Novel Docosanoids Inhibit Brain Ischemia-Reperfusion-mediated Leukocyte Infiltration and Pro-inflammatory Gene Expression

Marcheselli, Victor L.; Hong, Song; Lukiw, Walter J.; Tian, Xiao Hua; Gronert, Karsten; Musto, Alberto E.; Hardy, Marcia; Gimenez, J.; Chiang, Nan; Serhan, Charles N.; Bazán, Nicolás G.

doi:10.1074/jbc.m305841200

Cited by 737 publications

(784 citation statements)

References 34 publications

(46 reference statements)

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“…More recently, DHA-derived mediators D-series resolvins, docosatrienes and neuroprotectins, also produced by cyclooxygenase-2 and lipoxygenase under some conditions, have been identified that also appear to be antiinflammatory and inflammation resolving Marcheselli et al 2003;Mukherjee et al 2004). Only two studies in the current overview provide direct comparison of the effects of EPA and DHA.…”

Section: Discussionmentioning

confidence: 97%

Differential immunomodulation with long-chainn-3 PUFA in health and chronic disease

Sijben¹,

2007

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The balance of intake of n-6 and n-3 PUFA, and consequently their relative incorporation into immune cells, is important in determining the development and severity of immune and inflammatory responses. Some disorders characterised by exaggerated inflammation and excessive formation of inflammatory markers have become among the most important causes of death and disability in man in modern societies. The recognition that long-chain n-3 PUFA have the potential to inhibit (excessive) inflammatory responses has led to a large number of clinical investigations with these fatty acids in inflammatory conditions as well as in healthy subjects. The present review explores the presence of dose-related effects of long-chain n-3 PUFA supplementation on immune markers and differences between healthy subjects and those with inflammatory conditions, because of the important implications for the transfer of information gained from studies with healthy subjects to patient populations, e.g. for establishing dose levels for specific applications. The effects of long-chain n-3 PUFA supplementation on ex vivo lymphocyte proliferation and cytokine production by lymphocytes and monocytes in healthy subjects have been studied in twenty-seven, twenty-five and forty-six treatment cohorts respectively, at intake levels ranging from 0 . 2 g EPA + DHA/d to 7 . 0 g EPA + DHA/d. Most studies, particularly those with the highest quality study design, have found no effects on these immune markers. Significant effects on lymphocyte proliferation are decreased responses in seven of eight cohorts, particularly in older subjects. The direction of the significant changes in cytokine production by lymphocytes is inconsistent and only found at supplementation levels ‡ 2 . 0 g EPA + DHA/d. Significant changes in inflammatory cytokine production by monocytes are decreases in their production in all instances. Overall, these studies fail to reveal strong dose-response effects of EPA + DHA on the outcomes measured and suggest that healthy subjects are relatively insensitive to immunomodulation with longchain n-3 PUFA, even at intake levels that substantially raise their concentrations in phospholipids of immune cells. In patients with inflammatory conditions cytokine concentrations or production are influenced by EPA + DHA supplementation in a relatively large number of studies. Some of these studies suggest that local effects at the site of inflammation might be more pronounced than systemic effects and disease-related markers are more sensitive to the immunomodulatory effects, indicating that the presence of inflamed tissue or 'sensitised' immune cells in inflammatory disorders might increase sensitivity to the immunomodulatory effects of long-chain n-3 PUFA. In a substantial number of these studies clinical benefits related to the inflammatory state of the condition have been observed in the absence of significant effects on immune markers of inflammation. This finding suggests that conditionspecific clinical end points might be more sensitive markers...

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Section: Discussionmentioning

confidence: 97%

Differential immunomodulation with long-chainn-3 PUFA in health and chronic disease

Sijben¹,

2007

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“…Platelet-rich supernatant was further centrifuged at 1600 ϫ g for 15 minutes to collect platelets. Cell deposit was used to isolate PMNs by density gradient centrifugation using Histopaque 1.077 cell separation medium (Sigma-Aldrich 23 Samples and standards of lipid mediators were handled under dimmed light, stored at Ϫ80°C in vials purged with nitrogen gas and sealed tightly. Aqueous solutions of DHA and DHA derivatives were freshly prepared (ϳ4°C) immediately before use.…”

Section: Cell Culturesmentioning

confidence: 99%

Autacoid 14S,21R-Dihydroxy-Docosahexaenoic Acid Counteracts Diabetic Impairment of Macrophage Prohealing Functions

