MoD - Healing And Repair

Question 1

What is meant by the term labile tissues?

Give some examples

Answer 1

Continuously dividing tissues - proliferate throughout life replacing cells that are destroyed

E.g. Surface epithelia
Lining mucosa of Secetory ducts of glands of the body
Columnar epithelia of GI tract and uterus
Transitional epithelium of urinary tract
Cells of bone marrow
Haematopoietic tissues

Question 2

What is meant by the term stable tissues?

Give some examples

Answer 2

Quiescent tissues - normally have low level of replication but cells in these tissues can undergo rapid division in response to stimuli and reconstruct tissue of origin

E.g. Parenchymal cells of the liver, kidneys, pancreas
Mescenchymal cells such as fibroblasts and smooth muscle cells
Vascular endothelial cells
Resting lymphocytes and other WBCs

Question 3

What is meant by the term permenant tissues?

Give some examples

Answer 3

Non dividing tissues - these tissues contain cells that have left the cell cycle and can’t undergo mitotic division in post natal life.

E.g. Neurones, skeletal muscle and cardiac myoctyes

They have no or only a few stem cells that can be recruited to replace cells

Question 4

What are stem cells?

What is asymmetric replication?

Answer 4

Cells with prolonged proliferative activity which show asymmetric replication

One of the daughter cells remains as a stem cell while the other differentiates into a mature, non dividing cell

Question 5

What is the difference between embryonic stem cells and adult stem cells?

Answer 5

Embryonic stem cells = totipotent

Adult stem cells = unipotent

Question 6

What is meant by the terms:

Totipotent
Unipotent
Multipotent

Answer 6

Totipotent - give rise to any of the tissues of the human body

Unipotent - can only give rise to one type of adult cell (Lineage specific)

Multipotent - can produce several types of differentiated cell e.g. Haematopoietic stem cells

Question 7

Describe how liver cells heal.

Answer 7

Liver hepatocytes are usually non replicating but can be induced to enter the cell cycle and replicate if necessary. E.g. They are in G0 but can enter G1.

Stem cells are present in these tissues and are normally quiescent or proliferate very slowly, but they can profile rate persistently when required.

Question 8

What happens when there is damage to a permanent tissue? E.g. Neurones, skeletal and cardiac myoctyes

Answer 8

Terminally differentiated cells which cannot replicate. Although stem cells can be present within these tissues they cannot mount an effective proliferative response to significant cell loss.

Any damage - They heal with a scar

Or in the case of the CNS - the space where the neurones were is filled with glial cells (supporting cells of the CNS)

Question 9

When does fibrous repair occur?

Answer 9

If the collagen framework of a tissue is destroyed

If there is ongoing inflammation

If there is necrosis of specialised parenchymal called that cannot be replaced.

Fibrovascular connect tissue will grow into the area.

Question 10

How does fibrous repair differ from regeneration?

Answer 10

Regeneration - return of tissue to normal state following injury, essential for restoration of full functionality and normal appearance to injured tissue

Fibrovascular connective tissue will grow if the collagen framework has been destroyed, ongoing inflammation of necrosis of a specialised parenchymal cell that cannot be replaced

Question 11

Describe fibrous repair

Answer 11

Blood clot forms, acute inflammation around the edges.
Macrophages and lymphocytes migrate into the clot. Phagocytosis of necrotic tissue debris
Clot replaced by granulation tissue - Proliferation of endothelial cells which results in small capillaries that grow into the area
ECM produced by proliferation of fibroblasts and myofibroblasts that synthesize collagen and cause wound contraction (granulation tissue)
Granulation tissue becomes less vascular and matures into a scar
The scar matures and shrinks due to contraction of fibrils within myofibroblasts

Question 12

What cell types are involved in fibrous repair?

Answer 12

Fibroblasts and myofibroblasts - synthesise collagen and cause wound contraction

Question 13

What is angiogenesis?

Answer 13

Proliferation of endothelial cells which results in small capillaries that grow into the area

Question 14

What cells are involved in granulation tissue?

What does this cause?

