Resolution of Inflammation, Infection and Tissue Regeneration | The New York Academy of Sciences
Resolution of Inflammation, Infection and Tissue Regeneration

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WEBINAR

Resolution of Inflammation, Infection and Tissue Regeneration

Monday, June 25, 2018, 9:00 AM - Tuesday, June 26, 2018, 5:00 PM

The New York Academy of Sciences, 7 World Trade Center, 250 Greenwich St Fl 40, New York, USA

Presented By

The New York Academy of Sciences

 

Chronic, uncontrolled inflammation has been implicated in a wealth of human diseases, but the importance of controlled inflammation in response to pathogens, and the redundancy and complexity of the immune response creates a challenging environment for drug discovery. In recent years, our understanding of the molecular mechanisms underlying inflammation has improved dramatically, most notably the identification of resolution of inflammation as an active process has created a rapidly evolving field of research — Resolution Pharmacology — that promises novel approaches for the treatment of inflammatory diseases via resolution agonists.

This conference will convene pre-eminent researchers at the cutting edge of the field to discuss mechanisms of inflammation, tissue repair, and regeneration, and explore the existing hurdles to clinical approaches.

Registration

Member
By 05/11/2018
$175
After 05/11/2018
$200
Onsite
$250
Nonmember Academia, Faculty, etc.
By 05/11/2018
$250
After 05/11/2018
$300
Onsite
$375
Nonmember Corporate, Other
By 05/11/2018
$350
After 05/11/2018
$400
Onsite
$475
Nonmember Not for Profit
By 05/11/2018
$250
After 05/11/2018
$300
Onsite
$375
Nonmember Student, Undergrad, Grad, Fellow
By 05/11/2018
$175
After 05/11/2018
$200
Onsite
$350
Member Student, Post-Doc, Fellow
By 05/11/2018
$150
After 05/11/2018
$175
Onsite
$225
Member
$60
Nonmember Academia, Faculty, etc.
$130
Nonmember Corporate, Other
$170
Nonmember Not for Profit
$130
Nonmember Student, Undergrad, Grad, Fellow
$90
Member Student, Post-Doc, Fellow
$30
Member
$30
Nonmember Academia, Faculty, etc.
$65
Nonmember Corporate, Other
$85
Nonmember Not for Profit
$65
Nonmember Student, Undergrad, Grad, Fellow
$45
Member Student, Post-Doc, Fellow
$15
Member
$30
Nonmember Academia, Faculty, etc.
$65
Nonmember Corporate, Other
$85
Nonmember Not for Profit
$65
Nonmember Student, Undergrad, Grad, Fellow
$45
Member Student, Post-Doc, Fellow
$15
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Scientific Organizing Committee

Resolution of Inflammation, Infection and Tissue Regeneration
Charles N Serhan, PhD, DSc,
Brigham and Women's Hospital, Harvard Medical School
george-zavoico
George Zavoico, PhD,
B. Riley FBR
Resolution of Inflammation, Infection and Tissue Regeneration
Sara Donnelly, PhD,
The New York Academy of Sciences
sonya-dougal
Sonya Dougal, PhD,
The New York Academy of Sciences

Keynote Speakers

Resolution of Inflammation, Infection and Tissue Regeneration
Charles N Serhan, PhD, DSc,
Brigham and Women's Hospital, Harvard Medical School
Resolution of Inflammation, Infection and Tissue Regeneration
Catherine Godson, PhD,
University College Dublin
Resolution of Inflammation, Infection and Tissue Regeneration
Kevin J. Tracey, MD,
The Feinstein Institute for Medical Research
Resolution of Inflammation, Infection and Tissue Regeneration
Paul Ridker, MD, MPH,
Brigham & Women's Hospital, Harvard Medical School

Speakers

Resolution of Inflammation, Infection and Tissue Regeneration
Thomas E. Van Dyke, DDS, PhD,
Forsyth Center for Clinical and Translational Research
Resolution of Inflammation, Infection and Tissue Regeneration
Gabrielle Fredman, PhD,
Albany Medical Center
Resolution of Inflammation, Infection and Tissue Regeneration
Bruce Levy, MD,
Brigham & Women's Hospital, Harvard Medical School
Resolution of Inflammation, Infection and Tissue Regeneration
Patricia J. Sime, MD,
University of Rochester School of Medicine
Resolution of Inflammation, Infection and Tissue Regeneration
Bernd W. Spur, PhD,
Rowan University School of Osteopathic Medicine
Resolution of Inflammation, Infection and Tissue Regeneration
Matt Spite, PhD,
Brigham & Women's Hospital, Harvard Medical School
Resolution of Inflammation, Infection and Tissue Regeneration
Michael S Conte, MD,
University of California, San Francisco
Resolution of Inflammation, Infection and Tissue Regeneration
Ru-Rong Ji, PhD,
Duke University School of Medicine
Resolution of Inflammation, Infection and Tissue Regeneration
Ira Tabas, MD PhD,
Columbia University
Resolution of Inflammation, Infection and Tissue Regeneration
Jesmond Dalli, PhD,
William Harvey Research Institute, QMUL
Resolution of Inflammation, Infection and Tissue Regeneration
Nan Chiang, PhD,
Brigham & Women's Hospital, Harvard Medical School
Resolution of Inflammation, Infection and Tissue Regeneration
Mark Tepper, PhD,
Corbus Pharmaceuticals
Dipak Panigrahy
Dipak Panigrahy, MD,
Beth Israel Deaconess Medical Center, Harvard Medical School
Resolution of Inflammation, Infection and Tissue Regeneration
Katrin D. Mayer-Barber, PhD,
National Institute of Allergy and Infectious Diseases




