Cell injury:- a set of biochemical and morphologic changes that occur when

the state of
Homeostasis is perturbed by adverse influences
when cell injury occurs:1:- when the cell is no longer able to adapt with the stress.
2:- when the cell is exposed to damaging agents.
3:- suffer from intrinsic abnormalities (damaged DNA or Protein).
Causes of cell injury:1:- Oxygen Deprivation
a) Hypoxia, (oxygen deficiency)
b) Ischemia (Complete block in the oxygen supply in other words the cell
energy generation can't be continued because blockage of blood supply
will not block oxygen only but it will stop supply of other substances that
contributes glycolysis, so even anaerobic respiration will be stopped too
after consumption of necessary substrates)
so ischemia is faster and more severe than hypoxia.
In case of ischemic myocardial cells the heart will stop contraction with 60
seconds. But in hypoxic myocardial cells, cells will undergo ATP depletion,
swelling of membranes including mitochondria and ER, increased
concentration of water, NA+ and Cl- and a decreased concentration of K+.
In both cases if blood and oxygen supply return, myocardial cells will
restore all of the changes back again.
clinical examples of hypoxia and ischemia:angina:- is a partial blockage of coronary arteries and in different words
inadequate oxygen and blood supply to cardiac muscles, if any stress is
performed on cardiac muscles (EX running) the functional demands of the
heart will increase resulting in reversible cell injury ( not irreversible cell
injury because the patient will stop running because of a severe pain in
the chest), if the situation worsen the injury will become irreversible and
myocardial cells will undergo necrosis.
Diagnosis:the patient will suffer from a pain in the chest and the left shoulder.
* NOTE:- enzymes test (CDK , LDH , TROPONIN) will be useless because
myocytes are still alive.
We give the patient sublingual nitroglycerin (a strong vasodilator to
remove the stress by increasing blood supply)
ECG will show a depression in ST period if the artery is still blocked or if
ECG shows depression in ST period through exercise.
Myocardial infarction (MI):- is full blockage of coronary arteries in different
words no oxygen or blood supply to cardiac muscles, cardiac cells will stop
contraction in 60 seconds and brain cells will be dead within 4-5 minutes
(cardiac muscles can withstand oxygen deprivation for 20-30 minutes) so
the patient will die because of inability of the cardiac muscles to deliver
blood to the brain. So brain cells die not cardiac muscles. This
proportionally depends in the area of infarction.

Diagnosis:enzymatic test will be use full because myocardial cells died and their
levels will be high in blood.
ischemia reperfusion injury:in certain circumstances, the restoration of blood flow to ischemic but
alive tissues results, in the death of cells that are not irreversibly injured
by several mechanism:a) during oxygenation a new damage may arise from generation of ROS
from parenchymal and endothelial cells and from leukocytes (because of
mitochondrial damage and the activity of oxidases and compromising of
antioxidant because of ischemia).
b) The inflammation that's caused by the inflammation may be increased
by the reperfusion because of increased influx of leukocytes and plasma
proteins. (Products of leukocytes and activation of complement system)
*ischemia and hypoxia can result from:1) Inadequate supply of oxygen (e.g., low concentration of oxygen in air at
high altitude)
2) Obstruction of airways (e.g., strangulation and drowning)
3) Inadequate oxygenation of blood in the lungs (e.g., lung diseases)
4) Inadequate oxygen transport in blood (e.g., anemia)
5) Inadequate perfusion of blood in the tissues (ischemia resulting from
heart failure)
6) Inhibition of cellular respirationthat is, blocked utilization of oxygen
(e.g., cyanide
poisoning of respiratory enzymes)
2:- Chemical Agents
An increasing number of chemical substances that can injure cells are
being recognized ( Ex. CO ) even innocuous substances such as glucose,
salt, or even water can cause cell injury and death.
Chemicals induce cell injury by 2 different mechanisms:a) some chemicals act directly by combining with a critical molecular
component or cellular organelle. (such as mercuric chloride that binds to
sulfhydryl groups inhibiting ATP dependent transporters and increasing
membrane permeability)
b) other chemicals must be first metabolized (cytochrome P-450 in the
smooth ER) then act on target cell (such as carbon tetrachloride (CCl4) is
converted to the toxic free radical (CCl3) damaging cellular membranes
(by phospholipid peroxidation will be explained next). And finally resulting
in fatty liver (liver steatosis)).
3:- infectious agents (viruses)
4:- Immunologic Reactions (Ex. Autoimmune diseases)
5:- Genetic Factors ( Ex. Xeroderma pegmentosa or any other genetic
disorder)
6:- Nutritional Imbalances (Ex. Proteincalorie insufficiency, atherosclerosis
and type 2 diabetes mellitus)
inadequate or excessive nutritional supply to the tissue or the cell will
affect its ability to maintain the homeostasis and will perform a stress, cell

