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Chemical Mediators of Inflammation and Resolution in Post-Operative Abdominal Aortic Aneurysm Patients

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An Erratum to this article was published on 10 March 2011

Abstract

Temporal–metabolomic studies of local mediators during inflammation and its resolution uncovered novel pathways and mediators, e.g., lipoxins, resolvins, and protectins that stimulate key resolution responses. Since these studies were carried out with isolated human cells and in animal models, it is important to determine in humans whether temporal profiles between pro-inflammatory mediators and pro-resolving mediators are demonstrable in vivo. To this end, we examined patients undergoing abdominal aortic aneurysm (AAA) surgery. Profiles of mediators including eicosanoids were assessed in addition to pro-resolving mediators. The results demonstrate temporal relationships for local-acting peptides (e.g., VEGF, IL-10, TGFβ) and lipid mediators (leukotrienes and resolvins). In addition, profiles obtained for AAA patients divided into two groups based on their temporal profile: one group consistent with a pro-inflammatory and another with a resolving profile. Together, these translational metabolomic profiles demonstrate for the first time the temporal relationships between local mediators in humans relevant in inflammation resolution.

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Abbreviations

17-HDHA:

17S-hydroxy-docosa-4Z,7Z,10Z,13Z,15E,19Z-hexaenoic acid

18-HEPE:

18-hydroxy-eicosapentaenoic acid

12-HETE:

12-hydroxyeicosatetraenoic acid

15-HETE:

15-hydroxyeicosatetraenoic acid

LOX:

lipoxygenase

LTB4 :

leukotriene B4 5S,12R-dihydroxy-eicosa-6Z,8E,10E,14Z-tetraenoic acid

LXA4 :

lipoxin A4 5S,6R,15S-trihydroxy-eicosa-7E,9E,11Z,13E-tetraenoic acid

15-epi-LXA4 :

5S,6R,15R-trihydroxy-eicosa-7E,9E,11Z,13E-tetraenoic acid

PGE2 :

prostaglandin E2, 9-oxo-11a,15S-dihydroxy-prosta-5Z,13E-dien-1-oic acid

Rv:

resolvin

RvE1:

resolvin E1 (5S,12R,18R-trihydroxy-eicosa-6Z,8E,10E,14Z,16E-pentaenoic acid)

References

  1. Kumar, V., A.K. Abbas, N. Fausto, S.L. Robbins, and R.S. Cotran. 2005. Robbins and Cotran pathologic basis of disease, 7th ed. Philadelphia: Elsevier Saunders.

    Google Scholar 

  2. Serhan, C.N., S.D. Brain, C.D. Buckley, D.W. Gilroy, C. Haslett, L.A. O’Neill, M. Perretti, A.G. Rossi, and J.L. Wallace. 2007. Resolution of inflammation: State of the art, definitions and terms. The FASEB Journal 21: 325–332.

    Article  PubMed  CAS  Google Scholar 

  3. Perry, V.H., C. Cunningham, and C. Holmes. 2007. Systemic infections and inflammation affect chronic neurodegeneration. Nature Reviews. Immunology 7: 161–167.

    Article  PubMed  CAS  Google Scholar 

  4. Hansson, G.K., and P. Libby. 2006. The immune response in atherosclerosis: A double-edged sword. Nature Reviews. Immunology 6: 508–519.

    Article  PubMed  CAS  Google Scholar 

  5. Laffey, J.G., J.F. Boylan, and D.C. Cheng. 2002. The systemic inflammatory response to cardiac surgery: Implications for the anesthesiologist. Anesthesiology 97: 215–252.

    Article  PubMed  CAS  Google Scholar 

  6. Gelman, S. 1995. The pathophysiology of aortic cross-clamping and unclamping. Anesthesiology 82: 1026–1060.

    Article  PubMed  CAS  Google Scholar 

  7. Serhan, C.N. 2007. Resolution phase of inflammation: Novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annual Review of Immunology 25: 101–137.

    Article  PubMed  CAS  Google Scholar 

  8. Samuelsson, B., S.E. Dahlen, J.A. Lindgren, C.A. Rouzer, and C.N. Serhan. 1987. Leukotrienes and lipoxins: Structures, biosynthesis, and biological effects. Science 237: 1171–1176.

