1
Q
What does the degree of cell injury depend on?
A
- Type of injury
- Severity of injury
- Type of tissue
2
Q
What can severe changes in the environment lead to?
A
Cell adaptation, injury or cell death.
3
Q
What kind of things can cause cell injury?
A
- Hypoxia
- Toxins
- Physical agents
- Radiation
- Micro-organisms
- Immune mechanisms
- Dietary insufficiency and deficiencies
4
Q
What physical agents can cause cell injury?
A
Direct trauma, extremes of temperature, changes in pressure and electric currents.
5
Q
What is hypoxia?
A
Decreased oxygen supply to certain cells and tissues
6
Q
What is ischaemia?
A
Decreased blood supply to the tissue
7
Q
Which is worse, hypoxia or iscahemia? Why?
A
Ischaemia is worse because tissues isn’t getting oxygen and other nutrients such as glucose.
8
Q
What are the different causes/types of hypoxia?
A
Hypoxaemic hypoxia, anaemic hypoxia, ischaemic hypoxia, histiocytic hypoxia.
9
Q
What is hypoxaemic hypoxia?
A
- Arterial content of oxygen is low
- Due to reduced oxygen in air (high altitude) or reduced absorption in lungs.
10
Q
What is anaemic hypoxia?
A
- Decreased ability of haemoglobin to carry oxygen
- Due to anaemia or CO poisoning
11
Q
What is ischaemic hypoxia?
A
- Interruption of blood supply
- Due to blockage of a vessel or heart failure.
12
Q
What is histiocytic hypoxia?
A
- Inability to utilise oxygen in cells due to disabled oxidative phosphorylation enzymes
- Due to cyanide poisoning
13
Q
What type of cell in the body is very sensitive to hypoxia and ischaemia?
A
Neurones
14
Q
How does the immune system damage the body’s cells?
A
- Hypersensitivity reactions
- Autoimmune reactions
15
Q
What is a hypersensitivity reaction?
A
Host tissue is injured secondary to an overly vigorous immune reaction.
16
Q
What is an autoimmune reaction?
A
Immune system fails to distinguish self from non-self.
17
Q
Which cell components are most susceptible to injury?
A
Cell membrane, nucleus, proteins and mitochondria.
18
Q
What is happening at a molecular level in hypoxia?
A
notes - check the notes that are in the folder
19
Q
What about prolonged hypoxia?
A
Hypoxia is reversible but if it is prolonged, it does become irreversible.
20
Q
What happens in a cell if it undergoes prolonged hypoxia?
A
The point which leads to cell death leads to a massive influx of calcium into the cell. Calcium activates lots of enzymes, eg proteases which break down cytoskeleton of the cell.
21
Q
What are free radicals?
A
They are a reactive oxygen species.
22
Q
What is the configuration of a free radical?
A
Single unpaired electron in an outer orbit - an unstable configuration hence react with other molecules, often producing further free radicals.
23
Q
Which free radicals are of particular biological significance in cells?
A
- OH (hydroxyl) - the most dangerous
- O2 (superoxide)
- H2O2 (hydrogen peroxide)
24
Q
How are free radicals produced?
A
- Normal metabolic reactions eg oxidative phosphorylation
- Inflammation - oxidative burst of neutrophils
- Radiation
- Contact with unbound metals within the body
- Drugs and chemicals eg paracetamol
25
How does the body control free radicals?
- Antioxidant system; donate electrons to the free radical (vitamins A, C and E)
- Metal carrier and storage proteins (transferrin, ceruplasmin) sequester iron and copper
26
Name some enzymes that neutralise free radicals
Superoxide dismutase, catalase, glutathione peroxidase
27
How do free radicals injure cells?
- If the number of free radicals overwhelms the anti-oxidant system = oxidative imbalance
- Most important target are lipid in cell membranes
- Also oxidise proteins, carbohydrate and DNA
28
What effect can free radicals have on lipids in cell membrane?
- Causes lipid peroxidation
| - This leads to generation of further free radicals - autocatalytic chain reaction
29
What effect can free radicals have proteins, carbohydrates and DNA?
- Oxidise them
- The molecules become bent out of shape, broken or cross linked
- Mutagenic and therefore carcinogenic
30
How else can the cell protect itself?
