Definitions

There are 3 possible responses to cell STRESS

1) Adaptation: when physiologic or pathologic stress induces a new state.

2) Reversible injury: Pathological cell changes that can be restored to normal if stimulus is removed

3) Irreversible injury: Occurs when stressors exceed the cells ability to adapt. Leads to permanent changes.

Cell death occurs via 1)Necrosis or 2) Apoptosis

Necrosis: most common type of cell death, 'accidental'. ultimately leads to phagocytosis by leukocytes

Apoptosis: physiological process for programmed cell death

Initiation phase:

Intrinsic pathway- mitochondria: mitochondria release cytochrome C which binds to apoptosis activating factor 1, triggering caspase-9 activation

Extrinsic pathway – death receptor: TNF death receptors are activated which activates caspases

Execution phase: Executioner caspases cleave cytoskeletal proteins, nuclear matrix proteins and proteins involved in transcription. The intrinsic and extrinsic pathways converge to activate a caspase cascade that mediates the final phase of apoptosis. Therefore the presence of active caspases(enzymes) is a marker for cells undergoing apoptosis.

Residual Bodies: cellular vesicles or vacuoles that contain the leftover, indigestible materials remaining after lysosomal digestion. Over time, trapped un-degraded waste inside these bodies can turn into yellowish-brown pigment granules called lipofuscin. 

Hypoxia: reduced oxygen carrying capacity, but still allows delivery of substances and removal of waste (anaerobic glycolysis can continue)

Causes of hypoxia: ischemia(reduced blood flow), cardiorespiratory failure(reduced O2 in blood), anaemia/blood loss/carbon monoxide poisoning (reducing O2 carrying capacity)

Ischemia: due to reduced blood flow, injures tissue faster than hypoxia

Ischaemia-reperfusion injury: Increased injury to ischaemic cells with the restoration of perfusion, associated with neutrophilic infiltrates. Thought to be due to:

  1. Oxidative stress by generation of reactive O2 and NO,
  2. Calcium re-entering the cell (which favours opening of mitochondrial permeability transition pore),
  3. Inflammation including neutrophil influx
  4. Complement cascade activated by IgM, which is deposited in ischaemic tissues

Others causes of cell injury: chemicals, infectious agents, trauma/heat, immunologic, genetic derangements, nutritional imbalances

 

 

What is Autophagy?

Autophagy: when a cell eats its own contents to survive

Cell organelles are sequestered in cytoplasmic autophagic vacuoles (autophagosomes), which fuse with lysosomes, that digest the enclosed material. This is an adaptive responsive during nutrient deprivation or stress. It maintains cell integrity by recycling essential metabolites/clear debris. Excessive autophagy can lead to cell death. Dysregulation of autophagy occurs in a number of disease states.

What are some other types of cell death besides necrosis and apoptosis?

Necroptosis: resembles necrosis morphologically, but like apoptosis is a genetically controlled form of cell death

Pyroptosis: lytic death of microbe-infected cell>releasing inflammatory mediators i.e. IL-1 (fever)

Ferroptosis: iron-dependent pathway of cell death

Give examples of the patterns of necrosis

Patterns of necrosis:

  • Coagulation necrosis: most common, protein denaturation, underlying tissue architecture is preserved for days. Characteristic of hypoxic death in all tissues except the brain. Common after MI. Dry gangrenous is a form of coagulative necrosis which develops in ishaemic tissues.
  • Liquefaction necrosis: when autolysis or heterolysis predominates by enzymatic digestion. The necrotic area becomes fluid-filled and cell liquifies (pus). Mostly seen in CNS hypoxia and bacterial infections. Wet gangrene when superimposed bacterial infection.
  • Caseous necrosis: appears as soft, friable, cheesy material, exhibits coagulation and liquefaction e.g. TB
  • Fat necrosis: fat destruction due to release of activated lipase (e.g. in acute pancreatitis) into peritoneal cavity, chalky white areas where fatty acids combine with calcium (fat sponification), basophilic calcium deposits
  • Fibrinoid necrosis: due to antigen-antibody deposition in blood vessels, bright pink “fibrinoid” appearance

Contrast the morphological patterns of cell death

Feature Necrosis (accidental) Apoptosis (regulated)
Cell size Enlarged (swelling) Reduced (shrinkage)
Microscopic features Eeosinophilic (pink), glassy due to collagen loss, membranes fragmented, dead cells replaced by myelin figures>phagocytosed chromatin condensation (most characteristic feature of apoptosis), formation of cytoplasmic blebs and apoptotic bodies, phagocytosis by macrophage. The presence of active caspase enzymes are a marker for cells undergoing apoptosis
Nucleus Pyknosis: nuclear shrinking and increased basophilia Karyorrhexis: fragmentation of nucleus Karyoysis: basophilia fading Fragmented nucleus
Plasma membrane Disrupted, cell rupture Intact, altered structure
Cell contents Enzymatic destruction, may leak out of cell Intact, may be released in apoptotic bodies (but less leakage)
Adjacent inflammation Frequent No, minimal disruption to surrounding tissue
Physiologic VS pathologic Pathologic Physiologic (can be pathologic e.g. after DNA damage)

What changes are seen in reversible and irreversible cell death?

 

Reversible: Cell/organelle swells due to change in ion concentration and water influx(1st change), membrane blebbing, nuclear chromatin clumping, ribosomes detach from ER and ER dilates, and eosinophilia which becomes more pronounced as necrosis occurs. Fatty change occurs in organs such as the liver.

Irreversible: Nuclear destruction(pyknosis=small dense nucleus, karyolysis=faint dissolved nucleus, karyorrhexis=fragmented nucleus), lysosomal rupture, cell membrane disruption, severe mitochondrial vacuolisation, pronounced eosinophilia on H&E stain (red).

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