Unit II: Inflammatory Mediators

Question 1

IL-7

• downstream signaling
• associated disease?

Answer 1

• JAK/STAT
• IL-7 gamma receptor unit defect= SCID

Question 2

Why is inflammation difficult to treat?

Answer 2

Functional redundancy–

• mediators have multiple functions and functions can have multiple mediators,
• inflammation can be triggered by multple forms of injury

Question 3

Growth factor receptors

Answer 3

RTKs

Question 4

NF-kß

1. activation (upstream)
2. inhibition
3. function

Answer 4

1. TNF receptors
2. corticosteroids
3. IL-1,6, TNF

Question 5

Plasma proteins

1. function
2. time
3. area
4. types (x5)
5. Mechanisms of activation? (x3)

Answer 5

1. inactive components (serine proteases). Amplify inflammatory response
2. mins–> hours
3. local activation
4. • coagulation proteins= Haegman factor, plasmin
   • firbinopeptides (fibrin degradation products)
   • complement proteins (C3a, C5a, C3b)
   • kinins
   • immunoglobulins
5. injury associations
   
   • negatively charged surfaces (BM, collagen)
   • LPS
   • Enzymes (trypsin, plasmin)

Question 6

Lipid mediators- what are they? timeline? purpose?

Answer 6

• must be synthesized. Examples:
  
  • platelet activating factor,
  • arachidonic acid products (PGs, LTs, TX, PGI, SRS-As)-
• mins= early migration of leukocytes

Question 7

Protein Mediators

Answer 7

• Ex: cytokines (monokines, lymphokines) ILs, GFs
• mediate later phase of inflammation (must be synthesized)

Question 8

Platelet activation

Answer 8

from trauma=> release of serotonin, thromboxane

Question 9

Activation of “sentry” macrophages

Answer 9

from exotoxins, LPS, superantigens==> IL-1 production

Question 10

Vasoactive amines

Answer 10

histamine (from mast cells)

Serotonin (from platelets)

Question 11

What histamine receptor mediates inflammation?

Histamine release from mast cells can be due to (x6)

Answer 11

H1 receptor= inflammation

1. trauma/cold
2. IgE
3. C3a, C5a
4. histamine releasing factors from neutros, monocyts, platelets
5. IL-1
6. Toll receptor activation by LPS and peptidoglycan of G+ bacteria

Question 12

Serotonin release from? receptor it acts on?

Answer 12

• activated platelets; 90% of serotonin found in enterochromaffin cells in GI tract.
• acts through 5HT receptors

Question 13

Inflammatory responses to

1. Histamine
2. Serotonin
3. Both

Answer 13

1. axonal reflex of flare response
2. aggregation of platelets
3. SM contraction, vasodilation, increased vascular permeability, pain stimulator, itching

Question 14

Fibrinolysis- how, function?

Answer 14

Fibrin cleaved by plasmin

function: fibrin degradation producints increased vascular permeability in skin and lungs

Question 15

4 things Haefeman factor activates

Answer 15

Hageman factor= Factor 12a

• plasminogen==> plasmin= fibronolysis
• complement activation- C3a, C5a= anaphylotoxins
• clotting cascade
• activation of kallikrein==> kinin

Question 16

Anaphylotoxin (x2) mechanisms

1. 2. 3. one does some extra stuff

Answer 16

C3a and C5a.

1. increased vascular permeability
2. smooth muscle contrction
3. C5a= neutrophil chemotaxis, degranulation, superoxide production

Question 17

Phosphatidylcholine==> ______

enzyme?

Answer 17

• phosphatidyl choline==> arachidonic acid
  
  • Phospholipase A2

Question 18

Phosphatidylserine==>

Answer 18

phosphatidylserine==> DAG ==> arachidonic acid

• Enzymes: Phospholipase C ; diacylglycerol lipase

Question 19

bradykinin inactivation

Answer 19

ACE

ACEi = increased bradykinin levels==> nuisance cough

Question 20

Prostaglandins

1. what cell are they made in? what enzyme is used?
2. PGD2/E2- functions
3. PGF2a- functions

Answer 20

1. cyclooxygenase, made in macrophages
2. PGD2/E2= vasodilation, increased vascular permeability, pain, bronchoconstriction
3. bronchoconstriction, vasodilation

Question 21

Prostacyclin (PGI2)

1. where is it made, what enzyme
2. functions

Answer 21

1. endothelial cells, cyclooxygenase
2. vasodilation, increased vascular permeability, inhibits PMNs, inhibits platelet aggregation

Question 22

Thromboxane

1. where is it made, enzyme
2. functions

Answer 22

1. platelets, cyclooxygenase
2. vasoconstriction, bronchoconstriction, platelet aggregation, antagonizes prostacyclin

Question 23

SRSA’s-

1. where are they made, enzyme
2. functions
3. blocked by?

