Healing And Repair Flashcards
What does healing depend on
The type of tissue that is injured
The nature of the injury
Sufficient blood supply (angiogenesis)
Healing required
The regrowth of cells and ECM
ECM and cells composition in tissues
Differs between organs
E.g. Skin cells on the epidermis and the ECM basement membrane below
Types of tissue injury
Toxins Ischaemia Burns Trauma infection Surgical Inflammation - autoimmune
Tissue injury of all tissues causes
Inflammation
Which then promotes healing which is either resolution or repair
Example 1 - skin
Structure of normal skin
Epidermis - contains stem cells in constant cell cycle
Dermo-epidermal junction - connects the epidermis to the dermis via hemidesmosomes, basement membrane and collagens
Dermis - comprises fibroblasts, blood vessels and abundant extracellular matrix
The ECM in 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
Basement membrane - connect via hemidesomosomes
Elastic fibres- provide resilience by stretch and recoils functions
What is the basement membrane made out of
Laminin Type IV collagen fibres Plasma membrane Nidogen Perlecan Integrin --> main receptor type by which cells bind to the ECM
Types of wound healing in the skin
Primary intention
Secondary intention
What is primary intention healing
Primary intention wounds have the following characteristics
- clean and uninfected
- surgically incised
- without much loss of cells and tissue
- edges of wound are approximated by surgical sutures
What is secondary intention healing
The wound has the following characteristics
- open with large tissue defect
- having extensive loss of cells and tissues
- the wound is not approximated by surgical sutures but is left open
Wound healing phases
Clotting phase - fibrin clot providing rapid structural support Granulation tissue 'provisional ECM' Angiogenesis Fibroplasia Reepithelialisation Wound contraction
Granulation tissue
Provisional ECM
Network of inflammatory cells, blood vessels, fibroblasts, loose fibrous tissue
Stimulates healing but it is loose and friable and would not support epithelia
Inflammatory cells mainly neutrophils
Blood vessels provide nutrients for the repair
Fibroblasts provide the support
Fibrous tissue is early collagen
Angiogenesis
New blood vessels to provide the nutrients which are needed to supply the healing tissue
Proteolysis of ECM to make way for new endothelium
Chemotaxis following the growth signals migrates into the surrounding space
Proliferation of the cells
Once formed and matured inhibition of growth
Fibroplasia
Is fibroblast proliferation and migration
Production of collagen, proteoglycans and elastin to reform the ECM to repair the damage
Reepithelialisation
Regeneration of damaged endothelium
1) transformation - become less differentiated more stem cell like
2) cells at the edge of the wound undergo mitosis
3) migration: newly formed cells migrate along the basal lamina using pseudopodia
Cell to cell and basal to cell lamina junctions are continually for,ed and broken during this process so the cells remain anchored as they migrate.
Healing ceases when there is contact inhibition - no gaps between the cells are present
Wound contraction and scarring
Complete reepithelialisation and dermal scarring
Not like normal skin there are no sweat ducts or hair and in normal dermis the collagen is randomly arranged and the dermis is more dense with cells
Fibroblasts develop properties of smooth muscle (myofibroblasts) allowing contraction of the wound
Regulation of wound healing in skin
Macrophages, fibroblasts and endothelial cells produce GROWTH FACTORS which stimulate healing in the epidermis and dermis Integrins are major receptors for ECM and initiate growth factor signalling pathways Matrix metalloproteases (MMPs) are upregulated leading to the remodelling of the ECM. MMPs are inhibited by TIMPs (tissue inhibition of matrix metalloproteinases
Growth factor and its effect
EGF
Fibronectin secretion
Reepithelialisation
FGF1,2
Fibroblasts growth and reepithelialisation
IGF
Cell proliferation
KGF/FGF7
Reepithelialisation
PDGF
Fibroblasts chemotaxis
TGF- alpha
Fibronectin secretion
Repepithelialisation
TGFbeta
Fibroblast chemotaxis
Angiogenesis
Extracellular matrix deposition
Inhibits cell proliferation
Factors influencing wound healing
