11

Muath Al-Rjoob

Raghad Howari

Nadine Absy
 th
Alsalam Alaikum Yaqeen and welcome to the 11 Pathology sheet … Hmmm well congratulations for you Patho
exam and Inshallah you’ll do the same in the rest of exams … anyway be sure that both the slides and
the topics Dr.Muath spoke about during the lecture are included here

Chronic Inflammation
• We’ll start by the definition of chronic inflammation: It is an inflammation of prolonged
duration (weeks, months, or years) that starts either rapidly or slowly.
This type of inflammation could be a life-long process, which means that there are some things
that can cause chronic inflammation from the start, in addition to problems that starts as acute
inflammation and then turn into chronic ones. “can start rapidly or slowly”

Keep remembering that acute inflammation is an

inflammatory response that lasts for short duration
“minutes, days or at most one week”

• So, when we speak about chronic inflammation we should know that it is characterized by an
equilibrium of:
1. Persistent injurious agent: variety of infectious microorganisms, i.e.: we have certain
microorganisms that induce chronic inflammation because in this case acute
inflammation is not enough to kill those microorganisms.
For example: mycobacterium tuberculosis due to the persistent injury of these
microorganisms so acute inflammation cannot destroy them.
2. Inability of the host to overcome the injurious agent: if the patient has problems
in his acute inflammation reaction it will not overcome the infectious agent or if it's
"weapons" aren’t strong enough.

Now let’s move on to the characteristics of chronic inflammation:

• Chronic inflammatory cell infiltrate “the cells involved the most in the process”:
• Lymphocytes
Remember that in acute inflammation the main cells
• Plasma cells
involved are neutrophils
• Macrophages
**Later when we speak about the comparison between the two types of inflammation (Acute and
Chronic) we’ll see that we have different types of cells are responsible for both processes.

• Tissue destruction These two processes occur

together at the same time
• Repair
• Neovascularisation: formation of “new” blood vessels
• Fibrosis: only occurs in chronic inflammation but not acute one unless we have
substantial damage “damage that cannot be regenerated” , cells cannot
regenerate like myocardial cells
And this is the whole process of chronic inflammation, we have continuous destruction and
continuous repair … at the end either the destruction will continue or the repair will overcome the
destruction resulting in the end of chronic inflammation.
Note that in the pattern of tissue repair differs in acute from chronic inflammation, in acute
inflammation we have regeneration sometimes (the tissue may go back to it pre-injurious state) and also
we have fibrosis or turning into chronic inflammation in contrast to chronic repair methods(neo+fibrosis)

The following table also we’ve taken it before but the doctor said it’s very important:

Notice that we
did not mention
plasma cells in
chronic
inflammation,
and that’s
because
lymphocytes
after maturation
will turn into
plasma cells.

One of the
major events
Now after the theoretical comparison we’ll now see a microscopic one
between chronic and Acute Pneumonia:

A) represents chronic pneumonia and the pointer refers to chronic inflammatory cells “lymphocytes” in
blue arrow, we have also formation of new small blood vessels that are usually not present, fibrosis in
red arrow.
B) Represents acute inflammation the blood vessels are congested (vascular stasis) which results in
increasing the permeability and slowdown of the blood stream in addition to a collection of neutrophils
filling the alveolar spaces.
So, in short we have differences in the cells responsible for chronic and acute inflammation, we have
differences in the processes of chronic and acute inflammation and finally we have the main difference
which is the duration.
• Now why does chronic inflammation develop?! Or Under what circumstances, does it develop?!
1- Progression from acute inflammation: when the acute type is not sufficient or
ineffective in destroying the injurious stimulus that caused inflammation then the acute
inflammatory response will turn to a chronic inflammatory response for example:
Tonsillitis, osteomyelitis, etc.
2- Repeated exposure to toxic agents
e.g.: Silicosis, asbestosis, hyperlipidemia, etc.

Both silica and asbestos are inhaled toxic materials mostly inhaled by people working in mines and the
ship industry or insolation respectively … first and second exposure will cause acute inflammation but
repeated exposure after this will result in a chronic one.
 3- Viral infections: viruses are obligate-intracellular microorganisms* and in order to
destroy these viruses we need a special type of inflammatory response which is part of
the chronic inflammation because neutrophils cannot destroy viruses or viral infected
cells.
*Grow and replicate within host cells, acute inflammation cannot clear viral infections
due to this fact as it usually works against extracellular microorganisms.

