General Pathology 2022

Lecture 3
Cell death
Prepared by: Mohammed Taha
 Irreversible cell injury
Persistence of ischaemia or hypoxia results in irreversible damage to the structure and function of
the cell (cell death).
The stage at which this point of
no return or irreversibility is
reached from reversible cell
injury is unclear but the sequence
of events is a continuation of
reversibly injured cell. Two
essential phenomena always
distinguish irreversible from
reversible cell injury.
 When cells are exposed to any injuries agents, three different things are possible to occur:
1.Adaptation: cells try to adapt with the changes in the microenvironment using different
mechanisms such as hypertrophy, hyperplasia, metaplasia, or atrophy.
2.Reversible Cell Injury: some structural change is possible to occur at the level of the cytoplasmic
organelles & sometimes these changes will have some effect on the normal physiological
functioning of the cells. In this stage, cells are possible to return to their normal structure & function
3.Irreversible Cell Injury: is possible to occur either:
a.Indirectly, as the continuation of the reversible cell injury (continued stress)
b.Directly, without adaptation & reversible cell injury especially when the cell is exposed to a very
severe injuries agent (car accidents, burns)
• When cells reach this irreversible stage of cell injury, it eventually leads to cell death. Many
mechanisms are used by the body to terminate cells. The two main types of cell death are:
1.Apoptosis
2.Necrosis
Inability of the cell to reverse mitochondrial
dysfunction on reperfusion or re-oxygenation.
Disturbance in cell membrane function in
general, and in plasma membrane in particular.
In addition, there is further reduction in ATP,
continued depletion of proteins, reduced
intracellular pH, and leakage of lysosomal
enzymes into the cytoplasm. These
biochemical changes have effects on the
ultrastructural components of the cell.
• In general, the mechanism by which the cells reach the reversible & irreversible stages of cell
injury are somewhat similar but there are two main differences which distinguish them from one
another:
1.The inability of the cell to reverse mitochondrial dysfunction. When the function of the
mitochondria is disturbed by any stress, in case of the reversible, cells have the ability to reverse
these abnormalities. While, in case of the irreversible, cells aren’t able to reverse the
mitochondrial dysfunction.
2.The disturbances in the function of the cell membrane. Usually, during the reversible cell
injury, the cell membrane remains intact & their normal function are not changed dramatically.
While, in the irreversible cell injury, normal function of the cell membrane is disturbed & isn’t able
to be reversed. This is because the normal structure of the cell membrane is disrupted by many
mechanisms.
 → these following affect the ultrastructural component of cell (CAIAL)

1. Calcium influx: Mitochondrial damage. As a result of continued hypoxia, a large cytosolic influx of calcium
ions occurs, especially after reperfusion of irreversibly injured cell. Excess intracellular calcium collects in the
mitochondria disabling its function. Morphologically, mitochondrial changes are vacuoles in the mitochondria and
deposits of amorphous calcium salts in the mitochondrial matrix.
Calcium influx:- due to continued hypoxia, calcium enters cells and accumulates on mitochondria

2. Activated phospholipases: Membrane damage. Damage to membrane function in general, and plasma
membrane in particular, is the most important event in irreversible cell injury in ischaemia. As a result of sustained
Calcium
influx ischaemia, there is increased cytosolic influx of calcium in the cell. Increased calcium activates endogenous
phospholipases. These in turn degrade membrane phospholipids progressively which are the main constituent of the lipid
bilayer membrane. Besides, there is also decreased replacement-synthesis of membrane phospholipids due to reduced
ATP. Other lytic enzyme which is activated is ATPase which causes further depletion of ATP.

Membrane damage:- increased calcium activates phospholipidase which degrades membrane phospholipids
 2. Intracellular proteases: Cytoskeletal damage. The normal cytoskeleton of the cell (microfilaments,
microtubules and intermediate filaments) which anchors the cell membrane is damaged due to degradation by activated
Calcium
influx intracellular proteases or by physical effect of cell swelling producing irreversible cell membrane
injury.

Intracellular protease:- intracellular protease damages cytoskeleton which holds the cell together

4. Activated endonucleases: Nuclear damage. The nucleoproteins are damaged by the activated lysosomal
Calcium enzymes such as proteases and endonucleases. Irreversible damage to the nucleus can be in three forms:
influx
a. Pyknosis: Condensation and clumping of nucleus which becomes dark basophilic. b. Karyorrhexis:
Nuclear fragmentation in to small bits dispersed in the cytoplasm. c. Karyolysis: Dissolution of the nucleus.

Endonuclease:- nucleoproteins are damaged by endonuclease

Note// damage to nucleus is either by pyknosis (clumping), karyrhexis( bits), karyolysis ( degradation)
5. Lysosomal hydrolytic enzymes: Lysosomal damage, cell death and phagocytosis. The
lysosomal membranes are damaged and result in escape of lysosomal hydrolytic enzymes.
These enzymes are activated due to lack of oxygen in the cell and acidic pH. These
hydrolytic enzymes include: hydrolase, RNAase, DNAase, protease, glycosidase,
phosphatase, lipase, amylase, cathepsin etc) which on activation bring about enzymatic
digestion of cellular components and hence cell death. The dead cell is eventually replaced
by masses of phospholipids called myelin figures which are either phagocytosed by
macrophages or there may be formation of calcium soaps.

