‫ﺑﺎﺳﻤﻚ ﻧﺤﻴﺎ‬

A  We are going to have a quick lecture today, we will try to finish the
B chronic inflammation, and this is the final lecture included in the exam.
O  The exam will be on Saturday nshallah between 3:00 to 5:00 o’clock.
U  There are 2 groups, the first group from 3:00 to 3:45, and then directly
T after that the second group will do their exam.
 The exam is 40 questions, 30 questions are theoretical, and the
T
remaining 10 are practical.
H
 Make sure that you are stuck in your allocated computer lab and your
E
computer number. “the doctor emphasized on this point and he will
consider any change in your seat number or computer lab as a
E cheating”
X  You can find you computer number and computer lab in your site or
A you can find a hard copy with your CR.
M GOOD LUCK…

Chronic inflammation
Granulomatous Inflammation

I am just want to remind you of the chronic granulomatous diseases, and

as we said it is a very distinctive form of chronic inflammation
characterized by a collection of epithelioid histiocytes, and we
mentioned that these histiocytes when they are activated they become
larger, they become epithelioid like, and they will contain more
cytoplasmic granules and materials.
So granuloma might contain in addition to epithelioid macrophages,
lymphocytes, plasma cells, and multinucleated giant cells.
Sometimes these granulomas undergo necrosis, and when this necrosis
specifically becomes like caseous we call it caseous necrosis which is a
characteristic of tuberculosis (‫)ﻣﺮض اﻟﺴﻞ‬.

Histiocyte : A macrophage presents in connective tissue

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 And this is the typical granuloma
where you see the epithelioid
histiocytes admit with some
lymphocytes, and rimed by plasma
cells, lymphocytes and other lymphoid
cells, and sometimes this also includes
multinucleated giant cells, which is a
kind of aggregates of fusion of these
epithelioid histiocytes.

So what are the components of granuloma?

 Epithelioid histiocytes.
 Multinucleated giant cells.
 Lymphocytes.
 Plasma cells.

A granuloma may contain a surrounding rim of fibroblasts & fibrosis

And this is an example of caseating

granuloma, with a caseous necrosis,
and you see here in the center the
cheesy like material, and it has no
cellular details and that is why we call
it caseous necrosis.
It differs from the typical necrosis.

And we mentioned last time that when we suspecting tuberculosis, we

should do a special stain, and the special stain for Mycobacterium
tuberculosis is what we call Ziehl- Neelsen stain, in which the acid fast
bacilli will be stained by this eosinophilic stain, so these are the positive

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 M.Tuberculosis microorganisms which are usually present within the
granulomas, so once we see this we say this is a definite Tuberculosis,
and the physician will start to treat the patient directly without even
waiting for the culture.
Not in all cases with tuberculosis we will find these acid fast bacilli and
this is not excluded for TB.
So negative staining for acid fast bacilli in an otherwise granulomatous
inflammation with typical caseous necrosis doesn’t exclude the
possibility of TB and therefore we need to do culture, but the problem of
TB culture is that it takes time, it needs weeks.

“The growth of TB bacilli on traditional solid medium requires 4-8 weeks“

Examples of Granulomatous Inflammation

Mycobacterium As I told you, there are many cause of

tuberculosis granulomatous inflammation, including
Bacterial bacterial, parasitic, fungal….etc causes.
Mycobacterium Leprae

Treponema pallidum

Bartonella henselae  Regarding the bacterial causes, the

commonest and the most
Parasitic Schistosomiasis important one is Mycobacterium
tuberculosis, Mycobacterium
Histoplasma capsulatum Leprae which cause Leprosy,
Blastomycosis Treponema pallidum which cause
Fungal
syphilis, and Bartonella henselae
Cryptococcus neoformans
which causes Cat Scratch Disease
Coccidioides immitis which is another form of
granulomas occurring in the lymph
Inorganic Silicosis, Berylliosis nodes in the inguinal area.
metals

Suture, other prosthesis,  The parasitic causes include

Foreign body keratin Schistosomiasis (also known
as bilharzia, bilharziosis or snail fever).

