Immunopathology Of Sepsis (sepsis Part 2)

Question 1

What is the basic pathophysiology of sepsis?

Answer 1

.Body wise blood clotting and ‘leaky vessels’
. One or more organs begin to fail (sepsis - 10% in hospital mortality)
. Persistent hypotension (septic shock - 40% in hospital mortality)

Question 2

What are pattern-associated molecular patterns (PAMP’s)

Answer 2

Conserved exogenous (non-self) factors expressed by pathogens

Examples: LPS, peptidoglycan, nucleic acids

Question 3

What are Damage-Associated molecular patterns (DAMP’s)?

Answer 3

Endogenous (host) factors released following cell damage

Examples: heat shock proteins, nucleic acid

Question 4

What are the main functions of TNF alpha?

Answer 4

1. stimulates expression of adhesion molecules on endothelial cells
2. Stimulates expression of proteins that trigger blood clotting
3. recruits immune cells to site of infection
4. Prevents pathogen spreading via blood

CRUCIAL for controlling local infections

Question 5

When does TNF alpha contribute to onset of sepsis and septic shock?

Answer 5

When it is released systemically rather than locally

Question 6

What does systemic release of TNF alpha lead to?

Answer 6

1. Systemic vasodilation
2. Increased vascular permeability
3. Loss of blood pressure
4. Systemic blood clotting of microvasculature

Question 7

What peptides are generated via the compliment system in sepsis?

Answer 7

C3a and C5a

Question 8

Describe how peptide C5a exacerbates sepsis?

Answer 8

.C5a drives immunopathogenesis
. Potent chemoattractant (macrophages, neutrophils and monocytes)
. Further amplifies inflammation
. Contributes to vasodilation, tissue damage and organ failure

Question 9

How does sepsis cause endothelial barrier dysfunction?

Answer 9

.Sepsis produces changes that convert endothelium to a procoagulate state

. Disrupted endothelium mediates loss of fluid through tight junctions

. Also facilitated recruitment of inflammatory cells through the endothelium

. Leaky capillaries Result in massive loss of plasma proteins into the extra vascular space

Question 10

How does sepsis affect coagulation?

Answer 10

Results in a hypercoagulative state characterised by:

.Micro vascular thrombi
. Fibrin deposition
. Neutrophil extracellular trap formation
. Endothelial injury

Question 11

What are common signs and symptoms in sepsis

Answer 11

1. Neurological - altered mental status
2. Pulmonary (hypoxaemia) - Acute respiratory distress syndrome (ARDs)
3. Cardiovascular (shock)
4. Renal (oligouria - reduced urine output)

Question 12

Describe the immune suppression that often occurs with sepsis

Answer 12

1. Both innate and adaptive immunity suppressed
2. Apoptosis of T cells, B cells
3. Dysfunctional DC’s
4. Delayed apoptosis of immature dysfunctional neutrophil