Leukotrienes are produced in leukocytes and mast cells by the action of lipoxygenase and are involved in vascular and smooth muscle reactions and leukocyte recruitment. The synthesis of leukotrienes involves multiple steps, the first of which generates leukotriene A4 (LTA4), which in turn gives rise to LTB4 or LTC4. LTB4 is produced by neutrophils and some macrophages, and is a potent chemotactic agent and activator of neutrophils, causing aggregation and adhesion of the cells to venular endothelium, generation of ROS, and release of lysosomal enzymes. The cysteinyl-containing leukotriene LTC4 and its metabolites, LTD4 and LTE4, are produced mainly in mast cells and cause intense vasoconstriction, bronchospasm (important in asthma), and increased permeability of venules.
Lipoxins also are generated from arachidonic acid by the lipoxygenase pathway, but unlike prostaglandins and leukotrienes, the lipoxins suppress inflammation by inhibiting the recruitment of leukocytes. They inhibit neutrophil chemotaxis and adhesion to endothelium. They also are unusual in that two cell populations are required for the transcellular biosynthesis of these mediators. Leukocytes, particularly neutrophils, produce intermediates in lipoxin synthesis, and these are converted to lipoxins by platelets interacting with the leukocytes.
Pharmacologic Inhibitors of Prostaglandins and Leukotrienes
The importance of eicosanoids in inflammation has driven attempts to develop drugs that inhibit their production or actions and thus suppress inflammation. These anti-inflammatory drugs include the following: • Cyclooxygenase inhibitors include aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen. They inhibit both COX-1 and COX-2 and thus block all prostaglandin synthesis (hence their efficacy in treating pain and fever); aspirin does this by irreversibly inactivating cyclooxygenases. Selective COX-2 inhibitors are a newer class of these drugs that are 200to 300-fold more potent in blocking COX-2 than COX-1. There has been great interest in COX-2 as a therapeutic target because of the possibility that COX-1 is responsible for the production of prostaglandins that are involved in both inflammation and physiologic functions such as protecting gastric epithelial cells from acid-induced injury, whereas COX-2 generates prostaglandins that are involved only in inflammation. If this idea is correct, the selective COX-2 inhibitors should be anti-inflammatory without having the toxicities of the nonselective inhibitors, such as gastric ulceration. However, these distinctions are not absolute, as COX-2 also seems to play some role in normal homeostasis. Furthermore, selective COX-2 inhibitors may increase the risk of cardiovascular and cerebrovascular events, possibly because they impair endothelial cell production of prostacyclin (PGI2), which prevents thrombosis, while leaving intact the COX-1-mediated production by platelets of TXA2, which induces platelet aggregation. Thus, selective COX-2 inhibition may tilt the balance toward vascular thrombosis, especially in combination with other factors that increase the risk of thrombosis. Nevertheless, these drugs are used in individuals who do not have risk factors for cardiovascular disease and when the drugs’ benefits outweigh their risks.
Lipoxygenase inhibitors. 5-lipoxygenase is not affected by NSAIDs, and many new inhibitors of this enzyme pathway have been developed. Pharmacologic agents that inhibit leukotriene production (e.g., zileuton) are useful in the treatment of asthma.