1 Cell injury Flashcards
1
Q
3 methods cell injury can be visualised ? what can be visualised ?
A
- naked eye - gross appearance
- light microscope - microscopic features
- electron microscope - ultrastructural features
2
Q
Causes of cell injury ?
A
PINCHING
Physical agens
Infections
Nutritional imbalance
Chemical agents
Hypoxia
Immune-mediated processes
Neoplasia
Genetic derangement
3
Q
Which hypoxia is to do with cardiorespiratory failure ?
A
hypoxaemic
4
Q
Which hypoxia is to do with anaemia ?
A
anaemic
5
Q
Which hypoxia is to do with blocked vessel ?
A
ischaemic
6
Q
Which hypoxia is to do with cyanide poisoning ?
A
histiocytic
7
Q
Hypoxia may be …. or ….
A
generalised , localised
8
Q
Hypoxia may be generalised or localised, name 4 types of hypoxia …
A
- Hypoxemic hypoxia = low arterial O2 concentration e.g. cardiorespiratory failure
- Anemic hypoxia = decreased oxygen carrying capacity e.g. anaemia
- Ischemic hypoxia = interruption to blood supply e.g. blocked vessel
- Histiocytic hypoxia = unable to use oxygen due to disabled oxidative phosphorylation enzymes e.g. cyanide poisoning
9
Q
List 6 physical agents that can cause cell injury
A
MET RACES
* mechanical trauma
* extremes of temperature (burns and deep cold)
- radiation
- Atmospheric pressure sudden change in
- caustic agents, acids alkalis, e.g. domestic dishwasher agents. Iron tablets
- electric shock
10
Q
Irreversible cell injury is usually encompassed by major … changes
A
Morphological
11
Q
5 examples of chemical agents or drugs that can cause cell injury
A
TD DOG
- Trace amount of poison (arsenic, cyanide)
- Daily exposure to air/pollutant/insecticide/ asbestos
- Drugs (recreational e.g. cocaine, therapeutic)
- Oxygen in high concentration
- Glucose & salt in hypertonic concentrations
12
Q
How do infections cause cell injury / what microorganisms cause cell injury ?
A
- viruses
- bacteria
- fungi
- other infectious micro-organisms
13
Q
Neoplasia & cell injury :
* tumours may be ….. or …..
* local pressure effects by the …..
* ….. or ….. invasian by destruction of tissue by the tumour
* systemic effects, such as ….. and …..
A
- benign, malignant
- tumour
- local , distant
- malaise, weight loss
14
Q
Examples of immune-mediated that can cause cell injury
A
- Autoimmune disease
- Hypersensitivity reaction
15
Q
Autoimmune disease happen because of reaction to what antigens ?
A
endogenous self-antigens
16
Q
hypersensitivity reactions happen as a result of what ?
A
allergies are a result of vigorous (strong) immune reaction results in host tissue damage (asthma, anaphylaxis, urticaria)
17
Q
Examples of nutritional imbalance and how this can cause cell injury
A
- hypoglycaemia
- Dietary insufficiency = malnourished states in deprived population e.g. kwashiorkor, marasmus, self-imposed insufficiency e.g. anorexia
- Dietary excess = obesity, diabetes, atherosclerosis, cancer
18
Q
What are the genetic derangements causing cell injury ?
A
- genetic abnormalities → chromosomes and genes
- Inborn errors of metabolism → loss of production of an end product and/or build up of toxic intermediates of metabolism
19
Q
substrates of adenosine triphosphate
A
oxygen , glucose, ADP
20
Q
Which ATP generating method produces more ATP ?
A
oxidative phosphorylation results in considerably more ATP than anaerobic processes of glycolysis
21
Q
what happens at the cellular level for reversible injuries ?
A
decreased oxidative phosphorylation leading to decreased ATP production:
- decreased functioning of Na+ pump = swelling/blebbing
- detachment of ribosomes = lipid deposition
- increased anaerobic glycolysis = clumping of nuclear chromatin
22
Q
what happens at the cellular level for irreversible injuries ?
A
CAP !!
Calcium ion influx, increased cytosolic calcium concentration
*activation of cellular enzymes
- phospholipase -> decreased phospholipids = membrane damage
- protease -> disruption of membrane and cytoskeleton proteins = membrane damage
- endonuclease = nuclear damage
- ATPase = decreased ATP
*increased mitochondrial permeability transition
- decreased ATP
23
Q
What happens to cells undergoing reversible injury when oxidative phosphorylation decreases ?
