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احملقق كوانن
Last lecture the doctor talked about Chemical Mediators of-
Inflammation, and their two sub-divisions according to their
source: Circulating plasma proteins, Cell-derived ones. And
she discussed the Cell derived ones in details; so, today's
.lecture will be about the circulating plasma protein
… Let's start
- :Circulating plasma protein →
1. Coagulation (clotting) / fibrinolytic factors (both
names are highly correlated to each other).
2. Kinin system.
3. Complement.
1- Coagulation (clotting): -
✓ To activate the coagulative system, we have two different
pathways according to the type of stimulus:
A) Intrinsic Pathway B)Extrinsic Pathways.
These Pathways are: group of activating factors, in which
activating one factor induces the activation of other factors;
cascade-like reaction. The two pathways will produce the same
product but in different pathways depending on the stimulus. At
the end, they both meet at the same pathway.
✓ In intrinsic pathway the first factor activated usually is
factor 12(XII) and this is activated by
((High-molecular-weight kininogen-HMWK), Prekallikrein
and negative Surface) → once it gets activated, it activates
factor no. 11(XI) → and then this will activate factor no.9(IX)
→ then factor no.9 in the presence of (activating factor 8
-VIII-) will lead to the activation of the most important factor
in our series which is factor no.10(X). → factor no.10 in the
presence of factor no.5 will act on prothrombin and convert it
to thrombin → then thrombin acts on Fibrinogen and
converts it to fibrin. (P.s: if you didn't get it very well see
the image on the next page.)
✓ Fibrin is the most important product for coagulation since it
is the most important component in clot formation. The clot
is formed from fibrins and platelets → then fibrin monomers
are cross linked by activating factor 8 VIII.
✓ B) Extrinsic pathway: it starts with the activation of factor
no.7(VII) (because of tissue trauma) which requires the tissue
factor (TF) to initiate this process; by converting factor 7
directly to activated factor no. 10 (skipping all the sequences
that the intrinsic has to pass through) → prothrombin →
thrombin → fibrinogen → fibrin. (the same final product as
the intrinsic pathway).
From slides: -
❖ Fibrin clot at site of injury helps in containing the cause.
❖ Fibrin clot provides a framework for inflammatory cells;
kind of like threads holding the inflammatory cells.
❖ Xa (activated factor 10), aside from its function in converting
prothrombin into thrombin, it causes an increase in vascular
permeability and helps in leukocyte emigration.
❖ Thrombin causes leukocytes adhesion, platelets
aggregation, generation of fibrinopeptides, and is a
chemotactic factor.
❖ Fibrinopeptides are chemotactic & they induce
vasopermeability.
● The intrinsic and extrinsic pathways function is to produce a
clot, but we don't want them to be activated all the time →
because once they are turned on they need another system to
turn them off; if that didn't happen the body will be in a state
of widespread thrombosis. So, in order to prevent this from
happening, we use the Fibrinolytic pathway which is
always linked to the coagulative process. So briefly the
function of fibrinolytic pathway is to inhibit the
coagulation process. (negative feedback mechanism)
اﺣﻨﺎ ﺑﺪﻧﺎ ﻋﻤﻠﯿﺔ اﻟﺘﺨﺜﺮ و ﺗﻜﻮﯾﻦ اﻟﺨﺜﺮة ﺑﺲ ﺗﺤﺪث ﺑﺎﻟﻤﻨﻄﻘﺔ اﻟﻲ- : ﺑﺎﻟﻌﺮﺑﻲo
ﺑﺘﺤﺪث ﻓﯿﻬﺎ اﻹﺻﺎﺑﺔ أو اﻻﻟﺘﻬﺎب ﻣﺎ ﺑﺪﻧﺎ اﯾﺎﻫﺎ ﺗﺤﺪث وﺗﻀﻞ ﻣﺴﺘﻤﺮة ﺑﺸﻜﻞ ﻛﺒﯿﺮ
ﻓﻠﻬﯿﻚ اﺣﻨﺎ ﯾﻠﺰﻣﻨﺎ ﻃﺮﯾﻘﺔ ل ﻧﻘﺪر ﻧﻮﻗﻒ ﻋﻤﻠﯿﺔ اﻟﺘﺨﺜﺮ وﻧﻤﻨﻌﻬﺎ ﻣﻦ..ﺑﺎﻟﺠﺴﻢ
.اﻟﺤﺪوث ﺑﻌﺪ اﻟﻤﻨﻄﻘﺔ اﻟﻤﺮادة ف ﻟﻬﯿﻚ ﻟﺰﻣﺘﻨﺎ ﻫﺎي اﻻﻟﯿﺔ
● In Fibrinolytic pathway: Plasminogen will be activated by
kallikrein to form plasmin → which degrades fibrin. Not
only does plasmin function to degrade fibrin, it also activates
the complement system.
