Advertisement

Molecular Medicine

, Volume 21, Issue 1, pp 988–1001 | Cite as

Simvastatin and a Plant Galactolipid Protect Animals from Septic Shock by Regulating Oxylipin Mediator Dynamics through the MAPK-cPLA2 Signaling Pathway

  • Maria Karmella Apaya
  • Chih-Yu Lin
  • Ching-Yi Chiou
  • Chung-Chih Yang
  • Chen-Yun Ting
  • Lie-Fen Shyur
Research Article

Abstract

Sepsis remains a major medical issue despite decades of research. Identification of important inflammatory cascades and key molecular mediators are crucial for developing intervention and prevention strategies. In this study, we conducted a comparative oxylipin metabolomics study to gain a comprehensive picture of lipid mediator dynamics during the initial hyperinflammatory phase of sepsis, and demonstrated, in parallel, the efficacy of simvastatin and plant galactolipid, 1,2-di-O-α-linolenoyl-3-O-β-galactopyranosyl-sn-glycerol (dLGG) in the homeostatic regulation of the oxylipin metabolome using a lipopolysaccharide (LPS)-induced sepsis C57BL/6J mouse model. LPS increased the systemic and organ levels of proinflammatory metabolites of linoleic acid including leukotoxin diols (9-,10-DHOME, 12-,13-DHOME) and octadecadienoic acids (9-HODE and 13-HODE) and arachidonic acid-derived prostanoid, PGE2, and hydroxyeicosatetraenoic acids (8-, 12- and 15-HETE). Treatment with either compound decreased the levels of proinflammatory metabolites and elevated proresolution lipoxin A4, 5(6)-EET, 11(12)-EET and 15-deoxy-PGJ2. dLGG and simvastatin ameliorated the effects of LPS-induced mitogen-activated protein kinase (MAPK)-dependent activation of cPLA2, cyclooxygenase-2, lipoxygenase, cytochrome P450 and/or epoxide hydrolase lowered systemic TNF-α and IL-6 levels and aminotransferase activities and decreased organ-specific infiltration of inflammatory leukocytes and macrophages, and septic shock-induced multiple organ damage. Furthermore, both dLGG and simvastatin increased the survival rates in the cecal ligation and puncture (CLP) sepsis model. This study provides new insights into the role of oxylipins in sepsis pathogenesis and highlights the potential of simvastatin and dLGG in sepsis therapy and prevention.

Notes

Acknowledgments

We thank Bing-Ying Ho for technical assistance, Miranda Loney for English editorial assistance, and the Metabolomics Core Facility and Laboratory Animal Core Facility of the Agricultural Biotechnology Research Center, Academia Sinica, Taiwan. This study was supported by grant funding from the Ministry of Science and Technology (NSC 100-2321-B-400-002 and NSC-102-2325-B-001-007) and institutional grant funding from Academia Sinica, Taiwan.

Supplementary material

10020_2015_2101988_MOESM1_ESM.pdf (3.3 mb)
Supplementary material, approximately 3.33 MB.