You should know that viral infections don’t cause acute inflammation but they
start as chronic inflammation because acute inflammation needs a series of steps
which are not initiated by viruses for example.

4- Persistent microbial infections for example:

Mycobacteria, Treponema, Fungi, etc.

Like: 1)Mycobacterium tuberculosis which is similar to viruses also obligate-

intracellular microorganisms(goes inside the cell and lives there) they go inside
macrophages which try to destroy them but usually fails in achieving the destruction of
this microorganism which will cause the infection to continue and cause chronic
inflammation.
2)Treponema pallidum which is responsible for syphilis

5- Autoimmune disorders: an inflammatory response initiated by the immune system

against a certain part of the body itself (the body produces antibodies against its own
antigens) for example:
i. Rheumatoid arthritis: an autoimmune disease in which the boy produces
auto-antibodies against the synovial membrane which induces
inflammation and the destruction of joints. The inflammation will
continue because the antigen that causes it in the joints is persistent.
The antigen induces an inflammatory response that starts as acute at
first “but as in silica and asbestos” there will be repeated exposure
because even when the antigen is destroyed the body will produce
another antigen which will cause another inflammation and so on
“chronic inflammation”.
ii. SLE: systemic lupus erythematosus where usually we’ll have anti-DNA
antibodies and other types of autoantibodies that are targeting self-
antigens.
So regarding the immune system we have something called self-
tolerance which means that our immune system is not capable in
destructing our own antigens … so at some point cells that can
recognize and kill those antigens will be deleted/killed by apoptosis.
I know it is complicated but so far we are required to know that … later on, inshallah we’ll study more
about this subject.

Know that: it is not a rule that chronic inflammation comes from acute one and it is not a rule that
acute inflammation will develop a chronic one … but in case that the acute inflammation fails in
controlling the situation and turns to be a chronic one there will be an area of overlapping between
them (there is no solid partition between them), we’ll see part of the tissue in acute and the other in
chronic inflammation because of the process of transforming from acute to chronic but after 2-3 days if
we take a biopsy we won’t see any tissue in the acute phase.

‫ في بعض االحيان حيكون عنا لون رمادي‬.. ‫يعني الموضوع مش ابيض او اسود‬

-We’ve said that the inflammatory cells involved are: lymphocytes, macrophages and plasma cells … and
speaking of macrophages they are considered as a part of something called the Mononuclear Phagocytic
System

In contrast neutrophils are called PMN: polymorphonuclear leukocyte

because they have multiple nuclei

- All macrophages are derived from circulating monocytes but when they go to certain body part the
name changes … notice that monocytes will be macrophages when they go out from the blood and
arrive the injured tissue

-We have certain nomenclature of macrophages according to the tissue they are scattered in:
• Kupffer cells (liver),
• Sinus histiocytes (spleen & lymph nodes),
• Alveolar macrophages (lung),
• Microglia (CNS)
But the question is how does the process of leukocyte movement from blood vessels to these tissues
occur?! Simply as in acute inflammation we have chemical mediators that induce the travelling of
monocytes from blood vessels to the tissue and changing to macrophages resulting in the process of
chronic inflammation
What is that chemical mediator? They are activated mainly by IFN-gamma (interferon gamma) which
is usually secreted from activated T lymphocytes in addition to the activated macrophages themselves
which causes auto-activation of macrophages and activation of other macrophages in order to increase
and magnify the process of inflammation.
So what are the effects of this IFN-gamma ?! :
• Increase cell size
• Increase lysosomal enzymes which are responsible for the process of phagocytosis, to
increase the efficiency of macrophages by increasing their destructive capability. -
because we have a problem so phagocytosing should be increased in order to get rid of
the injurious agent.
• More active metabolism, i.e. greater ability to kill ingested organisms because as we
know one way to kill microorganisms is oxygen burst and production of toxic oxygen
free radicals … so when we have more active metabolism these products will increase
which will result in more ability to kill microorganisms
• Epithelioid appearance under the microscope which means macrophages would look
like epithelial cells; containing abundant cytoplasm and would have a large size (very
different from circulating monocytes)
Now let’s focus here guys to get the idea clear and simple:

We have 2 pathways:
 M1: Classically activated macrophages
 M2: Alternatively activated macrophages
Both of them can be seen in chronic inflammation as we used to say in the beginning of the
lecture “tissue destruction and tissue repair simultaneously” …. Now M1 is responsible for
inflammation and tissue destruction and M2 is responsible for tissue repair(fibrosis and
neovascularisation).
We also have mediators for each pathway (M1 and M2), and at the same time the mediators of
M1 pathway will inhibit M2 pathway and the mediators of M2 pathway will inhibit M1
pathway, so we have an inverse relationship: as M1 increases M2 decreases and vice versa.