    Article  PubMed  CAS  Google Scholar 

  9. Yedgar, S., M. Krimsky, Y. Cohen, and R.J. Flower. 2007. Treatment of inflammatory diseases by selective eicosanoid inhibition: A double-edged sword? Trends in Pharmacological Sciences 28: 459–464.

    Article  PubMed  CAS  Google Scholar 

  10. Levy, B.D., C.B. Clish, B. Schmidt, K. Gronert, and C.N. Serhan. 2001. Lipid mediator class switching during acute inflammation: Signals in resolution. Nature Immunology 2: 612–619.

    Article  PubMed  CAS  Google Scholar 

  11. Serhan, C.N., S. Hong, K. Gronert, S.P. Colgan, P.R. Devchand, G. Mirick, and R.L. Moussignac. 2002. Resolvins: A family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. The Journal of Experimental Medicine 196: 1025–1037.

    Article  PubMed  CAS  Google Scholar 

  12. Serhan, C.N., C.B. Clish, J. Brannon, S.P. Colgan, N. Chiang, and K. Gronert. 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. The Journal of Experimental Medicine 192: 1197–1204.

    Article  PubMed  CAS  Google Scholar 

  13. Serhan, C.N., R. Yang, K. Martinod, K. Kasuga, P.S. Pillai, T.F. Porter, S.F. Oh, and M. Spite. 2009. Maresins: Novel macrophage mediators with potent antiinflammatory and proresolving actions. The Journal of Experimental Medicine 206: 15–23.

    Article  PubMed  CAS  Google Scholar 

  14. Serhan, C.N., N. Chiang, and T.E. Van Dyke. 2008. Resolving inflammation: Dual anti-inflammatory and pro-resolution lipid mediators. Nature Reviews. Immunology 8: 349–361.

    Article  PubMed  CAS  Google Scholar 

  15. Schwab, J.M., N. Chiang, M. Arita, and C.N. Serhan. 2007. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 447: 869–874.

    Article  PubMed  CAS  Google Scholar 

  16. Claria, J., and C.N. Serhan. 1995. Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions. Proceedings of the National Academy of Sciences of the United States of America 92: 9475–9479.

    Article  PubMed  CAS  Google Scholar 

  17. Yang, R., Chiang, N., Oh, S. F., and Serhan, C. N. 2011. Metabolomics-lipidomics of eicosanoids and docosanoids generated by phagocytes. Curr. Protoc. Immunol. (in press).

  18. Samuelsson, B. 1982. From studies of biochemical mechanisms to novel biological mediators: prostaglandin endoperoxides, thromboxanes and leukotrienes. In Les Prix Nobel: Nobel Prizes, Presentations, Biographies and Lectures pp. 153–74, Almqvist & Wiksell, Stockholm

  19. Nathan, C., and A. Ding. 2010. Nonresolving inflammation. Cell 140: 871–882.

    Article  PubMed  CAS  Google Scholar 

  20. Clouse, W.D., J.W. Hallett Jr., H.V. Schaff, M.M. Gayari, D.M. Ilstrup, and L.J. Melton 3rd. 1998. Improved prognosis of thoracic aortic aneurysms: A population-based study. JAMA 280: 1926–1929.

    Article  PubMed  CAS  Google Scholar 

  21. Lederle, F.A., S.E. Wilson, G.R. Johnson, D.B. Reinke, F.N. Littooy, C.W. Acher, D.J. Ballard, L.M. Messina, I.L. Gordon, E.P. Chute, W.C. Krupski, S.J. Busuttil, G.W. Barone, S. Sparks, L.M. Graham, J.H. Rapp, M.S. Makaroun, G.L. Moneta, R.A. Cambria, R.G. Makhoul, D. Eton, H.J. Ansel, J.A. Freischlag, and D. Bandyk. 2002. Immediate repair compared with surveillance of small abdominal aortic aneurysms. The New England Journal of Medicine 346: 1437–1444.

    Article  PubMed  Google Scholar 

  22. Pronovost, P.J., M.W. Jenckes, T. Dorman, E. Garrett, M.J. Breslow, B.A. Rosenfeld, P.A. Lipsett, and E. Bass. 1999. Organizational characteristics of intensive care units related to outcomes of abdominal aortic surgery. JAMA 281: 1310–1317.

