Pathology Wound Healing
Terms
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- when is capacity for regeneration lost
- during development of fetal inflammatory response
- Provisional matrix characteristics
-
1 initial mechanical strength
2 substrate for cell migration
3 Reservoir for active factors released by platelets and inflammatory cells
4 contains fibrin, fibronectin, thrombospondin, platelet-derived growth factor -
identify A -
Fibrin -
Identify B -
Fibronectin - Growth factors inspiring cell division
-
1 Epidermal growth factor
2 Platelet-derived growth factor
3 Keratinocyte growth factor (FGF-7, 10)
4 Isulin-like growth factor - Angiogenesis inspiring growth factors
-
Fibroblast growth factor
VEGF - Matrix modfication growth factors
-
Transforming growth factor-Beta
Connective tissue growth factor - Growth factors which attract monocytes/macrophages
-
TGF Betas
TNF-alpha - Growth Factors which attract fibroblasts
-
PDGFs, FGFs, TGFBs, CTGF, EGF - Growth factors whch stimulate fibroblast proliferation
-
PDGF, FGF, EGF, IGF, CTGF, HGF - Growth factors which stimulate epithelial proliferation and migration
-
EGF
KGF
TGF-alpha - Growth factors which stimulate angiogenesis
-
VEGF,
FGF,
Ang-1 - Actions of Epidermal growth Factor (EGF)
-
Forms bind to the EGF-receptor
leads to activation of a tyrosine kinase
cross-phosphorylation of adjacent
receptor
EGF-EGFR complex is internalized
EGF degraded
receptor recycled to cell surface -
Vascular Endothelial Growth
Factor (VEGF) -
Selective action on endothelial cells
two receptors
multiple forms
⬢ Stimulates angiogenesis, collateral
vessel formation
⬢ Induced by hypoxia -
Transforming growth
factor-ß (TGF-ß) -
⬢ Strongly stimulates matrix formation
Increases matrix synthesis
Decreases matrix degradation
Turns off enzyme production
Turns on inhibitor production
⬢ Immunosuppression
⬢ Chemotaxis
⬢ 3 isoforms that are regulated differently
but produce the same response
complex receptor system (3 components) - Growth factors secreted by platelets
-
PDGF
IGF-1
EGF
TGF-Beta - Growth factors secreted by Endothelium
-
TNF-alpha
IL1-Beta
VEGF
bFGF
PDGF - Growth factors secreted by macrophages
-
TNF-alpha
IL1-Beta
TGF-Beta
TGF-alpha
HB-EGF
bFGF - Growth factors secreted by Fibroblast s
-
IGF-1
bFGF
TGF-beta
PDGF
KGF - growth factors secreted by Keratinocytes
-
TGF-beta
TGF-alpha
IL1-beta - Endothelial Cells secreted growth factors
-
VEGF
bFGF
PDGF -
Key Processes in The
Proliferative Phase -
• Epithelization
– Migration from margins
– Recruitment from resident stem cells
• Fibroplasia/Granulation Tissue
– Angiogenesis/Vasculogenesis
– Matrix elaboration -
A -
Granulation tissue -
B -
Epithelial Tongue-hyperplasia -
C -
Eschar - 3 populations of keratinocytes in helaing epidermis and MMP expression
-
a - Granulation Tissue
-
⬢ Replaces the provisional matrix
⬢ Restores blood supply and
connective tissue
⬢ Highly enriched in macrophages as
acute inflammation subsides - growth factors and receptors involved in induction of angioblasts in vasculogenesis
-
VEGF --> VEGF-R2 (proliferation)
VEGF --> VEGF-R1 (tube formation) - Growth factors and receptors in angiogenesis
-
VEGF --> VEGFR1/2
ANG2-->Tie2 (inhibitory signal) - Vascular maturation and remodeling growth factors and receptors
-
Ang2-->Tie2 (inhibitory signal)
PDGF-->PDGFR
TGFbeta-->TGFbeta-R - Mesenchymal Stem Cells Characteristics
-
⬢ Derived from adherent
bone marrow cell
populations
⬢ Culture conditions
determine
differentiation pattern
⬢ Can also form skeletal
muscle
⬢ Ex vivo genetic
manipulation for
inherited disease -
a
benign
overgrowth
beyond the
wound margin is a ___ - Keloid
-
disfiguring scar, but
within wound
margin ______ -
Hypertrophic
Scar - Operational Definition of Fibrosis—
-
⬢ Excessive accumulation of
extracellular matrix leading to
impaired organ function
⬢ Reflective of the need to maintain
mechanical integrity at the expense
of physiological activity
⬢ May not be under strong selective
pressure as a survival mechanism - Fibroplasia- Genetic
-
– Keloid
– Buschke-
Ollendorff
Syndrome
(Elastin)
– Progressive
Systemic
Sclerosis - Fibroplasia- Acquired
-
– Interstitial fibroses
• Hepatic
• Renal
• Pulmonary
– Atherosclerosis
– Primary Pulmonary
Hypertension
– Subglottic stenosis
– Hypertrophic scar - Fibrogenic Activities of TGF-ß
-
• Chemotaxis
• Elevated transcripts of matrix proteins
– Increased transcription
– Increased mRNA stability
• Reduced protease activity
– Decreased protease mRNA
– Increased TIMP
• Increased integrin expression
• Induction of PDGF, CTGF expression - Selection of a Fibrotic Phenotype factors
-
• Heterogeneity of responsiveness in cell
population
• Positive selection
– Development of resistance in the presence of
an inhibitor
– Loss of growth regulation (p53, RB)
• Hypersensitivity to normal stimuli
