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Published on: October 27, 2020
Hypothermia protects brain mitochondrial function from hypoxemia in a murine model of sepsis
Kim I Chisholm1, Keila K Ida2,3, Andrew L Davies2
1Institute of Neurology, University College London, UK k.chisholm@ucl.ac.uk.
Abstract:
Sepsis is commonly associated with brain dysfunction, but the underlying mechanisms remain unclear, although mitochondrial dysfunction and microvascular abnormalities have been implicated. We therefore assessed whether cerebral mitochondrial dysfunction during systemic endotoxemia in mice increased mitochondrial sensitivity to a further bioenergetic insult (hyoxemia), and whether hypothermia could improve outcome. Mice (C57bl/6) were injected intraperitoneally with lipopolysaccharide (LPS) (5 mg/kg; n = 85) or saline (0.01 ml/g; n = 47). Six, 24 and 48 h later, we used confocal imaging in vivo to assess cerebral mitochondrial redox potential and cortical oxygenation in response to changes in inspired oxygen. The fraction of inspired oxygen (FiO2) at which the cortical redox potential changed was compared between groups. In a subset of animals, spontaneous hypothermia was maintained or controlled hypothermia induced during imaging. Decreasing FiO2 resulted in a more reduced cerebral redox state around veins, but preserved oxidation around arteries. This pattern appeared at a higher FiO2 in LPS-injected animals, suggesting an increased sensitivity of cortical mitochondria to hypoxemia. This increased sensitivity was accompanied by a decrease in cortical oxygenation, but was attenuated by hypothermia. These results suggest that systemic endotoxemia influences cortical oxygenation and mitochondrial function, and that therapeutic hypothermia can be protective.
Insights
Sepsis increases brain mitochondrial sensitivity to low oxygen. Therapeutic hypothermia can protect against this sepsis-induced brain dysfunction by improving cortical oxygenation and mitochondrial function.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Critical Care Medicine
Background:
- Sepsis frequently causes brain dysfunction, with unclear mechanisms.
- Mitochondrial dysfunction and microvascular abnormalities are implicated in sepsis-related encephalopathy.
- Understanding these mechanisms is crucial for developing effective treatments.
Purpose of the Study:
- To investigate if endotoxemia increases cerebral mitochondrial sensitivity to hypoxemia.
- To determine if hypothermia mitigates these effects.
- To explore the impact of sepsis on cortical oxygenation and mitochondrial bioenergetics.
Main Methods:
- Mice were injected with lipopolysaccharide (LPS) or saline.
- In vivo confocal imaging assessed cerebral mitochondrial redox potential and cortical oxygenation under varying oxygen levels.
- Hypothermia was applied to a subset of animals during imaging.
- The fraction of inspired oxygen (FiO2) triggering redox potential changes was compared between groups.
Main Results:
- LPS-induced endotoxemia increased the FiO2 threshold at which cortical mitochondria became more reduced, indicating heightened sensitivity to hypoxemia.
- This sensitivity was associated with decreased cortical oxygenation around veins.
- Hypothermia attenuated the negative effects of endotoxemia on cortical oxygenation and mitochondrial redox state.
Conclusions:
- Systemic endotoxemia impairs cortical oxygenation and mitochondrial function during hypoxemia.
- Therapeutic hypothermia demonstrates a protective effect against sepsis-induced cerebral mitochondrial dysfunction.
- These findings highlight a potential therapeutic strategy for sepsis-related brain injury.
