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Intercal - Adaption in physiology > Adaptation in Sepsis 1 > Flashcards

Adaptation in Sepsis 1 Flashcards

1
Q

Define sepsis

A

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

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2
Q

Give some causes of sepsis

A

Bacteria (commonest)
Fungal
Viral

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3
Q

What is the commonest cause of ICU death

A

Sepsis

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4
Q

Features of sepsis

A

Tachycardia
Hypotension
Decreased urine output
Fever
SOB
Confusion
Biochemical derangements

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5
Q

Give some things that affect the immune response in sepsis

A

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

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6
Q

What are the pro-inflammatory mechanisms of infection

A

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

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7
Q

What are the anti-inflammatory mechanisms of infection

A

Inhibition of inflammation
Tissue repair
Return to homeostasis

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8
Q

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

A

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.

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9
Q

What are pathogen-associated molecular patterns (PAMPs)

A

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

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10
Q

Give some PAMP examples

A

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

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11
Q

What recognises PAMPs in the body

A

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

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12
Q

What are DAMPs

A

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

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13
Q

Give an example DAMPs

A

Mitochondria DNA

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14
Q

What do Toll-like receptors do

A

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

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15
Q

How many TLRs are there

A

10 - they all recognise specific PAMPs

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16
Q

Where are TLRs found

A

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

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17
Q

What are lipopolysaccharides

A

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

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18
Q

What TLR recognises lipopolysaccharides

A

TLR4

19
Q

What else does TLR4 need to respond to lipopolysaccharide

A

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

20
Q

What is nuclear factor kappa B

A

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

21
Q

How is nuclear factor kappa B activated

A

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

22
Q

What is the activation of complement

A

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

23
Q

What happens if the membrane attack complex isn’t controlled

A

Punctures holes in our own cell membranes

24
Q

What is the main factor of DIC

A

Tissue factor

25
Q

What happens in DIC

A

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

26
Q

What are NETs

A

Neutrophilic extracellular traps, released by neutrophils

27
Q

What makes up NETs

A

DNA
Histones and serine proteases

28
Q

What is the purpose of NETs

A

Entrap pathogens but can damage tissue and worsen coagulation

29
Q

What happens to the endothelium in sepsis

A

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.

30
Q

What do B cells in sepsis

A

Increase IL-3 which increases inflammation

31
Q

What happens to T reg cells in sepsis

A

Increases - anti-inflammatory response

32
Q

What are the three stages of an immune response in hosts to a pathogen

WIDER READING - Rajee 2018

A

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

33
Q

How many pattern recognition receptors are there and give some examples

WIDER READING - Rajee 2018

A

20-40

TLR are the commonest.

C-type lectin receptor, NOD-like receptor, retinoic acid inducible gene

34
Q

When are DAMPs and PAMPs released

WIDER READING - Bianchi 2007

A

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

35
Q

What is the 3 roles of the macrophage in pro-inflammatory response

WIDER READING - Rajee 2018

A

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

36
Q

What is HMGB1 and its role in sepsis

WIDER READING - Lotze MT 2005

A

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.

37
Q

Why is HMGB1 important in sepsis

WIDER READING - Hori 1995

A

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

38
Q

What role does mitochondria DNA (mtDNA) have in sepsis

WIDER READING -ZHANG 2010

A

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).

39
Q

What role do heat shock proteins, and in particular HSP70 have in sepsis

WIDER READING Asea 2000

A

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

40
Q

Why are HSPs important in sepsis

WIDER READING - Chatterjee 2007

A

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.

41
Q

What is the purpose of LBP bidning to LPS then CD14s to a single LBP/LPS

WIDER READING - Spink 1967

A

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

42
Q

What is PGN and where is it found

WIDER READING - Wang 2003

A

Peptidoglycan - the main cell wall component of gram positive bacteria

43
Q

How does PGN work as a PAMP

A

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

44
Q

Why is lipoprotein-lacking staphlococcus aureus so deadily

WIDER READING - WANG - 2003

A

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

Intercal - Adaption in physiology (11 decks)

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