Path 5: Repair

Front 1

What does regeneration depend on?

Back 1

Matrix Preservation
Parenchymal cells able to regenerate (divide)

Front 2

What are three things cells (stromal and epithelial) must do in order for regeneration?

Back 2

Migrate (chemotaxis)
Proliferate (mitogenesis)
Differentiate (angiogenesis, collagen synthesis)

Front 3

What is Rq'd for all three things that cells must do to regenerate?

Back 3

Intact matrix
(basement membrane (BM) + ECM (extracellular matrix))

Front 4

What is response to acute infllamtion w/ intact ECM?

Back 4

Regeneration

Front 5

What is response to acute inflammation w/ Damaged ECM

Back 5

not regeneration - Fibrosis

Front 6

What is response to acute inflammation w/ no replacement of myocardial cells?

Back 6

Fibrosis (myocardial scar)
-however, cells may undergo hypertrophy to replace cells

Front 7

What happens when Regeneration is not possible?

Back 7

Replacement

Front 8

What 2 things occur to have Replacement instead of Regeneration?

Back 8

1. Matrix disrupted OR
2. Permanent cell destroyed

Front 9

What forms in the early process of Replacement?

Back 9

Granulation tissue
-angiogenesis (and edema)
-fibroblasts
-evolving inflammation

Front 10

What is the end result of Replacement?

Back 10

Connective tissue scar end result
- replaces granulation tissue by maturation

Front 11

What is the time course of wound healing?

Back 11

1. Inflammation (0-3 days)
2. Granulation tissue (.5-3 days)
3. Wound contraction (3-30 days)
4. Collagen accululation/remodeling (Type III becomes Type I)

Front 12

What are the 3 types of cell surface receptors?

Back 12

1. IK (intrinsic Kinase)
2. CK (cytosol kinase-linked activity)
3. GPCR (G protein-linked)

Front 13

What is the surface receptor?
-transmembrane w/ binding and catalytic domains
-either Tyrosine kinase of Serine/Threonine kinase
-Mitogenic receptors

Back 13

Intinsic Kinase Activity
(PI3 kinase, MAP-kinase, IP3 pathway)

Front 14

What is the surface receptor?
-transmembrane with Extracellular and cytosolic enzyme binding
-activates cytosoic tyrosine kinase
-Cytokine receptor superfamily

Back 14

CK (cytosol kinase-linked activity)
JAK/STAT pathway (w/o intrinsic tyrosine kinase activity)

Front 15

What is the surface receptor?
-seven-spanning receptors (serpentine)
-Intracellular second messenger (cAMP or cGMP)
-Chemokines, epinephrine, glucagon, drug receptors

Back 15

G protein linked
cAMP pathway

Front 16

Labile tissue types?

Back 16

Epithelia, bone marrow
-respond promptly to regenerate

Front 17

Stable tissue types?

Back 17

Glands, Mesenchyme
G0 recruited to G1 (can be induced to reenter cell cycle)

Front 18

Permanet tissue types?

Back 18

Neurons, Striate muscle
- don't proliferate

Front 19

What are the 2 key checkpoints of completion of molecular events?

Back 19

G1 Checkpoint
G2M checkpoint

Front 20

What is the G1 checkpoint?

Back 20

Rb gene regulates
(is DNA fit to go on?)

Front 21

What regulates G2M checkpoint?

Back 21

p53 gene
(incomplete replication?, cell ready for division?, apoptosis if damaged?)

Front 22

Protein phosphorylation is Upregulated by cyclins:
Early G1?

Back 22

Cyclin D

Front 23

Protein phosphorylation is Upregulated by cyclins:
late G1, early S

Back 23

Cyclin E

Front 24

Protein phosphorylation is Upregulated by cyclins:
S, early G2

Back 24

Cyclin A

Front 25

Protein phosphorylation is Upregulated by cyclins:
late G2, early M

Back 25

Cyclin B

Front 26

What are the two key properties of stem cells?

Back 26

1. Self renewal
2. Asymmetric differentiation

Front 27

What is assymetric differentiation

Back 27

-stem cell
-progenitor cell

Front 28

Adult stem cells are most commonly found where?
and exhibit developmental plasticity in culture

Back 28

Bone marrow
-Hematopoietic stem cells (HSC)
-Mesodermal progenitor cells
-Multipotent adult progeniotr cells (MAPC)

Front 29

Where are some tissue stem cell Niche locations? (RQ particular enviro)?

