Inflammation

Acute inflammation

• Reaction to injury be it physical, chemical, infective, immunological
• Vascular phase followed by cellular phase
• Classic signs: redness, heat, swelling, pain, loss of function
• Hyperaemia: initial vasoconstriction then dilation
• Vasodilation slows blood flow causing cells to move to the sides (margination)
• Exudation: protein-rich fluid moves into interstitial fluid (dilutes toxins)
• Leucocyte migration for phagocytosis: extravasation and chemotaxis
• Non-adaptive, no memory, non-specific
• Lasts 1-2 days

• Outcome: resolve (if no tissue destruction and exudate is removed), suppurate, repair with organisation/scarring (if the exudate persists), progress to chronic inflammation

• If tissue is destroyed, regeneration can occur if cells are labile or stable
• If permanent cells are lost, a vascularised connective tissue scar forms.
• Chemical mediators of vascular phase:

• Histamine: from degranulated mast cells. Increases vascular permeability (C3a and C5a) and vasodilation of venules. 

• Kinins: more prolonged venule and capillary vasodilation response
• Prostaglandin: dilates arterioles.
• Cellular phase
• Neutrophils predominate in bacterial infection
• Eosinophils predominate in parasitical infection
• Monocytes predominate in viral infection
• Cell adhesion molecules are expressed on activated endothelial cells

• Bonds are established (by selectins and integrins) between endothelium and white cells following margination (normally, both neutrophils and endothelium have negative charge and so do not contact)

• So-called neutrophil rolling

• Platelet activating factor activates neutrophils and induces beta-integrins expression to promote adhesion with the endothelium

• Transmigration of the neutrophils between endothelial cells then
• Stimulated by IL-8

• Chemotaxis: after transmigration the movement of cells is mediated by chemotaxis, along the concentration gradient of chemotactic agents

• The movement of phagocytic cells towards areas of injury/invasion
• Steps:
• Reception of signals
• Response to signals (transduction)
• Examples of chemotactics:
• Cytokines from other leucocytes
• Complement components (C5 and C5a)
• Arachidonic acid derivatives (eicosanoids eg. leukotrienes and prostaglandin E)
• Pathogens
• Lymphokines (produced by T helper lymphocytes)

• Binding of chemotactic factors on the polymorph stimulates calcium influx leading to increased cGMP and microtubule assembly to aid migration

• Once within the injured tissue, leucocytes undertake phagocytosis
• Recognition, aided by opsonisation
• Opsonins: IgG and C3b
• Bacterium/foreign object engulfed by a phagosome

• Phagosome fuses with lysosome with “respiratory burst” of metabolic activity producing hydrogen peroxide

• Myeloperoxidase increases the effectiveness of hydrogen peroxide
• Lactoferrin inhibits microorganisms growth
• Oxygen-dependent free radical formation also kills bacteria

Macrophages

• Within tissues monocytes enlarge, increase lysosome numbers, Golgi, ER  development etc. Macrophage activation leads to:

• Increased phagocytic capacity

• Production of hydrolytic enzymes, pyrogen and interferon (blocks translation of viral mRNA)

• Stimulates fibroblast proliferation and further polymorph production
• Lymphocytes activating factor (IL-1) stimulates T helper cells
• Stimulated by C3b (also an opsonin)
• Capable of cell division
• Contribute to antigen presentation
• Can fuse to form multinucleated giant cells (increased phagocytic activity)

• Epithelioid cells within granulomas are derived from a single macrophage (increased secretory capacity)

Complement system

• Involved in acute inflammation, phagocytosis, clotting, immune and hypersensitivity reactions (C3a and C5a are anaphylatoxins)

• Classical and alternative pathways are both stimulated by plasmin
• C3a and C5a increases vascular permeability as above
• C5a is 1000x more active

• C5b joins with C6, C7, C8 and C9 to form the membrane attack complex (MAC) which is capable of cell lysis

Plasma cascade system

• Factor XII (Hageman factor) of the clotting cascade has a central role in activating 3 systems operating within plasma

• Kinin system (via prekallikrein) to produce potent vasodilators
• Clotting cascade (via stimulating factor XI)
• Complement system (via activating plasminogen to plasmin)
• All three have positive feedback loops to activate more Hageman factor

Chronic inflammation

• Response to persistent pathogen/irritant
• Cellular response predominates: mixed proliferation and destruction
• Unique cellular organisations: granuloma
• Granulomas represent failure of acute neutrophils to clear the pathogen
• Derived from macrophages and their lineage
• Inner core of macrophages and epithelioid cells with increased secretory capacity

• Core surrounded by activated macrophages (containing ingested micro-oganisms) and T lymphocytes

• Outer layer of fibroblasts and multinucleated giant cells
• Caseation is a feature of tuberculous granulomas

• Granulomatous inflammation may be non-infectious: example of delayed hypersensitivity response (type IV)

• Response to breakdown of endogenous materials 

• Non-granulomatous inflammation
• Characterised by lymphocytes and plasma cells
• Behcet’s disease
• Multiple sclerosis

Corneal angiogenesis

• Response to inflammation promoted by fibrin and its degradation products
• Latent period
• Vasodilation 
• Vascular permeability of neighbouring vessels
• Stromal oedema
• Endothelial activation (within 24 hours)
• Endothelium retracts and nucleoli enlarge
• Endothelial basal lamina broken down by plasminogen activator
• Produced by fibroblasts, macrophages and others
• Vascular sprouting
• Sprouts from post-capillary venules and capillaries
• Lumen formation and anastomosis of blind channels
• Vascular maturation: deposition of ECM and laminin and basal lamina formation