Chronic Inflammation Flashcards
name 3 important conditions caused/ propogated by chronic inflammation
- rheumatoid arthritis
- gout
- atherosclerosis
what is the predominant feature of inflammatory athritis?
synovial inflammation
what’s the synovial joint?
where 2 bones separated by space e.g. knee joint
what does synovial fluid contain?
albumin
hyaluronic acid
what is the purpose of albumin and hylaluronic acid in synovial joints?
nourish articular cartilage
what important role do macrophages play in synovial joint?
clear up debris from wear and tear of cartilage
what do cartilage and synovial fluid allow in the joint?
friction- free movement
what occurs in the synovial joint in rheumatoid arthritis?
- 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
what are the 2 overall causes of rheumatoid arthritis?
genetic suseptibility
environmental factors
(overall a suseptible host exposed to arthrogenic pathogen)- inflammatory response
which 3 cytokines are involved in rheumatoid arthritis?
TNF-a, IL-1B, IL-6
which TLRs are involved in rheumatoid arthritis?
2,3,4,7,8
which DAMP is key in rheumatoid arthritis?
Tenascin-C
give evidence that Tenascin-C plays an important role in RA
KO mice who were given inflammation inducing chemical had reduced inflammation and enhanced recovery
reduced immune cell infiltration
no chronic inflammation
what disease is gout a type of?
arthritis
what causes gout?
build up of uric acid, which form crystals in joints
what are the risk-factors that lead to gout?
diet- high alcohol/purine rich food
genetic predisposition
how is purine broken down?
to guanine and hypoxanthine to allow uric acid secretion - if not, it can’t be excreted and builds up in joints
what inflammasome is activated in gout?
NLRP3
how quickly is gout resolved if caused by diet- with simple diet changes?
days- weeks
what wider branch of disease is atherosclerosis a form of?
arteriosclerosis
what is arteriosclerosis?
thickening and hardening of arterial wall
what component is specific to atherosclerosis?
formation of a plaque
what, overall is a plaque?
lesion with a core of lipid covered by a white fibrous cap
what further complication can a plaque lead to?
blocking blood flow
causing rupture- thrombosis/ haemorrhage or aneurysm
what’s the most common cause of atherosclerosis?
high fat and cholesterol diet
where do we get cholesterol from?
diet and liver
what are chylomicrons?
a class of lipoproteins that transport dietary cholesterol after meals from small intestine to tissues for degradation
what removes remnant chylomicrons?
liver
how is cholesterol made in the liver?
conversion of HMG-CoA to melvalonic acid by the enzyme HMG-CoA reductase
what are generally, the 3 main steps of atherosclerosis?
1- endothetial damage/dysfunction
2- Vascular muscle cell proliferation and platelet aggregation
3- foam cell formation
what causes the endothelial damage? (4)
- high lipid levels
- hypertension
- chemicals from smoking tobacco
- pathogens
what does endothelial damage lead to?
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
what causes the proliferation of Vascular Smooth Muscle cells?
they are recruited by PDGF, TGF and FGF
cause VSM prolieration and growth to produce ECM, like collagen to stabilise plaque
what are the earliest lesions in atherosclerosis?
fatty streaks
what are fatty streaks made of?
foam cells
what are foam cells?
macrophages which have ingested and oxidised LDL- foam-like appearance
give 3 non-pharmacological treatments of atherosclerosis
- diet change- reduce cholesterol and lipid intake
- quit smoking- reduces damage
- exercise
give the 3 main families of lipid-lowering drugs used to treat atherosclerosis
- fibric acid (fibrates)
- statins
- bile acid binding resins
what do fibrates do?
promote metabolism and reduce levels of VLDLs and triglycerides
what do statins do?
lower LDL levels and are anti-inflammatory
what do bile acid binding resins do?
inhibit cholesterol absorption
what are 2 possible drug targets for atherosclerosis?
Inhibitors of IL-1
PPAR agonists
what would inhibitors of IL-1 do to treat atherosclerosis?
reduce adhesion molecles so reduce migration of monocytes into tunica intima (usually cause by high BP)
what would PPAR agonists do to treat atherosclerosis?
PPARs are nuclear receptors
binding of ligands to these receptors reduces expression of pro-inflammatory molecules
