Week 4 - Healing and Repair Flashcards
What is regeneration?
The growth of cells and tissues to replace lost structures
- Damage to the tissue cannot be extensive for it to occur, since it requires an intact connective tissue scaffold
What are labile tissues?
Continuously dividing tissues
- Proliferate rapidly throughout life, replacing cells that are destroyed
What are some examples of labile tissues?
- Surface epithelia
- Lining mucosa of secretory ducts of glands
- Columnar epithelia of GI tract and uterus
What are stable tissues?
Tissues that normally have a low level of replication
- Cells in these tissues can undergo rapid division in response to stimuli
- Can reconstruct tissue of origin
What are some examples of stable tissues?
- Parenchymal cell of liver, kidneys and pancreas
- Mesenchymal cells such as fibroblasts and smooth muscle cells
- Resting lymphocytes
- Other white blood cells
What are permanent tissues?
Non-dividing tissues
- Contain cells that have left the cell cycle and can’t undergo mitotic division in post-natal life
- Have no, or only a few, stem cells that can be recruited to replace cells
What are some examples of permanent tissues?
- Neurones
- Skeletal muscle cells
- Cardiac muscle cells
What are stem cells?
Cells that have the potential for limitless proliferation
- Daughter cells either remain as stem cells to maintain the stem cell pool or differentiate to a specialised cell type
- In early life, they develop into many different cell types
- ‘Internal repair system’ to replace lost or damaged cells in tissues
- Show asymmetric replication
- Multipotent (embryonic stem cells are totipotent)
What does totipotent mean?
Can produce any type of cell
- E.g. embryonic stem cells
What does multipotent mean?
Can produce several types of differentiated cell
- E.g. haematopoietic
What does unipotent mean?
Can only produce 1 type of differentiated cell
- E.g. epithelia
What does fibrous repair of a damaged tissue involve?
- Phagocytosis of necrotic tissue debris
- Proliferation of endothelial cells which results in small capillaries that grow into the area (angiogenesis)
- Proliferation of fibroblasts and myofibroblasts that synthesise collagen and cause wound contraction
- At this stage, the repair tissue is called granulation tissue
- The granulation tissue becomes less vascular and matures into a fibrous scar
- The scar matures and shrinks due to contraction of fibrils within myofibroblasts
What cell types are found in granulation tissue? (And what for?)
- Inflammatory cells (phagocytosis of debris [neutrophils, macrophages], chemical mediators [lymphocytes, macrophages])
- Endothelial cells (angiogenesis)
- Fibroblasts/myofibroblasts (extracellular matrix proteins/wound contraction)
What is the role of the extracellular matrix?
- Supports and anchors cells
- Separates tissue compartments
- Sequesters growth factors
- Allows communication between cells
- Facilitates cell migration
What is angiogenesis?
Endothelial proliferation induced by proangiogenic growth factors
- Pre-existing vessels sprout new vessels
- The development of a blood supply is vital to wound healing
- It provides access to the wound for inflammatory cells and fibroblasts
- Delivery of oxygen and other nutrients
How does angiogenesis occur?
- Endothelial proteolysis of basement membrane
- Migration of endothelial cell via chemotaxis
- Endothelial proliferation
- Endothelial maturation and tubular remodelling
- Recruitment of periendothelial cells, which provide support and stability
What is fibrous repair?
When fibrovascular connective tissues grows into an injured area
- Occurs because the cells cannot be replaced
When does fibrous repair occur?
- If the collagen framework of a tissue is destroyed
- If there is ongoing chronic inflammation
- If there is a necrosis of specialised parenchymal cells
What is Alport syndrome?
- Usually an X-linked disease
- Type II collagen is abnormal
- Results in dysfunction of the glomerular basement, the cochlea of the ear and the lens of the eye
- Patients are usually male
- Present with haematuria as children/adolescents
- This progresses to chronic renal failure
- Also have neural deafness and eye disorders
What are the control mechanisms for regeneration and repair?
