Jesmond Dalli

William Harvey Research Institute | WHRI · Lipid Mediator Unit

Lipid mediators derived from omega (n)-3 and n-6 long-chain polyunsaturated fatty acids (LCPUFA) play key roles in bronchoconstriction, airway inflammation, and resolution processes in asthma. This study compared the effects of dietary supplementation with either a combination of LCPUFAs or eicosapentaenoic acid (EPA) alone to investigate whether t...

While the treatment of inflammatory disorders is generally based on inhibiting factors that drive onset of inflammation, these therapies can compromise healing (NSAIDs) or dampen immunity against infections (biologics). In search of new antiinflammatories, efforts have focused on harnessing endogenous pathways that drive resolution of inflammation...

Resolution of acute inflammation is governed, in part, by lipid mediator class switching from proinflammatory eicosanoids to specialized proresolving mediators, including a recently identified new pathway of mediators, termed maresin conjugates in tissue regeneration (MCTR), which includes MCTR1, MCTR2, and MCTR3. Here, we addressed whether each MC...

Table S3 Summary of adverse events related, or possibly related, to aspirin

Table S1 Tuberculous meningitis diagnostic criteria

Table S5 Other MRI brain findings by treatment group on days 60 and month eight in the ITT population

Table S6 CSF individual lipid mediator Profiles at baseline and 30 days post aspirin and placebo administration†

Table S2 Reasons for exclusion of screened patients from the trial

Table S4 Full Rankin scores by treatment group by day 60 and 8 months in the ITT population

The severity of cardiac dysfunction predicts mortality in sepsis. Activation of transient receptor potential vanilloid receptor type (TRPV)-1, a predominantly neuronal nonselective cation channel, has been shown to improve outcome in sepsis and endotoxemia. However, the role of TRPV1 and the identity of its endogenous ligands in the cardiac dysfunc...

Rationale: Diurnal mechanisms are central to regulating host responses. Recent studies uncovered a novel family of mediators termed as specialized proresolving mediators that terminate inflammation without interfering with the immune response. Objective: Herein, we investigated the diurnal regulation of specialized proresolving mediators in huma...

ELife digest The deadliest form of tuberculosis is tuberculosis meningitis (TBM), which causes inflammation in the brain. Even with the best treatment available, about half of patients with TBM become disabled or die, often because they have a stroke. Strokes are caused by blood clots or other blockages in blood vessels in the brain. Aspirin is kno...

Solid-phase extraction coupled with liquid chromatography tandem mass spectrometry provides a robust and sensitive approach for the identification and quantitation of specialized pro-resolving mediators (lipoxins, resolvins, protectins, and maresins), their pathway markers and the classic eicosanoids. Here, we provide a detailed description of the...

Trypanosoma cruzi is a protozoan parasite that causes Chagas disease (CD). CD is a persistent, lifelong infection affecting many organs, most notably the heart, where it may result in acute myocarditis and chronic cardiomyopathy. The pathological features include myocardial inflammation and fibrosis. In the Brazil strain-infected CD-1 mouse, which...

The mechanisms underpinning the failure of inflammation to resolve in diseased musculoskeletal soft tissues are unknown. Herein, we studied bioactive lipid mediator (LM) profiles of tendon-derived stromal cells isolated from healthy donors and patients with chronic tendinopathy. Interleukin(IL)-1β treatment markedly induced prostaglandin biosynthes...

Cancer therapy reduces tumor burden by killing tumor cells, yet it simultaneously creates tumor cell debris that may stimulate inflammation and tumor growth. Thus, conventional cancer therapy is inherently a double-edged sword. In this study, we show that tumor cells killed by chemotherapy or targeted therapy (“tumor cell debris”) stimulate primary...

Understanding mechanisms that control immunity is central in the quest to gain insights into the etiopathology of many of the diseases that afflict modern societies. New results implicate the nervous system as a central player in controlling many aspects of both the innate and adaptive arms of the immune response. Furthermore it is now well appreci...

Macrophages are central in coordinating the host response to both sterile and infective insults. Clearance of apoptotic cells and cellular debris is a key biological action preformed by macrophages that paves the way to the resolution of local inflammation, repair and regeneration of damaged tissues, and re-establishment of function. The essential...

