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Healing & Repair

Dr. Srikumar Chakravarthi

Repair & Healing: Are they same?

� Repair :Regeneration of injured cells by cells of same type, as with regeneration

of skin/oral mucosa (requires basement membrane) Epidermis, GI, blood, liver.

� Healing :Replacement by fibrous tissue

(fibroplasia, scar formation) Incision, MI, stomach ulcers.

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

Varieties of Proliferative Potential

� Labile (always dividing) cells:

– Replace dying cells

– Epithelia: skin, oral cavity, exocrine ducts, GI tract, GYN, hematopoietic.

� Stable (quiescent) cells:

– Usually G0 and low rate of division

– Driven into G1 and rapid proliferation

– Liver, kidney, pancreas, endothelium, fibroblasts

� Permanent (non-dividing ) cells:

– Permanently removed from cell cycle

– Irreversible injury leads only to scar

– Nerve cells, myocardium, skeletal muscle

Stem cells� Remarkable potential to develop into many

different cell types in the body.

� Repair system for the body, they can theoretically divide without limit to replenish other cells.

� When a stem cell divides, each new cell has the potential to either remain a stem cell or become another type of cell with a more specialized function (muscle cell, RBC, neuron).

� Embryonic, Adult ( BM, tissue)

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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,

circulate in blood

Growth Factors and Molecular Events

� Polypeptide growth factors with many (pleiotropic) effects : Proliferation, migration, differentiation, remodeling (all part of wound

healing)

� EGF : Keratinocytes, fibroblasts

� VEGF : Angiogenesis

� TGF- α, β : Fibrogenesis

� PDGF : Migration and proliferation of

fibroblasts, smooth muscle, and monocytes

� FGF, HGF, KGF, IGF, Cytokines.

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 (fibrous structural proteins): most common; extracellular framework of body; 14 types

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ECM (Cont’d)

– Adhesive glycoproteins: e.g., Laminin, fibronectin, CAM, cadherins, integrins

which bind ECM components to each other, & to other cells

– Proteoglycans & hyaluronic acid: sugars linked to proteins; influence ECM permeability and structure

Connective Tissue Repair

(Healing/ 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

Granulation tissue

� Appearance of small, red, granular foci which bleed easily.

� Demonstrated in the base of skin

wounds below the overlying scab.

� It consists of clusters of fragile newly-formed capillary blood vessels which

proliferate and grow into damaged tissue along with fibroblasts.

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Angiogenesis

� New vessels derived

from budding of pre-existing vessels

– BM degradation

– Endothelial migration

– Endothelial proliferation

– Endothelial maturation

Fibrosis (Fibroplasia)

� Occurs within the granulation tissue framework (new blood vessels and loose ECM)

� Proliferation of fibroblasts at site of injury– Growth factors (TGF-β, PDGF, EGF,

FGF)

– Cytokines (IL-1, TNF-α)

� Deposition of ECM (collagen) & tissue remodelling

Scar Remodeling

� Remodeling to strengthen repair

– Metalloproteinases (interstitial collagenases, gelatinases, stromelysins)

degrade collagen.

– Produced by macrophages, neutrophils,

fibroblasts as inactive precursors

– Debris carried away by phagocytes

Wound Healing:

Primary Union / 1st intention� Successful wound healing is more

favourable, when less tissue is damaged.

� The best prognosis is seen with clean, smooth, closely abutting incision wounds in a well-vascularised area, with no foreign bodies.

� Line of closure fills with clotted blood

� Dehydration at surface creates scab

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Primary union Wound Healing: Primary

Union

� 24 hr: neutrophils, mitoses of basal

epithelium

� 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

Primary Union (Cont’d)

� Week 2: accumulation of collagen,

fibroblasts, and “blanching” begins (oedema 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

� When large tissue defects have to be refilled or when purulent infections prevent direct

association of the wound edges.

� Wound surfaces split away from each other.

� Granulation tissue has to be generated in order to close the dermal defect and may be

gradually transformed into stable scar tissue.

� More inflammation, Wound contraction -

myofibroblasts

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Fibrous scar

Factors Influence Repair - Local

� Persisting infection, foreign material (steel, glass, suture) or other stimulus to inflammation

� Inadequate blood supply

� Excessive movement

� Irradiation

� Size of wound

� Locally applied drugs, e.g. corticosteroids

Factors Influence Repair - Systemic

� Age: the healing process becomes slower and less effective with increasing age.

� Nutritional deficiencies, e.g. vitamin C, zinc, protein inhibit collagen synthesis

� Metabolic diseases, e.g. renal failure, diabetes mellitus (microangiopathy)

� Catabolic state associated with malignancies

� Systemic drugs, e.g. corticosteroids

� Circulatory disorders retarding blood flow –atherosclerosis.

Aberrations of Inflammation and

Repair

� Inadequate scar formation– Wound dehiscence - abdomen

– Ulceration – diabetic neuropathy

� Hypertrophic scar/ keloid – excess collagen

� Exuberant granulation tissue - “proud flesh”

� Wound contracture - burns

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Proud flesh

Summary� Regeneration of

injured cells by cells of same type.

� Replacement by fibrous tissue (fibroplasia, scar formation).

� Angiogenesis, fibroblasts

� Granulation tissue

� Primary & secondary union

References

Pathologic Basis of disease – Robbins & Cotran, 7th EdGeneral & Systematic pathology – Underwood, 4th Ed

Principles of Internal Medicine – Harrisons, 15th Ed

Textbook of Medical Physiology – Guyton, 9th EdAids to Pathology – Dixon & Quirke, 4th Ed

Thank you