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15-epi-lipoxin A4–mediated Induction of Nitric Oxide Explains How Aspirin Inhibits Acute Inflammation
- Source :
- The Journal of Experimental Medicine
- Publication Year :
- 2004
- Publisher :
- The Rockefeller University Press, 2004.
-
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-1β–induced peritonitis. It transpires that aspirin generates NO through its unique ability to trigger the synthesis of 15-epi-lipoxin A4. Aspirin and 15-epi-lipoxin A4 were shown to inhibit leukocyte trafficking in an NO-dependent manner using intravital microscopy on IL-1β–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 A4 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 A4, which increases NO synthesis through eNOS and iNOS. This aspirin-elicited NO exerts antiinflammatory effects in the microcirculation by inhibiting leukocyte–endothelium interactions.
- Subjects :
- Male
NF-KAPPA-B
nonsteroidal antiinflammatory drugs
Nitric Oxide Synthase Type II
CARRAGEENAN-INDUCED PLEURISY
Pharmacology
Research & Experimental Medicine
DEFICIENT MICE
chemistry.chemical_compound
Mice
Enos
Mechanism of action of aspirin
Leukocytes
Immunology and Allergy
ENDOTHELIAL CELL-ADHESION
Mice, Knockout
Aspirin
biology
LIPOXIN A(4)
Anti-Inflammatory Agents, Non-Steroidal
Nitric Oxide Synthase Type III
11 Medical And Health Sciences
Nitric oxide synthase
Lipoxins
STABLE ANALOGS
Medicine, Research & Experimental
medicine.symptom
Life Sciences & Biomedicine
Intravital microscopy
medicine.drug
Immunology
LEUKOCYTE ADHESION
Inflammation
Peritonitis
Nitric Oxide
Article
Nitric oxide
NO-RELEASING ASPIRIN
medicine
Animals
Endothelium
Rats, Wistar
Nitrites
leukocyte trafficking
Science & Technology
Dose-Response Relationship, Drug
business.industry
Microcirculation
resolution
biology.organism_classification
Rats
Mice, Inbred C57BL
chemistry
epi-lipoxins
biology.protein
microvascular endothelium
Nitric Oxide Synthase
business
PROSTAGLANDIN-H SYNTHASE
Interleukin-1
Subjects
Details
- Language :
- English
- ISSN :
- 15409538 and 00221007
- Volume :
- 200
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- The Journal of Experimental Medicine
- Accession number :
- edsair.doi.dedup.....f43b5d06a13064b34172f4c2b217bf03