Poorly understood
- Cells communicate with each other to produce a fibroproliferative response
- Can be via local mediators, by hormones or by direct cell-cell/cell-stroma contact
What are the different types of cell communication?
- Autocrine
- Paracrine
- Endocrine
- Intracrine
What is autocrine communication?
Cells respond to the signalling molecules that they themselves produce
What is paracrine communication?
A cell produces the signalling molecule and this acts on adjacent cells
- The responding cells are close to the secreting cell and are often of a different type
What is endocrine communication?
Hormones are synthesised by cells in an endocrine organ
- They are then conveyed in the bloodstream to target cells to effect physiological activity
What are growth factors?
Polypeptides that act on specific cell surface receptors
- They are particularly important in regeneration and fibrous repair
- Coded for by proto-oncogenes
- Can be considered as ‘local-hormones’ as they act only over a short distance or even on the secreting cell itself
- There are a large number of them
- Some act on many cell types, some have restricted targets
What do growth factors do?
They stimulate cell proliferation or inhibition May also affect: - Cell locomotion - Contractility - Differentiation - Viability - Activation - Angiogenesis They bind to specific receptors and stimulate transcription of genes that regulate the entry of the cell into the cycle and the cell's passage through it
What is contact inhibition?
When normal cells become isolated from other cells around them, they will replicate until they have cells touching them and then stop
- Cells adhere to each other and extracellular matrix by means of proteins on the cell membranes called adhesion molecules
- There is signalling through adhesion molecules, which inhibits proliferation in intact tissue
- Loss of contact inhibition promotes proliferation
What are the different types of adhesion molecules?
- Cadherins: ones that bind cells to each other
- Integrins: ones that bind cells to the extracellular matrix
How can wound healing be classified?
As primary intention or secondary intention
- Depends on the size of the wound and the amount of tissue that has been lost
Describe healing by primary intention
- Occurs in incisional, closed, non-infected and sutured wounds (i.e. clean wounds with opposed edges)
- There is disruption of the epithelial basement membrane continuity but death of only a limited number of epithelial and connective tissue cells
- These wounds have more favourable conditions for healing
- Heal with less scarring than those that heal with secondary intention
What happens in healing by primary intention after seconds to minutes of the wound occurring?
Haemostasis
- Severed arteries contract
- The narrowed space fills with clotted blood
- There is dehydration of the surface clot
- A scab forms, which seals the wound off from the environment and prevents bacteria entering
What happens in healing by primary intention after minutes to hours of the wound occurring?
Inflammation
- Neutrophils appear at the margins of the incision
- This wards off bacteria
- Inflammation is triggered automatically without waiting for bacteria to do so
What happens in healing by primary intention after 48 hours of the wound occurring?
Migration of cells
- Macrophages start to appear
- They begin to scavenge dead neutrophils
- They become activated and secrete cytokines that attract other cells
- Spurs of basal epidermal cells at the edge of the cut creep over the denuded cells
- They deposit basement membrane components as they go
- They fuse in the midline beneath the scab
What happens in healing by primary intention after 3 days of the wound occurring?
Regeneration
- Macrophages replace neutrophils
- Granulation tissue invades the space
- Epithelial cell proliferation thickens the epidermal layer
- Epidermal cells undermine the scab which then falls off
- Activated fibroblasts produce collagen
- Angiogenesis progresses
What happens in healing by primary intention after 7-10 days of the wound occurring?
Early scarring
- The wound is filled with granulation tissue
- The fibroblasts proliferate and deposit collagen fibres which form a fibrous mass
- The epidermis normalises and keratinises
- Skin appendages don’t form
- White cell infiltrate, oedema and increased vascularity disappear
- Regression of vascular channels
What happens in healing by primary intention after 1 month to 2 years of the wound occurring?
Scar maturation
- The scar is a mass of fibrous tissue with many collagen fibres, few cells and few vessels
- It also has few elastic fibres and therefore little recoil
- As capillaries disappear, old scars appear white (new scars are pink)
When is healing by secondary intention seen?
