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Inflammation and repair

repair

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Inflammation and repair

  1. 1. Inflammation & Repair
  2. 2. Healing by Regeneration
  3. 3. OBJECTIVES AND KEY PRINCIPLES TO BE TAUGHT: • Categorize cell types according to their regenerative ability • Identify the conditions that favours healing by regeneration • Enumerate molecular events involved in cell growth • Enumerate the components of repair by connective tissue • Identify the factors which favours healing by connective tissue. • Define granulation tissue and describe how it is formed • Describe the process of angiogenesis and enumerate its mediators • Describe the process of fibrosis, identify the cells involved and enumerate the mediators of this process • Enumerate the enzymes involved in scar remodelling and identify their function, and their inhibitors.
  4. 4. Tissue Renewal • The healing process of tissue damage caused by any cause e.g. surgical resection, wounds, and diverse types of chronic injury can be broadly separated into two processes, regeneration and repair Regeneration refers to growth of cells and tissues to replace lost structures requires an intact connective tissue framework. Regeneration results in restitution of lost tissues. Repair - occurs if the extracellular matrix (ECM) framework is damaged, causing alterations of the tissue architecture. - may restore original structures but involves collagen deposition and scar formation.
  5. 5. Cell types • Labile cells: continue to proliferate throughout life : squamous, columnar, transitional epithelia; hematopoitic and lymphoid tissues • Stable cells: retain the capacity of proliferation but they don’t replicate normally: parenchymal cells of all glandular organs & mesenchymal cells e.g. liver and kidney • Permanent cells: cannot reproduce themselves after birth: neurons and the skeletal and cardiac muscle cells.
  6. 6. CELL CYCLE • G0 – Quiescent (not a very long) • G1 – PRE-synthetic, but cell GROWTH taking place • S – Cells which have continuous “turnover” have longer, or larger S-phases, i.e., DNA synthesis – S-phase of TUMOR CELLS can be prognostic • G2 – PRE-mitotic • M (Mitotic:, P,M,A,T, Cytokinesis)
  7. 7. Cell Cycling is controlled by --- CYCLIN S
  8. 8. Slide 4.2
  9. 9. Polypeptide growth factors • Most Important Mediators affecting Cell Growth • Present in serum or produced locally • Exert pleiotropic effects; proliferation, cell migration, differentiation, tissue remodeling • Regulate growth of cells by controlling expression of genes that regulate cell proliferation
  10. 10. Growth Factors (GFs) • Epidermal • Transforming (alpha, beta) • Hepatocyte • Vascular Endothelial • Platelet Derived • Fibroblast • Keratinocyte • Cytokines (TNF, IL-1, Interferons)
  11. 11. Growth Factor-mediated Proliferation • Platelet Derived Growth Factor (PDGF) – promotes the chemotactic migration of fibroblasts and smooth muscles – chemotactic for monocytes – competence factor that promotes the proliferative response of fibroblasts and smooth muscles upon concurrent stimulation with progression factors • Epidermal Growth Factor (EGF) – promotes growth for fibroblasts, endothelial and epithelial cells – is a progession factor - promotes cell-cycle progression. • Fibroblast Growth Factor (FGF) – promote synthesis of fibronectin and other extracellular matrix proteins – chemotactic for fibroblast and endothelial cells – promotes angiogenesis – links extracellular matrix components (collagen, proteoglycans) and macromulocules (fibrin, heparin) to cell-surface integrins. • Transforming Growth Factors (TGFs) – TGF-α - similar to EGF – TGF-β - mitosis inhibitor that aids in modulating the repair process. May be responsible for hypertrophy by preventing cell division. Chemotactic for macropahges and fibroblasts • Macrophage-derived cytokines (IL-1 and TNF) – promote proliferation of fibroblasts, smooth muscle and endothelial cells
  12. 12. VE(Vascular Endothelial) GF • Made in mesenchymal cells • Increases vascular permeability • Mitogenic for endothelial cells • KEY substance in promoting “granulation” tissue
  13. 13. SIGNALING • Autocrine (same cell) • Paracrine (next door neighbor) (many GFs) • Endocrine (far away, delivered by blood, steroid hormones)
  14. 14. ExtraCellular Matrix (ECM) • Collagen(s) I-XVIII • Elastin • Fibrillin • CAMs (Cell Adhesion Molecules) – Immunoglobulins, cadherins, integrins, selectins • Proteoglycans • Hyaluronic Acid
  15. 15. Extracellular matrix (ECM) regulates cell behavior • It is not just a scaffold for cells to grow on • Regulates cell growth, motility and differentiation • Insoluble elements of the ECM include collagens, laminin and fibronectin • Soluble elements include polypeptide growth factors
  16. 16. Continuous assessment • Cell cycling is controlled by : A) Integrins B) PECAM-1 C) Cyclins D) Selectin
  17. 17. Inflammation & Repair
  18. 18. Healing by Repair ( Connective Tissue Replacement/scarring )
  19. 19. Repair by Connective Tissue Replacement • FOLLOWS INFLAMMATION • PROLIFERATION and MIGRATION of connective tissue cells • ANGIOGENESIS (Neovascularization) • Collagen, other ECM protein synthesis • Tissue Remodeling • Wound contraction • Increase in wound strength (scar = fibrosis)
  20. 20. ANGIOGENESIS (NEOVASCULARIZATION) • From endothelial precursor cells • From PRE-existing vessels • Stimulated/Regulated by GF’s, especially VEGF • Also regulated by ECM proteins
