prostaglandins

prostaglandins are a group of biologically active compounds with a plethora of different actions and produced in virtually all tissues of the body. Unlike most autacoids (substances formed by cells themselves, which act as ‘messengers’ to other cells) they are not synthesized and stored ready for use. Rather, they are produced on demand in response to a great variety of stimuli. They have a major role in the mediation and modulation of inflammatory states — from the response set up around a splinter lodged in a finger to involvement in a major asthmatic attack or in anaphylactic shock. Many drugs which can be bought over the counter in pharmacies are anti-inflammatory agents, from lowly aspirin to many more modern remedies. All these so-called NSAIDs (non-steroidal anti-inflammatory drugs) have their effects by reducing or preventing the actions of prostaglandins.

The name ‘prostaglandin’ was coined after it was found that semen contracted the smooth muscle of the uterus. It was considered that the substance in the semen responsible for this effect came from the prostate gland. There are many different prostaglandins and related substances, and the nomenclature is complex. All are derived from a membrane lipid called arachidonic acid, which has 20 carbon atoms and 4 double bonds. The substances derived from this acid are more properly called eicosanoids (eicosa-20; enoic-double bonds). There are three main groups of eicosanoids — prostaglandins, thromboxanes, and leukotrienes. The first two, prostaglandins and thromboxanes, are sometimes called prostanoids.

Arachidonic acid is part of some membrane phospholipids. Phospholipase enzymes liberate the arachidonic acid from its linkage to the phospholipid. (Anti-inflammatory steroids, such as cortisol, prevent this liberation and hence relieve inflammation.) The free arachidonic acid then undergoes a complex series of biochemical transformations, to produce the prostanoids (PGE₂, PGD₂, PGF_2a, PGI₂ (prostacyclin)) and the thromboxanes (TXA₂ and others). The cyclo-oxygenase enzymes are involved at this stage, and it is these that are inhibited by NSAIDs, including aspirin.

Bergstrom and Samuelsson, in Sweden, worked out the complex chemistry of arachidonic acid and its products, and Vane and colleagues, in England, showed that aspirin inhibited the cyclo-oxygenase system. Together they shared a Nobel Prize in 1982 for their work on the prostanoids. There is an alternative pathway for metabolism of arachidonic acid using lipoxygenase enzymes, rather than cyclo-oxygenase; the end products are a family of leukotrienes (B₄, C₄, D₄, E₄, and F₄).

The whole eicosanoid cascade is set off by a great variety of different types of stimuli. Three examples are these: following the action of thrombin on platelets during the clotting process; by the actions of kinins released on injury; and following the reaction of antibodies with antigens on the surface of cells, as in an allergic response.

Not all eicosanoids are produced in all tissues. For example, prostacyclin is produced predominantly from the cells lining blood vessels: this causes vasodilatation and inhibits platelet aggregation. On the other hand, the thromboxane TXA₂ is formed in platelets and causes vasoconstriction and platelet aggregation. Because the enzymes used in the production of prostacyclin and TXA₂ are different, a small daily dose of aspirin is able to prevent TXA₂ formation without affecting prostacyclin formation. This is therefore an effective way of preventing intravascular thrombosis, and thus reducing the risk of strokes and heart attacks. Many people now follow this simple routine. The prostanoid PGE₂ is effective in inhibiting gastric secretion and stimulates mucus secretion in the stomach; it is also a mediator of fever. Many prostaglandins have bronchoconstrictor actions. Leukotrienes generally cause bronchoconstriction and vasodilatation (except for the coronary arteries, which are constricted); they are important mediators in all types of inflammation, and responsible for the slow, second, histamine-resistant phase of anaphylaxis.

Alan W. Cuthbert

See also allergy; aspirin; fever; inflammation.