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BIOL21351 > Lecture 5 - chronic inflammation and atherosclerosis > Flashcards

Lecture 5 - chronic inflammation and atherosclerosis Flashcards

1
Q

nsaAcute inflammation vs chronic inflammation: what they result in

A

AI - Vascular changes, neutrophil recruitment, and limited tissue injury

CI - Angiogenesis, monocellular nuclear infiltrate, progressive tissue injury, fibrosis (collagen deposition and loss of function)

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2
Q

Acute inflammation vs chronic inflammation: their final resolution

A

AI resolutions - Either fibrosis, abscess, or full resolution (clearance of injurious stimuli, mediators, and acute inflammatory cells, replacement of injured cells, and regained function)

CI resolutions - Fibrosis (collagen deposition, loss of function)

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3
Q

Acute inflammation vs chronic inflammation: causes

A

AI - Infarction, bacterial infection, toxins, and trauma

CI - viral infections, chronic infections, persistent injury, autoimmune diseases

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4
Q

Acute inflammation vs chronic inflammation: causes

A

CI - (Low onset, prolonged period of inflammation (weeks to months)), possible systemic signs, predominantly monocytes/macrophages and lymphocytes, inflammation + tissue injury + repair (fibrosis & angiogenesis)

AI - (Rapid response to infection/injury (minutes to hours), often self-limiting), microbial infections, hypersensitivity reactions, physical foreign bodies, chemicals, and tissue necrosis

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5
Q

The general process of inflammation

A

Cellular infiltrate, tissue destruction, healing

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6
Q

Macrophages: where do they come from, how long do they last, what are they called in different locations, and what are the two activated forms of macrophages?

A

Bone marrow stem cells -> monoblast -> monocyte -> macrophage (t½ ~ 24hrs)

In tissue, macrophages can live up to many months

  • Alveolar macrophages - in the lungs
  • Microglia - macrophages in the brain
  • Kupffer cells - macrophages in the liver
  • Osteoclasts - macrophages in the bones

Classically activated and alternatively activated

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7
Q

Classically activated macrophages: what activates them and what do they do?

A

Usually microbial triggers - ie Toll-like receptors - or interferon-gamma (INF-γ) of the cytokines

Pro-inflammatory response:
* Microbial killing function - produces large amounts of ROS, NO, and lysosomal enzymes
* Inflammation- stimulating function - IL-1, IL-12, IL-23, and chemokines promote IF
* Displaying pathogen antigens to T cells

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8
Q

Alternatively activated macrophages: what activates them and what do they do?

A

IL-13 and IL-4

Anti-inflammatory response:
* Tissue repair and fibrosis stimulated - growth factors and TGF-β
* Anti-inflammatory effects stimulated - IL-10 and TGF-β

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9
Q

Adaptive immunity cycle

A
  • Macrophages activated
  • Macrophages become APC
  • T cell either is activated or not activated - inactive T cells increase the TGF-γ, activating more macrophages
  • Activated T cells activate more chemokines, TNF, and IL-17, recruiting more leukocytes to the area
  • Activated leukocytes stimulate more macrophages to be activated
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10
Q

Plasma cells

A

Present in chronic inflammation, produces antibodies which target antigens that are usually microbial but in some cases (autoimmune) may target self-antigens

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11
Q

Eosinophils: when are they present

A

Chronic inflammatory diseases - parasites and allergens mainly

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12
Q

Major basic protein

A

Important in histamine release from mast cells and causing basophils to be released

Toxic to parasites, indirectly causes increased vasodilation and vascular permeability

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13
Q

Mast cells in inflammation

A

Produce histamines and prostaglandins

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14
Q

Atherosclerosis: what is it, what is produced in people who suffer from atherosclerosis, and where/what are the targets?

