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Mechanisms of Disease > Cell Injury > Flashcards

Cell Injury Flashcards

0
Q

What is the difference between hypoxia and ischaemia?

A

Hypoxia = O2 deprivation in cells -> reduced aerobic respiration

Ischaemia = loss of blood supply -> insufficient O2 AND nutrients
(therefore injury more rapid and severe than hypoxia)

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1
Q

Name some examples of causes of cell injury and death.

A
  • hypoxia
  • toxins e.g. high O2 (free radicals), chemotherapy, alcohol, glucose & salt (hypertonic solution)
  • physical agents e.g. direct trauma, extreme temperature, changes in pressure, electric currents
  • radiation
  • micro-organisms
  • immune mechanisms e.g. hypersensitivity reaction, autotimmune reactions
  • malnutrition
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2
Q

What are some of the different causes/types of hypoxia?

A

Hypoxaemic = low arterial O2
e.g. low pO2 at altitude, secondary lung disease

Anaemic = decreased ability of Hb to carry O2
e.g. anaemia, CO poisoning

Ischaemic = interruption to blood supply
e.g. occluded vessel, heart failure

Histiocytic = inability to utilise O2 in cells due to decreased oxidative phosphorylation enzyme activity
e.g. cyanide poisoning

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3
Q

Why can the brain not survive hypoxia as long as other tissues?

A

Toleration time of hypoxia varies between tissues

Neurones = few minutes (high metabolic activity)

Fibroblasts = few hours

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4
Q

What are the consequences of reversible hypoxia?

A

Reduced oxidative phosphorylation -> reduced ATP

  • > Inhibited Na+/K+-ATP dependent pump -> influx of Na+ & Ca2+ -> ONCOSIS
  • > Increased glycolysis -> reduced glycogen & increased lactic acid -> reduced pH -> chromatin clumping & reduced enzyme activity
  • > Detachment of ribosomes -> reduced protein synthesis & increased lipid deposition
  • > mitochondrial swelling
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5
Q

What are the consequences of irreversible hypoxia ?

A

Increased [Ca2+] in cytoplasm

  • > ATPase activated -> reduced ATP
  • > Phospholipase activated -> breakdown of cell membrane
  • > Protease activated -> reduced cytoskeleton proteins
  • > Endonuclease activated -> damaged DNA
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6
Q

What is the definition of a free radical? What produces free radicals? What are antioxidants?

A

Free radical = single unpaired electron in outer orbit is unstable, allowing reactions with other molecules, producing further free radicals

Produced by cellular ageing and reperfusion injury

Cause damage by cross-linking proteins and oxidation of membrane lipids

Antioxidant = substance capable of neutralising free radicals e.g. ACE vitamins

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7
Q

How does bleeding cause damage by free radical generation?

A

Fe2+ & H2O2 –> Fe2+ & OH- & OH.

Ferrous iron (Fe2+) reacts with hydrogen peroxide to produce hydroxide free radicals

Hence why transferrin is used to transport Fe2+ in the blood

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8
Q

Describe the cause and consequences of ischaemic reperfusion injury.

A

Blood flow returned to a damaged (but not yet necrotic) tissue causes more damage than if blood flow had not been returned due to:

  • increased superoxide radicals due to increased oxygenation
  • increased neutrophils -> inflammation -> tissue injury
  • activation of complement pathway (pro-inflammatory effects)
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9
Q

How can cell death be recognised histologically?

A

Dye exclusion test - dead cells with damaged membranes take up dye whilst living cells with intact membranes do not

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10
Q

Define oncosis.

A

Swelling of a cell that may precede cell death

Cells appear pale; increased eoisin staining

Clumped chromatin, karyolysis, pyknosis, karyorrhexis

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11
Q

Define the different ways in which DNA can be affected by oncosis.

A

Karyolysis = chromatin dissolution (increased DNase)

Pyknosis = DNA condenses

Karyorrhexis = nuclear membrane ruptures and fragments

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12
Q

Define apoptosis.

A

Cell death with shrinkage.

Induced by a regulated intracellular program where a cell activates enzymes that degrade its own DNA and proteins (physiological or pathological) (active transcription of genes)

Non-random internuclear damage

Active process

Membrane integrity maintained (therefore no inflammation)

Lysosomal enzymes NOT activated

Rapid

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13
Q

Define necrosis.

A

Changes that occur when a cell has been dead for some time in a LIVING ORGANISM.

e.g. inflammation, damage to plasma membranes and organelle membranes -> leakage of cell contents

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14
Q

Describe coagulative necrosis.

A

Denaturation of proteins > Release of proteases

Preserved cellular architecture

e.g. occlusion of artery in myocardium

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15
Q

Describe liquefactive necrosis.

A

Enzyme degradation > denaturation of proteins

Enzymatic digestion of tissues

e.g. occlusion of artery in cerebrum, bacterial infection

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16
Q

Describe caseous necrosis.

A

Amorphous debris (soft “cream cheese” appearance)

No cellular architecture preserved

e.g. TB

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17
Q

Describe fat necrosis.