Answer 14

Fibroblasts and myofibroblasts that synthesise collagen

Causes wound contraction

Question 15

What is essential to the fibrous repair process?

Answer 15

Synthesis of collagen

Question 16

What are the types of collagen?

What type of collagen is most common in the body?

Where is it found?

Answer 16

Fibrillar collagen to Type 1 to 3
Amorphous collagenase type 4 to 6 (found in basement membrane)

Type 1 - fibrillar collagen

Present in hard and soft tissues. (Bones, tendons, ligaments, skin, sclera, blood vessels)

Question 17

What cells synthesise collagen?

Describe collagen synthesis

Answer 17

Fibroblasts and myofibroblasts

Cleavage of signal sequence by signal peptidase
Hydroxylation of proline/lysine by prolly hydroxylase
Addition of olgiosaccharide through N linked glycoslation
Disulphide bridge formation
Triple helix formation
O linked glycosylation
Golgi body secretion
Into the ECM
Removal of terminal domains
Lateral association with cross linking by lysyl oxidase (gives tensile strength)

Question 18

What gives collagen its tensile strength?

Answer 18

Considerable cross linking between molecules

Question 19

What is the difference between regeneration and repair?

Answer 19

Regeneration - proliferation of cells and tissues to replace lost or damaged cells and tissues. Normal structure is restored

Repair - response to injury involving both regeneration and scar formation (fibrosis)
Normal structure is permanently altered

Question 20

How is collagen made up?

Answer 20

Triple helix of three polypeptide alpha chains with repeating Gly-X-Y sequence.

Question 21

Name four diseases that are as a result of defective collagen synthesis

Answer 21

Scurvy
Ethers-Danlos syndrome
Osteogenesis imperfecta
Alport syndrome

Question 22

What is scurvy?

What are the effects?

Answer 22

Due to a vitamin C deficiency

Vitamin C is required for hydroxylation of pro collagen

Unable to heal wounds adequately and have a tendency to bleed

Question 23

What is Ethlers-Danlos syndrome?

What are the effects?

Answer 23

Genetic defect where collagen fibres lack adequate tensile strength

Hyperextensible skin, fragile, susceptible to injury and joint are hypermobile.

Wound healing is poor and predisposition to joint dislocation.

Internal organs collagen is also effected –> rupture of colon and sometimes large arteries.

Question 24

What is osteogenesis imperfecta? (Brittle bone diesase)

What is its inheritance?

What are the effects? And why?

Answer 24

Autosomal dominant

Patients have too little bone tissue, hence extreme skeletal fragility.

Blue sclera - too little collagen in sclera making them translucent

Hearing impairment and dental abnormalities

Question 25

What is Alport syndrome inheritance pattern? What type of collagen is abnormal? Who does it normal present in? And what do they present with? What does it progress to?

Answer 25

X linked Type 4 collagen - resulting in dysfunction of the glomerular basement membrane, cochlea of the ear and lens of the eye. Usually male, present with haematuria as childrens or adults Progresses to chronic renal failure Neural deafness and eye disorders

Question 26

How do cells communicate in regeneration and repair?

Answer 26

Cell to cell communication via local mediators (growth factors) Hormones Direct cell to cell or cell-stroma contact

Question 27

What are the ways in which cells can communicate via local mediators and hormones? Describe each.

Answer 27

Autocrine- cells respond to the signalling molecules that they themselves produce Paracrine - cells produces the signalling molecule that acts on adjacent cells. Responding cells are close to secreting cell but usually a different type Endocrine - hormones are synthesised by cells in an endocrine organ, conveyed in the blood stream to target cells to effect physiological activity

Question 28

Define autocrine.

Answer 28

Autocrine- cells respond to the signalling molecules that they themselves produce

Question 29

Define paracrine.

Answer 29

Paracrine - cells produces the signalling molecule that acts on adjacent cells. Responding cells are close to secreting cell but usually a different type

Question 30

Define endocrine

Answer 30

Endocrine - hormones are synthesised by cells in an endocrine organ, conveyed in the blood stream to target cells to effect physiological activity

Question 31

What are growth factors? How are they coded?

