PHAGOCYTE RESOLVING METABOLISM

Summary

Principal Investigator: C N Serhan
Abstract: Inflammation is usually self-limited and when "uncontrolled" leads to tissue damage and organ dysfunction. The resolution phase is a series of essential cellular processes that lead from acute inflammation to homeostasis, namely catabasis that has been widely believed to be a passive process 1, 2, 3. In this laboratory, new evidence has emerged indicating that resolution is an active process with the identification of novel specialized lipid-derived mediators (LM) we termed resolvins and docosatrienes (protectins) that limit key events in inflammation and tissue injury. It is now clear that the balance of novel LM within resolution is critical. The focus of this project is the systematic elucidation of further metabolic (likely inactivation) routes within resolution using mediator-lipidomics and in vivo models. In work in progress, we found that resolvins, namely, RvE1 and the docosatriene 10,17-DT, actively counter-regulate murine and human neutrophils (PMN). We will focus on the pathways that metabolically transform these LM and test the hypothesis that: Resolution requires timely metabolic breakdown of pro-resolving lipid mediators. Resolvins and docosatrienes are endogenous anti-inflammatory signals that temporally counter-regulate proinflammatory circuits and govern PMN traffic toward resolution. Local inactivation of these novel endogenous antiinflammatory mediators is essential for catabasis. To this end, four specific aims are proposed, which include: Aim 1. Establishing the structures and pathways of Rv and DT-derived metabolites in resolution in vivo and human PMN;2. Identify the resolution interval(s) when Rv &DT transformation pathways are operative;3. Determine the actions of the new RvE1 and 10,17-DT-derived metabolites with human PMN;4. Renal transplant rejection and protection studies. Long-term goals for this project are 2-fold: a) to elucidate the inactivation pathways for LM involved in resolution-inflammation and b) to provide biochemical map(s) of these essential resolution pathways to clinicians, knowledge of which can improve current treatments.
Funding Period: 2005-09-15 - 2010-07-31
more information: NIH RePORT

Top Publications

  1. pmc Docosahexaenoic acid metabolome in neural tumors: identification of cytotoxic intermediates
    Helena Gleissman
    Childhood Cancer Research Unit, Q6 05, Department of Woman and Child Health, Karolinska Institutet, Astrid Lindgren Children s Hospital, S 171 76 Stockholm, Sweden
    FASEB J 24:906-15. 2010
  2. pmc Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions
    Zhen Zhong Xu
    Department of Anesthesiology, Sensory Plasticity Laboratory, Pain Research Center, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts, USA
    Nat Med 16:592-7, 1p following 597. 2010
  3. ncbi Profiling in resolving inflammatory exudates identifies novel anti-inflammatory and pro-resolving mediators and signals for termination
    L V Norling
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    J Intern Med 268:15-24. 2010
  4. pmc Specialized pro-resolving lipid mediators in the inflammatory response: An update
    Gerard Bannenberg
    Department of Plant Molecular Genetics, Centro Nacional de Biotecnologia CSIC, Madrid, Spain
    Biochim Biophys Acta 1801:1260-73. 2010
  5. pmc Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not?
    Charles N Serhan
    Director, Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women s Hospital, 77 Avenue Louis Pasteur, HIM 8, Boston, MA 02115, USA
    Am J Pathol 177:1576-91. 2010
  6. pmc The endogenous pro-resolving mediators lipoxin A4 and resolvin E1 preserve organ function in allograft rejection
    Bruce D Levy
    Pulmonary and Critical Care Medicine, Department of Internal Medicine, Brigham and Women s Hospital, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
    Prostaglandins Leukot Essent Fatty Acids 84:43-50. 2011
  7. pmc MicroRNAs in resolution of acute inflammation: identification of novel resolvin D1-miRNA circuits
    Antonio Recchiuti
    Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women s Hospital and Harvard Medical School, 77 Ave Louis Pasteur, Harvard Institutes of Medicine 829, Boston, MA 02115, USA
    FASEB J 25:544-60. 2011
  8. pmc Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins
    Matthew Spite
    Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Circ Res 107:1170-84. 2010
  9. pmc Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation
    Sungwhan F Oh
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115 5727, USA
    J Clin Invest 121:569-81. 2011
  10. pmc Novel anti-inflammatory--pro-resolving mediators and their receptors
    Charles N Serhan
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Perioperative and Pain Medicine, Harvard Institute of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
    Curr Top Med Chem 11:629-47. 2011

