1 Cell injury Flashcards
3 methods cell injury can be visualised ? what can be visualised ?
- naked eye - gross appearance
- light microscope - microscopic features
- electron microscope - ultrastructural features
Causes of cell injury ?
PINCHING
Physical agens
Infections
Nutritional imbalance
Chemical agents
Hypoxia
Immune-mediated processes
Neoplasia
Genetic derangement
Which hypoxia is to do with cardiorespiratory failure ?
hypoxaemic
Which hypoxia is to do with anaemia ?
anaemic
Which hypoxia is to do with blocked vessel ?
ischaemic
Which hypoxia is to do with cyanide poisoning ?
histiocytic
Hypoxia may be …. or ….
generalised , localised
Hypoxia may be generalised or localised, name 4 types of hypoxia …
- 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
List 6 physical agents that can cause cell injury
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
Irreversible cell injury is usually encompassed by major … changes
Morphological
5 examples of chemical agents or drugs that can cause cell injury
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
How do infections cause cell injury / what microorganisms cause cell injury ?
- viruses
- bacteria
- fungi
- other infectious micro-organisms
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 …..
- benign, malignant
- tumour
- local , distant
- malaise, weight loss
Examples of immune-mediated that can cause cell injury
- Autoimmune disease
- Hypersensitivity reaction
Autoimmune disease happen because of reaction to what antigens ?
endogenous self-antigens
hypersensitivity reactions happen as a result of what ?
allergies are a result of vigorous (strong) immune reaction results in host tissue damage (asthma, anaphylaxis, urticaria)
Examples of nutritional imbalance and how this can cause cell injury
- hypoglycaemia
- Dietary insufficiency = malnourished states in deprived population e.g. kwashiorkor, marasmus, self-imposed insufficiency e.g. anorexia
- Dietary excess = obesity, diabetes, atherosclerosis, cancer
What are the genetic derangements causing cell injury ?
- 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
substrates of adenosine triphosphate
oxygen , glucose, ADP
Which ATP generating method produces more ATP ?
oxidative phosphorylation results in considerably more ATP than anaerobic processes of glycolysis
what happens at the cellular level for reversible injuries ?
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
what happens at the cellular level for irreversible injuries ?
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
What happens to cells undergoing reversible injury when oxidative phosphorylation decreases ?
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
what’s the difference at cellular level with reversible and irreversible injury ?
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
3 sources of ATP production ?
- mitochondria = oxidative phosphorylation (aerobic)
- glycolysis pathway (anaerobic)
- glycogenolysis
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
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
light microscopic changes to cell of reversible injury
- cell swelling
- vacuolar change
- fatty change
- surface blebs
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
light microscopic changes to cell of reversible injury
- increased eosinophilia
- cytoplasm has moth eaten appearance
- nuclear dissolution
What are the 3 characteristic nuclear changes that occur in irreversible cell injury ?
- pyknosis = nuclei condenses
- karyorrhexis = nuclei fragmentation
- karyolysis = nuclei dissolved
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
what are the changes of necrosis due to ?
progressive degradative action of enzymes on the lethally injured cell
what are the 2 main processes seen in necrosis ?
- denaturation of intracellular proteins
- enzymatic digestion by lysosomes inherent to the dying cell and lysosomes of leukocytes that are part of inflammatory reaction
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
what are the 5 types of necrosis ?
- coagulative
- liquefactive
- caseous
- fat
- fibrinoid
What does necrosis of tissues have several of ?
morphologically distinct patterns
why are the several morphologically distinct patterns of necrosis of tissues important to recognise ?
they may provide clues about the underlying cause
Cogaulative necrosis is a result of what ?
protein denaturation
microscopy features of coagulative necrosis ?
- ghost cells
- neutrophils can infiltrate but NOT a prominent feature
Gross features of coagulative necrosis
- firm
- pale wedge of tissue
- can become soft later
coagulative necrosis ?
* …… form
* occurs in ….. organs
- commonest
- most
what are free radicals ?
highly reactive molecules with unpaired electron
Alkalis result in …. of fat cells which is followed by ….