Answer 31

Polypeptides that act on specific cell surface receptors Coded for by proto-oncogenes

Question 32

What effect can growth factors have? How do they work?

Answer 32

Simulate cell proliferation or inhibition Affect cell locomotion, contractibility, differentiation, viability, activation and angiogenesis Bind to specific receptors and stimulate transcription of genes that regulate the entry of the cell into the cell cycle and the cells passage through it

Question 33

Name 4 growth factors What does each one do?

Answer 33

Epidermal growth factor - mitogenicfor epithelial cells, hepatocytes. Produced by keratinocytes, macrophages and inflammatory cells. Binds to epidermal growth factor receptor Vascular endothelial growth factor - potent inducer of blood vessel development and role in growth of new blood vessels in tumours, chronic inflammation and wound healing Platelet derived growth factor - stored in platelet alpha granules and released on platelet activation, produced by macrophages, endothelial cells, smooth muscle and tumour cells. Causes migration and proliferation of fibroblasts, smooth muscle and monocytes Tumour necrosis factor - induces fibroblast migration, proliferation and collagenase secretion.

Question 34

What is contact inhibition?

Answer 34

Normal cells when they become isolated from other cells around them will replicate until they have cells touching them then stop I.e. Form a monolayer sheet of cells with no cell overlap

Question 35

How do cells adhere to each other and ECM? What are they called?

Answer 35

Proteins on the cell membranes called adhesion molecules

Question 36

What are the adhesion molecules that bind cells to each other called? What are the adhesion molecules that bind cells to the extracellular matrix called? What are they important in?

Answer 36

Cadherins Integrins Contact inhibition and wound healing

Question 37

What are the two classifications of wound healing? What is it dependent on?

Answer 37

Primary intention wound healing Secondary intention wound healing Dependent on size of the wound and amount of tissue that has been lost

Question 38

What does healing by primary intention involve? How many cells have died? What is the size of the clot? What is the size of scar?

Answer 38

Incisional, closed, non infected and sutured wounds. Apposed edges. Disruption of basement membrane continuity but death of only a limited number of epithelial and connective tissue cells Minimal clot and granulation tissue Small

Question 39

What is the process of primary intention wound healing?

Answer 39

Haemostasis - blood clot forms, dehydration of clot --> scab. Inflammation - neutrophils appear at margin of incision, wards off bacteria. Migration of cells - macrophages start to appear and begin to scavenge dead neutrophils. They become activated and secrete cytokines that attract other cells such as fibroblasts and endothelial cells Regeneration - macrophages replace neutrophils. Granulation invades the space. Scab falls off when epidermal cell proliferation thickens epidermal layer. Activated fibroblasts produce collagen Early scarring - wound filled with granulation tissue. Fibroblasts proliferate and deposit collagen fibres which form fibrous mass (scar). Scar maturation

Question 40

What is the function of the extracellular matrix?

Answer 40

``` Support and anchor cells Separate tissue compartments Sequester growth factors Allow communication between cells Facilitate cell migration ```

Question 41

What makes up the extracellular matrix?

Answer 41

Matrix glycoproteins - organise and orientate cells, support cell migration Proteoglycans - matrix organisation, cell support , regulate availability of growth factors Elastin - provide tissue elasticity

Question 42

What controls fibrous repair?

Answer 42

Inflammatory cells recruited by chemotaxis Angiogenesis - platelets, ECM and others produce angiogenic cytokines in response to hypoxia Fibrosis - macrophages produce various pro-fibrotic cytokines. Fibroblasts proliferation and ECM production

Question 43

What are you at risk of with primary intention healing?

Answer 43

Infection --> abscess

Question 44

When does secondary intention wound healing occur?

Answer 44

Infarct, ulcer, abscess or any large wound

Question 45

What are the differences between primary and secondary wound healing?

Answer 45

Secondary - unopposed edges, large clot --> scab, epidermis regenerates from both up. Repair process produces much more granulation tissue. Produces more contraction due to volume of defect. Large scar. Takes longer. Primary - apposed edges, minimal clot, epidermis regenerates, minimal granulation tissue. No scar.

Question 46

How do bone fractures repair?

Answer 46

Haemoatoma forms - from ruptured vessels, provides framework for ingress of macrophages, endothelial cells, fibroblasts and osteoblasts. Necrotic tissue removed Fibrin mesh and granulation tissue is then formed. Platelets and inflammatory cells release cytokines which activate osteoprogenitor cells to osetoclastic and osteoblast in activity Soft callus formation (1wk) - irregular woven pattern, sometimes with islands of cartilage. External callus provides splint like support. Bulge around fracture site. Hard callus formation (2-3 wks) - bone laid down by osteoblasts. Woven bone gradually replaced by more organised and stronger lamellar bone Bone remodelling - lamellar bone gradually remodelled to the direction of mechanical stress

Question 47

What are the local factors influencing healing and repair?

Answer 47

