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

Mavroudis, Constantine D. ; Lewis, Alistair ; Greenwood, John C. ; Kelly, Matthew ; Ko, Tiffany S. ; Forti, Rodrigo M. ; Shin, Samuel S. ; Shofer, Frances S. ; Ehinger, Johannes K. LU orcid and Baker, Wesley B. , et al. (2024) In Journal of Medical Toxicology 20(1). p.39-48
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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Basic science, Biomarker, Carbon monoxide, Mitochondria
in
Journal of Medical Toxicology
volume
20
issue
1
pages
39 - 48
publisher
Springer
external identifiers
  • pmid:37847352
  • scopus:85174291593
ISSN
1556-9039
DOI
10.1007/s13181-023-00971-1
language
English
LU publication?
yes
id
938e5bf4-3cdf-469e-bc66-618adfece5a6
date added to LUP
2023-12-19 15:11:59
date last changed
2024-04-18 01:23:08
@article{938e5bf4-3cdf-469e-bc66-618adfece5a6,
  abstract     = {{<p>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.</p>}},
  author       = {{Mavroudis, Constantine D. and Lewis, Alistair and Greenwood, John C. and Kelly, Matthew and Ko, Tiffany S. and Forti, Rodrigo M. and Shin, Samuel S. and Shofer, Frances S. and Ehinger, Johannes K. and Baker, Wesley B. and Kilbaugh, Todd J. and Jang, David H.}},
  issn         = {{1556-9039}},
  keywords     = {{Basic science; Biomarker; Carbon monoxide; Mitochondria}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{39--48}},
  publisher    = {{Springer}},
  series       = {{Journal of Medical Toxicology}},
  title        = {{Investigation of Cerebral Mitochondrial Injury in a Porcine Survivor Model of Carbon Monoxide Poisoning}},
  url          = {{http://dx.doi.org/10.1007/s13181-023-00971-1}},
  doi          = {{10.1007/s13181-023-00971-1}},
  volume       = {{20}},
  year         = {{2024}},
}