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Concepts of Disease > Inflammation > Flashcards

Inflammation Flashcards

1
Q

What is inflammation?

A

The body’s attempt at self-protection to remove harmful stimuli and begin the healing process, it is part of the mmune response.

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2
Q

Who first defined the term inflammation?

A

Celsus 30 BC-38 AD

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3
Q

What are the 5 cardinal symptoms of inflammation?

A 
Rubor - redness.
Calor - warmth. 
Dolor - pain.
Tumour - swelling. 
Loss of function.
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4
Q

What does PRISH stand for?

A

Pain, Redness, Immobilisation, Swelling, Heat.

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5
Q

What are the differences between acute and chronic inflammation?

A
  1. Onset - acute inflammation is rapid onset whereas chronic inflammation is slower onset.
  2. Cell filtration - in acute inflammation we see predominantly neutrophils, mast cells, basophils and platelets, in chronic inflammation we see prominently macrophages, monocytes and lymphocytes.
  3. Tissue injury and fibrosis - in acute inflammation we see self-limiting and mild tissue necrosis and fibrosis and in chronic inflammation we see severe tissue injury and fibrosis.
  4. Local and systemic signs/cardinal signs - in acute inflammation we see 5 cardinal signs whereas these are absent in chronic inflammation.
  5. Causative agents - in acute inflammation causative gents include infections, phsyical agents, tissue necrosis and an immune response whereas in chronic inflammation, causes are persistent infection, presence of foreign bodies and autoimmunity.
  6. Duration - acute inflammation is short in duration (days) whereas chronic inflammation is long (weeks/months/years).
  7. They differ in onset - acute inflammation is rapid onset and chronic inflammation is slow/delayed onset.
  8. They differ in outcome - acute inflammation outcome is resolution, abcess formation or chronic inflammation and the outcome of chronic inflammation is tissue destruction and fibrosis.
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6
Q

What are the causative agents of acute inflammation?

A
  1. Physical and chemical damage.
  2. Pathogen invasion.
  3. Tissue necrosis.
  4. Immune response.
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7
Q

What are the causative agents of chronic inflammation?

A
  1. Persistent infection.
  2. Autoimmunity.
  3. Presence of foreign bodies.
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8
Q

What are the fundamental cells of acute inflammation?

A
  1. Neutrophils.
  2. Basophils.
  3. Mast cells.
  4. Platelets.
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9
Q

List some diseases that have a chronic inflammatory component

A 
All stages of cancer. 
Neurological diseases. 
Diabetic complications. 
Pulmonary disease.
Bone and joint disease. 
Metabolic disorders. 
Cardiovascular disease.
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10
Q

What are cytokines?

A

Small proteins approx. 5-20Kda that orchestrate the immune and inflammatory response.

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11
Q

List some families/classes of cytokines?

A 
Chemokines. 
Interferons. 
Interleukins. 
Lymphokines. 
Tumour necrosis factors.
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12
Q

List some cells that produce cytokines?

A 
Macrophages
B lymphocytes
T lymphocytes
Mast cells
Endothelial cells
Fibroblasts
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13
Q

Which class of macrophages are involved in promoting inflammation?

A

M1 macrophages.

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14
Q

Which class of macrophages are involved in resolving inflammation?

A

M2 macrophages.

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15
Q

What are decoy receptors?

A

Decoy receptors negate the actions of cytokines they are formed by cleavage of the extracellular domain which can bind the cytokine but cannot initiate signal transduction thus it mops up the cytokines.

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16
Q

What are the phagocytic white blood cells?

A

Macrophages
Neutrophils
Dendritic cells

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17
Q

What are the non-phagocytic white blood cells?

A

Natural killer cells
Mast cells
Eosinophils
Basophils

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18
Q

Which complement proteins comprise the membrane attack complex?

A

C5b, C6, C7, C8 and C9.

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19
Q

Where are acute phase plasma proteins synthesised?

A

Liver

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20
Q

Which acute phase plasma protein is a robust marker of inflammation?

A

C-reactive protein

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21
Q

What causes an increase in production of acute phase plasma proteins?

