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Pathological Processes > Cell Injury > Flashcards

Cell Injury Flashcards

1
Q

What does the degree of cell injury depend on?

A

Type of injury
Severity o injury
Type of tissue

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2
Q

As a physiological stimulus becomes more harmful, what is the cell response?

A

Homeostasis > cellular adaptation > cellular injury > cell death

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3
Q

What can cause cell injury?

A
  • Hypoxia
  • Toxins
• Physical agents
– Direct trauma 
– Extremes of temperature 
– Changes in pressure 
– Electric currents
  • Radiation
  • Micro-organisms
  • Immune mechanisms
  • Dietary insufficiency and deficiencies, dietary excess
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4
Q

What is hypoxia?

A

deficiency in the amount of oxygen reaching the tissues

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5
Q

Name and explain 4 causes of hypoxia

A

– Hypoxaemic hypoxia – arterial content of oxygen is low
• Reduced inspired p02 at altitude
• Reduced absorption secondary to lung disease

– Anaemic hypoxia – decreased ability of haemoglobin to carry oxygen
• Anaemia
• Carbon monoxide poisoning

– Ischaemic hypoxia - interruption to blood supply
• Blockage of a vessel
• Heart failure

– Histiocytic hypoxia – inability to utilise oxygen in cells due to disabled oxidative phosphorylation enzymes
• Cyanide poisoning

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6
Q

How long do a) neurones and b) fibroblasts survive w/ hypoxia?

A

Extent of injury depends on which tissues injured

Neurones = few mins
Fibroblasts = few hours
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7
Q

How does the immune system damage the body’s cells?

A
  • Hypersensitivity reactions - host tissue is injured secondary to an overly vigorous immune reaction, e.g., urticaria (= hives)
  • Autoimmune reactions - immune system fails to distinguish self from non-self, e.g., Grave’s disease of thyroid.
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8
Q

Which cell components are most susceptible to injury?

A
  1. Cell membranes - plasma and organnellar
  2. Nucleus - DNA
  3. Proteins - structural (enzymes)
  4. Mitochondria
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9
Q

What happens at the molecular level in hypoxia?

A

Less oxygen
Less oxyphos
Less ATP
- Decreased activity of Na pump so influx of Ca2+, H2O and Na+, efflux of K+. This causes swelling, loss of microvilli, Blebs, ER swelling, myelin figures
- Increased glycolysis leads to decreased pH and glycogen, leads to clumping of nuclear chromatin
- detachment of ribosomes leads to decreased protein synthesis, leading to lipid deposition

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10
Q

What happens in prolonged hypoxia?

A

Increase in intracellulr calcium leads to activation of

  • ATPase - decreased ATP
  • Phospholipase - decreased phospholipids
  • Protease - disruption o membrane and cytoskeletal proteins
  • Endonuclease - nuclear chromatin damage
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11
Q

Describe cell injury with causes other than hypoxia

A
  • Sequence of events for other insults may be different but as the cell has a limited responses to injury, outcome often similar.
  • Other forms of injury might attack different key structures, e.g., extreme cold (e.g., frostbite) damages membranes initially.
  • Free radicals also damage membranes primarily.
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12
Q

What are free radicals?

A
  • = reactive oxygen species
  • Single unpaired electron in an outer orbit – an unstable configuration hence react with other molecules, often producing further free radicals
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13
Q

Name 3 free radicals with a particular biological significance in cells

A
  • OH• (hydroxyl) - the most dangerous
  • O2- (superoxide)
  • H2O2 (hydrogen peroxide)
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14
Q

When are free radicals produced?

A
  1. Normal metabolic reactions: e.g., oxidative
    phosphorylation
  2. Inflammation: oxidative burst of neutrophils
  3. Radiation: H2O -> OH•
  4. Contact with unbound metals within the body: iron (by Fenton reaction) and copper
    • Free radical damage occurs in haemachromatosis and Wilson’s disease
  5. Drugs and chemicals: e.g., in the liver during metabolism of paracetamol or carbon tetrachloride by P450 system
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15
Q

How does the body control free radicals?

A
  1. Anti-oxidant scavengers: donate electrons to
    the free radical – vitamins A, C and E
  2. Metal carrier and storage proteins (transferrin, ceruloplasmin): sequester iron and copper
  3. Enzymes that neutralise free radicals
    – Superoxide dismutase
    – Catalase
    – Glutathione peroxidase
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16
Q

How do free radicals injure cells?

A

• If the number of free radicals overwhelms the anti-
oxidant system = oxidative imbalance
• Most important target are lipids in cell membranes.
– Cause lipid peroxidation.
– This leads to generation of further free radicals → autocatalytic chain reaction.
• Also oxidise proteins, carbohydrates and DNA
– These molecules become bent out of shape,
broken or cross-linked
– Mutagenic and therefore carcinogenic

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17
Q

How else can cell protect itself against injury?

