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 x 10(7) 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 x 10(6) neutrophils in BALF after Ad-
elafin/LPS treatment, 0.54 x 10(6) after Ad-lacZ/LPS (p < 0.05), 0.63 x 10(6) 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.