1. The document discusses physiological processes related to inflammation and immunity. It covers topics like the immune system's goals, types of immunity, and the inflammatory response. 2. A key point is that the inflammatory response involves local cellular responses that help eliminate antigens and damaged tissue to prevent spreading. If local responses fail, bacteria can enter the blood leading to systemic inflammatory response syndrome and potential multiple organ dysfunction. 3. Careful regulation of pro-inflammatory and anti-inflammatory mediators is needed to maintain an adequate inflammatory response and avoid too much or too little inflammation that could respectively cause shock or immunodepression. Loss of this regulation can result in systemic inflammation and multiple organ dysfunction syndrome.

1. Physiological Processes:
Basic Concepts
Systemic Inflammatory Response Syndrome (SIRS)
Multiple Organ Dysfunction Syndrome (MODS)

2. The Immune System Strives to:
• Eliminate infection and damaged tissue
• Maintain an appropriate response level
• Avoid or minimise disruption to homeostasis
• Promote healing

3. Types of Immunity:
• Non-specific (innate):
– Natural barriers
– Inflammation
• Specific (acquired):
- T and B lymphocytes

4. The Inflammatory Response
• The inflammatory response:
– A series of localised cellular responses
– Helps to eliminate invading antigens and damaged tissue,
and prevent them spreading to other areas of the body.
Complete the following multimedia tutorial on the basic
concepts of inflammation.
http://www.nottingham.ac.uk/nmp/sonet/rlos/bioproc
/inflam/index.html
Antigen - any substance that can trigger an immune response.

5. The Innate Immune System and Homeostasis
Invasiveness
of microbe.
Risk to
Homeostasis
Action of innate
immune system
BENEFICIAL
skin surface
natural barriers
superficial
tissue layers
localised
inflammation
DETRIMENTAL
circulation &
body systems
systemic
inflammatory
response (SIRS)

6. Immunity is mediated by:
• Soluble molecules:
– cytokines e.g. interleukin (IL)
– others: prostaglandin (PG), reactive oxygen species (ROS)
• Cytokines:
–
–
–
–
–
small proteins
alter behaviour of other cells
act via cell-surface receptors
short-lived
important examples in inflammation:
• IL-1, IL-6, IL-8, tumour necrosis factor–alpha (TNF-α).

7. Chemical mediators of the inflammatory response
Trigger: e.g.
invading bacteria
Key effector macrophage
cell:
Potent molecules
released
Key effector
cells:
e.g. ROS
neutrophil
endothelium
Physiological changes associated with immunity
i.e. inflammation

8. Chemical mediators of the inflammatory response
skin surface
tissue and
interstitial fluid
Invading bacteria
endotoxin (lipopolysaccharide - LPS)
IL-8
endothelium
plasma
neutrophil
macrophage
IL-1
TNFα
activates endothelia

9. Chemical mediators of the inflammatory response
skin surface
Invading bacteria
tissue and
interstitial fluid
endotoxin (lipopolysaccharide - LPS)
macrophage
IL-8
endothelium
plasma
IL-1
TNFa
Nitric oxide (NO)
Prostaglandin (PG)
rolling adhesion
vasodilation
permeability
adhesion

10. Chemical mediators of the inflammatory response
skin surface
tissue and
interstitial fluid
Invading bacteria
endotoxin (lipopolysaccharide - LPS)
macrophage
IL-8
IL-1
endothelium
plasma
TNFa
Nitric oxide (NO)
Prostaglandin (PG)
diapedesis
complement
fibrinogen
antibodies

11. Chemical mediators of the inflammatory response
skin surface
tissue and
interstitial fluid
migration and
phagocytosis
Invading bacteria
endotoxin (lipopolysaccharide - LPS)
macrophage
IL-8
endothelium
plasma
IL-1
TNFa
Nitric oxide (NO)
Prostaglandin (PG)
more neutrophils and monocytes.
complement
fibrinogen
antibodies

