Please use this identifier to cite or link to this item: http://theses.ncl.ac.uk/jspui/handle/10443/5228
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dc.contributor.authorWiscombe, Sarah-
dc.date.accessioned2022-01-13T14:38:04Z-
dc.date.available2022-01-13T14:38:04Z-
dc.date.issued2021-
dc.identifier.urihttp://hdl.handle.net/10443/5228-
dc.descriptionM. D. Thesis.en_US
dc.description.abstractAcute respiratory distress syndrome (ARDS) is a common condition presenting to the intensive care unit (ICU) and is associated with high morbidity and mortality. Experimental models in humans using bacterial lipopolysaccharide (LPS, delivered by nebulised inhalation or bronchial instillation) create reproducible acute lung inflammation and can be used to model early stages of the pathological process leading to ARDS. A significant body of evidence already exists from animal and human studies suggesting LPS inhalation results in rapid release of pro-inflammatory cytokines and movement of innate immune cells (neutrophils and monocytes) into the alveolar space. The functional status of neutrophils in response to this stimulus is largely unknown, based on circumstantial evidence provided by predominant cytokines, chemokines and cell surface protein expression. Most studies rely on invasive assessment of the alveolar space using bronchoalveolar lavage (BAL), and imaging modalities have been poorly explored in LPS respiratory models. This thesis aimed to test the hypothesis that, following inhalation of LPS, neutrophils circulating within peripheral blood increase their capacity for phagocytosis and generation of reactive oxygen species (ROS), and that dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) detects early increases in pulmonary vascular permeability. Forty-nine healthy human volunteers were recruited to an LPS inhalation study. Volunteers underwent inhalation of 60μg of LPS or Saline via a nebuliser dosimeter, with peripheral blood sampling. A subset underwent DCE MRI scans and bronchoscopy with BAL. Functional assays of phagocytosis and respiratory burst activity were performed on isolated neutrophils from blood. Neutrophils demonstrated a trend towards increased phagocytosis following LPS inhalation (change from baseline of 3.6% versus 1.2% in control subjects, p=0.058). This was not supported by any change in respiratory burst activity or flow cytometry assessment of cell surface protein expression. Analysis of DCE MRI of the lungs proved difficult and was complicated by significant artefact from surrounding structures and respiratory motion. In conclusion, LPS inhalation did not significantly affect phagocytosis or respiratory burst activity of neutrophils in the systemic circulation. DCE MRI was unable to detect changes in vascular permeability following LPS inhalation above the background noise.en_US
dc.language.isoenen_US
dc.publisherNewcastle Universityen_US
dc.titleA Lipopolysaccharide (LPS) inhalation model to characterise divergent innate cellular responses and presence of alveolar leak, early in the course of acute lung inflammationen_US
dc.typeThesisen_US
Appears in Collections:Institute of Cellular Medicine

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