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Mechanisms of disease > Week 1 - Cell injury > Flashcards

Week 1 - Cell injury Flashcards

1
Q

What is disease a result of ?

A

Intrinsic or extrinsic abnormalities or a combination of both

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2
Q

How does all diseases start?

A

Cell alterations

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3
Q

What happens to cells during periods of mild change?

A

They are able to maintain homeostasis

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4
Q

During increased severe changes what happens to cells?

A

Able to undergo physiological and morphological adaptations to remain viable

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5
Q

When a cell can no longer adapt to changed conditions what happens?

A

Start to show reversible or irreversible cell damage

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6
Q

What are the causes of injury?

A
  1. Hypoxia
  2. Physical agents
  3. Chemical agents and drugs
  4. Microorganisms
  5. Immune mechanism
  6. Dietary insufficiencies and deficiency
  7. Genetic abnormalities
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7
Q

Describe hypoxia

A

O2 deprivation leading to decreased aerobic oxidative respiration

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8
Q

How long can a cell survive hypoxia?

A

Varies depending on cell type - fibroblasts can last comparatively ages compared to neurones

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9
Q

What are the causes of hypoxia?

A
  1. Hypoxaemia
  2. Anaemia
  3. CO poisoning
  4. Histiocytic
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10
Q

Explain what hypoxaemia is

A

Low arterial content of O2 due to decreased inspired PPO2

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11
Q

Describe how anaemia can cause hypoxia

A

Decreased ability of haemoglobin to carry O2 leading to reduced O2 delivery to tissue

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12
Q

Describe what is meant by histiocytic causes of hypoxia

A

Inability of the cells to use O2 due to disabled oxidative phosphorylation

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13
Q

What may cause histiocytic hypoxia? Describe the mechanism

A

Posoining with the cyanide ion as this binds with the mitachondiral cytochrome oxidase and blocks OP

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14
Q

Why does ischaemia or decreased venous return causes effects much quicker than hypoxia?

A

Reduced delivery of both O2 and metabolic substrates. In hypoxia glycolytic respiration can continue but in ischaemia and lack of venous return respiration is stopped completely apart from stored fuel eg skeletal muscle

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15
Q

Give some examples of physical agents that can cause hypoxia

A

Direct trauma, extremes of temperature, sudden changes in atmospheric pressure, electrical currents and radiation

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16
Q

Give some examples of chemical agents that can cause hypoxia

A 
Glucose or salts in hypotonic solution
O2 at high conc
Pesticides
Insecticides 
Asbestos
Alcohol
Drugs
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17
Q

What are the 4 structures in cells that are vulnerable to damage during cell injury?

A

Cell membrane
Nucleus
Proteins ( cytoskeleton and enzymes)
Mitachondria

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18
Q

What is the sign of reversible hypoxic injury?

A

Oncosis - cell swelling

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19
Q

Describe how oncosis comes about?

A

Reduced O2 supply leads to reduced production of ATP by OP in mitachondria. Only a small drop is necessary for NA+ pump to stop working leading to influx of Na+ ions in and water follows.

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20
Q

What happens to intracellular Ca levels during cell injury ?

A

Increase

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21
Q

What happens to the pH of a cell during cell injury? What effect does this have on cellular components?

A

Decreased pH due to increased reliance on glycolytic respiration producing lactic acid. This affects enzymes and causes chromatin to clump.

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22
Q

What is activated by the fall in pH during hypoxic injury?

A

Heat shock stress response

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23
Q

What happens to the ER during reversible hypoxic cell damage? What is the effect of this ?

A

Ribsomes detach from ER leading to disrupted protein synthesis and intracellular accumulations of substance

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24
Q

What is the hallmark of irreversible damage to cells?

A

Loss of plasma membrane integrity

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25
Q

Describe the changes to the membrane and its effect during cell damage

A

Disturbances in membrane integrity leads to increase permeability to ions and other substances. This leads to a huge increase in Ca levels from extracellular, ER and mitachondria.

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26
Q

What is the effect of huge increases in Ca levels in a damaged cell?

A

Activation of potent enzymes such at ATPases, phospholipases, proteases and endonucleases.

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27
Q

What sign of membrane integrity loss can be seen under a microscope?

A

Blebbing

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28
Q

The leakage of enzymes is useful for what? Name two enzymes that may be lost when hepatocytes are damaged?

A

Enzymes and intracellular substances can be measured for diagnosis
AST and ALT

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29
Q

What is ischaemic reperfusion injury?

A

When blood flows back to an area of ischaemia but not yet necrotic the injury is worse than if no blood flows back.

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30
Q

What are the causes of ischaemia reperfusion injury?

