Acute Inflammation 2

Acute Inflammation 2

1. Mechanisms

   • Mechanical and Physical factors
   • Chemical factors
     • Derived from plasma or cells
       • Plasma (often from liver) - exist in precursor form
         • Complement activation - complement components
         • Factor XII (Hageman factor) activation - kinin system (bradykinin), coagulation/fibrinolysis system
       • Cells - stored in intracellular granules/synthesised de novo
         • Platelets, neutrophils, macrophages, mast cells, endothelial cells
         • Intracellular granules - Histamine, serotonin, lysosomal enzymes
         • Synthesised - Prostaglandins, PAFs, Nitric oxide, Cytokines
     • Most have a short half-life
       • Decay
       • Inactivated by enzymes
       • Have specific inhibitors
       • Tight regulation

2. Cell Mediator Examples

   • Histamine
     • Most widely distributed
     • Most comes from mast cells
       • Preformed in granules
     • Released by
       • Trauma
       • Immune reaction
       • Complement (anaphylotoxins)
       • Cytokines (IL-6/IL-8)
     • Causes arteriole vasodilation
     • Increased venule permeability
     • Binds to H1 receptors of endothelial cells
   • TNF/IL-1
     • Leukocyte adherence
     • PGI synthesis - prostaglandin inhibition
     • Cyokine increase
     • Increased procoagulant/decreased anticoagulant
   • Nitric oxide
     • Reduced leukocyte adhesion
     • Reduced platelet adhesion
     • Vasodilation/smooth muscle relaxation
     • Cytotoxic to microbes
   • Complement
     • 20 members
     • Vascular effects - C3a and C5a stimulate histamine release
     • C5a is chemotactic for neutrophils and monocytes
     • C5a activates lipooxygenase pathway of amino acid metabolism - inflammatory mediator release
     • C3b and its cleavage product iC3b act as opsonins

3. Plasma Mediator Examples

   • Factor XII (Hageman Factor)
     • Initiates clotting cascade
       • Also stimulates acute inflammation via thrombin and protease activated receptors
         • Activates complement cascade
     • Initiates kinin cascade
       • Stimulates fibrinolytic system
   • Arachidonic acid metabolism
     • Causes chemotaxis
     • Produces leukotrienes
     • Causes vasoconstriction/vasodilation
     • Promotes/inhibits platelet aggreagation
     • Stimulates monocyte adhesion
     • Potentiates oedema
     • Causes increased permeabilty
     • Inhibits neutrophil chemotaxis

4. Termination of Acute Inflammation

   • NPM undergo apoptosis and phagocytosis
   • Response dies away quickly due to short half-life
   • Stop signals
     • Anti-inflammatory lipoxins from arachidonic acid
     • Anti-inflammatory TGF-beta from macrophages
     • Neural impulses (cholinergic) that inhibit TNF production

5. Knowledge about inflammation allows new anti-inflammatories to be created

6. Leukocyte-induced tissue injury

   • Caused by lysosomal contents leaking into tissues - enzymes, ROIs, products of arachidonic acid metabolism
     • Partially opened phagosomes/granulocyte content exocytosis/phagocytosis of membranolytic substance (urate)
   • Sets up a cycle of tissue injury
     • Respiratory distress/septic shock
   • Respiratory distress syndrome
     • Shocked lung - diffuse alveolar capillary damage
     • Rapid onset of life-threatening respiratory insufficiency
     • Causes
       • Sepsis
       • Head injury
       • Gastric aspiration
       • Pneumonia egpneumocystis
     • Symptoms
       • Sloughed bronchial epithelium
       • Immune cells in lung
       • Cellular debris/necrotic cells
       • Oedema fluid in lung
       • Hyaline membrane