Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial

Abstract

There is increasing evidence that aspirin initiates biosynthesis of novel antiinflammatory mediators by means of interactions between endothelial cells and leukocytes. These mediators are classified as aspirin-triggered 15-epi-lipoxins. Such compounds may account at least in part for aspirin's clinical benefits, which are distinct from the well appreciated action of aspirin as a platelet inhibitor. Here, we addressed whether aspirin-triggered 15-epilipoxinA4 (ATL) formation is aspirin-dependent in humans and its relationship to aspirin's antiplatelet activity. We conducted a randomized clinical trial among 128 healthy subjects allocated to placebo or to 81-, 325-, or 650-mg daily doses of aspirin for 8 weeks. Plasma thromboxane (TX)B2, an indicator of platelet reactivity, and ATL were assessed from blood collected at baseline and at 8 weeks. Plasma ATL levels significantly increased in the 81-mg aspirin group (0.25 +/- 0.63 ng/ml, P = 0.04), with borderline increases in the 325-mg group (0.16 +/- 0.71 ng/ml) and no apparent significant changes in the 650-mg group (0.01 +/- 0.75 ng/ml, P = 0.96). When ATL and TXB2 were compared, levels changed in a statistically significant and opposite direction (P < 0.01) for all three aspirin doses. These results demonstrated that low-dose aspirin (81 mg daily) initiates production of antiinflammatory ATL opposite to the inhibition of TX. Monitoring ATL may represent a simple clinical parameter to verify an individual's vascular leukocyte antiinflammatory response with low-dose aspirin treatment. These results also emphasize the importance of cell-cell interactions in the modulation of hemostatic, thrombotic, and inflammatory processes.

Fig. 1.

Aspirin's acetylation-dependent regulation of TX and ATL. TX is a major eicosanoid from human platelets and a potent platelet activator (1). Acetylation of COX-1 blocks the endoperoxide intermediate for prostaglandins (PG-G/H) and TX. The ATL is generated by the acetylated COX-2 in the vasculature that blocks prostaglandin production and initiates COX-2 to produce 15R-hydroxy eicosatetraenoic acid (15R-HETE). Transcellular biosynthesis of 15-epi-lipoxin A₄ is enabled during vascular endothelial and leukocyte interactions. ATL is a local mediator and possesses potent actions in antiinflammation and proresolution (8, 32).

Fig. 2.

Changes in TXB₂ and ATL for each subject in the 81-mg daily aspirin and placebo groups. Changes in the amounts of TXB₂ (○) and ATL (•) are expressed in nanograms per milliliter (from before treatment to 8 weeks after treatment) in the 81-mg daily aspirin dose (A) or placebo group (B). In the 81-mg aspirin dose group (A), statistical differences were obtained for both TXB₂ (P < 0.01) and ATL (P = 0.04) when comparing values before versus after 8 weeks. All P values were calculated by using a two-tailed Student t test.

Fig. 3.

Changes in TXB₂ and ATL with all aspirin dose groups. Change in the amounts of TXB₂ or ATL are expressed in nanograms per milliliter (from before treatment to after 8 weeks of treatment). The horizontal lines represent median values. Statistical differences were obtained for all three aspirin groups when comparing changes in TXB₂ versus ATL values (^*, P < 0.01).