Initiation of the inflammatory cascade
Any damage to the cell membrane structure caused by physical (burn, trauma, radiation), chemical (acids, alkalis), or biological factors (microorganisms) triggers the primary biochemical reaction.
Under the action of the enzyme phospholipase A₂, arachidonic acid is released from the constituent membrane phospholipids. It is a universal precursor of eicosanoids—signaling molecules that regulate inflammation, nociception, and microcirculation.
Pharmacological blockade of this stage is carried out by glucocorticoids (hormonal anti-inflammatory drugs). By inhibiting phospholipase A₂, they completely halt the formation of arachidonic acid and all its downstream products.
Cyclooxygenase pathway: COX-1 and COX-2
The conversion of arachidonic acid via the cyclooxygenase pathway leads to the formation of prostaglandins and thromboxanes. This biochemical route is blocked by nonsteroidal anti-inflammatory drugs (NSAIDs). Two key isoforms of the enzyme function in the body:
- COX-1 (constitutive / physiological)
- Characterized by a constant level of expression in tissues.
- Responsible for physiological homeostasis: maintains the regulation of renal blood flow, uterine tone, and microcirculation.
- Provides gastroprotection by maintaining the balance between hydrochloric acid and the protective barrier (bicarbonates and mucus).
- Controls hemostasis through the regulation of platelet aggregation.
- COX-2 (inducible)
- Normally virtually absent, its synthesis increases sharply during inflammation.
- Induced by pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α).
- Products of COX-2 (prostaglandins $D_2$, $E_2$, $I_2$) produce the classic symptoms of inflammation: local edema, hyperemia, pain (reduced nociceptor threshold), and fever (elevated body temperature).
Effects of major COX products
Depending on the enzyme isoform and target tissue, different types of eicosanoids are synthesized from arachidonic acid:
| Eicosanoid | Origin | Physiological and pathophysiological effects |
|---|---|---|
| Thromboxane A₂ (Thromboxanum A₂) | COX-1 | Stimulates platelet aggregation, causes vasoconstriction (blood vessel narrowing). |
| Prostaglandin E₂ (Prostaglandinum E₂) | COX-1 / COX-2 | Normally: gastric mucosal protection and renal blood flow. In inflammation: fever and pain receptor sensitization. |
| Prostacyclin (PGI₂) (Prostacyclinum | COX-1 / COX-2 | Inhibits platelet aggregation, causes vasodilation (blood vessel widening), and participates in inflammation. |
| Prostaglandin F₂α (Prostaglandinum F₂α) | COX-1 | Regulates the contractile activity and tone of the uterine smooth muscle. |
Lipoxygenase pathway and leukotrienes
An alternative route of arachidonic acid conversion is catalyzed by the enzyme 5-lipoxygenase (5-LOX), which is expressed predominantly in leukocytes.
The end products of this pathway are leukotrienes (LTA₄, LTB₄, LTC₄, LTD₄, LTE₄). Their main biological functions include:
- Enhancement of neutrophil chemotaxis and migration to the focus of injury.
- Significant increase in vascular wall permeability.
- Development of bronchospasm and mediation of severe allergic reactions.
Briefly: answers to topical questions
What is the mechanism of the anti-inflammatory action of glucocorticoids?
The mechanism of the anti-inflammatory action of glucocorticoids is implemented predominantly through genomic effects and enzyme inhibition.
- Lipocortins—glucocorticoids induce the synthesis of these proteins, which inhibit phospholipase A2, blocking the release of arachidonic acid and the synthesis of inflammatory mediators.
- Cyclooxygenase-2 (COX-2)—these drugs suppress the gene responsible for the synthesis of this enzyme, reducing the production of pro-inflammatory prostaglandins.
Additionally, they suppress the synthesis of intercellular adhesion molecules, preventing leukocyte migration, and block cytokine production by macrophages and T-lymphocytes.
Which drugs block the lipoxygenase pathway and the effects of leukotrienes?
The lipoxygenase pathway and the effects of leukotrienes are blocked by antileukotriene agents.
- Zileuton—a 5-lipoxygenase inhibitor that prevents the synthesis of all leukotrienes from arachidonic acid.
- Montelukast—a leukotriene receptor blocker.
- Zafirlukast—a leukotriene receptor blocker that eliminates bronchospasm by blocking LTD₄ receptors on smooth muscle cells.
These drugs reduce the effect of cysteinyl leukotrienes on the bronchi and are used as basic anti-inflammatory therapy.
Which enzymes are involved in the arachidonic acid cascade?
The arachidonic acid metabolism cascade involves enzymes responsible for the synthesis of various eicosanoids.
- Phospholipase A2 (PLA₂) — releases arachidonic acid from cell membrane phospholipids.
- Cyclooxygenase-1 (COX-1) — constitutively expressed, synthesizes prostaglandins for physiological homeostasis.
- Cyclooxygenase-2 (COX-2) — inducible isoform, synthesizes pro-inflammatory prostaglandins.
- 5-Lipoxygenase (5-LOX) — catalyzes the formation of leukotrienes.
- Prostacyclin synthase — forms prostacyclin from cyclic endoperoxides.
- Thromboxane synthase — participates in the synthesis of thromboxane A₂ in platelets.
Remember the order of the cascade blocks: "First PHOSPHOLIPASE cleaves, COX and LOX process." GLUCOCORTICOIDS act at the highest level (on Phospholipase A₂), shutting down both the COX and LOX pathways, whereas NSAIDs act locally — exclusively on COX.
Class and exam questions
What is the main difference in the mechanisms of action between GCs and NSAIDs on arachidonic acid metabolism?
Glucocorticoids act at an early stage by inhibiting phospholipase A₂ and completely blocking the formation of arachidonic acid. NSAIDs act downstream in the cascade, selectively or non-selectively inhibiting cyclooxygenases (COX-1 and COX-2) only.
Why does inhibition of COX-1 lead to gastric damage?
COX-1 is a constitutive enzyme responsible for the synthesis of prostaglandin E₂, which maintains the secretion of protective mucus and bicarbonates. Inhibition of COX-1 disrupts this balance, making the mucosa vulnerable to hydrochloric acid.
What role do the products of the lipoxygenase pathway play in the development of pathology?
The products of the 5-lipoxygenase pathway — leukotrienes — stimulate neutrophil chemotaxis, increase vascular permeability, and play a leading role in the development of allergies and bronchospasm.
What else to study on this topic
- Mechanisms of COX-2 induction by pro-inflammatory cytokines (IL-1, TNF-α)
- Comparative pharmacology of selective and non-selective COX inhibitors
- The role of prostacyclin and thromboxane A₂ in the endothelial-platelet balance
- Pharmacological targets of leukotriene receptor blockade in bronchial asthma
- Effects of prostaglandin F₂α on myometrial tone in obstetric practice
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