Pharmacologic Resolution of Inflammation as a Novel Therapeutic Approach

Pharmacologic Resolution of Inflammation as a Novel Therapeutic Approach

Tuesday, October 28, 2014

The New York Academy of Sciences

Presented By

 

Uncontrolled, chronic inflammation is now considered a major component of many widespread diseases, which are now well-recognized as 'inflammatory diseases.' These include arthritis, asthma, atherosclerosis and peripheral vascular disease, Alzheimer’s disease, periodontal disease and cancer. There is general agreement that inflammation is not likely to be the causative factor in these diseases, but that it plays a key role in disease progression, tissue dysfunction and ultimately organ failure. In recent years, evidence has emerged that resolution of inflammation is a biochemically active process driven by multiple chemical mediators. Elucidation of the biochemical pathways contributing to the resolution of inflammation has provided many new anti-inflammatory targets and an opportunity for resolution-based pharmacology for treatment and prevention of inflammatory diseases. This symposium reviews recent discoveries and advances in the field, and demonstrates how this work translates into new approaches and new pharmacology to treat old diseases.

*Networking reception to follow.

This event will also be broadcast as a webinar.

Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City when possible.

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The Biochemical Pharmacology Discussion Group is proudly supported by



  • Merck
  • WilmerHale

Mission Partner support for the Frontiers of Science program provided by Pfizer

Agenda

* Presentation titles and times are subject to change.


October 28, 2014

8:30 AM

Registration and Continental Breakfast

9:00 AM

Welcome and Introductory Remarks
Sonya Dougal, PhD, New York Academy of Sciences
George B. Zavoico, PhD, MLV & Co.

9:15 AM

Pro-Resolving Lipid Mediators in Clearing Inflammation & Infection
Charles N. Serhan, PhD, DSc (hc), Brigham & Women's Hospital, Harvard Medical School

9:45 AM

Keynote Presentation
G Protein-Coupled Receptors in Resolution of Inflammation: Annexin, Lipoxin A4 and Resolvin D1

Mauro Perretti, PhD, Queen Mary University of London

10:20 AM

Resolving Vascular Injury: Resolvins and Maresins Influence Vascular Remodeling
Michael S. Conte, MD. University of California-San Francisco

10:50 AM

Networking Coffee Break

11:20 AM

New Mechanisms and Therapeutic Potential of Pro-resolving Mediators in Advanced Atherosclerosis
Gabrielle Fredman, PhD, Columbia University

11:50 AM

Genetics of Inflammation in the Brain and Alzheimer’s Disease Risk
Rudolph E. Tanzi, PhD, Massachusetts General Hospital

12:20 PM

Networking Lunch Break and Poster Session

1:30 PM

Omega-3 Fatty Acids with Antioxidants Increase Amyloid-β Phagocytosis and Attenuate Inflammation in Alzheimer Disease Patients: Role of Resolvin D1
Milan Fiala, MD, David Geffen School of Medicine at UCLA

2:00 PM

Resolvins in Airway Inflammation: An Effective Therapy for Chronic Obstructive Pulmonary Disease?
Patricia J. Sime, MD, University of Rochester School of Medicine

2:30 PM

Networking Coffee Break

3:00 PM

Specialized Pro-Resolving Mediators in Allergic Airway Responses, Asthma and Acute Lung Injury
Bruce D. Levy, MD, Brigham & Women's Hospital, Harvard Medical School

3:30 PM

Suppression of Cell Debris-stimulated Tumor Growth by Resolvin Mediated Clearance
Dipak Panigrahy, MD, Beth Israel Deaconess Medical Center, Harvard Medical School

Late-Breaking Early Career Investigator Presentations

4:00 PM *

Accelerating Inflammation Resolution to Counteract Chemical Cutaneous and Pulmonary Injury
Satya Achanta, DVM, PhD, Duke University School of Medicine

* The 4:00 pm talk will not be broadcast as part of the live webinar

4:15 PM

Specialized Proresolving Mediators Differentially Affect Platelet Function
Katie L Lannan, MS, University of Rochester

4:30 PM

ETC-1002 Modulates Macrophage Immune Response, Attenuates Vascular Inflammation and Prevents Progression of Experimental Atheroma in LDL Receptor-Deficient Mice
Sergey Filippov, MD, PhD, Esperion Therapeutics Inc.

4:45 PM

Spontaneous Pro-Resolution Mediators (SPM’s) in Paediatric Cystic Fibrosis (CF) Lung Disease
Fiona Ringholz, MBBChir, MRCPCH, National Children’s Research Centre

5:00 PM

Closing Remarks
Charles N. Serhan, PhD, DSc (hc), Brigham & Women's Hospital, Harvard Medical School

5:05 PM

Networking Reception

6:00 PM

Adjourn

Speakers

Organizers

Charles N. Serhan, PhD, DSc (hc)

