Mechanisms of Human Disease exam questions and answers fully solved
Reversible injury - AnswersMild + transient, allows cells to adapt and return to normal
Irreversible injury - AnswersSevere and progressive → cell death, cannot return to normal
function
Apoptosis vs necrosis - Answers• Apoptosis is benign and regulated, necrosis is unregulated and
pro-inflammatory
• Both are types of cell death
Earliest manifestation of most cell injuries - AnswersCellular swelling
Molecular changes that occur in cell injury - Answers• ↓Cellular energy due to ↓ATP synthesis
induced by mitochondrial damage
• Loss of calcium homeostasis
• Disrupted membrane permeability of cell + organelle membranes
• ↑Free radical production (ROS)
• Molecular damage affecting macromolecules (DNA + proteins) first
Protective response mechanisms in cell injury - Answers• Heat shock response (chaperone)
proteins: expression activated when cell is stressed, protects proteins from damage by refolding
misfolded proteins + eliminating damaged proteins
• Enzymes remove free radicals
• Pre-stressed tissues have been 'trained' to survive significant injury, physiological adaptation
Progression of reversible to irreversible injury - Answers• Cell function decline
• Biochemical alterations leading to cell death
• Ultrastructural changes (cell swelling, fragmented nuclei)
• Light microscopic changes (cytoplasmic, nuclear + fatty changes)
• Gross morphological changes
Hypoxia - Answers• Lack of oxygen due to ↓blood supply → ↓ATP production + accumulation
of waste toxins (interfere with enzymes/trigger damage of cell molecules)
• Outcome is time dependent: injury persists → damage increases
,Triggers of hypoxia - Answers• Ischaemia: inadequate/blocked blood supply; local (embolism) or
systemic (cardiac failure)
• Hypoxaemia: sustained oxygen deficiency; high altitude (low O2) or anaemia (abnormal
haemoglobin)
• Oxidative Phosphorylation Inhibition: prevents ETC; cyanide poisoning
Ischaemia - Answers• ↓Oxidative phosphorylation → ↓ATP → 1 of 3 pathways
• ↓ Na+ pump → ↑influx of Ca2+, H2O + Na+, ↑efflux of K+ → ER/cellular swelling, blebs, loss
of microvilli
• ↑ Anaerobic glycolysis → ↓glycogen, ↑lactic acid → ↓pH → clumping of nuclear chromatin
• Detachment of ribosomes → ↓ protein synthesis
Pathological effects of ROS - Answers• Produced by altered metabolism + inflammation
• Lipid peroxidation → membrane damage
• Protein modifications → breakdown, misfolding
• DNA damage → mutations
ROS elimination mechanisms - Answers• Conversion of O2- to H2O2 by SOD
• Decomposition of H2O2 to H2O by glutathione peroxidase
• ROS + ↓O2 → direct membrane damage via phospholipid loss, lipid breakdown + cytoskeletal
damage
• Sudden increase in oxygen can increase free radicals → reperfusion injury
Necrosis - Answers• Reversible: surface blebs, increased eosinophilia of cytoplasm, swelling
• Irreversible: loss of nuclei, fragmentation, cellular leakage
• Morphological changes: cell swelling, nucleus: pyknosis (condensation) → karyorrhexis
(fragmentation) → karyolysis (lysing by DNase), disrupted plasma membrane, cell contents
digested by enzymes/may leak out, adjacent inflammation (cell bursts)
Coagulative necrosis - Answers• Ischaemic necrosis + gangrene in lower limbs
• Cells die but tissue architecture remains, maintains solid consistency
• Necrotic cells removed by inflammatory cells (neutrophils)
• Necrotic regions regenerate or replaced by scar (fibrosis)
,Liquefactive necrosis - Answers• Ischaemic necrosis in brain
• Due to massive infiltration by neutrophils to form an abscess → high ROS + protease activity
• Complete dissolution of necrotic tissue, cell architecture obliterated
Causeous necrosis - Answers• Associated with granulomatous inflammation of tuberculosis +
fungal infections
• Accumulation of amorphous/unstructured debris within an area of necrosis
• Tissue architecture lost + unrecognisable
Infarction - Answers• Area of ischaemic necrosis in tissue/organ
• Red/haemorrhagic: due to venous occlusion in loose/floppy tissue
• White: due to arterial occlusion in solid tissues
Apoptosis - Answers• Programmed cell-autonomous suicide, requires energy expenditure
• Occurs during development (limbs) + for removal of certain cells (self, infected)
• Gross morphological changes: cytoplasm shrinks without membrane rupture, plasma/nuclear
membrane blebs, cell contents in membrane bounded bodies (intact + phagocytosed), no
adjacent inflammation due to shrinkage + blebs
Apoptosis triggers - Answers• Lack of growth stimuli (growth factors)
• Death signals (TNF, Fas)
• DNA damage (p53 → DNA damage sensing factor) or unfolded protein response (causing ER
stress)
