number 10

Done by سام أبو عوضح

Corrected by ها أبو عجميةم

Doctor Mousa Abbadi

Arachidonic Acids

Activation of phospholipases trigger the release of arachidonic acids from

membranes, Arachidonic acids are important because they are converted to

bioactive mediators, these mediators are synthesised by two classes of

enzymes:

1) Cyclooxygenases ( which generate prostaglandins)

- Here are some important prostaglandins in inflammation:

Prostacyclin (PGI2): a vasodilator and an inhibitor platelet

aggregation

Thromboxane A2: vasoconstrictor and a promoter of platelet

aggregation.

2) Lipoxygenases (which produce leukotrienes and -lipoxins-)

Here are some important points about Arachidonic acid metabolism:

- Aspirin blocks prostaglandin synthesis by inactivating cyclooxygenases.

- Steroids are anti-inflammatory inhibitors of phospholipase (they are only

used if there was no other alternative).

- Imbalance between PGI2 (prostacyclin) and TXA2 (thromboxane A2)

levels is related to ischemic heart disease and cerebrovascular accident,

according to new studies.

- Remember that: PGE2 in addition to kinins/bradykinins causes pain,

however, PGE2 in addition to IL-1 and TNF causes fever.

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Cytokines

Mediators secreted by

many cells but mainly by

(activated lymphocytes,

macrophages and

dendritic cells) to regulate

immune and inflammatory

response

[lymphokines are

cytokines secreted by

lymphocytes].

This table shows the main

cytokines involved in

inflammation, apparently they are important and they might be included in the

exam ( العربي احفظوهمب ).[Note: Interlukin-17 works in both chronic and acute

inflammations]

These cytokines are important in local inflammation, some of these cytokines

(and other groups of chemical mediators) act on endothelium cells (of blood

vessels) and get circulated to other areas causing different effects (e.g.:

activation of leukocytes and recruitment of other cells), in addition to playing a

role in acute inflammation locally, cytokines are important in reactions of

systemic inflammation, here are some effects:

1) protective

o [TNF, IL-1 and IL-6 act on brain causing fever and on bone marrow

causing leukocyte production.

o IL-1 and IL-6 act on liver causing production of acute phase

proteins, these can be tested in patients to check the presence of

acute inflammation [such as CRP test and C3 test]

2) Pathological

[TNF acts on the heart causing Low Cardiac Output, (very high

temperature due to too much fever), or endothelial cells can get injured

due to excessive response and thus formation of thrombus].

Chemokines

These are small proteins that function as chemo-attractants [attract WBC’s to

site of injury].

40 chemokines and 20 receptors for chemokines have been identified so far,

the GPCR (G-protein coupled receptors) are common here.

Chemokines are classified into 4 major types: (according to the arrangement of

cysteine ( C ) residues in the proteins:

- C-X-C

- C-C

- C

- CX3C

Main functions: Acute inflammation and trying to maintain the skeleton of the

tissue. (يعني شكل النسيج الخارجي يضل زي ما هو).

Complement System

Circulating soluble proteins (in blood) normally in the inactive state. C1 to C20

are known but the most effective ones are C1 to C9.

Activation of the complement system proteins occurs through pathways [i.e. if

you want to activate C8 you cannot simply go and activate it, you must activate

C3 then go through certain reactions, which involves the activation of other

complement proteins (for example, activating C5 and C4 until we end up with

the activation of C8)

Note: C3 is most abundant; cleavage of which is the critical in all pathways

Complement proteins are important in both innate (you are born with it) and

adaptive immunities (you acquire it, e.g. by vaccination).

They affect vascular permeability (allowing substances to leak out of the blood

vessels and perform their jobs in the required region). They also work as

chemotaxis and have a role in the opsonization process

Chemotaxis: the movement to the site of injury

Opsonization: the process at which microbes are coated by specific

proteins (opsonins), to be recognized by phagocytic cells.

Another function is the “attack complex”, (membrane attack complex MAC)

they form holes in the pathogen’s membrane and attack it causing its death.

This attack complex is activated by the action of some C9 couples.