Lysosomal damage:-
lysosomal hydrolytic enzymes escape and damage the lysosomes
• During the irreversible cell injury, some steps are possible to occur. These steps will affect the normal
structure of the cells & will eventually increase the risk of cell injury.
1. Calcium Influx: during the irreversible cell injury, the amount of the calcium ions is increased in the cytosol
of the cytoplasm of the cell. This occurs by two mechanisms:
a. Decrease in ATP: moving calcium from the cytoplasm to the outside is done by the process of active
transport which requires ATP. When cells are exposed to injuries agents, ATP production is decreased.
Hence sufficient ATP isn’t available to transport calcium ions outside leading to the accumulation of
high amounts of calcium inside the cell. The calcium ions are accumulated (deposited) in two important
sites which are the mitochondria & the lysosomes.
b. Rupture in the cell membrane: the cell membrane permeability is changed
• When excessive amount of calcium is accumulated in the cytoplasm cell, it has the ability to activate/increase
the following enzymes:
1. Phospholipase (makes changes in the phospholipids – in the cell membrane)
2. Protease (works to degrade proteins)
3. Endonuclease (is a group of enzymes working to degrade the nuclear proteins & nucleic acid – in the
nucleus)
• If calcium influx continues without any interruption, the calcium ions continue to increase while ATP
continues to decrease.
• The decrease in the levels of ATP is yet another major problem because the cells’ cell membrane,
when disrupted, is normally maintained by replacing the phospholipid that was destructed. This cell
maintenance requires the use of ATP; therefore, in cases where the ATP is decreased, the cell
membranes aren’t able to be maintained due to a lack of ATP.
• As Calcium influx continues, lysosomal membranes are disrupted, the enzymes present in them are
released within the cytoplasm of the affected cells and then work to destruct the rest of the
organelles present in the cytoplasm. At the end, it will probably make changes in the plasms
membrane & release the content of the cell into the outside which then activates the process of
phagocytosis & inflammation.
• This is the summary of the process of irreversible cell injury which ends by the death of the cell (cell
death).
 Cell death
The term “cell death” refers to the death of cells or tissues while the body as a whole still alive.
Cell death is an essential aspect of body development and homeostasis. Two main types of cell
death:

1. Apoptosis is a pathway of cell

death in which cells activate
enzymes that degrade the cells’
own nuclear DNA and nuclear and
cytoplasmic proteins. Fragments
of the apoptotic cells then break
off, giving the appearance that is
responsible for the name
(apoptosis, “falling off”).
 ▪ The plasma membrane of the apoptotic cell remains intact, but the membrane is altered in
such a way that the fragments, called apoptotic bodies, become highly “edible,” leading
to their rapid consumption by phagocytes. The dead cell and its fragments are cleared with
little leakage of cellular contents, so apoptotic cell death does not elicit an
inflammatory reaction. Thus, apoptosis differs in many respects from
necrosis.

APOPTOSIS:-

• should occur normally

• Cell itself activates enzyme to destroy its own DNA and cytoplasmic proteins
• Cell membrane doesn't rupture
• Content of cell isn’t released
• No inflammation
▪ Mechanisms of Apoptosis

Apoptosis is regulated by biochemical pathways that control the balance of death- and

survival-inducing signals and ultimately the activation of enzymes called caspases.

Caspases were so named because they are cysteine proteases that cleave proteins after

aspartic acid residues. Two distinct pathways converge on caspase activation: the

mitochondrial pathway and the death receptor Pathway.

intrinsic Extrinsic
• Cell Death: is a normal physiological condition, necessary to get rid of the cells reaching the end of
their life spans or those cells with abnormalities possible to have DNA damage or folded proteins
especially during the process of cell division. Cell death is of great importance for the regulation of
growth and development.
• Cell death can also occur during diseases. When cells are exposed to any harmful injurious agent,
cell death is possible to occur.
• Cell death can occur in the forms of apoptosis or necrosis.
• Apoptosis: is a programmed cell death. Usually occurs during normal conditions and is very
important that reach the end of their life span.
• During apoptosis, the enzymes which are present within the lysosome of the cell are released &
then the cells undergo the process of autophagy.
• Apoptosis is possible to occur in two forms; physiologically & pathologically.
Cells receive signals in two pathways, either from the intrinsic or the extrinsic. The difference between these pathways is for
example when the DNA is damaged inside the cell or when a specific protein is abnormally folded forming a misfolding
protein, a signal is produced inside the cell activating the intrinsic pathway. This signal is regulated by a group of proteins
called BH3. BH3 is a group of genes encoding a number of proteins. These proteins are responsible to regulate the process
of apoptosis. In the intrinsic pathways, the signal produced to activate the process of apoptosis is within the cytoplasm of the
cell and not outside. (Bcl-2 & Bcl-x) are two genes which work as an anti-apoptotic genes or proteins inhibiting the process of
apoptosis. While (Bax & Bak) are apoptotic genes or proteins enhancing the process of apoptosis. If cells are able to control
the misfolded protein, then the (Bcl-2 & Bcl-x) are required to be activated because the cell has to ability to repair the
problem without the need to proceed with the process of apoptosis. But if the cell isn’t able to control the abnormality, then
the (Bax & Bak) genes are activated and the process of apoptosis takes place. Therefore, depending on the ability of the cell
to control the problem, BH3 decides whether the apoptotic or anti-apoptotic genes are activated. In case of cancers, an
important clinical biomarker is the activity/mutations of the (Bcl-2 & Bcl-x) anti-apoptotic genes. Patients suffering from any
problems in the apoptotic or anti-apoptotic genes need to be indicated because sometimes the patients are given a drug to
increase the rate of cell destruction but the anti-apoptotic genes block their function. Mutations in the anti-apoptotic genes
inhibit the process of apoptosis to an abnormal rate not allowing cell death. Activational mutation of the anti-apoptotic genes
blocks the death of cells leading to a continues increase in the level of abnormal cells. So the intrinsic pathway is regulated
through internal signals produced as a result of DNA damage or misfolded protein. The signal activates the intrinsic pathway
through the mitochondria activating the cytochrome C which then activates a group of proteins called the caspase. The
caspase then enhances/controls the process of apoptosis. The second pathway is extrinsic, this pathways is activated
through the signal coming from the outside of the cell either as a normal or abnormal signal. They are received through the
cell death receptors of FAS & TNF. Once activated, they cause the destruction of the cell through the process of apoptosis.
At the end of both pathways, caspase are activated which regulate the process of apoptosis. During apoptosis, apoptotic
bodies are produced.
 A. Pathological:- low nutrition,
B. Physiological:- abnormal synthesis like
Causes of Apoptosis
growth H.
A. Physiologic apoptosis. (abnormal synthesis like growth H.) C. Accumulation of misfold proteins

