Sepsis - Immunopathogenesis

Question 1

What type of disease is sepsis

Answer 1

An inflammatory disease

Question 2

What cells express pattern-recognition receptors

Answer 2

Macrophages
Neutrophils
Epithelial cells

Question 3

What are DAMPs

Answer 3

Endogenous factors released during cell damage

Question 4

What are PAMPs

Answer 4

Exogenous molecules expressed by microbes

Question 5

What system most significantly contributes to the amplification of systemic inflammation in sepsis

Answer 5

Complement

Question 6

Which 2 systems are activated by leaky vessels and blood clotting

Answer 6

Vascular endothelium

Coagulation

Question 7

What significant phenomenon occurs to both T and B cells and characterises late immunosuppression in sepsis

Answer 7

Apoptosis

Question 8

Immunopathogenesis of sepsis is associated with the activation of what systems

Answer 8

Innate immunity
Complement system
Vascular endothelium
Coagulation system
Adaptive immunity

Question 9

What happens when PRRs are activated

Answer 9

Activation of inflammatory signalling pathways

Question 10

What are PRRs

Answer 10

Pattern recognition receptors

Question 11

What happens after inflammatory signalling pathways are activated

Answer 11

The pathways will converge and activate several important transcription factors which will each regulate transcription of genes encoding cytokines and chemokines

Question 12

What is TNFa

Answer 12

A master regulatory cytokine that has a diverse array of functions on multiple different immune cell types including innate and adaptive

Question 13

Describe the local effects of TNFa

Answer 13

TNFa stimulates expression of adhesion molecules on endothelial cells and proteins that trigger blood clotting
This recruits immune cells to the site of infection and prevents pathogens from spreading via the blood

Question 14

What happens if TNFa is unsuccessful in containing microbes

Answer 14

Macrophages in the liver and spleen will be activated which will release TMFa systemically which ultimately leads to intravascular coagulation, preventing blood flow to organs leading to organ failure and death

Question 15

What does the systemic release of TNFa lead to

Answer 15

Systemic vasodilation
Increased vascular permeability
Loss of blood pressure
Systemic blood clotting of microvasculature
Contributes to onset of sepsis and septic shock

Question 16

When is the complement system activated

Answer 16

Immediately upon recognition of PAMPs and DAMPs

Question 17

What occurs after the complement system is activated

Answer 17

The peptides C3a and C5a are generated

Question 18

What is C5a

Answer 18

A potent chemoattractant which significantly amplifies inflammation

Question 19

What is the effect on sepsis of the activation of complement

Answer 19

Contributes to vasodilation, tissue damage and organ failure

Question 20

What is the endothelial barrier

Answer 20

Continuous barrier that coats the vascular system and separates the fluid phase of the blood from the tissues
Normally serves as an anticoagulant surface

Question 21

Describe endothelial barrier dysfunction

Answer 21

Sepsis produces changes which converts the endothelium into a pro-coagulant state
This endothelium mediates loss of fluid through tight junctions and facilitates the recruitment and attachment of inflammatory cells

Question 22

How can endothelial barrier dysfunction lead to septic shock

Answer 22

Leaky capillary membranes create a loss of plasma proteins and fluid into the extravascular space
Vasodilation alters capillary blood flow which contributes to septic shock

Question 23

What should be used if a patient is in septic shock

Answer 23

A vasoconstrictive agent such as noradrenaline or vasopressin in order to maintain blood pressure and try to keep the patient alive

Question 24

What characterises hypercoagulation caused by sepsis

Answer 24

Microvascular thrombi
Fibrin deposition
Neutrophil extraction trap formation
Endothelial injury

Question 25

What can activate the coagulation cascade in sepsis

Answer 25

Microorganisms and DAMPs

Complement activation and the release of inflammatory cytokines

Question 26

What are the consequences of widespread coagulation

Answer 26

Uncontrolled bleeding - occurs as a result of the consumption of clotting factors leading to a situation where patients can suffer from the clotting and uncontrolled bleeding

Question 27

What are common signs and symptoms signalling that sepsis has affected a particular organ

Answer 27

Neurological - altered mental state
Pulmonary - hypoxaemia or ARDs
Cardiovascular - shock
Renal - oligouria

Question 28

What is ARDs

Answer 28

Acute Respiratory Distress Syndrome

When the lungs fill with inflammatory infiltrate and fluid - patients can’t get enough oxygen into the blood

Question 29

What is oligouria

Answer 29

A significantly reduced urine output

Question 30

What do sepsis patients experience besides inflammation

Answer 30

Immunosuppression

Question 31

What is caused by excessive inflammation

Answer 31

Sustained inflammation causes tissue injury
Strong activation of innate immunity via PAMPs and DAMPs
Sustained hyperinflammation
Activation of complement system, coagulation system and vascular endothelium

Question 32

What does immunosuppression cause in patients with sepsis

Answer 32

Apoptosis of T cells and B cells
Dysfunctional dendritic cells
Delayed apoptosis of immature dysfunctional neutrophils

Question 33

What is the best treatment for patients with sepsis

Answer 33

Intravenous early antibiotics within the 1st hour of diagnosis