Chemical Mediators of Acute Inflammation

Chemical Mediators of Acute Inflammation

• Proteases: plasma proteins produced in the liver, including kinins (bradykinin and kallikrein) and the complement system (C3a, C5a)
• Prostaglandins and leukotrienes: metabolites of arachidonic acid, synthesis blocked by NSAIDs (e.g. aspirin)
• Cytokines and chemokines: produced by WBCs, including interleukins, PAF, TNF alpha, PDGF, and TGF beta
• Other inflammatory mediators: from platelets (5-HT, histamine, ADP), neutrophils (lysosomal constituents), and endothelium (prostacyclin, nitric oxide, plasminogen activators/inhibitors)

Vascular Changes

• Three phases:
  • Phase I: Immediate early response (1/2 hr), histamine released from mast cells, basophils, and platelets, causing vascular dilatation, transient increase in vascular permeability, pain, and not chemotactic
  • Phase II: Immediate sustained response (not always seen), due to direct damage to endothelial cells
  • Phase III: Delayed response (peaks around 3 hrs), many and varied chemical mediators, interlinked and of varying importance

Mechanisms of Vascular Leakage

• Endothelial contraction, leading to gaps, caused by histamine, leukotrienes, and cytokines (IL-1 and TNF, hypoxia)
• Cytoskeletal reorganization, leading to gaps, caused by cytokines (IL-1 and TNF, hypoxia)
• Direct injury, leading to toxic burns, chemicals, and leukocyte-dependent injury
• Increased transcytosis, leading to channels across endothelial cytoplasm, caused by VEGF (vascular endothelial growth factor)

Mechanisms of Neutrophil Migration

• Neutrophil adhesion and emigration, due to binding of complementary adhesion molecules on endothelial and neutrophil surfaces
• Chemical mediators changing surface expression or avidity of adhesion molecules
• Relaxation of inter-endothelial cell junctions, digestion of vascular basement membrane, and movement
• Chemotaxis, movement along concentration gradients of chemoattractants, involving receptor-ligand binding, rearrangement of cytoskeleton, and production of pseudopod

Functions of Neutrophils

• Phagocytosis, involving contact, recognition, internalization, and cytoskeletal changes
• Microbial killing, facilitated by opsonins, involving recognition, phagocytosis, and killing mechanisms (O2-dependent and O2-independent)

Consequences of Acute Inflammation

• Local complications: swelling, blockage of tubes, exudate, compression, pain, and loss of function
• Systemic effects: fever, leukocytosis, acute phase response, spread of micro-organisms and toxins, and shock

Resolution of Acute Inflammation

• Morphology: changes gradually reverse, vascular changes stop, and vessel permeability returns to normal
• Mechanisms of resolution: mediators have short half-lives, may be inactivated by degradation, bound by inhibitors, or diluted in the exudate, and specific inhibitors may be involved

Morphological Patterns of Acute Inflammation

• Serous inflammation: outpouring of fluid
• Fibrinous inflammation: severe destruction, either resolution or organization
• Suppurative purulent inflammation: abscess formation
• Ulceration

Clinical Examples

• Lobar pneumonia: caused by Streptococcus pneumoniae, affecting young adults in confined conditions, with worsening fever, prostration, and hypoxaemia, and fairly sudden improvement with antibody appearance
• Skin blister: caused by heat, sunlight, or chemicals, with pain, exudate, and few inflammatory cells
• Abscess: solid tissues with inflammatory exudate, causing liquefactive necrosis, pain, and tissue damage
• Acute inflammation in serous cavities: exudate pours into cavity, causing respiratory or cardiac impairment, and localized fibrin deposition

Disorders of Acute Inflammation

• Rare diseases, including hereditary angio-oedema, alpha-1 antitrypsin deficiency, inherited complement deficiencies, defects in neutrophil function, and defects in neutrophil numbers