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Published ahead of print on October 29, 2004, doi:10.1164/rccm.200403-313OC

Am. J. Respir. Crit. Care Med., Volume 171, Number 3, February 2005, 204-211

A more recent version of this article appeared on February 1, 2005
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Submitted on March 10, 2004
Accepted on October 19, 2004

Gene Transfer of the Na+,K+-ATPase {beta}1 Subunit Using Electroporation Increases Lung Liquid Clearance

David Machado-Aranda1, Yochai Adir1, Jennifer L Young1, Arturo Briva1, G.R. Scott Budinger1, Anjana V Yeldandi2, Jacob I Sznajder1, and David A Dean1*

1 Division of Pulmonary and Critical Care Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA, 2 Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

* To whom correspondence should be addressed. E-mail: dean{at}northwestern.edu.

The development of non-viral methods for efficient gene transfer to the lung is highly desired for the treatment of a number of pulmonary diseases. We have developed a non-invasive procedure using electroporation to transfer genes to the lungs of rats. Purified plasmid (100 to 600 µg) was delivered to the lungs of anesthetized rats through an endotracheal tube and a series of square wave pulses were delivered via electrodes placed on the chest. Relatively uniform gene expression was observed in multiple cell types and layers throughout the lung, including airway and alveolar epithelial cells, airway smooth muscle cells, and vascular endothelial cells and was dose- and pulse length-dependent. Most importantly, no inflammatory response was detected. To demonstrate efficacy of this approach, the {beta}1 subunit of the Na+,K+-ATPase was transferred to the lungs of rats with or without electroporation, and three days later, alveolar fluid clearance was measured. Animals electroporated with the {beta}1 subunit plasmid showed a two-fold increase in alveolar fluid clearance and Na+,K+-ATPase activity as compared to animals receiving all other plasmids, with or without electroporation. These results demonstrate that electroporation is an effective method to increase clearance by introducing therapeutic genes (Na+,K+-ATPase) into the rat lung.
Key words: plasmid, electroporation, acute lung injury, edema




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