Lecture 7 - Healing 1 Flashcards Preview

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1
Q

Which process is vital for resolution and healing?

A

Turning off of acute inflammation

Removal of the injurious stimulus

2
Q

Describe the various cell populations in normal homeostasis

A
  • Stem cells
  • Baseline cell population
  • Proliferating cells
  • Differentiated cells
  • Apoptotic cells
3
Q

How do cells know whether to proliferate or undergo apoptosis?

A

Signalling
• Autocrine
• Paracrine
• Endocrine

4
Q

What are the different groups of cells in terms of proliferative capacity?

A
  • Labile cells
  • Stable cells
  • Permanent
5
Q

What are stable cells?

Give some examples

A
  • In G0 phase
  • Can re-enter the cell cycle when exposed to particular stimuli

For example:
• Liver
• Pancreas
• Kidney

6
Q

What are permanent cells?

Give some examples

A

Non dividing, can never re-enter the cell cycle
eg.
• Neurons
• Myocardium

7
Q

What are labile cells?

Give some examples

A

Constantly dividing

• Epithelia

8
Q

What does regeneration require?

What does replacement require?

A

Regeneration:
• Basement membrane
• Extracellular matrix interaction

Replacement:
• ECM interaction

9
Q

Which cell types are important in healing?

A
  • Fibroblasts
  • Endothelial cells
  • Epithelial cells
  • Osteoblasts
10
Q

Which ligands are important in proliferation?

A
  • Growth factors
  • Maxtrix proteins
  • Cytokines
  • Hormones
  • Chemokines
11
Q

Which receptors are important in proliferation?

A
  • Receptor tyrosine kinases
  • GPCR
  • Cytokine receptors
12
Q

Why is balance between stimulatory and inhibitory signals in proliferation important?

A

Stimulatory required to ‘re-awaken’ cells

However, inhibitory needed to prevent excessive proliferation and cancer

13
Q

How do receptors without intrinsic catalytic activity function?
Which receptors don’t have intrinsic catalytic function?

A

They interact with a second messenger which does have catalytic activity

Cytokine receptors don’t have intrinsic catalytic activity

14
Q

Which ligands commonly bind to GPCRs?

A
  • Chemokines

* Hormones

15
Q

What is the structure of GPCRs?

A

7 transmembrane domains

16
Q

Describe the activity of RTKs

A
  1. Ligand (often GFs) binds
  2. Dimerisation
  3. Auto-phosphorylation at tyrosine residues
  4. Activation of tyrosine kinase activity
  5. Activation of adaptor molecules

→ Proliferation

17
Q

Which general processes are brought about by growth factors?

A
  • Proliferation
  • Cell migration
  • Promotion of cell survival
18
Q

To which receptors do GFs mostly bind?

A

Receptor tyrosine kinases

19
Q

Describe an example of proliferation without GFs

A
  • Once cells fill out a space, they sense this and stop proliferating
  • Some cells are removed → loss of cell-cell contacts
  • Proliferation triggered
20
Q

What is EGF?

A

Epithelial GF

• mitogenic for epithelial cells and fibroblasts

21
Q

What is FGF?

A

Fibroblast GF

• angiogenesis

22
Q

What is HGF?

A

Hepatocyte GF

• mitogenic for epithelial cells

23
Q

What is VEGF?

A

Vascular endothelial GF

• vital for growth and proliferation of blood vessels

24
Q

Which major pathways are involved in growth and proliferation?

A
  • MAPK
  • cAMP
  • JAK / STAT
25
Q

Describe the sequence of events in the MAPK pathway

A
  1. GF ligand
  2. RTK (receptor tyrosine kinase)
  3. SOS
  4. Ras
  5. Raf
  6. Mek
  7. Erk
  8. Gene transcription
    → proliferation
26
Q

What is the major target of 2° messenger pathways?

A

Transcription factors

27
Q

What are transcription factors?

Describe their function

A

Molecules with DNA binding domains

→ activation or repression of gene transcription

28
Q

What are some growth promoting transcription factors?

What are these also known as?

A
  • c-fos
  • c-jun
  • c-myc

Also known as Proto-oncogenes

29
Q

What are some important Tumour suppressor genes?

A
  • p53
  • Rb (retinoblastoma protein)
  • PTEN
30
Q

What is the function of PTEN?

A

Inhibit growth promoting pathways

31
Q

What are some functions of TGF-β?

A

NB Pleiotropic: multiple functions

  • Decreased proliferation (stalls S phase)
  • Increased collagen production
  • anti-inflammatory
32
Q

What are the phases of the cell cycle?

A
( • G0)
 • G1
 • S
 • G2
 • Mitosis
33
Q

Why is the cell cycle tightly controlled?

A

There are many events occurring, and these must occur in a precise order

34
Q

Why is the cell cycle ‘cell autonomous’?

A

These means that within a tissue, each cell has its own time scale for the cell cycle

35
Q

What happens when there is loss of cell cycle control?

