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Medsci 203 > Cell Injury & Cell Death > Flashcards

Cell Injury & Cell Death Flashcards

1
Q

List the three ways that DNA can become damaged

A
  1. Physical: radiation
  2. Chemical: alkylation
  3. Biological: dietary deficiency
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2
Q

DNA damage can be followed by _____, _____ (that generates mutations) or if repair systems are overwhelmed, ____ _____.

A

DNA damage can be followed by repair, misrepair (that generates mutations) or if repair systems are overwhelmed, cell death.

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3
Q

List two types of radiation which damage DNA and how they function to do so

A
  1. Ionising radiation - xrays and gamma rays
    - have sufficient energy to break chemical bonds
    - main target: water
    - radiolysis of water to H• and OH•
    - DNA strand breaks
    - misrepair causes chromosomal translocations
  2. Ultraviolet radiation - damages DNA bases
    - Adjacent pyrimidines (C,T) become linked
    - misrepair = C to T mutations
    - contributes to cancer development
    - excessive damage = keratinocyte death
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4
Q

Death of endothelial cells via ionising radiation can lead to these three symptoms:

A
  1. ulceration
  2. scarring
  3. atrophy of surrounding tissues
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5
Q

List 3 types of damage to cells

A
  1. Damage to DNA
  2. Damage to lipids
  3. Damage to proteins
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6
Q

Describe how chemical damage to DNA via alkylation occurs:

A

Aflatoxin B1 accumulation in poorly stored food - alkylate reacts covalently with:

  • proteins to cause acute liver injury (aflatoxicosis) at high doses
  • DNA - G to T mutations and chronic liver cancer at low doses
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7
Q

Describe how biological damage to DNA via dietary deficiency occurs:

A

Folic acid (B9) and cyanocobalamin (B12) needed for DNA synthesis and repair

  • autoimmune gastritis = lack of intrinsic factor needed to absorb B12 = B12 deficiency and megaloblastic anaemia
  • dna synthesis and repair compromised
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8
Q

List three types of lipid damage

A
  1. Physical - crystals
  2. chemical - oxidants
  3. biological - lipases
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9
Q

Describe the mechanism of crystal damage to lipids

A
  • Cells take up crystals such as silica, asbestos, MSU, cholesterol and hydroxyapatite into lysosomes
  • Crystals puncture lysosomal membranes, releasing hydrolytic enzymes
  • hydrolytic enzymes activate inflammasomes to generate inflammation
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10
Q

List 3 oxidative reaction intermediates which can be toxic on their own, their general features and how they are detoxified

A
  1. Superoxide (O2-•) - relatively stable - detoxified by superoxide dismutase to O2 and H2O2
  2. Hydrogen peroxide - detoxified to catalase to O2 and H2O
  3. Hydroxyl radical (OH•) - highly destructive, can damage all biological molecules and underlies many types of injury
    - incredibly reactibve; will oxidise the first thing it hits
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11
Q

ROS injure cells under conditions of: (5)

A
  1. Oxygen therapy - premature babies exposed to supra-physiological O2 concentrations may lead to lung damage
  2. Inflammation - mediated by neutrophils and macrophages
  3. Damaged mitochondria - not able to reduce O2 completely
  4. UV radiation - excites biological molecules (photosensitisers) which transfer energy or electrons to O2
  5. Radiotherapy
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12
Q

Describe an example of biological damage to lipids

A

Acute haemorrhagic pancreatitis - arises from damage to exocrine cells (which synthesise digestive enzymes) or from blockage of ducts that deliver said enzymes to the duodenum

  • activated enzymes (phospholipases, lipases) are released into the pancreas and digest cell membranes and triglycerides
  • ie. inappropriate activation of lipases (should be stomach but actually activated in pancreas)
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13
Q

List 3 types of protein damage

A
  1. Physical - heat
  2. Chemical - glycation
  3. Biological - proteases
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14
Q

How can heat damage proteins?

