Last lecture we discussed the nitric oxide and the oxygen derived free radicals

and their role in increasing 1Chemokines,, 2Cytokines & 3Adhesion molecules. And at
higher levels this will lead to epithelial damage and thrombosis and protease
activation and inhibition of antiproteases and direct damage to other cells.

So protective mechanisms against the free radicals include: transferrin,

ceruloplasmin, catalase, superoxide dismutase, and glutathione which we call the
antioxidants.

And we discussed the lysosomal constituents and their effects and their
mechanisms of initiation. Which are released after death, and leakage of phagocytic
vacuoles frustrated phagocytosis (fixed on flat surfaces) and after phagocytosis of
membranolytic substance like urate.

And also they will have the effect of neutral proteases effects like:
 Elastases, collagenases, and cathepsin
Cleave C3 and C5 producing C3a & C5a
 Generate bradykinin like peptides

We have already discussed this in the different sections of inflammation.

They also minimize the damaging effects of proteases is accomplished by

antiproteases like:
 Alpha 2 macroglobulin
 Alpha 1 antitrypsin

SO after this we need to see the morphological appearance of acute

inflammation.

When the inflammation exist in an organ or tissue of your body there must be
morphological evidence; the features that we see by the naked eye, if we examine
the organ or the tissue what kind of stages do we see, these morphological stages
depend on the site of inflammation and the persistence of such inflammation and
therefore we get deferent effects and deferent morphological appearances!

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 We can subdivide the morphological appearances into:

1) Catarrhal appearance:
 Acute inflammation with mucous hypersecretion like common cold; the
patients will have flue with mucous hypersecretion in the oral cavity and the
oropharinx.

This is the kind of catarrhal inflammation which affects the mucosas or the
mucous secreting lining epithelium.

Sometimes it also occurs in the appendix,, when there is early appendicitis

where there is only catarrhal inflammation involving the lining epithelium we call
it catarrhal appendicitis .

2) Serous appearance:
There is abundant protein-poor fluid with low cellular content like in skin blisters
and in body cavities; like in the pleura, peritoneum, and in the pericardium .

We will have serous fluid with low protein content we call it serous
inflammation, or we call it serous pleuritis, serous pericarditis and so on…

3) fibrinous:
When this fluid is having a higher content of fibrin, which is (fibrin and
fibrinogen) are serum proteins, in this context this fibrin will form like a
meshwork which will lead to a thick fibrous tissue or accumulation of thick
exudate which is rich in protein and especially fibrin, this will lead to a fibrinous
inflammation.

Therefore we may have acute fibrinous Pericarditis, or fibrinous pleuritis.

With the presence of this thick protein-containing fluid at the surface of the
pleura or the pericardium and it's resolved by fibrinolysis. But if it's not resolved
by fibrinolysis this might lead to organization of this fibrinous material leading to
fibrous tissue formation and scarring and if this in the pericardium for example
this fibrous tissue will lead to restriction of the movement of the heart , so we
call it restricted cardiomyopathy or restricted Pericarditis . And if this occurs in
the pleura this will lead to restriction of the respiratory process.

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4) Suppurative (purulent):
Now when this fluid containing higher content of neutrophils, microorganisms
and tissue debris, this will lead to the formation of Pus like fluid or inflammatory
fluid and may lead to the formation of abscesses (focal localized collection of
Pus) and that’s why it's called suppurative or purulent inflammation.

When there is a collection of Pus within a hollow organ this is called Empyema.

5) Ulcers:
If the inflammation leads to a defect of lining of an organ or tissue this will lead
to ulceration.

These ulcers occurs mostly in the skin or the GI tract and the most of these
situations will have like a persistence infection for example in the GI tract where
we have the gastritis (the inflammation of the gastric mucosa) which is caused by
bacteria (like H. pylori) will lead to continuous inflammation and regeneration
incapability [the regeneration will not compensate the continuous inflammation]
this will lead eventually to slotting of the mucosa, and we call this Ulcer, and
that’s why we find most ulcers in the stomach and duodenum. And the same
thing will occur in the skin.

