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PA3.1-2 | Acute Inflammation — Vascular & Cellular Events, Mediators — SDL Guide (Part 3)

Vasoactive Amines: Histamine and Serotonin

Diagram showing mast cell histamine and platelet serotonin release, their vascular effects in acute inflammation, and the clinical role of H1 antihistamines. — **Panel A:** Mast cell, basophil, preformed histamine granules, IgE cross-linking, C3a/C5a, physical injury, cold, heat, cytokines, histamine release.. **Panel B:** Platelet, dense granules, serotonin or 5-hydroxytryptamine, collagen exposure, thrombin, PAF, enterochromaffin cell of gut.. **Panel C:** Post-capillary venule, endothelial contraction, intercellular gaps, vasodilation, increased blood flow, vascular permeability, plasma leakage, H1 receptors on nociceptors, rubor, calor, edema, itching, pain.. **Panel D:** H1 antihistamines, cetirizine, chlorphenamine, blocked H1 receptor, urticaria, anaphylaxis, rhinitis, mast cell coordination, prostaglandins, leukotrienes, TNF, IL-4, histamine versus serotonin species importance..

Histamine is the first mediator released in acute inflammation.

Source: Pre-formed, stored in mast cell and basophil granules. Also in platelets.
Release triggers: IgE cross-linking (allergy), C3a/C5a, physical injury, cold, heat, cytokines.
Actions: Vasodilation (↑blood flow → rubor, calor); ↑Vascular permeability by endothelial contraction (venules); Itching/pain via H₁ receptors on nociceptors.
Clinical link: Antihistamines (cetirizine, chlorphenamine) block H₁ receptors — used for urticaria, anaphylaxis, rhinitis.

Serotonin (5-hydroxytryptamine):
Source: Pre-formed in platelet dense granules. Also enterochromaffin cells (gut).
Actions: Similar to histamine — vasoactive; more important in rodents than humans.
Release: Platelet activation by collagen, thrombin, PAF.

> Mast cells are the master coordinators of early acute inflammation: they store histamine AND produce prostaglandins, leukotrienes, TNF, and IL-4 — connecting immediate and acquired immunity.

Arachidonic Acid Metabolites: Prostaglandins and Leukotrienes

A four-panel flowchart shows arachidonic acid released from membrane phospholipids and converted through COX, LOX, and lipoxin pathways with key mediators, effects, and drug targets. — **Panel A:** Membrane phospholipids, injury signals, phospholipase A₂, arachidonic acid, COX pathway, LOX pathway, 15-LOX to lipoxins. **Panel B:** COX-1, COX-2, PGH₂, PGE₂, PGD₂, PGI₂ prostacyclin, TXA₂ thromboxane A₂, vasodilation, vascular permeability, fever, pain sensitisation, platelet effects. **Panel C:** 5-LOX, neutrophils, mast cells, LTA₄, LTB₄, LTC₄, LTD₄, LTE₄, neutrophil chemotaxis, vascular permeability, bronchoconstriction, SRS-A. **Panel D:** NSAIDs, aspirin, ibuprofen, diclofenac, celecoxib, montelukast, COX inhibition, COX-2 selective inhibition, LTD₄ receptor blockade, lipoxins, inflammation resolution.

Arachidonic acid (AA) is released from membrane phospholipids by phospholipase A₂ (activated by injury signals). It is then metabolised by two divergent enzyme pathways:

COX (cyclooxygenase) pathway → prostaglandins and thromboxane:
• COX-1 (constitutive) + COX-2 (inducible, induced by IL-1, TNF) → PGH₂ → tissue-specific isomerases:
- PGE₂, PGD₂: vasodilation, ↑permeability, fever (hypothalamic action), pain sensitisation (hyperalgesia).
- PGI₂ (prostacyclin): vasodilation, inhibits platelet aggregation.
- Thromboxane A₂: vasoconstriction, platelet aggregation (from platelets).
• Pharmacology: NSAIDs (aspirin, ibuprofen, diclofenac) inhibit COX → ↓PGE₂ → antipyretic + analgesic + anti-inflammatory. Selective COX-2 inhibitors (celecoxib) spare gastric PGE₂ (↓ulcers) but ↑thrombotic risk (↓PGI₂ without ↓TXA₂).