● XIIa also activates the fibrinolytic pathway to prevent the
widespread thrombosis- negative feedback for the
degradation of fibrin.
● Fibrin split products increase vascular permeability.
● Plasmin cleaves C3 to form C3a, leading to vasodilation and
an increase in vascular permeability. (C3 and C3a are
anaphylatoxins)-complement system-.
● Plasmin activates XIIa amplifying the entire process
As you can see factor XII is able to activate the fibrinolytic system
and the fibrinolytic system itself can activate factor XII.
● Note: Thrombin is an important structure in our body not
only due to its role in coagulation process, but it has another
important role in the inflammatory process;it binds to a
certain receptor →called protease-activated. These receptors
are found in platelets, epithelial cells and even in smooth
muscles and this helps in selectin recognition.
Thrombin as an Inflammatory Mediator: -
→Binds to protease-activated receptors (PARs), expressed on
platelets, endothelial cells and sm. muscles leading to:
❖ P-selectin mobilization.
❖ Expression of integrin ligands.
❖ Chemokine production.
❖ Prostaglandin production by activating cyclooxygenase 2
which plays a role in generating arachidonic acid
metabolites.
❖ Production of PAF (platelet activating factor).
❖ Production of NO.
2- Kinin System:
➔ Leads to the formation of bradykinin from
HMWK.
➔ Effects of bradykinin:
✓ Increased vascular permeability.
✓ Arteriolar dilatation.
✓ Bronchial smooth muscle
contraction(bronchospasm)*.
✓ Pain.
✓ Short half-life (inactivated by kinases).
-Prostaglandin E2 and b radykinin are the only
factors that cause pain .
-Most mediators as you can see increase vascular
permeability.
*Remember that leukotriene C4 , D4 and E4 from aa
metabolism also cause bronchospasm (LTD4, LTC4,
LTE4).
[Please read the summary of effector functions from picture]
Defects in the Complement System:
❖ Defects could happen due to a deficiency in the main
components of the complement system or in the inhibitory
proteins that inhibit these components after completing their
job.
❖ If we have C3 Deficiency, It’s really a big problem because it
is abundant in both pathways so its deficiency will block the
whole complement system. → i ncrease susceptibility to
recurrent infections.
❖ If we have a Deficiency in C2 and C4: that will not affect the
two pathways → it will only affect the classic pathway, so
they will be more susceptible to SLE (_systemic lupus
erythematosus_) an autoimmune disease in which the body’s
immune system mistakenly attacks healthy tissue in many
parts of the body by the action autoantibodies (antibodies
that bind to the contents of the cell nucleus i.e: anti-double
stranded DNA and all our cells have DNA hence these
antibodies cause injury to any organ).
❖ If we have a Deficiency in late components (C5 and later):
then we will have a low MAC (membrane attack complex) →
so the patient struggles in killing those microorganisms →
patients will have a high susceptibility to a certain type of
infection which is Neisseria infection. That's Because this type
of bacteria needs MAC to be killed.
❖ A deficiency in the inhibitors of C3 and C5 convertase such
as ↓ DAF → Decay-accelerating factor, a deficiency in this
factor will cause the complement system to stay active → this
will cause hemolytic anemia (lysis of RBC's).
❖ A deficiency in C1 inhibitor → angioneurotic edema.
Morphologic Appearance of Acute Inflammation
- We have different types of Morphologic Appearance of
Acute Inflammation, divided into:
1) Catarrhal: Acute inflammation + mucus hypersecretion (e.g.
common cold: runny nose and mucus hypersecretion).
