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Pathology > Repair > Flashcards

Repair Flashcards

1
Q

REGENERATION

A

Regeneration: restoration of damaged or lost cells or tissues to their original state.

Requires:

1) Cell proliferation (parenchyma or stem cell population).
2) An intact extra-cellular matrix (ECM) scaffold.

ex) normal (homeostatic) replacement of skin cells

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2
Q

Repair

A

Repair: involves a combination of regeneration and scar formation by the deposition of collagen

Requires:

1) Cell proliferation (parenchyma or stem cell population).
2) ECM is usually damaged and new ECM (collagen) is deposited

ex) healing of a burn where there
is regeneration of the epithelium as well as scar formation.

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3
Q

Epidermal Growth Factor

  1. Receptor Type
  2. Cell of origin
  3. Target cell
  4. Effects
  5. Diseases
A

EGF

Large family -includes EGF and transforming growth factor alpha (TGF-α)

  1. Receptor type: EGFR 1 (ERB B1)
    – Receptor tyrosine kinase
    – Juxtacrine mechanism
  2. Cell of origin:
    – Macrophages
    – Inflammatory cells
    – Platelets
  3. Target cell:
    – Epithelial cells
    – Fibroblasts
  4. Effects:
    – Cellular proliferation
  5. Diseases:
    a) Psoriasis
    - TGF-alpha overproduction
    b) Breast Cancer
    - overexpression of HER2 receptor
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4
Q

• Platelet Derived Growth Factor

  1. Receptor Type
  2. Cell of origin
  3. Target cell
  4. Effects
  5. Diseases
A

PDGF

Family of secreted proteins

• Receptor type:
– Receptor tyrosine kinase
– 2 types
• PDGFR alpha
• PDGFR beta
• Cell of origin:
– Platelet alpha granules
– Macrophages
– Endothelial cells
– Fibroblasts
Target cell:
– Mesenchymal cells (no PDGFR
on epithelial cells)
• Hematopoietic cells (monocytes/macrophages, etc.)
• Fibroblasts

• Effects:
– Primary chemokine and mitogen for mesenchymal cells
– Stimulates fibroblasts to
secrete extracellular matrix
(ECM) and collagenase (to heal wound, does not re-epithelialize)

Disease:
Chronic eosinophilic leukemia
-fusion of the PDGFR alpha gene with FIP1L1 gene in a hematopoietic cell precursor.
-result: ligand (PDGF) independent activation of PDGFR alpha and uncontrolled proliferation of eosinophils.
-Treatment: imatinib, small molecule inhibitor of kinase region of PDGFR

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5
Q

• Fibroblast Growth Factor

  1. Receptor Type
  2. Cell of origin
  3. Target cell
  4. Effects
  5. Diseases
A

FGF

20 family members

• Receptor type:
– Receptor tyrosine kinase
– Requires FGF to be
bound to extracellular
matrix (syndecan) in
order to activate
receptor

• Cell of origin:
– Endothelial cells
– Macrophages

Target cell:
– Fibroblasts
– Endothelial cells

• Effects:
– Fibroblast chemotaxis
and proliferation
– ECM deposition
– Angiogenesis

Disease:

  • heart development and regeneration
  • eye development
  • squamous cell lung carcinoma
  • bladder cancer
  • breast cancer
  • clinical cartilage disorders
  • synapse formation
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6
Q

• Vascular Endothelial Growth Factor

  1. Receptor Type
  2. Cell of origin
  3. Target cell
  4. Effects
  5. Diseases
A

VEGF

Family of polypeptide
growth factors

• Receptor type:
– Receptor tyrosine kinase

• Cell of origin:
– Variety of mesenchymal
cells (leukocytes–monocytes/macros, neutorphils– and
fibroblasts)

Target cell:
– Endothelial cell
• Effect:
– Angiogenesis
– Endothelial cell
proliferation and
migration
– Increase vascular
permeability