A

• Multi-nucleation

→ Cancer

36
Q

What are the phases of mitosis?

A
  • Prophase
  • Prometaphase
  • Metaphase
  • Anaphase
  • Telophase
37
Q

At which two points is the cell cycle most tightly regulated?

A

Two checkpoints:
• G1 / S checkpoint
• G2 / M checkpoint

38
Q

What is being checked at the G2 / M checkpoint?

A

Proper DNA replication

39
Q

What is being checked at the G1 / S checkpoint?

A

Errors in DNA

40
Q

Which factors control the cell cycle?

A
  1. Cyclins & CDKs (cyclin dependent kinases)

2. Cell cycle checkpoints

41
Q

What are the different types of cyclins?

Describe their presence

A

• Cyclin A
• Cyclin B
• Cyclin D
• Cyclin E
The individual concentrations of each rise and fall throughout the cell cycle.
This dictates the start and stop of each particular stage

42
Q

Which organs can regenerate?

Why?

A

Liver
• hepatocytes are stable
• after partial hepatectomy the hepatocytes re-enter the cell cycle and proliferate to regrow the organ

43
Q

What are the portal triads in the liver?

A
  • Hepatic artery
  • Hepatic portal vein
  • Bile duct
44
Q

Describe the process of regeneration in the liver after injury with and w/o damage to the ECM

A

Injury to cells; ECM intact
• full regeneration from residual cells

Injury to cells & ECM
• disordered deposition of collagen a regeneration from residual cells

45
Q

What happens in Rat corneas when ECM is destroyed

A

Can’t develop properly

46
Q

Compare and contrast the different modes of cell signalling, and give examples of processes that use each

A

Autocrine:
• molecules released by a cell which bind to receptors on that same cell
• e.g. liver regeneration
Paracrine
• molecules released by cells which act on receptors on neighbouring cells
• e.g. wound healing
Endocrine:
• molecules released into the blood stream, which act on target cells far away
• e.g. hormones

47
Q

Compare normal and abnormal healing in the skin

A
Normal:
 • wounds
 • burns
Abnormal:
 • ulceration
 • pressure
48
Q

Compare normal and abnormal healing in the lungs

A

Normal:
• normal acute healing

Abnormal:
• ARDS
• COPD

49
Q

What happens when ‘permanent cells’ are irreversibly injured?

A

Scar; replacement with non-functional tissue

50
Q

Compare Regeneration and Replacement in the healing

A

Regeneration:
• damaged cells replaced with new cells of the same type

Replacement:
• damaged cells replaced with non functional fibrous tissue

51
Q

Why does the outcome of healing vary?

A
  • different cell types have different regeneration capacities
  • depending on severity of injury
  • whether ECM / basement membrane is intact
52
Q

What is the ‘dogma’ of the molecular mechanisms of healing?

A
  1. Ligand-receptor interaction
  2. Second messenger
  3. Transcription factor activation
  4. Gene expression

→ action

53
Q

Describe the generalised mechanism of cytokine signalling

A
  1. Cytokine binds cytokine receptor
    (receptor has no intrinsic catalytic function)
  2. JAK / STAT pathway induced
  3. Transcription factor activation
54
Q

Which pathway does GPCR activation generally trigger?

Compare this with cytokine receptors.

A

GPCR: cAMP

Cytokine receptors: JAK / STAT

55
Q

Which general processes are activated by JAK / STAT & cAMP pathways?

A
  • migration
  • synthesis
  • secretion

or inhibition of these processes

56
Q

What is PDGF?

A

Platelet derived GF
• migration and proliferation of fibroblasts
• pro-inflammatory

57
Q

What is the general outcome of the MAPK pathway?

A

Proliferation

58
Q

What is the ECM?

A

Extra-cellular matrix
• Gel-like meshwork of large proteins ground substance
• Structural support for cells
• Involved in signalling

59
Q

What are the five stages of the healing process?

A
  1. Demolition
  2. Proliferation
  3. Migration
  4. Synthesis
  5. Remodelling
60
Q

Compare the cellular outcomes of:
• MAPK
• JAK/STAT
• cAMP pathway

A

MAPK:
• Proliferation

JAK/STAT
• Synthesis
• Secretion
• Migration

cAMP:
• Synthesis
• Secretion
• Migration

61
Q

What are 5 important GFs, and what are their respective functions?

A
  1. EGF (TGF)
    • Mitogenic for epithelium & fibroblasts
  2. FGF
    • Angiogenesis
    • Migration of macrophages & fibroblasts during wound repair
  3. VEGF
    • Angiogenesis
  4. PDGF
    • Pro-inflammatory
    • Migration & proliferation of cells
  5. HGF
    • Mitogenic for epithelial cells
62
Q

Describe how cyclins control the cell cycle

A
  1. Specific cyclin expression up regulated
  2. Cyclin binds to CDK
  3. Cyclin/CDK complex phosphorylates Rb
  4. Rb cannot block the cell cycle