1-53 Cell injury and death Flashcards
All diseases are cause by…
Cell injury:
- external and internal distrubances can cause reversible and irreversible cell injury
- Once injury irreversible, the cell dies
- Loss of ATP is a critical step in cell injury
- Na/K-ATPase pump stops, increased intracellular Na+, causes cell swelling -somewhat reversible and we can see undermicroscope
- pH when O2 reduced: decreases, cells acidic
- Causes of cell injury
- •Oxygen deprivation
- •Physical agents
- •Chemical agents
- •Infectious agents
- •Immune system
- •Genetic disease
- •Nutritional abnormalities
Progress of reversible to irreersible cell injury
- all stressors of cells cause changees first the the molecular/biochemical level
- lag between molecular/biochem and morphologic changes
•Injury, if serious and sustained, can be irreversible and lead to cell death.
•Reversible cell injury: ATP depletion, inhibition of protein synthesis, loss of glycogen, and subtle failure of membrane function with entry of water into cell (hydropic change) with cell swelling.
•If the injury is sustained, irreversible cell injury occurs including: mitochondrial swelling, accumulations of dense inclusions in mitochondria, nuclear changes, rupture of lysosomes and membranes
Mitochondrial damage effects
•Damage to mitochondria can result in a mitochondrial transitional pore that leads to loss of mitochondrial membrane potential and function.
- Decreased ATP production and increased reactive oxygen species lead to necrosis
- Leakage of apoptotic proteins from the mitochondria can lead to apoptosis
Influx of calcium during cell death
- Ca+ is released from intracellular stores
- Increased Ca+ across the membranes
- opens the mitochondrial transition pore
- activates a number of enzymes
Accumulation of ROS during cell death
- ·Reactive oxygen species (ROS) are free radicals produced by injurious stimuli
- ROS lead to DNA damage/mutations, lipid peroxidation/membrane damage, and protein modifications/protein misfolding
Membrane permeability during cell death
Summary of biochemical changes that induce cell death
- Decreased generation of ATP
- Mitochondrial damage
- Influx of calcium: Increased cytosolic calcium
- Accumulation of oxygen-derived free radicals
- Membrane permeability
- DNA damage
- Genetic polymorphisms modulate response
Hypoxia and reperfusion in cell injury
- Hypoxia directly affects oxidative phosphorylation within the mitochondria, resulting in reduced ATP levels and membrane damage.
- When circulation (and re-oxygenation) is re-established after transient ischemia, there can be severe tissue damage called reperfusion injury.
- This explosive onset of necrosis during reperfusion is in most part due to the generation of a sudden burst of ROS.
Abnormal intracellular deposition seen in cell injury/death (4)
Necrosis vs Apoptosis
- Necrosis: always pathologic
- Necrosis means local death of groups of cells.
- All forms of necrosis are pathologic
- Inflammation is present in necrosis
- •Cell swelling
- •Increased eosinophilia (pinkness) due to loss of RNA
- •Glassy homogeneous pattern due to degradation of proteins
- •Loss of nuclear material:
- •Random DNA breaks- DNase activity- karyolysis (loss of basophilia); pyknosis (nuclear shrinkage); karyorrhexis (fragmentation)
- •Ghost-like appearance of necrotic cells
- •Inflammatory response- salvage operation
- Apoptosis: organized programmed cell death, cells get smaller, happens very fast and cleaned up quickly
- -Apoptosis is a pathway of cell death that is induced by a tightly regulated genetic suicide program
- -Cells destined to die activate intrinsic enzymes that degrade the cells’ own nuclear DNA and proteins
- -Apoptosis can be physiologic or pathologic
- -There is no associated unregulated inflammation with apoptosis.
- •Death of single cells
- •Cytoplasmic blebbing
- •Cell shrinkage
- •Chromatin condensation
- •Lysosomes and organelles intact
- •Fragmentation of nucleus
- •Phagocytosis but no increased inflammatory response
Apoptosis: requires energy, proteins are synthesize, de novo transccription, nonrandom DNA fragmentation ladder
Necrosis: no energy required, no protein synthesis, transcription ceases, random DNA degradation
Necrosis
- Necrosis: always pathologic
- Necrosis means local death of groups of cells.
- All forms of necrosis are pathologic
- Inflammation is present in necrosis
- •Cell swelling
- •Increased eosinophilia (pinkness) due to loss of RNA
- •Glassy homogeneous pattern due to degradation of proteins
- •Loss of nuclear material:
- •Random DNA breaks- DNase activity- karyolysis (loss of basophilia); pyknosis (nuclear shrinkage); karyorrhexis (fragmentation)
- •Ghost-like appearance of necrotic cells
- •Inflammatory response- salvage operation
Apoptosis
- Apoptosis: organized programmed cell death, cells get smaller, happens very fast and cleaned up quickly
- -Apoptosis is a pathway of cell death that is induced by a tightly regulated genetic suicide program
- -Cells destined to die activate intrinsic enzymes that degrade the cells’ own nuclear DNA and proteins
- -Apoptosis can be physiologic or pathologic
- -There is no associated unregulated inflammation with apoptosis.
- •Death of single cells
- •Cytoplasmic blebbing
- •Cell shrinkage
- •Chromatin condensation
- •Lysosomes and organelles intact
- •Fragmentation of nucleus
- •Phagocytosis but no increased inflammatory response
Two pathways of apoptosis
- Intrinsic (mitochondrial)
- Extrinsic (death receptor)
Necroptosis and pyroptosis
- cell death pathways with features of both apoptosis and necrosis
Coagulative necrosis
- MYOCARDIAL INFARCTION
- Most commonly encountered following severe acute cell injury from ischemia or due to exposure to toxic agents
- Nuclei can be absent but cell outlines and cytoplasm are still discernible (ghost cells)
- Occurs when enzymes are also denatured and can’t breakdown dead cells.
Liquefactive necrosis
- mostly in brain, ischemic event
- cells are actually liquid
- no cell borders, mushed together
Caseous necrosis
- Tuberculosis
- granuloma with central necrosis
Fat necrosis
- mostly happens in acute pancreatitis
Fibrinoid necrosis
- typically seen in immune reactions (immune complex depositions) in blood vessels
- leads to bright pink, amorphous apperance of vessel
Gangrenous necrosis
- Clinical variant of coagulation necrosis which is characteristically localized to the soft tissues of the lower limbs that have been compromised by protracted hypoxia and ischemia
