Flashcards in 4. Healing and repair Deck (44)
Which 3 processes are involved in wound healing?
1. haemostasis (as vessels are open)
2. inflammation (as tissue injury)
3. regeneration/resolution and repair/organisation (as structures injured or destroyed)
What is regeneration?
Restitution - growth of cells and tissues to replace lost structures - with no, or minimal, evidence of previous injury.
(healing by primary intention)
What is the difference between an abrasion and an ulcer?
Abrasion = loss of epidermis and a few cells of dermis
Ulceration = deep abrasion also affecting submucosa
Which cells replicate during regeneration to replace lost cells?
Stem cells used to replace terminally differentiated cells as many terminally differentiated cells can't divide.
What are stem cells?
1. prolonged proliferative activity
2. show asymmetric replication (1 daughter cell remains a stem cell, 1 differentiates into mature non-dividing cell)
Where in tissues are stem cells located?
Varies between tissues
- epidermis: basal layer adjacent to basement membrane
- intestinal mucosa: bottom of crypts of Lieberkuhn (move up crypts as they mature)
- liver: between hepatocytes and bile ducts
What is the difference between adult and embryonic stem cells?
Adult: mostly unipotent, some multipotent
What is the difference between unipotent, multipotent and totipotent stem cells? Give an example of each.
- embryonic stem cells
- can produce any cell type and thus any tissues of the body
- produce several types of differentiated cell
- e.g. haematopoietic stem cells
- only produce 1 type of differentiated cell
- most adult stem cells, e.g. epithelia
How are tissues grouped according to proliferative activity?
1. labile tissues
- e.g. surface epithelia, haematopoietic tissues
- short-lived cells replaced by cells derived from stem cells that are continuously dividing/proliferating
2. stable tissues
- e.g. parenchyma of liver, kidneys and pancreas, mesenchymal cells such as fibroblasts, bone osteoclasts, smooth muscle cells, vascular endothelial cells, resting lymphocytes and other white blood cells
- normally low levels of replication but cells (in G0) can undergo rapid proliferation in response to stimuli and can reconstruct tissue of origin
- both stem cells and mature cells proliferate
3. permanent tissues
- e.g. neural tissue, skeletal muscle, cardiac muscle
- mature cells that have left the cell cycle
- no or only a few stem cells present to replace cells
In what type of injury does regeneration occur as a healing process?
1. damage occurs in labile or stable tissue
2. tissue damage is not extensive - superficial abrasion - as requires intact connective tissue scaffold
What is fibrous repair/organisation?
Healing with formation of fibrous connective tissue (scar). Specialised tissue is lost.
(healing by secondary intention)
In what type of injury does fibrous repair occur as a healing process?
1. significant tissue loss with destruction of collagen framework
2. permanent or complex tissue (specialised parenchymal cells that cannot be replaced) is injured (e.g. whole kidney glomerulus)
3. on-going chronic inflammation
Describe the process of fibrous repair/scar formation.
1. Haemostasis (secs-mins):
- blood clots
2. Acute inflammation (mins-hrs):
- neutrophils infiltrate and digest clot
3. Chronic inflammation (1-2 days):
- macropages and lymphocytes are recruited - phagocytosis of necrotic tissue debris
4. Granulation tissue forms (3 days):
- BVs sprout
- myo/fibroblasts make glycoproteins
5. Early scar formation (7-10 days)
- angiogenesis (proliferation of endothelial cells resulting in small capillaries that grow into area)
- myo/fibroblasts synthesise collagen and cause wound contraction
- macrophages reduced
6. Scar maturation (wks-2 years)
- less vasculature and cells
- collagen fibrils mature and contract - scar shrinks
What is granulation tissue composed of?
- developing capillaries
- chronic inflammatory cells
- ECM: ground substance, fibrin and type III collagen (weaker form produced rapidly, later replaced by stronger type I)
What are the functions of granulation tissue?
1. fills gap
2. capillaries supply oxygen, nutrients and cells
3. contraction to close hole
4. protection of healing tissues via macrophages and neutrophils
Which cells are involved in fibrous repair?
1. inflammatory cells
- phagocytosis of debris (neutrophils and macrophages)
- production of chemical mediators (lymphocytes and macrophages)
2. endothelial cells
- proliferation results in angiogenesis
3. fibroblasts and myofibroblasts
- produce ECM proteins, e.g. collagen
- responsible for wound contraction (fibril contraction within myofibroblasts)
How is regeneration and repair controlled?
Complex and poorly understood process involving cells communicating with each other to produce a fibroproliferative response.
Which 3 processes are used for cell to cell signalling in repair?
