Lecture 9: Acute Inflammation: Cytokines And Cells Flashcards
(120 cards)
0
Q
What are cytokines produced by
A
Inflammatory cells and other cells during inflammation
1
Q
What are cytokines?
A
Low-molecular weight proteins
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Q
List some examples of cytokines
A
TNF tumour necrosis factor
ILs the 35 different species of interleukins
IFNs interferons
3
Q
What are chemokines
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More than 50 species of chemoattractants
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Q
What do chemokines do?
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Enable cells to locate to sites of injury and infection
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Q
What does TNF do?
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Up regulates inflammation
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Q
When were the effects of TNF first inferred?
A
A century ago
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Q
Who were they inferred by
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New York physician William Colely
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Q
What did Coley do?
A
Inoculated cancer patients with bacterial preparations
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Q
What happens to those cancer patients?
A
Tumour regression occurre
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Q
Which bacterial products were injected into mice?
A
Tuberculosis vaccine BCG and
Bacterial lipopolisaccharide LPS
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Q
What did these two bacterial products elicit in mice?
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The production of a protein (TNF) which caused some tumours to become necrotic
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Q
What was this protein called?
A
Tumour necrosis factor
13
Q
What is cachexia
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The loss of stores of fat and muscle protein
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Q
To whom does cachexia occur?
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To people with cancer and other chronic inflammatory conditions
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Q
How was cachexia in cancer / chronic inflammatory patients shown experimentally?
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Mice infected with sleeping sickness parasite trypanosoma. It was found the mediator of cachexia is cachectin (same as TNF)
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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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Q
What do cytokines like TNF and IL-1 induce at low concentrations?
A
Protein synthesis in target cells
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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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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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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)
21
Q
Which leukocyte comprises the major cell population in acute inflammation?
A
Neutrophils
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Q
What is the role of the neutrophil?
A
To exist in an armed and dangerous state
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Q
What do neutrophils possess that contain molecules used in defence and signalling?
A
Granules
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Name the three type of polymorphonuclear leukocytes
Neutrophil
Eosinophil
Mast cell / basophil
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What are polymorphonuclear leukocytes also known as?
Granulocytes
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Neutrophils comprise _% of leukocytes?
75%
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What is the function of a neutrophil
Phagocytosis of tissue debris, micrboes
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What harmful effects can neutrophils cause?
Tissue injury
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What percentage of leukocytes do eosinophils make up?
1%
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What are the function of eosinophils
Anti-parasitic (helminth)
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What harmful effects can eosinophils cause?
Allergies
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What percentage of leukocytes do mast cell/basophils make up?
<1%
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What is the function of a basophil
Regulation of inflammation
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What harmful effects can basophils produce on a cell?
Allergy
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What does injury without infection generate?
Sterile inflammation
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How are cellular responses initiated in sterile inflammation
They are initiated by molecules released from dead cells and damaged ECM
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When there is also infection, what do microbes release?
PAMPs- pathogen associated molecular patterns
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Name the 5 different types of damage associated molecular patterns which initiate cellular responses
ECM fragments
Intracellular proteins
DNA and RNA
ATP
Crystals
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Give an example of an ECM fragment acts as a DAMP
Hyaluronan
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Give an example of intracellular proteins that acts as a DAMP
HMGB1 from chromatin
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Give an example of crystals which act as a DAMP
MSU (monosodium urate), Cholesterol
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What receptor do ECM fragments like hyaluronan target?
Toll like receptors, TLRs
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What sort of receptors do intracellular proteins like HMGB1 from chromatin target?
TLRs, RAGE (receptors of advanced glycation end products)
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What kind of receptors do DNA and RNA target?
TLRs
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What sort of receptors does ATP target?
P2X7Rs purinergic
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What sort of receptors do crystals like MSU and cholesterol target?
Components of inflammasomes
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What does signalling from TLRs and P2X7Rs activate?
Inflammasomes
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What is activated that cleaves Pro-IL-1β into active IL-1β
Caspase -1
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Which intracellular cytokine is released when cells lyse?
IL-1α
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What do IL-1α induce endothelial cells to become?
Adhesive for leukocytes
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Recruitment of circulating neutrophils requires what?
Adherence to the endothelium
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What is marination?
Adherence to the endothelium
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What does blood flow rate decrease with?
Loss of plasma and increased blood viscosity
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Where do neutrophils in venules leave from?
The axial central stream
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Where do neutrophils concentrate?
In the plasma tic zone
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What is the plasmatic zone?
The boundary layer adjacent to the endothelium
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How do neutrophils loosely contact the endothelium?
By rolling along the surface
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What are neutrophil rolling mediated by?
P and E- selectins on stimulated endothelial cells
Glycoproteins with sugar residues (sialyl-Lewis-x) on neutrophils
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How long does maximal mediation take to occur?
Within a few minutes
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What is sialyl-Lewis-x?
A sugar residue (attached to glycoproteins on neutrophils, help mediate neutrophil rolling along endothelium
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When does firm adhesion with flattening occur?
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
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What is ICAM-1
Intercellular adhesion molecule-1
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What is VCAM-1
Vascular cell adhesion molecule-1
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What is LFA-1
Leukocyte function-associated antigen-1 which is an integrin
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What happens in neutrophil transmigration
Adherent neutrophils extrude pseudopodia and push their way between or through endothelial cells
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What protease do neutrophils release when transmigration?