A

Cytokines such as IL-1, IL-6, TNF-a

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22
Q

Give some examples of acute phase plasma proteins?

A 
C-reactive protein
Complement factors
Serum amyloid A
Haptoglobin
Factor VIII 
Prothrombin
Fibrinogen
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23
Q

What is the benefit of acute phase plasma protein haptoglobin?

A

It can inhibit iron uptake by microbes thereby inhibiting their growth.
It also binds haemoglobin that may be released from lysis of red blood cells.

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24
Q

What is the basis of the 5 cardinal symptoms of inflammation?

A

Redness and heat - increased blood flow.
Swelling - increased vascular permeability.
Pain - chemical mediators stimulate sensory nerve endings and nerves are stretched in response to oedema which causes pain.
Loss of function - caused by pain and swelling.

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25
Q

What are the molecules underlying vasodilation?

A

Prostaglandins and nitric oxide.

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26
Q

What are the molecules underlying increased vascular permeability?

A

Histamine, serotonin, C3a and C5a, bradykinin, leukotrines, C4, D4, E4, platelet activating factor.

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27
Q

What are the molecules underlying chemotaxis and leukocyte activation?

A

C5a, leukotrienes, B4, bacterial products, chemokines (IL-8).

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28
Q

What are the molecules underlying fever?

A

Cytokines (IL-1, IL-6, TNF-a), prostaglandins.

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29
Q

What are the molecules underlying pain?

A

Prostaglandins, bradykinin.

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30
Q

What are the moleucles underlying tissue damage?

A

Neutrophil and macrophage lysosomal enzymes, oxygen metabolites, nitric oxide.

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31
Q

What are the two most common classes of chemokines?

A

CXC and CC.

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32
Q

What are the two divisions of the inducers of inflammation?

A
  1. Exogenous - microbial or non-microbial.

2. Endogenous

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33
Q

What are the exogenous inducers of inflammation?

A

They may be microbial in nature, including virulence factors or PAMPs or they may be non-microbial incluidig allergens, toxic compouds, foregin bodies and irritants.

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34
Q

What are the endogenous inducers of inflammation?

A

They produce DAMPs, e.g. cell-derived like signals released from malfunctioning/dead cells, tissue derived, plasma derived and ECM derived.
E.g. cholesterol crystals, and products of extra-cellular matrix breakdown.

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35
Q

What type of receptor recognises PAMPs?

A

TLRs.

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36
Q

What are the basic steps in the toll-like signalling pathway?

A
  1. PAMPs interact with the extracellular leucine-rich portion of the extracellular domain of the TLR and bind.
  2. Various adaptor proteins are recruited such as MyD88
  3. This activates IkB kinase which phosphorylates IkB.
  4. This cause IkB to be ubiquitinated and degraded by the proteasme pathway.
  5. This exposes the nuclear localisation signal of NFkB which is free to translocate to the nucleus.
  6. NFkB, a transcription factor, binds regulatory sequences of target genes in the nucleus.
  7. Target genes include pro-inflammatory cytokines.
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37
Q

What type of receptors recognise DAMPs?

A

NLRs.

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38
Q

Name two cytokines produced as pro-peptides?

A

IL-1b and IL-18.

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39
Q

What are the basic steps of the nod-like signalling pathway?

A

DAMPs interact with NLRs.
Pro-caspase-1 is cleaved to generate active caspase-1.
Activate caspase-1 cleaves pro-IL-1b and pro-IL-18 to generate the active IL-1b and IL-18.

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40
Q

What are the 3 main types of inducers of inflammation?

A
  1. PAMPs - specific signatures, sequences, structures etc. present on the pathogen that are absent from self.
  2. Virulence factors
  3. DAMPs - endogenous molecules/molecular patterns associated with endogenous damage.
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41
Q

What recognises PAMPs and DAMPs generally?

A

Pattern recognition receptors.

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42
Q

What are the sensors of inflammation?

A

TLRs and NLRs, collectively known as PRRs.

Expressed by macrophages, monocytes, neutrophils, dendritic cells, lymphocytes, fibroblasts and endothelial cells.

43
Q

What cells express PRRs?

