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Flashcards in MOD 4 Deck (82):

Define regeneration

Is the growth of cells and tissues to replace lost structures.


Define resolution

Another term for regeneration, therefore it is the growth of cells and tissues to replace lost structures.


What is a labile tissue? Give some examples:

Continuously dividing tissues - proliferate throughout life continuously replacing cells that are lost through stem cells. E.g. surface epithelia, lining mucosa of secretory ducts of the glands of the body, columnar epithelia of GI tract and uterus, transitional epithelium of urinary tract, cells of bone marrow and haematopoietic tissues.


What is a stable (quiescent) tissue? Give some examples:

Tissues that normally have a low level of replication but cells in these tissues can undergo rapid division in response to stimuli and can reconstruct the tissue of origin. E.g. parenchymal cells of the liver, kidneys and pancreas, mesenchymal cells such as fibroblasts and smooth muscle cells, vascular endothelial cells, resting lymphocytes and other white blood cells.


What is a permanent tissue? Give some examples:

These are non-dividing tissues, containing cells that have left the cell cycle and can't undergo mitotic division in postnatal life e.g. neurones, skeletal and cardiac muscle cells. They have no or only a few stem cells (that can't mount an effective proliferative response to significant cell loss) to replace cells.


What are the roles of stem cells?

Stem cells can replace terminally differentiated cells that are lost - in tissues where regeneration is possible.


Define unipotent stem cells

Stem cells that can only give rise to one type of adult cell - lineage specific.


Define multipotent stem cells

Stem cells that can produce several types of differentiated cell e.g. haematopoietic cells.


Define totipotent stem cells

Stem cells that can give rise to any tissue in the body.


What is fibrous repair?

Replacement of tissue with fibrovascular connective tissues.


How does fibrous repair differ from regeneration/resolution?

Regeneration restores a tissue back to its full functionality and normal appearance.


List the steps involved in fibrous repair:

1. Phagocytosis of necrotic tissue debris
2. Angiogenesis
3. Formation of granulation tissue - proliferation of fibroblasts and myofibroblasts
4. Granulation tissue becomes less vascular -> fibrous scar
5. Scar matures and shrinks due to contraction of fibrils of myofibroblasts


What cells are involved in fibrous repair?

Other leukocytes
Endothelial cells


What is angiogenesis?

The physiological process through which new blood vessels form from pre-existing vessels.


What are the components of granulation tissue?

1. Cellular components: fibroblast, myofibroblasts, endothelial cells
2. Non-cellular components: collagen (intially type 3 then replaced by stronger type 1), fibrin and plasma fluid.


What types of collagen are their?

27 different types. Type I (fibrillar) is the most common type in the body.


How is fibrillar collagen synthesised?

It is synthesised by fibroblasts and myofibroblasts:
1. Preprocollagen synthesised into ER
2. Modified to procollagen which takes on a triple helix form and is secreted from the cell
3. Procollagen cleaved to produce fibrillar collagen
4. Cross-linking between fibrils to give tensile strength


List some diseases caused by defects in collagen synthesis:

Ehlers-Danlos syndrome
Osteogenesis imperfecta
Alport syndrome


What is the mechanism behind the disease scurvy?

Scurvy is caused by a deficiency of vitamin C. This is a cofactor for the enzymes prolyl hydroxylase and lysyl hydroxylase which hydroxylate proline and lysine residues on procollagen, enabling it to hydrogen bond into its triple helix form. Without as many hydrogen bonds, these triple helices are weak and therefore the collagen is weak. People with scurvy therefore are unable to heal wounds adequately and have a tendency to bleed.


What is the mechanism behind the disease Ehlers-danlos syndrome?

It is a heterogenous group of 6 inherited disorders where the collagen fibres lack adequate tensile strength. Skin is hyperextensible, fragile and susceptible to injury and joints are hypermobile. Wound healing is poor and patients have a predisposition to joint dislocation. Because the collagen in internal organs is also affected patients can suffer form rupture of the colon and , in some forms, large arteries. Corneal rupture and retinal detachment can also be seen.


What is the mechanism behind the disease osteogenesis imperfecta (brittle bones disease) ?

People with OI are born with defective connective tissue, or without the ability to make it, usually because of a deficiency of Type-I collagen. Patients have too little bone tissue and hence extreme skeletal fragility. They also have blue sclera as there is too little collagen in the sclerae making them translucent. They also can have hearing impairment and dental abnormalities.


What is the mechanism behind the disease Alport syndrome?

Usually an X-linked disease. Type 4 collagen is abnormal and this results in dysfunction of the glomerular basement membrane, the cochlear of the ear and the lens of the eye. Patients, usually male, present with haematuria as children or adolescents. This progresses to chronic renal failure. They also have neural deafness and eye disorders.


How is cell reparation and growth controlled?

The control mechanisms are poorly understood, but cells communicate with each other to produce a fibropoliferative response. This communication can be via local mediators (such as growth factors), hormone or by direct cell-cell stroma contact.


What are the different modes of action of growth factors

autocrine, paracrine, endocrine signalling


What is autocrine signalling?