References

  1. 1.
    Lever A, Mackenzie I. (2007). Sepsis: definition, epidemiology, and diagnosis. BMJ. 335:879–883.CrossRefGoogle Scholar
  2. 2.
    Dellinger RP, et al. (2008). Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock. Intensive Care Med. 39:165–228.CrossRefGoogle Scholar
  3. 3.
    Jawad I, Luksic I, Rafnsson SB. (2012). Assessing available information on the burden of sepsis: global estimates of incidence, prevalence and mortality. J. Glob. Health. 2:010404.CrossRefGoogle Scholar
  4. 4.
    Fullerton JN, O’Brien AJ, Gilroy DW. (2014). Lipid mediators in immune dysfunction after severe inflammation. Trends Immunol. 35:12–21.CrossRefGoogle Scholar
  5. 5.
    Serhan CN, et al. (2000). Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing. J. Exp. Med. 192:1197–204.CrossRefGoogle Scholar
  6. 6.
    Yang J, Schmelzer K, Georgi K, Hammock BD. (2009). Quantitative profiling method for oxylipin metabolome by liquid chromatography electrospray ionization tandem mass spectrometry. Anal. Chem. 81:8085–93.CrossRefGoogle Scholar
  7. 7.
    Bannenberg GL. (2010). Therapeutic applicability of anti-inflammatory and proresolving polyunsaturated fatty acid-derived lipid mediators. Scientific World Journal. 10:676–712.CrossRefGoogle Scholar
  8. 8.
    Aikawa M, Libby P. (2004). Lipid lowering therapy in atherosclerosis. Semin. Vasc. Med. 4:357–66.CrossRefGoogle Scholar
  9. 9.
    Merx MW, et al. (2005). Statin treatment after onset of sepsis in a murine model improves survival. Circulation. 112:117–24.CrossRefGoogle Scholar
  10. 10.
    Almuti K, Rimawi R, Spevack D, Ostfeld RJ. (2006). Effects of statins beyond lipid lowering: potential for clinical benefits. Int. J. Cardiol. 109:7–15.CrossRefGoogle Scholar
  11. 11.
    Birnbaum Y, Ye Y. (2012). Pleiotropic Effects of Statins: The Role of Eicosanoid Production. Curr. Atheroscler. Rep. 14:135–9.CrossRefGoogle Scholar
  12. 12.
    Almog Y, et al. (2004). Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation. 110:880–5.CrossRefGoogle Scholar
  13. 13.
    Novack V, et al. (2009). The effects of statin therapy on inflammatory cytokines in patients with bacterial infections: a randomized double-blind placebo controlled clinical trial. Intensive Care Med. 35:1255–60.CrossRefGoogle Scholar
  14. 14.
    Yang TF, et al. (2014). Effect of statin therapy on mortality in patients with infective endocarditis. Am. J. Cardiol. 114:94–9.CrossRefGoogle Scholar
  15. 15.
    Calder PC. (2006). n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am. J. Clin. Nutr. 83(6 Suppl):1505S–19S.CrossRefGoogle Scholar
  16. 16.
    Williams CM, Burdge G. (2006). Long-chain n-3 PUFA: plant v. marine sources. Proc. Nutr. Soc. 65:42–50.CrossRefGoogle Scholar
  17. 17.
    Hou CC, et al. (2007). A galactolipid possesses novel cancer chemopreventive effects by suppressing inflammatory mediators and mouse B16 melanoma. Cancer Res. 67:6907–15.CrossRefGoogle Scholar
  18. 18.
    Limdi JK, Hyde GM. (2003). Evaluation of abnormal liver function tests. Postgrad. Med. J. 79:307–12.CrossRefGoogle Scholar
  19. 19.
    Rittirsch D, Huber-Lang MS, Flierl MA, Ward PA. (2009). Immunodesign of experimental sepsis by cecal ligation and puncture. Nat. Protoc. 4:31–6.CrossRefGoogle Scholar
  20. 20.
    Gustot T. (2011). Multiple organ failure in sepsis: prognosis and role of systemic inflammatory response. Curr. Opin. Crit. Care. 17:153–9.CrossRefGoogle Scholar
  21. 21.
    Yasuda H, Yuen PS, Hu X, Zhou H, Star RA. (2006). Simvastatin improves sepsis-induced mortality and acute kidney injury via renal vascular effects. Kidney Int. 69:1535–42.CrossRefGoogle Scholar
  22. 22.
    Ejima K, et al. (2003). Cyclooxygenase-2-deficient mice are resistant to endotoxin-induced inflammation and death. FASEB J. 17:1325–7.CrossRefGoogle Scholar
  23. 23.
    Reddy RC, Narala VR, Keshamouni VG, Milam JE, Newstead MW, Standiford TJ. (2008). Sepsis-induced inhibition of neutrophil chemotaxis is mediated by activation of peroxisome proliferator-activated receptor-γ. Blood. 112:4250–8.CrossRefGoogle Scholar
  24. 24.
    Standiford TJ, Keshamouni VG, Reddy RC. (2005). Peroxisome proliferator-activated receptor-γ as a regulator of lung inflammation and repair. Proc. Am. Thorac. Soc. 2:226–31.CrossRefGoogle Scholar
  25. 25.
    Yuan ZQ, et al. (2002). Inhibition of JNK by cellular stress- and tumor necrosis factor alpha-induced AKT2 through activation of the NF-κB pathway in human epithelial cells. J. Biol. Chem. 277:29973–82.CrossRefGoogle Scholar
  26. 26.
    Dajani R, et al. (2007). Pleiotropic functions of TNF-α determine distinct IKKβ-dependent hepatocellular fates in response to LPS. Am. J. Physiol. Gastrointest Liver Physiol. 292:G242–52.CrossRefGoogle Scholar
  27. 27.
    Arthur JSC, Ley SC. (2013). Mitogen-activated protein kinases in innate immunity. Nat. Rev. Immunol. 13:679–92.CrossRefGoogle Scholar
