Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial.
Journal: 2004/November - Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
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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Proc Natl Acad Sci U S A 101(42): 15178-15183

Aspirin triggers antiinflammatory 15-epi-lipoxin A<sub>4</sub> and inhibits thromboxane in a randomized human trial

Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Center for Cardiovascular Disease Prevention and The Donald W. Reynolds Center for Cardiovascular Research, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115
To whom correspondence should be addressed at: Brigham and Women's Hospital, Thorn Building for Medical Research, 75 Francis Street, Room 724, Boston, MA 02115. E-mail: ude.dravrah.hwb.suez@nahresnc.
N.C. and E.A.B. contributed equally to this work.
Edited by Ralph M. Steinman, The Rockefeller University, New York, NY, and approved September 9, 2004
Edited by Ralph M. Steinman, The Rockefeller University, New York, NY, and approved September 9, 2004
Received 2004 Jul 27

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.

Abstract

Aspirin is the most commonly administered nonsteroidal antiinflammatory drug. In addition to its well documented antithrombotic and antiinflammatory actions, low doses of aspirin may evoke beneficial effects that go beyond prevention and treatment of cardiovascular diseases (1), such as possibly decreasing the incidence of lung, colon, and breast cancer and, perhaps, Alzheimer's disease (2-5). Although inhibition of specific cyclooxygenase (COX) products accounts for many of aspirin's therapeutic properties, effects that go beyond inhibition of prostaglandin and thromboxane (TX) are increasingly apparent (6). We recently identified a unique action of aspirin that involves cells containing COX-2, such as vascular endothelium, which are involved in transcellular communication with blood-borne and/or marginating leukocytes (Fig. 1). Briefly, acetylation of vascular COX-2 by aspirin redirects the catalytic activity of COX-2 from generating intermediates of prostaglandins and TX to instead produce intermediates of 15-epimeric lipoxin A4 formation (7). This epimer of lipoxin A4 is termed aspirin-triggered 15-epi-lipoxin A4 (ATL) and carries its carbon 15-hydroxyl group in the R-configuration, which is released by activated human neutrophils in vitro (7). Other widely used nonsteroidal antiinflammatory drugs of general COX inhibitors are unable to generate ATL. Hence, aspirin has the unique ability to generate an endogenous mimetic of natural lipoxin A4, namely ATL.

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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).

As a relatively new class of autacoids identified in 1995, ATL functions as a local endogenous antiinflammatory mediator. ATL acts on neutrophils and possesses protective activities in several target tissues and murine models of disease that include peritonitis, dermal inflammation, reperfusion injury, asthma, and angiogenesis (see ref. 8 for original citations). By using a newly developed specific ELISA along with liquid chromatography-tandem mass spectrometry (8, 9), ex vivo ATL formation was determined with cells from patients with asthma that were both aspirin-tolerant and aspirin-intolerant (10). Formation of ATL also was demonstrated as an endogenous autacoid in several murine models (8). It is of interest to note that COX-2, a critical enzyme in ATL biosynthesis, was initially conceptualized solely as an “inducible” COX. However, in many cell types, including mature megakaryocytes, COX-2 is constitutively expressed (11), and, in vascular endothelial cells, COX-2 is expressed after exposure to laminar shear (12). Whereas ATL clearly has antiinflammatory functions in experimental animal models and in isolated human cells (7), aspirin-dependent production of ATL has not been demonstrated in a randomized human trial. For these reasons, we initiated studies to ascertain whether aspirin administered in standard clinical doses to healthy volunteers would initiate antiinflammatory ATL generation.

The low-, medium-, and high-dose groups took 81-, 325-, and 650-mg daily doses of aspirin, respectively. All P values for comparisons across groups were >0.05. LDL, low-density lipoprotein cholesterol; HDL, high-density lipoprotein cholesterol.

The low-, medium-, and high-dose groups took 81-, 325-, and 650-mg daily doses of aspirin, respectively. Data are expressed in nanograms per milliliter (mean ± SD). Δ represents TXB2 or ATL levels after 8 weeks of treatment minus levels at baseline (BL). Δ values are expressed in either nanograms per milliliter or picograms per 10 cells. Sample sizes did not vary from those indicated at the top of the columns. P values for the net change were as follows: all groups, P = 0.02 (linear) and P = 0.03 (quadratic); aspirin groups, P = 0.91 (linear) and P = 0.93 (quadratic). N/A, not applicable; C.I., confidence interval.

Acknowledgments

We thank Mary Halm Small for skillful assistance in manuscript preparation and Dannie Chang for technical assistance. This work was supported in part by National Institutes of Health Grants GM 38765 and P01-DE13499 (to C.N.S.) and by grants from the Doris Duke Charitable Foundation and the Donald W. Reynolds Foundation (to P.M.R.). Statistical analyses were supported in part by the Biostatistics Consulting Service, Center for Clinical Investigation, Brigham and Women's Hospital.

Acknowledgments

Notes

Author contributions: N.C. and C.N.S. designed research; N.C., E.A.B., and C.N.S. performed research; N.C. and C.N.S. contributed new reagents/analytical tools; N.C., P.M.R., S.H., and C.N.S. analyzed data; and N.C., P.M.R., and C.N.S. wrote the paper.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: ATL, aspirin-triggered-15-epi-lipoxin A4; COX, cyclooxygenase; TX, thromboxane.

Notes
Author contributions: N.C. and C.N.S. designed research; N.C., E.A.B., and C.N.S. performed research; N.C. and C.N.S. contributed new reagents/analytical tools; N.C., P.M.R., S.H., and C.N.S. analyzed data; and N.C., P.M.R., and C.N.S. wrote the paper.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: ATL, aspirin-triggered-15-epi-lipoxin A4; COX, cyclooxygenase; TX, thromboxane.

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