A

A form of arteriosclerosis - thickening of the arterial wall and loss of elasticity

Atheromatous plaques - lesions with a core of lipid covered by a white fibrous cap

Occurs in tunica intima, medium/large sized arteries affected

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15
Q

Classical and ‘new’ risk factors for atherosclerosis

A

Classical: modifiable and non-modifiable risk factors

‘New’: Inflammatory markers, other miscellaneous

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16
Q

Modifiable risk factors in atherosclerosis

A
  • Hypertension (140/90mmhg)
  • Dyslipidaemia (more LDL, less HDL)
  • Smoking
  • Obesity
  • Diabetes
17
Q

Non-modifiable risk factors in atherosclerosis

A
  • Familial hypercholesterolaemia
  • Age
  • Sex
18
Q

Inflammation as a risk factor in atherosclerosis

A
  • More C-reactive protein (CRP)
  • Interleukins (e.g., IL-6)
  • Vascular and cellular adhesion molecules
  • increased coagulation factors
19
Q

Other risk factors in atherosclerosis

A
  • Insulin resistance (metabolic syndrome)
  • Hyperhomocysteinaemia
20
Q

Basal endothelial function: what occurs for this and what is the result?

A

Normotension, laminar flow, and growth factors

Non-adhesive, non-thrombogenic surface

21
Q

‘Activated’ endothelial action: what occurs for this and what is the result?

A
  • Turbulent flow
  • Hypertension
  • Cytokines
  • Complement (?)
  • Bacterial products,
  • Lipid products
  • Advanced glycation end products
  • Hypoxia
  • Acidosis
  • Viruses
  • Cigarette smoke

Increased expression of procoagulants, adhesion molecules, and proinflammatory factors
Altered expression of chemokines, cytokines, and growth factors

22
Q

Danger signals

A

PAMPs - bacteria/viruses

DAMPs - ECM proteins (e.g. fibronectin), cell death (e.g. fatty acids, HSP, nucleic acids, ATP), oxLDL & cholesterol crystals > NLRP3 activation and IL-1β secretion

23
Q

What is the general process of atherosclerosis?

A
  • Endothelial damage: hyperlipidaemia, hypertension, smoking, viruses/bacteria
  • Increased permeability occurs due to increased permeability (mediated by NO, PGI2, PDGF, AngII and endothelial)

*IVP and monocyte activation causes LDLs to enter the tunica intima as well as macrophages

  • LDLs become oxidised and bind to TLRs, causing NF-kb signalling and IL-1b and IL-1g (more IF stimulated) as well as the formation of the NLRP-3 inflammasome
  • LDLs are also taken into the cell by CD35 and enter the lysosome where cholesterol crystals are formed and lysosomal rupturing occurs
  • leukocyte adhesion - mainly monocytes & T cells (? neutrophils) - while there is an upregulated expression of adhesion molecules (VCAM-1, ICAM-1 & selectin) - which transform into macrophages and foam cells
  • While leukocyte adhesion occurs, more inflammation is signalled
24
Q

VSM cells & platelet aggregation: what are they and what are they stimulated by?

A

Vascular smooth muscle - stimulated by platelet-derived growth factors (PDGF,) FGF2 and TGF-β

platelets - stimulated by integrins, P-selectin, fibrin, TXA

25
Q

Fatty streaks in atherosclerosis: what are they caused by?

A

Macrophages and smooth muscle cells engulfing lipids

26
Q

Atherosclerosis treatments

A

non-pharmacological - diet, exercise, smoking cessation, alcohol intake

lipid-lowering drugs:
* Fibric acid derivatives - less VLDL and triglycerides, small increase in LDL-C, small decrease in HDL-C, agonists at PPARα nuclear receptors
* Statins, e.g. simvastatin, atorvastatin - inhibit HMG-CoA reductase (rate-limiting step in cholesterol synthesis) and anti-inflammatory effect

27
Q

The three major drug classes used to reduce circulating cholesterol and one of the top-selling drugs

A
  • Those inhibiting cholesterol absorption - the bile acid binding resins
  • Those reducing its synthesis - statins
  • Those promoting its metabolism (fibrates).

