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Flashcards in MOD - Cell Injury Deck (82):
1

What is ischaemia?

What are the effects?

Loss of blood supply to due to reduced arterial supply or reduced venous drainage.

Reduced supply of oxygen and nutrients, resultant injury more rapid and severe than hypoxia

2

What is a common form of cell death? And explain?

Hypoxia - oxygen deprivation, decreased aerobic respiration.

Length of time a cell can tolerate hypoxia varies, some neurones can only tolerate for a few minutes, dermal fibroblasts can tolerate for a number of hours.

3

What are the causes of hypoxia? (4)

Hypoxaemic - arterial content of oxygen is low

Anemic - decreased ability for Haemoglobin to carry oxygen

Ischaemia - interruption to blood supply

Histiocytic - inability to use oxygen in cells due to disabled oxidative phosphorylation enzymes

4

Name the other causes of cell death and describe (6)

Physical agents - Trauma, temperature extreme, electrical currents
Chemical agents and drugs - high O2 concentration, positions, insecticides, alcohol, asbestos
Microorganisms - viruses, bacteria, fungi
Immune mechanisms - hypersensitivity reactions (urticaria) and autoimmune (Graves' disease)
Dietary insufficiency and deficiencies
Genetic abnormalities - inborn error of metabolism

5

What are the four components of a cell that are principal targets of cell injury?

Cell membranes- role in homeostasis
Nucleus - genetic material of the cell
Proteins - structural proteins forming cytoskeleton and enzymes involved in metabolic processes of cell
Mitcochondria - oxidative phosphorylation and production of ATP

6

In what ways does reversible hypoxia affect the cell? And why? (3)

Cell swelling - Cell is deprived of oxygen, so produces less ATP
Loss of activity to Na+/K+ pump. Na+ conc rises = cell swells
Reduced cell pH - accumulation of lactic acid from anaerobic respiration
Disruption of protein synthesis - ribosomes detach from ER, can cause intracellular accumulation of substances e.g. fat and denatured proteins

7

What ways does irreversible hypoxia effect the cell?

Increased membrane permeability
Massive influx of Ca2+ ions Into cytoplasm
Calcium ions are biologically very active and high concentrations result in the activation of an array of potent enzymes such as ATPases, phospholipases, proteases and endonucleases.

8

What test can be undertaken to check for irreversible cell damage, and why?

Blood test - types of substance found indicates where cell damage is

When cell membranes are irreversibly damaged intracellular substances leak about into circulation and can be found in the blood

9

What is Ischaemia reperfusion injury?

Blood flow returning to a tissue that has been subjected to Ischaemia and sometimes the tissue injury is worse than if blood was not restored.

10

What may cause Ischaemia reperfusion injury?

Increased production of oxygen free radicals
Increased number of neutrophils
Delivery of complement proteins and activation of complement pathway

11

How does cyanide toxicity work on a cell?

Chemical combine with cyanide which binds to mitochondrial cytochrome oxidase and blocks oxidative phosphorylation

12

Why do free radicals cause cell damage?

They have a single unpaired electron, giving them an unstable configuration and so they react with other molecules producing further free radicals.

13

What do free radicals damage?

Lipids in cell membranes
Proteins, carbohydrates and nucleic acids

Known to be mutagenic

14

Why are free radicals essential? (2)

Kill bacteria.
Cell signalling

Produced by leucocytes

15

What are the three free radicals of particular biological importance?

OH (hydroxyl) most dangerous
O2- (superoxide)
H2O2 (hydrogen peroxide)

16

How is the OH free radical produced?

Radiation can directly lyse H20
Fenton and Haber-Weiss reactions produce OH. Fenton reaction important in injury where bleeding occurs as when blood is around iron is available for production of free radicals

17

What is the bodies defence against free radicals?

Anti-oxidant system which consists of
Enzymes - superoxidse dismutase (SOD) and Catalase
Free radical scavengers - neutralise free radicals e.g. Vitamin A,C,E
Storage proteins - sequester transition metals in the ECM

18

By what mechanism do cell utilise heat shock proteins (HSP)

What happens to the HSP?

Down regulate usual protein synthesis and up regulate heat protein synthesis.

They stay in the cell where they are concerned with protein repair

19

How do heat shock proteins work?

Recognise proteins that are incorrectly folded and repair them by ensuring they are folded correctly.

If they cannot repair them, they destroy them

20

Why are heat shock proteins important in cell injury?

Name a heat shock protein.

Heat shock response plays a key role in maintaining protein viability and maximising cell survival.

Ubiquitin

21

What is the best method to diagnose cell death?

