Beruflich Dokumente
Kultur Dokumente
Wenyan Zhang
Department of Pathology
West China School of Medicine
Sichuan University
March, 2018
Causes of cell injury
• Ischemia/hypoxia (e.g. heart attack)
• Chemical agents (toxins, acid, drugs)
– Active oxygen species: free radicals, oxidants,
electrophiles
• Infectious agents (bacterial, virus, parasite)
• Immunologic reactions (hypersensitivity)
• Genetic defects (e.g. Down’s syndrome)
• Nutritional imbalances (protein insufficiency)
• Physical agents (trauma, temperature)
• Iatrogenic causes
• Aging
Overview of Cell Injury and
Cell Death
Reversible cell injury
• Initially, injury is manifested as functional and
morphologic changes that are reversible if the
damaging stimulus is removed
• The hallmarks of reversible injury are reduced
oxidative phosphorylation, adenosine triphosphate
(ATP) depletion, and cellular swelling caused by
changes in ion concentrations and water influx
• These changes are called “ degenerations” in old
textbooks of pathology
Irreversible injury
• Irreversibly injured cells invariably undergo
morphologic changes that are recognized as cell
death
– Necrosis
– Apoptosis
• When damage to membranes is severe, lysosomal
enzymes enter the cytoplasm and digest the cell,
and cellular contents leak out, resulting in
necrosis
• Apoptosis, which is characterized by nuclear
dissolution without complete loss of membrane
integrity
Schematic representation of a normal cell and the changes in reversible and
irreversible cell injury.
Mechanisms of cell injury
• The cellular response to injurious
stimuli depends on the type of injury,
its duration, and its severity.
• The consequences of an injurious
stimulus depends on the type, status,
adaptability, and genetic makeup of
the injurious cell.
– Ischemia:
Skeletal muscle: 2-3 hours normal
Cardiac muscle: 20-30 minutes death
Mechanisms of cell injury
• The vulnerable intracellular systems:
– Cell membrane integrity (ionic and osmotic balance)
– ATP generation
– Protein synthesis
– DNA
• Cellular function is lost far before cell death
occurs, and the morphologic changes of cell
injury ( or death) lag far behind both
General Biochemical Mechanisms
of cell injury
• ATP depletion
• Oxygen deprivation or generation of
reactive oxygen species
• Loss of calcium homeostasis
• Defects in plasma membrane permeability
• Mitochondria damage
General Biochemical Mechanisms
of cell injury
• ATP depletion
• Oxygen deprivation or generation of
reactive oxygen species
• Loss of calcium homeostasis
• Defects in plasma membrane
permeability
• Mitochondria damage
General Biochemical Mechanisms
of cell injury
• ATP depletion
• Oxygen deprivation or generation of
reactive oxygen species
• Loss of calcium homeostasis
• Defects in plasma membrane
permeability
• Mitochondria damage
Mechanism of ischemic and hypoxic injury
General Biochemical Mechanisms
of cell injury
• ATP depletion
• Oxygen deprivation or generation of
reactive oxygen species
• Loss of calcium homeostasis
• Defects in plasma membrane
permeability
• Mitochondria damage
General Biochemical Mechanisms
of cell injury
• ATP depletion
• Oxygen deprivation or generation of
reactive oxygen species
• Loss of calcium homeostasis
• Defects in plasma membrane
permeability
• Mitochondria damage
Cell mechanisms of injury
Free radicals/ reactive chemicals
O 2 Cell membrane
Normal
Metabolisms OH• Mitochondria
Inflammation Endo. Retic.
H2O2 DNA
Radiation
Oxygen toxicity NO
Chemicals
Reperfusion injury
Detoxification
SOD/Catalase
Glutathione peroxidase/GSSG (Fenton reaction)
Vitamin E, C
Neutralization of free radicals
SOD
• 2O2 + 2H+ H2O 2 + O2
catalase
• 2H2O2 2H2O + O2
glutathione peroxidase
• 2OH• + 2GSH GSSH + 2H2O
glutathione reductase
General Biochemical Mechanisms
of cell injury
• ATP depletion
• Oxygen deprivation or generation of
reactive oxygen species
• Loss of calcium homeostasis
• Defects in plasma membrane
permeability
• Mitochondria damage
General Biochemical Mechanisms
of cell injury
• ATP depletion
• Oxygen deprivation or generation of
reactive oxygen species
• Loss of calcium homeostasis
• Defects in plasma membrane
permeability
• Mitochondria damage
General Biochemical Mechanisms
of cell injury
• ATP depletion
• Oxygen deprivation or generation of
reactive oxygen species
• Loss of calcium homeostasis
• Defects in plasma membrane
permeability
• Mitochondria damage
General Biochemical Mechanisms
of cell injury
• ATP depletion
• Oxygen deprivation or generation of
reactive oxygen species
• Loss of calcium homeostasis
• Defects in plasma membrane
permeability
• Mitochondria damage
General Biochemical Mechanisms
of cell injury
• ATP depletion
• Oxygen deprivation or generation of
reactive oxygen species
• Loss of calcium homeostasis
• Defects in plasma membrane
permeability
• Mitochondria damage
General Biochemical Mechanisms
of cell injury
• ATP depletion
• Oxygen deprivation or generation of
reactive oxygen species
• Loss of calcium homeostasis
• Defects in plasma membrane
permeability
• Mitochondria damage
Summary
• Any stimuli and stresses can result in cell injuries.
Cell Injury
Reversible cell injuries:
Intracellular Accumulations
So called “degeneration”
• “Degeneration” is a traditional word used in
old textbooks of pathology. You could
understand it as
• Accumulation of exceeding normal substances
and abnormal substances in cells, usually in
the cytoplasm and/or in the stroma
• Exceeding normal and abnormal substances
come from the affected cells or elsewhere
• When the stimulus is removed in time, it is
reversible if it occurs in cytoplasm, but
irreversible in the stroma
So called “degeneration”
According to the today’s view, so called
“degeneration” covers
• “real” reversible cellular injuries
– Cell swelling (hydropic change)
– Fatty change
• Intracellular accumulations (cholesterol,
proteins, glycogen)
• Extracellular accumulations (most proteins)
Cellular swelling
• Cellular swelling
When the injurious cell can not maintain its ionic
and fluid homeostasis, the water surrounding cell
can enter the cytoplasm
– Grossly, the affected organ becomes pallor,
increased turgor, increased weight with dulled
edge
– Microscopically, small and clear vacuoles in
cytoplasm (hydropic change, ballooning
degeneration)
Left: ballooning degeneration in liver cells
Right: hydropic change in proximal convoluted tubules of the kidney
Hydropic change in the proximal tubules of kidney
Morphologic changes
in reversible and
irreversible cell injury.
A, Electron
micrograph of a
normal epithelial cell
of the proximal
kidney tubule. Note
abundant microvilli
(mv) lining the lumen
(L). N, nucleus; V,
apical vacuoles.