A

Fat saponification -> production of fatty soaps due to fatty acids reacting with calcium

Yellow-white deposits

Due to extracellular release of lipases or direct damage to adipose tissue

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18
Q

Describe gangrene.

A

Necrosis modified by infection/exposure to air

  • wet: putrefactive decay e.g. gas gangrene - anaerobic bacteria produce gas; caused by crushed limbs
  • dry: withering of tissues due to infarct
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19
Q

Describe infarction.

A

Death of part or whole of an organ that occurs when the artery is obstructed (can result in gangrene)

e.g. thrombosis, embolism, compression/twisting of blood supply

20
Q

What is the difference between a white infarct and a red infarct?

A

WHITE - occlusion of end artery e.g. kidney, heart, spleen (no other arterial supply)

RED - haemorrhage into infarct (dual blood supply where one vessel infarcts and the other haemorrhages) e.g. lungs (collateral circulation pools)

21
Q

What factors determine the severity of the consequences of infarcts ?

A
  • alternative blood supply e.g. collateral/anastomosing blood supplies
  • speed of ischaemia
  • tissue involved
  • oxygen content of blood
22
Q

What are some of the features of reversible cell injury?

A

Generalised swelling/blebs

ER & mitochondrial swelling

Clumped chromatin

Dispersion of ribosomes

Autophagy of lysosomes

23
Q

What are some of the features of irreversible cell injury?

A

Rupture of lysosomes -> autolysis

Karyolysis, pyknosis, karyorrhexis

Myelin figures

24
Q

What can the presence of potassium indicate in terms of cell injury?

A

Injury to the heart - MI (note: heart stops when potassium is too high)

Massive necrosis e.g. burns

Tourniquet shock

Tumour lysis syndrome (breakdown of dying cancer cells)

25
Q

What can enzymes indicate in terms of cell injury?

A

Indicate organ damaged, extent of damage & timing/evolution of tissue damage

note: enzymes with lowest Mw released first

26
Q

What can the presence of myoglobin indicate in terms of cell injury?

A

Rhabdomyolysis = rapid breakdown of skeletal muscle cells with the release of myoglobin and other toxic cell components

Caused by severe trauma/burns, strenuous exercise

Dark brown urine (myoglobin present)

27
Q

List some physiological effects of apoptosis.

A
  • maintains homeostasis
  • returns organs to normal size after pregnancy
  • activates death of cells infected by viruses
  • activates death of neoplastic cells
  • sculpting of fingers during embryological development
28
Q

List some pathological causes of apoptosis.

A

DNA damage

Toxic injury

Graft v.s. Host

Tumours

29
Q

Describe the sequence of events during apoptosis.

A

Cell shrinks and blebs form. Proteins activated to break down cellular components

Blebs break off and become apoptotic bodies. Enzymes break down nucleus. Cytokines released by apoptotic bodies attract macrophages.

Cell breaks into smaller pieces containing cell components and destroyed nucleus

Macrophages recognise cell pieces and phagocytose (note: adjacent cells can also do this)

30
Q

What are the intrinsic and extrinsic mechanisms of apoptosis initiation?

A

INTRINSIC:
DNA damage -> p53 gene activated OR withdrawal of growth factors/hormones
Mitochondria membrane more permeable -> release of cytochrome C
Apoptosome formed -> caspases activated

EXTRINSIC:
Death ligands bind e.g. TRAIL
Caspases activated

31
Q

What is the role of caspases in apoptosis?

A

EXECUTION:

Caspases cleave proteins, break up the cytoskeleton, and initiate the degradation of DNA

32
Q

How can cells affected by oncosis/necrosis be differentiated by cells affected by apoptosis?

A

ONCOSIS/NECROSIS APOPTOSIS
Contiguous group of cells Single cells
Enlarged (swelling) Reduced (shrinkage)
Karyolysis, Karyorrhexis, Pyknosis Fragmentation
Disrupted plasma membrane Intact plasma membrane
Enzymes digest cell contents Cell contents intact (apoptotic bodies)
Adjacent inflammation frequent No inflammation
Pathological Physiological (mostly)

33
Q

What does the presence of water-filled vacuoles in cells indicate?

A

Osmotic disturbance e.g. hypoxia causing influx of Ca2+ and H2O

e.g. less pronounced sulci (dips) of brain indicates compression of brain into foramen magnum

34
Q

What does the presence of lipids in cells indicate?

A

Steatosis - triglyceride accumulation in liver
Indicates alcohol abuse (reversible), obesity, diabetes, toxins

Cholesterol accumulation - LDLs are saturated therefore liver cannot eliminate excess cholesterol 
Indicates atherosclerosis (cholesterol clefts)/hypercholesterolaemia (xanthoma)
35
Q

What does the presence of proteins in cells indicate?

A

Mallory bodies/Mallory’s hyaline = accumulation of altered keratin filaments in hepatocytes
Indicates alcoholic liver disease

alpha-1-antitrypsin deficiency = misfolded alpha-1-antitrypsin cannot be packaged by ER (accumulates in liver) & proteases act unchecked (emphysema)

36
Q

What does the presence of exogenous pigments indicate?

