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Electroporation-mediated gene delivery of Na+,K+ -ATPase, and ENaC subunits to the lung attenuates acute respiratory distress syndrome in a two-hit porcine model.

AbstractINTRODUCTION:
Acute respiratory distress syndrome (ARDS) is a common cause of organ failure with an associated mortality rate of 40%. The initiating event is disruption of alveolar-capillary interface causing leakage of edema into alveoli.
HYPOTHESIS:
Electroporation-mediated gene delivery of epithelial sodium channel (ENaC) and Na+,K+ -ATPase into alveolar cells would improve alveolar clearance of edema and attenuate ARDS.
METHODS:
Pigs were anesthetized and instrumented, and the superior mesenteric artery was clamped to cause gut ischemia/reperfusion injury and peritoneal sepsis by fecal clot implantation. Animals were ventilated according to ARDSnet protocol. Four hours after injury, animals were randomized into groups: (i) treatment: Na+,K+ -ATPase/ENaC plasmid (n = 5) and (ii) control: empty plasmid (n = 5). Plasmids were delivered to the lung using bronchoscope. Electroporation was delivered using eight-square-wave electric pulses across the chest. Following electroporation, pigs were monitored 48 h.
RESULTS:
The Pao2/Fio2 ratio and lung compliance were higher in the treatment group. Lung wet/dry ratio was lower in the treatment group. Relative expression of the Na+,K+ -ATPase transgene was higher throughout lungs receiving treatment plasmids. Quantitative histopathology revealed a reduction in intra-alveolar fibrin in the treatment group. Bronchoalveolar lavage showed increased surfactant protein B in the treatment group. Survival was improved in the treatment group.
CONCLUSIONS:
Electroporation-mediated transfer of Na+,K+ -ATPase/ENaC plasmids improved lung function, reduced fibrin deposits, decreased lung edema, and improved survival in a translational porcine model of ARDS. Gene therapy can attenuate ARDS pathophysiology in a high-fidelity animal model, suggesting a potential new therapy for patients.
AuthorsBryanna M Emr, Shreyas Roy, Michaela Kollisch-Singule, Louis A Gatto, Michael Barravecchia, Xin Lin, Jennifer L Young, Guirong Wang, Jiao Liu, Joshua Satalin, Kathleen Snyder, Gary F Nieman, David A Dean
JournalShock (Augusta, Ga.) (Shock) Vol. 43 Issue 1 Pg. 16-23 (Jan 2015) ISSN: 1540-0514 [Electronic] United States
PMID25004064 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Epithelial Sodium Channels
Topics
  • Animals
  • Disease Models, Animal
  • Electroporation (methods)
  • Epithelial Sodium Channels (biosynthesis, genetics)
  • Gene Transfer Techniques
  • Lung (metabolism, pathology, physiopathology)
  • Plasmids (genetics, pharmacology)
  • Respiratory Distress Syndrome (genetics, pathology, physiopathology, therapy)
  • Swine

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