injury and even death.

7:- Physical Agents (Ex. Trauma)
8:- aging
cell response to injurious stimuli depends on:1) type of injury
2) duration
3) severity
4) cell type and it's adaptability
5) nutritional status
6) genetic makeup of individuals (polymorphism) (Ex. Cytochrome p450)
cell injury could be :- 1) reversible
2) irreversible
reversible cell injury:include morphological, functional changes and structural abnormalitiesat
this stage the cell can adapt by several types of mechanisms and can get
into its normal state once the stress is removed. And there's no severe
damage to membranes and nucleus.
Intracellular changes associated with reversible injury:1) plasma membrane alterations (blebbing, blunting, or distortion of
microvilli).
2) Mitochondrial swelling and the appearance of the amorphous densities
3) dilation of the ER with detachment of ribosomes and dissociation of
polysomes.
4) Nuclear alterations, with clumping of chromatin.
5) Sometimes appearance of myelin figures (phospholipid masses), which
are derived from damaged cellular organelles membranes such as
mitochonderia (more prominent in necrotic cells than during reversible
injury).
Characteristics of reversible cell injury:1:- Cellular swelling
2:- Fatty change
1:- Cellular swelling (is the result of failure of energy-dependent ion pumps
in the plasma membrane, leading to an inability to maintain ionic and fluid
homeostasis) and its the first manifestation of cell injury, when it affects
many cells of the organ this will cause increased size and weight of the
organ, and it may include swelling of cellular organelles such as
mitochondria and ER (swelling of the ER known as hydropic change or
vacuolar degeneration.)
ATP depletion:ATP is mainly produced by oxidative phosphorylation reactions of ADP
during reduction of oxygen in the electron transport system of
mitochondria, in addition to glycolytic pathway that can produce ATP in
the absence of oxygen using glucose derived either from the circulation or
from the hydrolysis of intracellular glycogen.
in case of ATP depletion the cell will partially or fully stop its function to
use the available ATP in cell maintaining ( to keep physiologic balance) to

keep its existence.

The main causes of ATP depletion are: 1) decreased blood supply and nutrients
2) mitochondrial damage
3) actions of some toxins such as cyanide.
Consequences of ATP depletion:1:- ATP depletion will decrease or even stop the activity of NA+\K+ pump,
resulting in intracellular accumulation of sodium and efflux of potassium.
The net gain of solute is accompanied by iso-osmotic gain of water,
causing cell swelling and dilation of the ER.
2:- the cell will undergo a compensatory mechanisms such as anaerobic
glycolysis leading to accumulation of lactic acid lowering cellular PH and
the stored glycogen will be rapidly depleted resulting in decreased activity
of cellular enzymes.
3:- Failure of ATP-dependent Ca2+ pumps leads to influx of Ca2+, with
damaging effects on numerous cellular components.
4:- prolonged depletion of ATP causes detachment of ribosomes from RER,
dissociation of polysomes into monosomes and reduction of protein
synthesis, this will absolutely damage cellular organelles membrane such
as lysosomes and mitochondria.
And the cell will undergo necrosis except in a special case of
mitochondria will be explained next)

Mitochondrial Damage and Dysfunction:a) Normal mitochondrion has a double membrane and cristae.
b) Swollen mitochondrion. The water accumulates in the internal space
and between the inner and the outer mitochondrial membrane.
c) Rupture of the mitochondrion. This may be associated with calcification
of the remnant membranes.
d) Myelin figure forms from whorls of mitochondrial membranes.
e) Calcification of mitochondrial remnants.