  28. 28.
    Slomiany BL, Slomiany A. (2013). Induction in gastric mucosal prostaglandin and nitric oxide by Helicobacter pylori is dependent on MAPK/ERK-mediated activation of IKKβ and cPLA2: modulatory effect of ghrelin. Inflammopharmacol. 21:241–51.CrossRefGoogle Scholar
  29. 29.
    Bruegel M, et al. (2012). Sepsis-associated changes of the arachidonic acid metabolism and their diagnostic potential in septic patients. Crit. Care Med. 40:1478–86.CrossRefGoogle Scholar
  30. 30.
    Zingarelli B, Sheehan M, Hake PW, O’Connor M, Denenberg A, Cook JA. (2003). Peroxisome proliferator activator receptor-γ ligands, 15-deoxy-δ(12,14)-prostaglandin J2 and ciglitazone, reduce systemic inflammation in polymicrobial sepsis by modulation of signal transduction pathways. J. Immunol. 171:6827–37.CrossRefGoogle Scholar
  31. 31.
    Crouser ED, et al. (2004). Abnormal permeability of inner and outer mitochondrial membranes contributes independently to mitochondrial dysfunction in the liver during acute endotoxemia. Crit. Care Med. 32(2):478–88.CrossRefGoogle Scholar
  32. 32.
    Nie X, Song S, Zhang L, Qiu Z, Shi S, Liu Y. (2012). 15-Hydroxyeicosatetraenoic acid (15-HETE) protects pulmonary artery smooth muscle cells from apoptosis via inducible nitric oxide synthase (iNOS) pathway. Prostaglandins Other Lipid Mediat. 97:50–9.CrossRefGoogle Scholar
  33. 33.
    Sordi R, Menezes-de-Lima O Jr, Horewicz V, Scheschowitsch K, Santos LF, Assreuy J. (2013). Dual role of lipoxin A4 in pneumosepsis pathogenesis. Int. Immunopharmacol. 17:283–92.CrossRefGoogle Scholar
  34. 34.
    Porro B, Songia P, Squellerio I, Tremoli E, Cavalca V. (2014). Analysis, physiological and clinical significance of 12-HETE: a neglected platelet-derived 12-lipoxygenase product. J Chromatogr. B Analyt. Technol. Biomed. Life Sci. 964:26–40.CrossRefGoogle Scholar
  35. 35.
    Askari AA, Thomson S, Edin ML, Lih FB, Zeldin DC, Bishop-Bailey D. (2014). Basal and inducible anti-inflammatory epoxygenase activity in endothelial cells. Biochem. Biophys. Res. Commun. 446:633–7.CrossRefGoogle Scholar
  36. 36.
    Tunctan B, et al. (2012). A novel treatment strategy for sepsis and septic shock based on the interactions between prostanoids, nitric oxide, and 20-hydroxyeicosatetraenoic acid. Antiinflamm. Antiallergy Agents Med. Chem. 11:121–50.CrossRefGoogle Scholar
  37. 37.
    Serhan CN, Clish CB, Brannon J, Colgan SP, Gronert K, Chiang N. (2000). Anti-microinflammatory lipid signals generated from dietary N-3 fatty acids via cyclooxygenase-2 and transcellular processing: a novel mechanism for NSAID and N-3 PUFA therapeutic actions. J. Physiol. Pharmacol. 51(4 Pt 1):643–54.PubMedGoogle Scholar
  38. 38.
    Gladine C, et al. (2014). Lipid profiling following intake of the omega 3 fatty acid DHA identifies the peroxidized metabolites F4-neuroprostanes as the best predictors of atherosclerosis prevention. PLoS One. 9:e89393.CrossRefGoogle Scholar
  39. 39.
    Walker J, et al. (2011). Lipoxin A4 increases survival by decreasing systemic inflammation and bacterial load in sepsis. Shock. 36:410–6.CrossRefGoogle Scholar
  40. 40.
    Qi HY, Shelhamer JH. (2005). Toll-like receptor 4 signalling regulates cytosolic phospholipase A2 activation and lipid generation in lipopolysaccharide-stimulated macrophages. J Biol. Chem. 280:38969–75.CrossRefGoogle Scholar
  41. 41.
    Chakraborti S, et al. (2012). Role of PKCα-p(38) MAPK-G(i)α axis in NADPH oxidase derived O(2)(.-)-mediated activation of cPLA(2) under U46619 stimulation in pulmonary artery smooth muscle cells. Arch. Biochem. Biophys. 523:169–180.CrossRefGoogle Scholar
  42. 42.
    Kuan YH, Huang FM, Lee SS, Li YC, Chang YC. (2013). Bisgma stimulates prostaglandin E2 production in macrophages via cyclooxygenase-2, cytosolic phospholipase A2, and mitogen-activated protein kinases family. PLoS One. 8:e82942.CrossRefGoogle Scholar

Copyright information

© The Author(s) 2015

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  • Maria Karmella Apaya
    • 1
    • 2
    • 3
  • Chih-Yu Lin
    • 2
  • Ching-Yi Chiou
    • 2
  • Chung-Chih Yang
    • 2
    • 4
  • Chen-Yun Ting
    • 2
  • Lie-Fen Shyur
    • 1
    • 2
    • 4
    • 5
    • 6
  1. 1.Molecular and Biological Agricultural Sciences Program, Taiwan International Graduate ProgramAcademia SinicaTaipeiTaiwan
  2. 2.Agricultural Biotechnology Research CenterAcademia SinicaNankang, TaipeiTaiwan
  3. 3.Graduate Institute of BiotechnologyNational Chung Hsing UniversityTaichungTaiwan
  4. 4.Program for Cancer Biology and Drug Discovery, College of Medical Science and TechnologyTaipei Medical UniversityTaipeiTaiwan
  5. 5.Biotechnology CenterNational Chung Hsing UniversityTaichungTaiwan
  6. 6.Graduate Institute of PharmacognosyTaipei Medical UniversityTaipeiTaiwan

Personalised recommendations