Brigham & Women's Hospital, Harvard Medical School

Charles Nicholas Serhan is the Simon Gelman Professor of Anaesthesia (Biochemistry and Molecular Pharmacology) at Harvard Medical School and Professor of Oral Medicine, Infection and Immunity at HSDM Harvard University. Since 1995, he is Director of the Center for Experimental Therapeutics and Reperfusion Injury at BWH. Professor Serhan received Bachelor of Science in biochemistry from Stony Brook University and received his doctorate in experimental pathology and medical sciences New York University (NYU) School of Medicine. He was a visiting scientist at the Karolinska Institutet, Stockholm, Sweden and post-doctoral fellow. In 1996, he received an honorary degree from Harvard University. Dr. Serhan was awarded an NIH MERIT Award and the Outstanding Scientist Award in Inflammation Research. He delivered the 2005 NIH Kreshover Lecture and LSU Chancellor’s Award in Neuroscience in 2006. Received the 2008 William Harvey Outstanding Scientist Medal. In 2010, delivered the Kern Lecture and received Soc. Leukocyte Biology 2010-Bonazinga AwardDr. Serhan was elected Fellow of AAAS in 2011, delivered the Tabak NIH-Lectureship, 2011 ACR Hench Lecture and the Honorary Fellow from Queen Mary University. NIH/NCI Distinguished Lecturer STARS in Nutrition and Cancer (2012), 2013 JLR Lectureship Award, 2013 UC Dublin Honorary DSc and 2014 Sterling Drug Award.

George B. Zavoico, PhD

MLV & Co.

George B. Zavoico, PhD, is Director, Life Sciences Research and Senior Equity Research Analyst at MLV & Co, a boutique investment bank and institutional broker-dealer based in New York. He has 10 years of experience as a life sciences equity analyst writing research on publicly traded equities and, beginning in 2009, helped to establish and expand the Healthcare research team at MLV. From 2005 to 2009, Dr. Zavoico was an Equity Analyst at Westport Capital Markets and Cantor Fitzgerald. Prior to 2005, Dr. Zavoico established his own consulting company serving the biotech and pharmaceutical industries by providing competitive intelligence and marketing research, due diligence services, and guidance in regulatory affairs. He also wrote extensively on healthcare and the biotech and pharmaceutical industries for periodicals targeting the general public and industry executives. Dr. Zavoico began his career as a Senior Research Scientist at Bristol-Myers Squibb Co., moving on to management positions at Alexion Pharmaceuticals, Inc. and T Cell Sciences, Inc. (now Celldex Therapeutics, Inc.). He has a BS in Biology from St. Lawrence University and a PhD in Physiology from the University of Virginia. He held post-doctoral fellowships at the University of Connecticut School of Medicine and at Harvard Medical School/Brigham & Women’s Hospital. He has published over 30 papers in peer-reviewed journals and has co-authored four book chapters.

Jennifer S. Henry, PhD

The New York Academy of Sciences

Speakers

Satya Achanta, DVM, PhD

Duke University School of Medicine

Dr. Satya Achanta is a research associate at the Duke University School of Medicine. Dr. Achanta received his veterinary degree from India and worked as a mixed animal practitioner for two years before he moved to the United States. Dr. Achanta obtained his PhD in Veterinary Biomedical Sciences at the Center for Veterinary Health Sciences, Oklahoma State University. Then, he joined as a postdoctoral research associate in Dr. Sven Jordt’s laboratory at Yale University where he tested the therapeutic potential of pro-resolving agents in different injury models. As a North Carolina state-licensed veterinarian, with experience in large animal medicine, Dr. Achanta is interested in developing cutaneous and pulmonary injury models in large mammals and screen potential therapeutic agents based on mechanistic studies.

Michael S. Conte, MD

University of California-San Francisco

Dr. Michael Conte received his medical degree in 1986 at Albert Einstein College of Medicine. He completed his surgical residency at New York Hospital-Cornell Medical Center in 1993, which included a two year research fellowship at Brigham and Women's Hospital (BWH) and Massachusetts Institute of Technology in Boston. He completed his vascular surgery training in 1994 as the John Homans Fellow at BWH and Harvard Medical School (HMS), in Boston. Dr. Conte was an Assistant Professor of Surgery at Yale University from 1994-1997, and a member of the Boyer Center for Molecular Medicine. Subsequently he returned to BWH where he served as Assistant Professor (1997-2001) and then Associate Professor (2001-2008) of Surgery at HMS. From 2002-2008, he was the Director of Vascular Surgical Research at BWH and from 2005-2008, he was Co-Director of the Clinical Trials Group at the Center for Surgery and Public Health (a joint initiative between HMS, BWH, and the Harvard School for Public Health). Dr. Conte is a member of many professional organizations, including the Society for Vascular Surgery and the Society of University Surgeons. Dr. Conte has also been an invited lecturer for many regional, national, and international meetings and conferences. In 2006, he received the Distinguished Achievement Award from the New York Weill Cornell Medical Center Alumni Council. He is on the Editorial Board for Vascular and Endovascular Surgery, Vascular Medicine, Journal of Vascular Surgery, and Vascular. He has served as an Associate Editor for Circulation.

Milan Fiala, MD

David Geffen School of Medicine at UCLA

Milan Fiala, MD is a Research Professor in the UCLA Department of Surgery. After Internship, Dr. Fiala trained in Oncology at Massachusetts General Hospital and in Epidemiology at Harvard School of Public Health. He has had a long a research career at UCLA in Virology and Immunology of neurological diseases. His recent interests are immunological therapies of inflammation in neurological diseases, including Amyotrophic lateral sclerosis and Alzheimer disease. His recent discoveries open new approach to treating inflammation in ALS through IL-6 inhibition and preventing Alzheimer disease by nutritional supplementation with omega-3 fatty acids, antioxidants, vitamin D3 and resveratrol.

Sergey Filippov, MD, PhD

Esperion Therapeutics Inc.

