Mediators of Inflammation

Question 1

What are mediators of inflammation?

Answer 1

Substances that initiate and regulate inflammatory reactions

Question 2

Which cells secrete inflammatory mediators?

Answer 2

Macrophages, dendritic cells, mast cells

- other cells could also be induced: platelets, neutrophils, endothelial cells, epithelial cells

Question 3

Where are mediators located inside cells?

Answer 3

Sequestered in intracellular granules for rapid secretion (histamine) or may be synthesized de novo (prostaglandins, leukotrienes, cytokines)

Question 4

Mediators of inflammation are produced only _________

Answer 4

In response to various stimuli

Question 5

How do inflammatory mediators function?

Answer 5

Bind to receptors on target cell to secrete additional inflammatory mediators

Question 6

General characteristics of inflammatory mediators

Answer 6

• have short half lives and quickly decay
• are enzymatically destroyed
• are scavenged by antioxidants

Question 7

T/F: one mediator can stimulate the release of other mediators

Answer 7

True

Question 8

Prostaglandins, leukotrienes, and PAF are from the ______

Answer 8

Plasma membrane

Question 9

Nitric oxide is from ______

Answer 9

Macrophages

Question 10

Defensins are produced ______

Answer 10

At the epithelial surface, will up regulate production when cell is induced

Question 11

Inflammatory mediators from plasma proteins are constantly being secreted by the ________

Answer 11

Liver as precursors

- activated via proteolytic cleavage in circulatory system

Question 12

Look at list of mediators and their source!!!

Answer 12

1st ppt

Question 13

What are the 2 preformed inflammatory proteins?

Answer 13

Histamine: mast cells, basophils, platelets
Serotonin: mast cells, platelets

Question 14

What are the functions of histamine?

Answer 14

• vasodilation

- increased vascular permeability

Question 15

What are 3 synthesized mediators?

Answer 15

• cytokines
• chemokines
• arachidonic acid metabolites

Question 16

Cytokines

Answer 16

Primarily produced by activated macrophages, lymphocytes, dendritic cells

• regulate immune and inflammatory rxns
• acute inflammation: TNF, IL-1, IL-6!!!

Question 17

Functions of cytokines

Answer 17

• endothelial activation
• leukocyte recruitment
• leukocyte activation
• systemic acute phase response

Question 18

TNF

Answer 18

Macrophages, mast cells, T cells

• stimulates expression of endothelial adhesion molecules
• secretion of other cytokines = systemic effects

Question 19

IL-1

Answer 19

Macrophages, endothelial cells, some epithelial cells

- similar to TNF, greater role in liver

Question 20

IL-6

Answer 20

Macrophages

- systemic effects (acute phase response)

Question 21

Chemokines

Answer 21

Cytokines that promote leukocyte chemotaxis and migration

- IL-8: secreted by activated macrophages, endothelial cells = chemotaxis of neutrophils

Question 22

Arachidonic acid metabolites

Answer 22

Lipid mediators (prostaglandins, leukotrienes) produced from arachidonic acid present in membrane phospholipids

Question 23

What do prostaglandins and leukotrienes release?

Answer 23

Mechanical, chemical, physical stimuli releases AA from the membrane

• prostaglandins: cyclooxygenase
• leukotrienes and lipoxins: lipoxygnease

Question 24

AA metabolites function

Answer 24

Mediate virtually every step of acute inflammation!

• vasodilation: prostaglandins
• vasoconstriction: leukotrienes, thromboxane
• increased vascular permeability: leukotrienes
• chemotaxis, leukocyte adhesion: leukotrienes

Question 25

Which is more potent: leukotrienes or histamine?

Answer 25

Leukotrienes! | - more important for increasing vascular permeability

Question 26

Steroids inhibit ____

Answer 26

Phospholipases

Question 27

COX1 and COX2 inhibitors, aspirin, indomethacin inhibit _______

Answer 27

Cyclooxygenase

Question 28

Prostacyclin (PGI2)

Answer 28

Causes vasodilation, inhibits platelet aggregation

Question 29

Thromboxane A2

Answer 29

Causes vasoconstriciton, promotes platelet aggregation

Question 30

PGD2, PGE2

Answer 30

Causes vasodilation, increased vascular permeability | = pain, fever

Question 31

Leukotriene receptor antagonists inhibit

Answer 31

Leukotrienes C4, D4 and E4 | - funciton in bronchospasm, increased vascular permeability

Question 32

5-HETE

Answer 32

Chemotaxis

Question 33

Complement

Answer 33

Collection of soluble proteins and membrane receptors that function in host defense - present in inactive forms in the plasma, activated via antibody detection or direct microbe binding

Question 34

What are 3 functions of complement?

Answer 34

- inflammation: C3a and C5a to stimulate histamine release (anaphylatoxins) --> C5a is a chemotactic for leukocytes - opsonization and phagocytosis: C3b when fixed to microbial cell wall acts as opsonin and promotes phagocytosis - cell lysis: deposition of membrane attack complex, kills by making cells permeable to water

Question 35

Activated factor XII (Hageman factor)

Answer 35

Activates intrinsic coagulation and catalyzes formation of kallikrein

Question 36

Brakykinin

Answer 36

- short lived - increased vascular permeability - vasodilation - pain

Question 37

Kallikrein acts on ______ to form ______

Answer 37

Plasminogen; plasmin | - breaks down fibrin polymers and cleaves C3

Question 38

Coagulation factors require _______

Answer 38

Balance between formaiton and degradation of fibrin - fibrin polymers provide a surface to facilitate phagocytosis and prevent spread of infectious agents - excessive fibrin obstructs the microvasculature resulting in ischemic injury - excessive activation of fibrinolytic system leads to depletion of fibrinogen and possibly hemorrhage

Question 39

Oxygen derived free radicals

Answer 39

Released from neutrophils and macrophages following exposure to chemokines and after phagocytosis - lipid peroxidation - DNA damage - can alter signaling molecules (increase/decrease cytokines) - antioxidant mechanisms in place to minimize damage

Question 40

Nitric oxide

Answer 40

Synthesized by endothelial cells and macrophages - vasodilation - inhibits platelet aggregation and adhesion - oxidizes lipids

Question 41

Platelet activating factor

Answer 41

- phospholipid derived mediator - leukocytes, platelets, endothelial cells can elaborate the factor - vasoconstriction and bronchoconstriction - 100 to 1,000x more potent than histamine!!

Question 42

Vasodilation

Answer 42

- histamine | - prostaglandins (PGI2)

Question 43

Increased vascular permeability

Answer 43

- histamine - serotonin - C3a and C5a by liberating vasoactive amines from mast cells - leukotrienes

Question 44

Chemotaxis, leukocyte recruitment and activation

Answer 44

- TNF, IL-1, IL-8 (neutrophil chemotaxis) - chemokines - C3a, C5a - leukotriene B4

Question 45

Fever

Answer 45

- IL-1, TNF | - prostaglandins

Question 46

Pain

Answer 46

- prostaglandins | - bradykinin

Question 47

Tissue damage

Answer 47

- lysosomal enzymes of leukocytes | - reactive oxygen species