Tian

Lü

Shah

et al. 2011

The American Journal of Pathology

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Impaired macrophage functions imposed by diabetic complications and the suppressed formation of 14S, 2 1 R -d i h y d r o x y d o c o s a -4 Z , 7Z , 1 0 Z , 1 2 E , 1 6 Z , 19Z-hexaenoic acid (14S,21R-diHDHA) in wounds contribute significantly to deficient wound healing in diabetics, but how are macrophage functions and 14S,21R-diHDHA formation associated? We studied 14S,21R-diHDHA generation from macrophages using liquid chromatography/mass spectrometry. The role in macrophage-mediated wound healing functions was determined using a murine splinted excisional wound healing model and in vitro assays. 14S,21R-diHDHA acts as a macrophage-generated autacoid, and its attenuated formation in macrophages of diabetic db/db mice was accompanied by impairment of macrophage prohealing functions. 14S,21R-diHDHA restored db/db macrophage-impaired prohealing functions by promoting wound re-epithelialization, formulation of granulation tissue, and vascularization. Additionally, 12/15-lipoxygenase-deficient macrophages, which are unable to produce 14S,21R-diHDHA, exhibited impaired prohealing functions, which also were restored by 14S,21R-diHDHA treatment. The molecular mechanism for 14S,21R-diHDHA-induced recovery of impaired prohealing functions of db/db macrophages involves enhancing their secretion of vascular endothelial growth factor and platelet-derived growth factor BB, decreasing hyperglycemia-induced generation of reactive oxygen species, and increasing IL-10 expression under inflammatory stimulation. Taken together, these results indicate that deficiency of 14S,21R-diHDHA formation by diabetic macrophages contributes to their impaired prohealing functions. Our findings provide mechanistic insights into wound healing in diabetics and suggest the possibility of using autologous macrophages/monocytes, treated with 14S,21R-diHDHA, or related compounds, to promote diabetes-impaired wound healing. (Am J Pathol

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“…In experimental stroke, endogenous NPD1 synthesis was found to be upregulated during the initial eight hours of reperfusion [7]. When this lipid mediator was infused into the brain during ischemia-reperfusion, neuroprotective bioactivity was revealed [7].…”

Section: Experimental Strokementioning

confidence: 99%

“…Since lipoxygenase inhibitors were found to block this synthesis, an enzymatic process catalyzed by a lipoxygenase was implied [6] and the name "docosanoids" was suggested because they are derived from the 22C DHA. Upon the development of lipidomic analysis based on liquid chromatography, photodiode array, electrospray ionization, and tandem mass spectrometry (LC-PDA-ESI-MS-MS-based lipidomic analysis), a collaboration between the group of Charles Serhan (Harvard Medical School, http://hms.harvard.edu/hms/home.asp) and our group identified oxygenation pathways for the synthesis of the docosanoid neuroprotectin D1 (NPD1) and its bioactivity during brain ischemia-reperfusion [7] and in retinal pigment epithelial (RPE) cells challenged by oxidative stress [8]. We suggested the name 'neuroprotectin D1' [8] based upon its neuroprotective bioactivity in oxidatively stressed RPE cells and brain and its potent ability to inactivate pro-apoptotic and pro-inflammatory signaling.…”

Section: Introductionmentioning

confidence: 99%

Docosanoids are multifunctional regulators of neural cell integrity and fate: Significance in aging and disease

Mukherjee

Chawla

Loayza

et al. 2007

Prostaglandins, Leukotrienes and Essential Fatty Acids

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The identification of neuroprotectin D1 (NPD1), a biosynthetic product of docosahexaenoic acid (DHA), in brain and retina as well as the characterization of its bioactivity, is generating a renewed interest in the functional role and pathophysiological significance of omega-3 fatty acids in the central nervous system.Neurotrophins, particularly pigment epithelium-derived factor (PEDF), induce NPD1 synthesis and its polarized apical secretion, implying paracrine and autocrine bioactivity of this lipid mediator. Also, DHA and PEDF synergistically activate NPD1 synthesis and antiapoptotic protein expression and decreased proapoptotic Bcl-2 protein expression and caspase 3 activation during oxidative stress.In experimental stroke, endogenous NPD1 synthesis was found to be upregulated, and the infusion of the lipid mediator into the brain under these conditions revealed neuroprotective bioactivity of NPD1.The hippocampal CA1 region from Alzheimer's disease (AD) patients (rapidly sampled) shows a major reduction in NPD1.The interplay of DHA-derived neuroprotective signaling aims to counteract proinflammatory, celldamaging events triggered by multiple, converging cytokine and amyloid peptide factors, as in the case of AD. Generation of NPD1 from DHA thereby appears to redirect cellular fate toward successful preservation of retinal pigment epithelial (RPE)-photoreceptor cell integrity and brain cell aging. The Bcl-2 pro-and antiapoptotic proteins, neurotrophins, and NPD1, lie along a cell fateregulatory pathway whose component members are highly interactive, and have potential to function cooperatively in cell survival. Agents that stimulate NPD1 biosynthesis, NPD1 analogs, or dietary regimens may be useful as new preventive/therapeutic strategies for neurodegenerative diseases.

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Novel Docosanoids Inhibit Brain Ischemia-Reperfusion-mediated Leukocyte Infiltration and Pro-inflammatory Gene Expression

Cited by 737 publications

References 34 publications

Differential immunomodulation with long-chainn-3 PUFA in health and chronic disease

Differential immunomodulation with long-chainn-3 PUFA in health and chronic disease

Autacoid 14S,21R-Dihydroxy-Docosahexaenoic Acid Counteracts Diabetic Impairment of Macrophage Prohealing Functions

Docosanoids are multifunctional regulators of neural cell integrity and fate: Significance in aging and disease

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