MoD - Healing And Repair Flashcards
What is meant by the term labile tissues?
Give some examples
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
What is meant by the term stable tissues?
Give some examples
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
What is meant by the term permenant tissues?
Give some examples
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
What are stem cells?
What is asymmetric replication?
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
What is the difference between embryonic stem cells and adult stem cells?
Embryonic stem cells = totipotent
Adult stem cells = unipotent
What is meant by the terms:
Totipotent
Unipotent
Multipotent
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
Describe how liver cells heal.
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.
What happens when there is damage to a permanent tissue? E.g. Neurones, skeletal and cardiac myoctyes
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)
When does fibrous repair occur?
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.
How does fibrous repair differ from regeneration?
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
Describe fibrous repair
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
What cell types are involved in fibrous repair?
Fibroblasts and myofibroblasts - synthesise collagen and cause wound contraction
What is angiogenesis?
Proliferation of endothelial cells which results in small capillaries that grow into the area
What cells are involved in granulation tissue?
What does this cause?
Fibroblasts and myofibroblasts that synthesise collagen
Causes wound contraction
What is essential to the fibrous repair process?
Synthesis of collagen
What are the types of collagen?
What type of collagen is most common in the body?
Where is it found?
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)
What cells synthesise collagen?
Describe collagen synthesis
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)
What gives collagen its tensile strength?
Considerable cross linking between molecules
What is the difference between regeneration and repair?
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
How is collagen made up?
Triple helix of three polypeptide alpha chains with repeating Gly-X-Y sequence.
Name four diseases that are as a result of defective collagen synthesis
Scurvy
Ethers-Danlos syndrome
Osteogenesis imperfecta
Alport syndrome
What is scurvy?
What are the effects?
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
What is Ethlers-Danlos syndrome?
What are the effects?
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.
What is osteogenesis imperfecta? (Brittle bone diesase)
What is its inheritance?
What are the effects? And why?
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
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?
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
How do cells communicate in regeneration and repair?
Cell to cell communication via local mediators (growth factors)
Hormones
Direct cell to cell or cell-stroma contact
What are the ways in which cells can communicate via local mediators and hormones?
Describe each.
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
Define autocrine.
Autocrine- cells respond to the signalling molecules that they themselves produce
Define paracrine.
Paracrine - cells produces the signalling molecule that acts on adjacent cells. Responding cells are close to secreting cell but usually a different type
Define endocrine
Endocrine - hormones are synthesised by cells in an endocrine organ, conveyed in the blood stream to target cells to effect physiological activity
What are growth factors?
How are they coded?
Polypeptides that act on specific cell surface receptors
Coded for by proto-oncogenes
What effect can growth factors have?
How do they work?
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
Name 4 growth factors
What does each one do?
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.
What is contact inhibition?
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
How do cells adhere to each other and ECM?
What are they called?
Proteins on the cell membranes called adhesion molecules
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?
Cadherins
Integrins
Contact inhibition and wound healing
What are the two classifications of wound healing?
What is it dependent on?
Primary intention wound healing
Secondary intention wound healing
Dependent on size of the wound and amount of tissue that has been lost
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?
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
What is the process of primary intention wound healing?
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
What is the function of the extracellular matrix?
Support and anchor cells Separate tissue compartments Sequester growth factors Allow communication between cells Facilitate cell migration
What makes up the extracellular matrix?
Matrix glycoproteins - organise and orientate cells, support cell migration
Proteoglycans - matrix organisation, cell support , regulate availability of growth factors
Elastin - provide tissue elasticity
What controls fibrous repair?
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
What are you at risk of with primary intention healing?
Infection –> abscess
When does secondary intention wound healing occur?
Infarct, ulcer, abscess or any large wound
What are the differences between primary and secondary wound healing?
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.
How do bone fractures repair?
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
What are the local factors influencing healing and repair?
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
What are the systemic factors influencing healing and repair?
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
Why would steroids decrease healing?
Why would antibiotics increase healing?
Inhibit collagen synthesis
Treat bacterial infections, reduce inflammation, can speed up healing
What are the complications of fibrous repair?
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)
What is the difference between hypertrophic scar to keloid scar?
Hypertrophic - raises out of the skin
Keloid - raises up from skin and exceeds boarders of scar
What is a keloid scar?
Who are they common in?
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
What is meant by the term regeneration/resolution?
What does regeneration require?
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
How does repair occur in cardiac muscle?
Very limited, if any, regeneration capacity
Myocardial infarction –> scar formation
How does liver tissue heal/repair?
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
How does a peripheral nerve repair?
What cells are involved?
What is the axon growth rate?
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
What does cartilage lack in order for it to repair?
Does not heal well as it lacks
blood supply
Lymphatic drainage
Innervation
How does the CNS repair?
What type of tissue is it?
What cells are involved?
CNS tissue is a permanent (non proliferative tissue)
When damage occurs the neural tissue is replaced by proliferation of CNS supportive elements.
Glial cells