 IL-13 and IL-4 are inhibitory or anti-inflammatory cytokines which means they induce
the M2 pathway while microbes
 IFN-gamma and other mediators are pro-inflammatory cytokines which means they
induce M1 pathway.
 M1 will produce two groups:
1) ROS, NO and lysosomal enzymes which will cause microbicidal actions including phagocytosis
and killing of many bacteria and fungi.
2) IL-1, IL-12, IL-23 and other chemokines which will cause inflammation
As for M2 it will also produce two groups: TGF-β : Transforming growth factor
beta
1) Growth factors and TGF-β which will cause tissue repair and fibrosis
2) IL-10 and also TGF-β which will cause anti-inflammatory effects.

But why do we need to have this equation with these two pathways and all of these chemical
mediators?! The answer is that because we need to keep balance between destruction and repair “as
simple as that”, we do not want neither tissue destruction nor tissue repair to go on and become
unstoppable
And finally, you must pay attention to the previous picture and the included mediators as the doctor
emphasized on it </3

So, How do Macrophages Accumulate at Sites of Chronic Inflammation? … Simply by chemotaxis

which works as a magnet for the inflammatory cells “including macrophages” to the site of injury:
• Recruitment of monocytes from circulation by chemotactic factors that include:
 Chemokines, C5a (it is called anaphylatoxin and is part of the complement system, so
when this system is activated this C5a will be produced).
 PDGF (platelet deriving growth factor)
 TGF-α
 Fibrinopeptides (fibrin-degraded products which means that we have fibrin production
as a result of acute inflammation)
 Fibronectin
 Collagen breakdown fragments.
So all these will increase in the injured tissue and will act as chemotactic factors that attract
circulating monocytes and once they arrive to the tissue they will turn into macrophages and
cause:
• Proliferation of macrophages at foci of inflammation
• Immobilization of macrophages at sites of inflammation meaning that macrophages will stay at
the site of injury until the stimulus which is the chemotactic factors or infectious agent is
removed and that’s why chronic inflammation lasts for a long time/ year (prolonged process).

As the stimulus is not removed, the chronic inflammation will continue

Activated macrophages produce certain materials that help in chronic inflammatory response such as :
• Proteases: needed for killing microorganisms and extracellular matrix digestion which is part of
the inflammatory response.
• Complement(magnify the response) and clotting factors (which are responsible for coagulation)
• Oxygen species and NO: toxic products needed for killing microorganisms
• Arachidonic Acid metabolites: prostaglandins and leukotrienes (certain types of them)
• IL-1 & TNF: most potent pro-inflammatory cytokines which induce acute phase reactions such as
fever, anorexia, etc.
• Growth factors (PDGF, FGF, TGF-β) *FGF: fibroblast growth factor

**Details will be discussed later inshallah

Role of Activated Macrophages in Chronic Inflammation (the process we’ve talked about):

Fibrosis represents the repair process.

Quick recap:  As we said in the blood we have monocytes which due to chemotaxis move from the
bloodstream to tissue and become macrophages which will be activated by cytokines such as IFN-
gamma which is usually produced by activated t-lymphocytes and by activated macrophages in in order
to magnify the inflammatory response.
We also have non-immune activation of macrophages achieved by endotoxin (which is found
on the outer membrane gram negative bacteria), fibronectin, and other chemical mediators.

Now we have certain interactions between cells that are responsible for chronic
inflammation:
Macrophage-lymphocyte interaction

This picture represents the start of the process of inflammation let's take this scenario A certain
microbe entered the body, it has be to phagocytised by certain types of cell called antigen presenting
cells “one of them is macrophages” so they’ll take the microbe and display the antigen to the T
lymphocyte so it will be activated (especially T helper 1 and T helper 17).
 Now once these lymphocytes recognise the antigen they will be activated and they’ll start producing:
1)pro-inflammatory cytokines (IL-17 and TNF) which will recruit more leukocytes 2)other
inflammatory mediators 3) IFN-gamma which will activate macrophages that will produce pro-
inflammatory cytokines such as TNF and IL-1 and this will recruit more inflammatory cells resulting in
more inflammation …
“So in short T lymphocyte will recognize the antigen produced by macrophages and they’ll start the
process of inflammation by producing cytokines that activate macrophages and these macrophages will
also propagate the inflammatory response by also producing more and more cytokines and recruitment
of other inflammatory cells and inducing inflammatory response”.

