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Title: Mechanisms of Pathogen Sensing in Cardiac Myocytes
Author: Patel, Trupti
ISNI:       0000 0001 3476 3979
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2008
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Bacterial sepsis and septic shock are major causes ofdeath in the critically ill. The majority ofthese deaths are due to the development ofmyocardial contractile dysfunction. The pathophysiology ofthis phenomenon is incompletely understood,. with previous work focussing on the influence ofcirculating inflammatory mediators ofnon-cardiac origin. Despite the recognised importance ofthese factors in contrit>uting to myocardial dysfunction, how the heart itselfresponds to bacterial pathogens directly has not been fully elucidated. The aims ofthis study were, first, to characterise the functional changes induced in isolated cardiac myocytes by whole bacteria. With the recent identification ofToll-like receptors (TLR)s (pattern recognition receptors (PRR)s) within the cardiac compartment, the second aim was to examine their roles in any changes seen. Finally, the role ofkey inflammatory mediators was examined. A novel method ofevaluating how Gram positive Staphylococcus aureus (S. aureus) or Gram negative Escherichia coli (E. call) directly modified 'populations' ofcardiac rat and mouse myocytes is described. Bacteria not' only decreased the propot:tion ofviable rod-shaped cells, they also decreased the proportion ofcells able to contract to electrical stimulation. S. aureus was found to have more pronounced effects than E. coli. In separate experiments, extracellular oxidants mimicked the effects ofbacteria on cardiac myocytes. The effects ofS. aureus and E. coli were mediated by TLR2ffLR6 and TLR4 respectively. Although no role for nitric oxide was found in bacteria-induced changes in myocyte function, the adverse effects ofS. aureus were partly prevented by specific cyclo-oygenase-2 inhibitors. However, the central hormone mediating the effects of bacteria (and oxidants) was found to be endothelin-l (ET-l), acting on ETA receptors. Caspase activation, without leading to apoptosis, was also implicated in mediating the phenotype changes induced by bacteria. Finally, cardiac myocytes ofthe noncontracting phenotype showed a reduced myofilament sensitivity to calcium, explaining the functional changes seen. Although the data are limited, a similar phenomenon was seen in failing human myocytes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available