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Anti-inflammatory properties of omega-3 fatty acids in critical illness: novel mechanisms and an integrative perspective

Abstract

Introduction

Fish oil-based nutrition is protective in severe critical care conditions. Regulation of the activity of transcription factor NF-κB is an important therapeutic effect of the major omega-3 fatty acids in fish oil, eicosapentaenoic and docosahexaenoic acid (EPA and DHA).

Methods and results

Using the articles obtained by a Pubmed research, this article reviews three aspects of NF-κB/inflammatory inhibition by fish oil. (1) Inhibition of the NF-κB pathway at several subsequent steps: extracellular, free omega-3 inhibits the activation of the Toll-like receptor 4 by endotoxin and free saturated fatty acids. In addition, EPA/DHA blocks the signaling cascade between Toll-like/cytokine receptors and the activator of NF-κB, IKK. Oxidized omega-3 also interferes with the initiation of transcription by NF-κB. (2) The altered profile of lipid mediators generated during inflammation, with production of the newly identified, DHA-derived inflammation-resolving mediator classes (in addition to the formation of less pro-inflammatory eicosanoids from EPA). Resolvin D1 and Protectin D1 are potent, endogenous, DHA-derived lipid mediators that attenuate neutrophil migration and tissue injury in peritonitis and ischemia-reperfusion injury. Their production is increased in the later stages of an inflammatory response, at which time they enhance the removal of neutrophils. (3) Modulation of vagal tone with potential anti-inflammatory effects: vagal fibers innervating the viscera down-regulate inflammation by activating nicotinic receptors upon infiltrating and resident macrophages. Stimulation of the efferent vagus is therapeutic in experimental septic shock. Fish oil supplementation increases vagal tone following myocardial infarction and in experimental human endotoxinemia.

Conclusion

It remains to be shown whether these pleiotropic actions of EPA/DHA contribute to fish oil’s therapeutic effect in sepsis.

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Notes

  1. 1.

    Fatty acids are either saturated (SatFA) or unsaturated (UnSatFA), depending on the lack of (in SatFAs) or presence of (in UnSatFAs) carbon–carbon double bond(s) [-CH=CH-]. UnSatFAs may be mono- or polyunsaturated (MUFA and PUFA). A simple biochemical description of fatty acids is Cx:y, where x designates the number of carbons in the carbon chain and y designates the number of double bonds. Very long chain PUFAs are those containing 20 or more carbons. ω-n indicates that the first double bond appears as the nth carbon–carbon bond from the methyl end.

  2. 2.

    A protein that is not enzymatically active but instead mediates the formation of protein-receptor complexes responsible for post-receptor signal transduction.

  3. 3.

    The structure of Lipid A is more complex than described here; a more detailed and accurate overview can be found in [15]. To be slightly more accurate, Lipid A of these GNBs is a disaccharide of glucosamine, covalently bonded to lauric or myristic acid chains; these saturated fatty acids are further bonded to lauric, myristic or palmitic acid chains.

  4. 4.

    NIK is NF-κBNF-κBNF-κB-inducing kinase. It is downstream to MyD88 and activates IKK.

  5. 5.

    e.g. ceramides, diacylglycerol and fatty acyl-CoAs

  6. 6.

    A Saccharomyces cerevisiae PARPPARP that is recognized by TLR2. When administered at higher doses it produces lethal septic shock.

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Correspondence to Pierre Singer.

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Singer, P., Shapiro, H., Theilla, M. et al. Anti-inflammatory properties of omega-3 fatty acids in critical illness: novel mechanisms and an integrative perspective. Intensive Care Med 34, 1580 (2008). https://doi.org/10.1007/s00134-008-1142-4

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Keywords

  • Sepsis
  • Nutritional support
  • Omega-3 fatty acids
  • Nuclear factor kappa B
  • Endotoxins
  • Vagus nerve