Cells respond to signalling molecules that they themselves produce.


What is paracrine signalling?

Cells produce the signalling molecule, this acts on adjacent cells. The responding cells are close to the signalling cells and are often of a different type.


What is endocrine signalling?

Hormones are synthesised by cells in an endocrine organ, they are conveyed in the blood stream to target cells to effect physiological activity.


What is the importance of adhesion molecules?

These proteins allows cells to adhere to each other (called cadherins) and the extracellular matrix (integrins). They are important in contact inhibition and wound healing.


Explain the concept of contact inhibition:

Normally cells that have become isolated from surrounding cells will replicate until they have cells touching them and then stop. In this way they form monolayer sheets of cells with no overlap. This is altered in malignant cells.


When does healing by primary intention occur?

Incisional, closed, non-infected and sutured wounds i.e. clean wounds with opposed edges. There is a disruption of the epithelial basement membrane continuity but death of only a number of epithelial and connective tissue cells.


When does healing by secondary intention occur?

Excisional wounds or wounds with tissue loss and separated edges. It is also seen in infected wounds.


What are the main differences between healing by primary and secondary intention?

1. Primary intention - wound surface sealed off first then deep space filled with granulation tissue. Secondary - granulation tissue fills space from sides
2. Secondary - inflammatory reaction is more intense
3. Secondary - considerable wound contraction must occur to close the defect (first by drying scab then myofibroblasts)
4. Substantial scar formation is seen in secondary cf. to primary
5. Secondary - new epidermis is often thinner than is usual.


Explain how bone fractures are healed:

1. haematoma formation
2. granulation tissue formed
3. fibrocartilagenous callus formed - about 1 week
4. hard callus forms


List some local factors that influence the efficacy of healing and repair:

1. Size, location and type of wound
2. Blood supply
3. Denervation
4. Local infection
5. Foreign bodies
6. Haematoma - large and persistent can slow healing
7. Necrotic tissue - more -> longer to remove and heal
8. mechanical stress - pull apart delicate healing tissue in early stages
9. Protection (dressings)
10. Surgical technique - good techniques promote rapid healing and minimise scarring


List some systemic factors that influence the efficacy of healing and repair:

1. Age
2. Anaemia, hypoxia and hypovolemia
3. Obesity - increased tension on wound can -> dehiscence
4. Diabetes - microangiopathy -> impaired blood and resistance to infection
5. Malignancy - due to cachexia
6. Genetic disorders - e.g. Ehlers-Danlos syndrome
7. Drugs - steroids, cytotoxics impair wheras antibiotics can speed up
8. Vitamin deficiency - vit c impairs healing
9. Malnutrition - lack of amino acids etc for proteins synthesis.


What are the main complications of fibrous repair?

1. Insufficient fibrosis
2. Excessive fibrosis
3. Contracture


What are special aspects of healing and repair in cardiac muscle?

Limited if any regenerative capacity. MI is followed by invasion of fibroblasts and scar formation that can compromise cardiac function.


What are special aspects of healing and repair in the liver?

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 remaining lobes. Almost all hepatocytes replicate during regeneration. This is followed by regeneration of non-parenchymal cells.


What are special aspects of healing and repair in peripheral nerves?

When a nerve is severed the axons degenerate. The proximal stumps of the degenerated axons sprout and elongate. They use Schwann cells vacated by the distal degenerated axons to guide the back to the tissue that the nerve innervates.


What are special aspects of healing and repair in cartilage?

Does not heal well as it lacks blood supply, lymphatic drainage and nerve supply.


What are special aspects of healing and repair in the CNS?

Neural tissue is a permanent (non-proliferative) tissue and when tissue damage occurs in the CNS the neural tissue is replaced by proliferation of the CNS supportive elemnts (glial cells). This is called gliosis.


What three process occur in wound healing?

1. Haemostasis - as vessels are open
2. Inflammation - as there has been tissue injury
3. Regeneration/ resolution - and repair - as structures have been injured or destroyed.


Give some examples of tissues in which regeneration can occur?

Epithelia of skin and GI tract can regenerate after injury as long as the stem cells of these tissues aren't destroyed.


When is regeneration possible?

If that particular tissue is capable of regeneration (e.g. has stem cells or cells that are capable of dividing) and if there remains an intact connective tissue scaffold. Regeneration cannot occur if the tissue has been so damaged that this scaffold no longer remains.


What are stem cells?

These are cells with prolonged proliferative activity which show asymmetric replication.


Stem cells exhibit asymmetric replication. What is it?

In assymetric replication one of the daughter cells remains as a stem cell while the other differentiates into a mature, non-dividing cell.


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

Embryonic stem cells are totipotent whereas most adult stem cells are unipotent. Although some adult stem cells are described as multipotent because they can produce several types of differentiated cells e.g. haematopoietic cells.


What happens when permanent tissues are damaged?

They heal with a scar or in the case of the CNS with gliosis (the area of tissue loss is replaced by glial cells).


What are glial cells?

Supporting cells of the central nervous system.


In stable tissues, what cell types are involved in proliferation?