Acute inflammation is an immediate response to infection and injury characterised by the influx of granulocytes followed by phagocytosing mononuclear phagocytes. Provided the antigen is cleared and the immune system of the host is fully functional, the acute inflammatory response will resolve. Until now it is considered that resolution then leads b...

Elicited blister exudate lipid mediator profile. (PDF)

PD1n-3 DPA is a specialized pro-resolving lipid mediator that displays potent anti-inflammatory properties and pro-resolving bioactivities. Such naturally occurring compounds are of current interest in biomolecular chemistry and drug discovery. To investigate the involvement of an epoxide intermediate in the biosynthesis of PD1n-3 DPA from n-3 doco...

While protective, the acute inflammatory response when uncontrolled can lead to further tissue damage and chronic inflammation that is now widely recognized to play important roles in many commonly occurring diseases, such as cardiovascular disease, neurodegenerative diseases, metabolic syndrome, and many other diseases of significant public health...

Background & aims: Patients with acute decompensation and acute on chronic liver failure (AD/ACLF) have immune dysfunction, which increases their risk for infections; however there are no effective treatments to restore their immune function. We investigated whether the potentially immune-restorative effects of albumin are mediated by its effects...

Neutrophil swarms protect healthy tissues by sealing off sites of infection. In the absence of swarming, microbial invasion of surrounding tissues can result in severe infections. Recent observations in animal models have shown that swarming requires rapid neutrophil responses and well-choreographed neutrophil migration patterns. However, in animal...

Resolvins, protectins and maresins are individual families of specialized pro-resolving mediators biosynthesized from the dietary n-3 polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid. These enzymatically oxygenated polyunsaturated lipid mediators were first elucidated during the resolution phase of acute inflammation in an...

Rheumatoid arthritis is an inflammatory condition characterized by overzealous inflammation that leads to joint damage and is associated with an increased incidence of cardiovascular disease. Statins are frontline therapeutics for patients with cardiovascular disease and exert beneficial actions in rheumatoid arthritis. The mechanism that mediates...

Inflammation in now appreciated to be at the centre of may diseases that affect Western civilization. Current therapeutics for managing these conditions may interfere with the host response leading to immune suppression. We recently developed an annexin (Anx) A1-derived peptide, coined CR-AnxA12-50, which displays potent pro-resolving and tissue pr...

Significance We provide evidence for a functional role of bioactive lipid mediators of the docosapentaenoic acid (DPA) metabolome in intestinal inflammation. Supported by changes in DPA-derived mediators in colon biopsies from inflammatory bowel diseases, we studied the pharmacological properties of two mediators. Exogenous administration of protec...

Infections arise when the host response is overwhelmed by pathogens leading to organ dysfunction. In some instances patients progress to more severe conditions, including septic shock, that are associated with increased mortality. Current strategies in treating infections aim at either blocking inflammation using inhibitors to pro-inflammatory mole...

Several novel oxygenated polyunsaturated lipid mediators biosynthesized from n-3 docosapentaenoic acid were recently isolated from murine inflammatory exudates and human primary cells. These compounds belong to a distinct family of specialized pro-resolving mediators, and display potent in vivo anti-inflammatory and pro-resolution effects. The endo...

Rationale: Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, is a major public health concern with high mortality and morbidity. Although inflammatory responses triggered by infection are crucial for host defense against invading microbes, the excessive inflammation often causes tissue damage leading...

Background Premenopausal women have a lower incidence of cardiovascular disease, although the exact mechanism underlying this protection is unclear. Both systemic and localised inflammation have a crucial role in the progression of cardiovascular disease, and much preclinical and observational data in human beings suggest that differences in inflam...

The past two decades have witnessed major advancements in the clinical management of inflammatory arthritis, with new treatment strategies in some cases providing a marked improvement in patient outcomes. However, it is widely accepted that current strategies do not provide the 'total therapeutic solution', in view of the proportion of patients who...

Uncovering mechanisms that control immune responses in the resolution of bacterial infections is critical for the development of new therapeutic strategies that resolve infectious inflammation without unwanted side effects. We found that disruption of the vagal system in mice delayed resolution of Escherichia coli infection. Dissection of the right...

