PATHOLOGY PHT218
Unit 3
CELL INJURY & CELL DEATH
Overview of Cellular Injury
• Cells actively control the composition of their immediate
environment and intracellular surrounding within a narrow range
of physiological parameters (“homeostasis”)
• Under physiological stresses or pathological stimuli (“injury”),
cells can undergo adaptation to achieve a new steady state that
would be compatible with their viability in the new environment.
• Cellular injury may be a reversible process, in which case the
cells can recover their normal function, or it may be irreversible
and lead to cell death and necrosis
• If the injury is too severe (“irreversible injury”), the affected
cells die.
Overview of Cellular Injury
Reversible and Irreversible Cell Injury
Outcomes from cell injury depend upon:
1. Type of injury
2. Severity of the injury
3. Duration of the injury
4. Type of cell being injured-Some cell types sustain injury better
than others; some tissues (e.g. liver) have a capacity to
regenerate.
Causes of Cellular Injury (‫)أسباب اإلصابة الخلوية‬
1. Hypoxia (oxygen deficiency) and ischemia (blood flow deficiency)
2. Physical injury
• Mechanical trauma
• Temperature extremes (burn injury, frostbite )
• Electrical current
3. Chemical injury
• Chemicals, toxins, heavy metals, solvents, smoke,
• pollutants, drugs, gases
4. Radiation injury
• Ionizing radiation — gamma rays, X rays
• Non-ionizing radiation — microwaves, infrared, laser
5. Biologic agents
• Bacteria, viruses, parasites
6. Nutritional injury
• Malnutrition: Protein deficiency
• Over nutrition: Obesity
More Energy
Ionizing Radiation
Less Energy
Non -ionizing Radiation
Mechanisms of Cellular Injury
Although the causes of cellular injury are many, the underlying
mechanisms of cellular injury usually fall into one of two categories:
1. Uncontrolled free radical injury
2. hypoxic injury (impaired oxygen delivery or utilization)
.
Primary Site of Impact
1) Oxidative phosphorylation - ATP generation
2) Membrane integrity - osmotic pump
3) Protein synthesis - cell repair
4) Nuclear integrity - direction of cell functions
Free Radical Injury
• Free radicals are highly reactive chemical species that have one or
more unpaired electrons in their outer shell.
• Examples of free radicals include superoxide (O2−), hydroxyl
radicals (OH−) and hydrogen peroxide (H2O2).
• Free radicals are generated as by-products of normal cell
metabolism and are inactivated by free radical–scavenging
enzymes within the body such as catalase and glutathione
peroxidase
• When excess free radicals are formed from exogenous sources or
the free radical protective mechanisms fail, injury to cells can occur.
Oxygen molecule and generation of free radical
Free Radical Injury
• Free radicals are highly reactive and can injure cells through:
1. Peroxidation of membrane lipids
2. Damage of cellular proteins
3. Mutation of cellular DNA
• Exogenous sources of free radicals include tobacco smoke, organic
solvents, pollutants, radiation and pesticides.
• Free radical injury has been implicated as playing a key role in the
normal aging process as well as in a number of disease states such
as diabetes mellitus, cancer, atheroscelrosis, Alzheimer’s disease
and rheumatoid arthritis.
Effects of free radical cell injury
Hypoxic Cell Injury
• Hypoxia is a lack of oxygen in cells and tissues that generally
results from ischemia.
• During periods of hypoxia, aerobic metabolism of the cells begins
to fail.
• This loss of aerobic metabolism leads to dramatic decreases in
energy production (ATP) within the cells. Hypoxic cells begin to
swell as energy-driven processes (such as ATP-driven ion pumps)
begin to fail.
• The pH of the extracellular environment begins to decrease as waste
products (such as lactic acid, a product of anaerobic metabolism)
begin to accumulate.
Hypoxic Cell Injury
• The cellular injury process may be reversible, if oxygen is quickly
restored, or irreversible and lead to cell death.
• Certain tissues such as the brain are particularly sensitive to
hypoxic injury. Death of brain tissues can occur only 4 to 6 minutes
after hypoxia begins.
• The loss of ionic balance in hypoxic cells can also lead to the
accumulation of intracellular calcium, which is normally closely
regulated within cells.
• There are a number of calcium-dependent protease enzymes present
within cells that become activated in the presence of excess calcium
and begin to digest important cellular constituents.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Unit 3 Objectives
Define homeostasis of cells?
Write the types of cell injury?
Write the characteristics of reversible injury?
Write the characteristics of irreversible injury?
Write the factors on which the outcome of disease depends on?
Define the different cause or etiology of disease?
Name the 2 main mechanisms of cellular injury?
What are free radicals? Name the free radicals found in the body?
Name the free radical scavenging enzyme?
How does the free radical bring about cell injury?
Name the important disease caused as a result of free radical
injury?
Write the mechanism of hypoxic cell injury?
What happens when there is loss of ionic balance in hypoxic
cells?
Cell Death
Cell Death
• Like disease, cell death may be caused by
• internal (intrinsic) factors that limit the cell's life
span or
• external (extrinsic) factors that contribute to cell
damage and aging.
• When a stressor is severe or prolonged, the cell
can no longer adapt and it dies.
• Cell death, or necrosis, may manifest in different
ways, depending on the tissues or organs
involved.
Cell Death
Apoptosis :Individual Cell Death
• Apoptosis is genetically programmed cell
death.
• common event in some regenerating
tissues: such as skin and gut epithelium
and during embryogenesis
• Not a typical event in developed tissues
such as brain
• Becomes a serious occurrence when
many cells are involved in such organs as
the liver
Examples of Physiologic Apoptosis
(A) separation of webbed
fingers and toes in embryo,
(B) development of neural
connections,
(C) removal of cells from
intestinal villa, and
(D) removal of senescent
(old) blood cells.