Monday

June 25, 2018

8:30 AM

Registration and Continental Breakfast

9:00 AM

Welcome and Introductory Remarks

Speakers

Sonya Dougal, PhD
The New York Academy of Sciences
George Zavoico, PhD
B. Riley FBR
9:15 AM

KEYNOTE SPEAKER: Resolution Mediators and Mechanisms in Inflammation: Leads for 21st Century

Speaker

Charles N Serhan, PhD, DSc
Brigham and Women's Hospital, Harvard Medical School

Inflammation is now considered an integral component of many non-classic inflammatory diseases e.g. arthritis, periodontal disease, asthma, cardiovascular diseases and neurodegenerative diseases. Using a systems approach with self-limited inflammatory infectious exudates to map tissue events, cell traffic and identification of protein and chemical mediators, we identified three structurally distinct families of potent omega-3 essential fatty acid-derived (EPA, DPA, DHA) novel endogenous mediators, named resolvins, protectins and maresins coined specialized pro-resolving mediators (SPM). Complete structural elucidation and total organic synthesis of these new molecules demonstrated their functions in vivo in the resolution of acute inflammation in many animal models. Each member of this super-family is chemically distinct and functions as a pro-resolving local mediator that controls the duration and magnitude of acute inflammatory responses with actions in pico-nanogram range in animal disease models. Mapping of these resolution circuits provides new avenues to probe the molecular basis of many widely occurring diseases (CN Serhan, Nature 2014). This presentation shall focus on our recent advances in the biosynthesis and functions of SPM and their actions in counter-regulation of pro-inflammatory mediators. SPM possess potent multi-pronged anti-inflammatory, pro-resolving, and anti-microbial actions and stimulate tissue regeneration. We operationalized LC-MS-MS based mediator-metabololipidomics to profile SPM in human tissues (serum, plasma, breast milk, lung, adipose, tears and brain) uncovering new pathway/mechanisms that stimulate both tissue regeneration and bacterial clearance. Together these findings indicate that endogenous resolution pathways may underlie prevalent diseases associated with uncontrolled inflammation and open the potential for resolution-based physiology and pharmacology.

SESSION 1: Inflammatory Mediators and Cellular Mechanisms

Session Chairperson
George Zavoico, PhD, B. Riley FBR
10:00 AM

Cancer Progression: Failure to Resolve?

Speaker

Dipak Panigrahy, MD
Beth Israel Deaconess Medical Center, Harvard Medical School

Cancer therapy reduces tumor burden by killing tumor cells, yet simultaneously creates tumor cell debris that may stimulate inflammation and tumor growth. Thus, conventional cancer therapy is inherently a double-edged sword. Here, we show that tumor cells killed by chemotherapy or targeted therapy (“tumor cell debris”) stimulated primary tumor growth when co-injected with a subthreshold (non-tumorigenic) inoculum of tumor cells, by triggering macrophage pro-inflammatory cytokine release following phosphatidylserine exposure. Debris-stimulated tumors were inhibited by anti-inflammatory and pro-resolving lipid autacoids, namely resolvin (Rv) D1, RvD2, or RvE1. These mediators specifically inhibited debris-stimulated cancer progression by enhancing clearance of debris via macrophage phagocytosis in multiple tumor types. Resolvins counter-regulated release of cytokines/chemokines, including TNFα, IL-6, IL-8, CCL4, and CCL5, by human macrophages stimulated with cell debris. These results demonstrate that enhancing endogenous clearance of tumor cell debris is a new therapeutic target that may complement cytotoxic cancer therapies.

10:30 AM

Networking Coffee Break

11:00 AM

The Interplay between Efferocytosis and Inflammation Resolution

Speaker

Ira Tabas, MD, PhD
Columbia University

Clearance of apoptotic cells (ACs) by macrophages (efferocytosis) is a key resolution effector function. We have revealed the presence of a positive-feedback cycle in which activation of the efferocytosis receptor MerTK by ACs promotes the synthesis of 5-lipoxygenase-derived resolution mediators. In terms of efferocytosis itself, macrophages must be able to rapidly internalize multiple ACs ("continued efferocytosis"). For example, in mice in which macrophages can clear one AC normally but have a defect in continued efferocytosis, the accumulation of uncleared dead cells and consequent tissue necrosis and inflammation are prominent. Continued efferocytosis has two fundamental requirements: (1) recycling of membranes such that internalization of the plasma membrane during phagocytosis of the 1st AC is rapidly followed by vesicular trafficking of phagolysosomal membrane to the cell surface, i.e., to enable restoration of plasma membrane surface area for 2nd AC phagocytosis; and (2) "cargo handling" by the macrophage in response to the large load of molecules, e.g., amino acids and fatty acids, resulting from the phagolysosomal degradation of the 1st AC. We have shown that the first process is mediated by a mitochondrial fission-calcium pathway and that the second process features a specific amino acid metabolism-Rac1 pathway that licenses the macrophage to internalize a 2nd AC. In summary, efferocytosis is a key arm of the resolution response that participates in a mediator « effector positive-feedback cycle of resolution, and in order for efferocytosis to function properly, macrophages must carry out specific signaling and metabolism pathways to enable the uptake of multiple ACs.

