Not all eicosanoids are bad

Morris, Thea; Rajakariar, Ravindra; Stables, Melanie; Gilroy, Derek W.

doi:10.1016/j.tips.2006.10.001

Cited by 8 publications

(5 citation statements)

References 21 publications

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“…These data contrast with the pathogenic role PGD 2 plays in allergic inflammation through DP2 (6)(7)(8). However, as with the entire field of eicosanoid biology, lipid mediators can be either protective or pathogenic depending on disease etiology, cell types present, and eicosanoid receptor expression (17). For instance, signaling through DP2 causes bronchoconstriction as well as Th2 and eosinophil cell accumulation (6)(7)(8).…”

Section: Discussionmentioning

confidence: 97%

Hematopoietic prostaglandin D₂synthase controls the onset and resolution of acute inflammation through PGD₂and 15-deoxyΔ^12–14PGJ₂

Rajakariar

Hilliard²,

Lawrence

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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237

216

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Hematopoietic prostaglandin D2 synthase (hPGD2S) metabolizes cyclooxygenase (COX)-derived PGH 2 to PGD2 and 15-deoxy⌬ 12-14 PGJ2 (15d-PGJ2). Unlike COX, the role of hPGD2S in host defense is ambiguous. PGD 2 can be either pro-or antiinflammatory depending on disease etiology, whereas the existence of 15d-PGJ 2 and its relevance to pathophysiology remain controversial. Herein, studies on hPGD 2S KO mice reveal that 15d-PGJ2 is synthesized in a self-resolving peritonitis, detected by using liquid chromatography-tandem MS. Together with PGD 2 working on its DP1 receptor, 15d-PGJ 2 controls the balance of pro-vs. antiinflammatory cytokines that regulate leukocyte influx and monocyte-derived macrophage efflux from the inflamed peritoneal cavity to draining lymph nodes leading to resolution. Specifically, inflammation in hPGD 2S KOs is more severe during the onset phase arising from a substantial cytokine imbalance resulting in enhanced polymorphonuclear leukocyte and monocyte trafficking. Moreover, resolution is impaired, characterized by macrophage and surprisingly lymphocyte accumulation. Data from this work place hPGD 2S at the center of controlling the onset and the resolution of acute inflammation where it acts as a crucial checkpoint controller of cytokine/ chemokine synthesis as well as leukocyte influx and efflux. Here, we provide definitive proof that 15d-PGJ 2 is synthesized during mammalian inflammatory responses, and we highlight DP1 receptor activation as a potential antiinflammatory strategy.antiinflammatory ͉ cyclooxygnease ͉ drug development ͉ eicosanoids ͉ innate immunity C yclooxygenase (COX) metabolizes phospholipase A 2 -derived arachidonic acid to prostaglandin (PG)H 2 , which is further metabolized by a series of downsteam synthases to the prostanoids. Indeed, the expression of the particular downstream enzyme and its coupling either to constitutively expressed COX1 or to inducible COX2 will determine the profile and levels of arachidonic metabolites released by cells. Thus, targeting COX will diminish most if not all prostanoids, which, in the case of new-generation COX2 inhibitors, resulted in prostacyclin abatement, enhanced risk of cardiovascular side effects, and the eventual withdrawal of selective COX2 inhibitors from clinical usage. In this event, attention has now shifted to understanding the role of COX downstream synthases in inflammation and the cardiovascular system in the hope of adding more selectivity with fewer side effects.In an attempt to understand the role of COX-related downstream synthase in host defense, we found that the COX2/ hematopoietic PGD 2 synthase pathway resolves both acute innate (1, 2) and adaptive immune responses (3). Hematopoietic PGD 2 synthase (hPGD 2 S) metabolizes COX-derived PGH 2 to PGD 2 (4), which may activate two G protein-coupled receptors, DP1 and DP2. DP1 regulates dendritic cell function (5), and DP2 promotes allergic inflammation (6-8). Although controversial, it is believed that PGD 2 is initially converted to PGJ 2 and 15-deoxy-PGD 2 (15d-PG...

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Section: Discussionmentioning

confidence: 97%

Hematopoietic prostaglandin D₂synthase controls the onset and resolution of acute inflammation through PGD₂and 15-deoxyΔ^12–14PGJ₂

Rajakariar

Hilliard²,

Lawrence

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

237

216

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“…Our results further confirmed the essential role that AA‐derived lipid mediators could play in resolving inflammatory response in vivo (Serhan and Samuelsson, ). This notion has been well developed by a number of studies and AA is now considered not only as a precursor of proinflammatory bioactive lipids, but also of potent anti‐inflammatory mediators named lipoxins (Morris et al ., ; Schwab and Serhan, ; Wallace, ; Dufton and Perretti, ). Indeed, in our experimental conditions, we observed that ischaemia and ischaemia followed by reperfusion led to an increase of proinflammatory bioactive lipids or pathway marker derived from AA metabolism by COX (PGE 2 , 6kPGF 1α TxB 2 ) and LOX (5‐, 8‐, 12‐, 15‐HETE, LTB 4 ).…”