During normal development of an organism, some cells die and are replaced by new ones. In mature
organisms, highly proliferative and hormone responsive tissues undergo cycles of proliferation and
cell loss that are often determined by the levels of growth factors. In these situations, the cell death
is always by apoptosis, ensuring that unwanted cells are eliminated without eliciting potentially

harmful inflammation. In the immune

system, apoptosis eliminates excess
leukocytes left at the end of immune
responses as well as lymphocytes that
recognize self-antigens and could cause
autoimmune diseases if they were not
purged.
• Usually the cause of apoptosis is as a normal physiological condition. The mechanisms which
increase the rate of physiological apoptosis include the following:
1.During Embryogenesis: a huge number of cells are produced undergoing the process of cell
division very quickly and then loss the growth factor signaling which enhance the process of
apoptosis.
2.When the lymphocytes are produced inside the bone marrow or epithelial cells in the intestinal
epithelium and then loss the growth factor signaling which enhance the process of apoptosis.
a.In general, the more the activity an epithelial cell has, the lower its life span will be.
3.Hormonal Effects: in the endometrium, before & after pregnancy, the size needs to be reduced
meaning a large number of cells needs to be destructed. The endometrium, during pregnancy,
increases in size using hyperplasia & hypertrophy which then needs to be reduced in size after the
pregnancy is over using apoptosis. During the menstrual cycle, estrogen and progesterone cause
the production of a large amount of cells if pregnancy fails to occur, all cells need to be destructed
through apoptosis.
4.When inflammations occur, a large number of WBC arrives at the infectious/injurious site and after
a few days when the inflammation ends these cells needs to be removed/destructed also through
apoptosis.
5.When Lymphocytes (B/T-Cells) are produced that are self-reactive with the ability to interact with
the normal proteins of the human body, if such cells are not destructed, autoimmunity is produced.
 B. Apoptosis in pathologic conditions. (low
nutrition)
Apoptosis eliminates cells that are
damaged beyond repair. This is seen
when there is severe DNA damage, for
example, after exposure to radiation and
cytotoxic drugs. The accumulation of
misfolded proteins also triggers apoptotic
death; Certain infectious agents,
particularly some viruses, induce
apoptotic death of infected cells.
• Beside this we have some abnormal conditions which increase the rate of apoptosis, for example DNA
Damage, misfolded protein (the protein is abnormally folded) or the formation of a large number of proteins
inside the cell and sometimes some types of the infectious agents (viruses/cells) will activate the process of
apoptosis inside the cytoplasm of the host cell.
The unfolded protein response and endoplasmic reticulum (ER) stress

-Abnormal proteins are produced

-Interacts with structures on ER
-stimulates an unfold proteins response

1-Increased synthesis of chaperon

2-Decreased synthesis of abnormal proteins
3-Increased destruction of abnormal proteins
C. The accumulation of misfolded proteins in a cell can stress compensatory pathways in
the ER and lead to cell death by apoptosis. During normal protein synthesis, chaperones
in the ER control the proper folding of newly synthesized proteins, and misfolded
polypeptides are ubiquitinated and targeted for proteolysis. If unfolded or misfolded proteins
accumulate in the ER, they first induce a protective cellular response that is called the
unfolded protein response. This adaptive response activates signaling pathways that increase
the production of chaperones and decrease protein translation, thus reducing the levels of
misfolded proteins in the cell. When a large amount of misfolded protein accumulates and
cannot be handled by the adaptive response, the signals that are generated result in activation
of proapoptotic sensors of the BH3-only family as well as direct activation of caspases,
leading to apoptosis by the mitochondrial (intrinsic) pathway.
• How does the misfolded protein have the ability to activate apoptosis?
• Normally, the misfolded proteins are possible to be produced. When produced in low amounts, the misfolded
proteins interact with a specific receptor present in the endoplasmic reticulum (ER). This interaction will activate
three pathways:
1. Increased synthesis of Chaperones: chaperones are responsible to correct the misfolding which is
produced.
2. Reduced Protein Synthesis: the proteins produced needs to be halted or protein production needs to be
stopped.
3. Increased Proteins Degradation: in case the chaperones were unable to fix or repair the misfolded proteins,
they need to be destructed. Degradation of abnormal proteins.
• In case of cancer, when misfolded proteins are produced, the cells are unable to treat it using the above
mechanisms. Hence, the risks of forming misfolded proteins are increased dramatically and make changes in
the normal function of the cells and increase the rate of mutation in the other types of genes present here.
• What happens if the amount of misfolded proteins is too much?
• In this case, BH3 proteins are activated. When activated, it will activate the caspase which regulates the
process of apoptosis.
• So apoptosis is possible to occur when the misfolded proteins are produced in a huge amount and the cells

aren’t able to adapt to this condition hence why the process of apoptosis needs to be activated through the
activation of BH3 proteins which then activate caspases.
 Morphological features of apoptosis

a. Membrane blebbing: It is the formation of outward membrane blebs (bulges) from the cell
membrane due to breaking up of the cell's cytoskeleton.

b. These outward cell membrane blebs may separate from the cell, taking a portion of the cytoplasm
with them. Such separated outward cellular blebs are known as apoptotic bodies which are
eventually consumed by the phagocytic cells.

c. Cell shrinkage.
d. Chromatin condensation (Pyknosis).
e. Nuclear fragmentation (Karyorrhexis).
 Morphological features of apoptosis.
• If we have two cells, one undergoing the process of apoptosis & the other one under the process of necrosis, during
apoptosis, two important things come with the apoptotic cell which are completely different & absent in the necrotic cells: In
apoptotic cells: the cell membrane is not disturbed at all. So the cell membrane remains intact & the content of the cell are not
released into the outside of the cell. While in necrotic cells, the cell membrane is disrupted & the content of the cell are
released into the outside. In apoptotic cells, because the cell membrane remains intact, inflammation doesn’t occur.
Inflammations only occur in necrotic cells, because the cell membrane ruptures and the cells content is released outside. Other
morphological features of apoptosis include:
1. Cell Shrinkage: the size of the cell decreases.
2. Chromatin Condensation (Pyknosis)
3. Nuclear fragmentation (Karyorrhexis).
• Karyolysis does not occur during apoptosis. Karyolysis is the dissolution of the nucleus. The nucleus completely disappears in
necrosis but in apoptosis the case is not the same. In apoptosis only fragmentation occurs but karyolysis doesn’t occur.
• In apoptosis, apoptotic bodies are produced; the cell becomes fragmented, without any of the cells content being released to
the outside & the cell membrane remains intact, through the formation of apoptotic bodies which are engulfed by the
phagocytic cells.
 3. Necrosis is a form of cell death in which
cellular membranes fall apart, and cellular
enzymes leak out and ultimately digest the
cell. Necrosis elicits a local host reaction,
called inflammation, that is induced by
substances released from dead cells and
which serves to eliminate the debris and
start the subsequent repair process.

