Alistair Lewis1,2, Rodrigo M Forti2, Oladunni Alomaja3, Clementina Mesaros4, Sarah Piel5, John C Greenwood3, Fatima M Talebi3, Constantine D Mavroudis2, Matthew Kelly6, Shih-Han Kao5, Frances S Shofer3, Johannes K Ehinger7,8, Todd J Kilbaugh5, Wesley B Baker2, David H Jang9,10. 1. Department of Chemistry, University of Pennsylvania, PA, 19104, Philadelphia, USA. 2. Division of Neurology, The Children's Hospital of Philadelphia (CHOP), PA, 19104, Philadelphia, USA. 3. Department of Emergency Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. 4. Department of Systems Pharmacology and Translational Therapeutics (SPATT), University of Pennsylvania, Philadelphia, PA, 19104, USA. 5. Resuscitation Science Center of Emphasis, Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, 19104, USA. 6. Department of Emergency Medicine, The University of Alabama at Birmingham, 701 20th Street South, Birmingham, AB, 35233, UK. 7. Otorhinolaryngology, Head and Neck Surgery, Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden. 8. Mitochondrial Medicine, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. 9. Department of Emergency Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. david.jang@pennmedicine.uphs.edu. 10. Resuscitation Science Center of Emphasis, Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, 19104, USA. david.jang@pennmedicine.uphs.edu.
Abstract
INTRODUCTION: Carbon monoxide (CO) is a colorless and odorless gas that is a leading cause of environmental poisoning in the USA with substantial mortality and morbidity. The mechanism of CO poisoning is complex and includes hypoxia, inflammation, and leukocyte sequestration in brain microvessel segments leading to increased reactive oxygen species. Another important pathway is the effects of CO on the mitochondria, specifically at cytochrome c oxidase, also known as Complex IV (CIV). The purpose of this ongoing study is the preliminary development of a porcine model of CO poisoning for investigation of alterations in brain mitochondrial physiology. METHODS: Four pigs (10 kg) were divided into two groups: Sham (n = 2) and CO (n = 2). Administration of a dose of CO at 2000 ppm to the CO group over 120 minutes followed by 30 minutes of re-oxygenation at room air. The control group received room air for 150 minutes. Non-invasive optical monitoring was used to measure CIV redox states. Cerebral microdialysis was performed to obtain semi real-time measurements of cerebral metabolic status. At the end of the exposure, fresh brain tissue (cortical and hippocampal) was immediately harvested to measure mitochondrial respiration. Snap frozen cortical tissue was also used for ATP concentrations and western blotting. RESULTS: While a preliminary ongoing study, animals in the CO group showed possible early decreases in brain mitochondrial respiration, citrate synthase density, CIV redox changes measured with optics, and an increase in the lactate-to-pyruvate ratio. CONCLUSIONS: There is a possible observable phenotype highlighting the important role of mitochondrial function in the injury of CO poisoning.
INTRODUCTION: Carbon monoxide (CO) is a colorless and odorless gas that is a leading cause of environmental poisoning in the USA with substantial mortality and morbidity. The mechanism of CO poisoning is complex and includes hypoxia, inflammation, and leukocyte sequestration in brain microvessel segments leading to increased reactive oxygen species. Another important pathway is the effects of CO on the mitochondria, specifically at cytochrome c oxidase, also known as Complex IV (CIV). The purpose of this ongoing study is the preliminary development of a porcine model of CO poisoning for investigation of alterations in brain mitochondrial physiology. METHODS: Four pigs (10 kg) were divided into two groups: Sham (n = 2) and CO (n = 2). Administration of a dose of CO at 2000 ppm to the CO group over 120 minutes followed by 30 minutes of re-oxygenation at room air. The control group received room air for 150 minutes. Non-invasive optical monitoring was used to measure CIV redox states. Cerebral microdialysis was performed to obtain semi real-time measurements of cerebral metabolic status. At the end of the exposure, fresh brain tissue (cortical and hippocampal) was immediately harvested to measure mitochondrial respiration. Snap frozen cortical tissue was also used for ATP concentrations and western blotting. RESULTS: While a preliminary ongoing study, animals in the CO group showed possible early decreases in brain mitochondrial respiration, citrate synthase density, CIV redox changes measured with optics, and an increase in the lactate-to-pyruvate ratio. CONCLUSIONS: There is a possible observable phenotype highlighting the important role of mitochondrial function in the injury of CO poisoning.
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