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Investigation of Cerebral Mitochondrial Injury in a Porcine Survivor Model of Carbon Monoxide Poisoning

  • Preliminary Research
  • Published:
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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). One of the glaring gaps is the lack of rigorous experimental models that may recapitulate survivors of acute CO poisoning in the early phase. The primary objective of this preliminary study is to use our advanced swine platform of acute CO poisoning to develop a clinically relevant survivor model to perform behavioral assessment and MRI imaging that will allow future development of biomarkers and therapeutics.

Methods

Four swine (10 kg) were divided into two groups: control (n = 2) and CO (n = 2). The CO group received CO at 2000 ppm for over 120 min followed by 30 min of re-oxygenation at room air for one swine and 150 min followed by 30 min of re-oxygenation for another swine. The two swine in the sham group received room air for 150 min. Cerebral microdialysis was performed to obtain semi real-time measurements of cerebral metabolic status. Following exposures, all surviving animals were observed for a 24-h period with neurobehavioral assessment and imaging. At the end of the 24-h period, fresh brain tissue (cortical and hippocampal) was immediately harvested to measure mitochondrial respiration.

Results

While a preliminary ongoing study, animals in the CO group showed alterations in cerebral metabolism and cellular function in the acute exposure phase with possible sustained mitochondrial changes 24 h after the CO exposure ended.

Conclusions

This preliminary research further establishes a large animal swine model investigating survivors of CO poisoning to measure translational metrics relevant to clinical medicine that includes a basic neurobehavioral assessment and post exposure cellular measures.

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Funding

This publication was made possible by P30 ES013508 from the National Institute of Environmental Health Sciences, NIH. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NIEHS, NIH.

1. R21ES031243 (Jang).

2. R03HL154232 (Jang).

3. R56HL158696 (Jang).

4. R01HL166592 (Jang).

5. R01HL141386 (Kilbaugh).

6. R01NS113945 (Baker).

7. Thomas B. McCabe and Jeannette E. Laws McCabe Fund Pilot Award (Mavroudis).

Author information

Authors and Affiliations

  1. Divisions of Cardiothoracic Surgery, The Children’s Hospital of Philadelphia (CHOP), Philadelphia, PA, 19104, USA

    Constantine D. Mavroudis, Alistair Lewis & Matthew Kelly

  2. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Alistair Lewis, Matthew Kelly & Samuel S. Shin

  3. Anesthesia and Critical Care Medicine Mitochondrial Unit (ACMU), The Children’s Hospital of Philadelphia (CHOP), Lab 6200, Colket Translational Research Building, 3501 Civic Center Blvd, Philadelphia, PA, 19104, USA

    Alistair Lewis, Matthew Kelly, Tiffany S. Ko, Rodrigo M. Forti, Wesley B. Baker, Todd J. Kilbaugh & David H. Jang

  4. Department of Emergency Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    John C. Greenwood, Matthew Kelly, Frances S. Shofer & David H. Jang

  5. Emergency Medicine, University of Alabama, Birmingham, AL, USA

    Matthew Kelly

  6. Otorhinolaryngology, Head and Neck Surgery, Department of Clinical Sciences Lund, Lund University, Lund, Sweden

    Johannes K. Ehinger

  7. Mitochondrial Medicine, Department of Clinical Sciences Lund, Lund University, Lund, Sweden

    Johannes K. Ehinger

  8. Otorhinolaryngology, Head and Neck Surgery, Skåne University Hospital, Lund, Sweden

    Johannes K. Ehinger

Authors
  1. Constantine D. Mavroudis
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  2. Alistair Lewis
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  3. John C. Greenwood
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  4. Matthew Kelly
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  5. Tiffany S. Ko
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  6. Rodrigo M. Forti
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  7. Samuel S. Shin
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  8. Frances S. Shofer
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  9. Johannes K. Ehinger
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  10. Wesley B. Baker
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  11. Todd J. Kilbaugh
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  12. David H. Jang
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Correspondence to David H. Jang.

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Mavroudis, C.D., Lewis, A., Greenwood, J.C. et al. Investigation of Cerebral Mitochondrial Injury in a Porcine Survivor Model of Carbon Monoxide Poisoning. J. Med. Toxicol. 20, 39–48 (2024). https://doi.org/10.1007/s13181-023-00971-1

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  • DOI: https://doi.org/10.1007/s13181-023-00971-1

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