Dye exclusion technique - dye put into the cell medium, if it doesn't take it up = cell is alive

22

What are the three main alterations to cells that can be seen with injury in light microscope?

Cytoplasmic changes - reduced pink staining due to accumulation of water. Increased pink staining due to detachment of ribosomes from ER and accumulation of proteins
Nuclear changes - chromatin subtly clumped (reversible)
Abnormal intracellular accumulations

23

Name 4 reversible cell injury changes that can be seen under an electron microscope

Swelling - cell and organelles
Cytoplasmic blebs - symptomatic of cell swelling
Clumped chromatin - due to reduced pH
Ribosome separation from ER - due to failure of energy dependent processes of maintain ribosomes in right location

24

Name 4 irreversible changes that can be seen under an electron microscope in cell injury

Increased cell swelling
Nuclear changes - pyknosis, karyolysis or karyorrhexis
Swelling and rupture of lysosomes - reflects membrane damage
Membrane defects
Appearance of myelin figures
Lysis of ER due to membrane defects

25

Define oncosis

Cell death with swelling, the spectrum of changes that occur prior to death in cells injured by hypoxia and some other agents

26

Define apoptosis

Cell death with shrinkage.
Cell death induced by down regulated intracellular program where a cell activates enzymes that degrade its own nuclear DNA and proteins.

27

Define necrosis

In a living organism the morphological changes that occur after a cell has been dead some time e.g. 4-24hours.
The changes in appearance are largely due to the progressive degradative action of enzymes on lethally injured cell.

NOT a type of cell death, describes morphological changes.

28

Name the four types of necrosis.

Necrosis is seen with damage to cell membrane, cell contents leak out of the cell and inflammation is often seen.

Coagulative
Liquefactive
Caseous
Fat necrosis

29

Describe coagulative necrosis

Denature of proteins dominates over release of active proteases, meaning that dead tissue has a solid consistency.
Cells proteins uncoil and become less soluble
'Ghost Outline' outline of cells

After a few days, dead tissue incites an inflammatory reaction with consequent infiltration by phagocytes.

30

Describe liquifactive necrosis

Active enzyme degradation greater than denaturation and this leads to enzymatic digestion of tissues.
(Proteins undergo dissolution by cells own enzymes)
It is seen in massive neutrophil infiltration because neutrophils release proteases and therefore bacterial infections.

Seen in the brain - fragile tissue without support from robust collage nous matrix

Tissue becomes a viscous mass and if there is acute inflammation pus is present.

31

Describe caseous and fat necrosis.

Note - These special types of necrosis only occur under limited set of circumstances.

Caseous - cheesy appearance with naked eye. Characterised by amorphous debris (NOT ghost outline). Particularly associated with infections e.g. TB.

Fat - destruction of adipose tissue typically as consequence of acute pancreatitis, during inflammation of pancreas realise of lipases which act on pancreas and fat in abdo cavity - causes release of free fatty acids which can react with calcium to form chalky deposits. Can be seen on Xrays and with naked eye - candle wax appearance.
Can occur after direct trauma e.g. Breast tissue. Heals leaving an irregular scar that can mimic a nodule of breast cancer

32

What is a clinical term to describe necrosis visible to the naked eye?

Describe the three types.

Gangrene - can be wet or dry depending on whether necrosis is modified by exposure to air resulting in drying (dry or by infection with mixed bacteria (wet).
Dry gangrene - dry crisp appearance of umbilical cord, gangrenous toes
Gas gangrene - (wet gangrene) that has become infected with anaerobic bacteria that produces visible and palpable bubbles of gas within the tissue.

33

What type of necrosis is present in wet and dry gangrene.

Dry - coagulative
Wet - liquifactive

34

Why is wet gangrene very serious?

Bacteria can easily get into the blood stream and result in septicaemia.

35

What is a cause of necrosis?

Describe.

Infarction - mainly Ischaemia. Most caused by thrombosis or embolism. Can occasionally be due to external compression or twisting of vessels.
Necrosis can be coagulative (MI) or liquifactive (brain).
Infarcts can be described by their colour; white or red which describes how much haemorrhage there is into infarct.

Infarction can result in gangrene.

36

What is white infarct and where do they occur?

Occurs in 'solid' organs after occlusion of an end artery.
Solid nature of tissue limits the amount of haemorrhage that can occur into the infarct from adjacent capillaries

Occur in the heart, spleen and kidneys

White infarcts appear as coagulative necrosis.

37

What is a red infarct and where do they occur?

Extensive haemorrhaging into dead tissue.
Can occur in tissues with a dual blood supply e.g. Lung
Numerous anastomoses (capillary beds of two separate arterial supplies merge) are present in a tissue.
Loose tissue
Previous congestion
Raised venous pressure

38

What are the consequences of an infarct?

