Repair 2 Dr Heyam Awad FRCpath. Role of extracellular matrix in tissue repair ECM is composed of...
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Transcript of Repair 2 Dr Heyam Awad FRCpath. Role of extracellular matrix in tissue repair ECM is composed of...
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Repair 2
Dr Heyam AwadFRCpath
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Role of extracellular matrix in tissue repair
• ECM is composed of several proteins that assemble into a network which surrounds cells.
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ECM functions
• Mechanical support.• Sequesters water.• Provides turgor for soft tissue.• sequesters minerals .. Important in bone
rigidity.• Regulates proliferation, movement and
differentiation of cells.• Reservoir of growth factors.
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ECM
Two basic forms:• 1. interstitial matrix.• 2. basement membrane
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Interstitial matrix
• Present in spaces between cells in connective tissue.
• Also between epithelium and supportive vascular and smooth muscle structures.
• It is synthesized by mesenchymal cells, like fibroblasts.
• Forms 3D amorphous gel.
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ECM
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Basement membrane
• Highly organised matrix around epithelial cells, endothelial and smooth muscle cells.
• Composed of 1) Amorphous nonfibrillar type IV collagen and
2) laminin.
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Components of extracellular matrix
• Fibrous structural proteins: Collagen and Elastin
• Water hydrated gel :Proteoglycans and hyaluronon
• Adhesive glycoproteins and adhesion receptors
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collagen
• Fibrillar collagen (types I, II, III, and V) • Important for tensile strength.• Forms a major proportion of connective tissue
in healing. • Strength is vitamin C dependant.
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Nonfibrillar collagens
1. type IV present in basement membranes
2. type IX present in intervertebral disks3. type VII present in dermal-epidermal
junctions
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elastin
• Important for recoil and returning to a baseline structure after stress .
• Important in large blood vessels, skin and ligaments.
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Proteoglycans and hyaluronic acid
• Form compressible gel important for lubrication.
• Reservoir of growth factors.
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Adhesive Glycoproteins
- Involved in cell-to-cell adhesion, the linkage of cells to the ECM.
- include: Fibronectin, laminin and integrins
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Scar formation
Three steps:1. angiogenesis.2. Migration and proliferation of fibroblasts.3. Remodeling.
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angiogenesis
• Development of new blood vessels from existing vessels , mainly venules.
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Angiogenesis.. steps
• 1. vasodilation ( due to NO) and increased permeability (VEGF)
• 2. Separation of pericytes from abliminal surface.• 3. endothelial cell migration• 4. endothelial cell prolifeartion • 5. remodeling into capillary tubes• 6. recruitment of periendothelial cells: pericytes and
smooth muscle cells.• 7.Supression of endothelial proliferation • 8. Deposition of basement membrane
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GF in angiogenesis
• VEGF family.. Stimulate migration and proliferation of endothelial cells.
- Antibodies against VEGF can be used in treating some tumors and in age related macular degeneration• EGF• Angiopoietins ANG 1 AND ANG2 … especially
important for ECM production
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Scar formation
A. Migration and proliferation of fibroblasts into the site of injury and
B. Deposition of ECM proteins produced by these cells.
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Fibroblast migration and activation
• PDGF, TGF BETA.
• Stimulated fobroblasts: synthetic activity.• Synthesize ECM components.
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Note:- Collagen synthesis, is critical to the
development of strength . - Collagen synthesis by fibroblasts begins
early in wound healing and continues for several weeks, depending on the size of injury.
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Note:
- Net collagen accumulation at site of injury depends on increased synthesis and decreased degradation
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Granulation tissue
• The blood vessels , fibroblasts , inflammatory cells and ECM component = granulation tissue.
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The term granulation tissue Gross- Granular and pink in colorHistologically :a. Proliferation of fibroblasts b. Formation of new thin-walled,
delicate capillaries(angiogenesis)
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scar
• Granulation tissue changes to a scar… less cells, more collagen and loss of the blood vessels.
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Granulation tissue and Fibrosis
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Remodeling of the scar
- the scar continues to be modified and remodeled.
- Thus, the outcome of the repair process is a balance between synthesis and degradation of ECM proteins by MMPs= matrix metalloproteinases
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MMPs
1. Interstitial collagenases, cleave fibrillar collagen
2. Gelatinases ,degrade amorphous collagen and fibronectin
3.Stromelysins ,degrade laminin, fibronectin
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- The activity of the MMPs is tightly controlled.
a. produced as inactive precursors … activated by proteases (e.g., plasmin
b. can be inhibited by specific tissue inhibitors of metalloproteinases (TIMPs)
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.FACTORS THAT INFLUENCE TISSUE REPAIR 1. Infection: the most important cause of
delay in healing; because it prolongs inflammation and increase tissue destruction.
2. Nutrition A. protein deficiency, leads to deficiency of
fibrillar collagen B. Vitamin C deficiency inhibit collagen
synthesis .
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3 . steroids: decrease TGF beta
4. Poor perfusion, due to arteriosclerosis and diabetes or to obstructed venous drainage (e.g., in varicose veins),
5. Foreign bodies such as fragments of steel, glass..
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• Aberrations of cell growth and ECM production
1. Keloid- accumulation of very large amounts of
collagen forming prominent, raised scars
2. "proud flesh” - exuberant granulation tissue .
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keloid