    Article  PubMed  CAS  Google Scholar 

  23. Ernst, C.B. 1993. Abdominal aortic aneurysm. The New England Journal of Medicine 328: 1167–1172.

    Article  PubMed  CAS  Google Scholar 

  24. Lamblin, N., P. Ratajczak, D. Hot, E. Dubois, M. Chwastyniak, O. Beseme, H. Drobecq, Y. Lemoine, M. Koussa, P. Amouyel, and F. Pinet. 2010. Profile of macrophages in human abdominal aortic aneurysms: a transcriptomic, proteomic, and antibody protein array study. J Proteome Res 9(7): 3720–3729.

    Article  PubMed  CAS  Google Scholar 

  25. Abdul-Hussien, H., R. Hanemaaijer, R. Kleemann, B.F. Verhaaren, J.H. van Bockel, and J.H. Lindeman. 2010. The pathophysiology of abdominal aortic aneurysm growth: Corresponding and discordant inflammatory and proteolytic processes in abdominal aortic and popliteal artery aneurysms. Journal of Vascular Surgery 51: 1479–1487.

    Article  PubMed  Google Scholar 

  26. Brand, J.M., H. Kirchner, C. Poppe, and P. Schmucker. 1997. The effects of general anesthesia on human peripheral immune cell distribution and cytokine production. Clinical Immunology and Immunopathology 83: 190–194.

    Article  PubMed  CAS  Google Scholar 

  27. Barry, M.C., C. Kelly, P. Burke, S. Sheehan, H.P. Redmond, and D. Bouchier-Hayes. 1997. Immunological and physiological responses to aortic surgery: Effect of reperfusion on neutrophil and monocyte activation and pulmonary function. The British Journal of Surgery 84: 513–519.

    Article  PubMed  CAS  Google Scholar 

  28. Mayers, I., and D. Johnson. 1998. The nonspecific inflammatory response to injury. Canadian Journal of Anaesthesia 45: 871–879.

    Article  PubMed  CAS  Google Scholar 

  29. Franke, A., W. Lante, V. Fackeldey, H.P. Becker, C. Thode, W.D. Kuhlmann, and A. Markewitz. 2002. Proinflammatory and antiinflammatory cytokines after cardiac operation: Different cellular sources at different times. The Annals of Thoracic Surgery 74: 363–370. discussion 70-1.

    Article  PubMed  Google Scholar 

  30. Norwood, M.G., T. Horsburgh, M.J. Bown, and R.D. Sayers. 2005. Neutrophil activation occurs in the lower-limbs of patients undergoing elective repair of abdominal aortic aneurysm. European Journal of Vascular and Endovascular Surgery 29: 390–394.

    PubMed  CAS  Google Scholar 

  31. Wu, S.-H., P.-Y. Liao, P.-L. Yin, Y.-M. Zhang, and L. Dong. 2009. Elevated expressions of 15-lipoxygenase and lipoxin A4 in children with acute poststreptococcal glomerulonephritis. The American Journal of Pathology 174: 115–122.

    Article  PubMed  CAS  Google Scholar 

  32. Wu, S.-H., P.-Y. Liao, P.-L. Yin, Y.-M. Zhang, and L. Dong. 2009. Inverse temporal changes of lipoxin A4 and leukotrienes in children with Henoch-Schönlein purpura. Prostaglandins Leukotrienes and Essential Fatty Acids 80: 177–183.

    Article  CAS  Google Scholar 

  33. Morris, T., M. Stables, P. Colville-Nash, J. Newson, G. Bellingan, P.M. de Souza, and D.W. Gilroy. 2010. Dichotomy in duration and severity of acute inflammatory responses in humans arising from differentially expressed proresolution pathways. Proceedings of the National Academy of Sciences of the United States of America 107: 8842–8847.

    Article  PubMed  CAS  Google Scholar 

  34. Morris, T., M. Stables, A. Hobbs, P. de Souza, P. Colville-Nash, T. Warner, J. Newson, G. Bellingan, and D.W. Gilroy. 2009. Effects of low-dose aspirin on acute inflammatory responses in humans. Journal of Immunology 183: 2089–2096.

