MOD 5 Healing and Repair Flashcards
What is fibrous repair?
The replacement of functional tissue by scar tissue
What is regeneration?
The replacement of dead or damaged cells by functional, differentiated cells
What are differentiated cells derived from?
stem cells
What happens to daughter cells of proliferated stem cells?
Either remain as a stem cell to maintain stem cell pool or differentiates to a specialised cell type
What are the functions of stem cells?
In early life differentiate into many different cell types
Internal repair system to replace lost or damaged cells in tissues
Therapeutic utility in degenerative disease
What does unipotent mean?
Can only produce one type of differentiated cell e.g. epithelia
What does multipotent mean?
Can produce several types of differentiated cell e.g. haematopoietic
What does totipotent mean?
Can produce any type of cell e.g. embryonic stem cells
What are labile cells?
Continuously cycling cells whose normal state is active cell division
Usually rapid proliferation
e.g epithelial or haematopoietic cells
What are stable cells?
Cells who go into a resting state G0 after mitosis
They have varying speeds of regeneration
e.g. hepatocytes, osteoblasts, fibroblasts
What are permanent cells?
Cells that are unable to divide and regenerate
e.g neurones, cardiac mycocytes
What factors control regeneration?
Growth factors
Contact between basement membranes and adjacent cells
What do growth factors do?
Promote proliferation in stem cell population
Extracellular signals transduced into cell
Promote expression of genes controlling the cell cycle
What are examples of growth factors?
Proteins e.g. EGF, PDGF, FGF
Hormones e.g. oestrogen, testosterone, growth hormone
Autocrine, paracrine and endocrine signals from many cell types e.g inflammatory, mesenchymal
Some cytokines
How does contact between adjacent cells and basement membranes affect growth?
Signalling through adhesion molecules Inhibits proliferation in intact tissue 'Contact inhibition' Loss of contact promotes proliferation These mechanisms deranged in cancer
What are the key components of fibrous repair?
Cell migration
Blood vessels- angiogenesis
Extracellular matrix production and remodelling
What inititates fibrous repair?
The formation of granulation tissue
What kind of cells migrate to the area?
Inflammatory cells
-Phagocytosis of debri: neutrophils, macrophages
Chemical mediators: lymphocytes, macrophages
Endothelial cells: angiogenesis
Fibroblasts/ Myofibroblasts: ECM proteins e.g. collagen, wound contraction
What is angiogenesis?
The development of a blood supply to the wound
Why is a blood supply needed for wound healing to occur?
Provides acces for inflammatory cells and fibroblasts
Delivery of oxygen and other nutrients
What is endothelial proliferation induced by?
proangiogenic growth factors like VEGF
What are the steps in angiogenesis?
- Endothelial proteolysis of basement membrane
- Migration of endothelial cells via chemotaxis
- Endothelial proliferation
- Endothelial maturation and tubular remodelling
- Recruitment of periendothelial cells
What is the function of the extracellular matrix?
Supports and anchors cells Separates tissue compartments e.g basement membrane Sequesters growth factors Allows communication between cells Facilitates cell migration
What type of collagen is in the basement membrane?
IV
Give an overview of collagen synthesis
Polypeptide alpha chains made in ER
Enzymatic modification steps including vitamin C dependent hydroxylation
Alpha chains align and cross link to form procollagen triple helix
Soluble procollagen secreted
Procollagen cleaved to give tropocollagen
Tropocollagen poymerises to form fibrils
Bundles of fibrils form fibres which undergo slow remodelling by specific collagenases
Give some defects of collagen synthesis
Scurvy
Ehlers-Danlos Syndrome
Osteogenesis imperfecta
Alport syndrome
What do matrix glycoproteins do?
Organise and orientate cells, support cell migration
Fibronectin, laminin, tenascin
What do proteoglycans do?
Matrix organisation, cell support, regulate growth factor availability
e.g Heparan sulphate proteoglycan
What does elastin do?
Provide tissue elasticity
What is the rabbit ear chamber model?
