CELL INJURY, DEATH
AND ADAPTATIONS
Yingci Liu, DDS
Pathology – The study of disease
• Etiology – Cause
• Pathogenesis – Mechanism of development of
disease
• Morphology – Gross or microscopic appearance
A cell attempts to maintain normal
homeostasis
• As a cell encounters physiologic stresses or
pathologic stimuli, it can undergo
adaptation
• If the cell’s adaptive capability is exceeded,
cell injury develops
• Up to a point, cell injury is reversible
• With severe or persistent stress, the cell
suffers irreversible injury and ultimately
dies
Cellular Adaptations and Growth
Differentiation
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Physiologic Adaptation – Response of cells to
normal stimulation by hormones or endogenous
chemical mediators
Pathologic Adaptation
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Atrophy
Hypertrophy
Hyperplasia
Metaplasia
Hypertrophy
• An organ or structure becomes bigger because the
constituent cells enlarge.
• Physiologic (growth of uterus during pregnancy
stimulated by estrogen)
• Adaptive (skeletal muscle enlargement in a weight
lifter or cardiac enlargement in a patient with
chronic hypertension)
Hypertrophy
Hyperplasia
• An organ or structure gets bigger because
there is an increase in the number of cells.
• Physiologic
– Hormonal hyperplasia (proliferation of the
female breast during puberty or pregnancy).
– Compensatory hyperplasia occurs when a
portion of tissue is removed or diseased
(stimulated by growth factors, the liver
regenerates after a portion is removed).
Hyperplasia
• Pathologic –
– Usually due to excessive hormonal or growth
factor stimulation
• Endometrial hyperplasia
• Medication-induced gingival hyperplasia
– Provides a fertile soil in which a cancerous
proliferation may arise (endometrial cancer).
Atrophy
• Shrinkage in the size of the cell by loss of
cell substance.
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Decreased workload
Loss of innervation
Diminished blood supply, inadequate nutrition,
Loss of endocrine stimulation (menopause),
Aging.
• Often accompanied by marked increases in
the number of autophagic vacuoles.
Atrophy
Atrophy of the brain is caused by
aging and reduced blood supply
• Normal
82 y.o. with
atherosclerosis
Metaplasia
• A reversible change in which there is the
substitution of one adult cell type for another
• Better to withstand the adverse environment
• However, important protective mechanisms or
normal functions are lost.
• Increased propensity for malignant transformation
Metaplasia
• Examples
– Squamous change in respiratory epithelium in
habitual cigarette smokers (loss of ciliary
clearance).
– Gastric or intestine-type mucosa replacing
stratified squamous epithelium in chronic
gastric reflux. (e.g., Barrett’s esophagus)
Metaplasia
Dysplasia
• Pathologic change due to accumulation of
mutations
• Alteration in size, shape and organization of
cells, enlargement and hyperchromatism of
the nuclei, disorderly arrangement
• Preneoplastic
Dysplasia
Example: Oral dysplasia
Reversible Cell Injury
Reversible injury is the
stage of cell injury at
which the deranged
function and morphology
of the injured cells can
return to normal if the
damaging stimulus is
removed.
Reversible Cell Injury
• Cellular swelling- commonly
seen in cell injury associated
with increased permeability of
the plasma membrane.
• Fatty change- the
appearance of triglyceride
containing lipid vacuoles in the
cytoplasm, such as the liver.
Reversible Cell Injury
•
Cellular swelling
– AKA: hydropic change, vacuolar
degeneration
– Generally the 1st manifestation of almost all
forms of injury
– Organs may exhibit pallor, increased weight
and rigidity
– Small, clear vacuoles are seen in the
cytoplasm
Reversible and irreversible cell
injury, kidney
Normal
early ischemic
necrotic
Reversible Cell Injury
•
Fatty change (steatosis)
– Lipid vacuoles in cytoplasm
– Usually in cells that are important in fat
metabolism (liver, heart)
Reversible Cell Injury
Other cellular changes:
Plasma membrane alterations
such as blebbing, blunting, or
distortion of microvilli,
changes in organelles
(mitochondria, ER), nuclear
alterations, such as clumping
of chromatin.
