Download The Inflammatory Response

The Inflammatory
Response
A review
The 3 Lines of Defense
• FIRST line: Barrier protection
– non-specific (treats each pathogen the same)
– acts to prevent the pathogen from getting into the body
– skin, mucous membranes, tears, sweat
• SECOND line: Acts to destroy/inactivate a pathogen if it
breaks the barriers of the first line
– non-specific -phagocytic leukocytes
– neutrophils and macrophages
• THIRD line: Acts to destroy specific pathogens that are not
destroyed/inactivated by the second line
– specific
– Lymphocytes
– T cells, B cells
The Inflammatory Response
• Part of the second line of defense
– The pathogen has gotten through the barrier
protections and is in the tissues.
Uh…oh!
Splinter!!!!
What’s happening?
• Splinter (or pin) has broken through the barrier, carrying bacteria
into the tissue.
• Mast cells release histamine.
• Macrophages that are in the tissue secrete chemical signals
(cytokines) causes nearby capillaries to dilate and makes them
more permeable (leaky).
What’s happening?
• Histamine released from mast cells cause more
macrophages to enter from the blood stream.
• Cytokines released from macrophages increase
the blood flow to the site and “call” more
neutrophils and antimicrobial peptides to the
site.
– now arrive and pass through the leaky
capillaries into the tissue
– ingest and kill the invader by phagocytosis
and then fusion w/lysosomes
• More blood redness, increase in temp,
fluid leaks from the vessel into the tissue
swelling
What’s happening?
• Neutrophils continue to digest the bacteria
and cell debris.
• Inflammation subsides and tissue begins to
heal.
Hooray for the Inflammatory
Response!!!
The Inflammatory Response is a GOOD thing,
because it:
• Prevents the spread of infection.
• Helps remove pathogens and damaged
tissues.
But….there’s a dark side
• What if the inflammatory response of the immune
system is continually stimulated?
…too much of a good thing
For example, there can be different types of stimulants:
1)Infectious: unresolved viral or bacterial infection
2)Noninfectious: pollen, smoking, autoimmune reaction,
obesity and tissue damage from wounds, tumors, heart
disease, atherosclerosis and autoimmune disease
This can lead to…
Chronic
Inflammation
Chronic Inflammation
is NOT
a good thing:
CI can lead to:
Development of Type 2 diabetes, exacerbation of
heart, liver and kidney disease, Alzheimer’s, some
cancers (perhaps from increased mutational rate
and enhanced angiogenesis), fibrosis
What’s the difference between
Acute Inflammation and Chronic
inflammation?
Acute inflammation: the normal Inflammatory response
●neutrophils dominate.
●you feel and see it (pain, redness, swelling, heat).
●Inflammatory cytokines are expressed and do their job and
resolution occurs relatively quickly –it’s over and done with.
Chronic inflammation (CI):
● macrophages dominate.
●T cells and B cells become involved.
●CI is silent—progresses without one even knowing it’s happening
●Persistent, increased expression of inflammatory cytokines.
What are these cytokines?
A trio of 3 proinflammatory cytokines
always predominates.
• IL-1 (interleukin -1)
• IL-6 (interleukin -6)
• TNF-α (tumor necrosis factor-alpha)
What happens because of these
cytokines?
● IL-1
– stimulated very early by macrophages
– increases the permeability of capillaries
– calls more neutrophils to the tissue
●IL-6
– secreted by T cells and macrophages
– stimulates the inflammatory response
– increases the production of neutrophils in the bone marrow
● TNF-α
– activates macrophages
– increases permeability of capillaries
So secretion of these cytokines just
continues the inflammatory
process
Reminder
Why are we concerned about chronic
inflammation?
Recent studies have suggested that the constant
secretion of these cytokines and stimulation of the
inflammatory response can lead to….
•
•
•
•
•
Type 2 diabetes
Exacerbation of heart, liver and kidney disease
Alzheimer’s disease
Fibrosis of some tissues
Some cancers
HOW?????
• Let’s briefly review how cells communicate
with each other
cell-signaling
Three stages of Cell Signaling
1. RECEPTION
–
a signaling molecule binds to a SPECIFIC receptor protein
molecule
2. TRANSDUCTION
– This causes the receptor protein to change shape. Now the
signal is changed into another form that the cell can
recognize that will cause it to respond in a specific way.
– This may occur in multiple steps called a CASCADE.
3. RESPONSE
– The cell responds in a specific way and maybe the
production of a particular protein.
Reminder:
Causes of chronic inflammation can be
infectious or non-infectious
Infectious: such as an unresolved viral or
microbial infection, which results in continual
immune stimulation
• Example: Periodontitis from persistent dental
infections
• HOW?? -there is a constant source of bacteria –
the immune system is constantly being required
to try to rid the body of these bacteria
 constant inflammation
Non infectious causes
• pollen, smoking, pollution, autoimmune
reaction and tissue damage from wounds that
don’t heal, tumors, heart disease and
atherosclerosis …… and……obesity!
• Pollen and particles from smoking and
pollution can constantly irritate certain tissues
• Tissue damage from atherosclerosis, heart
disease and wounds that don’t heal can
constantly irritate certain tissues, as well.
Huh?…OBESITY???
How can having too many adipocytes (fat cells) lead to
a state of chronic inflammation?
1) Adipocytes can secrete IL-6
..but that’s not the end of the story…..
2) excess free fatty acids bind to receptors on the adipocytes
3) cell signaling now leads to increase of the release of IL-6
So what can happen now?
IL-6 then binds to receptors on the pancreatic
beta cell ……..
this prevents the cell from getting the signal to
make insulin
Result????
Type 2 Diabetes!
If CI is “silent”, but dangerous, is there
a way for someone to know if it’s
happening in their body?
Reminder: Inflammatory markers:
• 1) IL-6
• 2) IL-1
• 3) TNF-α
CI can be determined by measuring one of the
inflammatory markers in a sample of their blood.
THE ELISA
We can determine if too much
of the protein IL-6 is in
someone’s blood by doing a
laboratory test called an ELISA