Chronic Inflammation

Chronic Inflammation

1. Definition

   • Inflammation of prolonged duration (usually weeks)
     • Involves active inflammation, tissue destruction and attempts at repair
   • Causes
     • Persistent stimulus - gastric ulcer
     • Persistent infection - tuberculosis/parasites/Hepatitis
     • Prolonged exposure to toxic agent - non-degradable silica, coal dust, fatty products of atherosclerosis
     • Autoimmunity - rheumatoid arthritis
   • Characterised by
     • Infiltration by mononuclear cells - macropharges, lymphocytes, plasma cells
     • Healing - replacement of damaged tissue with fibrosis
     • Tissue destruction

2. Gastric Ulcer

   • Caused by persistent damage to stomach lining - by acid and peptic enzymes
   • Causes acute inflammation, tissue damage and fibrosis
   • H. pylori causes all duodenal ulcers and 70% of peptic ulcers
     • Stimulates IL-8 release - inflammatory response
     • Enhacnces gastric acid and secretes urease - causes direct epithelial damage

3. Macrophages

   • Development
     • Stem cell
       • Monoblast
         • Monocyte
           • Macrophage
             • Activated macrophage
             • Kupffer cell (liver), Microglia (CNS), Alveolar macrophage (lung), Osteoclasts (bone)
   • Activated in extravascular tissue by
     • Cytokines (IFN-gamma from activated T cell)
     • Bacterial endotoxins
     • Other chemical mediators
     • Fibronectin
   • Macrophage-Lymphocyte Interactions
     • Lymphocytes are frequently mobilised in chronic inflammation
       • Involved in antibody-mediated/cell-mediated immune reactions
     • Activated T cells activate macrophages (via IFN-gamma)
       • Activated macrophage releases TNF, IL-1 and other inflammatory mediators which stimulate inflammation
     • Activated macrophages activate T cells (via cytokines - IL-12)
       • Activated T cells release TNF and other inflammatory mediators which stimulate inflammation

4. Other Cells Involved

   • B/T lymphocytes
   • Plasma cells
     • Develop from activated B cells
     • Secrete antibodes
   • Eosinophils
     • Common in parasitic infections
   • Neutrophils
   • Mast cells
     • Bind to Fc part of IgE
     • Degranulate to release histamine
     • Found in allergies - food/drugs

5. Granulomatous Inflammation

   • Specific type of chronic inflammation
   • Granuloma - focus of chronic inflammation made of an aggregate of macrophages transformed into epithelioid cells
     • Epithelioid histiocytes are modified, immobile macrophages
     • Surrounded by lymphocytes and plasma cells
   • 2 types
     • Foreign body type
       • Due to macrophage ingestion of material which cannot be destroyed
     • Immune type
       • Generated by insoluble fragments (usually microbes) that cause a cell-mediated immune reaction
       • APC releases IL-12 and uses antigen to activate CD4+ cells
         • Activated T cells recruit macrophages and activate them with IFN-gamma
           • Activated macrophages have increased killing potential and become fibrogenic
             • Then release more IL-12
   • Caused by
     • Foreign material - glass, silica
     • Persistent infections - TB, syphilis, leprosy
     • Diseases of unknown aetiology - Crohn's, sarcoidosis

6. Tuberculosis

   • Mycobacteria tuberculosis
   • Initial infection in the mid zones of lung - Ghon focus
     • Spreads to hilar lymph nodes - Ghon complex
   • Primary pulmonary TB (0-3 weeks)
     • Bacterium mannose-capped glycolipid binds to mannose receptor of alveolar macrophage
       • Entry into cell
         • Endosomal manipulation - maturation arrest, lack of acid pH, ineffective phagolysosome formation
           • Polymorphism leads to unchecked bacillary proliferation
             • Bacteraemia with seeding of multiple sites
   • Primary pulmonary TB (>3 weeks)
     • Alveolar macrophage-T cell binding via MHC II with TB antigen
       • Th1 produces positive Heaf test - tuberculin positive/hypersensitive
       • Th1 cells produce IFN-gamma, activating macrophages with bacteriacidal activity
         • Dead bacteria produce nitric oxide and free radicals - increased iNOS in activated macrophage
           • Macrophage produces TNF which causes monocyte recruitment
             • Sensitized T cells surround caseous necrosis to form epithelioid granuloma
   • Primary complex (localized caseation)
     • Healed caseations (non-viable organisms)
     • Progressive primary TB - massive haematogenous dissemination
       • Miliary TB
     • Latent lesions - organisms dormant
       • Reactivation/Reinfection to secondary TB
         • Localized caseating destructive lesions
         • Progressive secondary TB
           • Mass hematogenous dissemination
             • Miliary TB

7. Major complication is tissue destruction and the effecs of repair - fibrosis

8. Rheumatoid Arthritis

   • Rheumatoid Arthritis
   • Chronic systemic inflammatory autoimmune disease
     • Autoimmune response causes inflammatory response, releasing inflammatory mediators which cause tissue destruction
       • Key mediators - TNF-alpha and IL-1
     • Synovium (joint lining) invaded by macrophages, lymphocytes and plasma cells
       • Cutaneous lesions and rheumatoid nodules
       • Central zone of necrosis surrounded by ring of epithlilioid macrophages
   • Affects multiple tissues and organs - joints, eyes, skin, blood vessels
   • Affects 1% of world population
   • Triggered by exposure of genetically susceptible person to antigen