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Title: Regulation of human neutrophil apoptosis by nitric oxide and peroxynitrite
Author: Taylor, Emma Louise
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2004
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Apoptosis studies demonstrated the biphasic pro- and anti-apoptotic effects of pure NO donors, SPER/NO and DEA/NO, and the pro-apoptotic effects of ONOO- donors, GEA 3162 and SIN-1, in human neutrophils. Low concentrations of the pure NO donors delayed the rate of neutrophils apoptosis, while high concentrations of all compounds tested accelerated cell death. Time course analyses of four independent events of apoptosis revealed that morphological and biochemical parameters of neutrophils apoptosis may proceed independently of internucleosomal DNA fragmentation, which has long been considered a key hallmark of apoptosis and is frequently used as the sole criterion for assessment of this form of cell death. Treatment with high concentrations of ONOO- donors and, to a lesser extent, with the longer-lasting pure NO donor, SPER/NO, induced morphological and cell surface (CD16 shedding and phosphatidylserine exposure) changes characteristic of neutrophils apoptosis, but paradoxically inhibited internucleosomal DNA fragmentation, as measured by propidium iodide intercalation and gel electrophoresis. In contrast, treatment with the short-lasting NO donor, DEA/NO, produced no such inhibition. An oxidation reaction was shown to be responsible for the suppression of the DNA fragmentation pathway, as the reducing agent, dithiothreitol, restored DNA fragmentation back to control levels. However, GEA 3162-mediated inhibition of DNA fragmentation did not occur upstream or at the level of degradation of inhibitor of caspase-activated DNase (ICAD/DFF45). Therefore, NO can exert either pro- or anti-apoptotic effects on human neutrophils apoptosis, depending on its concentration and flux, whereas only pro-apoptotic effects are achieved with ONOO- donors. Cell death promoted by ONOO- or SPER/NO is independent of an increase in internucleosomal DNA fragmentation. Thus, NO and ONOO- are able to modulate the rate of neutrophil apoptosis, which may have implications for chronic inflammatory conditions.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available