A

Temperatures higher than 42C denature proteins, which precipitate and form insoluble complexes in cells and disrupt cell function. This leads to the production of head shock proteins, which bind to denatured proteins.

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15
Q

What is glycation? What is the difference between glycation and glycosylation?

A

The non-enzymatic addition of sugars to proteins (Maillard reaction)

Glycation is the chemical reaction of sugar and proteins - harfmul

Glycosylation is the enzymatic addition of sugar to proteins

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16
Q

Describe the mechanism by which glucation damages proteins, and whether each step is reversible or not.

A

Reducing sugars (such as glucose) + amino groups (at N-terminus of proteins, or on lysine and arginine residues) generates:

  1. schiff-bases - reversible
    - rearranged to-
  2. amadori products - irreversible; stable result of saturated bond sticking sugar to protein
    - further rearrangements to -
  3. Advanced glycation end products (AGE)
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17
Q

What do advanced glycation end products do? (4)

A
  • prevent protein function
  • protein precipitation/cross-linking - clumping - disruption of cell function
  • can generate the creation of ROS
  • bind to receptors of AGE (RAGE) on vasuclar and inflammatory cells, reducing blood flow and causing inflammation
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18
Q

AGE accumulate during _______ (list 3 instances) and promote ______ disease.

A

ageing, diabetes and chronic inflammation

they promote cardiovascular disease

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19
Q

Describe how proteases damage proteins and list 3 types of proteases

A

Proteases cleave extracellular matrix proteins during inflammation

Collagen in arthritis is cleaved by collagenase
Elastin in emphysema is cleaved by elastase
Laminin during cancer invasion is cleaved by laminase

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20
Q

What happens in reversible cell injury?

A

Cells adapt and recover

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21
Q

What happens in irreversible cell injury?

A

Cell death

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22
Q

Describe Acute intracellular oedema - is it reversible?

A

Hydropic change - initially reversible- cell injury may compromise the ability of cells to regulate ion concentrations in the cytoplasm. May occur due to:

  • plasma membranes become permeable to Na+
  • Na+/K+ ATPase damaged
  • ATP synthesis disrupted and Na+/K+ ATPase inhibited

As a result, K+ leaks out o fthe cell and Na+ leaks in - cells and organelles swell osmotically

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23
Q

Accumulation of products such as ___ and ______ affect cell abilities to recycle components.

A

Accumulation of products such as fat and glycogen affect cell abilities to recycle components.

24
Q

Describe when triglycerides accumulate in normal hepatocytes

A

Triglycerides accumulate when normal hepatocytes are unable to metabolise increased concentrations of fatty acids arriving from adipose tissue - diabetes

25
Q

Describe when triglycerides accumulate in abnormal hepatocytes

A

Triglycerides accumulate when abnormal hepatocytes have a reduced ability to oxidise fatty acids (alcohol damage), or to export triglycerides complexed with lipid-acceptor proteins as VLDL (kwashiorkor, severe malnutrition)

26
Q

List three mechanisms that cells may utilise to adapt to stressors

A
  1. Activation of transcription factors
  2. Binding to response elements in gene promoters
  3. Transcription of genes encoding protective proteins
27
Q

List five kinds of adaptive responses

A
  1. DNA damage response
  2. Antioxidant response
  3. Heat shock (proteotoxic) response
  4. Hypoxia response
  5. Unfolded protein response
28
Q

What happens during a DNA damage response?

A

p53 transcription factor activated - regulates repair, cell cycle arrest or (with severe damage) cell suicide

29
Q

What happens during an antioxidant response?

A

Oxidative stress activates Nrf family transcription factors - induces genes encoding SOD1 and catalase

30
Q

What happens during a heat shock (proteotoxic) response?

A

Heat shock factors (HSFs) activated - induce the expression of molecular chaperones (heat shock proteins) which bind to denatured proteins and:

  • prevent their aggregation (which is cytotoxic)
  • aid in their renaturation
  • promote proteolytic destruction of proteins that are too damaged
31
Q

What happens during a hypoxia response?