NECROSIS:-

• should not occur normally

• Size of cell increases (in apoptosis it decreases)
• Karylysis occurs (but not in apoptosis)
• Cell membrane is ruptured (but not in apoptosis )
• And cell content leave cell
• Inflammation
• FA and glycerol are produced (apoptosis fate’I nia)
▪ The enzymes responsible for digestion of the cell are derived from lysosomes and may come from the
dying cells themselves or from leukocytes recruited as part of the inflammatory reaction. Necrosis
often is the culmination of reversible cell injury that cannot be corrected.
▪ The biochemical mechanisms of necrosis vary with different injurious stimuli. These mechanisms
include: failure of energy generation in the form of ATP because of reduced oxygen supply or
mitochondrial damage; damage to cellular membranes, including the plasma membrane and
lysosomal membranes, which results in leakage of cellular contents including enzymes; irreversible
damage to cellular lipids, proteins, and nucleic acids.
 • Cytoplasm
• Nucleus
• Organelles
Morphology ALL DISAPPEAR

Necrosis is characterized by changes in the cytoplasm and nuclei of the injured cells.

▪ Cytoplasmic changes. Necrotic cells show increased eosinophilia, attributable partly to increased
binding of eosin to denatured cytoplasmic proteins and partly to loss of basophilic ribonucleic acid
(RNA) in the cytoplasm. Compared with viable cells, the cell may have a glassy, homogeneous
appearance, mostly because of the loss of lighter staining glycogen
particles.

Normal Pyknosis Karyorrhexis

Karyorlysis
▪ Nuclear changes. Nuclear changes assume one of three patterns, all resulting from a
breakdown of DNA and chromatin. Pyknosis is characterized by nuclear shrinkage and
increased basophilia; the DNA condenses into a dark shrunken mass. The pyknotic nucleus
can undergo fragmentation; this change is called karyorrhexis. Ultimately, the nucleus
may undergo karyolysis, in which the basophilia fades because of digestion of DNA by
deoxyribonuclease (DNase) activity. In 1 to 2 days, the nucleus in a dead cell may
completely disappear.
▪ Fates of necrotic cells. Necrotic cells may persist for some time or may be digested by
enzymes and disappear. Dead cells may be replaced by myelin figures, which are either
phagocytosed by other cells or further degraded into fatty acids. These fatty acids bind
calcium salts, which may result in the dead cells ultimately becoming calcified
-Necrosis: Necrosis does not occur as a part of normal physiological condition.
• Necrosis is usually activated and the cell is exposed to any harmful injuries agent and the things which is possibile to be
occur during the necrosis from the begining the contents of the cell are degraded, the nucleus will undergo the process of
karyolysis.
• If you look at the cell in the figure above, abini hich asawareki nucleus namawa balam la apoptosis aw jora nia, and
cell’akan zyatr yak rangi abet, rangakan awa nia bgoret la naw cell’akaya hamushi rangeki pamai tery haya la bidayati
process’akawa ka ru ayat chunka dway agoret cell’akan, hokary away ka rangi pamaiyaka zya aka agaretawa bo 3 factor:

1- rezhayaki zor la protein la naw cytoplasm drust abe. Larg amount of protein is produced inside cytoplasm
2-aw RNA’ayay la cell’eki 3tyadia haya lera namene. RNA is’t the same RNA as normal cell
3-glycogen la naw cell’akaya namene. Lack of stored glycogen, becuase it’s already used for ATP
• Lanaw cell’y 3tyadia zorbay zory cell’akan glycogen’yan haya bas store krawa boi bakar bhenre la katy pewista ballam la
necrosis’a glycogen namawa chunka already bo ATP bakary henawa.
• “Bam 3 factor’a wa akat ka rangi cell’akan glassy homogenous darakawe wa hich asawareki nucleus’ish namene ballam
ama la marhalakani early stage’y necrosis’da dway wrda wrda step’akan agoret.
 Morphologic Patterns of Tissue Necrosis

In severe pathologic conditions, large areas of a tissue or even entire orgrans may undergo necrosis.
This may happen in association with marked ischemia, infections, and certain inflammatory
reactions. There are several morphologically distinct patterns of tissue necrosis that may provide
etiologic clues. Although the terms that describe these patterns do not reflect underlying
mechanisms, such terms are commonly used and their implications are understood by pathologists
and clinicians.
 Types of Necrosis
-Types of necrosis:
• Necrosis ka ru ayat agar injuries agent’aka jyawaz be type’y necrotic tissue’akay ka drust abe jyawaz abe.
• Jory necrosis la pathology bochi grnga katek ka lesion’ek habet, yakek la factor’a hara sarakyakan awaya
ka atwanet hokary naxoshyakat pe ble, handek jar bo nmuna kate kasaka TB habe yan TB nabe
mushkilayaki kai habe la lung’a lesionw yan foci yan nodule’k habe kate X-ray bo akai bo zorbay
7allatakan nodule’aka har darakawe la X-ray’akaya, ballam barasty naizanit ama tumor’a, TB’ya yan
hokary tra, biopsy waragire la naxoshakaw anerdre bo pathologist’aka, agar tumor bet waz7a agar TB bet la
shty kai jya katawa.
• TB 3adatan jorek la necrosis drus abe ka pey awtret Caseous necrosis. Zor jar cause’y disease’aka dyar nia,
to ta causey disease’aka nazani natwani 3ilaji kai. Aya kasek TB bet yan cancery habe yan infectioneky try
habe treatmentyan jyawaza yak treatment nabe, boya pesh away bgaita treatment abe cause’aka dyary bkait.
 1. Coagulative necrosis: This is the most common type of necrosis caused by irreversible focal
injury, mostly from sudden cessation of blood flow (ischaemia), and less often from bacterial
and chemical agents. The organs commonly affected are the heart, kidney, and spleen.