Systemic - nutrition - malnourished - metabolic status - diabetic - circulatory status - PVD - hormones - Cushings Local - local blood supply - infection - foreign body - mechanical factors - wound reopening after surgery
Wound strength
1 week back to 10% strength
Collagen levels inc would strength Inc
Plateau at 70/80% which is at 3 months
Ever return to 100%
Pathological healing
Keloid scar in pigmented skin
Contracture after burns collagen contraction prevents hands from moving
Chronic leg ulcer- healing doesn’t happen due to inadequate blood supply - insufficient nutrients
Liver organisation
Little ECM
Hepatocytes are packed closely together forming sinusoids
ECM is confined to the portal tracts with only a thin layer in contact with the heptocytes, composed mainly of collagen - line the edge of the sinusoids
Regeneration of the liver following injury
Hepatocytes are stimulated out of ‘quiescent’ G0 phase back into the cell cycle
New ECM is deposited between the hepatocytes
Angiogenesis establishes new sinusoids
Resolution vs repair
Resolution is where the same tissue is replaced so the proliferation of hepatocytes replaces old tissue
Repair is damaging in this case it is where the regenerating nodules are surrounded by fibrous tissue causing cirrhosis
Pathological repair- regenerating cells cause a damaging structure due to the surrounding cells
What cells regulate the liver healing process
Stellate and kupffer cells
Produce growth factors and cytokines which regulates healing
Key role in stimulating the hepatocytes to enter the cell cycle
What does HGF do
Hepatocytes growth factor
Hepatocyte replication
EGF
Endothelial cell growth factor
Hepatocyte replication and angiogenesis
PDGF
Platelet derived GF
Stellate cell proliferation and chemotaxis
Also angiogenesis
TNF
Tumour necrosis factor
Hepatocyte replication
Stellate cell activation and myofibroblastic differentiation
TGF-beta
Deposition of ECM
Inhibition of hepatocyte replication
It is one of the key regulators of fibrosis
As in the skin the collagen remodelled is mediated by MMPs a TIMPs
VEGF
Angiogenesis
IL-6
Hepatocyte replication
Factors effecting the development of cirrhosis
Time course of liver injury
- paracetamol overdose causes severe liver 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 the parenchyma by alcohol causes classical cirrhosis with fibrosis mediated largely by stellate cells in the sinusoids
- damage to the portal tracts in Primary biliary cirrhosis causes biliary pattern of fibrosis mainly affecting the portal structures
Clinical consequences of cirrhosis
Jaundice Spider naevi Palmar erythema Gynaecomastia Splenimegaly Flapping tremour Loss of parenchyma function: impaired protein synthesis, processing drugs and hormones and production of clotting factors Portal hypertension Infection - spontaneous bacterial peritonitis Hepatocellular carcinoma
What happens after an MI
Influx of inflammatory cells
Fibrous scar left behind
Regulation of fibrosis in the heart
Fibroblasts and myofibroblasts produce matrix proteins in response to inflammatory mediators released by macrophages and inflammatory cells
Mediators include inflammatory cytokines - TNF-alpha, IL1, IL6,and fibrogenic factors such as TGF-beta, PDGF and angiotensin2
Consequence of myocardial fibrosis
Contractile dysfunction Arrhythmia Myocardial rupture Pericarditis Ventricular aneurysm Papillary muscle dysfunction
What does healing depend on
Type of tissue that is injured
The nature of the injury
Sufficient blood supply - angiogenesis
What does a tissue need to do in order to heal
Regrowth of cells and ECM
Types of cells which and the levels of healing they permit
Labile cells - constant cells cycle repair often repairing with some tissue formation different than before - skin scarring
Stable cells - inflammation produces a stimulus to cause repair and growth in which damage doesn’t usually happen - but it can
Permanent cell - little to no capacity to regenerate
Types of labile cells
Squamous epithelium
Columnar epithelium
Urothelium
Haematopoietic cells
Type of stable cells
Hepatocytes Pancreatic acinar cells Fibroblasts Smooth muscle Endothelium
Types of permanent cells
Cardiac myocytes
Neurone
Skeletal muscle
ECM regrowth requires
Cell mediators - fibroblasts - macrophages - inflammatory cells Molecular mediators - TGF-beta - growth factors PDGF, EGF, HGF, FGF - inflammatory cytokines - TNF alpha, IL1, IL6 - MMPs, and TIMPs