A

Increased production of radicals with reoxygenation
Decreased number of neutrophils resulting in increased inflammation and tissue injury
Delivery of complement proteins and activation of complement pathways

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31
Q

What are the three oxygen free radicals

A

OH®, O2- and H2O2

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32
Q

Describe some of the properties of reactive oxygen species

A

They have a single unpaired electron
Unstable
Lead to a chain reaction
Particularly produced in chemical and radiation injury, ischaemia reperfusion injury, cellular aging and high O2 content
Mutagenic but also involved in physiological processes

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33
Q

How do free radicals cause damage

A

Attack lipids in the cell membrane causing lipid perioxidation and molecules to become bent, broken or cross linked.
Also affect carbohydrates and nucleic acids

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34
Q

How are hydroxyl residues produced?

A

Radiation directly lyses water to form radicals

Fenton and harber weiss reactions

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35
Q

When is the fenton reaction important ? Why?

A

Bruising - uses Fe2+ as a co factor which is abundant at the site

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36
Q

Why is it very important to remove O2- and H2O2 ?

A

These are the substrates fot the harber weiss reaction which produces hydroxyle radicals ( most dangerous)

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37
Q

Describe the body’s anti-oxidant system

A

SOD- O2- into H2O2
Catalases and perperoxidases complete process producing water and molecular oxygen
Free radical scavengers Vit ACE and glutathione
Storage proteins – sequester transition metals in extracellular matrix ( transferrin and ceruloplasmin( Cu2+ )- catalase production of free radicals

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38
Q

Give an example of a heat shock protein

A

Ubiquitin

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39
Q

What happens to heat shock proteins during injury?

A

Increases in concentration - ALWAYS PRESENT

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40
Q

Where do heat shock proteins act?

A

In the cell ( not secreted)

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41
Q

What is the function of heat shock proteins?

A

Recognize incorrectly folded proteins and repair them – if unable protein destroyed.
Maintaining protein viability gives increased chance of survival for the cell

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42
Q

How can we see increased membrane permeability ?

A

Dye exclusion technique

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43
Q

What is the alteration to the cytoplasmic seen by a cell that has undergone cell injury under a light microscope?

A

Decreased pink staining due to increased water followed by increased staining due to detachment of ribosomes from ER and accumulation of dentaured proteins

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44
Q

What is the alteration to the nucleus seen by a cell that has undergone cell injury under a light microscope?

A

Chromatin clumped followed by pyknosis ( shrinkage), Karryohexis( fragmenation) and karryolysis (dissolution)

45
Q

What is the alteration to the cytoplasm seen by a cell that has undergone cell injury under a light microscope?

A

Abnormal cellular accumulation

46
Q

Describe the reversible signs of cell injury seen with an electron microscope

A

swelling, cytoplasmic blebs , clumped chromatin, ribosome separation from the ER

47
Q

Describe the irreversible signs of cell injury seen with an electron microscope

A

increased cell swelling, nuclear changes – Pyknosis ( shrinkage), Karryohexis ( fragmentation) and karrryolysis ( dissolution), swelling and rupture of lysosomes, membrane defects, appearance of myelin figures, lysis of ER due to membrane defects, amorphous densities in swollen mitochondria

48
Q

Define oncosis

A

cell death will swelling- spectrum of changes that occur prior to cell death in cells injured by hypoxia and other agents

49
Q

Define apoptosis

A

cell death with shrinkage, cell induced by regulated intracellular programs where a cell activates enzymes that degrade own nuclear DNA and proteins

50
Q

Define necrosis

A

morphological changes that occur after a cell has been dead for some time- appearance largest due to progressive degradative actions of enzymes on dead cells
APPEARANCE NOT A PROCESS

51
Q

Are the changes seen in necrosis reversible?

A

NO

52
Q

What will happen if necrotic tissue is not removed?

A

dystrophic calcification

53
Q

How is necrotic tissue removed?

A

enzymatic degradation and phagocytosis

54
Q

What are the two main types of necrosis? What two other types can occur?

A

coagulative
Liquefactive
Fat
Caseous

55
Q

Describe coagulative necrosis

A

proteins undergo denaturation, clumping of dead cells seen in solid organs, white to the naked eye, cells proteins uncoil and become less soluble
Histologically – ghost outlines of cells (only seen in 1st few days after appearance modified inflammatory response and infiltration of phagocytes)

56
Q

Describe liquifactive necrosis

A

proteins dissolve in the cells own enzymes – autolysis, seen in massive neutrophil infiltration- abscess and bacterial infections, seen in the brain( fragile tissue without support from robust collagenous matrix)

57
Q

Describe caseous necrosis and when you might see it and its associated structure

A

cheesy appearance, characteristed by amporphous debris particularly associated with TB and granulomatous

58
Q

Describe fat necrosis and two occassions when it might occur

A

destruction of adipose tissue, acute pancreatitis- release of lipase of acinar cells which digests fat in pancreas and abdominal cavity causing release of FAs which react with Ca ions forming chalky deposits in fatty tissue. Can occur after breast trauma – confused with breast cancer.