– Chemical
– Mechanical - Examples of Chronic Wound Types
-
• Decubitus ulcer (pressure sore)
– Infarction of the skin over bony processes
• Arterial ulcer
– Insufficiency of blood supply
• Venous (stasis) ulcer
– Failure of valves to prevent lymphedema
• Diabetic ulcer
– Complication of hyperglycemia,
atherosclerosis, impaired microcirculation,
and hypoproliferation - Granulocyte Proteinases
-
Serine proteinases
elastase
cathepsin G
proteinase 3
azurocidin
N(MeMutPro-8p)hil collagenase - Macrophage proteinases
-
collagenase (MMP-1)
metalloelastase (MMP-12)
"recycled" neutrophil elastase - Mast cell proteinases
-
tryptase (human)
chymase (mast cell protease
mast cell protease II (rat) - Factors Modifying Repair
-
⬢ Age - thinning of skin and loss of elasticity; altered
protease activity; possible depletion of stem cells
⬢ Nutrition - crucial roles of zinc, arginine, and ascorbic acid;
protein intake and oxygen are rate limiting
⬢ Hematologic disorders - leukopenia can reduce resistance
to infection; clotting disorders and thrombocytopenia lead
to excessive bleeding
⬢ Blood supply - essential for perfusion; atherosclerotic
changes produce ischemia; venous changes lead to stasis
⬢ Other factors - excess glucocorticoids reduce inflammation,
neovascularization, and matrix synthesis; diabetic state is
more susceptible to infection and vascular disease - Steps of Resolution
-
1 tissue damage or necrosis
2 acute inflammation
3 tissue damage neutralized, tissue damage minimal
4 re-growth of dead cells
5 resolution - steps of healing by repair
-
1 tissue damage or necrosis
2 acute inflammation
3 damage neutralized some tissue damage
4 organization thru phagocytosis and granulation tissue formation
5 healing by repair - steps of chronic inflammation
-
1 tissue damaage or necrosis
2 acute inflammation
3 marked neutrophilic response with tissue destructuion
4 abscess formation
5 persistent, damaging agent, with tissue destruction
6 organizzation with continued inflammation
7 chronic inflammation - The repair cascade events of wound healing
-
1 Extravasation and Coagulation
2 Platelet degranulation
3 Clot formation
4 Invasion of Inflammatory cells
5 Angiogenesis
6 Granulation tissue
7 termination events - Steps of extravasation and coagulation
-
1 Acute trauma
2 Extravasationi of vessel contents into wound space
3 Contact of clottin gsystem with membrane phospholipids
4 formation of fibrin clot
5 activation of platelets & amplification of clot cascade and release of platelet granules
6 Vasoconstriction by local mediators and symp nerv system - Platelet degranulation. platelet granule contents
-
matrix glycoprotein
thrombospondin
serotonin
PDGF
TGF-a
TGF beta1 - fibronectin clot steps
-
activated factor XIII causes fibronectin dimers become covalently crosslinked to firbin and to themselves thru transglutaminase action.
Provisional matrix is created - neutrophil chemoattractants released by the processing of fibrinogen into fibrin
- fibrinopeptides
- neutrophil degredative secretory products
-
neutrophil-specific interstitial collegenase
neutrophil eslastase
cathepsin G
proteinase 3
superoxide radicals - results of release of oxygen species by neutrophils
-
local killing of bacteria
degradation of bacterial macromolecules
degradation of denatured matrix and damaged cells - early wound is characterized by...
-
neutrophil, macrophage, platelet derived products
matrix constituents which facilitate cell movemement
matrix components which facilitate cell adhesion - early markers of cell movement...
-
glycoproteins:
tenascin osteopontin and osteonectin/SPARC
glycosaminoglycan
hyaluronan
cellular form of fibronectin - first interstitial collagen type that appears
- collagen III, abundant in blood vessels and associated with finer collagen fibrils
- changes in fiber types of wound as wound matures
-
less col III
more coll I
less hyaluronan due to hyaluronidase activity
reduced cellular form of fibronectin - most likely stimulants of angiogenesis
-
bFGF--a heparin binding growth factor
VEGF - sources of type I coll in wound repair
- fibroblasts and myofibroblasts
- growth factors secreted by epithelium
- IL-1, TNF-a, PDGF, TGF-beta
- two differentiation events of epidermis migration
-
keratinocytes at wound edge dedifferentiate and move out over denuded collagenous substrate of wound bed, secrete collagenase and stromelysin 2 (both MMPs)
Behind migrating tip, new proliferative center where cells express stromelysin 1, accumulation of new basement membrane material (laminin) under migrating sheet - organs with regeneration
- bone and liver
- 2 main pathways of arachidonic acid oxidation; which makes LTB4?
-
cyclooxigenase and lipoxygenase-->LTB4 - TGF beta factors
- TGFB1, B2, B3
- TGFB receptors
-
Type I 55 kDa
Type II 75 kDa
Type III (betaglycan)