A

Monocytes, macrophages, neutrophils, dendritic cells, lymphocytes, fibroblasts and endothelial cells.

44
Q

Where are TLRs located?

A

Cell surface.

45
Q

Where are NLRs located?

A

Intracellularly.

46
Q

What are the effectors of inflammation?

A

Vasodilation is mediated by cells like macrophages or mast cells producing histamines, prostaglandins/leukotrienes.
Mast cells and macrophages are tissue-resident.
Neutrophils contain granules rich in proteases and when activated the O2 consumption is increased.
Phagocytic acitivty.
Large amount of cytokines that act systemically in an endocrine manner.

47
Q

What is meant by respiratory burst?

A

The massive increased in oxygen consumption associated with degranulation of neutrophils involving release of proteases and highly reactive oxygen and nitrogen species.

48
Q

What are the effects of inflammation?

A

Induction of acute-phase plasma proteins in the liver.
Platelet activation.
Fever, fatigue and anorexia are part of the hypothalamic response due to systemtic action of cytokines.
Activation of endothelial cells to increase vascular permeablity and facilitate entry of immune cells to the site of infection, associated with oedema.
Activation of the complement system.

49
Q

Which class of T cells produces anti-inflammatory cytokines?

A

T regulatory cells.

50
Q

What is produced by T regulatory cells?

A

IL-10 and TNF-b.

51
Q

Which cytokines activate a naive T cell into a Th1 cell?

A

INF-y, IL-12 and IL-18.

52
Q

Which cytokines are produced by Th1 cells?

A

IL-2, INF-y and TNF-a.

53
Q

Which cytokines induce a naive T cell into a Th2 cell?

A

IL-4.

54
Q

Which cytokines are produced by the Th2 cell?

A

IL-4, IL-5, IL-9 and IL-13.

55
Q

Which cytokines induce a naive T cell into a Th17 cell?

A

TGF-b, IL-6.

56
Q

Which cytokines are produced by Th17 cells?

A

IL-17, IL-6 and TNF-a.

57
Q

What induces the production of defensins and other antimicrobial peptides by epithelial cells?

A

IL-22 produced by Th17 cells.

58
Q

Name 3 anti-inflammatory cytokines

A

IL-10, IL-37 ad TNF-b

59
Q

What is the function of receptor antagonists in inflammation resolution?

A

Receptor antagonists such as IL-1Ra bind to the IL-1R and don’t elicit an intracelllular signal.

60
Q

What is the role of anti-inflammatory cytokines?

A

They prevent the production of pro-inflammatory cytokines by Th1 and Th17 cells.

61
Q

What is the name of the TNF-a decoy receptor?

A

sTNFR (soluble TNFa receptor).

62
Q

What are resolvins?

A

A class of lipid mediators that promote the resolution of inflammation by inhibiting transcription and release of pro-inflammatory cytokines.

63
Q

What are the 3 main clinical manifestations of atherosclerosis?

A
  1. Coronary heart disease: angina pectoris, myocardial infarction, sudden cardiac death, conestive heart failure and arrhythmias.
  2. Cerebrovascular disease: stroke.
  3. Peripheral vascular disease: gangene, cold feed, painful feet.
64
Q

Define atherosclerosis?

A

Atherosclerosis is a chronic inflammatory response in the walls of arteries in large part due to deposition of lipoproteins.

65
Q

What are lipoproteins?

A

Plasma proteins that carry cholesterol and triglyceride.

66
Q

Describe the structure of a lipoprotein?

A

There is a hydrophobic region on the inside e.g. triglyceride, or cholesterol ester.
The hydrophilic region may be protein e.g. apolipoprotein.

67
Q

What are the 3 types of lipoproteins?

A
  1. Triglyceride-rich lipoproteins/chylomicrons/very-low density lipoprotein.
  2. Cholesterol-rich lipoproteins/low-density lipoproteins, high-density lipoproteins.
  3. Intermediate-density lipoproteins or remnants produced from either chylomicrons or VLDL.
68
Q

What are the two pathways of lipid metabolism?

