Cell Injury and Cell Death

Cell Injury and Cell Death:
A Capsular Review
Companion Notes:
General Concepts in Pathology Prepared and presented by
(Q & A Rapid Review)
Marc Imhotep Cray, M.D.
Discussion Outline
Reversible Cell Injury
Hydropic Swelling
Intracellular Accumulations
Cellular Adaptation
Atrophy
Hypertrophy
Hyperplasia
Metaplasia
Dysplasia
Irreversible Cell Injury
Necrosis
Apoptosis
Marc Imhotep Cray, M.D. 2
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Stages of cellular response to stress & injurious stimuli
Kumar V and Abbas AK. Robbins and Cotran Pathologic Basis of Disease 8th ed.
Philadelphia: Saunders, 2014
Ultrastructural features of reversible cell injury
 Endoplasmic reticulum (ER): cisternae of the ER are
distended by fluid in hydropic swelling
 Mitochondria: In some forms of acute injury,
particularly ischemia (lack of adequate blood flow),
mitochondria swell
 Plasma membrane: Blebs of plasma membrane-
that is, focal extrusions of cytoplasm
 Nucleus: reflected mainly by segregation of fibrillar
and granular components of nucleolus
 These changes in cell organelles are reflected in
functional derangements (e.g., reduced protein
synthesis, impaired energy production)
 After withdrawal of the stress that caused the
Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis,
reversible cell injury, by definition, the cell returns Missouri: Saunders-Elsevier, 2013.
toImhotep
Marc its normal
Cray, M.D. state 5
Reversible Cell Injury: Hydropic Swelling
Cellular swelling in kidney tubule epithelial cells. A, Normal
kidney tubule with cuboidal cells; B, early ischemic changes
showing surface blebs and swelling of cells.
Marc Imhotep Cray, M.D. Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri: Saunders-Elsevier, 2013. 6
Reversible Cell Injury: Intracellular Accumulations
 Intracellular accumulations may be
Fatty liver showing large intracellular vacuoles of lipid.
categorized as
(1) excessive amounts of normal intracellular
substances such as fat
(2) accumulation of abnormal substances
produced by cell b/c of faulty metabolism or
synthesis, and
(3) accumulation of pigments and particles that
cell is unable to degrade
 Lipids may contribute to atherosclerotic
diseases and accumulate in blood vessels,
kidney, heart, and other organs
 Fat filled cells tend to compress cellular

components to one side and cause tissue Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri:
Saunders-Elsevier, 2013.
toImhotep
Marc appear yellowish and greasy
Cray, M.D. 7
Intracellular Accumulations
 Roles of chaperone proteins in protein refolding and ubiquitin in protein
degradation after stress-induced protein damage

Reversible Cell Injury Accumulations of silicon dust in tissues of the lung.
Intracellular Accumulations (1)

 Excess accumulations of substances in
cells may result in cellular injury b/c
substances are toxic or provoke an
immune response, or
merely b/c they occupy space needed for
cellular functions
 In some cases, accumulations do not in

themselves appear to be injurious but
rather are indicators of cell injury.
Marc Imhotep Cray, M.D. Copstead LC, Banksia JL. Pathophysiology, 5th Ed. 9
St. Louis, Missouri: Saunders-Elsevier, 2013.
Intracellular Accumulations (2)
Intracellular accumulations may be categorized as:
(1) excessive amts. of normal intracellular substances such as fat
 Abnormal metabolism as in fatty change in liver
(2) accumulation of abnormal substances produced by cell b/c of
faulty metabolism or synthesis
 Mutations causing alterations in protein folding and
transport so that defective proteins accumulate
 Deficiency of critical enzyme responsible for lysosomal
degradation
(3) accumulation of pigments and particles that cell is unable to
degrade
 an inability to degrade phagocytosed particles such as coal
dust
Copstead LC, Banksia JL. Pathophysiology, 5th Ed.
KEY POINTS
• Hydropic swelling is an early indicator of cell injury. It results from Na+-
K+ pump dysfunction at cell membrane.
• Intracellular accumulations of abnormal endogenous or exogenous
particles indicate a disorder of cellular metabolism.
• Damage from accumulation of abnormal intracellular protein is limited
by chaperone proteins that attempt to refold the protein into its correct
shape and by the ubiquitin-proteosome system that digests targeted
proteins into fragments.