Sergey Filippov, MD, PhD, has an extensive experience in the cardiovascular sciences and pharmaceutical industries. After completing his postdoctoral training in 2000, Sergey has been appointed as a Research Investigator at Molecular Medicine and Genetics, University of Michigan Medical School. In 2005, Sergey transitioned to the pharmaceutical industry by joining the Vascular Biology Department at the Esperion Division of Pfizer where he focused his research on mechanisms of oxidative modifications of lipoproteins and vascular inflammation. In 2007 Sergey transferred to the division of Cardiovascular and Metabolic Diseases, Pfizer Global R&D where he served as a Biology Lead on the team developing new therapeutic interventions for the treatment of cardiovascular diseases. In December 2010, Sergey joined Esperion Therapeutics as a Principal Scientist leading macrophage biology efforts focusing on further understanding of MOA for the lead compound. Sergey’s research interests include cell and matrix biology of chronic inflammation associated with atherosclerosis and vascular complications of type 2 diabetes. Sergey earned an MD from Ivanovo State Medical Academy and a PhD in Cell Biology from Yaroslavl State Medical Academy, Russia.

Gabrielle Fredman, PhD

Columbia University

Gabrielle Fredman received a PhD from Boston University in 2009. She then joined the laboratory of Dr. Charles Serhan at Brigham and Women’s Hospital/Harvard Medical School to study lipid mediators in the resolution of inflammation. After a brief post doc in the Serhan laboratory, Gabrielle joined the laboratory of Dr. Ira Tabas at Columbia University to apply her research interests, which are the actions of lipid mediators in advanced atherosclerosis.

Katie L Lannan, MS

University of Rochester

Katie Lannan is a graduate student in the Department of Microbiology and Immunology at the University of Rochester in the laboratory of Dr. Richard Phipps. Her research focuses on modulation of platelet function, with specific emphasis on the use of novel agents to improve platelet storage and mitigate platelet activation. Katie has published in the area of red blood cell and platelet transfusion, and continues to investigate the platelet storage lesion. Her most recent work focuses on the ability of specialized pro-resolving lipid mediators to mitigate platelet function. Katie has had multiple opportunities to expand her training in translational science, including attending a NIH Clinical and Translational Science course and serving as a Howard Hughes Medical Institute fellow.

Bruce Levy, MD

Brigham & Women's Hospital, Harvard Medical School

Dr. Levy is the Chief of the Pulmonary and Critical Care Medicine Division of the Department of Internal Medicine at Brigham and Women’s Hospital. He has a long-standing interest in internal medicine and training the next generation of academic physicians and spent 13 years as the Director of the Medical Residency Program for Academics and Career Development. After graduating from the University of Pennsylvania School of Medicine in 1988, he performed his internship and residency at BWH. After training in the Harvard joint fellowship program in pulmonary and critical care medicine, he returned to BWH to be a chief medical resident in 1993.  Since then, Dr. Levy has been a member of the Pulmonary and Critical Care Medicine Division at BWH where he sees patients in the Center for Chest Diseases and performs basic research. He is appointed as an Associate Professor of Medicine at Harvard Medical School and serves as a teacher of medical students, residents and fellows. Dr. Levy also volunteers in the community as the medical director of the New England Shelter for Homeless Veterans. He has been the recipient of several education and community service awards from BWH and HMS.

Dipak Panigrahy, MD

Beth Israel Deaconess Medical Center, Harvard Medical School

Dr. Panigrahy was accepted into medical school at Boston University at age 17. He trained in surgery with Dr. Roger Jenkins, who performed the first liver transplant in New England. Over the past decade, Dr. Panigrahy led angiogenesis and cancer animal modeling in the Judah Folkman laboratory. Dr. Panigrahy joined the Beth Israel Deaconess Medical Center in 2013, and in 2014 was appointed Assistant Professor of Pathology and currently has a laboratory in the Center for Vascular Biology Research.

Mauro Perretti, PhD

Queen Mary University of London

Since 1991 Dr. Perretti has been interested in studying the process of white blood cell trafficking with an initial focus on Annexin A1 (then called lipocortin). Determining the impact of endogenous Annexin A1 in human neutrophil biology (Nat Med 1996) forged the pioneering concept of ‘endogenous anti-inflammatory mediators’ (recapitulated in a groundbreaking 1997 review) that has contributed to the current appreciation of the impact of the resolution of inflammation, or its lack of, in the context of human inflammatory pathology. Over the last decade his interests have branched out on the investigation of specific endogenous mediators and pathways (e.g. melanocortins, galectins, calcitonin and, more recently, resolvins and chemerin peptides) – mainly studied in the context of experimental and human arthritis, sepsis and reperfusion injury, all in all making an internationally recognised contribution to the resolution of inflammation research area. Presently, the focus of Dr. Perretti group is on pro-resolving receptors (e.g. ALX/FPR2; MC1R and MC3R, ChemR23) attempting to understand their physio-pathology and define their pro-resolving signature, using mouse and human cells, models of acute inflammation and proof-of-concept experiments in models of disease, with the ultimate aim to inform innovative therapeutic approaches to exploit the resolution concept. Dr. Perretti long-term aim is to add Resolution Pharmacology to the textbooks of Pharmacology of next decade.

Fiona Ringholz, MBBChir, MRCPCH

National Children’s Research Centre

Fiona Ringholz graduated medicine from the University of Cambridge in 2005 and is engaged in Higher Specialist training in Paediatrics with the Royal College of Physicians in Ireland. She is involved in a translational research project based between Our Lady’s Children’s Hospital, Crumlin, Dublin (the national referral centre for Paediatric Cystic Fibrosis (CF)) and Valerie Urbach’s lab at the National Children’s Research Centre in Dublin, Ireland. The aim of the project is to investigate the role played by Pro-Resolution Mediators in the pathogenesis of CF lung disease, and their potential application as candidate therapeutics for CF. Fiona Ringholz is registered as a Doctoral candidate at the Royal College of Surgeons in Ireland.

