L1-4: Cell Pathology & Healing Flashcards
RMolecular and cellular triggers for apoptosis
- Reduced ATP synthesis/mitochondrial damage
- Loss of Ca2+ homeostasis
- Disrupted membrane permeability
- Free radicals
Hypoxia Triggers
- Ischaemia — loss of blood flow due to local thrombus or embolus or systemic (cardiac failure)
- Hypoxaemia — abnormally low oxygen level in blood due to altitude sickness or haemoglobin problems (anaemia)
- Oxidative phosphorylation inhibition e.g. cyanide poisoning
Define: reperfusion
Restoration of blood flow
Pathological effects of free radicals
- Lipid peroxidation which leads to membrane damage
- Protein modifications that lead to breakdown, misfolding
- DNA damage that leads to mutations
Pathological effects of mitochondrial damage
Decreased oxidative phosphorylation leads to decreased ATP which causes:
- Impaired function/activity of Na+ pump - influx of Ca2+, H2O, Na+, efflux of K+ causes ER and cellular swelling and loss of microvilli
- Increased anaerobic glycolysis causes decrease in glycogen and pH. The latter combined with increased lactic acid causes clumping of nuclear chromatin
- Detachment of ribosomes leads to disfunctional protein synthesis
Membrane components affected
Membrane damage can be attributed to:
- Loss of phospholipids
- Lipid breakdown products
- Cytoskeletal damage
Differences between apoptosis and necrosis
- Cell size shrinks during apoptosis, and swells during necrosis
- Nucleus undergoes fragmentation during apoptosis and undergoes pyknosis, karyorrhexis and karyolysis during necrosis
- Plasma membrane is altered but intact during apoptosis, and disrupted in necrosis
- Adjacent inflammation only occurs during necrosis
Role of heat shock proteins in cell injury
- Expression is upregulated in response to cell stressors.
- Serve to protect proteins from stress-related damage
- Clean up damaged proteins from the cell
True or false: many many tissues and organs can survive significant injury if they are “pre-stressed”
TRUE.
Coagulative necrosis
Cells have died but the basic shape and architecture of the tissue remains - tissue maintains solid consistency.
Most common manifestation of ischaemic necrosis in tissues.
In most cases necrotic cells are ultimately removed by inflammatory cells.
Which type of necrosis is most commonly associated with ischaemic injury?
Coagulative necrosis, except for in the case of ischaemic brain injury where liquefaction most commonly occurs.
Type of necrosis where basic architecture of tissue remains
Coagulative necrosis
Liquefactive necrosis occurs due to
infiltration by neutrophils which causes abscess formation - ROS and proteases are released
Which type of necrosis is associated with granulomatous inflammation of tuberculosis?
Caseous necrosis
Difference between red and white infarct
White - arterial occlusion.
Red/haemorrhagic - venous occlusion
Apoptosis triggers
- Withdrawal of growth stimuli
- Death signals - TNF and Fas
- DNA damage - p53
Peter Medawar’s mutation accumulation theory
Mutation accumulation theory predicts that genetic diseases should increase in frequency with age and that there could be a large heterogeneity in deleterious genes between different individuals.
The delayed disease response in Peter Medawar’s mutation accumulation theory is due to
The delayed disease response is due to cell repair mechanisms which gradually lose their activity
What is the DNA “end-replication problem”?
The shortening of the ends of chromosomes by about 20bp during replication.
Werner’s syndrome is characterised by
premature ageing
The WRN gene encodes a DNA helicase
Which cytokines contribute to maintaining the senescent phenotype?
IL-6 and IL-8
Why does restriction of calories
delay senescence?
Caloric restriction induces levels of some antioxidant enzymes
Reduces insulin and IGF-1 metabolic pathway signalling and increases SIRT1 which activates FOXO1
Caloric restriction on insulin and IGF-1 pathway
Caloric restriction reduces downstream effects due to activation of insulin receptor and IGF-1 receptor which cause inhibit FOXO1, a regulator gene responsible for inhibiting pro-ageing genes and activating longevity genes. Also activates SIRT1 which activates SIRT1
NFkB pathway and role of RelA vs. p50
This pathway can both promote and repress inflammation depending on the balance of RelA vs. p50:
If RelA is involved, activation of pro-inflammatory response will occur. p50/p50 will lead to repression of pro-inflammatory response.
Unique defining attributes of stem cells
- Ability to differentiate into many different cell types.
2. Capacity for self-renewal
The stem cells are located in which part of the blastocyst?
The inner cell mass
The three primary germ layers are established during
gastrulation
Neural stem cells are located in the
subventricular zone
Stem cells of the gut are called
crypt cells
Examples of unipotent stem cells
Germ cells and skin cells
True or false:
Adult stem cells are capable of giving rise to all of the cell types in the body including non-regenerative.
False, adult stem cells are capable of giving rise to functional cells in their tissue (but not other tissue types)
Fibroblasts secrete
collagen
EGF/TGFα are enriched in which cells
macrophages, platelets, epithelia and in most tissue fluids and secretions
PDGF enriched in which cells
platelets, mΦ, endothelial cells, smooth muscle cells, tumour cells
EGF/TGFα role
Mitogenic for epithelial cells and fibroblasts
PDGF role
Proliferation and migration of fibroblasts, smooth muscle cells, monocytes
FGF role
angiogenesis and migration during wound repair
haematopoiesis
Role of VEGF
Induce blood vessel formation
Role of HGF
Mitogenic for epithelial cells, cause cell migration, required for survival during embryogenesis
Role of Kupffer cells
Macrophages permanently residing in the liver that release cytokines which activate liver stem cells (stellate cells)
Functions of ECM in regards to healing
ECM guides cell/tissue regrowth and organisation:
Reservoir of growth factors
Scaffolding within which cells adhere, migrate, and proliferate
Sequester H2O for turgor (tissue rigidity); minerals for rigidity
Basement membrane exclusively associated with which cells
epithelial cells
Basement membrane is composed of
Type IV collagen, laminin, proteoglycan
Two types of ECM organisation and differences between them
- Interstitial matrix / aka. stroma - spaces between epithelial, endothelial & smooth muscle cells & in connective tissue
- Basement membrane - associated with cell surfaces (epithelial & mesenchymal)
Role of adhesive glycoproteins and integrins
Crucial role in transduction of signals (ECM to cell interior) and organisation of actin cytoskeleton into focal adhesion complexes
Basement membrane is composed of
Type IV collagen, laminin, proteoglycan
Two types of ECM organisation and differences between them
- Interstitial matrix / aka. stroma - spaces between epithelial, endothelial & smooth muscle cells & in connective tissue
- Basement membrane - associated with cell surfaces (epithelial & mesenchymal)
Most important GF and receptor in control of angiogenesis
VEGF and VEGFR-2
Define: Fibrosis
any abnormal deposition of connective tissue
Two types of ECM organisation and differences between them
- Interstitial matrix / aka. stroma - spaces between epithelial, endothelial & smooth muscle cells & in connective tissue
- Basement membrane - associated with cell surfaces (epithelial & mesenchymal)
Role of adhesive glycoproteins and integrins
Crucial role in transduction of signals (ECM to cell interior) and organisation of actin cytoskeleton into focal adhesion complexes
Role of proteoglycans
Regulate connective tissue structure and permeability
Modulate cell growth and differentiation
Define: fibroplasia
Formation of new connective tissue
