Tissue Repair

Banun Kusumawardani Dept. Biomedic-Faculty of Dentistry Univ. Jember

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Assigned Reading

Chapter 3, Tissue renewal and repair in Robbins and Cotran Pathologic Basis of Disease, 7th Edition, p 87-118.

Repair

Regeneration of injured cells by cells of same type as with regeneration of skin/oral mucosa (requires basement membrane) Replacement by fibrous tissue (fibroplasia, scar formation) Both require cell growth, differentiation, and cell-matrix interaction
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Tissue response to injury. Repair after injury can occur by regeneration , which restores normal tissue, or by healing, which leads to scar formation and fibrosis

Tissue Regeneration

Controlled by biochemical factors released in response to cell injury, cell death, or mechanical trauma
Most important control: inducing resting cells to enter cell cycle Balance of stimulatory or inhibitory factors Shorten cell cycle Decrease rate of cell loss
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Mechanisms regulating cell populations. Cell numbers can be altered by increased or decreased rates of stem cell input, by cell death due to apoptosis, or by changes in the rates of proliferation or differentiation
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Tissue-Proliferative Activity

Labile (always dividing) cells:

Replace dying cells Epithelia: skin, oral cavity, exocrine ducts, GI tract, hematopoietic

Stable (quiescent) cells:

Usually G0 and low rate of division Driven into G1 and rapid proliferation Liver, kidney, pancreas, endothelium, fibroblasts

Tissue-Proliferative Activity (Contd)

Permanent (non-dividing ) cells:

Permanently removed from cell cycle Irreversible injury leads only to scar Nerve cells, myocardium

Normal cell proliferation and cell cycle

Intercellular Signaling

3 pathways
Autocrine: cells have receptors for their own secreted factors (liver regeneration) Paracrine: cells respond to secretion of nearby cells (healing wounds) Endocrine: cells respond to factors (hormones) produced by distant cells

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Growth Factors and Molecular Events

Polypeptide growth factors (e.G., PDGF, FGF, TGF-) with many (pleiotropic) effects
Proliferation, migration, differentiation, remodeling (all part of wound healing) Gene expression (protooncogenes)

Sequence of events in factor signaling

Receptor binding (ligation)
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Molecular Events
Receptor activation: monomers > dimerization > autophosphorylation Signal transduction and second messengers (e.g., GTP-binding proteins, phospholipases, MAP kinases) Induce expression of transcription factor genes (e.g., myc, fos, jun) Cell cycle (growth) regulated by cyclins
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Growth Factors

Epidermal growth factor (EGF)

Keratinocytes, fibroblasts

Vascular endothelial growth factor (VEGF)

Angiogenesis

Transforming growth factor- (TGF-)

Fibrogenesis

Platelet-derived growth factor (PDGF)

Migration and proliferation of fibroblasts, smooth muscle, and monocytes
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Extracellular Matrix (ECM)

ECM provides turgor, rigidity, support, adhesion substrate, reservoir for factors ECM must remain intact for parenchymal healing Three ECM protein components
Collagens: most common; triple helix of polypeptide chains; extracellular framework of body
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ECM (Contd)
14 types
I-III: interstitial/fibrillar, most abundant IV-VI: non-fibrillar, basement membranes

Adhesive glycoproteins: e.g., Laminin, fibronectin, thrombospondin, integrins which bind ECM components to each other, and to other cells Proteoglycans: sugars linked to proteins; influence ECM permeability and structure
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Major components of the extracellular matrix (ECM), including collagens, proteoglycans, and adhesive glycoproteins. Both epithelial and mesenchymal cells (e.g., fibroblasts) interact with ECM via integrins. To simplify the diagram, many ECM components (e.g., elastin, fibrillin, hyaluronan, 16 syndecan) are not included

Steps in collagen synthesis

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Connective Tissue Repair (Scar Formation)

Loss of parenchyma and ECM Formation of new blood vessels (angiogenesis), fibroblast migration and proliferation (lay down collagen) < 24 hr Granulation tissue: pink, soft, granular grossly Maturation and organization (remodeling) of fibrous tissue
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Angiogenesis

Vessels derive from endothelial cell precursors (angioblasts) or from budding of pre-existing vessels
BM degradation Endothelial migration Endothelial proliferation Endothelial maturation Periendothelial cell recruitment (pericytes, smooth muscle) 19

Steps in the process of angiogenesis

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Fibrosis (Fibroplasia)

Occurs within the granulation tissue framework (new blood vessels and loose ECM) Proliferation of fibroblasts at site of injury
Growth factors (TGF-, PDGF, EGF, FGF) Cytokines (IL-1, TNF-)

Deposition of ECM (collagen)

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Scar Remodeling

Remodeling to strengthen repair

Metalloproteinases (interstitial collagenases, gelatinases, stromelysins) Produced by macrophages, neutrophils, fibroblasts as inactive precursors In response to local factors Debris carried away by phagocytes (debridement)
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Phase of wound healing

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Wound Healing: Primary Union

Clean incision Line of closure fills with clotted blood Dehydration at surface creates scab 24 hr: neutrophils, mitoses of basal epithelium

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Wound Healing: Primary Union (Contd)

1 - 2 days: epithelial basal cells grow along cut dermis 3 days: neutrophils gone, macrophages enter, granulation tissue forms 5 days: space filled with granulation tissue and collagen fibrils bridge line of closure, epidermis at pre-incision thickness
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Wound Healing: Primary Union (Contd)

Week 2: accumulation of collagen, fibroblasts, and blanching begins (edema and inflammation reduced) End of first month: connective tissue devoid of inflammation; epidermis intact Tensile strength increases to 70 - 80% of unwounded skin in 3 months
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Wound Healing: Secondary Union

Large tissue defect More inflammation More granulation tissue Wound contraction - myofibroblasts

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Host Factors Influence Inflammation and Repair

Nutrition Steroids Infection Mechanical factors Blood supply

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Aberrations of Inflammation and Repair

Inadequate scar formation

Wound dehiscence Ulceration

Hypertrophic scar/keloid Exuberant granulation tissue - proud flesh Wound contracture

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Summary

Wound healing as evolving, changing process Various mechanisms involved Various mediators Orderly movement, proliferation, and differentiation of cells

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Development of fibrosis in chronic inflammation. The persistent stimulus of chronic inflammation activates macrophages and lymphocytes, leading to the production of growth factors and cytokines, which increase the synthesis of collagen. Deposition of collagen is enhanced by decreased activity of metalloproteinases
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Thank you

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