1. The Inflammatory Response
A review

2. 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

3. The Inflammatory Response
Part of the second line of defense
The pathogen has gotten through the barrier protections and is in the tissues.

4. Uh…oh!
Splinter!!!!

5. 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).

6. 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

7. What’s happening?
Neutrophils continue to digest the bacteria and cell debris.
Inflammation subsides and tissue begins to heal.

8. 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.

9. 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…

10. Chronic Inflammation

11. 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

12. 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.

13. 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)

14. 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

15. So secretion of these cytokines just continues the inflammatory process

16. 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

17. HOW????? Let’s briefly review how cells communicate with each other
cell-signaling

18. Three stages of Cell Signaling
RECEPTION
a signaling molecule binds to a SPECIFIC receptor protein molecule
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.
RESPONSE
The cell responds in a specific way and maybe the production of a particular protein.

19. 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

20. 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.

21. 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

22. Result???? 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????

23. Type 2 Diabetes!

24. 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.

25. 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