Healing and repair Flashcards
How does healing and repair arise?
following acute or chronic inflammation
What type of healing occurs after acute inflammation?
complete restoration of tissues (resolution of structure and function)
What type of healing occurs following chronic inflammation?
healing associated with tissue damage (e.g. fibrosis) - no restoration
Regeneration definition
new functional, differentiated cells replace the damaged tissue (healing)
Repair definition
production of a fibrous scar and changes in tissue structure and function
What factors determine whether inflamed tissues undergo regeneration or repair?
tissue type and severity of damage (e.g. acute vs chronic inflammation)
What type of healing may occur after a mild, superficial injury?
regeneration
What type of healing may occur following severe injury?
repair (fibrosis)
Which cells are involved in healing and repair?
immune cells and labile, stable and permanent cells
What are labile cells?
cells whose normal state is active cell division and therefore undergo rapid regeneration
Examples of labile cells
immune cells and non-professional immune cells e.g. keratinocytes (epithelial cells)
What are stable cells?
cells that undergo variable rates of regeneration
When do stable cells proliferate/regenerate?
in response to injury
Example of stable cells
fibroblasts
What are permanent cells?
cells that are unable to divide or regenerate
Example of permanent cells
neurones and certain myocytes
What happens as a result of a minor cut to the skin periphery?
rapid regeneration occurs as only epithelial (labile) cells are involved
What happens as a result of a deeper cut involving the connective tissue underlying the epithelium?
regeneration occurs but at a slower rate due to the involvement of stable cells (e.g. fibroblasts in CT)
What happens as a result of an aggressive cut affecting nerve endings?
Repair occurs as permanent cells are unable to regenerate (collagen deposition and scarring results)
What are the 4 stages of healing for soft and hard tissues?
- coagulation phase
- inflammation phase
- proliferation phase
- maturation phase
What is the first stage of healing in soft tissues?
coagulation (hemostasis) phase
When does the coagulation phase of healing take place?
within minutes to hours of the injury
Which plasma system forms blood clots?
coagulation system
Which two plasma systems work alongside each other to balance excess bleeding or clotting?
coagulation and fibrinolytic systems
What forms the stable blood clot?
activated platelets weaved together by fibrin
Which phase of healing involves labile and stable cells dividing to replace dying cells?
coagulation (hemostasis) phase
What is the second stage of healing?
Inflammation phase (occurs at the same time as coagulation phase)
When does the inflammation stage of healing occur?
within hours to days of injury
What occurs during the inflammation stage?
diapedesis of immune cells which perform phagocytosis, antigen presentation (MHCI-TCR CD8+), increased fibroblast activity
Which molecules drive the inflammatory phase?
kinins, complement proteins, cytokines
Which plasma systems are involved in the inflammatory phase?
kinin and complement
Which molecule stimulates increased fibroblast activity in the inflammation phase?
cytokines
What is the role of fibroblasts in healing?
they are non-professional immune cells that play an important role in proliferation stage
What is the third stage of healing?
proliferative phase
What happens in the first stage of the proliferative phase?
red new tissue forms that is rich in vasculature (angiogenesis)
Why are capillaries ‘leaky’ during the first phase of the proliferative phase?
to allow for:
- diapedesis
- action of plasma factor systems
- movement of soluble mediators
- nutrient supply
Why are immune cells present in the proliferative phase?
there is an overlap with inflammation phase
What happens during the second stage of proliferative phase?
deposition of collagen and formation of fibrous CT
What is the name of the tissue that forms in the second phase of the proliferative phase?
fibrous granulation tissue
What happens to the capillaries in the second stage of the proliferative phase?
capillaries regress and are replaced by fibrous granulation tissue
Which protein makes up the majority of fibrous granulation tissue in the second phase of proliferation?
collagen
Which cells drive fibrosis (collagen deposition)?
fibroblasts (stable cells)
What is fibrosis?
deposition of collagen and the formation of fibrous CT
Which stage of healing involves fibrosis?
the second stage of the proliferative phase
What type of injury results in fibrosis?
severe or repeated damage (e.g. chronic inflammation)
Which cells control fibroblast function?
macrophages
What are the 2 subsets of macrophages?
