Impaired Production and Diurnal Regulation of Vascular RvD
            <sub>n-3 DPA</sub>
            Increase Systemic Inflammation and Cardiovascular Disease

Colas, Romain A.; Souza, Patricia R.; Walker, Mary E.; Burton, Maudrian; Zasłona, Zbigniew; Curtis, Anne M.; Marques, Raquel M.; Dalli, Jesmond

doi:10.1161/circresaha.117.312472

Cited by 58 publications

(60 citation statements)

References 25 publications

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“…The D-series resolvin RvD1 led to smaller necrotic cores, enhanced rates of lesional efferocytosis, and thicker collagen caps when administered to high-fat-fed Ldlr -/mice (14). Similarly, administration of RvD5 n-3 DPA (derived from n-3 docosapentaenoic acid) to high-fat-fed Apoe -/mice decreased atherosclerotic lesion size and reduced leukocyte and platelet activation (50). Treatment of Apoe -/mice with RvD2 and MaR1 also promoted plaque stability by decreasing lesional macrophage numbers, halting expansion of necrotic cores, and thickening collagen caps (15).…”

Section: Imbalance Of Inflammatory and Resolving Mediators Drives Athmentioning

confidence: 97%

“…Using lipid mediator profiling of healthy volunteers, Colas et al demonstrated that plasma concentrations of the DPA-derived D-series resolvins (RvD n-3 DPA ) are diurnally regulated. Further, the pattern of regulation was significantly impaired in patients with cardiovascular disease (50). These patients were also found to have increased leukocyte activation and higher levels of circulating platelet-leukocyte aggregates, which have been shown to be a marker of inflammation (50).…”

Section: R E V I E W S E R I E S : L I P I D M E D I At O R S O F D Imentioning

confidence: 99%

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The role of non-resolving inflammation in atherosclerosis

Kasikara¹,

Doran²,

Cai³

et al. 2018

Journal of Clinical Investigation

218

166

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Non-resolving inflammation drives the development of clinically dangerous atherosclerotic lesions by promoting sustained plaque inflammation, large necrotic cores, thin fibrous caps, and thrombosis. Resolution of inflammation is not merely a passive return to homeostasis, but rather an active process mediated by specific molecules, including fatty acid-derived specialized pro-resolving mediators (SPMs). In advanced atherosclerosis, there is an imbalance between levels of SPMs and proinflammatory lipid mediators, which results in sustained leukocyte influx into lesions, inflammatory macrophage polarization, and impaired efferocytosis. In animal models of advanced atherosclerosis, restoration of SPMs limits plaque progression by suppressing inflammation, enhancing efferocytosis, and promoting an increase in collagen cap thickness. This Review discusses the roles of non-resolving inflammation in atherosclerosis and highlights the unique therapeutic potential of SPMs in blocking the progression of clinically dangerous plaques.

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Section: Imbalance Of Inflammatory and Resolving Mediators Drives Athmentioning

confidence: 97%

Section: R E V I E W S E R I E S : L I P I D M E D I At O R S O F D Imentioning

confidence: 99%

The role of non-resolving inflammation in atherosclerosis

Kasikara¹,

Doran²,

Cai³

et al. 2018

Journal of Clinical Investigation

218

166

View full text Add to dashboard Cite

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“…In this context, recent studies in healthy volunteers found that supplementation with n‐3 DPA increased plasma RvD5 n‐3 DPA concentrations (Markworth et al ., ). Using a lipid mediator profiling approach, we found that in humans systemic concentrations of RvD n‐3 DPA diurnally regulated and their concentrations correlate with markers of both platelet and leukocyte activation including CD11b and CD62P (Colas et al ., ).…”

Section: The Identification and Structure Elucidation Of Novel Immunomentioning

confidence: 97%

Identification and structure elucidation of the pro‐resolving mediators provides novel leads for resolution pharmacology

Dalli

Serhan

2018

British J Pharmacology

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112

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Inflammatory diseases are a major socio‐economic burden, with the incidence of such conditions on the rise, especially in western societies. For decades, the primary treatment paradigm for many of these conditions was to develop drugs that inhibit or antagonize the production and biological actions of molecules that were thought to be the culprits in propagating disease; these include cytokines and eicosanoids. This approach is effective in controlling disease propagation; however, long‐term exposure to these anti‐inflammatories is also associated with many side effects, some of which are severe, including immune‐suppression. The discovery that termination of self‐limited acute inflammation is an active process orchestrated by endogenous mediators, including the essential fatty acid‐derived resolvins, protectins and maresins, has provided novel opportunities for the design of therapeutics that control inflammation with a lower burden of side effects. This is because at variance to anti‐inflammatories, pro‐resolving mediators do not completely inhibit inflammatory responses; instead, these mediators reprogramme the immune response to accelerate the termination of inflammation, facilitating the regain of function. The scope of this review is to highlight the biological actions of these autacoids and their potential utility as lead compounds in developing resolution pharmacology‐based therapeutics. Linked Articles This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc

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“…This relationship was coupled with a trend towards an increase in the concentrations of pro-inflammatory mediators in those with more severe disease (Figure 1B). Assessment of the resolution index, that is the ratio between the concentrations of pro-resolving mediators and pro-inflammatory eicosanoids, (16) also demonstrate a reduction in the resolution index, indicative of increased inflammation, in patients with the more severe disease (Figure 1C).…”

