Normal cells that are
subject to a damaging
stimulus may become
sublethally damaged. If the
stimulus abates, cells
recover but if it continues,
cells die and undergo
necrosis. Massively
damaging stimuli, e.g.
great heat or strong acids,
cause immediate death of
cells without any
sublethal damage. Certain
special stimuli can cause
pathological cell
death by switching on
apoptosis (see
Cell death,
• is one of the most crucial events in the
evolution of disease of any tissue or
organ.
Causes of cell injury
• External causes
– gross physical violence of an automobile
accident to
• internal endogenous causes,
– a subtle genetic mutation causing lack of a
vital enzyme that impairs normal metabolic
function.
Physical Agents.
• Prick of a thorn
• mechanical trauma,
• extremes of temperature (burns and deep
cold),
• sudden changes in atmospheric pressure,
• radiation,
• electric shock
Chemical Agents and Drugs
• Simple chemicals such as glucose or salt in
hypertonic concentrations may cause cell injury
directly or by deranging electrolyte balance
• Even oxygen, in high concentrations, is severely
toxic.
• Trace amounts of agents known as poisons,
such as arsenic, cyanide, or mercuric salts, may
destroy sufficient numbers of cells within
minutes to hours to cause death.
Chemical Agents and Drugs
• environmental and air pollutants,
• insecticides, and herbicides;
• industrial and occupational hazards, such
as carbon monoxide and asbestos;
• social stimuli, such as alcohol and narcotic
drugs;
• variety of therapeutic drugs.
Infectious Agents.
• viruses
• tapeworms. rickettsiae,
• bacteria,
• fungi,
Immunologic Reactions.
• immune system serves an essential
function in defense against infectious
pathogens,
• immune reactions may, in fact, cause cell
injury.
– The anaphylactic reaction to a foreign protein
or a drug is a prime example,
– reactions to endogenous self-antigens are
responsible for a number of autoimmune
disease
Oxygen Deprivation.
• Hypoxia is a deficiency of oxygen, which
causes cell injury by reducing aerobic
oxidative respiration.
• Hypoxia is an extremely important and
common cause of cell injury and cell
death.
hypoxia is inadequate oxygenation
• cardiorespiratory failure.
• Loss of the oxygen-carrying capacity of the blood, as in
anemia or
• carbon monoxide poisoning (producing a stable carbon
monoxyhemoglobin that blocks oxygen carriage),
• Depending on the severity of the hypoxic state, cells
may adapt, undergo injury, or die.
– if the femoral artery is narrowed, the skeletal muscle cells of the
leg may shrink in size (atrophy).
– a balance between metabolic needs and the available oxygen
supply may be achieved. More severe hypoxia induces injury
and cell death.
•
ischemia
• loss of blood supply from impeded arterial
flow or reduced venous drainage in a
tissue.
• Ischemia compromises the supply not only
of oxygen, but also of metabolic
substrates, including glucose (normally
provided by flowing blood).
• ischemic tissues are injured more rapidly
and severely than are hypoxic tissues.
Genetic Derangements.
• genetic injury may result in a defect as severe as
the congenital malformations associated with
Down syndrome, caused by a chromosomal
abnormality,
• subtle as the decreased life of red blood cells
caused by a single amino acid substitution in
hemoglobin S in sickle cell anemia.
– Variations in the genetic makeup can also influence
the susceptibility of cells to injury by chemicals and
other environmental insults.
Nutritional Imbalances.
• Protein-calorie deficiencies
• Deficiencies of specific vitamins
• Nutritional problems can be self-imposed
– as in anorexia nervosa or
– self-induced starvation.
• nutritional excesses have also become
important causes of cell injury.
•
Nutritional Imbalances.
• Excesses of lipids predispose to atherosclerosis,
• obesity is a manifestation of the overloading of
some cells in the body with fats.
• In addition to the problems of under nutrition and
over nutrition, the composition of the diet makes
a significant contribution to a number of
diseases.
• Metabolic diseases such as diabetes also cause
severe cell injury.
Reversible injury
• generalized swelling of the cell and its
organelles;
• blebbing of the plasma membrane;
• detachment of ribosomes from the endoplasmic
reticulum;
• and clumping of nuclear chromatin.
• Laminated structures (myelin figures) derived
from damaged membranes of organelles and
the plasma membrane appear
irreversible injury
•
•
•
•
increasing swelling of the cell;
disruption of cellular membranes;
swelling and disruption of lysosomes;
presence of large amorphous densities in
swollen mitochondria;
• and profound nuclear changes.
