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

BM Emr, S Roy, M Kollisch-Singule, LA Gatto… - Shock, 2015 - journals.lww.com
BM Emr, S Roy, M Kollisch-Singule, LA Gatto, M Barravecchia, X Lin, JL Young, G Wang
Shock, 2015journals.lww.com
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 and instrumented, and the superior mesenteric artery was clamped …
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 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 Pao 2/Fio 2 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.
Lippincott Williams & Wilkins