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NancyMEDSCI203 > Lecture 9: Acute Inflammation: Cytokines And Cells > Flashcards

Lecture 9: Acute Inflammation: Cytokines And Cells Flashcards

0
Q

What are cytokines produced by

A

Inflammatory cells and other cells during inflammation

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1
Q

What are cytokines?

A

Low-molecular weight proteins

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2
Q

List some examples of cytokines

A

TNF tumour necrosis factor
ILs the 35 different species of interleukins
IFNs interferons

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3
Q

What are chemokines

A

More than 50 species of chemoattractants

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4
Q

What do chemokines do?

A

Enable cells to locate to sites of injury and infection

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5
Q

What does TNF do?

A

Up regulates inflammation

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6
Q

When were the effects of TNF first inferred?

A

A century ago

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7
Q

Who were they inferred by

A

New York physician William Colely

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8
Q

What did Coley do?

A

Inoculated cancer patients with bacterial preparations

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9
Q

What happens to those cancer patients?

A

Tumour regression occurre

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10
Q

Which bacterial products were injected into mice?

A

Tuberculosis vaccine BCG and

Bacterial lipopolisaccharide LPS

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11
Q

What did these two bacterial products elicit in mice?

A

The production of a protein (TNF) which caused some tumours to become necrotic

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12
Q

What was this protein called?

A

Tumour necrosis factor

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13
Q

What is cachexia

A

The loss of stores of fat and muscle protein

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14
Q

To whom does cachexia occur?

A

To people with cancer and other chronic inflammatory conditions

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15
Q

How was cachexia in cancer / chronic inflammatory patients shown experimentally?

A

Mice infected with sleeping sickness parasite trypanosoma. It was found the mediator of cachexia is cachectin (same as TNF)

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16
Q

Why does TNF have limited use as an anti cancer agent?

A

Induces unpleasant flu like symptoms

Not effective against most common cancer types (from carcinogens)

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17
Q

What do cytokines like TNF and IL-1 induce at low concentrations?

A

Protein synthesis in target cells

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18
Q

What does protein synthesis in target cells lead to?

A

Vasodilation
Vasopermeability
Expression of endothelial cell adhesion molecules that recruit inflammatory cells

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19
Q

Name some endothelial cell adhesion molecules which are expressed when protein synthesis is induced in target cells, by cytokines

A

Selections, ICAM-1, VCAM-1

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20
Q

What do cytokines (such as TNF and IL-1) induce at high concentrations?

A

Fever
Coagulation cascade
Progressive development of scar tissue, fibrosis
Cachexia (over time)

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21
Q

Which leukocyte comprises the major cell population in acute inflammation?

A

Neutrophils

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22
Q

What is the role of the neutrophil?

A

To exist in an armed and dangerous state

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23
Q

What do neutrophils possess that contain molecules used in defence and signalling?

A

Granules

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24
Q

Name the three type of polymorphonuclear leukocytes

A

Neutrophil
Eosinophil
Mast cell / basophil

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25
Q

What are polymorphonuclear leukocytes also known as?

A

Granulocytes

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26
Q

Neutrophils comprise _% of leukocytes?

A

75%

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27
Q

What is the function of a neutrophil

A

Phagocytosis of tissue debris, micrboes

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28
Q

What harmful effects can neutrophils cause?

A

Tissue injury

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29
Q

What percentage of leukocytes do eosinophils make up?

A

1%

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30
Q

What are the function of eosinophils

A

Anti-parasitic (helminth)

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31
Q

What harmful effects can eosinophils cause?

A

Allergies

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32
Q

What percentage of leukocytes do mast cell/basophils make up?

A

<1%

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33
Q

What is the function of a basophil

A

Regulation of inflammation

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34
Q

What harmful effects can basophils produce on a cell?

A

Allergy

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35
Q

What does injury without infection generate?

A

Sterile inflammation

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36
Q

How are cellular responses initiated in sterile inflammation

A

They are initiated by molecules released from dead cells and damaged ECM

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37
Q

When there is also infection, what do microbes release?

A

PAMPs- pathogen associated molecular patterns

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38
Q

Name the 5 different types of damage associated molecular patterns which initiate cellular responses

A

ECM fragments

Intracellular proteins

DNA and RNA

ATP

Crystals

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39
Q

Give an example of an ECM fragment acts as a DAMP

A

Hyaluronan

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40
Q

Give an example of intracellular proteins that acts as a DAMP

A

HMGB1 from chromatin

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41
Q

Give an example of crystals which act as a DAMP

A

MSU (monosodium urate), Cholesterol

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42
Q

What receptor do ECM fragments like hyaluronan target?