11:30 AM

Resolution of Pain by Pro-resolution Mediators via Neural and Immune Regulations

Speaker

Ru-Rong Ji, PhD
Duke University School of Medicine

Pain is often associated with inflammation and is a cardinal features of inflammation. In collaboration with Dr. Serhan, we have demonstrated that specialized pro-resolution mediators (SPMs) such as resolvins (RvD1, RvE1, RvD2), protectins (eg. protectin D1/neuroprotectin D1 (PD1/NPD1) and maresin (MaR1) produce potent analgesic effects in animal models of inflammatory pain. As expected, the analgesic effects of SPMs could be associated with their regulation of inflammation (anti-inflammation and pro-resolution). However, we also found the existence of functional SPM receptors (e.g., ChemR23) in neurons, especially in primary sensory neurons in dorsal root ganglion (DRG) that can sense various nociceptive signals. Strikingly, SPMs rapidly modulate the function of ion channels, such as TRPV1 and TRPA1 that are critically involved in the induction of inflammatory pain. Electrophysiology revealed that resolvin E1 (RvE1) can potentially suppress the TRPV1 current induced by capsaicin in mouse and human DRG neurons. This effect is mediated by ChemR23 and beta-arrestin-2. I will also show evidence that SPMs prevent the development of neuropathic pain by controlling neuroinflammation such as activation of glial cells in the spinal cord. We also found a loss of SPMs (such as RvD1) during the development of chronic pain. Finally, I will demonstrate signaling mechanisms by which SPMs regulate phagocytosis and phenotypes of macrophages. Together, our data demonstrate that SPMs control the resolution of pain by both neural and immune regulations.

12:00 PM

Networking Lunch Break

SESSION 2: Resolution of Cardiovascular and Systemic Inflammation

Session Chairperson
Patricia J. Sime, MD, University of Rochester School of Medicine
1:00 PM

KEYNOTE SPEAKER: Providing Proof of Principle for Atherosclerosis, Lung Cancer, Kidney Disease, and Osteoarthritis: Lessons from CANTOS

Speaker

Paul Ridker, MD, MPH
Brigham & Women's Hospital

Inflammation and its resolution impact on multiple organ systems and multiple disease processes including atherosclerosis and cancer, yet until recently there has been no proof of concept that lowering inflammation could lower the risks of these life-threatening disorders. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), conducted between 2010 and 2017 in 39 countries and involving over 1000 investigators, randomly allocated 10,061 post-myocardial infarction patients with elevated hsCRP to placebo or one of three doses of canakinumab, a monoclonal antibody targeting intereukin-1-beta (50mg, 150mg, 300mg SC once every 3 months). Primary results of CANTOS demonstrate for the first time that, in the absence of lipid lowering or blood pressure reduction, inhibition of IL-1-beta and consequent lowering of IL-6 and hsCRP results in statistically significant benefits for major cardiovascular events as well as incident lung cancer. In his talk, Dr Ridker will provide updates on multiple CANTOS sub-studies as they relate to diabetes, kidney disease, chronic anemia, gout, and other rheumatologic conditions, emphasizing the “systems biology” approach used to design and run the trial and the importance of recognizing and treating “residual inflammatory risk”.

1:45 PM

Resolution of Vascular Injury: Mechanisms and Therapeutic Implications

Speaker

Michael S Conte, MD
University of California, San Francisco

Unresolved inflammation is central to the pathophysiology of commonly occurring vascular diseases such as atherosclerosis, aneurysm, and deep vein thrombosis—conditions that are responsible for considerable morbidity and mortality across the globe. Surgical or catheter-based procedures performed to treat vascular disease induce acute on chronic inflammatory responses. The resolution of vascular inflammation is an important driver of vessel wall healing and functional recovery in these clinical settings. Specialized pro-resolving lipid mediators (SPMs) derived from omega-3 polyunsaturated fatty acids orchestrate key cellular processes driving resolution and return to homeostasis. The identification of their potent effects in classic animal models of sterile inflammation triggered interest in their vascular properties. Recent studies have demonstrated that SPMs are locally synthesized in vascular tissues, have direct effects on vascular cells and their interactions with leukocytes, and play a protective role in the acute injury response. Early translational work has established the potential for SPMs as vascular therapeutics, and as candidate biomarkers in vascular disease. Specifically, targeted delivery of SPM to sites of vascular injury has emerged as a potential therapeutic approach to enhance vascular healing and patency. Further investigations are needed to understand the molecular and cellular mechanisms of resolution in the vasculature, improve tools for clinical measurement, and to better define the potential for resolution pharmaco-biology in cardiovascular patients.

2:15 PM

Dysregulation of Resolution Pathways in Atherosclerosis

Speaker

Gabrielle Fredman, PhD
Albany Medical Center

Non-resolving inflammation is the underpinning of several prevalent diseases including atherosclerosis. Understanding new mechanisms to promote the resolution of inflammation in atherosclerosis are of interest. Resolution is mediated in part by specialized pro-resolving mediators, including resolvins such as Resolvin D1 (RvD1). We recently showed that RvD1 prevents lesional necrosis in Ldlr-/- mice. However, the mechanisms underlying RvD1’s protective actions remain unknown. In this regard, the accumulation of necroptotic cells has recently emerged as a driver of plaque necrosis. Necroptotic cells are particularly harmful because they possess a highly pro-inflammatory and proteolytic phenotype. Because RvD1 decreased lesional necrosis, we questioned whether RvD1’s actions were through limiting necroptotic cells in plaques. Briefly, we administered RvD1 to Ldlr-/- mice during advanced atherosclerosis and observed a significant decrease in necroptotic cells and overall lesion necrosis compared with vehicle controls. To explore mechanism, we developed a method to quantify efferocytosis of necroptotic cells with the use of ImageStream flow cytometry as well as confocal imaging.  Briefly, we found that necroptotic cells have defective clearance mechanisms that can be rescued by RvD1. This talk will focus on mechanisms underlying delayed efferocytosis of necroptotic cells and how RvD1 rescues this impairment.

