07 - October 1, 2013.docx

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University of Toronto St. George
Laboratory Medicine and Pathobiology

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 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 ARNO Is GAP – GTP activating protein; GIT is GEF – G protein Exchange factor – regulate GTP/GDP bound protein ARF active when bound in GTP form ARNO activates ARF; GIT is GEF, removes GTP from ARF ARF is active when bound to GTP Vascular stability – adherens junctions – endothelium have different phenotypes in different organs; brain vasculature is closed, kidney is fenestrated so many gaps and quite open; VE cadherin – almost exclusively expressed in endothelial cells; two VE cadherin form complex between cells expressing them, creating vascular stability; VE cadherin molecules complexed with several protiens in cytosol, ex. P120 molecule that connects VE cadherin to actin cytoskeleton- creates firm conection between adjacent endothelial cells; very dynamic; turnover constant in cells Mechanisms of vascular stability Endocytosis regulates VE cadherins VE cadherins can be internalized and recycled – this process sped up by inflammatory cytokines; Degradation of VE cadherins is important fore gulating vascular stability ARF six is downstream of Slit/Robo4 signalling is required for endocytosis o
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