grossly
Microscopically

Coagulative:- due to hypoxia and ischemia/ dry area/ wont occur in brain (neurons have a higher
lysosomal content, leading to a higher tendency toward autolysis, and in part due to a high concentration
of neutrophils which swarm into an affected area and related to BBB
▪ Grossly, foci of coagulative necrosis in the early stage are pale, firm, and slightly swollen.
With progression, they become more yellowish, softer, and shrunken.
▪ Microscopically, the hallmark of coagulative necrosis is the conversion of normal cells into
their ‘tombstones’ i.e. outlines of the cells are retained so that the cell type can still be
recognized but their cytoplasmic and nuclear details are lost. The necrosed cells are swollen
and appear more eosinophilic than the normal, along with nuclear changes described above.
But cell digestion and liquefaction fail to occur. Eventually, the necrosed focus is infiltrated
by inflammatory cells and the dead cells are phagocytosed leaving granular debris and
fragments of cells
 1-coagulative necrosis: It is one of the types of necrosis which is usually produce in the results of the ischemia. This type of
the necrosis possible to the see in all the types of cells and tissues in our body apart of brain. Coagulative necrosis nabinret la
brain’a, am jora la necrosis kate drust abe ka cell tushi ischemia abet.
• Taibatmandyakani am joray necrosis: rangi shwenaka white or pale darakawe, firm, kamekish awset la sarataya, dway
The color appears as white or pala,a little swelling. after a
chan rozhek soft abet wa shrink aka bchuk abetawa, liquid lera nia. few days it becomes soften and shrinkage. lack of liquid
• Coagulative necrosis yak taibatmandy haya outliney cell’aka tek nachet la saratay naxoshyakaya ba hich jorek, cell
membrane’aka rupture naka, hamu contenty cell’akan tek ashke w namene ballam outline’aka amenetawa. Necrosis
yakek la taibatmandyakani ka jyay akatawa la apoptosis rapturey cell membrane’akaya.
Coagulative necrosis have a speciality in wich the outline of the cell membrane doesn’t rupture, but all of the contents of the cell degrades

Q/Bochi la coagulative necrosis cell membrane rupture naka?

Lysosome ka esh akat enzyme’akani, functionakai pewisty ba ATP haya, lera labar away bardawam ATP kam abetawa, am
enzyme’a tanha atwane bashek la organelle’akan tek bshkene lagal nucleus’akaya, twanay away nya cell membrane’aka tek
bshkene labar away ATP namene etr, kawata la sarataya outliney cell’aka wak xoi amenetawa, har labar awasha ka shweni
necrotic area’ka wshka, labar away contenty cell’aka nahatota darawa, wa inflammatory cell’akanish nahatun hata chemical
reactionakan darbrn away pei awtret inflammation drust abe w fluid ko abetawaw awana hichi rui nayawa.
• Katek acheta late stage enja inflammatory cell’akan yan cell’aka anasnawa ka cell’eka tek chwa (normal namawa) w
3amalay phagocytosis das pe aka tek ashkenret cell’aka etr dway awa wrda wrda inflammation ru aya shwenakai agore.
Lysosomal enzymes needs (ATP) to thier functions, during caogulative necroses the amount of ATP decreases dramatically so the
lysosome enzymes can only degrade (nucleus,organalles) but not the outline of the cell membrane ruptured due to lack of ATP, this is
why the necrotic are appears dry causing the contents of the cell isn’t released to outside, and this is why inflammatory reaction
doesn’t occur during earlier stages until later stages
 2. Liquefaction (colliquative) necrosis: is seen in focal bacterial and, occasionally, fungal
infections because microbes stimulate rapid accumulation of inflammatory cells, and the
enzymes of leukocytes digest (“liquefy”) the tissue. For obscure reasons, hypoxic death of cells
within the central nervous system often evokes liquefactive necrosis

Liquifactive:- occurs due to microbial infection/ fluid area/

in brain Ischemia
-In the affected area there is liquid
-happens because of bacterial infecton
• Grossly, the affected area is soft with liquefied center containing necrotic debris. Later, a cyst wall
is formed.
• Microscopically, the cystic space contains necrotic cell debris and macrophages filled with
phagocytosed material. The cyst wall is formed by proliferating capillaries, inflammatory cells, and
gliosis (proliferating glial cells) in the case of brain and proliferating fibroblasts in the case of
abscess cavity.
2-Liquefaction necrosis: Ballam agar sery jory dwam kain effective liquefaction necrosis lera rek ba 3aksi coagulative
necrosis’awa, small abe rezhayaki zor la la liquid Ko abetawa , ama la 7allaty infection am jora ru aya ba taibaty la
bacterial infection w ischemiay brain’ish liquefaction necrosis’a.
• Hokary away rezhayaki zory liquid ko abetawa la 7allaty infection’a awaya ka aslly cell’aka lera ba karigary
bacteriaka tek ashke, ya3ni xalalaka lanaw cell’aka xoi nya das ka ba tek shkann wakw away ATP aika, lera ATP
kam nabotawa hich keshashi nya blood supplysh zora, ballam away xalalaka drus aka karigary ama, lera rezhayaki
zor la ATP haya, lysosome’aka kate ka yata darawa ham organelle’akan w ham cell membrane’akanish tek ashkene
labar awa mushkilay ATP nya, hokary dwam awaya bacteriaka xoi enzymey haya ka cell membrane’aka tek
ashkene, hokary seyam zor ba xeray 3amalay inflammation abe, jyawaza lera chunka lera wtman contenty cell’aka
nayata darawa, ka nahata darawa zamaneki pe ache ta am cell’a anasretawa, ballam lera injury’aka ka drust bu cell
membrane’aka rupture aka contenty cell’aka acheta darawa ka chwa darawa yaksar enhance’y inflammation aka
labar awa shwenaka tarr darakawe, fluid’eky zor yaksar ko abetawa lamaway chan sa3ateki kama, ama la organakan
bam shewaya ru aya. The reason that a large amount of liquid accumulates is that the cell degrade by
bactrail infection. ATP and blood supply isn’t decreas, so the lysosome degrade
the cell membrane and all organelles because there is a huge amount of ATP
Q/ bochi la brain ischemia abe ba liquefaction? 2. The bacteria has it’s own enzymes to start degradation
3. In here information happens very fast because contents of the membrane
releases out that’s why necrotic are appears as wet and due to accumulation
Content is released because ATP is present. Inflammation happen, bacteria secrets enzyme, liquid increases,
then it grows and become cyst
3.Caseous necrosis:- due to microbial tuberculosis/ all tissues are destroyed
is most often encountered in foci of tuberculous infection. Caseous means “cheeselike,” referring to the friable yellow-
white appearance of the area of necrosis on gross examination. On microscopic examination, the necrotic focus appears
as a collection of fragmented or lysed cells with an amorphous granular pink appearance in H&E stained tissue sections.

