Inflammation

Question 1

Cardinal signs of inflammation

Answer 1

Heat
Redness
Swelling
Pain
Loss of function

Question 2

Heat/redness

Answer 2

Artery dialation
increased blood flow to tissue
Caused by endothelial NO

Question 3

Swelling

Answer 3

Vascular leakage of plasma into tissue

Tissue remodelling can occur due to fibrin deposition

Question 4

Pain

Answer 4

Chem mediators of inflammation cause pain by stim’ing nerves

Question 5

Loss of function

Answer 5

Follows from swelling

tissure remodelling results in destruction and really fucks you up

Question 6

Cells that cause inflammation

Answer 6

Granulocytes
Lymphocytes
Monocytes

Question 7

Histamine receptors in inflammation

Answer 7

H1-stim’s phospholipase c

• vasodilates with NO
• Causes oedema via vascular contraction
• Pain/itch

H4- Leucocyte chemotaxis, pain/itch, activates PLC

Question 8

Inflammatory mediators

Answer 8

BK- bradykinin formed from plasma precrusor, increases permeability

PGE2- Prostoglandin E2 from membrane lipid, increases blood flow

FMLP- activates neutrophils, increases permeability as a result

Question 9

Eicosanoids

Answer 9

Oxidation products of 20 fatty acids- Arachidonic acid

Classic-Prostaglandins

Question 10

Physiological functions of PG’s

Answer 10

1. Initiate labour- PGF2alpha, PGE2
2. Inhibit gastric secretion, increase Gast’ mucous production- PGE2
3. Inhibit platlet aggregation/vasodilation- PGI2
4. The opposite of 3- TXA2

Question 11

Pro/antiinflammatory

Answer 11

PG’s can increases inflam’ via elevation of cAMP causing vasodilation

But it also inhibits leukocyte function

Question 12

Fever

Answer 12

PGE2 in anterior hypothalamus activation can lead to fever as core temperature is elevated
Role for EP3 receptor

Question 13

Cyclo-oxygenase

Answer 13

COX-1: GI, nephro and platelet maintenance

COX-2: Causes inflammation

COX-3: Possible target for paracetamol. It role in humans questionable.

Question 14

Aspirin

Answer 14

acetylates COX

irreversible inhibition

Question 15

Ibuprofen

Answer 15

competes with arachodonate for COX binding

Question 16

Risks of COX selectivity

Answer 16

COX-1 selective: Causes GI bleeds

COX-2 selective: Causes strokes/blood clots

Question 17

Low dose aspirin

Answer 17

Antithrombotic effect
Inhibits platelets COX-1 (No TxA2) which are prothrombotic
Endothelial COX-2 can now produce PGI2 which is antithrombotic

Question 18

Leukotrines

Answer 18

LTC4/LTD4: ^ bronchoconstriction and oedema
LTB4:^Oedema, chemotactic for inflammatory cells
BLT1: chemotactic for inflammatory cells
Present in high levels for arthritis synovial fluid

Overall ^inflammation/bronchoconstriction/inflammatory cell migration

Question 19

Glucocorticoid action

Answer 19

Inhibits transcription of PLA2
Induces synthesis of PLA2 inhibitor ‘lipocortin’
Inhibits COX-2 synthesis

Question 20

EPA (Eicosapentaenoic acid)

Answer 20

Omega 3 fatty acid

COX metab’d to form:
PGI3- potent antiplatelet
TxA3- weak proplatelet

Question 21

Leukocyte diapedesis

Answer 21

1. Circulation
2. Tethering/rolling-guided by selectins, thethers leukocyte to vascular cells
3. Firm adhesion-guided by intergrins
4. Transmigration- guided by chemoattractants and CAM’s

Question 22

L, P and E selection

Answer 22

L-On leukocytes ^avidity
P-On platelets, translocated to surface by Hs (mins)
E-IL-1/TNF induce expression on endothelium (hours)

Question 23

Integrins

Answer 23

Proteins expressed on leukocytes
Common beta2 chain +
alpha l/m/x
Making 3 heterodimers Al/B2, Am/B2, Ax/B2

Question 24

Regulating adhesion

Answer 24

Leukocyte activation causes:

Conformational change in integrin-^affinity
Clustering-^avidity

Question 25

Integrin ligand

Answer 25

Intercellular adhesion molecule (ICAM)

ICAM-2: Basally expressed on endothelium
ICAM-1: induced by cytokines IL-1, TNF

ICAM on endothelium binds to integrin on leukocyte

Question 26

Chemotaxins

Answer 26

Attract and activate leukocytes

Source from site of inflammation

Sometimes immobilised and simply presented to leukocytes on:
Extracellular matrixes
endothelial cell surface

Question 27

Chemokines

Answer 27

chemotaxins that are cytokines
Produced in response to bacteria, IL-1 and TNF
Is a g protein coupled receptor
Mainly attract neutrophils and t cells (CXC)
All chemokines are chemotaxins but not the other way round

Question 28

Plasma proteases

Answer 28

Kinins
Complement
Clotting cascade

Question 29

Angioedema

Answer 29

Long lasting

• responsive to H1 antagonists
• mast cell degranulation

If not responsive then caused by ACE inhibitors or is hereditary

Question 30

MMP structure

Answer 30

4 parts- Propeptide, Catalytic Zn, hinge, c terminal

Propeptide bound to Zn by Cys residue keeping MMP inactive
Propeptide removed by proteases or chemically modified by RON
C terminal important for specificity and regulation

Question 31

MMP (Metallo matrixproteinase)

Answer 31

Breaks down collagen
Requires Zn2+ and active at neutral pH
inhibited by TIMPS (Tissue inhibitors of metallo-proteinases)

Question 32

Tissue damage in RA

Answer 32

Proteoglycans easily accesible to proteinases so quickly broken down
-results in loss of shock absorbtion and joint function

Cartilage made of collagen so broken down more slowly by MMP

Question 33

MMP inhibition

Answer 33

Tetracyclines- reduces MMP synthesis/activity

-can have high specificity

Question 34

Seriene/cysteine proteinases

Answer 34

Neutrophil elastase, cathepsin G
Breaks down matrix proteins: elastin, laminin
Endogenous inhibition by SERPIN
-SERiene Protease INhibitors
Serpins inactivated by oxidation

Question 35

Reactive Oxygen and Nitrogen species (RONS)

Answer 35

Produced by leukocytes and tissue resident cells

NADPH catalyses formation of superoxide O2-