Development of a Porcine Model of Carbon Monoxide Poisoning to Evaluate Cardiac and Mitochondrial Dysfunction

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Carbon monoxide (CO) is a colorless and odorless gas that is an important cause of poisoning annually with an estimated 50,000 emergency department visits occurring in the US and it is a leading cause of poisoning death globally. Various sources include faulty heat generators, suicidal attempts and fires. It is estimated that CO poisoning in the US results in over $1 billion annually related to hospital costs and lost earnings. CO poisoning has high mortality and morbidity with effects at the cardiovascular and neurologic system. The most serious complication of consequential CO exposure is delayed neurological sequela which occurs in up to 50% of survivors. However, the cardiac sequalae is less defined as well as the underlying cellular dysfunction that may occur. Our own work demonstrates that there are alterations in mitochondrial function (both bioenergetic and dynamic) in CO poisoning. The standard treatment for CO poisoning recommended by the Undersea & Hyperbaric Medical Society is hyperbaric oxygen (HBO) therapy. At this time, both diagnostics and treatments are aimed at early supportive care and select use of hyperbaric therapy. There is significant debate with currently available biomarkers and treatment for CO poisoning requiring a new approach to therapy that is mechanism-driven. Based on these existing gaps, there are ongoing investigations for improved treatment based primarily on small animal studies. However, many agencies that oversee toxicological testing require use of both rodent and non-rodent species which is lacking at this time. There is a paucity of large animal models to study both cellular dysfunction and potential therapy in CO poisoning. The primary limitations that this R03 proposal seeks to address are the following: (1) limited mechanistic understanding at a cellular level with regard to mitochondrial function (bioenergetics and dynamics); (2) the adverse cardiovascular effects of CO poisoning and the underlying cellular dysfunction that may occur; (3) the lack of adequate large animal models that more closely mimic human physiology. We propose to develop a large animal model of CO poisoning using the domestic pig (Sus scrofa domesticus). The pig may be considered a translational model of biomedical research because of anatomical, physiological and biochemical similarity to humans. This R03 proposal is strongly supported by preliminary data and feasibility that will ensure success. The PI (Jang) currently holds a NHLBI K08 award and will specifically leverage his K-supported research skills and techniques focused in the area of mitochondrial medicine with the full support of both his departmental chair (Ben Sun, MD) and K08 mentor (Todd Kilbaugh, MD) along with the outstanding environment that incorporates state-of-the-art equipment. The data and methods obtained with this R03 award will allow the PI to submit a competitive R01 as an ESI.