The effects of elafin gene augmentation on acute pulmonary inflammation

• Main Author: Simpson, A. John
• Published: University of Edinburgh 2002
• Subjects: 616.2
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.661938

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 <i>in vitro</i>. 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 <i>Pseudomonas aeruginosa </i>and <i>Staphylococcus</i> <i>aureus</i>. On the basis of these observations, the hypothesis that elafin may be protective against inflammatory injury was tested <i>in vivo</i>. Low dose IT Ad-elafin (3x10⁷ plaque forming units) was associated with a significant reduction in acute lung injury induced by <i>Pseudomonas aeruginosa </i>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.