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CGP ESA2 > MOD 1 Cell Injury > Flashcards

MOD 1 Cell Injury Flashcards

1
Q

What are the four types of Hypoxia

A

Hypoxaemic
Anaemic
Ischaemic
Histiocytic

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2
Q

What is Hypoxaemic hypoxia?

A

When arterial blood oxygen is low due to an issue in the lungs

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3
Q

What is anaemic hypoxia?

A

When blood O2 saturation is low due to a deficiency of Hb/RBCs

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4
Q

What is ischaemic hypoxia?

A

When the blood supply is interrupted eg. due to a thrombus

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5
Q

What is hypoxaemic hypoxia?

A

When oxygen usage of the cells is prevented. Eg cyanide poisoning prevents oxidative phosphorylation

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6
Q

What are the two key divisions of cell injury?

A

Environmental & Genetic

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7
Q

What examples of environmental injury causes are there?

A
  1. Hypoxia
  2. Chemicals
  3. Physical factors e.g. trauma, temperature and radiation
  4. Infection
  5. Nutritional deprivation e.g. lack of glucose for glucose-dependent neurones
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8
Q

Name two examples of genetic injury

A

Mutations leading to

i) Enzyme deficiencies
ii) Morphological changes e.g. SCD

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9
Q

What are the four key targets for cell injury within the cell?

A

Nucleus, Mitochondria, Membranes & Proteins

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10
Q

Describe reversible hypoxic injury

A
  1. Decrease in amount of available O2
  2. Less ATP made as the rate of oxidative phosphorylation is decreased
  3. The decrease in ATP prompts:
    i) Decreased activity of Na+/K+-ATPase, leading to SWELLING
    ii) Increased glycolysis leading to a decrease in pH and CLUMPING CHROMATIN
    iii) DETACHMENT OF RIBOSOMES leading to decreased protein synthesis and fewer membrane proteins
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11
Q

At what point does reversible hypoxic injury become irreversible?

A

If the pathological stimulus is large enough, there is an INFLUX OF Ca2+
This stimulates a FINAL COMMON PATHWAY

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12
Q

What are the observable microscopic features of reversible hypoxic injury?

A

Swelling, ribosome detachment from Rough ER, clumping of chromatin & denatured protein clumps

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13
Q

Describe irreversible cell injury

A

Elevated intracellular Ca2+ activates ATPases, Phospholipases, Proteases & Endonucleases

The MITOCHONDRIAL PERMEABILITY TRANSITION occurs This is where Ca2+ leaks from the mitochondria (it is necessary for use as a mitochondrial enzyme cofactor)

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14
Q

What do the activated enzymes in irreversible cell injury do?

A

ATPases decrease ATP
Phospholipases digest the cell membranes
Proteases digest cytoskeletal and membrane proteins
Endonucleases digest chromatin

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15
Q

How do the cells die in irreversible hypoxic injury?

A

ONCOSIS, possibly by a bleb bursting and releasing the intracellular contents

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16
Q

What is ischaemia-reperfusion injury?

A

Where after a period of ischaemia, blood supply is resorted to the tissue.
The sudden increase in O2 concentration leads to the production of FREE RADICALS, which can damage the cells.
The tissue injury sustained can be worse than if the blood supply was not restored.
This is because of increased neutrophil numbers and activation of the complement pathway

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17
Q

How do chemicals (e.g. cyanide) cause cell injury?

A

They can cause HISTOCYTIC HYPOXIA

Cyanide binds to CYTOCHROME OXIDASE, stopping the ETC & Oxidative phosphorylation

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18
Q

How do free radicals cause cell injury?

A

They cause LIPID PEROXIDATION, DAMAGE PROTEINS & DNA

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19
Q

What are the three key free radicals?

A

OH• (most damaging)
H2O2
O2•

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20
Q

How are free radicals made in cells?

A
  1. Radiation can directly photolyse water: H2O –> OH•+ H•
  2. FENTON EQUATION happens when IRON is present because of HAEMORRHAGE
  3. HABER EQUATION
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21
Q

What defences does the body have against free radicals?

A
  1. Superoxide Dismutase (SOD) O2•–> H2O2
    & Catalase H2O2–> O2 + H2O
  2. VITAMIN A, C & E “free radical scavengers”
  3. GLUTATHIONE GSH–> GSSG
  4. ION STORAGE PROTEINS eg Transferrin stores iron, preventing the FENTON equation
22
Q

What is the role of heat shock proteins (e.g. chaperonins)?

How do they defend against the effects of cell injury?

A

When cells are subjected to pathological stress, they down regulate protein synthesis & up regulate HSPs
They ensure correct FOLDING of proteins ; REFOLD damaged PROTEINS
example= UBIQUITIN

23
Q

What changes are visible under a light microscope in Oncosis?