Disease
-tumors secrete VEGF

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7
Q

• Transforming Growth Factor Beta

  1. Receptor Type
  2. Cell of origin
  3. Target cell
  4. Effects
  5. Diseases
A

TGF-B

Large family of polypeptide
growth factors

• Receptor type:
– Receptor serine/threonine
kinase

• Cell of origin: many
– Platelets
– Endothelial cells
– Fibroblasts
– Macrophages, lymphocytes

Target cell:
– Fibroblasts
– Leukocytes

• Functions:
– Multiple opposing effects
– Promotes fibrogenesis
– Stimulates proliferation of fibroblasts and smooth muscle
– Inhibits growth of epithelial and
mesenchymal cells
– Strong anti-inflammatory agent
– Attracts neutrophils, fibroblasts,
macrophages
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8
Q

What are Growth Factors?

A

Polypeptides that bind cellular receptors and
stimulate cell proliferation

Can also stimulate
• Cytoskeletal rearrangement – cellular motility and contractility
• Cellular differentiation
• Angiogenesis

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9
Q

Interferon

  1. Origin
  2. Target
  3. Effect
A

IFN-Down regulates collagen synthesis

Cell of origin:
– T-cells

• Target cells:
– Macrophages
– Fibroblasts

• Wound healing effect:
– Activates macrophages (major mediator of wound
healing)
– Down regulates collagen synthesis
– Inhibits fibroblast proliferation
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10
Q

Interleukin-1

  1. Origin
  2. Target
  3. Effect
A

IL-1: Mediates inflammatory cell functions in wound

Cell of origin:
– Macrophages

• Target cells:
– Inflammatory cells
– Fibroblasts

• Wound healing effect:
– Mediates inflammatory cell functions in wound
– Neutrophil and fibroblast chemotaxis

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11
Q

Tumor Necrosis Factor

  1. Origin
  2. Target
  3. Effect
A

TNF-a (made by macros, T’s, synovial)
TNF-B: made by T cells

Cell of origin:
– Macrophages
– T-cells

• Target cells:
– Macrophages
– T-cells

• Wound healing effects:
– Activates macrophages and stimulates IL-1 production
(autocrine)
– Activates T-cells
– Induces collagen production in fibroblasts
– Attracts neutrophils
-endogenous pyrogen
-alone or with IL-1 cause systemic inflammation

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12
Q

Cytokines

A

Secreted small molecules that regulate the inflammatory and immune response

Some GF effects, but mostly for communication/regulation

  • Cytokines important in wound healing:
  • Interferon
  • Interleukin-1 (IL-1)
  • Tumor necrosis factor (TNF)
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13
Q

Embryonic stem cells

A 
1.Derived from the
inner cell mass of the
blastocyst
2.Each cell is
pluripotent
3.Have self renewal
capacity
Potential uses
• Treatment of diseases
where there is a loss of
critical cell types
– Myocaridal infarction
– Alzheimer disease
– Parkinson disease
– Spinal cord injury
– Type I diabetes
Challenges
• Ethical issues of using
human blastocysts as
source of ESCs
• Transplant rejection
• Tumor formation
(teratomas)
• Persistence of underlying
disease
• Making differentiated cells function normally (proper neuron connections)
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14
Q

Induced pluripotent stem cells

A
  1. Take adult skin cells and use factors to transduce them back to pluripotent stem cells
  2. Solves ethical and rejection issues
  3. issue: may induce tumor formation
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15
Q

Adult Stem Cells

A 
Small reservoirs of
self-renewing cells
in multiple tissues
• Restricted in their
differentiation
potential
• Function is to
regenerate cells lost
by normal wear and
tea

Restricted niches
• Ability to transdifferentiate in vitro

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16
Q

Cell population response to injury

A 
1. Increase # of dividing
stem cells (growth
factors signaling)
2. Increase # of
replications of cells in
the amplifying pool
3. Decrease cell-cycle
time for each division
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17
Q

5 Functions of ECM

A

Acellular substance secreted locally that
surrounds, interacts with, and envelops cells