Charles N. Serhan, PhD, DSc (hc)

Brigham & Women's Hospital, Harvard Medical School

Charles Nicholas Serhan is the Simon Gelman Professor of Anaesthesia (Biochemistry and Molecular Pharmacology) at Harvard Medical School and Professor of Oral Medicine, Infection and Immunity at HSDM Harvard University. Since 1995, he is Director of the Center for Experimental Therapeutics and Reperfusion Injury at BWH. Professor Serhan received Bachelor of Science in biochemistry from Stony Brook University and received his doctorate in experimental pathology and medical sciences New York University (NYU) School of Medicine. He was a visiting scientist at the Karolinska Institutet, Stockholm, Sweden and post-doctoral fellow. In 1996, he received an honorary degree from Harvard University. Dr. Serhan was awarded an NIH MERIT Award and the Outstanding Scientist Award in Inflammation Research. He delivered the 2005 NIH Kreshover Lecture and LSU Chancellor’s Award in Neuroscience in 2006. Received the 2008 William Harvey Outstanding Scientist Medal. In 2010, delivered the Kern Lecture and received Soc. Leukocyte Biology 2010-Bonazinga AwardDr. Serhan was elected Fellow of AAAS in 2011, delivered the Tabak NIH-Lectureship, 2011 ACR Hench Lecture and the Honorary Fellow from Queen Mary University. NIH/NCI Distinguished Lecturer STARS in Nutrition and Cancer (2012), 2013 JLR Lectureship Award, 2013 UC Dublin Honorary DSc and 2014 Sterling Drug Award.

Patricia J. Sime, MD

University of Rochester School of Medicine

Dr. Patricia J. Sime, MD, FRCP is currently Professor of Medicine, Chief of Pulmonary and Critical Care, and the Associate Chair for Research in Medicine. She received her medical degree and training in Pulmonary Medicine from Edinburgh University, Scotland. Following this she spent four years at McMaster University, Canada, where she received basic and translational scientific training in lung inflammation, gene transfer, chronic obstructive lung disease and fibrosis. Dr. Sime joined the University of Rochester in 1999. She is board certified in internal medicine and pulmonary medicine, and has practiced in the UK, Canada and the United States. Dr. Sime is a physician-scientist who focuses on the identification of novel targets for therapy in lung diseases, particularly diseases associated with inflammation and its resolution, and those characterized by fibrosis. Her recent work has focused on fibroblast biology, mediators, matrix regulation and abnormal metabolism in lung fibrosis and the regulation and therapeutic interventions for chronic obstructive pulmonary disease. Dr. Sime is a member of American Society for Clinical Investigation and a Fellow of the Royal College of Physicians (UK).

Rudolph E. Tanzi, PhD

Massachusetts General Hospital

Dr. Rudolph Tanzi is the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard University, and Vice-Chair of Neurology and Director of the Genetics and Aging Research Unit at Massachusetts General Hospital. Dr. Tanzi has been investigating the genetics of neurological disease since the 1980’s when he worked on the first study that used human genetic markers to find a disease gene (Huntington's disease). Dr. Tanzi co-discovered all three familial early-onset Alzheimer's disease genes and several other neurological disease genes including that responsible for Wilson’s disease. As leader of the Alzheimer’s Genome Project, Dr. Tanzi has identified many other genes for the common late-onset form of AD, including CD33 and ADAM10. His research on the role of zinc and copper in AD has led recently to ongoing clinical trials at Prana Biotechnology. Dr. Tanzi serves on dozens of editorial and scientific advisory boards, and as Chair of the Cure Alzheimer’s Fund Research Consortium. He has received numerous awards, including the two highest awards for Alzheimer's disease research: The Metropolitan Life Award and The Potamkin Prize. Dr. Tanzi was included on the list of the "Harvard 100 Most Influential Alumni" by 02138 magazine, and was chosen by the Geoffrey Beene Foundation as a “Rock Star of Science”. He was also recently voted one of the “Most Influential Scientific Minds in the World” for 2014 and one of the “Top 20 Translational Scientists of 2013”. Dr. Tanzi has co-authored over 460 research articles, including three of the top ten most cited AD papers. He also co-authored the popular trade books “Decoding Darkness: The Search for the Genetic Causes of Alzheimer’s Disease” and the recent New York Times Bestseller, “Super Brain” (and PBS show). In musical pursuits, Dr. Tanzi plays keyboards professionally, most recently with the musical group, Aerosmith and with Joe Perry.

Sponsors

For sponsorship opportunities please contact Perri Wisotsky at pwisotsky@nyas.org or 212.298.8642.

Academy Friend

Auven Therapeutics

Maresins Pharma, Inc.