Unknown Schistosomiasis also leads to the

Sarcoidosis
formation of granulomas and especially in

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the bladder, so if you find a granuloma in a bladder biopsy it is
Schistosomiasis until proven otherwise and also you see the calcified
eggs there and you see the other features. Schistosomiasis can cause
granuloma anywhere in the body, in the liver, in the appendix in the GIT
in the bladder ...etc.
 According to the fungal infections the granuloma occurs in:
histoplasm capsulatum, Blastomycosis, Cryptococcus neoformans ,
and Coccidioides immitis.
 For inorganic materials like the dust, occupational hazards like
Silicosis and Berylliosis; all these can cause granuloma especially in
the lung and the cause is the occupational inhaled materials and
hazards. And this occurs with those who works with the asbestos
and woods (carpentry); they are prone to inhale these minute or
micro particles which might lead to inflammation and formation of
granuloma.
 Foreign bodies like sutures, other prosthesis (‫)اﻟﺒﺪاﺋﻞ اﻻﺻﻄﻨﺎﻋﯿﺔ‬, and
keratin.
Yesterday we had a specimen from a lung which has had lobectomy,
where one lobe of the lung was removed, from a thirty year old girl, and
causing a lot of destruction, a lot of inflammation (granulomatous
inflammation) and fibrosis that has led to complete destruction of the
lobe of the lung and the underlying cause of all this was foreign body
inhalation.
Also two years ago a Small kid was reported with inhalation of a small
toy which went directly to the lung and has led to destruction of her lung.
 Unknown causes like sarcoidosis, which is a kind of autoimmune
disease.
Prosthesis: A
Of course there are other systemic granulomatuos
Fabricated substitute for a
diseases, like chronic granulomatuos disease. diseased or missing part of
the body.

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Morphological appearance of chronic inflammation

So what are the morphological appearances of chronic inflammation:

 We can have ulceration which is a local defect or loss of continuity

in surface epithelia in the skin which is typical example of
ulceration, chronic inflammation.
 Formation of chronic abscess cavity.
 Induration and fibrosis; mentioned in previous lecture.
 Thickening of the wall of a hollow viscus; that means if you have a
chronic inflammatory process in the colon, like chronic
inflammatory bowel disease or ulcerative colitis, this is a chronic
long standing inflammatory process which goes for many years
and eventually leads to thickening in the wall, destruction of the
mucosa, and finally loss of the function of either the small
intestine if it is chron's disease, or the large intestine if it is
ulcerative colitis.
 And of course caseous necrosis; which has necrosis and
granuloma manifestation.

This is an example for chronic ulcer as a result of

chronic inflammation.

DON’T DELAY
GO AND PRAY

And this will lead us to: >>>

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 Systemic acute-phase reactions

They are the reactions that occur in the body due to many the
inflammatory process.
As we can see here there is a local acute inflammatory response, and
this will lead to the release of:

1- The interleukin 1 (IL-1), tumor necrosis factor-α (TNF-α), and the

interleukin 6 (IL-6); these systemic chemical mediators will stimulate the
hypothalamus and this will lead to:

A- Stimulation of further prostaglandin formation or other pyrogens,

these pyrogens lead to the increasing temperature and cause fever.
Fever is increasing the temperature of the body; and it is one of the
body mechanisms to counteract the action of the inflammation,
increasing the temperature will facilitate the killing of the
microorganisms, and also lead to more vasodilatation, and more delivery
of the blood to the site of inflammation.

B- Activation of the pituitary gland will lead to increase the levels of

ACTH. ACTH affecting the adrenal cortex and this will lead to
Increase the production of corticosteroid.
And we know that the corticosteroids are effective endogenous anti-
inflammatory products that synthesized in our body.

