Department of Pharmacology, Institute of Basic Medical Sciences,Royal College of Surgeons of England, Lincoln's Inn Fields, London WC2A 3PN NATURE NEW BIOLOGY VOL. 231 JUNE 23 1971
This extract is remarkable for several reasons: during the past 25 years of practical use, aspirin had become a drug whose name was not only well known to health professionals but also to the general public. Certainly, the flu pandemia with millions of victims alone in Europe at the beginning of the last century as well as the limited availability of antipyretic analgesics other than aspirin contributed to this. However, the compound was generally recommended - and accepted - by the lay man and doctors - as a "household remedy" for treating pain, fever, inflammation, and many other kinds of "feeling bad," although essentially nothing was known about the mechanisms of action behind these multiple activities of the drug. It was only in the 1950s, when the first report was published, that salicylates including aspirin at anti-inflammatory doses uncouple oxidative phosphorylation in a number of organs and tissues . However, this at the time was con
Prostaglandins, thromboxane A2, and leukotrienes are members of a group of natural lipid mediators that are generated by oxidation from arachidonic acid. Because of this origin, they all have a 20-carbon backbone and are summarized as "eicosanoids" (Greek: eikos = twenty). Today, more than 150 eicosanoids are known and have been structurally identified. Arachidonic acid, the precursor fatty acid, is a constituent of the cell membrane phospholipids and is released from them by phospholipases. Eicosanoid synthesis starts with the availability of free arachidonic acid.
The first oxidation step of arachidonic acid to generate prostaglandins is catalyzed by cyclooxygenases (COXs). These enzymes are widely distributed throughout the body. The primary products - the prostaglandin endoperoxides - are then converted to the terminal products of this pathway, that is, prostaglandins and thromboxane A2, in a more cell-specific manner. The active products are not stored but released, act on their cellular target, and are afterward degraded enzymatically.
Prostaglandins exert their multiple actions via specific G-protein-coupled receptors at the cell surface. The direction and intensity of these actions is determined by the kind and the number of available prostaglandin receptors from which today about 10 are known. Prostaglandins act as local mediators that dispatch signals between cells. Thus, prostaglandin generating cells, and these are probably all cells of the body, do not require prostaglandin biosynthesis for survival. Consequently, prostaglandins are not essential for vital functions, such as energy metabolism or maintenance of the cell cytoskeleton.
The cellular prostaglandin synthesis can be markedly increased in response to disturbed homoeostasis (injury) to adapt cellular functions to changes in the environmental conditions. An increased prostaglandin synthesis "on demand," therefore, reflects a tissue-specific response to increased needs. Examples for physiological stimuli are hemostasis and pregnancy, whereas the increased prostaglandin production in inflammation, atherosclerosis, and tumorigenesis rather reflects the response to pathological stimuli.
Thus, any change in generation of prostaglandins or the related thromboxanes perse is neither good nor bad but rather reflects a functioning cell-based adaptation or defense mechanism. Functional disorders may arise, when prostaglandins become limiting factors for control of cell and organ function, respectively. Thus, any pharmacological interference with these processes may be either positive or negative but in most cases is not associated with any measurable functional change at the organ level as long as other mediator systems can compensate for it.
Aspirin and Cyclooxygenases Aspirin blocks the biosynthesis of prostaglandins and thromboxane A2 at the level of prostaglandin endoperoxides or cyclooxygenase(s) by irreversible acetylation of a critical serine in the substrate channel of the COX enzyme (Section 2.2.1). This limits the access of substrate (arachidonic acid) to the catalytic active site of the enzyme  and explains the antiplatelet action of the substance, first described by the group of Philip Majerus . The group of William Smith and David DeWitt detected this unique mechanism of action and has made major other contributions to this issue. The contributions of William Smith in elucidating the molecular reaction kinetics of aspirin were acknowledged with the Aspirin Senior Award in 1997.
Two genes have been identified that encode for cyclooxygenases: COX-1 and COX-2. In addition, there is a steadily increasing number of splice variants of these two genes. They are also transcriptionally regulated and might cause synthesis of gene products. Both COX isoforms are molecular targets for aspirin. However, the inhibition of COX-1 appears to dominate at lower concentrations of the compound, whereas aspirin and its primary metabolite salicylate are about equipotent inhibitors of COX-2 (Section 2.2.1). Thus, aspirin contains two pharmacologically relevant groups: the reactive acetyl moiety and salicylate. Both components are biologically active and act independently of each other at different sites. The molecular interaction of aspirin with COX-1 was further elucidated after the crystal structure of the enzyme became clarified by Michael Garavito and his group. The contribution of Patrick Loll to this work was acknowledged with the Aspirin Junior Award .
The detection of inhibition of prostaglandin synthesis was the first plausible explanation for the multiple pharmacological actions of aspirin via an ubiquitary class of endogenous mediators, prostaglandins and thromboxanes. With increasing knowledge of the complex nature of these reactions, specifically the multiple interactions of prostaglandins with other mediator systems, some details of these findings are now interpreted in a different way. This is particularly valid for the anti-inflammatory activities of aspirin, which are mainly due to the formation of the more stable metabolite salicylate  and, possibly, the generation of aspirin-triggered lipoxin (ATL), resulting from the interaction of aspirin-treated (acetylated) COX-2 and the 5-lipoxygenase from white cells (Sections 2.2.1 and 2.3.2). This eventually resulted in the detection of resolvins, a new class of anti-inflammatory mediators, also involved in aspirin action by Charles Serhan and his group. The contributions of Jose Claria to this work  were acknowledged with the Aspirin Junior Award in 1996.
Aspirin and GeneTranscription After the discovery of the inducible isoform of COX-2, it became rapidly clear that aspirin was rather ineffective on this enzyme at low antiplatelet concentrations, and higher doses were required to suppress COX-2-dependent prostaglandin formation. This finding also confirmed the clinical experience that the analgesic and anti-inflammatory effects of the compound require substantially higher doses than those necessary for inhibition of platelet function. Kenneth Wu and colleagues were the first to show that aspirin and salicylate interact with the binding of transcription factors to the promoter region of the COX-2 gene . These factors regulate the gene expression level after stimulation by inflammatory mediators. Later work of Xiao-MingXu and others ofthis group eventually identified the binding of CCAAT/enhancer-binding protein-b (C/ EBP-b or NF/IL-6) as one critical control mechanism [33, 34]. It becomes now increasingly evident that the anti-inflammatory and antineoplastic actions of salicylates and aspirin, respectively, involve inhibition of COX-2 gene transcription because COX-2 overexpression is an important permissive factor in these disorders and also might generate compounds other than prostaglandins (Section 4.3.1). The molecular mechanisms of control of inducible COX activity are still under intense research. However, it is interesting to note that the upregulation of salicylate biosynthesis by plants -the natural sources of salicylates - represents a most effective, transcriptionally regulated defense system that becomes activated in response to about all kinds of noxious stimuli and exhibits a number of similarities to the prostaglandin pathway in animals and men (Section 2.2.2).
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