Grant Support

This program is supported in part by a grant from AstraZeneca

Promotional Partners

The American Society for Pharmacology and Experimental Therapeutics (ASPET)

The Angiogenesis Foundation

British Pharmacological Society

Chemistry Conferences

The Dana Foundation

the Eicosanoid Research Foundation (ERF)

International Chemical Biology Society

Nature

Society for Neuroscience


The Biochemical Pharmacology Discussion Group is proudly supported by



  • Merck
  • WilmerHale

Mission Partner support for the Frontiers of Science program provided by Pfizer

Abstracts

Pro-Resolving Lipid Mediators in Clearing Inflammation & Infection
Charles N. Serhan, PhD, DSc (hc), Brigham & Women's Hospital, Harvard Medical School

Uncovering mechanisms controlling inflammation are of paramount importance because persistent and chronic inflammation can impact all organs throughout the body and are involved in many widely occurring diseases. Recent advances in our appreciation of the mechanisms in resolution of acute inflammation (RoI) systematically uncovered several new families of potent pro-resolving autacoids, each biosynthesized from essential polyunsaturated fatty acids in resolving exudates. These include the resolvins (Rv), protectins (PD) and maresins (MaR), collectively termed specialized pro-resolving mediators (SPM) that act in pico-nanogram ranges. SPM are temporally and spatially biosynthesized by resolving- exudates, which proved to evoke potent anti-inflammatory and pro-resolving actions as well as enhance microbial clearance. The potent SPM actions and complete structures are confirmed, which also permitted use of LC-MS-MS-based metabololipidomics to identify SPM in human and murine tissues, isolated human cells types (e.g. apoptotic neutrophils, and macrophage phenotypes) CN Serhan Nature June vol 510, 2014 doi:10.1038/nature13479 . Specific SPM demonstrate potent stereoselective actions that involve specific G-protein-coupled receptors and are not immunosuppressive). This presentation will update advances in SPM mechanisms in RoI, their new sites of formation and actions that opened the door for their role(s) in resolution physiology and pharmacology.
 

G Protein-Coupled Receptors in Resolution of Inflammation: Annexin, Lipoxin A4 and Resolvin D1
Mauro Perretti, PhD, Queen Mary University of London

The recent success with anti-inflammatory therapy in chronic diseases should not make us complacent: as inflammation is critical for survival, the risk:benefit of anti-inflammatory drugs is still narrow. A fresh approach can derive from molecular detailing of the resolution of acute inflammation, a programmed response evoked by mediators with potent tissue-protective properties. Our understanding on how pro-resolving mediators operate led to the identification of specific receptor targets. Our own work has focused on pro-resolving G-protein couple receptors (GPCR) with the dual aim of i) defining their biology and ii) inform therapeutic opportunities. An exemplar is the receptor for Annexin A1, Lipoxin A4 (LXA4) and Resolvin D1, termed FPR2/ALX. What processes are controlled by FPR2/ALX in preclinical disease models? What is best strategy to exploit pro-resolving GPCRs for innovative drug discovery programmes? Using a mouse colony lacking FPR2/ALX orthologues, we identified specific and non-redundant protective properties of FPR2/ALX in settings of sepsis and vascular reperfusion injury. The observed over-exuberant responses in the absence of FPR2/ALX were linked to inadequate LXA4 production, indicating existence of FPR2/ALX-centred protective circuits. For therapeutic innovation, studies with distinct ligands led us to define at least one cell-specific proresolving signature for FPR2/ALX in macrophages, with of a specific signaling response downstream FPR2/ALX homodimerization, yielding IL-10 production, indicating again the existence of complex networks in resolution, with FPR2/ALX at its centre. We predict these efforts will lead to the establishment of novel inflammation therapies under the new branch of ‘Resolution Pharmacology’. Funding: Wellcome Trust (08667/Z/08/Z).
 

Resolving Vascular Injury: Resolvins and Maresins Influence Vascular Remodeling
Michael S. Conte, MD, University of California-San Francisco

The inflammatory response to acute vascular injury plays a central role in the subsequent remodeling response. Protracted inflammation has been associated with aberrant vascular healing leading to failure of common therapeutic procedures such as angioplasty, stenting, and bypass surgery. Mechanisms governing the resolution process in this setting are poorly understood, but may offer new opportunities to regulate vascular injury and restore homeostasis. We have explored the effects of the specialized pro-resolving lipid mediators (SPM) resolvins (Rv, D- and E- series) and maresins (MaR1) on vascular cells, and in models of acute vascular injury.
 
In cultured vascular smooth muscle cells (VSMC), SPM inhibit cell migration in a wound assay and chemotaxis to PDGF. They attenuate TNF-stimulated NFkB activation, monocyte adhesion, gene expression, and generation of reactive oxygen species. In a rabbit model of arterial angioplasty, local delivery of RvD2 attenuated leukocyte recruitment and reduced neointima formation. In a mouse model of carotid ligation, systemic (IP) administration of RvD2 and MaR1 reduced leukocyte recruitment, altered macrophage phenotype (favoring M2 vs M1), and significantly attenuated neointimal hyperplasia. We have measured local levels of SPM and their precursors in arterial tissues and in patients with vascular disease, and demonstrate the expression of some of the known SPM receptors in vascular cells. Taken together our findings indicate that i) biochemical pathways of resolution are operative in vascular injury; ii) SPM have direct effects on vascular cells; and iii) increased availability of SPM may favorably alter the healing response to acute vascular injury.
 

