Cellular Responses To Stress and Toxic Insults

Cellular Responses to
Stress and Toxic Insults

Overview of Cell Injury and
Cell Death
Reversible Cell Injury
• Hallmarks:
– Reduced oxidative phosphorylation resulting in
depleted ATP
– Cellular swelling caused by changes in ion
concentrations and water influx
Cell Death
• With continuing damage, injury becomes
irreversible, leading to cell death.
• Principal types:
– Necrosis
– Apoptosis
Necrosis
• “Accidental” and unregulated type of cell
death
• Damage to cell membranes and loss of ion
homeostasis
• Cellular contents leak into the extracellular
space, eliciting inflammation
• Always a pathologic process
Apoptosis
• When the cell’s DNA or proteins are damaged
beyond repair, the cell kills itself
• Characterized by nuclear dissolution,
fragmentation of the cell without complete
loss of membrane integrity, and rapid removal
of cell debris
• No inflammatory reaction
Apoptosis
• Highly regulated process driven by a series of
genetic pathways
• “Programmed cell death”
• Serves many normal functions
• Not necessarily associated with cell injury
Causes of Cell Injury
Oxygen Deprivation
• Hypoxia
– Oxygen deficiency
– Causes cell injury by reducing aerobic oxidative
respiration
Oxygen Deprivation
• Hypoxia
– Due to:
• Reduce blood flow (ischemia)
• Inadequate oxygenation (cardiorespiratory failure)
• Decreased oxygen carrying capacity (anemia)
• Severe blood loss
Oxygen Deprivation
• Depending on severity, cells may:
– Adapt
– Undergo injury
– Die
Physical Agents
• Mechanical trauma
• Extremes of temperature
– Burn
– Deep cold
• Sudden changes in atmospheric pressure
• Radiation
• Electric shock
Chemical Agents, Drugs
• Too many to compile!
• Simple chemicals like glucose and salt
• Oxygen at high concentrations
• Trace amounts of poison like arsenic and
cyanide
Chemical Agents, Drugs
• Pollution, insecticides, herbicides
• Carbon monoxide, asbestos
• Alcoholic beverage
• Therapeutic drugs
Infectious Agents
• From viruses to tapeworms
• Rickettsiae, bacteria, fungi and other parasites
Immunologic Reactions
• Immune System: defense against infectious
pathogens  but may also cause cell injury in
the process
• Autoimmune disease
Genetic Derangements
• Extra chromosome: Down Syndrome
• Base pair substitution: Sickle cell
• Deficiency of functional proteins: inborn
errors of metabolism
• Polymorphisms
Nutritional Imbalances
• Protein-calorie deficiencies
• Vitamin deficiencies
• Self-imposed (bulemia, anorexia nervosa)
• Nutritional excess
Mechanisms of Cell Injury
Depletion of ATP
• Fundamental cause of necrotic cell death
• Produced in two ways:
– Oxidative phosphorylation (major)
• Oxygen reduction in mitochondria
– Glycolytic pathway
• In the absence of oxygen using glucose
Mitochondrial Damage
• Supply ATP
• Critical in cell injury and cell death
• Can be damaged by:
– Increases in cytosolic Ca2+
– Reactive oxygen species (ROS)
– Oxygen deprivation
– Mutations in mitochondrial DNA
Influx of Calcium and
Loss of Calcium Homeostasis
• Cytosolic free calcium is normally maintained
at ~0.1 umol
– Extracellular at 1.3 mmol
• Most intracellular calcium sequestered in
mitochondria and ER
• Increased in calcium:
– Released from calcium stores
– Influx across plasma membrane
Oxidative Stress
• Accumulation of oxygen-derived free radicals
(reactive oxygen species)
– Have a single unpaired electron
– Highly reactive with adjacent molecules (organic
and inorganic chemicals)
• Proteins, lipids, carbohydrates, nucleic acids
– Convert molecules into reactive species
Defects in Membrane Permeability
• Early loss of selective membrane permeability,
leading ultimately to overt membrane damage
• Consistent feature of cell injury (except
apoptosis)
• Mitochondrial, plasma and lysosomal
membranes
Damage to DNA and Proteins
• Cells have mechanisms to repair DNA damage,
however, when damage is too severe to be
corrected, the cell initiates a
suicide program  APOPTOSIS
Morphologic Alterations in
Cell Injury
• Under the light microscope:
– Cellular swelling
• Occurs when cells are incapable of maintaining ionic
and fluid homeostasis
– Fatty change
• Lipid vacuoles appear in the cytoplasm
• Occurs in cells involved/dependent on fat metabolism
Cellular Swelling
• First manifestation of almost all forms of
injury to cells
• Difficult to appreciate in LM
more evident in gross of whole organ
– Pallor
– Increaser turgor
– Increase in weight
Cellular Swelling
• Microscopy:
– Small clear vacuoles in the cytoplasm
• Distended/pinched-off segments of ER
• Hydropic change or vacuolar degeneration
– Increased eosinophilic staining
Ultrastructural Changes of
• Plasma membrane alterations (blebbing,
blunting, loss of microvilli)
• Mitochondrial changes (swelling, appearance
of small amorphous densities)
• Dilation of the ER, with detachment of
polysomes)
• Nuclear alterations (disaggregation of granular
and fibrillar elements)
Irreversible Injury
• Inability to reverse mitochondrial dysfunction
• Profound disturbances in membrane function
Necrosis
• The result of denaturation of intracellular
proteins and enzymatic digestion of the
lethally injured cell
• Necrotic cells are digested by their own
lysozymes plus the lysozymes of leukocytes
Necrosis
• On electron microscopy:
– Discontinuities in plasma and organelle
membranes
– Marked dilation of mitochondria
– Intracytoplasmic myelin figures
– Amorphous debris
– Aggregates of fluffy material (denatured protein)
Patterns of Tissue Necrosis
Coagulative Necrosis
• Architecture of dead tissues is preserved for
some days
• Firm texture
• Injury denatures structureal proteins and
enzymes  NO proteolysis
– Eosinophilic, anucleate cells
• Removed by phagocytosis
• Localized area: INFARCT
• Seen in all organs except brain
Liquefactive Necrosis
• Characterized by digestion of dead cells
• Liquid viscous tissue mass
• Focal bacterial/fungal infections
• Creamy yellow “pus” due to dead leukocytes
• Seen in CNS infarcts
Gangrenous Necrosis
• Not a specific pattern of death, but used in
clinical practice
• Usually applied to a limb that has lost its
blood supply  leading to coagulative
necrosis of multiple tissue planes
• Wet gangrene: with superimposed bacterial
infection (C. perfringens)
Caseous Necrosis
• Most often in tuberculous infection
• “Cheese-like”
• Friable white appearance
• Granuloma: area of amorphous granular
necrosis enclosed by a distinctive
inflammatory border
Fat Necrosis
• Does not denote a specific pattern of necrosis
• Refers to focal areas of fat destruction
• E.g. Acute pancreatitis
• Fat saponification: fatty acids combine with
calcium
• Microscopic: outlines of necrotic fat cells with
basophilic calcium deposits surrounded by
inflammation
Fibrinoid Necrosis
• Special form usually seen in immune reactions
in blood vessels
• Typically occurs when complexes of antigens
and antibodies (“immune complexes”) are
deposited in the arterial walls
• Together with leaked fibrin, appears bright
pink and amorphous “fibrin-like”
See you next week (Prepare for a quiz)
Topics:
APOPTOSIS
AUTOPHAGY
INTRACELLULAR ACCUMULATIONS
PATHOLOGIC CALCIFICATION
CELLULAR AGING
INFLAMMATION AND REPAIR

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