2- Now again the IL-1, TNF, and more particularly the IL-6 which is here
probably the most important one will affect the liver to synthesize more
proteins, which we call the acute-phase proteins this include:

 The C-reactive protein (CRP) and that is what we measure in the

lab; this means that if somebody had an inflammation we go and
measure these acute phase reactive protein. So if it is high this

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 means we have ongoing inflammatory process this might be acute
inflammatory process or chronic one.
 And we have the serum amyloid A (SAA) which is another acute
phase protein.
 Fibrinogen; which produced in increasing abnormality and this
fibrinogen needs to be stocked On the RBCs, when they stick in
the RBCs; these RBCs become stickier. And by this we measure
what we call ESR (erythrocyte sedimentation rate), and in this case
it is very high.
So this is another non-specific measurement of inflammatory process
within the body this might be acute or chronic process.
How they measure the ESR?
They just have the blood sample in a special tube and they just hang this
tube and then see what is the sedimentation rate at many times, zero
time, one hour, two hours And this is made because of the sticking of
the fibrinogen on the RBCs.
 There are other proteins like complement components which they
have their important role in the inflammation.
 Finally the mannose-binding protein.

All these proteins are markers of

inflammation

3- And the other important thing that the IL-6and TNF-α also stimulate
the bone barrow; increasing the production of the colony stimulating
factor “CSF” by stromal cells and macrophages. Then this will lead to
increase the hematomesis, and this explains the increased white blood
cells in the peripheral blood; and there are more and more soldiers
recruited to the battle area which is the site of inflammation, so the
bone marrow will start producing that blood cells when there is
inflammation.
When there is increasing in the demand on the bone marrow, the bone
marrow increase the formation of WBC in the form which is not rather
mature, we call this shift to the left, where actually hematomesis
precursors are not able to finish the production of neutrophils in their

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mature form, so they will be produced as immature cells like Pan-
neutrophils or even less mature cells.
This will happen in bacterial infections but we know that for example in
viral infections, the demand increased on lymphocytes, so we can have
lymphocytosis, while in bacterial infections as we said we have
Neutrophilia, in hypersensitivity reactions or parasitic infections we have
eosinophilia.
But nonetheless, there are some infections in some situations where we
can see suppression of the formation of WBCs, and we call this
leucopoenia, which might occur in some bacterial infections like Typhoid
fever, or even some other viral infections.
So not every infection leads to leukocytosis, there are some specific
infections which might lead to leucopoenia, which means a decrease in
the number of WBCs.
And this is just a summery of the systemic reactions for inflammation
(look below)

-So it is Mediated by IL-1, IL6, TNF, which interact with vascular

receptors in the thermoregulatory center of hypothalamus via local PGE
production.
-And Systemic manifestations include:
• Fever
• Catabolism: when there is inflamation (espically in chronic
inflamtion) there is what we call cachexia which is enhacment of
catabolism of the body, and this means that there will be increasing

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 in the catabolism of protiens and fats that are present.thus leading to
cachexic condetion (which is chronic and long standing or septic
sepsis which means very severe form of inflamation)
• Increased slow wave sleep, decreased appetite & cachexia.
• Hemodynamic changes: so we will see increase in BP and HR.
• Synthesis of acute-phase proteins by liver, e.g. CRP, fibrinogen,
serum amyloid A protein (SAA).
• Leukocytosis: neutrophilia, lymphocytosis, eosinophilia
• Leukopenia: e.g. Typhoid fever.
• Increased ESR
• Septic shock: BP, DIC & hypoglycemia the severe form of
inflammation leads to sepsis or septic shock, it is a shock state which
leads to decrease in BP and DIC (disseminated intravascular
coagulation) , this mainly due to the injury of the endothelium which
will leads to the formation of small blood clots inside the blood
vessels throughout the body. We sometimes call DIC (death is
coming) because it is a very serious state; and this because the
microthromboemboli may lead to infarction (cerebral infarction,
myocardial …). Also the septic shock causes Hypoglycemia (reduction
in blood glucose) and this is mainly due to the systemic effect of the
liver which will reduce the glycogenlysis and glucenogenisis.
There is a question from a student that we couldn’t hear but this is the
answer!!!!
Septic in general it is a shock that is not related to septic but we say
septic, when there is sepsis when there is intoxication of bacterial or
viral toxins. Other types of shock (hypovolemic shock, other circulatory
shocks, neurological shock) are aseptic simply because there are no toxic
products.