A

Hypoxia-inducible factors (HIFs) induce a genetic programme to help cells adapt to hypoxia

Targets include glucose transporters, glycolytic enzymes and factors to increase production of erythrocytes and blood vessels

32
Q

What happens during an unfolded protein response?

A

e.g in ER stress - stressors induce the production of unfolded proteins in the ER - unfolded protein response induces synthesis of chaperones

33
Q

List five types of cell death

A
  1. Oncosis
  2. Necroptosis
  3. Pyroptosis
  4. Apoptosis
  5. Autophagic
34
Q

Describe when oncosis happens and how

A

Overwhelming injury

  • cell and organelle swelling/oncosis
  • membrane permeabilisation and lysis
  • leakage of intracellular components = inflammation
  • repair of tissue via scarring
35
Q

Describe when necroptosis happens and how

A

Programmed/regulated - shows morphological features of oncosis

  • death ligands (such as TNF and FasL) signal through their receptors (TNFR and Fas) and protein kinases RIPK1 and RIPK3
  • this leads to mitochondrial dysfunction, ROS generation, calcium entry, lipase activation
36
Q

What are necrostatins?

A

RIPK1 inhibitors - suppress cell death, inflammation and loss of function following ischaemic or traumatic brain injury

37
Q

Describe when pyroptosis happens and how

A

Products from pathogenic bacteria activate inflammasomes in the cytoplasm, and the protease caspase-1

  • cell lysis, inflammation
  • prevents replication of intracellular bacteria
  • alerts other immune cells to the presence of pathogens
38
Q

Describe when apoptosis happens and how

A

Removal of cells that are superfluous, worn out or damaged.

  • cell rounding, shrinkage and nuclei fragmentation into apoptotic bodies
  • membrane and organelles remain intact
    EITHER
  • engulfment of apoptotic bodies by phagocytes = no inflammation
    OR
    (if phagocytes overwhelmed) membrane eventually disintegrates = release of cellular contents = inflammation
39
Q

Describe when and how normal autophagy occurs

A

Normal function: removal of microbes, misfolded proteins and damaged organelles

Cytoplasmic vacuoles with double membranes enclose intracellular pathogens, protein aggregates or organelles to form autophagosomes

Autophagosomes fuse with lysosomes to generate autolysosomes in which acidic hydrolases degrade the contents

40
Q

Describe when and how autophagy in cells deprived of nutrients occurs

A

Autophagy degrades disposable components to generate energy and metabolites for essential protein synthesis
- process sustains cell viability

41
Q

How can autophagy lead to cell death?

A

Massive autophagic vacuolisation may lead to cell death

42
Q

Describe, in detail, the mechanism of oncosis in the event of ischaemia/hypoxia/anoxia (9 steps)

A

Oxidative phosphorylation ceases with the lack of oxygen, leading to the switching to glycolysis as primary source of ATP.

  1. reduced ATP = suppressed Na+K+ exchanger activity = increased intracellular Na+
  2. Glycolysis generates lactic acid = lowered cytoplasmic pH
  3. lowered pH activates Na+/H+ exchanger = more Na+ entering cell
  4. increased Na+ counterracted by Na+/Ca2+ exchanger = accumulation of Ca2+
  5. Reduced ATP = reduced activity of Ca2+ efflux pump = increasing levels of Ca2+
  6. Ca2+ dependent phospholipases activate = release FA and lysophospholipids which damage membranes
  7. Ca2+ dependent proteases (calpain, cathepsins) cleave cytoskeletal proteins
  8. cell lyses
  9. spilled cellular content = inflammation
43
Q

Apoptosis can be induced by: (5)

A
  1. Activation of death receptors such as TNFR1 and Fas by TNF and Fas
  2. Absence of growth (survival) factors
  3. Loss of cell adhesion to the ECM - anoikis
  4. damage to DNA
  5. stresses that activate p53 (DNA damage, hypoxia, oxidative stress)
44
Q