    Article  CAS  Google Scholar 

  35. Terrando, N., C. Monaco, D. Ma, B.M. Foxwell, M. Feldmann, and M. Maze. 2010. Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline. Proceedings of the National Academy of Sciences of the United States of America 107: 20518–22.

    Article  PubMed  CAS  Google Scholar 

  36. Ho, K.J., M. Spite, C.D. Owens, H. Lancero, A.H. Kroemer, R. Pande, M.A. Creager, C.N. Serhan, and M.S. Conte. 2010. Aspirin-triggered lipoxin and resolvin E1 modulate vascular smooth muscle phenotype and correlate with peripheral atherosclerosis. The American Journal of Pathology 177: 2116–2123.

    Article  PubMed  CAS  Google Scholar 

  37. Zhang, F., H. Yang, Z. Pan, Z. Wang, J.M. Wolosin, P. Gjorstrup, and P.S. Reinach. 2010. Dependence of resolvin-induced increases in corneal epithelial cell migration on EGF receptor transactivation. Investigative Ophthalmology and Visual Science 51: 5601–5609.

    Article  PubMed  Google Scholar 

  38. Baker, N., S.J. O’Meara, M. Scannell, P. Maderna, and C. Godson. 2009. Lipoxin A4: Anti-inflammatory and anti-angiogenic impact on endothelial cells. Journal of Immunology 182: 3819–3826.

    Article  CAS  Google Scholar 

  39. Maldonado-Pèriz, D., E. Golightly, F.C. Denison, H.N. Jabbour, and J.E. Norman. 2010. A role for lipoxin A4 as anti-inflammatory and proresolution mediator in human parturition. FASEB J. doi:10.1096/fj.10-170340.

    Google Scholar 

  40. Birnbaum, Y., Y. Ye, Y. Lin, S.Y. Freeberg, M.-H. Huang, J.R. Perez-Polo, and B.F. Uretsky. 2007. Aspirin augments 15-epi-lipoxin A4 production by lipopolysaccharide, but blocks the pioglitazone and atorvastatin induction of 15-epi-lipoxin A4 in the rat heart. Prostaglandins & Other Lipid Mediators 83: 89–98.

    Article  CAS  Google Scholar 

  41. Planagumà, A., M.A. Pfeffer, G. Rubin, R. Croze, M. Uddin, C.N. Serhan, and B.D. Levy. 2010. Lovastatin decreases acute mucosal inflammation via 15-epi-lipoxin A4. Mucosal Immunol 3: 270–279.

    Article  PubMed  Google Scholar 

  42. Di Gennaro, A., D. Wågsäter, M.I. Mäyränpää, A. Gabrielsen, J. Swedenborg, A. Hamsten, B. Samuelsson, P. Eriksson, and J.Z. Haeggström. 2010. Increased expression of leukotriene C4 synthase and predominant formation of cysteinyl-leukotrienes in human abdominal aortic aneurysm. Proceedings of the National Academy of Sciences of the United States of America 107: 21093–21097.

    Article  PubMed  Google Scholar 

  43. Galle, C., V. De Maertelaer, S. Motte, L. Zhou, P. Stordeur, J.P. Delville, R. Li, J. Ferreira, M. Goldman, P. Capel, J.C. Wautrecht, O. Pradier, and J.P. Dereume. 2000. Early inflammatory response after elective abdominal aortic aneurysm repair: A comparison between endovascular procedure and conventional surgery. Journal of Vascular Surgery 32: 234–246.

    Article  PubMed  CAS  Google Scholar 

  44. Chiang, N., S. Hurwitz, P.M. Ridker, and C.N. Serhan. 2006. Aspirin has a gender-dependent impact on antiinflammatory 15-epi-lipoxin A4 formation: A randomized human trial. Arteriosclerosis, Thrombosis, and Vascular Biology 26: e14–e17.

    Article  PubMed  CAS  Google Scholar 

  45. Chiang, N., E.A. Bermudez, P.M. Ridker, S. Hurwitz, and C.N. Serhan. 2004. Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial. Proceedings of the National Academy of Sciences of the United States of America 101: 15178–15183.

    Article  PubMed  CAS  Google Scholar 

  46. Dona, M., G. Fredman, J.M. Schwab, N. Chiang, M. Arita, A. Goodarzi, G. Cheng, U.H. von Andrian, and C.N. Serhan. 2008. Resolvin E1, an EPA-derived mediator in whole blood, selectively counterregulates leukocytes and platelets. Blood 112: 848–855.