New Mechanisms and Therapeutic Potential of Pro-resolving Mediators in Advanced Atherosclerosis
Gabrielle Fredman, PhD, Columbia University

Persistent inflammation and its failed resolution underlie the pathophysiology of prevalent human diseases, such as atherosclerosis. In this regard, many of the characteristics of clinically dangerous advanced atherosclerotic plaques including 1) imbalances between pro-inflammatory and pro-resolving mediators, 2) thinning of a protective "cap" of subendothelial collagen, 3) oxidative stress, 4) defective clearance of dead cells (efferocytosis), and 5) tissue-damaging necrosis, suggest that this resolution process is defective. The failure of the host to combat these maladaptive processes is likely due to a lack of pro-resolving agonists and/or a defect in their receptors. Hence, enhancing resolution in atherosclerosis by therapeutic administration of pro-resolving mediators is of interest. Here we report the pro-resolving agonists Resolvin D1 (RvD1) and Ac2-26 (that bind the G-protein coupled receptor, FPR2/ALX), decrease oxidative stress and necrosis and stimulate protective fibrous caps. Further, we uncovered a new signaling pathway of how RvD1, via FPR2/ALX, tempers inflammation to facilitate resolution. Together, the therapeutic potential of enhancing resolution in a chronic disease like atherosclerosis could be substantial in that mediators of resolution, unlike anti-inflammatory drugs, have a much greater potential to suppress inflammation and promote tissue repair without compromising host defense.
 

Genetics of Inflammation in the Brain and Alzheimer’s Disease Risk
Rudolph E. Tanzi, PhD, Massachusetts General Hospital

Alzheimer's disease (AD) is strongly influenced by genetic factors such as the APP, PSEN1, and PSEN2, and APOE. Since 2005, we have led the Alzheimer's Genome Project, which in 2008, reported novel AD genes including the spinocerebellar ataxia 1 gene, ATXN1, CD33, and ADAM10. ATXN1 knockout increases BACE1 levels in cortex and hippocampus, but not in cerebellum and brain stem. This increase of BACE1 is concordant with the shift of APP processing into the beta-secretase cleavage pathway along with an increase in Abeta levels and plaque load in the brains of APPswe/PS1deltaE9 mice. CD33 is one of several genes involved in the innate immune system of the brain that have been associated with AD risk. CD33 knock-out led to 1. decreased Abeta load owing to enhanced phagocytosis by microglia and 2. reduced numbers of M1-activated microglia in APP/PS1 and 5XFAD tg mouse brains. Re-sequencing of ADAM10 revealed two rare mutations that tightly co-segregated with AD and impair ADAM10 non-amyloidogenic cleavage of APP in transgenic mice. We also carried out whole genome sequencing on 440 subjects from 452 multiplex NIMH AD families. We then employed a multi-pronged approach to identify highly penetrant functional variants underlying the association of previously reported AD genes that emerged from genome-wide association studies. Our analyses revealed several novel pathogenic variants in the known and GWAS-confirmed AD genes. The elucidation of the genes and functional variants influencing risk for AD should continue to enhance our understanding of AD etiology and pathogenesis. Ultimately, these genes will be used to predict risk for AD and guide novel the development of therapies for the effective treatment and prevention of this terrible disease.
 

Omega-3 Fatty Acids with Antioxidants Increase Amyloid-β Phagocytosis and Attenuate Inflammation in Alzheimer Disease Patients: Role of Resolvin D1
Milan Fiala, MD, David Geffen School of Medicine at UCLA

Alzheimer disease (AD) patients have critical defects of innate immunity related to clearance of amyloid-β  (Aβ) from the brain: (a) Monocytes and macrophages are defective in phagocytosis and degradation of Aβ, and (b) the transcription of inflammatory genes in PBMCs is down regulated in “non-inflammatory” patients and is up regulated in ”inflammatory” patients. We tested Aβ phagocytosis by a flow cytometric test, inflammatory gene transcription by RT PCR, and cognitive status by Minimental State Examination (MMSE) in patients with minor cognitive impairment (MCI) (“early” patients) and advanced AD (”late” patients). The subjects were supplemented by a nutritional drink (Smartfish) with ω-3 fatty acids (ω-3) (1 gm DHA and 1 gm EPA), antioxidants (from pomegranate and chokeberry), vitamin D3 and Resveratrol. On supplementation of “early” patients we found that (a) Aβ phagocytosis by monocytes significantly increased (P=0.04); (b) the “Specialized proresolving mediator” resolvin D1 (RvD1), which stimulates Aβ phagocytosis in vitro, increased in 71% patients; (c) inflammatory gene transcription was up regulated in a non-inflammatory patient and down regulated in an inflammatory patient. The mean MMSE score was 26.1 at the first visit and 26.5 at the last visit after 4 to 12 months of follow-up. These results support a hypothesis that improvement of anti-Aβ immunity by ω-3 supplementation is mediated by specialized proresolving mediators (i.e. RvD1 and other mediators) and is associated with attenuation of cognitive impairment in MCI patients. A clinical trial of the ω-3 drink in prevention of AD is in preparation.
 

Resolvins in Airway Inflammation: An Effective Therapy for Chronic Obstructive Pulmonary Disease?
Patricia J. Sime, MD, University of Rochester School of Medicine

Rationale: Chronic obstructive pulmonary disease (COPD) is a major global health problem predominantly caused by smoking, but also by biomass smoke, and COPD is the third leading cause of death in the United States. Cigarette smoke is a profound inflammatory stimulus and curiously the effects of smoking persist long after smoking cessation. This supports the idea that cigarette smoke interferes with the normal processes that resolve inflammation.
 
Hypothesis: Pro-resolving lipid mediators (PRMs) have profound anti-inflammatory and pro-resolving effects on acute and chronic lung injury. Treatment with PRMs promote resolution: a novel and important therapeutic goal for inflammatory diseases caused by cigarette smoking.
 