Rosuvastatin (Crestor)

28
Q

Chylomicrons: what are they, what are their structures, where are they synthesised, what is their travel path, where are remnants broken down

A

A class of lipoproteins that transport dietary cholesterol (and triglycerides) after meals from the small intestine to tissues for degradation to chylomicron remnants

Consist of ~90 triglycerides (free fatty acid molecules bound to glycerol) with small amounts of cholesterol, phospholipids, fat-soluble vitamins, and protein (e.g. apoprotein B and apolipoprotein E).

Synthesized in the GI tract

They carry dietary fat from the intestinal mucosa via the thoracic lymphatic duct into the blood and ultimately to the liver and tissues.

Liver

29
Q

LPL: what is it, what does it do, where is it synthesised from, and where is it transported to?

A

Lipoprotein lipase

Hydrolyse chylomicron triglycerides and phospholipids

Adipose tissue, skeletal muscle and heart

Transported to capillary endothelial cells

30
Q

What happens to FFAs after being released from chylomicrons?

A

Diffuse into the adipose and peripheral tissues and are either stored, used as an energy source or repackaged into triglycerides

31
Q

How does the liver get cholesterol?

A

After removing the triglycerides and phospholipids from the chylomicrons, the chylomicron remnants - still containing cholesterol - bind to receptors on the endothelial cells in the liver where they are endocytosed and the cholesterol is stored in the liver

32
Q

What are the four types of lipoproteins synthesised from the liver?

A

Very low-density lipoproteins (VLDL) - contain high concentrations of triglycerides and moderate amounts of cholesterol and phospholipids

Intermediate-density lipoproteins (IDL) - VLDLs with some triglycerides removed - cholesterol and phospholipid concentrations are increased

Low-density lipoproteins (LDLs) - derived from IDLs with most triglycerides removed - high cholesterol concentration (‘bad cholesterol’)

High-density lipoproteins (HDLs) - contain high protein but low cholesterol concentrations (‘good cholesterol’) - important in ‘mopping up’ cholesterol derived from cell breakdown in tissues (transferring it to VLDL and LDLs)

33
Q

The two pathways of cholesterol production

A

Exogenous pathway - absorption from the GI tract

Endogenous pathway - Liver synthesis

34
Q

How do statins treat atherosclerosis?

A

HMG CoA reductase produces mevalonic acid from HMG CoA, mevalonic acid is vital in cholesterol production in the liver

LDL receptors in the liver bind LDL and break them down

Statins inhibit HMG CoA and upregulate LDL receptors, resulting in a reduced amount of cholesterol produced within the body and a higher amount of LDLs broken down

35
Q

Statins: anti-inflammatory actions

A
  • Suppression of platelet activation
  • Plaque stabilisation
  • Inhibit proliferation and migration of VSM cells
  • Reduced cytokine production: IL-1, IL-6, TNFα and IFNγ
  • Simvastatin reduced TLR2, TLR4 membrane expression and LPS-induced IL-6 and IL-1β production in monocytes of patients with hypercholesterolaemia
  • Upregulation of IL-10
36
Q

Atherosclerosis treatment: what other targets could there be?

A
  • Leukocyte recruitment & attachment - down-regulation of endothelial cell adhesion molecules → decreased plaque formation
  • IL-1β inhibition & CANTOS study (4 years) - canakinumab was effective at preventing adverse cardiac events over a median of 3.7 years, dose-dependent reduction in C-reactive protein (CRP) associated with an increased risk of fatal infection or sepsis
  • PPAR agonists, e.g. fibrates, thiazolidinediones
  • Apolipoprotein E - Functional ApoE inhibits oxidation of lipoproteins, VSM cell proliferation and migration, and platelet aggregation
37
Q

PPAR agonist: what is it, what are the three subtypes, where are they expressed, and what do they do?

A

Peroxisome proliferator-activated receptors - nuclear receptors, involved in sensing and regulating lipid metabolites

PPARalpha, PPARbeta/delta and PPARgamma.

expressed in all major cell types of atherosclerotic lesions, including expression in varying amounts on endothelial cells, VSM cells, monocytes, macrophages, lymphocytes

More stuff is involved but to summarise, PPARalpha and gamma-specific agonists inhibit the formation of macrophage foam cells

BIOL21351 (17 decks)

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