Document Detail


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.
MedLine Citation:
PMID:  25004064     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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: 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, instrumented, and the superior mesenteric artery was clamped to cause gut ischemia/reperfusion injury (I/R) and peritoneal sepsis (PS) by fecal clot implantation. Animals were ventilated according to ARDSnet protocol. Four hours after injury animals were randomized into groups: 1.Treatment Na,K-ATPase/ENaC plasmid (n=5), 2.Control Empty plasmid (n=5). Plasmids were delivered to the lung using bronchoscope. Electroporation was delivered using 8 square wave electric pulses across chest. Following electroporation pigs were monitored 48 hrs.
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.
CONCLUSION: 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.
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
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-7-4
Journal Detail:
Title:  Shock (Augusta, Ga.)     Volume:  -     ISSN:  1540-0514     ISO Abbreviation:  Shock     Publication Date:  2014 Jul 
Date Detail:
Created Date:  2014-7-8     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421564     Medline TA:  Shock     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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