Repair :Repair :Regeneration of injured tissue by parenchymal cells of the same type or replacement by connective tissue.

Chapter Three RepairChapter Three Repair Section ASection A

Repair

• Completely regeneration: Regeneration of injured tissue by parenchymal cells of the same type.

• Fibrous repair: Replacement by connective tissue

• In other words

– Regeneration

– Scar

Cell population and cell cycle phases

Proliferative Potential

• Labile cells - continuously dividing – Epidermis, mucosal epithelium, GI tract epithelium etc

• Stable cells - low level of replication– Hepatocytes, renal tubular epithelium, pancreatic acini

• Permanent cells - never divide– Nerve cells, cardiac myocytes, skeletal mm

1. Regeneration of epithelial tissues Skin regeneration : BM not breached,

repaired by the proliferation of epithelial cells. .

Regeneration of renal tubular cells and hepatocytes :

1) Renal tubular cells: repaired by surviving renal tubular epithelial cells.

If the basic framework is not intact, massive scar tissue is formed.

2) Hepatocytes are analogous to the above.

2. Regeneration of connective tissue

• connective tissue includes:

1) inactive fibroblasts(fibrocyte),

2) activated fibroblasts

3) extracellular matrix

Fibroblasts produce collagen, elastic, and reticular fibers and amorphous material.

3. Regeneration of cartilage and bone

Cartilage regeneration: weak of repair capability

Bone tissue: a strong regenerative ability

perichondrial cells

chondrocytes with new cartilage matrix

the quiescent cells and embed in the increased

matrix or the wall of lacunae.

4. Angiogenesis:

by two processes:

1) Vasculogenesis: from angioblasts

2) Angiogenesis: capillary sprouts

• Fig 4-15

5. Muscle

1) Cardiac muscle fibers and skeletal muscle :

• scar tissue.

• skeletal muscle: Repair may be possible only when sarcolemma keeps alive and portion of myofibrils destroy in muscle fiber.

2) Vascular smooth muscle: a limited replicative protential, new small vessels can be formed.

Sarcolemma: a coating of BM-like material adhering to the plasma membrane.

6. Neural tissue

• the central nervous system: scar formation.

• the peripheral nervous system: axonal regeneration.

Nerve fiber regeneration

Normal nerve fiber

Regeneration of Schwann cells and axon filaments at site of nerve lesion or section

New axon extending into original channel.

1. Cell-cell interaction1. Cell-cell interaction Conditioned mediumConditioned medium Contact inhibitionContact inhibition2. Growth factors2. Growth factors3. Extracellular matrix3. Extracellular matrix Laminin: Laminin: Epithelia Epithelia FibroblastsFibroblasts Fibronectin : Fibronectin : Epithelia Epithelia FibroblastsFibroblasts

Factors influencing regenerationFactors influencing regeneration

1. Chalon and contact inhibition

• Chalones is a number of growth inhibitory signals. Any different tissues can produce and release inhibitors to control its own proliferation.

• Contact inhibition: Cells continue dividing until they touch one another.

Cells anchor to dish surface and divide.

When cells have formed a complete single layer, they stop dividing.

If some cells are scraped away, the remaining cells divide to fill the dish with a single layer and then stop.

2. Growth factors

• 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

The common growth factors:

1) Platelet-derived growth factor (PDGF): activates fibroblasts, smooth muscle cells, and monocytes for their proliferation and migration; promotes mitosis of gliacytes.

2) Fibroblast growth factor (FGF): mitogenic for most mesenchymal cells and induces endothelial cell to release proteolytic enzyme.

3) Epidermal growth factor (EGF): mitogenic for epithelial cells, fibroblasts, glial cells and SMC.

4) Transforming growth factors(TGF): Two types:

alpha TGF shares homology with EGF. Beta TGF acts as either a growth stimulator or a growth inhibitor.

4) Vascular endothelial growth factor (VEGF): a central role in the growth of new blood.

5) Cytokines: IL-1 and TNF induce fibroblast proliferation and collagen synthesis. TNF can also stimulate angiogenesis.

