New York, 1995).

    Google Scholar 

  47. Weng, Z. et al. A DNA damage and stress inducible G protein-coupled receptor blocks cells in G2/M. Proc. Natl. Acad. Sci. USA 95, 12334–12339 (1998).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank J. Chun for advice and critical reading of the manuscript; J.-B. Kim and J.-I. Kim for comments; and J.-N. Suh, J.-G. Ahn and Y.-M. Kim for technical assistance. This work was supported by Hallym University and the 21st Century Frontier Research Program (M103KV010013 03K2201 01330 to S.-O.H.).

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Author notes

  1. Ji-Jing Yan, Jun-Sub Jung, Jung-Eun Lee, Jongho Lee and Sung-Oh Huh: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, Institute of Natural Medicine, Hallym University, 1 Okchon-dong, Chunchon, 200-702, Gangwon-do, South Korea

    Ji-Jing Yan, Jun-Sub Jung, Jung-Eun Lee, Jongho Lee, Sung-Oh Huh, Hee-Sung Kim, Jae-Young Cho, Ju-Suk Nam, Hong-Won Suh, Yung-Hi Kim & Dong-Keun Song

  2. Department of Pathology, College of Medicine, Institute of Natural Medicine, Hallym University, 1 Okchon-dong, Chunchon, 200-702, Gangwon-do, South Korea

    Kyeong Cheon Jung

  3. Biosynergen, Inc., 4th Floor, College of Medicine Bldg., Hallym University, 1 Okchon-dong, Chunchon, 200-702, Gangwon-do, South Korea

    Sung-Oh Huh, Hee-Sung Kim & Dong-Keun Song

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Correspondence to Dong-Keun Song.

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D.-K.S., S.-O.H. and H.-W.S. have over 5% equity in Biosynergen Inc., which has filed a license on the use of lysophosphatidylcholine in sepsis.

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Yan, JJ., Jung, JS., Lee, JE. et al. Therapeutic effects of lysophosphatidylcholine in experimental sepsis. Nat Med 10, 161–167 (2004). https://doi.org/10.1038/nm989

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