M1 - pro-inflammatory
M2 - anti-inflammatory
Function of M1 macrophages
drive inflammation
Function of M2 macrophages
drive tissue repair
Which subset of macrophages drive angiogenesis and fibrosis?
M2 (tissue repair)
Which cell type drives contraction of surrounding tissues for healing?
myofibroblasts
Which soluble mediators are essential in the proliferative phase?
growth factors and matrix metalloproteinases (MMPs)
Which cells release soluble mediators?
immune cells
Which cells produce MMPs?
different immune cells
What is the ECM composed of?
protein fibres (mainly collagen)
Function of matrix metalloproteinases
remodel ECM by cleaving through collagen to enable angiogenesis
Angiogenesis definition
formation of new blood vessels
What are growth factors?
signalling molecules that bind to receptors on cell surface to promote cell growth/differentiation
What happens if there is an imbalance of growth factors?
dysregulated cellular proliferation occurs
Which growth factor drives angiogenesis?
vascular endothelial growth factor (VEGF)
Which cells does VEGF target?
endothelial cells
What are the 2 ways angiogenesis can occur?
Sprouting or splitting
What happens during sprouting angiogenesis?
New endothelial cells grow from blood vessels towards an increasing vascular endothelial growth factor (VEGF) gradient
What happens during splitting angiogenesis?
endothelial cells grow into blood vessel lumen to split the blood vessel in 2. No VEGF gradient
Which type of angiogenesis requires vascular endothelial growth factor?
sprouting
What is the final stage of healing?
Maturation phase
What is the aim of the maturation phase of healing?
tissue remodelling (of disorganised granulation tissue) to regain tensile strength
How is tissue remodelled in the maturation phase?
collagen fibres are cross-linked, re-epithelization occurs with aid from myofibroblasts, fibrous scar remains in repair
Which chemical mediator is involved in the maturation phase of healing?
prostaglandins
Function of prostaglandins in tissue remodelling
decrease fibroblast activity
Re-epithelization definition
Process by which wounds are replaced by new keratinocytes (epithelial cells)
Which cells aid re-epithelization?
myofibroblasts (found in muscle cells - contract to bring epithelium together)
What forms in the coagulation phase of hard tissue healing?
hematoma
What a hematoma?
a blood clot within the bone and surrounding tissue
What is the name of the granulation tissue formed during the proliferation phase of hard tissue healing?
fibrocartilage callus
What is the name of the granulation tissue formed during the proliferation phase of soft tissue healing?
fibrous granulation tissue
Which cells make up a fibrocartilage callus?
fibroblasts, chondroblasts and osteoblasts
What happens during the maturation phase of hard tissue healing?
the fibrocartilage callus becomes ossified and requires constant remodelling
Which cells drive bone remodelling (production and degradation of bone?
osteoblasts, osteocytes, osteoclasts
Which stem cells are osteoblasts and osteocytes (matured osteoblasts) derived from?
mesenchymal stem cells (osteoprogenitor cells)
Which stem cells are osteoclasts derived from?
haemopoietic stem cells
What cells form osteoclasts?
monocyte/macrophage lineage precursor cells fuse together to form osteoclasts
What is the term for bone formation?
osteoblastogenesis
What is the term for bone resorption?
osteoclastogenesis
Approximately how many years does it take for a new skeleton to be formed?
new skeleton is formed every ten years (bone is constantly being remodelled)
What is the relationship between formation and resorption of bone in health?
formation and resorption are in equilibrium (no net bone loss)
Structural feature of osteoclasts
long protrusions on cell surface that allows the release of mediators to degenerate bone
What happens during osteoclastogenesis?
osteoblasts produce RANKL which activates the RANK receptor on osteoclasts resulting in osteoclast maturation
How is bone resorption controlled?
by the controlled production of RANKL from osteoblasts
What happens during osteoblastogenesis?
osteoblasts secrete osteoprotogerin (OPG) which inhibits RANKL (prevents osteoclast development therefore inhibiting osteoclastogenesis)
Examples of diseases in which there is an imbalance of bone remodelling
osteoporosis and periodontitis
Which molecule is secreted by osteoblasts during osteoclastogenesis?
RANKL
Which molecule is secreted by osteoblasts during osteoblastogenesis?
Osteoprotogerin (OPG)
