11.02.1 Synthesis, Receptors and Actions

When phospholipase A₂ is activated, arachidonic acid is released from the cell membrane.

Prostanoids, thromboxane, and leukotrienes are synthesised from arachidonic acid. Arachidonic acid is metabolised by cyclo-oxygenase to produce the prostaglandins, prostacyclin and thromboxane or by lipoxygenase to produce the leukotrienes (LTs). The eicosanoids are synthesised on demand and are not stored.

Cyclo-oxygenase metabolites activate specific receptors to influence a range of effects. There are two forms of the cyclo-oxygenase enzyme COX-1 and COX-2. COX-1 is a constitutively (always) expressed protein that produces prostanoids that have “house-keeping” roles, e.g. regulation of blood flow, and gastric protection via release of cytoprotective mucus and inhibition of gastric acid production. They also cause uterine contraction in pregnancy. COX-2 is induced at sites of inflammation, and prostanoids produced in this setting tend to have pro-inflammatory effects e.g. hyperalgesia, vasodilatation, increased vascular permeability. Prostanoid receptors are G-protein coupled receptors (GPCRs). There are 10 prostanoid receptors which correspond to their ligand: IP_1-2 (PGI₂), DP_1-2 (PGD₂), EP_1-4 (PGE₂), FP (PGF_2α), TP (TXA₂).

Lipoxygenase metabolites are broadly divided into 2 classes, the chemotactic agent LTB₄ and the cysteinyl leukotrienes LTC₄, LTD₄ and LTE₄, which cause bronchoconstriction and increase vascular permeability. Leukotrienes also act at cell surface GPCR on neutrophils (LTB₄). The cysteinyl-leukotrienes act at their cell-surface receptors CysLT₁ and CysLT₂ on target cells to contract bronchial and vascular smooth muscle, to increase permeability of small blood vessels, to enhance secretion of mucus in the airway and gut, and to recruit leukocytes to sites of inflammation.