Unlike coagulative necrosis, the tissue architecture is

completely obliterated and cellular outlines cannot be
discerned. Caseous necrosis is often surrounded by a
collection of macrophages and other inflammatory cells; this
appearance is characteristic of a nodular inflammatory
lesion called a granuloma.
3-Caseous necrosis: is another types of the necrosis, this type of the necrosis usually seen during microbacterial infection,
so with the microbacterial infection in the necrotic area shtek darakawe rangeki zard wakw panir waya taqriban texture’akai,
lam jora: Yellowish appearance is due mycolic acid that present
in yhe cell wall of the bacteria. When inflammatory cell
1-outliney cell’aka yaksar tekache start degrade the miobactria that mixture will produce
that called caseous necrosis
2-rangeki zardbawy haya wakw panir taqriban, ama Bahoy Mycolic acid’awa drust abe, mycolic acid la cell wall’y
microbacteriaya haya, kate inflammatory cell’akan das akan ba tekshkani bacteriaka law shwenay bacteriaka haya, tab3an
inflammatory cell’akan yan normal cell’akanish tek ashkenn, tekallayak abe la liquefactive and jory fat ka la diwary
bacteriakaya haya, joreki taibat la necrosis drust aka ka pei awtret caseous necrosis.
• Am jora la necrosis ka pathologistaka ainasetawa yaksar dllnyaya ka cause’y disease’aka jama3aty microbacteriumakan
chunka coagulative ru nayat, jyawazish abe la Liquefactive necrosis ba hoi buni mycolic acid’akawa ka texture’y
Indicator
necrotic tissue’aka agore, am gorankarya la texture’aka ka ru aya ba hoi aw fat’awa wa akat ka jori lesion’aka bzanret
chya (causative agentakai bzanret chya).
• (La 7alaty TB liquefactive drust nabe Caseous drust abe ka texture’akai jyawaz abe, texture’y necrotic tissue’aka agoret
ba karigary jore la fat ka la cell wally bacteriakaya haya, am fat’a lagal aw reaction mixture’ay ka drust abe la natijay
inflammation w tekshkani normal cell’akan texture’aka agoret. in the condition of TB, liquefactive doesn’t produce caseous
will produced wich have a different texture. This texture is
due to the fat that present in the cell wLl of the bacteria
 4. Fat necrosis: is a special form of cell death occurring at two anatomically different
locations but morphologically similar lesions. These are: following acute pancreatic
necrosis, and traumatic fat necrosis commonly in breasts. In the case of pancreas, there
is liberation of pancreatic lipases from injured or inflamed tissue that results in necrosis
of the pancreas as well as of the fat depots throughout the peritoneal cavity, and
sometimes, even affecting the extra abdominal adipose tissue. Fat necrosis hydrolyses
neutral fat present in adipose cells into glycerol and free fatty acids. The damaged
adipose cells assume cloudy appearance. The leaked out free fatty acids complex with
calcium to form calcium soaps (saponification) discussed later under dystrophic
calcification.

It is a type of fat lesion/ acute pancreatic

Necrosis:- in which pancreatic lipase is released and causes damage to pancreas

Traumatic fat necrosis:- Fa and glycerol are produced due to hydrolyzing fat in adipocytes
Grossly, fat necrosis appears as yellowish-white and firm deposits. Formation of calcium soaps
imparts the necrosed foci firmer and chalky white appearance.
Microscopically, the necrosed fat cells have cloudy appearance and are surrounded by an inflammatory
reaction. Formation of calcium soaps is identified in the tissue sections as amorphous, granular and
basophilic material.

Fat necrosis in acute pancreatitis. The areas of white chalky deposits represent foci of fat
necrosis with calcium soap formation (saponification) at sites of lipid breakdown in the
mesentery.
4-fat necrosis: is another type of necrosis which is usually seen due to the damage of the adipocyte. Fat necrosis
possible to seen during the pancreatic necrosis when the pancreas has the problem

Q/ pancreas ch enzym’ek dar aya ka rabty habe ba liver’awa?

Ans/ pancreatic lipase
• Katek pancreatic cell injury ru bat rezhayaki zor la lipase dar ayat ka lipase blaw bowa ta2sir akata sar adipocyte’akan ka
la peritonial cavity yan organakani abdomen’a habet, increase’y rate’y cell damage aka bo limphocyte’akan rezhayaki
zory chawry ko abetawa baw shewaya, yan la breast’a injuryak ru bat labar away breast rezhayaki zor la fat’y tyaya fat
necrosis abinret, rezhayaki zor la adipocyte tek ashket, adipose lipid’aka agoret abe ba glycerol w fatty acid ka bu ba
glycerol w fatty acid, fatty acid taibatmandyaki sairy haya bo yak grtn lagal calcium labar awa calcification abe, har labar
awasha la breast cancer’a calcification ru ayat w zorish bawa.
• Labar away ka tumor cell’aka drust bu lymphocyte destruction zorabe ka lymphocyte destruction zor bu ya3ni
lypocyte’akan lipid’akai agore bo fatty acid yan ba glycerol, fatty acid twanayaki zory haya boi lagal calcium yak bgret,
rezhay calcification zor barz abetawa, labar awa calcification abinret.
• Labar awa har keshayaki ka ka rabty habe ba breastawa yan har organeki ka fat’y zor be rezhay calcification law
organaya zor ba xeray zya akaw w labar away rezhayaki zor la fatty acid drust abe, fatty acidish twanayaki zory haya boi
lagal calcium yak bgre bamash rezhay calcification zor barz abetawa labar awa basheki zor lawanay tushi breast cancer
abn, tumoraka shwenakai zor raq abe labar away rezhayaki zori calcium deposition aka lagal tumor cell’akan.
1. When there is an injury in pancreas it releases alot of lipase whic
cause damage to adipocytes especially in peritonial cavity and
abdomen, and increasing rate of cell damage and destruction of
lymphocytes wich change adipose lipid into glycerol anf fatty acid,
or when there is an injury in breast because it has a lot of fat.
Adipcytes degradate and adipo lipid convert to glycerol and fatty
acide. Fatty acide can interact with calcium and cause calcification,
that’s why in case of breast cancer calcification very common
2. When tumor cells produce lymphocyte destruction increases
that cause change adipose lipids into glycerol and fatty acids,
and when fatty acids bind to calcium it will cause calcification
 deposition of fibrin like material and destruction of blood vessels

5. Fibrinoid necrosis: is characterized by deposition of fibrin-like material which has the staining
properties of fibrin. It is encountered in various examples of immunologic tissue injury (e.g. in
immune complexe vasculitis, autoimmune disease, Arthus reaction etc), arterioles in
hypertension, peptic ulcer etc.