Reversible changes of mitochondria:swelling

irreversible changes of mitochondria:a) Rupture of double membrane
b) Fragmentation
c) Myelin figures (concentric curling up of damaged membranes)
d) Calcification
Damaged mitochondria are taken up into autophagosomes and digested
damage and dysfunction of mitochondria consequences:a) failure of ATP production (oxidative phosphorylation) leads to
progressive depletion of ATP.
b) Abnormal oxidative phosphorylation leading to formation of ROS.
c) Damage of mitochondria often results in formation of high-conductance
channel in the mitochondrial membrane, called the mitochondrial
permeability transition pore resulting in loss of mitochondrial membrane
potential and changes of PH leading to further formation of ROS.
d) Releasing of proteins (pro-apoptotic) contained in the mitochondria
leading apoptotic death of the cell.

What's the role of calcium in cell injury:intracellular calcium concentration is maintained byATP-dependent
calcium transporters such as Ca\Mg pump
intracellular concentration of calcium is 10000 times lower than the extra
cellular calcium as well as mitochondria and ER.
Injurious cells will have increased concentration of free calcium in their
cytoplasm derived from ECM, mitochondria and RER.

Ionized calcium will activate several enzymes:1:- lytic ATPase:- Degrades ATP and further reduces the energy stores.
2:- Phospholipases: These enzymes remove phospholipids from the plasma
or mitochondrial
Membranes, further impairing their function.
3:- Proteases: These enzymes degrade cell membrane or cytoskeletal
proteins.
4:- Endonucleases: These enzymes act on the RNA and DNA.
All of these changes are initially reversible, but if prolonged or intensified
they may lead to irreversible cell injury.
Increased intracellular Ca2+ levels may also induce apoptosis, by direct
activation of caspases and by increasing mitochondrial permeability ( will
be explained later on )

accumulation of oxygen derived free radicals:free radicals:- are chemical species with a single unpaired electron in an
outer orbital ( they have 3 electrons in their out orbit). And are extremely
unstable
ROS (reactive oxygen species):- are a type of oxygenderived free radical.
ROS are naturally produced by the cell in normal metabolism (during
reduction oxidation reactions during mitochondrial respiration and energy
generation) in small amounts.
how the cell produce ROS naturally:during reduction oxidation reactions during mitochondrial respiration and
energy generation the cell produce ROS by adding 4 electrons to oxygen
to generate water
but when oxygen is not fully reduced the outcome will be ROS such as:Superoxide (O2_)
Hydrogen peroxide (H2O2)
Hydroxyl radical (OH1)

Superoxide is inactivated by superoxide dismutase and hydrogen peroxide

by catalase ( in peroxisomes ) and glutathione peroxidase ( in cytoplasm ).
Vitamin E and vitamin C also have antioxidant activity.
Superoxide (O2-) superoxide dismutase hydrogen
peroxideH2O2 fenton reaction Hydroxyl radical (OH)
leukocytes such as neutrophils and macrophages produce ROS in
phagosomes and phagolysosomes as a defending mechanism against
infections and this is known as respiratory burst.
Superoxide (O2-) superoxide dismutase hydrogen
peroxideH2O2 myeloperoxidase hypochlorite
( NO ) nitric oxide is also produced by leukocytes and other cell that can
react with superoxide to form peroxynitrite.
Oxidative stress:- excess amount of ROS in the cell.
Circumstances that increase ROS production:1) absorption of ionizing radiation that have the ability to hydrolyse water
into hydroxyl (OH) and hydrogen (H).
2) Metabolism of some exogenous chemicals (Ex.CCL4)
3) inflammation (by leukocytes)
how free radicals cause cell injury:1) Lipid peroxidation: This process leads to membrane damage.
2) Cross-linking of proteins: This leads to inactivation of enzymes.
3) DNA breaks: This injury may block DNA transcription and cause
mutations.