– The latter include nuclear codensation (pyknosis),
– followed by fragmentation (karyorrhexis)
– and dissolution of the nucleus (karyolysis).
• Laminated structures (myelin figures) become
more pronounced in irreversibly damaged cells.
Proverb of this week
There are two principal patterns
of cell death, necrosis and
apoptosis.
cell death the morphological
pattern of which is called
necrosis occurs after such
abnormal stresses as ischemia
and chemical injury, and it is
always pathological.
Apoptosis occurs when a cell dies
through activation of an internally
controlled suicide program.
Physiological
• It is designed to eliminate unwanted cells
during embryogenesis
• and in various physiologic processes, such
as involution of hormone-responsive
tissues upon withdrawal of the hormone.
Pathological apoptosis
• Immunological injuries
9 The sequential
ultrastructural changes seen
in necrosis (left) and
apoptosis (right).
In apoptosis, the initial
changes consist of nuclear
chromatin condensation and
fragmentation, followed by
cytoplasmic budding and
phagocytosis of the extruded
apoptotic bodies.
Feature
Necrosis
Apoptosis
Cell size
Enlarged (swelling)
Reduced (shrinkage)
Nucleus
Pyknosis → karyorrhexis
→ karyolysis
Fragmentation into nucleosome size fragments
Table 1-2. Features of Necrosis and Apoptosis
Plasma
membrane
Disrupted
Intact; altered structure, especially orientation of lipids
Cellular
contents
Enzymatic digestion; may
leak out of cell
Intact; may be released in apoptotic bodies
Adjacent
inflammation
Frequent
No
Physiologic
or pathologic
role
Invariably pathologic
(culmination of irreversible
cell injury)
Often physiologic, means of eliminating unwanted
cells; may be pathologic after some forms of cell
injury, especially DNA damage
Mechanism of injury
• The cellular response to injurious stimuli
depends on
– the type of injury,
– its duration, and
– its severity
• depend on
–
–
–


the type,
state,
and adaptability of the injured cell.
The cell's nutritional and hormonal status
and its metabolic needs.
Mechanism of injury
 How vulnerable is a cell, for example, to loss of
blood supply and hypoxia?
 The striated muscle cell is less vulnerable to
deprivation of its blood supply; not so the
striated muscle of the heart.
 Exposure of two individuals to identical
concentrations of a toxin, such as carbon
tetrachloride, may produce no effect in one and
cell death in the other.
 This may be due to genetic variations affecting
the amount and activity of hepatic enzymes that
convert carbon tetrachloride to toxic byproducts
targets of injury
• aerobic respiration involving mitochondrial
oxidative phosphorylation and production
of ATP;
• the integrity of cell membranes, on which
the ionic and osmotic homeostasis of the
cell and its organelles depends;
• protein synthesis;
• the integrity of the genetic apparatus of the
cell
Cellular and biochemical sites of damage in cell
injury
Mechanism of injury
• DEPLETION OF ATP
• MITOCHONDRIAL DAMAGE
• INFLUX OF CALCIUM AND LOSS OF
CALCIUM HOMEOSTASIS
• ACCUMULATION OF OXYGENDERIVED FREE RADICALS (OXIDATIVE
STRESS)
• DEFECTS IN MEMBRANE
PERMEABILITY
DEPLETION OF ATP
Functional and
morphologic
consequences
of decreased
intracellular
ATP during cell
injury.
INFLUX OF CALCIUM AND
LOSS OF CALCIUM
HOMEOSTASIS
INFLUX OF INTRACELLULAR
CALCIUM AND LOSS OF
CALCIUM HOMEOSTASIS
Sources and
consequences of
increased cytosolic
calcium in cell injury.
ATP, adenosine
triphosphate.
ACCUMULATION OF
OXYGEN-DERIVED FREE
RADICALS (OXIDATIVE
STRESS)
Reversible vs. irreversible cell
injury
• there are clearly many ways to injure a cell,
• the "point of no return," at which irreversible damage has
occurred, is still largely undetermined;
• thus, we have no precise cut-off point
• dissolution of the injured cell is characteristic of necrosis,
one of the recognized patterns of cell death.
