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Lipid Mediators Put an End to Inflammation

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Lipid Mediators Put an End to Inflammation Biochemistry Lipid mediators put an end to inflammation is the Director of the Center for than merely antagonising inflammatory Professor Charles N Serhan mechanisms. Experimental Therapeutics and Reperfusion Injury (CETRI) in the Department of Anesthesiology, Perioperative and Pain Medicine at BWH ACTIVE RESOLUTION MEDIATORS and Harvard Medical School, Boston. In his current research he leads a Prof Serhan’s research has discovered multidisciplinary team of experts whose goal is to reveal the mechanisms potent anti-inflammatory and pro-resolving of resolution of acute inflammation and tissue injury in the body. compounds made by the body that he calls specialised pro-resolving mediators (SPM). One group of SPM comes from the lipids that that we eat – namely from essential omega-3 fatty acids. Within this group, we nflammation is an essential part of our effective treatments for diseases with can distinguish between resolvins, protectins defence against infections, cancer and aberrant on-going inflammation such as and maresins. SPMs have been measured other attacks to our body’s normal Alzheimer's disease, cardiovascular disease at bioactive levels in body fluids like human function. Ideally, any inflammatory or arthritis. tears and blood, as well as tissues like the process should be self-limiting so that brain, lymph nodes, spleen and fat. the body returns to its previous healthy For a long time, there was only a vague idea Istate. But how does this happen? Prof about the passive mechanisms that stop the Interestingly, aspirin can enhance the Serhan's research aims to elucidate the inflammatory response. This has changed in formation of specific SPM: aspirin-triggered mechanisms underlying the resolution recent years thanks to researchers like Prof resolvins and protectins have been described. of inflammation with a view to drug Serhan who have taken a closer look. As it This is a further detail for understanding the development. turns out, the resolution of inflammation is mechanism of action for this widely-used drug an active process that involves much more and may indicate possible new uses. WHAT HAPPENS AFTER THE STORM? Historically, a lot of focus of immunological research has been on the build-up of an inflammatory reaction and its effects on Prof Serhan’s research has unveiled an the body or harmful intruders like bacteria. unexpected complexity to the resolution Little emphasis had been given to the events afterwards. What happens when phase of the inflammatory response, making all the action is no longer needed? It is important to understand how immune clear that we need much more clinical reactions resolve in order to develop research into this niche of immunology Lipid mediator cass sitchin eturn to cute esoution homeostasis Infammation PGE2 D2 LTB4 L Specialised pro-resolving mediators SPM resolvin europrotection dema s onocyte protectins Lipoins esoins rotectins acrophaes series series aresins OH HO OH COOH HO OH OH COOH Activity COOH OH OH RvE1 PD1 HO L4 OH COOH OH • Beginning signals the end OH • A signals Ω HO • Active resolution RvD1 a COOH secmin min hrs days Time amiies of speciaised proresoin mediators Ideal outcome of inflammation is complete resolution noe superfamiy of endoenous ipid mediators www.researchfeatures.com 7 Biochemistry Innate immunity Cardinal signs of inflammation: Lipoxins Detail Rubor calor tumor and dolor Resolvins Vasoconstriction TA and CysLTs 2 RESEARCH OBJECTIVES Barrier reak Vasodilation PGl PGD PGE PGE hronic Organ Tissue injury 2 2 1 2 Resolvins Prof Serhan’s research focuses on the Vascular permeaility CysLTs Infammation Firosis trauma Why has research into the resolution mediators (SPM)? structural elucidation of bioactive small Chemotaxis, adhesion LTB 4 PG of inflammation only come into focus Yes, they are interested. molecules that activate the resolution of Leukotrienes Maresins recently? acute inflammation. The overall mission Resolvins I am not sure – maybe no one thought it What are the advantages of SPM-based of his lab is to identify novel mediators, Invading Wound was going to be interesting. therapies over immunosuppressants? pathways, and cellular targets involved microes Acute inflammatory response healing The SPM stimulate natural mechanisms in in promoting resolution of inflammation, Vascuar response Pus (Purulent exudate) What initially interested you in this field resolution and control pain. They are not and the development of appropriate Exogenous chemical of immunology? immunosuppressive and hence do not treatments. signals Neutrophilmonocyte sequence The functions of white blood cells, disable the body’s defense mechanisms phagocytes in host defence mechanisms against