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Chapter 3: Mediators Flashcards

1
Q

What are cell-derived mediators and where are they produced?

A

Mediators that are produced locally by cells at the site of inflammation. These mediators are rapidly released in response to a stimulus.

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2
Q

What are the three major cell types that produce mediators?

A

Tissue macrophages, dendritic cells and mast cells.

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3
Q

What are plasma-derived mediators and where are they produced?

A

Mediators that are present in the circulation as inactive precursors that must be activated (mostly via proteolysis). They are produced in the liver.

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4
Q

Fill in:
…-derived mediators are most important for reactions against offending agents in tissues, while …-derived mediators are most effective against circulating microbes.

A

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.

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5
Q

Which requirement ensures that inflammation is triggered at the right time and place?

A

The requirement for a microbe or dead tissue to be present.

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6
Q

What limits mediators of causing more damage than is needed?

A

The fact that most mediators are short-lived. They decay quickly or are inactivated by enzymes.

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7
Q

Name two vasoactive amines.

A

Histamine and serotonin

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8
Q

What are characteristics of histamine (where are they stored, when are they released)?

A

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.

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9
Q

What 3 stimuli cause degranulation and release of histamine?

A

Physical injury (trauma, cold, heat), binding of antibodies to mast cells or binding of products of complement (anaphylatoxins).

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10
Q

What are anaphylatoxins (+ examples)?

A

Complement fragments that are produced as part of the activation of the complement system. Examples are C3a and C5a.

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11
Q

What is stimulated by histamine?

A

Dilation of arterioles and increase in permeability of venules (by creating interendothelial gaps in postcapillary venules). Can also cause contraction of some smooth muscles.

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12
Q

To which receptors does histamine bind? Where are they located?

A

H1 receptors located on microvascular endothelial cells.

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13
Q

What happens when swallowing an antihistamine pill during an allergic reaction?

A

The antihistamine pill is a H1 receptor antagonist that bind and block the receptor.

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14
Q

What is the primary function of serotonin? What can it also do?

A

It acts as a neurotransmitter in the gastrointestinal tract, but can also act as a vasoconstrictor.

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15
Q

Prostaglandins and leukotriens are lipid mediators. From what molecule are they produced and where is this molecule located?

A

Arachidonic acid present in membrane phospholipids.

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16
Q

What happens when membranes are stimulated (mechanically, chemically or physically)?

A

Arachidonic acid is released from the membrane and is converted to bioactive mediators like prostaglandin or leukotrien.

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17
Q

Mediators like prostaglandin, leukotrien or lipoxin are synthesized by two major classes of enzymes: cyclooxygenases and lipoxygenases. Which enzyme synthesises which mediator(s)?

A

Cyclooxygenase synthesises prostaglandins and lipoxygenase synthesises leukotrienes and lipoxins.

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18
Q

Why are mediators that are derived from arachidonic acid called eicosanoids?

A

Because they are

derived from 20-carbon fatty acids; Greek eicosa = 20

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19
Q

Prostaglandin is generated by the actions of two cycooxygenases called COX-1 and COX-2. What is the difference between them?

A

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.

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20
Q

Which prostaglandings are most important during inflammation?

A

PGE2, PGD2, PGF2a, PGI2 and TXA2.

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21
Q

PGD2 (and PGE2) is produced by mast cells. What is their function and result of this function?

A

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.

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22
Q

TXA2 is formed by the enzyme thromboxane synthase in platelets. What is the function of TXA2?

A

It is a platelet-aggregating agent and vasoconstrictor and thus important for thrombosis.

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23
Q

Which prostaglandin has the opposite effect of TXA2?

A

Prostacyclin/PGI2, it’s a vasodilator and an inhibitor of platelet aggregation. It prevents thrombus formation.

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24
Q

What can be a more general effect of prostaglandins?

A

They are involved in the pathogenesis of pain and fever.

