Chemical Mediators of Inflammation

Chemical Mediators: Overview & Vasoactive Amines - Rapid Responders

• Overview of Mediators:
  • Cell-derived: Preformed in granules (e.g., histamine) or newly synthesized (e.g., prostaglandins).
  • Plasma-derived: Synthesized mainly in liver (e.g., complement, kinins); circulate as inactive precursors.
  • Actions: Bind specific receptors; short-lived; tightly regulated; can stimulate other mediators.
• Vasoactive Amines (Rapid Responders):
  • Histamine:
    • Sources: Mast cells (primary), basophils, platelets.
    • Release triggers: Physical injury, IgE cross-linking, C3a/C5a (anaphylatoxins), neuropeptides (Substance P), cytokines (IL-1, IL-8).
    • Actions: Arteriolar dilation, ↑ venular permeability (via H1 receptors, endothelial contraction), bronchial constriction.

    ⭐ Histamine is pre-formed in mast cell granules.

  • Serotonin (5-Hydroxytryptamine, 5-HT):
    • Sources: Platelets, enterochromaffin cells.
    • Actions: Similar to histamine (↑ vascular permeability); released during platelet aggregation. Also involved in vasoconstriction during clotting.

Chemical Mediators: Arachidonic Acid Metabolites - Eicosanoid Orchestra

• Derived from membrane phospholipids via Phospholipase $A_2$ (inhibited by steroids).
• Cyclooxygenase (COX) Pathway:
  • Yields Prostaglandins (PGs) & Thromboxane $A_2$ ($TXA_2$).
  • PGs ($PGE_2, PGD_2, PGI_2$): Vasodilation, pain, fever. $PGI_2$ also inhibits platelet aggregation. $PGF_{2\alpha}$ causes vasoconstriction.
  • $TXA_2$: Vasoconstriction, promotes platelet aggregation.
  • 📌 Mnemonic: Prostaglandins = Pain, Pyrexia (fever); Thromboxane = Thrombosis.
• Lipooxygenase (LOX) Pathway:
  • Yields Leukotrienes (LTs) & Lipoxins.
  • $LTB_4$: Potent chemotactic agent.
  • $LTC_4, LTD_4, LTE_4$ (SRS-A): Bronchoconstriction, ↑vascular permeability.
  • Lipoxins ($LXA_4, LXB_4$): Anti-inflammatory, inhibit neutrophil chemotaxis & adhesion.
• Pharmacological Modulation:
  • NSAIDs (e.g., Aspirin, Ibuprofen): Inhibit COX.
  • Zileuton: Inhibits LOX.
  • Montelukast: LT receptor antagonist.

⭐ Aspirin irreversibly inhibits cyclooxygenase (COX), affecting platelet function for their entire lifespan.

Chemical Mediators: Cytokines & Complement - Inflammation's Conductors

• Cytokines: Soluble proteins; orchestrate inflammatory responses.
  • Pro-inflammatory:
    • TNF-α, IL-1: Key acute inflammation mediators. Systemic: Fever, ↑endothelial adhesion molecules, ↑cytokines/chemokines; TNF → cachexia.
    • IL-6: Induces liver's Acute Phase Protein synthesis (e.g., CRP); systemic fever.
    • Chemokines (e.g., IL-8/CXCL8): Leukocyte chemotaxis, esp. neutrophils to injury site.

  ⭐ TNF, IL-1, and IL-6 are major cytokines mediating acute phase response.

• Complement System: Plasma proteins; activated via cascade.
  • Activation Pathways: Classical (Antibody-Antigen complexes), Alternative (microbial surfaces), Lectin (mannose-binding lectin).
  • Key Functions:
    • C3b: Opsonization (tags microbes for phagocytosis). 📌 C3b Binds Bacteria.
    • C3a, C5a: Anaphylatoxins (mast cell degranulation → histamine release, ↑vascular permeability); C5a also potent chemotactic agent.
    • C5b-C9 (MAC): Cell lysis via Membrane Attack Complex. 📌 MAC punches holes.

Chemical Mediators: Kinins, Clotting & Others - The Diverse Crew

• Kinin System: Plasma-derived; activated by Factor XII (Hageman factor).
  • Bradykinin: ↑Vascular permeability, vasodilation, smooth muscle contraction, pain.

  ⭐ Bradykinin is a potent mediator of pain.

• Clotting System: Interlinked with inflammation.
  • Thrombin: ↑Leukocyte adhesion, fibroblast proliferation.
  • Fibrinopeptides: ↑Vascular permeability, chemotaxis.
• Platelet-Activating Factor (PAF): From diverse cells (platelets, leukocytes, endothelium). Actions: Vasodilation, ↑vascular permeability (potent: 100-10,000x > histamine), platelet aggregation, chemotaxis.
• Nitric Oxide (NO): Synthesized via $L-arginine \xrightarrow{NOS} NO$. Vasodilator, ↓platelet aggregation & adhesion, microbicidal.
• Lysosomal Components: From neutrophils & macrophages. Enzymes (e.g., elastase, collagenase) cause tissue damage.
• Oxygen Radicals: E.g., $O_2^{\cdot-}$, $H_2O_2$, $OH^{\cdot}$. Cause endothelial damage, inactivate antiproteases, injure cells.

High‑Yield Points - ⚡ Biggest Takeaways

• Histamine & Serotonin: Early vasodilation & ↑ vascular permeability.
• Prostaglandins (COX): PGE2 (pain, fever); PGI2 (vasodilation, inhibits platelet aggregation).
• Leukotrienes (LOX): LTB4 (chemotaxis); Cysteinyl LTs (bronchospasm, ↑ permeability).
• Cytokines (TNF, IL-1, IL-6): Drive fever, acute phase proteins, endothelial activation.
• Complement C3a & C5a: Anaphylatoxins; C5a also for chemotaxis & leukocyte activation.
• Bradykinin: Key mediator of pain and vasodilation.
• Chemokines (e.g., IL-8): Crucial for leukocyte recruitment (chemotaxis).