11β-hydroxysteroid dehydrogenase glucocorticoid metabolism within the lung and its influence on macrophage function in the acute respiratory distress syndrome
Bassford, Christopher R. (2011) 11β-hydroxysteroid dehydrogenase glucocorticoid metabolism within the lung and its influence on macrophage function in the acute respiratory distress syndrome. PhD thesis, University of Warwick.
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The acute respiratory distress syndrome (ARDS) is an important cause of respiratory failure in critically ill patients characterised by severe inflammation within the lungs. This inflammation is limited by anti-inflammatory glucocorticoid hormones released from the hypothalamus-pituitary-adrenal (HPA) system. This thesis reports a series of investigations into glucocorticoid concentrations and glucocorticoid metabolism within the lungs of patients with ARDS. It also contains an investigation into a potential biomarker for ARDS. Our study of glucocorticoid concentrations in alveolar epithelial lining fluid showed increased cortisol concentrations within the lungs at onset of ARDS. These concentrations have a positive relationship with critical illness severity indices, but negative relationships with alveolar permeability and alveolar neutrophil counts. In peripheral tissues cortisone and cortisol are inter-converted by iso-enzymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). We have shown that healthy primary resident alveolar macrophages increase their production of active cortisol by the oxo-reduction of inactive cortisone in response to inflammatory stimuli. Alveolar macrophages are responsible for the removal of spent and apoptotic inflammatory cells, failure of this process causes further inflammation. We have shown that glucocorticoids increase the rate of uptake of apoptotic cells by alveolar macrophages, and that macrophage 11β-HSD production of cortisol increases this process. We have shown however that alveolar macrophages extracted from patients with established ARDS have decreased 11β-HSD oxo-reductase activity. This decreased conversion of cortisone to cortisol will cause a diminished response to the anti-inflammatory signal of the HPA system. The implications of this are that they will have a limited capacity to up-regulate efferocytosis and a diminished anti-inflammatory potential. The receptor for advanced glycation end-products (RAGE) is a potential biomarker in ARDS. We have shown that RAGE concentrations in plasma and BALF had excellent diagnostic compatibility with ARDS diagnostic criteria. The use of a threshold RAGE concentration could assure pulmonary inflammation in future investigations.
|Item Type:||Thesis or Dissertation (PhD)|
|Subjects:||Q Science > QP Physiology
R Medicine > RC Internal medicine
|Library of Congress Subject Headings (LCSH):||Respiratory distress syndrome, Adult -- Pathophysiology, Glucocorticoids|
|Institution:||University of Warwick|
|Theses Department:||Warwick Medical School|
|Sponsors:||Intensive Care Society (Great Britain) (ICS)|
|Extent:||260 leaves : ill., charts|
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