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What are the two ways in which cell-derived mediators of acute inflammation are made?

they are preformed in granules or synthesized in response to a stimulus


How do cell-derived mediators of acute inflammation work?

most mediators act by binding to specific receptors on different target cells


T or F. The actions of most mediators are loosely regulated and long-lived.

F. They are tightly regulated and short-lived


What are two examples of preformed mediators in secretory granules?

1) Histamine
2) Serotonin

termed 'vasoactive' amines


What cells make histamine?

mast cells next to vessels and circulating basophils and platelets

In humans, histamine causes arteriolar dilation and rapidly increases vascular permeability by inducing venular endothelial contraction and formation of interendothelial gaps. Soon after its release, histamine is inactivated by histaminase.


What cells make serotonin?

platelets. It induces vasoconstriction during clotting.


What are some examples of newly synthesized mediators?

prostaglandins, leukotrienes, platelet-activating factor, ROS, NO, cytokines


New synthesized mediators of acute inflammation are mainly made by which kids of cells?

leukocytes. These AA (arachidonic acid)-derived mediators act locally at the site of generation and then decay sponta- neously or are enzymatically destroyed.


One of the first events in acute inflammation is vasodilation of blood vessels to allow leukocyte diapedesis. Which cell-derived mediators aid in causing this to occur?

Histamine (increases permeabiltiy and causes dilation) and Serotonin (released during platelet aggregation)


Study Arachidonic Acid pathway

Study Arachidonic Acid pathway.

AA is released from these phospholipids through the action of cellular phospholipases that have been activated by mechanical, chemical, or physical stimuli, or by inflamma- tory mediators such as C5a.


Which arachidonic acid metabolites cause Vasodilation?

Prostaglandins PGI2 (prostacyclin),
PGE1 , PGE2 , PGD2

Endothelial cells, on the other hand, lack throm- boxane synthase but contain prostacyclin synthase, which is responsible for the formation of PGI2, a vasodilator and a potent inhibitor of platelet aggregation.

PGD2 is the major metabolite of the cyclooxygenase pathway in mast cells; along with PGE2 and PGF2α (which are more widely distributed), it causes vasodilation and potentiates edema formation.

The prostaglandins also contribute to the pain and fever that accompany inflammation; PGE2 augments pain sensitivity to a variety of other stimuli and interacts with cytokines to cause fever.


Which arachidonic acid metabolites cause Vasoconstriction?

Thromboxane A2 ,
leukotrienes C4 ,D4 , E4

platelets contain the enzyme thromboxane synthase, and hence TXA2, a potent platelet-aggregating agent and vasocon- strictor, is the major prostaglandin produced in these cells.


Which leukotriene metabolites cause Increased vascular permeability?

Leukotrienes C4, D4, E4 (produced mainly in mast cells and cause bronchoconstriction and increased vascular permeability.


Which arachidonic acid metabolites cause Chemotaxis, leukocyte recruitment/adhesion?

Leukotriene B4 , HETE

Once leukocytes enter tissues, they gradually change their major lipoxygenase-derived AA products from leukotrienes to anti-inflammatory mediators called lipoxins, which inhibit neutrophil chemotaxis and adhesion to endothelium and thus serve as endogenous antagonists of leukotrienes.

Platelets alone cannot synthesize lipoxins A4 and B4 (LXA4 and LXB4), but they can form these media- tors from an intermediate derived from adjacent neutro- phils, by a transcellular biosynthetic pathway.


Platelet-Activating Factor is derived from what?

phospholipids (like AA).

Originally named for its ability to aggregate platelets and cause their degranulation, platelet-activating factor (PAF) is another phospholipid-derived mediator with a broad spectrum of inflammatory effects.

it is generated from the membrane phospholipids of neutrophils, monocytes, basophils, endo- thelial cells, and platelets (and other cells) by the action of phospholipase A2.


How does PAF work?

PAF acts directly on target cells through the effects of a specific G protein–coupled receptor


What does PAF cause?

• Stimulates platelets to aggregate and causes their degranulation
• Bronchoconstriction (potent)
• is 100 to 1000 times more potent than histamine in inducing vasodilation and increased vascular permeability.
• can elicit many of the reactions of inflammation, including enhanced leukocyte adhesion, chemotaxis, leukocyte degranulation, and the respiratory burst.


What are the major cytokines in acute inflammation?

TNF-alpha (tumor necrosis factor), IL-1 (does some chronic too), IL-6, and a group of chemoattractant cytokines called chemokines.


What are the major cytokines in Chronic inflammation?

include interferon-γ (IFN-γ) and IL-12


TNF-alpha and IL-1 are mostly produced by which cells?

ACTIVATED macrophages (some mast cells and endothelial cells)

As mentioned earlier, IL-1 is also the cytokine induced by activation of the inflammasome.

these stimulate adhesion expression on endothelial surfaces


T or F. TNF-alpha decreases thrombogenicity

F. it increases the risk of having a clot


IL-1 activates which cells?

fibroblasts resulting in increased proliferation and production of ECM. Thus involved in chronic inflammation


Why do people that are acutely ill have an increased erythrocyte sedimentation rate?

IL-6 causes production of fibrinogen in the liver that causes red cells to 'stack'


What is an example of a negative acute-phase reactant (i.e. levels drops in acute illness)?



What PATHOGENIC effects can TNF-a have on the heart and endothelial cells?

thrombos formation risk


What PATHOGENIC effects can TNF-a AND IL-1 have on skeletal muscle?

they are both involved in insulin resistance


Plasma protein derived inflammation mediators mainly come from which organ?

the liver


Review coagulation pathway

Review coagulation pathway


Deficiency in C1INH leads to what disease?

HANE, hereditary angioneuotic edema, in which excessive production of kinins secondary to complement activation results in edema of multiple tissues including the larynx


Paroxysmal nocturnal hemoglobinuria is caused by what?

Genetic defect in the pigA gene resulting in lack of anchoring lipid of DAF and CD59 which results complement mediated lysis of red cells

Pee blood at night due to pH increase due to slower breathing