This project is intended to develop a technology that regulates pulmonary vascular reactivity through a new method that delivers inhaled nitric oxide (NO) without the presence of a detectable level of the toxic impurity nitrogen dioxide (NO2). Currently, concentrated NO in Nitrogen is mixed with oxygen just prior to inhalation, resulting in the formation of toxic NO2 from the very act of mixing. Although it may seem illogical and a paradox, the GeNO approach starts with NO2 and reduces it to NO in special ascorbic acid reactors which are located immediately prior to the patient. The result is a 100 fold reduction in the amount of NO delivered to the patient. A system based on the use of NO2 stored in gas bottles has been built and tested. Subject to approval from the FDA, GeNO is preparing to use this equipment in clinical trials later this year. We propose in this Phase I SBIR to establish a research partnership involving GeNO, LLC and Caritas St. Elizabeth's Medical Center, Boston, MA to study the physiological performance and biocompatibility of the GeNO liquid source delivery system for the delivery of inhaled NO compared with the gas cartridge system in a porcine model of acute respiratory failure. Accordingly, we propose the following specific aims: Specific Aim 1. Optimize and then test a prototype liquid source system for NO inhalation therapy. Specific Aim 2. Assess the physiological effect of inhaled NO delivery via the new GeNO liquid system in a swine model of acute respiratory failure, and ascertain the extent and mechanism associated with possible toxicities. Given the demonstrated effect of inhaled NO on pulmonary vasoreactivity and oxygenation, and the potential technical and economic advantages of the proposed NO delivery system compared with existing technologies, we perceive this research providing a significant societal benefit to this world-wide public health problem. PUBLIC HEALTH RELEVANCE: In order to address respiratory disease and pulmonary hypertension, GeNO has developed a means to generate inhaled nitric oxide (NO) for medical therapy through a method that is safer, simpler, and less expensive than what is now available. Currently, concentrated NO in Nitrogen is mixed with oxygen just prior to inhalation, resulting in the formation of toxic NO2 from the very act of mixing. Although it may seem illogical and a paradox, the GeNO approach starts with NO2 and reduces it to NO in a special ascorbic acid reactor which is located at the gas bottle. A redundant reactor, for safety reasons, is located immediately prior to the patient. The result is >100 fold reduction in the amount of NO2 delivered to the patient. We propose to optimize a liquid N2O4 source of the NO2, and compare its performance to the NO2 delivered from a gas tank. We also plan to study the physiological performance and biocompatibility of the two GeNO platforms for the delivery of inhaled NO in a porcine model of respiratory failure. This Phase I proposal is to optimize the liquid delivery system and begin preliminary animal studies.