59
Q

Which organ is necrosis hard to classify in ?

A

Pancreas

60
Q

When does necrosis start?

A

When the tissue is still alive

61
Q

What is gangrene?

A

Necrosis visible to the naked eye

62
Q

Where is gangrene most common?

A

ischaemic limbs

63
Q

How is gangrene classified?

A

Whether it is modified by exposure to the air or bacteria

64
Q

What are the three types of gangrene?

A

wet
dry
gas

65
Q

Describe wet gangrene and name its associated type of necrosis
Why is it considered very dangerous?

A

liquefactive necrosis modified by presence of bacteria ( v. serious as bacteria can get into blood stream and cause septicaemia )

66
Q

Why is dry gangrene associated with coagulative necrosis?

A

bacteria unable to grow in dry tissue

67
Q

What is gas gangrene?

A

tissue infected by anaerobic bacteria producing visible and palpable bubbles of gas within tissue

68
Q

What is infarction?

A

Necrosis caused by ischaemia- area of tissue where death has been caused by obstruction of a tissues blood supply usually due to a thrombosis/embolism/compression or twisting of vessels can result in gangrene.

69
Q

How are infarcts classified?

A

How much haemorhaging occurs

70
Q

What are the two classes of infarcts?

A

White and red

71
Q

Describe white infarct, where they occur and why?

A

solid organs after occlusion of end artery- nature limits the amount of haemorrhaging that can occur

72
Q

Describe red infarct.

A

extensive haemorrhaging into dead tissue

73
Q

Describe why red infarcts occur

A

o Dual blood supply e.g. lungs – secondary arterial supply insufficient to rescue tissue but allows blood in
o Numerous anastomoses e.g. intestines – capillary beds of 2 separate arterial supplies merge
o Loose tissue e.g. lung – poor stromal support for capillaries
o Previous congestion – congestive heart failure results in more than usual amounts of blood in tissue
o Raised venous pressure – increased pressure transmitted to capillary bed as tissue pressure increases eventually arterial pressure falls causing ischaemia and necrosis resulting in red infarct as tissue engorged with blood

74
Q

What do the consequences of ischaemia depend on?

A
  • Whether alternative blood supply
  • How rapidly occurred – time for development of alternative pathway of perfusion
  • How vulnerable tissue is to hypoxia
  • O2 conc of blood – increase severe in anaemia
75
Q

Why are molecules released by injured, dead or dying cells useful in diagnosis? give an example

A

Can be measure eg AST and ALT in liver cells

76
Q

What is the issue with high potassium concentrations ?

A

Cardiac arrhythmias

77
Q

Which enzymes are released first by dying or dead cells?

A

ones with smaller molecular weights

78
Q

What is the problem with the release of myoglobin?

A

plugs renal tubes leading to kidney failure

79
Q

What happens if large amounts of skeletal muscle is broken down? when is this seen?

A

rhabdomyolysis occurs

severe burns, strenuous exercise, potassium depletion, substance abuse

80
Q

Define apoptosis

A

Cell death with shrinkage death of single cell due to activation of internally controlled suicide programme- characterised by non-random internucleosomal cleavage of DNA

81
Q

How does apoptosis appear under a light microscope?

A

shrunken and appear intensely eosinophilic, chromatin condensed, pykinosis and karyorrhexis , affects single or small cluster of cells

82
Q

How does apoptosis appear under a electron microscope?

A

cytoplasmic budding  fragmentation into membrane bound apoptotic bodies which are eventually removed by macrophages

83
Q

What are the 3 phases of apoptosis?

A

initiation, execution and degradation/phagocytosis

84
Q

Describe the intrinsic pathway of activation of apoptosis

A

mitochondrial central player all machinery within cell- various triggers DNA damage or removal of growth factors or hormones and p53 which lead to increased mitochondrial permeability and release of cytochrome c that interacts with APAF1 and caspase 9 forming an apoptosome and activation of downstream caspases

85
Q

The intrinsic and extrinsic pathway if apoptosis culiminate on what?

A

activation of caspases – proteases that mediate cellular effects of apoptosis act by cleaving proteins breaking up the cytoskeleton and initiating degradation of DNA.

86
Q

Describe the extrinsic pathway of apoptosis

A

external ligands TRAIL and Fas bind to death receptors – caspases are activated independently of mitochondria.

87
Q

Describe degradation of apoptosis

A

Cell breaks into membrane bound fragments – apoptotic bodies express molecules on surface that induces phagocytosis by neighbouring cells and phagocytes.

88
Q

Name some important molecules in apoptosis

A

 P53- mediates apoptosis in response to damaged DNA
 Cytochrome c, APAF1, caspase 9- apoptosome
 BCL 2- prevents cytochrome c release – inhibits apoptosis
 Death ligands and death receptors
 Caspases – effector molecules of apoptosis e.g. caspase 3

89
Q

Where might have abnormal cellular accumulations come from?

