Lecture 7 - Healing 1 Flashcards Preview

PATH30001 - Mechanisms of Disease > Lecture 7 - Healing 1 > Flashcards

Flashcards in Lecture 7 - Healing 1 Deck (62):
1

Which process is vital for resolution and healing?

Turning off of acute inflammation
Removal of the injurious stimulus

2

Describe the various cell populations in normal homeostasis

• Stem cells
• Baseline cell population
• Proliferating cells
• Differentiated cells
• Apoptotic cells

3

How do cells know whether to proliferate or undergo apoptosis?

Signalling
• Autocrine
• Paracrine
• Endocrine

4

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

• Labile cells
• Stable cells
• Permanent

5

What are stable cells?
Give some examples

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

For example:
• Liver
• Pancreas
• Kidney

6

What are permanent cells?
Give some examples

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

7

What are labile cells?
Give some examples

Constantly dividing
• Epithelia

8

What does regeneration require?

What does replacement require?

Regeneration:
• Basement membrane
• Extracellular matrix interaction

Replacement:
• ECM interaction

9

Which cell types are important in healing?

• Fibroblasts
• Endothelial cells
• Epithelial cells
• Osteoblasts

10

Which ligands are important in proliferation?

• Growth factors
• Maxtrix proteins
• Cytokines
• Hormones
• Chemokines

11

Which receptors are important in proliferation?

• Receptor tyrosine kinases
• GPCR
• Cytokine receptors

12

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

Stimulatory required to 're-awaken' cells
However, inhibitory needed to prevent excessive proliferation and cancer

13

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

They interact with a second messenger which does have catalytic activity

Cytokine receptors don't have intrinsic catalytic activity

14

Which ligands commonly bind to GPCRs?

• Chemokines
• Hormones

15

What is the structure of GPCRs?

7 transmembrane domains

16

Describe the activity of RTKs

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

Which general processes are brought about by growth factors?

• Proliferation
• Cell migration
• Promotion of cell survival

18

To which receptors do GFs mostly bind?

Receptor tyrosine kinases

19

Describe an example of proliferation without GFs

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

20

What is EGF?

Epithelial GF
• mitogenic for epithelial cells and fibroblasts

21

What is FGF?

Fibroblast GF
• angiogenesis

22

What is HGF?

Hepatocyte GF
• mitogenic for epithelial cells

23

What is VEGF?

Vascular endothelial GF
• vital for growth and proliferation of blood vessels

24

Which major pathways are involved in growth and proliferation?

• MAPK
• cAMP
• JAK / STAT

25

Describe the sequence of events in the MAPK pathway

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

26

What is the major target of 2° messenger pathways?

Transcription factors

27

What are transcription factors?
Describe their function

Molecules with DNA binding domains
→ activation or repression of gene transcription

28

What are some growth promoting transcription factors?
What are these also known as?

• c-fos
• c-jun
• c-myc

Also known as Proto-oncogenes

29

What are some important Tumour suppressor genes?

• p53
• Rb (retinoblastoma protein)
• PTEN

30

What is the function of PTEN?

Inhibit growth promoting pathways

31

What are some functions of TGF-β?

NB Pleiotropic: multiple functions

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

32

What are the phases of the cell cycle?

( • G0)
• G1
• S
• G2
• Mitosis

33

Why is the cell cycle tightly controlled?

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

34

Why is the cell cycle 'cell autonomous'?

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

35

What happens when there is loss of cell cycle control?

• Multi-nucleation
→ Cancer

36

What are the phases of mitosis?

• Prophase
• Prometaphase
• Metaphase
• Anaphase
• Telophase

37

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

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

38

What is being checked at the G2 / M checkpoint?

Proper DNA replication

39

What is being checked at the G1 / S checkpoint?

Errors in DNA

40

Which factors control the cell cycle?

1. Cyclins & CDKs (cyclin dependent kinases)
2. Cell cycle checkpoints

41

What are the different types of cyclins?
Describe their presence

• 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

Which organs can regenerate?
Why?

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

43

What are the portal triads in the liver?

• Hepatic artery
• Hepatic portal vein
• Bile duct

44

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

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

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

45

What happens in Rat corneas when ECM is destroyed

Can't develop properly

46

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

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

Compare normal and abnormal healing in the skin

Normal:
• wounds
• burns
Abnormal:
• ulceration
• pressure

48

Compare normal and abnormal healing in the lungs

Normal:
• normal acute healing

Abnormal:
• ARDS
• COPD

49

What happens when 'permanent cells' are irreversibly injured?

Scar; replacement with non-functional tissue

50

Compare Regeneration and Replacement in the healing

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

Replacement:
• damaged cells replaced with non functional fibrous tissue

51

Why does the outcome of healing vary?

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

52

What is the 'dogma' of the molecular mechanisms of healing?

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

→ action

53

Describe the generalised mechanism of cytokine signalling

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

54

Which pathway does GPCR activation generally trigger?
Compare this with cytokine receptors.

GPCR: cAMP
Cytokine receptors: JAK / STAT

55

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

• migration
• synthesis
• secretion

or inhibition of these processes

56

What is PDGF?

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

57

What is the general outcome of the MAPK pathway?

Proliferation

58

What is the ECM?

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

59

What are the five stages of the healing process?

1. Demolition
2. Proliferation
3. Migration
4. Synthesis
5. Remodelling

60

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

MAPK:
• Proliferation

JAK/STAT
• Synthesis
• Secretion
• Migration

cAMP:
• Synthesis
• Secretion
• Migration

61

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

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

Describe how cyclins control the cell cycle

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