A

Toll like receptors, TLRs

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43
Q

What sort of receptors do intracellular proteins like HMGB1 from chromatin target?

A

TLRs, RAGE (receptors of advanced glycation end products)

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44
Q

What kind of receptors do DNA and RNA target?

A

TLRs

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45
Q

What sort of receptors does ATP target?

A

P2X7Rs purinergic

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46
Q

What sort of receptors do crystals like MSU and cholesterol target?

A

Components of inflammasomes

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47
Q

What does signalling from TLRs and P2X7Rs activate?

A

Inflammasomes

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48
Q

What is activated that cleaves Pro-IL-1β into active IL-1β

A

Caspase -1

49
Q

Which intracellular cytokine is released when cells lyse?

A

IL-1α

50
Q

What do IL-1α induce endothelial cells to become?

A

Adhesive for leukocytes

51
Q

Recruitment of circulating neutrophils requires what?

A

Adherence to the endothelium

52
Q

What is marination?

A

Adherence to the endothelium

53
Q

What does blood flow rate decrease with?

A

Loss of plasma and increased blood viscosity

54
Q

Where do neutrophils in venules leave from?

A

The axial central stream

55
Q

Where do neutrophils concentrate?

A

In the plasma tic zone

56
Q

What is the plasmatic zone?

A

The boundary layer adjacent to the endothelium

57
Q

How do neutrophils loosely contact the endothelium?

A

By rolling along the surface

58
Q

What are neutrophil rolling mediated by?

A

P and E- selectins on stimulated endothelial cells

Glycoproteins with sugar residues (sialyl-Lewis-x) on neutrophils

59
Q

How long does maximal mediation take to occur?

A

Within a few minutes

60
Q

What is sialyl-Lewis-x?

A

A sugar residue (attached to glycoproteins on neutrophils, help mediate neutrophil rolling along endothelium

61
Q

When does firm adhesion with flattening occur?

A

Inflammatory mediators up-regulate intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 on endothelial cells and the leukocyte function-associated antigen-1 on neutrophils

62
Q

What is ICAM-1

A

Intercellular adhesion molecule-1

63
Q

What is VCAM-1

A

Vascular cell adhesion molecule-1

64
Q

What is LFA-1

A

Leukocyte function-associated antigen-1 which is an integrin

65
Q

What happens in neutrophil transmigration

A

Adherent neutrophils extrude pseudopodia and push their way between or through endothelial cells

66
Q

What protease do neutrophils release when transmigration?

A

Elastase

67
Q

What is the purpose of elastase release when neutrophils are transmigration?

A

It digests the basement membrane so neutrophils can enter the extravasulcar tissue

68
Q

Leukocytes move directionally in response to what?

A

Chemical signals

69
Q

What kind of chemical signals elicit leukocyte directional response?

A

Chemotaxis (or necrotaxis if sterile inflammation)

70
Q

What kind of chemo signals guide the cells in circulation?

A

Chemotactic signals

71
Q

Give an example of chemotactic signals

A

Chemokine IL-8 on endothelial cells

72
Q

What do chemotactic cells in the tissues include?

A

Proteins - released from broken cells

Chemokines, leukotriene and complement products C3a and C5a

Bacterial products

73
Q

What kind of proteins are released from broken cells which act as a chemotactic signal

A

Mitochondrial proteins with an N-formulated methione (like N-formylated peptides, NFPs)

74
Q

What are mT proteins like N-formylated peptides recognised by?

A

Formylated peptide receptor-1 (FPR-1)

75
Q

What effects does the recognition of NFPs override?

A

The effects of Chemokines in the circulation

76
Q

What is LTB4?

A

Leukotriene B4

77
Q

What are the three coordinated processes which phagocytes undergo to remove damaged tissues and destroy microbes

A

Phagocytosis
Degranulation
Respiratory burst

78
Q

What makes damaged cells or bacterial get phagocytosed more readily?

A

When cells or bacterial are coated with molecules called opsonins

79
Q

Give some examples of opsonins

A

Immunoglobulins and C3b

80
Q

How do phagocytes attach to opsonised micro-organisms

A

They use receptors for immunoglobulins and for C3b

81
Q

What is the receptor for C3b?

A

The Mac-1 integrin

82
Q

Which receptors bind bacteria directly? (Non opsonic phagocytosis)

A

Receptors for LPS (lipopolisaccharide)

83
Q

What do pseudopodia extend around

A

Particles

84
Q

Where are particles internalised during phagocytosis?

A

In membrane bound vesicles called phagosomes

85
Q

What is the fluid in the phagosome

A

A sample of the extracellular medium, non toxic

86
Q

What do phagosomes fuse with?