2:45 PM

Presentation to Dr Richard Okita in Recognition of Service to the Field

Speaker

Charles N Serhan, PhD, DSc
Brigham and Women's Hospital, Harvard Medical School
2:50 PM

Networking Coffee Break

3:20 PM

The Role of n-3 Docosapentaneoic Acid-derived Pro-resolving Mediators in Systemic Protection

Speaker

Jesmond Dalli, PhD
William Harvey Research Institute, QMUL

Understanding processes occurring within the vasculature may shed light onto events leading to both vascular as well as peripheral tissue disease. We recently found that during both sterile and infectious inflammation n-3 docospaentaenoic acid is precursor to two novel autacoid families termed as D-series resolvins (RvDn-3 DPA) and 13-series resolvins (RvT). These mediators carry potent leukocyte and endothelial-directed actions counter-regulating the production of inflammatory mediators including prostaglandins and leukotrienes. Using liquid chromatography-tandem mass spectrometry-based lipid mediator profiling we found that RvDn-3 DPA are diurnally regulated in the plasma of healthy volunteers. These changes in peripheral blood RvDn-3 DPA correlated with a circadian regulation of peripheral blood leukocyte and platelet activation. The diurnal regulation of RvDn-3 DPA was lost in patients with cardiovascular disease (CVD) that also displayed increase platelet and leukocyte activation. Of note, addition of RvDn-3 DPA to peripheral blood from CVD patients led to a significant downregulation of activation markers on both platelet and leukocytes. RvT were also found to display potent actions in the circulation regulating systemic inflammation via downregulating the levels of inflammation initiating factors including PAI-1 and inflammasome components and the upregulation of circulating prostacyclin during bacterial infections. In addition, we found that these autacoids were responsible for mediating the host protective actions of statins during both sterile and infectious inflammation. Together these findings establish the vasculo-protective actions of n-3 docospaentaenoic acid derived resolvins. They also identify novel biomarkers in assessing vascular inflammation and the effectiveness therapeutics at regulating local and systemic inflammation.

3:50 PM

Pro-resolving Receptors: Mechanisms and Signaling

Speaker

Nan Chiang, PhD
Harvard Medical School

Endogenous mechanisms that govern resolutions programs during acute inflammation are essential for hose defense. Specialized pro-resolving mediators (SPM) including lipoxins, resolvins, protectins and maresins constitute a superfamily of potent endogenous lipid mediators that stimulate resolution of inflammation and infection. We identified several G Protein-coupled Receptors (GPCR) that contribute to pro-resolving actions of SPM, including ALX, ERV1/ChemR23, DRV1/GPR32 and recently identified DRV2/GPR18 (Chiang and Serhan, Mol Aspects Med. 2017). As an example, the RvD2-receptor (DRV2/GPR18) resolution axis activates intracellular signaling pathways, contributing to endogenous resolution mechanisms in bacterial infections, sepsis and intrinsic organ protection (Chiang et al., J Exp Med. 2015 and J Immunol. 2017). These SPM receptors provide a template for resolution physiology and pharmacology that may offer new opportunities to control unwanted inflammation and infection.

We recently identified new pathway of mediators termed Maresin Conjugates in Tissue Regeneration (MCTR), including MCTR1, MCTR2 and MCTR3. We addressed whether each MCTR can impact known vascular actions of cysteinyl leukotrienes. Leukotriene D4 (LTD4, 1.5 nmol/mouse) initiated vascular leakage in mouse cremaster vessels that was markedly reduced (>75%) by MCTR1 and MCTR2 (0.15 nmol each). With isolated Ciona intestinalis (sea squirt) primordial hearts, LTD4 (1-100 nM) gave negative inotropic action, lowering heartbeats 20-30%. Each MCTR (1-100nM) blocked LTD4-reduced heart rates. With human cysteinyl leukotriene receptor-1 (CysLT1) expressed in CHO cells, each MCTR (10-100nM) significantly reduced LTD4-initiated signaling. To assess the contribution of CysLT1 in MCTR’s pro-resolving actions, we carried out human macrophage phagocytosis. Each MCTR (0.1-10nM) stimulated human macrophage phagocytosis of live E. coli, while LTD4 did not stimulate phagocytosis. MCTR-activated phagocytosis was significantly blocked by a pharmacological receptor antagonist (MK571). With both CHO-CysLT1 and human macrophages, each MCTR competed for specific 3H-LTD binding with apparent lower affinity than LTD4. Thus, each MCTR functionally interact with human CysLT1 to pharmacologically counter-regulate vascular responses and stimulate physiologic phagocytosis with macrophages (Chiang et al., FASEB J. 2018). Taken together, these findings demonstrate the opposing bioactions of CysLTs and MCTR in vivo and in vitro, that open new opportunities to address the pharmacologic interactions of these mediators and potentially to the physiologic roles of MCTRs.

This work was supported in part by NIH grants GM38765 and P01-GM095467 (CNS).