Unresolved inflammation is key in linking metabolic dysregulation and the immune system in type 2 diabetes. Successful regulation of acute inflammation requires biosynthesis of specialized proresolving lipid mediators, such as E-series resolvin (RvE) 1, and activation of cognate G protein-coupled receptors. RvE1 binds to leukotriene B4 (BLT-1) on n...

Purpose of review: Inflammation is a unifying component of many of the diseases that afflict Western civilizations. Nutrition therapy and, in particular, essential fatty acid supplementation is one of the approaches that is currently in use for the treatment and management of many inflammatory conditions. The purpose of the present review is to di...

Background: Cardiovascular disease occurs at lower incidence in premenopausal females compared with age-matched males. This variation may be linked to sex differences in inflammation. We prospectively investigated whether inflammation and components of the inflammatory response are altered in females compared with males. Methods: We performed 2...

Maresin 1 (MaR1) is an immunoresolvent that governs resolution of acute inflammation, and its local metabolism in the context of infectious inflammation is of interest. In this study, we investigated the MaR1 metabolome in infectious exudates and its bioactions in regulating leukocyte responses in the context of bacterial infection. In Escherichia...

Significance We recently uncovered a family of macrophage-derived molecules, coined maresin conjugates in tissue regeneration, that regulate the system’s ability to clear bacteria as well as repair and regenerate damaged tissues. In the present study, we identified enzymes involved in the formation of these potent molecules in human macrophages. Th...

Persistent activation of the innate immune system greatly influences the risk for developing metabolic complications associated with obesity. In this study, we explored the therapeutic potential of the specialized proresolving mediator (SPM) resolvin D1 (RvD1) to actively promote the resolution of inflammation in human visceral adipose tissue from...

Specialized pro-resolving lipid mediators are biosynthesized during the resolution phase of acute inflammation from n-3 polyunsaturated fatty acids. Recently, the isolation and identification of the four novel mediators denoted 13-series resolvins, namely, RvT1 (1), RvT2 (2), RvT3 (3) and RvT4 (4), were reported, which showed potent bioactions char...

Objective: To identify and measure recently described chemical mediators, termed specialized pro-resolving mediators that actively regulate the resolution of acute-inflammation, and correlate measurements with clinical outcomes. Design: Herein, deidentified plasma was collected from sepsis patients (n = 22 subjects) within 48 hours of admission...

Supplemental Movie 1. Mouse physical activity after E. coli pneumonia Time-lapse movie of vehicle (right cage) or AT-RvD1 (100 ng, IV, left cage) treated mice 6 hrs after E.coli infection (106 CFU, IB)

Figure S1. AT-RvD1 enhances bacterial clearance. (a) Representative lung sections from mice 24 hrs after infection (E. coli, 106 CFU, IB) and treatment with AT-RvD1, stained with an anti-E. coli antibody, bar = 10 μm. (c) Levels of IL-1α 6, MCP-1, and IL-10, 6 hrs after infection determined by bead-based immunoassay. In all experiments, AT-RvD1 (10...

Resolution of inflammation is a finely regulated process mediated by specialized proresolving lipid mediators (SPMs), including docosahexaenoic acid (DHA)-derived resolvins and maresins. The immunomodulatory role of SPMs in adaptive immune cells is of interest. We report that D-series resolvins (resolvin D1 and resolvin D2) and maresin 1 modulate a...

Uncontrolled inflammation is a unifying component of many chronic inflammatory diseases, such as arthritis. Resolvins (Rvs) are a new family from the endogenous specialized proresolving mediators (SPMs) that actively stimulate resolution of inflammation. In this study, using lipid mediator metabololipidomics with murine joints we found a temporal r...

Objectives: Mesenchymal stromal cells are being investigated as a cell-based therapy for a number of disease processes, with promising results in animal models of systemic inflammation and sepsis. Studies are ongoing to determine ways to further improve the therapeutic potential of mesenchymal stromal cells. A gas molecule that improves outcome in...