Section: Discussionmentioning

confidence: 99%

Protective effects of n‐6 fatty acids‐enriched diet on intestinal ischaemia/reperfusion injury involve lipoxin A₄ and its receptor

Gobbetti

Ducheix

Faouder

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSELong-term intake of dietary fatty acids is known to predispose to chronic inflammation, but their effects on acute intestinal ischaemia/reperfusion (I/R) injury is unknown. The aim of this study was to determine the consequences of a diet rich in n-3 or n-6 polyunsaturated fatty acids (PUFA) on intestinal I/R-induced damage. EXPERIMENTAL APPROACHMice were fed three different isocaloric diets: a balanced diet used as a control and two different PUFA-enriched diets, providing either high levels of n-3 or of n-6 PUFA. Intestinal injury was evaluated after intestinal I/R. PUFA metabolites were quantitated in intestinal tissues by LC-MS/MS. KEY RESULTSIn control diet-fed mice, intestinal I/R caused inflammation and increased COX and lipoxygenase-derived metabolites compared with sham-operated animals. Lipoxin A4 (LxA4) was significantly and selectively increased after ischaemia. Animals fed a high n-3 diet did not display a different inflammatory profile following intestinal I/R compared with control diet-fed animals. In contrast, intestinal inflammation was decreased in the I/R group fed with high n-6 diet and level of LxA4 was increased post-ischaemia compared with control diet-fed mice. Blockade of the LxA4 receptor (Fpr2), prevented the anti-inflammatory effects associated with the n-6 rich diet. CONCLUSIONS AND IMPLICATIONSThis study indicates that high levels of dietary n-6, but not n-3, PUFAs provides significant protection against intestinal I/R-induced damage and demonstrates that the endogenous production of LxA4 can be influenced by diet. 6kPGF1α, 7(S) Abbreviations

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“…In recent years it has become widely appreciated that, in addition to the classic diseases associated with inflammation such as psoriasis, periodontal disease and arthritis, uncontrolled inflammation governs the pathogenesis of many other prevalent diseases including cardiovascular and cerebrovascular disease, cancer, obesity and Alzheimer's disease (3). Of interest, another class of arachidonic acid-derived mediators, the lipoxins (LXs) and aspirin-triggered lipoxins (ATLs), were the first mediators recognized to have both endogenous anti-inflammatory and pro-resolving actions (4,5) indicating that not all lipid mediators are "bad guys" in controlling inflammation and resolution (6).…”

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory and Proresolving Lipid Mediators

Serhan

Yacoubian

Rong

2008

Annu. Rev. Pathol. Mech. Dis.

440

380

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The popular view that all lipid mediators are pro-inflammatory arises largely from the finding that non-steroidal anti-inflammatory drugs block the biosynthesis of prostaglandins. The resolution of inflammation was widely held to be a passive event until recently, with the characterization of novel biochemical pathways and lipid-derived mediators that are actively turned on in resolution possessing potent anti-inflammatory and pro-resolving actions. A lipid mediator informatics approach was employed to systematically identify new families of endogenous local-acting mediators from omega-3-polyunsaturated fatty acids (eicosapentaenoic acid and docosahexaenoic acid) in resolving exudates in addition to the lipoxins and aspirin-triggered lipoxins generated from arachidonic acid. These new chemical mediator families were coined resolvins and protectins, given their potent bioactions. In this annual review, we present recent advances on the biosynthesis and stereospecific actions of these new pro-resolving mediators, which have also proven to be organ protective and anti-fibrotic.

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Not all eicosanoids are bad

Cited by 8 publications

References 21 publications

Hematopoietic prostaglandin D₂synthase controls the onset and resolution of acute inflammation through PGD₂and 15-deoxyΔ^12–14PGJ₂

Hematopoietic prostaglandin D₂synthase controls the onset and resolution of acute inflammation through PGD₂and 15-deoxyΔ^12–14PGJ₂

Protective effects of n‐6 fatty acids‐enriched diet on intestinal ischaemia/reperfusion injury involve lipoxin A₄ and its receptor

Anti-Inflammatory and Proresolving Lipid Mediators

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Not all eicosanoids are bad

Cited by 8 publications

References 21 publications

Hematopoietic prostaglandin D2synthase controls the onset and resolution of acute inflammation through PGD2and 15-deoxyΔ12–14PGJ2

Hematopoietic prostaglandin D2synthase controls the onset and resolution of acute inflammation through PGD2and 15-deoxyΔ12–14PGJ2

Protective effects of n‐6 fatty acids‐enriched diet on intestinal ischaemia/reperfusion injury involve lipoxin A4 and its receptor

Anti-Inflammatory and Proresolving Lipid Mediators

Contact Info

Product

Resources

About

Hematopoietic prostaglandin D₂synthase controls the onset and resolution of acute inflammation through PGD₂and 15-deoxyΔ^12–14PGJ₂

Hematopoietic prostaglandin D₂synthase controls the onset and resolution of acute inflammation through PGD₂and 15-deoxyΔ^12–14PGJ₂

Protective effects of n‐6 fatty acids‐enriched diet on intestinal ischaemia/reperfusion injury involve lipoxin A₄ and its receptor