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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.
-
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).
-