A

e.g. coal dust/soot phagocytosed by macrophages -> discoloured tissues
Benign = anthracosis
Malignant = coal worker’s pneumoconiosis (inflammation, fibrosis, & necrosis of lungs)

Tattoos = pigment phagocytosed by macrophages and remains in dermis (some travels to lymph nodes)

37
Q

What does the presence of endogenous pigments indicate?

A

Lipofuscin = “age pigment” (brown) accumulates due to free radical injury (lipid peroxidation)

Haemosiderin = (yellow/brown) local excess of Fe2+ (bruise)

  • haemosiderosis = systemic overload of Fe2+ -> haemosiderin deposited in organs (bleed to treat)
    e. g. haemolytic anaemias, blood transfusions, haemochromatosis, diabetes (liver, heart, pancreas damage)

Bilirubin = bile pigment -> jaundice
note: cannot be reformed into Hb (porphyrin ring broken)

38
Q

Describe the causes and effects of pathological calcification.

A

DYSTROPHIC = local deposits of calcium-hydroxyapatite crystals in dying tissues, lymph nodes (TB), aortic vessels, atherosclerotic plaques, DCIS
note: no association with hypercalcaemia/abnormal calcium metabolism

METASTATIC = systemic hypercalcaemia

e. g. increased PTH due to parathyroid tumours, ectopic-PTHrp secreting tumours (BLTKP)
e. g. bone tumours - Paget’s, leukaemia, immobilisation
e. g. reduced vit. D
e. g. renal failure

39
Q

How do cells age? Why can’t cells live forever?

A

Cells accumulate damage to cellular constituents and DNA & accumulate lipofuscin & abnormally folded proteins

With each replication, the telomeres of the chromosomes are shortened - when these reach a critical length the cells can no longer divided (replicative senescence)

note: in stem cells/germline cells/cancer cells telomerase maintains the original length of the telomeres -> indefinite replication

40
Q

What are some of the effects of alcohol on the liver?

A

Fatty liver: steatosis -> hepatomegaly
(acute, reversible, asymptomatic)

Acute alcoholic hepatitis: focal hepatocyte necrosis, formation of Mallory bodies (pink “glassy” appearance), formation of Councilman hyaline bodies (apoptotic cells), neutrophilic infiltrate -> fever, liver tenderness, jaundice
(reversible)

Cirrhosis: hard, shrunken liver & micronodules of regenerating hepatocytes surrounded by bands of collagen
(irreversible - can be fatal)

41
Q

What factors determine lower reserves of glutathione, and therefore mean death due to liver failure from paracetamol overdose is more likely?

A 
Alcohol taken with overdose 
Alcohol-dependents 
Malnourished people
People on enzyme-inducing drugs e.g. carbamazepine 
HIV+/AIDS
42
Q

How do you decide when it is appropriate to give N-acetyl cysteine to those who have taken a paracetamol overdose?

A

Check serum [paracetamol] 4 hours after overdose and compare to graph

Prothrombin time (INR) measured 24 hours after overdose to determine severity of overdose

43
Q

What are the effects of aspirin overdose?

A

Aspirin acetylates platelets -> prevents platelet aggregation
(petechiae = small, round, flat dark red spots caused by bleeding into the skin or beneath the mucous membranes)

Respiratory alkalosis -> Metabolic alkalosis (increased lactate, pyruvate, ketone bodies) -> acute erosive gastritis (reduced stomach mucous membranes due to decreased pH?) -> GI bleeding

44
Q

How do you determine whether someone who has taken a paracetamol overdose needs N-acetyl cysteine or not? What happens if you don’t treat the overdose?

A

Graph blood serum paracetamol against NAPQI and see whether it trends upwards (give treatment) or downwards (wait)

Depletion of glutathione -> liver necrosis -> hepatic encephalopathy

45
Q

How can you measure the extent of liver damage by examining the acinar zones?

A

1st acinar zone = closest to artery (highest pO2) therefore last affected by circulation problems (outer layer)

3rd acinar zone = closest to vein (lowest pO2) therefore first affected by circulation problems (inner layer)

46
Q

Describe the progression of liver disease.

A

INFLAMMATION (hepatomegaly) (reversible)

FIBROSIS (scarring; reversible over time)

CIRRHOSIS (irreversible scarring):

  • itching
  • jaundice
  • portal hypertension
  • oedema
  • Type II diabetes
  • bleeding
  • toxins

LIVER FAILURE: nausea, loss of appetite, fatigue -> confusion, drowsiness -> coma -> death

47
Q

What is a haemorrhagic stroke? What are the different areas of the brain that can be affected? What are some of the symptoms?

A

Stroke causing rupture of blood vessels in the brain

Symptoms depend on area of brain affected e.g. hemiplegia (paralysis on one side of body)

INTRA-AXIAL: intraparenchymal or intraventricular

EXTRA-AXIAL: epidural, subdural, subarachnoid

48
Q

Can infarcts in the brain heal?

A

Yes - by gliosis

Mechanisms of Disease (8 decks)

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