Chapter 3: Mediators Flashcards
What are cell-derived mediators and where are they produced?
Mediators that are produced locally by cells at the site of inflammation. These mediators are rapidly released in response to a stimulus.
What are the three major cell types that produce mediators?
Tissue macrophages, dendritic cells and mast cells.
What are plasma-derived mediators and where are they produced?
Mediators that are present in the circulation as inactive precursors that must be activated (mostly via proteolysis). They are produced in the liver.
Fill in:
…-derived mediators are most important for reactions against offending agents in tissues, while …-derived mediators are most effective against circulating microbes.
Cell-derived mediators are most important for reactions against offending agents in tissues, while plasma-derived mediators are most effective against circulating microbes.
This is because of the fact that plasma-derived mediators circulate through the blood and cell-derived mediators are produced locally.
Which requirement ensures that inflammation is triggered at the right time and place?
The requirement for a microbe or dead tissue to be present.
What limits mediators of causing more damage than is needed?
The fact that most mediators are short-lived. They decay quickly or are inactivated by enzymes.
Name two vasoactive amines.
Histamine and serotonin
What are characteristics of histamine (where are they stored, when are they released)?
Like serotonin, histamine is stored as preformed molecules in cells and therefore are among the first mediators to be released during inflammation. They are mostly stored in mast cells, but can also be found om basophils and platelets.
What 3 stimuli cause degranulation and release of histamine?
Physical injury (trauma, cold, heat), binding of antibodies to mast cells or binding of products of complement (anaphylatoxins).
What are anaphylatoxins (+ examples)?
Complement fragments that are produced as part of the activation of the complement system. Examples are C3a and C5a.
What is stimulated by histamine?
Dilation of arterioles and increase in permeability of venules (by creating interendothelial gaps in postcapillary venules). Can also cause contraction of some smooth muscles.
To which receptors does histamine bind? Where are they located?
H1 receptors located on microvascular endothelial cells.
What happens when swallowing an antihistamine pill during an allergic reaction?
The antihistamine pill is a H1 receptor antagonist that bind and block the receptor.
What is the primary function of serotonin? What can it also do?
It acts as a neurotransmitter in the gastrointestinal tract, but can also act as a vasoconstrictor.
Prostaglandins and leukotriens are lipid mediators. From what molecule are they produced and where is this molecule located?
Arachidonic acid present in membrane phospholipids.
What happens when membranes are stimulated (mechanically, chemically or physically)?
Arachidonic acid is released from the membrane and is converted to bioactive mediators like prostaglandin or leukotrien.
Mediators like prostaglandin, leukotrien or lipoxin are synthesized by two major classes of enzymes: cyclooxygenases and lipoxygenases. Which enzyme synthesises which mediator(s)?
Cyclooxygenase synthesises prostaglandins and lipoxygenase synthesises leukotrienes and lipoxins.
Why are mediators that are derived from arachidonic acid called eicosanoids?
Because they are
derived from 20-carbon fatty acids; Greek eicosa = 20
Prostaglandin is generated by the actions of two cycooxygenases called COX-1 and COX-2. What is the difference between them?
COX-1 is produced in response to inflammatory stimuli and also is constitutively expressed in most tissues, where it may serve a
homeostatic function. COX-2 is induced by inflammatory stimuli, but is low or absent in most normal tissues.
Which prostaglandings are most important during inflammation?
PGE2, PGD2, PGF2a, PGI2 and TXA2.
PGD2 (and PGE2) is produced by mast cells. What is their function and result of this function?
They cause vasodilation and increase the permeability of postcapillary venules. This results in stimulating exudation and forming of edema. PGD2 is als a chemoattractant for neutrophils.
TXA2 is formed by the enzyme thromboxane synthase in platelets. What is the function of TXA2?
It is a platelet-aggregating agent and vasoconstrictor and thus important for thrombosis.
Which prostaglandin has the opposite effect of TXA2?
Prostacyclin/PGI2, it’s a vasodilator and an inhibitor of platelet aggregation. It prevents thrombus formation.
What can be a more general effect of prostaglandins?
They are involved in the pathogenesis of pain and fever.
What is first generated when generating leukotrienes? What is generated after this?
LTA4, gives rise to LTB4 or LTC4.
By which cells is LTB4 produced and what is it’s function?
It is produced by neutrophils and some macrophages. It’s function is activating neutrophils, this causes adhesion of cells to the endothelium, generation of ROS and release of lysosomal enzymes.
What is the function of LTC4 and its metabolites LTD4 and LTE4?
They cause vasoconstriction, bronchospasm (asthma!) and increased permeability of venules.
Lipoxins are also generated from arachidonic acid by the lipoxygenase pathway. But what is the function of lipoxins?
They suppress inflammation by inhibiting the recruitment of leukocytes. Specifically, they inhibit neutrophil chemotaxis and adhesion to endothelium.
What is the function of cyclooxygenase inhibitors in aspirin and other NSAIDs like ibuprofen?
They inhibit COX-1 and COX-2 and thus block all prostaglandin synthesis (and thus inhibit fever and pain).
Why is there such an interest in selective COX-2 inhibitors?
COX-1 is involved in more than inflammation (also homeostasis), while COX-2 is only involved in inflammation. Besides this, the normal cyclooxygenase inhibitor blocks important homeostatic functions (by blocking COX-1).
It seems COX-2 also plays a role in homeostasis, like the fact that it produces PGI2. Why is the use of selective COX-2 inhibitors risky and for what?
PGI2 is an important anti-thrombotic mediator. Blocking COX-2 means blocking the production of PGI2. On top of this COX-1 is involved in the production of the pro-thrombotic mediator TXA2. This causes an increased risk in cardiovascular or cerebrovascular events.
What is the function of lipoxygenase inhibitor? For what disease is this treatment useful?
Lipoxygenase is responsible for producing leukotrienes. By inhibiting the enzyme, leukotrienes are no longer produced. Since LTD4 and LTE4 cause bronchospasm, the inhibitor can be used against asthma.
What is the function of corticosteroids, what genes are transcribed upon release of a corticosteriod?
These are anti-inflammatory agents that reduce the transcription of genes encoding COX-2, phospholipase A2, pro-inflammatory cytokines and iNOS.
What cytokines are mainly produced by activated macrophages and dendritic cells? What is their main function?
TNF and IL-1, they play critical roles in leukocyte recruitment
by promoting adhesion of leukocytes to endothelium
and their migration through vessels.
What is different in the production/stimulation of TNF and IL-1?
TNF production is induced by signals through TLRs and other microbial sensors. This is also the case for IL-1, except production is dependent on the inflammasome (and caspase-1).
What are the changes that occur when endothelials activation occurs through TNF and IL-1?
Increased expression of adhesion molecules like E- and P-selectin and of ligands for leukocyte integrins on the endothelium. Increased production of mediators like cytokines, chemokines and eicosanoids. And increased procoagulant activity of the endothelium.
