Healing and Repair Flashcards
What things cause tissue injury?
surgical infection burns inflammation ischaemia toxins trauma
What three things does healing depend on?
- the type of tissue that is injured
- the nature of the injury
- sufficient blood supply (angiogenesis)
Describe the layers of the skin
- epidermis = contains stem cells in constant cell cycle
- dermo-epidermal junction = connects epidermis to dermis via hemidesmosomes, basement membrane and collagen
- dermis = comprises fibroblasts, blood vessels and abundant ECM
What is the ECM of the dermis comprised of?
- collagen fibres - provide structural support
- proteoglycans - form a hydrated gel which resist compressive forces whilst permitting rapid diffusion of nutrients, metabolite and hormones
- elastic fibres - provide resilience by stretch and recoil functions
- basement membrane
What is the basement membrane made up of?
- laminin
- Type IV collagen
- plasma membrane
- perlecan
- nitrogen
- integrin = main receptor type by which cells bind to ECM, anchors to BM
What is the different between wound healing by primary and secondary intention?
Primary intention = when the wound edges of the epidermis can be brought close together.
Secondary intention = wound edges far apart, gap fills in by granulation tissue,
What are the phases of wound healing?
- clotting
- granulation tissue
- angiogenesis
- fibroplasia
- re-epithelialisation
- wound contraction and scarring
Describe the clotting phase
fibrin clot provides rapid structural support following injury
Describe the granulation tissue phase
the ‘provisional ECM’
- inflammatory cells blood vessels, fibroblasts, loose fibrous tissue
- will not support epithelial layer until angiogenesis and fibroplasia have taken place
Describe the angiogenic phase
- proteolysis of ECM
- migration and chemotaxis
- proliferation of endothelial cells
- lumen formatin, maturation and inhibition of growth
- increased permeability through gaps and transcytosis
Describe fibroplasia
- fibroblast proliferation and migration
- production of collagen, proteoglycans and elastic to re-form the ECM
- few inflammatory cells now
Describe re-epithelialisation
- keratinocyte migration from edge of wound and skin appendages begins within 24hrs of injury
- keratinocyte proliferation is inhibited until migration is complete
- depends upon re-establishment of the derma-epidermal junction
Describe wound contraction and scarring
- complete re-epithelialisation and dermal scarring
- note the parallel orientation of collagen fibres and the more densely cellular dermis (normally random organisation)
- fibroblasts develop properties of SM cells (myofibroblasts) allowing contraction of the wound
- some residual inflammation is present
Describe the regulation of wound healing in skin
- macrophages, fibroblasts and endothelial cells produce growth factors which stimulate healing in epidermis and dermis
- integrins are major receptors of ECM and initiate growth factors signalling pathways
- MMPs are unregulated leading to remodelling of ECM, MMPs are inhibited by TIMPs (tissue inhibitor metalloproteases)
- regulated by growth factors, importantly TGF-beta
What systemic and local factors influence wound healing?
Systemic - nutrition - metabolic status - circulatory status - hormones Local - local blood supply - infection - foreign body - mechanical factors
What is the wound strength at 1 week, w month and 3 months?
1 week = 10%
2 months = 50-60%
3 months = 70-80% –> plateau (collagen is deposited)
Give 3 examples of pathological healing of skin
Keloid scarring
- normally in pigmented skin, hypertrophic collagen fibres,
Contractures
- following injury over a large surface e.g. burns
Chronic leg ulcer
- no healing especially in PVD or diabetes as insufficient blood supply and nutrients for healing
Describe the location and appearance of ECM in the liver
- ECM is predominately confined to the portal tracts with only a thin layer in contact with hepatocytes, composed mainly of collagen (reticulin)
Describe regeneration of the liver following injury
- hepatocytes stimulated out of ‘quiescent’ G0 phase back into cell cycle
- new ECM is deposited between hepatocytes
- angiogenesis establishes new sinusoids
What is the difference between resolution and repair in the liver?
Resolution = regrowth to normal tissue Repair = e.g. cirrhosis, repaired structured are not normal
Describe the regulation of liver healing/fibrosis
- stellate and Kupferr cells produce growth factors and cytokines which stimulate healing
- hepatocyte growth factor (HGF) plays a key role in stimulating hepatocytes to enter cell cycle
- TGF-beta is one of the key regulators of fibrosis
- as in skin, the deposited collagen is remodelled by MMPs and TIMPs
What factors affect the development of cirrhosis?
Time cours of liver injury
- paracetamol overdose causes severe liver injury at one point in time - does not lead to cirrhosis
- alcohol generally causes much less severe injury but over a longer time period - can cause cirrhosis
Anatomic site of injury
- damage to parenchyma (e.g. alcohol) causes classical cirrhosis with fibrosis mediated largely by stellate cells in the sinusoids
- damage to portal tracts (e.g. primary biliary cholangitis) causes a biliary pattern of fibrosis mainly affecting the portal structures
What are the clinical consequences of cirrhosis?
- jaundice
- spider naevi, palmer erythema, gynaecomastia, splenomegaly, flapping tremor
- loss of parenchymal function: impaired protein synthesis, processing drugs and hormones and production of clotting factors
- portal hypertension
- infection (spontaneous bacterial peritonitis)
- hepatocellar carcinoma
Describe the regulation of fibrosis in myocardial infarction
- fribroblasts and myofibroblasts produce matrix proteins in response to inflammatory mediates released by macrophages and inflammatory cells
- mediators of fibrosis include inflammatory cytokines such as TNF-alpha, IL-1, IL-6 and fibrogenic factors such as TGF-beta, PDGF and angiotensin II
What are the consequences of myocardial fibrosis?
- contractile dysfunction
- arrhythmia
- myocardial rupture
- pericarditis
- ventricular aneurysm
- papillary muscle dysfunction
What are labile cells?
Give 4 examples
Labile cells = can regrow
- haemopoietic cells
- squamous epithelium
- columnar epithelium
- urothelium
What are stable cells?
Give 5 examples
Stable cells = normally in G0 but do have the ability to regrow
- hepatocytes
- pancreatic acinar cells
- fibroblasts
- smooth muscle
- endothelium
What are permanent cells?
Give 3 examples
Permanent cells = low capacity to divide
- cardiac myocytes
- neurones
- skeletal muscle