Describe, in detail, the mechanism of apoptosis (4 steps)

A
  1. Activated death receptors recruit Fas-associated death domain (FADD) adaptor protein - assembles initiator caspase complexes
  2. Multiple signals = opening of pores in the outer mitochondrial membrane
  3. Release of cytochrome C (death signal when outside mitochondria) - activates apoptotic protease-activating factor-1 (Apaf-1) and initiator caspases
  4. executioner/effector caspases cleave multiple protein substrates
45
Q

Apoptotic cells release _______ signals (_____) and display ______ signals (___,)

A

Apoptotic cells release “find me” signals (ATP) and display “eat me” signals (phosphatidylserine, PS)

46
Q

When macrophages phagocytose apoptotic bodies, their inflammatory signalling is _____, releasing ___ pro-inflammatory TNF and ____ anti-inflammatory transforming growth factor β (TGFβ)

A

When macrophages phagocytose apoptotic bodies, their inflammatory signalling is suppressed, releasing less pro-inflammatory TNF and more anti-inflammatory transforming growth factor β (TGFβ)

47
Q

Inadequate apoptosis occurs in: (2)

A
  • autoimmune diseases; self-reactive lymphocytes are not eliminated
  • neoplastic diseases (cancers) - cells accumulate due to reduced ability to undergo apoptosis
48
Q

Excessive apoptosis occurs in: (3)

A
  • acute ishaemic injury to the heart (myocardial infarcts) and brain (strokes) - especially at the margins of the injured area
  • chronic heart failure (cardiomyocytes) and neurodegeneration (motor neuron disease, alzheimer’s, parkinson’s)
  • pancreatic islet β-cells in diabetes
49
Q

List the four types of ischaemic necrotic changes in tissues

A
  1. Coagulative necrosis
  2. Colliquative/liquefactive necrosis
  3. Gas gangrene
  4. Dry gangrene
50
Q

Describe coagulative necrosis

A

E.g in Myocardial infarcts

  • Dead tissue firm and initially retains general architecture
  • Generally, necrotic tissue removed by inflammatory reaction and replaced by scar
  • Large infarcts may be inaccessible to inflammatory cells and persist
51
Q

Describe colliquative/liquefactive necrosis

A

E.g cerebral artery occlusion

  • released lysosomal hydrolases digest brain tissue (which lack a supporting ECM) to a gel
  • glial cells react to form a cyst
52
Q

Describe gas gangrene

A

Occurs when deep wounds sever the blood supply, allowing growth of anaerobes such as the soil bacterium Clostridium perfringens

  • α toxin (phospholipase) destroys cells, leading to putrefaction
  • affected tissues feel crepitant with CO2 bubbles
  • turn black as haemoglobin is degraded and iron sulfide deposited
53
Q

Describe dry gangrene

A

Occurs in limbs when arteris slowly, progressively narrow (by atherosclerosis, as with diabetes or tobacco smoking)

Ischaemia leads to necrosis, desiccation (mummification) and discolouration from the breakdown of blood

54
Q

List the two types of necrosis with infection and how they occur

A
  1. Liquefactive suppurative (pus-forming) necrosis
    - occurs with bacterial infections when neutrophil hydrolases liquify tissue and form abscesses
  2. Caseous necrosis - associated with tuberculosis
    - granulomas contain central necrosis composed of the remains of inflammatory and tissue cells and bacteria.
    - amorphous, lipid- and protein-rich
55
Q

Describe how necrosis can happen with injury

A

Fat necrosis occurs with injury to adipose tissue, and in acute haemorrhagic pancreatitis

  • released proteases nad phospholipases digest cell membranes
  • lipases digest intracellular triglycerides
  • FAs released precipitate with Ca2+ to form white opque soaps

Medsci 203 (10 decks)

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