Back 29

Hair follicles, GI crypts, muscle satellite cells, canals of Herring, corneal limbus

Front 30

Embryonic stem cells can be collected up to?

Back 30

blastocyst stage (32 cells)

Front 31

What are some characteristics of developmental plasticity of human embryonic stem cells (HES) is culture?

Back 31

Chimeras in all organs when reimplanted in another mouse blastocyst
-HES proliferate over 70 passages in vitro
-HES DO NOT form teratomas in nude mice (cont. to prolif. but don't grow tumors)

Front 32

Do embryonic stem cells have any therapeutic uses?

Back 32

Not yet

Front 33

What are 3 key roles of ECM (extracellular matrix)? - necessary for Regeneration

Back 33

1. Scaffold and support for cell adherence, migration, proliferation
2. binds GROWTH FACTORS and factors for CELL MIGRATION and DIFFERENTIATION
3. Binds water and ions for turgor, mineralizaiton and mechanical properties

Front 34

What are the 3 major components of ECM?

Back 34

1. Structural
2. Adhesive glycoproteins
3. Stabilizing gel

Front 35

What are the 3 major components of ECM?:
Collagen and Elastin?

Back 35

Structural

Front 36

What are the 3 major components of ECM?
-Fibronectin, laminin

Back 36

Adhesive glycoproteins

Front 37

What are the 3 major components of ECM?
-Stabilizing gel

Back 37

Proteoglycans, hyaluronan

Front 38

Why are fibroblasts important?

Back 38

Integrins comm. w/ fibroblasts and fibroblasts help produce a lot ofthe stuff for healing

Front 39

What are the 2 unique Basement Membrane molecules?

Back 39

Collagen Type IV
Laminin

Front 40

What does Laminin do?

Back 40

Links cells to Basement Membrane matrix by collagen IV and Heparan

Front 41

What are some characteristics of developmental plasticity of human embryonic stem cells (HES) is culture?

Back 41

Chimeras in all organs when reimplanted in another mouse blastocyst
-HES proliferate over 70 passages in vitro
-HES DO NOT form teratomas in nude mice (cont. to prolif. but don't grow tumors)

Front 42

Do embryonic stem cells have any therapeutic uses?

Back 42

Not yet

Front 43

What are 3 key roles of ECM (extracellular matrix)? - necessary for Regeneration

Back 43

1. Scaffold and support for cell adherence, migration, proliferation
2. binds GROWTH FACTORS and factors for CELL MIGRATION and DIFFERENTIATION
3. Binds water and ions for turgor, mineralizaiton and mechanical properties

Front 44

What are the 3 major components of ECM?

Back 44

1. Structural
2. Adhesive glycoproteins
3. Stabilizing gel

Front 45

What are the 3 major components of ECM?:
Collagen and Elastin?

Back 45

Structural

Front 46

What are the 3 major components of ECM?
-Fibronectin, laminin

Back 46

Adhesive glycoproteins

Front 47

What are the 3 major components of ECM?
-Stabilizing gel

Back 47

Proteoglycans, hyaluronan

Front 48

Why are fibroblasts important?

Back 48

Integrins comm. w/ fibroblasts and fibroblasts help produce a lot ofthe stuff for healing

Front 49

What are the 2 unique Basement Membrane molecules?

Back 49

Collagen Type IV
Laminin

Front 50

What does Laminin do?

Back 50

Links cells to Basement Membrane matrix by collagen IV and Heparan

Front 51

What are some characteristics of developmental plasticity of human embryonic stem cells (HES) is culture?

Back 51

Chimeras in all organs when reimplanted in another mouse blastocyst
-HES proliferate over 70 passages in vitro
-HES DO NOT form teratomas in nude mice (cont. to prolif. but don't grow tumors)

Front 52

Do embryonic stem cells have any therapeutic uses?

Back 52

Not yet

Front 53

What are 3 key roles of ECM (extracellular matrix)? - necessary for Regeneration

Back 53

1. Scaffold and support for cell adherence, migration, proliferation
2. binds GROWTH FACTORS and factors for CELL MIGRATION and DIFFERENTIATION
3. Binds water and ions for turgor, mineralizaiton and mechanical properties

Front 54

What are the 3 major components of ECM?

Back 54

1. Structural
2. Adhesive glycoproteins
3. Stabilizing gel

Front 55

What are the 3 major components of ECM?:
Collagen and Elastin?

