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

Pathology, Lecture 12 (Lecture Notes)

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Page 1: Pathology, Lecture 12 (Lecture Notes)

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Granulomatous Inflammation

باسمك نحيا

Chronic 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).

We are going to have a quick lecture today, we will try to finish the

chronic inflammation, and this is the final lecture included in the exam. The exam will be on Saturday nshallah between 3:00 to 5:00 o’clock. There are 2 groups, the first group from 3:00 to 3:45, and then directly

after that the second group will do their exam. The exam is 40 questions, 30 questions are theoretical, and the

remaining 10 are practical. Make sure that you are stuck in your allocated computer lab and your

computer number. “the doctor emphasized on this point and he will consider any change in your seat number or computer lab as a cheating”

You can find you computer number and computer lab in your site or you can find a hard copy with your CR.

GOOD LUCK…

ABOUT THE

EXAM

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.

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

A granuloma may contain a surrounding rim of fibroblasts & fibrosis

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Examples of Granulomatous Inflammation

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“

As I told you, there are many cause of granulomatous inflammation, including bacterial, parasitic, fungal….etc causes.

Regarding the bacterial causes, the commonest and the most important one is Mycobacterium tuberculosis, Mycobacterium Leprae which cause Leprosy, Treponema pallidum which cause syphilis, and Bartonella henselae which causes Cat Scratch Disease which is another form of granulomas occurring in the lymph nodes in the inguinal area.

The parasitic causes include Schistosomiasis (also known as bilharzia, bilharziosis or snail fever).

Schistosomiasis also leads to the formation of granulomas and especially in

Bacterial

Mycobacterium tuberculosis

Mycobacterium Leprae

Treponema pallidum

Bartonella henselae

Parasitic Schistosomiasis

Fungal

Histoplasma capsulatum

Blastomycosis

Cryptococcus neoformans

Coccidioides immitis

Inorganic metals

Silicosis, Berylliosis

Foreign body

Suture, other prosthesis, keratin

Unknown Sarcoidosis

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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 االصطناعیة), 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. Of course there are other systemic granulomatuos

diseases, like chronic granulomatuos disease.

Prosthesis: A Fabricated substitute for a 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

قل وال ضل وال ذلومن اعتمد على هللا ال

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Consequences of Defective Inflammation

Consequences of Excessive 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.

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

Allergic reactions (whether it is acute or chronic)

Autoimmune disorders

Atherosclerosis ( تصلب الشرایین) we 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.

Vasodilatation

Prostaglandins

Nitric Oxide

Histamine

Increased vascular permeability

Histamine and serotonin

C3a and C5a (by liberating vasoactive amines from mast cells, other cells)

Bradykinin

Leuktrienees C4, D4, E4

PAF (platelet activating factor)

Substance P

Leukocyte recruitment and

activation

TNF, IL-1

Chemokines

C3a, C5a

Lukotriene B4

(Bacterial products, e.g., N-formyl methyl peptides)

Fever (Pyrogen )

IL-1, TNF

Prostaglandins

Pain

Prostaglandins (espically prostacyclin I2)

Bradykinin

Neuropeptides (not neuropathies)

Tissue damage

Lysosonal enzymes of leukocytes

Reactive oxygen species

Nitric oxide

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The Happy End Good luck in your exam

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

Done by your brothers:

Rasheed Elayyan Omar Abu-Ghaneemeh Maulla Al-Ali

بذرة الشر تهيج، ولكن بذرة الخير تثمر، إن االولى ترتفع في الفضاء سريعاً، و لكن جذورها في التربة قريبة، حتى لتحجب عن شجرة الخير النور و الهواء، ولكن شجرة الخير

.....تظل في نموها البطيء، ألن عمق جذورها في التربة يعوضها عن الماء و الهواء

الحقيقية و مع أننا حين نتجاوز المظهر المزور البراق لشجرة الشر، و نفحص عن قوتها على حين تصبر شجرة !...نافشة في غير صالبة حقيقية نة هشة صالبتها،تبدو لنا واه

الخير على البالء، و تتماسك للعاصفة، و تظل في نموها الهادئ البطيء، ال تحفل بما .قذاء و أشواكترجمها به شجرة الشر من أ

سيد قطب