Answer 23

LTC4,D4, E4

1. lipooxygenase, mast cells
2. anaphylaxis: contraction of smooth muscle (vasoconstriction, bronchoconstriction), increased vascular permeability
3. lipotoxins block SRS-A receptors

Question 24

LTB4

1. where is it formed, enzyme
2. function

Answer 24

1. lipoxygenase, neutrophils (mainly, but also in endothelial cells)
2. mediate neutrophil response via: chemotaxis, aggregation, degranulation

Question 25

PAFs 1. where are they made, enzyme used 2. functions (x5)

Answer 25

1. **acetylated lysophospholipid-** mast cells, basophils, neutrophils, macrophages 2. * platelet aggregation and degranulation, * release of histamine and serotonin, * increased vascular permeability, * increased leukocyte adhesion, * chemotoxis

Question 26

Lipotoxins 1. where are they made, from what? structure is similar to? 2. functions

Answer 26

1. neutrophils, monocytes and macrophages, from arachidonic acid--similar to LT 2. anti-inflammatory, block SRS-A receptor, increased leukocyte adhesion, chemotaxis

Question 27

Early LIPID mediators- action and mediator 1. 2.

Answer 27

Early lipid mediators= platelets and mast cells 1. **platelet aggregation=** TXA2 (platelets), PAF (mast cells) 2. **Increased vascular permeability=** SRS-A (mast cells and platelets)

Question 28

Middle platelet mediators

Answer 28

Middle platelet mediators= neutrophils, mast cells 1. **Chemotaxis**= LTB4 (Neutro), PAF (mast cells), SRS-A (mast cells) 2. **Sustaining Vasc Perm-** SRS-A; LTB4

Question 29

Late lipid mediators

Answer 29

neutrophils, macrophages 1. **vascular permeability, vasodilation-** SRS-A (neutros); PGs (MQs)

Question 30

Lymphokines- define, give example

Answer 30

cytokines that control lymphocyte response ex: IL-1 (from macrophages)==\> increaed IL-2 Receptors on T-cells==\> increased IL-2 GF

Question 31

IL-1, 6, TNF-a 1. Systemic response- what are they, which ones? 2. local effects (x3) 3. 4.

Answer 31

1. **Systemic (IL-1)** Fever, acute phase response, leukocytosis 2. **Endothelial cells:** leukocyte adhesion, cytokine synthesis 3. **Fibrobralst:** proliferation, collagen synthsis 4. **Leukocytes:** increased cytokine secretion

Question 32

Chemokines 1. receptors 2. structures 3. co-receptors for HIV?

Answer 32

1. GPCR; 2. C-C= chemokine with adjacent cysteines; CXC= amino acid separates two cysteines 3. CSCR4, CCR5= coreceptors for HIV

Question 33

IFN-Gamma 1. released from 2. acts on 3. function

Answer 33

Augment cellular immune response and inflammation (ex: granuloma) 1. t-cells, NK cells 2. leukocytes, tissue cells, TH2 cells 3. induce MHC I/II expression, activates phagocytosis, inhibits TH2, enhances leukocyte endothelial adherence

Question 34

TGF-Beta- function

Answer 34

fibrogenesis, scar healing

Question 35

IL-12

Answer 35

* made by lymphocytes * Fxn: Lymphocyte proliferation, IL-2 production, IL-2 receptors

Question 36

Chemokines for: 1. neutrophils 2. monocytes 3. eosinophils

Answer 36

1. IL-8/CXC8= neutrophil adhesion and migration 2. MCP= monocyte migration 3. RANTES/MCP3= eosinophil migration

Question 37

NO 1. synthesis 2. expression 3. endhances 4. inhibits

Answer 37

1. Arginine==\> NO; **NO synthase** 2. eNOS, nNOS (endothelial, neuron) always expressed. **i**NOS= **i**nduced in inflammation 3. vasodilation, platelet aggregation, bacteriocidal 4. inhibits leukocyte migration