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Dose-dependent cerebral metabolic impairment in a swine model of carbon monoxide poisoning

Lewis, Alistair ; Forti, Rodrigo M. ; Ko, Tiffany S. ; Greenwood, John C. ; Kelly, Matthew ; Shofer, Frances S. ; Kao, Shih Han ; Shin, Samuel S. ; Bungatavula, Devesh and Mason, Mckenna , et al. (2026) In NeuroToxicology 114.
Abstract

Carbon monoxide (CO) poisoning is a leading cause of environmental poisoning in the United States and can impair cellular metabolism through both hypoxia and direct mitochondrial toxicity, particularly via inhibition of cytochrome c oxidase (Complex IV, CIV). In this study, we performed a comprehensive assessment of the cerebral metabolic response to CO exposure in a swine model. Twenty-nine swine (∼10 kg) were assigned to three groups: Sham (n = 10), CO 1000 ppm (n = 8), and CO 2000 ppm (n = 11). Animals in the CO groups were exposed to CO for 120 min followed by 30 min of room air. Cerebral metabolism was assessed using invasive cerebral microdialysis and continuous non-invasive diffuse optical monitoring of cerebral blood flow,... (More)

Carbon monoxide (CO) poisoning is a leading cause of environmental poisoning in the United States and can impair cellular metabolism through both hypoxia and direct mitochondrial toxicity, particularly via inhibition of cytochrome c oxidase (Complex IV, CIV). In this study, we performed a comprehensive assessment of the cerebral metabolic response to CO exposure in a swine model. Twenty-nine swine (∼10 kg) were assigned to three groups: Sham (n = 10), CO 1000 ppm (n = 8), and CO 2000 ppm (n = 11). Animals in the CO groups were exposed to CO for 120 min followed by 30 min of room air. Cerebral metabolism was assessed using invasive cerebral microdialysis and continuous non-invasive diffuse optical monitoring of cerebral blood flow, oxygenation, and CIV redox state. Following the exposure period, brain tissue was harvested for mitochondrial respiration analysis and western blotting. Severe CO exposure (2000 ppm) produced significant cerebral metabolic impairment, demonstrated by decreased oxidation of cytochrome-c-oxidase, reduced oxygen metabolism, and increased microdialysis markers of metabolic stress including lactate-to-pyruvate ratio and glycerol. In contrast, moderate CO exposure (1000 ppm) resulted in minimal metabolic changes despite elevated carboxyhemoglobin levels. Ex-vivo mitochondrial respirometry also demonstrated impaired mitochondrial respiration in CO-exposed animals. These findings demonstrate greater cerebral metabolic dysfunction with higher CO exposure and suggest that carboxyhemoglobin levels alone may not accurately reflect the degree of cerebral metabolic injury.

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type
Contribution to journal
publication status
published
subject
keywords
Carbon monoxide poisoning, Cerebral metabolism, Diffuse optical spectroscopy, Mitochondrial dysfunction,Cytochrome c oxidase
in
NeuroToxicology
volume
114
article number
103454
publisher
Elsevier
external identifiers
  • pmid:42002104
  • scopus:105036439042
ISSN
0161-813X
DOI
10.1016/j.neuro.2026.103454
language
English
LU publication?
yes
id
5aa11d91-1c54-475d-9de2-c39507386de4
date added to LUP
2026-06-23 13:19:38
date last changed
2026-07-08 20:20:54
@article{5aa11d91-1c54-475d-9de2-c39507386de4,
  abstract     = {{<p>Carbon monoxide (CO) poisoning is a leading cause of environmental poisoning in the United States and can impair cellular metabolism through both hypoxia and direct mitochondrial toxicity, particularly via inhibition of cytochrome c oxidase (Complex IV, CIV). In this study, we performed a comprehensive assessment of the cerebral metabolic response to CO exposure in a swine model. Twenty-nine swine (∼10 kg) were assigned to three groups: Sham (n = 10), CO 1000 ppm (n = 8), and CO 2000 ppm (n = 11). Animals in the CO groups were exposed to CO for 120 min followed by 30 min of room air. Cerebral metabolism was assessed using invasive cerebral microdialysis and continuous non-invasive diffuse optical monitoring of cerebral blood flow, oxygenation, and CIV redox state. Following the exposure period, brain tissue was harvested for mitochondrial respiration analysis and western blotting. Severe CO exposure (2000 ppm) produced significant cerebral metabolic impairment, demonstrated by decreased oxidation of cytochrome-c-oxidase, reduced oxygen metabolism, and increased microdialysis markers of metabolic stress including lactate-to-pyruvate ratio and glycerol. In contrast, moderate CO exposure (1000 ppm) resulted in minimal metabolic changes despite elevated carboxyhemoglobin levels. Ex-vivo mitochondrial respirometry also demonstrated impaired mitochondrial respiration in CO-exposed animals. These findings demonstrate greater cerebral metabolic dysfunction with higher CO exposure and suggest that carboxyhemoglobin levels alone may not accurately reflect the degree of cerebral metabolic injury.</p>}},
  author       = {{Lewis, Alistair and Forti, Rodrigo M. and Ko, Tiffany S. and Greenwood, John C. and Kelly, Matthew and Shofer, Frances S. and Kao, Shih Han and Shin, Samuel S. and Bungatavula, Devesh and Mason, Mckenna and Starr, Jonathan and Ehinger, Johannes K. and Kilbaugh, Todd J. and Yodh, Arjun G. and Baker, Wesley B. and Jang, David H.}},
  issn         = {{0161-813X}},
  keywords     = {{Carbon monoxide poisoning; Cerebral metabolism; Diffuse optical spectroscopy; Mitochondrial dysfunction,Cytochrome c oxidase}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{NeuroToxicology}},
  title        = {{Dose-dependent cerebral metabolic impairment in a swine model of carbon monoxide poisoning}},
  url          = {{http://dx.doi.org/10.1016/j.neuro.2026.103454}},
  doi          = {{10.1016/j.neuro.2026.103454}},
  volume       = {{114}},
  year         = {{2026}},
}