This is a kind of subcutaneous abscess

formation, and as you can see here we said
that the features of inflammation is redness,
hotness and it contain Pus and this might
impair the function of the organ.

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Another example is the lung abscess, and to
the right is a cross section where we have
multiple abscesses where we see the
localization of Pus, multiple localized
accumulations of Pus and neutrophils in the
lung tissue.

Fibrinous Pericarditis is where we have

these fibrous material coating the
pericardium, which we said that it may
eventually resolved by fibrinolysis action, or
not resolving which will lead to the
formation of fibrous tissue.

Gastric ulcers are an example of persistence

continuous acute inflammatory process in
the GI tract, where this lead to ulceration of
the mucosa of the stomach.

This is an ulcer of the foot and the skin

ulceration is because of recurrent infections,
recurrent acute inflammatory processes.

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 Burn Blister: there is again accumulation of
fluid in the subepidermal layer of the skin
usually caused by friction, burning, freezing,
chemical exposure or infection.

What are the outcomes of acute inflammation?

So either we have a complete resolution with back to normal status in the tissue
or organ and this through the clearance of injuries stimuli and removal of the
exudate fibrin and debris and reversal of the changes in the microvasculature and
the replacement of the lost cells and regeneration. So this is what we call it
complete resolution after acute inflammation.

Or this will be to heal and we will see organization like fibrosis through formation
of granulation tissue and while we get such organization by fibrosis we get it in
situation where we have substantial tissue destruction where there is very massive
tissue destruction. so regeneration or complete resolution can't be achieved by this
pattern so we need to repair by fibrosis so substantial tissue destruction or the
tissue itself" the kind of the tissue" there are some specific form of tissue that can't
have the ability or can't regenerate so they will repair by healing or by fibrosis or
sometime when we have extensive fibrinous exudates as we suggested this will heal
by fibrosis.

Now sometimes we can have abscess formation again where there is an

infection or acute inflammation become localized in one area like lung abscess or
liver abscess we well have an abscess formation.

Development of abscess formation especially if they are in the body inside

organs they are difficult to treat even with antibiotics and therefore we need IV
antibiotics to treat these abscesses because we need the maximum concentration
of the antibiotics to reach the areas of abscesses of coarse all progression of acute
inflammation into chronic inflammation. So this is one of the pathways or one of
the outcomes of the acute inflammation is to progress into chronic inflammation.

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 This is again just to summarize the acute inflammation and resolution and
healing. So if we have an injury this injury might be infarction bacterial infection or
toxin or trauma and lead to acute inflammation with its vascular and cellular
changes that we have mentioned and with time this will resolve by clearance of
these harmful stimuli "or mediators " and replacement of the injury cells and
normal functions so that go normal. Now if there is localization and Pus formation
or abscess here this might lead to abscess formation and or healing leading to
fibrosis if there is massive destruction of the site of the injury such healing or the
abscess formation which will heal may lead to fibrosis such fibrosis will lead to loss
of function.

Now if there is progression or continues and persistent stimulation of this acute

inflammation this will lead to progression to chronic inflammation and this chronic
inflammation progression will be associated with other changes that we will discuss
now .

Which are:
1) Angiogenesis: formation of new blood vessels
2) Fibrosis: scar formation
3) Mononuclear inflammatory cell infiltrates.

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 Now this diagram to illustrate the complete resolution of inflammation putting
the action of inflammation and the sequence of events:

Of course some of the fluid and proteins will be reabsorbed by the lymphatic
system which present at the site of infection.

And this will bring edema and fluid and proteins again into the lymphatic
circulation at the site of injury.

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 The local inflammatory reaction may fail in containing the injurious agent, so
there is like secondary lines of defense which are:

 The Lymphatic system:

 Lymph vessels drain offending agent, edema fluid and cellular debris, and
may become inflamed, and that’s why we have what we call Lymphangitis
[the inflammation of the lymphatic vessels], these lymphoid vessels drains all
these materials and microbes back to the lymph nodes and then we may have
Lymphadenitis [inflammation of the draining lymph nodes of that site of
infection], and that’s why when you have an ulcer or inflammation in your lip
or inside the mucosa or even acne after a while you will feel palpation , and
that’s an enlarged lymph node.