Reversible Cell Injury
•
Ultrastructural
changes
1. Plasma membrane
alterations (blebs)
2. Mitochondrial
swelling
3. Dilation of the ER
4. Nuclear alterations
Causes of Cell Injury
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Hypoxia
Chemical agents
Infectious agents
Immunologic Agents
Genetic defects
Nutritional imbalances
Physical Agents
Aging
Causes of Cell Injury
• Hypoxia –
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Deprives the cell of aerobic respiration
Common cause of cell injury and death
Not the same as ischemia
Ischemia most common form of hypoxia
Chemical agents
Infectious agents
Immunologic Agents
Genetic defects
Causes of Cell Injury
• Hypoxia
• Chemical agents:
– Many chemicals cause primary injury to cell membranes, or to the
membranes of critical cell organelles.
– O2, CO, pollutants, asbestos, alcohol
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Infectious agents
Immunologic Agents
Genetic defects
Nutritional imbalances
Causes of Cell Injury
• Hypoxia
• Chemical agents
• Infectious agents
– Bacteria release enzymes or toxins (which act
as chemicals) to injure cells.
– Viruses may produce direct cytopathic injury or
may elicit an immune response, which injures
cells.
– Fungi, rickettsiae, protozoa, tapeworms, etc.
Causes of Cell Injury
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Hypoxia
Chemical agents
Infectious agents
Immunologic Agents: inducing an immune
response
– Allergic/anaphylactic reactions
– Autoimmune diseases
• Genetic defects
• Nutritional imbalances
Causes of Cell Injury
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Hypoxia
Chemical agents
Infectious agents
Immunologic Agents
Genetic defects
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From chromosomal to single base pair mutation
Accumulation of damaged or mis-folded proteins
Deficiency of enzymes, etc.
Accumulation of damaged DNA
• Nutritional imbalances
Causes of Cell Injury
• Nutritional imbalances
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Protein-calorie insufficiency
Vitamin deficiencies
Excess nutrition/obesity
Excess animal fat
• Physical Agents
• Aging
Causes of Cell Injury
• Nutritional imbalances
• Physical Agents
– trauma, extremes of temperature, radiation,
electric shock, atmospheric pressure, etc.
• Aging (senescence)
– Alterations in replication and repair
Morphology of Cell and Tissue
Injury
• Cellular function may be lost long before
cell death
• Morphologic changes after injury happen
far later than injury or loss of function
Subcellular Responses to Injury
• Autophagy
– Lysosomal digestion of the cell's own
components.
– Survival mechanism in times of nutrient
deprivation, so that the starved cell can live by
eating its own contents
Subcellular Responses to Injury
• Autophagy
– Removal of damaged or senescent organelles.
The intracellular organelles are sequestered in a
sac of RER (autophagosome), which fuses with
a primary lysosome (autophagolysosome).
– Extensive autophagy is seen in ischemic injury
– If the stress is too severe -> cell death by
apoptosis.
Cell Death
When cells are injured, they die by different mechanisms, depending
on the nature and severity of the insult.
•
Necrosis
•
Apoptosis
• Pyknosis -nuclear shrinkage and increased basophilia; the DNA
condenses into a dark shrunken mass.
• Karyorrhexis – DNA fragmentation
• Karyolysis- digestion of DNA by deoxyribonuclease (DNase)
activity.
• In 1 to 2 days, the nucleus in a dead cell may completely disappear.
Types of Necrosis
• Coagulative necrosis – Due to hypoxic death,
ischemia
– Gangrenous necrosis – Ischemic necrosis with
superimposed liquefactive changes, often in limbs
• Liquefactive necrosis – Hydrolytic enzymes
rapidly digest cells, turns to liquid, often in brain
• Caseous necrosis – Necrotic debris with
granulomatous inflammation, ‘cheesy consistency’
• Fat necrosis- necrosis in fat tissue
• Fibrinoid necrosis- necrosis in blood vessels
Coagulative necrosis
• Characteristic of hypoxic death of cells in
all tissues except the brain.
• Preservation of the basic structural outline
of the cell or tissue is seen for several days.
• Common for infarcts (ischemic necrosis)
(e.g., Myocardial infarction)
Coagulative necrosis, Kidney
Coagulative necrosis, Kidney
Liquefactive necrosis
• Liquefactive necrosis – Usually associated with
the presence of large amounts of hydrolytic
enzymes and is particularly prevalent in bacterial
infections. The enzymes rapidly digest the cells
so that no structural evidence of the cell remains.
