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PATH30001 - Mechanisms of Disease > Lecture 8 - Healing 2 > Flashcards

Lecture 8 - Healing 2 Flashcards

1
Q

What is the structure of proteoglycans?

Name an important proteoglycan

A

Core protein + glycosaminoglycans

Draw this

• Many -ve charges

Aggrecan

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2
Q

What is the function of cadherins?

A

Adherence of two neighbouring cells of the same type

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3
Q

What happens when cells aren’t bound by integrins?

A

Apoptosis is triggered

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4
Q

Describe the function of proteoglycans

A

• Hold a lot of water, forming a gel-like structure
• Reservoir for GFs (bind GFs on their G3 region)
→ Modulate cell growth and differentiation

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5
Q

What are the essential processes in healing?

Describe briefly which factors mediate these processes

A
  1. Angiogenesis
    • EPCs: endothelial precursor cells
    • VEGF
  2. Fibroplasia
    • Fibroblasts
  3. Remodelling
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6
Q

Describe angiogenesis

A

‘Explosion’ of new blood vessels

– Proliferation from existing vasculature –

  1. VEGF binds to VEGFR on endothelium
  2. Endothelial cells re-enter cell cycle
  3. Sprouting of capillaries
  4. Reorganisation, maturation

– Proliferation from EPCs from BM –

  1. VEGF released from ECM stimulated EPCs in BM
  2. EPCs migrate to vasculature
  3. EPCs start to proliferate
  4. New branches made
  5. Stabilisation of vessels:
    • Pericytes
    • Smooth muscle
    • Connective tissue
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7
Q

What is vasculogenesis?

Describe the process

A

Specialised form of angiogenesis during embryogenesis

Laid down for the first time

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8
Q

What is fibroplasia?

Compare this with fibrosis

A

Formation of new connective tissue

Fibrosis is any abnormal laying down of connective tissue

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9
Q

What is remodelling?

A

Maturation and reorganisation of fibrous tissue

Vascular granulation tissue → avascular scar

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10
Q

Which stem cells give rise to new vasculature?

A

EPCs

Endothelial precursor cells

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11
Q

Where does VEGF come from?

When is it induced?

A 
ECM cells
Indued by:
 • Hypoxia
 • TGF-β
 • PDGF
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12
Q

How is angiogenesis controlled?

A 
Interactions between:
 • GFs
 • Vascular cells
 • ECM
Stabilisation of vessels
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13
Q

Describe stabilisation of new vasculature and how this is initiated

A

Must be stabilised
• Pericytes
• ECM
• Smooth muscle

Initiated by:
• Angiopoietin
• PDGF
• TGF-β

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14
Q

Which cytokine plays a central role in fibroplasia?

A

TGF-β

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15
Q

What is the role of macrophages in fibroplasia?

A
  • Clear debris

* Secrete GFs

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16
Q

What happens to vasculature as the scar matures?

A

Vascular regression

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17
Q

Compare healing of small and large wounds

A

Small:
1. Scab formation, neutrophil infiltrate
2. Regeneration of epithelium
NB Minimal inflammation

Large
1. Big scab
2. Fibrosis, replacement of tissue
3. Scar formation
NB Inflammation
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18
Q

What is the definition of ECM?

A
  • Macromolecules outside cells
  • Formed by local secretion
  • Assembled into network surrounding cells
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19
Q

What are the general functions of the ECM?

A
  • Reservoir for GFs
  • Reservoir for water
  • Scaffold
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20
Q

What is the basement membrane?

Describe its structure

A

Specialised part of the ECM

Structure:
• Laminin
• Proteoglycan
• Collagen type IV

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21
Q

What are the two groups of matrix components?

A
  • Basement membrane

* Interstitial matrix

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22
Q

What are the three types of molecules found in ECM?

A
  • Fibrous proteins
  • Adhesive proteins
  • Gelatinous-like molecules
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23
Q

What are some examples of fibrous proteins?

A
  • Collagen

* Elastin

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24
Q

What are some examples of adhesion proteins?

A
  • Fibronectin

* Laminin

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25
Q

What are some examples of gelatinous-like molecules?

A
  • Proteoglycan

* Hyaluronan

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26
Q

Why is collagen important in terms of abundance?

A

Most common protein in the animal world

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27
Q

Describe the structure of collagen

A
  • 3 right handed triple alpha helices

* Gly-X-Y repeating units

28
Q

How many types of collagen are there?

What are the two main groups?

A

27 types
• Fibrillar
• Amorphous

29
Q

What are some disorders caused by mutation in collagen?

A

Ehlers-Danlos syndrome
Achondrogenesis
Osteogenesis imperfect
Alport syndrome

30
Q

Describe the formation of collagen

A
  1. Protocollagen
  2. Cleavage of ends to form Tropocollagen
  3. Association of tropocollagen into collagen fibrils
  4. Cross linking of collagen fibrils to form collagen fibres
31
Q

Describe the structure of elastic fibres

A

Elastin core

Fibrillin surrounding

32
Q

In which tissues are elastic fibres important?

