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66 Cards in this Set

  • Front
  • Back
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
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)