Chemical Mediators of Acute Inflammation

Study Notes

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)

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

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)

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

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

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

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

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

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