STEPTRACKERGENERAL PRINCIPLES | PATHOLOGY + IMMUNOLOGY | HIGH-YIELD REVIEW

Acute Inflammation Mediators

The chemical signals that make tissue red, hot, swollen and painful — and call neutrophils in.

FOCUS ON
Match each cardinal sign to its mediator, and each mediator to the drug that blocks it (COX, 5-lipoxygenase, leukotriene receptor). Bradykinin angioedema (ACE inhibitors, C1-inhibitor deficiency) is the classic look-alike for histamine reactions.
MEDIATOR
SOURCE · TRIGGER
MAIN ACTIONS
CLINICAL LINK
Toll-like receptors
the starter
On macrophages and dendritic cells; recognize PAMPs (e.g., LPS via CD14/TLR4).
Activate NF-κB → cytokines and mediator genes switched on
Gram-negative sepsis
Histamine
preformed
Mast cells, basophils, platelets; released by trauma, C3a/C5a, IgE cross-linking, heat.
Arteriolar dilation + ↑ venular permeability — immediate and short-lived
Wheal and flare; urticaria
Prostaglandins
COX pathway
Arachidonic acid → COX → PGI₂, PGD₂, PGE₂ (macrophages, endothelium).
PGI₂, PGD₂: vasodilation, ↑ permeability · PGE₂: pain and fever
NSAIDs block COX
Thromboxane A₂
COX pathway
Platelet COX-1.
Vasoconstriction, platelet aggregation
Aspirin irreversibly blocks it (antiplatelet)
Leukotrienes
5-lipoxygenase
Arachidonic acid → 5-LO → LTB₄ and LTC₄/D₄/E₄.
LTB₄: neutrophil chemotaxis · LTC₄, D₄, E₄: bronchospasm, vasoconstriction, ↑ permeability
Zileuton (5-LO), montelukast (receptor); aspirin-exacerbated respiratory disease
Complement
plasma cascade
Classical (C1 + IgG/IgM), alternative (microbial surface), lectin (mannose-binding lectin).
C3a, C5a: mast cell degranulation · C5a: chemotaxis · C3b: opsonin · C5b-9: lysis (MAC)
C5–C9 deficiency → recurrent Neisseria
Hageman factor (XII)
plasma
Activated by contact with subendothelial collagen or negatively charged surfaces.
Switches on coagulation, fibrinolysis, complement and kinins together
Contributes to DIC in sepsis
Bradykinin
kinin system
Kallikrein cleaves kininogen; ACE degrades bradykinin.
Vasodilation, ↑ permeability, pain
ACE-inhibitor angioedema; hereditary angioedema (C1-inhibitor ↓)
Cytokines
IL-1, TNF, IL-6, IL-8
Activated macrophages and other cells.
IL-1/TNF: endothelial adhesion molecules, fever · IL-6: acute-phase proteins · IL-8: neutrophil chemotaxis
Systemic signs — page 2.05

Mechanism — injury to exudate

Injury / microbePAMPs, damage
→
SensorsTLRs, mast cells, plasma cascades
→
VasodilationRubor, calor
→
Permeability ↑Protein-rich exudate (tumor)
→
NeutrophilsPage 2.02

Postcapillary venules are where fluid leaks and leukocytes exit.

Cardinal signs and their mediators

SIGN
CAUSE
MEDIATORS
Rubor, calor
Arteriolar dilation
Histamine, prostaglandins, bradykinin
Tumor
Leaky venules → exudate
Histamine, LTC₄–E₄, tissue damage
Dolor
Sensitized nerve endings
PGE₂, bradykinin
Fever
Hypothalamic set point ↑
IL-1, TNF → PGE₂
Chemotaxis
Neutrophil attraction
C5a, LTB₄, IL-8, kallikrein, bacterial peptides

How it's tested

COMMON CONFUSIONExudate (inflammation: protein- and cell-rich) vs transudate (pressure or oncotic change: protein-poor).
THE TRAPLip and tongue swelling without hives in a patient on lisinopril is bradykinin-driven. Antihistamines don't fix it; stop the ACE inhibitor.
YOUR APPROACHName the sign, then the mediator, then where the drug acts on the arachidonic acid map. COX inhibition shifts substrate toward leukotrienes.

If you see… think…

Angioedema after starting an ACE inhibitor → ↑ bradykinin
Recurrent airway/facial swelling, low C4, no urticaria → C1-esterase inhibitor deficiency
Asthma + nasal polyps + reaction to aspirin → leukotriene excess
Fever in infection → IL-1/TNF → hypothalamic PGE₂
Septic shock from E coli → LPS via CD14/TLR4
Recurrent meningococcal infection → MAC (C5–C9) deficiency
Neutrophil chemoattractants → C5a, LTB₄, IL-8, bacterial products
Daily low-dose aspirin → irreversible ↓ platelet TXA₂
Immediate wheal after a bee sting → histamine from mast cells