 Secondary lines of defense may contain infection, or may be overwhelmed

resulting in Bacteremia [the presence of bacterial toxin in the circulation].

 The Macrophage phagocytic system (MPS) [the reticuloendothelial system

(RES)]:

It is the combination of the phagocytic cells of the spleen, liver and bone
marrow.

In massive infections, bacterial seeding may occur in distant tissues, which

means if I had a sever pneumonia in the lung for example, and the bacteria had
access to the circulation this will to dissemination of the bacteria to the deferent
parts of the body, and this will lead to infection and abscess in deferent parts of
the body; this will go to the liver, kidney causing for example liver or kidney
abscesses or in any other part of the body the microbe get access to. And we call
this dissemination of the bacterial infection.

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 Now in summary, the effects of acute inflammation in general are:

The acute inflammation process facilitates the entry

of Antibiotics to the specific site of infection by
cytokines and the angiogenesis and without the
acute inflammation it will be difficult to secure
enough concentration of these antibiotics at the site
of infection.

On the other hand acute inflammation might lead to

an inappropriate inflammatory response like
anaphylaxis or hypersensitivity reactions.

Definition:

Inflammation of prolonged duration (weeks, months, or years) that starts

either rapidly or slowly and characterized by equilibrium of:

 Persistent injurious agent.

 Inability of the host to overcome the injurious agent.

Characteristics:

Chronic inflammatory cells infiltrate:

 Lymphocytes
 Plasma cells
 Macrophages

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 Tissue destruction [more than in acute]

Repair:
 Newvascularization (angiogenesis)
 Fibrosis

 Progression from acute inflammation like Tonsillitis, osteomyelitis which start as

acute inflammation then progress into chronic one.

 Repeated exposure to toxic agents like Silicosis [exposure to silica], asbestosis

[exposure to asbestos, used in building ships], hyperlipidemia which is increased
lipid concentration in the blood and may lead to atherosclerosis.

 Persistent microbial infections; like 1Mycobacterium which is the cause of

Tuberculosis (TB) and other infectious diseases, or 2Treponema such as
trepoenma palladium which is the cause of syphilis, or 3Fungi; those microbes
known as persistence microbial agents that cause chronic inflammation.

 Viral infections are also a major cause of chronic inflammation because viruses
do not actually lead to the stimulation of neutrophils, they stimulate directly the
lymphocytes. And that’s why viral infections are characterized by seeing
lymphocytes.

 Autoimmune and allergic disorders are specific for chronic inflammation like
Rheumatoid arthritis, Systemic lupus erythematosus (SLE), inflammatory bone
disease (IBD), and B. asthma.

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Macrophages:

Derived from the circulating monocytes; when the cells are in the circulation we
call the monocytes but when they go out to the tissues we call them macrophages.

In the circulation they have some sort of short half life (1 day), on the other hand
the tissue macrophages in the tissues they have longer half life and become
activated there.

They are usually scattered in the tissues:

 In the liver we call them kupffer cells.
 In the spleen and lymph nodes we call them sinus histiocytes.
 In the lung, Alveolar macrophages.
 And at the CNS we call them microglial cells.

All these are macrophages that are scattered in deferent tissues or organs.

They are mainly activated by Interferon-gamma (IFN-‎γ) secreted from T

lymphocytes; such activation will lead to deferent morphological and functional
changes in the macrophages:
 Increase the cell size, and this is what gives the macrophages its epithelioid
appearance, they become large and flat, and that’s also why we call them
epithelioid macrophages; when you see epithelioid macrophages in the tissue
you know that those are activated macrophages.
 This also will increase the lysosomal enzymes.
 More active metabolism.
 Greater ability to kill ingested organisms.

How do Macrophages Accumulate at Sites of Chronic Inflammation?