In excisional wounds or wounds with tissue loss and separated edges
- Also seen in infected wounds (but this delays healing)
What is the process of healing by secondary intention?
- The open wound is filled by abundant granulation tissue, which grows in from the wound margins
- There is a larger clot and more necrotic debris, so the inflammatory reaction is more intense than in primary intentions
- Considerable wound contraction must take place to close the defect
- Initially this occurs as the scab contracts when it dries and shrinks
- After about a week, myofibroblasts appear and contract
- This draws the margins into the centre
What does the final shape of a scar depends on?
The original shape of the wound
What are some characteristics of healing by secondary intention
- New epidermis is often thinner than usual
- Substantial scar formation is seen
What local factors influence the efficacy of healing and repair?
- Size, location and type of wound (indicates if healing is be primary or secondary intention and if regeneration or scarring will occur)
- Blood supply (areas with high vascularity heal well)
- Denervation (impairs healing)
- Foreign bodies (produce persistent inflammation and favour infection)
- Local infection (produces persistent tissue injury and inflammation)
- Haematoma (can slow healing if large and persistent)
- Necrotic tissue (can slow healing if there is lots)
- Mechanical stress (can pull apart deliate tissue in the early stages of healing)
- Protection
- Surgical techniques
- Radiation damage
What systemic factor
- Age (children heal quickly, elderly more slowly)
- Anaemia, hypoxia and hypovolaemia (poorer O2 delivery to healing tissues)
- Obesity (can cause increased tension on wounds)
- Diabetes *decreased resistance to infection)
- Malignancy
- Genetic disorders
- Drugs
- Vitamin deficiency (vitamin C deficiency inhibits collagen synthesis)
- Malnutrition (lack of essential substances for protein synthesis)
How can drugs influence the efficacy of healing and repair?
- Steroids: inhibit collagen synthesis
- Cytotoxics: antimitogenic and impair cell proliferation and healing
- Antibiotics: treat bacterial infections, reducing inflammation and speeding up healing
What are some complications of fibrous repair?
- Delayed healing due to local/systemic factors
- Formation of fibrous adhesions, compromising organ function (also by blocking tubes)
- Loss of function due to replacement of specialised functional parenchymal cells by non-functioning scar tissue
- Disruption of complex tissue relationships within an organ
- Overproduction of fibrous scar tissue (keloid scar)
- Excessive scar contraction causing obstruction of tubes
- Disfiguring scars following burns or joint contractures
What is a keloid scar?
Overproduction of fibrous scar tissue
- Due to an overproduction of collagen that exceeds the borders of the scar
- Don’t regress and excision just creates another
- More common in Afro-Carribbeans
What is the regenerative capacity of cardiac muscle?
Very limited, if any
- MI is followed by scar formation
- This can compromise cardiac function
What is the regenerative capacity of the liver?
A remarkable capacity
- If part of the liver is removed, compensatory growth of liver tissue occurs
How is liver mass restored?
By enlargements of the lobes that remain
- Almost all hepatocytes replicate during regeneration
- This is followed by replication of non-parenchymal cells
How does a peripheral nerve repair after being severed?
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 them back to the tissue that the nerve innervates
- Axon growth occurs at approximately 1-3 mm/day
What is the regenerative capacity of cartilage?
Does not heal well, since it lacks:
- Blood supply
- Lymphatic drainage
- Innervation
How does the CNS cope with tissue damage within it?
- Neural tissue is a permanent (non-proliferative) tissue
- So the neural tissue is replaced by proliferation of CNS supportive elements (glial cells)
What is intracrine signalling?
A type of autocrine signalling
- The cell synthesises a factor which has an effect by binding to intracellular receptors within the cell
What is Wallerian degeneration?
- Degeneration of severed axons
- Distally to the lesion there is degeneration of the axon, proximally new axons are sprouted
