RESEARCH - Anti-inflammatory fish-oil EPA product resolvin is blocked by COX-2 inhibitors

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Anti-inflammatory fish-oil EPA product resolvin is blocked by COX-2

inhibitors

Rheumawire

Mar 7, 2005

Janis

Boston, MA - The anti-inflammatory effect of fish oils appears to be due to

a powerful anti-inflammatory compound called resolvin (resolution-phase

interaction product) E1, which is produced from eicosapentaenoic acid (EPA),

Dr Makoto Arita (Brigham and Women's Hospital and Harvard Medical School,

Boston, MA) and colleagues report in the March 7, 2005 issue of the Journal

of Experimental Medicine [1]. Arita writes, " At nanomolar levels, resolvin

E1 dramatically reduced dermal inflammation, peritonitis, dendritic cell

migration, and interleukin (IL)-12 production. "

Senior author Dr N Serhan (Brigham and Women's Hospital, Harvard

Medical School) tells rheumawire that the resolvin E1 pathway might also

explain some of the untoward cardiovascular effects of the COX-2 inhibitors.

" In vitro, we found that inhibiting vascular endothelial cells' COX-2 blocks

the biosynthesis of resolvin E1. In humans, in vivo evidence is needed, and

this would require a clinical trial. Maybe our findings can serve as the

base for such future clinical studies, " says Serhan.

Aspirin increases, coxibs decrease resolvin E1 biosynthesis

In contrast to the coxib effect, Serhan's group had previously found that

aspirin triggers the conversion of EPA to various resolvins and had

identified resolvin E1 in the plasma of human subjects given omega-3 fatty

acids and aspirin.

Resolvin E1 was discovered in vivo during the resolution phase of

inflammation in exudates from inflamed tissues in a mouse model. The main

task of resolvin E1 appears to be to serve as a counterregulator to

proinflammatory mediators and turn down acute inflammatory processes before

too much damage is done to normal tissue.

" The resolution of inflammation is an active process controlled in part by

endogenous chemical mediators that counterregulate proinflammatory gene

expression and cell trafficking as well as stimulate inflammatory cell

clearance, " the authors write.

The current study showed that as little as 100 ng/mouse of synthetic

resolvin E1 could decrease leukocyte infiltration into inflammatory loci by

50% to 60% in a mouse model of tumor-necrosis-factor (TNF)--induced

inflammation. By comparison, local administration of dexamethasone produced

60% inhibition in this model, aspirin produced 70% inhibition, and

indomethacin gave 25% inhibition.

Resolvin counteracts the effect of TNF-

The investigators found that the resolvin E1 anti-inflammatory effect is

mediated via the ChemR23 receptor, activation of which inhibits NF-B

activation. Resolvin E1 thus acts as a selective agonist that

counterregulates TNF-. The ChemR23 receptor was mapped in cardiovascular,

brain, kidney, gastrointestinal, and myeloid tissues.

" It is possible that loss of resolvin pathways like the one we documented

here could give rise to ongoing chronic inflammatory phenotypesas being

unable to actively turn off acute responses, rather then [as suggested by]

the current thinking that chronic inflammatory diseases arise by enhanced

inflammation, " Serhan says. He adds that resolvin E1 and its receptor

present possible targets for therapeutic intervention.

The researchers conclude, " Together, our findings offer an endogenous

agonist-driven molecular mechanism that can underlie some of the beneficial

actions of omega-3 EPA observed in many clinical situations, as well as

identify novel components in endogenous anti-inflammation/resolution, namely

resolvin E1 and its receptor, that are of interest as new checkpoint

regulators that may be involved in the pathogenesis of a wide range of human

diseases. "

Source

Arita M, Bianchini F, Aliberti J, et al. Stereochemical

assignment, anti-inflammatory properties, and receptor for the omega-3 lipid

mediator resolving E1. J Exp Med 2005; 201: DOI:10.1084/jem.20042031.

Available at: http://www.jem.org.

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