22 - Cell injury, death & adaptations Flashcards
Causes of cell injury
- Hypoxia and ischaemia
- Toxins
- Infectious agents
- Immunologic reactions
- Genetic abnormalities
- Nutritional imbalances
- Physical agents
- Aging
Reversible cell injury
Stage of cell injury where the function and morphology of the injured cells can return to normal if damaging stimulus is removed
Characteristics of reversible cell injury
- Cellular swelling (increased permeability of cell membrane)
- Fatty change
- Eosinophilic cytoplasm (red)
- Plasma membrane alterations
- Nuclear alterations
Irreversible cell injury
With persistent or excessive exposure, cells pass a “point of no return” and undergo cell death
Three phenomena in irreversible cell injury
- Inability to restore mitochondrial function
- Loss of structure & function of the plasma membrane and intracellular membranes
- Loss of DNA and chromatin structural integrity
Necrosis
- ‘Accidental’ cell death due to severe disturbance
- Cell membranes fall apart, cell enzymes leak and digest cell
- Elicits inflammation
Apoptosis
- ‘programmed’ cell death due to less severe injury
- Elimination of cells during normal processes
- Occurs in healthy tissues during development
Cytoplasmic changes of necrosis
- ↑ eosinophilia due to increased binding of eosin (red) to denatured proteins and loss of basophilic (blue) RNA
- Vacuolated (“moth-eaten”) due to enzymes digesting cytoplasmic organelles
Nuclear changes of necrosis
- DNA and chromatin degradation result in one of three patterns (Pyknosis, Karyorrhexis, Kayolysis)
Pyknosis
Basophilia of nucleus due to condensation of DNA
Karyorrhexis
Fragmentation of pyknotic nucleus
Karyolysis
Basophilia fades due to digestion of DNA by DNAase
Purpose of apoptosis
To eliminate:
- Potentially harmful cells
- Cells that have outlived their usefulness
- Irreparably damaged cells
Process of apoptosis
- Activation of cellular enzymes (caspases) leads to
degradation of nuclear DNA and cytoplasmic proteins - Fragments (apoptotic bodies) of the cells break off
- Plasma membrane remains intact but is altered and apoptotic bodies are consumed by phagocytes
- Little leakage of cell contents & thus no inflammation
Cell size in Necrosis vs Apoptosis
Enlarged (swelling) vs reduced (Shrinkage)
Nucleus in necrosis vs apoptosis
Pyknosis, karyorrhexis and karyolysis vs fragmentation into neucleosome sized fragments
Plasma membrane in necrosis vs apoptosis
Disrupted vs intact
Cellular contents in necrosis vs apoptosis
Enzymatic digestion (may leak out of cell) vs intact (may be released in apoptotic bodiesA
Adjacent inflammation in necrosis vs apoptosis
Frequent vs no inflammation
Physiologic or pathologic role in necrosis vs apoptosis
Invariably pathologic (culmination of irreversible cell injury) vs physiologic means of eliminating unwanted cells (can be pathologic after cell injury)
Necroptosis
includes features of both necrosis and apoptosis and is regulated by particular signalling pathways, not well understood
Pryoptosis
Associated with activation of the inflammasome, can lead to the release of proinflammatory cytokines that can initiate apoptosis
Autophagy
- An adaptation to nutrient deprivation in which cells digest their own organelles and recycle them to provide energy and substrates
- If the stress is too severe for autophagy to cope with, cell death by apoptosis will occur
What causes a reversible cell injury
Low doses of toxins or a brief period of ischaemia
What causes irreversible injury and cell death
Larger toxin doses or longer ischemic times
What do consequences of an injurious stimuli depend on
The type, status, adaptability, and genetic makeup of the injured cell. (e.g. skeletal muscle in leg can tolerate ischemia for 2 - 3 hours but cardiac muscle dies after 20 mins)
What triggers necrosis
Deprivation of oxygen and nutrients primarily impairs energy-dependent cellular
functions
What triggers apoptosis
damage to proteins and DNA
Hypoxia
Tissues deprived of oxygen
Ischaemia
Reduced blood supply leading to oxygen deprivation and deficiency of essential nutrients
Causes of hypoxia
- Ischemia resulting from an arterial obstruction (most common)
- Inadequate oxygenation of the blood (less common)
Examples of Inadequate oxygenation of the blood causing hypoxia
- Variety of diseases affecting the lung
- Reduction in the oxygen-carrying capacity of the blood (anemia)
- Carbon monoxide (CO) poisoning.
