LMP299Y1 Lecture Notes - Disseminated Intravascular Coagulation, Cytokine Storm, Robo4

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16 Dec 2013
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Appendicitis bacteria
If appendix bursts bacteria toxin access to circulation; inflammatory cytokines important in initial
phase of sepsis get access to circulation that’s why get systemic effects
In animal models of sepsis PAPER
Correlation between sepsis in humans and animal model s
Set of systemic reactions to overwhelming infection
It is a disease of aged, though young people can get sepsis but have much better prognosis
Other concurrent illnesses that severely compromise their health and make outcome much worse
So mortality rate is very high in severe sepsis
Leads to mlutorgan failure
Leads to failure of lungs, kidneys, - most clinically significant if leads to liver failure, that is very severe
because difficult to support liver failure; lung failure, patient on ventilator can cover for that; if have
kidney failure, can put on dialysis; for liver failure, no therapy other than transplantation
FDA only approved activated protein C zymogen must be activated proteolytically
It is an inhibitor of factor 5 and factor 7 in the clotting cascade and alos has effects on endothelial
receptor known as protein C receptor, which can be cytoprotective effects
Influence clotting cascade and unclear why affectd, but oe of the things known is that often patients
with sepsis can suffer from disseminated intravascular coagulation, where spontaneous activation of
clotting cascade by 12 or tissue factors and thse patients will get deposition of fibrin within their
microvasculature, which further compromises blood flow to various organs; this is why activated protein
c is effective in soe patients it would block both the factor 12 and intrinsic patway and tissue
pathway/extrinci pathwy and may have cytoprotetive effects on endothelilal cells
Sepsis into several different categories do not memorize this
Different degrees of sepsis starting from the systemic inflammatory response; basically have fever and
WBC count applicable to any infection, some leakage of inflammatory mediators such as IL-1 and IL-6
These mediators will go to hypothalamus and get fever response
And will get bone marrow releasing leukocytes or immature neutrophils so have left shift in circulating
leukocytes
If have circulating bacteria in bloodk this is called sepsis if there is organ hyperfusion, severe sepsis
Then get into changes in blood pressure; if drop below certain level, 60mmHg, known as shock
Sepsis in future will refer to bottom half of the table, more severe categories
Phases of sepsis first phase is hyperdynamic state where the patient has increased cardiac output and
their decreased blood pressue due to decreased vascular resistenc; cardiac output is way up but the
blood pressure is low and then it changes to hypodynamic state where bacteria can produce various
factors that can suppress myocyte function, cardiac output goes down, patients treated with pressor
agents that work by constricting arterioles that elevate blood pressure;
Transition to hypodynamic
Inflammatory cytokines in first stage release of various enzymes; activation of coagulation and clotting
syste; everything can be activated
DIC is disseminated intravascular coagulation
Concurrent with this increase in pro-inflammatory cytokines; interleukin 10 some early changes
influence the immune system and at hypodynamic state, patients can develop decreased ability to fight
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infections as result of lymphocyte apoptosis or anergy or decreased antigen presentation, so mores
uscpetible to secondary infections
Patients who prolonged stay in hospital due to immunosuppresio, will develop secondary infection
from hospital-acquired bacteria known as nosocomial and will succumb to that infection
Predisposing comorbidities
Patients who develop several sepsis will have chronic liver disease or chronic kidney disease or diabetes,
etc, - high mortality
Animal models of sepsis
This approach has not panned out; can cure animals of sepsis; but these therapies do not translate well
to humans
Animal models
LPS injection in human, infection grows gradually as bacteria replicate; an injection is a sudden dose of
bacteria
CLP or CASP lie off portion of cecum in mouse; puncture that portion with standardized needle, which
releases some of the bacteria; this model releases a number of different bacteria; multiple bacteria
involved but the problem is reproducibility is an issue; extent of puncture, extent of bowel tied off all
of these can affect oucome of model; does not have early hypoddynmaic period in human sepsis
People have also tried to do other models; tried to replicate some of the risk factors; do this in aged
mice or mice with renal faioure or so on to mimic the clinical picture found in humans; the problem with
those models is that those models are difficult to establish
Vascular permeability
Targeting Robo4-dependent slit signalling to survie the cytokine storm in sepsis
In common: cytokine storm, which is massive response of proinflammatory cytokines secreted; the
purpose of this cytokine storm is to increase inflammation but this can have collateral damage as well
This storm really increases permeability can contribute to organ damage
Robo/Slit signalling
Identified in screens of drosophila for mutants that have defects in neuronal patterning; start on one
side of the body, cross over midline, go over to other side of the body, and never cross over again
Large scale screen inflies certain mutants, can continually kept crossing
Slits are family of ligands for robo transmembrane receptors
Slit is very large, do not diffuse easily or very far; secreted form cells and cells that express robo receptor
will bind them
4 roboreceptors 1 and 4 important for endothelium
Neuronal guidance cues found to regulate vasculature
Vasculature forms completely normal in normal of pathological angiogenesis these knockout mice
had exaggerated response; in response to angiogenic factors, the slit robo signalling, the robo4 receptor
could inhibit signalling through this signalling pathway and importantly this vegf pathway also involved
in permeability vascular
Robo positive neuron sees slit, so neurons turned away from source of slit
For blood vessles, different; slit/robo signalling affects signalling of the VeGF signalling pathway
Robo4 regulates vascular leak
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