Abstract | INTRODUCTION:
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: 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.
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Authors | Bryanna 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 |
Journal | Shock (Augusta, Ga.)
(Shock)
Vol. 43
Issue 1
Pg. 16-23
(Jan 2015)
ISSN: 1540-0514 [Electronic] United States |
PMID | 25004064
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Epithelial Sodium Channels
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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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