‫بعرف نوعا ً ما انقلب راسكم بس اقرؤوا شوي شوي و تبعوا الصورة و اموركم تمام ان شاء هللا‬
We know that the fate of acute inflammation is one of the following:
1- Complete resolution: meaning that the tissue will go back to pre-inflammatory state “normal
state”
2- Turning to chronic inflammation
3- Fibrosis and tissue repair “when the destruction is substantial or the cells aren’t capable of
regeneration”

In this picture we have monocytes, neutrophils, fluids, necrotic tissue and proteins which are
the components of acute and chronic inflammation …
so regarding Neutrophils they release their proteases and destructive enzymes causing
necrosis then they will undergo apoptosis Macrophages will engulf them after their role has
ended, in addition macrophages also take debris produced by necrotic tissue and fluids and
proteins that have been extravasated from the blood “ it will take all the results of the
inflammation”, disintegrate them and produce growth factors that will induce repair such that
one of the aims of inflammation is that it paves the way for repair
So once we have tissue destruction there must be an inflammatory process which will start the
process of repair “by regeneration: production of new cells that takes the role of early
destroyed cells, or by fibrosis”
Now the last thing to talk about is Granulomatous Inflammation:
• Granulomatous Inflammation: A distinctive form of chronic inflammation
characterized by collections of epithelioid macrophages “histiocytes”
• Granuloma, in addition to epithelioid macrophages “main component”,
may contain one or more of the following:
• A surrounding rim of lymphocytes & plasma cells
• A surrounding rim of fibroblasts & fibrosis
• Giant cells: cells with multiple nuclei resulted from fusion of
macrophages (10-15 macrophages)
• Central area necrosis (contained in necrotising granuloma) e.g.
caseating granulomas in TB

‫ رح انام‬:‫انا‬
HAHAHAHA :‫االرق‬
HAHAHAHAHA :‫االوفر ثينكنق‬
HAHAHAHAHA :‫الذكريات الزفت‬
HAHAHAHAHA :‫المواقف المحرجة‬
HAWHAWHAW :‫كالب الشارع‬
Acute inflammation, chronic , macrophages, :‫الدكتور‬
‫آخر ساليدين‬,granuloma ,‫ طولت عليكم بعرف‬,Tb
Histopathology of Granuloma:

This is the typical appearance

of granuloma we have large
epithelioid macrophages,
scattered lymphocytes in
between plus a surrounding
rim of lymphocytes and
plasma cells

The picture shows a

giant cell with multiple
nuclei … actually we
have many types of
multi-nucleated giant
cells according to the
arrangement of nuclei
inside it but the most
important thing to
remember is that giant
cells can be part of the
Granulomatous
Inflammation.
 Here we have central area of
necrotic material surrounded
by epithelioid histiocytes
“macrophages” … which is
called caseating granuloma
which are mainly seen in
tuberculosis

‫مع انه الموضوع مبين سهل بالنسبة النا بس هو بالحياة الواقعية اصعب‬
: ‫من هيك بكتير عشان هيك‬
#respect_for_pathologists <3

This is a special stain called

acid fast stain (AFB Stain)
which is used to recognize
the presence of
mycobacterium TB or
mycobacterium in general
… and the red rods within
the macrophages are the
mycobacterium organism
highlighted by this stain.
When seen you can
establish the diagnosis of
TB
 Examples of Granulomatous Inflammation:

Mycobacterium tuberculosis (cause TB)

Mycobacterium Leprae (cause leprosy ‫) الجذام‬
Bacterial
Trepnema pallidum (cause syphilis)
Bartonella henslae (cause cat scratch disease)

Parasitic Scistosomiasis (the scientific name of bilharzia)

Histoplasma capsulatum (can mimic TB by producing caseating granuloma)