Back 55

Structural

Front 56

What are the 3 major components of ECM?
-Fibronectin, laminin

Back 56

Adhesive glycoproteins

Front 57

What are the 3 major components of ECM?
-Stabilizing gel

Back 57

Proteoglycans, hyaluronan

Front 58

Why are fibroblasts important?

Back 58

Integrins comm. w/ fibroblasts and fibroblasts help produce a lot ofthe stuff for healing

Front 59

What are the 2 unique Basement Membrane molecules?

Back 59

Collagen Type IV
Laminin

Front 60

What does Laminin do?

Back 60

Links cells to Basement Membrane matrix by collagen IV and Heparan

Front 61

Why is the basement membrane important?

Back 61

Spreading of Epithelial or Endothelial cells

Front 62

What are 4 components of basement membrane?

Back 62

Collagen Type IV*
Laminin*
Fibronectin
Heparan sulfate

Front 63

Basement membrane component?
- links cells to BM matrix by collagen IV and heparan

Back 63

Laminin

Front 64

Basement membrane component?
-adheres to cells by RGD integrin-binding motif
-also attaches to heparan, collagen, and fibrin

Back 64

Fibronectin (also helps tell which direction to go/chemotxis)

Front 65

Basement membrane component?
-Ligand for both laminin and fibronectin?

Back 65

Heparan sulfate

Front 66

What are some binding sites on laminin?

Back 66

-Type IV collagen
-Cell-binding domain
-Heparan sulfate proteoglycan binding site

Front 67

What is the basic unit of collagen?

Back 67

Tropocallagen (monomer)

Front 68

Describe each unit of collagen?

Back 68

3 alpha chains in each unit
-triple helix, left-handed

Front 69

27 collagen types are determined by

Back 69

41 genes on 14 chromosomes

Front 70

What are the fibrillar collagens (#'s)?

Back 70

I
II
III
V
IX

Front 71

What are the nonfibrillary collagens (#'s)

Back 71

IV and others

Front 72

Fibrillar or nonfibrillar collagen?
-have 67 nm banding from linking zones
-present in tendon, scar, strong ct

Back 72

Fibrillar collagens: I, II, III, V, IX

Front 73

Fibrillar or nonfibrillar collagen?
-amorphous
-present in interstitium, submucosa, BM

Back 73

Nonfibrillary collagens: IV, others

Front 74

What is a component of myometrium and smooth muscle arterioles?

Back 74

Type III collagen, quickly synthesized, inital scarring but later replaced by Type I collagen

Front 75

What is the strongest collagen type?

Back 75

Type I

Front 76

What events of collagen synthesis begin in ER?

Back 76

translation, hydroxylation, glycosylation, chain selection

Front 77

What event of collagen synthesis takes place in Gogi?

Back 77

Helix formation

Front 78

When/where does procollagen become Collagen?

Back 78

Extracellular space
-cleavage of propeptides

Front 79

What is the final step in collagen synthesis?

Back 79

Cross linking (Lysyl hydroxylysyl oxidation)

Front 80

What are the 5 stages of repair?

Back 80

1. Angiogenesis
2. Fibroblast invasion and proliferation
3. Collagen and ECM synthesis
4. Granulation tissue into scar
5. Tissue remodeling

Front 81

With regard to the zones of repair, what is the leading zone (I or III) that is strongly affected by chemotactic factos?

Back 81

Zone I
*note, new blood vessels are intrinsically leaky

Front 82

What are 5 key growth factors?

Back 82

1. EGF
2. TGF-Beta
3. VEGF
4. PDGF
5. FGF (fibroblast growth factor)

Front 83

Note: there are a vareity of principle mediators of repair

Back 83

functions inculde monocyte chemotaxis, fibroblast migration/replication, keratinocyte replication, angiogenesis, collagen synthesis, collagenase secretion

Front 84

Angiogenic factors include such things as?

Back 84

VEGF (vascular endothelial growht factor)
bFGF
Angiopoietins
Endostatin

Front 85

Angiogenic factors include such things as?:
-receptors have instrsic tyrosine kinase activity

Back 85

VEGF (vascular endothelial growth factor)
-VEGF-R2 for proliferation
-VEFG-R1 for tube formation (zone I)

Front 86

Angiogenic factors include such things as?
-stimulates other non-endothelial mesenchymal cells, too

Back 86

bFGF

Front 87

Angiogenic factors include such things as?
-binds endothelial Tie2 receptor to recruit pericytes

Back 87

Ang1 (angiopoietins)

Front 88

Collagen fragment that inhibits angiogenesis

Back 88

Endostatin

Front 89

What are some Fibroplasia factors?

