‫بسم الله الرحمن الرحيم‬

‫ و أن‬،‫" و أن ليس للنسان إل ما سعى‬:‫قال تعالى‬

‫"سعيه سوف يرى‬
We already said in the last lecture that there are
reversible and irreversible injuries, and here is
the outline of this (figure on slide #5), you can
see here that u have a normal cell, which is
always under stress or injury. This cell can show
no change, or it can adapt to the change , or
shows some reversible changes of injury, or the
injury is so bad that there is irreversible damage
and death.
Causes of cell injury:
1- Hypoxia ( oxygen deficiency) and
Ischemia (loss of blood supply in a tissue)
.
Hypoxia is one of the most common causes of
cell injury, it can be caused by many factors such
as:
a-Low levels of oxygen in the air.
b- Poor or absent hemoglobin function, the
hemoglobin itself may be abnormal, and cannot
carry proper amount of oxygen.
c-Decreased erythropoiesis: production of red
blood cells (the main cells carrying hemoglobin),
so cells are not well oxygenated.
d- Reduction of oxygen capacity of the blood, as
in respiratory disorders ( e.g. pneumonia) or
cardiovascular disorders can also cause hypoxia.
Both of them - hypoxia & ischemia - induce
mitochondrial damage, because the mitochondria
are the main components that deal with the
respiratory function in the cell.
When the mitochondria are defected , then we’ll
have a decreased generation in energy (ATP), &
this affects cell functions. If the defection is
persistent and severe it leads to cell death.
As you see in this figure, once oxidative
phosphorylation is reduced due to Ischemia, the
Na pump and the anaerobic glycolysis are
effected and so on.

In the case of hypoxia (oxygen deficiency) the

cell resorts to anaerobic glycolysis (doesn’t
use oxygen), so lactic acid will accumulate and
this will generate acidosis.
Ischemia (the most common cause of
hypoxia) injures the cell faster than pure
hypoxia, why?
In the case of hypoxia, the cell resorts to
anaerobic glycolysis. While in Ischemia, when
blood that carries substrates (nutrients) needed
for the cell to perform anaerobic glycolysis is
blocked or reduced, anaerobic glycolysis cannot
take place so the injury will be faster.
Now sometimes reperfusion (restoration of the
flow of blood to a previously ischemic tissue or
organ (as the heart or brain) - reperfusion
following heart attack for example-) although it
is helpful, in some cases it may lead to recovery
or further damage through something called
Ischemia/ reperfusion recovery. This can
affect the cell and lead to progressive cell
damage.
*examples where this occurs: frequently occurs
in Myocardial and Cerebral Infarction in the heart,
sometimes you see that the patient is first stable,
and then he deteriorates after any of these
infarctions.
Infarction: a localized area of tissue, as
in the heart or kidney, that is dying or dead,
having been deprived of its blood supply because
of an obstruction by embolism or thrombosis.
And this can be explained as the following:
Restoration of blood flow leads to generation of
high levels of calcium, and we shall see later that
when Ca enters the cell, it produces a rapid
damage.
At the same time, reperfusion increases the
recruitment of inflammatory cells. In every
infarction, we see that inflammatory cells come
to the area of infarction, these cells produce free
radicals and free radical injuries.
Also, the damaged mitochondria –due to the
ischemia- increase free radical production, and
compromise antioxidant defence mechanisms;
there is a defence mechanism against the
generation of free radicals, some of it is in the
mitochondria itself.
Mitochondrial damage Free radicals
 Anti-free radical systems.
At the same time, the dead tissue itself, behaves
foreign to the body, it becomes antigenic, it
induces immune reaction in the body (antibody –
antigen reaction), & activates the complement
system . Now this complement also induces
further cell damage!
All of these factors induce further cell damage
when we have ischemia/reperfusion injury.
In some cases it is recommended that when we
have ischemia in the heart or the brain, high
oxygen therapy is not given to improve hypoxia
because it generates oxygen derived free
radicals.
Now, what is the free radical injury ?
Free radicals are chemical species , with a single
unpaired electron in an outer orbit , they are
chemically unstable, they are unstable electrons
present in the cell , they react with other
molecules resulting in further chemical damage .
And once the free radical are induced , they bind
to various components of the cell and cause
damage such as proteins , carbohydrates and
lipids . In pathology free radicals can be
produced by: (Source of free radicals in
Pathology)
 1.Chemical injuries .
2. Physical injuries .
3. Inflammation ( inflammatory cells produce
free radicals).
4.Oxygen toxicity ( when you have high level of
oxygen in ischemic tissue ) .
5.Reperfusion injuries .
6.Malignant transformation ( malignant
tumours generate free radicals).
7.Aging ( anyone who's old has more free
radical than anyone who's young ) .
Now free radicals in the body can be produced by
one of two ways, either endogenous (in the
body), or exogenous.
Endogenous Free Radicals:
physiologically are produced by Redox
(reduction-oxidation reaction) reactions in the
mitochondria.
Also metals in the body , which usually are
carried by various components in the blood,
when they are free like copper & iron, they
catalyse the formation of free radicals unstable
molecules, by donating or accepting free
electrons.
In iron, we get what we call Fenton reaction
where ferrous Iron(II) is oxidized by hydrogen
peroxide to ferric iron(III), a hydroxyl radical and
a hydroxyl anion.
Exogenous Free Radicals:
1-Ionizing radiation
2-Certain drugs can be very active and induce
free radical formation.

