Resolving Inflammation: A Revolutionary Therapeutic in Progress and How It Came to Be
Posted September 26, 2007
Inflammation is a protective response to injury and infection. Resolution—the timely end to this response—is equally fundamental to health because it prevents damage to surrounding healthy tissues. When resolution is dysregulated, a number of chronic inflammatory diseases can occur, and it can be an invisible first step in various pathologies.
This eBriefing covers a February 27, 2007, meeting of the Academy's Biochemical Pharmacology Discussion Group, and provides an in-depth overview of the field. Five scientists in the forefront of research into resolution of inflammation discussed their discoveries and insights. Speakers focused on important components of resolution—particularly lipid mediators such as lipoxins, resolvins, and neuroprotectins, which serve as stop signals to the inflammatory process—and looked at ways to amplify the body's endogenous ability to resolve inflammation and restore a healthy equilibrium to tissue. More specifically, they considered topics including the role of lipoxin in cystic fibrosis and in the host inflammatory response to Toxoplasma gondii infection; the protective role of adenosine against inflammation; the return of lymphocyte populations during resolution; the fundamental role played by omega-3 fatty acids in resolution; and early signs of the potential viability of lipoxin A4 as a therapeutic.
Use the tabs above to find a meeting report and multimedia from this event.
Resolvins and Protectins: Novel Lipid Mediators in Resolution of Inflammation
Bannenberg GL, Chiang N, Ariel A, et al. 2005. Molecular circuits of resolution: formation and actions of resolvins and protectins. J. Immunol. 174: 4345-4355. Full Text
Serhan CN, ed. 2005. Special Issue on Lipoxins and Aspirin-Triggered Lipoxins. Prostaglandins Leukotrienes Essent. Fat. Acids 73: 139-322.
Serhan CN, Brain SD, Buckley CD, et al. 2007. Resolution of inflammation: state of the art, definitions and terms. FASEB J. 21:325-332. Full Text
Serhan CN, Clish CB, Brannon J, et al. 2000. Novel functional sets of lipid-derived mediators with anti-inflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal anti-inflammatory drugs and transcellular processing. J. Exp. Med. 192: 1197-1204. Full Text
Lipid Anti-Inflammatory Mediators and the Cystic Fibrosis Lung
Freedman SD, Blanco PG, Zaman MM, et al. 2004. Association of cystic fibrosis with abnormalities in fatty acid metabolism. N. Engl. J. Med. 350: 560-569.
Karp CL, Flick LM, Yang R, et al. 2005. Cystic fibrosis and lipoxins. Prostaglandins Leukot. Essent. Fatty Acids 73: 263-270.
Karp CL, Flick LM, Park KW, et al. 2004. Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway. Nat. Immunol. 5: 388-392.
Mall M, Grubb BR, Harkema JR, et al. 2004. Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice. Nat. Med. 10: 452-454.
Soluble Mediators and Cellular Players of Acute Inflammatory Resolution
Gilroy DW, Colville-Nash PR, McMaster S, et al. 2003. Inducible cyclooxygenase-derived 15-deoxy(Delta)12-14PGJ2 brings about acute inflammatory resolution in rat pleurisy by inducing neutrophil and macrophage apoptosis. FASEB J. 17: 2269-2271. Full Text
Gilroy DW, Colville-Nash PR, Willis D, et al. 1999. Inducible cyclooxygenase may have anti-inflammatory properties. Nat. Med. 5: 698-701.
Gilroy DW, Lawrence T, Perretti M, et al. 2004. Inflammatory resolution: new opportunities for drug discovery. Nat. Rev. Drug Discov. 3: 401-416.
Lawrence T, Gilroy DW. 2007. Chronic inflammation: a failure of resolution? Int. J. Exp. Pathol. 88: 85-94.
Lawrence T, Willoughby DA, Gilroy DW. 2002. Anti-inflammatory lipid mediators and insights into the resolution of inflammation. Nat. Rev. Immunol. 2: 787-795.
Rajakariar R, Lawrence T, Bystrom J, et al. 2008. Novel biphasic role for lymphocytes revealed during resolving inflammation. Blood 111: 4184-4192.
Rajakariar R, Hilliard M, Lawrence T, et al. 2007. Hematopoietic prostaglandin D2 synthase controls the onset and resolution of acute inflammation through PGD2 and 15-deoxyDelta12 14 PGJ2. Proc. Natl. Acad. Sci. USA 104: 20979-20984. Full Text
Lipoxins and Regulation of Innate Immunity to Infection
Aliberti J, Serhan C, Sher A. 2002. Parasite-induced lipoxin A4 is an endogenous regulator of IL-12 production and immunopathology in Toxoplasma gondii infection. J. Exp. Med. 196: 1253-1262. Full Text
Aliberti J, Hieny S, Reis e Sousa C, et al. 2002. Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity. Nat. Immunol. 3: 76-82.
Machado FS, Johndrow JE, Esper L, et al. 2006. Anti-inflammatory actions of lipoxin A4 and aspirin-triggered lipoxin are SOCS-2 dependent. Nat. Med. 12: 330-334.