A
  1. Initially reduced staining due to SWELLING
    Then increased staining once RIBOSOMES DETACH
  2. CLUMPED CHROMATIN
  3. ABNORMAL ACCUMMULATIONS e.g. Mallory bodies
24
Q

What changes are seen under the electron microscope in oncosis?

A 
Swelling
Pyknosis, karyorrhexis, karyolysis
Rupture of lysosomes
Membrane defects
Lysis of ER
BLEBS
25
Q

Why do cells swell in cell injury?

A

Decrease in amount of ATP (due to hypoxia or another mechanism), so primary and thus secondary active transporters fail. Ions accumulate intracellularly and water moves into the cells.

26
Q

By which two ways do cells die?

A

ONCOSIS or APOPTOSIS

27
Q

Define Oncosis

A

Cell death with associated swelling, including the spectrum of changes occurring within the injured cell beforehand.

28
Q

Define Necrosis

A

The morphological changes associated with the death of cells, after the event. e.g. 4-24 hours. This is NOT a type of cell death.

29
Q

Define Apoptosis

A

Cell death with associated shrinkage. Follows an automated program of enzyme activation. Genetically coded for.

30
Q

Define AUTOLYSIS

A

When a cell is digested by its own enzymes . This can release enzymes into the extracellular matrix, digesting it also. This occurs in LIQUEFACTIVE necrosis.

31
Q

How does membrane degradation prompt acute inflammation in necrosis?

A

When PHOSPHOLIPASE digests the membrane lipid into ARACHIDONIC ACID, arachidonic acid is converted into PROSTAGLANDINS by COX1/2 or LEUKOTRIENES by LIPOXYGENASE. Prostaglandins are vasodilators and leukotrienes are permeability local mediators.

32
Q

What are the two main types of necrosis? Why are they different?

A

COAGULATIVE & LIQUEFACTIVE

Coagulative necrosis occurs when the proteins within the dying cell DENATURE. It normally occurs in solid organs e.g. heart after infarction. This is because there is a STRONG COLLAGEN EXTRACELLULAR ARCHITECTURE.

Liquefactive necrosis occurs when the cell undergoes AUTOLYSIS. The enzymes then leak into the extracellular matrix, digesting the collagen architecture. In organs when this architecture is already sparse e.g. the brain, this leads to the ‘liquid’ appearance.

33
Q

What other types of necrosis are there?

A

CASEOUS - associated to TB ‘Cheese-like’
FAT- Destruction of ADIPOSE tissue e.g. in acute pancreatitis. This causes lipase release. Fatty acids react with calcium to form CALCIUM SOAPS, which can be seen on X-Ray. Can also happen after direct trauma to a fatty tissue e.g breast.

34
Q

What is Gangrene? What types are there?

A

Necrosis visible to the naked eye.

WET (exposed to bacteria)
DRY (Exposed to the air)
GAS (Wet gangrene with anaerobic bacteria, make gas bubbles)

35
Q

What is infarction? What is the most likely cause? What types are there?

A

Necrosis caused by ischaemia. This can lead to gangrene.

Most is caused by thrombosis or embolism.
Can also be caused by twisting (testitcular torsion) or compression (tumour/hernia) of a vessel.

WHITE or RED

White occurs in ‘solid’ organs, caused by the OCCLUSION OF AN END ARTERY. e.g. in heart, kidney, spleen. Typically coupled with COAGULATIVE NECROSIS

Red occurs when there is extensive haemorrhage into an infarct. It occurs where there is dual blood supply e.g. lungs or extensive ANASTAMOSES, in loose tissue or when CVP is raised.

36
Q

What are the main molecules released by dying cells (3)?

A

POTASSIUM —> Potassium bomb can cause the HEART TO STOP (hyperkalaemia, HCN channels, slower rate)
ENZYMES —> CKMB can be used to diagnose MI
MYOGLOBIN –> RHABDOMYOLOSIS

37
Q

Describe the stages of APOPTOSIS

A
  1. INITIATION
  2. EXECUTION
  3. DEGRADATION & PHAGOCYTOSIS
  4. INITIATION
    There is an INTRINSIC and EXTRINSIC initiation process.
    EXTRINSIC:
    A DEATH LIGAND (e.g. TRAIL & Fas & TNF) bind to a DEATH RECEPTOR. This prompts a transduction cascade, activating CASPASES.
    INTRINSIC:
    At rest, there is a balance between BCL2 & BAX proteins. BAX is a promoter of apoptosis, BLC2 is an inhibitor (both are members of the BCL2 family). When DNA Is damaged, the ratio of these two proteins changes, in favour of BAX.
    p53 induces CELL CYCLE ARREST in response to DNA damage.
  5. EXECUTION:
    The Bcl2 family proteins promote the release of CYTOCHROME C from the MITOCHONDRIAL MEMBRANE. This combines with PROCASPASE 9 & APAF1 to form an APOPTOSOME. (7 arms)
    The apoptosome recruits the INITIATOR procaspase, PROCASPASE 8. A procaspase CASCADE begins, culminating in the activation of the EXECUTIONER CASPASE, CASPASE 3, which ACTIVATES DNase, causing KARYORRHEXIS.
  6. DEGRADATION & PHAGOCYTOSIS
    Pyknosis and then karyorrhexis occurs. The cell SHRINK, with the MEMBRANE INTACT.
    APOPTOTIC BODIES are formed, containing cell contents.
    The apoptotic bodies are PHAGOCYTOSED
38
Q

Why does apoptosis not cause acute inflammation?