A
  • Heat shock proteins
  • In cell injury heat shock response aims to ‘mend’ mis-folded proteins and maintain cell viability.
  • Unfoldases or chaperonins.
  • An example – ubiquitin.
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18
Q

What do injured/dying cells look like under a light microscope?

A

In hypoxia:
•Cytoplasmic changes
•Nuclear changes
•Abnormal cellular accumulations

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19
Q

What are some irreversible changes to injured cells?

A

Pyknosis - nucleus shrinks
Karyorrhexis - nucleus breaks up
Karyolysis - nucleus dissolves

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20
Q

What do injured and dying cells look like under an electron microscope?

A

Reversible - blebs, generalised swelling, clumping of chromatin, autophagy by lysosomes, ER swelling, dispersion of ribosomes, mitochondrial swelling, small densities, aggregation of intramembranous particles

Irreversible - rupture of lysosomes and autolysis, nucleus pykinosis/karyolysis/karyorrhexis, defects in cell membrane, muslin figures, lysis of ER, mitochondrial swelling, large densities

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21
Q

How is cell death diagnosed?

A

Best way to tell when cell is irreversibly damaged - not by look, by function
Dye cells - when membranes leaky, dye taken up into cells

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22
Q

Define oncosis and necrosis

A

• Oncosis: cell death with swelling, the spectrum of
changes that occur in injured cells prior to death

• Necrosis: in a living organism the morphologic
changes that occur after a cell has been dead some
time
– Seen after 12-24 hours

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23
Q

What are the 2 main types of necrosis?

A

• Two main types:
– Coagulative
– Liquefactive (colliquitive)

• Two other special types:
– Caseous
– Fat necrosis

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24
Q

Why are there 2 types of necrosis?

A

2 causes

1) protein desaturation -> coagulate necrosis e.g. ischaemia of solid organs
2) enzyme release -> liquefaction necrosis e.g. ischaemia in loose tissues; presence of many neutrophils

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25
Q

What does coagulation necrosis look like?

A

•Denaturation of proteins dominates over release of active proteases.
•Cellular architecture is somewhat preserved, “ghost outline” of cells.
(SEE SLIDE)

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26
Q

What does liquefactive necrosis look like?

A

•Enzyme degradation is substantially greater than denaturation.
•Leads to enzymatic digestion (liquefaction) of tissues.
(SEE SLIDE)

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27
Q

What is caseous necrosis?

A

•Contains amorphous (structureless) debris. (c.f. ghost outline in coagulative necrosis).
•Particularly associated with infections, especially tuberculosis.
(SEE SLIDE)

28
Q

What is fat necrosis and what does it look like?

A 
Macrophages reacting  to dead adipocytes - hard firm lump often mistaken as malignancy 
Melting wax (SEE SLIDE)
29
Q

What do the terms gangrene, infarction and infarct mean?

A

• Gangrene = necrosis visible to the naked eye
– An appearance of necrosis

• Infarction = necrosis caused by reduction in arterial blood flow
– A cause of necrosis
– Can result in gangrene

• Infarct = an area of necrotic tissue which is the result of loss of arterial blood supply
– An area ischaemic necrosis

30
Q

What do the terms dry and wet gangrene mean?

A

• Dry gangrene = necrosis modified by exposure to air
(coagulative necrosis)
• Wet gangrene = necrosis modified by infection (liquefactive necrosis)

31
Q

What is gas gangrene?

A

• Wet gangrene where the infection is with anaerobic

bacteria that produce gas

32
Q

What are the commonest causes of infarction?

A

Thrombosis and embolism

33
Q

How else can tissue become infarcted?

A

Twisting e.g. of the gut or spermatic cord

34
Q

What does infarcted tissue look like?

A

Can be white or red

35
Q

Why are some infarcts white?

A
  • = anaemic infarcts
  • ‘Solid organs’, occlusion of an end artery
  • Often wedge-shaped
  • Coagulative necrosis
36
Q

Why are some infarcts red?

A
  • = haemorrhagic infarct
  • Loose tissue
  • Dual blood supply
  • Numerous anastomoses
  • Prior congestion
  • Re-perfusion
  • Raised venous pressure (Heart cannot handle amount of blood coming in from venous system - pressure builds higher than arterial system - o2 cant get in, tissue wil die - but nothing wrong with art bold supply
37
Q

What is the consequence of infarction?

A 
• None to death 
• Depends on:
– Alternative blood supply
– Speed of ischaemia
– Tissue involved
– Oxygen content of the blood
38
Q

What is ischaemia-reperfusion injury?

A

• Paradoxically, 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.

• Possible causes:
– 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.

39
Q

When membranes are leaky, can molecules leak out as well as in?

