Lesson 4 Flashcards
What is the underlying principle of wound healing?
- Close the gap
- Repair it with a scar
- The smaller the scar the better
What process are involved in wound healing?
- Haemostasis – as vessels are open
- Inflammation – as there has been tissue injury
- Regeneration (resolution, restitution) and/or repair (organisation) – as structures have been injured or destroyed
What is the difference between an abrasion and an ulcer?
Abrasion superficial scrapes
Ulcers - deeper ‘gouges’/more superficial injury by bacteria or other pathogen
Which cells replicate in regeneration?
New differentiated cells are mainly derived from stem cells (many terminally differentiated cells can’t divide)
What are stem cells?
- Prolonged proliferative activity
- Show asymmetric replication
- ‘Internal repair system’ to replace lost or damaged cells in tissues
Whereabouts in the tissues are the stem cells?
- Epidermis – basal layer adjacent to the basement membrane
- Intestinal mucosa – bottom of crypts
- Liver – between hepatocytes and bile ducts
What are the three types of stem cells?
Unipotent
Multipotent
Totipotent
Explain unipotent cells
Most adult stem cells
Only produce one type of differentiated cell, e.g. epithelia
Describe multipotent cells
Produce several types of differentiated cell
e.g. haematopoietic stem cells
Describe totipotent cells
- Embryonic stem cells
* Can produce any type of cell and therefore any tissues of the body
Can all tissues regenerate?
No depends where the tissues are:
Labile tissues - surface epithelia, haematopoietic tissues
Stable tissues - liver parenchyma, bone, fibrous tissue
Permanent tissues - neural tissue, skeletal/cardiac muscle
What are examples of Labile tissues?
Surface epithelia, haematopoietic tissues
What are examples of Stable tissue?
Liver parenchyma, bone, fibrous tissue, endothelium
What are examples of Permanent tissues?
neural tissue, skeletal muscle, cardiac muscle
In what circumstances can regeneration take place?
- If the damage occurs in a labile or stable tissue
- If the tissue damage is not extensive
- Regeneration requires an intact connective tissue scaffold
What is fibrous repair (organisation) and when does it occur?
- Healing with formation of fibrous connective tissue = scar
- Specialised tissue is lost
- Healing by secondary intention
- Occurs with:
- Significant tissue loss
- If permanent or complex tissue is injured
How does a scar form?
- Seconds - minutes: haemostasis
- Minutes - hours: acute inflammation
- 1-2 days: chronic inflammation
- 3 days: granulation tissue forms
- 7-10 days: early scar
- Weeks – 2 years: scar maturation
What is granulation tissue?
- Has a granular appearance and texture
- Consists of:
- Developing capillaries
- Fibroblasts and myofibroblasts
- Chronic inflammatory cells
- Functions:
- Fills the gap
- Capillaries supply oxygen, nutrients and cells
- Contracts and closes the hole
State the steps of fibrous repair?
- Blood clots
- Neutrophils infiltrate/digest clot
- Macrophages/lymphocytes are recruited
- Vessels sprout, myo/fibroblasts make glycoproteins
- Vascular network, collagen synthesised, macrophages reduced
- Maturity, cells reduced, collagen matures, contracts/remodels
Which cells are involved fibrous repair?
• Inflammatory cells
–Phagocytosis of debris – neutrophils, macrophages
–Production of chemical mediators – lymphocytes, macrophages
• Endothelial Cells
–Proliferation results in angiogenesis
• Fibroblasts and myofibroblasts
–Produce extracellular matrix proteins, e.g. collagen
– Responsible for wound contraction - contraction of fibrils within myofibroblast
What is collagen?
- Most abundant protein in animals, 28 different types known numbered in order of discovery
- Accounts for almost a third of mammalian body’s proteins
- Provides extracellular framework for all multicellular organisms
- Composed of triple helices of various polypeptide alpha chains, rope-like appearance
- Fibrillar collagens: I – III, responsible for tissue strength
- Amorphous collagens: IV-VI, e.g. basement membrane
Where is type 1 collagen found?
- Type I most common, found in hard and soft tissues:
* Bones, tendons, ligaments, skin, sclera, cornea, blood vessels, hollow organs
Where is Type IV collagen found?
•Type IV makes up basement membranes • Secreted by epithelial cell
How are fibrillar collagens made?
- Whole process takes 1-2 hours
- Polypeptide alpha chains synthesised in ER of fibroblasts and myofibroblasts
- Enzymatic modification steps including vitamin C dependent hydroxylation
- Alpha chains align and cross-link to form procollagen triple helix
- Soluble procollagen is secreted
- After secretion procollagen cleaved to give tropocollagen
- Tropocollagen polymerises to form microfibrils and then fibrils
- Bundles of fibrils form fibres
- Cross-linking between molecules produces tensile strength
- Slow remodelling by specific
What diseases are the result of defective collagen synthesis?
Acquired • Scurvy Inherited • Ehlers-Danlos syndrome • Osteogenesis imperfecta • Alport syndrome
Describe scurvy
- Vitamin C Deficiency
- Inadequate vitamin C dependent hydroxylation of procollagen alpha chains leads to reduced cross-linking and defective helix formation
- Lacks strength, vulnerable to enzymatic degradation
- Particularly affects collagens supporting blood vessels
What is the impact of scurvy on the body?
