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

作者：Kirkby Nicholas S^*; Chan Melissa V; Lundberg Martina H; Massey Karen A; Edmands William M B; MacKenzie Louise S; Holmes Elaine; Nicolaou Anna; Warner Timothy D; Mitchell Jane A

来源：The FASEB Journal, 2013, 27(10): 3938-3946.

DOI：10.1096/fj.12-215533

• 15-HETE
• COX-2 biomarker
• vascular inflammation
• nonsteroidal anti-inflammatory drugs

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 C57Bl6 mice (vehicle: 25.5 +/- 9.3 ng/ml; 100 mg/kg: 112.0 +/- 7.4 ng/ml; P%26lt;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. 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.

• 出版日期2013-10