• Functions:
1. Provide turgor by sequestering water or rigidity by
sequestering minerals
2. Reservoir for secreted growth factors
3. Framework for cells to adhere, migrate, and
proliferate in
4. Mediates cell-cell interactions
5. Site of remodeling during wound healing

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18
Q

Composition of the ECM

A

Composition of the ECM:

  1. Fibrous Structural Proteins
    a. Collagen
    b. Elastin and Fibrillin
  2. Cell Adhesion Proteins
    a. Secreted
    i. Fibronectin
    ii. Laminin
    b. Cell surface bound
    i. Integrins
    ii. Cadherins
  3. Proteoglycans and hyaluronic acid
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19
Q

Two types of ECM

A
  1. Interstitial Matrix
    – Space between cells
  2. Basement Membrane
    – Structure that separates epithelial cells from mesenchymal cells

*Both comprised of:
i. Fibrous structural
proteins
ii. Adhesive glycoproteins
iii. Proteoglycans and hyaluronic acid

20
Q

Collagen

A 
27 types of collagen
• Triple helix of 3
polypeptide chains
• Modified by
hydroxylation and
glycosylation
• Secreted, cleaved, and
cross-linked into fibrils
• Cross-linking occurs at
lysine and proline
residues (Vit C dependent)
21
Q

Types of Collagen

A

Type I - most common in mammals (bone, tendon, mature scars)
Type II - articular and hyaline cartilage.
Type III - embryonic collagen. In adults found in blood vessels, uterus & GI tract. First collagen deposited during
wound healing. Eventually degraded and replaced by Type I
collagen.
Type IV - basement membranes. Non-fibrillar.

22
Q

Other Fibrous Structural Proteins: Elastin, Fibrillin, Elastic Fibers

A

Elastic fibers are composed of
a core of elastin surrounded by fibrillin

  • Specialized fiber that allows for recoil after stretching
  • Found in arteries, skin, uterus,and lung
23
Q

Cell Adhesion Proteins: Fibronectin

A

Paperclip

Plasma fibronectin:
– Stabilizes early clot (fibrinplug)

• Cellular fibronectin:
– Secreted from
fibroblasts, macrophages,
endothelial cells

• Binds numerous
molecules

• First ECM deposited
during wound healing

Functions:

  1. Adds structural integrity to clot
  2. Chemotactic for many cells
  3. Substrate for cellular adhesion (RGD domain)
  4. Substrate for other ECM protein attachment and assembly
24
Q

Cell Adhesion Proteins: Laminin

A

Found primarily in basement membranes

– Forms tight polymer networks with Type IV
collagen to help maintain basement membrane integrity

• Similar functions as fibronectin:
– Substrate for ECM protein binding (heparin,
collagen)
– Substrate for cell adhesion

25
Q

Surface Bound Cell Adhesion Proteins: Integrins

A

Function as receptors (transmembrane or cytoplasmic)
• Allow cells to interact with each other and the ECM

Integrins:
-Transmembrane receptors
• Facilitates cell-cell interaction
• Facilitates cellular interaction
with ECM by binding collagen, fibronectin, and laminin
• Links the cell surface to the cytoskeleton
– Conformation changes in cytoskeleton can initiate signal transduction to result
in cell proliferation,
apoptosis, or differentiation

26
Q

Surface Bound Cell Adhesion Proteins: Cadherins

A 
Facilitate cell-cell interactions
between similar cell types
• Facilitate formation of cell junctions
• Linked to the cytoskeleton
through catenins to regulate cell motility, proliferation,
and differentiation
27
Q

Proteoglycans

A

See Slide 80

Repeating polymers of
disaccharides (chondroitin sulfate, heparan sulfate,
dermatan sulfate) bound to a protein core

