15-epi-lipoxin A4-mediated induction of nitric oxide explains how aspirin inhibits acute inflammation.
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.
Paul-Clark
Mark J
MJ
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
T
Moradi-Bidhendi
Niloufar
N
Cooper
Dianne
D
Gilroy
Derek W
DW
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism* / Q000494:pharmacology; D001241:Aspirin / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004727:Endothelium / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D044045:Lipoxins / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000097:blood; D010538:Peritonitis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007375:Interleukin-1; D044045:Lipoxins; D009573:Nitrites; C040527:lipoxin A4; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; C496315:Nos3 protein, mouse; C496316:Nos3 protein, rat; D001241:Aspirin