‫ﻣن اﻋﺗﻣد ﻋﻠﻰ ﻣﺎﻟﮫ ﻗل‬

‫وﻣن اﻋﺗﻣد ﻋﻠﻰ ﻋﻘﻠﮫ ﺿل‬
‫وﻣن اﻋﺗﻣد ﻋﻠﻰ ﺟﺎھﮫ ذل‬
‫وﻣن اﻋﺗﻣد ﻋﻠﻰ ﷲ ﻻ ﻗل وﻻ ﺿل وﻻ ذل‬

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 Consequences of Defective Inflammation

Susceptibility to infections
 Defective innate immunity the body is not able to defend
itself!
Delayed repair
 Delayed clearance of debris and necrotic tissue.
 Lack of stimuli for repair.
So the one who has any kind of infection (and the defense system is
defected) this will lead to delay the repair and this might lead to
ulceration, and that’s why the diabetic patient are more likely to have
ulcer (diabetic ulcer or diabetic foot) because they have neuropathy and
vasculopathy, so this will delay the overall protective mechanism against
any stimuli.

Consequences of Excessive Inflammation

If we have exaggerated inflammation process, this may lead to:

 Allergic reactions (whether it is acute or chronic)

 Autoimmune disorders
 Atherosclerosis ( ‫ )ﺗﺼﻠﺐ اﻟﺸﺮاﯾﯿﻦ‬we said that atherosclerosis is a
chronic inflammation caused by the injury of endothelial cells by high
lipid content In the blood, so the cells will become injurious (toxic) and
this will activate the process of atherosclerosis.
 Ischemic heart disease.

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 Role of Mediators in Different Reactions of Inflammation

Now this table is very important (as the Dr said) it is found in your
book and it summarizes the important actions of the mediators in
inflammation. the Dr read it as it is , adding some information that we
put it in the table bold and underlined.

 Prostaglandins

Vasodilatation  Nitric Oxide

 Histamine

 Histamine and serotonin

 C3a and C5a (by liberating vasoactive amines from mast cells,
other cells)
 Bradykinin
Increased vascular  Leuktrienees C4, D4, E4
permeability
 PAF (platelet activating factor)
 Substance P

 TNF, IL-1
 Chemokines
 C3a, C5a
Leukocyte
recruitment and  Lukotriene B4
activation  (Bacterial products, e.g., N-formyl methyl peptides)

Fever (Pyrogen )  IL-1, TNF

 Prostaglandins

 Prostaglandins (espically prostacyclin I2)

Pain  Bradykinin
 Neuropeptides (not neuropathies)

 Lysosonal enzymes of leukocytes

Tissue damage  Reactive oxygen species

 Nitric oxide

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 ‫‪The Happy End‬‬
‫‪Good luck in your exam ‬‬

