Mediators of Inflammation Flashcards
where are mediators produced?
site of inflammation
or
by liver and activated at site of inflammation
when are mediators produced?
soon! - on released/activated they are quickly decayed, inactivated, eliminated, inhibited
how do mediators work?
most act by binding specific receptors, some (enzyme, ROS) have broad and non-specific effects
derivation?
vasoactive amines
cell
derivation?
compliments
plasma protein
derivation:
NO
cell
derivation
coagulative factors?
plasma
derivations
ROS?
Cell
derivation
cytokines?
cell
derivation
kinin?
plasma
derivation
lysosomal enzymes?
cell
derivation
neuropeptides?
cell
derivation
platelet activation factor?
cell
derivation
arachidonic acid metabolites?
cell
Histamine and seratonin are examples of?
vasoactive amines
Histamine and seratonin
response time?
stored in cells and ready for release, allowing for quick response
histamine causes?
arterial dilation and endothelial contraction
histamine comes from (3)
mast
basophils
platelets
what inactivates histamine
histaminase
what causes mast cells to release their histamine (6)
physical immune (binding IgE) compliment (c3a, c5a) histamine releasing protein (from leukocytes) neuropeptides cytokines (IL1, IL8)
Serotonin causes?
vasoconstriction to aid in clotting
where is serotonin?
present in platelet granules
Where does arachidonic acid derived from?
derived from cell membrane phospholipids and is transformed into a number of compounds that mediate inflammation and hemostasis
Cell sources of AA? (4)
leukocytes
mast cells
endothelium
platelets
AA inactivation?
spontaneous decay
enzymes
AA metabolite formation
2 pathways
- cyclooxygenase –> prostaglandins and thromboxanes
2. lipoxygenase –> leukotrienes and lipoxins
Where do NSAIDS play a role in AA pathway?
block COX (thus shut down prostaglandins and thromboxanes)
Where do glucocorticoids play a role in AA pathway?
block phosphlipase A (thus shut down whole AA pathway)
Prostaglandins contribute to which symptoms of inflammation?
dolor
calor
what determine which prostaglandins / thromboxanes are made?
the presence of specific enzymes
endothelial cells have which enzymes in AA metabolism
prostacyclin synthase - which produces PGI2 - a vasodilator and inhibitor of platelet aggregation - but don’t make TXA2, which has opposite effect
AA –> leukotrienes - what do they do?
mediate specific functions of inflammation
what does LTB4 do?
chemotactic agent for neutrophils
what do LTC4 LTD4 and LTE4 do?
cause vascular permeability
Lipoxins - what are they?
AA metabolites that are generated as leukocytes enter tissues
they antagonize leukotrienes and are anti-inflammatory (inhibit neutorphil chemotaxis and endothelial adhesion)
what is platelet activating factor?
A cell derived mediator of inflammation
how is platelet activating factor produced?
similar to AA - phospholipase A2 cleaves lipids from cell membranes
what does platelet activating factor do?
name is misleading - does much
- platelet aggregation
- vasodilation
- vascular permeability
- bronchoconstriction
- stimulus for other mediators
what are cytokines?
cell derived mediators - specifically polypeptides that function as mediators in both the innate and adaptive immune system
what are important acute inflammatory cytokines? (5)
TNF1 IL1 Chemokines (CXC, CC) IFN gamma IL-12
TNF & IL-1
Who produces them
what stimulates production
what do they do
produced in a range of cells, but especially macrophages, mast cells, endothelial cells
production is stimulated by microbial products, immune complexes, and T cell mediators
cause endothelial activation (leukocyte binding and recruitment)
also induce systemic effects of inflammation - fever, acute phase protein synthesis, etc.
what are chemokines
cytokines - specifically small proteins separated into 2 groups (CXC, CC) based on structure
what are chemokine primary function?
chemotaxis - but also activate leukocytes
CXC is chemotactic for
neutrophils
CC is chemotactic for
variety of cells (e.g. eotaxin for eosinophils)
Which cytokines are imporant chronic inflammation cytokines
IFN-gamma - stimulates classical macrophage activation
IL-12 - stimulates the growth and function of T cells
What are ROS?
cell derived mediators of inflammation
who releases ROS?
activated neutrophils and macrophages
what are ROS made from?
NADPH oxidase pathway which produces superoxide radical
what does superoxide spontaneously change to?
hydrogen peroxide which can also be converted to hypochlorous radical via myeloperoxidase in neutrophils
What do ROS do?
highly toxic oxidizers that not only damage microbes, but also host tissue (endogenous antioxidants (e.g. superoxide dismutase) mitigate effect on host
NO what is it / what does it do?
Nitric oxide is a cell derived mediator
Like ROS is is a free radical that can be used to kill microbes
It is also a mediator of vasodilation, antagonizes platelet activation, and reduces leukocyte recruitment
What makes NO ?
Nitric oxide synthase (NOS) from L arginine (3 isoforms)
What is Type II NOS?
Inducible NOS: induced in macrophages and endothelial cells
What induces Type II NOS?
IL-1
TNF
IFN-gamma
bacterial endotoxins
What is Type II NOS responsible for?