Section: Resultsmentioning

confidence: 91%

“…Using targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based profiling of CSF we identified mediators from all four major bioactive metabolomes, including the AA-derived lipoxin (LX)s, leukotriene (LT)s and prostaglandin (PG)s and the n-3 DPA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)-derived resolvin (Rv)s (Supplemental Table 2). In order to gain insights into the relationship between CSF lipid mediator concentrations and disease severity we first grouped the mediators by biological function assessing the differences between pro-resolving mediators (lipoxins, resolvins, protectins and maresins) and pro-inflammatory mediators (leukotrienes, prostaglandins and thromboxane) in patients with moderate or severe disease (MRC grades 2 and 3) when compared with those with mild disease (MRC grade 1)(16)(Figure 1A, Supplemental Table 2). Results of this analysis demonstrated that with increasing disease severity there was a decrease in overall pro-resolving lipid mediator concentrations in the CSF of patients with TBM (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

Pro-Resolving Mediator Profiles And 5-Lipoxygenase Activity In Cerebrospinal Fluid Correlate with Disease Severity and Outcome in Adults with Tuberculous Meningitis

Colas

Nhat

Thuong

et al. 2019

Preprint

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29Tuberculous meningitis (TBM) is the most lethal form of tuberculosis infection, 30 characterized by a dysregulated immune response that frequently leads to 31 neurological injury and death despite the best available treatment. The mechanisms 32 driving the inflammatory response in TBM are not well understood. To gain insights 33 into these mechanisms we used a lipid mediator profiling approach to investigate the 34 regulation of a novel group of host protective mediators, termed specialized pro-35 resolving mediators (SPM), in the cerebrospinal fluid (CSF) of adults with TBM 36 enrolled into a randomised placebo-controlled trial of adjunctive aspirin treatment. 37We found distinct lipid mediator profiles with increasing disease severity, changes 38 that were linked with an upregulation of inflammatory eicosanoids in patients with 39 severe TBM and a decrease in the production of a number of 5-lipoxygenase 40 (ALOX5)-derived SPM. CSF pro-resolving mediator concentrations were also 41 associated with 80-day survival. In survivors, we found a significant increase in pro-42 resolving mediator concentrations, including the ALOX5-derived resolvin (Rv)T2, 43RvT4 and 15-epi-Lipoxin (LX)B4, compared to those who died. Aspirin administration 44 increased the ratio of pro-resolving to pro-inflammatory mediators decreasing the 45 concentrations of the prothrombic mediator TxA2, changes that were linked with early 46 reductions in brain infarcts and deaths. Together, these findings identify a CSF SPM 47 signature that is associated with disease severity and 80-day mortality in TBM. 48Furthermore, the therapeutic manipulation of the ratio between pro-resolving 49 mediators and pro-inflammatory/thrombogenic mediators in the CSF, by aspirin for 50 example, offers a novel treatment strategy to reduce the morbidity and mortality 51 caused by TBM. Authors Summary 54Infections of the brain and the meninges by Mycobacterium tuberculosis (M. tb) lead 55 to severe inflammation and are associated with poor outcomes. The mechanisms 56 leading to this disease remain poorly defined. Herein, we investigated how M. tb 57 infection regulates the concentrations of specialized pro-resolving mediators that are 58 central in controlling the body's ability to clear infections. In these investigations, we 59 found that disease survival was linked with increased concentrations of a number of 60 these protective molecules including resolvins and lipoxins. Treatment of M. tb-61 infected patients with aspirin decreased the production of the immunosuppressive 62 and thrombogenic mediator thromboxane A2 improving the balance between 63 protective and inflammatory molecules. Of note, these changes were linked with 64 reduced disease severity and improved survival. Therefore, the present findings 65 suggest a previously unappreciated role for pro-resolving mediators in TBM 66 pathogenesis.67 90 mediate the protective actions of several widely used therapeutics, including 91 atorvastatin, pravastatin and aspirin (7, 12, 13). 92We recently tested the hypot...

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Impaired Production and Diurnal Regulation of Vascular RvD _{n-3 DPA} Increase Systemic Inflammation and Cardiovascular Disease

Abstract: These results demonstrate that peripheral blood RvD are diurnally regulated in humans, and dysregulation in the production of these mediators may lead to cardiovascular disease.

Cited by 58 publications

References 25 publications

The role of non-resolving inflammation in atherosclerosis

The role of non-resolving inflammation in atherosclerosis

Identification and structure elucidation of the pro‐resolving mediators provides novel leads for resolution pharmacology

Pro-Resolving Mediator Profiles And 5-Lipoxygenase Activity In Cerebrospinal Fluid Correlate with Disease Severity and Outcome in Adults with Tuberculous Meningitis

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Impaired Production and Diurnal Regulation of Vascular RvD n-3 DPA Increase Systemic Inflammation and Cardiovascular Disease

Abstract: These results demonstrate that peripheral blood RvD are diurnally regulated in humans, and dysregulation in the production of these mediators may lead to cardiovascular disease.

Cited by 58 publications

References 25 publications

The role of non-resolving inflammation in atherosclerosis

The role of non-resolving inflammation in atherosclerosis

Identification and structure elucidation of the pro‐resolving mediators provides novel leads for resolution pharmacology

Pro-Resolving Mediator Profiles And 5-Lipoxygenase Activity In Cerebrospinal Fluid Correlate with Disease Severity and Outcome in Adults with Tuberculous Meningitis

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Impaired Production and Diurnal Regulation of Vascular RvD _{n-3 DPA} Increase Systemic Inflammation and Cardiovascular Disease