Perflubron enhances adenovirus-mediated gene expression in lungs of transgenic mice with chronic alveolar filling.
Perfluorochemical (PFC) liquids have both low surface tension and a high capacity to dissolve O2 and CO2, and have been shown to improve gas exchange and lung compliance in animal models of lung injury. We have previously demonstrated that perflubron and other PFC liquids enhance transgene expression in lungs of spontaneously breathing normal rodents after intratracheal instillation of either adenoviral or liposomal vectors followed by a single instillation of PFC liquid. We reasoned that PFC liquids may also be useful for enhancing transgene expression in abnormal lungs. GM-CSF knockout mice develop chronic accumulation of surfactant lipids and proteinaceous material in alveolar spaces and serve as a useful model of chronic alveolar filling. Intratracheal instillation of the adenoviral vector Adlac-Z resulted in patchy in situ distribution of beta-Gal activity, predominantly in larger proximal airways. In contrast, in mice instilled with Adlac-Z followed by instillation of a single dose of perflubron (10 ml/kg body weight), increased expression was observed in distal airway and alveolar epithelial cells. In particular, expression was observed in epithelial cells of debris-filled alveoli. Spectrophotometric measure of quantitative beta-Gal activity in lung homogenates demonstrated increased activity in lungs of mice receiving Adlac-Z plus perflubron compared with lungs of animals receiving Adlac-Z alone. These studies demonstrate that use of perflubron enhances transgene expression in lungs of animals with a chronic alveolar filling process. This approach may be applicable for gene delivery in diseases marked by chronic airway or alveolar filling such as cystic fibrosis.
Weiss
D J
DJ
Pulmonary and Critical Care, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Strandjord
T P
TP
Liggitt
D
D
Clark
J G
JG
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D005466:Fluorocarbons / Q000737:chemistry / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency; D006842:Hydrocarbons, Brominated; D008081:Liposomes; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011649:Pulmonary Alveolar Proteinosis / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D011650:Pulmonary Alveoli / Q000378:metabolism; D019076:Transgenes / Q000187:drug effects*
D005466:Fluorocarbons; D006842:Hydrocarbons, Brominated; D008081:Liposomes; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C003072:perflubron