A

Blood vessels
Skin
Uterus
Lungs

33
Q

What is an important disorder resulting from mutation in fibrillin?

List the features

A

Marfan Syndrome

Features:
• Very long bones
• defects in organs where elastic fibres are important (heart valves, lungs, eyes, aorta)
• Chronic inflammation

34
Q

Why is chronic inflammation seen in Marfan syndrome?

A

Fibrillin (in which there is a defect) is needed for regulation of TGF-B-dependent inflammation

35
Q

Where are the adhesive proteins found?

A
  • Membrane bound (thus, receptors)

* Cytoplasm

36
Q

What are the four major families of adhesion proteins?

A
  • ICAMs
  • Cadherins
  • Integrins
  • Selectins
37
Q

What are ICAMs?

A

Integral cell adhesion molecules

38
Q

Describe the structure of fibronectin

A

Two chains linked by disulphide bonds

39
Q

What are the functions of fibronectin?

A
  • Cell migration

* Cell attachment

40
Q

What are some features of laminin?
What is its structure?
Where is it found?

A
  • Adhesion molecule
  • Most abundant protein in the basement membrane
  • 3 chains, cross shaped

Location:
• Basement membrane

41
Q

What are the functions of laminin?

A

• Cell - ECM attachment

Important for:
• Growth
• Survival
• Motility

42
Q

Describe the structure of integrins

A

Two chains:
• α
• β

43
Q

Describe the function of integrins

A 
Attachment:
 • Cell-cell
 • Cell-ECM
Important for:
 • Development
 • Leukocyte extravasation
44
Q

How does fibronectin connect to cells?

A

Via Integrin

45
Q

Describe the structural interaction of integrins and cells

Why is this structure important?

A
  • Transmembrane integrin
  • Focal adhesion inside the cell
  • Actin skeleton associated with focal adhesion

This structure has a role in signalling from outside the cell to the nucleus

46
Q

In which cellular junctions are cadherins found?

A

Desmosomes

47
Q

Describe the structure of hyaluronan

Draw this

A

Long protein core with proteoglycan associated.

Slide 25

48
Q

What gives a tissue its turgor pressure?

What does this mean?

A

Hyaluronan

Able to resist compressive forces

49
Q

What are the general functions of VEGF?

A
  • Angiogenesis
  • Vascular permeability
  • Endothelial proliferation and migration
50
Q

When does fibrosis normally occur?

A

In chronic disease

51
Q

What is new granulation tissue?

A

This is new connective tissue

52
Q

What is seen in granulation tissue?

A
  • Tiny blood vessels

* ECM

53
Q

Which cells are the main players in fibroplasia?

A

Fibroblasts

54
Q

Why is TGF-β important for fibroplasia?

A
  • Recruitment & proliferation of fibroblasts

* Increased synthesis

55
Q

Which molecule do fibroblasts lay down in fibroplasia?

A

Fibrillar collagen

56
Q

What does the outcome of healing depend on?

A
  • Severity of injury
  • Duration of injurious stimulus
  • Tissue type
  • Patient factors (immunosupression etc.)
57
Q

What is the process that predominates in small wound healing?
Compare this with large wound healing

A

Small wound: epithelial regeneration
• minimal inflammation
Large wound: fibrosis
• chronic inflammation occurs

58
Q

What do the chronic inflammation cytokines lead to?

A

Collagen synthesis

59
Q

What are the chronic inflammation cytokines?

A

TNF
IL-1
IL-4
IL-13

60
Q

What does decreased metalloprotinase activity lead to?

A

Decreased collagen degradation

61
Q

What are the steps in generic wound healing?

A
  1. Demolition (injurious stimulus)
  2. Proliferation
  3. Migration
  4. Synthesis
  5. Remodelling
62
Q

List some of the components of the interstitial matrix

A
  • Fibrillar collagens
  • Elastin
  • Fibronectin
  • Proteoglycans
63
Q

Compare location of fibronectin and laminin

A

Laminin: basement membrane
Fibronectin: interstitial matrix (stromal)

64
Q

What is the stroma?

A

AKA the interstitial matrix of the ECM

65
Q

Which GF and receptor is most important in angiogenesis?

What does it bring about

A

VEGF: ligand, released by ECM

VEGFR-2: receptor, located on endothelial cells

Brings about proliferation of endothelial cells

66
Q

Why is the ECM important in angiogenesis?

What are the important components of the ECM?

A 
Direction of migration of endothelial cells
Components:
 • Integrins
 • Matricellular proteins
 • Proteases
67
Q

Describe the pathway to fibrosis

A
  1. Chronic inflammation
  2. Chronic activation of macrophages and lymphocytes, which produce:
    3a. GFs
    3b. Cytokines (TGF-beta)
    3c. Decreased MMPs
    4a. GFs stimulate fibroblasts
    4b. Cytokines stimulate fibrogenic cells to make collagen
    4c. Decreased MMPs means decreased collagen destruction
  3. This all leads to collagen deposition, and thus fibrosis

PATH30001 - Mechanisms of Disease (34 decks)

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