Cellular Adaptation
 Adaptive cellular responses of atrophy, hypertrophy, hyperplasia, metaplasia,
and dysplasia
Marc Imhotep Cray, M.D. Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri: Saunders-Elsevier, 2013. 12
Cellular Adaptation (2)
A, Normal brain of a young adult.
B, Atrophy of the brain in an 82- year-old male with atherosclerotic cerebrovascular
disease, resulting in reduced blood supply.
Cellular Adaptation (2)
A, Hypertrophy of cardiac muscle in left ventricular chamber.
B, Compare with the thickness of normal left ventricle.
This is an example of cellular adaptation to an increased cardiac workload.
Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri: Saunders-Elsevier, 2013.
Cellular Adaptation
KEY POINTS
• Adaptive cellular responses indicate cellular stress caused by altered
functional demand or chronic sublethal injury.
• Hypertrophy and hyperplasia generally result from increased functional
demand.
• Atrophy results from decreased functional demand or chronic ischemia.
• Metaplasia and dysplasia result from persistent injury.

Irreversible Cell Injury: Necrosis
 Type of necrosis is dependent on nature, intensity and duration of injurious
agent, and type of cell involved
 N.B.-initial membrane damage allows Ca+2 leakage with subsequent activation of Ca-
dependent phosphatases and lipases
 Coagulative necrosis – cytoplasm of necrosed cells becomes eosinophilic and
persists for many days (myocardial infarction)
 Liquefactive necrosis – cells undergo lysis rapidly (brain infarcts)
 Caseous necrosis – Mycobacterium tuberculosis interacts with macrophages
 Gangrenous necrosis – primary (bacterial toxins) or secondary (ischemia,
infection)
 Fibrinoid necrosis – smooth muscle necrosis, fibrin release (malignant
hypertension)
 Fat necrosis – inflammatory response to liberated fat  fibrosis (pancreas)
16
Irreversible Cell Injury: Necrosis (2)
 There are also nuclear changes related to necrosis:
 Margination of chromatin-chromatin condensing around

periphery of nucleus
o Chromatin clumping is reversible, but dissolution of entire nucleus is
not, and when nucleus is lost, cell will die
 Pyknosis – small and dense nuclei
 Karyolysis – complete lysis of the nuclei
 Karyorrhexis – fragmented nuclei (generally seen in apoptosis)
17
Irreversible Cell Injury: Necrosis (3)
 Irreversible cell injury is typically accompanied by:
 Release of intracellular enzymes:
o Cardiac muscle – creatine kinase (MB isoform), aspartate
transaminase, lactate dehydrogenase
o Hepatocytes – alanine transaminase
o Striated muscle – creatine kinase (MM isoform)
o Exocrine pancreas – amylase
 Loss of membrane selectivity – may be helpful in diagnosis through
uptake of dyes
 Inflammatory response – initiated by products (mediators) of the
necrotic cells
18
Coagulative necrosis/Dry gangrene
Gangrene is a term used to describe cellular death
involving a large area of tissue
Gangrene usually results from interruption of major
blood supply to a particular body part such as toes,
leg, or bowel
Depending on appearance and subsequent infection
of necrotic tissue it is described as dry gangrene vs
wet gangrene vs gas gangrene
 Dry gangrene is a form of coagulative necrosis

characterized by blackened, dry, wrinkled tissue
that is separated from adjacent healthy tissue by an
obvious line of demarcation (as see in illustration) Copstead LC, Banksia JL. Pathophysiology, 5th Ed.