2) Serous: Abundant protein-poor fluid (Transudate) with
low cellular content, e.g. skin blisters (such as in burns)
and accumulation of transudate in body cavities (usually
seen in patients with heart failure and renal failure because
they have increased hydrostatic pressure due to increased
fluids in the body).
3) Fibrinous: Accumulation of a thick exudate, which is rich
in fibrin, may resolve by fibrinolysis or organize into thick
fibrous tissue (e.g. in the cases of rheumatic fever, renal
failure leading to fibrinous pericarditis). -More
explanation-→ The problem is that the body can't get rid
of the fibrin-rich fluid so it will accumulate in thick
fibrous tissue and a problem appears when this occurs in
a critical site.
➔ Remember that the body needs to activate the fibrinolytic
system to get rid of the fibrin but sometimes when it is too
much the system cannot cause fibrinolysis of all this fibrin
and this ultimately leads to healing by fibrosis)
For example, if the pericardium of a patient with lupus is
attacked due to the condition, the pericardium will form an
exudate of fibrin or fibrous tissue or fluid that compress the
pericardium to the inside. This results in constrictive pericarditis,
in which the pericardium gets close to the heart muscle so it will
not have the ability to expand leading to h eart failure.
➔ Note: You need to know that the formation of fibrinous
tissue in critical organs interferes with the patient's quality
of life and leads to serious problems(such as pericarditis).
ﻗﺪ ﺗﺘﺤﻠﻞ ﻋﻦ ﻃﺮﯾﻖ اﻧﺤﻼل اﻟﻔﯿﺒﺮﯾﻦ أو ﺗﻨﻈﻢ،ﺗﺮاﻛﻢ اﻻﻓﺮازات اﻟﺴﻤﯿﻜﺔ اﻟﻐﻨﯿﺔ ﺑﺎﻟﻔﯿﺒﺮﯾﻦ
- ﻣﺰﯾﺪ ﻣﻦ اﻟﺘﻮﺿﯿﺢ- .(ﻓﻲ اﻧﺴﺠﺔ ﻟﯿﻔﯿﺔ ﺳﻤﯿﻜﺔ )ﻋﻠﻰ ﺳﺒﯿﻞ اﻟﻤﺜﺎل اﻟﺘﻬﺎب اﻟﺘﺎﻣﻮر اﻟﺤﺎد
اﻟﻤﺸﻜﻠﺔ ﻫﻲ أن اﻟﺠﺴﻢ )ﻧﻈﺎم ﻓﺒﺮﯾﻨﻮﻟﯿﺘﯿﻚ( ﻻ ﯾﻤﻜﻦ اﻟﺘﺨﻠﺺ ﻣﻦ اﻟﺴﻮاﺋﻞ اﻟﻐﻨﯿﺔ ﻓﻲ
، ﻋﻠﻰ ﺳﺒﯿﻞ اﻟﻤﺜﺎل.ﺑﺎﻟﻔﯿﺒﺮﯾﻦ ﻟﺬﻟﻚ ﺳﻮف ﺗﺘﺮاﻛﻢ ﻓﻲ اﻷﻧﺴﺠﺔ اﻟﻠﯿﻔﯿﺔ ﻓﻲ ﻣﻮﻗﻊ ﻏﯿﺮ ﻣﺮادة
،(pericardium) وﻫﺬا ﯾﻀﻐﻂ ﻋﻠﻰ اﻟﺘﺎﻣﻮر،lupus إذا ﻛﺎن اﻟﻤﺮﯾﺾ ﻣﺼﺎب ﺑﺎل
ﺑﺤﯿﺚ ﯾﻜﻮن ﻟﺪﯾﻪ ﺗﺮاﻛﻤﺎت اﻻﻓﺮازات أو اﻷﻧﺴﺠﺔ اﻟﻠﯿﻔﯿﺔ أو اﻟﺴﻮاﺋﻞ اﻟﺘﻲ ﻣﻦ ﺷﺄﻧﻬﺎ ﺿﻐﻂ
اﻟﺘﻬﺎب اﻟﺘﺎﻣﻮر ﻓﺈﻧﻪ ﯾﺠﻌﻞ اﻟﺘﺎﻣﻮر ﻗﺮﯾﺒﺔ ﻣﻦ ﻋﻀﻠﺔ اﻟﻘﻠﺐ أي:اﻟﺘﺎﻣﻮر إﻟﻰ اﻟﺪاﺧﻞ ﯾﺴﻤﻰ
.أﻧﻪ ﻟﻦ ﯾﻜﻮن ﻟﺪﯾﻬﺎ اﻟﻘﺪرة ﻋﻠﻰ ﺗﻤﺪﯾﺪ
4) Suppurative (purulent):
- accumulation of Pus: Creamy yellow or blood-stained fluid
consisting of neutrophils, microorganisms & tissue debris
e.g. acute appendicitis (when you open the cavity). ﺣﺐ اﻟﺸﺒﺎب
acne ﻣﺜﻼ.
