Physiological Processes:Basic Concepts
Systemic Inflammatory Response Syndrome (SIRS)
Multiple Organ Dysfunction Syndrome (MODS)
The Immune System Strives to:
• Eliminate infection and damaged tissue
• Maintain an appropriate response level
• Avoid or minimise disruption to homeostasis
• Promote healing
Types of Immunity:
• Non-specific (innate):
– Natural barriers
– Inflammation
• Specific (acquired):
- T and B lymphocytes
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.
The Innate Immune System and Homeostasis
Invasiveness of microbe.
Risk to Homeostasis
Action of innate immune system
skin surface
superficial tissue layers
circulation &
body systems
natural barriers
localised inflammation
systemic
inflammatory
response (SIRS)
BENEFICIAL
DETRIMENTAL
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).
Trigger: e.g.invading bacteria
endothelium
Potent molecules released
e.g. ROS
Key effector cells:
neutrophil
Physiological changes associated with immunity i.e. inflammation
macrophageKey effector cell:
Chemical mediators of the inflammatory response
Invading bacteria
endotoxin (lipopolysaccharide - LPS)
endotheliumplasma
macrophageIL-8
neutrophil
skin surface
tissue and interstitial fluid
Chemical mediators of the inflammatory response
IL-1 TNFα
activates endothelia
vasodilation
permeabilityadhesion
rolling adhesion
Chemical mediators of the inflammatory response
Invading bacteria
macrophage
skin surface
tissue and interstitial fluid
endotheliumplasma
IL-1 TNFa
IL-8
Check NO
endotoxin (lipopolysaccharide - LPS)
Nitric oxide (NO)
Prostaglandin (PG)
endotheliumplasma
diapedesis
Chemical mediators of the inflammatory response
Invading bacteria
macrophage
skin surface
tissue and interstitial fluid
IL-1 TNFa
IL-8
complement
fibrinogen
antibodies
endotoxin (lipopolysaccharide - LPS)
Nitric oxide (NO)
Prostaglandin (PG)
skin surface
tissue and interstitial fluid
endotheliumplasma
migration and phagocytosis
more neutrophils and monocytes.
Chemical mediators of the inflammatory response
macrophage
skin surface
IL-1 TNFa
IL-8
Nitric oxide (NO)
Prostaglandin (PG)
complement
fibrinogen
antibodies
Invading bacteria
endotoxin (lipopolysaccharide - LPS)
• reactive oxygen species (ROS)
• antimicrobial molecules
• hydrolytic enzymes
Chemical mediators of the inflammatory response
Neutrophils release powerful chemicals that
destroy the pathogen.
Some ROS may leak onto nearby tissues
TNF-alpha (TNFα) is a powerful pro-inflammatory mediator
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
TNFα
with
IL-1 and IL-6
Chemical mediators of the inflammatory response
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
Regulation of the inflammatory response by
chemical mediators.
What happens if local inflammatory responses fail?
Natural barriers and local
inflammatory response
Specific immune
response
Chronic inflammation:
infiltration of lymphocytes
and plasma cells
But cannot prevent
microbial invasion into
the blood.
Acute inflammation:
infiltration of neutrophils and
macrophages
Immediate 2-4 days
Potential outcome
bacteraemia / septicaemia
systemic inflammatory response (SIRS)
multiple organ dysfunction syndrome (MODS)
What could happen if local inflammatory responses fail
L
H
L
H
1. Macrophages activated inthe liver and spleen secreteTNFα into the blood.
2. Systemic shift of fluid from plasma to tissue spaces causesa drop in blood volume and collapse of dilated blood vessels.
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H
3. Disseminated intravascularcoagulation leads to wastingand multiple organ dysfuction.
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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
bacterial
LPS
macrophages in
liver, spleen
TNFα, IL-1, IL-6
vascular
endothelium
nitric oxide prostaglandin
Systemic Inflammation: 1. systemic vasodilation and vasopermeability
hypotension, circulation problems
fluid resuscitation
remedy remedy
vasopressor
medication
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
Systemic Inflammation: 1. systemic vasodilation and vasopermeability (regulation)
* Compensatory anti-inflammatory response syndrome (CARS)
magnitude of
response
excessive PRO -
inflammatory response
*excessive ANTI-
inflammatory response
adequate inflammatory
response
Shock: early mortality
Immunodepression: later mortality
Time
Systemic Inflammation: 1. systemic vasodilation and vasopermeability (regulation)
plasma
endothelium
interstitial fluid
TNFα, IL-1
capillary leak
Systemic Inflammation: 2. Increased capillary leak (b) Altered endothelial integrity
ROS
proteinases
destroys
capillary leak
Systemic Inflammation: 2. Increased capillary leak (b) Endothelial injury
plasma
endothelium
interstitial fluid
neutralises
anti-proteinases
TNFα, IL-1ROS
intrinsic coagulation
pathway activated
blood clotting
factor VIIa
extrinsic coagulation
pathway activated
disseminated Intravascular Coagulation
microvascular
occlusion
collagen matrix exposed
Systemic Inflammation: 3. microvascular occlusion
Organ
Blood vessel
capillary leak and build-up of IF increases diffusion distance
“sticky” neutrophils form a plug
thrombus
ischaemia
Functional
inadequate supply / movement of gases & metabolites
organ dysfunction
Development of Multiple Organ Dysfunction Syndrome (MODS)
Interstitial
Fluid (IF)
Oxygen and nutrients
Carbon dioxide and wastes