microbes. LAB VIDEO Chemo Neutrophil attractants Lipoxins stimulate migration Lipid nonphlogistic Homeostasis and in human diseases. www.bwhclinicalandresearchnews. mediator monocyte Restitution of Will chronic inflammatory diseases be org/2017/01/04/searching-for-answers-in- class recruitment Neutrophil Resolving normal structure switching Are pharmaceutical companies completely preventable one day? inflammation/ LTB apoptosis macrophage esoed 4 SPM T cells amplification eudate interested in specialised pro-resolving Won’t that be a great world to live in! Post B cells capillary PMN influx Lipoxins Adaptive immunity FUNDING venule Resolvins National Institutes of Health (NIH) RvE1 Limit PMN SPM infiltration Resolvins Sins of resolution Protectins proresolving stimulates COLLABORATORS Resolvins Time Omega PUFA, SPM Sequestration of proinflammatory cytokines Dr Serhan's Program Project team and Protectins project leaders include Drs Bruce Levy, Maresins PMN clearance from epithelial surfaces Removal of inflammatory deris Matthew Spite, Nicos Petasis, Nan Chiang and Paul Norris Resolution of inflammation is an active process with novel mediators & control mechanisms BIO Prof Serhan received a BS in Biochemistry A main function of SPM is stimulating the DRUG TEMPLATES to block immune functions. If any of those before completing his PhD in uptake and clearance of dying immune cells In addition to uncovering the mechanisms hopefuls make it on to the market as new Experimental Pathology and Medical and microbes by cells with the capability of immune resolution, Prof Serhan is drugs, they could not only be used in the Sciences. He was a visiting scientist and to engulf, i.e., phagocytes (neutrophils and on a quest to develop synthetic SPM treatment of inflammatory diseases, but post-doctoral fellow at the Karolinska macrophages). Resolvins and protectins analogues with the potential to become also to control inflammation and even pain Institutet, Stockholm before joining the improve survival and regulate both the effective new therapeutics. Together with resulting from surgery. faculty at Harvard Medical School in intensity and duration of inflammation in other researchers he has already created 1987, receiving an honorary degree from animal models. a number of candidates. The team has That's not all. Early findings demonstrate Harvard University in 1996, DSc from UCD generated templates for designer drugs that some SPM are crucially involved in and Honorary Fellow in Medical Sciences, Often, we cannot predict whether a serious by systematically isolating and scrutinising wound healing, as maresins and resolvins University of London, 2010. inflammatory condition will resolve or the molecular structures of SPM and their stimulate tissue regeneration and reduce the become chronic and elicit pathologies receptor targets. burden of infections in animal systems. As CONTACT such as inflammatory bowel disease, sepsis such, it may be possible to drastically speed Prof Charles N Serhan, Director or multi-organ failure. It is tempting to Prof Serhan’s research programme up tissue repair after injury in the future. This Center for Experimental Therapeutics and speculate that measurements of SPM levels now aims to test new SPM analogues in could draw these substances into an entirely Reperfusion Injury could be used as indicators of the bias of experimental disease models to establish new realm of therapeutic medicine. Brigham and Women's Hospital ongoing inflammation in a patient or healthy their unique mechanism of action and Serhan Lab members, from left: Stephania Libreros, Nan Chiang, Xavier de la Rosa Siles, Charles Serhan, Simon Gelman Professor of Anaesthesia individual. Such a prediction could inform gather pharmacological data. Further clinical PREVENTION RATHER THAN CURE? Paul Norris, Justin English, Jeremy Winkler, Molly Jenssen, Iliyan Vlasakov, Ian Riley (Biochemistry & Molecular Pharmacology) medical staff as to whether the patient’s testing is envisaged with the most promising Studies into the benefits of nutrition on Harvard Medical School & Professor, immune system needs to be manipulated to candidates. It is expected that SPM will human health are notoriously difficult to Harvard School of Dental Medicine prevent any deterioration of their condition. cause fewer adverse side effects than analyse and compare. Variations in the enhanced SPM levels achieved by additional all organs of the body. These novel insights Transformative Medicine Blg A personalised medicine and nutrition current anti-inflammatories that become quality of over-the-counter preparations of omega-3 fatty acid consumption can indeed force us to rethink approaches to treat acute 60 Fenwood Rd approach using metabololipidomics profiling immunosuppressive, due to their function dietary supplements make it even
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