There are three pathways in which the complement system can be activated

1- Classical Pathway

Antigen-antibody complex is formed (adaptive immunity) then the

complement protein(s) act on the microorganism.

2- Alternative Pathway

The complement system proteins immediately act on the microorganism

recognizing it from its proteins or sugars on its cell wall without need for

antibody formation.

3- Lectin Pathway

In which plasma mannose-binding lectin, which is a circulating protein, binds

to carbohydrates in microbes & directly activates C1, in the absence of the

antibody.

All these pathways meet at the C3 point (activate it) then a cascade occurs to

activate other complement system proteins bringing about many functions.

[Histamine-like functions (vasodilation), MAC, etc.]

(each of the C proteins C3, C4 and C5 is “cleaved” (بنقسم) when activated into

two fragments (a and b), the “a” is called “Anaphylatoxins”).

C5a is the strongest anaphylatoxin

C3b is the main opsonizing protein

C9 is the one responsible for the MAC formation.

Regulation of the Complement System

If not regulated, the complement system will cause collateral damage (happens

sometimes in auto-immune diseases). So they have to be controlled (the 4th R

which is regulation), enzymes are needed. The most important ones are:

- C1 inhibitor, is the first protein in the cascade (remember in

biochemistry, in any pathway the first reaction is among the ones to be

regulated).

Angioedema (which is rare) occurs as a result of this inhibitor’s

deficiency. (it is a swelling in the neck causing suffocation (اختناق), that

could be lethal).

- Decay accelerating factor (DAF) inhibits C3 convertase, the common

initial stimulated complement in the 3 pathways, this inhibitor with the

CD59 inhibit the MAC. Its deficiency leads to Paroxysmal nocturnal

hemoglobinuria (PNH) (paroxysmal= attack, Nocturnal= at night,

hemoglobinuria= hemoglobin seen in urine) so urine becomes bloody

and this usually happens at night.

- Factor H causes proteolysis of C3 convertase enzyme (C3 is also

inhibited); mutations in factor H cause hemolytic uremic syndrome

(HUS) (sometimes seen in ICU (intensive care unit), hemolysis and renal

failure happens too).

The C-proteins themselves can be deficient (often seen with marriages from

the same family) making the person more susceptible to infections.

Other Mediators

Here are main ones, (defects here can cause many diseases, which are targets

for many therapies):

- Platelet activating factor (PAF): causes platelet aggregation, and

enhances thromboembolism, some drugs work against this factor to

decrease blood clotting (especially in atherosclerosis).

- Protease activating receptors (PARs): similar to PAF.

- Kinins: active by-product is bradykinin (active form), responsible for pain,

vasodilation, vascular permeability and smooth muscles contraction.

- Neuropeptides: in CNS. Include substance P and neurokinin A.

Neuropeptides are behind the neural response to inflammation.

This table is very important. (شكله عليها أكثر من سؤال في الاختبار)

Morphology of Acute Inflammation

Main changes are vasodilation and accumulation of WBCs and fluids in the

extravascular tissues leading to the following morphological changes:

Edema Fluid and proteins in interstitium Redness Rubor

Warmth Calor

Swelling Tumor Loss of function Laesa

Pain Dolor

- The words in italic (not bold) in the right column of the table are the

medical terms to the conditions and morphological changes described in

the left column. (i.e Pain is called dolor in the medical field).

- Morphological changes are macroscopic (seen by naked eye) and

microscopic (seen with microscopic examination).

Serous Inflammation

Vesicles filled with clear fluid are seen, if left with no treatment they can “pop”

and cause problems (exacerbation)

It is a transudate not an exudate (only small amount of cells and proteins in

the fluid). Rarely do pathologists get biopsies of this case (other medical

personnel identify this inflammation easily with no need of further

examination).

Fibrinous Inflammation

A lot of fibrin product (usually on the surface of the organs such as on the

pericardium and pleura. In case of pericardium, this causes pericarditis in

which the heart can no longer pump blood normally due to the pericardium

becoming stiff and strong, not allowing the heart to pump and work easily),

this happens by a large vascular leakage and coagulation of fibrin product from

the blood (lots of fibrin seen under microscope, categorized by its red color in

H&E stain)

Purulent (Suppurative) Inflammation

If the inflamed area gets infected then pus accumulates and it can be seen

under the microscope, with lots of neutrophils. In addition to that, bacteria can

be detected in gram-stain test. So, pus is rich in neutrophils, cell debris and

sometimes bacteria (exudate).