Examples of Pathologic Apoptosis
1. Irradiated tissues
2. Viral infections e.g. Viral Hepatitis
3. Hormone-dependent atrophy of tissue (e.g.,
endometrial cell breakdown after withdrawal
of estrogen and progesterone in the menstrual
cycle)
4. Death of tumor cells by cytotoxic T cells
Types of Necrosis
1) Liquefactive necrosis: in brain,
2) Caseous necrosis: Infection with Mycobacterium
tuberculosis
3) Fat necrosis: Liver and pancreas
4) Coagulative necrosis: Necrosis of kidney, liver, or
heart muscle
5) Gangrene: Necrosis of an appendage, usually
limbs
Necrosis
1. Liquefactive necrosis
occurs when a lytic (dissolving) enzyme liquefies
necrotic cells.
• It is generally associated with abscess formation
• Typically, liquefaction necrosis occurs in brain
infarcts and pancreatic necrosis.
• Liquefaction by leukocytic enzymes is called
suppuration, and the resultant fluid is called pus.
Liquefactive necrosis (brain abscess), ovine
2. In caseous necrosis,
the necrotic cells disintegrate but
the cellular pieces remain
undigested for months or years.
*This type of necrotic tissue gets its
name from its crumbly, cheese- like
(caseous) appearance.
It commonly occurs in lung tuberculosis.
caseous necrosis
Necrosis
3. In
fat necrosis,
*enzymes called lipases break down intracellular
triglycerides into free fatty acids.
These free fatty acids combine with sodium,
magnesium, or calcium ions to form soaps.
The tissue becomes opaque and chalky white.
It is characteristic of tissues adjacent to pancreatic
necrosis.
4. Coagulative necrosis
*is the most common form of necrosis in
cells without large numbers of lysosomes.
*Commonly occurs when the blood supply to
any organ (except the brain) is interrupted
(ischemia).
*It typically affects the kidneys, heart, and
adrenal glands.
Lytic (lysosomal) enzyme activity in the cells
is inhibited, so that the necrotic cells
maintain their shape, at least temporarily.
fat necrosis
Coagulative
Necrosis in liver
Coagulative necrosis
Necrosis
• 5- Gangrenous necrosis,
• a form of coagulative necrosis, typically results
from a lack of blood flow and is complicated by
an overgrowth and invasion of bacteria.
• It commonly occurs in the lower legs as a result
of arteriosclerosis or in the gastrointestinal tract(
GIT).
Necrosis
Gangrene can occur in one of three forms: dry, moist (or wet), or gas.
1. Dry gangrene occurs when bacterial invasion is minimal. It's
marked by dry, wrinkled, dark brown or blackened tissue on an
extremity.
2. Moist (or wet) gangrene develops with liquifactive necrosis that
includes extensive lytic activity from bacteria and white blood
cells to produce a liquid center in an area of tissue. It can occur in
the internal organs as well as the extremities.
3. Gas gangrene develops when anaerobic bacteria of the genus
Clostridium infect tissue. It's more likely to occur with severe
trauma and may be fatal. The bacteria release toxins that kill
nearby cells and the gas gangrene rapidly spreads. Release of gas
bubbles from affected muscle cells indicates that gas gangrene is
present.
Cell Death
Difference between Apoptosis & Necrosis
Apoptosis
Regulation
Genetic programmed
Control
Cell shape
Plasma membrane
integrity
Cellular process
Controlled
Skrinkage, condensed
Necrosis
Ischemia, trauma or ATP
depletion
Uncontrolled
Swelling
Maintained
Collasped
Budding
Packaged in apoptoic
bodies
Fragmentation,
chromatin condensation
ATP required
Absent
Caspase
Blebbing ‫فقاعة‬
Leakage to extracellular
fluid
Cellular content
DNA
Energy
Inflammatory response
Mediator
No fragmentation
Not required
Present
Caspase-independent
Pathology of Necrosis OR Necrotic Changes
When a cell dies, enzymes inside the cell are released and start to
dissolve cellular components. This triggers an acute inflammatory
reaction in which white blood cells migrate to the necrotic area and
begin to digest the dead cells. At this point, the dead cells —
primarily the nuclei — begin to change morphologically in one of
three ways:
Pyknosis, in which the nucleus shrinks, becoming a dense mass of
genetic material with an irregular outline.
Karyorrhexis, in which the nucleus breaks up, strewing pieces of
genetic material throughout the cell.
Karyolysis, in which hydrolytic enzymes released from intracellular
structures called lysosomes simply dissolve the nucleus.
Necrotic Changes
Enzyme Markers of Cell Death
Unit 3 Objectives
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Define apoptosis?
Give examples of physiological apoptosis?
Give examples of pathological apoptosis?
Name the types of Necrosis and the organs affected by them?
What is liquefactive necrosis?
Which type of necrosis is associated with abscess formation?
Where would you find liquefactive necrosis?
What is caseous necrosis?
Which type of necrosis there cheese like appearance?
Define fat necrosis?
In which type of necrosis the tissue becomes chalky white?
Which is the most common form of necrosis?
Unit 3 Objectives
13.
14.
15.
16.
17.
18.
19.
20.
In which type of cells would you find fat necrosis?
Define coagulative necrosis?
What is gangrenous necrosis?
Define the 3 forms of gangrene?
Write the difference between apoptosis and necrosis?
Write about the necrotic changes in the nucleus?
What is pyknosis, karyolysis, and karyorrhexis
Name the Enzyme Markers of Cell Death?