Chronic Inflammation

Question 1

name 3 important conditions caused/ propogated by chronic inflammation

Answer 1

• rheumatoid arthritis
• gout
• atherosclerosis

Question 2

what is the predominant feature of inflammatory athritis?

Answer 2

synovial inflammation

Question 3

what’s the synovial joint?

Answer 3

where 2 bones separated by space e.g. knee joint

Question 4

what does synovial fluid contain?

Answer 4

albumin

hyaluronic acid

Question 5

what is the purpose of albumin and hylaluronic acid in synovial joints?

Answer 5

nourish articular cartilage

Question 6

what important role do macrophages play in synovial joint?

Answer 6

clear up debris from wear and tear of cartilage

Question 7

what do cartilage and synovial fluid allow in the joint?

Answer 7

friction- free movement

Question 8

what occurs in the synovial joint in rheumatoid arthritis?

Answer 8

• there’s a loss of space between bones- increased friction
• synovial tissue releases lymphocytes- inflammation
• destruction of articular cartilage
• anyklosis of joints (stiffening due to bone fusion)
• increased permeability- oedema- swelling
• neutrophils die and release PADA which changes AA arginine to citrilline- alters proteins- attacked by immune system
• osteoplasts break-down bone
• loss of movement

Question 9

what are the 2 overall causes of rheumatoid arthritis?

Answer 9

genetic suseptibility
environmental factors
(overall a suseptible host exposed to arthrogenic pathogen)- inflammatory response

Question 10

which 3 cytokines are involved in rheumatoid arthritis?

Answer 10

TNF-a, IL-1B, IL-6

Question 11

which TLRs are involved in rheumatoid arthritis?

Answer 11

2,3,4,7,8

Question 12

which DAMP is key in rheumatoid arthritis?

Answer 12

Tenascin-C

Question 13

give evidence that Tenascin-C plays an important role in RA

Answer 13

KO mice who were given inflammation inducing chemical had reduced inflammation and enhanced recovery
reduced immune cell infiltration
no chronic inflammation

Question 14

what disease is gout a type of?

Answer 14

arthritis

Question 15

what causes gout?

Answer 15

build up of uric acid, which form crystals in joints

Question 16

what are the risk-factors that lead to gout?

Answer 16

diet- high alcohol/purine rich food

genetic predisposition

Question 17

how is purine broken down?

Answer 17

to guanine and hypoxanthine to allow uric acid secretion - if not, it can’t be excreted and builds up in joints

Question 18

what inflammasome is activated in gout?

Answer 18

NLRP3

Question 19

how quickly is gout resolved if caused by diet- with simple diet changes?

Answer 19

days- weeks

Question 20

what wider branch of disease is atherosclerosis a form of?

Answer 20

arteriosclerosis

Question 21

what is arteriosclerosis?

Answer 21

thickening and hardening of arterial wall

Question 22

what component is specific to atherosclerosis?

Answer 22

formation of a plaque

Question 23

what, overall is a plaque?

Answer 23

lesion with a core of lipid covered by a white fibrous cap

Question 24

what further complication can a plaque lead to?

Answer 24

blocking blood flow

causing rupture- thrombosis/ haemorrhage or aneurysm

Question 25

what's the most common cause of atherosclerosis?

Answer 25

high fat and cholesterol diet

Question 26

where do we get cholesterol from?

Answer 26

diet and liver

Question 27

what are chylomicrons?

Answer 27

a class of lipoproteins that transport dietary cholesterol after meals from small intestine to tissues for degradation

Question 28

what removes remnant chylomicrons?

Answer 28

liver

Question 29

how is cholesterol made in the liver?

Answer 29

conversion of HMG-CoA to melvalonic acid by the enzyme HMG-CoA reductase

Question 30

what are generally, the 3 main steps of atherosclerosis?

Answer 30

1- endothetial damage/dysfunction 2- Vascular muscle cell proliferation and platelet aggregation 3- foam cell formation

Question 31

what causes the endothelial damage? (4)

Answer 31

- high lipid levels - hypertension - chemicals from smoking tobacco - pathogens

Question 32

what does endothelial damage lead to?

Answer 32

an inflammatory response increased permeability of chemical mediators and immune cells neutrophils trigger recruitment of macrophages which internalise LDL - T-cells recruited and release further cytokines

Question 33

what causes the proliferation of Vascular Smooth Muscle cells?

Answer 33

they are recruited by PDGF, TGF and FGF | cause VSM prolieration and growth to produce ECM, like collagen to stabilise plaque

Question 34

what are the earliest lesions in atherosclerosis?

Answer 34

fatty streaks

Question 35

what are fatty streaks made of?

Answer 35

foam cells

Question 36

what are foam cells?

Answer 36

macrophages which have ingested and oxidised LDL- foam-like appearance

Question 37

give 3 non-pharmacological treatments of atherosclerosis

Answer 37

- diet change- reduce cholesterol and lipid intake - quit smoking- reduces damage - exercise

Question 38

give the 3 main families of lipid-lowering drugs used to treat atherosclerosis

Answer 38

- fibric acid (fibrates) - statins - bile acid binding resins

Question 39

what do fibrates do?

Answer 39

promote metabolism and reduce levels of VLDLs and triglycerides

Question 40

what do statins do?

Answer 40

lower LDL levels and are anti-inflammatory

Question 41

what do bile acid binding resins do?

Answer 41

inhibit cholesterol absorption

Question 42

what are 2 possible drug targets for atherosclerosis?

Answer 42

Inhibitors of IL-1 | PPAR agonists

Question 43

what would inhibitors of IL-1 do to treat atherosclerosis?

Answer 43

reduce adhesion molecles so reduce migration of monocytes into tunica intima (usually cause by high BP)

Question 44

what would PPAR agonists do to treat atherosclerosis?

Answer 44

PPARs are nuclear receptors | binding of ligands to these receptors reduces expression of pro-inflammatory molecules