12. Chemical mediators of the inflammatory response
Neutrophils release powerful chemicals that
destroy the pathogen.
Some ROS may leak onto nearby tissues
• reactive oxygen species (ROS)
• antimicrobial molecules
• hydrolytic enzymes

13. Chemical mediators of the inflammatory response
TNF-alpha (TNFα) is a powerful pro-inflammatory mediator
TNFα
with
IL-1 and IL-6
Activates endothelium:
- adhesion molecules are displayed
- active substances released
Increases vascular permeability
Releases C-reactive protein
Induces fever via hypothalamus
Mobilises neutrophils from bone marrow

14. Regulation of the inflammatory response by
chemical mediators.
pro-inflammatory
mediators
TNFα
IL-1
IL-6
anti-inflammatory
mediators
IL-10
IL-4
glucocorticoids
Maintains inflammation at an appropriate
magnitude to promote health

15. What happens if local inflammatory responses fail?
Immediate
2-4 days
Natural barriers and local
inflammatory response
Acute inflammation:
infiltration of neutrophils and
macrophages
Specific immune
response
Chronic inflammation:
infiltration of lymphocytes
and plasma cells
But cannot prevent
microbial invasion into
the blood.
Potential outcome
bacteraemia / septicaemia
systemic inflammatory response (SIRS)
multiple organ dysfunction syndrome (MODS)

16. What could happen if local inflammatory responses fail
H
H
L
L
H
L
H
L
1. Macrophages activated in
the liver and spleen secrete
TNFα into the blood.
3. Disseminated intravascular
coagulation leads to wasting
and multiple organ dysfuction.
2. Systemic shift of fluid from plasma to tissue spaces causes
a drop in blood volume and collapse of dilated blood vessels.

17. Systemic Inflammation:
A systemic inflammatory response causes:
1. systemic vasodilation
2. increased capillary leak due to:
(b) altered endothelial integrity
(c) endothelial injury
3. microvascular occlusion

18. Systemic Inflammation:
1. systemic vasodilation and vasopermeability
macrophages in
liver, spleen
bacterial
LPS
TNFα, IL-1, IL-6
vascular
endothelium
nitric oxide
remedy
fluid resuscitation
prostaglandin
remedy
hypotension,
circulation problems
vasopressor
medication

19. Systemic Inflammation:
1. systemic vasodilation and vasopermeability (regulation)
pro-inflammatory
mediators
TNFα
IL-1
IL-6
anti-inflammatory
mediators
IL-10
IL-4
glucocorticoids
Maintains inflammation at an appropriate
magnitude to promote health

20. Systemic Inflammation:
1. systemic vasodilation and vasopermeability (regulation)
excessive PRO inflammatory response
magnitude of
response
*excessive ANTIinflammatory response
adequate
inflammatory
response
Time
Shock:
early mortality
Immunodepression:
later mortality
* Compensatory anti-inflammatory response syndrome (CARS)

21. Systemic Inflammation:
2. Increased capillary leak (b) Altered endothelial integrity
plasma
TNFα, IL-1
endothelium
interstitial fluid
capillary leak

22. Systemic Inflammation:
2. Increased capillary leak (b) Endothelial injury
proteinases
plasma
endothelium
interstitial fluid
ROS neutralises
destroys anti-proteinases
capillary leak

23. Systemic Inflammation: 3. microvascular occlusion
ROS
TNFα, IL-1
collagen matrix
exposed
factor
intrinsic coagulation
VIIa
pathway activated
extrinsic coagulation
pathway activated
microvascular
occlusion
disseminated
Intravascular
Coagulation
blood
clotting

24. Development of Multiple Organ Dysfunction Syndrome (MODS)
Interstitial
Fluid (IF)
Blood vessel
Oxygen and
nutrients
“sticky” neutrophils
form a plug
thrombus
Carbon dioxide
and wastes
Organ
Functional
capillary leak and build-up of IF
increases diffusion distance
ischaemia
inadequate supply / movement
of gases & metabolites
organ dysfunction