3. Extracellular matrix(ECM)

• ECM provides turgor to soft tissue and rigidity to bone, and supplies a substratum for cell adhesion and critically regulates the growth, movement, and differentiation of the cells living within it.

Components of the ECMs:

1) Collagen: Fibrous structural proteins confers tensile strength.

2) Elastin: Provides the ability to recoil and return to a baseline structure after physical stress.

3) Proteoglycans: Help regular ECM structure and permeability; modulate cell growth, differentiation and even maintain cell morphology.

4) Adhesive glycoproteins: Include fibronectin, laminin and so on. Link ECM components and link ECM to cells via cell surface integrins.

5) Integrins: A family of cell surface receptors mediating adhesion of cells to ECMs.

Section BSection BFibrous RepairFibrous Repair

Granulation tissues:Granulation tissues:• Newly formed Newly formed

capillariescapillaries• FibroblastsFibroblasts• Inflammatory cellsInflammatory cells

Repair by connective tissue

• Occurs when repair by parenchymal regeneration alone cannot be accomplished

• Involves production of Granulation Tissue

• replacement of parenchymal cells with proliferating fibroblasts and vascular endothelial cells

Granulation tissue• Gross: soft, pink, and granular.

• LM: fibroblasts, new thin-walled capillaries and inflammatory cells in a loose ECM with edema.

•Fibroblasts -- divide and secrete collagen.

•Eeventually results in fibrosis with connective tissue matrix.

Granulation tissue : with numerous new blood vessels, fibroblasts and inflammatory cells.

Granulation tissue

Components of the processof fibrosis

• Angiogenesis - New vessels budding from old

• Fibrosis, consisting of emigration and proliferation of fibroblasts and deposition of ECM

• Scar remodeling, tightly regulated by proteases and protease inhibitors

Roles of granulation tissue:

1) Anti-infection and protecting the wound surface from further injure.

2) Filling incision or wound and any defect of tissue.

3) Replacing necrosis tissue, effusion and other foreign body.

• Fig 4-14

Scar formation (Fibrosis)

1. Angiogenesis - New vessels budding from old

2. Fibrosis: emigration and proliferation of fibroblasts and deposition of ECM.

3. Scar remodeling: tightly regulated by proteases and protease inhibitors

Scar tissue

• a pale, avascular scar with largely inactive fibroblasts, dense collagen, fragments of elastic tissue, and other ECM components.

• may undergo a reduction in size of 90 percent.

Scar tissue: dense collagen, fibrocytes, scattered fibroblasts and sparse vessels.

Advantage of scar:

1) provides a resilient permanent patch

2) provides a tensile strength and can keep the reparative site solid.

• Fig 4-19

• Healing by first intentionHealing by first intention

• Healing by second intentionHealing by second intention

• Healing under scabHealing under scab

Section CSection CWound healingWound healing

Wound healing

• Induction of acute inflammatory response by an initial injury

• Parenchymal cell regeneration

• Migration and proliferation of parenchymal and connective tissue cells

Wound healing (cont’d)

• Synthesis of ECM proteins

• Remodeling of parenchymal elements to restore tissue function

• Remodeling of connective tissue to achieve wound strength

Healing byFirst Intention

Focal Disruption of Basement Membrane and loss of only a

few epithelial cellse.g. Surgical Incision

Healing by Second Intention

Larger injury, abscess, infarction

Process is similar butResults in much larger Scar and then CONTRACTION

Wound Strength

• After sutures are removed at one week, wound strength is only 10% of unwounded skin (Walker’ Law)

• By 3-4 months, wound strength is about 80% of unwounded skin (Walker’s Law)

Healing Skin wound

Healing - Skin Scar

Factors affecting Healing:

SystemicSystemic

• Age

• Nutrition

• Vitamin def.

• Immune status

• Other diseases

LocalLocal

• Infection

• Size or extent.

• apposition

• Blood supply

• Mobility

• Foreign body

• Fig 4-18

Summary:

• Healing – Proliferation & Differentiation.

• Labile, Stabe & Permanent cells

• Stages of Healing: 1-2-3-4….

• Healing by First or Second intention.

• Skin wound healing - bone healing.

• Factors affecting healing – Local / Systemic