A
ATP levels decrease
- sodium pump decreases -> influx of Ca2+, H2O, Na+, efflux of K+ -> ER swelling, cellular swelling, loss of microvilli, blebs
- increased anaerobic glycolysis -> decreased glycogen, increased lactic acid (-> decrease pH) -> clumping of nuclear chromatin
- detachment of ribosomes -> decreased protein synthesis -> lipid deposition -> results in atherosclerosis
24
Q
what’s the difference at cellular level with reversible and irreversible injury ?
A
cellular level →
* ER swelling, cellular swelling, loss of microvilli , formation of blebs
* clumping of nuclear chromatin
* lipid deposition because detachment of ribosomes = decreased protein synthesis
irreversible injury →
* influx of calcium
* membrane damage, nuclear damage , decreased level of ATP
25
3 sources of ATP production ?
1. mitochondria = oxidative phosphorylation (aerobic)
2. glycolysis pathway (anaerobic)
3. glycogenolysis
26
Which ultrastructural organelles and changes that are responsible for the morphological changes ?
* cell membranes - plasma membrane & organelle membranes
* nucleus - DNA
* proteins - structural (enzymes)
* mitochondria - oxidative phosphorylation
27
Ultrastructural changes to cell of reversible injury
* plasma membrane blebbing, blunting and loss of microvilli
* swelling of the mitochondria and appearance of small densities
* dilation of ER (endoplasmic reticulum) detachment of ribosomes
28
light microscopic changes to cell of reversible injury
* cell swelling
* vacuolar change
* fatty change
* surface blebs
29
Ultrastructural changes to cell of irreversible injury
* breakdown of plasma membrane
* degradation of cellular organelles
* formation of myelin figures
* pyknosis, karyorrhexis and karyolysis of nuclei
30
light microscopic changes to cell of reversible injury
* increased eosinophilia
* cytoplasm has moth eaten appearance
* nuclear dissolution
31
What are the 3 characteristic nuclear changes that occur in irreversible cell injury ?
1. pyknosis = nuclei condenses
2. karyorrhexis = nuclei fragmentation
3. karyolysis = nuclei dissolved
32
Necrosis involve what changes ? that occur when ?
morphological changes that occur after a cell has been dead some time, not a type of cell death i.e. it's an appearance and not a process
33
what are the changes of necrosis due to ?
progressive degradative action of enzymes on the lethally injured cell
34
what are the 2 main processes seen in necrosis ?
1. denaturation of intracellular proteins
2. enzymatic digestion by lysosomes inherent to the dying cell and lysosomes of leukocytes that are part of inflammatory reaction
35
In necrosis:
The host response may take .... to develop. The ..... microscopic evidence of necrosis may not become apparent until ..... hours.
* hours
* earliest
* 4 to 12
36
what are the 5 types of necrosis ?
1. coagulative
2. liquefactive
3. caseous
4. fat
5. fibrinoid
37
What does necrosis of tissues have several of ?
morphologically distinct patterns
38
why are the several morphologically distinct patterns of necrosis of tissues important to recognise ?
they may provide clues about the underlying cause
39
Cogaulative necrosis is a result of what ?
protein denaturation
40
microscopy features of coagulative necrosis ?
* ghost cells
* neutrophils can infiltrate but NOT a prominent feature
41
Gross features of coagulative necrosis
* firm
* pale wedge of tissue
* can become soft later
42
coagulative necrosis ?
* ...... form
* occurs in ..... organs
* commonest
* most
43
what are free radicals ?
highly reactive molecules with unpaired electron
44
Alkalis result in .... of fat cells which is followed by ....
* saponofication
* liquefaction necrosis
45
5 examples of free radicals that are of biological significance
* OH* (hydroxyl ions) -the most dangerous
* O2- (superoxide anion radical)
* H2O2 (hydrogen peroxide)
* Reactive oxygen species (ROS)
* Nitric oxide (NO) made by microphages, endothelia, and neurones
46
In normal state what concentration are free radicals present at ?
low
47
What are free radicals required for ?
* killing bacteria
* cell signaling
48
In excess what do free radicals do ?