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25
What is first generated when generating leukotrienes? What is generated after this?
LTA4, gives rise to LTB4 or LTC4.
26
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.
27
What is the function of LTC4 and its metabolites LTD4 and LTE4?
They cause vasoconstriction, bronchospasm (asthma!) and increased permeability of venules.
28
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.
29
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).
30
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).
31
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.
32
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.
33
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.
34
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.
35
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).
36
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.
37
What is the function of TNF in leukocytes?
TNF augments respones of neutrophils to other stimuli such as bacterial endotoxins.
38
What happens when IL-1 activates fibroblast? What else does IL-1 stimulate?
They will synthesize collagen and stimulate the proliferation of synovial cells and other mesenchymal cells. Synovial cells produce matrix-degrading enzymes that cause cartilage destruction.
39
What is a complication that arises when using TNF-antagonists?
It increases susceptibility to mycobacterial infections, because of the reduced ability of macrophages to kill intracellular microbes.
40
What is a simple definition for chemokines?
They act primarily as chemoattractants for specific types of leukocytes.
41
``` Chemokines are classified into four major groups: C-X-C C-C C CX3C What is the meaning of these names? ```
C-X-C have one amino acid residue (X) seperating the first two of the four conserved cysteines. C-C have the first two conserved cysteine residues (C) adjacent. C lack the first and third of the four conserved cysteines CX3C contain three amino acids between the first two cysteines.
42
Name an example of a C-X-C chemokine, which cytokines/products induce secretion of these chemokines, where is it secreted and where does it primarily act upon?
IL-8, it's inducers are microbial products and IL-1 and TNF. It is secreted by activated macrophages and endothelial cells. It causes activation and chemotaxis of neutrophils.
43
MCP-1, CCL2, CCL11, MIP-1a/CCL3 are examples of C-C chemokines. For what cells do they serve as chemoattractants?
Monocytes, eosinophils, basophils, and lymphocytes
44
Lymphotactin or XCL1 are examples of C chemokines. For what cells do they serve as chemoattractants?
Lymphocytes
45
There's only one known member of the CX3C chemokines. This chemokine exists in two forms on two different cells. What is the name of this chemokine and what forms are there?
The name is fractalkine (CXCL1). It can be a cell surface-bound protein (it is then induced on endothelial cells by inflammatory cytokines) or it can be in a soluble form (derived from the surface-bound protein). The surface-bound form is there for adhesion of monocytes and T cells, the soluble form is there for chemotaxis.
46
To which kind of receptor can chemokines bind?
They bind to proteoglycans
47
The simplest definition of chemokines is that they act primarily as chemoattractants for specific types of leukocytes. What else is an important function of chemokines?
They stimulate leukocyte attachment to endothelium by acting on leukocytes to increase the affinity of integrins.
48
What is the difference between inflammatory chemokines and homeostatic chemokines?
Inflammatory chemokines mediate aspects of the inflammatory reaction and are only produced in reaction to certain stimuli. Homeostatic chemokines are produced constitutively by stromal cells.
49
What is the most critical step in complement activation? Why is this?
The proteolysis of the third component C3. This is because activation of complement by different pathways leads to cleavage of C3. The functions of the complement system are mediated by primarily breakdown products of C3.
50
Through which pathways is the complement system activated? Describe them briefly.
1. Classical pathway, this is an antigen-antibody reaction 2. Alternative pathway, complement gets activated through a bacterial endotoxin. 3. Lectin pathway, complement gets activated through a mannose binding lectin protein.
51
What do the three pathways have in common?
They all directly/indirectly lead to the formation of the enzyme called C3 convertase.
52
What happens when C3 convertase splits C3 into C3a and C3b?
C3a is released, C3b binds to the cell where the complement is activated. C3b binds with previously formed C4b and C2b and forms C5 convertase.
53
What happens when C5 convertase is made out of C4b, C2b and C3b?
C5 is cleaved into C5a and C5b. C5a is again released whereas C5b forms a membrane attack complex (MAC) with C6-C9.
54
What are three main functions of the complement system?
Inflammation, opsonization and phagocytosis, cell lysis.
55
What complement component is important during inflammation? How does it help inflammation and what are other functions?
Mainly C5a, it stimulates histamine release from mast cells (and thereby increase vascular permeability and cause vasodilation). C5a also acts as a chemotactic agent for neutrophils, monocytes, eosinophils and basophils. C5a is also important in the arachidonic acid metabolism in neutrophils and monocytes (this causes release of inflammatory mediators).
56
What complement components can acts as opsonins? What do they enhance?
C3b (and also inactive C3b), they bind to a microbial cell wall, act as opsonins and promote phagocytosis by neutrophils and macrophages (they have receptors for C3b).
57
How is cell lysis accomplished during complement activation?
MAC drills holes in the cell membrane, making the cells permeable to water and ions and resulting in their osmotic death.
58
For what kind of microbes is complement mainly used?
For the killing of microbes with thin cell walls, such as Neisseria bacteria.
