2.3. Pathophysiology of Sepsis

Question 1

What are the 3 defences the body has against Sepsis?

Answer 1

1. Physical Barrier
2. Innate Immune System
3. Adaptive Immune System

Question 2

What does the Physical Barrier, defending against Sepsis, consist of?

Answer 2

1. Skin
2. Mucosa
3. Epithelial Lining

Question 3

What does the Innate Immune System, defending against Sepsis, consist of?

Answer 3

1. IgA in Gastrointestinal Tract
2. Dendritic Cells
3. Macrophages

Question 4

What does the Adaptive Immune System, defending against Sepsis, consist of?

Answer 4

1. Lymphocytes
2. Immunoglobulins

Question 5

What is the origin of the Pathophysiology Sepsis?

Answer 5

It originates from a breach of integrity of a host barrier, whether physical or immunological

Question 6

What does a breach of integrity of a host barrier, defending against sepsis, allow for?

Answer 6

Organisms enter the bloodstream creating a septic state

Question 7

What are the 3 phases in the Pathogenesis of Sepsis?

Answer 7

Phase 1. Release of bacterial toxins
Phase 2. Release of mediators, in response to the infection
Phase 3. Effects of specific excessive mediators

Question 8

What does the Release of bacterial toxins (Phase 1 of the Pathogenesis of Sepsis) involve?

Answer 8

1. Bacterial invasion into body tissue is a source of dangerous toxins
2. This may / may not be neutralized and cleared by the existing immune system

Question 9

What are some commonly released Gram Negative bacterial toxins?

Answer 9

Lipopolysaccharide (LPS)

Question 10

What are some commonly released Gram Positive bacterial toxins?

Answer 10

1. Microbial-associated molecular pattern (MAMP):
2. a) Lipoteichoic Acid (LTA)
3. b) Muramyl Dipeptides
4. Superantigens
5. a) Staphylococcal Toxic Shock Syndrome Toxin (TSST)
6. b) Streptococcal Exotoxins (SPE)

Question 11

What does the Release of mediators, in response to the infection (Phase 2 of the Pathogenesis of Sepsis) involve?

Answer 11

1. Effects of infections due to Endotoxin release
2. Effects of infections due to Exotocin release
3. Effects of Specific Excessive Mediators

Question 12

What is the difference between an Endotoxin and Exotoxin?

Answer 12

Endotoxin - bacterial toxins (consisting of lipids) within the cell
Exotoxin - Toxic substances secreted by bacteria outside the cell

Question 13

Why does Endotoxin release occur (in Phase 2 of the Pathogenesis of Sepsis)?

Answer 13

1. The Lipopolysaccharide (LPS) toxin (released from Gram Negative bacteria) needs an LPS-binding protein to bind to macrophages
2. The Lipoteichoic Acid (LTA) toxin (released from Gram Positive bacteria) binds directly onto macrophages
3. Macrophages then release mediators

Question 14

Why does Exotoxin release occur (in Phase 2 of the Pathogenesis of Sepsis)?

Answer 14

1. Superantigens toxins (TSST or SPE) are released from Gram Positive bacteria, which act on T-Lymphocytes
2. The T-Lymphocytes then activate:
   a) Macrophages (via IL-2 and IFN-gamma)
   b) Endothelial Cells (Via IFN-gamma)
3. a) Macrophages then release IL-1 and TNF-Alpha (mediators)
4. b) Endothelial Cells then release Nitric Oxide (mediators)

Question 15

What type of response occurs with Exotoxin release?

Answer 15

1. This is a pro-inflammatory response
2. Small amounts of Superantigens will cause a large amount of mediators to be secreted

Question 16

What are the 2 types mediators which are released?

Answer 16

1. Th1 - Pro-inflammatory mediators
   These cause the inflammatory response which characterizes Sepsis
2. Th2 - Compensatory anti-inflammatory secretion
   These can cause immunoparalysis

Question 17

What is the desired relationship of Th1 and Th2 mediator release, in relation to toxins from bacterial infection?

Answer 17

Initially want a high stimulation of Th1 (pro-inflammatory)
And then Th2 will check this

Question 18

What is the effect of the Pro-Inflammatory mediators (Th1 type)?

Answer 18

1. Promote Endothelial Cell causing Leukocyte adhesion
2. Release Arachidonic Acid Metabolites (important for the production of Interleukins)
3. Complement Activation
4. Vasodilation of Blood Vessels by Nitric Oxide
5. Increase coagulation by release of Tissue Factors and Membrane Coagulants
6. Cause Hyperthermia (TNF-Alpha stimulates temp.)

Question 19

What is the effect of the Anti-Inflammatory mediators (Th2 type)?

Answer 19

1. Inhibition of TNF-Alpha (A pro-inflammatory mediator)
2. Augment acute phase reaction
3. Inhibit activation of coagulation system
4. Provide negative feedback mechanisms to the pro-inflammatory mediators

Question 20

What happens if there is too much Th1 (pro-inflammatory mediators) present?

Answer 20

Septic Shock with Multi-organ Failure and Death
Note - this is a hyperimmune state

Question 21

What happens if there is too much Th2 (anti-inflammatory mediators) present?

Answer 21

Immunoparalysis with uncontrolled infection and Multi-organ failure
Note - this is a hypoimmune state

Question 22

What do patients with Sepsis have features consistent with?

Answer 22

Immunosuppression:
1. Loss of delayed hypersensitivity
2. Inability to clear infection
3. Predisposition to nosocomial infection

Question 23

What is the probable change of Sepsis Syndrome over time?

Answer 23

1. Initially there is an increase in inflammatory mediators
2. Later, there is a shift towards an anti-inflammatory immunosuppressive state
   Note - this is dependent on the health of the individual patient