Mature cells and stem cells. Mature cells that are normally non-replicating are induced to enter the cell cycle and replicate if necessary (i.e. cells are in Go but can enter G1). Stem cells are present in these tissues and are normally quiescent or proliferate very slowly but can proliferate persistently when required.


When does fibrous repair occur instead of regeneration/r resolution?

1. Collagen framework of a tissue is destroyed
2. Ongoing chronic inflammation
3. Necrosis of specialised parenchymal cells that cannot be replaced


What is another word that is sometimes used for fibrous repair?



What is the most common type of protein in the animal world?



What is the purpose of collagen?

It provides the extracellular framework for all multicellular organisms. It is present in hard and soft tissues (bones, tendons, ligaments, skin, sclera, cornea, blood vessels and hollow organs).


What are growth factors?

They are polypeptides that act on specific cell surface receptors and stimulate the transcription of genes which regulate the entry of the cell into the cell cycle and the cell's passage through it. Coded for by proto-oncogenes, they can be considered as 'local hormones' which act over a short distance or on themselves. There are a large number of them.


What is the specificity of action of growth factors?

Some act on many cell types, some have restricted targets.


What response can growth factors illicit on target cells?

1. Stimulate cell proliferation
2. Inhibit cell proliferation
3. Affect cell locomotion
4. Contractility
5. Differentiation
6. Viability
7. Activation
8. Angiogenesis


What response does epidermal growth factor illicit?

It binds to epidermal growth factor receptor (EGFR) and is mitogenic for epithelial cells, hepatocytes and fibroblasts.


Which cells produce epidermal growth factor?

Keratinocytes, macrophages and inflammatory cells.


What response does vascular endothelial growth factor illicit?

It is a potent inducer of blood vessel development and has a role in the growth of new blood vessels in tumours, chronic inflammation and wound healing.


What is the difference between vasculogenesis and angiogenesis?

Vaculogenesis is the production of new blood vessel de novo from endothelial precursor cells (angioblasts), whereas angiogenesis is the production of new capillaries from pre-existing blood vessels.


What response does platelet-derived growth factor illicit?

It causes migration and proliferation of fibroblasts, smooth muscle cells and monocytes.


What cells produce platelet-derived growth factors?

1. Platelets - it is stored in alpha granules and released on platelet activation
2. Macrophages
3. Endothelial cells
4. Smooth muscle cells
5. tumour cells


What response does tumour necrosis factor illicit?

It induces fibroblast migration, fibroblast proliferation and collagenase secretion - enzymes that break the peptide bonds in collagen.


What are the basic steps to healing by primary intention?

1. Haemostasis - blood clot -> scab seal
2. Minutes to hours - neutrophil migration
3. Up to 48 hours - migration of cells: macrophages activate and secrete cytokines which attract fibroblasts, endothelial cells etc... Basal epidermal cells grow in from edge of cut fusing underneath scab
4. Granulation tissue invades space. Epithelial cell proliferation and scab falls off
5. Early scarring - wound filled with granulation tissue
6. Scar maturation


What are the basic steps to healing by secondary intention?

1. Open wound fills with granulation tissue from wound edges


Describe the phenotype of myofibroblasts

They are fibroblasts which develop into a contractile phenotype. They resemble a smooth muscle and are intermediates between fibroblasts and smooth muscle cells.


In which direction does an open wound contract?

As if its margins are being drawn into the centre.


Why do scars tend to stretch?

They contain few elastic fibres and therefore have little recoil.


Why are scars hairless?

Although scars have normal epidermis, skin appendages such as hair follicles and sweat glands don't reform.


Why are new scars pink but older scars white?

Scars become whiter as capillary density decreases.


What happens to wound healing if an infection is present?

It is delayed.


What is a haematoma?

a solid swelling of clotted blood within the tissues


How can steroids impair wound healing?

They inhibit collagen synthesis.


How can cytotoxic drugs impair wound healing?

They are anti-mitogenic and impar cell proliferation and therefore healing.


How can antibiotics speed up wound healing?

They can treat bacterial infections therefore reduce infalmmation.


How fast do axons grow?

1-3 mm/day


Apart from being disfiguring, what other problems can scars cause?

1. Joint contractures - affecting stretch and range of movement/ function
2. Loss of sensation
3. Impeded circulation e.g. cirrhotic liver


What is a traumatic neuroma?

Is a growth or tumour of nerve tissue which results from trauma to a nerve, usually during a surgical procedure.


What is a keloid scar?

It is one of the main complications of wound healing. Keloid is an overgrowth of the scar tissue that develops around a wound, usually after the wound has healed. A keloid scar is sometimes confused with a hypertrophic scar. However, keloid usually grows beyond the borders of the original wound whereas in a hypertrophic scar the tissue stays within the wound border.


What is the most common complication of wound healing?



What is proud flesh? How is it treated?

It is large amounts of soft, oedematous, unhealthy-looking granulation tissue developing during healing of large surface wounds (looks like a cauliflower). It is normally treated by surgical intervention e.g. a skin graft, or antibiotics and silver nitrate.