• Forms an ECM scaffold for tissue structure and
permeability

*Binds syndecan which FGF binds to in order to interact with its receptor

28
Q

Hyaluronic Acid

A 
Huge molecule of long
repeating polysaccharides
without a protein core (in
contrast to proteoglycans)
• Can bind a large amount of water
• Forms a viscous hydrated gel
• Allows ECM to resist
compressive forces-turgor
• Deposited early during
wound healing to facilitate cell migration and proliferation

-Lots of HA in granulation tissue

slide 81

29
Q

Phases of Wound Healing

A
  1. Hemostasis Phase
  2. Inflammatory Phase
  3. Proliferative Phase
    a. Angiogenesis
    b. Granulation tissue
    c. Fibroplasia
    d. Epithelialization
    e. Contraction
  4. Maturation Phase
30
Q

Hemostasis

A

Stop the bleeding and facilitate inflammation:

a) Platelets activated by exposed collagen
– Aggregate at injury site
– Secrete inflammatory
agents (serotonin, bradykinin, prostaglandins,
histamine) from alpha granules

b) Plasma fibrin/ fibronectin forms plug
- early structural support

c) Platelets release cytokines to activate clotting and complement cascades

***thromboxane:Transient vasoconstriction &
platelet aggregation – lasts
about 10 minutes

***histamine: 
– Vasodilation
– Increased vascular
permeability
....Water moves into wound (edema)
.....Allows extravasation of
inflammatory cells into
wound
31
Q

Inflammatory

A

Stop infection, clear debris, induce repair

EARLY: 
– Neutrophils appear within
hours (short lived)
• Attracted by chemokines
(fibronectin, PDGF, TGF-b,
C5b, TNF)
• Phagocytose debris and
pathogens
– Macrophages become
predominant cell after 2 days
(long lived)
• Secrete growth factors,
cytokines, and proteases
• Phagocytose debris and
pathogens
-----------------------
LATE:

– Macrophage secretion peaks on day 3-4
– Secreted factors attract and activate multiple cell types needed for the proliferative
phase
– Neutrophil/macrophage
numbers begin to decline
– Fibroblasts become
predominant cell
– Early wound ECM consists of fibrin, fibronectin, and
hyaluronic acid
• Serves as an anchor for cell adhesion and collagen deposition

32
Q

Proliferative

A

Repair: replacement of lost tissue w/scar

Provides structural support - does not regenerate normal tissue.

Begins 2-3 days after injury.

Characterized by:

1) Migration/activation of fibroblasts
2) Deposition of provisional ECM
3) Constant tissue remodeling and collagen deposition

Artificially composed of multiple overlapping processes:

1) Angiogenesis
2) Formation of granulation tissue
3) Fibroplasia
4) Epithelialization
5) Wound contraction

33
Q

Proliferative Phase: Angiogenesis

A

Restore perfusion to the wound

VEGF
– Increased vascular permeability
– Endothelial cell migration
– Promotes angiogenesis

• Fibronectin/fibrin in ECM
facilitates endothelial cell
migration
– Proteases degrade existing ECM for endothelial migration

• New thin walled vessels in
wound site (granulation tissue)

• Most vessels regress via
apoptosis

34
Q

Proliferative Phase: Granulation

Tissue

A

Fills defect left by injury prior to vigorous collagen deposition (fibrosis)

2-5 days after injury
• Composed of highly vascular loose fibrous tissue with scattered inflammatory cells and proliferating fibroblasts

• Provisional ECM composed of:
– Fibronectin
– Type III collagen
– Hyaluronic acid

• Growth factors:
– PDGF and TGF-beta facilitate fibroblast migration and proliferation

See slide 100

35
Q

Proliferative Phase: Fibroplasia

A

Influx and proliferation of fibroblasts w/subsequent collagen deposition

TGF-Beta

• Fibroblasts attracted and activated by TGF-b, PDGF, EGF, FGF, and cytokines from platelets, inflammatory cells and endothelial cells

• TGF-b is a critical mediator of fibrogenesis
– Increases fibroblasts proliferation/migration
– Increases collagen and fibronectin synthesis
– Decreases degradation of ECM
– Chemotactic for monocytes

• Fibroplasia ends 2-4 weeks after injury, when collagen degradation exceeds deposition.