Intrinsic (mitochondrial) pathway of apoptosis - Answers• Internal cell injury results in apoptosis
of the cell
• Lack of GFs/protein misfolding/DNA damage → activation of sensors (BH3-only proteins) →
activation of BAX/BAK channel, cytochrome C leakage from mitochondria → activation of
caspase cascade → apoptosis
• BCL2 (anti-apoptotic protein) antagonises pro-apoptotic factors to oppose apoptosis →
abnormally high in acute myeloid leukemia patients → cells that should die do not
Extrinsic (death receptor) pathway - Answers• Receptor-ligand interactions induce cell death
, • Fas ligand located on cytotoxic T cell binds to Fas on target cell → receptor-ligand interaction
activates death receptor, initiating caspases through adaptor proteins → target
infected/tumour/damaged cells
ER stress (protein folding >> protein folding capacity) - Answers• Leads to decrease in anti-
apoptotic expression
• Unfolded protein response (cellular adaptation): ↓ protein synthesis + ↑ chaperone
production
• Can trigger autophagy: intrinsic breakdown of cellular organelles, regulated cell death
• Stress/starvation can result in autophagic vacuolisation within cell
• Outcomes: autophagic survival or autophagic cell death (depends on Beclin-1 levels)
Mitochondria - Answers• Low O2 → mitochondrial damage → low ATP, high ROS → necrosis
• More pro-apoptotic proteins (BH3-only), less anti-apoptotic proteins (BCL2) → leakage of
mitochondrial proteins (cytochrome C) → apoptosis
Tissue proliferative capacities - AnswersAbility of tissues to repair themselves is determined
partially by intrinsic proliferative capacity
Labile tissues - AnswersConstant proliferation to allow turnover, surface epithelia,
hematopoietic cells
Stable tissues - AnswersQuiescent, proliferation can be sporadically activated (e.g. by wound
healing), parenchyma of most solid organs (liver, kidney, pancreas), endothelial cells, fibroblasts,
smooth muscle cells
Permanent tissues - AnswersNo proliferation, injury irreversible, repair → scar formation, most
neurons + cardiac muscle cells
Healing mechanisms - Answers• Controlled by biochemical factors released in response to cell
injury, cell death or trauma
• Tightly regulates + induces resting cells entering the cell cycle
• Balance stimulatory + inhibitory factors → prevent over-proliferation
• Shorten cell cycle → faster cell division
• Decrease rate of cell loss → inhibit apoptosis
Reversible injury - AnswersMild + transient, allows cells to adapt and return to normal
Irreversible injury - AnswersSevere and progressive → cell death, cannot return to normal
function
Apoptosis vs necrosis - Answers• Apoptosis is benign and regulated, necrosis is unregulated and
pro-inflammatory
• Both are types of cell death
Earliest manifestation of most cell injuries - AnswersCellular swelling
Molecular changes that occur in cell injury - Answers• ↓Cellular energy due to ↓ATP synthesis
induced by mitochondrial damage
• Loss of calcium homeostasis
• Disrupted membrane permeability of cell + organelle membranes
• ↑Free radical production (ROS)
• Molecular damage affecting macromolecules (DNA + proteins) first
Protective response mechanisms in cell injury - Answers• Heat shock response (chaperone)
proteins: expression activated when cell is stressed, protects proteins from damage by refolding
misfolded proteins + eliminating damaged proteins
• Enzymes remove free radicals
• Pre-stressed tissues have been 'trained' to survive significant injury, physiological adaptation
Progression of reversible to irreversible injury - Answers• Cell function decline
• Biochemical alterations leading to cell death
• Ultrastructural changes (cell swelling, fragmented nuclei)
• Light microscopic changes (cytoplasmic, nuclear + fatty changes)
• Gross morphological changes
Hypoxia - Answers• Lack of oxygen due to ↓blood supply → ↓ATP production + accumulation
of waste toxins (interfere with enzymes/trigger damage of cell molecules)
• Outcome is time dependent: injury persists → damage increases
,Triggers of hypoxia - Answers• Ischaemia: inadequate/blocked blood supply; local (embolism) or
systemic (cardiac failure)
• Hypoxaemia: sustained oxygen deficiency; high altitude (low O2) or anaemia (abnormal
haemoglobin)
• Oxidative Phosphorylation Inhibition: prevents ETC; cyanide poisoning
Ischaemia - Answers• ↓Oxidative phosphorylation → ↓ATP → 1 of 3 pathways
• ↓ Na+ pump → ↑influx of Ca2+, H2O + Na+, ↑efflux of K+ → ER/cellular swelling, blebs, loss
of microvilli
• ↑ Anaerobic glycolysis → ↓glycogen, ↑lactic acid → ↓pH → clumping of nuclear chromatin
• Detachment of ribosomes → ↓ protein synthesis
Pathological effects of ROS - Answers• Produced by altered metabolism + inflammation
• Lipid peroxidation → membrane damage