What is one of the most frequent causes of cell injury and necrosis in clinical medicine
Oxygen deprivation as it leads to failure of many energy dependent metabolic pathways (no oxygen = no ATP)
What is ATP needed for
membrane transport, protein synthesis, lipogenesis, and the deacylation-reacylation reactions necessary for phospholipid turnover
What produces ATP
ATP is produced from ADP by oxidative phosphorylation during reduction of oxygen in the electron transport system of mitochondria
Ischaemia reperfusion injury
Restoration of blood flow to ischaemic but viable tissues can paradoxically result in further cell injury
Mechanisms of ischaemia reperfusion injury
- Increased generation of reactive oxygen species (ROS)
- Inflammation may increase with reperfusion due to influx of leukocytes and plasma proteins
Reactive oxygen species (ROS)
- Free radicals (chemical species with unpaired electron in outer orbit –> unstable)
- Produced in all cells during reduction oxidation reactions
- Produced in phagocytes for inflammation and host defence
Accumulation of ROS
Leads to cell injury by:
- Damage to cell membrane by peroxidation
- protein cross-linking
- DNA damage
Two general mechanisms of cell injury caused by toxins
- Direct-acting toxins act by combining with a critical
molecular component or cellular organelle - Latent toxins must first be converted to reactive metabolites, which then act on target cells
Endoplasmic reticulum stress
- The accumulation of misfolded proteins in a cell can stress compensatory pathways in the ER and lead to apoptosis
- Caused by ↑ production of misfolded proteins and ↓ ability to eliminate them
What causes ↑ production of misfolded proteins and ↓ ability to eliminate them
- Gene mutations (increased proteins that cannot fold properly)
- Aging, (decreased capacity to correct misfolding)
- Infections (when large amounts of microbial
proteins are synthesized within cells) - Increased demand for secretory proteins such as insulin in insulin-resistant
states
How can protein misfolding cause disease
By creating a deficiency of an essential protein or by inducing apoptosis
What induces DNA damage
- Exposure of cells to radiation, chemotherapeutic agents
- Intracellular generation of ROS
- Acquisition of mutations
DNA damage
- Sensed by intracellular sentinel proteins, which transmit signals that lead to the accumulation of p53
protein - p53 first arrests the cell cycle (at the G1 phase) to allow the DNA to be repaired before it is replicated
- If the damage is too great to be repaired, apoptosis is triggered
What elicits an inflammatory reaction
- Pathogens
- Necrotic cells
- Dysregulated immune responses (Autoimmune diseases and Allergy)
Cellular adaptations to stress
Reversible changes in the number, size, phenotype, metabolic activity, or functions of cells in response to changes in their environment
Physiological adaptations to stress
responses of cells to normal stimulation by hormones or endogenous chemical mediators or the demands of mechanical stress (e.g. enlargement of uterus during pregnancy and muscle growth with weightlifting)
Pathologic adaptations to stress
Responses to stress that allow cells to modulate their structure and function and thus escape injury, but at the expense of normal function
Example of pathologic adaptions to stress
Squamous metaplasia of bronchial epithelium in smokers
Examples of cellular adaptations to stress
- Hypertrophy
- Hyperplasia
- Atrophy
- Metaplasia
Hypertrophy
- Increased cell and organ size, in response to increased workload
- Induced by growth factors produced in response to mechanical stress or other stimuli
- Occurs in tissues incapable of cell division
Hyperplasia
- Increased cell numbers in response to hormones and other growth factors
- Occurs in tissues whose cells are able to divide or contain abundant tissue stem cells
- Can be physiologic or pathologic
Atrophy
- Decreased cell and organ size, as a result of decreased
nutrient supply or disuse - Decreased synthesis of cellular building blocks
- Increased breakdown of cellular organelles and autophagy
Metaplasia
- Change in phenotype of differentiated cells, due to chronic irritation that makes cells better able to withstand the stress
- May result in reduced functions or increased propensity for malignant transformation