* attack lipids in cell membranes
* damage mitochondrial proteins
* damage carbohydrates and nucleic acids
49
which cell may free radicals be produced ? [check and alter Q + A]
leucocytes
50
What are free radicals also known to be ?
mutagenic
51
what 2 events are free radicals involved in ?
pathological & physiological
52
List 5 methods where free radicals may be produced
* chemical and radiation injury
* ischaemia - re-perfusion injury
* cellular ageing
* high oxygen concentraiton
* killing of pathogens by phagocytes (ROS)
53
Increased free radicals (oxidative stress) is sourced from activated ...1... in response to 4 factors :
...2...
...3...
...4....
...5...
1. leukocytes
2. toxins
3. UV light
4. ionising radiation
5. pollutant exposure
54
When are there decreased scavenging of free radicals ?
* decreased levels of scavenging enzyme (catalase, peroxidase)
* decreased vitamins A , C, E (antioxidants)
* decreased glutathione
55
heat shock proteins (HSPs) are what class of molecular chaperones ?
chaperonins
56
What 3 functions do HSPs fulfill ?
1. Provide optimal condition for denatured protein folding
2. Prevent protein aggregation
3. Label misfolded proteins as degradation at proteasome
57
Give one example of HSP
Ubiquitin
58
What does the heat shock response aim to do?
What does the heat shock response aim to do?
59
What is heat shock or the cellular stress reponse triggered by ?
any form of injury, not just heat
60
Apart from stressed cells where else are HSPs also present ?
lower concentrations in unstressed cells
61
all cell from any organism that have been so far tested when submitted to stress what happens to the protein synthesis ?
turn down their usual protein synthesis and turn up the synthesis of HSPs
62
If Heat shock proteins aren't secreted where do they remain ?
within the cell where they are concerned with protein repair (similar to DNA repair)
63
when are HSPs important ?
when the folding step in protein synthesis goes astray or when proteins become denatured during cell injury
64
What does the anti-oxidant system consist of ?
* enzymes e.g. superoxide dismutase, catalases , peroxidases
* free radical scavengers that neutralise free radicals e.g. vitamins A, C, E, glutathione
* storage proteins that sequester transition metals in the extracellular matrix
65
Examples of storage proteins that sequester transition metals in the extracellular matrix
* transferrin and ceruloplasmin
* sequester iron and copper
* catalyse the formation of free radicals
66
1. Infarction is a cause of necrosis which 2 types
2. what are the 2 main types of infarction ?
3. what do the consequences range from ?
1. coagulative + liquefactive necrosis
2. white (ischemic) & red (haemorrhagic) infarct
3. none to death
67
Aetiology of infarcation ?
* thrombosis
* embolism
* arterial torsion
* external compression of vessel
68
Liquefactive necrosis :
1. usually seen in which organ ?
2. seen in .....resulting in abscess (swollen area within body tissue, containing accumulation of pus) formation
3. ...... of tissues by .......
1. brain
2. infections
3. degradation , enzymes
69
what is the necrotic material in liquefactive necrosis frequently like ? why is it like that ? what is it called ?
* creamy yellow because of presence of dead leukocytes
* called pus (accumulation of neutrophils and other cellular debris)
70
gross appearance of caseous necrosis
cheese like
71
Most common cause of caseous necrosis ?
tuberculosis
72
caseous necrosis :
...1... debris surrounded by histiocytes resulting in a ...2.... inflammation
1. amorphous
2. granulomatous
73
# refer to ? and may include what ?
In caseous necrosis....
"Amorphous debris surrounded by histiocytes resulting in a granulomatous inflammation"
* what is amorphous debris ?
* refers to irregularly shaped, non-specific material
* may include dead cells, cellular debris and other components associated with tissue damage or infection
74
In caseous necrosis....
"Amorphous debris surrounded by histiocytes resulting in a granulomatous inflammation"
* what is granulomatous inflammation ?
* what are granulomas ?
specific type of chronic inflammation characterised by formation of granulomas
granulomas = organised collections of immune cells surrounding a central core of foreign material or debris
75
What is fat necrosis ?
* destruction of adipocytes
* consequence of trauma or secondary to release of lipases from damaged pancreatic tissue
76
1. what does fatty necrosis cause?
2. what does the caused substance react with to form ...?
1. fatty acids
2. react with calcium to form white deposits in fatty tissue
77
Where is fat necrosis seen and what can it mimic ?