Blastomycosis
Fungal
Cryptococcus neoformans
Coccidioides immitis

Inorganic metals Silicosis, Byrelliosis (non-viable materials)

Foreign body Suture, other prosthesis, keratin (‫)او حتى انه تدخل بإيدك خشبة يعتبر جسم غريب‬

Sarcoidosis : its’ pathogenesis is not well-established but some people say

that it is an auto-immune pathogenesis that results in infusion of
Unknown
granulomas (characterisied by granulomatous inflammation)
in most parts of the body mainly the lungs and Hilary lymph nodes

Not all granulomas are TB because

Granulomatous Inflammation is a big topic and under it we
have tons of different diagnoses.
Morphologic Appearance of Chronic Inflammation:
• Ulceration
• Ulcer: Local defect or loss of continuity in surface epithelia
like gastric ulcer or duodenal ulcer (loss of surface
epithelium and exposure of underlying tissue)
• Chronic abscess “collection of neutrophils and surrounding tissue
debris that are known as pus” cavity *once this collection can not
be cleared it will be rimmed by chronic inflammatory cells in order
to prevent the damage from this toxic material to surrounding
tissue.
• Induration “‫ & ” َت َيبُس‬fibrosis (large injuries e.g. deep burns)
• Thickening of the wall of a hollow viscous (e.g.: chronic gastritis)
• Caseous necrosis
All of them can be seen in chronic inflammation depending on the site,
the cause and the duration

Systemic effects of inflammation

(Acute phase reaction "‫)"يللي بتخلي الجسم بحالة تأهب لاللتهاب‬:
• Mediated by IL-1, IL-6, TNF, which interact with vascular receptors
in the thermoregulatory centre of hypothalamus they induce
fever(elevation of body temp.) via local prostaglandins
production … these are called pyrogenic cytokines meaning
chemical mediators inducing fever
• Systemic manifestations include:
• Fever
 • Catabolism “increase the rate of metabolism”
• Increased slow wave sleep(no restful sleep), decreased
appetite
• Hypotension & other hemodynamic changes
• Synthesis of acute-phase proteins by the liver, e.g. CRP “C-
reacting proteins”, fibrinogen, serum amyloid A protein
(SAA)  these proteins are so important to memorize
• Leukocytosis: neutrophilia, lymphocytosis, eosinophilia
• Leukopenia: decrease the number of WBCs in some cases
• Increased ESR: “Erythrocyte Sedimentation Rate” which is a
marker of inflammation … once its’ concentration increases
that means that there is a process of inflammation going on
in the body.
ESR: We put blood in a tube and place it in the lab for
about 6 hours (ideally 24) and we see how much
erythrocytes sediment RBC's go down ‫ ترسيب‬and plasma
goes up. They then measure the rate of sedimentation
which is called ESR and is usually increased in acute
inflammation because the viscosity of blood will be
increased).
These mediators are produced when the body is in an emergency
state)
Systemic Acute-phase Reactions “a simple cartoon of what we’ve just
said”:
 So in short we have local inflammation that produces

1) IL-1, TNF and IL-6 which will affect the pituitary gland hypothalamus
that will produce
a) Prostaglandins which produce fever
b) ACTH which will cause the production of corticosteroids from the
adrenal cortex and these will induce the liver to produce the Acute-
phase proteins (CRP, SAA, fibrinogen, mannose binding protein and
complement components; which are all very important and have a
major role in inflammation)
2) IL-6 and TNF-α can go to the bone marrow and increase the
production of something called colony-stimulating growth factor which
induces stem cells to produce more leukocytes resulting in leukocytosis
which means an increase in the total number of WBCs.
I know … I know, so much to know and memorize but the thing is :
:P ‫احمدوا هللا انه الدكتور وقف هون النه لسا كان ضايل ساليدين‬

‫ واصدق‬،‫ وأي مصلحة تطـلبها إذا أنزلتـها بباب هللا فإن هللا لن يخذلك‬،‫أي أمر تريده‬
‫ فإن هللا ال يخيـبك‬،‫مع هللا في دعائك‬

‫ ال تنسونا من دعائكم يقين‬.. ‫و بالحديث عن الدعاء‬

‫بعد التدقيق اكتشفنا إنو‬

‫السليدين إنشرحو بحزمة‬
‫ فإن شاء هللا بنضيفهم‬2
‫بالتفريغ الجاي لماً ينشرحو‬
‫لحزمة واحد‬