4:20 PM

Exercise-stimulated Catecholamine Release Enhances Resolution of Acute Inflammation

Speaker

Jason Hellmann, PhD
University of Louisville School of Medicine

The mechanisms by which regular exercise prevents the development and progression of chronic inflammatory diseases are largely unknown. We find that exercise (Exe) enhances resolution of acute inflammation by promoting macrophage (Mɸ) phagocytosis and by augmenting resolvin D1 (RvD1) levels. When compared with sedentary controls (Sed), mice adapted to a 4-week treadmill exercise regimen displayed 1.48-fold higher Mɸ phagocytotic activity, enhanced RvD1 levels (Sed 28.08±1.5 vs Exe 48.01±8.6 pg/mL, n=6), and earlier neutrophilic clearance (ΔRi ~7 h) during peritonitis. Peritonitis cell extracts from exercise-adapted mice showed elevated expression of Alox15 (48 h: Sed 0.97±0.15 vs Exe 1.5±0.16 relative expression, n=8-9), Alox5 (48 h: Sed 0.77±0.15 vs Exe 1.7±0.27 relative expression, n=4-5), and RvD1 levels (48 h: 29.0±2.1 vs 52.6±8.9 pg/mL, n=5). Because exercise stimulates epinephrine (Epi) release, which has immunomodulatory effects, we questioned if Epi exerts pro-resolving actions on macrophages. Epi-treated macrophages displayed higher 15-lipoxygenase 1 expression and RvD1 levels, which were prevented by incubation with the α1 adrenergic receptor (AR-α1) blocker, Prazosin (Praz). During zymosan-induced peritonitis, Praz abrogated exercise-enhanced neutrophilic clearance (48 h: Exe+Veh 2.07±0.41 vs Exe+Praz 5.2±1.04 x106 PMN, n=5), Mɸ phagocytosis (Exe+Veh 33463.0±2174.0 vs Exe+Praz 8303.0±2748.0 MFI, n=5-7), and RvD1 biosynthesis (Exe+Veh 211.0±55.4 vs Exe+Praz 81.79±11.8 pg/mL, n=6). These results suggest that exercise-stimulated Epi release enhances resolution of acute inflammation in an AR-α1 dependent manner. These findings provide new mechanistic insights into the pro-resolving effects of exercise and may lead to the identification of novel pathways to stimulate resolution biology.

4:35 PM

Subacute Exposure of Carprofen Facilitate Splenocardiac Resolution Deficit in Cardiac Injury

Speaker

Ganesh V. Halade, PhD
The University of Alabama at Birmingham

Inflammation limiting non-steroidal pain-relievers magnifies myocardial infarction (MI) and re-admission in heart failure (HF) patients. However, the molecular and cellular basis of this provocative adverse effect is unclear. To determine whether carprofen (CAP) impede splenic leukocyte directed acute inflammation- resolving response in cardiac injury. After subacute CAP exposure, mice were subjected to coronary occlusion maintaining non-CAP MI- and naïve-controls. Post ligation, acute decompensated HF developed in CAP and MI-controls within 24 hour. Subacute CAP over activated don’t eat me signal with preactivation of splenic neutrophils and reduced total and reparative macrophages compared with control in left ventricle (LV) and spleen. Subacute CAP exposure facilitated leukocyte death in LV and was more evident post-MI compared with MI-control. Post-MI, CAP preactivated neutrophils were intensified and reduced reparative neutrophils and macrophages in LV was indicative of non-resolving inflammation compared with MI-control. In CAP, preactivated splenic neutrophils tailored the macrophage phagocytosis thereby increased splenocardiac leukocyte death. CAP over amplified cyclooxygenase (COX)-1 and COX-2 compared with MI-control and failed to limit prostaglandins and thromboxane in post-MI setting. Further, CAP reduced cardiac protective epoxyeicosatrienoic acids and over amplified inflammatory cytokines and reduced reparative cytokines thereby non-resolving inflammation. Subacute CAP exposure intensified marked neutrophil swarming indicative of inflammation-resolution-deficit in cardiac injury. Thus, pre-clinical and clinical studies are warranted to determine inflammation-resolution deficit in HF.

4:50 PM

Poster Viewing and Networking Reception

Speaker

Presenters to be available at their posters during this time
5:50 PM

Adjourn

Tuesday

June 26, 2018

8:30 AM

Registration and Continental Breakfast

9:00 AM

Welcome Remarks

Speaker

Charles N Serhan, PhD, DSc
Brigham and Women's Hospital, Harvard Medical School
9:15 AM

KEYNOTE SPEAKER: Molecular Approaches to Bioelectronic Medicine

Speaker

Kevin Tracey, MD
The Feinstein Institute for Medical Research

Reflex neural circuits maintain physiological homeostasis.  Recent advances in immunology and neuroscience converge on discovery of reflexes activated by pathogens, cytokines, and other molecules associated with infection and injury. Mapping the specific and functional organization of reflexes in the vagus nerve nerves has revealed anatomical, neurophysiological and molecular mechanisms for reflex control of immunity. This also provided direct paths to clinical testing in the treatment of rheumatoid arthritis and inflammatory bowel disease, and a framework for the new field of bioelectronic medicine.