- Abscess: focal localized collection of pus (it accumulates in
subcutaneous tissue or in any organ).
- Empyema: A collection of pus within a hollow organ(e.g:
gall bladder).
5) Ulcers: happens in the epithelial surface. ()ﺗﻘﺮح
- Defect of the surface lining of an organ or tissue.
- Mostly occurs in the GI tract or on skin.
Note: you will study these pictures in full details in the lab, so just
distinguish between them now and later on you will know the details.
Foot Ulcer- commonly occurs in
patients with diabetes or ischemia to
limbs; decreased blood flow causes
loss of epithelium and ulceration
Outcome of acute inflammation:
1) Complete resolution (back to normal) → removes the bad
agent.
Conditions:
• Clearance of injurious stimuli.
• Removal of the exudate, fibrin & debris.
• Reversal of the changes in the microvasculature.
• Replacement of lost cells (regeneration).
→If we don’t have a complete resolution with its full
steps, then we will skip to healing.
2) Healing by fibrosis:
• Organization by fibrosis through formation of
Granulation tissue (a collection of fibroblasts and
blood vessel formation)→collagen, and that happens
in the following cases:
✓ Substantial tissue destruction affects the frame
and it can't get back to normal.
✓ Tissue cannot regenerate such as heart myocytes
and neurons.
✓ Extensive fibrinous exudates.
3) Abscess formation (if the microorganism was very virulent).
(ﻣﻜﺎن اﻟﺠﺮح ﻟﻔﺘﺮة ﻃﻮﯾﻠﺔ ﻋﺸﺎن ﺻﺎر ﻓﻲ ﻓﯿﺮوﺳﺎت )ﻋﺸﺎن ﻫﯿﻚ ﻟﻤﺎ ﺗﻨﺼﺎب ﻣﺮات ﺑﻀﻞ ﻣﺒﯿﻦ
4) Progression to chronic
inflammation: if it was
too extreme it will
develop to a chronic
one and also if the
acute one failed to
destroy it.
* All outcomes will
eventually lead to fibrosis
Role of Lymphatic System
in inflammation
If ihe local -
inflammatory
reaction failed in containing the injurious agent, we have
another defensive mechanism: Secondary lines of defense
1. Lymphatic system:
• Lymphatic vessels drain offending agents,
edema fluid & cellular debris, and may become
inflamed (LYMPHANGITIS).
• Lymph nodes may become inflamed
(LYMPHADENITIS).
• Secondary lines of defense may fail to contain
infections, or may be overwhelmed (meaning
that this defense system will fail) resulting in
BACTEREMIA ﺗﺴﻤﻢ اﻟﺪ مor toxemia.- which
requires the third line of defence (MPS)
2. MPS (mononuclear phagocyte system):
• Phagocytic cells of spleen, liver & BM.
• In massive infections, bacterial seeding may occur in distant
tissues. (Virulent types of bacteria may overcome all these lines of
defences and eventually lead to septicemia, which can be fatal
especially in immunocompromised patients), the bacteria would be
able to go to anywhere through the bloodstream and cause
inflammation in any organs it reaches. Hence if not controlled this
condition can be
fatal).