• Please refer to slide # 18 and read free radicals

examples.

Now, how do free radicals injure the cell??

(Mechanism of injury by free radicals)
1 . It produces what is called Lipid Peroxidation
( oxidative degradation of lipids ) and here there
will be destruction of unsaturated fatty acids by
binding to methylene groups (CH2) that posses
reactive hydrogen molecules usually in the
membranes .
2. It also produces Protein Destruction , By
cross linking proteins forming disulfide bonds (S-
S) → inactivate various enzyme systems in the
cell , & degradation of various polypeptides.

3- Also these free radicals go to the nucleus, and

there they induce DNA alteration producing
single strand breaks in DNA, this Induces
mutation that interfere with cell growth.

Inactivation of free radicals:

In Any physiological system in the body, we have
activators and a deactivators. For example in
blood clotting, we have factors that induce blood
clotting, and others that prevent it, & this is
always balanced.
So free radicals are deactivated either by
spontaneous decay, or we have enzymes, these
enzymes include:

 Superoxide dismutase,
 glutathione peroxidase, and catalase
These are present in various components in the
cell, some are in the mitochondria, and they
destroy these free radicals. In many cases these
reactions end up by production of water.
Or we have what we call antioxidants, that
actually block the synthesis of free radicals, or
inactivate them. These include: vitamin E,
vitamin C, albumin, transferrin (a blood plasma
protein for iron delivery), & ceruloplasmin (the
major copper-carrying protein in the blood,
Ceruloplasmin carries about 70% of the total
copper in human plasma while albumin carries
about 15%. )
Eat vegetables and fruits rich with vitamins because they are
antioxidants; they prevent free radicals formation. 

• Any questions so far?

Ra3ed asks his question 3 times, until finally he gets to set
in the first row to ask:
How is Nitric oxide related to inflammation?? (I couldn’t
hear the question clearly as well :P).
The doctor answers: Nitric oxide doesn’t
produce inflammation, it is an agent present in
blood vessels, it causes dilatation of blood
vessels, this (dilatation) is one of the changes
that occur in acute inflammation. So nitric
oxide NO is one of the factors produced in the
case of inflammation, and it can change to
nitrite, which is toxic.
Ya3ni some components in our body can act as
free radicals, many factors are induced during
the inflammatory response in the body, and
these generate free radicals, but we have
specialized techniques that compensate this
generation as the one we mentioned above.

CHEMICAL AGENTS :
It can act in many ways :
1-Act directly on the cell , they go to a
certain part in the cell and they cause
damage in that part . (Direct contact of the
chemical with molecular components of the
cell) .

2-Act indirectly on the cell , they go to the

liver and in the liver they change to
something active and this produces the
injury .

3-Responsible for the formation of free

radicals, or lipid peroxidation.

Examples of chemical injuries :

 Cyanide => disrupts cytochrome
oxidase which presents in mitochondria .
 Mercuric chloride => binds to cell
membrane in cell resulting in increased
permeability.
 Chemotherapeutic agents & antibiotics
which means the drugs used in the
 treatment of cancer , they generate free
radicals and so cause chemical injury .
 Carbon monoxide ( CO ) => it causes
chemical injury through binding to
hemoglobin instead of oxygen
( hemoglobin has higher affinity to CO
than to O2 ).
 Ethanol (alcohol) produces toxics.
 Lead .
Action of Carbon Monoxide (CO): Carbon
Monoxide has a very high affinity to hemoglobin
producing carboxyhemoglobin (COHb) , and this
will cause death , because hemoglobin then
cannot bind to oxygen. In some cases when it is
not severe smaller quantities of COHb leads to
tiredness, dizziness & unconsciousness.
Action Of Ethanol : the conversion of ethanol to
acetaldehyde leads to the formation of free
radicals, and this will initiate changes in the
liver :
 Fatty change

 Liver enlargement

 Liver cell necrosis.