(Abscess formation)
Liquefactive necrosis, brain
Liquefactive necrosis, tooth
• Triple-O, Bolan
Liquefactive necrosis, tooth
Dental Dimensions in Hygiene
Caseous necrosis
• Seen most often in a focus of tuberculous
infection
• “Cheesy” white gross appearance.
• Microscopically, the necrotic focus is
composed of amorphous granular debris
with a distinctive ring of granulomatous
inflammation.
• Tissue architecture is obliterated
Caseous Necrosis in a
tuberculous lung
Lung
Fat necrosis
• Enzymatic fat necrosis – Focal areas of fat
destruction
• In pancreatic injury, pancreatic enzymes
(lipases) are released and digest abdominal
adipose tissue.
• Fatty acids are released and complex with
calcium to form grossly visible chalkywhite areas (“soaps”)
Fat necrosis, acute pancreatitis
saponification
Fibrinoid necrosis
• Usually in immune reactions involving
blood vessels.
• Ag-Ab complexes plus fibrin
• Look bright pink on H&E (fibrin-like)
Fibrinoid necrosis
Apoptosis
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“Programmed cell death”
Examples of Normal apoptosis:
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Destruction of embryonic structures
Involution of the lactating breast after weaning
Cell deletion in a proliferating population
Death of cells after they have served their purpose
(neutrophils and lymphocytes in inflammation)
Elimination of potentially harmful self-reactive
lymphocytes
Cell death induced by cytotoxic T-lymphocytes
Apoptosis
•
Pathologic apoptosis
– DNA damage
– Accumulation of misfolded proteins
– Cell injury from certain infections (usually
viral)
– Pathologic atrophy in organs after duct
obstruction (pancreas, parotid, kidney)
Apoptosis
•
Histologic features:
1. Single cell death
2. Condensation of chromatin
3. Nuclear fragmentation (karyorrhexis)
4. Cytoplasmic budding and fragmentation
5. Degradation and phagocytosis of cell
fragments by macrophage
6. Minimal inflammation
Sequence of events in apoptosis
Apoptosis
karyorrhexis
Apoptosis vs. Necrosis
Apoptotic Cell of
Epidermis
Apoptotic Cell in the Liver
The End
Intracellular Accumulations
• Cells may accumulate abnormal amounts of
various substances, which may be harmless
or may cause varying degrees of injury.
Intracellular Accumulations
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Examples
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Fatty change (steatosis)
• Abnormal accumulation of triglycerides
• Caused by toxins, protein malnutrition,
DM, obesity, and anoxia
– Cholesterol and cholesteryl esters
– Xanthoma (foam) cells
Fatty change in the liver
Intracellular Accumulations
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Proteins
– Russell bodies in plasma cells
(immunoglobulins)
Pigmented Intracellular Accumulations
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Exogenous –
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Carbon or coal dust accumulates in
macrophages in the pulmonary parenchyma
or lymph nodes
Foreign bodies, e.g. shrapnel, amalgam
Dermatology Online Journal 14(5):19
Dermatology Online Journal 14(5):19
Pigmented Intracellular Accumulations
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Endogenous
1. Lipofuscin
2. Melanin
3. Hemosiderin
Pigmented Intracellular Accumulations
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Endogenous
1. Lipofuscin
• “Wear and tear”
pigment as a
function of age
or atrophy
• Marker of past
free radical
injury
Lipofuscin in cardiac muscle
Pigmented Intracellular Accumulations
•
Endogenous
2. Melanin
• Synthesized as a
screen against
harmful UV
radiation
Pigmented Intracellular Accumulations
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Endogenous
3. Hemosiderin
• Results from local excesses of iron due to
hemorrhage or overload
AFIP-Hematoma
Hemosiderin granules
• Liver, H&E
Prussian blue
Pathologic Calcifications
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Abnormal deposition of calcium salts
Dystrophic calcifications - Calcium
phosphate is deposited on mitochondria of
dead cells
– Seen in calcific aortic stenosis
– Atherosclerosis
Calcific Aortic Stenosis
Pathologic Calcifications
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Metastatic calcifications – Due to
hypercalcemia caused by:
1. Hyperparathyroidism (primary or secondary)
2. Myeloma or metastatic carcinoma
(destruction of bone)
3. Vitamin D-related disorders (D intoxication,
sarcoidosis)
4. Renal failure (phosphate retention)