title: Aspirin-triggered 15-epi-lipoxin A4 predicts cyclooxygenase-2 in the lungs of LPS-treated mice but not in the circulation: implications for a clinical test.
abstract: Inhibition of cyclooxygenase (COX)-2 increases cardiovascular deaths. Identifying a biomarker of COX-2 is desirable but difficult, since COX-1 and COX-2 ordinarily catalyze formation of an identical product, prostaglandin H2. When acetylated by aspirin, however, COX-2 (but not COX-1) can form 15(R)-HETE, which is metabolized to aspirin-triggered lipoxin (ATL), 15-epi-lipoxin A4. Here we have used COX-1- and COX-2-knockout mice to establish whether plasma ATL could be used as a biomarker of vascular COX-2 in vivo. Vascular COX-2 was low but increased by LPS (10 mg/kg; i.p). Aspirin (10 mg/kg; i.v.) inhibited COX-1, measured as blood thromboxane and COX-2, measured as lung PGE2. Aspirin also increased the levels of ATL in the lungs of LPS-treated wild-type C57Bl6 mice (vehicle: 25.5±9.3 ng/ml; 100 mg/kg: 112.0±7.4 ng/ml; P<0.05). Despite this, ATL was unchanged in plasma after LPS and aspirin. This was true in wild-type as well as COX-1(-/-) and COX-2(-/-) mice. Thus, in mice in which COX-2 has been induced by LPS treatment, aspirin triggers detectable 15-epi-lipoxin A4 in lung tissue, but not in plasma. This important study is the first to demonstrate that while ATL can be measured in tissue, plasma ATL is not a biomarker of vascular COX-2 expression.
authors.affiliation: 1Cardiothoracic Pharmacology, National Heart and Lung Institute, Imperial College London, Dovehouse St., London SW3 6LY, UK. J.A.M., j.a.mitchell@imperial.ac.uk.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Kirkby
authors.forename: Melissa V
authors.initials: MV
authors.lastname: Chan
authors.forename: Martina H
authors.initials: MH
authors.lastname: Lundberg
authors.forename: Karen A
authors.initials: KA
authors.lastname: Massey
authors.forename: William M B
authors.initials: WM
authors.lastname: Edmands
authors.forename: Louise S
authors.initials: LS
authors.lastname: MacKenzie
authors.forename: Elaine
authors.initials: E
authors.lastname: Holmes
authors.forename: Anna
authors.initials: A
authors.lastname: Nicolaou
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Warner
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology*; D015415:Biomarkers; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000633:toxicity*; D044045:Lipoxins / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000201:enzymology*; D051379:Mice
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D008070:Lipopolysaccharides; D044045:Lipoxins; C040527:lipoxin A4; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D001241:Aspirin
keywords: 15-HETE; COX-2 biomarker; nonsteroidal anti-inflammatory drugs; vascular inflammation