Back 89

-Fibrinogen, plasma fibronectin
-PDGF, EGF,FGF
-IL-1, TNF-alpha
-TGF-beta most pleotrophic fibrogenic mediator

Front 90

What are some Fibroplasia factors?
-chemotactic mediotrs from leaky new vessels

Back 90

fibrinogen, plasma fibronectin

Front 91

What are some Fibroplasia factors?
- from platelets, epithelia, and histiocytes
-fibroblast migration and proliferation

Back 91

PDGF, EGF, FGF

Front 92

What are some Fibroplasia factors?
-"Fibrogenic cytokines"
-Induce PDGF, bFGF, TGFbeta from MPs
-induce collagen and collagenase in fibroblasts

Back 92

IL-1, TNF-alpha (stimulate early collagen synthesis)

Front 93

What are some Fibroplasia factors?
-most pleotrophic fibrogenic mediator
-all of the above plus inhibit collagenase seretion

Back 93

TGF-beta

Front 94

Clean, closely approximated margins
-minimal clot/granulation tissue, motion, bacteria?

Back 94

Primary intention wound healing

Front 95

-large tissue defect or reopened surgical wound
-greater inflammation nad granulation tissue
-healing time depends on time of defect
-wound contraction up to 95% at 6 weeks

Back 95

Secondary intention wound healing

Front 96

What assits in wound contraction?

Back 96

Myofibroblasts
Elastin remodeling

Front 97

What are some traits of fresh wound?

Back 97

clean incision
limit motion
no infection
minimal foreign material
adequate nutrition and circulation

Front 98

What kind of tissue comes in with Replacement injury?

Back 98

Granulation tissue

Front 99

Describe collagen accumulation with Replacement injury

Back 99

Accumulation is dynamic
-Type III collagen first, then broken down and replaced by Type I collagen

Front 100

What do metalloproteinases do and what do they RQ?

Back 100

Break down type III collagen (so type I collagen can come in to replace it)
- Requires Zinc ions

Front 101

What are some Fibroplasia factors?
- from platelets, epithelia, and histiocytes
-fibroblast migration and proliferation

Back 101

PDGF, EGF, FGF

Front 102

What are some Fibroplasia factors?
-"Fibrogenic cytokines"
-Induce PDGF, bFGF, TGFbeta from MPs
-induce collagen and collagenase in fibroblasts

Back 102

IL-1, TNF-alpha (stimulate early collagen synthesis)

Front 103

What are some Fibroplasia factors?
-most pleotrophic fibrogenic mediator
-all of the above plus inhibit collagenase seretion

Back 103

TGF-beta

Front 104

Clean, closely approximated margins
-minimal clot/granulation tissue, motion, bacteria?

Back 104

Primary intention wound healing

Front 105

-large tissue defect or reopened surgical wound
-greater inflammation nad granulation tissue
-healing time depends on time of defect
-wound contraction up to 95% at 6 weeks

Back 105

Secondary intention wound healing

Front 106

What assits in wound contraction?

Back 106

Myofibroblasts
Elastin remodeling

Front 107

What are some traits of fresh wound?

Back 107

clean incision
limit motion
no infection
minimal foreign material
adequate nutrition and circulation

Front 108

What kind of tissue comes in with Replacement injury?

Back 108

Granulation tissue

Front 109

Describe collagen accumulation with Replacement injury

Back 109

Accumulation is dynamic
-Type III collagen first, then broken down and replaced by Type I collagen

Front 110

What do metalloproteinases do and what do they RQ?

Back 110

Break down type III collagen (so type I collagen can come in to replace it)
- Requires Zinc ions

Front 111

What are some Fibroplasia factors?
- from platelets, epithelia, and histiocytes
-fibroblast migration and proliferation

Back 111

PDGF, EGF, FGF

Front 112

What are some Fibroplasia factors?
-"Fibrogenic cytokines"
-Induce PDGF, bFGF, TGFbeta from MPs
-induce collagen and collagenase in fibroblasts

Back 112

IL-1, TNF-alpha (stimulate early collagen synthesis)

Front 113

What are some Fibroplasia factors?
-most pleotrophic fibrogenic mediator
-all of the above plus inhibit collagenase seretion

Back 113

TGF-beta

Front 114

Clean, closely approximated margins
-minimal clot/granulation tissue, motion, bacteria?

