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* Centre for Clinical Pharmacology and Therapeutics, Division of Medicine and
Department of Pharmacology, University College London, Medical Sciences Building, London, United Kingdom;
Cardiothoracic Pharmacology Department, Unit of Critical Care Medicine, National Heart and Lung Institute, Imperial College, London, United Kingdom;
St. Helier Hospital, Carshalton, Surrey, United Kingdom;
¶ Centre for Translational Medicine and Therapeutics, Bart’s and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, United Kingdom; and
|| Critical Care, Maples Bridge Link, University College London Hospitals National Health Service Foundation Trust, London, United Kingdom
Aspirin is a unique nonsteroidal anti-inflammatory drug; at high doses (aspirinhigh, 1g), it is anti-inflammatory stemming from the inhibition of cyclooxygenase and proinflammatory signaling pathways including NF-
B, but is cardioprotective at lower doses (aspirinlow, 75 mg). The latter arises from the inhibition of thromboxane (Tx) B2, a prothrombotic eicosanoid also implicated in polymorphonuclear leukocyte trafficking. As a result, aspirinlow is widely used as a primary and secondary preventative against vascular disease. Despite this and its ability to synthesize proresolution 15-epi-lipoxin A4 it is not known whether aspirinlow is anti-inflammatory in humans. To address this, we generated skin blisters by topically applying cantharidin on the forearm of healthy male volunteers, causing an acute inflammatory response including dermal edema formation and leukocyte trafficking. Although not affecting blister fluid volume, aspirinlow (75 mg, oral, once daily/10 days) reduced polymorphonuclear leukocyte and macrophage accumulation independent of NF-B-regulated gene expression and inhibition of conventional prostanoids. However, aspirinlow triggered 15-epi-lipoxin A4 synthesis and up-regulated its receptor (FPRL1, ALX). From complimentary in vitro experiments, we propose that 15-epi-lipoxin A4 exerts its protective effects by triggering antiadhesive NO, thereby dampening leukocyte/endothelial cell interaction and subsequent extravascular leukocyte migration. Since similar findings were obtained from murine zymosan-induced peritonitis, we suggest that aspirinlow possesses the ability to inhibit mammalian innate immune-mediated responses. This highlights 15-epi-lipoxin A4 as a novel anti-inflammatory working through a defined receptor and suggests that mimicking its mode of action represents a new approach to treating inflammation-driven diseases.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 D.W.G. is a Wellcome Trust-funded Career Development Fellow and G.B. acknowledges support from the University College London Hospital/University College London and the Department of Health’s National Institute for Health Research Biomedical Research Centers funding scheme. Funding was provided by the Wellcome Trust and Medical Research Council, U.K. to D.W.G.
2 Address correspondence and reprint requests to Dr. Derek W. Gilroy, Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, 5 University Street, University College London, London WC1E 6JJ, U.K. E-mail address: d.gilroy{at}ucl.ac.uk
3 Abbreviations used in this paper: NSAID, nonsteroidal anti-inflammatory drug; Tx, thromboxane; PMN, polymorphonuclear leukocyte; COX, cyclooxygenase; HETE, hydroxyeicosatetraenoic acid; BOC-2, N-t-BOC-Phe-Leu-Phe-Leu-Phe; L-NMMA, NG-monomethyl-L-arginine.
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