- Unable to heal wounds, tendency to bleed
- Tooth loss
- Collagen in periodontal ligament has short half life and normal collagen is replaced by defective collagen
- Old scars break down and open up as fresh wounds
- Collagen turnover in scars remains high long after healing process appears clinically complete
Describe Ehlers-Danlos syndrome
- Heterogeneous group of 13 subtypes of inherited disorders
- Defective conversion of procollagen to tropocollagen
- Collagen fibres lack adequate tensile strength
- Wound healing poor
- Skin - hyperextensible, thin, fragile and susceptible to injury
NB. Skin can recoil because elastic fibres are normal, it is just missing the tethering effect of normal collagen fibres
Where does Ehlers-Danlos syndrome effect the body?
- Joints – hypermobile, predisposition to joint dislocation
- In some forms:
- Rupture of colon, large arteries or cornea
- Retinal detachment
- ‘Rubber people’
Describe osteogenesis imperfecta
- = brittle bone disease, Lobstein’s disease
- Too little bone tissue -> extreme skeletal fragility
- Affected people - avoid mechanical stress
- Some develop severe, progressive deformation of long bones
- Blue sclerae – too little collagen within them, translucent
- Hearing impairment/dental abnormalities
Describe Alpert syndrome
- Usually X-linked disease -> patients usually male
- Type IV collagen abnormal
- Dysfunction of glomerular basement membrane, cochlea of ear and lens of eye
- Presents with haematuria in children/adolescents progressing to renal failure
- Also neural deafness and eye disorders
How are regeneration and repair triggered and controlled?
- Complex/poorly understood processes
- Cells communicate with each other to produce a proliferative response
- Cell to cell signalling can be via:
- Hormones
- Local mediators (e.g., growth factors)
- Direct cell-cell or cell-stroma contact
What are growth factors?
- Particularly important in wound healing
- Polypeptides that act on cell surface receptors
- Coded by proto-oncogenes
- ‘Local hormones’
- Bind to specific receptors, stimulate transcription of genes that regulate entry of cell into cell cycle and the cell’s passage through it
Apart from cell proliferation, what other effects can growth factors have?
- Inhibition of division
- Locomotion
- Contractility
- Differentiation
- Viability
- Activation
- Angiogenesis
What are examples of growth factors?
- Epidermal growth factor
- Vascular endothelial growth factor
- Platelet derived growth factor
- Tumour necrosis factor
- Produced by cells such as platelets, macrophages, endothelial cells
- NB: Names can be obsolete or misleading!
What is the role of cell-cell and cell-stroma contact?
Contact inhibition
– Signalling through adhesion molecules
– Cadherins bind cells to each other
– Integrins bind cells to the extracellular matrix
Inhibits proliferation in intact tissue, promotes proliferation in damaged tissues
Altered in malignant cells
What is meant by healing by primary intention and healing by secondary intention?
- Descriptions of wound healing related to the size of the wound and the amount of lost tissue
- Most often used for skin wounds
What is healing by primary intention?
- Incised, closed, non-infected and sutured wounds
- Disruption of basement membrane continuity but death of only small number of epithelial and connective tissue cells
- Minimal clot and granulation tissue
What occurs in healing by primary intention?
- Epidermis regenerates
- Dermis undergoes fibrous repair
- Sutures out at about 10 days - approximately 10% normal strength
- Minimal contraction & scarring, good strength
What is healing by secondary intention?
- Excisional wound, wounds with tissue loss and separated edges, infected wounds, e.g., infarct, ulcer, abscess
- Open wound filled by abundant granulation tissue – grows in from wound margins
How does bone heal?
- Haematoma: fills gap and surrounds injury
- Granulation tissue forms: cytokines activate osteoprogenitor cells
- Soft callus: at 1 week, fibrous tissue and cartilage within which woven bone forms
- Hard callus: after several weeks, initially woven bone – weaker and less organised than lamellar bone but can form quickly
- Lamellar bone: replaces woven bone, remodelled to direction of mechanical stress, bone not stressed is resorbed and outline is re-established
What are the four stages of bone healing?
Haematoma -> soft callus -> hard callus -> remodelling
What things can influence wound healing?
Local factors:
- Type, size, location of wound
- Mechanical stress
- Blood supply
- Local infection
- Foreign bodies
What things can influence wound healing?
General Factors:
- Age
- Anaemia, hypoxia and hypovolaemia
- Obesity
- Diabetes
- Genetic disorders
- Drugs
- Vitamin deficiency
- Malnutrition
What are the complications of fibrous repair?
•Insufficient fibrosis
• Wound dehiscence, hernia, ulceration
• For example obesity, elderly, malnutrition, steroids
•Formation of adhesions
• Compromising organ function or blocking tubes
e.g., intestinal obstruction following abdominal surgery
•Loss of function
• Due to replacement of specialised functional parenchymal cells by scar tissue
e.g., healed myocardial infarction with non-contracting area of myocardium
• Disruption of complex tissue relationships within an organ
• Distortion of architecture interfering with normal function
e.g., liver cirrhosis
• Overproduction of fibrous scar tissue
• Keloid scar
• Excessive scar contraction
• Can cause obstruction of tubes, disfiguring scars following burns or joint contractures (fixed flexures)
