Healing and repair Flashcards
What are the 2 main pathways a tissue can undergo following injury and inflammation?
Resolution or repair
- resolution = tissue essentially goes back to normal
- repair = once inflammation subsides tissues doesn’t go back to normal
What does healing require and what is it dependent upon?
Requires regrowth of cells and ECM Depends on: 1) type of tissue that is injured 2) nature of the injury 3) sufficient blood supply (angiogenesis)
What are the 3 main structural elements/junctions of the skin and what do they do?
Epidermis - contains stem cells in constant cell cycle
Dermo-epidermal junction- connects epidermis to dermis via hemidesmosomes, basement membrane and collagens
Dermis - comprises fibroblasts, blood vessels and abundant extracellular matrix
What are the roles of the collagen, proteoglycans and elastic fibres in the ECM of the dermis?
Collagen fibres - provide structural support
Proteoglycans - form a hydrated gel which resists compressive forces whilst permitting rapid diffusion of nutrients, metabolites and hormones
Elastic fibres - provide resilience by stretch and recoil functions - more important for stretching, not present in scar so therefore they are not as stretchy as normal skin
What are the 2 ways of wound healing in the skin?
Primary intention- most common, single incision during surgery allows this process to occur
Secondary intention - not possible to bring 2 ends of skin together e.g. leg ulcer - skin can heal but it takes longer as it has to heal up through the layers, the scar tissue is in the dermis and the epidermis is normal
What are the phases of clotting?
Fibrinogen to fibrin (monomer) to fibrin (polymer, unstable), to fibrin (polymer, stable)
Fibrin protects and provides structural support
Why is granulation tissue important?
“Provisional ECM” - much stronger than fibrin clot therefore provides support to defect to help support healing process
What are the stages of angiogenesis?
1) proteolysis of ECm
2) Migration and chemotaxis
3) Proliferation
4) Lumen formation, maturation and inhibition of growth
5) increased permeability through gaps ans transcytosis
What happens in fibroplasia?
Fibroblast proliferation and migration
Production of collagen, proteoglycans and elastin to re-form the ECM
- collagen forms the scar
What happens in re-epithelialisation?
Keratinocyte migration from edge of wound and skin appendages begins within 24 hours of injury (migrate along base of wound, covering it and then signal to move up and repair wound)
Keratinocyte proliferation is inhibited until migration is complete
Depends upon re-establishment of the dermo-epidermal junction
What occurs in wound contraction and scarring?
Complete re-epithelisation and dermal scarring
- collagen fibres orientate themselves parallel with cellular dermis
Fibroblasts develop properties of smooth muscle cells allowing contraction of the wound (myofibroblasts)
What stimulates epidermal and dermal healing?
Macrophages, fibroblasts and endothelial cells produce growth factors that stimulate healing
- integrins are major receptors for ECM and initiate growth factor signalling pathways
- MMPs are upregulated leading to remodelling of ECM - MMPs are inhibited by TIMPs
What systemic and local factors influence wound healing ?
Systemic- nutrition (malabsorption), metabolic status (diabetes), circulatory status, hormones
Local - local blood supply, infection, foreign body, mechanical factors
Wound strength
- 10% at 1 week
- 50-60% at 1 month
- 70-80% at 3 months - dermis is never as strong as before due to scarring
What is the ECM like in a normal liver?
Predominantly confined to the portal tracts with only a thin layer in contact with hepatocytes composed mainly of collagen
- sinusoids are lined by collagen
How does regeneration work in the liver following injury?
Hepatocytes stimulated out of Go into cell cycle
New ECM is deposited between hepatocytes
Angiogenesis establishes new sinusoids
How is the healing/fibrosis process regulated in the liver?
Stellate and kupffer cells produce growth factors and cytokines which stimulate healing
Hepatocyte growth factor plays a key role in stimulating hepatocytes to enter cell cycle
TGF-beta is one of the ket regulators of fibrosis
As in skin, the deposited collagen is remodelled by MMPs and TIMPs
What factors affect the development of cirrhosis?
Time course of liver injury
- Paracetamol overdose causes severe liver injury at one point in time = doesn’t lead to cirrhosis
- alcohol generally causes much less severe injury but over a longer time period - causes cirrhosis
Anatomic site of injury
- damage to parenchyma causes classical cirrhosis with fibrosis mediated largely by stellate cells in the sinusoids
- damage to portal tracts causes a biliary pattern of fibrosis mainly affecting portal structures
What are the clinical consequences of cirrhosis ?
Jaundice, spider naevi, palmar erytherma, gynaecomastia, splenomegaly, flapping tremor, loss of parenchymal function (impaired protein synthesis, processing drugs and hormones and production of clotting factors), portal hypertension, infection (SBP), hepatocellular carcinoma
How is fibrosis regulated?
Fibroblasts and myoblasts produce matrix proteins in response to inflammatory mediators released by macrophages and inflammatory cells
Mediators of fibrosis include- cytokines (TNF-alpha, IL-1, IL-6) and fibrogenic factors (TGF-beta and PDGF) and angiotensin 2
What are the consequences of myocardial fibrosis?
Contractile dysfunction Arrhythmia - damage to electrical pathways Myocardial rupture Pericarditis Ventricular aneurysm Papillary muscle dysfunction
What are examples of labile cells?
squamous epithelium
Columnar epithelium
Urothelium
Haemopoietic cells
What are examples of stable cells?
hepatocytes pancreatic acinar cells fibroblasts smooth muscle endothelium
What are examples of permanent cells?
cardiac myocytes
neurons
skeletal muscle
What are the cell mediators for ECM regrowth?
fibroblasts
macrophages
inflammatory cells
What are the molecular mediators for ECM regrowth?
TGF-beta
growth factors - PDGF, FGF
inflammatory cytokines - TNF-alpha, IL-6,
MMPs and TIMPs