SESSION 3: Tissue Repair and Infection

Session Chairperson
Jesmond Dalli, PhD, William Harvey Research Institute, QMUL
10:00 AM

Temporal Biosynthesis of Pro-Resolving Lipid Mediators by Distinct Immune Cell Subsets during Skeletal Muscle Injury and Regeneration

Speaker

Matthew Spite, PhD
Harvard Medical School; Brigham and Women's Hospital

Specialized pro-resolving lipid mediators (SPM) generated during the resolution phase of acute inflammation have been shown to blunt tissue infiltration of neutrophils and to promote the removal of apoptotic cells by macrophages. Emerging evidence indicates that SPM play diverse roles during tissue injury and actively promote the transition from inflammation to tissue repair and regeneration. Using murine models of acute sterile tissue injury, including chemical or exercise-induced skeletal muscle damage, our recent results indicate that D-series resolvins and related SPM are biosynthesized by distinct immune cell subsets and actively signal tissue repair in part by modulating transcriptional programs in macrophages. This presentation will highlight our recent results on the biosynthesis and actions of SPM in tissue repair.

10:30 AM

Networking Coffee Break

11:00 AM

COPD: Inflammation, Infection and Resolution

Speaker

Patricia J. Sime, MD
University of Rochester School of Medicine

Inflammation is a protective response to injurious stimuli, but when left unchecked, chronic inflammation can lead to tissue damage and disease. It is now known that resolution of inflammation is an active process mediated by a recently discovered family of specialized pro-resolving lipid mediators (SPMs). Tobacco smoking is the leading preventable cause of multiple respiratory diseases including lung cancer and COPD. It is a profound pro-inflammatory stimulus. Importantly, chronic inflammation persists long after smoking cessation in both humans and animal models, suggesting that tobacco smoke impairs the normal mechanisms of resolution. Using patient samples, in vitro systems, and preclinical animal models of tobacco smoke exposure, we will identify how smoke dysregulates resolution mechanisms, and investigate potential therapeutic use of SPMs in lung disease. Pro-resolving lipid mediators have anti-inflammatory and pro-resolving effects in primary human lung fibroblasts, epithelial cells and alveolar macrophages when stimulated with either cigarette smoke or other pro-inflammatory mediators. RvD1 profoundly inhibits lung inflammation in an acute mouse model of cigarette smoke exposure, accelerates resolution and inhibits the develop of emphysema when given concurrently with cigarette smoke over 16 weeks. RvD1 also dampens lung inflammation and enhances clearance of Nontypeable Haemophilus influenzae, a Gram-negative pathogen that frequently causes bronchitis and pneumonia in patients with underlying lung disease. Taken together, our data demonstrate that pro-resolving lipid mediators are effective in therapeutically promoting a pro-resolving phenotype in human lung cells and animal models of smoke-induced lung disease and have tremendous therapeutic potential.

11:30 AM

Specialized Pro-Resolving Mediators in Lung Health and Disease

Speaker

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 (ERV1) are expressed in lung and are dynamically regulated with lung inflammation. Evidence will be presented for cellular and molecular mechanisms for representative SPMs in their protective actions in the regulation of airway inflammation during innate and adaptive immune responses.

12:00 PM

ODSH Improves Bacterial Clearance in Cystic Fibrosis by Reducing HMGB1 Release and Improving Phagocytosis of Airway Macrophages

Speaker

Lin L. Mantell, MD, PhD
St. John’s University & The Feinstein Institute for Medical Research

Cystic fibrosis (CF) is characterized by chronic infection and inflammation in the airways. We previously reported that levels of airway HMGB1, significantly elevated in CF patients and animals, can compromise innate immunity against bacterial infections via impairing phagocytic function of macrophages, contributing to the poor clinical outcomes in the lungs. In this study, we show that CF epithelial IB3 cells (with CFTR deficiency) release more HMGB1 at basal levels as well as upon stimulation with bacterial components than their genetically corrected epithelia S9 cells. CF macrophages treated with LPS also released more HMGB1 than WT ones. In addition, CF IB3 cells exhibited significantly less NO release upon exposure to LPS. These data suggest that CFTR deficiency contributes to the decreased bacterial killing capacity in CF by releasing more HMGB1 into the airways from both airway epithelia and macrophages and impairing NO production upon infections. Both alveolar macrophages (AM) and bone marrow derived macrophages (BMDM) from CF mice had significantly lower phagocytic functions than their wildtype counterparts. The extent of such impairment is more prominent in AM, suggesting microenvironment in CF airways also contributes to the compromised macrophage functions. To investigate if neutralizing airway HMGB1 pharmacologically can improve innate immunity against bacterial infections, ODSH, that can block HMGB1 binding to its receptors, was used to treat both AM and BMDM in the presence of rHMGB1. Indeed, ODSH improved macrophage phagocytic functions compromised by rHMGB1, while exhibited no effects on macrophages in the absence of rHMGB1. CF Mice treated with ODSH had significantly reduced bacterial load in the lungs and attenuated acute lung injury with improved epithelial lining integrity upon bacterial infections. These data demonstrate that airway HMGB1 released by epithelial cells and macrophages in CF contribute to the compromised innate immunity, by compromising bacterial clearance. ODSH may provide a targeted therapeutic approach by attenuating the effects of airway HMGB1 in bacterial clearance to improve clinical outcomes in CF.

