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PMID: 15238606 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

15-epi-lipoxin A4-mediated induction of nitric oxide explains how aspirin inhibits acute inflammation.

The Journal of experimental medicine ·Vol. 200 ·No. 1 ·2004-07-05 ·Pages 69-78

Paul-Clark MJ, Van Cao T, Moradi-Bidhendi N, Cooper D, Gilroy DW

Abstract

The established model for the mechanism of action of aspirin is the inhibition of prostaglandin synthesis. However, this has never fully explained aspirin's repertoire of antiinflammatory properties. We found in acute pleuritis that aspirin, but not salicylate, indomethacin, or piroxicam, increased plasma nitric oxide (NO), which correlated with a reduction in inflammation. Inhibiting aspirin-elicited NO pharmacologically in this model nullified the antiinflammatory effects of aspirin. Moreover, aspirin was not antiinflammatory in either constitutive (eNOS) or inducible NO synthase (iNOS) knockout mice with IL-1beta-induced peritonitis. It transpires that aspirin generates NO through its unique ability to trigger the synthesis of 15-epi-lipoxin A(4). Aspirin and 15-epi-lipoxin A(4) were shown to inhibit leukocyte trafficking in an NO-dependent manner using intravital microscopy on IL-1beta-stimulated mouse mesentery. Not only did aspirin inhibit leukocyte-endothelial interaction in a manner similar to NO in wild-type mice but both aspirin and 15-epi-lipoxin A(4) had markedly reduced effects on leukocyte-endothelial cell adherence in eNOS- and iNOS-deficient mice compared with wild type. Collectively, these data suggest that aspirin triggers the synthesis of 15-epi-lipoxin A(4), which increases NO synthesis through eNOS and iNOS. This aspirin-elicited NO exerts antiinflammatory effects in the microcirculation by inhibiting leukocyte-endothelium interactions.

MeSH Terms
Animals Anti-Inflammatory Agents, Non-Steroidal/metabolism,pharmacology Aspirin/metabolism,pharmacology,therapeutic use Dose-Response Relationship, Drug Endothelium/metabolism Inflammation/drug therapy,metabolism Interleukin-1/metabolism Leukocytes/drug effects,metabolism Lipoxins/metabolism,pharmacology Male Mice Mice, Inbred C57BL Mice, Knockout Microcirculation Nitric Oxide/metabolism Nitric Oxide Synthase/genetics,metabolism Nitric Oxide Synthase Type II Nitric Oxide Synthase Type III Nitrites/blood Peritonitis/metabolism Rats Rats, Wistar
Chemicals
Anti-Inflammatory Agents, Non-Steroidal Interleukin-1 Lipoxins Nitrites lipoxin A4 Nitric Oxide Nitric Oxide Synthase Nitric Oxide Synthase Type II Nitric Oxide Synthase Type III Nos2 protein, mouse Nos2 protein, rat Nos3 protein, mouse Nos3 protein, rat Aspirin
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Paul-Clark Mark J
Department of Biochemical Pharmacology, William Harvey Research Institute, St. Bartholomew's Hospital and The Royal London School of Medicine and Dentistry, Charterhouse Sq., London EC1M 6BQ, England, UK.
Van Cao Thong
Moradi-Bidhendi Niloufar
Cooper Dianne
Gilroy Derek W
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20040566
Published
2004-07-05
Pages
69-78
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2213311
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.20040566 PMC Full Text View journal details
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