Defects in membrane permeability:increased membrane permeability leads to membrane damage and is a

feature of necrosis.
What are the factors that affect membrane permeability:1) decreased phospholipid synthesis:- associated with ATP depletion.

2) Increased phospholipid break down:- associated with increased Ca++

levels in the cytoplasm that activates endogenous phospholipases.
3) ROS:- associated with lipid peroxidation.
4) Cytoskeletal abnormalities:- associated with increased Ca++ levels in
the cytoplasm that activates proteases.
5) Lipid break down products:- products of lipid break down such as:a) unesterified free fatty acid
b) acyl carnitine
c) lysophospholipids
accumulates in injured cell affecting it's permeability.
And the cell will undergo necrosis.
Damage to DNA and proteins:if the damage in the DNA is too severe that the cell can't repair it the cell
suicides by apoptosis by accumulation of misfolded proteins in the
cytoplasm.
2:- Fatty change (occurs in hypoxic injury and in various forms of toxic or
metabolic injury and is manifested by the appearance of small or large
lipid vacuoles in the cytoplasm) It is principally encountered in cells
participating in fat metabolism (e.g., hepatocytes, myocardial cells)
what determines the irreversibility of the cell injury :1:- the inability to correct mitochondrial dysfunction (lack of oxidative
phosphorylation and ATP generation)
2:- profound disturbances in membrane function ( such as in lysosomal
membrane )

Irreversible cell injury (cell death):when the stress becomes severe and the cell can't deal with it anymore
the injury becomes irreversible and the cell suicides or in different words it
kills itself.
Examples of irreversible cell injury:Myocardial cell injury: loss of heart contraction
Motor neuron: muscle paralysis
Islets of Langerhans: diabetes
There're 2 different types of cell death:-1) Necrosis.
2) Apoptosis.
1:- Necrosis:1) localized death of cells, tissues, organs, or parts of the body in a living
organism.
2)is a type of cell death that is associated with loss of membrane integrity
and leakage of cellular contents into the ECM as a result of cell membrane
rupture or cellular organelles membrane rupture such as lysosome, so
digestive enzyme will leak out of it and digest the cellular contents
including the cell membrane and the leakage of cellular content often
elicit a local host reaction (inflammation)
and digestive enzymes could be derived from the recruited leukocytes in

response to the inflammation which is caused by the leakage of the

cellular contents.
Characteristics of necrosis:1) increased eosinophilic cytoplasm ( eosin and hematoxylin dye ) as a
result of binding of eosin to the denatured cytoplasmic proteins and loss of
basophilia that is normally imparted by the RNA in the cytoplasm.
2) Cell will have more glassy, homogeneous appearance because of the
loss of glycogen particles.
3) Appearance of myelin figures as a result of digestion of cytoplasmic
organelles such as mitochondria (they look like vacuoles in the cytoplasm
under electronic microscope).
4) Necrotic cell are characterized by discontinuities in plasma and
organelle membranes.
5) break down of the nucleus, and this will be accomplished by:a) Pyknosis:
1) condensation of chromatin
2) nuclear shrinkage
3)increased basophilia
b) karyolysis:loss of basophilia and lysis of chromatin due to the action of
endonucleases.
c) karyorrhexis:fragmentation of nuclear material. And it is described as formation of
nuclear dust.
Main forms of necrosis:1:- coagulative necrosis:- its the most common form of necrosis as in
myocardial infarction, kidney, spleen and even cancers.
This type of necrosis needs:a) very low PH
b) hypoxia.
As mentioned before that cell injury causes lactic acid accumulation in
case of hypoxia and this will decrease the acidity of the cytoplasm,
resulting in protein denaturation coagulation complete stop of cell activity
and the cytoplasm become firm. The necrotic tissue appears paler than
normal and its architecture is preserved
in some cases lysosomal activies in the necrotic cells form vacuoles.
This type of necrosis infarcts in all of the solid organs except the brain,
why?
Because of the high fat content of the brain and proportionally the low
protein content of its cell.
2:- liquefactive necrosis:softening of the necrotic tissue and occurs in situationsin which enzymatic
breakdown is more prominent than protein denaturation.
this type of necrosis is most commonly associated with organs that have a
high fat and low protein content (Ex. brain) those with a high enzymatic
content (Ex.Pancreas)
examples of liquefactive necrosis:a) Brain infarct: The necrotic area softens (encephalomalacia), and the
necrotic tissue is
Phagocytized by macrophages. The remaining cavity is filled by diffusion
of fluid from