‫ﺳﺎﻣﺤﻮﻧﺎ ﻋﻠﻰ ﺃﻱ ﺧﻄﺄ‪،‬ﺗﻢ ﺗﻔﺮﻳﻎ ﺍﻟﻤﺤﺎﺿﺮﺓ ﻓﻲ ﻇﺮﻭﻑ ﻏﺎﻣﻀﺔ‪ ،‬ﻭ ﺍﺩﻋﻮﺍ‬

‫ﻟﻨﺎ ﺑﺎﻟﺨﻴﺮ‪.‬‬
‫‪Done by your brothers:‬‬

‫‪Rasheed Elayyan‬‬
‫‪Omar Abu-Ghaneemeh‬‬
‫‪Maulla Al-Ali‬‬
‫ﺒﺫﺭﺓ ﺍﻟﺸﺭ ﺘﻬﻴﺞ‪ ،‬ﻭﻟﻜﻥ ﺒﺫﺭﺓ ﺍﻟﺨﻴﺭ ﺘﺜﻤﺭ‪ ،‬ﺇﻥ ﺍﻻﻭﻟﻰ ﺘﺭﺘﻔﻊ ﻓﻲ ﺍﻟﻔﻀﺎﺀ ﺴﺭﻴﻌﺎﹰ‪ ،‬ﻭ ﻟﻜﻥ‬
‫ﺠﺫﻭﺭﻫﺎ ﻓﻲ ﺍﻟﺘﺭﺒﺔ ﻗﺭﻴﺒﺔ‪ ،‬ﺤﺘﻰ ﻟﺘﺤﺠﺏ ﻋﻥ ﺸﺠﺭﺓ ﺍﻟﺨﻴﺭ ﺍﻟﻨﻭﺭ ﻭ ﺍﻟﻬﻭﺍﺀ‪ ،‬ﻭﻟﻜﻥ ﺸﺠﺭﺓ ﺍﻟﺨﻴﺭ‬
‫ﺘﻅل ﻓﻲ ﻨﻤﻭﻫﺎ ﺍﻟﺒﻁﻲﺀ‪ ،‬ﻷﻥ ﻋﻤﻕ ﺠﺫﻭﺭﻫﺎ ﻓﻲ ﺍﻟﺘﺭﺒﺔ ﻴﻌﻭﻀﻬﺎ ﻋﻥ ﺍﻟﻤﺎﺀ ﻭ ﺍﻟﻬﻭﺍﺀ‪.....‬‬

‫ﻤﻊ ﺃﻨﻨﺎ ﺤﻴﻥ ﻨﺘﺠﺎﻭﺯ ﺍﻟﻤﻅﻬﺭ ﺍﻟﻤﺯﻭﺭ ﺍﻟﺒﺭﺍﻕ ﻟﺸﺠﺭﺓ ﺍﻟﺸﺭ‪ ،‬ﻭ ﻨﻔﺤﺹ ﻋﻥ ﻗﻭﺘﻬﺎ ﺍﻟﺤﻘﻴﻘﻴﺔ ﻭ‬
‫ﺼﻼﺒﺘﻬﺎ‪،‬ﺘﺒﺩﻭ ﻟﻨﺎ ﻭﺍﻫﻨﺔ ﻫﺸﺔ ﻨﺎﻓﺸﺔ ﻓﻲ ﻏﻴﺭ ﺼﻼﺒﺔ ﺤﻘﻴﻘﻴﺔ !‪...‬ﻋﻠﻰ ﺤﻴﻥ ﺘﺼﺒﺭ ﺸﺠﺭﺓ‬
‫ﺍﻟﺨﻴﺭ ﻋﻠﻰ ﺍﻟﺒﻼﺀ‪ ،‬ﻭ ﺘﺘﻤﺎﺴﻙ ﻟﻠﻌﺎﺼﻔﺔ‪ ،‬ﻭ ﺘﻅل ﻓﻲ ﻨﻤﻭﻫﺎ ﺍﻟﻬﺎﺩﺉ ﺍﻟﺒﻁﻲﺀ‪ ،‬ﻻ ﺘﺤﻔل ﺒﻤﺎ‬
‫ﺘﺭﺠﻤﻬﺎ ﺒﻪ ﺸﺠﺭﺓ ﺍﻟﺸﺭ ﻤﻥ ﺃﻗﺫﺍﺀ ﻭ ﺃﺸﻭﺍﻙ‪.‬‬

‫ﺳﻴﺪ ﻗﻄﺐ‬

‫‪12‬‬