▪ Microscopically, fibrinoid necrosis is identified

by brightly eosinophilic, hyaline-like deposition
in the vessel wall. Necrotic focus is surrounded
by nuclear debris of neutrophils
(leucocytoclasis). Local hemorrhage may occur
due to rupture of the blood vessel.
This Photo by Unknown Author is licensed under CC

Fibrinoid necrosis in an artery in a patient with polyarteritis nodosa. The

wall of the artery shows a circumferential bright pink area of necrosis
with protein deposition and inflammation.
5-Fibrinoid necrosis: is another types of necrosis, the type of necrotic tissue is looks like a fiber in the microscope, this like
is a necrosis is very common in the blood vessels. La fiber ache boya pei awtre fibrinoid necrosis. La necrotic area’aka
rezhayaki zor la protein’y tya abe. Am jora la necrotic ka badawrya rezhayaki zor la inflammatory cell’akan haya lera
necrotic area’aka la natijay damage’y cell membrane’akanawa drust abe, cell’a abe ba necrosis, w ka la microscope sery akai
wakw fiber darakawe shwenaka labar away rezhayaki zor la proteiny tedaya la blood yata darawa bo sar diwary blood
vessel’aka la shweni necrotic area’ka protein’eky zor ko abetawa wakw fiber darakawn.

is another types of necrosis, the type of necrotic tissue is looks like a fiber under microscope
because it has a lot of proteins wich caming out from blood. It’s very common in blood vessels.
in necrotic area alot of protein accumilate. as a result of cell membrane damage Inflammatory
cells cover the necrotic area
 A form of necrosis from the combination of coagulative
and putrefaction (rotting)

Gangrene 3 forms:

Gangrene is a form of necrosis of tissue with superadded putrefaction. The type of necrosis is
usually coagulative due to ischaemia (e.g. in gangrene of the bowel, gangrene of limb). On the
other hand, gangrenous or necrotising inflammation is characterized by primarily inflammation
provoked by virulent bacteria resulting in massive tissue necrosis.

Thus, the end-result of necrotising inflammation and

gangrene is the same but the way the two are produced, is
different. The examples of necrotising inflammation are:
gangrenous appendicitis, gangrenous stomatitis (noma,
cancrum oris). There are 2 main forms of gangrene—dry
and wet, and a variant form of wet gangrene called gas
gangrene. In all types of gangrene, necrosis undergoes
liquefaction by the action of putrefactive bacteria.
 ‫ ئەوە‬fibrinoid ‫ ئەمانە پێیان ئەوترێ‬،‫• رێژەیەکی زۆر پرۆتین کۆئەبێتەوە وەكو فایبەر دەرەکەون رەنگەکەی بەم شێوەیە دەرئەکەوێت‬
‫ من لە نەزەری زیاتر تەرکیز‬،‫تایبەت بوو بە تایپەکانی هین لێرە زۆر تەرکیز ناکەمە سەرسترەکچەر بۆیە پێتان ئەڵێم بۆ ئەوەی بیزانن‬
.‫ئەکەمە سەر میکانیزمەکان لە عەمەلیەکە زیاتر گرنگی ئەدرێت بە سترەکچەرەکان‬

• Gangrene is a type of necrosis but somethings are possible to occur in gangrene which does not
usually happen in other types of necrosis, gangrene is produced of results of ischemia in the
from of coagulative necrosis and gangrene also possible to be occur as a result of necrotizing
inflammation when the inflammation is produced as a result of necrosis it will increase the
chance of getting the gangrene. We have two types of gangrene dry and wet gangrene, dry
gangrene usually occurs .

‫ كێشەی نییە ؟‬blood supply ‫ ەکە‬inflammation ‫• لە‬

blood supply ‫ یەعنی‬، ‫ زۆر جار موشکیلە بۆ ڤەینەکان دروست ئەبێ نەک ئارتری‬necrotizing inflammation ‫نا هەندێ جار لە‬
‫ناوەستێ بەاڵم خوێن کۆئەبێتەوە فەرقەکەی ئەوەیە‬
Because necrotizing inflammation is produce in the veins not
arteries so blood supply isn’t stop but blood accumulate
 DRY:-
• occurs in dry area
• Low bacterial infection
1. Dry Gangrene • Blood supply to artery is decreased or stopped (infraction)
This form of gangrene begins in the distal part of a limb due to ischaemia. The typical example is
the dry gangrene in the toes and feet of an old patient due to arteriosclerosis. Other causes of dry
gangrene foot include thromboangiitis obliterans (Buerger’s disease), Raynaud’s disease, trauma,
ergot poisoning. It is usually initiated in one of the toes which is farthest from the blood supply,
containing so little blood that even the invading
bacteria find it hard to grow in the necrosed
tissue. The gangrene spreads slowly upwards until
it reaches a point where the blood supply is
adequate to keep the tissue viable. A line of
separation is formed at this point between the
gangrenous part and the viable part.
 Grossly, the affected part is dry, shrunken and dark black, resembling the foot of a mummy. It is
black due to liberation of haemoglobin from haemolysed red blood cells which is acted upon by
hydrogen disulfide (H2S) produced by bacteria resulting in formation of black iron sulfide. The line
of separation usually brings about complete separation with eventual falling off of the gangrenous
tissue if it is not removed surgically.
Histologically, there is necrosis with smudging of the tissue. The line of separation consists of
inflammatory granulation tissue.

• Dry gangrene mosty affect lower part of the limbs especially toes and start to rais up to the
upper limbs. Blood supply decreased in the necrotic area cause obstruction of arteries and cell
strart to destruct and affected area becames black and raises up until bllod supply increases, a
demarcation line is produce above that line cells are completely normal, if the necrosis doesn’t
treat below that area will completely break off
• Dry gangrene zyatr tushi palakani xwarawa abet ba taybati panjakani qach u lawewa wrda wrda sarakwe. La dry

gangrene yakam blood supply kam abetawa this type of gangrene is produced due to the obstruction of arteries,

blood supply is decresed to the necrotic area. Lera blood supply kam abetawa wrda wrda cell kan tek ashke u

rangyan rash abet sarakawe hata aw 7aday ka blood supply zya abet, la kweya blood supply zor bwo demarcation

line ek drust abet saraway demarcation line 100% normal cell a la xwaraway hamu nercotic cell a, hata agar

gangrene wazi lebeni xoy lam line awa break off abetu qachi kasaka ley abetawa (agar hich 3ilajeki bo nakre).