Results: Using pre-clinical mouse models of acute and chronic cigarette smoke-incited inflammation, we have demonstrated that PRMs such as resolvin D1 (RvD1) dampen acute neutrophilic inflammation and promote its resolution through M2 pro-resolving macrophages. PRMs also prevent smoke-induced chronic inflammation and emphysema with reductions in apoptosis and oxidative stress. Studies in primary human lung cells revealed that RvD1 inhibits pro-inflammatory signaling by blocking both the MAPK and NF-kB inhibitors through a common regulatory kinase.
 
Conclusions: These studies show for the first time that pro-resolving mediators can be used to prevent inflammation and accelerate resolution/repair of lung injury due to both acute and chronic cigarette smoke exposure. Our results will pave the way for translational development of these exciting new compounds that have the potential to be effective therapies against human diseases of chronic inflammation and smoking. Supported by: NIH T32 HL066988, NIH R01HL110759-01, NIH P30ES01247, NIEHS T32ES007026, PhRMA Foundation, ULITR000042, GM038765
 

Specialized Pro-resolving Mediators in Allergic Airway Responses, Asthma and Acute Lung Injury
Bruce Levy, MD, Brigham & Women's Hospital, Harvard Medical School

Acute lung inflammation is fundamentally important to host defense, but chronic or excessive inflammation can lead to several important diseases. The resolution of inflammation is an active process that is directed, in part, by specialized pro-resolving mediators that are enzymatically derived from polyunsaturated fatty acids. In health, cell-cell interactions at the onset of acute inflammation establish biosynthetic circuits for these pro-resolving mediators, including the omega-3 fatty acid-derived resolvins, protectins and maresins, which serve as agonists to orchestrate a return of the inflamed tissue to homeostasis.  Understanding the cellular and molecular mechanisms for pro-resolving mediators in catabasis is providing new insights into lung tissue responses for resolution of inflammation in health and the pathophysiology of disease; as well as opportunities for therapeutic intervention. E-series and D-series resolvins are enzymatically derived from the essential omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid, respectively. Protectin D1 and maresin 1 (MaR1) are also derived from DHA. Relevant to lung inflammation, lipoxin A4 (LXA4), Resolvin E1 (RvE1), resolvin D1 (RvD1) and protectin D1 (PD1) are generated in murine lung. LXA4 and PD1 are generated in human lung.  Receptors for LXA4 and RvD1 (ALX/FPR2) and for RvE1 (CMKLR1) are expressed in lung and are dynamically regulated with lung inflammation. Evidence will be presented for cellular and molecular mechanisms for representative pro-resolving mediators in their protective actions in the regulation of airway inflammation during innate and adaptive immune responses.
 

Suppression of Cell Debris-stimulated Tumor Growth by Resolvin Mediated Clearance
Dipak Panigrahy, MD, Beth Israel Deaconess Medical Center, Harvard Medical School

Chemotherapy and radiotherapy reduce tumor burden by killing tumor cells, but simultaneously generate tumor cell debris that stimulates inflammation promoting tumor growth and progression. This effect is recapitulated in tumor models; co-injection of irradiated, dead cells with tumor cells has been long known to reduce the inoculum of tumor cells needed to produce tumors in rodents (Révész phenomenon). Irradiation and chemotherapy trigger a cytokine storm in the tumor stroma, including the release of the tumor promoting cytokines IL-6 and TNFα. Thus, overcoming the dilemma of debris-induced tumor progression is paramount to prevent tumor recurrence and eventual resistance to cytotoxic drugs, including targeted therapy. Here, we show that tumor cells killed by chemotherapy drastically stimulated tumor growth when co-injected with a sub-optimal inoculum of tumor cells. However, debris-stimulated tumors were suppressed by resolvin (Rv) D1 or RvD2, novel pro-resolving lipid autacoid mediators derived from omega-3 fatty acids. Resolvins specifically inhibited debris-stimulated cancer progression and metastasis by enhancing the endogenous clearance of debris. Resolvin mediated clearance was critically dependent on phagocytosis by macrophages. Furthermore, resolvins counter-regulated the release of cytokines/chemokines, including TNFα, IL-6, IL-8, CCL4, and CCL5 from cell debris-stimulated human macrophages. Our results demonstrate that enhancing endogenous clearance of tumor cell debris represents a novel biological target to complement current cytotoxic cancer therapy and may address the inevitable, intrinsic limitation of current cancer therapy involving cell death.
 

Accelerating Inflammation Resolution to Counteract Chemical Cutaneous and Pulmonary Injury
Satya Achanta, DVM, PhD, Duke University School of Medicine

Inflammation has three temporal phases, initiation, amplification and maintenance, and resolution. Inflammation resolution was thought of as a passive process but recent studies show that resolution is an active process controlled by fatty acid derived specialized pro-resolving mediators. Chemical tissue injuries are often associated with strong and protracted inflammation. These include injuries by exposures to oxidants (inhalation of chlorine gas), electrophiles (smoke inhalation and exposure to tear gas), acids (hydrochloric acid reflux injury, HCl) and skin blistering agents (vesicants, mustard gas). In the past, classical anti-inflammatory strategies were investigated as treatments, interfering with initiation and maintenance of inflammation, with mixed outcomes. We hypothesize that accelerating resolution of inflammation will attenuate the exaggerated inflammatory response following chemical exposures, leading to decreased morbidity and improved recovery. In these studies, pro-resolving agents, Resolvin D1, Resolvin D2, Lipoxin A4, Protectin DX, and 17(R)Resolvin D1 were administered to mice at a dose rate of 2 or 5 µg/kg body weight i.p., following respiratory exposure to chlorine gas or HCl, or cutaneous exposures to a blistering agent (2-Chloroethyl ethyl sulfide) or a tear gas agent (CS). In the cutaneous injury models, pro-resolving agents decreased edema, pro-inflammatory cytokines, and vascular leakage while improving histopathological scores. In the pulmonary injury models, administration of pro-resolving mediators decreased levels of pro-inflammatory cytokines in the lung and serum and reduced deterioration of pulmonary function and tissue integrity. These results support our hypothesis and pave the way for more definitive studies in larger sample sizes and in higher mammalian species.
 