LOX (lipoxygenase) pathway → leukotrienes:
• 5-LOX (neutrophils, mast cells) → LTA₄ → LTB₄ or cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄).
• LTB₄: powerful chemotactic agent for neutrophils; also activates neutrophils.
• LTC₄/LTD₄/LTE₄: ↑Vascular permeability (10× more potent than histamine); bronchoconstriction — the principal mediators of slow-reacting substance of anaphylaxis (SRS-A).
• Pharmacology: Montelukast (leukotriene receptor antagonist) blocks LTD₄ receptor → used in asthma, allergic rhinitis.

Lipoxins (from AA, via 15-LOX): anti-inflammatory — inhibit neutrophil chemotaxis, promote monocyte recruitment → resolution signal.

Platelet-Activating Factor, Cytokines, Nitric Oxide

Four-panel infographic summarizing PAF, TNF/IL-1, chemokines, and nitric oxide as inflammatory mediators with their sources and major actions. — **Panel A:** Overview of inflamed venule showing endothelium, mast cell, macrophage, neutrophil, platelet, smooth muscle, and mediator groups PAF, TNF/IL-1, chemokines, and NO.. **Panel B:** PAF sources and actions: mast cells, basophils, endothelium, neutrophils, monocytes, platelet aggregation, bronchoconstriction, increased vascular permeability, chemotaxis, and arachidonic acid metabolite synthesis.. **Panel C:** TNF and IL-1 sources and targets: macrophage, endothelium, hypothalamus, liver, systemic circulation, adhesion molecules, fever via PGE2, acute-phase response, septic shock, and IL-8 activation of neutrophils through CXCR1/CXCR2.. **Panel D:** Nitric oxide sources and actions: endothelial eNOS, macrophage iNOS, vasodilation via cGMP, antimicrobial peroxynitrite ONOO-, and inhibition of platelet aggregation..

Platelet-activating factor (PAF):
Source: Mast cells, basophils, endothelium, neutrophils, monocytes.
Actions: Platelet aggregation; bronchoconstriction; 100–1,000× more potent than histamine in increasing vascular permeability; chemotaxis; synthesis of other mediators (AA metabolites).

Cytokines — TNF and IL-1:
Source: Primarily macrophages (also mast cells, endothelium, T cells).
Actions: Both are pleiotropic — multiple targets:
• Endothelium: ↑adhesion molecule expression (E-selectin, ICAM-1, VCAM-1), ↑procoagulant activity.
• Hypothalamus: fever (via PGE₂ induction by COX-2).
• Liver: acute-phase protein synthesis (CRP, fibrinogen, complement) — the acute-phase response.
• Systemic (high dose): hypotension, DIC — septic shock.
• TNF also promotes cachexia (muscle wasting in chronic inflammation/cancer).

Chemokines:
• Family of ~40 proteins; primary function: leucocyte chemotaxis and activation.
• IL-8 (CXCL8): secreted by macrophages, endothelium → strong neutrophil chemoattractant; presented on endothelial surface to activate rolling neutrophils.
• CXCR1/CXCR2 are the receptors on neutrophils.

Nitric oxide (NO):
Source: Endothelial cells (eNOS, constitutive); macrophages (iNOS, inducible by LPS/cytokines).
Actions:
• Vasodilation: relaxes vascular smooth muscle (↑cGMP).
• Antimicrobial: reacts with O₂•⁻ → peroxynitrite (ONOO⁻), toxic to microbes.
• Anti-platelet: inhibits aggregation.
• Regulates leucocyte recruitment (inhibits excessive rolling/adhesion at low concentrations).