Pathogenesis and Chronic Inflammation

Pathogenesis of Chronic Inflammation

• Progression from acute inflammation that is not totally resolved
• Involves macrophages, lymphocytes, and plasma cells

Mechanism of Chronic Inflammation

• Excessive macrophage accumulation due to continuous recruitment, local proliferation, and immobilization of peripheral macrophages

Morphology of Chronic Inflammation

• Granuloma: aggregation of macrophages that form in response to chronic inflammation
  • Macrophages secrete IL-1, interferon alpha, and TNF
  • Macrophage elongation leads to formation of epithelioid histiocytes
  • Epithelioid histiocytes and macrophage accumulation leads to giant cell formation
  • Types of granulomas: necrotising granuloma (central area of necrosis, occurs in TB) and non-necrotising granuloma (no necrosis, occurs in Sarcoidosis)
• Granulation tissue: new connective tissue and microscopic blood vessels that form during healing

Difference between Acute and Chronic Inflammation

• Longer time span
• Tissue destruction, inflammation, and healing all happen simultaneously
• Cells involved: polymorphonuclear cells in acute inflammation, macrophages, plasma cells, and lymphocytes in chronic inflammation

Diagnostic Laboratory Tests

• ESR (Erythrocyte Sedimentation Rate): measures rate at which RBC separate from plasma and fall to the bottom of the tube
  • Quicker sedimentation rate means inflammation more likely
• CRP (C-Reactive Protein): CRP is produced by the liver and increases if there's inflammation
• PV (Plasma viscosity): more viscosity means inflammation more likely

Granulomatous Inflammation

• Purpose: granulation tissue repairs pre-existing defects, granulomas destroy foreign material but may destroy tissue as well
• Components: new vessel formation occurs in granulation tissue, no new vessels occur in granulomas
• Fibroblasts: play an essential role in granulation tissue formation, sometimes involved in the final stages of granuloma formation
• Activity of macrophages: in granulation tissue, macrophages clear debris and fibrin, direct new vessel formation and fibroblast accumulation through secretion of growth factors; in granulomas, macrophages try to kill foreign material through release of lysosomal content and cytokine secretion

Chronic Inflammation in Relation to Tuberculosis

• Mycobacterium TB (mt hominis or mt bovis)
• Pathogenesis:
  • 0-3 weeks: MT enter macrophages via endocytosis, fever and malaise, nodule at site of infection or asymptomatic, delayed hypersensitivity to MT antigen (TM skin test)
  • 4-6 weeks: Th1 response activates macrophages to become bactericidal, Th1 release IFN-gamma, stimulates macrophages to fuse with lysosome, Th1 stimulates formation of granulomas

Healing and Repair

• Regeneration: growth of cells and tissues to replace lost structures
• Repair by fibrosis/scarring: laying down of fibrous tissue
• Examples:
  • Skin: labile cells with good capacity to proliferate, will regenerate and repair quickly
  • Liver: stable cells with slow proliferative rate unless necessary, permanent cells with no effective regeneration

Process of Healing by Primary and Secondary Intention

• Primary Intention: healing of a clean, uninfected surgical incision
  • Wound edges joined by fibrin
  • Regrowth of basal layer of epidermis
  • Lysis of fibrin and re-epithelialisation
  • Restoration of skin
• Secondary Intention: more extensive loss of cells and tissue
  • Large defect filled via blood clot
  • Granulation tissue grows from dermis into fibrin
  • Granulation tissue fibroblasts lay down collagen
  • Maturation of collagen restores skin integrity and regrowth of epidermis