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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

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