Chemical mediators of inflammation

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Chemical Mediators of Inflammation

Inflammatory mediators are soluble factors that initiate and regulate inflammatory reactions. They are derived either from cells (preformed in granules or newly synthesized) or from plasma proteins (primarily synthesized in the liver).

1. Cell-Derived Mediators

A. Vasoactive Amines

  • Histamine: Released by mast cell degranulation, basophils, and platelets in response to trauma, cold, or IgE binding. Causes arteriolar vasodilation and immediately increases venular permeability (via endothelial contraction).
  • Serotonin (5-HT): Preformed in platelet granules. Released during platelet aggregation, causing vasoconstriction during clotting but mimicking histamine’s actions in inflammation.

B. Arachidonic Acid (AA) Metabolites (Eicosanoids)

When cell membranes are injured, phospholipases cleave AA from membrane phospholipids. AA is then metabolized via two distinct pathways:

Pathway Key Metabolites Primary Actions
Cyclooxygenase (COX) PGI_2 (Prostacyclin)
TXA_2 (Thromboxane A2)
PGE_2		 Vasodilation inhibits platelet aggregation
Vasoconstriction promotes platelet aggregation
Pain (dolor), Fever (calor) via the hypothalamus
Lipoxygenase (LOX) LTB_4
LTC_4, LTD_4, LTE_4		 Neutrophil chemotaxis
Intense bronchospasm, increased vascular permeability

C. Cytokines and Chemokines

  • TNF and IL-1: Produced primarily by activated macrophages. They upregulate endothelial adhesion molecules (E-selectin, ICAM-1) and induce the systemic acute-phase response (fever, lethargy, hepatic synthesis of acute-phase proteins).
  • IL-8 (CXCL8): A powerful chemoattractant specific for neutrophils.

2. Plasma Protein-Derived Mediators

These circulate in inactive forms and must be cleaved to become biologically active.

A. The Complement System

  • Anaphylatoxins (C3a, C5a): Stimulate mast cells to release histamine, leading to vasodilation and increased permeability.
  • Chemotaxis (C5a): Potent chemoattractant for neutrophils, monocytes, eosinophils, and basophils. Also activates the lipoxygenase pathway in these cells.
  • Opsonization (C3b, iC3b): Acts as an opsonin, binding to microbial cell walls to augment phagocytosis by neutrophils and macrophages.
  • Membrane Attack Complex (MAC / C5b-9): Drills holes into microbial cell membranes, causing osmotic lysis.

B. The Kinin and Coagulation Cascade

  • Bradykinin: Generated via the kinin cascade following activation of Hageman factor (Factor XII). It increases vascular permeability, causes smooth muscle contraction, dilates blood vessels, and **induces pain** (similar to $PGE_2$).
  • Factor XII (Hageman Factor): Synthesized by the liver. When activated by exposed collagen or basement membrane, it simultaneously triggers four interconnected plasma systems: the coagulation cascade, the fibrinolytic system, the kinin system, and the complement cascade.

3. High-Yield Summary of Functional Roles

Inflammatory Process Principal Chemical Mediators
Vasodilation Histamine, Prostaglandins (PGI_2, PGE_2), Nitric Oxide (NO)
Increased Vascular Permeability Histamine, Serotonin, C3a, C5a, Leukotrienes ($LTC_4, LTD_4, LTE_4$), Bradykinin
Chemotaxis / Leukocyte Activation LTB_4, C5a, IL-8, Bacterial formyl peptides
Fever IL-1, TNF, Prostaglandins ($PGE_2$)
Pain Prostaglandins (PGE_2), Bradykinin
Tissue Damage Lysosomal enzymes (neutrophils, macrophages), Reactive Oxygen Species (ROS)

4. Pharmacology / Exam Pearls

  • Corticosteroids: Inhibit Phospholipase A2, thereby blocking the synthesis of both prostaglandins and leukotrienes.
  • NSAIDs: Non-selectively block Cyclooxygenase (COX-1 and COX-2), blocking prostaglandin production to reduce pain and fever. They do not inhibit the LOX pathway.
  • Zileuton and Montelukast: Zileuton inhibits 5-lipoxygenase (blocking leukotriene synthesis), while Montelukast blocks leukotriene receptors (LTD_4). Both are used in asthma management to counteract bronchoconstriction.