Macrophage Proresolving Mediators—the When and Where, Page 1 of 2 Abstract Inflammation is the organism’s response to local injury in vascularized tissues programmed to traffic leukocytes and plasma delivery to an injured site or point of bacterial invasion ( 1 ); this protective response, when uncontrolled in humans, is associated with many wide...

Background When inflammation is self-limited it is host protective and leads to the repair and regeneration of damaged tissues. Chronic conditions, such as inflammatory arthritis, are though to arise from a failure of the host response to engage resolution mechanisms. The pro-resolving mechanisms engaged by the host response to promote tissue regen...

Background Dietary supplementation with fish oils has proved efficacious in reducing joint pain, swollen joint count and NSAID usage in RA patients, yet there is an unmet need to determine how they act. Omega-3 PUFA, which are abundant in fish oils are precursors to a new genus of protective bioactive lipids comprised of lipoxins, resolvins, protec...

Acute lung injury is a life-threatening condition caused by disruption of the alveolar-capillary barrier leading to edema, influx of inflammatory leukocytes, and impaired gas exchange. Specialized proresolving mediators biosynthesized from essential fatty acids, such as docosahexaenoic acid, have tissue protective effects in acute inflammation. Her...

Supplemental Table 1. Individual bioactive LM profile of human milk (4-8 weeks post-partum)* Supplemental Table 2. Comparison of SPM impact on the resolution interval (Ri) in mouse peritonitis* Fig. S1. Identification of LM in human milk. (a) Representative multiple reaction monitoring (MRM) of signature ion pairs obtained using the precursor ion (...

Inflammation in arterial walls leads to coronary artery disease (CAD). Because specialized proresolving lipid mediators (SPMs; lipoxins, resolvins, and protectins) stimulate resolution of inflammation in animal models, we tested whether n-3 fatty acids impact SPM profiles in patients with CAD and promote clot remodeling. Six patients with stable CA...

Rheumatoid arthritis (RA) is a debilitating disease characterized by persistent accumulation of leukocytes within the articular cavity and synovial tissue. Metabololipidomic profiling of arthritic joints from omega-3 supplemented mice identified elevated levels of specialized proresolving lipid mediators (SPM) including resolvin D1 (RvD1). Profilin...

The n-3 polyunsaturated fatty acids are substrates for lipoxygenases and cyclooxygenases. During inflammatory processes, these enzymes form several distinct families of oxygenated polyunsaturated fatty acids coined specialized pro-resolving lipid mediators. Structural elucidation of these natural products using LC-MS/MS based metabololipidomics wit...

Maresin conjugates in tissue regeneration (MCTR) are a new family of evolutionarily conserved chemical signals that orchestrate host responses to promote tissue regeneration and resolution of infections. Herein, we identified the novel MCTR3 and established rank order potencies and matched the stereochemistries of MCTR1, MCTR2 and MCTR3 using mater...

MCTRs and human PMN Survival in vitro. Human PMN were incubated for either 24 or 48 hours in DPBS+/+ (pH 7.2, 37°C, 5% CO2) in vehicle (DPBS+/+ alone) or with the addition of 10nM MCTR1, MCTR2, or MCTR3 at time zero. Cell viability was assessed using flow cytometry with surface staining for Annexin V and Propidium Iodide. Results are mean ± SEM fro...

MCTRs enhance human PMN phagocytosis and human macrophage efferocytosis of apoptotic PMN. (A) Human neutrophil phagocytosis. Human neutrophils (1 × 105 cells per well) were incubated with vehicle (DPBS+/+), MCTR 1, 2 or 3 (at the indicated concentrations, 15 min, 37°C). Fluorescently labeled E. coli (1:50) was then added and phagocytosis assessed a...

Inflammation and its natural resolution are host-protective responses triggered by infection or injury. The resolution phase of inflammation is regulated by enzymatically produced specialized pro-resolving mediators. We recently identified a new class of peptide-conjugated specialized pro-resolving mediators that carry potent tissue regenerative ac...

Resolvins of the D-series are specialized pro-resolving lipid mediators that regulate cellular response by orchestrating resolution networks involved in host responses to injury and infection. Here, endogenous resolvin D4 was identified in human tissues and found to persist late into the resolution phase of acute murine Staphylococcus aureus infect...