- Heat shock proteins aim to 'mend' misfolded proteins and maintain cell viability
- Unfoldases or chaperonins eg ubiquitin
31
In hypoxia, what does an injured/dying cell look like under a microscope?
Cytoplasmic changes, nuclear changes, abnormal accumulations
32
Describe what an injured cell looks like under a microscope
Cell become pale and swollen (membrane not working properly)
33
Describe what you see in the cytoplasm when the cell has died
When the cell dies, the cytoplasm looks very pink because the proteins have been denatured and they have clumped and clotted together hence stain strongly.
34
What can happen to a dead cell's nucleus?
- Pyknosis - nucleus shrinks and becomes dark
- Karyorrhexis - nucleus breaks up into little bits
- Karyolysis - nucleus disappears (shrinks to nothing)
35
What does a reversible injury of a cell look like under an electron microscope?
Blebs form, generalised swelling, clumping of nuclear chromatin, ER swelling, mitochondria swelling and autophagy by lysosomes.
36
What does an irreversible injury of a cell look like under an electron microscope?
Rupture of lysosomes and autolysis, nuclear changes, lysis of ER, mitochondrial swelling, defects in cell membrane
37
How can we diagnose cell death?
A good of way of knowing when a cell is dead is by testing its function. ( can use a dye exclusion test )
38
What is a dye exclusion test?
If the membrane has holes in it, the dye will enter the cell. The cells that are alive will keep the dye out.
39
What is the actual PROCESS of cell death called?
Oncosis
40
Define oncosis
Cell death with swelling, the spectrum of changes that occur in injured cells prior to death
41
Define necrosis
In a living organism the morphologic changes that occur after a cell has been dead some time (seen after 12-24 hours)
42
What are the different types of necrosis?
- Two main types - coagualative and liquefactive
| - Two special types - caseous and fat necrosis
43
Why are there two types of necrosis?
Depend on the tissue, you get protein denaturation or enzyme release. Protein denaturation leads to clumping but what often dominates is enzyme release from lysosomes.
44
Where is coagulation necrosis found?
Happens when you have ischaemia of solid organs (organs with lots of connective tissue eg kidney)
45
Where is liquifactive necrosis found?
Happens when you have ischaemia in loose tissues or in the presence of many neutrophils eg during infection.
46
What does coagulative necrosis look like?
- Denaturation of proteins dominates over release of active proteases.
- Cellular architecture is somewhat preserves "ghost outline" of cells.
47
What does liquefactive necrosis look like?
- Enzyme degradation is substantially greater than denaturation
- Leads to enzymatic digestions (liquefaction) of tissues.
48
What is caseous necrosis?
- Contains amorphous (structureless) debris
| - Particularly associated with infections, especially TB
49
What does caseous necrosis look like?
Caseous necrotic dermis looks like cheese.
50
What is fat necrosis?
Fat necrosis is a form of necrosis characterised by the action upon fat by digestive enzymes.
51
What does fat necrosis look like?
White dots seen. Under microscope - big white spaces.
52
Define gangrene
Necrosis visible to the naked eye
53
Define infarction
Necrosis caused by reduction in arterial blood flow. (A cause of necrosis, can result in gangrene)
54
Define infarct
An area of necrotic tissue which is the result of loss of arterial blood supply
55
What is dry gangrene?
Necrosis modified by exposure to the air (coagulative necrosis)
56
What is wet gangrene
Necrosis modified by infection (liquefactive necrosis)
57
What is gas gangrene?
Type of wet gangrene where the infection is with anaerobic bacteria that produce gas.
58
What are the commonest causes of infarction?
- Thrombus
| - Embolism
59
How else can tissue become infarcted?
Something like testicular torsion - spermatic cord can twist itself and cut off the blood supply.
60
What does infarcted tissue look like?
White or red
61
Why are some infarcts white?
- Coagulative necrosis
- Happens in solid organs
- Happen s when you haven't got blood supply to it.
62
Why are some infarcts red?
- Liquefactive necrosis
- Loose tissue
- Dual blood supply
- Numerous anastomoses
- Prior congestion
- Raised venous pressure
- Re-perfusion
63
What is the consequence of infarction
- No consequences to death
64
What does the consequence of infarction depend on?