Scientific Experts

  • C N Serhan
  • B D Levy
  • Nina M Agabian
  • Helena Gleissman
  • Yan Lu
  • Gerard Bannenberg
  • JEREMY DUFFIELD
  • Yee Ping Sun
  • Makoto Arita
  • Sungwhan F Oh
  • Antonio Recchiuti
  • Rong Yang
  • Nan Chiang
  • Nicos A Petasis
  • Song Hong
  • Amiram Ariel
  • Padmini S Pillai
  • Gabrielle Fredman
  • Jan M Schwab
  • Matthew Spite
  • Zhen Zhong Xu
  • L V Norling
  • M Spite
  • Maria Dona
  • Raewyn C Poulsen
  • Mojgan Masoodi
  • Eric J Haas-Stapleton
  • Siva Elangovan
  • Jasim Uddin
  • Wen Liu
  • Sriram Krishnamoorthy
  • Temugin Berta
  • Tong Liu
  • Ling Zhang
  • Jong Yeon Park
  • Ru Rong Ji
  • Raquel Keledjian
  • Min Zhu
  • S Srivastava
  • A Bhatnagar
  • T F Porter
  • L Summers
  • Eric Tjonahen
  • Ahmad Goodarzi
  • Katherine H Gotlinger
  • Anna Nicolaou
  • Timothy F Porter
  • Guiying Cheng
  • Adnan A Mir
  • Marlena C Kruger
  • Ulrich H von Andrian
  • Silvio Favoreto
  • Katherine Gotlinger
  • Eric Campbell
  • Sean P Colgan
  • Taisuke Ohira
  • Santosh Nigam
  • Richard J Kulmacz
  • Thomas E Van Dyke
  • Tomomichi Chonan
  • Dazhe Cao
  • Andrew D Luster
  • Alpdogan Kantarci

