Adaptation in Sepsis 1

Question 1

Define sepsis

Answer 1

A life threatening organ dysfunction caused by a dysregulated host respone to infection

Question 2

Give some causes of sepsis

Answer 2

Bacteria (commonest)
Fungal
Viral

Question 3

What is the commonest cause of ICU death

Answer 3

Sepsis

Question 4

Features of sepsis

Answer 4

Tachycardia
Hypotension
Decreased urine output
Fever
SOB
Confusion
Biochemical derangements

Question 5

Give some things that affect the immune response in sepsis

Answer 5

Nutritional state
Surgery
Anesthesia - ventilation etc
Biological variation - age, genetics etc
Drugs - steroids
Disease - comorbdities

Question 6

What are the pro-inflammatory mechanisms of infection

Answer 6

Pro-inflammatory responses - release of pro-inflammatory mediators –> leukocyte recruitment –> complement activation and coagulation

Question 7

What are the anti-inflammatory mechanisms of infection

Answer 7

Inhibition of inflammation
Tissue repair
Return to homeostasis

Question 8

What happens in sepsis to pro and anti-inflammatory mechanisms and give examples

Answer 8

They become unbalanced -

Platelets - microvascular thrombi
Endothelium - release of pro-inflammatory mediators and barrier dysfunction
Leukocytes - release of pro-inflammatory mediators

CD4 cells trigger apoptosis
CD8 cells trigger apoptosis
Antigen-presenting cells try to reporgramme macrophages.

Question 9

What are pathogen-associated molecular patterns (PAMPs)

Answer 9

small molecular motifs conserved within a class of microbes. They activate innate immune responses

Question 10

Give some PAMP examples

Answer 10

Repeated sugar molecules
Lipopolysaccharide (gram-negative cell wall)
Peptidoglycan (gram-positive cell wall)
Flagellin (moving proteins)
Glucans (fungal cell walls)

Question 11

What recognises PAMPs in the body

Answer 11

Pattern recognition receptors (PRRs)
Receptors match up with these PAMPs and trigger immune response

Question 12

What are DAMPs

Answer 12

Substances that are released by the body during trauma or injury and are released and recognise by PRRs

Question 13

Give an example DAMPs

Answer 13

Mitochondria DNA

Question 14

What do Toll-like receptors do

Answer 14

Correlate PAMPs with intracellular response by binding to them in the membrane.
This causes an imune response

Question 15

How many TLRs are there

Answer 15

10 - they all recognise specific PAMPs

Question 16

Where are TLRs found

Answer 16

Antigen-presenting cells - T cells, B cells, granulocytes, neutrophils, macrophages

Question 17

What are lipopolysaccharides

Answer 17

Large molecule from the outer membrane of gram negative bacteria - type of PAMP

Question 18

What TLR recognises lipopolysaccharides

Answer 18

TLR4

Question 19

What else does TLR4 need to respond to lipopolysaccharide

Answer 19

CD14 - soluble antigen
Protein MD-2
Lipopolysaccharide binding protein (LBP)

Question 20

What is nuclear factor kappa B

Answer 20

A transcription factor found inactive in the cytoplasm by IkappaB alpha inhibitor

Question 21

How is nuclear factor kappa B activated

Answer 21

Lipopolysaccharide and TLR4 binding causes IkB to be removed and this reveals a nuclear recognition site on NFK B which allows it to enter the nucleus and start transcription of cytokines

Question 22

What is the activation of complement

Answer 22

Part of the innate immune system, this triggers the release of anaphylatoxins - which make a membrane attack complex and this punctures holes in bacteria cell wall and kills it

Question 23

What happens if the membrane attack complex isn’t controlled

Answer 23

Punctures holes in our own cell membranes

Question 24

What is the main factor of DIC

Answer 24

Tissue factor

Question 25

What happens in DIC

Answer 25

Consumption of clotting factors and activated protein C (inhibits microthrombi) Induces pro-inflammatory signalling pathways and microvascular thrombi

Question 26

What are NETs

Answer 26

Neutrophilic extracellular traps, released by neutrophils

Question 27

What makes up NETs

Answer 27

DNA Histones and serine proteases

Question 28

What is the purpose of NETs

Answer 28

Entrap pathogens but can damage tissue and worsen coagulation

Question 29

What happens to the endothelium in sepsis

Answer 29

Activated by the loss of glycocalyx, it causes loss of adhesion and leakage Results in poor microvascular perfusion Benefit as - allows leukocytes to get in and attack pathogens but usually overdone causing leaks etc as stated above.