Consequences range from none to death. Dependent on:
Whether tissue has alternative blood supply
How quickly Ischaemia occured
How vulnerable tissue is to hypoxia
Oxygen content of the blood

39

What molecules are released by injured cells?

Potassium
Enzymes
Myoglobin

40

What are the consequences of the molecules released following cellular injury?

Local irritation and inflammation
General toxic effects on the body
High concentrations in the blood - may aid diagnosis

41

What effect does the release of potassium from cellular injury have?

Potassium is normally in high concentration in cells compared to ECF.
Dying cell 'potassium bomb'
Heart stops with high potassium

42

What effect does the release of enzymes from cellular injury have?

Indicate the organ involved and the extent, timing and evolution of tissue damage.

Enzymes with smallest molecular weight are released first.

43

What effect does the release of myoglobin from cellular injury have?

Released from dead myocardium and striated muscle.
If large amounts are released from striated muscle Rhabdmyolysis occurs. Which is seen in severe burns, trauma or strenuous exercise, with potassium depletion.
Myoglobin released can plug renal tubules resulting in renal failure.

44

How does apoptosis occur?

How is it characterised?

Activation of internally controlled suicide programme.

Morphology and type of DNA breakdown that occurs which is characteristic, non rang one, internucleosomal cleavage of DNA.

45

When does apoptosis occur?

Occurs when a cell is damaged
Normal physiological process that occurs:
when cells are no longer needed to maintain steady state
During hormone controlled involution
Cytotoxic T cell killing of virus-infected or neoplastic cells
Also seen in embryogenesis

46

How does apoptosis occur? (3)

Cell activates enzymes that degrade its own nuclear DNA and proteins.
Membrane integrity is maintained.
Active process that requires energy.

47

What do apoptotic cells show under the light and electron microscope?

Light - Shrunken and intensely eosinophillic, chromosome condensation, pyknosis and karyorrhexis

Electron - cytoplasmic budding which progresses to fragmentation into membrane bound apoptotic bodies which contain cytoplasm, organelles and often nuclear fragments.
Apoptotic bodies eventually removed by phagocytosis

48

Why does apoptosis not induce cell inflammation?

There is no leakage of cell contents

49

What are the three key phases of apoptosis and describe them.

Apoptosis - triggered by two key mechanisms. Intrinsic and extrinsic which cumulate in activation of proteases.

1. Initiation
2. Execution
2. Degradation and phagocytosis

50

How to capases (proteases) work in apoptosis?

They cleave proteins, breaking up the cytoskeleton and initiating the degradation of DNA.

51

What is the name of the important protein in apoptosis?

P53 - mediates apoptosis in response to DNA damage

52

Name important apoptotic molecules.

P53 - mediates apoptosis in response to DNA damage
Cytochrome C
APAF 1,
Capase 9
Bcl-2 - prevents cytochrome C release from mitochondria, inhibits apoptosis.
Death ligands
Death receptors
Capases

53

What effect does Bcl-2 have on apoptosis?

Bcl-2 - prevents cytochrome C release from mitochondria, inhibits apoptosis

54

What does the degree of cell damage depend on? (3)

Type
Duration
Severity of injury

55

What happens during degradation phase of apoptosis?

Cell breaks into membrane bound fragments called apoptotic bodies.

56

What is the role of cytochrome C, APAF 1, caspase 9 in apoptosis?

Together they are the apoptosome

57

What is the role of Bcl-2 in apoptosis?

Inhibits apoptosis by preventing cytochrome C release from mitochondria

58

What do abnormal cellular accumulations derive from?

Cells own metabolism
Extracellular space
Outer environment

59

What are the five main groups of intracellular accumulations?

Water and electrolytes
Lipids
Proteins
Pigments
Carbohydrates

60

What may fluid in a cell appear as?

Discrete droplets or diffuse water logging of the entire cell resulting in it swelling

61

What does hydrophic cell swelling indicate?

Severe cellular distress

Can also cause further problems e.g. In the brain where there is no room for expansion so as cell and brain swelling occurs, blood vessels are squeezed and blood flow to the brain is reduced.

62

What is steatosis (fatty change)?
Where is it often seen?
What causes it?
How is it diagnosed?
What happens in advanced steatosis?

Accumulation of triglycerides
Liver
Alcohol abuse, diabetes, obesity and toxins
It is reversible in 10 days if person stops drinking alcohol
Can be diagnosed with naked eye - liver is golden yellow rather than red
Increase in the size of organ - body part covered in grease
First stage of alcoholic liver disease

63

Where is excess cholesterol stored? And where is it found?

