Adaptation in Sepsis 1 Flashcards
Define sepsis
A life threatening organ dysfunction caused by a dysregulated host respone to infection
Give some causes of sepsis
Bacteria (commonest)
Fungal
Viral
What is the commonest cause of ICU death
Sepsis
Features of sepsis
Tachycardia
Hypotension
Decreased urine output
Fever
SOB
Confusion
Biochemical derangements
Give some things that affect the immune response in sepsis
Nutritional state
Surgery
Anesthesia - ventilation etc
Biological variation - age, genetics etc
Drugs - steroids
Disease - comorbdities
What are the pro-inflammatory mechanisms of infection
Pro-inflammatory responses - release of pro-inflammatory mediators –> leukocyte recruitment –> complement activation and coagulation
What are the anti-inflammatory mechanisms of infection
Inhibition of inflammation
Tissue repair
Return to homeostasis
What happens in sepsis to pro and anti-inflammatory mechanisms and give examples
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.
What are pathogen-associated molecular patterns (PAMPs)
small molecular motifs conserved within a class of microbes. They activate innate immune responses
Give some PAMP examples
Repeated sugar molecules
Lipopolysaccharide (gram-negative cell wall)
Peptidoglycan (gram-positive cell wall)
Flagellin (moving proteins)
Glucans (fungal cell walls)
What recognises PAMPs in the body
Pattern recognition receptors (PRRs)
Receptors match up with these PAMPs and trigger immune response
What are DAMPs
Substances that are released by the body during trauma or injury and are released and recognise by PRRs
Give an example DAMPs
Mitochondria DNA
What do Toll-like receptors do
Correlate PAMPs with intracellular response by binding to them in the membrane.
This causes an imune response
How many TLRs are there
10 - they all recognise specific PAMPs
Where are TLRs found
Antigen-presenting cells - T cells, B cells, granulocytes, neutrophils, macrophages
What are lipopolysaccharides
Large molecule from the outer membrane of gram negative bacteria - type of PAMP
What TLR recognises lipopolysaccharides
TLR4
What else does TLR4 need to respond to lipopolysaccharide
CD14 - soluble antigen
Protein MD-2
Lipopolysaccharide binding protein (LBP)
What is nuclear factor kappa B
A transcription factor found inactive in the cytoplasm by IkappaB alpha inhibitor
How is nuclear factor kappa B activated
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
What is the activation of complement
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
What happens if the membrane attack complex isn’t controlled
Punctures holes in our own cell membranes
What is the main factor of DIC
Tissue factor
What happens in DIC
Consumption of clotting factors and activated protein C (inhibits microthrombi)
Induces pro-inflammatory signalling pathways and microvascular thrombi
What are NETs
Neutrophilic extracellular traps, released by neutrophils
What makes up NETs
DNA
Histones and serine proteases
What is the purpose of NETs
Entrap pathogens but can damage tissue and worsen coagulation
What happens to the endothelium in sepsis
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.
What do B cells in sepsis
Increase IL-3 which increases inflammation
What happens to T reg cells in sepsis
Increases - anti-inflammatory response
What are the three stages of an immune response in hosts to a pathogen
WIDER READING - Rajee 2018
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
How many pattern recognition receptors are there and give some examples
WIDER READING - Rajee 2018
20-40
TLR are the commonest.
C-type lectin receptor, NOD-like receptor, retinoic acid inducible gene
When are DAMPs and PAMPs released
WIDER READING - Bianchi 2007
In response to tissue injury by pathogen and are recognised by PRRs on the surface of immune cells
What is the 3 roles of the macrophage in pro-inflammatory response
WIDER READING - Rajee 2018
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
What is HMGB1 and its role in sepsis
WIDER READING - Lotze MT 2005
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.
Why is HMGB1 important in sepsis
WIDER READING - Hori 1995
Known to cause organ failure and barrier distruption and its blockade has been shown to reduce mortality rates of sepsis
What role does mitochondria DNA (mtDNA) have in sepsis
WIDER READING -ZHANG 2010
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).
What role do heat shock proteins, and in particular HSP70 have in sepsis
WIDER READING Asea 2000
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
Why are HSPs important in sepsis
WIDER READING - Chatterjee 2007
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.
What is the purpose of LBP bidning to LPS then CD14s to a single LBP/LPS
WIDER READING - Spink 1967
Allows for LPS to be identified from structurally similar molecules and therefore play an important role in preventing autoimmune disorders
What is PGN and where is it found
WIDER READING - Wang 2003
Peptidoglycan - the main cell wall component of gram positive bacteria
How does PGN work as a PAMP
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
Why is lipoprotein-lacking staphlococcus aureus so deadily
WIDER READING - WANG - 2003
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
