title: Effects of low-dose aspirin on acute inflammatory responses in humans.
abstract: Aspirin is a unique nonsteroidal anti-inflammatory drug; at high doses (aspirin(high), 1g), it is anti-inflammatory stemming from the inhibition of cyclooxygenase and proinflammatory signaling pathways including NF-kappaB, but is cardioprotective at lower doses (aspirin(low), 75 mg). The latter arises from the inhibition of thromboxane (Tx) B(2), a prothrombotic eicosanoid also implicated in polymorphonuclear leukocyte trafficking. As a result, aspirin(low) is widely used as a primary and secondary preventative against vascular disease. Despite this and its ability to synthesize proresolution 15-epi-lipoxin A(4) it is not known whether aspirin(low) 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, aspirin(low) (75 mg, oral, once daily/10 days) reduced polymorphonuclear leukocyte and macrophage accumulation independent of NF-kappaB-regulated gene expression and inhibition of conventional prostanoids. However, aspirin(low) triggered 15-epi-lipoxin A(4) synthesis and up-regulated its receptor (FPRL1, ALX). From complimentary in vitro experiments, we propose that 15-epi-lipoxin A(4) 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 aspirin(low) possesses the ability to inhibit mammalian innate immune-mediated responses. This highlights 15-epi-lipoxin A(4) 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.
authors: Division of Medicine, University College London, Centre for Clinical Pharmacology and Therapeutics, London, United Kingdom.
authors: Thea
authors: T
authors: Morris
authors: Melanie
authors: M
authors: Stables
authors: Adrian
authors: A
authors: Hobbs
authors: Patricia
authors: P
authors: de Souza
authors: Paul
authors: P
authors: Colville-Nash
authors: Tim
authors: T
authors: Warner
authors: Justine
authors: J
authors: Newson
authors: Geoffrey
authors: G
authors: Bellingan
authors: Derek W
authors: DW
authors: Gilroy
mesh_terms: D000208:Acute Disease; D001241:Aspirin / Q000008:administration & dosage* / Q000494:pharmacology; D001768:Blister / Q000139:chemically induced; D002193:Cantharidin; D002448:Cell Adhesion / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D044045:Lipoxins / Q000096:biosynthesis*; D008264:Macrophages; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D044042:Receptors, Formyl Peptide / Q000096:biosynthesis; D044067:Receptors, Lipoxin / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C105101:FPR2 protein, human; D044045:Lipoxins; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C040527:lipoxin A4; D009569:Nitric Oxide; D002193:Cantharidin; D001241:Aspirin