    Article  PubMed  CAS  Google Scholar 

  47. Vane, J. R. 1982. Adventures and excursions in bioassay: the stepping stones to prostacyclin. In Les Prix Nobel: Nobel Prizes, Presentations, Biographies and Lectures pp. 181–206, Almqvist & Wiksell, Stockholm

  48. Massagué, J. 1990. The transforming growth factor-beta family. Annual Review of Cell Biology 6: 597–641.

    Article  PubMed  Google Scholar 

  49. Ferrara, N. 2004. Vascular endothelial growth factor: Basic science and clinical progress. Endocrine Reviews 25: 581–611.

    Article  PubMed  CAS  Google Scholar 

  50. Serbina, N., T. Jia, T. Hohl, and E. Pamer. 2008. Monocyte-mediated defense against microbial pathogens. Annual Review of Immunology 26: 421–452.

    Article  PubMed  CAS  Google Scholar 

  51. Andre, P. 2004. P-selectin in haemostasis. British Journal Haematology 126: 298–306.

    Article  CAS  Google Scholar 

  52. DiStasi, M.R., and K. Ley. 2009. Opening the flood-gates: How neutrophil-endothelial interactions regulate permeability. Trends in Immunology 30: 547–556.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Mary H. Small for skillful manuscript preparation. Some additional reagents were purchased with support from the Anesthesia Research and Education Foundation.

Grant support

The authors acknowledge the support of National Institutes of Health grants R37 GM 38765 (CNS), R01 HL75771 (MSC, CDO) and K23 HL092163 (CDO). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIGMS or the NIH.

Conflict of Interest

The results reported herein were obtained by the authors in part prior to licensing of patents for clinical development of the resolvins. Charles N. Serhan is an inventor on patents assigned to Brigham and Women’s Hospital and Partners HealthCare covering the composition of matter, uses, and clinical development of anti-inflammatory and pro-resolving lipid mediators. These are licensed for clinical development. Also, CNS retains founder stock in Resolvyx Pharmaceuticals. All other authors have no conflict of interest.

Author Contributions

S.L., S.G., C.N.S. planned research. P.S.P., T.P. performed research, analyzed data. C.N.S. analyzed data. S.L., S.G., J.M.K., M.S.C. recruited patients, obtained informed consent and some samples. P.S.P., S.L., C.D.O., S.G. collected patient samples. P.S.P., S.G., C.N.S. contributed to manuscript preparation. C.N.S., S.G. designed overall research.

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Authors and Affiliations

  1. Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, 02115, USA

    Padmini S. Pillai, Timothy F. Porter, Charles N. Serhan & Simon Gelman

  2. Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, 02115, USA

    Stanley Leeson & Simon Gelman

  3. Division of Vascular and Endovascular Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, 02115, USA

    Christopher D. Owens, Ji Min Kim & Michael S. Conte

  4. Director, Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Harvard Institutes of Medicine, Room 829, 77 Avenue Louis Pasteur, Boston, MA, 02115, USA

    Charles N. Serhan

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  1. Padmini S. Pillai
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  2. Stanley Leeson
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  7. Charles N. Serhan
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Corresponding author

Correspondence to Charles N. Serhan.

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Author Contributions

PSP, SL, SG, and CNS designed the research. PSP and TP performed research and analyzed data. CNS analyzed data. SL, SG, JMK, and MSC recruited patients, and obtained informed consent and samples. PSP, SL, CDO, and SG collected patient samples. PSP, SL, SG, and CNS wrote the paper. CNS and SG designed overall research.

Grant support: The authors acknowledge the support of National Institutes of Health grants GM 38765 (CNS) and HL75771 (MSC, CDO). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIGMS or the NIH.

An erratum to this article can be found at http://dx.doi.org/10.1007/s10753-011-9312-x.

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Pillai, P.S., Leeson, S., Porter, T.F. et al. Chemical Mediators of Inflammation and Resolution in Post-Operative Abdominal Aortic Aneurysm Patients. Inflammation 35, 98–113 (2012). https://doi.org/10.1007/s10753-011-9294-8

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