Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.645041
Title: Modulation of granulocyte apoptosis by glucocorticoids
Author: Cousin, Joanne Marie
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1998
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Abstract:
The purpose of these studies was to determine the effects and mechanisms of action of glucocorticoids on eosinophil and neutrophil apoptosis and to examine the effects of these drugs on the phagocytosis of apoptotic granulocytes by macrophages. Dexamethasone exerts diametrically opposed effects on these two cell types; promoting eosinophil apoptosis and inhibiting neutrophil apoptosis. Similarly, elevation of [Ca2+]i also differentially affects the rate of constitutive granulocyte apoptosis. In contrast, elevation of cAMP inhibits the rate of apoptosis in both granulocytes, whereas inhibition of PKC promotes the rate of granulocyte apoptosis. Moreover, inhibition of protein phosphatases inhibits the rate of granulocyte apoptosis at lower concentrations and promotes the rate of granulocyte apoptosis at higher concentrations. Inhibition of the MAP/ERK kinase cascade inhibits the rate of constitutive eosinophil apoptosis, while having no effect upon the rate of constitutive neutrophil apoptosis. However, inhibition of this cascade selectively blocks the neutrophil survival-promoting effects of LPS, but exerts no effect on the glucocorticoid-mediated neutrophil survival-promoting effects of LPS, but exerts no effect on glucocorticoid-mediated inhibition of neutrophil apoptosis. Dexamethasone mediates inhibition of neutrophil apoptosis by a PKA-dependent mechanism, whereas the pro-apoptotic effect of dexamethasone upon eosinophil apoptosis appears to the PKA-independent. Dexamethasone potentiates macrophage recognition and phagocytosis of apoptotic eosinophils and neutrophils. Demonstration of the marked apoptosis-promoting effects of corticosteroids on eosinophil apoptosis together with the augmentation of macrophage clearance of apoptotic eosinophils, may in part explain the known beneficial therapeutic effects of corticosteroids on established 'eosinophilic' inflammatory diseases such as asthma. The opposite effect on neutrophil apoptosis may underlie the lower efficacy of these drugs in 'neutrophilic' inflammatory diseases such as SRDs. Further dissection of the intracellular mechanisms governing the divergent effects of corticosteroids on eosinophil and neutrophil apoptosis may lead to new therapeutic targets with which selective induction of apoptosis could be achieved.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.645041  DOI: Not available
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