MoD session 4: regeneration and repair Flashcards
What is regeneration?
Growth of cells and tissues to replace lost structures
Examples of cells that can regenerate
Epithelia of the skin and GI tract, as long as the stem cells aren’t destroyed
Labile tissues?
Cells constantly dividing throughout life replacing cells that are destroyed. Normal state: G1-M-G1. Rapid proliferation. Cells short-lived, constantly replaced by cells derived from stem cells
E.g. surface epithelia, mucosa lining secretory ducts of glands,cells of bone marrow
Stable tissues?
Low level of replication but cells can rapidly divide in response to stimuli and can reconstruct the tissue of origin. Resting state: G0, activated to replicate sometimes. Mature, usually quiescent or v slow but can divide persistently when required
E.g. parenchymal cells of liver/kidneys/pancreas, mesenchymal cells e.g. fibroblasts, WBCs, vascular endothelial cells, osteoblasts
Permanent tissues?
Non-dividing (stuck in G0). Cells have left the cell cycle and can’t undergo mitosis. No stem cells that can be recruited to replace.
E.g. neurones, skeletal muscle, cardiac muscle
Different types of stem cell?
Totipotent: can divide into any cell type. Found in zygotes (give rise to entire organism)
Pluripotent: can divide into any cell type. In embryonic stem cells
Multipotent: can produce several types of differentiated cells from within their lineage e.g. haematopoietic cells
Unipotent: can only give rise to one type of cell
Describe fibrous repair (organisation)
- Phagocytosis of necrotic tissue debris
- Angiogenesis
- Wound contraction (FBs and MFBs synthesise collagen producing granulation tissue)
- Granulation tissue becomes less vascular and starts to form fibrous scar
- Scar matures and shrinks due to fibril contraction in MFBs, fewer vessels, more collagen, fewer cells
Growth factors?
Most important local mediators, act over a short distance.Bind to specific receptors to stimulate transcription of genes that regulate the entry of the cell into the cell cylce and its passage through.
Effects: stimulate/inhibit proliferation, differentiation, cell locomotion, contractility, angiogenesis and others
Epidermal growth factor?
Mitogenic for epithelial cells, hepatocytes and fibroblasts. Binds to EDGFR. Produced by keratinocytes, macrophages and inflammatory cells
Vascular endothelial growth factor?
Induces vasculogenesis and role in angiogenesis in wound healing and tumours
Platelet-derived growth factor?
Stored in platelet alpha granules and released on platelet activation. Also produced by macrophages, endothelial cells, smooth muscle cells and tumours.
Causes migration and proliferation of FBs, smooth muscle cells and monocytes
Tumour necrosis factor?
Induces FB migration and proliferation and collagenase secretion
What is contact inhibition?
When normal cells are isolated they replicate until they have cells touching them: so form a monolayer sheet with no overlap
Loss of contact promotes proliferation e.g. in wound healing
This quality is altered in neoplasia
How do cells adhere?
By adhesion molecules:
- to each other by CADHERINS
- to the ECM by INTEGRINS
Scenario for healing by primary intention?
Clean wounds with apposed edges & minimal tissue loss. Disrupted basement membrane continuity, only a few cell deaths, minimal granulation tissue
E.g. in incisional, non-infected and sutured wounds
Describe the process of healing by primary intention
- s-min: haemostasis and scab (dehydration of surface clot)
- m-hours: acute inflammation
3.
Risk of healing by primary intention?
Infection gets trapped–>abscess
How do the epidermis and dermis regenerate in primary intention healing?
Dermis undergoes fibrous repair
Epidermis regenerates from superficial to deep
Scenario for healing by secondary intention
Excisional wounds or wounds with tissue loss and separated edges (unapposed). Takes longer
Often in infected wounds, infarcted areas, ulcers or abscesses
Process of healing by secondary intention
- Open wound has lots of granulation tissue growing inwards from wound margins
- Big inflammatory reaction (clots and necrotic cells)
- Scab contracts and shrinks
- Substantial scar formation, new epidermis often thinner
Risk of healing by secondary intention?