- saponofication
- liquefaction necrosis
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
In normal state what concentration are free radicals present at ?
low
What are free radicals required for ?
- killing bacteria
- cell signaling
In excess what do free radicals do ?
- attack lipids in cell membranes
- damage mitochondrial proteins
- damage carbohydrates and nucleic acids
which cell may free radicals be produced ? [check and alter Q + A]
leucocytes
What are free radicals also known to be ?
mutagenic
what 2 events are free radicals involved in ?
pathological & physiological
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)
Increased free radicals (oxidative stress) is sourced from activated …1… in response to 4 factors :
…2…
…3…
…4….
…5…
- leukocytes
- toxins
- UV light
- ionising radiation
- pollutant exposure
When are there decreased scavenging of free radicals ?
- decreased levels of scavenging enzyme (catalase, peroxidase)
- decreased vitamins A , C, E (antioxidants)
- decreased glutathione
heat shock proteins (HSPs) are what class of molecular chaperones ?
chaperonins
What 3 functions do HSPs fulfill ?
- Provide optimal condition for denatured protein folding
- Prevent protein aggregation
- Label misfolded proteins as degradation at proteasome
Give one example of HSP
Ubiquitin
What does the heat shock response aim to do?
What does the heat shock response aim to do?
What is heat shock or the cellular stress reponse triggered by ?
any form of injury, not just heat
Apart from stressed cells where else are HSPs also present ?
lower concentrations in unstressed cells
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
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)
when are HSPs important ?
when the folding step in protein synthesis goes astray or when proteins become denatured during cell injury
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
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
- Infarction is a cause of necrosis which 2 types
- what are the 2 main types of infarction ?
- what do the consequences range from ?
- coagulative + liquefactive necrosis
- white (ischemic) & red (haemorrhagic) infarct
- none to death
Aetiology of infarcation ?
- thrombosis
- embolism
- arterial torsion
- external compression of vessel
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 …….
- brain
- infections
- degradation , enzymes
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)
gross appearance of caseous necrosis
cheese like
Most common cause of caseous necrosis ?
tuberculosis
caseous necrosis :
…1… debris surrounded by histiocytes resulting in a …2…. inflammation
- amorphous
- granulomatous
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
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
What is fat necrosis ?
- destruction of adipocytes
- consequence of trauma or secondary to release of lipases from damaged pancreatic tissue
- what does fatty necrosis cause?
- what does the caused substance react with to form …?
- fatty acids
- react with calcium to form white deposits in fatty tissue
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
Where is fibrinoid necrosis usually seen ?
In immune reactions involving blood vessels : vasculitis
In fibrinoid necrosis what has leaked out of vessels ?
deposits of “immune complexes” together with fibri
What’s the appearance of fibrinoid necrosis in H&E stains ? what is it “called” by pathologists ?
bright pink and amorphous
“fibrinoid”
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:
- solid
- robust stromal support
- arterial
- end
- heart, spleen , kidney
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
What results in the arterial insufficiency in red infarct ?
raised venous pressure leading to increased capillary pressure and tissue pressure
Clinical term to describe visible necrosis ?
gangrene
Wet gangrene is necrosis modified by what ?
bacteria
Dry gangrene is necrosis modified by what ?
air
gas gangrene is necrosis modified by what ?
gas forming bacteria
3 types of gangrene:
- wet
- dry
- gas
What type of cell death is apoptosis ?
energy dependent programmed
Apoptosis can be …. or ….
physiological , pathological
3 features/ characteristics of apoptosis :
- non-random inter-nucleosomal cleavage of DNA
- distinct morphological features
- doesn’t result in inflammatory response
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)
Apoptosis in pathologic conditions ?
- neoplasia
- autoimmune conditions
- immunodepletion from activation of CD4 by AIDS - HIV proteins
Relationship between neoplasia and apoptosis ?
failure of normal apoptosis
Relationship between autoimmune conditions and apoptosis ?
failure of induction of apoptosis in lymphoid cells directed against host antigens
Relationship between immunodepletion and apoptosis?
