Subject(s)
Blood Platelets/metabolism , Curriculum , Hemorrhage/diagnosis , Hemorrhage/etiology , Hemorrhage/metabolism , HumansABSTRACT
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.
Subject(s)
Aspirin/administration & dosage , Inflammation/drug therapy , Lipoxins/biosynthesis , Acute Disease , Aspirin/pharmacology , Blister/chemically induced , Cantharidin , Cell Adhesion/drug effects , Chemotaxis, Leukocyte/drug effects , Dose-Response Relationship, Drug , Humans , Macrophages , Male , Nitric Oxide/biosynthesis , Receptors, Formyl Peptide/biosynthesis , Receptors, Lipoxin/biosynthesis , Up-Regulation/drug effectsABSTRACT
Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat the condition of rheumatoid arthritis, where levels of prostaglandin E2 (PGE2) and granulocyte macrophage-colony stimulating factor (GM-CSF) are elevated in the synovial fluid. NO-NSAIDs are a new class of cyclooxygenase (COX)-inhibitors developed by coupling a nitric oxide (NO)-donating moiety to conventional NSAIDs. We show that, in cytokine-treated synoviocytes (from non-rheumatic patients), NO-naproxen and NO-flurbiprofen like their parent compounds concentration-dependently reduce the levels of PGE2 (an index of COX-2 activity), with a corresponding rise in the release of GM-CSF. Unlike acetylsalicylic acid (ASA), NO-ASA reduces the levels of PGE2, without increasing GM-CSF release, although cell viability is reduced at the highest concentration (1 mM). The effects of NSAIDs and NO-NSAIDs on GM-CSF release were attributable to the PGE2 mediated cyclic (c) AMP pathway because PGE2 reversed the effects of COX blockade. Second, phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine (IBMX) and Ro-201724 (both of which elevate cAMP levels) decreased GM-CSF release, in the presence of PGE2. Finally, neither sodium nitroprusside nor zaprinast (both of which elevate cGMP levels) affected GM-CSF or PGE2 release. Our findings demonstrate that GM-CSF is regulated by NSAIDs and NO-NSAIDs via inhibition of COX and appears to be mediated via the cAMP pathway. NO-ASA is the exception, because it does not increase GM-CSF release, although at millimolar concentrations cell viability is reduced.