• Bashi am joray gangrene lawyaya ka blaw nabetawa. this type of gangrene isn’t spreadable

• Bacterial infection lera zor kama bochi? Bacterial infection is very low because blood supply
is absence in that area
• Chunka ka blood supply nama etr am medium a bo zhyan nabet boya bacterial infection zor kama (nutrient y le

nya boya bacteria shi le nya)

• Prognosis is good if you compare it to wet gangrene.

2. Wet Gangrene
Wet gangrene occurs in naturally moist tissues and organs such as the mouth, bowel, lung, cervix, vulva etc.
Diabetic foot is another example of wet gangrene due to high sugar content in the necrosed tissue which favours
growth of bacteria. Bed sores occurring in a bed-ridden patient due to pressure on sites like the sacrum, buttocks
and heels are the other important clinical conditions included in wet gangrene.

WET:-
• occurs in wet areas
• High bacterial infection
• Due to accumulation of deoxygenated
blood in vein so the circulation stops
Causes; wet gangrene usually develops rapidly due to blockage of venous, and less commonly, arterial blood
flow from thrombosis or embolism. The affected part is stuffed with blood which favors the rapid growth of
putrefactive bacteria. The toxic products formed by bacteria are absorbed causing profound systemic
manifestations of septicemia, and finally death. The spreading wet gangrene generally lacks clear-cut line of
demarcation and may spread to peritoneal cavity causing peritonitis.
 Grossly, the affected part is soft, swollen, putrid, rotten and dark. The classic example is gangrene
of bowel, commonly due to strangulated hernia, volvulus or intussusception. The part is stained
dark due to the same mechanism as in dry Gangrene.
Histologically, there is coagulative necrosis with stuffing of affected part with blood. There is
ulceration of the mucosa and intense inflammatory infiltration. Lumen of the bowel contains
mucus and blood. The line of demarcation between gangrenous segment and viable bowel is
generally not clear-cut.

2- This type of gangrene is usually occurs due to venous obstruction no arterial obstruction. And due to
accumulation of larg amount of blood it will be a suitable medium for bacterial infection especially pecially
those type of bacteria wich are called putrefactive bacteria. Demarcation line is only happens in dry
gamgrene.
It have unpleasant smell because of the bacteria infection. wet gangrene exists in the limbs of the affected
patients wich have diabetes because of accumulation of large amount of sugar, and it cause damage to the
 • Wet gangrene usually la soft tissue kan ru ayat balam ashgunje la limbakan ru bat.
Wet gangrene usually affect soft tissue’s as well as it might happen in the limbs
• This type of gangrene is usually due to venous obstruction not arterial obstruction, and due to accumulation of

large amount of blood it will be a suitable medium for bacterial infection specially those types of bacterial

which are called putrefactive bacteria. Jyawazi lagal dry gangrene wet bahoy venouse obstruction, dry ba hoy

arterial obstruction. Bacterial infection la wet gangrene zor zora balam la dry gangrene zor kama yan

nya(chunka blood supply namawa). Demarcation line tanha la dry gangrene haya. Wet gangrene boneki zor

naxosh haya because of the bacteria. Diabetes wet gangrene drus aka chunka paywandi ba blood supply

yawa nya paywandi ba zori sugar awa haya labar awa wet gangrene la palakani aw kasanay shakrayan haya

drus abet chunka aw rezha zoray sugar damage y cell kan akat u bacterial infection drus akat.

• 7alateki tr ka zor xatara la wet gangrene drus abet septicemia ya la la dry gangrene nya.
Another severe condition wich is produce in wet gangrene is septicemia due to bacterial toxins in blood
• septicemia (large amount of bacterial toxins are in the blood).

• Wet gangrene blaw abetawa unlike dry gangrene.

Unlike dry gangrene wet gangrene is spreadable
3. Gas gangrene
It is a special form of wet gangrene caused by gas-forming clostridia (gram-positive anaerobic bacteria) which
gain entry into the tissues through open contaminated wounds, especially in the muscles, or as a complication of
operation on colon which normally contains clostridia. Clostridia produce various toxins which produce necrosis
and oedema locally and are also absorbed producing profound systemic manifestations.

GAS:-
• Subtype of wet gangrene
• Accumulation of gas
• Clostridium is an example
Grossly, the affected area is swollen, oedematous, painful and crepitant due to accumulation of
gas bubbles within the tissues. Subsequently, the affected tissue becomes dark black and foul
smelling.
Microscopically, the muscle fibres undergo coagulative necrosis with liquefaction. Large
number of gram-positive bacilli can be identified. At the periphery, a zone of leucocytic
infiltration, oedema and congestion are found. Capillary and venous thrombi are common
• Gas gangrene is another type of gangrene usually it’s a sub type of wet gangrene, but this type of
gangrene is produced as a result of infection of those bacteria which can produce gas.Ex;Clostridium
• La zorbay sarchawakan har waku basheki wet gangrene danrawa hanekyan nabe ba hane
jyawazyawa dayan nawa.
• Akre gas gangrene la palakan ru bat (balam ba rezhayaki kamtr la wet gangrene) also la colon esh
Gas gangrene is possible to occur in the limbs but at lower rate than wet gangrene,
ru ayat. also it produces in colon
• Ba shewayaki gshti dry la limbakan u wet la soft tissue ru ayat.
• Har gangrenek bacteria drusti kat wet gangrene a .
Any gangrene that produce as result of bacteria is wet gangrene
• Aw shwenay gas gangrene y tush bwa raqa dasi pya bkesha taqay yat.
The region wich has gas gangrene has a hard like sound
• La har shwenek la circulation obstruction ru bat blood supply awastet, kati shwenek vein kay block
abet etr natwani xweni tr warbgret.
• Hatuchoy xwen paywanid bawa haya ka nabet la hich shwnek obstruction drus bet, lahar shwenek
obstruction habet hamu systemaka awaste yan xaw abetawa