• Overview of cell injury and cell death

• Causes of cell injury

• Sequence of events in cell injury and cell death
• Reversible cell injury
• Cell death
• Necrosis
• Apoptosis
• Autophagy
• Mechanisms of cell injury and cell death
• Cellular adaptations to stress
• Intracellular accumulations
• Pathologic calcification
• Cellular aging
Patterns of Cell Injury and Cell Death - 1

• Causes of cell injury: ischemia, toxins, infections,

immunologic reactions, genetic, nutritional imbalances,
physical agents (e.g., trauma, burns), aging
• Reversible cell injury: cell swelling, fatty change, plasma
membrane blebbing and loss of microvilli, mitochondrial
swelling, dilation of the ER, eosinophilia (due to
decreased cytoplasmic RNA), myelin figures
Patterns of Cell Injury and Cell Death - 2

• Necrosis: eosinophilia; nuclear shrinkage, fragmentation,

and dissolution; breakdown of plasma membrane and
organellar membranes; leakage and enzymatic digestion
of cellular contents; elicits inflammation
• Morphologic types of tissue necrosis: coagulative,
liquefactive, gangrenous, caseous, fat, and fibrinoid.
 Liquefactive necrosis brain
(abces)

caseous necrosis lung (TB)

fat necrosis pancreatitis

(deposition calcium-fat salts)
Patterns of Cell Injury and Cell Death - 3

• Apoptosis: regulated mechanism of cell death that

eliminates unnecessary and irreparably damaged cells,
without injurious host reaction; characterized by
enzymatic degradation of proteins and DNA, initiated by
caspases, and by recognition and removal of dead cells
by phagocytes
Patterns of Cell Injury and Cell Death - 4
• Two major pathways of apoptosis:
• Mitochondrial (intrinsic) pathway is triggered by loss
of survival signals, DNA damage, and accumulation of
misfolded proteins (ER stress); associated with
leakage of proapoptotic proteins from mitochondrial
membrane into the cytoplasm, where they trigger
caspase activation; inhibited by antiapoptotic
members of the BCL family, which are induced by
survival signals including growth factors.
• Death receptor (extrinsic) pathway is responsible for
elimination of self-reactive lymphocytes and damage
by cytotoxic T lymphocytes; initiated by engagement
of death receptors (members of the TNF receptor
family) with ligands on adjacent cells.
Cellular features of necrosis and apoptosis
Patterns of Cell Injury and Cell Death - 5

• Autophagy is triggered by nutrient deprivation;

characterized by degradation and recycling of cellular
contents to provide energy during stress; can trigger
apoptosis if the stress is not relieved.
Mechanisms of Cell Injury - 1

• Different initiating events cause cell injury and death by

diverse mechanisms.
• Mitochondrial damage and increased permeability of
cellular membranes are often late events in cell injury
and necrosis from different causes.
• Oxidative stress refers to accumulation of ROS, which
can damage cellular lipids, proteins, and DNA and is
associated with numerous initiating causes.
Mechanisms of Cell Injury - 2

• ER stress: Protein misfolding depletes essential proteins

and, if the misfolded proteins accumulate within cells,
triggers apoptosis.
• DNA damage, e.g., by radiation, can also induce
apoptosis if it is not repaired.
Mechanisms of Cell Injury - 3

• Hypoxia and ischemia lead to ATP depletion and failure

of many energy-dependent functions, resulting first in
reversible injury and, if not corrected, necrosis.
• In ischemia-reperfusion injury, restoration of blood flow
to an ischemic tissue exacerbates damage by increasing
production of ROS and by increasing inflammation.
Cellular adaptation to stress - 1

• Hypertrophy: increased cell and organ size, often 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
• Atrophy: decreased cell and organ size, as a result of
decreased nutrient supply or disuse; associated with
decreased synthesis of cellular building blocks and
increased breakdown of cellular organelles
Cellular adaptation to stress - 2

• Metaplasia: change in phenotype of differentiated cells,

often in response to chronic irritation, that makes cells
better able to withstand the stress; usually induced by
altered differentiation pathway of tissue stem cells; may
result in reduced functions or increased propensity for
malignant transformation
Abnormal Intracellular Depositions - 1

• Abnormal deposits of materials in cells and tissues are

the result of excessive intake or defective transport or
catabolism.
• Depositions of lipids
• Fatty change: accumulation of free triglycerides in
cells, resulting from excessive intake or defective
transport (often because of defects in synthesis of
transport proteins); manifestation of reversible cell
injury
• Cholesterol deposition: result of defective catabolism
and excessive intake; in macrophages and smooth
muscle cells of vessel walls in atherosclerosis
Abnormal Intracellular Depositions - 2

• Deposition of proteins: reabsorbed proteins in kidney

tubules; immunoglobulins in plasma cells
• Deposition of glycogen: in macrophages of patients with
defects in lysosomal enzymes that break down glycogen
(glycogen storage diseases)
• Deposition of pigments: typically indigestible pigments,
such as carbon, lipofuscin (breakdown product of lipid
peroxidation), or iron (usually due to overload, as in
hemosiderosis)
Pathologic calcifications

• Dystrophic calcification: deposition of calcium at

sites of cell injury and necrosis
• Metastatic calcification: deposition of calcium in
normal tissues, caused by hypercalcemia (usually
a consequence of parathyroid hormone excess)
Cellular aging
• Results from combination of multiple and progressive
cellular alterations
• Accumulation of DNA damage and mutations
• Replicative senescence: reduced capacity of cells to divide
secondary to progressive shortening of chromosomal ends
(telomeres)
• Defective protein homeostasis: loss of normal proteins and
accumulation of misfolded proteins
• Exacerbated by chronic diseases, especially those
associated with prolonged inflammation, and by stress;
slowed down by calorie restriction and exercise
Cellular aging
Role of telomere length