- Alternative blood supply
- Speed of ischaemia
- Tissue involved
- Oxygen content of the blood
65
What is ischaemia-reperfusion injury?
If blood flow is returned to a damaged but not yet necrotic tissue, damage sustained can be worse than if blood flow hadn't been returned.
66
Why does return of blood to a ischaemic are bad?
- Increased production of oxygen free radicals with reoxygenation
- Increased number of neutrophils resulting in more inflammation and increased tissue injury
- Delivery of complement proteins and activation of the complement pathway
67
When membranes are leaky, can molecules leak out as well as in?
Yes and they can have both local and systemic effects
- can cause local inflammation
- may have general toxic effects on body
- may appear in high concentrations in blood and can aid in diagnosis
68
When the cell membrane is damaged, what can leak out of the cell?
- Potassium
- Enzymes
- Myoglobin
69
What happens when potassium leaks out of the cell?
Potassium is in high concentration in the cell, so lots leaks out when the membrane is leaky. Can lead to cardiac arrest.
70
What happens if myoglobin leaks out of the cell?
- Myoglobin leaks when you have damage to skeletal muscle.
| - Blocks glomeruline in the kidney and causes renal failure.
71
Define apoptosis
Cel death with shrinkage, induced by a regulated intracellular program where a cell activates enzymes that degrade its own nuclear DNA and proteins
72
What does a cell undergoing apoptosis look like under a microscope?
- Internucleosomal cleavage of DNA
| - Membrane integrity is maintained
73
When does apoptosis occur physiologically?
- In order to maintain a steady state
- Hormone controlled involution - ovaries of post menopausal woman are smaller
- Embryogenesis
74
When does apoptosis occur pathologically?
- Cytotoxic T cell killing of virus-infected or neoplastic cells
- When cells are damaged, particularly with damaged DNA
75
What does apoptosis look like?
- The chromatin gets broken down and it starts to clump.
- Karyorrhexis occurs
- Cell fragments into apoptotic bodies (due to budding)
76
How does apoptosis occur?
Three phases
- Initiation
- Execution
- Degradation & phagocytosis
77
Describe initiation and execution of apoptosis
- Triggered by two mechanisms - intrinsic and extrinsic
| - Both result in activation of caspases
78
What are caspases?
- Enzymes that control and mediate apoptosis
| - Cause cleavage of DNA and proteins of the cytoskeleton
79
How is the intrinsic pathway initiated?
- Initiating signal comes from within the cell
| - Triggers: most commonly irreparable DNA damage and withdrawal of growth factors or hormones
80
How is the intrinsic pathway carried out?
- p53 protein is activated and this results in the outer mitochondrial membrane becoming leaky.
- Cytochrome C is released from the mitochondria and this causes activation of caspases.
81
How is the extrinsic pathway initiated?
- Initiated by extracellular signals
| - Trigger: cells that are a danger e.g. tumour cells, virus infected cells
82
How is the extrinsic pathway carried out?
One of the signals is TNF alpha.
- Secreted by T killer cells
- Binds to cell membrane receptor
- Results in activation of caspases
83
What do both the intrinsic and extrinsic pathways cause the cell to do?
The cells shrink and break up into apoptotic bodies.
84
Why and how are apoptotic bodies phagocytosed?
- The apoptotic bodies express proteins on their surface
- They can now be recognised by phagocytes or neighbouring cells
- Finally degradation takes place within the phagocyte/neighbour.
85
Where do abnormal cellular accumulations come from?
- If a cell can't metabolise something, it will remain within the cell.
- They can derive from; cell own metabolism; the extracellular space and the outer environment.
86
What kind of things can accumulate in cells?
There are five main groups of intracellular accumulations; water/electrolytes; lipids, carbohydrates, proteins and pigments.
87
When does fluid accumulate in cells?
- Hydropic swelling
- Occurs when energy supplies are cut off (hypoxia)
- Indicates severe cellular diseases
- Na+ and water flood into cell
- Particular problem in the brain
88
When do lipids accumulate in cells?
- Steatosis (accumulation of triglycerides)
| Causes; alcohol, diabetes mellitus, obesity and toxins.
89
Where is lipid accumulation often seen?
liver - major organ of fat metabolism
90
In what conditions do proteins accumulate in cells?