12:15 PM

Inflammatory Cytokines and Lipid Mediators in Host Resistance to Tuberculosis

Speaker

Katrin Mayer-Barber, PhD
National Institute of Allergy and Infectious Disease

During infection distinct arms of innate inflammatory responses establish counter regulatory cytokine and lipid mediator networks that ultimately determine the outcome of infection. We have studied these processes in the context of pulmonary infection with Mycobacterium tuberculosis, which is the causative agent of TB and currently the single most deadly global pathogen. We found that IL-1 and Type I IFN driven inflammation is tightly linked to eicosanoids and that manipulation of the host lipid mediators during TB is a promising avenue for host-directed therapies in TB. Understanding different classes of inflammation and the corresponding innate effector cells, lipids, and cytokines that orchestrate protective versus detrimental inflammatory responses will provide critical insight for the development of new treatment strategies for a variety of inflammatory diseases, including non-infectious chronic inflammatory conditions.

12:30 PM

Networking Lunch Break

SESSION 4: Clinical Development and Therapeutic Potential for Inflammatory Disease

Session Chairperson
Charles N Serhan, PhD, DSc, Brigham and Women's Hospital, Harvard Medical School
1:30 PM

KEYNOTE SPEAKER: Lipoxins and Lipoxin Mimetics Attenuate Diabetic Complications

Speaker

Catherine Godson, PhD
University College Dublin

The failure of effective resolution underlies chronic inflammatory conditions including complications of diabetes such as kidney disease and atherosclerosis. The identification of endogenously generated molecules including lipoxins, [LXs], which promote the physiologic resolution of inflammation suggests that these bioactions may have therapeutic potential in the context of chronic inflammation. Here we investigated the potential of LXA4 and a synthetic LX mimetics to modulate diabetic complications in the streptozotocin-induced diabetic ApoE-/- mice and in human carotid plaque tissue ex vivo.

Diabetes-induced kidney disease including albuminuria, mesangial expansion and collagen deposition was attenuated by LXs in mice administered LXs 10 weeks after disease onset, with evidence of preserved kidney function. Kidney transcriptome profiling defined a diabetic signature [725 genes; FDR P≤0.05]. Comparison of this murine gene signature with human DKD identified shared renal pro-inflammatory/pro-fibrotic signals (TNF-α, IL-1β, NF-κB). In diabetic mice we identified transcripts regulated by LXs and pathway analysis identified established (TGF-β1, PDGF, TNF-α, NF-κB) and novel (Early growth response-1 - EGR-1) networks activated in diabetes and regulated by LXs.

The development of diabetes-induced aortic plaques and associated inflammatory responses were significantly attenuated by LXs in diabetic ApoE-/- mice. In mice with established atherosclerosis, treatment with LXs led to a significant reduction in aortic arch plaque development. Treatment of human carotid plaques explants with LXs ex vivo attenuated secretion of distinct protein networks. LXs inhibited PDGF-stimulated vascular smooth muscle cells proliferation and transmigration and endothelial cell inflammation. These data demonstrate that LXs can reverse established diabetic complications and support a therapeutic paradigm to promote the resolution of inflammation in this context.

2:15 PM

Targeting the Endocannabinoid-Specialized Pro-resolution Mediator Pathway with Lenabasum to Treat Chronic inflammatory/Fibrotic Diseases

Speaker

Mark Tepper, PhD
Corbus Pharmaceuticals

The endocannabinoid system plays an important role in resolution of inflammation. Lenabasum is a synthetic analog of D8-tetrahydrocannabinol (THC)-11-oic acid, currently in clinical development for the treatment of rare chronic inflammatory/fibrotic diseases such as systemic sclerosis, dermatomyositis, lupus and Cystic Fibrosis. Lenabasum is a selective CB2 agonist having demonstrated promising clinical benefit and a favorable safety profile in three double-blind placebo-controlled clinical studies for systemic sclerosis, dermatomyositis and Cystic Fibrosis, respectively. In each of these studies, lenabasum treatment for 12 weeks resulted in clinical benefit as seen by an improvement in the ACR combined response index of systemic sclerosis (CRISS) score; an improvement in the cutaneous dermatomyositis disease area and severity index (CDASI) score; and a reduction in the number of and time to pulmonary exacerbations in Cystic Fibrosis. A clinical study was also conducted in a human model of acute inflammation triggered by intradermal injection of ultraviolet light-killed E coli on the forearms of healthy subjects followed by blister formation to tap the inflammatory exudate.  Lenabasum increased blood flow during the resolution phase; reduced IL-8 levels and neutrophil counts in blister exudates post-challenge; reduced the proinflammatory lipid mediators LTB4, PGF2a, TxB2 and PGE2; increased the specialized pro-resolution lipid mediators (SPMs), lipoxins (LXA4, LXB4) and resolvins (RvD1, RvD3, RvD5); and hastened bacterial clearance. Thus, lenabasum exerts a profound therapeutic effect by accelerating the resolution phase of the innate immune response and supports the hypothesis that endocannabinoids play a natural role to trigger resolution through CB2 agonism.

2:45 PM

Total Synthesis of Lipid Mediators of Resolution of Inflammation and Tissue Regeneration

Speaker

Bernd W. Spur, PhD
Rowan University School of Osteopathic Medicine, NJ

The acute inflammatory response is a protective reaction if resolved. However uncontrolled inflammation is the underlying basis of many chronic diseases including asthma, rheumatoid arthritis, diabetes, and cardiovascular and neurological diseases. The studies by Serhan and collaborators have identified powerful specialized pro-resolving mediators (SPMs) that are central in the resolution of inflammation and tissue repair. These SPMs include the recently discovered sulfido conjugates of maresin, protectin and resolvin. In order to fully characterize these new SPMs we have prepared them by total organic syntheses and verified their structures by spectroscopic techniques. Serhan and collaborators compared these synthetic SPMs with native derived materials by LC-MS-MS and bioassays and confirmed their identity. Our chemical syntheses not only provide sufficient amounts for the initial biological testing but help to assist the pharmacological testing. The final goal is to develop robust synthetic routes that ultimately allow the large scale production of SPMs from readily available starting materials for clinical trials. We have evaluated several SPMs in the animal model of sepsis and have found increased survival with reduced bacterial load. New mechanisms of action were discovered that could have a profound impact on infection control and might be an addition or alternative to the current antibiotic therapy.