An experiment done where plastic chamber surgically inserted into ear of lop eared rabbit
Thin tissue bed develops between the layers of the chamber enabling in vivo microscopic visualisation of healing and repair
What are the first steps after a wound has occurred?
Blood clot forms
Acute inflammation occurs around the edges: neutrophils infiltrate and digest clot
Chronic inflammation: macrophages and lymphocytes migrate into clot
What us the blood clot replaced by?
Granulation tissue
What are the next steps after macrophage and lymphocyte infiltration?
Angiogenesis- capillaried and lymphatics sprout and infiltrate
Myo/fibroblasts migrate and differentiate
The myo/fibroblasts synthesis collagen and an extracellular matrix is produced
Macrophage numbers reduce
What happens in maturation of a wound?
Comparatively long lasting Cell population falls Collagen increases, matures and remodels Myofibroblasts contract reducing wound volume Vessels differentiate and are reduced Left with fibrous scar
How are inflammatory cells recruited?
chemotaxis
How is angiogenesis controlled?
Platelets, ECM and others produce angiogenic cytokines in response to hypoxia e.g VEGF and bFGF
How is fibrosis controlled?
Macrophages produce various pro-fibrotic cytokines e.g IL1, TNF alpha
Fibroblast proliferation and ECM production
What type of wound heals by primary intention?
An incised wound with apposed edges
What is the process of healing by primary intention?
Minimal clot and granulation tissue
Epidermis regenerates
Dermis undegoes fibrous repair
Sutured- sutures removed after approx 10 days (10% original strength)
Transition from granulation tissue to scar tissue
Maturation of scar taking up to 2 years
Minimal contraction and scarring, good strength
What is there a risk of in healing by primary intention?
Trapping infection-abscess
What type of wounds heal by secondary intention?
Infarct, ulcer, abscess or any large wound
What is the process of healing by secondary intention?
Unapposed edges Large clot dries to form scab/eschar Epidermis regenerates from base up Much more granulation tissue produced More contraction to reduce volume of defect Larger scar produced
What are the differences between primary intention healing and secondary intention healing?
More granulation tissue in secondary
Eschar produced in secondary
Unapposed edges, more contraction and larger scar produced in secondary
Secondary takes longer
Give an overview of fracture repair?
HAEMATOMA forms from ruptured vessels within marrow cavity and periosteum
SOFT CALLUS forms as haematoma organises and there is an ingress of macrophages, endothelial cells, fibroblasts and osteoblasts
HARD CALLUS forms as bone is laid down in an irregular woven pattern sometimes with islands of cartilage
REMODELLING occurs as woven bone gradually replaced by lamellar bone which is remodelled to shape in the direction of mechanical stress
What happens when cardiac muscle is injured?
Fibrosis occurs
What happens when there is liver injury?
Acute damage->regeneration
Chronic damage->cirrhosis
Liver hepatocytes have some regenerative capacity but the architecture cannot regenerate. The imbalance that occurs between these leads to nodules and cirrhosis
What occurs in Wallerian degeneration?
Nerve axons have been cut and there is corresponding atrophy in the muscle and degeneration of distal axons
Proximal nerve terminals send sprouts towards the schwann cell tubes
Some of the sprouts make it into the tubes and reinnervate the muscle which has undergone neurogenic rearrangement
Where does Wallerian degeneration occur?
Peripheral nervous system
What happens when there is damage to the CNS
The CNS has no regenerative capacity
Gliosis occurs where astrocytes enlarge and proliferate to form a glial scar which blocks axonal growth
Does skeletal muscle regenerate?
The muscle cells can’t proliferate but some regeneration can occur due to differentiation of satellite cells
What local factors can affect wound healing?
Type size and location Apposition and lack of movement Blood supply Infection Foreign material Radiation damage
What general factors affect wound healing?
Age Drugs and hormones Dietary deficiencies General health General CVS health
What are some complications of wound healing?
Insufficient fibrosis- hernia, wound dehiscence, ulceration. Found in elderly, obese, malnutrition etc,
Excessive fibrosis- keloid, excessive scarring, lung fibrosis, cirrhosis
Excessive contraction- occluding channels(strictures), limiting movement (contractures)