A

• 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

NKX doesn’t work, sodium in and water follows

40
Q

What can leak out of cell?

A

Potassium
Enzymes
Myoglobin (Leaks out when significant skeletal muscle damage - significant trauma or very vigorous exercise in hot enveironment - Myoglobin stuck in enal tubules)

41
Q

What is apoptosis?

A
  • Apoptosis: cell death with shrinkage, induced by a regulated intracellular program where a cell activates enzymes that degrade it’s own nuclear DNA and proteins
  • Characteristic microscopic appearance
  • Characteristic DNA breakdown
  • Non-random, internucleosomal cleavage of DNA (in oncosis, DNA is chopped into pieces of random length)
  • Equal and opposite force to mitosis
  • Active process
  • Enzymes activated that degrade nuclear DNA and protein
  • Membrane integrity is maintained
  • Lysosomal enzymes not involved
  • Quick, cells gone in a few hours
  • Pathological or physiological
42
Q

When does apoptosis occur physiologically?

A
  1. In order to maintain a steady state
  2. Hormone-controlled involution
  3. Embryogenesis - stain for apoptotic cells in the developing paw of a foetal mouse.
  • Cytotoxic T cell killing of virus-infected or neoplastic cells
  • When cells are damaged, particularly with damaged DNA
  • Graft versus host disease
43
Q

What is graft vs host disease?

A

Leukaemia - need bone marrow destroyed - strong chemo
Then get given graft bone marrow - injected - enter bone marrow - produce blood cells again
Sometimes graft cells produce WBC’s - attack host cells
Rapid turn over

44
Q

What does apoptosis look like

A

Condensation (clumping of material under nuclear memb) -> fragmentation (buds not blebs) -> apoptotic bodies

45
Q

What are the 3 phases in apoptosis?

A

Initiation
Execution
Degradation and phagocytosis

46
Q

What are initiation and execution?

A

• Triggered by two mechanisms
– intrinsic and extrinsic
• Both result in activation of caspases
– Enzymes that control and mediate apoptosis
– Cause cleavage of DNA and proteins of the cytoskeleton

47
Q

How is the intrinsic pathway initiated and carried out?

A

• Initiating signal comes from within the cell
• Triggers:
– Most commonly irreparable DNA damage
– Withdrawal of growth factors or hormones

  • 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
48
Q

How is the extrinsic pathway initiated and carried out?

A

• Initiated by extracellular signals
• Triggers:
– Cells that are a danger, e.g., tumour cells, virus- infected cells
• One of the signals is TNFα
– Secreted by T killer cells
– Binds to cell membrane receptor (‘death receptor’)
– Results in activation of caspases

49
Q

Why are apoptotic bodies phagocytosed?

A

• Both intrinsic and extrinsic pathways cause the cells
to shrink and break up into apoptotic bodies
• 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

50
Q

Compare apoptosis and oncosis

A

A: Shrinkage and chromatin condensation, nucleus fragments into nucleosome sized fragments, from clumps between nuclear memb
N: Swelling, nucleus - pykinosis, karyorrhexis, karyolysis

A: Budding but memb in tact
N: Blebbing and memb disruption

A: Apoptotic bodies phagocytosed with no inflammation
N: Release of proteolytic enzymes with important inflammatory reaction

A: single cells
N: contagious groups

A: often physiologic, means of laminating unwanted cells, may be pathological after some forms of cel injury esp DNA damage
N: invariably pathologic

51
Q

Where do abnormal cellular accumulations come from?

A

• Seen when metabolic processes become deranged
• Often occur with sublethal or chronic injury
• Can be reversible
• Can be harmless or toxic
• They can derive from the:
– Cell’s own metabolism
– The extracellular space, e.g., spilled blood
– The outer environment, e.g., dust

52
Q

What can accumulate in cells?

A 
• There are five main groups of intracellular
accumulations:
– Water and electrolytes 
– Lipids 
– Carbohydrates 
– Proteins 
– ‘Pigments’
53
Q

When does fluid accumulate in cells?

A
  • Hydropic swelling
  • Occurs when energy supplies are cut off, e.g., hypoxia
  • Indicates severe cellular distress
  • Na+ and water flood into cell
  • Particular problem in the brain
54
Q

When do lipids accumulate in cells?

A 
• Steatosis (accumulation of triglycerides) 
• Often seen in liver (major organ of fat metabolism) 
• If mild - asymptomatic 
• Causes:
– Alcohol (reversible in about 10 days)
– Diabetes mellitus
– Obesity
– Toxins (e.g., carbon tetrachloride)
55
Q

Where is cholesterol stored?