* seen in breast tissue, pancreas
* mimic breast tumour on radiology and is biopside to exclude cancer
78
Where is fibrinoid necrosis usually seen ?
In immune reactions involving blood vessels : vasculitis
79
In fibrinoid necrosis what has leaked out of vessels ?
deposits of "immune complexes" together with fibri
80
What's the appearance of fibrinoid necrosis in H&E stains ? what is it "called" by pathologists ?
bright pink and amorphous
"fibrinoid"
81
White infarct :
1. found in what organs ?
2. what limits haemorrhage into necrotic area from adjacent capillaries ?
3. insufficiency in what ?
4. involves what artery ?
5. 3 common sites:
1. solid
2. robust stromal support
3. arterial
4. end
5. heart, spleen , kidney
82
In what organs is red / haemorrhagic infarct found ?
organs with/ that have :
* dual blood supply
* those with numerous anastomoses between capillary beds
* have loose stromal support
83
What results in the arterial insufficiency in red infarct ?
raised venous pressure leading to increased capillary pressure and tissue pressure
84
Clinical term to describe visible necrosis ?
gangrene
85
Wet gangrene is necrosis modified by what ?
bacteria
86
Dry gangrene is necrosis modified by what ?
air
87
gas gangrene is necrosis modified by what ?
gas forming bacteria
88
3 types of gangrene:
1. wet
2. dry
3. gas
89
What type of cell death is apoptosis ?
energy dependent programmed
90
Apoptosis can be .... or ....
physiological , pathological
91
3 features/ characteristics of apoptosis :
* non-random inter-nucleosomal cleavage of DNA
* distinct morphological features
* doesn't result in inflammatory response
92
4 Examples of physiological apoptosis
* embryogenesis and fetal development (loss of webbing)
* hormone dependent involution (endometrium shedding at menstruation)
* cell deletion in proliferating cell populations (regulation of immune system or intestinal crypts)
* death of cells that have served their function (neutrophils and lymphocytes)
93
Apoptosis in pathologic conditions ?
* neoplasia
* autoimmune conditions
* immunodepletion from activation of CD4 by AIDS - HIV proteins
94
Relationship between neoplasia and apoptosis ?
failure of normal apoptosis
95
Relationship between autoimmune conditions and apoptosis ?
failure of induction of apoptosis in lymphoid cells directed against host antigens
96
Relationship between immunodepletion and apoptosis?
AIDS - HIV proteins may activate CD4 on uninfected T helper lymphocytes resultin in apoptosis leading to immunodepletion
97
What is apoptosis regulated by ?
* many genes
* inhibitors
* inducers
98
What inhibitors regulate apoptosis ?
* growth factors
* extracellular cell matrix
* sex steroids
* some viral proteins
99
What inducers regulate apoptosis?
* growth factor withdrawl
* loss of extracellular matrix attachment
* glucocorticoids
* viruses
* free radicals
* ionising radiation
100
Mechanism of apoptosis involves the activation of what ?
cascade of caspases
101
what is the full name for caspases ?
cysteine-dependent aspartate-directed proteases
102
What do the 2 pathways of apoptosis (extrinsic and intrinsic) result in ? which does what ?
* activated caspase 3
* cleave proteins
* causing: chromatin condensation, nuclear fragmentation and blebbing
103
What is the extrinisc pathway in the mechanism of apoptosis ?
external “death receptors” (TNF receptors or Fas receptors) are activated by a ligand
104
what is the intrinsic pathway in the mechanism of apoptosis ?
withdrawal of growth factors or hormones causes molecules to be released from mitochondria (e.g. Bcl2, Bax, p53)
105
What's the difference in what the 2 pathways in the mechanism of apoptosis are initiated by ?
extrinsic - initiated by external death receptor signalling
intrinsic - triggered by internal cellular stressors
106
What eventually happens to a apoptotic cell ? but there is no...
