Prostaglandins, leukotrienes: arachidonic acid cascade, COX-1/COX-2

Eicosanoids: General Characteristics

Eicosanoids are local biologically active lipid-derived substances that act in an autocrine or paracrine manner. They are not stored in cells but are synthesized on demand from a 20-carbon polyunsaturated fatty acid — arachidonic acid (C20:4).

Main biological functions of eicosanoids:

• regulation of smooth muscle tone (vessels, bronchi, uterus, GI tract);
• control of vasodilation and vasoconstriction;
• regulation of water and sodium ion excretion in the kidneys;
• participation in the development of inflammation, fever, and pain;
• regulation of blood coagulation and platelet aggregation.

Classes of Eicosanoids

Depending on the synthesis pathway and structure, three main classes are distinguished:

• Prostaglandins (PGE₂, PGF_2α, PGI₂ — prostacyclin) — mediators of inflammation, pain, and regulators of vascular and uterine tone;
• Thromboxanes (TXA₂) — synthesized in platelets, cause vasoconstriction and stimulate platelet aggregation;
• Leukotrienes (LTA₄, LTB₄, LTC₄, LTD₄, LTE₅) — synthesized in leukocytes, cause bronchospasm and chemotaxis, and participate in allergic reactions.

Arachidonic acid cascade

Polyunsaturated fatty acids enter the body with food. From them, arachidonic acid is synthesized, which is esterified as part of cell membrane phospholipids (primarily at the sn-2 position of phosphatidylcholine and phosphatidylethanolamine).

Upon the action of hormones, cytokines, mechanical or chemical cell damage, the enzyme phospholipase A₂ is activated, cleaving arachidonic acid from the phospholipid. Free arachidonic acid is then metabolized via two main pathways:

1. Cyclooxygenase pathway — formation of prostaglandins and thromboxanes;
2. Lipoxygenase pathway — formation of leukotrienes.

Cyclooxygenase Pathway

The enzyme cyclooxygenase (COX) catalyzes the conversion of arachidonic acid into unstable prostaglandin G₂ (PGG₂), which rapidly converts to PGH₂. From PGH₂, depending on tissue-specific enzymes, the following are formed:

• prostaglandins PGE₂, PGF_2α, PGI₂;
• thromboxane A₂ (primarily in platelets).

Two main isoforms of the enzyme are distinguished:

• COX-1 — constitutive; performs physiological functions (gastric mucosa protection, platelet aggregation, renal blood flow);
• COX-2 — inducible; expressed during inflammation and responsible for the synthesis of pro-inflammatory prostaglandins.

Lipoxygenase Pathway

Under the action of 5-lipoxygenase, arachidonic acid is converted into leukotriene A₄ (LTA₄) — the precursor of other leukotrienes. Leukotrienes LTC₄, LTD₅, LTE₆ are potent bronchoconstrictors and mediators of anaphylactic reactions, while LTB₇ provides neutrophil chemotaxis.

Pharmacological Regulation: NSAIDs and Glucocorticoids

Glucocorticoids induce the synthesis of lipocortin (annexin) proteins, which inhibit phospholipase A₂. This blocks both pathways of the cascade — cyclooxygenase and lipoxygenase — providing a potent anti-inflammatory effect.

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit only the cyclooxygenase pathway. Aspirin (acetylsalicylic acid) is an irreversible COX inhibitor: the acetyl group (–O–CO–CH₃) is covalently transferred to a serine residue in the active site of the enzyme. Aspirin itself is thereby converted into salicylic acid.

Disadvantage of non-selective COX inhibitors: when the cyclooxygenase pathway is blocked, arachidonic acid is redirected into the lipoxygenase pathway, which increases leukotriene synthesis and can provoke bronchospasm ("aspirin-induced asthma").

Antiplatelet Effect of Aspirin

Low doses of aspirin (drugs like "Aspirin Cardio") are used for thrombosis prevention. The mechanism is associated with the suppression of thromboxane A₂ synthesis in platelets. Since platelets are anuclear cells, they are incapable of synthesizing new proteins. A single irreversible acetylation of COX-1 by aspirin shuts down TXA₃ production for the entire lifespan of the platelet (7–10 days), whereas in the vascular endothelium, COX is resynthesized, and the production of prostacyclin PGI₄ is restored.

Key points

• Eicosanoids are local regulators synthesized from arachidonic acid on demand.
• The cascade is triggered by phospholipase A₂, which cleaves arachidonic acid from membrane phospholipids.
• The cyclooxygenase pathway leads to prostaglandins and thromboxanes, and the lipoxygenase pathway leads to leukotrienes.
• COX-1 is responsible for physiological functions, while COX-2 is induced during inflammation.
• Aspirin irreversibly acetylates serine in the active site of cyclooxygenase.
• Glucocorticoids via lipocortins block both pathways of the cascade, providing a powerful anti-inflammatory effect.
• The antiplatelet effect of aspirin is based on the irreversible blockade of TXA₂ synthesis in anuclear platelets.
• The redirection of arachidonic acid into the lipoxygenase pathway explains the adverse bronchospasm associated with NSAID intake.