2. local mediators (e.g. growth factors)
3. direct cell-cell or cell-stroma contact
1 and 2 can be autocrine, paracrine or endocrine
What are growth factors in relation to repair?
- Type of local mediator particularly important in wound healing
- Polypeptides coded by proto-oncogenes.
- 'Local hormones' as only act over short distance or on secreting cell.
-Act on specific cell surface receptors:
1. cell proliferation/inhibition: stimulation of transcription of genes that regulate entry of cell into cell cycle and cell's passage through it
2. cell locomotion and contractility
3. cell differentiation and viability
Which type of cell produce growth factors?
platelets, macrophages, endothelial cells
Give examples of growth factors.
1. epidermal growth factor
- mitogenic (trigger mitosis/division) for epithelial cells, hepatocytes and fibroblasts
- produced by keratinocytes, macrophages and inflammatory cells
- binds to epidermal growth factor receptor (EGFR)
2. vascular endothelial growth factor
- potent inducer of BV development (vasculogenesis) and role in growth of new BVs (angiogenesis) in tumours, chronic inflammation and wound healing
3. platelet-derived growth factor
- stored in platelet alpha granules and released on platelet activation (also produced by macrophages, endothelial cells, SM cells and tumour cells)
- causes migration and proliferation of fibroblasts, SM cells and monocytes
4. tumour necrosis factor
- induces fibroblast migration, proliferation and collagenase secretion
What is the role of cell-cell and cell-stroma contact in wound healing?
- Contact inhibition: isolation of normal cell causes proliferation until they have cells touching them and then stop (i.e. form a monolayer sheet of cells with no cell overlap) - inhibits proliferation in intact tissue, promotes proliferation in damaged tissue.
- Involves signalling through adhesion molecules: cadherins bind cells to each other, integrins binds cells to the extracellular matrix.
What is the difference between healing by primary or secondary intention?
Descriptions of wound healing related to size of wound and amount of tissue lost:
1. primary intention
- incisional, closed, non-infected and sutured wounds
- disruption of basement membrane continuity but death of only a limited no of epithelial and CT cells
- minimal clot and granulation tissue - less scarring
2. secondary intention
- excisional wounds, wounds with tissue loss and separated edges or infected wounds
- open wound filled by abundant granulation tissue - grows in from wound margins
What occurs to the dermis and epidermis in healing by primary intention?
1. epidermis regenerates: basal epidermal cells at edge of cut creep over denuded cells, approx. 0.5mm/day, deposit basement membrane, fuse in midline beneath scab and undermine scab which falls off
2. dermis undergoes fibrous repair
How are the processes of secondary intention healing different to those of primary intention?
Same processes but more so:
1. considerable wound contraction must take place to close wound. Initially occurs a scab contracts when it dries and shrinks... after 1 wk myofibroblasts appear and contract (contracts as if margins are drawn into the centre) - final shape of scar depends on original shape of wound
2. substantial scar formation , new epidermis often thinner than usual
3. takes longer than healing by primary intention
How does the donor site heal in split skin grafts?
Graft taken from half thickness of dermis rather than full thickness
Describe the process of bone healing.
1. haematoma: fills gap and surrounds injury
2. granulation tissue forms: cytokines activate osteoprogenitor cells
3. soft callus (at 1 wk): fibrous tissue and cartilage within which woven bone forms
4. hard callus (after several wks): initially woven bone - weaker and less organised than lamellar bone but can form quickly
5. lamellar bone: replaces woven bone, remodelled to direction of mechanical stress, bone not stressed is resorbed and outline is re-established
Name 6 local factors influencing wound healing.
1. type, size, location of wound - indicates if healing is by primary or secondary intention and if regeneration or scarring will occur
2. blood supply - e.g. arteriosclerosis impedes healing, areas with high vascularity (e.g. face) heal well
3. denervation - impairs healing
4. mechanical stress - can pull apart delicate tissue in the early stages of healing
5. local infection - produces persistent tissue injury and inflammation
6. foreign bodies - persistent infection and favour infection
Name 6 systemic factors influencing wound healing.
1. age - children heal quickly, elderly more slowly
2. anaemia, hypoxia and hypovolaemia - poorer oxygen delivery to healing tissue
3. obesity - increased tension on wounds and wound dehiscence
4. diabetes - microangiopathy impairs blood supply to damaged area, decreased resistance to infection
5. genetic disorders - e.g. Ehlers-Danlos
6. drugs - steroids (inhibit collagen synthesis), cytotoxics (anti-mitogenic and impair cell proliferation and healing), antibiotics (treat bacterial infections, reduce inflammation and can speed healing)
7. vitamin deficiency - vitC deficiency inhibits collagen synthesis
8. malnutrition - lack of essential substances such as aa for protein synthesis