New Perspectives on Aspirin and the Endogenous Control of Acute Inflammatory Resolution

Abstract

Aspirin is unique among the nonsteroidal anti-inflammatory drugs in that it has both anti-inflammatory as well as cardio-protective properties. The cardio-protective properties arise form its judicious inhibition of platelet-derived thromboxane A2 over prostacyclin, while its anti-inflammatory effects of aspirin stem from its well-established inhibition of prostaglandin (PG) synthesis within inflamed tissues. Thus aspirin and the other NSAIDs have popularised the notion of inhibiting PG biosynthesis as a common anti-inflammatory strategy based on the erroneous premise that all eicosanoids are generally detrimental to inflammation. However, our fascination with aspirin has shown a more affable side to lipid mediators based on our increasing interest in the endogenous control of acute inflammation and in factors that mediate its resolution. Epi-lipoxins (epi-LXs), for instance, are produced from aspirins acetylation of inducible cyclooxygenase 2 (COX-2) and together with Resolvins represent an increasingly important family of immuno-regulatory and potentially cardio-protective lipid mediators. Aspirin is beginning to teach us what nature knew all along — that not all lipid mediators are bad. It seems that while some eicosanoids are pathogenic in a variety of diseases, others are unarguable protective. In this review we will re-count aspirins colorful history, discuss its traditional mode of action and the controversies associated therewith, as well as highlight some of the new pathways in inflammation and the cardiovascular systems that aspirin has recently revealed.

Effects of Lipoxin A₄ on CoCl₂-Induced Angiogenesis and Its Possible Mechanisms in Human Umbilical Vein Endothelial Cells

“…Lipoxin A 4 (LXA 4 ), generated via biosynthetic pathways involving the dual lipoxygenation of arachidonic acid by either 5-and 15-lipoxygenases or 5-and 12-lipoxygenases, has been extensively studied preclinically for its anti-inflammatory or inflammatory pro-resolving effect [13] . Our group previously investigated some new values of lipoxins, including the antioxidant ability in lipopolysaccharide-stimulated macrophages and the influence on stored-operated channels in erythroleukemia cells [14][15] .…”

Aspirin metabolites are GPR35 agonists

“…Aspirin is known to cause asthma in some patients, leading to aspirin-exacerbated respiratory disease (AERD), aspirin triad or Samter's triad; and the MMOA may be due to the ability of aspirin to switch arachidonic acid metabolism from prostaglandin E2 and thromboxane to lipoxin A4 and 15-epi-lipoxin A4 (Morris et al 2006). The acetyl group may be primarily responsible for AERD, since salicylate is well-tolerant to these patients.…”

“…The primary molecular mode of action (MMOA) of aspirin is due to its ability to cause marked inhibition of prostaglandin synthesis via the selective acetylation of the hydroxyl group of the serine 530 residue of cyclooxygenase-1 (COX-1) (Vane 1971;Sweeny et al 2009). However, the clinical features of aspirin and aspirin-like drugs are unlikely due entirely to the inhibition of COX activity (Pillinger et al 1998;Morris et al 2006;Moon et al 2010;Chan et al 2012).…”

Influence of acetylsalicylic acid on hematotoxicity of benzene

“…There are reports that the peroxidase of macrophages of the marrow stromal may take part in oxidizing quinone metabolites of benzene and, thus, mediate its hematotoxicity [12,34,35]. Liberation of lipoxin A4 by ASA decreases activity of myeloperoxidase and also influences chemotaxis and stimulation of leukocytes [17,36]. Moreover, the secondary bioactivation of benzene metabolites by myeloperoxidase is inhibited by a quinone oxidoreductase present in fibroblasts of the marrow which reduces quinone biotransformation to nonreactive forms [21,37].…”

“…Therefore, its prolonged administration for the purpose of prevention of cardiac and cerebral infarcts may lead to metabolic interactions with other xenobiotics, including benzene [14][15][16]. ASA may also modify toxic effects of benzene by inhibition of transcription factor kB, which participates in activation of genes involved in synthesis of inflammatory factors as well as being responsible for proliferation and maturation of T lymphocytes [17,18]. Hydroquinone, a benzene metabolite, exhibits a similar activity -it inhibits transcription and translocation of the kB factor to the cell nucleus by suppression of the translocation pathway composed of protein kinase B (Akt), kinase IkBβ (IKKβ) and inhibitor α of kB protein (IkBα) [10,19,20].…”