Detail Information

Publications35

  1. pmc Docosahexaenoic acid metabolome in neural tumors: identification of cytotoxic intermediates
    Helena Gleissman
    Childhood Cancer Research Unit, Q6 05, Department of Woman and Child Health, Karolinska Institutet, Astrid Lindgren Children s Hospital, S 171 76 Stockholm, Sweden
    FASEB J 24:906-15. 2010
    ..Gleissman, H., Yang, R., Martinod, K., Lindskog, M., Serhan, C. N., Johnsen, J. I., Kogner, P. Docosahexaenoic acid metabolome in neural tumors: identification of cytotoxic intermediates...
  2. pmc Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions
    Zhen Zhong Xu
    Department of Anesthesiology, Sensory Plasticity Laboratory, Pain Research Center, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts, USA
    Nat Med 16:592-7, 1p following 597. 2010
    ..Given the potency of resolvins and the well-known side effects of opioids and COX inhibitors, resolvins may represent new analgesics for treating inflammatory pain...
  3. ncbi Profiling in resolving inflammatory exudates identifies novel anti-inflammatory and pro-resolving mediators and signals for termination
    L V Norling
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    J Intern Med 268:15-24. 2010
    ..Together these findings indicate that defective mechanisms and pathways in resolution may underlie our current appreciation of the inflammatory phenotype(s) that characterize some prevalent human diseases...
  4. pmc Specialized pro-resolving lipid mediators in the inflammatory response: An update
    Gerard Bannenberg
    Department of Plant Molecular Genetics, Centro Nacional de Biotecnologia CSIC, Madrid, Spain
    Biochim Biophys Acta 1801:1260-73. 2010
    ....
  5. pmc Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not?
    Charles N Serhan
    Director, Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women s Hospital, 77 Avenue Louis Pasteur, HIM 8, Boston, MA 02115, USA
    Am J Pathol 177:1576-91. 2010
    ....
  6. pmc The endogenous pro-resolving mediators lipoxin A4 and resolvin E1 preserve organ function in allograft rejection
    Bruce D Levy
    Pulmonary and Critical Care Medicine, Department of Internal Medicine, Brigham and Women s Hospital, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
    Prostaglandins Leukot Essent Fatty Acids 84:43-50. 2011
    ..0 days with RvE1 and 37.5 days with a LXA(4) analog). Together, these results highlight the potential for pro-resolving mediators in prolonging survival of solid organ transplants...
  7. pmc MicroRNAs in resolution of acute inflammation: identification of novel resolvin D1-miRNA circuits
    Antonio Recchiuti
    Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women s Hospital and Harvard Medical School, 77 Ave Louis Pasteur, Harvard Institutes of Medicine 829, Boston, MA 02115, USA
    FASEB J 25:544-60. 2011
    ..Taken together, these results indicate that resolvin-regulated specific miRNAs target genes involved in resolution and establish a novel resolution circuit involving RvD1 receptor-dependent regulation of specific miRNAs...
  8. pmc Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins
    Matthew Spite
    Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Circ Res 107:1170-84. 2010
    ..Here, we overview and update the biosynthesis and actions of proresolving lipid mediators, highlighting their diverse protective roles relevant to vascular systems and their relation to aspirin and statin therapies...
  9. pmc Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation
    Sungwhan F Oh
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115 5727, USA
    J Clin Invest 121:569-81. 2011
    ....
  10. pmc Novel anti-inflammatory--pro-resolving mediators and their receptors
    Charles N Serhan
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Perioperative and Pain Medicine, Harvard Institute of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
    Curr Top Med Chem 11:629-47. 2011
    ..This approach may offer new targets suitable for drug design for treating inflammation related diseases, for the new terrain of resolution pharmacology...
  11. ncbi Controlling the resolution of acute inflammation: a new genus of dual anti-inflammatory and proresolving mediators
    Charles N Serhan
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women s Hospital, Harvard Medical School, 20 Shattuck Street, Boston, MA 02115, USA
    J Periodontol 79:1520-6. 2008
    ..The new families of endogenous proresolving and anti-inflammatory agonists constitute a new genus of anti-inflammatories...
  12. pmc Systems approach with inflammatory exudates uncovers novel anti-inflammatory and pro-resolving mediators
    Charles N Serhan
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women s Hospital and Harvard Medical School, Thorn 724, MA 02115, USA
    Prostaglandins Leukot Essent Fatty Acids 79:157-63. 2008
    ....
  13. pmc Resolvin D1 controls inflammation initiated by glutathione-lipid conjugates formed during oxidative stress
    M Spite
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Br J Pharmacol 158:1062-73. 2009
    ..Here, we sought to determine whether GS-HNE is a mediator of oxidative stress-initiated inflammation and if its actions can be regulated by the anti-inflammatory and pro-resolving lipid mediator, resolvin D1 (RvD1)...
  14. ncbi Systems approach to inflammation resolution: identification of novel anti-inflammatory and pro-resolving mediators
    C N Serhan
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    J Thromb Haemost 7:44-8. 2009
    ..Moreover, identification of functional SPM biosynthesized during inflammation-resolution indicates that resolution is an active process...
  15. pmc Anti-inflammatory and pro-resolving properties of benzo-lipoxin A(4) analogs
    Yee Ping Sun
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Prostaglandins Leukot Essent Fatty Acids 81:357-66. 2009
    ..These benzo-LXA(4) analogs are promising tools for new therapeutic approaches as well as assessing endogenous mechanisms in anti-inflammation and resolution...
  16. pmc Resolvin E1, an EPA-derived mediator in whole blood, selectively counterregulates leukocytes and platelets
    Maria Dona
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Blood 112:848-55. 2008
    ..Moreover, the results demonstrate novel agonist-specific antiplatelet actions of RvE1 that are potent and may underlie some of the beneficial actions of EPA in humans...
  17. pmc Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators
    Charles N Serhan
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    Nat Rev Immunol 8:349-61. 2008