Membrane bound droplets that accumulate within smooth muscle cells and macrophages within atherosclerotic plaques

64

What are foam cells?

Cells that have too much cholesterol in and a foamy cytoplasm

65

What are the small masses macrophages full of cholesterol form?

Xanthomas

66

Describe how an alpha 1 antitrypsin deficiency contribute to emphysema.

Liver produces a version of alpha 1 antitrypsin that is incorrectly folded
Cannot be packaged by the ER, accumulates in the cell
Not secreted by the liver
Enzyme deficiency means proteases within the lung act unchecked and patients can develop emphysema as lung tissue is broken down.

67

What is Mallory's hyaline?

Damaged protein seen in hepatocyte in alcoholic liver disease and due to the accumulation of altered keratin filaments

68

Give two examples of exogenous pigments and describe.

Carbon/coal/dust - once inhaled it is phagocytosed by macrophages within lung tissue
Turns lung tissue black (anthracosis), discolours tissue for life
Usually harmless unless in high concentrations - lungs can become fibrotic or emphysematous.
This is called pneumoconiosis.

Tattooing - pigments phagocytosed by macrophages within the dermis. Some pigment reaches the draining lymph nodes and remains there.

69

Give three examples of endogenous pigments and describe.

Lipofuscin - brown pigment seeing in aging. Sign of previous free radical injury and lipid peroxidation.
Seen under microscope as yellow-brain gains within cytoplasm
Rarely seen in rapidly turning over cell e.g. Epilthelia.

Haemosiderin - iron storage molecule. Forms when there is an excess of iron and deposits within organs (haemosiderosis). Seen in haemolytic anaemia a blood transfusions and hereditary haemochromatosis. Associated with scarring in liver and pancreas

Bilirubin - bile pigment that is bright yellow. Heme is broken down into biliverdin which is broken down into bilirubin. Bile flow obstructed = bilirubin levels in the blood rise and jaundice results

70

What is the treatment for Haemosiderosis?

Repeated bleeding

71

What are the symptoms of haemosiderosis?

Liver damage, heart dysfunction and multiple endocrine failures especially of pancreas.

72

Where is bilirubin formed and why?

Can be formed anywhere in the body as all cells contain heme as cytochromes and therefore all cells can form bilirubin.
It is deposited in the tissues intra or extracellularly.

73

Why is a build up of bilirubin a concern?

What happens to bilirubin once it is taken into the tissues?

Bilirubin is very toxic

It is taken by albumin to the liver where it is conjugated with glucaronic acid and excreted in bile.

74

What are the two types of calcification? And which is more common?

Dystrophic and metastatic

Dystrophic more common

75

Describe dystrophic calcification
Where does it occur?
What happens?

Occurs in an area of dying tissue, atherosclerotic plaques, aging or damaged heart valves and in tuberculous lymph nodes.

No abnormality in calcium metabolism.
Change or disturbance in tissue function favours the nuclear ion of hydroxyapatite crystals.
Can cause organ dysfunction.

76

What valve never calcifies?

Pulmonary valve

77

Describe metastatic calcification

Disturbance is body wide
Hydroxyapatite crystals are deposited in normal tissues throughout the body when there is hypercalcaemia secondary to disturbance in calcium metabolism.
Usually asymptomatic - can be lethal

78

What are the main causes of hypercalcaemia

Increased secretion of the parathyroid hormone resulting in bone resorption.
Primary - due to parathyroid hyperplasia.
Secondary - due to renal failure
Ectopic - secretion of PTHrP

Destruction of bone tissue e.g. Primary tumours of bone marrow, diffuse skeletal metastases, pagets disease of the bone, immobilisation

79

What is replicative senescence?

Decline in cells ability to replicate due to cellular aging

80

What prevents cell from dividing in cellular aging?

Length of the chromosomes.
With every replication the telomere is shortened, once they reach critical length they can no longer divide.

81

How can germ and stem cells maintain the length of the original chromosome and continue to divide?

Contain an enzyme telomerase which maintains original length of the telomeres - they can continue to replicate

Many cancer cells produce telomerase and so have the ability to replicate multiple times

82

What are the three major effects of chronic excessive alcohol intake?
Describe the effects of each one.

Fatty change - fat metabolism within the liver effected resulting in steatosis. Acutely it is reversible and generally asymptomatic.
Acute alcoholic hepatitis - alcohol and metabolites directly toxic, a binge can result acute hepatitis with focal hepatocyte necrosis, formation of Mallory's bodies and a neutrophillic infiltrate. Usually reversible
Cirrhosis - hard shrunken liver and histologically appears as micronodules of regenerating hepatocytes surrounded by bands of collagen. Irreversible.