A

There is no release of cell contents as the cell remnants are contained in APOPTOTIC BODIES & so neutrophils are not recruited to the site.

39
Q

What are the differences between oncosis & APOPTOSIS?

A

groups of cells SINGLE CELLS
swelling SHRINKING
pyknosis/karyorrhexis/karyolysis FRAGMENTATION INTO NUCLEOSOME SIZE FRAGMENTS
autolysis & possible leak INTACT APOPTOTIC BODIES
frequent inflammation NO INFLAMMATION
pathological cause PATHOLOGICAL OR PHYSIOLOGICAL CAUSE EG FINGER FORMATION IN FOETUS

40
Q

List examples of intracellular abnormal accumulations

A

Water, lipids, proteins, pigments, carbohydrates

41
Q

What is steatosis?

A

Fatty change. The accumulation of triglycerides.

Seen in liver (liver goes yellow). When mild, not much effect on function.

42
Q

What is Mallory’s Hyaline?

A

Accumulation of KERATIN in the cytoplasm bound to HSPs, seen in hepatocytes affected by ALCOHOLIC LIVER DISEASE.

43
Q

What is anthracosis

A

Carbon (exogenous pigment) causing blackened lungs and lymph nodes. If very high exposure, Coal workers PNEUMOCONIOSIS.
A similar situation is seen with tattoos, where macrophages move the pigment after phagocytosis to the nearest lymph nodes.

44
Q

What is LIPOFUSCIN?

A

Brown pigment seen in ageing cells. Seen in long lived cells and not those with a fast turnover. A sign of free radical damage and lipid peroxidaton.

45
Q

What is hameosiderin?

A

Iron storage molecule, seen at the site of a bruise. Also seen in hereditary haemochromatosis.

46
Q

What is hereditary haemochromatosis?

A

A genetic condition causing increased dietary uptake of iron. Iron is deposited in the organs. Causes most damage in the liver, leading to Cirrhosis.
Termed ‘Bronze diabetes’ as it can cause pancreatic failure and brownish skin.
Treat by bleeding/diet control

47
Q

What is Haemosiderosis?

A

Systemic overload of iron, leading to haemosiderin deposition in the organs.

48
Q

What is bilirubin?

A

A yellow pigment, which is a breakdown product of haemoglobin. When the excretion pathway is overwhelmed (normally conjugated to albumin and excreted in bile), it can accumulate in the skin causing a yellowish appearance.

49
Q

Whats is the difference between dystrophic and metastatic calcification?

A

DYSTROPHIC is the deposition of calcium in dying/damaged/aging tissue e.g. heart valves (aortic stenosis)
METASTATIC is a systemic hypercalcaemia. Hydroxyapatite crystals are deposited in many tissues, not just bone.
Causes include:
INCREASED PTH: parathyroid hyperplasia (primary), renal failure & phosphate retention (secondary), PTHrp release from a tumour (e.g. lung carcinoma)(ectopic)
INCREASED BONE DESTRUCTION: Paget’s, skeletal metastases, multiple myeloma, immobilisation

50
Q

What determines the start of replicative senescence?

A

Telomere length. At the HAYFLICK LIMIT, cells will cease to replicate (unless neoplastic).
Germ cells and stem cells have TELOMERASE, to lengthen the telomeres to overcome this issue.

51
Q

Which pigment accumulates in ageing cells?

A

LIPOFUSCIN

52
Q

What diseases and changes can excessive alcohol intake cause? Briefly describe each.

A
  1. FATTY CHANGE (STEATOSIS)
    Alcohol effects alcohol metabolism. The detoxification pathway of alcohol exhausts the NAD supply and so less is available for fatty acid metabolism. This leads to accumulation in the liver. Mallory’s hyaline & fat globules present.
  2. ACUTE ALCOHOLIC HEPATITIS
    A large binge leads to hepatocyte death & necrosis. AST & ALT will be elevated. Acute inflammation, tenderness and jaundice are consequences.
  3. CIRRHOSIS
    Replacement of the liver parenchyma with fibrous scar tissue. This reduces blood flow. The liver architecture is replaced with nodules.

CGP ESA2 (7 decks)

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