Elastase
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What is the purpose of elastase release when neutrophils are transmigration?
It digests the basement membrane so neutrophils can enter the extravasulcar tissue
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Leukocytes move directionally in response to what?
Chemical signals
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What kind of chemical signals elicit leukocyte directional response?
Chemotaxis (or necrotaxis if sterile inflammation)
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What kind of chemo signals guide the cells in circulation?
Chemotactic signals
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Give an example of chemotactic signals
Chemokine IL-8 on endothelial cells
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What do chemotactic cells in the tissues include?
Proteins - released from broken cells
Chemokines, leukotriene and complement products C3a and C5a
Bacterial products
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What kind of proteins are released from broken cells which act as a chemotactic signal
Mitochondrial proteins with an N-formulated methione (like N-formylated peptides, NFPs)
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What are mT proteins like N-formylated peptides recognised by?
Formylated peptide receptor-1 (FPR-1)
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What effects does the recognition of NFPs override?
The effects of Chemokines in the circulation
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What is LTB4?
Leukotriene B4
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What are the three coordinated processes which phagocytes undergo to remove damaged tissues and destroy microbes
Phagocytosis
Degranulation
Respiratory burst
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What makes damaged cells or bacterial get phagocytosed more readily?
When cells or bacterial are coated with molecules called opsonins
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Give some examples of opsonins
Immunoglobulins and C3b
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How do phagocytes attach to opsonised micro-organisms
They use receptors for immunoglobulins and for C3b
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What is the receptor for C3b?
The Mac-1 integrin
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Which receptors bind bacteria directly? (Non opsonic phagocytosis)
Receptors for LPS (lipopolisaccharide)
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What do pseudopodia extend around
Particles
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Where are particles internalised during phagocytosis?
In membrane bound vesicles called phagosomes
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What is the fluid in the phagosome
A sample of the extracellular medium, non toxic
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What do phagosomes fuse with?
Lysosomes
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What do lysosomes contain?
Hydrolytic enzymes
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What do phagosomes and lysosomes form?
Phagocytic vacuoles or phagolysosomes
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Why is this step termed degranulation
The lysosomal granules disappear from the cytoplasm
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What is the pH of the fluid in phagocytic vacuoles?
Acidified. PH 4.5-5.0
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What then, do phagocytes undergo?
A respiratory burst
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How does this respiratory burst occur
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
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List the processes of leukocyte function in order
Opsonisation, adhesion, phagocytosis, degranulation, respiratory burst
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What reduces oxygen to superoxide?
NADPH oxidase, from the electron transport complex (NOX2)
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What are the two things the superoxide could do
1. Depolarise the vacuole which induces a K+ influx
| 2. Be reduced to hydrogen peroxide by superoxide dismutase
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What does K+ influx cause?
K+ releases cationic proteases like cathespin G, elastase from anionic sulphated proteoglycans
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What does super oxide reduction to hydrogen peroxide affect?
Causes a reaction with chloride, catalysed by myeloperoxidase. This generates hypochlorous acid
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List the outcomes acute inflammation can have on the body
Liquefactive necrosis
Systemic responses
Out of control inflammation
Processing of microbial molecules activating immunity
Repair with resolution
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What is liquefactive necrosis also known as?
Suppuration
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Infection with pus forming agents in solid tissues leads to what?
The accumulation of dead neutrophils and tissue cells
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What is pyogenic
Pus forming
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What is pus
Dead neutrophils and tissue cells
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Give the two kinds of lesions that may form as a result
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Localised (like an abscess such as a boil)
Or spreading (like cellulitis)
```
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What are three different kinds of systemic responses?
Fever, acute phase response and leucytosis
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What is fever caused by?
Pyrogens like TNF, IL-1 and PGE2
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What are pyrogens produced by?
Peripheral macrophages, and in the brain
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What do pyrogens affect?
Hypothalamic thermoregulation
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What is the acute phase response stimulated by?
IL-6 , when the liver produces many plasma proteins like coagulation factors and opsonins
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What is leukocytosis
An increase in the number of leukocytes due to the release of leukocytes from the bone marrow
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What are the two cases of out of control inflammation?
Systemic inflammatory response syndrome (SIRS, occurs with sterile injury) and sepsis (occurs with infection)
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What are SIRS and sepsis induced by?
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
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What results from induced SIRS or sepsis?
Widespread vascular dilation and permeability >> blood volume loss
Formation of thrombi in small blood vessels (disseminated intravascular coagulation DIC)
Depletion of clotting factors >> uncontrolled bleeding
Inadequate organ perfusion, ischaemia
Multi organ failure (of which morality is greater than 30%)
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What is the inflammatory response turned off by?
Eliminating stimulators effects of dead cell and bacterial products
Negative feedback loops involving anti-inflammatory cytokines and lipid mediators and protease inhibitors
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During inflammation the life time of neutrophils is extend by what?
Cytokines, growth factors and activated endothelium
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During phagocytosis, the C3b receptor Mac-1 induces what?
Respiratory burst
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What does respiratory burst generate?
Reactive oxidative species
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What do ROS directly activate?
Caspases
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What follows after caspase activation?
Neutrophil apoptosis
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Failure to resolve acute inflammation leads to what?
Chronic inflammation
