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Flashcards in Inflammation Deck (46)
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1

What is the 'Triple Therapy' for RA?

A treatment with 3 csDMARDS

 

Methotrexate, Sulfasalazine and Hydroxychloroquine

2

What are Matrix Metalloproteinases (MMPs)?

Enzymes that break down collagen

 

Active at neutral pHs, and require Zn2+

 

Activated by the removal of propeptides by other proteases

 

Can be inhibited by Tissue Inhibitors of Metallo-Proteinases (TIMPs)

3

What are the main 'risk' genes for RA?

Genes in the MHC region

 

Eg, HLA-DRB1

4

Explain the Reactive Oxygen Species pathway

5

What is LAD-1?

An adhesion deficincy

 

Leukocytes do not adhere to extracellular material or endothelium

 

Leukocytes deficient in the B2 integrin

6

What is Rheumatoid Arthritis?

The persistant joint inflammation (of synovium) of at least 3 joint areas

 

Early morning stiffness of at least 30 min duration

 

1% of people in the UK have RA

7

What are Anti-Citrullinated Protein Antibodies (ACPA)?

These are highly specific for RA

 

Can be found in the body up to 14yrs before the onset of RA symptoms

 

Can predict erosive and progressive disease

8

What is the main active ingrediant in Sulfasalazine?

Sulfinpyradone

9

What is Leflunomide?

A new DMARD

 

Inhibits dihydro-oroate dehydrogenase --> used in the ynthesis of pyrimidines

10

Explain Prostanoid receptors

PGE2 (prostaglandins)--> EP1 - 4     Act on very specific GPCRs on target cells

 

PGI2 (prostacyclin) --> IP

 

Thromboxane receptor = TP

 

PGD2 --> DP1 + 2

11

What are the effect of RONS?

Activation of inflammatory gene transcription

 

Amino acid modifications

 

DNA damage --> cell apoptosis

12

What is the EP3 receptor?

A prostaglandin receptor

 

Activates leukocytes and mast cells

 

Promotes oedema formation

13

What are Chemokines?

Chemotactic Cytokines

 

Produced in responce to bacteria, TNF and IL-1

 

Act on GPCRs

 

2 Types

 

CXC --> Neutrophil attractants

 

CC

14

What are eicosanoids?

Oxidation products of 20carbon long fatty acids

 

Primerily from Arachidonic Acid

 

Main type is prostaglandins

15

What are chemotaxins?

Molecules that attract and activate leukocytes (increasing integrin avidity and affinity)

 

2 types...

 

Non Selective

 

Selective = Chemokines

16

Explain how low dose aspirin is beneficial......and how therefore taking a COX-2 selective NSAID can have adverse effects

Aspirin is selective to COX-1, and so prevents (pro-thrombotic) thromboxane from platelets, which will decrease the chances of clotting)

This is effective as platelets cannot remake proteins as they have no nucleus, so this effect occurs for a period of time. Also the endothelial produced PGI2 is unaffected

 

However, when a COX-2 inhibitor is used, PGI2 production stops, and so clotting becomes much more common, as the pro-thrombotic thromboxane is still present (as COX-1 isn't inhibited)

17

What are the key indications of poor outcome in RA?

Genetics --> eg, the HLA-DRB1 genotype present

 

Lab Results --> RF or ACPA presence.....high CRP level

 

Clinical Assessment --> Many active joints and poor scores

 

Low educational / social-economical circumstances

18

What is Rheumatoid Factor?

Antibodies that bind to the Fc domain of IgG

19

What are the 2 neuropeptides that can positively feedback on histamine release and oedema formation?

NKA (Neurokinin A)

 

CGRP

20

Explain which each of the 3 selectins are

L - Expressed on inactivated leukocytes

This causes leukocyte activation, which increases avidity (stickability)

There is rapid shredding of the selectin by proteolytic cleavage (shedase)

 

P - Expressed on platelets and endothelium

Start in granules, and are rapidly translocated to the cell surface upon activation

 

E - Endothelial expression is induced by cytokines or LPS

Required 'de novo' synthesis --> made on demand --> so takes time (hours)

Their expression is inhibited by glucocorticoids

21

What is Rituximab?

A B cell depleting monoclonal anti-CD20 antibody

22

What are the 5 cardinal signs of inflammation?

Heat

Redness

Swelling

Pain

Loss of Function

23

What is the enzyme that primarily controls steroid biosynthesis?

HMG-CoA Reductase

 

Produces mevalonic acid

24

What are the 3 things that plasma proteases are used to create, in reference to inflammation

Kinins (Bradykinin) --> Increases permeability/vasodialtion and pain

 

Complement --> Activates leukocytes, mast cell degranulation, and bacterial lysis and opsonisation

 

Clotting Cascade --> Amplifies the kinin and complement pathways

Also causes thrombosis and platelet activation

25

What are Leukotrienes (LTs)? And what are their actions?

A classic eiconisoid

 

Bronchoconstriction

 

Oedema

 

Chemotaxis

 

Present in inflammation

26

What is a selectin?

A lectin-like adhesion molecule

 

So bind to carbohydrate molecules weakly

 

Important in the tethering of leukocytes to the endothelium

27

What is leukocyte adhesion deficiency II (LAD-II)?

Patients have defective fucose (a CHO) metabolism

 

So leukocytes do not express the correct ligands for selectins..... which causes a reduced 'rolling' response (for E/P selectins only)

 

So less white blood cells where the inflammation has taken place

 

Reccurent infections without pus

28

What are integrins?

Heterodimeric proteins that re expressed on the surface of leukocytes

 

Important for 'Firm Adhesion'

 

When leukocytes are activates, a conformational change of the integrin occurs, increasing avidity (stickiness) and affinity

29

What is Angioedema?

Deep cutaneous and mucosal swelling

 

Can be induced from ACE inhibitors

 

Driven mainly from mast cell degranulation (release of histamine) --> due to the activation of plasma proteases

30

How does Oedema (swelling) occur?

H1 receptor binding of histamine causes endothelial-derived Nitric Oxide to be released, causing arteriolar dialation

 

The endothelium then contracts, which makes venules leaky --> increasing permeability