A

Lysosomes

87
Q

What do lysosomes contain?

A

Hydrolytic enzymes

88
Q

What do phagosomes and lysosomes form?

A

Phagocytic vacuoles or phagolysosomes

89
Q

Why is this step termed degranulation

A

The lysosomal granules disappear from the cytoplasm

90
Q

What is the pH of the fluid in phagocytic vacuoles?

A

Acidified. PH 4.5-5.0

91
Q

What then, do phagocytes undergo?

A

A respiratory burst

92
Q

How does this respiratory burst occur

A

Electron transport complex NADPH oxidase assembles on phagocytic vacuole membranes and reduces oxygen to superoxide

The superoxide may depolarise the value which induces a K+ influx that releases cationic proteases from anionic sulphated proteoglycans

The super oxide reduces to hydrogen peroxide by superoxide dismutase . Myeloperoxidase catalyses reaction of hydrogen peroxide with chloride to generate hypochlorous acid.

Reactive proteases and oxidants degrade cell debris and kill microorganisms

93
Q

List the processes of leukocyte function in order

A

Opsonisation, adhesion, phagocytosis, degranulation, respiratory burst

94
Q

What reduces oxygen to superoxide?

A

NADPH oxidase, from the electron transport complex (NOX2)

95
Q

What are the two things the superoxide could do

A
  1. Depolarise the vacuole which induces a K+ influx

2. Be reduced to hydrogen peroxide by superoxide dismutase

96
Q

What does K+ influx cause?

A

K+ releases cationic proteases like cathespin G, elastase from anionic sulphated proteoglycans

97
Q

What does super oxide reduction to hydrogen peroxide affect?

A

Causes a reaction with chloride, catalysed by myeloperoxidase. This generates hypochlorous acid

98
Q

List the outcomes acute inflammation can have on the body

A

Liquefactive necrosis

Systemic responses

Out of control inflammation

Processing of microbial molecules activating immunity

Repair with resolution

99
Q

What is liquefactive necrosis also known as?

A

Suppuration

100
Q

Infection with pus forming agents in solid tissues leads to what?

A

The accumulation of dead neutrophils and tissue cells

101
Q

What is pyogenic

A

Pus forming

102
Q

What is pus

A

Dead neutrophils and tissue cells

103
Q

Give the two kinds of lesions that may form as a result

A 
Localised (like an abscess such as a boil)
Or spreading (like cellulitis)
104
Q

What are three different kinds of systemic responses?

A

Fever, acute phase response and leucytosis

105
Q

What is fever caused by?

A

Pyrogens like TNF, IL-1 and PGE2

106
Q

What are pyrogens produced by?

A

Peripheral macrophages, and in the brain

107
Q

What do pyrogens affect?

A

Hypothalamic thermoregulation

108
Q

What is the acute phase response stimulated by?

A

IL-6 , when the liver produces many plasma proteins like coagulation factors and opsonins

109
Q

What is leukocytosis

A

An increase in the number of leukocytes due to the release of leukocytes from the bone marrow

110
Q

What are the two cases of out of control inflammation?

A

Systemic inflammatory response syndrome (SIRS, occurs with sterile injury) and sepsis (occurs with infection)

111
Q

What are SIRS and sepsis induced by?

A

Release and circulation of DAMPs (NFPs and mT DNA), proinflammatory cytokines (TNF, IL-1)

Increase in pro-coagulants to anti-coagulant ratio

Activation if complement

Generation of reactive oxygen species

112
Q

What results from induced SIRS or sepsis?

A

Widespread vascular dilation and permeability&raquo_space; blood volume loss

Formation of thrombi in small blood vessels (disseminated intravascular coagulation DIC)

Depletion of clotting factors&raquo_space; uncontrolled bleeding

Inadequate organ perfusion, ischaemia

Multi organ failure (of which morality is greater than 30%)

113
Q

What is the inflammatory response turned off by?

A

Eliminating stimulators effects of dead cell and bacterial products

Negative feedback loops involving anti-inflammatory cytokines and lipid mediators and protease inhibitors

114
Q

During inflammation the life time of neutrophils is extend by what?

A

Cytokines, growth factors and activated endothelium

115
Q

During phagocytosis, the C3b receptor Mac-1 induces what?

A

Respiratory burst

116
Q

What does respiratory burst generate?

A

Reactive oxidative species

117
Q

What do ROS directly activate?

A

Caspases

118
Q

What follows after caspase activation?

A

Neutrophil apoptosis

119
Q

Failure to resolve acute inflammation leads to what?

A

Chronic inflammation

NancyMEDSCI203 (12 decks)

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