NO in inflammation (can also be induced in other cell types)
What is type III NOS?
Endothelial NOS: constitutively expressed in endothelial cells
What are the azurophil granules of neutrophils and granules of monocytes?
they are either similar to lysosomes or are modified lysosomes
What do the granules of monocytes and neutrophils contain?
enzymes that can kill microbes and digest ingested materials
In addition to containing enzymes that kill microbes and digest ingested materials, what else are granules a significant source of?
substances that damage normal host tissue -
- acid proteases active within phagolysosomes (low pH)
- neutral proteases (e.g. collagenases) are active outside the cell (neutral pH)
What helps to minimize the damage that lysosomal enzymes do to host tissue?
protease inhibitors - present in blood and body tissue
- alpha 1 antitrypsin
- alpha 2 macroglobulin
where are acid protease (lysosomal enzyme) active?
phagolysosomes (low pH)
where are neutral proteases (E.g. collagenase) active?
outside the cells (neutral pH)
what does alpha 1 antitrypsin do
neutrophil elastase inhibitor
what does alpha 2 macroglobulin do?
inhibits a large variety of proetinases (e.g. collagenase)
are all granules in neutrophils the same?
no - they have different constituents and function differently which includes tendency for extra-versus intra-cellular activity
what are nueropeptides and what do they do
cell derived mediator
can initiate inflammation
when and where are neuropeptides active?
in vascular tone and permeability
particularly in lung and GI
Substance P is what?
a neuroactive peptide (11 aa)
who secretes substance P
nerves and inflammatory cells (macs, eos, lymphs, dends)
what does substance P do?
binds to neurokinin-1 receptor to generate a pro-inflammatory effec in immune ant epithelial cells
compliment - where is it from
plasma protein derived
what does compliment do?
opsonize pathogens and induce a series of inflammatory responses that help to fight infection
specific immune functions include increasing vascular permeability and luekocyte chemotaxis
what does the final activated compliment do?
forms membrane attack complex (MAC) that forms holes in the membranes of microbes
under normal conditions what are the compliment dudes doing?
components of compliment system (C1-9) circulate as inactive molecules in the plasma
what activates compliment
proteolysis
what happens once compliment is activated
the components are able to proteolyze and amplify the reaction
What is the key factor in compliment
c3 convertase that cleave c3 into c3a and c3b
what does c3b do
binds to c3 convertase to from c5 convertase, which initates c5b-9 formation (The MAC)
What are the three separate pathways that lead to C3 convertase formation
- classical
2 alternative - lectin
what happens in the classical compliment pathway
fixation of c1 to antigen-antibody complexes
what happens in teh alternative compliment pathway
microbe cell wall components combine with plasma proteins (Factors b,d)
what happens in the lectin compliment pathway?
plasma lectin binds microbial mannose and stimulates classical pathway
c3a, c5a results
increase vascular permeability and simulate mast cells to release histamine
c5a activates what
the lipogenous pathway for AA metabolism
c5a, c4a, c3a activate?
leukocytes - increasing their endothelial adhesion
- also chemotatic agents for neuts, eos, basos, and monos
c3b acts as?
opsonin for enhanced phagocytosis
what is the MAC?
essentially multiple C9 proteins (formed by 5b-c9)
- creates pores that violate the membranes of some bacteria
most of the time we do not want to activate compliment - so what do we do?
inhibitors free within the plasma and associated with cells protect host tissue
- c1 inhibitor blocks activation of c1
- decay acclerating factor (DAF) and factor H limit C3/C5 convertase formation
coagulation / kinin systems overlap?
the cogaulation system overlaps with mediators fo inflammation
what is Hageman factor?
factor XII is an important clotting factor that activates the kinin system
what is the kinin system
ultimately system leads to bradykinin which causes increased vascular permeability, vascular dilation, and pain
intermediate product kalikrein is chemotatic and activates factor XII
Factor XII (Hageman factor) is an important clotting factor, what does it do?
Stimulates the clotting cascade, including several other factors that impact inflammation
What other factors does factor XII stimulate that impact inflammation?
factor Xa - which lead to vascular permeability
thrombin
What does factor Xa do?
leads to vascular permeability
what does thrombin do (3)
binds to protease activated receptors on endothelial cells, activating them
cleaves fibrinogen creating fibrinopeptides which increase vascular permeability and are chemotatic
thrombin cleaves compliment factor 5 forming factor 5a
Whenever clotting system is activated, what other system is activated?
fibrinolytic
- multiple of these factors are active inflammatory mediators resulting in vascular permeability, dilation, and C3a formation
what helps tamp down inflammation?
several factors serve to antagonize the driving / facilitating mediators of inflammation
what destroys many of the circulating inflammatory mediators?
circulating enzymes - that have short active periods
what doe lipoxins do?
antagonize luekotrienes
what do compliment regulatory proteins do?
antagonize mediators of inflammation (C1 inhibitor)
IL-10 what does it do? where does it come from?
secreted by macrophages
down regulates activated macrophages
TGF beta
what does it do?
promotes fibrosis
is an anti-inflammatory
do only extracellular compounds antagonize pro-inflammatory cells?
no - intracellular compounds also antagonize pro-inflammatory cell states