59
Why are regulators important in the complement-system?
Regulators are expressed on normal (not-injured) host cells and thus prevent healthy tissues from being injured at sites of complement activation.
60
What is the function of the complement-system regulator C1 inhibitor?
C1 inhibitor blocks the activation of C1.
61
What is the function of the complement-system regulator Decay accelerating factor (DAF)?
DAF is linked to plasma membranes and prevents formation of C3 convertases.
62
What is the function of the complement-system regulator CD59?
CD59 is also linked to plasma membranes and inhibits formation of MAC.
63
There are other complement regulatory proteins, what is their main function?
They proteolytically cleave active complement components.
64
PAF (mediator) is produced by platelets, neutrophils, mast cells, macrophages and endothelial cells. What is its function? What is its function at low concentrations?
It is responsible for platelet aggregation, causes vasoconstriction and bronchoconstriction and at low concentrations it induces vasodilation and increased vascular permeability.
65
Are coagulation and inflammation linked? By which molecule was this theory confirmed and why?
Yes, the theory was confirmed when researchers saw that Protease-activated receptors (PARs) are activated by thrombin (thus very important during coagulation) and are expressed on leukocytes (suggesting a role in inflammation).
66
Kininogen is cleaved by the enzyme kallikrein. What is the product of this cleavage?
Bradykinin
67
What is the function of bradykinin?
It increases vascular permeability and causes contraction of smooth muscle, dilation of blood vessels and pain when injected into the skin.
68
Which mediator resembles the function of bradykinin?
Histamine
69
What is the collective name of substance P and neurokinin A?
Neuropeptides.
70
What is the acute-phase response?
Inflammation causes cytokine-induced systemic reactions (like fever).
71
What are three common clinical/pathological changes during the acute-phase response?
Fever, acute-phase proteins and leukocytosis.
72
What are substances called that induce fever?
Pyrogens
73
What is the difference between exogenous and endogenous pyrogens?
Bacterial product are exogenous pyrogens and stimulate leukocytes to release cytokines that are endogenous pyrogens.
74
What do pyrogens do to cause fever?
Pyrogens increase the enzymes cyclooxygenase that convert arachadonic acid into prostaglandins. Prostaglandins (PGE2 in particular) stimulate the hypothalamus to produce neurotransmitters that elevate body temperature.
75
In which organ are acute-phase proteins mostly produced?
In the liver.
76
Name three examples of acute-phase proteins:
C-reactive protein (CRP), fibrinogen and serum amyloid A (SAA).
77
What is a function of CRP and SAA? What is a function of fibrinogen?
CRP and SAA bind to microbial cell walls and act as opsonins and fix complement. Fibrinogen binds to red cells and causes them to form stacks that sediment more rapidly than individual red cells.
78
Why do we measure the erythrocyte sedimentation rate?
It is a test for an inflammatory response caused by any stimuli.
79
What disease is caused when acute-phase protein production is prolonged during chronic inflammation (TRI)?
Secondary amyloidosis (TRI)
80
What is the meaning of elevated serum levels of CRP?
It is a marker for increased risk of myocardial infarction.
81
Why is an extreme climb in leukocyte count (40.000-100.000) in inflammation referred to as as a leukemoid reaction?
Because this amount of leukocytes resembles the white cell counts observed in leukemia.
82
Why does leukocytosis initially occur?
Because of the accelerated release of cells from the bone marrow postmitotic reserve pool, stimulated by cytokines.
83
A rise in the number of immature neutrophils in the blood is referred to as a shift to the left. (left shift/blood shift).
Just remember that a rise in the number of immature cells (particularly neutrophils) is called a shift to the left :)!
84
What is another factor that induces the proliferation of precursors in the bone marrow (except cytokines)?
Colony-stimulating factors (CSFs).
85
What two factors compensate for the loss of leukocytes during inflammation (and with that make sure more leukocytes are produced)?
The shift to the left by cytokine stimulation and the colony-stimulating factors (CSFs).
86
``` Bacterial infections, viral infections and some allergies and parasitic infections stimulate an increase in certain cells. Match the infection to the type of cell. Infection: -Viral infection -Bacterial infection -Allergies or parasitic infection ``` Cell increase: - Neutrophilia - Lymphocytosis - Eosinophilia
- Viral infections induce lymphocytosis - Bacterial infections induce neutrophilia - Allergies or parasitic infections induce eosinophilia
87
Which diseases are associated with a decreased number of circulating white cells (leukopenia)? Only meant as example, don't learn by heart.
``` Certain infections (typhoid fever and infections caused by some viruses, rickettsiae, and certain protozoa). ```
88
What are other (more general) manifestations of the acute-phase response? TRI (you probably can think of this yourself).
Increase in heartrate and blood pressure, decreased sweating ( mainly because of redirection of blood flow from cutaneous to deep vascular beds). Minimizing heat loss through the skin: rigors (shivers), chills (search for warmth), anorexia, somnolence, malaise.
89
What is sepsis? What happens during sepsis?
A severe bacterial infection, where large amounts of bacteria stimulate production of enormous quantities of several cytokines which cause widespread clinical and pathological abnormalities.
90
A syndrome similar to septic shock (Systemic Inflammatory Response Syndrome (SIRS)) may occur as a complication of noninfectious disorders. What can cause this?
Severe burns, trauma, pancreatitis and others..

Pathology (28 decks)

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