• Protein modifications → breakdown, misfolding
• DNA damage → mutations
ROS elimination mechanisms - Answers• Conversion of O2- to H2O2 by SOD
• Decomposition of H2O2 to H2O by glutathione peroxidase
• ROS + ↓O2 → direct membrane damage via phospholipid loss, lipid breakdown + cytoskeletal
damage
• Sudden increase in oxygen can increase free radicals → reperfusion injury
Necrosis - Answers• Reversible: surface blebs, increased eosinophilia of cytoplasm, swelling
• Irreversible: loss of nuclei, fragmentation, cellular leakage
• Morphological changes: cell swelling, nucleus: pyknosis (condensation) → karyorrhexis
(fragmentation) → karyolysis (lysing by DNase), disrupted plasma membrane, cell contents
digested by enzymes/may leak out, adjacent inflammation (cell bursts)
Coagulative necrosis - Answers• Ischaemic necrosis + gangrene in lower limbs
• Cells die but tissue architecture remains, maintains solid consistency
• Necrotic cells removed by inflammatory cells (neutrophils)
• Necrotic regions regenerate or replaced by scar (fibrosis)
,Liquefactive necrosis - Answers• Ischaemic necrosis in brain
• Due to massive infiltration by neutrophils to form an abscess → high ROS + protease activity
• Complete dissolution of necrotic tissue, cell architecture obliterated
Causeous necrosis - Answers• Associated with granulomatous inflammation of tuberculosis +
fungal infections
• Accumulation of amorphous/unstructured debris within an area of necrosis
• Tissue architecture lost + unrecognisable
Infarction - Answers• Area of ischaemic necrosis in tissue/organ
• Red/haemorrhagic: due to venous occlusion in loose/floppy tissue
• White: due to arterial occlusion in solid tissues
Apoptosis - Answers• Programmed cell-autonomous suicide, requires energy expenditure
• Occurs during development (limbs) + for removal of certain cells (self, infected)
• Gross morphological changes: cytoplasm shrinks without membrane rupture, plasma/nuclear
membrane blebs, cell contents in membrane bounded bodies (intact + phagocytosed), no
adjacent inflammation due to shrinkage + blebs
Apoptosis triggers - Answers• Lack of growth stimuli (growth factors)
• Death signals (TNF, Fas)
• DNA damage (p53 → DNA damage sensing factor) or unfolded protein response (causing ER
stress)
Intrinsic (mitochondrial) pathway of apoptosis - Answers• Internal cell injury results in apoptosis
of the cell
• Lack of GFs/protein misfolding/DNA damage → activation of sensors (BH3-only proteins) →
activation of BAX/BAK channel, cytochrome C leakage from mitochondria → activation of
caspase cascade → apoptosis
• BCL2 (anti-apoptotic protein) antagonises pro-apoptotic factors to oppose apoptosis →
abnormally high in acute myeloid leukemia patients → cells that should die do not
Extrinsic (death receptor) pathway - Answers• Receptor-ligand interactions induce cell death
, • Fas ligand located on cytotoxic T cell binds to Fas on target cell → receptor-ligand interaction
activates death receptor, initiating caspases through adaptor proteins → target
infected/tumour/damaged cells
ER stress (protein folding >> protein folding capacity) - Answers• Leads to decrease in anti-
apoptotic expression
• Unfolded protein response (cellular adaptation): ↓ protein synthesis + ↑ chaperone
production
• Can trigger autophagy: intrinsic breakdown of cellular organelles, regulated cell death
• Stress/starvation can result in autophagic vacuolisation within cell
• Outcomes: autophagic survival or autophagic cell death (depends on Beclin-1 levels)
Mitochondria - Answers• Low O2 → mitochondrial damage → low ATP, high ROS → necrosis
• More pro-apoptotic proteins (BH3-only), less anti-apoptotic proteins (BCL2) → leakage of
mitochondrial proteins (cytochrome C) → apoptosis
Tissue proliferative capacities - AnswersAbility of tissues to repair themselves is determined
partially by intrinsic proliferative capacity
Labile tissues - AnswersConstant proliferation to allow turnover, surface epithelia,
hematopoietic cells
Stable tissues - AnswersQuiescent, proliferation can be sporadically activated (e.g. by wound
healing), parenchyma of most solid organs (liver, kidney, pancreas), endothelial cells, fibroblasts,
smooth muscle cells
Permanent tissues - AnswersNo proliferation, injury irreversible, repair → scar formation, most
neurons + cardiac muscle cells
Healing mechanisms - Answers• Controlled by biochemical factors released in response to cell
injury, cell death or trauma
• Tightly regulates + induces resting cells entering the cell cycle
• Balance stimulatory + inhibitory factors → prevent over-proliferation
• Shorten cell cycle → faster cell division
• Decrease rate of cell loss → inhibit apoptosis
