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Published Online: 6 July 2004

Regulation of Adenovirus-Mediated Elafin Transgene Expression by Bacterial Lipopolysaccharide

Publication: Human Gene Therapy
Volume 12, Issue Number 11

Abstract

Lipopolysaccharide (LPS) is a mediator of inflammatory lung injury. Selective augmentation of host defense molecules such as elafin (an elastase inhibitor with antimicrobial activity) at the onset of pulmonary inflammation is an attractive potential therapeutic strategy. The aim of this study was to determine whether elafin expression could be induced by LPS administered after transfection with adenovirus (Ad) encoding human elafin downstream of the murine cytomegalovirus (CMV) promoter (known to be potentially responsive to LPS). In addition, we aimed to determine the effect of local elafin augmentation on neutrophil migration to the lung. LPS significantly up-regulated elafin expression from pulmonary epithelial cells transfected with Ad-elafin in vitro. In murine airways expression of human elafin was achieved using doses low enough (3 × 107 plaque forming units) to circumvent overt vector-induced inflammation. LPS significantly up-regulated human elafin secretion in murine airways treated with Ad-elafin [117 ng/ml in bronchoalveolar lavage fluid (BALF) after LPS administration, 5.9 ng/ml after PBS, p < 0.01)]. Over-expression of elafin significantly augmented LPS-mediated neutrophil migration into the airways in vivo (1.30 × 106 neutrophils in BALF after Ad-elafin/LPS treatment, 0.54 × 106 after Ad-lacZ/LPS (p < 0.05), 0.63 × 106 after PBS/LPS (p < 0.05)) and significantly enhanced human neutrophil migration in vitro. These data suggest novel functions for elafin in neutrophil migration, and that judicious selection of promoters may allow single, low-dose adenoviral administration to effect inflammation-specific expression of potentially therapeutic transgenes.

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Published In

cover image Human Gene Therapy
Human Gene Therapy
Volume 12Issue Number 11July 2001
Pages: 1395 - 1406
PubMed: 11485631

History

Published online: 6 July 2004
Published in print: July 2001

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    A. John Simpson
    Rayne Laboratory, Respiratory Medicine Unit, MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh EH8 9AG
    Gráinne A. Cunningham
    Rayne Laboratory, Respiratory Medicine Unit, MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh EH8 9AG
    David J. Porteous
    Medical Genetics Section, University of Edinburgh Molecular Medicine Centre, Western General Hospital, Edinburgh EH9
    Chris Haslett
    Rayne Laboratory, Respiratory Medicine Unit, MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh EH8 9AG
    Jean-Michel Sallenave
    Rayne Laboratory, Respiratory Medicine Unit, MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh EH8 9AG

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