Lecture 7 - Healing 1 Flashcards
Which process is vital for resolution and healing?
Turning off of acute inflammation
Removal of the injurious stimulus
Describe the various cell populations in normal homeostasis
- Stem cells
- Baseline cell population
- Proliferating cells
- Differentiated cells
- Apoptotic cells
How do cells know whether to proliferate or undergo apoptosis?
Signalling
• Autocrine
• Paracrine
• Endocrine
What are the different groups of cells in terms of proliferative capacity?
- Labile cells
- Stable cells
- Permanent
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
What are permanent cells?
Give some examples
Non dividing, can never re-enter the cell cycle
eg.
• Neurons
• Myocardium
What are labile cells?
Give some examples
Constantly dividing
• Epithelia
What does regeneration require?
What does replacement require?
Regeneration:
• Basement membrane
• Extracellular matrix interaction
Replacement:
• ECM interaction
Which cell types are important in healing?
- Fibroblasts
- Endothelial cells
- Epithelial cells
- Osteoblasts
Which ligands are important in proliferation?
- Growth factors
- Maxtrix proteins
- Cytokines
- Hormones
- Chemokines
Which receptors are important in proliferation?
- Receptor tyrosine kinases
- GPCR
- Cytokine receptors
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
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
Which ligands commonly bind to GPCRs?
- Chemokines
* Hormones
What is the structure of GPCRs?
7 transmembrane domains
Describe the activity of RTKs
- Ligand (often GFs) binds
- Dimerisation
- Auto-phosphorylation at tyrosine residues
- Activation of tyrosine kinase activity
- Activation of adaptor molecules
→ Proliferation
Which general processes are brought about by growth factors?
- Proliferation
- Cell migration
- Promotion of cell survival
To which receptors do GFs mostly bind?
Receptor tyrosine kinases
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
What is EGF?
Epithelial GF
• mitogenic for epithelial cells and fibroblasts
What is FGF?
Fibroblast GF
• angiogenesis
What is HGF?
Hepatocyte GF
• mitogenic for epithelial cells
What is VEGF?
Vascular endothelial GF
• vital for growth and proliferation of blood vessels
Which major pathways are involved in growth and proliferation?
- MAPK
- cAMP
- JAK / STAT
Describe the sequence of events in the MAPK pathway
- GF ligand
- RTK (receptor tyrosine kinase)
- SOS
- Ras
- Raf
- Mek
- Erk
- Gene transcription
→ proliferation
What is the major target of 2° messenger pathways?
Transcription factors
What are transcription factors?
Describe their function
Molecules with DNA binding domains
→ activation or repression of gene transcription
What are some growth promoting transcription factors?
What are these also known as?
- c-fos
- c-jun
- c-myc
Also known as Proto-oncogenes
What are some important Tumour suppressor genes?
- p53
- Rb (retinoblastoma protein)
- PTEN
What is the function of PTEN?
Inhibit growth promoting pathways
What are some functions of TGF-β?
NB Pleiotropic: multiple functions
- Decreased proliferation (stalls S phase)
- Increased collagen production
- anti-inflammatory
What are the phases of the cell cycle?
( • G0) • G1 • S • G2 • Mitosis
Why is the cell cycle tightly controlled?
There are many events occurring, and these must occur in a precise order
Why is the cell cycle ‘cell autonomous’?
These means that within a tissue, each cell has its own time scale for the cell cycle
What happens when there is loss of cell cycle control?
• Multi-nucleation
→ Cancer
What are the phases of mitosis?
- Prophase
- Prometaphase
- Metaphase
- Anaphase
- Telophase
At which two points is the cell cycle most tightly regulated?
Two checkpoints:
• G1 / S checkpoint
• G2 / M checkpoint
What is being checked at the G2 / M checkpoint?
Proper DNA replication
What is being checked at the G1 / S checkpoint?
Errors in DNA
Which factors control the cell cycle?
- Cyclins & CDKs (cyclin dependent kinases)
2. Cell cycle checkpoints
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
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
What are the portal triads in the liver?
- Hepatic artery
- Hepatic portal vein
- Bile duct
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
What happens in Rat corneas when ECM is destroyed
Can’t develop properly
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
Compare normal and abnormal healing in the skin
Normal: • wounds • burns Abnormal: • ulceration • pressure
Compare normal and abnormal healing in the lungs
Normal:
• normal acute healing
Abnormal:
• ARDS
• COPD
What happens when ‘permanent cells’ are irreversibly injured?
Scar; replacement with non-functional tissue
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
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
What is the ‘dogma’ of the molecular mechanisms of healing?
- Ligand-receptor interaction
- Second messenger
- Transcription factor activation
- Gene expression
→ action
Describe the generalised mechanism of cytokine signalling
- Cytokine binds cytokine receptor
(receptor has no intrinsic catalytic function) - JAK / STAT pathway induced
- Transcription factor activation
Which pathway does GPCR activation generally trigger?
Compare this with cytokine receptors.
GPCR: cAMP
Cytokine receptors: JAK / STAT
Which general processes are activated by JAK / STAT & cAMP pathways?
- migration
- synthesis
- secretion
or inhibition of these processes
What is PDGF?
Platelet derived GF
• migration and proliferation of fibroblasts
• pro-inflammatory
What is the general outcome of the MAPK pathway?
Proliferation
What is the ECM?
Extra-cellular matrix
• Gel-like meshwork of large proteins ground substance
• Structural support for cells
• Involved in signalling
What are the five stages of the healing process?
- Demolition
- Proliferation
- Migration
- Synthesis
- Remodelling
Compare the cellular outcomes of:
• MAPK
• JAK/STAT
• cAMP pathway
MAPK:
• Proliferation
JAK/STAT
• Synthesis
• Secretion
• Migration
cAMP:
• Synthesis
• Secretion
• Migration
What are 5 important GFs, and what are their respective functions?
- EGF (TGF)
• Mitogenic for epithelium & fibroblasts - FGF
• Angiogenesis
• Migration of macrophages & fibroblasts during wound repair - VEGF
• Angiogenesis - PDGF
• Pro-inflammatory
• Migration & proliferation of cells - HGF
• Mitogenic for epithelial cells
Describe how cyclins control the cell cycle
- Specific cyclin expression up regulated
- Cyclin binds to CDK
- Cyclin/CDK complex phosphorylates Rb
- Rb cannot block the cell cycle
