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  • Acquired Diseases
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Pretreatment with cationic lipid-mediated transfer of the Na+K+-ATPase pump in a mouse model in vivo augments resolution of high permeability pulmonary oedema

Gene Therapy volume 7, pages 960–966 (2000)Cite this article

Abstract

Resolution of pulmonary oedema is mediated by active absorption of liquid across the alveolar epithelium. A key component of this process is the sodium-potassium ATPase (Na+K+-ATPase) enzyme located on the basolateral surface of epithelial cells and up-regulated during oedema resolution. We hypothesised that lung liquid clearance could be further up-regulated by lipid-mediated transfer and expression of exogenous Na+K+-ATPase cDNA. We demonstrate proof of this principle in a model of high permeability pulmonary oedema induced by intraperitoneal injection of thiourea (2.5 mg/kg) in C57/BL6 mice. Pretreatment of mice (24 h before thiourea) by nasal sniffing of cationic liposome (lipid #67)–DNA complexes encoding the α and β subunits of Na+K+-ATPase (160 μg per mouse), significantly (P < 0.01) decreased the wet:dry weight ratios measured 2 h after thiourea injection compared with control animals, pretreated with an equivalent dose of an irrelevant gene. whole lung na+K+-ATPase activity was significantly (P < 0.05) increased in mice pretreated with na+K+-ATPase cDNA compared both with untreated control animals as well as animals pretreated with the irrelevant gene. Nested RT-PCR on whole lung homogenates confirmed gene transfer by detection of vector-specific mRNA in three of four mice studied 24 h after gene transfer. This demonstration of a significant reduction in pulmonary oedema following in vivo gene transfer raises the possibility of gene therapy as a novel, localised approach for pulmonary oedema in clinical settings such as ARDS and lung transplantation.

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Acknowledgements

These studies were funded by the Wellcome Trust and by a Wellcome Trust Senior Clinical Fellowship (EWFWA).

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Authors and Affiliations

  1. Department of Gene Therapy, Imperial College at the National Heart and Lung Institute, London, UK

    M Stern, K Ulrich, C Robinson, J Copeland, U Griesenbach, F Munkonge, D Geddes & E Alton

  2. Hôtel-Dieu de Montréal and Department of Medicine, Centre de Recherche, Université de Montréal, Montreal, Quebec, Canada

    C Masse & Y Berthiaume

  3. Genzyme Corporation, Framingham, MA, USA

    S Cheng

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  1. M Stern
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  2. K Ulrich
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Stern, M., Ulrich, K., Robinson, C. et al. Pretreatment with cationic lipid-mediated transfer of the Na+K+-ATPase pump in a mouse model in vivo augments resolution of high permeability pulmonary oedema. Gene Ther 7, 960–966 (2000). https://doi.org/10.1038/sj.gt.3301193

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