 Recruitment of monocytes from circulation by chemotactic factors; the

monocytes will be activated from the circulation to go the outside, and those
chemotactic factors include:
 Chemokines, C5a, PDGF, TGFa, fibrinopeptides, fibronectin, collagen
breakdown fragments.

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 Proliferation of macrophages at the site of inflammation.

 Immobilization of macrophages also at the site of inflammation.

That’s means that the inflammation will try to keep all the macrophages at the
site of infection or inflammation.

Products of Activated macrophages

 Proteases
 Complement and clotting factors
 Reactive oxygen species & Nitric oxide.
 Amino acids metabolites
 IL-1 & tumor necrosis factor (TNF)
 Growth factors (PDGF, FGF, TGFb) [leading to newvasculerization/
angiogenesis]

As we see in the figure below, the circulating monocytes become adherent to

the wall of the vessel then emigrate out of the vessel to become tissue
macrophages, and then the activated T cells will secrete the cytokines like IFN- γ or
by other things like endotoxin, fibronectin, or chemical mediators leading to
activation of the macrophages.

Those activated macrophages will lead to either Tissue injury or Fibrosis (STUDY
the figure below)

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 There are other cells than macrophages are involved in the process of chronic
inflammation such as:

 Lymphocytes:
 T-1 lymphocytes will secrete cytokines that will lead to the activation of
macrophages.
 B lymphocytes will lead to the formation of Plasma cells which are important
in the secretion of antibodies.

 Eosinophils:
 They are numerous in parasitic infections and allergic conditions.
 Recruited by Eotaxin (chemokine) and other mediators.
 Release major basic protein.

 Mast cells:
 They are usually coated by Immunoglobulin-E (IgE) and once the cells are
activated by allergens leading to the release of histamine and Amino acid
metabolites.

 Neutrophils although it is one of the features of acute inflammation but it also

there with persistent microbes, necrotic cells or mediators.

The most important cytokine that will be released from an activated macrophage
is IL-12 which will activate the T-lymphocytes.

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 A distinctive form of chronic inflammation characterized by collections of
epithelioid macrophages that means it is characterized by the predominance of
activated macrophages.

Now such collection of activated macrophages with the presence of

multinucleated giant cells we call it granuloma and such granuloma may have one
or more of the following:
» a surrounding rim lymphocytes & plasma cells.
» a surrounding rim of fibroblasts & fibrosis.
» giant cells.
» central necrosis a special type of necrosis called caseating necrosis like in
caseating granulomas in TB.

This is the histopathological appearance of

Granuloma, all these are epithellioid
macrophages and infiltration with some
lymphocytes, plasma cells.

And this is another type of granuloma which

include multinucleated giant cells; which are
more than one epithelioid macrophages fused
together to form the giant cell.

Now if this granuloma is undergoing necrosis they are two types: one is the usual
necrotic granuloma where we still can see the shadow of the cells.

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 The other is the caseating granuloma where you
don’t see any shadow of the cells , and morphologically
it is cheesy like or pus like appearance and this is very
characteristic of TB.

Now if we want to identify the underlying cause of

such granuloma ( caseating granuloma) is the
Mycobacterium tubercoli which is acid fast bacilli we do
a special stain we call the Ziehl–Neelsen stain, and the
mycobacterium will be seen as short rods at the center of
the caseating necrosis.

So there are many types and causes of granuloma as you can see below:

Bacterial Mycobacterium tuberculosis

Mycobacterium Leprae
Treponema pallidum
Bartonella henselae
Parasitic Schistosomiasis
Fungal Histoplasma capsulatum
Blastomycosis
Cryptococcus neoformans
Coccidioides immitis
Inorganic metals Silicosis, Berylliosis (caused by kind of dust in people
raising chickens or birds)
Foreign body Suture, other prosthesis, keratin
Unknown Sarcoidosis (systemic granulmoatous disease)

P.S: The exam will be 40 questions 30 regarding cell injury and inflammation, and 10
about the 3 practical labs u had and the time of the exam will be about 40 mnts.

Good luck 

DONE by:

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