Initiation of the Inflammatory Cascade
Any disruption of cell membrane integrity caused by physical factors (burns, trauma, radiation), chemical agents (acids, alkalis), or biological agents (microorganisms) triggers a primary biochemical reaction.
Under the action of the enzyme phospholipase A₂, arachidonic acid is released from membrane phospholipids. It serves as a universal precursor for eicosanoids—signaling molecules that regulate inflammation, nociception, and microcirculation.
Pharmacological blockade of this step is achieved using glucocorticoids (steroidal anti-inflammatory agents). By inhibiting phospholipase A₂, they completely halt the production of arachidonic acid and all of 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 operate in the body:
- COX-1 (Constitutive / Physiological)
- Characterized by constant baseline tissue expression.
- Responsible for physiological homeostasis: regulates renal blood flow, uterine tone, and microcirculation.
- Provides gastroprotection by maintaining a balance between hydrochloric acid and the protective mucosal barrier (bicarbonates and mucus).
- Controls hemostasis by regulating platelet aggregation.
- COX-2 (Inducible)
- Normally virtually undetectable; its synthesis increases dramatically during inflammation.
- Induced by proinflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α).
- Products of COX-2 ($D_2$, $E_2$, and $I_2$ prostaglandins) drive classic symptoms of inflammation: local edema, hyperemia, pain (lowering nociceptor thresholds), and fever (elevating 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 and causes vasoconstriction. |
| Prostaglandin E₂ (Prostaglandinum E₂) | COX-1 / COX-2 | Normally: gastric mucosal protection and renal blood flow. During inflammation: fever and pain receptor sensitization. |
| Prostacyclin ($PGI_2$) (Prostacyclinum) | COX-1 / COX-2 | Inhibits platelet aggregation, induces vasodilation, and participates in inflammation. |
| Prostaglandin F₂α (Prostaglandinum F₂α) | COX-1 | Regulates smooth muscle contractility and tone in the uterus. |
Lipoxygenase Pathway and Leukotrienes
An alternative metabolic route for arachidonic acid is catalyzed by 5-lipoxygenase (5-LOX), which is expressed predominantly in leukocytes.
The end products of this pathway are leukotrienes ($LTB_4$, $LTC_4$, $LTD_4$, $LTE_4$). Their primary biological functions include:
- Enhancing neutrophil chemotaxis and migration into sites of injury.
- Markedly increasing vascular permeability.
- Inducing bronchospasm and mediating severe allergic reactions.