• There is also widespread leakage of potentially
destructive cellular enzymes into the extracellular space,
with damage to adjacent tissues
Reversible vs. irreversible cell
injury
• leakage of intracellular proteins across the degraded cell
membrane into the peripheral circulation provides a
means of detecting tissue-specific cellular injury and
death using blood serum samples.
– Cardiac muscle, for example, contains a specific isoform of the
enzyme creatine kinase and of the contractile protein troponin;
– liver (and specifically bile duct epithelium) contains a
temperature-resistant isoenzyme of the enzyme alkaline
phosphatase;
– and hepatocytes contain transaminases.
– Irreversible injury and cell death in these tissues are
consequently reflected in increased levels of such proteins in the
blood.
Nuclear changes in necrosis
Necrosis
• Necrosis refers to a spectrum of morphologic
changes that follow cell death in living tissue,
• resulting from the progressive degradative
action of enzymes on the lethally injured cell
(cells placed immediately in fixative are dead but
not necrotic
• Necrotic cells are unable to maintain membrane
integrity and their contents often leak out.
• This may elicit inflammation in the surrounding
tissue.
Necrosis
• The morphologic appearance of necrosis is the result of
– denaturation of intracellular proteins and
– enzymatic digestion of the cell.
• The enzymes are derived either from the lysosomes of
the dead cells themselves, in which case the enzymatic
digestion is referred to as autolysis,
• or from the lysosomes of immigrant leukocytes, during
inflammatory reactions.
• These processes require hours to develop, and so there
would be no detectable changes in cells ,
for example, a myocardial infarct
caused sudden death.
• The only telling evidence might be
occlusion of a coronary artery.
• The earliest histologic evidence of
myocardial necrosis does not become
manifest until 4 to 12 hours later,
• but cardiac-specific enzymes and proteins
that are released from necrotic muscle can
be detected in the blood as early as 2
hours after myocardial cell death.
Necrosis
• Necrotic cells show increased eosinophilia
– Loss of ribosomes responsible for the of the normal basophilia
imparted by the RNA in the cytoplasm
– increased binding of eosin to denatured intracytoplasmic
proteins
• The necrotic cell may have a more glassy homogeneous
appearance than that of normal cells,
– mainly as a result of the loss of glycogen particles.
• the cytoplasm becomes vacuolated and appears motheaten.
– enzymes have digested the cytoplasmic organelles,
• Finally, calcification of the dead cells may occur.
Necrosis
• myelin figures
– Dead cells may ultimately be replaced by
large, whorled phospholipid masses
• These phospholipid precipitates are then
either phagocytosed by other cells or
further degraded into fatty acids;
• calcification of such fatty acid residues
results in the generation of calcium soaps.
Necrosis
• Nuclear changes appear in the form of one of three
patterns,
– due to nonspecific breakdown of DNA
• A pattern (also seen in apoptotic cell death) is pyknosis,
characterized by nuclear shrinkage and increased
basophilia.
• A pattern, known as karyorrhexis, the pyknotic or
partially pyknotic nucleus undergoes fragmentation.
• A pattern The basophilia of the chromatin may fade
(karyolysis), a change that presumably reflects DNase
activity.
• With the passage of time (a day or two), the nucleus in
the necrotic cell totally disappears.
Once the necrotic cells have
undergone the early alterations,
the mass of necrotic cells may
have several morphologic
patterns.
Necrosis
• . coagulative necrosis When
denaturation is the primary pattern
• liquefactive necrosis
• dominant enzyme digestion,
• caseous necrosis
• fat necrosis
– in special circumstances,
Coagulative necrosis
• preservation of the basic outline of the
coagulated cell for a span of at least some
days
• The affected tissues exhibit a firm texture.
• the injury or the subsequent increasing
intracellular acidosis has denatured not
only structural proteins but also enzymes
• Blocking of the proteolysis of the cell.
Coagulative necrosis
• The heart is an excellent example
– acidophilic, coagulated, anucleate cells may persist for weeks.
– the necrotic myocardial cells are removed by fragmentation and
phagocytosis of the cellular debris
– scavenger leukocytes and by the action of proteolytic lysosomal
enzymes brought in by the immigrant white cells.
• The process of coagulative necrosis, with preservation of
the general tissue architecture, is characteristic of
hypoxic death of cells in all tissues except the brain
Micrograph
shows a
section of
liver
damaged by
the
poison
paraquat.
Normal liver
cells contrast
with injured
cells, which
are swollen,
pale and
vacuolated.
