Aspirin‐triggered 15‐epi‐lipoxin A 4 predicts cyclooxygenase‐2 in the lungs of LPS‐treated mice but not in the circulation: implications for a clinical test

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 H 2 . 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 A 4 . 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 PGE 2 . Aspirin also increased the levels of ATL in the lungs of LPS‐treated wild‐type C57B16 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 A 4 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.—Kirkby, N. S., Chan, M. V., Lundberg, M. H., Massey, K. A., Edmands, W. M. B., MacKenzie, L. S., Holmes, E., Nicolaou, A., Warner, T. D., Mitchell, J. A., Aspirint‐riggered 15‐epi‐lipoxin A4 predicts cyclooxygenase‐2 in the lungs of LPS‐treated mice but not in the circulation: implications for a clinical test. FASEB J. 27, 3938–3946 (2013). www.fasebj.org