A

• Cholesterol:
– Cannot be broken down and is insoluble
– Can only be eliminated through the liver
– Excess stored in cell in vesicles
– Accumulates in smooth muscle cells and macrophages in atherosclerotic plaques = foam cells
– Present in macrophages in skin and tendons of people with hereditary hyperlipidaemias = xanthomas
(SEE SLIDE)

56
Q

In what conditions do proteins accumulate in cells?

A

• Seen as eosinophilic droplets or aggregations in the
cytoplasm
• Alcoholic liver disease:
– Mallory’s hyaline (damaged keratin filaments)
• α1-antitrypsin deficiency:
– Liver produces incorrectly folded α1-antitrypsin protein (a protease inhibitor)
– Cannot be packaged by ER, accumulates within ER and is not secreted
– Systemic deficiency
– proteases in lung act unchecked resulting in emphysema
(SEE SLIDE)

57
Q

When do pigments accumulate in cells?

A

• Carbon/coal dust/soot – urban air pollutant
• Inhaled and phagocytosed by alveolar macrophages
• Anthracosis and blackened peribronchial lymph
nodes
• Usually harmless, unless in large amounts = fibrosis and emphysema = coal worker’s pneumoconiosis
• Tattooing – pigments pricked into skin
• Phagocytosed by macrophages in dermis and remains there
• Some pigment will reach draining lymph nodes

58
Q

When do endogenous pigments accumulate?

A
  • Haemosiderin:
  • Iron storage molecule
  • Derived from haemoglobin, yellow/brown
  • Forms when there is a systemic or local excess of iron, e.g., bruise
  • With systemic overload of iron, haemosiderin is deposited in many organs = haemosiderosis
  • Seen in haemolytic anaemias, blood transfusions and hereditary haemochromatosis
59
Q

What is hereditary haemochromatosis?

A

• Genetically inherited disorder - results in increased
intestinal absorption of dietary iron
• Iron is deposited in skin, liver, pancreas, heart and endocrine organs - often associated with scarring in liver (cirrhosis) and pancreas.
• Symptoms include liver damage, heart dysfunction and multiple endocrine failures, especially of the pancreas.
• Was called ‘bronze diabetes’
• Treatment is repeated bleeding
(SEE SLIDE)

60
Q

What accumulates in jaundice?

A
  • Accumulation of bilirubin – bright yellow
  • Breakdown product of heme, stacks of broken porphyrin rings
  • Formed in all cells of body (cytochromes contain heme) but must be eliminated in bile
  • Taken from tissues by albumin to liver, conjugated with bilirubin and excreted in bile
  • If bile flow is obstructed or overwhelmed, bilirubin in blood rises and jaundice results
  • Deposited in tissues extracellularly or in macrophages (SEE SLIDE)
61
Q

What is calcification of tissues?

A

• Abnormal deposition of calcium salts within tissues. • Can be localised (dystrophic) or generalised (metastatic)
• Dystrophic:
• Much more common that metastatic
• Occurs in an area of dying tissue, atherosclerotic plaques, aging or damaged heart valves, in tuberculus lymph nodes, some malignancies
(SEE SLIDE)
Heart valves on left side

62
Q

Why does dystrophic calcification occur?

A
  • No abnormality in calcium metabolism, or serum calcium or phosphate concentrations
  • Local change/disturbance favours nucleation of hydroxyapatite crystals
  • Can cause organ dysfunction, e.g., atherosclerosis, calcified heart valves
63
Q

Why does metastatic calcification occur?

A
  • Due to hypercalcaemia secondary to disturbances in calcium metabolism
  • Hydroxyapatite crystals are deposited in normal tissues throughout the body
  • Usually asymptomatic but it can be lethal
  • Can regress if the cause of hypercalcaemia is corrected
64
Q

What causes hypercalcaemia?

A

•Increased secretion of parathyroid hormone (PTH)
resulting in bone resorption:
• Primary - due to parathyroid hyperplasia or tumour
• Secondary – due to renal failure and the retention of phosphate
• Ectopic - secretion of PTH-related protein by malignant tumours (e.g., carcinoma of the lung)
• Destruction of bone tissue:
• Primary tumours of bone marrow, e.g., leukaemia, multiple myeloma
• Diffuse skeletal metastases
• Paget’s disease of bone – when accelerated bone turnover occurs
• Immobilisation
See slides

65
Q

Can cells live forever?

A

• As cells age they accumulate damage to cellular
constituents and DNA
• After a certain number of divisions they reach replicative senescence - related to the length of chromosomes
• Ends of chromosomes are called telomeres, with every replication the telomere is shortened. When the telomeres reach a critical length, the cell can no longer divide
• Germ cells and stem cells contain an enzyme called telomerase maintains the original length of the telomeres. In this way they can continue to replicate, indefinitely in the case of germ cells
• Many cancer cells produce telomerase and so have the ability to replicate multiple times

Pathological Processes (12 decks)

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