A
  1. Exogenous pathway

2. Enodegenous pathway

69
Q

Describe the exogenous pathway of lipid metabolism?

A

Triglycerides of dietary origin will be transported from the intestine in the blood as chylomicrons.
Lipoprotein lipase causes breakdown of the triglyceride component of the chylomicron to generate FFAs and 2-mono-acyl glycerol.
The FFAs and glycerol can be used by adipose tissue (stored as excess fat) or by skeletal muscle (to provide energy).
This processing of chylomicrons to generate FFAs and glycerol will also generate chylomicron remnants which can either be cleared by the liver or can accumulate in an artery leading to an atheroma.

70
Q

Describe the endogenous pathway of lipid metabolism?

A

This involves triglycerides that originate in the liver.
The liver is the site of metabolism and lots of triglycerides are synthesised here and secreted as VLDL.
VLDL is processed by lipoprotein lipase and hepatic lipase.
These hydrolyse the triglyceride component of VLDL converting the VLDL to an IDL and subsequently LDL.

71
Q

Which type of lipoprotein is the “bad” cholesterol?

A

LDL

72
Q

How does increase in LDL increase risk of cardiovascular disease?

A

10% increase in LDL cholesterol results in a 20% increase in coronary heart diseae risk.

73
Q

Chylomicrons carry TAGs of what origin?

A

Dietary origin.

74
Q

VLDL carry TAGs of what origin?

A

Liver.

75
Q

Who discovered the pathway by which LDL is cleared from the plasma and when?

A

Brown and Goldstein in 1960’s discovered the pathway of receptor-mediated LDL uptake into cells and that it was under negative control - they won a Nobel prize.

76
Q

Describe the receptor-mediated uptake of LDL by cells?

A

LDL binds to the LDL receptor and this undergoes endocytosis to form an endosome which transports the LDL particle to the lysosome for their digestion.
The LDL receptor is recycled back to the surface.
The LDL that has been digested is hydrolysed into free cholesterol and amino acids, the cholesterol is stored as lipid droplets.
Brown and Goldstein identified that this pathway was under negative feedback control.
Increased uptake of LDL reduces the number of LDLr.

77
Q

Other than LDL receptors, what other receptors can take up LDL, particularly modified LDL?

A

Scavenger receptors.

78
Q

Which cholesterol is considered to be “good” cholesterol?

A

HDL.

79
Q

What is the key apolipoprotein in HDL?

A

Apolipoprotein A1.

80
Q

What is the key apolipoprotein in LDL?

A

Apolipoprotein B.

81
Q

Why is HDL considered to be good cholesterol?

A

HDL transports cholesterol effluxed from cells to the liver for secretion as bile in a process known as reverse cholesterol transport.
HDL acts as an anti-inflammatory and is generally cardio-protective.

82
Q

What is reverse cholesterol transport?

A

The process where cholesterol goes from the blood to the liver to the bile and this involves HDL.

83
Q

What percentage of cholesterol in the blood is of dietary origin?

A

20%

84
Q

What percentage of cholesterol in the blood is of de novo origin?

A

80%

85
Q

What kind of rhythm does cholesterol synthesis following?

A

Circadian rhythm.

86
Q

When does cholesterol biosynthesis peak?

A

4am.

87
Q

What are statins?

A

Competitive inhibitors of HMG-CoA reductase.

88
Q

How is cholesterol produced (de novo)?

A

Acetate gives rise to HMG-CoA which undergoes a reduction via HMG-CoA reductase to form mevalonate.

89
Q

Why are statins taken at 7-9pm?

A

Statins are taken between 7-9pm so that levels of statin in the blood peak around 4am which is when cholesterol biosynthesis is at its peak.

90
Q

What are the modifiable risk factors for cardiovascular disease?

A 
Smoking
Dyslipidaemia - raised LDL-C, low HDL-C, raised triglycerides. 
Raised blood pressure - hypertension. 
Diabetes mellitus. 
Obesity. 
Dietary factors. 
Thrombogenic factors. 
Lack of exercise. 
Exercise alcohol consumption.
91
Q

What are the non-modifiable risk factors for cardiovascular disease?

