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.