Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.661938
Title: The effect of elafin gene augmentation on acute pulmonary inflammation
Author: Simpson, A. J.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2002
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Abstract:
The hypothesis driving this work was that genetic augmentation of elafin may protect the lung against acute inflammatory injury. A replication-deficient adenovirus encoding human elafin cDNA under the control of the powerful murine cytomegalovirus promoter (Ad-elafin) was used to augment elafin production because of the natural tropism of adenovirus for respiratory epithelium. Ad-elafin significantly protected pulmonary epithelial cells against the effects of both HNE and whole activated human neutrophils in vitro. These findings were extended by studying the effect of Ad-elafin on pulmonary neutrophilia induced by lipopolysaccharide (LPS) in mice. Intratracheal (IT) Ad-elafin, administered in doses low enough to obviate overt vector-induced inflammation, significantly augmented LPS-mediated neutrophilia. In addition, LPS significantly up-regulated elafin secretion in Ad-elafin transfected murine airways and in Ad-elafin transfected human pulmonary epithelial cells. The demonstration of a cytoprotective effect for a low molecular weight, cationic elastase inhibitor capable of augmenting neutrophil recruitment during inflammation suggested a potential antimicrobial function for elafin. Elafin was shown to have significant antimicrobial activity against the respiratory pathogens Pseudomonas aeruginosa and Staphylococcus aureus. On the basis of these observations, the hypothesis that elafin may be protective against inflammatory injury was tested in vivo. Low dose IT Ad-elafin (3x107 plaque forming units) was associated with a significant reduction in acute lung injury induced by Pseudomonas aeruginosa in mice. These findings suggest that genetic augmentation of endogenous host defence molecules can protect the lung against acute inflammatory injury. They further suggest that adenoviral constructs containing selective promoters may allow inflammation-specific expression of transgene using low doses of vector.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.661938  DOI: Not available
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