Extensive collagen deposition can cause a big scar and deformity–>more contraction
Describe the bone healing process
- Following fracture a HAEMATOMA forms around the injury (rupture of vessels in marrow cavity and periosteum)
- SOFT CALLUS at ~1w: not for weight-bearing but splints the fracture on the outside as extends beyond the injury, sometimes has islands of cartilage
- HARD/BONY CALLUS after several weeks. Laid down by osteoblasts; initially woven bone then more organised & stronger lamellar bone
- REMODELLING of bone in response to mechanical stresses. Bone that is not physically stressed gets resorbed
Give some local factors that can affect wound healing
Size/location/type of wound-indicates type of healing
Blood supply-atherosclerosis and low vascularity impede healing
Denervation
Local inflammation
Foreign bodies-persistent inflammation, favour infection
Haematoma-large can slow healing
Necrotic tissue-body needs to clear
Mechanical stress-can pull apart delicate tissue
Protection-e.g. dressings help keep clean
Surgical techniques-can promote rapid healing
Infection-supparation (pus), gangrene, systemic
Give some systemic factors that can affect wound healing
Age
Anaemia/hypoxia/hypovolaemia
Obesity (more tension on wound and wound dehiscence)
Malignancy
Diabetes (microangiopathy impairs blood and decreases infection resistance)
Genetic disorders
Drugs (steroids, cytotoxics decrease, antibiotics increase healing)
Vitamin deficiency-e..g vit C deficiency decreases collagen synthesis
Malnutrition-lack of essential substances e.g. amino acids for protein synthesis
Other co morbidities e.g. RA, cardiovascular disease
State the possible complications of fibrous repair
Fibrous adhesions-block tubes or compromise organs
Loss of function-replacement of cells by collagenous scar tissue
Disrupted tissue architecture
Keloid scar
Excess scar contraction
Insufficient fibrosis-causes wound dehiscence
Healing in cardiac muscle?
Limited/no regeneration
MI results in a scar that doesn’t heal; can compromise function
Liver healing?
High regenerative capacity: if part of the liver is removed, compensatory liver tissue growth occurs via enlargement of the lobes that remain
What is Wallerian degeneration?
Axon degeneration when a nerve is severed
Peripheral nerve healing?
Proximal stumps of degenerated axons sprout and elongate. Schwann cells guide them back to the tissue the nerve innervates
How fast do peripheral nerves grow?
1-3mm per day
Cartilage healing?
Heals poorly: lack of blood supply, lymphatic drainage and innervation
CNS healing?
Neural tissue is permanent. When neural tissue is damaged it is replaced by glial cells
Scurvy?
Vitamin C deficiency results in symptoms including swollen/bleeding gums, peripheral skin haemorrhage and susceptibility to bruising.
Vitamin C is a cofactor for prolyl hydroxylase which is used in the production of hydroxyproline from proline in collagen synthesis
Ehlers-Danlos syndrome?
Fragile connective tissue due to disrupted collagen synthesis.
Symptoms: bruising, dissecting aortic aneurysm, joint laxity, hernias, hyperelasticity of skin
Osteogenesis imperfecta?
Inborn error of type I collagen synthesis. Dominant or recessive
Type I collagen most abundant in bone, so disease causes skeletal weakness and deformity, fracture susceptibility and blue sclerae (as they are thinned)
Marfans syndrome?
Defect in the gene for fibrillin (a protein essential for elastic fibre integrity)
Signs: unusually tall, long arm span, dislocation of eye lenses, aortic and mitral valve incompetence, weakness of aortic media, predisposed to dissecting aneurysms
Alport syndrome?
Genetic abnormality in type IV collagen, so glomeruli are abnormal. Blood not filtered properly so protein and blood pass into the urine
Causes kidney disease, hearing loss and eye abnormalities
Liver cirrhosis?
Presence of fibrous septa that subdivide the parenchyma into nodules.
Is the end stage of all chronic liver disease
Irreversible
Associated with symptoms of liver failure + portal hypertension
Coal worker’s pneumocconiosis?
Coal dust phagocytosed by alveolar macrophages and aggregates around the bronchioles. Black pigment seen in lungs. Can be asymptomatic or cause large irregular nodules which may contract leading to emphysema and lung disruption
Keloid scar?
Excess proliferation of fibroblasts and excess collagen production, that moves outside the borders of an injury/scar. Often raised
Does not regress, and excision will just create another one. Different from a hypertrophic scar as moves outside the boundary of the wound
Common in Afro-Caribbean individuals
Oesophageal strictures?
Narrowing or tightening of the oesophagus due to inflammation/fibrosis/neoplasia/lymph node enlargement/diseases affecting oesophageal smooth muscle
Contractures?
Tissue distortion resulting in permanent shortening of a muscle. Excess contraction of the wound during healing
Traumatic neuroma?
Growth of nerve tissue due to acute or chronic nerve injury, especially happens after surgery
Causes a focal area of pain tender on palpation with a firm skin nodule
What is ‘proud flesh’?
Excess persistent granulation tissue above the surface of the skin that blocks re-epithelialisation
What is a pressure sore?
Area of persistently red, broken, blistered or necrotic skin. Commonly over bony prominences such as the sacrum. Common in bed-bound patients due to pressure and friction.