A

 Cells own metabolism
 Extracellular space
 Outer environment

90
Q

Name the types of abnormal cellular accumulations that can occur

A 
fluid
lipid
proteins
pigments
carbohydrates
91
Q

How can fluid appear as an anbormal accumulation?

A

In droplets or diffuse waterlogging of the entire cell

92
Q

What complication can occur due to increased water in a body of cells?

A

compression of vessels especially in the brain

93
Q

What is an abnormal build up of fats in a cell called?

A

steatosis

94
Q

How is excess cholesterol stored?

A

In membrane bound droplets, accumulations within SM and macrophages- atherosclerotic plaques

95
Q

What happens when the phospholipids in the cell membrane are disrupted?

A

myelin figures

96
Q

How are proteins seen as abnormal accumulations?

A

eosinophilic droplets or aggregations in the cytoplasm

97
Q

When are mallory’s hyaline damaged proteins seen?

A

Hepatocytes in alcoholic liver disease - they are accumulation of keratin filaments

98
Q

What is Alpha 1 antitrypsin deficiency? What is the problem with the defective protein produced?

A

liver produces incorrectly folded alpha 1 antitrypsin which cannot be packaged by ER so accumulates and is not secreted  proteases act unchecked leading to emphysema

99
Q

Name some exogenous pigments and where they would be seen

A
  • Carbon, coal, soot once they are inhaled phagocytised by macrophages within lung tissue can be seen as blackened lung tissue or as blackened peribronchial lymph nodes – permanent discolouration, usually harmless but high exposure lungs can become fibrotic or emphysematous .
  • Tattoos – pigment phagocytised by macrophages in the dermis remains there indefinitely – some drained into the lymph nodes
100
Q

Name some endogenous pigments

A

• Lipofuscin – age pigment, brown seen in aging cells, no injury caused – sign of previous free radical injury and lipid peroxidation, consists of a polymer of oxidised indigestible brownish intracellular lipid, only seen in long lived cells
• Haemosiderin – iron storage molecule derived from haemoglobin, forms when systemic or local excess of iron e.g. bruise. If systematic overload of iron haemosiderin deposited in many organs called haemosiderosis (seen in hereditary haemochromatosis- increase absorption of iron in intestines)
Haemochromatosis iron is deposited in skin, liver, pancreas, heart and endocrine organs  bronze diabetes
• Bilirubin- must be removed when bile flow obstructed or overwhelmed increased bilirubin leads to jaundice- deposited in tissues extracellular or in macrophages

101
Q

Where is bilirubin produced in the body?

A

Any cell

102
Q

Describe what calcification is

A

abnormal deposits of calcium salts within tissues – can be local or general dystrophic or metastatic

103
Q

Describe dystrophic calcification

A

area of dying tissue, occurs when atherosclerotic plaque, aging or damaged heart valves and tuberculous lymph nodes.
Local changes in tissue favours nucleation of hypoxyappatite crystals leading to organ dysfunction

104
Q

Describe metastatic calcification

A

disturbances body wide crystals deposited in normal tissue throughout the body when hypercalcaemia secondary to disturbances in calcium metabolism

105
Q

What are the causes of metastatic calcification

A

Increased PTH levels and therefore bone reabsorption
• Primary parathyroid hyperplasia or tumour
• Secondary renal failure retention of phosphate
• Ectopic secretion of PTHrp by malignant tumour
Destruction of bone tissue
• Primary tumour of bone marrow
• Diffuse skeletal metastases
• Pagets disease of bone – accelerated bone turnover
• Immobilisation

106
Q

What happens during cellular aging ?

A

Accumulate damage to cellular constitutes and DNA- get lipofusion and other abnormally folded proteins
Decreased ability to replicate – replicative senescence – cannot divide independently – relates to chromosome length, during every replication telomere gets shorter at a critical point no longer able to divide

107
Q

Why are germ and stem cells able to divide indefinately?

What other type of cell makes use of this ?

A

Possess telomerase which restores the original length of the chromosomes telomeres
cancerous cells

108
Q

Describe the changes in the liver of an alcoholic

A

• Fatty change – affects fat metabolism  steatosis marked as a cause to hepatomegaly ( reverse acute change)
• Acute alcohol hepatises- alcohol and metabolites directly toxic – binge results in acute hepatitis with local hepatocyte necrosis, formation of Mallory bodies and neutrophil infiltration
Symptoms – fever, liver tenderness, and jaundice – reversible
• Cirrhosis – hard shrunken liver and microscopically micro-nodules of regenerating hepatocytes surrounded by bands of collagen. Irreversible and serious

Mechanisms of disease (5 decks)

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