W1 4 Healing And Repair

Question 1

What 2 processes does healing and repair occur by?

Answer 1

Regeneration - after mild superficial injury
Scar formation (fibrosis) - after severe injury

Question 2

The ability of a tissue to regenerate depends on the type of cell it is composed of. What are the 3 types of cells and can they regenerate or not?

Answer 2

Labile cells - continuously dividing so easy to replace damaged tissues
Stable cells - quiescent (in G0), can divide under adequate stimulation
Permanent cells - unable to divide

Question 3

Give examples of labile cells

Answer 3

Squamous epithelium
Columnar epithelium
Urothelium
Haemopoietic cells

Question 4

Give examples of stable cells

Answer 4

Hepatocytes
Pancreatic acinar cells
Fibroblasts
Smooth muscle
Endothelium

Question 5

Give examples of permanent cells

Answer 5

Cardiac myocytes
Neurons
Skeletal muscle

Question 6

How do growth factors promote cell cycle progression? (PG34)

Answer 6

Growth factors release in local area
Bind to receptors in the membranes of cells
Activate a pathway of intracellular signalling cascades
End result is activation of transcription factors in the nucleus, leading to cell cycle progression

Question 7

Give some examples of epithelial growth factors

Answer 7

EGf, HGF, KGF, TGF-a

Question 8

Give some examples of mesenchymal growth factors

Answer 8

VEGF, FGFs, TGF-b

Question 9

Why can the liver regenerate?

Answer 9

Because hepatocytes are stable cells and can be readily stimulated to re-enter the cell cycle from G” by growth factors released during tissue injury.

Question 10

What does regeneration of bone depend on?

Answer 10

Mesenchymal growth factors, production of steroid and remodelling of newly formed bone.

Question 11

What is an osteoid?

Answer 11

Consists of type 1 collagen, glycosaminoglycans and proteoglycans. It can form the ECM that gives bone its rigidity and structural integrity.

Question 12

After bone fracture occurs, what happens in the first 2 weeks? (PG37)

Answer 12

Soft callus formation:
- blood vessels in the bone become damaged, forming a haematoma (day 1)
- elicits an inflammatory
- thrombotic response - fibrin formation and platelet aggregation
- leads to the release of several growth factors, including PDGF, TGF-b, FGF
- these stimulate the activation and proliferation of osteoclasts and osteoblasts, as well as chondrocyte differentiation in progenitor cells
- fibrin mesh work provides a soft structural integrity for the area of fracture = soft callus

Question 13

What happens after about 2-3 weeks of a fracture? (PG38)

Answer 13

Bony callus formation:
- soft develops into a bony callus
- consists of new bone which has been deposited by osteoblasts and remodelled by osteoclasts
- hyaline and fibrocartilage deposited by the new chondrocytes, which then undergoes endochondral ossification

Question 14

How has a fracture transformed after a few weeks to months?

Answer 14

Woven bone gradually matures to lamellar bone. Mature bone is formed. Normal trabeculae and normal bone repaired.

Question 15

How does scar tissue differ to regeneration tissue?

Answer 15

It does not return to normal, it is permanently damaged.

Question 16

What are the 4 stages of scar formation? Images pg39

Answer 16

Haemorrhage, acute inflammation, cell proliferation, connective tissue deposition

Question 17

What occurs in haemorrhage stage of scar formation?

Answer 17

Platelet and fibrin deposition

Question 18

What cells proliferate in stage 3 of scar formation?

Answer 18

Epithelial cells
Endothelial cells
Fibroblasts

Question 19

What proliferating cells result in granulation tissue formation?

Answer 19

Endothelial cells and fibroblasts

Question 20

What does endothelial cell proliferation result in?

Answer 20

Angiogenesis

Question 21

Why is angiogenesis needed for scar formation?

Answer 21

Needs adequate blood supply, otherwise the tissue becomes ischaemic and won’t regenerate properly.

Question 22

What controls angiogenesis?

Answer 22

Growth vascular slide VEGF - vascular endothelial growth factor

Question 23

How are new vessels formed?

Answer 23

Vascular stalks from existing blood vessels migrate into surrounding stroma in ECM to link with other stalks, forming new vessels.

Question 24

What happens in stage 4 of scar formation?

Answer 24

Connective tissue deposition (fibroplasia)
Collagen, proteoglycans and elastin are produced by fibroblasts to create scar tissue/fibrosis. Increases the structural integrity of the damaged tissue.

Question 25

What mediates connective tissue deposition?

Answer 25

FGF, PDGF, TGF-b

Question 26

What response is fibrosis driven by?

Answer 26

The M2 macrophage response (link to inflammation)

Question 27

Describe the M2 macrophage response

Answer 27

In fibrosis and scarring, macrophages tend to polarise to the M2 phenotype, driven by the TH2 phenotype and IL13 and IL4.

Question 28

Describe the layers of a scar

Answer 28

Epidermis on top with a keratin layer with dermis beneath
Abnormal as has lost its adenxal structures like sweat glands and hair follicles.

Question 29

How does a scar remodel?

Answer 29

Collagen fibres remodel as the scar matures
Some fibroblasts develop properties of smooth muscle cells (myofibroblasts) allowing contraction of th wound (beneficial to pull in and make scar smaller and stronger over time)

Question 30

What controls scar remodelling?

Answer 30

Mediated by metalloproteinases (which degrade collagen) and their tissue inhibitors (TIMPs)

Question 31

Describe damage done by small defects - skin healing by primary intention (PG43)

Answer 31

Small defects can be ‘closed’ by sutures
Damage to only a small amount of epidermis and basement membrane
Healing is quick leaving a small scar

Question 32

What makes up scars from large defects that can’t be ‘closed’ following severe trauma? - skin healing by secondary intention

Answer 32

More granulation tissue, inflammation and fibroplasia (connective tissue deposition)

Question 33

What happens in large defects that can’t be ‘closed’ following severe trauma? - skin healing by secondary intention (PG4)

Answer 33

Re-epithelialisation occurs first along the base of the defect
Myofibroblasts mediate contraction of the maturing scar

Question 34

What systemic factors affect wound healing?

Answer 34

Nutrition, metabolic status, circulatory status, hormones

Question 35

What local factors influence wound healing?

Answer 35

Local blood supply - ischaemia will cause tissue to be chronically hypoxic and unable to regenerate
Infection
Foreign body
Mechanical factors

Question 36

How does wound strength differ with time?

Answer 36

As wound matures, amount of collagen accumulation and remodelling increases, and so does strength. At around 3 months it will stop healing at stay at abt 80% original strength.

Question 37

What can happen when scarring goes wrong and causes disease?

Answer 37

Keloid scar
Contractures
Chronic leg ulcers
(pg45 for image examples)

Question 38

What is a keloid scar?

Answer 38

Excessive exuberant production of collagen in response to often minor trauma

Question 39

How does a keloid scar form?

Answer 39

Damaged tissue undergoes process of scarring with deposition of very abnormal thick collagen fibres, producing a modular tumour on the surface of the skin.
(If try to remove it can cause further damage to the tissue and recur more than before)

Question 40

What happens in contractures?

Answer 40

Connective tissue deposited doesn’t have the elasticity of normal healthy dermis. Can impair motor function.

Question 41

When do contractures occur?

Answer 41

Usually following severe burns injury

Question 42

Why do chronic leg ulcers occur? (mainly in elderly)

Answer 42

Occur due to poor blood flow either by impaired delivery in arteriole system due to atherosclerosis or venous disease leading to impaired drainage from the area. So healing cannot occur here.
Once lost the protective barrier of the epidermis, ulcers are prone to secondary infection, further impairing wound healing.