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Leicester Warwick Medical School

Leicester Warwick Medical School. Mechanisms of Disease Regeneration and Fibrous Repair Dr Peter Furness pnf1@le.ac.uk Department of Pathology. REGENERATION AND REPAIR. Regeneration: replacement of functional, differentiated cells Repair: production of a fibrous scar. REGENERATION.

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Leicester Warwick Medical School

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  1. Leicester Warwick Medical School Mechanisms of Disease Regeneration andFibrous Repair Dr Peter Furness pnf1@le.ac.uk Department of Pathology

  2. REGENERATION AND REPAIR • Regeneration: replacement of functional, differentiated cells • Repair: production of a fibrous scar

  3. REGENERATION • Labile cells: - normal state is active cell division - usually rapid regeneration • Stable cells: - not normally dividing at a significant rate - speed of regeneration variable • Permanent cells: - unable to divide - unable to regenerate

  4. Factors controlling regeneration: Complex and poorly understood. • ‘Growth factors’ • EGF, PDGF, FGF, IGF ... • Hormones e.g. ACTH, œstrogen, growth hormone... • Contact with basement membranes & adjacent cells • Signalling through integrins • NOTE: importance of growth control in CANCER.

  5. Mitotic figures Acute damage to kidney - regeneration

  6. FIBROUS REPAIR: The development of a fibrous scar. • Rabbit ear chamber example. • Blood clot forms. • Acute inflammation around the edges. • Chronic inflammation: Macrophages infiltrate the clot. • Capillaries and lymphatics sprout and infiltrate. • Myofibroblasts infiltrate and differentiate. • Glycoproteins and COLLAGEN are produced • Cell population falls, vessels differentiate and are reduced in number. • Collagen matures AND CONTRACTS.

  7. Rabbit Ear Chamber: Direct observation of fibrous repair. 1) Exudate clots. 2) Neutrophils infiltrate and digest clot 3) Macrophages and lymphocytes are recruited

  8. Rabbit Ear Chamber: Direct observation of fibrous repair. 4) Vessels sprout, myofibroblasts make glycoproteins 5) Vascular network; collagen synthesised; macrophages reduced 6) Maturity. Cells much reduced; collagen matures, contracts, remodels

  9. Angiogenesis

  10. The Extracellular Matrix • Collagen • Type I - Bone, tendon, scars. Type III - ‘tissue scaffold’. Type IV - non-fibrous, basement membranes ... • Elastin • Glycoproteins • Fibronectin, Osteonectin, Tenascin,... • Proteoglycans • Heparan sulphate proteoglycan, ...

  11. Specific features of fibrous collagens • Triple helical fibrils • Fibrils arrange in ‘quarter stagger’ mode to form insoluble fibres • Relatively resistant to general proteases; slow remodelling by specific collagenases

  12. SKIN WOUNDS:Healing by “Primary Intention” • Epidermis regenerates • Dermis undergoes fibrous repair. • Sutures out at 5-10 days: approx. 10% normal strength. • Maturation of scar continues up to 2 years. • Minimal scarring, good strength • Risk of trapping infection under skin - produces abscess.

  13. Healing by ‘primary intention’: A clean, sutured wound.

  14. SKIN WOUNDS:Healing by “Secondary Intention” • Quantitative differences. • Initial contraction (in furry animals!) • Clot dries to form a ‘scab’ or ESCHAR • Epidermis regenerates beneath. • Repair process produces GRANULATION TISSUE • Comparison with primary intention: • Takes longer • Produces a larger scar; not necessarily weaker • Produces more late contraction

  15. An open wound: Healing by ‘secondary intention’

  16. Regeneration and repair combined:A chronic peptic ulcer

  17. Regeneration and repair combined:A chronic peptic ulcer

  18. CONTROL OF REPAIR Poorly understood. • Angiogenesis • Various angiogenic cytokines, e.g. VEGF, bFGF ... • Fibrosis • various pro-fibrotic cytokines, e.g. TGF beta, PDGF, ... • Limitation of fibrosis and remodelling • Hardly anything known!

  19. FACTORS INFLUENCING WOUND HEALING • Local factors: • Type, size, location of wound • Apposition, lack of movement • Infection: Suppuration, Gangrene, Tetanus • (Secondary hæmorrhage) • Blood supply: Arterial, Venous • Foreign material: dirt, glass, sutures, necrotic tissue • Radiation damage

  20. FACTORS INFLUENCING WOUND HEALING • General Factors: • Age • General state of health • chronic diseases e.g. diabetes, rheumatoid arthritis etc. • Drugs (n.b. steroids) and hormones • General cardiovascular status • General dietary deficiencies e.g. protein • Specific dietary deficiencies • Vitamin C • sulphur-containing amino acids

  21. Complications of Repair • Insufficient fibrosis: • Wound dehiscence; hernia; ulceration • Excessive fibrosis: • Cosmetic scarring; hypertrophic scars; keloid • Excessive contraction: • Limitation of joint movement (Contractures); obstruction of tubes & channels (Strictures)

  22. Coal worker’s pneumoconiosis

  23. Alcoholic cirrhosis in the liver

  24. Special features of healing in specific organs For self-directed study. As a minimum, learn about: • Liver (n.b. regeneration in acute versus chronic damage) • Kidney (n.b. ‘acute tubular necrosis’) • Heart (see ‘myocardial infarction’) • Bone (n.b. ‘Callus’) • Cartilage (Can it???) • Peripheral nerve (n.b. ‘Wallerian degeneration’; axon sprouting) • Central nervous system (n.b. gliosis)

  25. ‘Contracture’following a major burn

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