A

Personal history of CVD e.g. mutation in LDL receptor gene preventing plasma clearance of LDL.
Family history of CVD.
Age.
Gender.

92
Q

Why does gender affect CVD risk?

A

Up to a certain age, males have a much higher incidence of CVD thought to be attributable to the protective effect of oestrogen in pre-menopausal women.
Post-menopausal, females have a slighter higher CVD rate than males.

93
Q

Describe the synergistic actions of multiple risk factors?

A

If you carry more than one risk factor, your chages of developing CVD increase dramatically.

94
Q

If you smoke, have high serum cholesterol and hypertension by what fold does the risk of CVD increase?

A

16-fold.

95
Q

During atherosclerosis from where and to where do the smooth muscle cells move?

A

From tunica media to intima.

96
Q

What are the two in vivo mouse models for atherosclerosis?

A

ApoE-/- deficient mouse - spontaenously forms atherosclerosis in the aortic root after 20 weeks.
LDLr-/- deficient mouse - must be fed high fat diet to develop atherosclerosis.

97
Q

What is the evidence that atherosclerosis is an inflammatory disorder?

A
  1. Markers of inflammation are elevated in individuals with cardiovascular disease.
  2. Epidemiological studies have demonstrated increased vascular risk in individuals with elevated levels of certain cytokines, cell adhesion molecule and acute phase plasma proteins.
  3. Presence of immune and inflammatory cells in atherosclerotic lesions.
  4. Increased exression of pro-inflammatory cytokines in atherosclerotic lesions.
  5. Immune cell recruitment initiates atherosclerotic plaque formation.
  6. ApoE-/- or LDLr-/- mice that are also deficient for chemokines, chemokine receptors or adhesion molecules have reduced severity of atherosclerosis.
  7. Reduced atherosclerosis in mouse models lacking proinfllammatory cytokines or their receptors.
  8. Increased atheorsclerosis in mouse model sinjected with IFN-y.
  9. Increased atherosclerosis in hypercholesterolaemia mice lacking anti-inflammatory cytokines such as TGF-b or IL-10.
98
Q

List some current anti-atherosclerosis therapies?

A

Statins are competitive inhibitors of the rate-limiting enzyme HMG-CoA reductase which converts HMG-CoA to mevalonate.
Metaformin, sulphonylureas, insulin, incretins and thiazolidendiones can be used to treat hyperglycaemia and insulin resistance which can promote atherosclerosis.
Aspirin and Clopidogrel can be used to prevent platelet aggregation which promotes atherosclerosis.
ACE inhibitors, angiotensinogen II blockers, calcium blocers and diuretics can be used to treat hypertension which promotes atherosclerosis.
Statins and fibrates are used to treat dyslipiaemia and inflammation which promote atherosclerosis.

99
Q

How much of the % decline in cardiovascular mortality can be attributed to the action of statins?

A

30%

100
Q

What is the rate-limiting enzyme in cholesterol biosynthesis?

A

HMG-CoA reductase.

101
Q

What is CANTOS? Was it successful?

A

A randomised double-blind trail with canakinumab (a monoclonal antibody targeting IL-1B) involving 10,061 patients with previous myocardial inflammation and high levels of CRP with 3 doses (50mg, 100mg, 150mg).
It was found that 150mg every 3 months led to significant lowering of cardiovascular events compared to placebo control and this effect was independent of lipid lowering.

102
Q

What is CIRT? Was it successful?

A

CIRT was a trial of low dose methotrexate (found to be of use in lowering inflammation in rheumatoid arthritis) however this was found to have no effect.

103
Q

What was Jupiter?

A

A large international clinical trial with 18,000 participants worldwide who under current guidelines wouldn’t recieve a statin, but these individuals had high CRP but low cholesterol and had never had a heart attack.
They were prescribed a statin and the results were released in 2008 revealing a 44% reduction in ever having a first heart attack, stroke or cardiovascular death, a 55% reduction in myocardial infarction, a 50% reduction in stroke and a 20% reduction in overall mortality simply by giving a statin to individuals with low cholesterol but high CRP.

Concepts of Disease (11 decks)

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