Synthetic Lipoxin Analogs: New Therapeutic Concepts in Inflammation, Allergy, and Gastroenterology
Bannenberg G, Moussignac RL, Gronert K, et al. 2004. Lipoxins and novel 15-epi-lipoxin analogs display potent anti-inflammatory actions after oral administration. Br. J. Pharmacol. 143: 43-52. Full Text
Fiorucci S, Wallace JL, Mencarelli A, et al. 2004. A β-oxidation-resistant lipoxin A4 analog treats hapten-induced colitis by attenuating inflammation and immune dysfunction. Proc. Natl. Acad. Sci. USA 101: 15736-15741. Full Text
Gewirtz AT, Collier-Hyams LS, Young AN, et al. 2002. Lipoxin A4 analogs attenuate induction of intestinal epithelial proinflammatory gene expression and reduce the severity of dextran sodium sulfate-induced colitis. J. Immunol. 168: 5260-5267. Full Text
Guilford WJ, Parkinson JF. 2005. Second-generation β-oxidation resistant 3-oxa-lipoxin A4 analogs. Prostaglandins Leukot Essent Fatty Acids 73: 245-250.
Levy BD, Lukacs NW, Berlin AA, et al. 2007. Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism. FASEB J. (Epub ahead of print)
Parkinson JF. 2006. Lipoxin and synthetic lipoxin analogs: an overview of anti-inflammatory functions and new concepts in immunomodulation. Inflamm. Allergy Drug Targets 5: 91-106.
Schottelius AJ, Giesen C, Asadullah K, et al. 2002. An aspirin-triggered lipoxin A4 stable analog displays a unique topical anti-inflammatory profile. J. Immunol. 169: 7063-7070. Full Text
Charles N. Serhan, MD
Charles N. Serhan was recently appointed the first Endowed Distinguished Scientist at Brigham and Women's Hospital and currently serves as director of the Center for Experimental Therapeutics and Reperfusion Injury (CET&RI) at BWH. He is also the Simon Gelman Professor at Harvard Medical School.
The research undertaken in the Serhan laboratory focuses on structural elucidation of bioactive molecules. The overall mission is to identify novel pathways and cellular targets critical in regulating neutrophil-mediated inflammation and to establish the templates for physiologic small molecule-based interventions. In the CET&RI, the overarching mission is to define the molecular mechanisms underlying reperfusion injury and to identify novel therapeutic interventions that can prevent cell injury.
Christopher Karp, MD
Christopher Karp is the Gunnar Esiason/Cincinnati Bell Chair and director of the Division of Molecular Immunology. He is also a professor of pediatrics, associate director of the Graduate Program in Immunobiology and director of the Cystic Fibrosis Research Center at the University of Cincinnati.
Karp received his MD from University of North Carolina School of Medicine.The Karp lab focuses on understanding the molecular mechanisms underlying regulation and dysregulation of inflammatory responses in human infectious, autoimmune and genetic diseases.
Derek W. Gilroy, PhD
Derek Gilroy's scientific career started out at the Imperial College School of Medicine, Royal Postgraduate Medical School, University of London, where he received his MSc degree in 1993, followed by a PhD degree four years later. At present, he is Wellcome Trust Career Development Fellow at the Department of Medicine, Rayne Institute, University College of London. Here, he conducts his research activities that mainly center on the pathogenesis of chronic inflammation and auto-immunity.
In the course of his scientific career, Gilroy collected important experience abroad: He first worked as research fellow at the Institute of Biomedical Sciences in Taipeh, Taiwan, from 1998–1999. One year later, he deepened his knowledge as postdoctorate research fellow at the Vascular Biology Research Center and Division of Hematology at the University of Texas-Houston Health Science Center Medical School, USA. After his return, he continued as honorary lecturer and postdoctorate research scientist at the William Harvey Research Institute, St. Bartholomew's, and the Royal London School of Medicine and Dentistry, London.
Gilroy is particularly interested in the biochemical pathways that orchestrate the innate and adaptive immune response.
Julio Aliberti, PhD
Julio Aliberti is an assistant professor in the Divisions of Molecular Immunology and Pulmonary Medicine at Cincinnati Children’s Hospital Medical Center. Aliberti received his PhD from the Faculdade de Medicina de Ribeirão Preto (FMRP) /Universidade de São Paulo (USP), Ribeirão Preto, Brazil, in 1998. He completed postdoctoral work in the Laboratory of Parasitic Diseases at the National Institute of Allergy and Infectious Disease at the National Institutes of Health. After his postdoc, he was an assistant professor at Duke University Medical Center until his move to Cincinnati in 2006.Aliberti was the recipient of the Young Investigator Award from the Brazilian Society of Immunology in 1997 and the Fellow Award in Research Excellence from the NIH in 2000 and 2002. He was also awarded the Woods Hole Immunoparasitology Research Excellence Award in 2002.
John F. Parkinson, PhD
John Parkinson is a senior research scientist at Berlex Biosciences/Bayer Schering Pharma. He is currently responsible for research in two development stage projects for GBU-Specialized Therapeutics (chronic immune disorders) with emerging responsibilities in project management on biologics for treating hemophilia.
As a senior scientist in the immunology department of Berlex Biosciences, Parkinson led projects on inflammatory bowel disease (IBD) and established external collaborations for lipoxin efficacy in colitis models of IBD, allergic airway inflammation, acute inflammation, and autoimmunity. He was also a leader or mentor for a number of other projects, including validation of a novel immunoreceptor target in animal models of IBD, validation of a novel kinase target in CD4+ CD8+ T cells and macrophages in EAE models of multiple sclerosis, and studies on metalloenzyme inhibitors. He has given numerous invited lectures and served on the supervisory board of several institutions and conferences.
Parkinson obtained a PhD from the Department of Biochemistry at the University of Bristol, Bristol, U.K.
Sheila Sperber Haas
Sheila Sperber Haas is a freelance science and health care writer living in New York City who writes about issues ranging from molecular biology and immunology to complementary and alternative medicine. Her varied projects include Dermatology Focus, bringing the forefront of molecular investigative dermatology to a clinical readership.