3:15 PM

Networking Coffee Break

3:45 PM

The Role of Resolution Phase Mediators in Oral Medicine

Speaker

Thomas E. Van Dyke, DDS PhD
Forsyth Center for Clinical and Translational Research

The periodontal diseases are the most common inflammatory diseases of man.  Gingivitis is ubiquitous affecting >90% of people, but periodontitis with irreversible tissue destruction affects more than 47% of the US population. Periodontitis is an infectious/inflammatory disease associated with dysbiosis of the commensal oral microbiome. Importantly, recent studies demonstrate a relationship between oral infectious/inflammatory conditions, in particular periodontal disease, and risk for the development of cardiovascular disease and stroke, and studies in diabetics have revealed that untreated periodontal disease can lead to diabetic complications and have a direct impact on glycemic control. As our understanding of pathways of inflammation has matured, a better understanding of the molecular basis of resolution of inflammation, which is distinct from pharmacologic anti-inflammation, has emerged. Resolution of inflammation is an active; receptor agonist mediated well-orchestrated return of tissue homeostasis, not inhibition of proinflammatory pathways. The isolation and characterization of endogenous lipid mediators of resolution, called lipoxins and resolvins, has open new doorways for the management of periodontitis and systemic inflammatory diseases. Preclinical studies have demonstrated that specialized proresolving mediators (SPMs) are potent when topically applied in the prevention and treatment of periodontitis. Characterization of the molecular basis for these findings has changed our understanding of the relationship between infection and inflammation in the oral cavity. Moreover, the inflammatory mechanistic link between systemic conditions, including cardiovascular disease and type 2 diabetes, is revealed to be modifiable with SPMs. This presentation will review resolution of inflammation in the context of periodontal disease and the role of inflammation and its control in the link between periodontal inflammation and inflammatory systemic diseases, including type 2 diabetes and cardiovascular disease.

4:15 PM

Panel Discussion: Barriers to Translation in Inflammatory Disease

Speakers

Moderator: Charles N Serhan, PhD, DSc
Brigham and Women's Hospital, Harvard Medical School
Catherine Godson, PhD
University College Dublin
Patricia J. Sime, MD
University of Rochester School of Medicine
Michael S Conte, MD
University of California, San Francisco
Mark Tepper, PhD
Corbus Pharmaceuticals
5:15 PM

Closing Remarks and F1000 Poster Prize Award Presentation

5:30 PM

Adjourn

To view full attendee list, you must first register for the event, then log in to the Academy website. This list is provided for the personal, noncommercial and informational use only of event attendees, in a manner that is consistent with the New York Academy of Sciences’ mission, goals and activities.
  • Albany Medical College

  • Ambiotis

  • Avanti Polar Lipids, Inc.

  • B. Riley FBR, Inc.

  • Beth Israel Deaconess Medical Center, Harvard Medical School

  • Brigham & Women's Hospital, Harvard Medical School

  • Brigham and Women's Hospital

  • Brigham and Women's Hospital and Harvard Medical School

  • Bristol-Myers Squibb Company

  • Cayman Chemical

  • Children’s Hospital at Montefiore

  • Columbia University Medical Center

  • Corbus Pharmaceuticals

  • Corbus Pharmaceuticals Inc.

  • Duke University

  • Duke University Medical Center

  • Eli Lilly and Company

  • Feinstein Institute for Medical Research

  • Forsyth Institute, Harvard University

  • Fresenius Kabi Deutschland GmbH

  • Harvard Medical School

  • Harvard Medical School and Brigham and Women's Hospital

  • Henry Ford Hospital

  • Hunter College, CUNY

  • Intra-Cellular Therapies, Inc

  • Johns Hopkins University

  • Johnson & Johnson

  • Journal of Clinical Investigation

  • LifeExtension

  • Maresins Pharma

  • Maresins Pharma, Inc.

  • Merck Sharp & Dohme Corp.

  • Metagenics, Inc

  • National Cancer Institute, National Institutes of Health

  • NeuroLipid Research

  • New York University Medical Center

  • NIH, NIAID

  • NYU Division of Rheumatology

  • NYU Langone Health

  • Ono Pharmaceuticals Co., Ltd

  • Pfizer Global Research and Development

  • Rowan University School of Osteopathic Medicine

  • Rutgers University Robert Wood Johnson Medical School

  • Salzman Group

  • Set Point Medical

  • SetPoint Medical

  • SQI Diagnostics

  • St. John's University

  • Standard Process

  • The Feinstein Institute for Medical Research

  • The New York Academy of Sciences

  • The New York Academy of Sciences NYAS

  • The Rockefeller University

  • Trillium Medical Ventures

  • University College Dublin

  • University of California, San Francisco

  • University of Rochester Medical Center

  • University of Southern California USC

  • University of Utah

  • Vasa Rx

  • Wayne State University

  • Weill Cornell Graduate School of Medical Sciences

  • William Harvey Research Institute, Queen Mary University of London

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