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β1-Na+,K+-ATPase gene therapy upregulates tight junctions to rescue lipopolysaccharide-induced acute lung injury

Gene Therapy volume 23, pages 489–499 (2016)Cite this article

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Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with diverse disorders and characterized by disruption of the alveolar-capillary barrier, leakage of edema fluid into the lung, and substantial inflammation leading to acute respiratory failure. Gene therapy is a potentially powerful approach to treat ALI/ARDS through repair of alveolar epithelial function. Herein, we show that delivery of a plasmid expressing β1-subunit of the Na+,K+-ATPase (β1-Na+,K+-ATPase) alone or in combination with epithelial sodium channel (ENaC) α1-subunit using electroporation not only protected from subsequent lipopolysaccharide (LPS)-mediated lung injury, but also treated injured lungs. However, transfer of α1-subunit of ENaC (α1-ENaC) alone only provided protection benefit rather than treatment benefit although alveolar fluid clearance had been remarkably enhanced. Gene transfer of β1-Na+,K+-ATPase, but not α1-ENaC, not only enhanced expression of tight junction protein zona occludins-1 (ZO-1) and occludin both in cultured cells and in mouse lungs, but also reduced pre-existing increase of lung permeability in vivo. These results demonstrate that gene transfer of β1-Na+,K+-ATPase upregulates tight junction formation and therefore treats lungs with existing injury, whereas delivery of α1-ENaC only maintains pre-existing tight junction but not for generation. This indicates that the restoration of epithelial/endothelial barrier function may provide better treatment of ALI/ARDS.

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Acknowledgements

This project was supported by the National Institutes of Health grants HL81148, HL92801 and HL120521 (DD) and T32 HL66988 (XL). We thank Steve N Georas (University of Rochester, Rochester, NY, USA) for 16HBE14o- cells and Fabeha Fazal (University of Rochester, Rochester, NY, USA) for HPAEC.

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  1. Department of Pediatrics, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA

    X Lin, M Barravecchia, P Kothari, J L Young & D A Dean

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Correspondence to D A Dean.

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Lin, X., Barravecchia, M., Kothari, P. et al. β1-Na+,K+-ATPase gene therapy upregulates tight junctions to rescue lipopolysaccharide-induced acute lung injury. Gene Ther 23, 489–499 (2016). https://doi.org/10.1038/gt.2016.19

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