Gangrene cont.
Liquefactive necrosis may result in wet gangrene typically found in
internal organs, appears cold and black, and may be foul smelling b/c of
invasion of bacteria
 Rapid spread of tissue damage and release of toxins into bloodstream
make wet gangrene a life-threatening problem
Gas gangrene is characterized by formation of bubbles of gas in damaged

tissue
 Gas gangrene is result of infection of necrotic tissue by anaerobic
bacteria Clostridium perfringens
 bacteria produce toxins and degradative enzymes that allow infection
to spread rapidly through necrotic tissue
 Gas gangrene may be fatal if not managed rapidly and aggressively
Coagulative necrosis
 Coagulative necrosis is most common Two large infarctions (areas of coagulative
 Manifestations of coagulative necrosis are necrosis) are seen in this sectioned spleen
same, regardless of cause of cell death
 In general, steps leading to coagulative
necrosis may be summarized as follows:
(1) ischemic cellular injury leading to
(2) loss of plasma membrane’s ability to
maintain electrochemical gradients, which
results in
(3) an influx of calcium ions and http://library.med.utah.edu/WebPath/CINJHTML/CINJ018.html
mitochondrial dysfunction, and

(4) degradation of plasma membranes and
nuclear structures
Coagulative necrosis (2)
A. Normal heart. All myocytes are nucleated, and striations are clear.
B. Myocardial infarction. The heart from a patient following acute myocardial
infarction. The necrotic cells are deeply eosinophilic and most have lost their nuclei.
Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: LLW, 2012

Mechanisms by which ischemia leads to
cellular death by necrosis
1. Loss of oxygen due to vascular occlusion
impairs mitochondrial function resulting in
decreased energy (adenosine triphosphate
[ATP]) production by aerobic processes
2. Decreased ATP impairs ATP-dependent ion
exchangers
3. Loss of aerobic processes causes anaerobic
glycolysis to predominate, with consequent
intracellular acidosis, eventually leading to
increased cytosolic [Ca2+]
4. Ca2+-dependent phospholipases are then
activated, causing loss of cell membrane
integrity and necrosis
Marc Imhotep Cray, M.D. Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic 23
Foundations of Medicine, 6th Ed. Baltimore: LLW, 2012
Liquefactive necrosis
 When rate at which necrotic cells dissolve greatly
exceeds rate of repair resulting appearance is
termed liquefactive necrosis
 PMN cells of acute inflammatory reaction
contain potent hydrolases capable of
Copstead LC, Banksia JL. Pathophysiology, 5th Ed.
digesting dead cells St. Louis, Missouri: Saunders-Elsevier, 2013.
Liquefactive necrosis in an abscess of the skin.

 A sharply localized collection of these acute
inflammatory cells (generally in response to
bacterial infection) produces rapid cell death and
tissue dissolution
 Result is often an abscess a cavity formed by
liquefactive necrosis in a solid tissue

Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic
Foundations of Medicine, 6th Ed. Baltimore: LLW, 2012
Fat necrosis
 Fat necrosis refers to death of adipose tissue 
usually results from trauma or pancreatitis
 Process begins with release of activated digestive

enzymes from pancreas or injured tissue
 Enzymes attack cell membranes of fat cells

causing release of their stores of triglycerides
 Pancreatic lipase can then hydrolyze triglycerides to Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis,
Missouri: Saunders-Elsevier, 2013.
free fatty acids and glycerol which precipitate as
calcium soaps (saponification)
 Fat necrosis appears as a chalky white area of tissue

Caseous necrosis
 Caseous necrosis is characteristic of
lung tissue damaged by tuberculosis
 Areas of dead lung tissue are white,
soft, and fragile resembling
clumpy cheese
 Dead cells are walled off from rest of
lung tissue by inflammatory WBCs
 In center, dead cells lose their
cellular structure but are not totally
degraded
 Necrotic debris may persist Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri:
Saunders-Elsevier, 2013.
indefinitely
Caseous necrosis (2) tuberculous lymph node
 Hilar lymph node from a
patient with active tuberculosis
 Irregular pink areas of caseous
necrosis (arrow) are evident
against a background of
lymphocytes
 Inset: Granulomas on the
periphery of necrotic areas
show epithelioid macrophages
and multinucleated giant Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine,
6th Ed. Baltimore: LLW, 2012
(Langhans) cells (arrows)
Apoptosis
 Cell death can also occur through apoptosis 
 it may be physiological deletion of selected cells (e.g.
morphogenesis, cyclic hyperplasia of reproductive processes) or
 it may occur in response to a pathological stimuli
 Number of cells in tissues is tightly regulated by controlling rate of

cell division and rate of cell death
 If cells are no longer needed they activate a cellular death
pathway resulting in cell suicide
Note: there are no gross structural changes involved with apoptosis