AIDS - HIV proteins may activate CD4 on uninfected T helper lymphocytes resultin in apoptosis leading to immunodepletion
What is apoptosis regulated by ?
- many genes
- inhibitors
- inducers
What inhibitors regulate apoptosis ?
- growth factors
- extracellular cell matrix
- sex steroids
- some viral proteins
What inducers regulate apoptosis?
- growth factor withdrawl
- loss of extracellular matrix attachment
- glucocorticoids
- viruses
- free radicals
- ionising radiation
Mechanism of apoptosis involves the activation of what ?
cascade of caspases
what is the full name for caspases ?
cysteine-dependent aspartate-directed proteases
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
What is the extrinisc pathway in the mechanism of apoptosis ?
external “death receptors” (TNF receptors or Fas receptors) are activated by a ligand
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)
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
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
How do the 2 pathways of apoptosis differ ?
in their induction and regulation
Difference between necrosis + apoptosis in the pattern feature
N: contiguous groups of cells
A: single cells
Difference between necrosis + apoptosis in the cell size feature
N: enlarged (swelling)
A: reduced (shrinkage)
Difference between necrosis + apoptosis in the nucleus feature
N: pyknosis - karyorrhexis - karyolysis
A: fragmentation into nucleosome size fragments
Difference between necrosis + apoptosis in the plasma membrane feature
N: disrupted, early lysis
A: intact; altered structure, especially orientation of lipids
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
Difference between necrosis + apoptosis in the adjacent inflammation feature
N: frequent
A: No
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
Biochemical findings related to cell death-Molecules released because of cell injury and death ?
- Potassium
- Enzymes
- Myoglobin
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
In myocardial infarction name 3 molecules are released by injured and dying cells ?
- troponin I
- CK-MB (creatine kinase-MB)
- myoglobin
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
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
- myoglobin
- kidneys
- renal
- dialysis
- brown
Abnormal cellular accumulations happen as a result of what injury?
sub-lethal or chronic injury
When do abnormal cellular accumulations occur ?
when metabolic processes are deranged
Abnormal cellular accumulations:
may be …..
reversible
Abnormal cellular accumulations:
can be ….. or ……
harmless , fatal
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
5 examples of substances that undergo intracellular accumulations ?
- water and electrolytes e.g. cerebral oedema
- lipids e.g. fatty liver
- carbohydrates
- proteins
- pigments
example of abnormal fluid accumulation
hydropic swelling: oedema in brain
example of abnormal lipid accumulation
steatosis
examples of abnormal proteins accumulation
- mallory hyaline body-damaged protein
- alpha - 1 antitrypsin globules
what is rhabdomyolysis ?
destruction of muscle to produce myoglobin
Classic triad for symptoms of rhabdomyolysis ?
- muscle pain
- weakness
- dark coca cola/brown urine (myoglobinuria)
what is steatosis ?
Abnormal condition of fat accumulation (increased fat at the cellular level often affecting the liver)
Endogenous pigment accumulation causes
- Lipofuscin
- Haemosiderin (iron accumulation)
- Hereditary haemochromatosis
Lipofuscin endogenous pigment
Age Pigment
Lysosomes with degradation products (residual body)
Haemosiderin endogenous pigment
Iron pigment from breakdown of blood or ingestion of iron
Golden brown pigment seen in macrophages
Bruising
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
Hereditary haemochromatosis
Hereditary - autosomal recessive
Excessive absorption of iron from GI tract
Bilirubin can accumulate in what pathologies?
Liver disease
Hemolytic anemia
Pathological calcifications causes
- Parathyroid overactivity e.g., tumour/hyperplasia
- Malignant tumours e.g., breast/lung/bone
Other causes of calcification apart from the pathological causes being parathyroid overactivity and malignant tumours
- Vitamin D overdosage
- Paget’s disease
- Prolonged immobilisation
Cellular ageing
Telomeres shorten
