Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial - PubMed (original) (raw)

Clinical Trial

. 2004 Oct 19;101(42):15178-83.

doi: 10.1073/pnas.0405445101. Epub 2004 Oct 7.

Affiliations

Clinical Trial

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

Nan Chiang et al. Proc Natl Acad Sci U S A. 2004.

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.

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Figures

Fig. 1.

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 15_R_-hydroxy eicosatetraenoic acid (15_R_-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.

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.

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).

Comment in

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