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Physiological Processes:
Basic Concepts
Systemic Inflammatory Response Syndrome (SIRS)
Multiple Organ Dysfunction Syndrome...
The Immune System Strives to:
• Eliminate infection and damaged tissue
• Maintain an appropriate response level
• Avoid or...
Types of Immunity:

• Non-specific (innate):
– Natural barriers
– Inflammation

• Specific (acquired):
- T and B lymphocyt...
The Inflammatory Response
• The inflammatory response:
– A series of localised cellular responses
– Helps to eliminate inv...
The Innate Immune System and Homeostasis
Invasiveness
of microbe.

Risk to
Homeostasis

Action of innate
immune system
BEN...
Immunity is mediated by:
• Soluble molecules:
– cytokines e.g. interleukin (IL)
– others: prostaglandin (PG), reactive oxy...
Chemical mediators of the inflammatory response
Trigger: e.g.
invading bacteria

Key effector macrophage
cell:
Potent mole...
Chemical mediators of the inflammatory response
skin surface
tissue and
interstitial fluid

Invading bacteria

endotoxin (...
Chemical mediators of the inflammatory response
skin surface

Invading bacteria

tissue and
interstitial fluid

endotoxin ...
Chemical mediators of the inflammatory response
skin surface
tissue and
interstitial fluid

Invading bacteria

endotoxin (...
Chemical mediators of the inflammatory response
skin surface
tissue and
interstitial fluid
migration and
phagocytosis

Inv...
Chemical mediators of the inflammatory response
Neutrophils release powerful chemicals that
destroy the pathogen.
Some ROS...
Chemical mediators of the inflammatory response
TNF-alpha (TNFα) is a powerful pro-inflammatory mediator

TNFα
with
IL-1 a...
Regulation of the inflammatory response by
chemical mediators.

pro-inflammatory
mediators
TNFα
IL-1
IL-6

anti-inflammato...
What happens if local inflammatory responses fail?
Immediate

2-4 days

Natural barriers and local
inflammatory response
A...
What could happen if local inflammatory responses fail
H

H

L

L

H

L

H

L

1. Macrophages activated in
the liver and s...
Systemic Inflammation:
A systemic inflammatory response causes:
1. systemic vasodilation
2. increased capillary leak due t...
Systemic Inflammation:
1. systemic vasodilation and vasopermeability
macrophages in
liver, spleen

bacterial
LPS

TNFα, IL...
Systemic Inflammation:
1. systemic vasodilation and vasopermeability (regulation)

pro-inflammatory
mediators
TNFα
IL-1
IL...
Systemic Inflammation:
1. systemic vasodilation and vasopermeability (regulation)
excessive PRO inflammatory response

mag...
Systemic Inflammation:
2. Increased capillary leak (b) Altered endothelial integrity

plasma

TNFα, IL-1

endothelium
inte...
Systemic Inflammation:
2. Increased capillary leak (b) Endothelial injury

proteinases
plasma
endothelium
interstitial flu...
Systemic Inflammation: 3. microvascular occlusion

ROS

TNFα, IL-1

collagen matrix
exposed
factor
intrinsic coagulation
V...
Development of Multiple Organ Dysfunction Syndrome (MODS)
Interstitial
Fluid (IF)
Blood vessel
Oxygen and
nutrients

“stic...
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Physiological Processes

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Physiological Processes

  1. 1. Physiological Processes: Basic Concepts Systemic Inflammatory Response Syndrome (SIRS) Multiple Organ Dysfunction Syndrome (MODS)
  2. 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. 3. Types of Immunity: • Non-specific (innate): – Natural barriers – Inflammation • Specific (acquired): - T and B lymphocytes
  4. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 21. Systemic Inflammation: 2. Increased capillary leak (b) Altered endothelial integrity plasma TNFα, IL-1 endothelium interstitial fluid capillary leak
  22. 22. Systemic Inflammation: 2. Increased capillary leak (b) Endothelial injury proteinases plasma endothelium interstitial fluid ROS neutralises destroys anti-proteinases capillary leak
  23. 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. 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

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