It's phagocytised by macrophages or histiocytes or by neighbouring cells but there is no acute inflammation
107
How do the 2 pathways of apoptosis differ ?
in their induction and regulation
108
Difference between necrosis + apoptosis in the pattern feature
N: contiguous groups of cells
A: single cells
109
Difference between necrosis + apoptosis in the cell size feature
N: enlarged (swelling)
A: reduced (shrinkage)
110
Difference between necrosis + apoptosis in the nucleus feature
N: pyknosis - karyorrhexis - karyolysis
A: fragmentation into nucleosome size fragments
111
Difference between necrosis + apoptosis in the plasma membrane feature
N: disrupted, early lysis
A: intact; altered structure, especially orientation of lipids
112
Difference between necrosis + apoptosis in the cellular contents feature
N: enzymatic digestion, may leak out of cell
A: intact, may be released in apoptotic bodies
113
Difference between necrosis + apoptosis in the adjacent inflammation feature
N: frequent
A: No
114
Difference between necrosis + apoptosis in the physiologic or pathologic role feature
N: invariably pathologic
A: often physiologic, means of eliminating unwanted cells; may be pathologic after some forms of cell injury especially DNA damage
115
Biochemical findings related to cell death-Molecules released because of cell injury and death ?
* Potassium
* Enzymes
* Myoglobin
116
As calcium enters damaged membranes other molecules leak out, what effects does this have ?
* can cause local inflammation
* may have toxic effects on body e.g. potassium
* may appear in high concentrations in blood and can aid in diagnosis
117
In myocardial infarction name 3 molecules are released by injured and dying cells ?
* troponin I
* CK-MB (creatine kinase-MB)
* myoglobin
118
After how many hours after onset of chest pain does troponin I reach it's peak relative concentration close to 40 ? [slide 62 graph]
after 20 hours
119
Rhabdomyolysis can be serious with ...1....as a breakdown product of muscle causing damage to the ...2... and even ....3.... failure requiring ...4...
Typical ...5... urine in myoglobinuria
1. myoglobin
2. kidneys
3. renal
4. dialysis
5. brown
120
Abnormal cellular accumulations happen as a result of what injury?
sub-lethal or chronic injury
121
When do abnormal cellular accumulations occur ?
when metabolic processes are deranged
122
Abnormal cellular accumulations:
may be .....
reversible
123
Abnormal cellular accumulations:
can be ..... or ......
harmless , fatal
124
4 mechanisms of intracellular accumulations :
* abnormal metabolism - normal substance accumulates at an increased rate e.g. fatty liver
* alterations in protein folding and transport
* deficiency of critical enzymes - e.g. lysosomal storage disease (hurler's syndrome, tay sachs)
* inability to degrade phagocytosed particles
125
5 examples of substances that undergo intracellular accumulations ?
* water and electrolytes e.g. cerebral oedema
* lipids e.g. fatty liver
* carbohydrates
* proteins
* pigments
126
example of abnormal fluid accumulation
hydropic swelling: oedema in brain
127
example of abnormal lipid accumulation
steatosis
128
examples of abnormal proteins accumulation
* mallory hyaline body-damaged protein
* alpha - 1 antitrypsin globules
129
what is rhabdomyolysis ?
destruction of muscle to produce myoglobin
130
Classic triad for symptoms of rhabdomyolysis ?
* muscle pain
* weakness
* dark coca cola/brown urine (myoglobinuria)
131
what is steatosis ?
Abnormal condition of fat accumulation (increased fat at the cellular level often affecting the liver)
132
Endogenous pigment accumulation causes
* Lipofuscin
* Haemosiderin (iron accumulation)
* Hereditary haemochromatosis
133
Lipofuscin endogenous pigment
Age Pigment
Lysosomes with degradation products (residual body)
134
Haemosiderin endogenous pigment
Iron pigment from breakdown of blood or ingestion of iron
Golden brown pigment seen in macrophages
Bruising
135
Haemosiderosis
when does an overload of iron in the body result from ? most common in patients with what condition ?
Iron overload
An overload of iron in the body resulting from repeated blood transfusions.
Hemosiderosis occurs most often in patients with thalassemia.
Abnormal deposit of hemosiderin
136
Hereditary haemochromatosis
Hereditary - autosomal recessive
Excessive absorption of iron from GI tract
137
Bilirubin can accumulate in what pathologies?
Liver disease
Hemolytic anemia
138
Pathological calcifications causes
- Parathyroid overactivity e.g., tumour/hyperplasia
- Malignant tumours e.g., breast/lung/bone
139
Other causes of calcification apart from the pathological causes being parathyroid overactivity and malignant tumours
- Vitamin D overdosage
- Paget's disease
- Prolonged immobilisation
140
Cellular ageing
Telomeres shorten