Surrounding interstitial spaces of the brain. Such a fluid-filled pseudocyst.

b) Abscess: This is formed of localized infection. Typically it presents as a
cavity filled
With pus.
3:- gangrenous necrosis:-: Typically seen in patients with diabetes or in
case of losing blood supply in the extremities, it is a form of coagulative
necrosis with superimposed bacterial infection (Ex. Clostridium infection).
The tissue becomes liquefied through the action of bacterial lytic enzymes
and the recruited leukocytes, resulting in what's called as wet gangrene.
Some references refer it as a liquefactive necrosis.
Heart and brain cells will not undergo gangrenous necrosis because such a
type requires a lot of time and these organs die rapidly.
4:- Caseous necrosis:Caseous necrosis:- is a cheesy-looking necrosis,typically found in
tuberculous and fungal granulomas. Histologically, the necrotic tissue has
lost its normal structure and appears amorphous.
The area of caseous necrosis is often enclosed within a distinctive
inflammatory border which is known as granuloma. As in case on TB.
5:- Fat necrosis:- is a change in adipose tissue due to trauma or the
release of enzymes from adjacent organs mostly lipase enzyme of
pancreas (in case of acute pancreatitis, alcoholism
toxins and gall bladder stones). The trauma or enzymatic action causes a
breakdown of lipid and release of fatty acids, which combine with calcium
to form chalky deposits (fat saponification) by splitting the triglyceride
esters contained within fat cells.
Saponification is an example of dystrophic calcification in which calcium
deposits on dead tissues acts as a nidus or a source for calcification in the
setting of normal serum calcium and phosphate.
diagnosis
hypocalcemia because the calcium will form chalky deposits
clinical symptoms (severe abdominal pain to the back)
high lipase enzyme level in blood
6:- Fibrinoid necrosis:is a necrotic damage to blood vessels wall and is limited to small blood
vessels including small arteries, arterioles and glomeruli affected by
malignant hypertension or by an autoimmune disease such as systemic
lupus erythematosus. Also this type of necrosis seen in polyarteritis
Nodosa.
Usually in immune reactions in which complexes of antigens and
antibodies are deposited in the walls of arteries. The deposited immune
complexes, together with fibrin that has leaked out of vessels, produce a
bright pink and amorphous appearance on H&E preparations called
fibrinoid.
7:- hemorrhagic necrosis:a type of necrosis that occurs in organs that are supplied by more than
one artery such as the lung for example if the pulmonary artery is blocked
this will cause infarction of the lung

then blood from bronchial arteries will get into the dead tissue so it will
escape to the necrotized tissue. (that's all what Dr.maqboul mentioned
about it and there's no information about this type of necrosis in books)
Fate of necrotic cells:1) complete restitution (regeneration):- dead cells are replaced by almost
parenchymal cell. Regeneration occurs in organs composed of facultative
mitotic cells, such as the kidneys or liver.
2) Repair:- dead cells are replaced by fibrous tissue forming microscopic or
macroscopic scars.
3) Calcification (dystrophic calcification).
4) Resorption of necrotic tissue:- In the brain, the necrotic tissue is
removed by macrophages,
And the infarct is transformed into a fluid-filled pseudocyst.

Type of cell death

Cause

Necrosis
External stimulus of
stress (ischemia,
toxins, infections of
trauma)

Characteristics

Loss of plasma or
cellular organelles
membrane integrity
( Lysosome,
mitochondriaext)
Uncontrolled
breakdown of cells in
response to injurious
.stimuli

Programming

GOOD LUCK

Apoptosis
Internal stimulus
(irreparable DNA
protein damaging or
insufficient or no
growth factors)
.Nuclear dissolution

Controlled breakdown
of cells occurring in
response to damage to
DNA or as part of
normal growth and
.development