- Seen as eosinophilic droplets or aggregation in the cytoplasm
- Alcohol liver disease
- alpha 1 antitrypsin deficiency
91
Alpha 1 antitrypsin deficiency
- Liver produces incorrectly folded alpha 1 antitrypsin protein
- Can't be packaged by ER, accumulates within ER and is not secreted
- Systemic deficiency - proteases in lung act unchecked resulting in emphysema.
92
Why do pigments accumulate in cells?
- Carbon/coal dust/ soot
- Inhaled and phagocytksed by alveolar macrophages
- Anthracosis and blackened peribronchial lymph nodes
- Usually harmless, unless in large amounts= fibrosis and emphysema
- Tattooing
93
Why does tattooing lead to pigment accumulation in cells?
The pigment is pricked into skin. It is phagocytosed by macrophages in dermis and remains there. Some pigment will reach draining lymph nodes.
94
Give an example of the accumulation of endogenous pigments
Haemosidirin
95
What is haemosiderin?
- Iron storage molecule
| - Derived from haemoglobin, yellow/brown
96
What causes haemosiderin to form?
Forms when there is a systemic or local excess of iron e.g. bruise
97
What is haemosiderosis?
With systemic overload of iron, haemosiderin is deposited in many organs, this leads to haemosiderosis.
98
Where is haemosideris commonly seen?
Seen in haemolytic anaemias, blood transfusions and hereditary haemochromatosis.
99
What is hereditary haemochromatosis?
- Genetically inherited disorder
- Increased intestinal absorption of dietary iron
- Iron is deposited in the skin, liver, pancreas, heart and endocrine organs.
100
What are the symptoms of hereditary haemochromatosis?
Liver damage, heart dysfunction and multiple endocrine failures, esp those of the pancreas
101
What does hereditary haemochromatosis look like?
- Darkening of the skin - patient looks permanently tanned
102
What's accumulating in jaundice?
Accumulation of bilirubin - bright yellow.
103
How does bilirubin accumulate in the body?
- Breakdown product of heme
- Formed in all cells but must be eliminated in the bile
- Bilirubin normally taken from tissues by albumin to liver, conjugated and excreted in bile.
- If bile flow is obstructed or overwhelmed, bilirubin in blood rises and jaundice results.
- Deposited in cells extracellularly or in macrophages.
104
What does jaundice look like?
Yellowing of the skin
| - Good place to look for jaundice is in the sclera
105
What are the different mechanisms of intracellular accumulations?
- Abnormal metabolism
- Alterations in protein folding and transport
- Deficiency of critical enzymes
- Inability to degrade phagocytosed particles
106
What is calcification of tissues and what are the different types?
- Abnormal deposition of calcium salts within tissues
| - Can be localised (dystrophic) or generalised (metastatic)
107
Dystrophic calcification
- More common than metastatic
- Occurs in an area of dying tissue, atherosclerotic plaques, raging or damaged heart valves, in tubercles lymph nodes and some malignancies.
108
Why does dystrophic calcification occur?
- No abnormality in calcium metabolism, or serum calcium or phosphate concentrations
- Local change/disturbance favour nucleation of hydroxyapatite crystals
- Can cause organ dysfunction e.g. atherosclerosis, calcified heart valves
109
Why does metastatic calcification occur?
- Due to hypercalcaemia secondary to disturbances in calcium metabolism
- Hydroxyapatite crystals are deposited in normal tissues throughout the body
110
What causes hypercalcaemia?
- Increased secretion of parathyroid hormone (PTH) resulting in bone resorption
- Destruction of bone tissue
111
What are the causes of increased secretion of PTH?
1. Primary - due to parathyroid hyperplasia or tumour
2. Secondary - due to renal failure and the retention of phosphate
3. Ectopic - secretion of PTH-related protein by malignant tumours
112
What are the causes of destruction of bone tissue?
- Primary tumours of bone marrow e.g. leukaemia
- Diffuse skeletal masses
- Paget's disease of bone - when accelerated bone turnover occurs
- Immobilisation
113
Can cells live forever?
- As cells are, they accumulate damage to cellular constituents and DNA
- After certain number of divisions they reach replicative senescence
- When telomeres reach a certain length the cell can no longer divide
114
How do cancer cells manage to replicate multiple times?
Many cancer cells produce telomerase and this maintain the original length of the telomeres.