Back 114

Primary intention wound healing

Front 115

-large tissue defect or reopened surgical wound
-greater inflammation nad granulation tissue
-healing time depends on time of defect
-wound contraction up to 95% at 6 weeks

Back 115

Secondary intention wound healing

Front 116

What assits in wound contraction?

Back 116

Myofibroblasts
Elastin remodeling

Front 117

What are some traits of fresh wound?

Back 117

clean incision
limit motion
no infection
minimal foreign material
adequate nutrition and circulation

Front 118

What kind of tissue comes in with Replacement injury?

Back 118

Granulation tissue

Front 119

Describe collagen accumulation with Replacement injury

Back 119

Accumulation is dynamic
-Type III collagen first, then broken down and replaced by Type I collagen

Front 120

What do metalloproteinases do and what do they RQ?

Back 120

Break down type III collagen (so type I collagen can come in to replace it)
- Requires Zinc ions

Front 121

What forms leaky vessels (and cause continual turnover of ECM in granulation tissue)?

Back 121

Serine proteases

Front 122

When a fresh wound is replaced by Granulation tissue, what are some traits?

Back 122

-Thin wall vessels
-Edematous/disorganized stroma
-Fibroblasts
-Decreasing inflammation
-Type III collagen
-Reepithelialization (clot is replaced and will eventually fall off)

Front 123

What are some key features of Maturing Granulation Tissue?

Back 123

-Vessels decreasing
-Fibrocytes decreasing
-Type III collagen replaced by TYpe I collagen (Rq's action metalloproteinases)
-Inflammation resolved
-Epithelium restored

Front 124

What is wound strength (primary intention) when?
-sutures removed (4-10 days_

Back 124

10%

Front 125

What is wound strength (primary intention) when?
after 4 weeks and granulation tissue remodeling occurs

Back 125

rapid increase in 4 weeks

Front 126

What is wound strength (primary intention) when?
- 3months

Back 126

70-80% strength
-synthesis>degradation first 2 mos.
-collagen III replaced by I
-cross-binding and increase in fiber size strengthen

Front 127

Secondary intention wound strength contraction at 6 weeks?

Back 127

95%
- myofibroblasts and elastin remodeling participate

Front 128

Describe Remodeling scar (by end of 3 mos.)

Back 128

-Vessels absent
-Fibrocytes few
-Type III replaced by Type I collagen
- Contraction complete
- Inflammation resolved
- Epithelium restored

Front 129

Injury can lead to 3 outcomes?

Back 129

1. Regeneration
2. Repair (scar formation)
3. Fiborosis (tissue scar)

Front 130

What does persisten tissue damage lead to?

Back 130

Fibrosis (scar) such as cirrhosis, chronic pancreatitis, pulmonary fibrosis)

Front 131

What are some things observe with Pathologic wound healing

Back 131

1. deficient scar
2. Excessive repair
3. Contracture at flexor surfaces

Front 132

Deficient scar may result from

Back 132

tension or infection
-nonhealing ulcer such as in DB or peripheral vascular disease

Front 133

What causes excessive repair?

Back 133

Granualtion tissue excess "pyogenic granuloma"
-Keloid
-Fibromatoses "excessive accum. collagen locally"
(desmoid, aggressive fibromatosis, uncertain whether neoplastic)

Front 134

1. Regeneration vs replacement

Back 134

stable or labile cells, BM and ECM preserved

Front 135

2. 3 cell surface receptor types

Back 135

IK-mitogenic; Ck-cytokines; GPCR-hormones

Front 136

3. Cell cycle, 4 cyclins, 2 checkpoints

Back 136

G0G1SG2M; Cyclins DEAB; midG1(Rb) G2M (P53)

Front 137

2 unique BM molecules

Back 137

Collagen IV
Laminin

Front 138

5. Collagen synthesis and structures?

Back 138

Pro
OHPro
Glycos
Select3alpha
LysOX
/C,N peptidase to tropocollagen
LysOx
Agg

Front 139

6. 5 growth factors

Back 139

EGF Ep mitogenic
-PDGF MpEn mito/tactic
-FGF En angio SkmsLung maturing
-VEGF En angio
-TGFbeta Ep inhibits Fb collagen sythesis-collagenase inhib.

Front 140

7. wound healing and maturation, zinc function

Back 140

Angiogenesis
Fibroblast invasion/mitosis
ECM synthesis
Remodeling (Zn metalloproteinase)