    ..These mediators have anti-inflammatory and pro-resolution properties, thereby protecting organs from collateral damage, stimulating the clearance of inflammatory debris and promoting mucosal antimicrobial defence...
  18. ncbi Identification of inflammatory and proresolving lipid mediators in bone marrow and their lipidomic profiles with ovariectomy and omega-3 intake
    Raewyn C Poulsen
    Institute of Food Nutrition and Human Health, Massey University, Palmerston North, New Zealand
    Am J Hematol 83:437-45. 2008
    ....
  19. ncbi Metabolic inactivation of resolvin E1 and stabilization of its anti-inflammatory actions
    Makoto Arita
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women s Hospital, Harvard School of Dental Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biol Chem 281:22847-54. 2006
    ..Moreover, the designed RvE1 analog, which resisted further metabolism/inactivation, could be a useful tool to evaluate the actions of RvE1 in complex disease models...
  20. ncbi Divergent cyclooxygenase responses to fatty acid structure and peroxide level in fish and mammalian prostaglandin H synthases
    Wen Liu
    Department of Internal Medicine, University of Texas Health Science Center at Houston, 6431 Fannin St, Houston, Texas 77030, USA
    FASEB J 20:1097-108. 2006
    ..The divergence in cyclooxygenase characteristics between the trout and mammalian PGHS proteins may reflect accomodations to differences among vertebrates in tissue lipid composition and general redox state...
  21. ncbi Novel chemical mediators in the resolution of inflammation: resolvins and protectins
    Charles N Serhan
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women s Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
    Anesthesiol Clin 24:341-64. 2006
    ..In view of the essential roles of DHA and EPA in human biology and medicine uncovered to date, the physiologic relevance of the resolvins and protectins is likely to extend beyond our current appreciation...
  22. pmc Apoptotic neutrophils and T cells sequester chemokines during immune response resolution through modulation of CCR5 expression
    Amiram Ariel
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    Nat Immunol 7:1209-16. 2006
    ..Our results suggest that CCR5+ apoptotic leukocytes act as 'terminators' of chemokine signaling during the resolution of inflammation...
  23. ncbi Resolvin D series and protectin D1 mitigate acute kidney injury
    Jeremy S Duffield
    Renal Division, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    J Immunol 177:5902-11. 2006
    ..These data may also have therapeutic implications for potentiation of recovery from acute kidney injury...
  24. ncbi Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways
    Charles N Serhan
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Annu Rev Immunol 25:101-37. 2007
    ..Given the potent actions of lipoxins, resolvins, and protectins in models of human disease, deficiencies in resolution pathways may contribute to many diseases and offer exciting new potential for therapeutic control via resolution...
  25. ncbi Resolvin D1 and its aspirin-triggered 17R epimer. Stereochemical assignments, anti-inflammatory properties, and enzymatic inactivation
    Yee Ping Sun
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biol Chem 282:9323-34. 2007
    ..These results may contribute to the beneficial actions of aspirin and omega-3 fish oils in humans...
  26. ncbi Resolvins and protectins in the termination program of acute inflammation
    Amiram Ariel
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women s Hospital, Boston, MA 02115, USA
    Trends Immunol 28:176-83. 2007
    ..Here, we review recent advances on the biosynthesis and actions of these novel anti-inflammatory and proresolving mediators...
  27. ncbi Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation
    Makoto Arita
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women s Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
    J Immunol 178:3912-7. 2007
    ..g., ChemR23-mediated counterregulatory actions) to mediate the resolution of inflammation...
  28. pmc Resolvin E1 and protectin D1 activate inflammation-resolution programmes
    Jan M Schwab
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    Nature 447:869-74. 2007
    ..Together, these results identify new active components for postexudate resolution traffic, and demonstrate that RvE1 and PD1 are potent agonists for resolution of inflamed tissues...
  29. pmc Endogenous pro-resolving and anti-inflammatory lipid mediators: a new pharmacologic genus
    C N Serhan
    Department of Anesthesiology, Center for Experimental Therapeutics and Reperfusion Injury, Perioperative and Pain Medicine, Brigham and Women s Hospital, Boston, MA, USA
    Br J Pharmacol 153:S200-15. 2008
    ..These may be useful in the design of new therapeutics and treatments for diseases with the underlying trait of uncontrolled inflammation and redox organ stress...
  30. pmc Simultaneous lipidomic analysis of three families of bioactive lipid mediators leukotrienes, resolvins, protectins and related hydroxy-fatty acids by liquid chromatography/electrospray ionisation tandem mass spectrometry
    Mojgan Masoodi
    School of Pharmacy, University of Bradford, Richmond Road, Bradford, UK
    Rapid Commun Mass Spectrom 22:75-83. 2008
    ....
  31. pmc Candida albicans modulates host defense by biosynthesizing the pro-resolving mediator resolvin E1
    Eric J Haas-Stapleton
    Department of Cell and Tissue Biology, University of California at San Francisco, San Francisco, California, United States of America
    PLoS ONE 2:e1316. 2007
    ..These results reveal an inter-species chemical signaling system that modulates host immune functions and may play a role in balancing host carriage of commensal and pathogenic C. albicans...
  32. pmc Anti-inflammatory and proresolving lipid mediators
    Charles N Serhan
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Annu Rev Pathol 3:279-312. 2008
    ..Here, we review the recent advances in our understanding of the biosynthesis and stereospecific actions of these new proresolving mediators, which have also proven to be organ protective and antifibrotic...
  33. ncbi Resolvin E1 metabolome in local inactivation during inflammation-resolution
    Song Hong
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    J Immunol 180:3512-9. 2008
    ..e., RvE1, to permit the coordinated return to homeostasis. Moreover, the RvE1 metabolome may serve as a biomarker of these processes...
  34. ncbi Lipid mediator informatics and proteomics in inflammation resolution
    Yan Lu
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    ScientificWorldJournal 6:589-614. 2006
    ....