The liver becomes very big because it contains a
lot of fat, such case can be found with alcoholic
patients .
Action Of Lead :
This mimics the action of other metals such as
( Iron , Zinc, and Calcium ) and acts as cofactors
in many catalyzing enzymatic reactions (they
stop the enzyme from working ) .It acts on the
CNS by interfering with neurotransmitters and
blocking glutamate receptors . It also affects
hemoglobin synthesis . Chronic lead poising
which used to occur many years ago from using
lead pipes for transporting water , which causes
water contamination (but now they are all
changed ) .
Indirect injury of some chemicals :

Other chemicals are not intrinsically

biologically active, but must be first converted
to reactive toxic metabolites, which then acts
on target cells, this is what we call an indirect
injury.
This modification is usually accomplished by
the P-450 mixed function oxidases in the SER
of the liver.
Now when CCl4 is converted to the toxic free
radical CCl3, this causes membrane
 phospholipid peroxidation with rapid break
down of the ER.
This will induce fatty liver, because it destroys
proteins and lipids, and since liver needs
apoprotiens for transport, when we don't have
proteins to transport, this will induce fatty liver.

Mitochondrial injury follows → ↓ATP → Failure of

cell function → increased cytosolic Ca+ → cell
death.
Acetaminophen(paracitamol) – is a widely used
analgesic (pain reliever) and antipyretic (fever
reducer) – when given in large doses can act
similarly.

Physical agents:
This can be caused by:
1. Mechanical Injury , resulting in tearing, or
crushing of tissues.
e.g. : blunt injuries , car accidents , falling of a
roof …etc .
2. Ionizing Radiation , it ionizes the water inside
the cell and generates free radicals , and by this
also the DNA might be hit producing
mutations(!).
3. Extreme Temperatures, hypothermia (very low
temperature) & hyperthermia; prolonged
exposure to elevated temperatures can result in
heat cramps, heat exhaustion, and heat stroke.
4- Changes in the atmospheric pressure, is
produced by blast injuries, you may be not
injured externally but it causes ruptures of
internal organs. Pressure in water can decrease
or increase rapidly, this causes air embolism
which we’ll discuss later.
Infectious injuries:
Bacteria produces toxins; endotoxin and
exotoxin.
Bacterial exotoxins are secreted proteins that
directly cause cellular injury and frequently
underlie disease manifestations.
Viruses can produce damage by many ways, they
decrease the ability of producing proteins. Some
viruses enter the cell and bind to the nucleus and
change the host’s genetic properties.
5-Immunological reactions
Usually injures the cell membrane by contact
with immune components such as lymphocytes,
macrophages,…etc. exposure to these agents
cause changes in membrane permeability.
6. Genetic diseases
Play a substantial role in cellular structure and
function. For example , sickle cell anemia , in
which the RBC’s have a sickle shape and has
sharp ends instead of being round , and this can
block the capillaries producing obstruction. Or for
example, this genetic defect may affect an
enzyme system in the body causing destruction
and inability to metabolize a certain substance in
the body.

7. Nutritional imbalance
Adequate amounts of proteins, lipids,
carbohydrates are required. However, Low levels
or high levels may affect the cell.Low levels of
plasma proteins, like albumin, encourages
movement of water into the tissues, thereby
causing edema (swelling of the cells ) .
Blood sugar; Hyperglycemia, hypoglycemia is
what happens in all cases of diabetes. ketone
bodies are produced which are very toxic.
Vitamin deficiencies are important sources of
injury (vitamins E, D, K, A, and folic acid), just like
too little food, too much food and obesity is also
a type of cell injury. Because these patients
develop many diseases including cardiovascular
diseases and diabetes, so obesity is classified as
a nutritional imbalance.
Mechanism of cell injury & sites of damage
Generally, when any cell is damaged, what
happens is that the function is lost before
morphological changes occur. The first thing that
happens in the cell is that it has disturbed
function. We don’t see it by any microscope.
After that we have the electron microscope
changes. Then we’ll have the microscopic
changes, and later on, we’ll have the naked eye
(gross) changes.
So it is a step-by- step change in the morphology
and function of the cell.
Check slide # 37 to see the figure !

‫الحمد لله الذي بنعمته تتم الصالحات‬

Sorry if it took you a long time to read
my lecture, I really made my best to
give the best. Some of the information
are copied from the internet and the
book since the doctor’s explaining
wasn’t that clear. Excuse me for any
mistakes !
Special thanks to my dearest friend
and sister Samah Abu Omar for her
HUGE support and help, I really can’t
thank you enough! Ibrahim Miqdadi,
thank you very much for your help
always  Thank you all llll my friends, I
will write a special dedication for you
all in my next lecture ;).
Good luck folks!
‫ "إذ استغنى الناس بالدنيا‬:‫قال المام ابن القيم‬
‫ وإذا فرح الناس بالدنيا فافرح‬،‫فاستغن أنت بالله‬
‫ وإذا أنس الناس بأحبائهم فأنس أنت‬،‫أنت بالله‬
‫ وإذا ذهب الناس إلى ملوكهم وكبرائهم‬،‫بالله‬
‫يسألونهم الرزق ويتوددون إليهم فتودد أنت إلى‬
‫"الله‬