2.3. Pathophysiology of Sepsis Flashcards
What are the 3 defences the body has against Sepsis?
- Physical Barrier
- Innate Immune System
- Adaptive Immune System
What does the Physical Barrier, defending against Sepsis, consist of?
- Skin
- Mucosa
- Epithelial Lining
What does the Innate Immune System, defending against Sepsis, consist of?
- IgA in Gastrointestinal Tract
- Dendritic Cells
- Macrophages
What does the Adaptive Immune System, defending against Sepsis, consist of?
- Lymphocytes
2. Immunoglobulins
What is the origin of the Pathophysiology Sepsis?
It originates from a breach of integrity of a host barrier, whether physical or immunological
What does a breach of integrity of a host barrier, defending against sepsis, allow for?
Organisms enter the bloodstream creating a septic state
What are the 3 phases in the Pathogenesis of Sepsis?
Phase 1. Release of bacterial toxins
Phase 2. Release of mediators, in response to the infection
Phase 3. Effects of specific excessive mediators
What does the Release of bacterial toxins (Phase 1 of the Pathogenesis of Sepsis) involve?
- Bacterial invasion into body tissue is a source of dangerous toxins
- This may / may not be neutralized and cleared by the existing immune system
What are some commonly released Gram Negative bacterial toxins?
Lipopolysaccharide (LPS)
What are some commonly released Gram Positive bacterial toxins?
- Microbial-associated molecular pattern (MAMP):
- a) Lipoteichoic Acid (LTA)
- b) Muramyl Dipeptides
- Superantigens
- a) Staphylococcal Toxic Shock Syndrome Toxin (TSST)
- b) Streptococcal Exotoxins (SPE)
What does the Release of mediators, in response to the infection (Phase 2 of the Pathogenesis of Sepsis) involve?
- Effects of infections due to Endotoxin release
- Effects of infections due to Exotocin release
- Effects of Specific Excessive Mediators
What is the difference between an Endotoxin and Exotoxin?
Endotoxin - bacterial toxins (consisting of lipids) within the cell
Exotoxin - Toxic substances secreted by bacteria outside the cell
Why does Endotoxin release occur (in Phase 2 of the Pathogenesis of Sepsis)?
- The Lipopolysaccharide (LPS) toxin (released from Gram Negative bacteria) needs an LPS-binding protein to bind to macrophages
- The Lipoteichoic Acid (LTA) toxin (released from Gram Positive bacteria) binds directly onto macrophages
- Macrophages then release mediators
Why does Exotoxin release occur (in Phase 2 of the Pathogenesis of Sepsis)?
- Superantigens toxins (TSST or SPE) are released from Gram Positive bacteria, which act on T-Lymphocytes
- The T-Lymphocytes then activate:
a) Macrophages (via IL-2 and IFN-gamma)
b) Endothelial Cells (Via IFN-gamma) - a) Macrophages then release IL-1 and TNF-Alpha (mediators)
- b) Endothelial Cells then release Nitric Oxide (mediators)
What type of response occurs with Exotoxin release?
- This is a pro-inflammatory response
2. Small amounts of Superantigens will cause a large amount of mediators to be secreted
What are the 2 types mediators which are released?
- Th1 - Pro-inflammatory mediators
These cause the inflammatory response which characterizes Sepsis - Th2 - Compensatory anti-inflammatory secretion
These can cause immunoparalysis
What is the desired relationship of Th1 and Th2 mediator release, in relation to toxins from bacterial infection?
Initially want a high stimulation of Th1 (pro-inflammatory)
And then Th2 will check this
What is the effect of the Pro-Inflammatory mediators (Th1 type)?
- Promote Endothelial Cell causing Leukocyte adhesion
- Release Arachidonic Acid Metabolites (important for the production of Interleukins)
- Complement Activation
- Vasodilation of Blood Vessels by Nitric Oxide
- Increase coagulation by release of Tissue Factors and Membrane Coagulants
- Cause Hyperthermia (TNF-Alpha stimulates temp.)
What is the effect of the Anti-Inflammatory mediators (Th2 type)?
- Inhibition of TNF-Alpha (A pro-inflammatory mediator)
- Augment acute phase reaction
- Inhibit activation of coagulation system
- Provide negative feedback mechanisms to the pro-inflammatory mediators
What happens if there is too much Th1 (pro-inflammatory mediators) present?
Septic Shock with Multi-organ Failure and Death
Note - this is a hyperimmune state
What happens if there is too much Th2 (anti-inflammatory mediators) present?
Immunoparalysis with uncontrolled infection and Multi-organ failure
Note - this is a hypoimmune state
What do patients with Sepsis have features consistent with?
Immunosuppression:
- Loss of delayed hypersensitivity
- Inability to clear infection
- Predisposition to nosocomial infection
What is the probable change of Sepsis Syndrome over time?
- Initially there is an increase in inflammatory mediators
- Later, there is a shift towards an anti-inflammatory immunosuppressive state
Note - this is dependent on the health of the individual patient