The normal
Cells
cell
cytoplasm is
pink with a a
decrease of
purple, the
purple
coloration
(basophilia)
being due to
ribosomes,
mainly on the
RER
Damaged cells .
With swelling of
ER, ribosomes
become detached
and reduced in
number, so the
normal purple
cytoplasmic tint is
reduced.
• Apoptosis is a more orderly process of cell death in which there is
individual cell necrosis, not necrosis of large numbers of cells. liver
cells are dying individually (arrows) from injury by viral hepatitis. The
cells are pink and without nuclei.
• Here is myocardium in which the cells are dying. The nuclei of the
myocardial fibers are being lost. The cytoplasm is losing its
structure, because no well-defined cross-striations are seen.
•
This is an example of coagulative necrosis. This is the typical pattern with ischemia
and infarction (loss of blood supply and resultant tissue anoxia). Here, there is a
wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the
kidney.
•
Microscopically, the renal cortex has undergone anoxic injury at the left so that the
cells appear pale and ghost-like. There is a hemorrhagic zone in the middle where
the cells are dying or have not quite died, and then normal renal parenchyma at the
far right. This is an example of coagulative necrosis
Figure 1-19 Coagulative. A, Kidney infarct exhibiting
coagulative necrosis, with loss of nuclei and clumping of
cytoplasm but with preservation of basic outlines of
glomerular and tubular architecture.
Two large infarctions (areas of coagulative necrosis) are
seen in this sectioned spleen. etiology of coagulative
necrosis is usually vascular with loss of blood supply,
the infarct occurs in a vascular distribution.
Thus, infarcts are often wedge-shaped with a base on the
organ capsule.
Cell Injury
•
The contrast between normal adrenal cortex and the small pale infarct is good. The
area just under the capsule is spared because of blood supply from capsular arterial
branches. This is an odd place for an infarct, but it illustrates the shape and
appearance of an ischemic (pale) infarct well
Liquefactive necrosis
• is characteristic of focal bacterial or, occasionally, fungal
infections, because microbes stimulate the accumulation
of inflammatory cells
• For obscure reasons, hypoxic death of cells within the
central nervous system often evokes liquefactive
necrosis.
• Whatever the pathogenesis, liquefaction completely
digests the dead cells.
• The end result is transformation of the tissue into a
liquid viscous mass.
• If the process was initiated by acute inflammation the
material is frequently creamy yellow because of the
presence of dead white cells and is called pus.
A focus of liquefactive necrosis in the kidney caused by
fungal infection. T
he focus is filled with white cells and cellular debris,
creating a renal abscess that obliterates the normal
architecture.
liquefactive necrosis in the kidney caused by fungal
infection.
The focus is filled with white cells and cellular debris,
creating a renal abscess that obliterates the normal
architecture.
• The liver shows a small abscess here filled with many
neutrophils. This abscess is an example of liquefactive
necrosis.
• Grossly, the cerebral infarction at the upper left here
demonstrates liquefactive necrosis. Eventually, the
removal of the dead tissue leaves behind a cavity.
• As this infarct in the brain is organizing and being resolved, the
liquefactive necrosis leads to resolution with cystic spaces.
•
This is liquefactive necrosis in the brain in a patient who suffered a "stroke"
with focal loss of blood supply to a portion of cerebrum. This type of
infarction is marked by loss of neurons and neuroglial cells and the
formation of a clear space at the center left.
gangrenous necrosis
• It is usually applied to a limb, generally the
lower leg, that has lost its blood supply
and has undergone coagulative necrosis.
•
•
This is gangrene, or necrosis of many tissues in a body part. In this case, the toes
were involved in a frostbite injury. This is an example of "dry" gangrene in which there
is mainly coagulative necrosis from the anoxic injury.
wet gangrene).
• When bacterial infection is superimposed,
coagulative necrosis is modified by the
liquefactive action of the bacteria and the
attracted leukocytes
• This is gangrene of the lower extremity. In this case the term "wet"
gangrene is more applicable because of the liquefactive component
from superimposed infection in addition to the coagulative necrosis
from loss of blood supply. This patient had diabetes mellitus.
Caseous necrosis
• a distinctive form of coagulative necrosis,
encountered most often in foci of
tuberculous infection
• caseous is derived from the cheesy white
gross appearance of the area of necrosis
A tuberculous lung with a large area of caseous necrosis. The caseous debris is yellowwhite and cheesy.