The common bacteria in skin inflammation is staphylococcus. (e.g white/yellow

spots, people used to drain these “abscesses” (الدمل) by themselves, this is not

wrong, drainage is the correct treatment for this situation).

Ulcers

Another feature of inflammation. A discontinuation of the epithelium. it could

be either superficial (called Superficial erosion), or deep (acute) and then can

become chronic (called acute/chronic ulceration). Quite common in the GI,

skin and mucosal surfaces.

Outcomes of Acute Inflammation

The most preferred outcome is a complete resolution, with very little collateral

damage and a return to normal as much as possible (as if not infected), this is

the most common outcome.

However, the acute inflammation sometimes can become chronic

inflammation due to many reasons (e.g. the pathogen being very virulent and

withstanding all efforts of WBC’s like TB and hepatitis C). In some cases, the

healing process of a severe acute inflammation can only be completed by

fibrosis (fiber replaces original cells), if the fibrosis covers a small scale and

minimal, then no problems arise, but if it is recurrent and each time a new

region undergoes fibrosis, this can lead to serious problems, this is the

mechanism of liver cirrhosis [liver can function even if only 1/7 of it, is still

functional, this is good in terms of small damages, but we won’t be able to see

symptoms till it is actually late (when approximately 90% of the liver has been

damaged)].

Chronic Inflammation

When chronically inflamed, neutrophils are not present because of their short

life-span, but lymphocytes, macrophages and sometimes eosinophils are

present (allergy/parasitic infection), which have longer life-span, because

chronic inflammation lasts for longer time when compared to the acute

inflammation.

In addition to the difference in the activated sentinel cells, another important

difference is that the chronic inflammation causes more tissue injury when

compared with acute the inflammation, because our body always tries to

repair by producing new chemical mediators, especially those that promote

fibrosis, this may damage the organ, and the damage varies according to the

site of damage and the time of fibrosis.

Chronic inflammation can either follow acute inflammation or may be

insidious, smoldering, de novo (انت مش داري عنها) like liver cirrhosis.

General causes of chronic inflammation:

Persistent infections Mycobacteria (TB), viruses, fungi, parasites. Delayed hypersensitivity reaction. Granulomatous inflammation

Hypersensitivity diseases RA, asthma, MS. May end in fibrosis of end organs

Prolonged exposure to toxic agents (exogenous or endogenous)

Silica (silicosis) Atherosclerosis (cholesterol)

Other associated diseases Alzheimer's, Metabolic syndrome of Diabetes Mellitus

Morphological Features of Chronic Inflammation

- Infiltration by chronic inflammatory cells (Macrophages, lymphocytes

and plasma cells, NOT neutrophils).

- Characterized by more tissue destruction in comparison to acute

inflammation.

- Attempts at healing by fibrosis and angiogenesis (production of new

blood vessels, laydown of collagen and fibroblastic proliferation due to

stimulation by specific fibrogenic factors).

Cells and Mediators of Chronic Inflammation

- There are lots of interactions between Macrophages and lymphocytes

and the mediators they release.

- Eosinophils and mast cells (and the mediators they produce), can also

play a role in allergic reactions

- Macrophages they are the major players in chronic inflammation; they

produce many mediators: TNF, IL-1 and Chemokines.

- Feedback loop with T-cells (a lymphocyte) (one cell releases mediators

and the other regulates it).

- Phagocytosis.

o Circulating monocytes have a 1 day half-life, but when they enter

the tissue they become macrophages and survive longer.

o Remember: some macrophage-like cells originate from

monocytes, they have longer half-lives, which can reach months

long, they have different names in different organs such as

Kupffer cells in the liver, Langerhans cells in skin, osteoclasts in

bones, alveolar macrophages, microglia in CNS, sinus histocytes

etc.; (the Mononuclear phagocytic system, see introduction to

histology).

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