Question 30

What do B cells in sepsis

Answer 30

Increase IL-3 which increases inflammation

Question 31

What happens to T reg cells in sepsis

Answer 31

Increases - anti-inflammatory response

Question 32

What are the three stages of an immune response in hosts to a pathogen WIDER READING - Rajee 2018

Answer 32

1 - Immune mediated response - seconds to hrs which is when the host recognises the invading pathogen (skin, neutrophils and macrophages) 2 - early innate response (hrs to days) DAMPs and PAMPs occur here and recruit effector cells 3 - Adaptive immune system with T-cells and B-cells

Question 33

How many pattern recognition receptors are there and give some examples WIDER READING - Rajee 2018

Answer 33

20-40 TLR are the commonest. C-type lectin receptor, NOD-like receptor, retinoic acid inducible gene

Question 34

When are DAMPs and PAMPs released WIDER READING - Bianchi 2007

Answer 34

In response to tissue injury by pathogen and are recognised by PRRs on the surface of immune cells

Question 35

What is the 3 roles of the macrophage in pro-inflammatory response WIDER READING - Rajee 2018

Answer 35

Release cytokines to induce inflammation along with releasing free radicals to attack the pathogen Recruitment of neutrophils, monocytes and other macrophages Antigen processing and presenting cell to the adaptive immune system

Question 36

What is HMGB1 and its role in sepsis WIDER READING - Lotze MT 2005

Answer 36

Released by damaged macrophages, monocytes and neutrophils to activate the innate immune system - this amplifies local and systemic inflammatory response by acetylating HMGB1 in the nucleus - this secretes NF kappaB.

Question 37

Why is HMGB1 important in sepsis WIDER READING - Hori 1995

Answer 37

Known to cause organ failure and barrier distruption and its blockade has been shown to reduce mortality rates of sepsis

Question 38

What role does mitochondria DNA (mtDNA) have in sepsis WIDER READING -ZHANG 2010

Answer 38

Release of mtDNA occurs in injured or dying cells which can be detected by TLR9 and NF kappa B which stimultaes circulating leukoctes to increase inflammation (TNF alpha and IL-6).

Question 39

What role do heat shock proteins, and in particular HSP70 have in sepsis WIDER READING Asea 2000

Answer 39

They are upregulated in sepsis and are expressed in T and B cells when cellular stress or shock occurs. HSP70 binds to TLR4 and TLR2 leading to NF-kappa B activation

Question 40

Why are HSPs important in sepsis WIDER READING - Chatterjee 2007

Answer 40

Significantly increased survival in lipopolysaccharide induced shock in mice if given HSP90-induced inhibitors. This was because it prevented a rise in monocyte chemo-attractant protein and TNF-alpha which decreased lung injury and vascular leak.

Question 41

What is the purpose of LBP bidning to LPS then CD14s to a single LBP/LPS WIDER READING - Spink 1967

Answer 41

Allows for LPS to be identified from structurally similar molecules and therefore play an important role in preventing autoimmune disorders

Question 42

What is PGN and where is it found WIDER READING - Wang 2003

Answer 42

Peptidoglycan - the main cell wall component of gram positive bacteria

Question 43

How does PGN work as a PAMP

Answer 43

TLR2, CD14, NOD1 and NOD2 recognise PGN and trigger an innate immune response PGN also idnuces caspase-1-activty which is pro-inflammatory (cytokine production) Caspase-1 - converts the inactive proform of IL-1β to the active inflammatory cytokine

Question 44

Why is lipoprotein-lacking staphlococcus aureus so deadily WIDER READING - WANG - 2003

Answer 44

Lipoproteins are PAMPs which bind to TLR2 resulting in an inflammatory response mediated by MyD88 Lipoprotein PAMPs are good because they are found on all bacterial cells except LL staph A resulting in life threatening infections because it can bypass the typical immune recognition