•
This is the gross appearance of caseous necrosis in a hilar lymp node infected with tuberculosis.
The node has a cheesy tan to white appearance. Caseous necrosis is really just a combination of
coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation.
•
This is more extensive caseous necrosis, with confluent cheesy tan granulomas in the upper portion of this lung in
a patient with tuberculosis. The tissue destruction is so extensive that there are areas of cavitation (cystic spaces)
being formed as the necrotic (mainly liquefied) debris drains out via the bronchi.
• Microscopically, caseous necrosis is characterized by acellular pink
areas of necrosis, as seen here at the upper right, surrounded by a
granulomatous inflammatory process.
microscopic examination,
• the necrotic focus appears as amorphous
granular material
• looks like composed of fragmented,
coagulated cells
• amorphous granular debris enclosed
within a distinctive inflammatory border
known as a granulomatous reaction
• Unlike coagulative necrosis, the tissue
architecture is completely obliterated.
Fat necrosis
• acute pancreatitis
• activated pancreatic enzymes escape from
acinar cells and ducts,
• the activated enzymes liquefy fat cell
membranes,
• the activated lipases split the triglyceride
contained within fat cells.
• The released fatty acids combine with calcium to
produce grossly visible chalky white areas (fat
saponification),
•
This is fat necrosis of the pancreas. Cellular injury to the pancreatic acini leads to release of
powerful enzymes which damage fat by the production of soaps, and these appear grossly
as the soft, chalky white areas seen here on the cut surfaces.
Foci of fat necrosis with saponification in the mesentery. The areas of white chalky
deposits represent calcium soap formation at sites of lipid breakdown.
Fat necrosis
• the surgeon and the pathologist can
identify the lesions
• focal areas of fat destruction, typically
occurring as a result of release of
activated pancreatic lipases into the
substance of the pancreas and the
peritoneal cavity.
•
Microscopically, fat necrosis is seen here. Though the cellular outlines
vaguely remain, the fat cells have lost their peripheral nuclei and their
cytoplasm has become a pink amorphous mass of necrotic material.
Fat necrosis/ On histologic
examination,
• the necrosis takes the form of foci of
shadowy outlines of necrotic fat cells,
• with basophilic calcium deposits,
• surrounded by an inflammatory reaction.
Final outcome
• in the living patient, most necrotic cells and their
debris disappear
– enzymatic digestion
– fragmentation,
– phagocytosis of the particulate debris by leukocytes.
• If necrotic cells and cellular debris are not
promptly destroyed and reabsorbed, they tend to
attract calcium salts and other minerals and to
become calcified.
• This phenomenon, called dystrophic
calcification,
Fibrinoid necrosis
• is a term used to describe the
•
histological appearance of arteries in
cases of vasculitis
• (primary inflammation of vessels) and
hypertension,
•
when fibrin is deposited in the
damaged necrotic vessel wall
•
The small intestine is infarcted. The dark red to grey infarcted bowel contrasts with
the pale pink normal bowel at the bottom. Some organs such as bowel with
anastomosing blood supplies, or liver with a dual blood suppy, are hard to infarct.
This bowel was caught in a hernia and the mesenteric blood supply was constricted
by the small opening to the hernia sac.
Haemorrhagic necrosis
• describes dead tissues that are suffused
with extravasated red cells.
• This pattern is
–
seen particularly when cell death is due to
blockage of
–
the venous drainage of a tissue, leading to
massive congestion by blood and to
subsequent arterial failure of perfusion
Gummatous necrosis
•
tissue is firm and rubbery. As in caseous
necrosis the dead
•
cells form an amorphous proteinaceous mass
•
•
no original architecture can be seen histologically.
However, the gummatous pattern is restricted
to describing necrosis in the spirochaetal
infection
•
syphilis
Patterns of reversible cell injury
• cellular swelling
• fatty change.
Cellular swelling
• Cellular swelling appears whenever cells
are incapable of maintaining ionic and fluid
homeostasis
• and is the result of loss of function of
plasma membrane energy-dependent ion
pumps.
Fatty change
• Fatty change occurs in hypoxic injury and
various forms of toxic or metabolic injury.
• It is manifested by the appearance of small or
large lipid vacuoles in the cytoplasm and occurs
in hypoxic and various forms of toxic injury.
• It is principally encountered in cells involved in
and dependent on fat metabolism, such as the
hepatocyte and myocardial cell.
3 Reactive oxygen metabolites damage cells