Slide 103

36
Q

Proliferative Phase: Epithelialization

A

Restoration of the injured epithelium

Basal keratinocytes (in skin
wounds)
– Proliferate from edges of wound migrate until contact
inhibition
– Proliferation and migration
stimulated by EGF, KGF, FGF
– Migration is facilitated by
interaction with
fibronectin/fibrin in the
provisional ECM of granulation tissue
• Migrate over granulation tissue,but under scab

slide 105

37
Q

Proliferative Phase: Contraction

A

Pulls edges of a wound together to reduce the wound surface area

• Decreases wound size by
40-80%

• Mediated by myofibroblasts 
– TGF-b induces
differentiation of fibroblasts
to myofibroblasts
– Myofibroblasts contain actin filaments that are linked to the ECM and facilitate contraction

Issues w/excessive wound contractures

38
Q

Maturation Phase

A

Remodeling of the ECM with mature scar formation to increase tensile strength

Starts around Day 6

  • Collagen production = collagen degradation
  • Process can last over 1 year
  • Degradation of collagen and ECM by matrix metalloproteinases (MMPs)

• Replacement of Type III collagen with Type I collagen
– Collagen is organized, cross-linked, and
aligned along lines of tension
– Final wound strength = 80% of normal

• Replacement of hyaluronic acid with proteoglycans (heparan sulfate,
chondroitin sulfate)

• Mature scar:
– Dense type I collagen, elastic fibers, proteoglycans, scattered fibroblasts

39
Q

Factors that Affect Wound Healing

A 
1.  Injury:
– Tissue involved
– Extent of injury
• Intensity of injurious stimulus
• Duration of injurious stimulus
  1. Local Factors
  2. Systemic Factors
40
Q

Factors that Affect Wound Healing: Local Factors

A

• Type, size, and location
of wound

• Vascular supply
– Ischemic wounds don’t
heal

• Oxygen supply
– Increased O2 promotes
wound healing

• Infection
– Infection delays or
prevents wound healing

• Necrosis
– Necrotic tissue lowers pH,
causes inflammation, and
prevents healing

• Foreign material
– Impairs wound healing,
nidus for infection

• Movement
– Can pull wound apart

• Radiation
– Injures cells necessary for
healing

41
Q

Factors that Affect Wound Healing: Systemic Factors

A

• Circulatory compromise
– Heart failure, anemia

• Nutritional status
– Decreased protein synthesis in malnutrition
– Zinc is critical for matrix
metalloproteinase function
– Vitamin C is critical for
collagen cross-linking
– Vitamin A important in reepithelialization
– Thiamine and riboflavin
deficiency associated with
poor wound healing

• Diabetes mellitus
– Impairs microvascular
circulation

• Obesity

• Hormones
– Glucocorticoids inhibit
inflammation and
collagen synthesis

• Chemotherapy
– Prevents cell
proliferation

42
Q

Complications of Cutaneous Wound Healing

A
  1. Deficient scar formation
    • Wound dehiscence or
    ulceration
  2. Excessive scar formation
    • Hypertrophic scars or
    keloids
  3. Contractures
    • Deformation of wound
    • Muscle or joint fixation
43
Q

Types of Injuries

A 
Abrasion
Laceration
Incision
Avulsion
Amputation
Puncture
44
Q

Surgical Wound Healing: Primary Intention

A

Close it up w/stiches, staples, glue, etc.

45
Q

Surgical Wound Healing: Delayed Primary Intention

A

Wound is initially left open, when granulation tissue is judged to be clean
and viable the wound is closed as in primary intention

46
Q

Surgical Wound Healing: Secondary Intention

A

Considered for contaminated wounds (warfare).

Left open to scar-in from below.

Greater inflammatory response, more granulation tissue, increased
wound contraction, often larger scar.

Pathology (5 decks)

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