Apoptosis (2)
In contrast to necrosis, which is messy and results in inflammation and
collateral tissue damage
 apoptosis is tidy and does not elicit inflammation
Apoptosis is not a rare event large numbers of cells are continually

undergoing programmed cell death as tissues remodel
For example:
 During fetal development more than half of nerve cells that form
undergo apoptosis
 It is estimated that more than 95% of T lymphocytes that are
generated in bone marrow are induced to undergo apoptosis after
reaching thymus
Apoptosis (3)
The initiation of apoptosis requires two processes:
Priming – a reversible stage in which specialist machinery for apoptosis
(e.g. transglutamase, calcium/magnesium endonucleases) are activated
Triggering – the irreversible point which leads to a sustained rise in
cytosolic calcium, and induction of new mRNA species for c-fos, c-myc
and heat-shock proteins
Apoptosis then proceeds:
1. Cytosol and nucleus lost half their volume
2. Fragmentation of nucleus and cytosol ( activation of transglutamase that forms an
insoluble layer beneath the intact cell membrane)
3. Condensation of chromatin (pyknosis)
4. Macrophages bind to cell fragments prior to phagocytosis (non-specific mechanism)
Comparison of cellular changes in necrosis and apoptosis
 Pathological cell death is more

often due to necrosis
 process releases intracellular
enzymes (useful diagnostically)
and
 mediators that stimulate
inflammation followed by
healing by repair, scarring,
contracture & distortion of
tissue architecture
Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri: Saunders-Elsevier, 2013.
IVMS General Pathology Lecture Notes.pdf

Necrosis and Apoptosis
KEY POINTS
• Necrosis occurs when the injury is too severe or prolonged to allow adaptation and is
usually a consequence of disrupted blood supply.
• Local and systemic indicators of cell death include pain, elevated serum enzyme levels,
inflammation (fever, elevated WBC count, malaise), and loss of function.
• Different tissues exhibit necrosis of different types: heart (coagulative), brain (liquefactive),
lung (caseous), and pancreas (fat).
• Gangrene refers to a large area of necrosis that may be described as dry, wet, or gas
gangrene. Gas gangrene and wet gangrene may be rapidly fatal.
• Apoptosis is cell death resulting from activation of intracellular signaling cascades that
cause cell suicide. Apoptosis is tidy and not usually associated with systemic manifestations of
inflammation.

THE END
Marc Imhotep Cray, M.D. Further study tools and resources on last slide. 34
Further study:
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Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of
Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012

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Cell Injury and Cell Death:

 Fat filled cells tend to compress cellular

Marc Imhotep Cray, M.D. 8

Intracellular Accumulations (1)

 In some cases, accumulations do not in

Marc Imhotep Cray, M.D. 11

Marc Imhotep Cray, M.D. 15

 Margination of chromatin-chromatin condensing around

 Dry gangrene is a form of coagulative necrosis

Marc Imhotep Cray, M.D. 19

Gas gangrene is characterized by formation of bubbles of gas in damaged

mitochondrial dysfunction, and

Marc Imhotep Cray, M.D. 22

Liquefactive necrosis in an abscess of the skin.

Marc Imhotep Cray, M.D. 24

 Process begins with release of activated digestive

 Enzymes attack cell membranes of fat cells

 Fat necrosis appears as a chalky white area of tissue

 Number of cells in tissues is tightly regulated by controlling rate of

Note: there are no gross structural changes involved with apoptosis

Marc Imhotep Cray, M.D. 28

Apoptosis is not a rare event large numbers of cells are continually

 Pathological cell death is more

Marc Imhotep Cray, M.D. 32

Marc Imhotep Cray, M.D. 33

Internet Pathology Laboratory for Medical Education

Marc Imhotep Cray, M.D. 35

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