Specialized Proresolving Mediators Differentially Affect Platelet Function
Katie L Lannan, MS, University of Rochester

Antiplatelet therapy is a cornerstone of modern medical practice and is commonplace in preventing myocardial infarction, thrombosis, and stroke. Current antiplatelet therapies, such as aspirin, however often have adverse side effects, including increased risk of bleeding and 4-45% of the human population are “aspirin-resistant”. Platelets are intimately involved in hemostasis and inflammation, and can cause severe problems when excessively or insufficiently activated. A major unmet need in the field of hematology is the development of new agents that safety prevent unwanted platelet activation in patients with underlying cardiovascular disease, without increasing the risk of bleeding. Here, we investigate the potential of endogenously produced, specialized proresolving mediators (SPMs), to be used as novel anti-platelet agents. SPMs are a recently discovered class of lipid-derived molecules that drive the resolution of inflammation, without being overtly immunosuppressive. Our data demonstrate that SPMs differentially regulate platelet hemostatic function, by altering platelet spreading on fibrinogen. Additionally, SPMs suppress release of the proinflammatory and prothrombotic mediators, soluble CD40 ligand and thromboxane B2. Furthermore, we show for the first time that human platelets express the SPM receptors, GPR32 and ALX, which may mediate the beneficial effects of SPMs on platelet function. Taken together, these data support the idea that SPMs differentially regulate platelet function and may represent a novel class of anti-platelet agents. Additionally, SPMs may play an important role in the resolution of inflammation in cardiovascular diseases, such as atherosclerosis.
 

ETC-1002 Modulates Macrophage Immune Response, Attenuates Vascular Inflammation and Prevents Progression of Experimental Atheroma in LDL Receptor-Deficient Mice
Sergey Filippov, MD, PhD, Esperion Therapeutics Inc.

ETC-1002 is a novel non-statin lipid regulating drug that lowers LDL-c and hs‑CRP in patients with hypercholesterolemia. In several long term clinical trials, hs-CRP lowering has been correlated with favorable cardiovascular outcomes. Anti-inflammatory as well as atheroprotective effects of ETC-1002 have been evaluated in vitro and in vivo. In primary human monocyte-derived macrophages treated with ETC-1002, decreased production of pro-inflammatory cytokines and chemokines coincided with increased levels of AMPK phosphorylation and reduced activity of JNK and p38 MAP kinases. Experiments with siRNA-mediated gene silencing revealed that ETC-1002 activates macrophage AMPK and exerts its anti-inflammatory effects via a mechanism linked to the LKB1/AMPK axis. In high-fat high-cholesterol-fed LDL receptor-deficient mice, treatment with ETC-1002 reduced the size of experimental atheroma and reduced the sub-endothelial retention of free and esterified cholesterol. Furthermore, consistent with the anti-inflammatory properties, ETC-1002 lowered expression of MCP-1, VCAM-1, CD68 and CD36 in atherosclerotic lesions. These findings support that ETC-1002 may offer additional clinical benefits by improving vascular inflammation associated with hypercholesterolemia and coronary artery disease.
 

Spontaneous Pro-Resolution Mediators (SPM’s) in Paediatric Cystic Fibrosis (CF) Lung Disease
Fiona Ringholz, MB BChir, National Children’s Research Centre

CF is caused by a mutation in the CFTR and results in airway surface liquid (ASL) dehydration, impaired muco-ciliary clearance, chronic pulmonary infection and inflammation leading to progressive lung destruction. Lipoxin A4 (LXA4) and Resolvin D1 (RvD1) are SPM’s involved in the active resolution of inflammation. We previously reported that LXA4 restores ASL height in CF bronchial epithelium. We sampled the airways of control children and young children with CF at clinical baseline and during CF Pulmonary Exacerbation (CFPE) (PRINCE Study). We studied the physiological effects of RvD1 in CF using primary CF alveolar macrophages and polarized, differentiated NuLi-1 and CuFi-1 cells as a bronchial epithelial model. Ethical approval was granted by Our Lady’s Children’s Hospital, Crumlin. We report an imbalance in LXA4 versus Leukotriene B4 (LTB4) production in CF airways, despite the absence of infection, related to a deficiency of the LXA4 synthetic enzyme 15 LO-2 in CF macrophages. The reported defect in eicosanoid mediator “class switching” from propagation of inflammation to active resolution of inflammation in CF may play a mechanistic role in the failure to resolve inflammation in CF airways. We report that RvD1 restores ASL height and architecture and attenuates TNFα induced IL8 secretion in CuFi-1 cells. Furthermore RvD1 restores phagocytic capacity to CF alveolar macrophages. We present the findings of the PRINCE study; relating SPM production in the airway to the time course of clinical resolution of inflammation during CFPE. Our findings strongly recommend the development of SPM's as candidate therapeutics for CF airways disease.
 

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