  21. 21. 2nd Yr Pathology 2010 Critical steps in angiogenesis
  22. 22. The repair process Three main phases of cutaneous wound healing: (1) Inflammation (Removal of debris, by tissue macrophages). (2) formation of granulation tissue (3) ECM deposition (scar formation) and remodeling
  23. 23. Slide 4.19
  24. 24. Granulation tissue • As early as 24 hr. after injury, fibroblasts and vascular endothelial cells begin proliferating to form (by 3-5 days) granulation tissue :pink soft granular appearance on the surface of the wound. • histologically : granulation tissue is composed of : • proliferation of new small blood vessels • proliferation of fibroblasts
  25. 25. • Scaring: as the amount of collagen in granulation tissue progressively increase, the tissue become gradually less vascular and less cellular
  26. 26. Factors that Impede Repair • Retention of debris or foreign body • Impaired circulation • Persistent infection • Metabolic disorders – diabetes • Dietary deficiency – ascorbic acid – protein
  27. 27. Continuous assessment All the following are correct regarding granulation tissue EXCEPT: A) Formed mainly of fibroblasts and capillary buds. B) It is a specialized type of tissue that is a characteristic of healing by fibrosis. C) It indicates tuberculosis infection. (T.B.) D) Gradually it accumulates connective tissue matrix and form scar.
  28. 28. Inflammation
  29. 29. Wound Healing& Factors impair healing
  30. 30. OBJECTIVES AND KEY PRINCIPLES TO BE TAUGHT: Upon completion of this lecture, the student should: 1- Compare and contrast the difference between healing by primary intention and healing by secondary intention. 2- Define tensile strength and identify the timing and strength of the scar. 2- List factors which are associated with delayed wound healing. 3- List complication of wound healing.
  31. 31. Wound healing 1. Primary union (healing by 1st intention) clean surgical incision no significant bacterial contamination minimal loss of tissue clot formation scab formation
  32. 32. Wound healing Primary union (healing by 1st intention) Events: 24 hr.: neutrophils,mitotic activity of basal layer, thin epithelial layer day 3: macrophages, granulation tissue day 5: collagen bridges the incision, epidermis thickens 2nd week: continued collagen and fibroblasts, blanching End of 1st month: scar(cellular connective tissue, intact epidermis, lost appendages).
  33. 33. Wound healing 2. Secondary union (healing by 2nd intention) Occurs when there is : more extensive necrosis and laceration with inability to achieve apposition of wound margins and in the presence of foreign body and infection .
  34. 34. Wound healing Secondary union (healing by 2nd intention) Differs from primary healing: 1. inflammatory reaction is more intense 2. larger amounts of granulation tissue are formed 3. wound contraction reaching 5-10%of the original one,achieved by myofibroblasts 4.re-epithelialization may take several weeks and may need skin grafting
  35. 35. DIFFERENCES BETWEEN PRIMARY AND SECONDARY UNION OF WOUNDS Feature Primary Union Secondary Union Cleanliness of wound Clean Unclean Infection Generally uninfected May be infected Margins Surgical clean Irregular Sutures Used Not used Healing Scanty granulation Exuberant tissue at the incised granulation tissue gap and along suture to fill the gap Outcome Neat linear scar Contracted irregular wound
  36. 36. Scar Formation and remodeling • In both types of healing, the wound contracts in the later stages due to the presence of the myofibroblast, a contractile cell that has properties of both fibroblasts and smooth muscle cells. • Tensile strength of the wound in both kinds of healing gradually increases with more fibroblast activity and the laying down of collagen.
  37. 37. Tensile Wound Strength • After sutures are removed at one week, wound strength is only 10% of unwounded skin • By the third month, wound strength is about 80% of unwounded skin • Result from the excess of collagen synthesis during the first 2 months , and later from structural modifications as cross linking and increase collagen fiber size .
  38. 38. Causes of delayed wound healing (LOCAL) • Local Infection • Decreased blood supply • Foreign bodies and necrotic tissue • Mechanical stress • Irradiation
  39. 39. (SYSTEMIC) • Advanced age • Diabetes mellitus • Decreased Blood supply • Anemia • Malignancy • Malnutrition
  40. 40. Complications of wound healing • 1.Retarded wound healing and deficient scar formation may cause wound separation at wound margin: a wound dehiscence. • 2.If a large wound cannot be totally covered by epithelium, the resulting ulcer may require a skin graft. • 3. The laying down of excessive collagen results in keloid which is prominent raised scar covered by thin epithelium • 4. Exuberant granulation tissue “ Proud Flesh”: excessive granulation tissue growth Protrudes above skin not covered by epithelium • 5. Wound contractures is related to the action of myofibroblasts. This is seen especially following burns.
  41. 41. Wound dehiscence Wound ulceration Keloid Contracture Proud Flesh
  42. 42. Continuous assessment Following laparotomy with a midline abdominal incision, the maximum tensile strength to be obtained in wound healing in skin is achieved within: A) One week B) Two weeks. C) Three months D) One year

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