``` Size, location and type of wound - indicates primary or secondary intention Blood supply Denervation - impairs healing Local infection - persistent tissue injury and inflammation Foreign bodies Haematoma Necrotic tissue Mechanical stress Protection Surgical techniques ```

Question 48

What are the systemic factors influencing healing and repair?

Answer 48

Age Anaemia, hypoxia and hypovolamia - poor O2 delivery to healing tissue Obesity Diabetes - microvascular impairs blood supply to damaged area. Decreased resistance to infection Malignancy Genetic disorders Drugs- steroids - Vitamin deficiency - vit C inhibit collagen synthesis Malnutrition e.g. Amino acids for protein synthesis

Question 49

Why would steroids decrease healing? Why would antibiotics increase healing?

Answer 49

Inhibit collagen synthesis Treat bacterial infections, reduce inflammation, can speed up healing

Question 50

What are the complications of fibrous repair?

Answer 50

Formation of fibrous adhesions compromising organ function or blocking tubes Loss of function due to replacement of specialised functional parenchymal cells by non functioning collage nous scar tissue Disruption of complex tissue relationships within an organ Overproduction of fibrous scar tissue e.g. Keloid scar. Excessive scar contraction causing obstruction of tubes, disfiguring burns or joint contracture (if severe - can impair blood circulation)

Question 51

What is the difference between hypertrophic scar to keloid scar?

Answer 51

Hypertrophic - raises out of the skin Keloid - raises up from skin and exceeds boarders of scar

Question 52

What is a keloid scar? Who are they common in?

Answer 52

An overgrowth of fibrous tissue, due to overproduction of collagen that exceeds the boarders of the scar. They don't regress and excision just creates another one. Afrocarribeans

Question 53

What is meant by the term regeneration/resolution? What does regeneration require?

Answer 53

Growth of cells and tissues to replace lost structures e.g. Epithelia of skin and GI can regenerate after injury as long as the stem cells of these tissues aren't destroyed NORMAL STRUCTURE IS RESTORED In order for regeneration to take place damage to the tissue cannot be extensive as regeneration requires an intact connective tissue scaffold

Question 54

How does repair occur in cardiac muscle?

Answer 54

Very limited, if any, regeneration capacity Myocardial infarction --> scar formation

Question 55

How does liver tissue heal/repair?

Answer 55

Remarkable capacity to regenerate If part of the liver is removed compensatory growth of liver tissue occurs and there is restoration of liver mass by enlargement of the lobes that remain All hepatocytes replicate during regeneration, followed by replication of non-parenchymal cells

Question 56

How does a peripheral nerve repair? What cells are involved? What is the axon growth rate?

Answer 56

Nerve is severed - axons degenerate. Proximal stumps of degenerated axons spout and elongate. Schwaan cells guide them back to the tissue that the nerve innervates. 1-3mm/day

Question 57

What does cartilage lack in order for it to repair?

Answer 57

Does not heal well as it lacks blood supply Lymphatic drainage Innervation

Question 58

How does the CNS repair? What type of tissue is it? What cells are involved?

Answer 58

CNS tissue is a permanent (non proliferative tissue) When damage occurs the neural tissue is replaced by proliferation of CNS supportive elements. Glial cells